TW201704211A - Biphenyl derivative having beta2 receptor excitement and m receptor antagonistic activities and application therefof in medicament - Google Patents

Abstract

The present invention provides a compound shown in a general formula (I) and a general formula (II) or a stereoisomer, a hydrate, a metabolic product, a solvate, salt which is pharmaceutically receivable, eutectic crystals or a prodrug therefor, a preparation method therefor and application therefof in preparing a medicine for treating an airway obstructive disease. The compound in a general formula (I) and a general formula (II) is as shown in a figure, wherein a definition of each substituent group is consistent with that in the description.

Description

Biphenyl derivative having β 2 receptor agonism and M receptor antagonistic activity and its use in medicine

The invention relates to a biphenyl derivative, a preparation method thereof and application in medicine, in particular to a novel acridine derivative having dual activity of muscarinic receptor antagonist and β ₂ -adrenergic receptor agonism or a stereo thereof Isomers, hydrates, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or prodrugs, pharmaceutical compositions thereof, and their use in medicine.

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 agonists. 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. β ₂ -adrenergic agonists bronchodilate by stimulating the adrenergic receptors of 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, currently the clinically muscarinic receptor antagonists and beta ₂ - Adrenergic agonists are prepared as a combination preparation for the treatment of asthma and moderate to severe COPD. These combination preparations mainly include Anoro Ellipta (Ambroxol / Verantrol), Ultibro Breezhaler (Glycopyrrolate / 茚Datrol) 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.

The present invention provides a compound of the formula (I) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, Where: B is selected from , , , , , Q is selected from -CH ₂ CH ₂ -, -CH=CH-, -O-, -S-, -CH ₂ O-, -OCH ₂ -, -C(CH ₃ ) ₂ O- or -OC (CH ₃ ) ₂ -; Y is selected from And Y is attached to the 3 or 4 position of the phenylene ring relative to the R ⁶ group; A is selected from or Said or Optionally further from 0 to 4 selected from the group consisting of F, Cl, Br, I, OH, NH ₂ , carboxyl, cyano, nitro, C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkane Oxyl, -OC _3-6 cycloalkyl, C _1-4 alkylthio, 5 to 6 membered heteroaryl, -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 -C Substituted by a substituent of (=O)NH ₂ , the alkyl, alkoxy, cycloalkyl, alkynyl, carboxyl, NH ₂ , -C(=O)NH ₂ and heteroaryl groups are optionally further 1, 2, 3 or 4 are selected from the group consisting of F, Cl, Br, I, CF ₃ , C _1-4 alkyl, C _1-4 alkoxy or -C(=O)-C _1-4 alkyl Substituted, and said heteroaryl contains 1, 2, 3 or 4 heteroatoms selected from N, O or S; X ₁ and X ₂ are each independently selected from -C(=O)NR ^x -, -NR ^x C(=O)-, -OC(=O)NR ^x - or -NR ^x C(=O)O-; R ^{x is} selected from H or C _1-4 alkyl; R ¹ , R ² independently selected from the group consisting of F, Cl, Br, I, CF ₃ , C _1-4 alkyl, cyano, -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 is independently selected from H or C _1-4 Group; selective, R ^1f, R ^1g together with the nitrogen atom attached form a 5-6 heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from N, O or S; W is - O- or -NW ^a -; W ^{a is} selected from H or C _1-4 alkyl; R ^{3 is} independently selected from the group consisting of F, Cl, Br, I, CF ₃ , C _1-4 alkyl, C _2-4 Alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, cyano, -OR ^3a , -C(O)OR ^3b , -SR ^3c , -S(O)R ^3d , -S(O) ₂ R ^3e or -NR ^3f R ^3g ; or two R ³ groups are bonded to form a C _1-3 alkylene group, a C _2-3 alkenylene group or an ethylene oxide-2,3-diyl group; R ^3a , R ^3b , R ^3c , R ^3d , R ^3e , R ^3f and R ^3g are each independently selected from H or C _1-4 alkyl; R ^{4 is} selected from C _1-6 alkylene, C _2-6 alkylene Or a C _2-6 alkynylene group, the alkylene, alkenylene or alkynylene group optionally further selected from 0, 1, 2, 3, 4 or 5 selected from the group consisting of F, Cl, Br, I, OH Substituted with a substituent of cyano, C _1-4 alkyl, C _1-4 alkoxy, phenyl or phenyl-C _1-4 alkyl; R ^{5 is} independently selected from F, Cl, Br , I, OH, NH ₂ , carboxyl, cyano, nitro, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, -OC _3-6 Cycloalkyl, C _1-4 alkylthio, 5- to 6-membered heteroaryl, -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 -C(=O)NH ₂ , the alkyl, alkane The oxy, cycloalkyl, alkenyl, alkynyl, carboxy, NH ₂ , -C(=O)NH ₂ and heteroaryl groups are further further selected from 0, 1, 2, 3 or 4 selected from F, Cl, Substituted with a substituent of Br, I, CF ₃ , C _1-4 alkyl, C _1-4 alkoxy or -C(=O)-C _1-4 alkyl, and said heteroaryl contains 1 , 2, 3 or 4 heteroatoms selected from N, O or S; R ^{6 is} selected from C _1-6 alkylene, said alkylene optionally further being 0, ₁ , 2, 3, 4 or 5 Substituted by a substituent selected from R ^6a ; R ^{6a 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; optionally, two R ^6a may form a 3 to 6 membered carbocyclic ring together with the atoms to which they are attached, optionally further 0, 1, 2, 3, 4 or 5 Substituted by a substituent selected from F, Cl, Br, I, cyano, OH, C _1-4 alkyl or C _1-4 alkoxy; R ⁷ and R ⁸ are each independently selected from H or C _{1 -4} alkyl; a is selected from 0, 1, 2, 3, 4 or 5; b is selected from 0, 1, 2, 3 or 4; c is selected from 0, 1, 2, 3 or 4; d is selected from 0, 1, 2, 3 or 4; n is 0 or 1; Is 0, 1, 2, 3, 4, 5 or 6; the constraint is that when n is 0, m is 1, 2, 3, 4, 5 or 6; p is 0, 1, 2, 3, 4, 5 or 6; the limitation is: 1) d is selected from 0, X _{2 is} selected from -NHCO- or -CONH-, and R ⁴ -X _{1 is} selected from -CH ₂ CH ₂ C(=O)NR ^x -, B Not for Or 2) R ^{5 is} not a C _2-4 alkynyl group or a 5 to 6 membered heteroaryl group, X _{2 is} selected from -NHCO- or -CONH-, and R ⁴ -X _{1 is} selected from -CH ₂ CH ₂ C (= O) NR ^x - when B is not .

Another embodiment of the present invention provides a compound of the formula (I): or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein: B is selected from , , , , , Q is selected from -CH ₂ CH ₂ -, -CH=CH-, -O-, -S-, -CH ₂ O-, -OCH ₂ -, -C(CH ₃ ) ₂ O- or -OC (CH ₃ ) ₂ -; Y is selected from And Y is attached to the 3 or 4 position of the phenylene ring relative to the R ⁶ group; A is selected from or Said or Optionally further 0, 1, ₂ , 3 or 4 selected from the group consisting of F, Cl, Br, I, OH, NH ₂ , carboxyl, cyano, C _1-4 alkyl, C _2-4 alkynyl, C ₁ Substituted by a substituent of _-4 alkoxy, -OC _3-6 cycloalkyl or 5 to 6 membered heteroaryl, said alkyl, alkoxy, cycloalkyl, alkynyl, carboxy, NH ₂ or hetero The aryl group is 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(=O) Substituted with a -C _1-4 alkyl group, and said heteroaryl group contains 1, 2, 3 or 4 heteroatoms selected from N, O or S; X ₁ and X ₂ are each independently selected from - C(=O)NR ^x -, -NR ^x C(=O)-, -OC(=O)NR ^x - or -NR ^x C(=O)O-; R ^{x is} selected from H or C _1-4 Alkyl; preferably H, methyl or ethyl; R ¹ and R ² are each independently selected from the group consisting of F, Cl, Br, I, CF ₃ , C _1-4 alkyl, cyano, hydroxy or C _{1- 4} alkoxy; preferably F, Cl, Br, I, CF 3, cyano, hydroxy, methyl, ethyl, methoxy or ethoxy; W is -O- or -NW ^a -; W ^{a is} selected from H or C _1-4 alkyl; preferably H, methyl or ethyl; R ^{3 is} independently selected from the group consisting of F, Cl, Br, I, CF ₃ , C _1-4 alkyl, C _{2 -4} alkenyl, C _{2- 4} alkynyl, C _3-6 cycloalkyl, cyano, -OR ^3a , -C(O)OR ^3b , -SR ^3c , -S(O)R ^3d , -S(O) ₂ R ^3e or -NR ^3f R ^3g ; or two R ³ groups are bonded to form a C _1-3 alkylene group, a C _2-3 alkenylene group or an ethylene oxide-2,3-diyl group; R ^3a , R ^3b , R ^3c , R ^3d , R ^3e , R ^3f and R ^3g are each independently selected from H or C _1-4 alkyl; R ^{4 is} selected from C _1-6 alkylene; preferably C _1-4 alkylene; more preferably Is a methylene group, an ethylene group or a propylene group; the alkylene group, methylene group, ethylene group or propylene group is further further selected from 0, 1, 2, 3, 4 or 5 selected from F, Substituted by a substituent of Cl, Br, I, OH, cyano, C _1-4 alkyl or C _1-4 alkoxy; R ^{5 is} independently selected from the group consisting of F, Cl, Br, I, OH, NH ₂ ,carboxy, cyano, nitro, C _1-4 alkyl, C _2-4 alkynyl, 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- a 4-} alkyl or 5- to 6-membered heteroaryl group, optionally substituted by 0, 1, 2, 3 or 4, alkyl, alkynyl, alkoxy, heteroaryl, carboxy, cycloalkyl or NH ₂ Selected from F, Cl, Br, I, CF ₃ , C _1-4 alkyl, Substituted with a C _1-4 alkoxy group or a -C(=O)-C _1-4 alkyl group, and the heteroaryl group contains 1, 2, 3 or 4 selected from N, O or S a hetero atom; R ^{6 is} selected from C _1-6 alkylene; preferably C _1-4 alkylene; further preferably methylene, ethylene, propylene or The alkylene, methylene, ethylene, propylene or Optionally further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from R ^6a ; R ^{6a is} selected from F, Cl, Br, I, cyano, OH, C _1-4 alkyl, C _1-4 alkoxy or phenyl; preferably F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy; optionally, two R ^6a may be The atoms to which they are joined together form a 3 to 6 membered carbon ring; the carbon ring is optionally further 0, 1, 2, 3, 4 or 5 selected from the group consisting of F, Cl, Br, I, cyano, OH, C Substituted by a substituent of _1-4 alkyl or C _1-4 alkoxy; preferably further substituted by 0, 1, 2, 3, 4 or 5 selected from the group consisting of F, Cl, Br, I, cyano, OH Substituted with a methyl, ethyl, methoxy or ethoxy group; R ⁷ and R ⁸ are each independently selected from H or C _1-4 alkyl; preferably H, methyl or ethyl; Further preferably H or methyl; a, b are each independently selected from 0, 1, 2, 3 or 4; preferably 0, 1, 2 or 3; c is selected from 0, 1, 2, 3 or 4 ;d is selected from 0, 1, 2, 3 or 4; n is 0 or 1; m is 0, 1, 2, 3, 4, 5 or 6; the constraint is that when n is 0, m is 1, 2 , 3, 4, 5 or 6; p is 0, 1, 2, 3, 4, 5 or 6; restrictions : 1) d is selected from 0, X ₂ is selected from -NHCO- or -CONH-, R ⁴ -X ₁ is selected from _{-CH 2 CH 2 C (= O} ) NR x - , B is not as Or 2) R ^{5 is} not a C _2-4 alkynyl group or a 5 to 6 membered heteroaryl group, X _{2 is} selected from -NHCO- or -CONH-, and R ⁴ -X _{1 is} selected from -CH ₂ CH ₂ C (= O) NR ^x - when B is not .

Another embodiment of the present invention provides a compound of the formula (I): or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein: B is selected from , , , , , Y is selected from And Y is attached to the 3 or 4 position of the phenylene ring relative to the R ⁶ group; A is selected from or Said or Optionally further 0, 1, 2, 3 or 4 selected from the group consisting of F, Cl, Br, cyano, methyl, ethyl, propyl, isopropyl, ethynyl, CHF ₂ , CF ₃ , methoxy Or substituted with a substituent of an ethoxy group; X ₁ and X ₂ are each independently selected from -C(=O)NR ^x -, -NR ^x C(=O)-, -OC(=O)NR ^x - or - NR ^x C(=O)O-; R ^{x is} selected from H or C _1-4 alkyl; preferably H, methyl or ethyl; R ¹ and R ² are each independently selected from F, Cl, Br, I, CF ₃ , C _1-4 alkyl, cyano, hydroxy or C _1-4 alkoxy; preferably F, Cl, Br, I, CF ₃ , cyano, hydroxy, methyl, ethyl, Methoxy or ethoxy; W is -O- or -NW ^a -; W ^{a is} selected from H or C _1-4 alkyl; preferably H, methyl or ethyl; R ^{3 is} each independently Selected from F, Cl, Br, I, CF ₃ , OH, cyano, C _1-4 alkyl or C _1-4 alkoxy; preferably F, Cl, Br, I, CF ₃ , OH, cyanide a group, a methyl group, an ethyl group, a methoxy group or an ethoxy group; R ^{4 is} selected from a C _1-4 alkylene group; preferably a methylene group, an ethylene group or a propylene group; The methyl, ethylene or propylene group is further optionally 0, 1, 2, 3, 4 or 5 selected from the group consisting of F, Cl, Br, I, cyano Substituted by a substituent of OH, methyl, ethyl, methoxy or ethoxy; R ^{4 is} preferably methylene, ethylene, propylene, -CH(CH ₃ )CH ₂ - or - CH ₂ CH(CH ₃ )-; R ^{5 is} selected from the group consisting of F, Cl, Br, cyano, methyl, ethyl, propyl, isopropyl, CHF ₂ , CF ₃ , methoxy, ethoxy, - OCHF ₂ , -OCF ₃ , ethynyl, propynyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, thiazolyl or oxazolyl; R ^{6 is} selected from C _1-4 alkylene, Good for methylene, ethylene, propylene or The alkylene, methylene, ethylene, propylene or Optionally further substituted by 0, 1, 2, 3, 4 or 5 substituents of F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy; R ⁶ Preferred are methylene, ethylene, propylene, -C(CH ₃ ) ₂ CH ₂ -, -CH ₂ C(CH ₃ ) ₂ -, -CH(CH ₃ )CH ₂ -, -CH ₂ CH(CH ₃ )-, -CH ₂ C(CH ₃ ) ₂ - or ; R ⁷ , R ⁸ are each independently selected from H or C _1-4 alkyl; preferably H, methyl or ethyl; further preferably H or methyl; a, b are each independently selected from 0, 1, 2 or 3; preferably 0, 1 or 2; c is selected from 0, 1 or 2; preferably 0; d is selected from 0, 1, 2, 3 or 4; n is 0 or 1; m is 0, 1, 2, 3, 4 or 5; the constraint is that when n is 0, m is 1, 2, 3, 4 or 5; p is 0, 1, 2, 3, 4 or 5; the constraint is :1) d is selected from 0, X _{2 is} selected from -NHCO- or -CONH-, and R ⁴ -X _{1 is} selected from -CH ₂ CH ₂ C(=O)NR ^x -, B is not Or 2) R ^{5 is} not ethynyl, propynyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, thiazolyl or oxazolyl, and X _{2 is} selected from -NHCO- or -CONH-, When R ⁴ -X _{1 is} selected from -CH ₂ CH ₂ C(=O)NR ^x -, B is not .

Another embodiment of the present invention provides a compound of the formula (I): or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein: B is selected from , , , , , Y is selected from And Y is attached to the 3 or 4 position of the phenylene ring relative to the R ⁶ group; A is selected from , , , , or ; X ₁ or X ₂ are each independently selected from -C(=O)NR ^x -, -NR ^x C(=O)-, -OC(=O)NR ^x - or -NR ^x C(=O)O- ; R ^{x is} selected from H, methyl or ethyl; R ¹ and R ² are each independently selected from the group consisting of F, Cl, Br, I, CF ₃ , cyano, hydroxy, methyl, ethyl, methoxy or B. Alkyl; W is -O-, -NH- or -NCH ₃ -; R ^{4 is} selected from methylene, ethylene, propylene, -CH(CH ₃ )CH ₂ - or -CH ₂ CH (CH ₃ )-; R ^{5 is} selected from the group consisting of F, Cl, Br, methyl, ethyl, methoxy, ethoxy, ethynyl, propynyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furanyl , thiazolyl or oxazolyl; R ^{6 is} selected from the group consisting of methylene, ethylene, propylene, -C(CH ₃ ) ₂ CH ₂ -, -CH ₂ C(CH ₃ ) ₂ -, -CH(CH ₃ ) CH ₂ -, -CH ₂ CH(CH ₃ )-, -CH ₂ C(CH ₃ ) ₂ - or Preferably, it is methylene, ethylene or -CH ₂ CH(CH ₃ )-; R ⁷ and R ⁸ are each independently selected from H, methyl or ethyl; preferably H; a or b are each independently Selected from 0, 1 or 2; preferably 0; c is 0; d is selected from 0, 1, 2, 3 or 4; n is 0 or 1; m is 0, 1, 2, 3, 4 or 5; The constraint is that when n is 0, m is 1, 2, 3, 4 or 5; p is 0, 1, 2, 3 or 4; the constraint is that R ⁵ : 1) d is selected from 0, and X _{2 is} selected from -NHCO- or -CONH-, R ⁴ -X _{1 is} selected from -CH ₂ CH ₂ C(=O)NR ^x -, B is not Or 2) R ^{5 is} not ethynyl, propynyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, thiazolyl or oxazolyl, and X _{2 is} selected from -NHCO- or -CONH-, When R ⁴ -X _{1 is} selected from -CH ₂ CH ₂ C(=O)NR ^x -, B is not .

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

Where: B is selected from , , , , , Q is selected from -CH ₂ CH ₂ -, -CH=CH-, -O-, -S-, -CH ₂ O-, -OCH ₂ -, -C(CH ₃ ) ₂ O- or -OC (CH _{3 2} -; X _{1 is} selected from -C(=O)NR ^x -, -NR ^x C(=O)-, -OC(=O)NR ^x - or -NR ^x C(=O)O-;R ^{x is} selected from H or C _1-4 alkyl; R ¹ and R ² are each independently selected from the group consisting of F, Cl, Br, I, CF ₃ , C _1-4 alkyl, cyano, -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; optionally, R ^1f , R ^1g and its attached nitrogen atom form a 5- to 6-membered heterocyclic ring, said heterocyclic ring containing 1 Up to 3 heteroatoms selected from N, O or S; W is -O- or -NW ^a -; W ^{a is} selected from H or C _1-4 alkyl; R ^{3 is} independently selected from F, Cl, Br , I, CF ₃ , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, cyano, -OR ^3a , -C(O)OR ^3b , -SR ^3c , -S(O)R ^3d , -S(O) ₂ R ^3e or -NR ^3f R ^3g ; or two R ³ groups are bonded to form a C _1-3 alkylene group, a C _2-3 alkylene group or ^{oxirane-2,3-diyl; R 3a, R 3b, R} 3c, R 3d, R 3e, R 3f and R ^3g is independently selected from H C _1-4 alkyl; R ⁴ is selected from C _1-6 alkylene, C _2-6 alkenylene or C _2-6 alkynylene, said alkylene, alkenylene or alkynylene group optionally Further, 0, 1, 2, 3, 4 or 5 are selected from the group consisting of F, Cl, Br, I, OH, cyano, C _1-4 alkyl, C _1-4 alkoxy, phenyl or phenyl- Substituted by a C _1-4 alkylene group; R ^{5 is} independently selected from the group consisting of F, Cl, Br, I, OH, NH ₂ , carboxyl, cyano, nitro, C _1-4 alkyl, C _{2 -4} alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, -OC _3-6 cycloalkyl, C _1-4 alkylthio, 5 to 6 membered heteroaryl, -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 -C(=O)NH ₂ , said alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, carboxy, NH ₂ , -C (=O) NH ₂ and heteroaryl are optionally further 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 Substituted with a substituent of -C(=O)-C _1-4 alkyl, and said heteroaryl contains 1, 2, 3 or 4 heteroatoms selected from N, O or S; R ⁶ is selected from C _1-6 alkylene, said alkylene being optionally further substituted 0,1,2,3,4, or 5 substituents selected R ^6a of substituents; R ^6a is selected from F, Cl, Br, I, cyano, OH, C _1-4 alkyl, C _1-4 alkoxy, phenyl or phenyl -C _1-4 An alkylene group; optionally, two R ^6a together with the atoms to which they are attached form a 3 to 6 membered carbocyclic ring, optionally further 0, 1, 2, 3, 4 or 5 selected from F Substituted with a substituent of Cl, Br, I, cyano, OH, C _1-4 alkyl or C _1-4 alkoxy; R ⁷ and R ⁸ are each independently selected from H or C _1-4 alkyl ; a is selected from 0, 1, 2, 3, 4 or 5; b is selected from 0, 1, 2, 3 or 4; c is selected from 0, 1, 2, 3 or 4; d is selected from 0, 1, 2 , 3 or 4; the restriction is that R ^{5 is} not a C _2-4 alkynyl group or a 5 to 6 membered heteroaryl group, or when d is selected from 0, B is not , , , or .

According to another embodiment of the present invention, there is provided a compound of the formula (II): or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein: B is selected from , , , , , Q is selected from -CH ₂ CH ₂ -, -CH=CH-, -O-, -S-, -CH ₂ O-, -OCH ₂ -, -C(CH ₃ ) ₂ O- or -OC (CH _{3 2} -; X _{1 is} selected from -C(=O)NR ^x -, -NR ^x C(=O)-, -OC(=O)NR ^x - or -NR ^x C(=O)O-;R ^{x is} selected from H or C _1-4 alkyl; preferably H, methyl or ethyl; R ¹ and R ² are each independently selected from the group consisting of F, Cl, Br, I, CF ₃ , C _1-4 alkyl , cyano, hydroxy or C _1-4 alkoxy; preferably F, Cl, Br, I, CF ₃ , cyano, hydroxy, methyl, ethyl, methoxy or ethoxy; W is - O- or -NW ^a -; W ^{a is} selected from H or C _1-4 alkyl; preferably H, methyl or ethyl; R ^{3 is} independently selected from the group consisting of F, Cl, Br, I, CF ₃ , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, cyano, -OR ^3a , -C(O)OR ^3b , -SR ^3c , -S (O) R ^3d , -S(O) ₂ R ^3e or -NR ^3f R ^3g ; or two R ³ groups bonded to form a C _1-3 alkylene group, a C _2-3 alkenylene group or an ethylene oxide -2,3-diyl; R ^3a , R ^3b , R ^3c , R ^3d , R ^3e , R ^3f and R ^3g are each independently selected from H or C _1-4 alkyl; R ^{4 is} selected from C _1-6 alkylene group; preferably C _1-4 alkylene; more preferably methylene, ethylene or propylene; said alkylene Methylene, ethylene or propylene optionally further substituted 0,1,2,3,4, or 5 substituents selected from F, Cl, Br, I, OH, cyano, C _1-4 alkyl or C Substituted by a substituent of _1-4 alkoxy; R ^{5 is} independently selected from the group consisting of F, Cl, Br, I, OH, NH ₂ , carboxyl, cyano, nitro, C _1-4 alkyl, C _{2 - 4} alkynyl, 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; preferably F, Cl, Br, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, ethynyl, propynyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, thiazole Alkyl, oxazolyl or tetrazolyl; said alkyl, alkynyl, alkoxy, heteroaryl, carboxy, cycloalkyl, NH ₂ , methyl, ethyl, propyl, isopropyl, methoxy Base, ethoxy, ethynyl, propynyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, thiazolyl, oxazolyl or tetrazolyl, optionally further substituted by 0, 1, 2, 3 Or 4 selected from F, Cl, Br, I, CF ₃ , C _1-4 alkyl, C _1-4 alkane Substituted by an oxy group or a substituent of -C(=O)-C _1-4 alkyl; preferably further selected from 0, 1, 2 or 3, selected from F, Cl, Br, I, methyl or B Substituted with a substituent; and said heteroaryl contains 1, 2, 3 or 4 heteroatoms selected from N, O or S; R ^{6 is} selected from C _1-6 alkylene; preferably C _{1 -4} alkylene; further preferably methylene, ethylene, propylene or The alkylene, methylene, ethylene, propylene or Optionally further substituted by 0, 1, 2, 3, 4 or 5 substituents selected from R ^6a ; R ^{6a is} selected from F, Cl, Br, I, cyano, OH, C _1-4 alkyl, C _1-4 alkoxy or phenyl; preferably F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy; optionally, two R ^6a and their together with the atom attached to a 3-6 carbon ring, said carbocyclic ring is optionally further substituted 0,1,2,3,4, or 5 substituents selected from F, Cl, Br, I, cyano, OH, C ₁ Substituted with a substituent of _-4 alkyl or C _1-4 alkoxy; preferably further 0, 1, 2, 3, 4 or 5 selected from the group consisting of F, Cl, Br, I, cyano, OH, Methyl, ethyl, methoxy or ethoxy; R ⁷ and R ⁸ are each independently selected from H or C _1-4 alkyl; preferably H, methyl or ethyl; further preferably H or Methyl; a, b are each independently selected from 0, 1, 2, 3 or 4; preferably 0, 1, 2 or 3; c is selected from 0, 1, 2, 3 or 4; d is selected from 0, 1, 2, 3 or 4; the restriction is that R ^{5 is} not a C _2-4 alkynyl group, a 5 to 6 membered heteroaryl group or an ethynyl group, a propynyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a thienyl group, Furanyl, thiazolyl, oxazolyl or tetrazole Base, or d is selected from 0, B is not , , ,

According to another embodiment of the present invention, there is provided a compound of the formula (II): or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein: B is selected from , , , , , X _{1 is} selected from -C(=O)NR ^x -, -NR ^x C(=O)-, -OC(=O)NR ^x - or -NR ^x C(=O)O-; R ^{x is} selected from H Or C _1-4 alkyl; preferably H, methyl or ethyl; R ¹ , R ² are each independently selected from the group consisting of F, Cl, Br, I, CF ₃ , C _1-4 alkyl, cyano, Hydroxy or C _1-4 alkoxy; preferably F, Cl, Br, I, CF ₃ , cyano, hydroxy, methyl, ethyl, methoxy or ethoxy; W is -O- or - NW ^a -; W ^{a is} selected from H or C _1-4 alkyl; preferably H, methyl or ethyl; R ^{3 is} each independently selected from the group consisting of F, Cl, Br, I, CF ₃ , OH, Cyano, C _1-4 alkyl or C _1-4 alkoxy; preferably F, Cl, Br, I, CF ₃ , OH, cyano, methyl, ethyl, methoxy or ethoxy R ^{4 is} selected from C _1-4 alkylene; preferably methylene, ethylene or propylene; the alkylene, methylene, ethylene or propylene is optionally further 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 ^{4 is} preferably methylene, ethylene, _{propylene, -CH (CH 3) CH 2} - or _{-CH 2 CH (CH 3) -} ; R 5 is selected from F, Cl, Br, cyano, methyl, Group, propyl, isopropyl, CHF _2, CF _3, methoxy, ethoxy, -OCHF _2, -OCF _3, ethynyl, propynyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl , furyl, thiazolyl, oxazolyl or tetrazolyl; R ^{5 is more} preferably F, Cl, Br, methyl, ethyl, methoxy, ethoxy, ethynyl, propynyl, pyrrolyl, Imidazolyl, pyrazolyl, thienyl, furyl, thiazolyl, oxazolyl or tetrazolyl; R ^{6 is} selected from C _1-4 alkylene; preferably methylene, ethylene, propylene or The alkylene, methylene, ethylene, propylene or Optionally further substituted by 0, 1, 2, 3, 4 or 5 substituents of F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy; R ⁶ Preferred are methylene, ethylene, propylene, -C(CH ₃ ) ₂ CH ₂ -, -CH ₂ C(CH ₃ ) ₂ -, -CH(CH ₃ )CH ₂ -, -CH ₂ CH(CH ₃ )-, -CH ₂ C(CH ₃ ) ₂ - or ; R ⁷ , R ⁸ are each independently selected from H or C _1-4 alkyl; preferably H, methyl or ethyl; further preferably H or methyl; a, b are each independently selected from 0, 1, 2 or 3; preferably 0, 1 or 2; c is selected from 0, 1 or 2; preferably 0; d is selected from 0, 1, 2, 3 or 4; the limitation is that R ^{5 is} not C _2-4 alkynyl, 5 to 6 membered heteroaryl, ethynyl, propynyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, thiazolyl, oxazolyl or tetrazolyl, or When selected from 0, B is not , , or .

According to another embodiment of the present invention, there is provided a compound of the formula (II): or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein: B is selected from , , , , , X _{1 is} selected from -C(=O)NR ^x -, -NR ^x C(=O)-, -OC(=O)NR ^x - or -NR ^x C(=O)O-; R ^{x is} selected from H , methyl or ethyl; R ¹ , R ² are each independently selected from the group consisting of F, Cl, Br, I, CF ₃ , cyano, hydroxy, methyl, ethyl, methoxy or ethoxy; W is - O-, -NH- or -NCH ₃ -; R ^{4 is} selected from methylene, ethylene, propylene, -CH(CH ₃ )CH ₂ - or -CH ₂ CH(CH ₃ )-; R ⁵ Selected from F, Cl, Br, methyl, ethyl, methoxy, ethoxy, ethynyl, propynyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, thiazolyl, oxazole Or a tetrazolyl group; R ^{6 is} selected from the group consisting of methylene, ethylene, propylene, -C(CH ₃ ) ₂ CH ₂ -, -CH ₂ C(CH ₃ ) ₂ -, -CH(CH ₃ ) CH ₂ -, -CH ₂ CH(CH ₃ )-, -CH ₂ C(CH ₃ ) ₂ - or ; R ⁷ , R ⁸ are each independently selected from H, methyl or ethyl; a and b are each independently selected from 0, 1 or 2; c is 0; d is selected from 0, 1, 2, 3 or 4; The restriction is that when R ^{5 is} not ethynyl, propynyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, thiazolyl, oxazolyl or tetrazolyl, or when d is selected from 0, B Not for

According to another embodiment of the present invention, the present invention relates to the following compounds, but is not limited thereto:

The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of the formula (I) or a stereoisomer, hydrate, metabolite, solvate thereof, pharmaceutically An acceptable salt, co-crystal or prodrug, and a pharmaceutically acceptable carrier, diluent, adjuvant, vehicle or excipient; said composition may further comprise one or more additional therapeutic agents; preferably The other therapeutic agent is selected from one or more of a PDE4 inhibitor, a muscarinic receptor antagonist, a corticosteroid, and a β -adrenergic receptor agonist.

The present invention also provides a compound of the formula (I) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, for use in the treatment of airway obstruction Use in medicines for diseases; preferably, in the preparation of a medicament for the treatment of asthma, chronic obstructive pulmonary disease or bronchitis.

A ditrifluoroacetic acid salt of a compound of the present invention may be dissolved in a polar organic solvent such as a mixed solvent of methanol and dichloromethane (v/v = 1/90) by adding a base. 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 a corresponding The free base form of the compound.

Unless otherwise stated, the terms used in the specification and claims have the following meanings.

The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen referred to in the groups and compounds of the present invention includes their isotopes, that is, the groups and compounds mentioned in the present invention, carbon, hydrogen, oxygen, sulfur 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 ruthenium (H), ruthenium (D, also known as heavy hydrogen ), 氚 (T, also known as super heavy hydrogen), oxygen isotopes include ¹⁶ O, ¹⁷ O and ¹⁸ O, sulfur isotopes include ³² S, ³³ S, ³⁴ S and ³⁶ S, nitrogen isotopes including ¹⁴ N and ¹⁵ N, the fluorine isotope ¹⁹ F, the chlorine isotope includes ³⁵ Cl and ³⁷ Cl, and the bromine isotopes include ⁷⁹ Br and ⁸¹ Br.

"Alkyl" means a straight-chain and branched monovalent saturated hydrocarbon group, and the main chain includes 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, further preferably 1 to 6 carbon atoms, more preferably The linear and branched groups of 1 to 4 carbon atoms are preferably 1 to 2 carbon atoms, and examples of the alkyl group include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl Base, isobutyl, t-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, An n-hexyl, n-heptyl, n-octyl, n-decyl and n-decyl group; the alkyl group may be further optionally 0, 1, 2, 3, 4 or 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 ¹⁸ , nitro, cyano, isocyano, alkyl, hydroxy Alkyl, alkoxy, carbocyclyl, heterocyclyl, C _2-8 alkenyl, C _2-8 alkynyl, -(CH ₂ ) _q -C(=O)-R ¹⁸ , -(CH ₂ ) _q -C(=O)-OR ¹⁸ , -(CH ₂ ) _q -C(=O)-NR ¹⁸ R ^18a , -(CH ₂ ) _q -S(=O) _k -R ¹⁸ , -OC(= O) -OR ¹⁸ or -NR ¹⁸ R ^18a group substituted with a substituent, wherein R ¹⁸ and R ^18a are each independently selected from H, hydroxy, amino, carboxy, C _1-8 alkyl, C _1-8 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl groups, 3-10 carbon cycloalkyl groups, 4-10 heteroaryl a cyclic group, a 3 to 10 membered carbocyclyloxy group or a 4 to 10 membered heterocyclic oxy group, q is selected from 0, 1, 2, 3, 4 or 5, and k is selected from 0, 1 or 2. The alkyl groups, 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 be further optionally 0, 1, 2, 3, 4 or 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 ¹⁸ , nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, Carbocyclyl, heterocyclyl, C _2-8 alkenyl, C _2-8 alkynyl, -(CH ₂ ) _q -C(=O)-R ¹⁸ , -(CH ₂ ) _q -C(=O) -OR ¹⁸ , -(CH ₂ ) _q -C(=O)-NR ¹⁸ R ^18a , -(CH ₂ ) _q -S(=O) _k -R ¹⁸ , -OC(=O)-OR ¹⁸ or - Substituted by a substituent of NR ¹⁸ R ^18a wherein the definitions of k, q, R ¹⁸ and R ^18a are as defined above. 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 one, usually having 1, 2 or 3 carbon-carbon double bonds, and the main chain comprising 2 to 10 carbon atoms, further preferably It is 2 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-hexyl Alkenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1 - octenyl, 3-octenyl, 1-decenyl, 3-decenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene , 1,4-pentadiene and 1,4-hexadiene, etc.; the alkenyl group may be further optionally 0, 1, 2, 3, 4 or 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 ^18, a nitro group, a cyano group, Cyano, alkyl, hydroxyalkyl, alkoxy, carbocyclic group, heterocyclic group, C _2-8 alkenyl, C _{2-8 alkynyl, - (CH 2) q -C} (= O) -R ¹⁸ , -(CH ₂ ) _q -C(=O)-OR ¹⁸ , -(CH ₂ ) _q -C(=O)-NR ¹⁸ R ^18a , -(CH ₂ ) _q -S(=O) _k - Substituents of R ¹⁸ , -OC(=O)-OR ¹⁸ or -NR ¹⁸ R ^18a are substituted, wherein the definitions of k, q, R ¹⁸ and R ^18a are as defined above. The alkenyl groups appearing herein are as defined above.

"Alkenylene" means a straight-chain or branched divalent alkenyl group, and the alkenyl group is as defined above.

"Alkynyl" means a straight-chain or branched monovalent unsaturated hydrocarbon group having at least one, usually having 1, 2 or 3 carbon-carbon triple bonds, and the main chain comprising 2 to 10 carbon atoms, further preferably It is 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms in the main chain, and examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexyne , 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-decynyl and 4-decynyl, etc.; Optionally further 0, 1, ₂ , ₃ , 4 or 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 ¹⁸ , nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C _2-8 alkenyl, C _{2 -8} alkynyl, -(CH ₂ ) _q -C(=O)-R ¹⁸ , -(CH ₂ ) _q -C(=O)-OR ¹⁸ , -(CH ₂ ) _q -C(=O)- ^{NR 18 R 18a, - (CH} 2) q -S (= O) k -R 18, -OC (= O) -OR 18 or -NR ¹⁸ R ^18a substituents of which , K, q, R ¹⁸ and R ^18a is the same as defined above. The alkynyl groups appearing herein are as defined above.

"Alkynylene" means a straight-chain or branched divalent alkynyl group, and the alkynyl group is as defined above.

"Carbocycle" means a monocyclic or 4 to 12 membered bicyclic ring system of 3 to 10 members which is saturated or unsaturated. The carbocyclic ring 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, cycloheptyl, cyclooctyl, cyclodecyl, cyclodecyl and . The carbocyclic group may be further optionally 0, 1, ₂ , ₃ , 4 or 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 ¹⁸ , nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C _{2- 8} alkenyl, C _2-8 alkynyl, -(CH ₂ ) _q -C(=O)-R ¹⁸ , -(CH ₂ ) _q -C(=O)-OR ¹⁸ , -(CH ₂ ) _q - Substitution of a substituent of C(=O)-NR ¹⁸ R ^18a , -(CH ₂ ) _q -S(=O) _k -R ¹⁸ , -OC(=O)-OR ¹⁸ or -NR ¹⁸ R ^18a wherein The definitions of k, q, R ¹⁸ and R ^18a are consistent with the above. The carbocyclic rings appearing herein are defined as described above.

"Heterocyclic" means a saturated or unsaturated non-aromatic ring, and the non-aromatic ring may be a monocyclic ring of 3 to 10 members or a bicyclic ring of 4 to 12 members, and contains 1 to 4 hetero atoms selected from N, O or S. Preferably, it is a 4- to 8-membered heterocyclic group, and the optionally substituted N, S in the ring of the heterocyclic group can be oxidized to various oxidation states. 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, thiazepine, acridinyl, homoacridinyl, furyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl , pyridazinyl, oxazinyl, acridinyl, fluorenyl, morpholinyl, thiomorpholinyl, thiamethane, 1,3-dithia, dihydrofuranyl, dihydropyran , dithienyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzene And imidazolyl, benzopyridyl, pyrrolopyridyl, 2-pyrroline, 3-pyrrolyl, indanyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithiaalkyl, dithiane , Dihydro thienyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl. The heterocyclic group may be further optionally 0, 1, ₂ , ₃ , 4 or 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 ¹⁸ , nitro, cyano, isocyano, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, C _{2- 8} alkenyl, -(CH ₂ ) _q -C(=O)-R ¹⁸ , -(CH ₂ ) _q -C(=O)-OR ¹⁸ , -(CH ₂ ) _q -C(=O)-NR Substituted by a substituent of ¹⁸ R ^18a , -(CH ₂ ) _q -S(=O) _k -R ¹⁸ , -OC(=O)-OR ¹⁸ or -NR ¹⁸ R ^18a wherein k, q, R ¹⁸ And the definition of R ^18a is consistent with the above. The heterocyclic group appearing herein is as defined above.

"Heteroaryl" means a monovalent aryl group having a single ring or two fused rings and containing at least one hetero atom selected from N, O or S in the ring, usually having an atomic composition of 5 to 8 members, Non-limiting examples include pyrrolyl, imidazolyl, thiazolyl, thienyl, furyl, pyrazolyl, isoxazolyl, oxazolyl, pyridyl or pyrazinyl. The heteroaryl group may be further optionally 0, 1, ₂ , ₃ , 4 or 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 ) _a -C(=O)-R ¹⁹ , -(CH ₂ ) _k -C(=O)-OR ¹⁹ , -(CH ₂ ) _k - Substituents of C(=O)-NR ¹⁹ R ^19a , -(CH ₂ ) _k -S(=O) _j -R ¹⁹ , -OC(=O)-OR ¹⁹ or -NR ¹⁹ R ^19a are substituted. The heteroaryl groups appearing herein are as defined above.

"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 be, but is not necessarily, 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 a physiologically/pharmaceutically acceptable carrier and excipient.

"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, granulation. Agents, lubricants, binders, disintegrators, etc.

"Prodrug" means a compound which 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 routine manipulation or in vivo to provide the parent compound.

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

"Effective dose" means the amount of a compound that causes a physiological or medical response to a tissue, system or subject, which amount is sought, including when administered to a subject, sufficient to prevent the condition being treated Or an amount of a compound that occurs or reduces one or more symptoms of the condition 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.

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 expressed in units of 10 ^-6 (ppm). NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic resonance spectrometer, and the solvent was deuterated dimethyl hydrazine (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD _{3 ).} OD), the internal standard is tetramethyl decane (TMS).

The measurement of MS was carried out (Agilent 6120B (ESI) and Agilent 6120B (APCI)).

The HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatography (Zorbax SB-C18 100 x 4.6 mm).

The thin layer chromatography tantalum sheet uses Yantai Yellow Sea HSGF254 or Qingdao GF254 tannin sheet. The specification of the tannin sheet used for thin layer chromatography (TLC) is 0.15mm~0.20mm. The specification for thin layer chromatography separation and purification is 0.4. Mm~0.5mm.

Pipe column chromatography generally uses Yantai Huanghai Tanji 200~300 mesh silicone as carrier.

The starting materials known in the present invention may be synthesized by or according to methods known in the art, or may be purchased from Titan Technology, Anike Chemical, Shanghai Demo, Chengdu Kelon Chemical, Suiyuan Chemical Technology, Belling Technology, etc. the company.

The nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon of about 1 L volume.

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.

If not specified in the examples, the solution means an aqueous solution.

Unless otherwise stated in the examples, the temperature of the reaction is room temperature.

Unless otherwise stated in the examples, M represents moles per liter.

The optimum reaction temperature at room temperature is 20 ° C to 30 ° C.

Bn: refers to a benzyl group.

TBS: refers to tert-butyldimethyl.

Example 1: [1-[3-[2-Chloro-4-[[[(2R)-2-hydroxy-2-[4-hydroxy-3-(methylsulfonylamino)phenyl]ethyl]] Amino]methyl]-5-methoxy-anilino]-3-oxopropyl]-4-acridinyl]-N-(2-phenylphenyl)carbamate ( Compound 1 ) synthesis

[1-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-[4-hydroxy-3-(methanesulfonamido)phenyl]ethyl]amino]methyl]-5-methoxy-anilino ]-3-oxo-propyl]-4-piperidyl]-N-(2-phenylphenyl)carbamate

First step: 4-benzyloxy-3-nitroacetophenone ( 1B )

1-(4-benzyloxy-3-nitro-phenyl)ethanone

4-Hydroxy-3-nitroacetophenone ( 1A ) (1.0 g, 5.52 mmol) was dissolved in N,N-dimethylformamide (10 mL) and benzyl bromide (1.89 g, 11.02 mmol) Heat to 80 ° C for 4 hours. After cooling to room temperature, water (20 mL), EtOAc (EtOAc m. After that, the residue was purified by silica gel column chromatography (eluent methylene chloride) to give the title compound 4-benzyloxy-3-nitroacetophenone ( 1B ) as a yellow solid (0.9 g, yield The rate is 60.1%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.42 (d, 1H), 8.10 (dd, 1H), 7.47-7.31 (m, 5H), 7.18 (d, 1H), 5.31 (s, 2H), 2.58 (s , 3H).

LCMS m/z = 294.2 [M+23].

The second step: 1-(4-benzyloxy-3-nitro-phenyl)-2-bromoethyl ketone ( 1C )

1-(4-benzyloxy-3-nitro-phenyl)-2-bromo-ethanone

4-Benzyloxy-3-nitroacetophenone ( 1B ) (0.9 g, 3.3 mmol) was dissolved in tetrahydrofuran (10 mL), anhydrous methanol (2 mL) was added, and tetrabutylammonium bromide (1.6 g) , 3.3 mmol) was dissolved in tetrahydrofuran (2.5 mL), and slowly added dropwise to a solution of 4-benzyloxy-3-nitroacetophenone ( 1B ). After the addition, the mixture was heated to 25 ° C for 3 hours. The mixture was diluted with aq. EtOAc (EtOAc (EtOAc) After concentration, the residue was purified by silica gel column chromatography (eluent: petroleum ether: methylene chloride (v: v) = 1:0 to 1:1) to give the title compound 1-(4-benzyloxy) 3-Nitro-phenyl)-2-bromoethyl ketone ( 1C ), yellow solid (0.5 g, yield 43.2%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.47 (d, 1H), 8.14 (dd, 1H), 7.47-7.33 (m, 5H), 7.21 (d, 1H), 5.33 (s, 2H), 4.37 (s , 2H).

LCMS m/z = 372.1 [M+23].

The third step: (1R)-1-(4-benzyloxy-3-nitro-phenyl)-2-bromoethanol ( 1D )

(1R)-1-(4-benzyloxy-3-nitro-phenyl)-2-bromo-ethanol

1-(4-Benzyloxy-3-nitro-phenyl)-2-bromoethyl ketone ( 1C ) (13 g, 37.12 mmol) was dissolved in dry tetrahydrofuran (100 mL). °C, slowly add (R)-2-methyl-CBS-oxazol borane (CAS: 112022-83-0) (1.0M in toluene solution) (53.8mL, 53.8 mmol), slower after adding Borane dimethyl sulfide (2.0 M in tetrahydrofuran) (23.6 mL, 47.2 mmol) was added dropwise, and the reaction was continued for 15 min. The reaction was quenched with EtOAc (EtOAc) (EtOAc (EtOAc) After drying and filtration, the filtrate was concentrated under reduced pressure. -Phenyl)-2-bromoethanol ( 1D ), pale yellow solid (13 g, yield 99.43%)

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.90 (d, 1H), 7.52 (dd, 1H), 7.44 (d, 2H), 7.42-7.30 (m, 3H), 7.12 (d, 1H), 5.24 (s , 2H), 4.91 (dd, 1H), 3.62 (dd, 1H), 3.50 (dd, 1H), 2.71 (d, 1H).

LCMS m/z = 374.1 [M+23].

The fourth step: [(1R)-1-(4-benzyloxy-3-nitrophenyl)-2-bromoethoxy]-tert-butyldimethyloxane ( 1E )

[(1R)-1-(4-benzyloxy-3-nitro-phenyl)-2-bromo-ethoxy]-tert-butyldimethyl-silane

(1R)-1-(4-Benzyloxy-3-nitro-phenyl)-2-bromoethanol ( 1D ) (13 g, 36.91 mmol) was dissolved in N,N-dimethylformamide (30 mL) Imidazole (5.78 g, 84.89 mmol) was added, and further butyl dimethyl chloro decane (11.13 g, 73.82 mmol) was added, and the mixture was heated to 45 ° C for 5 hours. After cooling to room temperature, water (50 mL), EtOAc (EtOAc)EtOAc. The residue was purified by silica gel column chromatography (eluent petroleum ether: ethyl acetate (v/v) = 1:0 to 19:1) to give the title compound [(1R)-1-(4-benzyl) Oxy-3-nitrophenyl)-2-bromoethoxy]-tert-butyldimethyloxane ( 1E ), light yellow oil (16 g, yield 92.94%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.86 (d, 1H), 7.50 (dd, 1H), 7.46 (d, 2H), 7.42-7.37 (m, 2H), 7.36-7.31 (m, 1H), 7.11 (d, 1H), 5.23 (s, 2H), 4.85 (dd, 1H), 3.42 (m, 2H), 0.90 (s, 9H), 0.12 (s, 3H), -0.06 (s, 3H).

LCMS m/z = 488.0 [M+23].

Step 5: 2-Benzyloxy-5-[(1R)-2-bromo-1-[tert-butyl(dimethyl)carbinyl]oxyethyl)aniline ( 1F )

2-benzyloxy-5-[(1R)-2-bromo-1-[tert-butyl(dimethyl)silyl]oxy-ethyl]aniline

Dissolving [(1R)-1-(4-benzyloxy-3-nitrophenyl)-2-bromoethoxy]-tert-butyldimethyloxane ( 1E ) (16 g, 34.31 mmol) in To the ethanol (150 mL), water (30 mL) was added, and iron powder (9.56 g, 171.5 mmol), ammonium chloride (9.18 g, 171.5 mmol) was added, and the mixture was heated to 90 ° C for 3 hours. The mixture was cooled to room temperature, filtered, and the residue was washed with methylene chloride (500 mL×1), and the filtrate was washed with saturated aqueous sodium chloride (100 mL×3), dried over anhydrous sodium sulfate -Benzyloxy-5-[(1R)-2-bromo-1-[t-butyl(dimethyl)carbenyl]oxyethyl)phenylamine ( 1F ) as a crude product as a pale yellow solid (13 g, The yield was 86.8%) and used directly in the next reaction.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.45-7.33 (m, 5H), 6.80 (d, 1H), 6.71 (d, 1H), 6.65 (dd, 1H), 5.06 (s, 2H), 4.72 (dd , 1H), 3.44 - 3.37 (m, 2H), 0.89 (s, 9H), 0.09 (s, 3H), -0.07 (s, 3H).

LCMS m/z = 488.0 [M+23].

Step 6: N-[2-Benzyloxy-5-[(1R)-2-bromo-1-[t-butyl(dimethyl)carbinyl]oxyethyl]phenyl]methane Guanamine ( 1G )

N-[2-benzyloxy-5-[(1R)-2-bromo-1-[tert-butyl(dimethyl)silyl]oxy-ethyl]phenyl]methanesulfonamide

Dissolve 2-benzyloxy-5-[(1R)-2-bromo-1-[t-butyl(dimethyl)carbenyl]oxyethyl)aniline ( 1F ) (10 g, 22.91 mmol) In acetonitrile (50 mL), the mixture was cooled to 0 ° C under nitrogen, pyridine (3.62 g, 45.82 mmol) was added, and then sulfonium chloride (3.15 g, 27.49 mmol) was added slowly. After the addition, the temperature was raised to room temperature. hour. After adding water (20 mL) and ethyl acetate (200 mL), EtOAc (EtOAc m. Separation and purification (eluent is petroleum ether / ethyl acetate (v / v) = 1: 0 ~ 19: 1, petroleum ether: dichloromethane (v / v) = 1:1) to obtain the title compound N-[ 2-Benzyloxy-5-[(1R)-2-bromo-1-[t-butyl(dimethyl)carbinyl]oxyethyl]phenyl]methanesulfonamide ( 1G ), white Solid (8 g, yield 67.8%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.54 (d, 1H), 7.45-7.35 (m, 5H), 7.12 (dd, 1H), 6.98 (d, 1H), 6.80 (s, 1H), 5.10 (s , 2H), 4.81 (dd, 1H), 3.44 (m, 2H), 2.90 (s, 3H), 0.89 (s, 9H), 0.10 (d, 3H), -0.07 (s, 3H).

LCMS m/z = 536.0 [M+23].

Seventh step: N-[5-[(1R)-2-azido-1-[t-butyl(dimethyl)carbinyl]oxyethyl]-2-benzyloxyphenyl] Methionamide ( 1H )

N-[5-[(1R)-2-azido-1-[tertbutyl(dimethyl)silyl]oxy-ethyl]-2-benzyloxyphenyl]methanesulfonamide

N-[2-Benzyloxy-5-[(1R)-2-bromo-1-[t-butyl(dimethyl)carbinyl]oxyethyl]phenyl]methanesulfonamide 1G ) (4.5 g, 8.74 mmol) was dissolved in N,N-dimethylformamide (15 mL), sodium azide (1.1 g, 16.9 mmol) was added, and the mixture was heated to 90 ° C for 6 hours. After cooling to room temperature, water (30 mL), EtOAc (EtOAc m. After that, the residue was separated and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate (v/v) = 9:1) to give the title compound N-[5-[(1R)-2- Nitrol-1-[t-butyl(dimethyl)methylidene]oxyethyl]-2-benzyloxyphenyl]methanesulfonamide ( 1H ), white solid (3.8g, yield 91.2 %).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.45 (d, 1H), 7.36-7.27 (m, 5H), 7.05 (dd, 1H), 6.91 (d, 1H), 6.72 (s, 1H), 5.02 (s , 2H), 4.70 (dd, 1H), 3.25 (dd, 1H), 3.15 (dd, 1H), 2.83 (s, 3H), 0.83 (s, 9H), 0.04 (s, 3H), -0.14 (s , 3H).

LCMS m/z = 499.0 [M+23].

Step 8: N-[5-[(1R)-2-Amino-1-[t-butyl(dimethyl)carbamido]oxyethyl]-2-hydroxyphenyl]methanesulfonamide ( 1I )

N-[5-[(1R)-2-amino-1-[tertbutyl(dimethyl)silyl]oxy-ethyl]-2-hydroxyphenyl]methanesulfonamide

N-[5-[(1R)-2-azido-1-[tert-butyl(dimethyl)formamidine]oxyethyl]-2-benzyloxyphenylmethanesulfonamide ( 1H ) (3 g, 6.29 mmol) was dissolved in anhydrous methanol (20 mL), and palladium carbon (Pd/C, 10% (w/w), 3 g) was added, and hydrogenation was carried out at 30 ° C for 6 hours. After filtration and concentration of the filtrate under reduced pressure, the residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol (v/v) = 1:0 to 92:8) to give the title compound N-[5 -[(1R)-2-amino-1-[tert-butyl(dimethyl)methyl decyl]oxyethyl]-2-hydroxyphenyl]methanesulfonamide ( 1I ), pale yellow solid ( 1.3 g, yield 57%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.31 (d, 1H), 6.95 (dd, 1H), 6.74 (d, 1H), 5.07 (s, 3H), 4.69 (t, 1H), 2.92 (s, 3H ), 2.90-2.81 (m, 2H), 0.90 (s, 9H), 0.05 (s, 3H), -0.09 (s, 3H).

LCMS m/z = 361.3 [M + 1].

Step 9: [1-[3-[4-[[[(2R)-2-[T-butyl(dimethyl)methyl)alkyl]oxy-2-[4-hydroxy-3-(A) Sulfoamino)phenyl]ethyl]amino]methyl]-2-chloro-5-methoxyaniline]-3-oxopropyl]-4-indanyl]-N-(2-benzene Phenyl)carbamate ( 1J )

[1-[3-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-[4-hydroxy-3-(methanesulfonamido)phenyl]ethyl]amino]methyl]- 2-chloro-5-methoxyanilino]-3-oxopropyl]-4-piperidyl]-N-(2-phenylphenyl)carbamate

[1-[3-(2-Chloro-4-methylindolyl-5-methoxy-anilino)-3-oxo-propyl]-4-oxaridinyl]-N-(2-benzene (Phenylphenyl)carbamate ( 1K ) (prepared by the synthesis example in WO2010119064A1) (0.536g, 1.00mmol) was dissolved in a mixed solvent of dichloromethane (10mL) and anhydrous methanol (10mL), and added to N- [5-[(1R)-2-Amino-1-[t-butyl(dimethyl)methylidene]oxyethyl]-2-hydroxyphenyl]methanesulfonamide ( 1I ) (0.361g) The reaction was stirred at 30 ° C for 1.5 hours, then sodium triethoxysulfonate hydride (0.636 g, 3.00 mmol) was added and the reaction was continued at 30 ° C for 2 hours. A saturated aqueous solution of ammonium chloride (15 mL) was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated After that, the residue was separated and purified by silica gel column chromatography (eluent: methylene chloride:methanol (v/v)=97:3 to 92:8) to give the title compound [1-[3-[4-[ [[(2R)-2-[T-butyl(dimethyl)carbamido]oxy-2-[4-hydroxy-3-(methylsulfonylamino)phenyl]ethyl]amino]- 2-chloro-5-methoxyaniline]-3-oxopropyl]-4-acridinyl]-N-(2-phenylphenyl)carbamate ( 1J ), light yellow Solid (0.755 g, yield 85.7%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.05 (d, 2H), 7.49 (t, 2H), 7.42-7.32 (m, 6H), 7.22 (dd, 1H), 7.14-7.10 (m, 2H), 6.95 (d, 1H), 6.68 (s, 1H), 5.16-5.10 (m, 1H), 4.90-4.80 (m, 1H), 4.23 (d, 1H), 4.11 (d, 1H), 3.81 (s, 3H) ), 3.18-3.00 (m, 2H), 2.95-2.85 (m, 6H), 2.83-2.71 (m, 2H), 2.15-2.05 (m, 2H), 1.95-1.85 (m, 2H), 0.85 (s) , 9H), 0.08 (s, 3H), -0.16 (s, 3H).

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

Step 10: [1-[3-[2-Chloro-4-[[[(2R)-2-hydroxy-2-[4-hydroxy-3-(methylsulfonylamino)phenyl]ethyl]] Amino]methyl]-5-methoxy-anilino]-3-oxopropyl]-4-acridinyl]-N-(2-phenylphenyl)carbamate ( Compound 1 )

[1-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-[4-hydroxy-3-(methanesulfonamido) )phenyl]ethyl]amino]methyl]-5-methoxy-anilino]-3-oxo-propyl]-4-piperidyl]-N-(2-phenylphenyl)carbamate

[1-[3-[4-[[[(2R)-2-[T-butyl(dimethyl)methyl)alkyl]oxy-2-[4-hydroxy-3-(methylsulfonamide) Phenyl]ethyl]amino]methyl]-2-chloro-5-methoxyaniline]-3-oxopropyl]-4-indanyl]-N-(2-phenylphenyl) The carbamate ( 1J ) (0.5 g, 0.57 mmol) was dissolved in dichloromethane (8 mL), triethylamine trihydrofluoric acid salt (1.83 g, 11.3 mmol) was added and the mixture was heated to 30 ° C overnight. Dichloromethane (10 mL) was added, and a saturated aqueous sodium hydrogencarbonate solution was added dropwise to adjust the pH to 9 and extracted with a mixed solvent of methanol and dichloromethane (v/v = 1/9) (100 mL × 2). The mixture was washed with saturated aqueous sodium chloride (20 mL×1), dried over anhydrous sodium sulfate, filtered, and evaporated. =97:3~92:8) The title compound [1-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-[4-hydroxy-3-(methylsulfonate) Amino)phenyl]ethyl]amino]methyl]-5-methyl-anilino]-3-oxopropyl]-4-acridinyl]-N-(2-phenylphenyl)amino Formate ( Compound 1 ), pale yellow solid (0.26 g, yield 59.5%).

_{^{1 H NMR (400MHz, CD 3}} OD) δ 7.81 (s, 1H), 7.55 (d, 1H), 7.45-7.21 (m, 11H), 7.02 (dd, 1H), 6.85 (d, 1H), 4.70- 4.59 (m, 2H), 3.78 (s, 3H), 3.75 (s, 2H), 2.91 (s, 3H), 2.82-2.68 (m, 6H), 2.62 (t, 2H), 2.41-2.30 (t, 2H), 1.92-1.85 (m, 2H), 1.72-1.65 (m, 2H).

LCMS m/z = 766.1 [M + 1].

Example 2: [1-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazine) -8-yl)ethyl]amino]methyl]-5-methoxyanilino]-3-oxopropyl]-4-acridinyl]-N-(2-phenylphenyl)carbamate Synthesis of acid ester ( compound 2 )

[1-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino ]methyl]-5-methoxy-anilino]-3-oxo-propyl]-4-piperidyl]-N-(2-phenylphenyl)carbamate

First step: [1-[3-[4-[[[(2R)-2-[t-butyl(dimethyl)carbamyl]oxy-2-(5-hydroxy-3-oxo) -4H-1,4-benzoxazine-8-yl)ethyl]amino]methyl]-2-chloro-5-methoxy-phenylamino]-3-oxopropyl]-4-indole Pyridyl]-N-(2-phenylphenyl)carbamate ( 2B )

[1-[3-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8- Yl)ethyl]amino]methyl]-2-chloro-5-methoxy-anilino]-3-oxo-propyl]-4-piperidyl]-N-(2-phenylphenyl)carbamate

[1-[3-(2-Chloro-4-carbamimido-5-methoxy-anilino)-3-oxo-propyl]-4-oxaridinyl]-N-(2-benzene (Phenylphenyl)carbamate ( 1K ) (prepared by the preparation of the synthesis example in step 3 of WO2010119064A1) (0.30g, 5.6mmol) was dissolved in a mixed solvent of dichloromethane (5mL) and anhydrous methanol (5mL), added 8-[(1R)-2-Amino-1-[t-butyl(dimethyl)methylidene]oxyethyl]-5-hydroxy-4H-1,4-benzoxazine-3- Ketone ( 2A ) (prepared according to the synthesis method of intermediate 65 of WO2008149110A1) (0.19g, 5.6mmol), stirred at 30 ° C for 1.5 hours and then added sodium triethoxysulfonate hydride (0.36g, 1.67mmol), continue 30 ° C Reaction for 2 hours. A saturated aqueous solution of ammonium chloride (15 mL) was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated After that, the residue was separated and purified by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 97:3 to 92:8) to give the title compound [1-[3-[4-[ [[(2R)-2-[t-butyl(dimethyl)methyl)alkyl-2-yl-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazine-8- Ethyl]amino]methyl]-2-chloro-5-methoxy-phenylamino]-3-oxopropyl]-4-acridinyl]-N-(2-phenylphenyl) Carbamate ( 2B ), pale yellow solid (0.4 g, yield 83.8%).

¹ H NMR (400 MHz, CD ₃ OD) δ 7.83 (s, 1H), 7.46 (d, 1H), 7.35-7.32 (m, 1H), 7.32-7.22 (m, 6H), 7.22-7.14 (m, 2H) ), 6.86 (d, 1H), 6.49 (d, 1H), 5.18-5.16 (m, 1H), 4.65-4.57 (m, 1H), 4.38 (q, 2H), 4.03 (q, 2H), 3.72 ( s, 3H), 3.11-2.98 (m, 2H), 2.90-2.80 (m, 4H), 2.68 (t, 2H), 2.62-2.53 (m, 2H), 1.92-1.83 (m, 3H), 1.70- 1.61 (m, 2H), 0.81 (s, 9H), -0.00 (s, 3H), -0.15 (s, 3H).

LCMS m/z = 429.7 [M+2]/2.

Step 2: [1-[3-[2-Chloro-4-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazine) -8-yl)ethyl]amino]methyl]-5-methoxyanilino]-3-oxopropyl]-4-acridinyl]-N-(2-phenylphenyl)carbamate Acid ester ( compound 2 )

[1-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino ]methyl]-5-methoxy-anilino]-3-oxo-propyl]-4-piperidyl]-N-(2-phenylphenyl)carbamate

[1-[3-[4-[[[(2R)-2-[T-butyl(dimethyl)methyl)alkyl]oxy-2-(5-hydroxy-3-oxo-4H- 1,4-Benzoxazine-8-yl)ethyl]amino]methyl]-2-chloro-5-methoxy-phenylamino]-3-oxopropyl]-4-indolyl] -N-(2-Phenylphenyl)carbamate ( 2B ) (0.4 g, 0.46 mmol) was dissolved in dichloromethane (8 mL) and triethylamine trihydrofluoric acid salt (1.5 g, 9.3 mmol) ), heated to 30 ° C for reaction overnight. Dichloromethane (10 mL) was added, and a saturated aqueous sodium hydrogencarbonate solution was added dropwise to adjust the pH to 9 and extracted with a mixed solvent of methanol and dichloromethane (v/v) = 1/9 (100 mL × 2), and the organic layer was combined. The organic layer was washed with saturated aqueous sodium chloride (20 mL×1), dried over anhydrous sodium sulfate, filtered and evaporated. /v)=97:3~92:8) The title compound [1-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxy) -4H-1,4-benzoxazine-8-yl)ethyl]amino]methyl]-5-methoxyanilino]-3-oxopropyl]-4-acridinyl]- N-(2-Phenylphenyl)carbamate ( Compound 2 ), pale yellow solid (0.16 g, yield 46.7%).

^{1 H NMR (400MHz, DMSO-} d6) δ 10.21 (s, 1H), 9.79 (s, 1H), 8.65 (s, 1H), 7.75 (s, 1H), 7.44-7.26 (m, 10H), 6.85 ( d,1H), 6.48(d,1H), 5.02(s,1H),4.86-4.83(m,1H),4.55-4.46(m,1H),4.45(s,2H),4.32(d,1H) , 3.73(s,3H), 3.64(q,2H), 2.77-2.70(m,2H),2.62-2.59(m,3H),2.55-2.52(m,2H),2.52-2.47(m,2H) 2.26-2.17 (t, 2H), 1.80 - 1.72 (m, 2H), 1.55-1.45 (m, 2H).

LCMS m/z = 774.3 [M + 1].

Example 3: 3-[3-[4-[(2-Phenylphenyl)carbamoyloxy)-1-indanyl]propanylamino]propyl-N-[2-chloro-4 -[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino]methyl]-2-chloro Synthesis of 5-5-methoxyphenyl]carbamate ( Compound 3 )

3-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoylamino]propyl-N-[2-chloro-4-[[[(2R)-2-hydroxy-2-(4- hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino]methyl]-2-chloro-5-methoxy-phenyl]carbamate

First step: 3-[4-[(2-phenylphenyl)carbamoyloxy)-1-acridinyl]propionic acid ( 3B )

3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoic acid

4-Acridine-N-(2-phenylphenyl)carbamate ( 3A, prepared according to WO2004074246A2) (4.0g, 13.50mmol), acrylic acid (4.862g, 67.48mmol) was added to 2-A The mixture was heated to 100 ° C in tetrahydrofuran (20 mL) and subjected to microwave reaction for 1 hour. After completion of the reaction, the reaction solution was cooled to room temperature, and concentrated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc The compound 3-[4-[(2-phenylphenyl)carbamoyloxy)-1-indanyl]propanoic acid ( 3B ) was obtained as a white solid (4.4 g, yield: 89%).

1H NMR (400MHz, CDCl ₃ ) δ 8.00 (d, 1H), 7.48 (m, 2H), 7.41 (m, 1H), 7.35 (m, 3H), 7.23 (m, 1H), 7.15 (m, 1H) , 6.73 (s, 1H), 4.91 (s, 1H), 3.14 (m, 6H), 2.70 (br, 2H), 2.16br, 2H), 2.04-1.90 (m, 2H).

Second step: [1-[3-(3-hydroxypropyl)-3-oxo-propyl]-4-acridinyl]-N-(2-phenylphenyl)carbamate ( 3C )

[1-[3-(3-hydroxypropylamino)-3-oxo-propyl]-4-piperidyl]-N-(2-phenylphenyl)carbamate

3-[4-[(2-Phenylphenyl)carbamoyloxy)-1-indanyl]propanoic acid ( 3B ) (0.1 g, 0.271 mmol) was dissolved in tetrahydrofuran (10 mL). -(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, CAS: 148893-10-1) (0.206 g, 0.543 mmol), After stirring at room temperature for 30 minutes, 3-amino-1-propanol was added and the mixture was reacted at room temperature for 2 hours. After the reaction was completed, water (20 mL), EtOAc (EtOAc (EtOAc) The title compound [1-[3-(3-hydroxypropyl)-3-) was purified by hydrazine column chromatography (eluent: methanol / dichloromethane (v: v) = 1:100 to 20:1). Oxo-propyl]-4-acridinyl]-N-(2-phenylphenyl)carbamate ( 3C ), white solid (0.08 g, yield, 69%).

^{1 H NMR (400MHz, DMSO-} d6) δ 8.64 (s, 1H), 7.90 (s, 1H), 7.49-7.22 (m, 9H), 4.48 (br, 1H), 4.40 (m, 1H), 3.41 ( m, 2H), 3.10 (m, 2H), 2.70 (s, 2H), 2.21 (br, 2H), 2.22-2.12 (m, 2H), 1.97-1.83 (m, 2H), 1.75 (br, 2H) , 1.54 (m, 4H).

LCMS m/z = 426.1 [M + 1].

The third step: 3-[3-[4-[(2-phenylphenyl)carbamomethoxy)-1-indanyl]propanylamino]propyl-N-(2-chloro-4) -Methylmercapto-5-methoxy-phenyl)carbamate ( 3E )

3-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoylamino]propyl-N-(2-chloro-4-formyl-5-methoxy-phenyl)carbamate

4-Amino-5-chloro-2-methoxy-benzaldehyde ( 3D ) (0.1 g, 0.539 mmol) was dissolved in toluene (15 mL) and added to phosgene (BTC, 0.08 g, 0.269 mmol), 120 ° C The reaction was carried out for 2 hours, and the solvent was removed under reduced pressure to give a liquid. [1-[3-(3-Hydroxypropyl)-3-oxo-propyl]-4-acridinyl]-N-(2-phenylphenyl)carbamate ( 3C ) (0.1 g, 0.235 mmol) and the reaction solution 1 were dissolved in tetrahydrofuran (10 mL), and triethylamine (0.0713 g, 0.705 mmol) was added and reacted at 75 ° C for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified eluting with EtOAc EtOAc EtOAc EtOAc The title compound 3-[3-[4-[(2-phenylphenyl)carbamoyloxy)-1-indanyl]propanylamino]propyl-N-(2-chloro-4- Methyl decyl-5-methoxy-phenyl)carbamate ( 3E ), yellow solid (40 mg, yield 40%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.28 (s, 1H), 8.1 (s, 1H), 7.81 (s, 1H), 7.49 (m, 3H), 7.45-7.39 (m, 1H), 7.39-7.33 (m, 3H), 7.23 (dd, 1H), 7.17 (m, 1H), 6.66 (s, 1H), 4.92 (s, 1H), 4.27 (t, 2H), 3.93 (s, 3H), 3.38 ( m, 2H), 3.13 (m, 6H), 3.00-2.86 (m, 2H), 2.78 (br, 2H), 2.24 (br, 2H), 1.97-1.89 (m, 2H).

LCMS m/z = 637.2 [M + 1].

The fourth step: 3-[3-[4-[(2-phenylphenyl)carbamoyloxy)-1-indanyl]propanylamino]propyl-N-[2-chloro-4 -[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino]methyl]-2-chloro -5-methoxyphenyl]carbamate ( compound 3 )

3-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoylamino]propyl-N-[2-chloro-4-[[[(2R)-2-hydroxy-2-(4- hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino]methyl]-2-chloro-5-methoxy-phenyl]carbamate

3-[3-[4-[(2-Phenylphenyl)carbamoyloxy)-1-indanyl]propanylamino]propyl-N-(2-chloro-4-carboxamidine) 5--5-methoxy-phenyl)carbamate ( 3E ) (0.3 g, 0.471 mmol) and 7-[(1R)-2-amino-1-hydroxy-ethyl]-4-hydroxy-3H -1,3-benzothiazol-2-one ( 3F , prepared by reference to Bioorganic & Medicinal Chemistry Letters, 21 (15), 4612-4616; 2011) (0.117 g, 0.518 mmol) dissolved in dichloromethane / methanol ( The mixed solvent (15 mL) of v/v) = 1/1 was stirred at room temperature for 30 minutes, and sodium triethyloxyborohydride (0.299 g, 1.41 mmol) was added, and the mixture was reacted at room temperature for 2 hours. After completion of the reaction, water (30 mL) was added, and the mixture was evaporated with methylene chloride (30 mL×2). Concentration, the residue was purified by column chromatography (eluent: methanol/dichloromethane (v/v) = 1/100~5/100) to give the title compound 3-[3-[4-[( 2-Phenylphenyl)carbamomethoxy)-1-indolyl]propanylamino]propyl-N-[2-chloro-4-[[[(2R)-2-hydroxy-2-) (4-Hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino]methyl]-2-chloro-5-methoxyphenyl]carbamate ( Compound 3 ), pale yellow solid (0.11 g, yield 28%).

^{1 H NMR (400MHz, DMSO-} d6) δ 8.90 (s, 1H), 8.59 (s, 1H), 7.93 (s, 1H), 7.47-7.19 (m, 10H), 6.87 (d, 1H), 6.71 ( d, 1H), 4.68-4.59 (m, 1H), 4.44 (s, 1H), 4.09 (t, 2H), 3.74 (s, 3H), 3.67 (s, 2H), 3.19-3.11 (m, 2H) , 2.82 (m, 1H), 2.74-2.55 (m, 4H), 2.21 (t, 2H), 2.15 (m, 2H), 1.80-1.63 (m, 4H), 1.51-1.34 (m, 3H), 1.24 (m, 2H), 1.08 (t, 2H).

LCMS m/z = 847.2 [M + 1].

Ditrifluoroacetate salt of compound 3: 3-[3-[4-[(2-phenylphenyl)carbamomethoxy)-1-indanyl]propanylamino]propyl-N-[ 2-Chloro-4-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino]methyl ]-2-chloro-5-methoxyphenyl]carbamate ditrifluoroacetate

3-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoylamino]propyl-N-[2-chloro-4-[[[(2R)-2-hydroxy-2-(4- hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino]methyl]-2-chloro-5-methoxy-phenyl]carbamate ditrifluoroacetic acid salt

3-[3-[4-[(2-Phenylphenyl)carbamoyloxy)-1-indanyl]propanylamino]propyl-N-[2-chloro-4 was obtained by the above method. -[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino]methyl]-2-chloro -5-Methoxyphenyl]carbamate ( Compound 3 ) crude product (0.90 g), further purified by liquid chromatography column (liquid phase preparation conditions: C18 reverse chromatography column, mobile phase For the deionized water (A) containing 0.05% TFA, acetonitrile (B), isocratic elution of 25% B, elution time 20 minutes) to give the title compound 3-[3-[4-[(2-phenyl) Phenyl)carbamethoxyoxy)-1-indolyl]propanylamino]propyl-N-[2-chloro-4-[[[(2R)-2-hydroxy-2-(4-hydroxyl) -2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino]methyl]-2-chloro-5-methoxyphenyl]carbamate ditrifluoroacetate , white solid (0.3 g).

_{^{1 H NMR (400MHz, CD 3}} OD) δ 7.77 (s, 1H), 7.54 (d, 1H), 7.38 (ddd, 9H), 6.97 (d, 1H), 6.76 (d, 1H), 5.00 (t, 1H), 4.84 (s, 1H), 4.24 (t, 4H), 3.90 (s, 3H), 3.59 (d, 1H), 3.38 (m, 5H), 3.13 (d, 4H), 2.73 (s, 2H) ), 2.18 (dd, 1H), 2.00-1.87 (m, 4H), 1.76 (s, 1H).

LC-MS m/z = 424.4 [M/2+1].

Example 4: [1-[3-[2-Ethynyl-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-4H-quinolin-5-yl)) Ethyl]amino]methyl]-5-methoxyanilino]-3-oxo-propyl]-4-acridinyl]-N-(2-phenylphenyl)carbamate ( compound) 4 ) Synthesis

[1-[3-[2-ethynyl-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-4H-quinolin-5-yl)ethyl]amino]methyl]- 5-methoxy-anilino]-3-oxo-propyl]-4-piperidyl]-N-(2-phenylphenyl)carbamate

First step: 4-ethylamino-5-iodo-2-methoxy-benzoic acid methyl ester ( 4B )

Methyl 4-acetamido-5-iodo-2-methoxy-benzoate

Methyl 4-acetamido-2-yloxybenzoate ( 4A ) (1.0 g, 4.48 mmol) was dissolved in dichloromethane (10 mL), EtOAc (5 mL), N- Amine (1.0 g, 4.48 mmol) and trifluoroacetic acid (0.026 g, 0.22 mmol). Dichloromethane (20 mL) was added to give a mixture, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate (20 mL×2), saturated aqueous sodium thiosulfate (20 mL×2) and saturated aqueous sodium chloride (10 mL×2) sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 4-acetylamino-5-iodo-2-methoxy - benzoic acid methyl ester (4B), as a yellow solid (1.38 g of, 88.2% yield).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.25 (s, 1H), 8.23 (s, 1H), 7.59 (s, 1H), 3.92 (s, 3H), 3.87 (s, 3H), 2.27 (s, 3H ).

LCMS m/z = 350.0 [M + 1].

Step 2: 4-Ethylamino-2-methoxy-5-(2-trimethylsulfonylacetylene)benzoic acid methyl ester ( 4C )

Methyl 4-acetamido-2-methoxy-5-(2-trimethylsilylethynyl)benzoate

4-Ethylamino-5-iodo-2-methoxy-benzoic acid methyl ester ( 4B ) (0.2 g, 0.6 mmol) was dissolved in dry dichloromethane (5 mL) and triethylamine (0.08 g) , 0.8mmol), replacing nitrogen, adding bistriphenylphosphine palladium dichloride (0.02g, 0.03mmol) and cuprous iodide (0.04g, 0.06mmol), after replacement, replacing nitrogen, cooling under ice protection in ice bath To 0 ° C, trimethyldecylacetylene (0.06 g, 0.7 mmol) was slowly added dropwise, and after stirring for 15 minutes, the mixture was allowed to react to room temperature for 165 minutes. The reaction mixture was concentrated under reduced pressure and the residue was purified and purified eluted eluted eluted eluted eluted elution Methyl 2-methoxy-5-(2-trimethylsulfonylacetylene)benzoate ( 4C ), yellow solid (0.17 g, yield 90%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.19 (s, 1H), 8.05 (s, 1H), 7.88 (s, 1H), 3.87 (s, 3H), 3.79 (s, 3H), 2.16 (s, 3H) ), 0.22 (s, 9H).

LCMS m/z = 320.0 [M + 1].

The third step: N-[4-(hydroxymethyl)-5-methoxy-2-(2-trimethylsulfonylethynyl)phenyl]acetamide ( 4D )

N-[4-(hydroxymethyl)-5-methoxy-2-(2-trimethylsilylethynyl)phenyl]acetamide

Methyl 4-ethylguanidino-2-methoxy-5-(2-trimethylsulfonylacetylene)benzoate ( 4C ) (9.0 g, 28 mmol) was dissolved in tetrahydrofuran (300 mL) After cooling to 0 ° C, lithium tetrahydroaluminum (2.4 g, 56 mmol) was added, and the mixture was reacted for 2 hours in an ice bath. Water (7 mL) was added dropwise under ice-cooling, and the mixture was filtered over Celite. The filtrate was washed with dichloromethane (100 mL), and the filtrate was concentrated under reduced pressure. /ethyl acetate (v/v) = 1/0 to 3/2) gave the title compound N-[4-(hydroxymethyl)-5-methoxy-2-(2-trimethyl-decynyl) Phenyl]acetamide ( 4D ), yellow solid (5.0 g, yield 61%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.14 (s, 1H), 8.02 (s, 1H), 7.33 (s, 1H), 4.59 (s, 2H), 3.89 (s, 3H), 2.21 (s, 3H ), 0.28 (s,, 9H).

LCMS m/z = 292.1 [M + 1].

The fourth step: N-[4-carbamimido-5-methoxy-2-(2-trimethylsulfonylethynyl)phenyl]acetamide ( 4E )

N-[4-formyl-5-methoxy-2-(2-trimethylsilylethynyl)phenyl]acetamide

Dissolving N-[4-(hydroxymethyl)-5-methoxy-2-(2-trimethylsulfonylethynyl)phenyl]acetamide ( 4D ) (2.0 g, 6.9 mmol) in dichloro In methane (5 mL), the mixture was cooled to 0 ° C under a nitrogen atmosphere, and then evaporated, and then evaporated. The mixture was diluted with aq. EtOAc (EtOAc (EtOAc) The residue was purified by silica gel column chromatography (eluent petroleum ether/ethyl acetate (v/v) = 1/0 to 4/1) to give the title compound N-[4-carbazin-5 -Methoxy-2-(2-trimethylsulfonylethynyl)phenyl]acetamide ( 4E ), pale yellow solid (1.35 g, yield 68%).

^{1 H NMR (400MHz, CDCl3)} δ 10.22 (s, 1H), 8.19 (s, 1H), 8.14 (s, 1H), 7.84 (s, 1H), 3.89 (s, 3H), 2.18 (s, 3H) , 0.22 (s, 9H).

LCMS m/z = 290.1 [M + 1].

Step 5: 4-Amino-5-ethynyl-2-methoxy-benzaldehyde ( 4F )

4-amino-5-ethynyl-2-methoxy-benzaldehyde

Dissolving N-[4-carbamimido-5-methoxy-2-(2-trimethylsulfonylethynyl)phenyl]acetamide ( 4E ) (1.35 g, 4.66 mmol) in methanol / tetrahydrofuran ( In a mixed solvent of v/v = 2/1, 30 mL), an aqueous solution (20 mL) of sodium hydroxide (1.87 g, 46.6 mmol) was added and heated to 80 ° C for 1 hour. After cooling to room temperature, methylene chloride (50 mL) was added, and the mixture was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 4-amino-5-ethynyl-2-methoxy - benzaldehyde (4F), as a yellow solid (0.7 g, 90% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.13 (s, 1H), 7.78 (s, 1H), 6.15 (s, 1H), 4.83 (s, 2H), 3.88 (s, 3H), 3.32 (s, 1H) ).

LCMS m/z = 176.1 [M + 1].

Step 6: N-(2-ethynyl-4-methylindolyl-5-methoxy-phenyl)prop-2-enylamine ( 4G )

N-(2-ethynyl-4-formyl-5-methoxy-phenyl)prop-2-enamide

4-Amino-5-ethynyl-2-methoxy-benzaldehyde ( 4F ) (0.44 g, 2.5 mmol) was suspended in ethyl acetate (10 mL), EtOAc (0.45 g, 6.3 mmol) Amine (1.9 g, 7.5 mmol), heated to 40 ° C, 2,4,6-tripropyl-1,3,5,2,4,6-trioxytriphosphate-2,4,6-three was added dropwise Oxide (T3P, CAS: 68957-94-8) (2.0g, 6.3mmol), after the addition, the temperature was raised to 80 ° C reflux for 1.5 hours, then cooled to room temperature, 2M aqueous hydrochloric acid was added to adjust the pH to 5, added Ethyl acetate (100 mL), EtOAc (EtOAc) (EtOAc m. After concentration, the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 1 / 0 to 5 / 1) to give the title compound N-(2-ethynyl-4 -Methylmercapto-5-methoxy-phenyl)prop-2-enylamine ( 4G ), yellow solid (0.37 g, yield 64%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 10.31 (s, 1H), 8.41 (s, 1H), 8.27 (s, 1H), 7.97 (s, 1H), 6.48 (dd, 1H), 6.31 (dd, 1H ), 5.89 (dd, 1H), 3.99 (s, 3H), 3.51 (s, 1H).

LCMS m/z = 230.1 [M + 1].

Step 7: [1-[3-(2-ethynyl-4-carbamimido-5-methoxyanilino)-3-oxo-propyl]-4-acridinyl]-N-( 2-phenylphenyl)carbamate ( 4I )

[1-[3-(2-ethynyl-4-formyl-5-methoxy-anilino)-3-oxo-propyl]-4-piperidyl]-N-(2-phenylphenyl)carbamate

Dissolving N-(2-ethynyl-4-methylindolyl-5-methoxy-phenyl)prop-2-enylamine ( 4G ) (0.12 g, 0.52 mmol) in 2-methyltetrahydrofuran (4 mL) , 4- 4-Acryl-N-(2-phenylphenyl)carbamate ( 4H ) (prepared by reference to WO2004074246A1) (0.16g, 0.52mmol), glacial acetic acid (0.063g, 1.0mmol) After the addition, the microwave was reacted at 100 ° C for 30 minutes. Ethyl acetate (30 mL) was added to give ethyl acetate (30 mL). Separation and purification by gel column chromatography (eluent petroleum ether / ethyl acetate (v / v) = 4 / 1 ~ 0/1) gave the title compound [1-[3-(2-ethynyl)- 4-Mercapto-5-methoxyanilino)-3-oxo-propyl]-4-acridinyl]-N-(2-phenylphenyl)carbamate ( 4I ), shallow Yellow solid (0.17 g, yield 62%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ10.22 (s, 1H), 8.15 (s, 1H), 8.01 (d, 1H), 7.90 (s, 1H), 7.45-7.39 (m, 2H), 7.38- 7.33(m,1H),7.32-7.26(m,3H),7.16-7.14(m,1H),7.09-7.03(m,1H),6.52(s,1H),4.77-4.67(m,1H), 3.88(s,3H), 3.25(s,1H),2.83-2.75(m,2H), 2.75-2.65(m,2H), 2.60-2.50(m,2H), 2.35-2.25(m,2H), 1.96-1.86 (m, 2H), 1.76-1.66 (m, 2H).

LCMS m/z = 526.1 [M + 1].

Step 8: [1-[3-[4-[[[(2R)-2-[T-butyl(dimethyl)carbamyl]oxy-2-(8-hydroxy-2-oxo) -4H-quinolin-5-yl)ethyl]amino]methyl]-2-ethynyl-5-methoxy-anilino]-3-oxo-propyl]-4-acridinyl]- N-(2-phenylphenyl)carbamate ( 4K )

[1-[3-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-4H-quinolin-5-yl)ethyl] Amino]methyl]-2-ethynyl-5-methoxy-anilino]-3-oxo-propyl]-4-piperidyl]-N-(2-phenylphenyl)carbamate

[1-[3-(2-ethynyl-4-carbamimido-5-methoxyanilino)-3-oxo-propyl]-4-oxaridinyl]-N-(2-benzene Phenyl phenyl) carbamate ( 4I ) (0.605 g, 1.15 mmol) was dissolved in anhydrous methanol (25 mL), dichloromethane (10 mL) was added, and 5-[(1R)-2-amino-1-[ Tert-butyl(dimethyl)carbinyl]oxyethyl]-8-hydroxy-4H-quinolin-2-one ( 4J ) (prepared by reference WO2007102771A1) (0.385 g, 1.15 mmol), room temperature After stirring for 1 hour, sodium triethoxysulfonate hydride (0.732 g, 3.45 mmol) was added, and the mixture was further reacted at room temperature for 2 hours. Dichloromethane (100 mL) was added to give a mixture, and the mixture was washed successivelylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylylyly The product was separated and purified by silica gel column chromatography (eluent: dichloromethane (m/v) = 1/0 to 19/1) to give the title compound [1-[3-[4-[[[ 2R)-2-[t-butyl(dimethyl)formamyl]oxy-2-(8-hydroxy-2-oxo-4H-quinolin-5-yl)ethyl]amino]methyl ]-2-ethynyl-5-methoxy-anilino]-3-oxo-propyl]-4-acridinyl]-N-(2-phenylphenyl)carbamate ( 4K ) , pale yellow solid (0.13 g, yield 48%).

LCMS m/z = 422.7 [M+2]/2.

The ninth step: [1-[3-[2-ethynyl-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-4H-quinolin-5-yl)) Ethyl]amino]methyl]-5-methoxyanilino]-3-oxo-propyl]-4-acridinyl]-N-(2-phenylphenyl)carbamate ( compound) 4 )

[1-[3-[2-ethynyl-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-4H-quinolin-5-yl)ethyl]amino]methyl]- 5-methoxy-anilino]-3-oxo-propyl]-4-piperidyl]-N-(2-phenylphenyl)carbamate

[1-[3-[4-[[[(2R)-2-[T-butyl(dimethyl)methyl)alkyl]oxy-2-(8-hydroxy-2-oxo-4H- Quinoline-5-yl)ethyl]amino]methyl]-2-ethynyl-5-methoxy-anilino]-3-oxo-propyl]-4-acridinyl]-N-( 2-Phenylphenyl)carbamate ( 4K ) (0.700 g, 0.829 mmol) was dissolved in dichloromethane (10 mL) and triethylamine trihydrofluoric acid salt (2.67 g, 16.6 mmol) was added. After the reaction at room temperature for 6 hours. The mixture was slowly added dropwise with a saturated aqueous solution of sodium bicarbonate, and the mixture was evaporated to m.jjjjjjjjjjjjjjjjj Chromatographic separation and purification (eluent to dichloromethane / methanol (v / v) = 1 / 0 ~ 19 / 1) to give the title compound [1-[3-[2-ethynyl-4-[[[ 2R)-2-hydroxy-2-(8-hydroxy-2-oxo-4H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxyanilino]-3-oxo -Phenyl-4-pyridinyl]-N-(2-phenylphenyl)carbamate ( Compound 4 ), pale yellow solid (0.2 g, yield 30%).

_{^{1 H NMR (400MHz, CD 3}} OD) δ 8.11 (d, 1H), 7.63 (s, 1H), 7.45 (d, 1H), 7.34--7.12 (m, 10H), 7.06 (d, 1H), 6.87 (d, 1H), 6.49 (d, 1H), 5.09-5.05 (m, 1H), 4.58-4.48 (m, 1H), 3.72 (s, 1H), 3.70 (s, 2H), 3.69 (s, 3H) ), 2.83-2.73 (m, 2H), 2.70-2.60 (m, 4H), 2.53 (t, 2H), 2.29 (t, 2H), 1.82-1.74 (m, 2H), 1.63-1.53 (m, 2H) ).

LCMS m/z = 730.2 [M + 1].

Example 5: [1-[3-[2-Ethynyl-4-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazole) -7-yl)ethyl]amino]methyl]-5-methoxyanilino]-3-oxo-propyl]-4-acridinyl]-N-(2-phenylphenyl)amino Synthesis of formate ( compound 5 )

[1-[3-[2-ethynyl-4-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino ]methyl]-5-methoxy-anilino]-3-oxo-propyl]-4-piperidyl]-N-(2-phenylphenyl)carbamate

[1-[3-(2-ethynyl-4-carbamimido-5-methoxyanilino)-3-oxo-propyl]-4-oxaridinyl]-N-(2-benzene Phenyl phenyl) carbamate ( 4I ) (0.100 g, 0.190 mmol) was dissolved in dichloromethane (3 mL), anhydrous methanol (3 mL) was added, and 7-[(1R)-2-amino-1-hydroxyl was added. -ethyl]-4-hydroxy-3H-1,3-benzothiazol-2-one ( 3F ) (0.0646 g, 0.285 mmol), stirred at room temperature for 1 hour, and added sodium triethyloxyborohydride (0.124) g, 0.571 mmol), and allowed to react at room temperature overnight after the addition. The mixture was diluted with aq. EtOAc (EtOAc (EtOAc) (EtOAc) The organic layer was concentrated under reduced pressure and the residue was purified eluting eluting eluting eluting eluting elution -ethynyl-4-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino]methyl ]-5-Methoxyanilino]-3-oxo-propyl]-4-acridinyl]-N-(2-phenylphenyl)carbamate ( Compound 5 ), pale yellow solid ( 0.046 g, yield 33%).

¹ H NMR (400 MHz, CD ₃ OD) δ 7.68 (s, 1H), 7.44 (d, 1H), 7.34 - 7.20 (m, 8H), 7.19-7.13 (m, 2H), 6.81 (d, 1H) , 6.62 (d, 1H), 4.76-4.70 (m, 1H), 4.58--4.48 (m, 1H), 3.78 (s, 2H), 3.73 (s, 1H), 3.72 (s, 3H), 2.86- 2.74 (m, 2H), 2.69-2.63 (m, 4H), 2.53 (t, 2H), 2.30 (t, 2H), 1.80-1.74 (m, 2H), 1.62-1.54 (m, 2H).

LCMS m/z = 736.3 [M + 1].

Example 6: [1-[3-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-4H-quinolin-5-yl)ethyl]amino] Methyl]-5-methoxy-2-prop-1-ynyl-anilino]-3-oxo-propyl]-4-acridinyl]-N-(2-phenylphenyl)amino Synthesis of formate ( compound 6 )

[1-[3-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-4H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy- 2-prop-1-ynyl-anilino]-3-oxo-propyl]-4-piperidyl]-N-(2-phenylphenyl)carbamate

First step: 4-ethylamino-2-methoxy-5-prop-1-ynyl-benzoic acid methyl ester ( 6A )

Methyl 4-acetamido-2-methoxy-5-prop-1-ynyl-benzoate

4-Ethylamino-5-iodo-2-methoxy-benzoic acid methyl ester ( 4B ) (5.00 g, 14.3 mmol) was dissolved in tetrahydrofuran (80 mL) and tetratriphenylphosphine palladium was added under nitrogen. 0.827 g, 0.716 mmol) and triethylamine (4.78 g, 47.3 mmol) were replaced with nitrogen, and cuprous iodide (0.818 g, 4.3 mmol) and trimethyldecylpropyne (3.24 g, 28.6 mmol) were added. Further, a solution of tetrabutylammonium fluoride (3.75 g, 14.3 mmol) in tetrahydrofuran (20 mL) was added dropwise, and the mixture was stirred at room temperature overnight. Ethyl acetate (100 mL) was added to give a mixture, and the mixture was washed successively with 2M aqueous hydrochloric acid (100 mL×2), saturated aqueous sodium hydrogen carbonate (50 mL×1) and saturated aqueous sodium chloride (50 mL×1) After drying over sodium sulfate, filtration and concentration of the filtrate under reduced pressure, the residue was purified by silica gel column chromatography (eluent petroleum ether/dichloromethane (v/v) = 1/0~0/1). Compound 4-Ethylamino-2-methoxy-5-prop-1-ynyl-benzoic acid methyl ester ( 6A ), yellow solid (3.50 g, yield 93.5%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.26 (s, 1H), 8.04 (s, 1H), 7.90 (s, 1H), 3.93 (s, 3H), 3.85 (s, 3H), 2.25 (s, 3H ), 2.14 (s, 3H).

LCMS m/z = 262.2 [M + 1].

Second step: N-[4-(hydroxymethyl)-5-methoxy-2-prop-1-ynyl-phenyl]acetamide ( 6B )

N-[4-(hydroxymethyl)-5-methoxy-2-prop-1-ynyl-phenyl]acetamide

4-Ethylamino-2-methoxy-5-prop-1-ynyl-benzoic acid methyl ester ( 6A ) (3.50 g, 13.4 mmol) was dissolved in tetrahydrofuran (50 mL). To 0 ° C, lithium tetrahydroaluminum (1.02 g, 26.8 mmol) was added, and after the addition, the reaction was carried out for 1 hour in an ice bath. Water (6 mL) was slowly added dropwise under ice-cooling, and the mixture was filtered and filtered, and the filtrate was washed with methylene chloride (100 mL), and the filtrate was concentrated to give the title compound N-[4-(hydroxymethyl)-5- Oxy-2-prop-1-ynyl-phenyl]acetamide ( 6B ), yellow solid (3.0 g, yield 96%).

LCMS m/z = 234.2 [M + 1].

The third step: N-(4-carbamimido-5-methoxy-2-prop-1-ynyl-phenyl)acetamide ( 6C )

N-(4-formyl-5-methoxy-2-prop-1-ynyl-phenyl)acetamide

Dissolving N-[4-(hydroxymethyl)-5-methoxy-2-prop-1-ynyl-phenyl]acetamide ( 6B ) (3.0 g, 13 mmol) in dichloromethane (50 mL) The mixture was cooled to 0 ° C under an ice-cooling atmosphere, and then ss. s. oxidant (9.8 g, 23 mmol) was added. After the addition, the reaction was carried out for 2 hours in an ice bath. The mixture was diluted with aq. EtOAc (EtOAc (EtOAc) The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v/v) = 1/0 to 4/1) to give the title compound N-(4-carbazin-5- Methoxy-2-prop-1-ynyl-phenyl)acetamidine ( 6C ), pale yellow solid (3.0 g, yield 100%).

LCMS m/z = 232.2 [M + 1].

The fourth step: 4-amino-2-methoxy-5-prop-1-ynyl-benzaldehyde ( 6D )

4-amino-2-methoxy-5-prop-1-ynyl-benzaldehyde

N-(4-Methylinden-5-methoxy-2-prop-1-ynyl-phenyl)acetamide ( 6C ) (3.00 g, 13.0 mmol) was dissolved in methanol / tetrahydrofuran (10 mL, v In /v = 1/1), an aqueous solution (10 mL) of sodium hydroxide (5.19 g, 130 mmol) was added, and the mixture was heated to 80 ° C for 30 minutes. After cooling to room temperature, dichloromethane (50 mL) was added, and the mixture was separated and evaporated, evaporated, evaporated, evaporated. The sodium was dried, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified and purified by silica gel column chromatography (eluent petroleum ether/dichloromethane (v/v) = 1/0 to 1/1). -Amino-2-methoxy-5-prop-1-ynyl-benzaldehyde ( 6D ), yellow solid (0.800 g, yield 32.6%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 10.11 (s, 1H), 7.76 (s, 1H), 6.14 (s, 1H), 4.79 (s, 2H), 3.85 (s, 3H), 2.09 (s, 3H ).

LCMS m/z = 190.1 [M + 1].

The fifth step: N-(4-carbamimido-5-methoxy-2-prop-1-ynyl-phenyl)prop-2-enylamine ( 6E )

N-(4-formyl-5-methoxy-2-prop-1-ynyl-phenyl)prop-2-enamide

4-Amino-2-methoxy-5-prop-1-ynyl-benzaldehyde ( 6D ) (0.500 g, 2.64 mmol) was dissolved in ethyl acetate (50 mL). , triethylamine (2.04 g, 19.8 mmol), heated to 40 ° C dropwise 2,4,6-tripropyl-1,3,5,2,4,6-trioxytriphosphate-2,4, 6-Trioxide (T3P, CAS: 68957-94-8) (2.10 g, 6.61 mmol), after the addition was completed, the temperature was raised to 80 ° C and reflux for 1.5 hours. After cooling to room temperature, ethyl acetate (40 mL) was added, and the layers were separated, and the organic layer was successively applied with 2M aqueous hydrochloric acid (20mL×1), 10% aqueous sodium hydroxide (50mL×1) and saturated aqueous sodium chloride (10mL) ×1) Washing, drying with anhydrous sodium sulfate, filtration, and concentrating the filtrate under reduced pressure. The residue was purified and purified by column chromatography (eluent petroleum ether / dichloromethane (v/v) = 1/0~3 / 2) The title compound N-(4-carbamimido-5-methoxy-2-prop-1-ynyl-phenyl)prop-2-enylamine ( 6E ) was obtained as a yellow solid (0.37 g, Yield 57.5%)

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 10.30 (s, 1H), 8.37 (s, 1H), 8.29 (s, 1H), 7.87 (s, 1H), 6.46 (dd, 1H), 6.31 (dd, 1H ), 5.87 (dd, 1H), 3.97 (s, 3H), 2.15 (s, 3H).

The sixth step: [1-[3-(4-carbamimido-5-methoxy-2-prop-1-ynyl-anilino)-3-oxo-propyl]-4-indolyl ]-N-(2-phenylphenyl)carbamate ( 6F )

[1-[3-(4-formyl-5-methoxy-2-prop-1-ynyl-anilino)-3-oxo-propyl]-4-piperidyl]-N-(2-phenylphenyl)carbamate

Dissolving N-(4-carbamimido-5-methoxy-2-prop-1-ynyl-phenyl)prop-2-enylamine ( 6E ) (0.370 g, 1.52 mmol) in 2-A 4-Acridine-N-(2-phenylphenyl)carbamate ( 4H ) (0.496 g, 1.67 mmol), triethylamine (0.308 g, 3.04 mmol), After the addition, the microwave was reacted at 100 ° C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified and purified eluting eluting eluting eluting eluting -(4-methylindolyl-5-methoxy-2-prop-1-ynyl-anilino)-3-oxo-propyl]-4-indanyl]-N-(2-phenyl Phenyl)carbamate ( 6F ), pale yellow solid (0.680 g, yield 82.9%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 10.29 (s, 1H), 9.56 (s, 1H), 8.16 (s, 1H), 8.09 (d, 1H), 7.87 (s, 1H), 7.52-7.45 (m , 3H), 7.45-7.40 (m, 1H), 7.39-7.33 (m, 4H), 7.22 (dd, 1H), 7.14-7.10 (m, 1H), 6.59 (s, 1H), 4.82-4.74 (m ,1H),3.94(s,3H),2.86-2.74(m,4H),2.66-2.60(m,2H),2.42-2.34(m,2H),2.06(s,3H),2.02-1.96(m , 2H), 1.80-1.72 (m, 2H).

LCMS m/z = 540.3 [M + 1].

Step 7: [1-[3-[4-[[[(2R)-2-[T-butyl(dimethyl)carbamyl]oxy-2-(8-hydroxy-2-oxo) -4H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy-2-prop-1-ynyl-anilino]-3-oxo-propyl]-4-indole Pyridyl]-N-(2-phenylphenyl)carbamate ( 6G )

[1-[3-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-4H-quinolin-5-yl)ethyl] Amino]methyl]-5-methoxy-2-prop-1-ynyl-anilino]-3-oxo-propyl]-4-piperidyl]-N-(2-phenylphenyl)carbamate

[1-[3-(4-Mercapto-5-methoxy-2-prop-1-ynyl-anilino)-3-oxo-propyl]-4-acridinyl]-N -(2-Phenylphenyl)carbamate ( 6F ) (0.200 g, 0.371 mmol) was dissolved in anhydrous methanol (4 mL), dichloromethane (2 mL) was added, and 5-[(1R)-2- Amino-1-[t-butyl(dimethyl)methylidene]oxyethyl]-8-hydroxy-4H-quinolin-2-one ( 4J ) (0.149 g, 0.445 mmol), stirred at room temperature After 1 hour, sodium triethoxysulfonate hydride (0.236 g, 1.11 mmol) was added, and the mixture was stirred at room temperature overnight. The aqueous solution was adjusted to pH 9 with saturated aqueous sodium hydrogen sulfate, and dichloromethane (20 mL) was added, and the mixture was separated, and the aqueous layer was extracted with dichloromethane (10 mL×1). 1) Washing, drying with anhydrous sodium sulfate, filtration, and concentrating the filtrate under reduced pressure. The residue was purified by chromatography on silica gel column (eluent: dichloromethane/methanol (v/v) = 1/0 to 19/1) The title compound [1-[3-[4-[[[(2R)-2-[t-butyl(dimethyl)methyl)alkyl]oxy-2-(8-hydroxy-2-oxo) -4H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy-2-prop-1-ynyl-anilino]-3-oxo-propyl]-4-indole Pyridyl]-N-(2-phenylphenyl)carbamate ( 6G ), pale yellow solid (0.240 g, yield 75.5%).

LCMS m/z = 858.4 [M + 1].

Step 8: [1-[3-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-4H-quinolin-5-yl)ethyl]amino]] Methyl]-5-methoxy-2-prop-1-ynyl-anilino]-3-oxo-propyl]-4-acridinyl]-N-(2-phenylphenyl)amino Formate ( compound 6 )

[1-[3-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-4H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy- 2-prop-1-ynyl-anilino]-3-oxo-propyl]-4-piperidyl]-N-(2-phenylphenyl)carbamate

[1-[3-[4-[[[(2R)-2-[T-butyl(dimethyl)methyl)alkyl]oxy-2-(8-hydroxy-2-oxo-4H- Quinoline-5-yl)ethyl]amino]methyl]-5-methoxy-2-prop-1-ynyl-anilino]-3-oxo-propyl]-4-acridinyl] -N-(2-Phenylphenyl)carbamate ( 6G ) (0.240 g, 0.280 mmol) was dissolved in tetrahydrofuran (2 mL) and triethylamine trihydrofluoric acid salt (0.180 g, 1. After the addition, the reaction was carried out at room temperature overnight. The supernatant liquid (upper liquid and supernatant) in the reaction flask was removed, and the remaining viscous material was washed with tetrahydrofuran (10 mL×2) to remove the tetrahydrofuran solution, and the viscous material was mixed with dichloromethane and methanol (20 mL, v/v=9/1) Dissolve, add saturated aqueous sodium hydrogencarbonate solution to adjust the pH to 9, extract the layers, extract the aqueous layer with dichloromethane (20 mL × 2), and combine the organic layer, saturated aqueous sodium chloride (10 mL) ×1) Washing, drying with anhydrous sodium sulfate, filtration, and concentrating the residue under reduced pressure. The residue was purified by column chromatography (eluent: methylene chloride/methanol (v/v) = 1/0 to 9/1) The title compound [1-[3-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-4H-quinolin-5-yl)ethyl]amino]] Methyl]-5-methoxy-2-prop-1-ynyl-anilino]-3-oxo-propyl]-4-acridinyl]-N-(2-phenylphenyl)amino Formate ( Compound 6 ), pale yellow solid (0.110 g, yield 52.9%).

_{^{1 H NMR (400MHz, CD 3}} OD) δ 8.10 (d, 1H), 7.57 (s, 1H), 7.44 (d, 1H), 7.32-7.20 (m, 7H), 7.20-7.13 (m, 3H), 7.05(d,1H), 6.87(d,1H), 6.49(d,1H), 5.08-5.04(m,1H),4.52-4.48(m,1H),3.69(s,2H),3.67(s, 3H), 2.83-2.71 (m, 2H), 2.71-2.62 (m, 4H), 2.54 (t, 2H), 2.34-2.24 (s, 2H), 1.98 (s, 3H), 1.83-1.73 (m, 2H), 1.60-1.50 (m, 2H).

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

Example 7: 3-[3-[4-[(2-Phenylphenyl)carbamoyloxy]-1-indanyl]propanylamino]propyl-N-[2-chloro-4 -[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy-phenyl Synthesis of carbamate; ditrifluoroacetate ( compound 7 )

3-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoylamino]propyl-N-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8- Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy-phenyl]carbamate;ditrifluoroacetic acid salt

First step: 3-[3-[4-[(2-phenylphenyl)carbamomethoxy]-1-indolyl]propanylamino]propyl-N-[4-[[[ (2R)-2-[t-butyl(dimethyl)methanyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]- 2-chloro-5-methoxy-phenyl]carbamate ( 7A )

3-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoylamino]propyl-N-[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]carbamate

3-[3-[4-[(2-Phenylphenyl)carbamomethoxy]-1-indolyl]propanylamino]propyl-N-(2-chloro-4-carboxamidine) 5--5-methoxy-phenyl)carbamate ( 3E ) (1.0 g, 1.57 mmol) and 5-[(1R)-2-amino-1-[tert-butyl(dimethyl)-methyl矽alkyl]oxyethyl]-8-hydroxy-1H-quinolin-2-one ( 4J ) (0.577 g, 1.727 mmol) was dissolved in methanol (20 mL), and zinc chloride (0.856 g, 6.278 mmol) was added. The reaction was carried out at 55 ° C for 1 hour, sodium cyanoborohydride (0.296 g, 4.709 mmol) was added, and the reaction was continued for 2 hours. After adding water (30 mL), it was extracted with dichloromethane (30 mL×2), washed with saturated aqueous sodium chloride (30 mL×1), dried over anhydrous sodium sulfate, filtered and evaporated. Separation and purification with dichloromethane/methanol = 100/1~100/5) gave the title compound 3-[3-[4-[(2-phenylphenyl)carbamomethoxy]-1- Acridine]propionylamino]propyl-N-[4-[[[(2R)-2-[t-butyl(dimethyl)methyl)alkyl]oxy-2-(8-hydroxy- 2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-2-chloro-5-methoxy-phenyl]carbamate ( 7A ), yellow solid (0.6 g, Yield 40%).

LC-MS m/z = 478.3 [M+2]/2.

Second step: 3-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-indanyl]propanylamino]propyl-N-[2-chloro-4 -[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy-phenyl Carbamate; ditrifluoroacetic acid ( compound 7 )

3-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoylamino]propyl-N-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8- Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy-phenyl]carbamate;ditrifluoroacetic acid

3-[3-[4-[(2-Phenylphenyl)carbamomethoxy]-1-indolyl]propanylamino]propyl-N-[4-[[[(2R)-) 2-[Third butyl(dimethyl)methanyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-2 -Chloro-5-methoxy-phenyl]carbamate ( 7A ) (0.6 g, 0.628 mmol) was dissolved in tetrahydrofuran (5 mL x 1) and triethylamine trihydrofluoride (0.405 g, 2.51) Methyl), reacted at room temperature overnight. The mixture was adjusted to pH 9 with aq. EtOAc. EtOAc (EtOAc (EtOAc) The residue was separated and purified by liquid chromatography column (liquid phase preparation conditions: C18 reverse chromatography column, mobile phase was deionized water (A) containing 0.05% TFA, acetonitrile (B) containing 0.05% TFA, Gradient elution A: B = 5% ~ 100%, elution for 10 minutes, then elution with 100% B for 5 minutes, flow rate 1.0 mL / min, column temperature: 40 ° C), the title compound 3-[3- [4-[(2-Phenylphenyl)carbamomethoxy]-1-indolyl]propanylamino]propyl-N-[2-chloro-4-[[[(2R)-2 -hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy-phenyl]carbamate; ditrifluoro Acetic acid ( Compound 7 ), grey solid (0.077 g, yield 11%).

_{^{1 H NMR (400MHz, CD 3}} OD) δ 8.22 (d, 1H), 7.79 (s, 1H), 7.56 (d, 1H), 7.48 (s, 1H), 7.39 (m, 8H), 7.29 (d, 2H), 7.05 (d, 1H), 6.66 (d, 1H), 5.42 (dd, 1H), 4.88 (br, 1H), 4.27 (m, 4H), 3.91 (s, 3H), 3.50-3.36 (m , 6H), 3.24 (m, 2H), 3.16-3.00 (m, 2H), 2.75 (t, 2H), 2.17 (br, 1H), 2.00 (br, 2H), 1.94 (m, 2H), 1.79 ( Br, 1H).

LC-MS = 841.1 [M + 1].

Free base of compound 7 : 3-[3-[4-[(2-phenylphenyl)carbamomethoxy]-1-indolyl]propanylamino]propyl-N-[2-chloro -4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy- Phenyl]carbamate

3-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoylamino]propyl-N-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8- Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy-phenyl]carbamate

3-[3-[4-[(2-Phenylphenyl)carbamomethoxy]-1-indolyl]propanylamino]propyl-N-[2-chloro-4-[[[ (2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy-phenyl]carbamic acid The ester ditrifluoroacetate ( Compound 7 ) (28 g, 26.2 mmol) was dissolved in a mixed solvent of methanol and dichloromethane (v/v = 1/90, 1000 mL), and a saturated sodium hydrogencarbonate solution was added dropwise to adjust the pH to the base. The mixture was stirred at room temperature for 1 hour, and the aqueous layer was separated, and then evaporated and evaporated. The filtrate was concentrated under reduced pressure to give the title compound 3-[3-[4-[(2-phenylphenyl)carbamomethoxy]-1-pyridinyl]propanylamino]propyl-N-[2 -Chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy Base-phenyl]carbamate, pale yellow solid (20.6 g, yield 93.6%).

1H NMR (400MHz, CD ₃ OD) δ 8.22 (d, 1H), 7.54 (d, 2H), 7.43-7.37 (m, 2H), 7.37-7.22 (m, 6H), 7.21 (s, 1H), 7.12 (d, 1H), 6.93 (d, 1H), 6.57 (d, 1H), 5.15-5.12 (m, 1H), 4.62-4.54 (m, 1H), 4.22 (t, 2H), 3.73 (s, 3H) ), 3.71 (s, 2H), 3.33 - 3.28 (m, 2H), 2.88-2.76 (m, 2H), 2.68-2.60 (m, 4H), 2.37 (t, 2H), 2.29 (t, 2H), 1.94-1.86 (m, 2H), 1.86-1.78 (m, 2H), 1.65-1.55 (m, 2H). LC-MS m/z = 841.1 [M+1].

Example 8: 3-[Methyl-[3-[4-[(2-phenylphenyl)carbamomethoxy]-1-indanyl]propanyl]amino]propyl-N-[ 2-Chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-carbonyl-1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy Synthesis of phenyl-phenyl]carbamate ditrifluoroacetate ( Compound 8 )

3-[methyl-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoyl]amino]propyl-N-[2-chloro-4-[[[(2R)-2-hydroxy- 2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy-phenyl]carbamate;ditrifluoroacetic acid salt

First step: [1-[3-[3-hydroxypropyl(methyl)amino]-3-oxo-propyl]-4-acridinyl]-N-(2-phenylphenyl)amino Formate ( 8A )

[1-[3-[3-hydroxypropyl(methyl)amino]-3-oxo-propyl]-4-piperidyl]-N-(2-phenylphenyl)carbamate

3-[4-[(2-Phenylphenyl)carbamoyloxy]-1-indanyl]propanoic acid ( 3B ) (0.368 g, 1 mmol) was dissolved in tetrahydrofuran (50 mL). (7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (0.76 g, 2 mmol), stirred at room temperature for 30 minutes, added 3-( Methylamino)-1 propanol (0.267 g, 3 mmol) was reacted at room temperature for 2 hours. After the reaction was completed, water (50 mL) was evaporated, evaporated, evaporated, evaporated, evaporated. After that, the residue was purified by silica gel column chromatography (eluent: methylene chloride / methanol = 100/1 to 20/1) to give the title compound [1-[3-[3-hydroxypropyl (methyl) Amino]-3-oxo-propyl]-4-acridinyl]-N-(2-phenylphenyl)carbamate ( 8A ), white solid (0.3 g, yield, 70%) .

^{1 H NMR (400MHz, DMSO-} d6) δ 8.88-8.65 (m, 1H), 7.37 (m, 9H), 4.60 (m, 2H), 3.52-3.34 (m, 6H), 3.29 (d, 2H), 3.07 (s, 1H), 2.96 (d, 2H), 2.92-2.82 (m, 3H), 2.82-2.74 (m, 1H), 1.95 (d, 2H), 1.85-1.53 (m, 4H).

LCMS m/z = 440.4.

The second step: 3-[methyl-[3-[4-[(2-phenylphenyl)carbamomethoxy]-1-indanyl]propanyl]amino]propyl-N-( 2-chloro-4-methylindolyl-5-methoxy-phenyl)carbamate ( 8B )

3-[methyl-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoyl]amino]propyl-N-(2-chloro-4-formyl-5-methoxy-phenyl)carbamate

4-Amino-5-chloro-2-methoxy-benzaldehyde ( 3D ) (2.03 g, 10.9 mmol) was dissolved in toluene (15 mL) and added to phosgene (1.62 g, 5.46 mmol). In an hour, the solvent was removed under reduced pressure to give a liquid. [1-[3-[3-Hydroxypropyl(methyl)amino]-3-oxo-propyl]-4-acridinyl]-N-(2-phenylphenyl)carbamate ( 8A ) (0.6 g, 1.36 mmol) and the reaction mixture 1 were dissolved in tetrahydrofuran (10 mL), and triethylamine (0.691 g, 6.82 mmol) was added and reacted at 75 ° C for 4 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified and purified using EtOAc EtOAc (EtOAc/EtOAc The title compound 3-[methyl-[3-[4-[(2-phenylphenyl)carbamomethoxy]-1-indolyl]propanyl]amino]propyl-N-(2 -Chloro-4-carbamimido-5-methoxy-phenyl)carbamate ( 8B ), (0.34 g, yield 38%).

LCMS m/z = 651.3 [M + 1].

The third step: 3-[methyl-[3-[4-[(2-phenylphenyl)carbamomethoxy]-1-indolyl]propanyl]amino]propyl-N-[ 4-[[[(2R)-2-[T-butyl(dimethyl)indolyl]oxy-2-(8-hydroxy-2-carbonyl-1H-quinolin-5-yl)ethyl] Amino]methyl]-2chloro-5-methoxy-phenyl]carbamate ( 8C )

3-[methyl-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoyl]amino]propyl-N-[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]carbamate

3-[Methyl-[3-[4-[(2-phenylphenyl)carbamomethoxy]-1-indanyl]propanyl]amino]propyl-N-(2-chloro 4-Methylmercapto-5-methoxy-phenyl)carbamate ( 8B ) (0.400 g, 0.614 mmol) was dissolved in methanol (10 mL) and 5-[(1R)-2-amino- 1-[Third butyl(dimethyl)carbinyl]oxyethyl]-8-hydroxy-4H-quinolin-2-one ( 4J ) (0.247 g, 0.737 mmol), added anhydrous zinc chloride (0.335 g, 2.46 mmol), reacted at 55 ° C for 1 hour. Sodium cyanoborohydride (0.116 g, 1.84 mmol) was added, and the mixture was reacted at 55 ° C for 2 hours. The reaction mixture was added with dichloromethane (50 mL), EtOAc (EtOAc) After filtration and concentration of the filtrate under reduced pressure, the residue was purified and purified using EtOAc EtOAc (EtOAc/EtOAc (EtOAc) v/v)=3/97~1/9), the title compound 3-[methyl-[3-[4-[(2-phenylphenyl)carbamomethoxy]-1-indanyl) Propionyl]amino]propyl-N-[4-[[[(2R)-2-[t-butyl(dimethyl)indolyl]oxy-2-(8-hydroxy-2-) Carbonyl-1H-quinolin-5-yl)ethyl]amino]methyl]-2chloro-5-methoxy-phenyl]carbamate ( 8C ), yellow solid (0.20 g, yield 33.6%) ).

LCMS m/z = 485.4 [M+2]/2.

Fourth step: 3-[Methyl-[3-[4-[(2-phenylphenyl)carbamomethoxy]-1-indolyl]propanyl]amino]propyl-N-[ 2-Chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-carbonyl-1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy Base-phenyl]carbamate; ditrifluoroacetate ( compound 8 )

3-[methyl-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoyl]amino]propyl-N-[2-chloro-4-[[[(2R)-2-hydroxy- 2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy-phenyl]carbamate ditrifluoroacetic acid salt

3-[Methyl-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-indanyl]propanyl]amino]propyl-N-[4-[ [[(2R)-2-[T-butyl(dimethyl)indolyl]oxy-2-(8-hydroxy-2-carbonyl-1H-quinolin-5-yl)ethyl]amino]- (2) chloro-5-methoxy-phenyl]carbamate ( 8C ) (0.200 g, 0.206 mmol) was dissolved in tetrahydrofuran (5 mL) and triethylamine trihydrofluoric acid salt (0.333 g, 2.06 mmol), reacted at room temperature for 24 hours. The reaction solution was added to dichloromethane (50 mL), and then filtered, and then evaporated, and evaporated. The organic phase was washed with a saturated aqueous solution of sodium chloride (20 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by liquid chromatography column (liquid phase preparation conditions: C18 reverse chromatography Column, mobile phase is deionized water (A) containing 0.05% TFA, acetonitrile (B) containing 0.05% TFA, gradient elution A: B = 5% ~ 100%, elution for 10 minutes, then use 100 The % B was eluted for 5 minutes at a flow rate of 1.0 mL/min, and the column temperature was 40 ° C. The title compound 3-[methyl-[3-[4-[(2-phenylphenyl)carbamomethoxy) was obtained. ]-1-acridinyl]propanyl]amino]propyl-N-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-carbonyl-1H-) Quinoline-5-yl)ethyl]amino]methyl]-5-methoxy-phenyl]carbamate; ditrifluoroacetate ( compound 8 ), white solid (0.040 g, yield 18%) ).

¹ H NMR (400 MHz, CD ₃ OD) δ 8.21 (m, 1H), 7.79 (d, 1H), 7.56 (s, 1H), 7.48-7.28 (m, 10H), 7.05 (d, 1H), 6.65 ( Dd, 1H), 5.42 (dd, 1H), 4.89 (s, 1H), 4.33-4.18 (m, 4H), 3.92 (s, 3H), 3.58 (m, 3H), 3.52-3.38 (m, 3H) , 3.21 (m, 2H), 3.14 - 2.89 (m, 7H), 2.23 - 2.08 (m, 1H), 2.01 (dd, 4H), 1.79 (s, 1H).

¹⁹ F NMR (376 MHz, CD ₃ OD) δ -77.04.

LCMS m/z = 428.3 [M+2]/2.

Example 9: [1-[3-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino] Methyl]-5-methoxy-2-pyrazol-1-yl-phenylamino]-3-oxo-propyl]-4-acridinyl]-N-(2-phenylphenyl)amino Synthesis of formate ( compound 9 )

[1-[3-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy- 2-pyrazol-1-yl-anilino]-3-oxo-propyl]-4-piperidyl]-N-(2-phenylphenyl)carbamate

First step: 4-ethylamino-2-methoxy-5-pyrazol-1-yl-benzoic acid methyl ester ( 9A )

Methyl4-acetamido-2-methoxy-5-pyrazol-1-yl-benzoate

4-Ethylamino-5-iodo-2-methoxy-benzoic acid methyl ester ( 4B ) (2.0 g, 5.729 mmol) was dissolved in 1,4-dioxane (1,4-dioxane, 10 mL) In the middle, under nitrogen protection, pyrazole (0.448 g, 6.588 mmol), (1R, 2R)-N1, N2-dimethylcyclohexane-1,2-diamine (0.057 g, 0.401 mmol), cesium carbonate were sequentially added. (3.733 g, 11.46 mmol) and cuprous iodide (0.0764 g, 0.401 mmol) were reacted at 100 ° C for 1.5 hours. After cooling to room temperature, water (20 mL) and methylene chloride (50 mL) were added, and the mixture was separated, and the aqueous layer was extracted with dichloromethane (20 mL×1). ×1) Washing, drying over anhydrous sodium sulfate, filtration, and the filtrate was concentrated under reduced pressure. The residue was crystallised from EtOAc (EtOAc/EtOAc) - Ethylamino-2-methoxy-5-pyrazol-1-yl-benzoic acid methyl ester ( 9A ), yellow solid (1.40 g, yield 84.5%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 10.55 (s, 1H), 8.43 (s, 1H), 7.87 (s, 1H), 7.83 (d, 1H), 7.79 (d, 1H), 6.51 (t, 1H ), 3.98 (s, 3H), 3.89 (s, 3H), 2.18 (s, 3H).

LCMS m/z = 290.1 [M + 1].

Second step: N-[4-(hydroxymethyl)-5-methoxy-2-pyrazol-1-yl-phenyl]acetamide ( 9B )

N-[4-(hydroxymethyl)-5-methoxy-2-pyrazol-1-yl-phenyl]acetamide

4-Ethylamino-2-methoxy-5-pyrazol-1-yl-benzoic acid methyl ester ( 9A ) (1.40 g, 4.84 mmol) was dissolved in tetrahydrofuran (20 mL). To 0 ° C, lithium tetrahydroaluminum (0.367 g, 9.68 mmol) was added, and after the addition, the reaction was carried out for 2 hours in an ice bath. Water (1 mL) was slowly added dropwise under ice-cooling, and the mixture was filtered over Celite (EtOAc), and the filtrate was washed with methylene chloride (100 mL), and the filtrate was concentrated under reduced pressure. /ethyl acetate (v/v) = 1/0~3/2) gave the title compound N-[4-(hydroxymethyl)-5-methoxy-2-pyrazol-1-yl-phenyl Ethylamine ( 9B ), yellow solid (0.600 g, yield 47.4%).

1H NMR (400MHz, CDCl3) δ 10.20 (s, 1H), 8.21 (s, 1H), 7.77 (d, 1H), 7.76 (d, 1H), 6.48 (t, 1H), 4.67 (s, 2H), 3.92 (s, 3H), 2.14 (s, 4H).

LCMS m/z = 262.2 [M + 1].

The third step: N-(4-carbamimido-5-methoxy-2-pyrazol-1-yl-phenyl)acetamide ( 9C )

N-(4-formyl-5-methoxy-2-pyrazol-1-yl-phenyl)acetamide

N-[4-(Hydroxymethyl)-5-methoxy-2-pyrazol-1-yl-phenyl]acetamide ( 9B ) (0.600 g, 2.30 mmol) was dissolved in dichloromethane (5 mL) In the ice bath, the ice bath was cooled to 0 ° C, and Dess Martin oxidant (1.95 g, 4.59 mmol) was added. After the addition, the reaction was carried out for 2 hours in an ice bath. The mixture was diluted with aq. EtOAc (EtOAc (EtOAc) The residue was purified by silica gel column chromatography (eluent petroleum ether/ethyl acetate (v/v) = 1/0 to 4/1) to give the title compound N-(4-carbamid-5) -Methoxy-2-pyrazol-1-yl-phenyl)acetamidine ( 9C ), pale yellow solid (0.600 g, yield 99.1%).

LCMS m/z = 260.0 [M + 1].

The fourth step: 4-amino-2-methoxy-5-pyrazol-1-yl-benzaldehyde ( 9D )

4-amino-2-methoxy-5-pyrazol-1-yl-benzaldehyde

N-(4-Methylinden-5-methoxy-2-pyrazol-1-yl-phenyl)acetamide ( 9C ) (0.600 g, 2.31 mmol) was dissolved in methanol / THF (15 mL, v In /v = 2/1), an aqueous solution (10 mL) of sodium hydroxide (0.925 g, 23.1 mmol) was added, and the mixture was heated to 80 ° C for 1 hour. After cooling to room temperature, dichloromethane (50 mL) was added, and the mixture was evaporated. mjjjjjjjjjjjjjjjj The title compound was 4-amino-2-methoxy-5-pyrazol-1-yl-benzaldehyde ( 9D ) as a yellow solid (0.796 g, yield: 79.6%).

LCMS m/z = 218.1 [M + 1].

The fifth step: N-(4-carbamimido-5-methoxy-2-pyrazol-1-yl-phenyl)prop-2-enylamine ( 9E )

N-(4-formyl-5-methoxy-2-pyrazol-1-yl-phenyl)prop-2-enamide

4-Amino-2-methoxy-5-pyrazol-1-yl-benzaldehyde ( 9D ) (0.400 g, 1.84 mmol) was suspended in ethyl acetate (10 mL). EtOAc (0.332 g, 4. ), triethylamine (1.40 g, 13.8 mmol), 2,4,6-tripropyl-1,3,5,2,4,6-trioxytriphosphate-2,4,6 was added dropwise under nitrogen. - Trioxide (T3P, CAS: 68957-94-8) (1.46 g, 4.60 mmol). After the addition was completed, the mixture was heated to reflux at 80 ° C for 5 hours. The mixture was cooled to room temperature, cooled to EtOAc. EtOAc (EtOAc m. The residue was concentrated under reduced pressure and purified by silica gel column chromatography (eluent petroleum ether/ethyl acetate (v/v) = 1/0~5/1) to give the title compound N-(4-carbazinyl) 5-5-Methoxy-2-pyrazol-1-yl-phenyl)prop-2-enylamine ( 9E ), yellow solid (0.12 g, yield 24.0%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ11.20 (s, 1H), 10.39 (s, 1H), 8.58 (s, 1H), 7.89 (d, 1H), 7.84 (s, 1H), 7.80 (d, 1H), 6.52 (t, 1H), 6.41 (dd, 1H), 6.25 (dd, 1H), 5.82 (dd, 1H), 4.02 (s, 3H).

LCMS m/z = 272.0 [M + 1].

The sixth step: [1-[3-(4-carbamimido-5-methoxy-2-pyrazol-1-yl-anilino)-3-oxo-propyl]-4-indolyl ]-N-(2-phenylphenyl)carbamate ( 9F )

[1-[3-(4-formyl-5-methoxy-2-pyrazol-1-yl-anilino)-3-oxo-propyl]-4-piperidyl]-N-(2-phenylphenyl)carbamate

Dissolving N-(4-carbamimido-5-methoxy-2-pyrazol-1-yl-phenyl)prop-2-enylamine ( 9E ) (0.180 g, 0.663 mmol) in 2-A 4-Acridine-N-(2-phenylphenyl)carbamate ( 4H ) (0.236 g, 0.796 mmol), triethylamine (0.134 g, 1.33 mmol), After the addition, the microwave was reacted at 100 ° C for 1 hour. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. The residue was purified and purified using EtOAc EtOAc (EtOAc (EtOAc) The compound [1-[3-(4-carbamimido-5-methoxy-2-pyrazol-1-yl-anilino)-3-oxo-propyl]-4-acridinyl]-N -(2-Phenylphenyl)carbamate ( 9F ), pale yellow solid (0.300 g, yield 79.7%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ10.82 (s, 1H), 10.37 (s, 1H), 8.40 (s, 1H), 8.08 (d, 1H), 7.81 (d, 1H), 7.79 (s, 1H), 7.76 (d, 1H), 7.51-7.46 (m, 2H), 7.43-7.39 (m, 1H), 7.37-7.33 (m, 3H), 7.24-7.19 (m, 1H), 7.15-7.11 (m, 1H), 6.58 (s, 1H), 6.48 (t, 1H), 4.77-4.67 (m, 1H), 3.99 (s, 3H), 2.76-2.66 (m, 4H), 2.60-2.54 (m , 2H), 2.30-2.22 (m, 2H), 1.92-1.84 (m, 2H), 1.68-1.56 (m, 4H).

LCMS m/z = 568.1 [M + 1].

Step 7: [1-[3-[4-[[[(2R)-2-[T-butyl(dimethyl)carbamyl]oxy-2-(8-hydroxy-2-oxo) -1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy-2-pyrazol-1-yl-phenylamino]-3-oxo-propyl]-4-oxime Pyridyl]-N-(2-phenylphenyl)carbamate ( 9G )

[1-[3-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]] Amino]methyl]-5-methoxy-2-pyrazol-1-yl-anilino]-3-oxo-propyl]-4-piperidyl]-N-(2-phenylphenyl)carbamate

[1-[3-(4-Methylinden-5-methoxy-2-pyrazol-1-yl-anilino)-3-oxo-propyl]-4-acridinyl]-N -(2-Phenylphenyl)carbamate ( 9F ) (0.300 g, 0.592 mmol) was dissolved in anhydrous methanol (3 mL), dichloromethane (3 mL) was added, and 5-[(1R)-2- Amino-1-[t-butyl(dimethyl)carbinyl]oxyethyl]-8-hydroxy-1H-quinolin-2-one ( 4J ) (0.212 g, 0.634 mmol), stirred at room temperature After 1 hour, sodium triethoxysulfonate hydride (0.336 g, 1.59 mmol) was added, and the mixture was allowed to react at room temperature overnight. The mixture was diluted with aq. EtOAc (EtOAc (EtOAc) (EtOAc) The residue was concentrated under reduced pressure and purified by silica gel column chromatography (eluent methylene chloride/methanol (v/v) = 1/0~19/1) to give the title compound [1-[3-[4- [[[(2R)-2-[T-butyl(dimethyl)carbamyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl] Amino]methyl]-5-methoxy-2-pyrazol-1-yl-phenylamino]-3-oxo-propyl]-4-acridinyl]-N-(2-phenylphenyl) Carbamate ( 9G ), pale yellow solid (0.22 g, yield 47.0%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 10.41 (s, 1H), 8.13 (d, 1H), 8.00 (d, 1H), 7.95 (s, 1H), 7.64--7.58 (m, 2H), 7.42- 7.36 (m, 2H), 7.35-7.31 (m, 1H), 7.31-7.25 (m, 3H), 7.16-7.12 (m, 2H), 7.10--7.02 (m, 1H), 6.91 (d, 1H) ), 6.76 (d, 1H), 6.56 (s, 1H), 6.46 (d, 1H), 6.37-6.32 (m, 1H), 5.18-5.12 (m, 1H), 4.68-4.60 (m, 1H), 3.81 (s, 2H), 3.75 (s, 3H), 3.71-3.67 (m, 1H), 3.01-2.93 (m, 1H), 2.91-2.85 (m, 1H), 2.68-2.56 (m, 4H), 2.49(t,2H), 2.28-2.18(m,2H),1.86-1.76(m,2H),1.60-1.52(m,2H),0.77(s,9H),-0.05(s,3H),- 0.29 (s, 3H).

LCMS m/z = 887.5 [M + 1].

Step 8: [1-[3-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino] Methyl]-5-methoxy-2-pyrazol-1-yl-phenylamino]-3-oxo-propyl]-4-acridinyl]-N-(2-phenylphenyl)amino Formate ( compound 9 )

[1-[3-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxy- 2-pyrazol-1-yl-anilino]-3-oxo-propyl]-4-piperidyl]-N-(2-phenylphenyl)carbamate

[1-[3-[4-[[[(2R)-2-[T-butyl(dimethyl)carbamyl]oxy-2-(8-hydroxy-2-oxo-1H-) Quinoline-5-yl)ethyl]amino]methyl]-5-methoxy-2-pyrazol-1-yl-phenylamino]-3-oxo-propyl]-4-acridinyl] -N-(2-Phenylphenyl)carbamate ( 9G ) (0.220 g, 0.248 mmol) was dissolved in dichloromethane (3 mL) and triethylamine trihydrofluoric acid salt (0.16 g, 0.993 mmol) ), after the addition, the reaction was carried out at room temperature overnight. Dichloromethane (50 mL) was added, and aq. EtOAc EtOAc (EtOAc) The residue was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. mjjjjjjjjjjjjjjjjjjj 1-[3-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-5 -Methoxy-2-pyrazol-1-yl-phenylamino]-3-oxo-propyl]-4-acridinyl]-N-(2-phenylphenyl)carbamate ( compound) 9 ), pale yellow solid (0.086 g, yield 45%).

¹ H NMR (400 MHz, CD ₃ OD) δ 8.15 (d, 1H), 7.78 (d, 1H), 7.65 (d, 1H), 7.61 (s, 1H), 7.45 (d, 1H), 7.34 - 7.19 ( m,8H),7.19-7.14(m,2H),7.05(d,1H),6.86(d,1H),6.46(d,1H),6.44-6.39(m,1H),5.08-5.05(m, 1H), 4.50-4.42 (m, 1H), 3.72 (s, 5H), 2.82-2.70 (m, 2H), 2.56-2.48 (m, 4H), 2.42 (t, 2H), 2.18-2.12 (m, 2H), 1.68-1.62 (m, 2H), 1.50-1.36 (m, 4H).

LCMS m/z = 772.4 [M + 1].

Example 10: [1-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(6-hydroxy-3-oxo-4H-1,4-benzoxazine) -8-yl)ethyl]amino]methyl]-5-methoxyanilino]-3-oxo-propyl]-4-acridinyl]-N-(2-phenylphenyl)amino Synthesis of formate ( compound 10 )

[1-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(6-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino ]methyl]-5-methoxy-anilino]-3-oxo-propyl]-4-piperidyl]-N-(2-phenylphenyl)carbamate

First step: 1-(5-benzyloxy-2-hydroxy-phenyl)ethanone ( 10B )

1-(5-benzyloxy-2-hydroxy-phenyl)ethanone

2,5-Dihydroxyacetophenone ( 10A ) (3.04 g, 20 mmol) was dissolved in acetone (50 mL), potassium carbonate (4.15 g, 30 mmol) and benzyl bromide (3.42 g, 20 mmol) were added and reacted at room temperature. 6 hours. After adding water (50 mL), EtOAc (EtOAc) (EtOAc) /v)=100/1~10/1) gave the title compound 1-(5-benzyloxy-2-hydroxy-phenyl)ethanone ( 10B ) as a yellow solid (1 g, yield: 20.7%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 11.84 (s, 1H), 7.46-7.31 (m, 5H), 7.27-7.22 (m, 1H), 7.20-7.14 (m, 1H), 6.92 (d, 1H) , 5.04 (s, 2H), 2.57 (s, 3H).

LC-MS m/z =243.1 [M+1].

The second step: 1-(5-benzyloxy-2-hydroxy-3-nitro-phenyl)ethanone ( 10C )

1-(5-benzyloxy-2-hydroxy-3-nitro-phenyl)ethanone

1-(5-Benzyloxy-2-hydroxy-phenyl)ethanone ( 10B ) (50 g, 206.4 mmol) was dissolved in acetic acid (150 mL), and EtOAc (15.5 g, 246 Reaction for 1 hour. Water (200 mL) was added at 0<0>C, filtered, and dried to give the title compound 1-(5-benzyloxy-2-hydroxy-3-nitro-phenyl)ethanone ( 10C ) as a yellow solid (52 g, The yield was 87.71%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 12.30 (s, 1H), 7.84 (d, 1H), 7.69 (d, 1H), 7.44-7.33 (m, 5H), 5.10 (s, 2H), 2.67 (s , 3H).

The third step: 1-(3-amino-5-benzyloxy-2-hydroxy-phenyl)ethanone ( 10D )

1-(3-amino-5-benzyloxy-2-hydroxy-phenyl)ethanone

1-(5-Benzyloxy-2-hydroxy-3-nitro-phenyl)ethanone ( 10C ) (4.0 g, 13.9 mmol) was dissolved in a mixed solvent of ethanol (20 mL) and water (5 mL). Reduced iron powder (3.89 g, 69.6 mmol) and ammonium chloride (3.69 g, 69.6 mmol) were added and reacted at 90 ° C for 2 hours. After completion of the reaction, the mixture was cooled to room temperature, water (50 mL) was evaporated, evaporated, evaporated. The residue was purified with EtOAc EtOAc EtOAc (EtOAc (EtOAc) Phenyl)ethanone ( 10D ), yellow solid (1.3 g, yield 36.3%).

^{1 H NMR (400MHz, DMSO-} d6) δ 12.53-11.57 (m, 1H), 7.39 (m, 5H), 6.70 (d, 1H), 6.63 (d, 1H), 5.04 (s, 4H), 2.59 ( s, 3H).

LC-MS m/z = 258.2 [M + 1].

Step 4: 8-Ethyl-6-benzyloxy-4H-1,4-benzoxazin-3-one ( 10E )

8-acetyl-6-benzyloxy-4H-1,4-benzoxazin-3-one

1-(3-Amino-5-benzyloxy-2-hydroxy-phenyl)ethanone ( 10D ) (1.0 g, 3.887 mmol) was dissolved in N,N-dimethylformamide (10 mL). Add sodium bicarbonate (0.653 g, 7.773 mmol), add chloroacetic acid chloride (0.527 g, 4.664 mmol) dropwise at 0 ° C, and react at room temperature for 1 hour after adding dropwise, and add cesium carbonate (2.553 g, 7.773 mmol), 100 ° C Reaction for 2 hours. The reaction mixture was cooled to room temperature, and ethyl acetate (50 mL) was evaporated. 8-Ethyl-6-benzyloxy-4H-1,4-benzoxazin-3-one ( 10E ), yellow solid (1.0 g, yield 87%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 9.20 (s, 1H), 7.43-7.30 (m, 5H), 7.07 (d, 1H), 6.69 (d, 1H), 5.03 (s, 2H), 4.66 (s , 2H), 2.63 (s, 3H).

LC-MS m/z = 298.1 [M + 1].

Step 5: 6-Benzyloxy-8-(2-chloroethenyl)-4H-1,4-benzoxazin-3-one ( 10F )

6-benzyloxy-8-(2-chloroacetyl)-4H-1,4-benzoxazin-3-one

8-Ethyl-6-benzyloxy-4H-1,4-benzoxazin-3-one ( 10E ) (1.0 g, 3.336 mmol) was dissolved in ethanol (10 mL). Ammonium dichloroiododate (2.34 g, 6.727 mmol) was heated to reflux for 1 hour. After adding water (20 mL), it was extracted with ethyl acetate (30 mL×2), washed with saturated aqueous sodium chloride (30 mL×1), dried over anhydrous sodium sulfate, filtered and evaporated. The compound 6-benzyloxy-8-(2-chloroethenyl)-4H-1,4-benzoxazin-3-one ( 10F ) was obtained as a pale yellow solid (0.8 g, yield 70%).

^{1 H NMR (400MHz, DMSO-} d6) δ 10.89 (s, 1H), 7.47-7.30 (m, 5H), 6.98 (d, 1H), 6.81 (d, 1H), 5.09 (s, 2H), 5.01 ( s, 2H), 4.67 (s, 2H).

LC-MS m/z = 332.0 [M + 1].

Step 6: 8-(2-azidoethyl)-6-benzyloxy-4H-1,4-benzoxazin-3-one ( 10G )

8-(2-azidoacetyl)-6-benzyloxy-4H-1,4-benzoxazin-3-one

The starting material 6-benzyloxy-8-(2-chloroethenyl)-4H-1,4-benzoxazin-3-one (0.5 g, 1.51 mmol) was dissolved in N,N-dimethylformamide Azide (0.147 g, 2.26 mmol) was added to the amine (10 mL) and stirred at room temperature for 2 hr. Ethyl acetate (30 mL) was added to give ethyl acetate (30 mL). 2-Azidoacetamido)-6-benzyloxy-4H-1,4-benzoxazin-3-one ( 10G ), m.p. (0.35 g, yield 69%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.90 (s, 1H), 7.42-7.30 (m, 5H), 7.19 (d, 1H), 6.71 (d, 1H), 5.05 (s, 2H), 4.68 (s , 2H), 4.51 (s, 2H).

LC-MS m/z = 361.0 [M+23].

Step 7: 8-[(1R)-2-Azido-1-hydroxy-ethyl]-6-benzyloxy-4H-1,4-benzoxazin-3-one ( 10H )

8-[(1R)-2-azido-1-hydroxy-ethyl]-6-benzyloxy-4H-1,4-benzoxazin-3-one

8-(2-Azidoacetamido)-6-benzyloxy-4H-1,4-benzoxazin-3-one ( 10G ) (4.0 g, 11.82 mmol) was suspended in methanol (40 mL) Sodium borohydride (0.674 g, 17.74 mmol) was added at 0 ° C for 30 minutes. Ethyl acetate (30 mL) was added to give a mixture. The mixture was washed with water (30 mL×2) and saturated aqueous sodium chloride (30mL×1), dried over anhydrous sodium sulfate, filtered, Purification (petroleum ether/ethyl acetate (v/v) = 2/1), a total of 2.5 g of a mixture containing both R and S configurations was obtained, and the mixture was further subjected to supercritical carbon dioxide extraction (Chroma column Chiralpak AS) , 250 × 4.6 mm ID, 5 um, mobile phase A = CO ₂ , B = isopropanol (0.05% N, N-diethylamine), 50% B isocratic elution, flow rate 200 mL / min, back pressure 100 bar Purification by column temperature 38 ° C, elution time 15 min) gave the title compound 8-[(1R)-2-azido-1-hydroxy-ethyl]-6-benzyloxy-4H-1,4 - benzoxazin-3-one ( 10H ), off-white solid (1.33 g, yield 33.25%).

^{1 H NMR (400MHz, DMSO-} d6) δ 10.63 (s, 1H), 7.47-7.37 (m, 4H), 7.37-7.30 (m, 1H), 6.78 (d, 1H), 6.49 (d, 1H), 5.81 (d, 1H), 5.02 (d, 2H), 5.00 (m, 1H), 4.57 - 4.46 (m, 2H), 3.28 (m, 2H).

LC-MS m/z = 341.0 [M + 1].

Step 8: 8-[(1R)-2-Amino-1-hydroxy-ethyl]-6-hydroxy-4H-1,4-benzoxazin-3-one ( 10I )

8-[(1R)-2-amino-1-hydroxy-ethyl]-6-hydroxy-4H-1,4-benzoxazin-3-one

8-[(1R)-2-Azido-1-hydroxy-ethyl]-6-benzyloxy-4H-1,4-benzoxazin-3-one ( 10H ) (0.4 g, 1.18 Methyl acetate was dissolved in methanol (50 mL), a small amount of dichloromethane was added to dissolve, and 10% (w/w) palladium carbon (0.2 g) was added thereto, and hydrogen gas was introduced thereto, and the mixture was reacted at room temperature for 6 hours. The palladium carbon was filtered, and the filtrate was concentrated to give the title compound 8-[(1R)-2-amino-1-hydroxy-ethyl]-6-hydroxy-4H-1,4-benzoxazin-3-one ( 10I) ), pale yellow solid (0.2 g, yield 76%).

^{1 H NMR (400MHz, DMSO-} d6) δ 6.52 (d, 1H), 6.35 (d, 1H), 4.94 (dd, 1H), 4.57-4.40 (m, 2H), 2.92 (dd, 1H), 2.67 ( Dd, 1H).

LC-MS m/z = 225.1 [M + 1].

Step 9: [1-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(6-hydroxy-3-oxo-4H-1,4-benzoxazine) -8-yl)ethyl]amino]methyl]-5-methoxyanilino]-3-oxo-propyl]-4-acridinyl]-N-(2-phenylphenyl)amino Formate ( compound 10 )

[1-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(6-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino ]methyl]-5-methoxy-anilino]-3-oxo-propyl]-4-piperidyl]-N-(2-phenylphenyl)carbamate

[1-[3-(2-Chloro-4-carbamimido-5-methoxy-anilino)-3-oxo-propyl]-4-oxaridinyl]-N-(2-benzene Phenyl)carbamate ( 1K ) (0.33g, 062mmol) and 8-[(1R)-2-amino-1-hydroxy-ethyl]-6-hydroxy-4H-1,4-benzaldehyde Pyrazin-3-one ( 10I ) (0.15g, 0.68mmol) was dissolved in a mixed solvent of dichloromethane / methanol (v / v = 1 / 1, 15mL), stirred at room temperature for 30 minutes, added triethyl decyloxy Sodium borohydride (0.39 g, 1.8 mmol) was reacted at room temperature for 2 hours. After the reaction was completed, water (30 mL) was evaporated, evaporated, evaporated, evaporated The residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 100/1~100/5) to give the title compound [1-[3-[2-chloro-4-[[ [(2R)-2-hydroxy-2-(6-hydroxy-3-oxo-4H-1,4-benzoxazine-8-yl)ethyl]amino]methyl]-5-methoxy Anilino]-3-oxo-propyl]-4-acridinyl]-N-(2-phenylphenyl)carbamate ( Compound 10 ), off-white solid (0.2 g, yield 44%) ).

^{1 H NMR (400MHz, DMSO-} d6) δ 10.51 (s, 1H), 10.24 (s, 1H), 9.08 (s, 1H), 8.65 (s, 1H), 7.79 (s, 1H), 7.46-7.26 ( m, 10H), 6.48(d,1H), 6.27(d,1H), 5.28(s,1H), 4.90(d,1H),4.54-4.47(m,1H),4.45-4.35(m,2H) , 3.76 (s, 3H), 3.74-3.66 (m, 2H), 2.79-2.64 (m, 3H), 2.61 (d, 2H), 2.55 (m, 3H), 2.24 (s, 2H), 1.77 (s , 2H), 1.50 (dd, 2H).

LCMS m/z = 372.6 [M/2+1].

Example 11: 3-[3-[4-[(2-Phenylphenyl)carbamoyloxy]-1-indanyl]propanylamino]propyl-N-[4-[[ [(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]phenyl]carbamate; ditrifluoroacetic acid Synthesis of salt ( Compound 11 )

3-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoylamino]propyl-N-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2- oxo-1H-quinolin-5-yl)ethyl]amino] Methyl]phenyl]carbamate;ditrifluoroacetic acid salt

First step: 3-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-indanyl]propanylamino]propyl-N-[4-(1 ,3-dioxolan-2-yl)phenyl]carbamate ( 11A )

3-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoylamino]propyl-N-[4-(1,3-dioxolan-2-yl)phenyl]carbamate

[1-[3-(3-Hydroxypropyl)-3-oxo-propyl]-4-acridinyl]-N-(2-phenylphenyl)carbamate ( 3C ) (0.258 g, 0.605 mmol) was dissolved in dichloromethane (50 mL), diisopropylethylamine (0.196 g, 1.51 mmol) was added, and the mixture was cooled to 0 ° C under nitrogen atmosphere, and phosgene (0.090 g, 0.303 mmol) was added. After the addition was completed, the temperature was raised to room temperature for 2 hours, and the reaction solution was added dropwise to a solution of 4-(1,3-dioxolan-2-yl)phenylamine (0.100 g, 0.605 mmol) in tetrahydrofuran (5 mL). After the addition, the reaction was carried out for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was purified and purified eluting eluting eluting eluting 1~97:3) The title compound 3-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-indanyl]propanylamino]propyl-N - [4- (1,3-dioxolan-2-yl) phenyl] carbamate (11A), as a pale yellow solid (0.300g, yield 80.4%).

LCMS m/z = 617.3 [M + 1].

The second step: 3-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-indanyl]propanylamino]propyl-N-(4-formamidine) Phenyl)carbamate ( 11B )

3-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoylamino]propyl-N-(4-formylphenyl)carbamate

3-[3-[4-[(2-Phenylphenyl)carbamoyloxy]-1-indanyl]propanylamino]propyl-N-[4-(1,3- Dioxol-2-yl)phenyl]carbamate ( 11A ) (0.450 g, 0.730 mmol) was dissolved in tetrahydrofuran (5 mL), and aq. Reaction for 30 minutes. The pH was adjusted to basic with a saturated aqueous solution of sodium bicarbonate, and extracted with dichloromethane (20 mL×2). The organic layer was combined, washed with saturated sodium chloride (10 mL×1), dried over anhydrous sodium sulfate The title compound 3-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-indanyl]propanylamino]propyl-N-(4-A) The crude product was decylphenyl)carbamate ( 11B ) as a beige solid (0.310 g, yield 74.2%). Not used directly in the next step without purification.

LCMS m/z = 573.4 [M + 1].

The third step: 3-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-indanyl]propanylamino]propyl-N-[4-[[ [(2R)-2-[t-butyl(dimethyl)carbamyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino] Methyl]phenyl]carbamate ( 11C )

3-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoylamino]propyl-N-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy- 2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]phenyl]carbamate

3-[3-[4-[(2-Phenylphenyl)carbamoyloxy]-1-indanyl]propanylamino]propyl-N-(4-carboxyphenyl) Carbamate ( 11B ) (0.300 g, 0.524 mmol) and 5-[(1R)-2-amino-1-[tert-butyl(dimethyl)carbamyl]oxyethyl]-8 -Hydroxy-4H-quinolin-2-one ( 4J ) (0.193 g, 0.576 mmol) was dissolved in 10 mL of a mixed solvent of methanol and dichloromethane (v/v = 1/1), and reacted at 30 ° C for 1 hour. Sodium triethoxysulfonium borohydride (0.333 g, 1.57 mmol) was added, and after the addition was completed, the reaction was continued at 30 ° C for 2 hours. The mixture was adjusted to pH with a saturated aqueous solution of sodium bicarbonate, and extracted with dichloromethane (20 mL×2). The organic layer was combined, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The title compound is 3-[3-[4-[(2-phenylphenyl)carbamoyloxy]-) after methylene chloride:methanol (v/v)=99:1~20:1 1-acridinyl]propanylamino]propyl-N-[4-[[[(2R)-2-[t-butyl(dimethyl)methyl)alkyl]oxy-2-(8- Hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]phenyl]carbamate ( 11C ), pale yellow solid (0.093 g, yield 19.9%).

LCMS m/z = 892.5 [M + 1].

Step 4: 3-[3-[4-[(2-Phenylphenyl)carbamoyloxy]-1-indanyl]propanylamino]propyl-N-[4-[[ [(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]phenyl]carbamate; ditrifluoroacetic acid Salt ( compound 11 )

3-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoylamino]propyl-N-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2- oxo-1H-quinolin-5-yl)ethyl]amino]methyl]phenyl]carbamate;ditrifluoroacetic acid salt

3-[3-[4-[(2-Phenylphenyl)carbamoyloxy]-1-indolyl]propanylamino]propyl-N-[4-[[[(2R) )-2-[t-butyl(dimethyl)carbinyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl] Phenyl]carbamate ( 11C ) (0.093 g, 0.10 mmol) was dissolved in tetrahydrofuran (2 mL), and triethylamine trihydrofluoric acid salt (0.067 g, 0.42 mmol) was added. The supernatant was removed, the viscous material was added to tetrahydrofuran (10 mL), the pH was adjusted to basic with a saturated sodium hydrogen carbonate solution, and the mixture was partitioned. The aqueous layer was extracted with tetrahydrofuran (20 mL×1). The crude product obtained by concentration under reduced pressure was purified to give the title compound 3-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-indanyl]propanylamino] propyl-N-[4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]phenyl) Carbamate; ditrifluoroacetate ( Compound 11 ), white solid (0.018 g, yield 17%).

_{^{1 H NMR (400MHz, CD 3}} OD) δ 8.18 (d, 1H), 7.53 (m, 3H), 7.45-7.23 (m, 11H), 7.01 (d, 1H), 6.62 (d, 1H), 5.38- 5.33 (m, 1H), 4.23 (s, 2H), 4.19 (t, 2H), 3.56 (s, 1H), 3.48-3.33 (m, 6H), 3.18 (d, 2H), 3.12-3.09 (m, 2H), 2.72 (t, 2H), 2.20-2.10 (m, 1H), 2.02-1.96 (m, 2H), 1.95-1.85 (m, 2H), 1.80-1.70 (m, 1H).

¹⁹ F NMR (376 MHz, CD ₃ OD) δ -74.97.

LCMS m/z = 777.4 [M + 1].

Example 12: 3-[3-[4-[(2-Phenylphenyl)carbamoyloxy]-1-indanyl]propanylamino]propyl-N-[2-chloro- 4-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]methyl]-5 Synthesis of -methoxyphenyl]carbamate ( Compound 12 )

3-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoylamino]propyl-N-[2-chloro-4-[[[(2R)-2-hydroxy-2-(5- Hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]methyl]-5-methoxy-phenyl]carbamate

First step: 3-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-indanyl]propanylamino]propyl-N-[4-[[ [(2R)-2-[t-butyl(dimethyl)methylidene]oxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazine-8-yl Ethyl]amino]methyl]-2-chloro-5-methoxy-phenyl]carbamate ( 12A )

3-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoylamino]propyl-N-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy- 2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]methyl]-2-chloro-5-methoxy-phenyl]carbamate

3-[3-[4-[(2-Phenylphenyl)carbamoyloxy)-1-indanyl]propanylamino]propyl-N-(2-chloro-4-carboxamidine) 5--5-methoxy-phenyl)carbamate ( 3E ) ( 3E (1.25 g, 1.962 mmol) was dissolved in dry methanol (10 mL), dichloromethane (10 mL), 8-[(1) -2-amino-1-[t-butyl(dimethyl)carbinyl]oxyethyl]-5-hydroxy-4H-1,4-benzoxazin-3-one ( 2A ) (0.73 g, 2.16 mmol), react at 30 ° C for 1 hour, then add sodium triethoxysulfonate borohydride (1.25 g, 5.89 mmol), continue to react at 30 ° C for 2 hours. Adjust pH to 9 with dilute sodium bicarbonate solution, dichloro The organic layer was extracted with methylene chloride (100 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: methylene chloride: methanol (v/v) = 100 :1~20:1) The title compound 3-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-indanyl]propanylamino]propyl- N-[4-[[[(2R)-2-[T-butyl(dimethyl)methyl)alkyl-2-yl-2-(5-hydroxy-3-oxo-4H-1,4-benzene) And oxazin-8-yl)ethyl]amino]methyl]-2-chloro-5-methoxy-phenyl]carbamate ( 12A ), beige solid (1.10 g, yield 58.4%).

LCMS m/z = 480.3 [M/2 + 1].

Second step: 3-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-indanyl]propanylamino]propyl-N-[2-chloro- 4-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]methyl]-5 -Methoxyphenyl]carbamate ( Compound 12 )

3-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoylamino]propyl-N-[2-chloro-4-[[[(2R)-2-hydroxy-2-(5- Hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)ethyl]amino]methyl]-5-methoxy-phenyl]carbamate

3-[3-[4-[(2-Phenylphenyl)carbamoyloxy]-1-indolyl]propanylamino]propyl-N-[4-[[[(2R) )-2-[t-butyl(dimethyl)formamidinyl]oxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazine-8-yl)ethyl Amino]methyl]-2-chloro-5-methoxy-phenyl]carbamate ( 12A ) (0.600 g, 0.625 mmol) was dissolved in tetrahydrofuran (6 mL) and triethylamine trihydrofluoric acid was added. The salt (0.403 g, 2.50 mmol) was reacted at room temperature overnight. The remaining residue of the reaction supernatant was poured out and added to tetrahydrofuran (10 mL), and the mixture was stirred for 1 minute, the supernatant was removed, and the viscous material was further added with tetrahydrofuran (10 mL), stirred for 1 minute, the supernatant was removed, and the viscous material was added to dichloromethane/methanol ( v/v=9/1) mixed solution (20mL), add saturated sodium bicarbonate solution to adjust the pH to alkaline, liquid, and then use water and dichloromethane (v/v=9/1) The mixed solution (20 mL×1) was extracted, and the organic layer was combined, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel column (eluent: methylene chloride: methanol (v/v) =100:3~100:7) The title compound 3-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-indanyl]propanylamino]propyl --N-[2-chloro-4-[[[(2R)-2-hydroxy-2-(5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl)) Amino]methyl]-5-methoxyphenyl]carbamate ( Compound 12 ), beige solid (0.19 g, yield 35.9%).

¹ H NMR (400 MHz, CD ₃ OD) δ 7.49 (s, 1H), 7.45 (d, 1H), 7.34-7.28 (m, 2H), 7.27-7.21 (m, 4H), 7.20-7.12 (m, 3H) ), 6.79 (d, 1H), 6.41 (d, 1H), 4.92-4.88 (m, 1H), 4.52-4.45 (m, 1H), 4.37 (s, 2H), 4.12 (t, 2H), 3.69 ( s, 3H), 3.70-3.60 (m, 2H), 3.26-3.20 (m, 2H), 2.70-2.60 (m, 2H), 2.58-2.50 (m, 4H), 2.27 (t, 2H), 2.20 ( t,, 2H), 1.84-1.76 (m, 2H), 1.76-1.69 (m, 2H), 1.56-1.45 (m, 2H).

LCMS m/z = 847.3 [M + 1].

Example 13: 3-[Methyl-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-indolyl]propanyl]amino]propyl-N- [2-Chloro-4-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino] A Synthesis of 5-methyloxyphenyl]aminomethyl ester; ditrifluoroacetate ( compound 13 )

3-[methyl-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoyl]amino]propyl-N-[2-chloro-4-[[[(2R)-2-hydroxy- 2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino]methyl]-5-methoxy-phenyl]carbamate;ditrifluoroacetic acid salt

First step: 7-[(1R)-2-azido-1-[t-butyl(dimethyl)indolyl]oxyethyl]-4-[t-butyl(dimethyl) Mercapto]oxy-3H-1,3-benzothiazol-2-one ( 13B )

7-[(1R)-2-azido-1-[tert-butyl(dimethyl)silyl]oxy-ethyl]-4-[tert-butyl(dimethyl)silyl]oxy-3H-1,3-benzothiazol-2- One

7-[(1R)-2-Azido-1-hydroxy-ethyl]-4-hydroxy-3H-1,3-benzothiazol-2-one ( 13A ) (prepared by reference to WO2009098448A1) (0.56g) .2.2 mmol) was dissolved in N,N-dimethylformamide (20 mL), then imidazole (0.6 g, 8.9 mmol) was added, and butyl dimethyl chloro decane (1.3 g, 8.9 mmol) was added portionwise. Further, a catalytic amount of 4-dimethylaminopyridine was further added, and the temperature was raised to 40 ° C and stirred for 7 hours. The reaction mixture was poured into water (100 mL), EtOAc (EtOAc m. The residue was purified by silica gel column chromatography (eluent ethyl acetate / petroleum ether (v/v) = 0/1 to 5/95) to give the title compound 7-[(1R)-2-azide -1-[t-butyl(dimethyl)indolyl]oxyethyl]-4-[t-butyl(dimethyl)indenyl]oxy-3H-1,3-benzothiazole 2-ketone ( 13B ), white solid (0.85 g, yield 80%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.25 (s, 1H), 6.92 (d, 1H), 6.71 (d, 1H), 4.78 (dd, 1H), 3.41 (dd, 1H), 3.25 (dd, 1H ), 1.05-0.98 (m, 9H), 0.92-0.88 (m, 9H), 0.28 (t, 6H), 0.12 (d, 3H), -0.04 (d, 3H).

Second step: 7-[(1R)-2-amino-1-[tert-butyl(dimethyl)indolyl]oxyethyl]-4-[t-butyl(dimethyl)decyl ]oxy-3H-1,3-benzothiazol-2-one ( 13C )

7-[(1R)-2-amino-1-[tert-butyl(dimethyl)silyl]oxy-ethyl]-4-[tert-butyl(dimethyl)silyl]oxy-3H-1,3-benzothiazol-2- One

7-[(1R)-2-azido-1-[t-butyl(dimethyl)indolyl]oxyethyl]-4-[t-butyl(dimethyl)indenyl] Oxy-3H-1,3-benzothiazol-2-one ( 13B ) (0.85 g, 1.8 mmol) was dissolved in ethyl acetate (20 mL) and 10% (w/w) palladium carbon (0.085 g) ), stirring under a constant pressure hydrogen balloon overnight. The residue was filtered and concentrated to give the title compound 7-[(1R)-2-amino-1-[t-butyl(dimethyl)indolyl]oxyethyl]-4-[t-butyl (Dimethyl)decyl]oxy-3H-1,3-benzothiazol-2-one ( 13C ), light black solid (0.7 g, yield 90%).

_{1H NMR (400MHz, CDCl 3)} δ 6.89 (d, 1H), 6.69 (d, 1H), 4.64 (dd, 1H), 2.94-2.82 (m, 2H), 1.04-0.96 (m, 9H), 0.95- 0.87 (m, 9H), 0.33-0.23 (m, 6H), 0.12-0.06 (m, 3H), -0.04--0.11 (m, 3H).

The third step: 3-[methyl-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-indanyl]propanyl]amino]propyl-N- [4-[[[(2R)-2-[T-butyl(dimethyl)methyl)alkyl]oxy-2-[4-[t-butyl(dimethyl)methyl)alkyl]oxy -2-oxo-3H-1,3-benzothiazol-7-yl]ethyl]amino]methyl]-2-chloro-5-methoxy-phenyl]carbamate ( 13D )

3-[methyl-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoyl]amino]propyl-N-[4-[[[(2R)-2-[tert-butyl(dimethyl) Silyl]oxy-2-[4-[tert-butyl(dimethyl)silyl]oxy-2-oxo-3H-1,3-benzothiazol-7-yl]ethyl]amino]methyl]-2-chloro-5- Methoxy-phenyl]carbamate

3-[Methyl-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-indanyl]propanyl]amino]propyl-N-(2- Chloro-4-methylindolyl-5-methoxy-phenyl)carbamic acid ( 8B ) (0.9 g, 1.38 mmol) and 7-[(1R)-2-aminot-butyl(dimethyl)methyl矽alkyl]oxyethyl]-4-[t-butyl(dimethyl)methylidenealkyl]oxy-3H-1,3-benzothiazol-2-one ( 13C ) (0.691 g, 1.52 mmol) Dissolved in methanol (10 mL), zinc chloride (0.754 g, 5.53 mmol) was added, the mixture was heated to 55 ° C for 1 hour, sodium cyanoborohydride (0.261 g, 4.15 mmol) was added and the reaction was continued for 2 hours. After the completion of the reaction, water (30 mL) was added, and the mixture was evaporated to methylene chloride (30 mL×2), and the organic layer was washed with saturated brine (30 mL×1), dried over anhydrous sodium sulfate Purification by column chromatography (eluent: methylene chloride:methanol (v/v) = 100:1 to 20:1) to give the title compound 3-[methyl-[3-[4-[(2-benzene) Phenyl)aminocarbamidooxy]-1-indolyl]propanyl]amino]propyl-N-[4-[[[(2R)-2-[t-butyl (dimethyl) Carbenyl]oxy-2-[4-[t-butyl(dimethyl)methylidene]oxy-2-oxo-3H-1,3-benzothiazol-7-yl]B Amino]methyl]-2-chloro-5-methoxy-phenyl]carbamate ( 13D ), yellow solid (0.9 g, yield 60%).

LCMS m/z = 545.4 [M/2+1].

Step 4: 3-[Methyl-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-indolyl]propanyl]amino]propyl-N- [2-Chloro-4-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino] A 5-yloxyphenyl]aminomethyl ester; ditrifluoroacetic acid salt ( compound 13 )

3-[methyl-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoyl]amino]propyl-N-[2-chloro-4-[[[(2R)-2-hydroxy- 2-(4-hydroxy-2-oxo-3H-1,3-benzothiazol-7-yl)ethyl]amino]methyl]-5-methoxy-phenyl]carbamate

3-[Methyl-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-indanyl]propanyl]amino]propyl-N-[4- [[[(2R)-2-[T-butyl(dimethyl)carbamyl]oxy-2-[4-[t-butyl(dimethyl)methyl)alkyl-2-oxy-2- Oxo-3H-1,3-benzothiazol-7-yl]ethyl]amino]methyl]-2-chloro-5-methoxy-phenyl]carbamate ( 13D ) (0.5g, 0.459 mmol) was dissolved in tetrahydrofuran (5 mL), and triethylamine trihydrofluoric acid salt (0.296 g, 1.84 mmol). The mixture was adjusted to pH 9 with saturated sodium bicarbonate, and extracted with dichloromethane (30 mL×1). The organic phase was washed sequentially with saturated brine (30 mL×1), dried over anhydrous sodium sulfate The crude product and the crude product are further purified by liquid chromatography column (liquid phase preparation conditions: C18 reverse chromatography column, mobile phase is deionized water (A) containing 0.05% TFA, acetonitrile (B), etc. Degree elution 25% B, elution time 20 minutes) to give the title compound 3-[methyl-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-indanidine Propionyl]amino]propyl-N-[2-chloro-4-[[[(2R)-2-hydroxy-2-(4-hydroxy-2-oxo-3H-1,3-benzene) And thiazol-7-yl)ethyl]amino]methyl]-5-methoxyphenyl]aminomethyl ester; ditrifluoroacetic acid salt ( Compound 13 ), yellow solid (0.19 g, yield 38%).

_{^{1 H NMR (400MHz, CD 3}} OD) δ 7.78 (d, 1H), 7.54 (s, 1H), 7.46 (d, 1H), 7.41-7.28 (m, 8H), 6.97 (d, 1H), 6.76 ( d, 1H), 4.99 (t, 1H), 4.86 (s, 1H), 4.32-4.16 (m, 4H), 3.89 (s, 3H), 3.58-3.52 (m, 3H), 3.50-3.36 (m, 3H), 3.13-3.10 (m, 3H), 3.08 (s, 3H), 2.98 (s, 1H), 2.96-2.88 (m, 2H), 2.11 s, 1H), 2.07-2.03 (m, 1H), 2.02-1.91 (m, 3H), 1.76 (s, 1H).

LCMS m/z = 861.1 [M + 1].

Biological test case

Test Example 1: Inhibitory activity against human muscarinic M3 receptor

CHO cells (PerkinElmer, ES-212-AF) stably expressing human muscarinic acetylcholine receptor M3 (hM3) and apo-Aequorin were cultured in 10% fetal bovine serum (FBS) (Gibico 10099-141) , 400 μg/mL G418 (sigma G5013) and 250 ug/mL Zeocin (invivogen ant-zn-5p) in Ham'S F12 medium (Invitrogen 12500-062), cultured at 37 ° C, 5% CO ₂ to reach 90-100 % fusion. The cells were washed with PBS/5 mM EDTA, collected by centrifugation, and resuspended in 0.1% BSA (BOVOGEN BSAS 100) phenol red-free Ham's F12 medium (Invitrogen 11039-021) and counted to adjust the cell concentration 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 dissolved 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 at 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. A 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). For 20 seconds, calculate and analyze the IC ₅₀ 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.

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 the human adrenergic receptor 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 for cAMP by LANCE Ultra cAMP Assay kit (PerkinElmer TRF0263) Excitatory. The cells were detached with PBS/5 mM EDTA, collected by centrifugation, and the cells were resuspended with Stimulation Buffer (1×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 compounds of the examples were dissolved in DMSO, diluted in a Stimulation Buffer gradient, and added to a 384-well plate at 5 μl per well. Add 5 μL of cell suspension (3000 cells/well) to each well, incubate for 30 minutes at room temperature, add 5 μl of 4×Eu-cAMP tracer working solution to each well, and then add 5 μl of 4×Ulight-anti-cAMP working solution to each well. Incubate for 1 hour at room temperature. TR-FRET detection plate 384 using a plate reader (Perkin Elmer, Envision), calculated and analyzed using origin7.5 EC _50. The agonistic activity of the compounds of the present invention on human adrenergic receptors was determined by the above experiment, and the measured EC ₅₀ values are shown in Table 2:

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

Test Example 3: Inhibition of bronchoconstriction induced by methotrexate in guinea pigs

Eight-week old male guinea pigs were purchased in Vitalivic, and the experiment was started after 3 days of adaptation. The positive compound bafetenrol was formulated into a 6 mM stock solution using 83% absolute ethanol + 17% Tween 80, and the test compound was formulated into a 0.6 mM stock solution using 83% absolute ethanol + 17% Tween 80. It was diluted 500 times with water before administration. Prior to administration, animals were anesthetized with 5% isoflurane using a small animal anesthesia machine (Matrx; VME2) for an anesthesia time of 1.5-2 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, in 4 hours, The guinea pig enhanced expiratory pause (PenH) values were measured using a full volume oximeter (DSI; GS220A12-R7B) for 24 hours. 3 mg/ml acetylcholine (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)

* The stock solution was diluted 1000 times with water before administration.

Batefenterol is prepared by the method disclosed in WO2006023454A1.

Conclusion: The compound of the present invention has better inhibitory effect on the bronchial contraction induced by methotrexate in guinea pigs, and has a good bronchoconstriction inhibitory effect after 24 hours of administration.

Test Example 4: Histamine-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. Both the positive baftenterol and the test compound were formulated into a 10 mM stock solution using 83% absolute ethanol + 17% Tween 80. It was diluted 125 times with water before administration. 8 animals per group. Prior to administration, animals were anesthetized with 5% isoflurane using a small animal anesthesia machine for an anesthesia time of 1.5-2 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 PenH value was measured using a full volume oximeter (DSI; GS220A12-R7B) at 4 hours and 24 hours. 0.5 mg/ml histamine (His) was administered by nebulization, the atomization time was 1 minute, and the recording time was 5 minutes. Calculate the PenH average.

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)

Conclusion: The compounds of the present invention have better inhibitory effects on histamine-induced bronchial contraction in guinea pigs than the positive control, and some compounds still have good bronchoconstriction inhibition effects after 24 hours of administration.

Test Example 5: Pharmacokinetic Evaluation

Eighteen SD rats, male, 8 weeks old, were purchased in Vitalivic, and the experiment was started after 3 days of adaptation. SD rats were randomly divided into 3 groups. One day before the administration, the rats were fasted to avoid water; the three groups were injected intravenously (iv) or intratracheally (it) 1 mg/kg. The compound was formulated into a mother liquor of 20 mg/mL concentration using 83% ethanol and 17% Tween. 0.1 ml of the stock solution was administered intravenously and orally, and diluted to a final volume by adding 9.9 ml of physiological saline. The intratracheal administration was carried out with 0.25 ml of a stock solution, and diluted with 4.75 ml of physiological saline to a final volume. Intravenous administration group was separated from plasma before and after administration (0h) and 5min, 15min, 30min, 1.0, 2.0, 4.0, 8.0, 24.0h after administration. Heparin was anticoagulated and centrifuged at 3000C for 10min at 4°C for 10min. Store at -80 ° C for testing. The rats in the intragastric administration and the intratracheal administration group were collected before the administration and 5 minutes, 15 minutes, 30 minutes, 1.0, 2.0, 4.0, 8.0, 24.0 hours after the administration, and the treatment method was the same as the intravenous administration group. Take 30 μL of rat plasma at each time point, add 200 μL of acetonitrile solution containing internal standard, mix, vortex for 1 minute, centrifuge at 11300 rpm for 10 minutes, and take 175 μL of supernatant solution in 96-well plate for LC-MS/MS analysis. . The main pharmacokinetic parameters were analyzed using the WinNonlin 6.3 software non-compartmental model.

Conclusion: After administration of iv and it, the in vivo exposure level of compound 7 was significantly lower than that of positivity, and it is expected to have better system safety.

Claims (13)

A compound of the formula (I) or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof: Where: B is selected from , , , , , Q is selected from -CH ₂ CH ₂ -, -CH=CH-, -O-, -S-, -CH ₂ O-, -OCH ₂ -, -C(CH ₃ ) ₂ O- or -OC (CH ₃ ) ₂ -; Y is selected from And Y is attached to the 3 or 4 position of the phenylene ring relative to the R ⁶ group; A is selected from or Said or Optionally further from 0 to 4 selected from the group consisting of F, Cl, Br, I, OH, NH ₂ , carboxyl, cyano, nitro, C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkane Oxyl, -OC _3-6 cycloalkyl, C _1-4 alkylthio, 5 to 6 membered heteroaryl, -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 -C Substituted by a substituent of (=O)NH ₂ , the alkyl, alkoxy, cycloalkyl, alkynyl, carboxyl, NH ₂ , -C(=O)NH ₂ and heteroaryl groups are optionally further Substituted to four substituents selected from the group consisting of F, Cl, Br, I, CF ₃ , C _1-4 alkyl, C _1-4 alkoxy or -C(=O)-C _1-4 alkyl, And the heteroaryl group contains 1 to 4 hetero atoms selected from N, O or S; X ₁ and X ₂ are each independently selected from -C(=O)NR ^x -, -NR ^x C(=O) -, -OC(=O)NR ^x - or -NR ^x C(=O)O-; R ^{x is} selected from H or C _1-4 alkyl; R ¹ and R ² are each independently selected from F, Cl, Br, I, CF ₃ , C _1-4 alkyl, cyano, -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 is independently selected from H or C _1-4 alkyl; selectivity R ^1f, R ^1g nitrogen atom attached thereto form a 5-6 heterocyclic ring, said heterocyclic ring containing 1 to 3 heteroatoms selected from N, O or S; W is -O- or -NW ^a -W ^{a is} selected from H or C _1-4 alkyl; R ^{3 is} independently selected from the group consisting of F, Cl, Br, I, CF ₃ , C _1-4 alkyl, C _2-4 alkenyl, C _{2 - 4} alkynyl, C _3-6 cycloalkyl, cyano, -OR ^3a , -C(O)OR ^3b , -SR ^3c , -S(O)R ^3d , -S(O) ₂ R ^3e or -NR ^3f R ^3g; or two R ³ groups combine to form a C _1-3 alkylene group, C _2-3 alkenylene or ethylene ^{oxide-2,3-diyl; R 3a, R 3b, R} 3c, R ^3d , R ^3e , R ^3f and R ^3g are each independently selected from H or C _1-4 alkyl; R ^{4 is} selected from C _1-6 alkylene, C _2-6 alkenylene or C _2-6 sub Alkynyl, the alkylene, alkenylene or alkynylene group optionally further from 0 to 5 selected from the group consisting of F, Cl, Br, I, OH, cyano, C _1-4 alkyl, C _1-4 Substituted with alkoxy, phenyl or phenyl-C _1-4 alkylene; R ^{5 is} independently selected from the group consisting of F, Cl, Br, I, OH, NH ₂ , carboxyl, cyano, nitro , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, -OC _3-6 cycloalkyl, C _1-4 alkylthio, 5 to 6 Heteroaryl, -S(= O)-C _1-4 alkyl, -S(=O) ₂ -C _1-4 alkyl, -C(=O)-C _1-4 alkyl, -C(=O)OC _1-4 alkane a group, -OC(=O)-C _1-4 alkyl or -C(=O)NH ₂ , said alkyl group, alkoxy group, cycloalkyl group, alkenyl group, alkynyl group, carboxyl group, NH ₂ , - C(=O)NH ₂ and heteroaryl are optionally further selected from 0 to 4 selected from F, Cl, Br, I, CF ₃ , C _1-4 alkyl, C _1-4 alkoxy or -C ( Substituted with a substituent of -O _1-4 alkyl, and said heteroaryl contains 1 to 4 heteroatoms selected from N, O or S; R ^{6 is} selected from C _1-6 alkylene The alkylene group is optionally further substituted with 0 to 5 substituents selected from R ^6a ; R ^{6a 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; selectively forming a 3-6 ring together with the two carbon atoms to which they are attached R ^6a, said carbocyclic ring optionally further Substituted by 0 to 5 substituents selected from F, Cl, Br, I, cyano, OH, C _1-4 alkyl or C _1-4 alkoxy; R ⁷ and R ⁸ are each independently selected from H or C _1-4 alkyl; a is selected from 0, ₁ , 2, 3, 4 or 5; b is selected from 0, 1, 2, 3 or 4; c is selected from 0, 1, 2, 3 or 4; d is selected from 0, 1, 2, 3 or 4; n is 0 or 1 m is 0, 1, 2, 3, 4, 5 or 6; the constraint is that when n is 0, m is 1, 2, 3, 4, 5 or 6; p is 0, 1, 2, 3, 4, 5 or 6; the constraint is: 1) d is selected from 0, X _{2 is} selected from -NHCO- or -CONH-, and R ⁴ -X _{1 is} selected from -CH ₂ CH ₂ C(=O)NR ^x - , B is not Or 2) R ^{5 is} not a C _2-4 alkynyl group or a 5 to 6 membered heteroaryl group, X _{2 is} selected from -NHCO- or -CONH-, and R ⁴ -X _{1 is} selected from -CH ₂ CH ₂ C (= O) NR ^x - when B is not . The compound of claim 1, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein: A is selected from the group consisting of or Said or Optionally further from 0 to 4 selected from the group consisting of F, Cl, Br, I, OH, NH ₂ , carboxyl, cyano, C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, Substituted by a substituent of -OC _3-6 cycloalkyl or 5 to 6 membered heteroaryl optionally further protected by an alkyl group, an alkoxy group, a cycloalkyl group, an alkynyl group, a carboxyl group, an NH ₂ or a heteroaryl group 0 to 4 substituents selected from F, Cl, Br, I, CF ₃ , C _1-4 alkyl, C _1-4 alkoxy or -C(=O)-C _1-4 alkyl And the heteroaryl group contains 1 to 4 hetero atoms selected from N, O or S; R ¹ and R ² are each independently selected from the group consisting of F, Cl, Br, I, CF ₃ , C _1-4 alkane a cyano group, a cyano group, a hydroxy group or a C _1-4 alkoxy group; R ^{4 is} selected from a C _1-4 alkylene group, and the alkylene group is optionally further further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, Substituted by a substituent of OH, cyano, C _1-4 alkyl or C _1-4 alkoxy; R ^{5 is} independently selected from the group consisting of F, Cl, Br, I, OH, NH ₂ , carboxyl, cyano, Nitro, C _1-4 alkyl, C _2-4 alkynyl, 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, the alkane , An alkynyl group, an alkoxy group, a heteroaryl group, a carboxyl group, cycloalkyl, NH ₂ and optionally 0-4 further selected from F, Cl, Br, I, CF 3, C 1-4 -alkyl, C _{1 -4} alkoxy or -C (= O) -C _1-4 alkyl substituents, and said heteroaryl group containing 1 to 4 heteroatoms selected from N, O or S; R ⁶ Selected from a C _1-4 alkylene group, the alkylene group optionally further substituted with 0 to 5 substituents selected from R ^6a ; R ^{6a is} selected from the group consisting of F, Cl, Br, I, cyano, OH, C _1-4 alkyl, C _1-4 alkoxy or phenyl; optionally, two R ^6a together with the atoms to which they are attached form a 3 to 6 membered carbocyclic ring, optionally further 0 Substituted to 5 substituents selected from F, Cl, Br, I, cyano, OH, C _1-4 alkyl or C _1-4 alkoxy; a, b are each independently selected from 0, 1, 2 or 3. The compound of claim 2, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein: B is selected from the group consisting of , , , , , A selected from or Said or Optionally further substituted by 0 to 4 substituents selected from F, Cl, Br, cyano, methyl, ethyl, propyl, isopropyl, ethynyl, CHF ₂ , CF ₃ , methoxy or ethoxy Substituted; R ^{x is} selected from H, methyl or ethyl; R ¹ and R ² are each independently selected from the group consisting of F, Cl, Br, I, CF ₃ , cyano, hydroxy, methyl, ethyl, methoxy Or ethoxy; W is -O- or -NW ^a -; W ^{a is} selected from H, methyl or ethyl; R ^{4 is} selected from methylene, ethylene or propylene, said The base, ethylene or propylene group is optionally further substituted with from 0 to 5 substituents selected from the group consisting of F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy. ; R ^{5 is} selected from the group consisting of F, Cl, Br, cyano, methyl, ethyl, propyl, isopropyl, CHF ₂ , CF ₃ , methoxy, ethoxy, -OCHF ₂ , -OCF ₃ , acetylene Alkyl, propynyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, thiazolyl or oxazolyl; R ^{6 is} selected from methylene, ethylene, propylene or , the methylene, ethylene, propylene or Optionally further substituted by 0 to 5 substituents selected from the group consisting of F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy; R ⁷ and R ⁸ are each independently Selected from H, methyl or ethyl; a and b are each independently selected from 0, 1 or 2; c is 0; n is 0 or 1; m is 0, 1, 2, 3, 4 or 5; When n is 0, m is 1, 2, 3, 4 or 5; p is 0, 1, 2, 3 or 4; the constraint is: 1) d is selected from 0, and X _{2 is} selected from -NHCO- or -CONH-, R ⁴ -X _{1 is} selected from -CH ₂ CH ₂ C(=O)NR ^x -, B is not Or 2) R ^{5 is} not ethynyl, propynyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, thiazolyl or oxazolyl, and X _{2 is} selected from -NHCO- or -CONH-, When R ⁴ -X _{1 is} selected from -CH ₂ CH ₂ C(=O)NR ^x -, B is not . The compound of claim 3, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein: W is -O-, -NH - or -NCH ₃ -; R ^{4 is} selected from methylene, ethylene, propylene, -CH(CH ₃ )CH ₂ - or -CH ₂ CH(CH ₃ )-; or ; R ^{5 is} selected from the group consisting of F, Cl, Br, methyl, ethyl, methoxy, ethoxy, ethynyl, propynyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, thiazolyl Or oxazolyl; R ^{6 is} selected from the group consisting of methylene, ethylene, propylene, -C(CH ₃ ) ₂ CH ₂ -, -CH ₂ C(CH ₃ ) ₂ -, -CH(CH ₃ )CH ₂ -, -CH ₂ CH(CH ₃ ), -CH ₂ C(CH ₃ ) ₂ - or ; R ⁷ and R ⁸ are each independently selected from H, methyl or ethyl. A compound of the formula (II): or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof: Where B is selected from , , , , Q is selected from -CH ₂ CH ₂ -, -CH=CH-, -O-, -S-, -CH ₂ O-, -OCH ₂ -, -C(CH ₃ ) ₂ O- or -OC (CH _{3 2} -; X _{1 is} selected from -C(=O)NR ^x -, -NR ^x C(=O)-, -OC(=O)NR ^x - or -NR ^x C(=O)O-;R ^{x is} selected from H or C _1-4 alkyl; R ¹ and R ² are each independently selected from the group consisting of F, Cl, Br, I, CF ₃ , C _1-4 alkyl, cyano, -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; optionally, R ^1f , R ^1g and its attached nitrogen atom form a 5- to 6-membered heterocyclic ring, said heterocyclic ring containing 1 Up to 3 heteroatoms selected from N, O or S; W is -O- or -NW ^a -; W ^{a is} selected from H or C _1-4 alkyl; R ^{3 is} independently selected from F, Cl, Br , I, CF ₃ , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, cyano, -OR ^3a , -C(O)OR ^3b , -SR ^3c , -S(O)R ^3d , -S(O) ₂ R ^3e or -NR ^3f R ^3g ; or two R ³ groups are bonded to form a C _1-3 alkylene group, a C _2-3 alkylene group or ^{oxirane-2,3-diyl; R 3a, R 3b, R} 3c, R 3d, R 3e, R 3f and R ^3g is independently selected from H C _1-4 alkyl; R ⁴ is selected from C _1-6 alkylene, C _2-6 alkenylene or C _2-6 alkynylene, said alkylene, alkenylene or alkynylene group optionally Further from 0 to 5 selected from the group consisting of F, Cl, Br, I, OH, cyano, C _1-4 alkyl, C _1-4 alkoxy, phenyl or phenyl-C _1-4 alkylene Substituted by a substituent; R ^{5 is} independently selected from the group consisting of F, Cl, Br, I, OH, NH ₂ , carboxyl, cyano, nitro, C _1-4 alkyl, C _2-4 alkenyl, C _{2- 4} alkynyl, C _1-4 alkoxy, -OC _3-6 cycloalkyl, C _1-4 alkylthio, 5 to 6 membered heteroaryl, -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 -C(=O)NH ₂ , said alkyl, alkoxy, cycloalkyl, alkenyl, alkynyl, carboxyl, NH ₂ , -C(=O)NH ₂ and hetero The aryl group is optionally further selected 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 _1-4 alkane. Substituted by a substituent, and said heteroaryl contains 1 to 4 heteroatoms selected from N, O or S; R ^{6 is} selected from C _1-6 alkylene, said alkylene optionally further It is substituted with 0-5 substituents selected from R ^6a; R ^6a is selected from F, Cl, Br I, cyano, OH, C _1-4 alkyl, C _1-4 alkoxy, phenyl or phenyl -C _1-4 alkylene; selectivity, two R ^6a together with the atoms to which they are attached 3-6 form a carbocyclic ring, the carbocyclic ring is optionally further selected from 0-5 F, Cl, Br, I, cyano, OH, C _1-4 alkyl or C _1-4 alkoxy Substituted by a substituent; R ⁷ and R ⁸ are each independently selected from H or C _1-4 alkyl; a is selected from 0, ₁ , 2, 3, 4 or 5; b is selected from 0, 1, 2, 3 Or 4; c is selected from 0, 1, 2, 3 or 4; d is selected from 0, 1, 2, 3 or 4; the restriction is that R ^{5 is} not a C _2-4 alkynyl group or a 5 to 6 membered heteroaryl group , or d is selected from 0, B is not , , , or The compound of claim 5, 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 F, Cl, Br, I, CF ₃ , C _1-4 alkyl, cyano, hydroxy or C _1-4 alkoxy; R ^{4 is} selected from C _1-4 alkylene, said alkylene Optionally further substituted by 0 to 5 substituents selected from the group consisting of F, Cl, Br, I, OH, cyano, C _1-4 alkyl or C _1-4 alkoxy; R ^{5 is} independently selected from F, Cl, Br, I, OH, NH ₂ , carboxyl, cyano, nitro, C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, -OC _3-6 naphthenic group, C _1-4 alkylthio, -S (= O) -C _{1-4 alkyl, -S (= O) 2 -C} 1-4 alkyl, -C (= O) -C _1-4 An alkyl group, -C(=O)OC _1-4 alkyl or a 5 to 6 membered heteroaryl group optionally substituted with an alkyl group, an alkynyl group, an alkoxy group, a heteroaryl group, a carboxyl group, a cycloalkyl group and NH ₂ Further substituted by 0 to 4 substituents selected from F, Cl, Br, I, CF ₃ , C _1-4 alkyl, C _1-4 alkoxy or -C(=O)-C _1-4 alkyl Substituted, and the heteroaryl group contains 1 to 4 hetero atoms selected from N, O or S; R ^{6 is} selected from C _1-4 alkylene groups, The alkylene group is optionally further substituted with 0 to 5 substituents selected from R ^6a ; R ^{6a is} selected from the group consisting of F, Cl, Br, I, cyano, OH, C _1-4 alkyl, C _1-4 Alkoxy or phenyl; optionally, two R ^6a together with the atoms to which they are attached form a 3 to 6 membered carbocyclic ring, optionally further 0 to 5 selected from the group consisting of F, Cl, Br, Substituting for a substituent of cyano, OH, C _1-4 alkyl or C _1-4 alkoxy; a, b are each independently selected from 0, 1, 2 or 3. The compound of claim 6, or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein: B is selected from the group consisting of , , , , , R ^{x is} selected from H, methyl or ethyl; R ¹ and R ² are each independently selected from the group consisting of F, Cl, Br, I, CF ₃ , cyano, hydroxy, methyl, ethyl, methoxy or ethoxy. W is -O- or -NW ^a -; W ^{a is} selected from H, methyl or ethyl; R ^{4 is} selected from methylene, ethylene or propylene, said methylene, ethylene group or a propylene group optionally further substituted with 0-5 selected from F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy substituent; R ⁵ each Independently selected from the group consisting of F, Cl, Br, cyano, methyl, ethyl, propyl, isopropyl, CHF ₂ , CF ₃ , methoxy, ethoxy, —OCHF ₂ , —OCF ₃ , ethynyl , propynyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, thiazolyl, oxazolyl or tetrazolyl; R ^{6 is} selected from methylene, ethylene, propylene or , the methylene, ethylene, propylene or Optionally further substituted by 0 to 5 substituents selected from the group consisting of F, Cl, Br, I, cyano, OH, methyl, ethyl, methoxy or ethoxy; R ⁷ and R ⁸ are each independently Selected from H, methyl or ethyl; a and b are each independently selected from 0, 1 or 2; c is 0; the restriction is that R ^{5 is} not ethynyl, propynyl, pyrrolyl, imidazolyl, pyrazole a group, a thienyl group, a furyl group, a thiazolyl group, an oxazolyl group or a tetrazolyl group, or when d is selected from 0, B is not , The compound of claim 7 or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein: W is -O-, -NH- Or -NCH ₃ -; R ^{4 is} selected from the group consisting of methylene, ethylene, propylene, -CH(CH ₃ )CH ₂ - or -CH ₂ CH(CH ₃ )-; R ^{5 is} selected from F, Cl, Br, methyl, ethyl, methoxy, ethoxy, ethynyl, propynyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, thiazolyl, oxazolyl or tetrazolyl; R ^{6 is} selected from the group consisting of methylene, ethylene, propylene, -C(CH ₃ ) ₂ CH ₂ -, -CH ₂ C(CH ₃ ) ₂ -, -CH(CH ₃ )CH ₂ -, -CH ₂ CH(CH ₃ )-, -CH ₂ C(CH ₃ ) ₂ - or R ⁷ and R ⁸ are each independently selected from H, methyl or ethyl; the restriction is that R ^{5 is} not ethynyl, propynyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, thiazole When the group is oxazolyl or tetrazolyl, or when d is selected from 0, B is not The compound of any one of claims 1 to 8 or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, wherein The compound is selected from one of the following structures: A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 9 or a stereoisomer, hydrate, metabolite, solvate thereof, pharmacy thereof. An acceptable salt, co-crystal or prodrug, and a pharmaceutically acceptable carrier, A diluent, adjuvant, vehicle or excipient; the pharmaceutical composition may further comprise one or more additional therapeutic agents. The pharmaceutical composition according to claim 10, wherein the other therapeutic agent is one or more selected from the group consisting of a PDE4 inhibitor, a muscarinic receptor antagonist, a corticosteroid, and a β -adrenergic receptor agonist. . A compound according to any one of claims 1 to 9 or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, which is prepared in the preparation Use of a medicament for treating an airway obstructive disease. A compound according to any one of claims 1 to 9 or a stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, which is prepared in the preparation Use of a medicament for the treatment of asthma, chronic obstructive pulmonary disease or bronchitis.