Substituted phenol derivative and application thereof

Abstract

The invention discloses substituted phenol derivatives and application thereof, and relates to the field of medicinal chemistry. The substituted phenol derivative is a compound as shown in a formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or a deuterated derivative thereof. The derivative not only has sedative, hypnotic and / or anesthetic effects, but also has an analgesic effect, can control the state of epilepsy, and is good in safety during use. Therefore, the derivative has wide application prospects in preparation of drugs which have sedative, hypnotic and / or anesthetic effects and analgesic effects and can control the epileptic status. The invention provides a new choice for clinically preparing medicines which have the effects of easing pain, calming, hypnotizing and / or anesthetizing, controlling the epileptic status and the like. # imgabs0 #

Description

A class of substituted phenol derivatives and their uses Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and in particular to a class of substituted phenol derivatives and uses thereof. Background Art

[0002] Propofol is a fast-acting, short-acting intravenous general anesthetic currently used clinically for induction and maintenance of general anesthesia, as well as sedation of critically ill patients in the ICU. It offers advantages such as rapid onset of anesthesia induction, rapid awakening and complete functional recovery, and a low incidence of postoperative nausea and vomiting.

[0003] However, clinically used intravenous general anesthetics, including propofol, etomidate, fospropofol disodium, and propofol, have no analgesic effect. Therefore, opioid analgesics, such as fentanyl, alfentanil, sufentanil, or remifentanil, need to be given simultaneously during clinical anesthesia.

[0004] In order to solve the above problems, it is urgent to develop a drug that not only has sedative, hypnotic and / or anesthetic effects, but also has analgesic effects. If a compound has analgesic effects while having sedative, hypnotic and / or anesthetic effects, it can achieve more complete analgesia, significantly reduce the usage of opioid analgesics, reduce the adverse reactions of opioid analgesics, and make the sedation, hypnosis and / or anesthesia process more stable. At the same time, it can also reduce the usage of other drugs during combined anesthesia, accelerate the patient's recovery from sedation, hypnosis and / or anesthesia, and increase the patient's safety. If the drug can also control status epilepticus, it will further expand the use of the drug.

[0005] Summary of the Invention

[0006] The present invention aims to provide a class of substituted phenol derivatives and their uses. The substituted phenol derivatives have analgesic, sedative, hypnotic and / or anesthetic effects and / or can control status epilepticus.

[0007] The present invention provides a compound represented by Formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or a deuterated derivative thereof:

[0008] in,

[0009] R is selected from hydrogen, COR a 、COCH(NH2)R a 、COOR h1 、(CH2COO) v R h1 、(CH2CO) v Rh1 、PO(OR h1 )(OR h2 ) or CH2OPO(OR h1 )(OR h2 );R a Selected from hydrogen, C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, aryl or heteroaryl; R h1 、R h2 are each independently selected from hydrogen, C 1-4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, aryl or heteroaryl; v is an integer selected from 1 to 2;

[0010] R 11 、R 12 、R 21 、R 22 Each independently selected from hydrogen, halogen, hydroxyl, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, NR h3 R h4 ;

[0011] X is selected from N or CR 4 ;

[0012] R 1 、R 2 、R 4 Each independently selected from hydrogen, halogen, hydroxyl, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, NR h3 R h4 ; or R 1 、R 2 、R 4 Any two of them form = R 5 , the remaining one is selected from hydrogen, halogen, hydroxyl, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, NR h3 R h4 ;

[0013] R h3 、R h4 are each independently selected from hydrogen, C 1～4Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group;

[0014] R 5 Selected from CHR 6 NR 6 ;

[0015] R 6 Selected from C 1～4 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group;

[0016] U is selected from None, CR 7 R 8 、C2~C 10 Alkylene, C2~C 10 Alkenylene, C2~C 10 Alkynylidene, NR 7 、O、S(O)、S、S(O)R 7 R 8 , 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, aryl, heteroaryl; in this case, R 33 of For single key Or U selected from CR 7 , then connect R 33 of Double bond The carbon atoms in the main chain of the alkylene, alkenylene, and alkynylene groups in U may be replaced by one or more heteroatoms selected from O, S, or N;

[0017] R 7 、R 8 Each independently selected from hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Alkoxy, hydroxy, mercapto, 3- to 6-membered heterocyclic group, 3- to 6-membered cycloalkyl, NR d1 R d2 、C(O)R d1 ; or R 7 、R 8 Formation = R 9 ;

[0018] R 9 Selected from O, S, NR d3 , CR d3 R d31 , 3- to 6-membered heterocyclic group, 3- to 6-membered cycloalkyl group;

[0019] R d3 、R d31 Selected from hydrogen, hydroxyl, C 1～4 Alkyl, C 1～4Alkoxy, (CH2) m C(O)R d4 ;

[0020] R 33 Selected from hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Alkoxy, hydroxy, mercapto, NR d1 R d2 、C(O)R d1 , OR d1 、Being s R 3’ substituted 3- to 8-membered heterocyclic group, substituted by s R 3’ Substituted 3- to 8-membered cycloalkyl, substituted by s R 3’ substituted 5-10 membered aryl, substituted by s R 3’ substituted 5- to 10-membered heteroaryl;

[0021] s is an integer selected from 0 to 8, each R 3’ are each independently selected from hydrogen, C 1～8 Alkyl, halogenated C 1～4 Alkyl, C 2～8 Alkenyl, C 2～8 Alkynyl, hydroxyl, carboxyl, cyano, nitro, 3-6 membered heterocyclic group, 3-6 membered cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl, tert-butyloxycarbonyl, (CR a1 R a2 ) n1 COR b 、(CR a1 R a2 ) n1 COOR b1 、O(CR a1 R a2 ) n1 COR b 、(CR a1 R a2 ) n1 NR c1 R c2 、(CR a1 R a2 ) n1 OR b1 、(CR a1 R a2 ) n1 CO(CR a3 R a4 ) n2 NR c1 R c2 、(CR a1 R a2 ) n1CO(CR a3 R a4 ) n2 COOR b1 、(CR a1 R a2 ) n1 CO(CR a3 R a4 ) n2 CONR c1 R c2 ;

[0022] n1 is selected from 0, 1, 2;

[0023] n2 is selected from 0, 1, 2;

[0024] R a1 、R a2 、R a3 、R a4 are each independently selected from hydrogen, halogen, C 1～8 Alkyl, C 2～8 Alkenyl, C 2～8 Alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, 5-10 membered aryl, 5-10 membered heteroaryl, CN, OR f SR f or NR d1 R d2 ; or R a1 and R a2 Together with the carbon atom to which it is attached, it forms a 3-6 membered ring structure containing 0 or 1 heteroatom selected from N, O, and S;

[0025] R b1 Selected from hydrogen, C 1～4 Alkyl, C 1～4 Alkoxy, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, aryl or heteroaryl;

[0026] R b Selected from hydrogen, C 1～4 Alkyl, C 1～4 Alkoxy, C 2～4 Alkenyl, C 2～4 Alkynyl, NR d1 R d2 , 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, aryl or heteroaryl;

[0027] R c1 、R c2 are each independently selected from hydrogen, C 1～4 Alkyl, (CR a1 R a2 ) n1 COR b ;

[0028] R d1 、R d2 are each independently selected from hydrogen, OR f 、C 1～4 Alkyl, C 1～4 Alkoxy, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, benzyl, S(O)(O)R f 、S(O)R f 、(CH2) m C(O)R d4 ; or R d1 and R d2 Together with the carbon atom to which it is attached, it forms a 3-6 membered ring structure containing 0 or 1 heteroatom selected from N, O, and S;

[0029] The above R, R 1 、R 2 、R 3’ 、R 4 、R 6 、R 7 、R 8 、R 9 、R 11 、R 12 、R 21 、R 22 、R a1 、R a2 、R a3 、R a4 、R b 、R b1 、R c1 、R c2 、R d1 、R d2 The alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl in U is unsubstituted or optionally substituted by one or two or more of the following groups: halogen, hydroxyl, C 1～4 Alkyl, C 1～4 Alkoxy, halogenated C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, CN, NO2, OR f SR f NR d1 R d2 、COR i 、(CH2) m COOR f 、(CH2) m COR f , OCOR i 、CONRd1 R d2 NR d1 COR i NR d1 SO2R i or SO2R i ;

[0030] R f Selected from hydrogen, 3-6 membered cycloalkyl, C 1～4 Alkyl or halogenated C 1～4 alkyl;

[0031] R i Selected from hydrogen, C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocyclic group;

[0032] R d4 Selected from hydroxyl, C 1～4 alkoxy;

[0033] m is selected from 0, 1, 2, 3, and 4.

[0034] Furthermore, the structure of the compound is shown in Formula IA:

[0035] in,

[0036] R is selected from hydrogen, COR a 、COCH(NH2)R a 、COOR h1 、(CH2COO) v R h1 、(CH2CO) v R h1 、PO(OR h1 )(OR h2 ) or CH2OPO(OR h1 )(OR h2 );R a Selected from hydrogen, C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, aryl or heteroaryl; R h1 、R h2 are each independently selected from hydrogen, C 1-4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, aryl or heteroaryl; v is an integer selected from 1 to 2;

[0037] R 11 、R12 、R 21 、R 22 Each independently selected from hydrogen, halogen, hydroxyl, C 1～4 Alkyl, C 2～4 alkenyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, NR h3 R h4 ;

[0038] X is selected from N or CR 4 ;

[0039] R 1 、R 2 、R 4 Each independently selected from hydrogen, halogen, hydroxyl, C 1～4 Alkyl, C 2～4 alkenyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, NR h3 R h4 ; or R 1 、R 2 、R 4 Any two of them form = R 5 , the remaining one is selected from hydrogen, halogen, hydroxyl, C 1～4 Alkyl, C 2～4 alkenyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, NR h3 R h4 ;

[0040] R h3 、R h4 are each independently selected from hydrogen, C 1～4 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group;

[0041] R 5 Selected from CHR 6 NR 6 ;

[0042] R 6 Selected from C 1～4 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group;

[0043] U is selected from None, CR 7 R 8 、C2~C 10 Alkylene, C2~C 10 Alkenylene, C2~C 10 Alkynylidene, NR 7 、O、S(O)、S、S(O)R 7 R 8, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, aryl, heteroaryl; the carbon atoms in the main chain of the alkylene, alkenylene, and alkynylene groups in U may be replaced by one or more heteroatoms selected from O, S, or N;

[0044] R 7 、R 8 Each independently selected from hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Alkoxy, hydroxy, mercapto, 3- to 6-membered heterocyclic group, 3- to 6-membered cycloalkyl, NR d1 R d2 、C(O)R d1 ; or R 7 、R 8 Formation = R 9 ;

[0045] R 3 Selected from hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Alkoxy, hydroxy, mercapto, 3- to 6-membered heterocyclic group, 3- to 6-membered cycloalkyl, NR d1 R d2 、C(O)R d1 , OR d1 ;

[0046] R 9 Selected from O, S, NR d3 , CR d3 R d31 , 3- to 6-membered heterocyclic group, 3- to 6-membered cycloalkyl group;

[0047] R d3 、R d31 Selected from hydrogen, hydroxyl, C 1～4 Alkyl, C 1～4 Alkoxy, (CH2) m C(O)R d4 ;

[0048] The above R, R 1 、R 2 、R 3 、R 4 、R 6 、R 7 、R 8 、R 9 、R 11 、R 12 、R 21 、R 22The alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl in U is unsubstituted or optionally substituted by one or two or more of the following groups: halogen, hydroxyl, C 1～4 Alkyl, C 1～4 Alkoxy, halogenated C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, CN, NO2, OR f SR f NR d1 R d2 、COR i 、(CH2) m COOR f 、(CH2) m COR f , OCOR i 、CONR d1 R d2 NR d1 COR i NR d1 SO2R i or SO2R i ;

[0049] R d1 、R d2 are each independently selected from hydrogen, OR f 、C 1～4 Alkyl, C 1～4 Alkoxy, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, benzyl, S(O)(O)R f 、S(O)R f 、(CH2) m C(O)R d4 ; or R d1 and R d2 Together with the carbon atom to which it is attached, it forms a 3-6 membered ring structure containing 0 or 1 heteroatom selected from N, O, and S;

[0050] R f Selected from hydrogen, 3-6 membered cycloalkyl, C 1～4 Alkyl or halogenated C 1～4 alkyl;

[0051] R i Selected from hydrogen, C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocyclic group;

[0052] R d4Selected from hydroxyl, C 1～4 alkoxy;

[0053] m is selected from 0, 1, 2, 3, and 4.

[0054] Furthermore, the structure of the compound is shown in Formula IIA:

[0055] in,

[0056] R 11 、R 12 , X, R 1 、R 2 、R 3 , U as shown above.

[0057] Furthermore,

[0058] X is selected from N or CR 4 ;

[0059] R 1 、R 2 、R 4 Each independently selected from hydrogen, halogen, hydroxyl, C 1～4 Alkyl, C 2～4 alkenyl, 3-6 membered cycloalkyl, aziridinyl, oxirane, azetidinyl, oxetane, tetrahydrofuranyl, tetrahydropyranyl, NR h3 R h4 ; or R 1 、R 2 、R 4 Any two of them form = R 5 , the remaining one is selected from hydrogen, halogen, hydroxyl, C 1～4 Alkyl, C 2～4 alkenyl, 3-6 membered cycloalkyl, aziridinyl, oxirane, azetidinyl, oxetane, tetrahydrofuranyl, tetrahydropyranyl, NR h3 R h4 ;

[0060] R h3 、R h4 are each independently selected from hydrogen, C 1～4 Alkyl, 3-6 membered cycloalkyl, aziridine, oxirane, azetidinyl, oxetane, tetrahydrofuranyl, tetrahydropyranyl,

[0061] R 5 Selected from CHR 6 NR 6 ;

[0062] R 6 Selected from C 1～4 Alkyl, 3-6 membered cycloalkyl, aziridine, oxirane, azetidinyl, oxetane, tetrahydrofuranyl, tetrahydropyranyl,

[0063] U is selected from None, CR 7 R 8 、C2~C 10 Alkylene, C2~C 10 Alkenylene, C2~C 10 Alkynylidene, NR 7 、O、S(O)、S、S(O)R 7 R 8 , 3-6 membered cycloalkyl, aziridine, oxirane, azetidinyl, oxetane, tetrahydrofuranyl, tetrahydropyranyl, Phenyl, pyridyl; the carbon atoms in the main chain of the alkylene, alkenylene, and alkynylene groups in U may be replaced by one, 1, 2, 3, 4, or 5 heteroatoms selected from O, S, or N;

[0064] R 7 、R 8 Each independently selected from hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Alkoxy, hydroxy, mercapto, aziridinyl, oxetanyl, azetidinyl, oxirane, tetrahydrofuranyl, tetrahydropyranyl, 3-6 membered cycloalkyl, NR d1 R d2 、C(O)R d1 ; or R 7 、R 8 Formation = R 9 ;

[0065] R 3 Selected from hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Alkoxy, hydroxy, mercapto, aziridinyl, oxetane, azetidinyl, oxirane, tetrahydrofuranyl, tetrahydropyranyl, 3-6 membered cycloalkyl, NR d1 R d2 、C(O)R d1 , OR d1 ;

[0066] R9 Selected from O, S, NR d3 , CR d3 R d31 , aziridinyl, oxirane, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 3-6 membered cycloalkyl;

[0067] R d3 、R d31 Selected from hydrogen, hydroxyl, C 1～4 Alkyl, C 1～4 Alkoxy, (CH2) m C(O)R d4 ;

[0068] The above R 1 、R 2 、R 3 、R 4 、R 6 、R 7 、R 8 、R 9 , alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy, cycloalkyl, aziridinyl, oxirane, azetidinyl, oxetane, tetrahydrofuranyl, tetrahydropyranyl, Phenyl and pyridyl are unsubstituted or optionally substituted by one or two or more of the following groups: halogen, hydroxyl, C 1～4 Alkyl, C 1～4 Alkoxy, halogenated C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3-6 membered cycloalkyl, aziridinyl, oxirane, azetidinyl, oxetane, tetrahydrofuranyl, tetrahydropyranyl, CN, NO2, OR f SR f NR d1 R d2 、COR i 、(CH2) m COOR f 、(CH2) m COR f , OCOR i 、CONR d1 R d2 NR d1 COR i NR d1 SO2R i or SO2R i ;

[0069] R d1 、Rd2 are each independently selected from hydrogen, OR f 、C 1～4 Alkyl, C 1～4 Alkoxy, 3-6 membered cycloalkyl, aziridinyl, oxirane, azetidinyl, oxetane, tetrahydrofuranyl, tetrahydropyranyl, Benzyl, S(O)(O)R f 、S(O)R f 、(CH2) m C(O)R d4 ; or R d1 and R d2 3-6 membered cycloalkyl, aziridine, oxirane, azetidinyl, oxetane, tetrahydrofuranyl, tetrahydropyranyl,

[0070] R f Selected from hydrogen, 3-6 membered cycloalkyl, C 1～4 Alkyl or halogenated C 1～4 alkyl;

[0071] R i Selected from hydrogen, C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3-6 membered cycloalkyl, aziridinyl, oxirane, azetidinyl, oxetane, tetrahydrofuranyl, tetrahydropyranyl,

[0072] R d4 Selected from hydroxyl, C 1～4 alkoxy;

[0073] m is selected from 0, 1, 2, 3, and 4.

[0074] Furthermore, the structure of the compound is shown in Formula IVA:

[0075] in,

[0076] X, R 1 、R 2 As shown above.

[0077] Furthermore, the structure of the compound is shown in Formula VA:

[0078] in,

[0079] X, R 1 、R 2 、R 3 、R 7 、R8 As shown above.

[0080] Furthermore, the structure of the compound is shown in Formula VIA1 or Formula VIA2:

[0081] in,

[0082] m1 is selected from 0, 1, 2;

[0083] m2 is selected from 0, 1, 2;

[0084] R 10 Selected from hydrogen, C 1～4 alkyl;

[0085] R 7 、R 8 As shown above.

[0086] Furthermore, the structure of the compound is shown in Formula VIIA1 or Formula VIIA2:

[0087] in,

[0088] m3 is selected from 0, 1, 2;

[0089] m4 is selected from 0, 1, 2;

[0090] R 3 As shown above.

[0091] Furthermore, the structure of the compound is shown in Formula VIIIA1 or Formula VIIIA2:

[0092] in,

[0093] R' is selected from hydrogen, C 1～4 alkyl;

[0094] R 7 、R 8 As shown above.

[0095] Furthermore, the structure of the compound is shown in Formula IXA1 or Formula IXA2:

[0096] in,

[0097] R 3 As shown above.

[0098] Furthermore, the structure of the compound is shown in Formula XA1 or Formula XA2:

[0099] in,

[0100] R7 、R 8 、R d1 、R d2 As shown above.

[0101] Furthermore, the structure of the compound is shown in Formula XIA1 or Formula XIA2:

[0102] in,

[0103] R 3 、R d3 As shown above.

[0104] Furthermore, the structure of the compound is shown in Formula IB:

[0105] in,

[0106] R is selected from hydrogen, COR a 、COCH(NH2)R a 、COOR h1 、(CH2COO) v R h1 、(CH2CO) v R h1 、PO(OR h1 )(OR h2 ) or CH2OPO(OR h1 )(OR h2 );R a For hydrogen, C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, 5- to 10-membered aryl or 5- to 10-membered heteroaryl; R h1 、R h2 are each independently selected from hydrogen, C 1-4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 5-10 membered aryl or 5-10 membered heteroaryl; v is an integer selected from 1 to 2;

[0107] R 1 、R 2 、R 11 、R 12 、R 21 、R 22 Each independently selected from hydrogen, halogen, hydroxyl, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl or 3- to 6-membered cycloalkyl;

[0108] U is selected from None, CR7 R 8 、C2~C 10 Alkylene, C2~C 10 Alkenylene, C2~C 10 Alkynylidene, NR 7 、O、S(O)、S、S(O)R 7 R 8 , 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, 5-10 membered aryl, 5-10 membered heteroaryl, in which case the group connected to the A ring For single key Or U selected from CR 7 , then connect the A ring Double bond The carbon atoms in the main chain of the alkylene, alkenylene, and alkynylene groups in U may be replaced by one or more heteroatoms selected from O, S, or N;

[0109] R 7 、R 8 Each independently selected from hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Alkoxy, hydroxy, mercapto, 3- to 6-membered heterocyclic group, 3- to 6-membered cycloalkyl, NR d1 R d2 ; or R 7 、R 8 Formation = R 9 ;

[0110] R 9 Selected from O, S, NR d3 , 3- to 6-membered heterocyclic group, 3- to 6-membered cycloalkyl group;

[0111] R d3 Selected from hydrogen, hydroxyl, C 1～4 Alkyl, C 1～4 Alkoxy, (CH2) m C(O)R d4 ;

[0112] Ring A is selected from 3- to 8-membered heterocyclic groups, 3- to 8-membered cycloalkyl groups, 5- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups;

[0113] R 3’ is a substituent on the A ring, s is the number of substituents, s is an integer selected from 0 to 8, each R 3’ are each independently selected from hydrogen, C 1～8 Alkyl, halogenated C 1～4 Alkyl, C 2～8 Alkenyl, C 2～8Alkynyl, hydroxyl, carboxyl, cyano, nitro, 3-6 membered heterocyclic group, 3-6 membered cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl, tert-butyloxycarbonyl, (CR a1 R a2 ) n1 COR b 、(CR a1 R a2 ) n1 COOR b1 、O(CR a1 R a2 ) n1 COR b 、(CR a1 R a2 ) n1 NR c1 R c2 、(CR a1 R a2 ) n1 OR b1 、(CR a1 R a2 ) n1 CO(CR a3 R a4 ) n2 NR c1 R c2 、(CR a1 R a2 ) n1 CO(CR a3 R a4 ) n2 COOR b1 、(CR a1 R a2 ) n1 CO(CR a3 R a4 ) n2 CONR c1 R c2 ;

[0114] n1 is selected from 0, 1, 2;

[0115] n2 is selected from 0, 1, 2;

[0116] R a1 、R a2 、R a3 、R a4 are each independently selected from hydrogen, halogen, C 1～8 Alkyl, C 2～8 Alkenyl, C 2～8 Alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, 5-10 membered aryl, 5-10 membered heteroaryl, CN, OR f SRf or NR d1 R d2 ; or R a1 and R a2 Together with the carbon atom to which it is attached, it forms a 3-6 membered ring structure containing 0 or 1 heteroatom selected from N, O, and S;

[0117] R b1 Selected from hydrogen, C 1～4 Alkyl, C 1～4 Alkoxy, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, aryl or heteroaryl;

[0118] R b Selected from hydrogen, C 1～4 Alkyl, C 1～4 Alkoxy, C 2～4 Alkenyl, C 2～4 Alkynyl, NR d1 R d2 , 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, aryl or heteroaryl;

[0119] R c1 、R c2 are each independently selected from hydrogen, C 1～4 Alkyl, (CR a1 R a2 ) n1 COR b ;

[0120] R d1 、R d2 are each independently selected from hydrogen, OR f 、C 1～4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group; or R d1 and R d2 Together with the carbon atom to which it is attached, it forms a 3-6 membered ring structure containing 0 or 1 heteroatom selected from N, O, and S;

[0121] The above R, R 1 、R 2 、R 11 、R 12 、R 21 、R 22 、R 7 、R 8 、R 9 、R 3’ 、R a1 、R a2 、R a3 、R a4 、R b 、R b1 、R c1、R c2 、R d1 、R d2 The alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl in U is unsubstituted or optionally substituted by one or more of the following groups: halogen, C 1～4 Alkyl, C 1～4 Alkoxy, halogenated C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, CN, NO2, OR f SR f NR d1 R d2 、COR i 、COOR f , OCOR i 、CONR d1 R d2 NR d1 COR i NR d1 SO2R i or SO2R i ;

[0122] R f Selected from hydrogen, C 1～4 Alkyl or halogenated C 1～4 alkyl;

[0123] R i Selected from hydrogen, C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocyclic group;

[0124] R d4 Selected from hydroxyl, C 1～4 alkoxy;

[0125] m is selected from 0, 1, and 2.

[0126] Furthermore, the structure of the compound is shown in Formula IIB:

[0127] in,

[0128] m5 is selected from 0, 1, 2, 3, 4;

[0129] m6 is selected from 0, 1, 2, 3, 4;

[0130] R 3’ is a substituent at any position on the ring;

[0131] For single key When X is selected from CR d5 or N; Key When X is selected from C; Y is selected from N or CR d5 ; and X and Y are not C at the same time;

[0132] R d5 Selected from hydrogen, C 1～4 alkyl;

[0133] R, R 1 、R 2 、R 11 、R 12 , U, R 3’ As shown above.

[0134] Furthermore, the structure of the compound is shown in Formula IIaB:

[0135] in,

[0136] R, R 1 、R 2 、R 11 、R 12 , U, R 3’ , X, Y, m5, and m6 are as shown above.

[0137] Furthermore,

[0138] U is selected from None, CR 7 R 8 、C2~C 10 Alkylene, C2~C 10 Alkenylene, C2~C 10 Alkynylidene, NR 7 、O、S(O)、S、S(O)R 7 R 8 , 3-6 membered cycloalkyl, oxirane, aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, Phenyl, pyridyl, thienyl, furyl, pyrimidinyl, imidazolyl, at this time For single key Or U selected from CR 7 ,at this time Double bond The carbon atoms in the main chain of the alkylene, alkenylene, and alkynylene groups in U may be replaced by one or more heteroatoms selected from O, S, or N;

[0139] R 7 、R8 Each independently selected from hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Alkoxy, hydroxy, mercapto, oxirane, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, 3-6 membered cycloalkyl, NR d1 R d2 ; or R 7 、R 8 Formation = R 9 ;

[0140] R 9 Selected from O, S, NR d3 , oxirane, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, 3-6 membered cycloalkyl;

[0141] R d3 Selected from hydrogen, hydroxyl, C 1～4 Alkyl, C 1～4 Alkoxy, (CH2) m C(O)R d4 ;

[0142] For single key When X is selected from CR d5 or N; Key When X is selected from C; Y is selected from N or CR d5 ; and X and Y are not C at the same time;

[0143] R d5 Selected from hydrogen, C 1～4 alkyl;

[0144] m5 is selected from 0, 1, 2, 3, 4;

[0145] m6 is selected from 0, 1, 2, 3, 4;

[0146] R 3’ Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, halogenated C 1～4 Alkyl, C 2～8 Alkenyl, C 2～8 Alkynyl, hydroxyl, carboxyl, cyano, nitro, oxirane, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, Phenyl, pyridyl, thienyl, furyl, pyrimidinyl, imidazolyl, 3-6 membered cycloalkyl, tert-butyloxycarbonyl, (CR a1 R a2 ) n1 COR b 、(CR a1 R a2 ) n1 COOR b1 、O(CR a1 R a2 ) n1 COR b 、(CR a1 R a2 ) n1 NR c1 R c2 、(CR a1 R a2 ) n1 OR b1 、(CR a1 R a2 ) n1 CO(CR a3 R a4 ) n2 NR c1 R c2 、(CR a1 R a2 ) n1 CO(CR a3 R a4 ) n2 COOR b1 、(CR a1 R a2 ) n1 CO(CR a3 R a4 ) n2 CONR c1 R c2 ;

[0147] n1 is selected from 0, 1, 2;

[0148] n2 is selected from 0, 1, 2;

[0149] R a1 、R a2 、R a3 、R a4 Each is independently selected from hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, C 2～6 Alkenyl, C 2～6 Alkynyl, 3-6 membered cycloalkyl, oxirane, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, Phenyl, pyridyl, thienyl, furyl, pyrimidinyl, imidazolyl, CN, OR f SR f or NR d1 R d2 ; or R a1 and R a2 Together with the carbon atom to which it is attached, it forms oxirane, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, Phenyl, pyridyl, thienyl, furyl, pyrimidinyl, imidazolyl;

[0150] R b1 Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, C 1～4 Alkoxy, 3-6 membered cycloalkyl, oxirane, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, Phenyl, pyridyl, thienyl, furyl, pyrimidinyl, imidazolyl;

[0151] R b Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, C 1～4 Alkoxy, C 2～4 Alkenyl, C 2～4 Alkynyl, NR d1 R d2 , 3-6 membered cycloalkyl, oxirane, aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, Phenyl, pyridyl, thienyl, furyl, pyrimidinyl, imidazolyl;

[0152] R c1 、R c2 are each independently selected from hydrogen, C 1～4 Alkyl, (CR a1 R a2 ) n1 COR b ;

[0153] R d1 、R d2 are each independently selected from hydrogen, OR f 、C 1～4 Alkyl, 3-6 membered cycloalkyl, oxirane, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, or R d1and R d2 Together with the carbon atom to which it is attached, it forms an aziridine group, an azetidinyl group, a tetrahydropyranyl group, a pyrrolidinyl group, a piperidinyl group, pyridyl, pyrimidinyl, imidazolyl;

[0154] The above R, R 1 、R 2 、R 11 、R 12 、R 7 、R 8 、R 9 、R 3’ 、R a1 、R a2 、R a3 、R a4 、R b 、R b1 、R c1 、R c2 、R d1 、R d2 , U in alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy, cycloalkyl, oxirane, aziridinyl, azetidinyl, oxetane, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, Phenyl, pyridyl, thienyl, furyl, pyrimidinyl, imidazole are unsubstituted or optionally substituted by one or more of the following groups: halogen, C 1～4 Alkyl, C 1～4 Alkoxy, halogenated C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3-6 membered cycloalkyl, oxirane, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, CN, NO2, OR f SR f NR d1 R d2 、COR i 、COOR f , OCOR i 、CONR d1 R d2 NR d1 COR i NR d1 SO2R i or SO2R i ;

[0155] R f Selected from hydrogen, C 1～4Alkyl or halogenated C 1～4 alkyl;

[0156] R i Selected from hydrogen, C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3-6 membered cycloalkyl, oxirane, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl,

[0157] R d4 Selected from hydroxyl, C 1～4 alkoxy;

[0158] m is selected from 0, 1, and 2.

[0159] Furthermore, the structure of the compound is shown in Formula IIIB:

[0160] in,

[0161] R, R 1 、R 2 、R 11 、R 12 , U, R 3’ , m5, and m6 are as shown above.

[0162] Furthermore, the structure of the compound is shown in Formula IVB:

[0163] in,

[0164] R, R 1 、R 2 、R 11 、R 12 , U, R 3’ , m5, and m6 are as shown above.

[0165] Furthermore, the structure of the compound is shown in Formula VB1 or Formula VB2:

[0166] in,

[0167] R, U, R 3’ , m5, and m6 are as shown above.

[0168] Furthermore, the structure of the compound is shown in Formula VIB1 or Formula VIB2:

[0169] in,

[0170] R, R 7 、R3’ , m5, and m6 are as shown above.

[0171] Furthermore, the structure of the compound is shown in Formula VIIB1 or Formula VIIB2:

[0172] in,

[0173] R, R 7 、R 8 、R 3’ , m5, and m6 are as shown above.

[0174] Furthermore, the structure of the compound is shown in Formula VIIIB1 or Formula VIIIB2:

[0175] in,

[0176] R, R 3’ , m5, and m6 are as shown above.

[0177] Furthermore, the structure of the compound is shown in Formula XB:

[0178] in,

[0179] R 7 、R 8 、R 3’ , m5, and m6 are as shown above.

[0180] Furthermore, the structure of the compound is shown in Formula XIB:

[0181] in,

[0182] m5, m6, R 3’ As shown above.

[0183] Furthermore, the structure of the compound is selected from:

[0184] Further, the pharmaceutically acceptable salt is acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate, carbonate, bisulfate, sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrochloride, hydrobromide, hydroiodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, teasulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, dihydroxynaphthenate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate, xinafoate, methanesulfonate or p-toluenesulfonate.

[0185] The present invention also provides a drug, which is a preparation prepared with the aforementioned compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite, or its deuterated derivative as the active ingredient, and pharmaceutically acceptable excipients.

[0186] The present invention also provides the use of the above-mentioned compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite, or its deuterated derivative in the preparation of a drug with analgesic effect.

[0187] The present invention also provides the use of the above-mentioned compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite, or its deuterated derivative in the preparation of a drug having a sedative, hypnotic and / or anesthetic effect and / or capable of controlling status epilepticus.

[0188] The present invention also provides the use of the above-mentioned compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite, or its deuterated derivative in the preparation of a drug having both analgesic and sedative, hypnotic and / or anesthetic effects and / or capable of controlling status epilepticus.

[0189] The term "simultaneously having analgesic effect" as used in the present invention means that when the compound of the present invention produces sedative, hypnotic and / or anesthetic effects, it does not respond to noxious stimuli or increases the response threshold to noxious stimuli.

[0190] The "drug with sedative effect" mentioned in the present invention refers to a drug that effectively helps sleep and effectively improves sleep. That is, it can avoid the serious harm of insomnia to the human body, treat insomnia, and improve sleep quality.

[0191] The term "drug with hypnotic effect" as used herein refers to a drug that can induce drowsiness and promote sleep. This means that the drug has an inhibitory effect on the central nervous system, causing sedation in small doses and general anesthesia in excessive doses.

[0192] The "drug with anesthetic effect" mentioned in the present invention refers to a reversible functional inhibition of the central nervous system and (or) peripheral nervous system produced by the drug, and the main characteristic of this inhibition is the loss of sensation, especially pain sensation.

[0193] Preferably, the anesthesia is general anesthesia.

[0194] The "general anesthesia" mentioned in the present invention is referred to as general anesthesia, which refers to the temporary inhibition of the central nervous system after the anesthetic enters the body. The clinical manifestations are loss of consciousness, loss of pain sensation throughout the body, amnesia, reflex inhibition and skeletal muscle relaxation.

[0195] "Status epilepticus," as used herein, refers to frequent recurrences of epileptic seizures with incomplete recovery of consciousness between consecutive seizures, or seizures that persist for more than 30 minutes without spontaneous cessation. Prolonged seizures, if left untreated, can lead to irreversible brain damage due to hyperthermia, circulatory failure, or neuronal excitotoxicity, resulting in high disability and mortality rates. Therefore, status epilepticus is a common medical emergency.

[0196] The compounds and derivatives provided herein can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0197] Definitions of terms used in the present invention: Unless otherwise stated, the initial definitions provided for groups or terms in this document apply to the groups or terms throughout the specification; for terms that are not specifically defined herein, they should be given the meaning that a person skilled in the art would give them based on the disclosure and context.

[0198] "Substitution" refers to the replacement of a hydrogen atom in a molecule by another different atom or molecule.

[0199] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a～b Alkyl refers to any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, "C 1～6 "C1-C6 alkoxy" refers to an alkoxy group containing 1 to 6 carbon atoms.

[0200] "Alkyl" refers to a saturated hydrocarbon chain having the specified number of carbon atoms. For example, C 1～6Alkyl refers to an alkyl group having 1 to 6 carbon atoms, i.e., 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group can be straight or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl, etc.

[0201] "Alkenyl" refers to an unsaturated hydrocarbon chain with at least one carbon-carbon double bond. 2～6 Alkenyl refers to an alkenyl group having 2 to 6 carbon atoms, i.e., 2, 3, 4, 5 or 6 carbon atoms. Alkenyl groups can be straight-chain or branched. Alkenyl groups include wait.

[0202] "Alkynyl" refers to an unsaturated hydrocarbon chain having at least one carbon-carbon triple bond. 2～6 Alkynyl refers to an alkenyl group having 2 to 6 carbon atoms, i.e., 2, 3, 4, 5 or 6 carbon atoms. Alkenyl groups can be straight or branched. Alkynyl groups include wait.

[0203] "Halogen" is fluorine, chlorine, bromine or iodine.

[0204] In the present invention, "forming a 3- to 6-membered cyclic structure" means forming a 3- to 6-membered cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group.

[0205] "Cycloalkyl" refers to a saturated or unsaturated all-carbon monocyclic or polycyclic ring (including fused, spiro or bridged rings) without a conjugated π electron system, including but not limited to:

[0206] "Heterocyclyl" refers to a cycloalkyl group in which at least one carbon atom is replaced by a heteroatom, wherein the heteroatom is O, N or S, and is a saturated or unsaturated monocyclic or polycyclic ring (including fused rings, spiro rings or bridged rings) without a conjugated π electron system, including but not limited to: Oxiranyl, aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl,

[0207] "Aryl" refers to an all-carbon monocyclic or polycyclic ring (including fused, spiro or bridged rings) with a conjugated π electron system, including but not limited to phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl and indenyl. The aromatic ring may be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as O, N or S. At the same time, the point of attachment to the parent group must be on a carbon atom on the ring with a conjugated π electron system, including but not limited to

[0208] "Heteroaryl" refers to an aromatic group in which at least one carbon atom of the conjugated π-electron system is replaced by a heteroatom, such as O, N or S, including but not limited to:

[0209] A "deuterated derivative" refers to a compound in which one or more hydrogen atoms are replaced by deuterium.

[0210] "Pharmaceutically acceptable" means that a carrier, vehicle, diluent, excipient, and / or formed salt is generally chemically or physically compatible with the other ingredients that constitute a pharmaceutical dosage form and physiologically compatible with the receptor.

[0211] "Salts" are acidic and / or basic salts formed by a compound or its stereoisomers with inorganic and / or organic acids and / or bases, including zwitterionic salts (inner salts) and quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final isolation and purification of the compound. They can also be obtained by mixing the compound, or its stereoisomers, with a suitable amount of acid or base (e.g., an equivalent amount). These salts may be precipitated in solution and collected by filtration, or recovered after evaporation of the solvent, or produced by freeze-drying after reaction in an aqueous medium.

[0212] The pharmaceutically acceptable salt of the present invention can be acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate, carbonate, bisulfate, sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrochloride, hydrobromide, hydroiodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, teasulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, dihydroxynaphthenate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate, xinafoate, methanesulfonate, p-toluenesulfonate or quaternary ammonium salt.

[0213] Compounds of the present invention or compositions thereof and methods of use:

[0214] The compounds of the present invention, their various crystalline forms, pharmaceutically acceptable inorganic or organic salts, hydrates, or solvates, and pharmaceutical compositions containing the compounds of the present invention as the primary active ingredient can be used to administer sedation, hypnosis, and / or general anesthesia, where analgesia is also desired. The compounds of the present invention can also be used to control status epilepticus, among other conditions.

[0215] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier.

[0216] The administration of the compound or pharmaceutical composition of the present invention includes (but is not limited to): intragastric, enteral, parenteral (intravenous, intramuscular or subcutaneous), oral and various topical administrations.

[0217] Compositions for parenteral (intravenous, intramuscular, subcutaneous) injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0218] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0219] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0220] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0221] Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0222] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0223] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0224] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0225] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage when administered is a pharmaceutically safe and effective dosage.

[0226] Compared with the prior art, the compounds provided by the present invention have achieved the following beneficial effects:

[0227] 1. As is well known to those skilled in the art, clinically used intravenous general anesthetics, such as propofol, etomidate, fospropofol disodium, and propofol, do not have analgesic effects. However, the compounds of the present invention have analgesic effects in addition to their sedative, hypnotic, and / or anesthetic effects.

[0228] 2. Since the compounds of the present invention have analgesic effects, the use of opioid analgesics such as fentanyl, alfentanil, sufentanil or remifentanil can be reduced or eliminated during clinical application, thereby reducing the occurrence of adverse reactions such as circulatory depression, respiratory depression, urinary retention, and skin itching caused by opioid analgesics.

[0229] In summary, the present invention provides a substituted phenol derivative that not only has sedative, hypnotic, and / or anesthetic effects, but also has analgesic effects, can control status epilepticus, and has good safety when used. Therefore, the derivative provided by the present invention has broad application prospects in the preparation of drugs that have sedative, hypnotic, and / or anesthetic effects, analgesic effects, and can control status epilepticus, providing a new option for the clinical preparation of drugs that have both analgesic and sedative, hypnotic, and / or anesthetic effects and can control status epilepticus.

[0230] Obviously, based on the above contents of the present invention, according to common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modifications, replacements or changes can be made.

[0231] The following further describes the above content of the present invention in detail through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention. DETAILED DESCRIPTION

[0232] The raw materials and equipment used in the specific embodiments of the present invention are all known products and are obtained by purchasing commercial products.

[0233] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker Avance III 400 nuclear magnetic spectrometer. The solvents used were deuterated methanol (CD3OD), deuterated dimethyl sulfoxide (d6-DMSO), or deuterated chloroform (CDCl3), with tetramethylsilane (TMS) as the internal standard.

[0234] LCMS analysis was performed using an Agilent LCMS 1260-6110 (ESI) column: Waters X-Bridge C18 (50 mm x 4.6 mm x 3.5 μm). Column temperature: 40°C; flow rate: 2.0 mL / min; mobile phase: gradient from 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] to 0% [water + 0.05% TFA] and 100% [CH3CN + 0.05% TFA] over 3 minutes, maintained at these conditions for 1 minute, then to 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] over 0.05 minutes, and maintained at these conditions for 0.7 minutes.

[0235] 1) Medicinal materials and reagents

[0236] The thin layer chromatography silica gel plate used was HSGF254 silica gel plate produced by Yantai Xinnuo Chemical Co., Ltd., with a thickness of 1 mm.

[0237] Thin layer chromatography (TLC) was performed using a silica gel product from Yantai Jiangyou Silica Gel Development Co., Ltd. with a specification of 0.2 ± 0.03 mm.

[0238] Column chromatography generally uses 100-200 mesh or 200-300 mesh silica gel produced by Rushan Sun Desiccant Co., Ltd. (Weihai, Shandong) as a carrier.

[0239] 2) Main instruments

[0240] Sartorius BSA124S electronic balance (Sartorius Scientific Instruments Beijing Co., Ltd.);

[0241] 98-2 magnetic stirrer (Shanghai Silu Instrument Co., Ltd.);

[0242] SCI280-Pro Sartorius BSA124S electronic balance (Sartorius Scientific Instruments Beijing Co., Ltd.);

[0243] 98-2 magnetic stirrer (Shanghai Silu Instrument Co., Ltd.);

[0244] SCI280-Pro CNC heating magnetic stirrer (Beijing Dalong Xingchuang Experimental Instrument Co., Ltd.);

[0245] ZF-I three-purpose UV instrument (Shanghai Anting Electronic Instrument Factory);

[0246] RE-2000B rotary evaporator (Zhengzhou Ketai Experimental Equipment Co., Ltd.);

[0247] SHB-III circulating water vacuum pump (Zhengzhou Huicheng Science and Technology Industry and Trade Co., Ltd.);

[0248] DLSK-5 / 20℃ low-temperature cooling circulation pump (Gongyi Yuhua Instrument Co., Ltd.);

[0249] 2XZ-2 rotary vane vacuum pump (Linhai Yonghao Vacuum Equipment Co., Ltd.);

[0250] VRD-16 bipolar rotary vane vacuum pump (Zhejiang Feiyue Electromechanical Co., Ltd.);

[0251] DGJ-10C vacuum freeze dryer (Shanghai Boden Biotechnology Co., Ltd.);

[0252] Biotage Isolera One fast preparative liquid chromatography (Biotage Sweden AB).

[0253] Example 1. Preparation of compounds 15-1 to 15-3 and their hydrochlorides 15-1D to 15-3D, and compounds 15-4 and 15-6

[0254] 1. Preparation of intermediate compound A

[0255] Compound CDI (3.599 g, 22.20 mmol) was added portionwise to a solution of compound A-1 (2.00 g, 11.10 mmol) in dry tetrahydrofuran (30 mL) in an ice-water bath at 0°C. After complete addition, the mixture was stirred at room temperature for 1 hour. The temperature was then lowered to 0°C using an ice-water bath. N,O-dimethylhydroxylamine hydrochloride (2.165 g, 22.20 mmol) and DIEA (3.160 g, 24.42 mmol) were then added sequentially to the reaction system, and stirred at room temperature overnight. After the reaction was complete as monitored by LC-MS, the mixture was extracted with ethyl acetate (3×10 mL). The organic phases were combined and washed sequentially with dilute hydrochloric acid (20 mL, 2 mol / L), saturated sodium bicarbonate (50 mL), and saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0-3%) and monitored by TLC (ethyl acetate / petroleum ether (V / V) = 1 / 5). The fraction with Rf = 0.6-0.7 was collected to obtain compound A-2 (1.8 g, yield 72.6%) as a colorless oil. ESI [M+H] + =224.1.

[0256] Compound A-2 (1.8 g, 8.06 mmol) was dissolved in dry tetrahydrofuran (15 mL) in an ice-water bath at 0°C. Methyllithium (18.6 mL, 1.3 mol / L in Et2O, 24.18 mmol) was slowly added to the reaction system via syringe and stirred at room temperature for 4 hours. After the reaction was complete, as monitored by LC-MS, the reaction system was slowly poured into ice water and acidified to pH 4-5 with 2M hydrochloric acid. The mixture was extracted with ethyl acetate (3 x 5 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0-10%) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5). Fractions with Rf = 0.4-0.5 were collected to obtain Compound A (820 mg, 57.1% yield) as a pale yellow solid. ESI [M+H] + =179.1.

[0257] 2. Preparation of compounds 15-1 to 15-3 and corresponding hydrochlorides 15-1D to 15-3D of the present invention

[0258] Compound A (100 mg, 0.562 mmol, 1 eq) and the corresponding amine compound (2.247 mmol, 4 eq) were dissolved in dichloromethane (5 mL) at room temperature and stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (2.247 mmol, 4 eq) was then added to the reaction system and stirred at room temperature overnight. After completion of the reaction as monitored by TLC, H₂O (20 mL) was added to the reaction system and extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography or Prep-TLC to obtain compounds 15-1 to 15-3 of the present invention.

[0259] Preparation of compounds 15-1D to 15-3D of the present invention.

[0260] The free bases 15-1 to 15-3 were dissolved in ether (5 mL), cooled to 0°C with an ice-water bath, and HCl / Et2O (2 eq) solution was slowly added to the reaction system with a syringe. The mixture was stirred for 10 minutes, filtered, and the solids were washed with ether and dried to obtain the target products 15-1D to 15-3D.

[0261] 3. Preparation of compound 15-4

[0262] Dissolve A (150 mg, 0.84 mmol) in dry tetrahydrofuran (5 mL) in an ice-water bath at 0°C. Slowly add methyllithium (0.78 mL, 1.3 mol / L in Et2O, 1.01 mmol) to the reaction system via syringe and stir at room temperature for 1 hour. Concentrate under reduced pressure to obtain the crude product, which is then purified by Prep-TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10). Fractions with Rf = 0.4-0.5 are collected to obtain compound 15-4 (97.7 mg, 59.8% yield) as a colorless oil. ESI [M+H] + =179.1.

[0263] 15-1D: white solid, 20.1 mg, ESI [M+H] + =208.1.

[0264] 1 H NMR (400MHz, CD3OD) δ7.32 (dd, J=7.8, 1.4Hz, 1H), 7.16 (dd, J=7.6, 1.5Hz, 1H), 6.98 (t, J=7.7Hz, 1H), 4.69 (q, J=6. 9Hz,1H),3.29–3.17(m,1H),2.94–2.60(m,6H),1.70(d,J=7.0Hz,3H),1.24(d,J=8.3Hz,4H),1.22(d,J=8.3Hz,4H).

[0265] 15-2D: white solid, 32.9 mg, ESI [M+H] + =220.1.

[0266] 1 H NMR (400MHz, CD3OD) δ7.27(dd,J=7.7,1.4Hz,1H),7.09(dd,J=7.6,1.5Hz,1H),6.95(t,J=7.7Hz,1H),4.70(q,J=6.7Hz,1H),4.35–4.15(m,2H) ,4.01–3.86(m,1H),3.84–3.68(m,1H),3.28–3.18(m,1H),2.64–2.44( m,1H),2.39–2.23(m,1H),1.54(d,J=6.8Hz,3H),1.21(t,J=6.9Hz,6H).

[0267] 15-3D: white solid, 5.5 mg, ESI [M+H] + =248.2.

[0268] 1H NMR (400MHz, CD3OD) δ7.26(d,J=7.0Hz,1H),7.10(d,J=6.2Hz,1H),7.00–6.89(m,1H),4.70–4.53(m,1H),4.15–3.87(m,2H), 3.71–3.51(m,2H),3.24–3.18(m,1H),1.52(d,J=6.7Hz,3H),1.39–1.26(m,6H),1.22(d,J=6.8Hz,3H),1.21(d,J=6.8Hz,3H).

[0269] 15-4: colorless oil, 31.2 mg, ESI[M-OH] + =177.1.

[0270] 1 H NMR (400MHz, CD3OD) δ7.02 (dd, J=7.6, 1.3Hz, 1H), 6.93 (dd, J=7.8, 1.6Hz, 1H) ,6.71(t,J=7.7Hz,1H),3.37–3.31(m,1H),1.58(s,6H),1.18(d,J=6.9Hz,6H).

[0271] Example 2. Preparation of compounds 15-10 to 15-14 of the present invention

[0272] 1. Preparation of intermediate compound B

[0273] Compound B-1 (20 g, 112.2 mmol) and HMTA (31.46 g, 224.4 mmol) were added to H2O / acetic acid (19 mL / 93 mL) at room temperature and stirred under reflux for 20 hours. After the reaction was complete as monitored by TLC, H2O (150 mL) was added to the reaction system and extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0-15%) and monitored by TLC (ethyl acetate / petroleum ether (V / V) = 1 / 6). Fractions with Rf = 0.4-0.5 were collected to obtain compound B-2 (24.8 g) as a white solid. ESI [M+H] + =207.1.

[0274] To a solution of compound B-2 (24.8 g, 120.2 mmol) in dry tetrahydrofuran (150 mL) was added portionwise to a 0°C ice-water bath. The mixture was stirred at 0°C for 30 minutes. TIPSCl (27.8 g, 144.2 mmol) was then slowly added to the mixture, and the mixture was stirred at room temperature for 20 hours. After completion of the reaction as monitored by TLC, the reaction mixture was slowly poured into ice water and extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0-7%), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 6), and fractions with Rf = 0.4-0.5 were collected to afford compound B (20.2 g, 49.6% yield for two steps) as a white solid. ESI[M+H] + =363.3.

[0275] 2. Preparation of compounds 15-10 to 15-14 of the present invention

[0276] In an ice-water bath at 0°C, slowly add the corresponding Grignard reagent R1MgBr to a dry THF solution of compound B (1.0 eq) via syringe and stir at room temperature for 3 hours. After the reaction is complete as monitored by TLC, slowly add ice to the reaction system and extract with EtOAc (3 × 10 mL). The combined organic phases are washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography or Prep-TLC to obtain intermediates 15-10-1 to 15-14-1. Dissolve the intermediate compound in THF solution, lower the reaction temperature to 0°C in an ice-water bath, and add TBAF (1.0 eq, 1 mol / L in THF) via syringe to the reaction system and stir for 10 minutes. After the reaction was completed as monitored by TLC, it was extracted with EtOAc (3×10 mL), the combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography or Prep-TLC to obtain compounds 15-10 to 15-14 of the present invention.

[0277] 15-10: pale yellow solid, 118.0 mg, ESI[M-OH] + =205.1.

[0278] 1H NMR (400MHz, CD3OD) δ7.05 (s, 2H), 4.76 (q, J = 6.5Hz, 1H), 3.39–3.36 (m, 1H), 3.33–3.28 (m, 1H), 1.44 (d, J = 6.5Hz, 3H), 1.25 (d, J = 6.9Hz, 12H).

[0279] 15-11: Pale yellow solid, 59.1 mg, ESI[M-OH] + =219.1.

[0280] 1 H NMR(400MHz,CD3OD)δ7.01(s,2H),4.44(t,J=6.7Hz,1H),3.40–3.36(m,1H),3.3 2–3.27(m,1H),1.87–1.62(m,2H),1.25(d,J=6.9Hz,12H),0.89(t,J=7.4Hz,3H).

[0281] 15-12: white solid, 95.7 mg, ESI[M-OH] + =233.2.

[0282] 1 H NMR (400MHz, CD3OD) δ6.98 (s, 2H), 4.18 (d, J = 7.4Hz, 1H), 3.40–3.25 (m, 2H), 1.89 (dq,J=13.7,6.8Hz,1H),1.24(d,J=6.9Hz,12H),1.02(d,J=6.6Hz,3H),0.75(d,J= 6.8Hz,3H).

[0283] 15-13: white solid, 151.0 mg, ESI[M-OH] + =217.2.

[0284] 1 H NMR(400MHz,CD3OD)δ7.04(s,2H),6.43–5.57(m,1H),5.33–5.23(m,1H),5.18– 5.09(m,1H),5.06(d,J=5.8Hz,1H),3.43–3.10(m,2H),1.24(d,J=6.9Hz,12H).

[0285] 15-14: Gray solid, 66.6 mg, ESI[M-OH] + =215.4.

[0286] 1H NMR (400MHz, CD3OD) δ7.23(s,2H),5.33(d,J=2.1Hz,1H),3.40–3.37(m,1H),3.33–3.26(m,1H),3.00(d,J=2.2Hz,1H),1.26(d,J=6.9Hz,12H).

[0287] Example 3. Preparation of compounds 15-16 to 15-30 of the present invention

[0288] 1. Preparation of intermediate compound C

[0289] NBS (50 g, 9.83 mmol) was added portionwise to a solution of compound B-1 (50 g, 280.5 mmol) in acetonitrile (400 mL) in an ice-water bath at 0°C. The mixture was stirred at reflux for 10 hours. After completion of the reaction as monitored by TLC, H₂O (1 L) was added to the reaction system and extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / petroleum ether (v / v) = 1 / 200 to 1 / 50) and monitored by TLC (dichloromethane / petroleum ether (v / v) = 1 / 20). Fractions with Rf = 0.4 to 0.5 were collected to obtain compound C-1 (67.4 g) as a yellow oil. ESI [M+H] + =257.1.

[0290] NaH (11.52 g, 60%, 288.0 mmol) was added portionwise to a solution of compound C-1 (67.4 g, 262.1 mmol) in dry tetrahydrofuran (400 mL) in an ice-water bath at 0°C. After stirring for 30 minutes, TIPSCl (60.62 g, 314.4 mmol) was added and stirred at 0°C for 5 hours. After completion of the reaction as monitored by TLC, the reaction system was slowly poured into ice water and extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0-7%). Fractions with Rf = 0.6-0.7 were collected to obtain white compound C (87.5 g, 75.4% yield over two steps). ESI [M+H] + =413.3.

[0291] 2. Preparation of compounds 15-16 to 15-22 of the present invention

[0292] At room temperature, compound C (1.0 g, 2.42 mmol) was dissolved in dry tetrahydrofuran (15 mL). The system was replaced with argon three times, and the reaction system was protected with argon. The reaction system was cooled to -60°C using a dry ice-ethanol bath. n-Butyl lithium (1.2 mL, 2.5 mol / L in THF, 3.0 mmol) was slowly added to the reaction system via syringe and stirred at -60°C for 1 hour. A solution of p-valeraldehyde (312.4 mg, 3.63 mmol) in tetrahydrofuran (2 mL) was slowly added to the reaction system via syringe and stirred at -60°C for 5 hours. After the reaction is complete, the reaction system is slowly poured into a saturated ammonium chloride solution at 0°C, extracted with ethyl acetate (3×10 mL), the organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to give a crude product, which is purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0-6%), monitored by TLC (ethyl acetate / petroleum ether (V / V) = 1 / 6), and the Rf = 0.7-0.8 fraction is collected to give a light yellow intermediate 15-16-1 (991 mg, yield 97.3%).

[0293] In an ice-water bath at 0°C, TBAF (1 mol / L in THF) was added to a solution of 15-16-1 (200 mg, 0.48 mmol) in dry THF (3 mL) via syringe and stirred at 0°C for 10 minutes. After the reaction was complete as monitored by TLC, saturated brine was added to the reaction system and extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0-8%), monitored by TLC (ethyl acetate / petroleum ether (V / V) = 1 / 6). Fractions with Rf = 0.5-0.6 were collected to obtain 15-16 (112.5 mg, 88.6% yield) as a white solid. ESI [M-OH] + =247.2.

[0294] 1 H NMR (400MHz, CD3OD) δ6.97 (s, 2H), 4.28 (s, 1H), 3.41–3.26 (m, 2H), 1.24 (d, J = 6.9Hz, 12H), 0.90 (s, 9H).

[0295] The preparation of compounds 15-17 to 15-22 of the present invention is similar to that of compound 15-16 of the present invention: Compound C is reacted with R2CHO to obtain 15-17-1 to 15-22-1, which are then deprotected with TBAF and purified.

[0296] 15-17: white solid, 99.5 mg, ESI[M-OH] + =247.2.

[0297] 1 H NMR(400MHz,CD3OD)δ6.98(d,J=1.8Hz,2H),4.41–4.18(m,1H),3.41–3.37(m,1H),3.32–3.25(m,1H),1.82–1.56(m,1H),1.43 –1.31(m,1H),1.24(d,J=6.9Hz,12H),1.20–1.00(m,1H),0.97(d,J=6.6Hz,3H),0.88(t,J=7.4Hz,2H),0.70(d,J=6.7Hz,1H).

[0298] 15-18: Gray solid, 625.1 mg, ESI[M-OH] + =245.0.

[0299] 15-19: white solid, 84.5 mg, ESI[M-OH] + =261.2.

[0300] 1 H NMR (400MHz, CD3OD) δ6.99 (s, 2H), 4.44 (d, J = 7.0Hz, 1H), 3.40–3.36 (m, 1H), 3.33–3.28 (m, 1H), 1.69–1.56 (m, 1H), 1.55– 1.39(m,2H),1.36–1.28(m,1H),1.24(d,J=6.9Hz,12H),1.18–1.05(m,1H),0.93(t,J=7.3Hz,3H),0.81(t,J=7.5Hz,3H).

[0301] 15-20: white solid, 139.2 mg, ESI[M-OH] + =231.2.

[0302] 1 H NMR (400MHz, CD3OD) δ7.04(s,1H),5.17(s,1H),5.00(s,1H),3.39–3.35(m,0H),3.33–3.27(m,0H),1.61(s,2H),1.24(d,J=6.9Hz,6H).

[0303] 15-21: white solid, 79.9 mg, ESI[M-OH] + =245.2.

[0304] 1H NMR(400MHz,CD3OD)δ7.03(s,2H),5.24(s,1H),5.04(s,1H),4.96(s,1H),3.39 –3.26(m,2H),2.02–1.80(m,1H),1.23(d,J=6.9Hz,12H),1.01(t,J=7.5Hz,3H).

[0305] 15-22: white solid, 31.2 mg, ESI[M-OH] + =248.0.

[0306] 3. Preparation of compounds 15-23 to 15-25 of the present invention

[0307] NaH (1.0 eq, 60%) was added portionwise to a solution of 15-23-1 to 15-25-1 (1.0 eq) in dry tetrahydrofuran (10 mL) in an ice-water bath at 0°C. After stirring at 0°C for 30 minutes, iodomethane (1.5 eq) was slowly added to the system via syringe and stirred at room temperature overnight. After completion of the reaction as monitored by TLC, the reaction system was slowly poured into ice water and extracted with EtOAc. The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain intermediates 15-23-2 to 15-25-2.

[0308] TBAF (1.0 eq, 1 mol / L in THF) was added to a dry solution of compounds 15-23-2 to 15-25-2 (1.0 eq) using a syringe in an ice-water bath at 0°C. The mixture was stirred at 0°C for 10 minutes. After the reaction was complete as monitored by TLC, saturated brine was added to the reaction system, and the mixture was extracted with EtOAc. The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography or Prep-TLC to obtain compounds 15-23 to 15-25 of the present invention.

[0309] 15-23: white solid, 115.6 mg, ESI [M-OMe] + =233.2.

[0310] 1 H NMR(400MHz,CD3OD)δ6.90(s,2H),3.71(d,J=7.5Hz,1H),3.40–3.25(m,2H),3.17(s,3H),1.94–1.7 9(m,1H),1.25(d,J=6.8Hz,3H),1.24(d,J=6.8Hz,3H),1.01(d,J=6.6Hz,3H),0.71(d,J=6.8Hz,3H).

[0311] 15-24: white solid, 127.7 mg, ESI [M+H] + =263.4.

[0312] 1 H NMR(400MHz,CD3OD)δ6.99(s,2H),5.12(s,1H),4.96(s,1H),4.56(s,1H),3.38–3.3 6(m,1H),3.32(s,3H),3.31–3.29(m,1H),1.58(s,3H),1.23(dd,J=6.9,1.6Hz,12H).

[0313] 15-25: white solid, 27.5 mg, ESI [M+H] + =279.0.

[0314] 1 H NMR (400MHz, CD3OD) δ6.89(s,2H),3.76(s,1H),3.40–3.36(m,1H),3.32–3.29(m,1H),3.19(s,3H),1.23(t,J=6.3Hz,12H),0.88(s,9H).

[0315] 4. Preparation of compounds 15-26 to 15-30 of the present invention

[0316] PCC (431 mg, 2 mmol) was added in batches to a solution of 15-26-1 (406 mg, 1 mmol) and silica gel (1 g) in dichloromethane (10 mL) in an ice-water bath at 0°C. The mixture was stirred at room temperature for 3 hours. After the reaction was completed by TLC, the mixture was filtered and the filter cake was washed with dichloromethane (3×10 mL). The filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0-4%) and monitored by TLC (ethyl acetate / petroleum ether (V / V) = 1 / 20). The Rf = 0.7-0.8 fraction was collected to obtain 15-26-2 (375 mg, yield 92.7%) as a white solid.

[0317] In an ice-water bath at 0°C, TBAF (1 mL, 1 mol / L in THF, 0.9 mL) was added to a solution of 15-26-2 (375 mg, 0.93 mmol) in dry THF (3 mL) via syringe and stirred at 0°C for 10 minutes. After completion of the reaction as monitored by TLC, saturated brine was added to the reaction system and extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0-10%), monitored by TLC (ethyl acetate / petroleum ether (V / V) = 1 / 15). Fractions with Rf = 0.5-0.6 were collected to obtain 15-26 (189.5 mg, 82.0% yield) as a white solid. ESI [M+H] + =249.2.

[0318] 1 H NMR (400MHz, CD3OD) δ7.74(s,2H),3.75–3.56(m,1H),3.42–3.29(m,2H),1.28(d,J=6.9Hz,12H),1.20(d,J=6.8Hz,6H).

[0319] The preparation of compounds 15-27 to 15-30 of the present invention is similar to that of compound 15-26 of the present invention. 15-27-1 to 15-30-1 are obtained by PCC oxidation, TBAF deprotection, and purification.

[0320] 15-27: white solid, 15.6 mg, ESI [M+H] + =233.2.

[0321] 15-28: yellow solid, 37.0 mg, ESI [M+H] + =230.2.

[0322] 1 H NMR (400MHz, CD3OD) δ7.92(s,2H),4.22(s,1H),3.42–3.36(m,1H),3.33–3.27(m,1H),1.29(d,J=6.9Hz,12H)

[0323] 15-29: white solid, 113.2 mg, ESI [M+H] + =263.2.

[0324] 1H NMR (400MHz, CD3OD) δ7.62 (s, 2H), 3.41–3.28 (m, 2H), 1.40 (s, 9H), 1.27 (d, J = 6.9Hz, 12H).

[0325] 15-30: white solid, 115.5 mg, ESI [M+H] + =277.2.

[0326] 1 H NMR (400MHz, CD3OD) δ7.75 (s, 1H), 3.45–3.37 (m, J=13.8, 7.2, 4.6Hz, 1H), 3.33–3.25 (m, 0H),1.85–1.70(m,1H),1.66–1.51(m,1H),1.29(d,J=6.9Hz,6H),0.90(t,J=7.4Hz,3H).

[0327] Example 4. Preparation of compounds 15-31 to 15-33 of the present invention

[0328] 1. Preparation of intermediate compound D

[0329] D-1 (10.0 g, 72.4 mmol) and isopropanol (16.6 mL) were added sequentially to a solution of Con H2SO4 / H2O (36 mL / 2.5 mL) in an ice-water bath at 5°C. The mixture was stirred at 57°C for 40 hours. After completion of the reaction, as monitored by LC-MS, the mixture was poured into ice water and extracted with ethyl acetate (3×20 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0-50%) and monitored by TLC (ethyl acetate / petroleum ether (V / V) = 1 / 2). Fractions with Rf = 0.6-0.7 were collected to obtain compound D-2 (13.9 g, 86.4% yield) as a white solid. ESI [M+H] + =223.0.

[0330] In an ice-water bath at 0°C, TIPSCl (18.08 g, 93.78 mmol) was slowly added to a solution of D-2 (13.9 g, 62.53 mmol) and DIEA (16.16 g, 125.04 mmol) in dry tetrahydrofuran (150 mL). After stirring for 30 minutes, TIPSCl (27.8 g, 144.2 mmol) was slowly added to the system and stirred at room temperature for 20 hours. After the reaction was complete as monitored by TLC, the reaction system was slowly poured into water and extracted with EtOAc (3×15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0-30%), monitored by TLC (ethyl acetate / petroleum ether (V / V) = 1 / 3), and the fraction with Rf = 0.6-0.7 was collected to obtain Compound D (11 g, yield 46.5%) as a white solid. ESI [M+H] + =379.2.

[0331] 2. Preparation of compounds 15-31 to 15-33 of the present invention

[0332] DCC (1.5 eq) was added portionwise to a dichloromethane solution of compound D (1 eq), diethylamine or dimethylhydroxylamine hydrochloride (1.5 eq), and DMAP (1.5 eq) at room temperature and stirred overnight. After completion of the reaction as monitored by TLC, the reaction system was slowly poured into water and extracted with EtOAc (3 × 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel column chromatography to afford intermediates 15-32-1 and 15-33-1, respectively. Deprotection with TBAF afforded the target compounds 15-31 and 15-33. Intermediate 15-32-1 was reduced with sodium borohydride and deprotected with TBAF to afford target compound 15-32.

[0333] 15-31: white solid, 212.9 mg, ESI [M+H] + =278.2.

[0334] 1 H NMR (400MHz, CD3OD) δ7.08 (s, 2H), 3.63–3.34 (m, 6H), 1.26 (d, J = 6.9Hz, 18H).

[0335] 15-32: white solid, 115.5 mg, ESI[M-OH] + =262.3.

[0336] 15-33: white solid, 10.5 mg, ESI [M+H] +=266.2.

[0337] 1 H NMR (400MHz, CD3OD) δ7.43 (s, 2H), 3.64 (s, 3H), 3.41–3.36 (m, 4H), 3.33–3.29 (m, 1H), 1.26 (d, J = 6.9Hz, 12H).

[0338] Example 5. Preparation of compounds 15-34 to 15-37 of the present invention

[0339] 1. Preparation of Compound 15-34 of the Present Invention

[0340] 1-(3,5-Diisopropyl-4-((triisopropylsilyl)oxy)phenyl)ethan-1-one (200 mg, 0.53 mmol) and hydroxylamine hydrochloride (110.5 mg, 1.59 mmol) were dissolved in ethanol (5 mL) and stirred at room temperature overnight. After the reaction was completed as monitored by TLC, the reaction system was slowly poured into water and extracted with EtOAc (3×5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was dissolved in dry THF (3 mL). TBAF (0.5 mL, 1 mol / L in THF, 0.5 mL) was added to the reaction system with a syringe in an ice-water bath at 0°C and stirred at 0°C for 10 minutes. After the reaction was complete as monitored by TLC, saturated brine was added to the reaction system, and the mixture was extracted with EtOAc (3×5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by Prep-TLC (ethyl acetate / petroleum ether (V / V) = 1 / 6) and the fraction with Rf = 0.5-0.6 was collected to obtain 15-34 as a white solid (87.3 mg, yield 82.0%). ESI [M+H] + =236.1.

[0341] 1 H NMR (400MHz, CD3OD) δ7.31 (s, 2H), 3.39–3.26 (m, 2H), 2.24 (s, 3H), 1.26 (d, J = 6.9Hz, 12H).

[0342] 2. Preparation of 15-36 of the present invention

[0343] 1-(3,5-Diisopropyl-4-((triisopropylsilyl)oxy)phenyl)ethan-1-one (200 mg, 0.53 mmol) and methoxyamine hydrochloride (444 mg, 5.32 mmol) were dissolved in methanol (8 mL) and stirred at room temperature overnight. After the reaction was completed as monitored by TLC, the reaction system was slowly poured into water and extracted with EtOAc (3×5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was dissolved in dry THF (3 mL). TBAF (0.5 mL, 1 mol / L in THF, 0.5 mL) was added to the reaction system with a syringe in an ice-water bath at 0°C and stirred at 0°C for 10 minutes. After the reaction was complete as monitored by TLC, saturated brine was added to the reaction system, and the mixture was extracted with EtOAc (3×5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by Prep-TLC (ethyl acetate / petroleum ether (V / V) = 1 / 7) and the fraction with Rf = 0.5-0.6 was collected to obtain 15-36 as a white solid (127.1 mg, yield 96.2%). ESI [M+H] + =250.2.

[0344] 1 H NMR (400MHz, CD3OD) δ7.32 (s, 2H), 3.96 (s, 3H), 3.40–3.35 (m, 1H), 3.33–3.26 (m, 1H), 2.21 (s, 3H), 1.26 (d, J = 6.9Hz, 12H).

[0345] Example 6. Preparation of compounds 15-38 to 15-40 of the present invention

[0346] 1. Preparation of Compound 15-38 of the Present Invention

[0347] Methylpropane-2-sulfinamide (2.0 g, 16.50 mmol), isobutyraldehyde (2.38 g, 33.01 mmol), PPTS (208 mg, 0.83 mmol), and MgSO4 (4.0 g) were dissolved in dichloromethane (20 mL) at room temperature and stirred overnight. The mixture was filtered, the filter cake was washed with dichloromethane (20 mL), and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / petroleum ether (v / v) = 95 / 5) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3). Fractions with Rf = 0.6-0.7 were collected to obtain 15-38-1 (2.282 g, 78.9% yield) as a white solid.

[0348] At room temperature, compound C (2.36 g, 5.71 mmol) was dissolved in dry tetrahydrofuran (50 mL). The system was replaced with argon three times, and the reaction system was protected by argon. The reaction system was cooled to -60°C in a dry ice-ethanol bath. n-Butyl lithium (2.7 mL, 2.5 mol / L in THF, 3.0 mmol) was slowly added to the reaction system via syringe and stirred at -60°C for 1 hour. 15-38-1 (1.0 g, 5.71 mmol) in tetrahydrofuran (5 mL) was slowly added to the reaction system via syringe and stirred at -60°C for 2 hours. After the reaction was complete, the reaction system was slowly poured into a saturated ammonium chloride solution and extracted with ethyl acetate (3×10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0-10%) and monitored by TLC (ethyl acetate / petroleum ether (V / V) = 1 / 5). The Rf = 0.6-0.7 fraction was collected to obtain a light yellow solid 15-38-2 (2.15 g, yield 73.8%).

[0349] In an ice-water bath at 0°C, TBAF (0.4 mL, 1 mol / L in THF, 0.4 mmol) was added to a solution of 15-38-2 (200 mg, 0.39 mmol) in dry THF (3 mL) via syringe and stirred at 0°C for 10 minutes. After the reaction was complete as monitored by TLC, saturated brine was added to the reaction system and extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by Prep-TLC (ethyl acetate / petroleum ether (V / V) = 1 / 1). Fractions with Rf = 0.5-0.6 were collected to obtain 15-38 (102.5 mg, 74.3% yield) as a white solid. ESI [M+H] + =354.3.

[0350] 1 H NMR (400MHz, CD3OD) δ6.92(s,2H),4.76(d,J=3.5Hz,1H),3.98(dd,J=7.1,3.7Hz,1H),3.40–3.26(m,2H),2.10–1. 96(m,1H),1.24(d,J=6.8Hz,6H),1.22(d,J=6.8Hz,6H),1.20(s,9H),1.03(d,J=6.7Hz,3H),0.80(d,J=6.7Hz,3H).

[0351] 2. Preparation of Compound 15-39 of the Present Invention

[0352] At room temperature, HCl (2.45 mL, 4 mmol / L in dioxane, 9.8 mmol) was added to a solution of 15-38-2 (1.0 g, 1.96 mmol) in methanol (20 mL) via syringe and stirred overnight at room temperature. The reaction system was concentrated under reduced pressure, and ether (20 mL) was added, stirred and dispersed, filtered, and the solid was washed with ether (20 mL). The filter cake was dried to give 15-39-1 (781.8 mg, 90.2% yield). 15-39-1 was subjected to reductive amination with paraformaldehyde to 15-39-2, which was then deprotected with TBAF to give 15-39 (7.2 mg) as a white solid. ESI [M+H] + =233.4

[0353] 1 H NMR(400MHz,CD3OD)δ6.85(s,2H),3.41–3.36(m,1H),3.32–3.27(m,1H),3.02– 2.88(m,1H),2.37–2.25(m,1H),2.18(s,6H),1.24(d,J=6.9Hz,12H),0.92(d,J= 6.6Hz, 3H), 0.78 (d, J = 6.6Hz, 1H).

[0354] 3. Preparation of Compound 15-40 of the Present Invention

[0355] In an ice-water bath at 0°C, MsCl (77.7 mg, 0.68 mmol) was slowly added to a solution of 15-39-1 (200 mg, 0.45 mmol) and triethylamine (137.3 mg, 1.36 mmol) in dry dichloromethane (5 mL) using a syringe. The mixture was stirred at 0°C for 1 hour. After the reaction was complete, the mixture was extracted with dichloromethane (3 × 5 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0-10%) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5). Fractions with Rf = 0.6-0.7 were collected to obtain a white crude product 15-40-1 (288.5 mg).

[0356] In an ice-water bath at 0°C, TBAF (0.5 mL, 1 mol / L in THF, 0.5 mmol) was added to a solution of 15-40-1 (288.5 mg) in dry THF (3 mL) via syringe and stirred at 0°C for 10 minutes. After the reaction was complete as monitored by TLC, saturated brine was added to the reaction system and extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by Prep-TLC (ethyl acetate / petroleum ether (V / V) = 1 / 1) and fractions with Rf = 0.5-0.6 were collected to obtain 15-40 (120.3 mg, 81.6% yield over two steps) as a white solid. ESI [M+NH4] + =345.3

[0357] 1 H NMR(400MHz,CD3OD)δ6.99(s,2H),3.91(d,J=8.7Hz,1H),3.41–3.28(m,2H),2.37(s,3H) ,2.00–1.87(m,1H),1.25(d,J=6.9Hz,12H),1.10(d,J=6.6Hz,3H),0.78(d,J=6.7Hz,3H).

[0358] Example 7. Preparation of compounds 15-41 to 15-42 of the present invention

[0359] Hexamethylenetetramine (3.92 g, 313.29 mmol) was added portionwise to a solution of 15-41-1 (8 g, 39.16 mmol) in acetic acid (80 mL) at room temperature. The mixture was stirred at 100°C for 20 hours. After completion of the reaction, as monitored by LC-MS, water (500 mL) was added to the reaction solution, which was then extracted with ethyl acetate (3 × 80 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 20 / 1 to 10 / 1) and monitored by TLC (petroleum ether / ethyl acetate (v / v) = 10 / 1). The fractions with Rf = 0.4 to 0.5 were collected to obtain 15-41-2 (2.1 g, 41.0% yield) as a light yellow solid. 3.5 g of the starting material 15-41-1 was recovered. ESI [M+H] + =233.2.

[0360] Dissolve 15-41-3 (600 mg, 6.73 mmol) in methanol (10 mL) in an ice-water bath at 0°C. Slowly add thionyl chloride (600 mg, 6.73 mmol) to the reaction system using a syringe. Stir at room temperature for 1 hour. Concentrate under reduced pressure to obtain the crude product 15-41-4.

[0361] 15-41-2 (1.0 eq) and crude product 15-41-4 (3.0 eq) were dissolved in dichloromethane and stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (3.0 eq) was then added to the reaction system and stirred at room temperature overnight. After the reaction was complete as monitored by TLC, H2O (20 mL) was added to the reaction system and extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography or Prep-TLC to obtain the target compound 15-41.

[0362] 15-41 was dissolved in diethyl ether, and the temperature was cooled to 0°C with an ice-water bath. HCl / Et2O solution was slowly added to the reaction system with a syringe, and the mixture was stirred for 10 minutes. The mixture was filtered, washed with diethyl ether, and dried to obtain the compound 15-41D of the present invention.

[0363] 15-41D: white solid, 35.4 mg, ESI [M+H] + =320.0.

[0364] 1H NMR (400MHz, CDCl3) δ13.21(s,1H),7.38(d,J=15.8Hz,1H),7.28(d,J=14.3Hz,1 H),5.23(s,1H),4.51–4.30(m,2H),3.81(d,J=2.2Hz,3H),3.77–3.54(m,2H),3.2 1–3.08(m,1H),3.01(s,3H),2.53–2.39(m,1H),1.33–1.23(m,9H),1.12–1.02(m, 1H),0.65–0.55(m,1H),0.55–0.42(m,1H),0.29–0.19(m,1H),0.18–0.07(m,1H).

[0365] Example 8. Preparation of compounds 15-43 to 15-47 of the present invention

[0366] 1. Preparation of Compound 15-43 of the Present Invention

[0367] At room temperature, compound C (2.0 g, 4.84 mmol), propane-2-thiol (368.6 mg, 4.84 mmol), Pd2(dba)3 (221.4 mg, 0.24 mmol), DIPA (489.4 mg, 4.84 mmol), and Xantphos (139.9 mg, 0.24 mmol) were dissolved in 1,4-dioxane (50 mL). The reaction system was purged with argon three times, protected by argon, and stirred at 100°C overnight. After completion of the reaction, as monitored by TLC (n-heptane), the reaction was concentrated under reduced pressure to obtain the crude product. The crude product was purified by Biotage (petroleum ether) and monitored by TLC (petroleum ether). The fraction with Rf = 0.5 was collected to obtain the crude product 15-43-1 (1.9637 g, 99.3% yield) as a colorless oil.

[0368] In an ice-water bath at 0°C, TBAF (0.6 mL, 1 mol / L in THF, 0.6 mmol) was added to a solution of 15-43-1 (250 mg, 0.61 mmol) in dry THF (3 mL) via syringe and stirred at 0°C for 5 minutes. After the reaction was complete as monitored by TLC, saturated brine was added to the reaction system and extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by Prep-TLC to obtain 15-43 (112.2 mg, 72.9% yield) as a white solid. ESI [M+H] + =253.2

[0369] 1H NMR (400MHz, CD3OD) δ7.11 (s, 2H), 3.37–3.25 (m, 2H), 3.19–3.08 (m, 1H), 1.24 (d, J = 6.9Hz, 12H), 1.23 (d, J = 6.7Hz, 6H).

[0370] 2. Preparation of Compound 15-44 of the Present Invention

[0371] At room temperature, 15-43-1 (600 mg, 1.47 mmol) and NaIO4 (1.58 g, 7.34 mmol) were dissolved in methanol (8 mL) and stirred at room temperature overnight. After the reaction was complete, as monitored by TLC (n-heptane), the mixture was filtered, the filter cake was washed with methanol, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5 to 1 / 1) and monitored by TLC (petroleum ether / ethyl acetate (V / V) = 1 / 1). The fractions with Rf = 0.4 to 0.5 were collected to obtain 15-44-1 (608 mg, 97.5% yield) as a white solid. ESI [M+H] + =425.2.

[0372] In an ice-water bath at 0°C, TBAF (0.5 mL, 1 mol / L in THF, 0.5 mmol) was added to a solution of 15-44-1 (200 mg, 0.47 mmol) in dry THF (3 mL) via syringe and stirred at 0°C for 5 minutes. After the reaction was complete as monitored by TLC, saturated brine was added to the reaction system and extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by Prep-TLC (petroleum ether / ethyl acetate (V / V) = 1 / 1) to obtain 15-44 (103.4 mg, 82.0% yield) as a white solid. ESI [M+H] + =269.2

[0373] 1 H NMR(400MHz,CD3OD)δ7.33(s,2H),3.45–3.36(m,2H),2.99–2.87(m,1H),1.28(d, J=6.6Hz,6H),1.27(d,J=6.5Hz,6H),1.20(d,J=6.8Hz,3H),1.15(d,J=6.9Hz,3H).

[0374] 3. Preparation of Compound 15-45 of the Present Invention

[0375] At room temperature, 15-43-1 (200 mg, 0.49 mmol) and m-CPBA (298 mg, 1.47 mmol) were dissolved in dichloromethane (5 mL) and stirred overnight. After the reaction was complete, as monitored by TLC (n-heptane), the mixture was filtered and the filter cake was washed with dichloromethane (10 mL). The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0-16%), monitored by TLC (petroleum ether / ethyl acetate (V / V) = 1 / 1), and the fraction with Rf = 0.3-0.4 was collected to obtain 15-45-1 (267 mg) as a white solid. ESI [M+H] + =441.2.

[0376] In an ice-water bath at 0°C, TBAF (0.5 mL, 1 mol / L in THF, 0.5 mmol) was added to a solution of 15-45-1 (267 mg) in dry THF (3 mL) via syringe and stirred at 0°C for 5 minutes. After the reaction was complete as monitored by TLC, saturated brine was added to the reaction system and extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by Prep-TLC (dichloromethane) to obtain 15-45 (101.7 mg, 73.0% yield over two steps) as a white solid. ESI [M+H] + =285.3

[0377] 1 H NMR (400MHz, CD3OD) δ7.52(s,2H),3.46–3.35(m,2H),3.30–3.18(m,1H),1.28(d,J=6.9Hz,12H),1.26(d,J=6.9Hz,6H).

[0378] 4. Preparation of Compound 15-46 of the Present Invention

[0379] 15-44-1 (250 mg, 0.59 mmol), iodophenyl diacetic acid (474.76 mg, 1.47 mmol), and ammonium bicarbonate (90.65 mg, 0.95 mmol) were dissolved in methanol (5 mL) at room temperature and stirred at room temperature for 1 hour. After the reaction was complete, as monitored by TLC (petroleum ether / ethyl acetate (V / V) = 1 / 1), the mixture was filtered, the filter cake was washed with methanol, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0-30%), monitored by TLC (petroleum ether / ethyl acetate (V / V) = 1 / 1), and fractions with Rf = 0.6-0.7 were collected to obtain the crude product 15-46-1 as a white solid.

[0380] In an ice-water bath at 0°C, TBAF (0.5 mL, 1 mol / L in THF, 0.5 mmol) was added to a solution of 15-46-1 in dry THF (3 mL) via syringe and stirred at 0°C for 5 minutes. After completion of the reaction, as monitored by TLC (petroleum ether / ethyl acetate (V / V) = 1 / 2), saturated brine was added to the reaction system and extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the crude product. The crude product was purified by Prep-TLC (EA / dichloromethane (V / V) = 1 / 1) to afford 15-46-1 as a white solid (135.4 mg, 81.0% yield over two steps). ESI [M+H] + =284.2

[0381] 1 H NMR (400MHz, CD3OD) δ7.61(s,2H),3.44–3.36(m,2H),3.31–3.21(m,1H),1.28(d,J=6.8Hz,6H),1.27(d,J=6.8Hz,6H),1.25(d,J=6.9Hz,6H).

[0382] 5. Preparation of Compound 15-47 of the Invention

[0383] In an ice-water bath at 0°C, NaH (33.84 mg, 60%, 0.85 mmol) was added portionwise to a solution of 15-46-1 (248 mg, 0.56 mmol) in dry tetrahydrofuran (10 mL). After stirring for 30 minutes, MeI (120.65 mg, 0.85 mmol) was slowly added to the system and stirred at room temperature overnight. After the reaction was complete as monitored by TLC (ethyl acetate / petroleum ether (V / V) = 1 / 3), the reaction system was slowly poured into ice water and extracted with EtOAc (3×5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0-30%), monitored by TLC (ethyl acetate / petroleum ether (V / V) = 1 / 3, and the fractions with Rf = 0.4-0.5 were collected to give 15-47-1 (200 mg) as a white product. ESI [M+H] + =454.3.

[0384] In an ice-water bath at 0°C, TBAF (0.5 mL, 1 mol / L in THF, 0.5 mmol) was added to a solution of 15-47-1 (200 mg) in dry THF (3 mL) via syringe and stirred at 0°C for 5 minutes. After completion of the reaction, as monitored by TLC (ethyl acetate / petroleum ether (V / V) = 1 / 3), saturated brine was added to the reaction system and extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by Prep-TLC (ethyl acetate / petroleum ether (V / V) = 1 / 3) to afford 15-47 (103.3 mg, 62.0% yield over two steps) as a white solid. ESI [M+H] + =298.3

[0385] 1 H NMR(400MHz,CD3OD)δ7.45(s,2H),3.45–3.37(m,2H),3.32–3.24(m,1H),2.65 (s,3H),1.32(d,J=6.8Hz,3H),1.28(d,J=6.8Hz,12H),1.19(d,J=6.8Hz,3H).

[0386] Example 9. Preparation of compounds 15-48 to 15-62 of the present invention

[0387] 1. Preparation of Compound 15-48 of the Present Invention

[0388] Dissolve compound C (3.0 g, 7.254 mmol) in dry tetrahydrofuran (50 mL) at room temperature and replace the reaction mixture with argon three times. Cool the mixture to -70°C in a dry ice-ethanol bath under argon protection. Slowly add n-butyllithium (3.48 mL, 2.5 mol / L in THF, 8.70 mmol) to the reaction mixture via syringe and stir at -70°C for 1 hour. Slowly add a solution of oxetane-3-carbaldehyde (625 mg, 6.24 mmol) in THF (2 mL) via syringe. After addition, allow the mixture to warm to room temperature and stir for 2 hours. After the reaction was complete as monitored by TLC, the reaction system was slowly poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate (3×10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0-35%), monitored by TLC (ethyl acetate / petroleum ether (V / V) = 1 / 2), and the Rf = 0.4-0.5 fraction was collected to obtain 15-48-1 (1.84 g, yield 70.1%) as a white solid.

[0389] In an ice-water bath at 0°C, TBAF (0.3 mL, 1 mol / L in THF, 0.3 mmol) was added to a solution of 15-48-1 (115 mg, 0.27 mmol) in dry THF (3 mL) via syringe and stirred at 0°C for 5 minutes. After completion of the reaction, as monitored by TLC (ethyl acetate / petroleum ether (V / V) = 1 / 3), saturated brine was added to the reaction system and extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by Prep-TLC (ethyl acetate / petroleum ether (V / V) = 1 / 2) to afford 15-48 (51.7 mg, 72.4% yield) as a white solid. ESI[M-OH] + =248.2

[0390] 1 H NMR (400MHz, CD3OD) δ7.01(s,2H),4.84(t,J=7.2Hz,2H),4.75(t,J=6.0Hz,1H),4.60(d d,J=8.0,6.3Hz,1H),4.41(t,J=6.2Hz,1H),3.33–3.27(m,2H),1.24(d,J=6.9Hz,12H).

[0391] 2. Preparation of Compound 15-49 of the Present Invention

[0392] NaH (47.8 mg, 60%, 1.19 mmol) was added portionwise to a solution of 15-48-1 (250 mg, 0.597 mmol) in dry DMF (10 mL) in an ice-water bath at 0°C. After stirring for 10 minutes, MeI (423.8 mg, 2.98 mmol) was slowly added to the system and stirred at 0°C for 2 hours. After the reaction was complete as monitored by TLC, the reaction system was slowly poured into ice water and extracted with EtOAc (3×5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0-10%) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 8). Fractions with Rf = 0.4-0.5 were collected to obtain 15-49-1 (243.3 mg, 93.7% yield) as a white product.

[0393] In an ice-water bath at 0°C, TBAF (0.6 mL, 1 mol / L in THF, 0.6 mmol) was added to a solution of 15-49-1 (243.3 mg, 0.56 mmol) in dry THF (3 mL) via syringe and stirred at 0°C for 5 minutes. After completion of the reaction, as monitored by TLC (ethyl acetate / petroleum ether (V / V) = 1 / 5), saturated brine was added to the reaction system and extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by Prep-TLC (ethyl acetate / petroleum ether (V / V) = 1 / 6) to afford 15-49 (136.1 mg, 87.3% yield) as a white solid. ESI [M-OMe] + =247.2

[0394] 1 H NMR (400MHz, CD3OD) δ6.91 (s, 2H), 4.78–4.70 (m, 1H), 4.66 (t, J = 6.0Hz, 1H), 4.49 (dd, J = 8.1, 6.2Hz, 1H),4.39–4.23(m,2H),3.32–3.18(m,3H),3.17(s,2H),1.19(d,J=6.8Hz,6H),1.18(d,J=6.8Hz,6H).

[0395] 3. Preparation of Compound 15-50 of the Present Invention

[0396] At room temperature, PCC (1.64 g, 7.60 mmol) was added in batches to a solution of 15-48-1 (1.59 g, 3.80 mmol) and silica gel (2 g) in dichloromethane (20 mL), and stirred at room temperature for 2 hours. After the reaction was completed by TLC, the mixture was filtered, and the filter cake was washed with dichloromethane (3×10 mL). The filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0-10%) and monitored by TLC (ethyl acetate / petroleum ether (V / V) = 1 / 2). The fraction with Rf = 0.7-0.8 was collected to obtain 15-50-1 (1.489 g, yield 93.6%) as a white solid.

[0397] In an ice-water bath at 0°C, TBAF (0.5 mL, 1 mol / L in THF, 0.5 mL) was added to a solution of 15-50-1 (150.3 mg, 0.36 mmol) in dry THF (5 mL) via syringe and stirred at 0°C for 5 minutes. After the reaction was complete as monitored by TLC, saturated brine was added to the reaction system and extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by Prep-TLC (ethyl acetate / petroleum ether (V / V) = 1 / 4) to obtain 15-50 (71.2 mg, 75.4% yield) as a white solid. ESI [M+H] + =263.2

[0398] 1 H NMR (400MHz, CD3OD) δ7.58 (s, 2H), 5.11–4.97 (m, 2H), 4.90–4.76 (m, 3H), 3.41–3.27 (m, 2H), 1.27 (d, J = 6.9Hz, 12H).

[0399] 4. Preparation of Compound 15-51 of the Present Invention

[0400] 15-50-1 (1.338 g, 3.20 mmol) was dissolved in dry tetrahydrofuran (8 mL) in an ice-water bath at 0°C. Methylmagnesium bromide (4.8 mL, 1.0 mol / L in THF, 4.8 mmol) was slowly added to the reaction system via syringe and stirred at 0°C for 1 hour. After the reaction was complete, the reaction system was slowly poured into ice water and extracted with ethyl acetate (3 × 5 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0-20%) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2). The fractions with Rf = 0.4-0.5 were collected to obtain 15-51-1 (1.339 g, 96.3% yield) as a colorless oil.

[0401] In an ice-water bath at 0°C, TBAF (0.4 mL, 1 mol / L in THF, 0.4 mL) was added to a solution of 15-51-1 (150.0 mg, 0.345 mmol) in dry THF (5 mL) via syringe and stirred at 0°C for 5 minutes. After the reaction was complete as monitored by TLC, saturated brine was added to the reaction system and extracted with EtOAc (3×5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by Prep-TLC (ethyl acetate / petroleum ether (V / V) = 1 / 2.5) to obtain 15-51 (87.1 mg, 90.7% yield) as a white solid. ESI[M-OH] + =261.2

[0402] 1 H NMR (400MHz, CD3OD) δ7.08(s,2H),4.86(t,J=6.3Hz,1H),4.75(dd,J=8.4,5.8Hz,1H),4.65(t,J=6.5Hz,1H ),4.53(dd,J=8.4,6.0Hz,1H),3.59–3.49(m,1H),3.38–3.26(m,2H),1.44(s,3H),1.24(d,J=6.9Hz,12H).

[0403] 5. Preparation of Compound 15-52 of the Invention

[0404] TFA (262.7 mg, 2.30 mmol) was added to a solution of 15-51-1 (500 mg, 1.15 mmol) in dichloromethane (5 mL) in an ice-water bath at 0°C and stirred at 0°C for 1 hour. After completion of the reaction as monitored by TLC, the mixture was concentrated under reduced pressure, basified with saturated aqueous sodium bicarbonate (10 mL), extracted with dichloromethane (3×10 mL), and the combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by Prep-TLC (ethyl acetate / petroleum ether (v / v) = 1 / 20). The fractions with Rf = 0.4-0.5 were collected to obtain 15-52-1 (450 mg) as a colorless oil.

[0405] In an ice-water bath at 0°C, TBAF (1.0 mL, 1 mol / L in THF, 1.0 mL) was added to a solution of 15-52-1 (450.0 mg) in dry THF (5 mL) via syringe and stirred at 0°C for 5 minutes. After the reaction was complete as monitored by TLC, saturated brine was added to the reaction system and extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0-7%), monitored by TLC (ethyl acetate / petroleum ether (V / V) = 1 / 20). Fractions with Rf = 0.4-0.5 were collected to obtain 15-52 (190.7 mg, 63.7% yield over two steps) as a white solid. ESI [M+H] + =261.2

[0406] 1 H NMR (400MHz, CD3OD) δ6.84(s,2H),5.42(d,J=18.9Hz,4H),3.40–3.25(m,2H),1.87(s,3H),1.24(d,J=6.9Hz,12H).

[0407] 6. Preparation of Compound 15-53 of the Present Invention

[0408] TFA (776.56 mg, 6.8 mmol) was added to a solution of 15-51-1 (294 mg, 0.68 mmol) and triethylsilane (393.2 mg, 3.38 mmol) in dichloromethane (5 mL) in an ice-water bath at 0°C and stirred at 0°C for 1 hour. After the reaction was complete as monitored by TLC, the mixture was basified with saturated aqueous sodium bicarbonate (10 mL) and extracted with dichloromethane (3 × 10 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product 15-53-1, which was used directly in the next step without purification.

[0409] The crude product 15-53-1 obtained in the previous step was dissolved in dry THF (5 mL). TBAF (1.0 mL, 1 mol / L in THF, 1.0 mL) was added to the reaction system using a syringe in an ice-water bath at 0°C and stirred at 0°C for 5 minutes. After the reaction was complete as monitored by TLC, saturated brine was added to the reaction system and extracted with EtOAc (3×5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by Prep-TLC (ethyl acetate / petroleum ether (V / V) = 1 / 3) to obtain 15-53 (154.8 mg, two-step yield 86.8%) as a white solid. ESI [M+H] + =263.2

[0410] 1 H NMR(400MHz,CD3OD)δ6.84(s,2H),4.88(dd,J=7.7,6.0Hz,1H),4.60–4.51(m,2H),4.32(t,J=6.3Hz,1H) ,3.32–3.27(m,2H),3.26–3.13(m,1H),3.09–2.95(m,1H),1.23(d,J=6.9Hz,12H),1.17(d,J=6.9Hz,3H).

[0411] 7. Preparation of compounds 15-54 to 15-62 of the present invention

[0412] The preparation of compounds 15-54, 15-57 and 15-60 of the present invention is similar to that of Example 15-51.

[0413] The preparation of compounds 15-55, 15-58 and 15-61 of the present invention is similar to that of Example 15-52.

[0414] The preparation of compounds 15-56, 15-59 and 15-62 of the present invention is similar to that of Example 15-53.

[0415] 15-54: white solid, 127.8 mg, ESI[M-OH] + =275.2.

[0416] 1 H NMR(400MHz,CD3OD)δ7.04(s,2H),4.96–4.90(m,1H),4.78–4.71(m,1H),4.60–4 .53(m,1H),4.50–4.44(m,1H),3.74–3.61(m,1H),3.39–3.25(m,2H),1.77–1.62 (m,2H),1.24(d,J=6.9Hz,12H),0.73(t,J=7.4Hz,3H).

[0417] 15-55: yellow oil, 11.9 mg, ESI [M+H] + =275.3.

[0418] 1 H NMR (400MHz, CD3OD) δ6.83(s,2H),5.39(s,4H),3.40–3.23(m,2H),2.31(q,J=7.6Hz,2H),1.23(d,J=6.9Hz,12H),1.03(t,J=7.5Hz,3H).

[0419] 15-56: white solid, 126.9 mg, ESI [M+H] + =277.3.

[0420] 1 H NMR (400MHz, CD3OD) δ6.81(s,2H),4.88(dd,J=7.8,6.0Hz,1H),4.57(t,J=6.2Hz,1H),4.49(dd,J=7.9,6.1Hz,1H),4.28(t,J=6.4H z,1H),3.34–3.20(m,3H),2.82–2.72(m,1H),1.66–1.53(m,1H),1.50–1.37(m,1H),1.23(d,J=6.8Hz,12H),0.78(t,J=7.4Hz,3H).

[0421] 15-57: white solid, 118.5 mg, ESI[M-OH] + =289.3.

[0422] 1 H NMR (400MHz, CD3OD) δ7.02(s,2H),5.01(dd,J=7.2,5.7Hz,1H),4.72(dd,J=8.5,5.6Hz,1H),4.46–4.36(m,2H),3.98(p,J=8.2Hz,1H ),3.39–3.26(m,2H),1.95–1.83(m,1H),1.24(d,J=6.8Hz,6H),1.23(d,J=6.8Hz,6H),0.80(d,J=6.8Hz,3H),0.72(d,J=6.9Hz,3H).

[0423] 15-58: gray solid, 107.8 mg, ESI [M+H] + =289.3.

[0424] 1 H NMR(400MHz,CD3OD)δ6.79(s,2H),5.45(d,J=2.3Hz,2H),5.14(s,2H),3.34–3 .25(m,2H),2.71–2.57(m,1H),1.23(d,J=6.9Hz,12H),1.09(d,J=7.0Hz,6H).

[0425] 15-59: white solid, 126.8 mg, ESI [M+H] + =291.3.

[0426] 1H NMR (400MHz, CD3OD) δ6.75(s,2H),4.86(dd,J=7.8,5.9Hz,1H),4.64–4.57(m,1H),4.40(dd,J=8.2,6.0Hz,1H),4.20–4.12(m,1H),3.65–3.48(m ,1H),3.39–3.23(m,2H),2.67(dd,J=11.2,7.4Hz,1H),1.81–1.68(m,1H),1.23(d,J=6.8Hz,12H),0.87(d,J=6.8Hz,3H),0.72(d,J=6.7Hz,3H).

[0427] 15-60: white solid, 92.6 mg, ESI[M-OH] + =289.3.

[0428] 1 H NMR(400MHz,CD3OD)δ7.00(s,2H),4.92–4.87(m,1H),4.71(dd,J=8.4,5.7Hz,1H),4.55–4.50(m,1H),4.46–4.39(m,1H),3 .70–3.59(m,1H),3.30–3.22(m,2H),1.66–1.50(m,2H),1.20(d,J=6.9Hz,12H),1.17–0.99(m,2H),0.81(t,J=7.3Hz,3H).

[0429] 15-61: yellow oil, 30.1 mg, ESI [M+H] + =289.3.

[0430] 1 H NMR(400MHz,CD3OD)δ6.83(s,2H),5.39(s,4H),3.39–3.26(m,2H),2.27(t,J= 7.3Hz, 2H), 1.50–1.38 (m, 2H), 1.23 (d, J = 6.9Hz, 12H), 0.92 (t, J = 7.4Hz, 3H).

[0431] 15-62: white solid, 113.6 mg, ESI [M+H] + =291.3.

[0432] 1H NMR (400MHz, CD3OD) δ6.81(s,2H),4.91–4.83(m,1H),4.55(t,J=6.2Hz,1H),4.48(dd,J=7.9,6.1Hz,1H),4.27(t,J=6.4Hz,1H ),3.34–3.19(m,3H),2.92–2.81(m,1H),1.56–1.37(m,2H),1.23(d,J=6.9Hz,12H),1.22–1.10(m,2H),0.88(t,J=7.3Hz,3H).

[0433] Example 10. Preparation of compounds 15-63 to 15-72 of the present invention

[0434] 1. Preparation of Compound 15-63 of the Present Invention

[0435] At room temperature, dissolve C (1.0 g, 2.42 mmol) in dry tetrahydrofuran (50 mL). Replace the system with argon three times, and protect the reaction system with argon. Cool the reaction system to -70°C using a dry ice-ethanol bath. Slowly add n-butyllithium (1.2 mL, 2.5 mol / L in THF, 3.0 mmol) to the reaction system via syringe, and stir at -70°C for 1 hour. Slowly add 3-methyloxetane-3-carbaldehyde (201.9 mg, 2.0 mmol) in tetrahydrofuran (1 mL) to the reaction system via syringe, and stir at -70°C for 2 hours. After the reaction is complete, the reaction system is slowly poured into a saturated ammonium chloride solution at 0°C, extracted with ethyl acetate (3×10 mL), the organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to give a crude product, which is purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0-30%), monitored by TLC (ethyl acetate / petroleum ether (V / V) = 1 / 2), and the Rf = 0.7-0.8 fraction is collected to give 15-63-1 (551 mg, yield 63.4%) as a white solid.

[0436] In an ice-water bath at 0°C, TBAF (0.6 mL, 1 mol / L in THF, 0.6 mmol) was added to a solution of 15-63-1 (278 mg, 0.64 mmol) in dry THF (3 mL) via syringe and stirred at 0°C for 5 minutes. After the reaction was complete as monitored by TLC, saturated brine was added to the reaction system and extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by Prep-TLC (ethyl acetate / petroleum ether (V / V) = 1 / 2) to obtain 15-63 (111.0 mg, 88.6% yield) as a white solid. ESI [M-OH] + =275.2.

[0437] 1 H NMR (400MHz, CD3OD) δ6.98(s,2H),4.97(d,J=5.6Hz,1H),4.84(d,J=5.7Hz,1H),4.77(s,1H),4.3 0(d,J=5.6Hz,1H),4.18(d,J=5.6Hz,1H),3.39–3.27(m,2H),1.24(s,3H),1.23(d,J=6.8Hz,12H).

[0438] 2. Preparation of Compound 15-64 of the Present Invention

[0439] At room temperature, PCC (469.9 mg, 2.18 mmol) was added in batches to a solution of 15-63-1 (315.6 mg, 0.73 mmol) and silica gel (500 mg) in dichloromethane (10 mL). The mixture was stirred at room temperature for 2 hours. After the reaction was completed by TLC, the mixture was filtered and the filter cake was washed with dichloromethane (3×10 mL). The filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0-10%) and monitored by TLC (ethyl acetate / petroleum ether (V / V) = 1 / 4). The Rf = 0.7-0.8 fraction was collected to obtain 15-64-1 (243.3 mg, yield 77.0%) as a white solid.

[0440] In an ice-water bath at 0°C, TBAF (0.2 mL, 1 mol / L in THF, 0.2 mL) was added to a solution of 15-64-1 (80 mg, 0.185 mmol) in dry THF (3 mL) using a syringe and stirred at 0°C for 5 minutes. After the reaction was complete as monitored by TLC, saturated brine was added to the reaction system and extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by Prep-TLC (ethyl acetate / petroleum ether (V / V) = 1 / 3) to obtain 15-64 (41.2 mg, 80.6% yield) as a white solid. ESI [M+H] + =277.2

[0441] 1 H NMR(400MHz,CD3OD)δ7.40(s,2H),5.12(d,J=5.9Hz,2H),4.62(d,J=6.0Hz,2H ),3.39–3.35(m,1H),3.33–3.29(m,1H),1.84(s,3H),1.26(d,J=6.9Hz,12H).

[0442] 3. Preparation of Compound 15-65 of the Present Invention

[0443] 15-64-1 (432 mg, 1.0 mmol) was dissolved in dry tetrahydrofuran (5 mL) in an ice-water bath at 0°C. Methylmagnesium bromide (1.2 mL, 1.0 mol / L in THF, 1.2 mmol) was slowly added to the reaction system via syringe and stirred at 0°C for 1 hour. After the reaction was complete, the reaction system was slowly poured into ice water and extracted with ethyl acetate (3×5 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0-20%) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2). The fractions with Rf = 0.4-0.5 were collected to obtain 15-65-1 (160 mg, 35.7% yield) as a colorless oil.

[0444] TFA (419.59 mg, 3.68 mmol) was added to a solution of 15-65-1 (160 mg, 0.368 mmol) and triethylsilane (213.96 mg, 1.84 mmol) in dichloromethane (5 mL) in an ice-water bath at 0°C and stirred at 0°C for 1 hour. After the reaction was complete as monitored by TLC, the mixture was basified with saturated aqueous sodium bicarbonate (10 mL) and extracted with dichloromethane (3 × 5 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product 15-65-2, which was used directly in the next step without purification.

[0445] The crude product 15-65-2 obtained in the previous step was dissolved in dry THF (5 mL). TBAF (0.4 mL, 1 mol / L in THF, 0.4 mmol) was added to the reaction system via syringe in an ice-water bath at 0°C and stirred at 0°C for 5 minutes. After the reaction was complete as monitored by TLC, saturated brine was added to the reaction system and extracted with EtOAc (3×5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by Prep-TLC (ethyl acetate / petroleum ether (V / V) = 1 / 3) to obtain 15-65 (70.4 mg, two-step yield 69.2%) as a white solid. ESI [M+H] + =263.2

[0446] 1 H NMR(400MHz,CD3OD)δ6.85(s,2H),4.70(dd,J=11.5,5.7Hz,2H),4.32(d,J=5.6Hz,1H),4.0 8(d,J=5.7Hz,1H),3.33–3.27(m,2H),3.20–3.10(m,1H),1.28(s,3H),1.27–1.16(m,15H).

[0447] 4. Preparation of compounds 15-66 to 15-68 of the present invention

[0448] The preparation of 15-66 to 15-68 of the present invention is similar to that of Example 15-63.

[0449] 15-66: white solid, 73.4 mg, ESI[M-OH] + =275.3.

[0450] 1 H NMR (400MHz, CD3OD) δ6.95(s,2H),5.03(d,J=5.6Hz,1H),4.92(d,J=3.7Hz,1H),4.66(s,1H),4.37(d,J=5.6Hz,1H),4.29 (d,J=5.6Hz,1H),3.41–3.22(m,2H),1.84–1.67(m,1H),1.52–1.36(m,1H),1.23(d,J=6.9Hz,12H),1.03(t,J=7.5Hz,3H).

[0451] 15-67: white solid, 23.7 mg, ESI[M-OH] + =289.3.

[0452] 15-68: white solid, 7.9 mg, ESI[M-OH] + =233.2.

[0453] 5. Preparation of compounds 15-69 to 15-72 of the present invention

[0454] The preparation of compounds 15-69 to 15-72 of the present invention is similar to that of compounds 15-48 to 15-53 in Example 9.

[0455] 15-69: white solid, 140.1 mg, ESI[M-OH] + =275.0.

[0456] 1 H NMR (400MHz, CD3OD) δ6.98 (s, 2H), 4.22 (d, J = 7.9Hz, 1H), 4.00 (dd, J = 11.6, 3.8 Hz,1H),3.88(dd,J=11.3,2.9Hz,1H),3.41(dd,J=17.1,6.6Hz,1H),3.37(s,1H) ,3.31(d,J=6.8Hz,2H),1.95(d,J=13.3Hz,1H),1.88–1.73(m,1H),1.41(qd,J= 12.3, 4.5Hz, 1H), 1.33–1.26 (m, 1H), 1.24 (d, J = 6.8Hz, 12H), 1.22–1.11 (m, 1H).

[0457] 15-70: white solid, 121.0 mg, ESI [M+H] + =291.2.

[0458] 1 H NMR (400MHz, CD3OD) δ7.74(s,2H),4.08–3.95(m,2H),3.72–3.60(m,3H),3.42–3.25(m,2H),1.90–1.70(m,4H),1.28(d,J=6.9Hz,12H).

[0459] 15-71: colorless oil, 135.0 mg, ESI [M+H] + =307.2.

[0460] 1H NMR (400MHz, CD3OD) δ6.92(s,2H),4.03–3.93(m,1H),3.91–3.82(m,1H),3.79(d,J=7.8Hz,1H),3.46–3.25(m,4H),3.18(s,3 H),2.02–1.90(m,1H),1.86–1.72(m,1H),1.49–1.28(m,2H),1.25(d,J=6.8Hz,6H),1.24(d,J=6.8Hz,6H),1.19–1.02(m,1H).

[0461] 15-72: colorless oil, 143.0 mg, ESI [M+H] + =291.0.

[0462] 1 H NMR (400MHz, CD3OD) δ6.80(s,2H),3.99(dd,J=11.3,3.9Hz,1H),3.86(dd,J=11.2,3.5Hz,1H),3.47–3.37( m,1H),3.33–3.25(m,2H),2.37(p,J=7.1Hz,1H),1.86–1.76(m,1H),1.67–1.50(m,1H),1.44–0.96(m,19H).

[0463] Example 11. Preparation of compounds 16-5 to 16-9 of the present invention

[0464] 1. Preparation of intermediate compound A

[0465] NBS (50 g, 9.83 mmol) was added portionwise to a solution of compound A-1 (50 g, 280.5 mmol) in acetonitrile (400 mL) in an ice-water bath at 0°C. The mixture was stirred at reflux for 10 hours. After completion of the reaction as monitored by TLC, H2O (1 L) was added to the reaction system and extracted with EtOAc (3 × 150 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / petroleum ether (v / v) = 1 / 200 to 1 / 50) and monitored by TLC (dichloromethane / petroleum ether (v / v) = 1 / 20). Fractions with Rf = 0.4 to 0.5 were collected to obtain compound A-2 (67.4 g) as a yellow oil. ESI [M+H] + =257.1.

[0466] NaH (11.52 g, 60%, 288.0 mmol) was added portionwise to a solution of compound A-2 (67.4 g, 262.1 mmol) in dry tetrahydrofuran (400 mL) in an ice-water bath at 0°C. After stirring for 30 minutes, TIPSCl (60.62 g, 314.4 mmol) was added. The mixture was stirred at 0°C for 5 hours. After completion of the reaction as monitored by TLC, the reaction system was slowly poured into ice water and extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0-7%). Fractions with Rf = 0.6-0.7 were collected to obtain white compound A (87.5 g, 75.4% yield over two steps). ESI [M+H] + =413.3.

[0467] 2. Preparation of Compound 16-5 of the Present Invention

[0468] At 0°C in an ice-water bath, CDI (8.76 g, 54.0 mmol) was added portionwise to a solution of 16-5-1 (6.04 g, 30.0 mmol) in dry dichloromethane (100 mL). After the addition, the mixture was stirred at room temperature for 1 hour. The temperature was then lowered to 0°C using an ice-water bath. N,O-dimethylhydroxylamine hydrochloride (4.39 g, 45.0 mmol) was added to the reaction system, and the mixture was stirred at room temperature overnight. After the reaction was completed as monitored by LC-MS, the system was extracted with dichloromethane (3×10 mL) in sequence, and the organic phases were combined and washed with hydrochloric acid (20 mL, 2M), saturated sodium bicarbonate (50 mL), and saturated brine (50 mL) in sequence, and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0-25%), monitored by TLC (ethyl acetate / petroleum ether (V / V) = 1 / 3), and the Rf = 0.6-0.7 portion was collected to obtain a light colorless oily crude product 16-5-2 (11.328 g).

[0469] At room temperature, compound A (12.8 g, 30.95 mmol) was dissolved in dry tetrahydrofuran (100 mL). The system was replaced with argon three times, and the reaction system was protected by argon. The reaction system was cooled to -60°C using a dry ice ethanol bath. n-Butyl lithium (16 mL, 2.5 mol / L in THF, 40.24 mmol) was slowly added to the reaction system using a syringe, and stirred at -60°C for 1 hour. A solution of crude product 16-5-2 (11.328 g) in tetrahydrofuran (10 mL) was slowly added to the reaction system using a syringe, and the temperature was naturally increased and stirred overnight. After the reaction is complete, the reaction system is slowly poured into a saturated ammonium chloride solution and extracted with ethyl acetate (3×10 mL). The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0-15%), monitored by TLC (ethyl acetate / petroleum ether (V / V) = 1 / 8), and the Rf = 0.4-0.5 fraction is collected to obtain a light yellow solid 16-5-3 (2.68 g, two-step yield 8.6%).

[0470] In an ice-water bath at 0°C, TBAF (0.4 mL, 1 mol / L in THF, 0.4 mmol) was added to a solution of compound 16-5-3 (201 mg, 0.388 mmol) in dry THF (3 mL) via syringe and stirred at 0°C for 5 minutes. After the reaction was complete as monitored by TLC, saturated brine was added to the reaction system and extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by Prep-TLC (ethyl acetate / petroleum ether (V / V) = 1 / 1). Fractions with Rf = 0.5-0.6 were collected to obtain 16-5 (40.0 mg, 28.5% yield) as a white solid. ESI [M+H] + =362.3.

[0471] 1 H NMR (400MHz, CD3OD) δ7.69(s,2H),5.69(dd,J=9.3,5.7Hz,1H),3.99(t,J=7.3Hz,2H),3.39–3.36(m,1H),3.33 –3.30(m,1H),2.83–2.71(m,1H),2.14–2.03(m,1H),1.41(s,9H),1.29(d,J=6.8Hz,6H),1.28(d,J=6.8Hz,6H).

[0472] Example 12: Preparation of compounds 16-10 to 16-16 of the present invention

[0473] 1. Preparation of 16-10 to 16-16 of the present invention

[0474] At room temperature, compound A (6.7 g, 16.2 mmol) was dissolved in dry tetrahydrofuran (20 mL). The system was purged with argon three times, and the reaction system was protected by argon. The reaction system was cooled to -70°C using a dry ice-ethanol bath. n-Butyl lithium (7.8 mL, 2.5 mol / L in THF, 19.5 mmol) was slowly added to the reaction system via syringe and stirred at -70°C for 1 hour. A solution of tert-butyl 3-formylazetidine-1-carboxylate (3.0 g, 16.2 mmol) in tetrahydrofuran (10 mL) was slowly added to the reaction system via syringe and stirred for 4 hours, then the temperature was naturally increased. After the reaction is complete, the reaction system is slowly poured into a saturated ammonium chloride solution and extracted with ethyl acetate (3×10 mL). The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0-15%), monitored by TLC (ethyl acetate / petroleum ether (V / V) = 1 / 2), and the Rf = 0.5-0.6 portion is collected to obtain a light yellow solid 16-13-1 (6.89 g, yield 81.8%).

[0475] In an ice-water bath at 0°C, TBAF (0.3 mL, 1 mol / L in THF, 0.3 mmol) was added to a solution of 16-13-1 (150 mg, 0.289 mmol) in dry THF (3 mL) via syringe and stirred at 0°C for 5 minutes. After the reaction was complete as monitored by TLC, saturated brine was added to the reaction system and extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by Prep-TLC (ethyl acetate / petroleum ether (V / V) = 1 / 2). Fractions with Rf = 0.5-0.6 were collected to obtain 16-11 (83.1 mg, 79.1% yield) as a white solid. ESI [M+Na] + =386.3.

[0476] 1 H NMR(400MHz,CD3OD)δ7.03(s,2H),4.65(d,J=8.0Hz,1H),4.04–3.91(m,2H),3.84–3.73(m,1H) ,3.68–3.57(m,1H),3.40–3.25(m,2H),2.93–2.82(m,1H),1.46(s,9H),1.25(d,J=6.9Hz,12H).

[0477] PCC (6.972 g, 32.35 mmol) was added in batches to a solution of 16-13-1 (1.68 g, 3.235 mmol) and silica gel (8 g) in dichloromethane (50 mL) in an ice-water bath at 0°C. The mixture was stirred at room temperature for 2 hours. After the reaction was completed by TLC, the mixture was filtered and the filter cake was washed with dichloromethane (3×10 mL). The filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0-10%) and monitored by TLC (ethyl acetate / petroleum ether (V / V) = 1 / 6). The Rf = 0.6-0.7 fraction was collected to obtain 16-13-2 (1.519 g, yield 90.7%) as a white solid.

[0478] In an ice-water bath at 0°C, TBAF (0.3 mL, 1 mol / L in THF, 0.3 mL) was added to a solution of compound 16-13-2 (150 mg, 0.29 mmol) in dry THF (3 mL) via syringe and stirred at 0°C for 5 minutes. After the reaction was complete as monitored by TLC, saturated brine was added to the reaction system and extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by Prep-TLC (ethyl acetate / petroleum ether (V / V) = 1 / 4) to obtain 16-10 (83.1 mg, 79.3% yield) as a white solid. ESI [M+Na] + =384.3.

[0479] 1 H NMR (400MHz, CD3OD) δ7.64 (s, 2H), 4.42–4.31 (m, 1H), 4.24 (t, J = 8.4Hz, 2H) ,4.18–4.05(m,2H),3.42–3.27(m,2H),1.48(s,9H),1.28(d,J=6.9Hz,12H).

[0480] TFA (1.102 g, 9.65 mmol) was added to a solution of 16-13-2 (1.0 g, 1.93 mmol) in dichloromethane (10 mL) in an ice-water bath at 0°C, and the mixture was stirred at 0°C for 3 hours. After completion of the reaction as monitored by TLC, the mixture was concentrated under reduced pressure, basified with saturated sodium bicarbonate (10 mL), and extracted with dichloromethane (3×10 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (V / V) = 0-10%) and monitored by TLC (methanol / dichloromethane (V / V) = 1 / 10). Fractions with Rf = 0.6-0.7 were collected to obtain 16-13-3 (783 mg, 97.1% yield) as a white solid.

[0481] In an ice-water bath at 0°C, TBAF (0.3 mL, 1 mol / L in THF, 0.3 mmol) was added to a solution of compound 16-13-3 (130 mg, 0.311 mmol) in dry THF (3 mL) via syringe and stirred at 0°C for 5 minutes. After completion of the reaction as monitored by TLC, saturated brine was added to the reaction system and extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (V / V) = 1 / 10). Fractions with Rf = 0.4-0.5 were collected to obtain 16-12 (66.6 mg, 81.9% yield) as a white solid. ESI [M+H] + =262.2

[0482] 1 H NMR (400MHz, CD3OD) δ7.64 (s, 2H), 4.72–4.61 (m, 1H), 4.45–4.26 (m, 4H), 3.40–3.28 (m, 2H), 1.29 (d, J = 6.9Hz, 12H).

[0483] In an ice-water bath at 0°C, 16-13-3 (310 mg, 0.742 mmol) was dissolved in dry tetrahydrofuran (8 mL). Methylmagnesium bromide (0.9 mL, 1.0 mol / L in THF, 0.9 mmol) was slowly added to the reaction system via syringe and stirred at 0°C for 1 hour. After the reaction was complete, the reaction system was slowly poured into ice water and extracted with ethyl acetate (3 × 5 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product 16-13-4, which was used directly in the next reaction without purification.

[0484] In an ice-water bath at 0°C, TBAF (0.8 mL, 1 mol / L in THF, 0.8 mL) was added to a solution of the crude product 16-13-4 in dry THF (5 mL) via syringe and stirred at 0°C for 5 minutes. After the reaction was complete as monitored by TLC, saturated brine was added to the reaction system and extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (V / V) = 1 / 10). Fractions with Rf = 0.3-0.4 were collected to obtain 16-13 (9.2 mg, 4.5% yield over two steps) as a yellow solid. ESI [M-OH] + =260.2

[0485] 1H NMR (400MHz, CD3OD) δ6.90 (s, 2H), 4.84–4.73 (m, 4H), 3.41–3.36 (m, 1H), 3.31–3.26 (m, 1H), 1.97 (s, 3H), 1.24 (d, J = 6.9Hz, 12H).

[0486] In an ice-water bath at 0°C, 16-13-2 (365 mg, 0.705 mmol) was dissolved in dry tetrahydrofuran (8 mL). Methylmagnesium bromide (0.8 mL, 1.0 mol / L in THF, 0.8 mmol) was slowly added to the reaction system via syringe and stirred at 0°C for 2 hours. After the reaction was complete, the reaction system was slowly poured into ice water and extracted with ethyl acetate (3 × 5 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product 16-14-1, which was used directly in the next reaction without purification.

[0487] TFA (803.69 mg, 7.05 mmol) was added to a solution of the crude compound 16-14-1 from the previous step and triethylsilane (409.8 mg, 3.52 mmol) in dichloromethane (5 mL) in an ice-water bath at 0°C and stirred at 0°C for 2 hours. After completion of the reaction as monitored by TLC, the mixture was basified with saturated sodium bicarbonate (10 mL) and extracted with dichloromethane (3 × 5 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the crude product 16-14-2, which was used directly in the next step without purification.

[0488] In an ice-water bath at 0°C, TBAF (0.7 mL, 1 mol / L in THF, 0.7 mmol) was added to a solution of crude product 16-14-2 in dry THF (5 mL) via syringe and stirred at 0°C for 5 minutes. After completion of the reaction as monitored by TLC, saturated brine was added to the reaction system and extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (V / V) = 1 / 10). Fractions with Rf = 0.3-0.4 were collected to obtain 16-14 (10.2 mg, 5.5% yield for three steps) as a light yellow solid. ESI [M+H] + =262.3

[0489] 1H NMR(400MHz,CD3OD)δ6.87(s,2H),4.22–4.14(m,1H),3.97–3.79(m,2H),3.72–3.64(m,1H),3.32– 3.26(m,2H),3.17–3.04(m,1H),2.99–2.87(m,1H),1.24(d,J=6.9Hz,12H),1.22(d,J=7.1Hz,3H).

[0490] Example 13. Preparation of Compounds 16-17 and 16-18 of the Invention

[0491] 1. Preparation of Compounds 16-17 of the Invention

[0492] Compound 16-13-3 (150 mg, 0.359 mmol) and paraformaldehyde (150 mg, 0.359 mmol) were dissolved in methanol (3 mL) at room temperature and stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (228.3 mg, 1.077 mmol) was then added to the reaction system and stirred at room temperature overnight. After completion of the reaction as monitored by TLC, H₂O (20 mL) was added to the reaction system and extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to afford the crude product 16-17-1, which was used directly in the next step without purification.

[0493] In an ice-water bath at 0°C, TBAF (0.4 mL, 1 mol / L in THF, 0.4 mmol) was added to a solution of crude compound 16-17-1 in dry THF (5 mL) via syringe and stirred at 0°C for 5 minutes. After the reaction was complete as monitored by TLC, saturated brine was added to the reaction system and extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by Prep-TLC (ethyl acetate / petroleum ether (V / V) = 1 / 2) to obtain 16-17 (90.0 mg, 91.0% yield) as a white solid. ESI [M+Na] + =276.2.

[0494] 1 H NMR (400MHz, CD3OD) δ7.62(s,2H),4.23(p,J=7.8Hz,1H),3.75(t,J=8.4Hz,2H),3.50(t, J=7.8Hz,2H),3.40–3.35(m,1H),3.33–3.26(m,1H),2.40(s,3H),1.27(d,J=6.9Hz,12H).

[0495] 2. Preparation of Compounds 16-18 of the Invention

[0496] Compound 16-13-3 (200 mg, 0.48 mmol), potassium carbonate (99.5 mg, 0.72 mmol), and 2-bromopropane (70.7 mg, 0.575 mmol) were dissolved in acetonitrile (3 mL) at room temperature and stirred overnight. After completion of the reaction as monitored by TLC, the mixture was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0-50%), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1), and fractions with Rf = 0.4-0.5 were collected to obtain 16-18-1 (139 mg, 63.0% yield) as a white solid.

[0497] In an ice-water bath at 0°C, TBAF (0.4 mL, 1 mol / L in THF, 0.4 mmol) was added to a solution of 16-18-1 (139 mg, 0.30 mmol) in dry THF (5 mL) using a syringe and stirred at 0°C for 5 minutes. After the reaction was complete as monitored by TLC, saturated brine was added to the reaction system and extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by Prep-TLC (ethyl acetate / petroleum ether (V / V) = 1 / 1) to obtain 16-18 (44.0 mg, 48.3% yield) as a white solid. ESI [M+H] + =304.3.

[0498] Example 14. Preparation of compounds 16-20 to 16-34 of the present invention

[0499] 1. Preparation of compounds 16-20 to 16-25, 16-27 and 16-28 of the present invention

[0500] Methyl chloroformate (102 mg, 1.08 mmol, 1.5 eq) was slowly added to a solution of compound 16-13-3 (300 mg, 0.72 mmol, 1.0 eq) and triethylamine (219 mg, 2.16 mmol, 3.0 eq) in dry dichloromethane (5 mL) in an ice-water bath at 0°C using a syringe. The mixture was stirred at 0°C for 1 hour. After the reaction was complete, the mixture was extracted with dichloromethane (3 × 5 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0-20%) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2). The fractions with Rf = 0.6-0.7 were collected to obtain 16-20-1 (242.4 mg, 70.9% yield) as a white solid.

[0501] In an ice-water bath at 0°C, TBAF (0.3 mL, 1 mol / L in THF, 0.3 mmol) was added to a solution of 16-20-1 (110.6 mg, 0.23 mmol) in dry THF (3 mL) via syringe and stirred at 0°C for 5 minutes. After the reaction was complete as monitored by TLC, saturated brine was added to the reaction system and extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0-29%), monitored by TLC (ethyl acetate / petroleum ether (V / V) = 1 / 2). Fractions with Rf = 0.6-0.7 were collected to obtain 16-20 (41.1 mg, 55.9% yield) as a white solid. ESI [M+H] + =320.3

[0502] 1 H NMR(400MHz,CD3OD)δ7.64(s,2H),4.46–4.35(m,1H),4.34–4.25(m,2H),4.23–4.12 (m,2H),3.70(s,3H),3.40–3.36(m,1H),3.33–3.28(m,1H),1.28(d,J=6.9Hz,12H).

[0503] The preparation of compounds 16-21 to 16-25 of the present invention is similar to that of 16-20. 16-13-3 reacts with the corresponding R1Cl to give 16-21-1 to 16-25-1, which is then deprotected with TBAF and purified.

[0504] During the preparation of 16-21 and 22, since the TIPS protecting groups of some intermediates 16-21-1 and 16-22-1 were removed in the reaction system, the generated phenolic hydroxyl compounds continued to react with the corresponding acyl chlorides to obtain 16-27 and 16-28.

[0505] 16-21: white solid, 50.6 mg, ESI [M+H] + =334.4.

[0506] 1 H NMR (400MHz, CD3OD) δ7.64 (s, 2H), 4.46–4.35 (m, 1H), 4.29 (t, J = 8.5Hz, 2H), 4.24 –4.03(m,4H),3.41–3.36(m,1H),3.34–3.25(m,1H),1.30–1.25(m,J=6.4Hz,15H).

[0507] 16-22: white solid, 53.1 mg, ESI [M+H] + =348.4.

[0508] 1 H NMR (400MHz, CD3OD) δ7.64 (s, 2H), 4.90–4.83 (m, 1H), 4.45–4.34 (m, 1H), 4.28 (t, J = 8. 5Hz,2H),4.21–4.07(m,2H),3.40–3.36(m,1H),3.33–3.28(m,1H),1.30–1.25(m,18H).

[0509] 16-23: white solid, 70.1 mg, ESI [M+H] + =346.5.

[0510] 1 H NMR (400MHz, CD3OD) δ7.66(s,2H),4.79–4.65(m,2H),4.52–4.23(m,2H),4.17–3.97(m,1H),3.41–3.26(m,2H),1.29(d,J=6.9Hz,12H),1.24(s,9H).

[0511] 16-24: white solid, 118.6 mg, ESI [M+H] + =304.2.

[0512] 1H NMR(400MHz,CD3OD)δ7.66(s,2H),4.55–4.48(m,1H),4.48–4.37(m,2H),4.31(t,J=8 .9Hz,1H),4.20–4.08(m,1H),3.41–3.28(m,2H),1.91(s,3H),1.28(d,J=6.9Hz,12H).

[0513] 16-25: white solid, 77.0 mg, ESI [M+H] + =332.3.

[0514] 1 H NMR(400MHz,CD3OD)δ7.66(s,2H),4.57–4.39(m,3H),4.31(t,J=9.0Hz,1H),4.16–4.07(m,1H),3.41–3.36(m,1H ),3.33–3.28(m,1H),2.67–2.54(m,1H),1.29(d,J=6.8Hz,12H),1.12(d,J=11.6Hz,3H),1.11(d,J=11.6Hz,3H).

[0515] 16-27: colorless oil, 12.4 mg, ESI [M+H] + =406.3.

[0516] 1 H NMR(400MHz,CD3OD)δ7.77(s,2H),4.53–4.42(m,1H),4.40–4.28(m,4H),4.25–4.16(m,2 H),4.13(q,J=7.1Hz,2H),3.13–3.02(m,2H),1.40(t,J=7.1Hz,3H),1.30–1.24(m,15H).

[0517] 16-28: white solid, 10.1 mg, ESI [M+H] + =434.3.

[0518] 1H NMR (400MHz, CD3OD) δ7.77(s,2H),5.03–4.94(m,1H),4.89–4.82(m,1H),4.51–4.41(m,1H),4.36–4.26(m,2H ),4.23–4.12(m,2H),3.16–3.00(m,2H),1.40(d,J=6.2Hz,6H),1.28(d,J=6.8Hz,12H),1.27(d,J=5.6Hz,6H).

[0519] 2. Preparation of 16-30 to 16-34 of the present invention

[0520] Sodium borohydride (20.96 mg, 0.554 mmol, 2.0 eq) was added portionwise to a solution of 16-20-1 (131.8 mg, 0.277 mmol, 1.0 eq) in methanol (3 mL) in an ice-water bath at 0°C. The mixture was stirred at 0°C for 1 hour. After completion of the reaction as monitored by TLC, H2O (20 mL) was added to the reaction system, and the mixture was extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product 16-30-1, which was used directly in the next reaction without purification.

[0521] In an ice-water bath at 0°C, TBAF (0.3 mL, 1 mol / L in THF, 0.3 mmol) was added to a solution of the crude product 16-30-1 in dry THF (3 mL) via syringe and stirred at 0°C for 5 minutes. After the reaction was complete as monitored by TLC, saturated brine was added to the reaction system and extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0-33%), monitored by TLC (ethyl acetate / petroleum ether (V / V) = 1 / 2). Fractions with Rf = 0.6-0.7 were collected to obtain 16-30 (71.4 mg, 80.2% yield over two steps) as a white solid. ESI [M-OH] + =304.3

[0522] 1 H NMR (400MHz, CD3OD) δ7.03 (s, 2H), 4.66 (d, J = 8.0Hz, 1H), 4.09–3.96 (m, 2H), 3.92–3.78 (m, 1H), 3.73–3. 68(m,1H),3.67(s,3H),3.41–3.37(m,1H),3.32–3.24(m,1H),2.99–2.81(m,1H),1.25(d,J=6.9Hz,12H).

[0523] The preparation of 16-31 to 16-34 of the present invention is similar to that of 16-30. 16-31-1 to 16-34-1 are obtained by reduction with sodium borohydride, deprotection with TBAF, and purification.

[0524] 16-31: white solid, 69.2 mg, ESI[M-OH] + =318.3.

[0525] 1 H NMR (400MHz, CD3OD) δ7.03 (s, 2H), 4.66 (d, J = 8.0Hz, 1H), 4.10 (q, J = 7.1Hz, 2H), 4.06–3.96 (m, 2H), 3.92–3. 79(m,1H),3.74–3.65(m,1H),3.41–3.36(m,1H),3.32–3.27(m,1H),2.98–2.82(m,1H),1.28–1.21(m,15H).

[0526] 16-32: white solid, 119.9 mg, ESI[M-OH] + =332.4.

[0527] 1 H NMR (400MHz, CD3OD) δ7.03 (s, 2H), 4.84 (dt, J = 12.5, 6.2Hz, 1H), 4.66 (d, J = 8.0Hz ,1H),4.09–3.95(m,2H),3.91–3.76(m,1H),3.75–3.60(m,1H),3.40–3.36(m,1H), 3.33–3.28(m,1H),2.97–2.86(m,1H),1.25(d,J=6.7Hz,18H).

[0528] 16-33: white solid, 117.2 mg, ESI [M+H] + =348.4.

[0529] 1 H NMR(400MHz,CD3OD)δ7.05(s,2H),4.71–4.64(m,1H),4.44–4.30(m,1H),4.19–4.08(m,1H),4.04–3.95(m,1H),3 .87–3.65(m,1H),3.41–3.36(m,1H),3.33–3.27(m,1H),2.99–2.87(m,1H),1.25(d,J=6.9Hz,12H),1.21(s,9H).

[0530] 16-34: white solid, 89.6 mg, ESI [M+H] + =306.3.

[0531] 1 H NMR(400MHz,CD3OD)δ7.05(d,J=3.2Hz,2H),4.69(d,J=8.2Hz,1H),4.31–3.66(m,4H), 3.40–3.27(m,2H),3.02–2.86(m,1H),1.87(d,J=15.8Hz,3H),1.25(d,J=6.8Hz,12H).

[0532] Example 15. Preparation of compounds 16-35 to 16-42 of the present invention

[0533] 1-bromo-3-methylbutan-2-one (94.8 mg, 0.575 mmol, 1.2 eq) was slowly added to a solution of 16-13-3 (200 mg, 0.479 mmol, 1.0 eq) and triethylamine (96.9 mg, 0.957 mmol, 2.0 eq) in dry dichloromethane (2 mL) in an ice-water bath at 0°C via syringe. The mixture was stirred at 0°C for 1 hour. After the reaction was complete, the mixture was extracted with dichloromethane (3 × 3 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0-33%) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.6-0.7 were collected to obtain 16-35-1 (172 mg, 71.6% yield) as a white solid.

[0534] In an ice-water bath at 0°C, TBAF (0.4 mL, 1 mol / L in THF, 0.4 mmol) was added to a solution of 16-35-1 (172 mg, 0.34 mmol) in dry THF (3 mL) via syringe and stirred at 0°C for 5 minutes. After the reaction was complete as monitored by TLC, saturated brine was added to the reaction system and extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0-50%) and monitored by TLC (ethyl acetate / petroleum ether (V / V) = 1 / 12). Fractions with Rf = 0.5-0.6 were collected to obtain 16-35 (99 mg, 84.3% yield) as a white solid. ESI [M+H] + =346.0

[0535] 1H NMR (400MHz, CD3OD) δ7.62(s,2H),4.30(p,J=8.0Hz,1H),3.83(t,J=8.4Hz,2H),3.47(t,J=8.0Hz,2H),3.4 0–3.35(m,1H),3.34–3.27(m,1H),2.64(hept,J=7.0Hz,1H),1.27(d,J=6.9Hz,12H),1.10(d,J=6.9Hz,6H).

[0536] The preparation of compounds 16-36 to 16-42 of the present invention is similar to that of 16-35. 16-13-3 reacts with the corresponding R3Br to obtain 16-36-1 to 16-42-1, which are then deprotected with TBAF and purified.

[0537] 16-36: yellow solid, 28 mg, ESI [M+H] + =332.0.

[0538] 1 H NMR (400MHz, CD3OD) δ7.62(s,2H),4.29(p,J=8.0Hz,1H),3.83(t,J=8.4Hz,2H),3.57–3.44(m,3H),3.4 0–3.35(m,2H),3.33–3.27(m,1H),2.44(q,J=7.3Hz,2H),1.27(d,J=6.9Hz,12H),1.05(t,J=7.3Hz,3H).

[0539] 16-37: yellow solid, 20.9 mg, ESI [M+H] + =347.0.

[0540] 1 H NMR (400MHz, CD3OD) δ7.63 (s, 2H), 4.29 (p, J = 8.0Hz, 1H), 3.87 (t, J = 8.3Hz, 2H), 3 .51(t,J=8.0Hz,2H),3.47(s,2H),3.40–3.35(m,1H),3.33–3.27(m,1H),3.01(s, 3H), 2.94 (s, 3H), 1.27 (d, J = 6.9Hz, 12H).

[0541] 16-38: yellow solid, 53 mg, ESI [M+H] + =344.0.

[0542] 1H NMR (400MHz, CD3OD) δ7.62(s,2H),4.29(p,J=8.0Hz,1H),3.82(t,J=8.3Hz,2H),3.67(d,J=12.8Hz,1H),3.52–3 .45(m,2H),3.40–3.35(m,2H),3.33–3.28(m,1H),2.07–1.99(m,1H),1.27(d,J=6.9Hz,12H),1.00–0.91(m,4H).

[0543] 16-39: yellow solid, 21 mg, ESI [M+H] + =318.0.

[0544] 1 H NMR (400MHz, CD3OD) δ7.62 (s, 2H), 4.29 (p, J = 8.1Hz, 1H), 3.82 (t, J = 8.4Hz, 2H ),3.57–3.43(m,3H),3.40–3.26(m,3H),2.11(s,3H),1.27(d,J=6.9Hz,12H).

[0545] 16-40: white solid, 96 mg, ESI [M+H] + =318.0.

[0546] 1 H NMR (400MHz, CD3OD) δ7.63(s,2H),4.31(p,J=8.1Hz,1H),3.84(t,J=8.5Hz,2H),3.48(t, J=8.0Hz,2H),3.40–3.35(m,1H),3.33–3.28(m,1H),1.27(d,J=6.9Hz,12H),1.17(s,9H).

[0547] 16-41: white solid, 140 mg, ESI [M+H] + =334.0.

[0548] 1 H NMR (400MHz, CD3OD) δ7.62(s,2H),4.28(p,J=7.9Hz,1H),3.84(t,J=8.4Hz,2H),3.73(s,2H),3. 54(t,J=8.0Hz,2H),3.39(s,2H),3.38–3.36(m,1H),3.33–3.29(m,1H),1.27(d,J=6.9Hz,12H).

[0549] 16-42: white solid, 68 mg, ESI [M+H] + =362.0.

[0550] 1 H NMR (400MHz, CD3OD) δ7.62(s,1H),5.04(dt,J=12.5,6.2Hz,0H),4.28(p,J=8.0Hz,1H),3.84(t,J=8.4Hz,1H),3. 54(t,J=8.0Hz,1H),3.38–3.35(m,J=7.0Hz,1H),3.34(s,2H),3.33–3.29(m,J=7.0Hz,1H),1.27(d,J=6.7Hz,9H).

[0551] Example 16. Preparation of compounds 16-43 to 16-47 of the present invention

[0552] 1. Preparation of Compounds 16-43 and 16-45 of the Invention

[0553] TFA (427.58 mg, 3.75 mmol) was added to a solution of 16-14-1 (200 mg, 0.375 mmol) in dichloromethane (5 mL) in an ice-water bath at 0°C and stirred at 0°C for 1 hour. After the reaction was complete as monitored by TLC, the mixture was basified with saturated sodium bicarbonate (5 mL) and extracted with dichloromethane (3×5 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product 16-45-1, which was used directly in the next step without purification.

[0554] In an ice-water bath at 0°C, TBAF (0.4 mL, 1 mol / L in THF, 0.4 mmol) was added to a solution of the crude product 16-45-1 in dry THF (5 mL) via syringe and stirred at 0°C for 5 minutes. After the reaction was complete as monitored by TLC, saturated brine was added to the reaction system and extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (V / V) = 1 / 10). Fractions with Rf = 0.3-0.4 were collected to obtain 16-45 (38.5 mg, 39.6% yield over two steps) as a white solid. ESI [M+H] + =260.3

[0555] The preparation of compound 16-43 of the present invention is similar to that of compound 16-45

[0556] 2. Preparation of 16-46 of the present invention

[0557] In an ice-water bath at 0°C, 16-13-1 was dehydroxylated with TFA to remove the Boc protection to give 16-46-1, which was then deprotected with TBAF to give 16-46. ESI [M+H] + =246.4

[0558] 1 H NMR (400MHz, CD3OD) δ6.81 (s, 2H), 6.35 (s, 1H), 4.98 (s, 2H), 4.79 (s, 2H), 3.32–3.26 (m, 2H), 1.24 (d, J = 6.9Hz, 12H).

[0559] 3. Preparation of 16-44 of the present invention

[0560] In an ice-water bath at 0°C, isopropyl carbonochloridate (54.97 mg, 0.449 mmol, 1.2 eq) was slowly added to a solution of 16-46-1 (150 mg, 0.374 mmol, 1.0 eq) and triethylamine (75.6 mg, 0.748 mmol, 2.0 eq) in dry dichloromethane (2 mL) via syringe. The mixture was stirred at 0°C for 1 hour. After the reaction was complete, the mixture was extracted with dichloromethane (3 × 3 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0-40%) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.6-0.7 were collected to obtain 16-44-1 (135 mg, 74.0% yield) as a white solid.

[0561] In an ice-water bath at 0°C, TBAF (0.3 mL, 1 mol / L in THF, 0.3 mmol) was added to a solution of 16-44-1 (135 mg, 0.277 mmol) in dry THF (3 mL) via syringe and stirred at 0°C for 5 minutes. After the reaction was complete as monitored by TLC, saturated brine was added to the reaction system and extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by Prep-TLC (ethyl acetate / petroleum ether (V / V) = 1 / 6). Fractions with Rf = 0.5-0.6 were collected to obtain 16-44 (53.6 mg, 58.4% yield) as a yellow solid. ESI [M+H] + =332.5

[0562] 1H NMR(400MHz,CD3OD)δ6.82(s,2H),6.28(s,1H),4.96–4.90(m,1H),4.87(s,2H) ,4.68(s,2H),3.33–3.25(m,2H),1.30(d,J=6.2Hz,6H),1.24(d,J=6.8Hz,12H).

[0563] Example 17. Preparation of compounds 16-48 to 16-51 and 16-55 of the present invention

[0564] 1. Preparation of intermediate compound B

[0565] B-1 (20 g, 112.2 mmol) and HMTA (31.46 g, 224.4 mmol) were refluxed in H2O / acetic acid (19 mL / 93 mL) at room temperature and stirred for 20 hours. After the reaction was complete as monitored by TLC, H2O (150 mL) was added to the reaction system and extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0-15%) and monitored by TLC (ethyl acetate / petroleum ether (V / V) = 1 / 6). Fractions with Rf = 0.4-0.5 were collected to obtain white compound B (24.8 g). ESI [M+H] + =207.1.

[0566] 2. Preparation of intermediates 16-48-2 to 16-49-2, 16-51-3 and 16-55-2

[0567] Preparation of intermediate 16-48-2

[0568] At room temperature, 16-48-1 (300 mg, 1.39 mmol) was dissolved in dry dichloromethane (5 mL). Trifluoroacetic acid (1 mL) was slowly added to the reaction system via syringe and stirred at room temperature for 4 hours. The mixture was concentrated under reduced pressure to afford the crude product 16-48-2, which was used directly in the preparation of 16-48 and 16-48D without further purification.

[0569] Preparation of intermediate 16-51-3

[0570] NaH (463.5 mg, 60%, 11.59 mmol) was added portionwise to a solution of 16-51-1 (2.0 g, 9.65 mmol) in dry DMF (10 mL) at 0°C. After stirring for 30 minutes, methyl bromoacetate (1.77 g, 11.57 mmol) was added. The reaction system was warmed to room temperature and stirred for 3 hours. After the reaction was completed as monitored by TLC, H2O (20 mL) was added to the reaction system, and the mixture was extracted with EtOAc (3×10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 10 / 1 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3). The Rf = 0.5 to 0.6 fraction was collected to give 16-51-2 (2.0 g, yield 74.2%) as a colorless oil.

[0571] 16-51-2 (2.0 g, 7.16 mmol) and palladium carbon (200 mg, 10%) were dissolved in methanol (10 mL), the reaction system was replaced with hydrogen, stirred at room temperature for 30 minutes, filtered, the filter cake was washed with methanol, and concentrated to give the crude product 16-51-3. The crude product was directly used in the preparation of 16-51 without purification.

[0572] Preparation of intermediate 16-55-2

[0573] Dissolve 16-55-1 (600 mg, 6.73 mmol) in methanol (10 mL) in an ice-water bath at 0°C. Slowly add thionyl chloride (600 mg, 6.73 mmol) to the reaction system via syringe and stir at room temperature for 1 hour. Concentrate under reduced pressure to obtain the crude product 16-55-2, which was used directly in the preparation of 16-55 without purification.

[0574] 3. Preparation of 16-48 to 16-51 and 16-55, 16-48D and 16-49D of the present invention

[0575] Compound B (1.0 eq) and the corresponding amine compound prepared in the previous step or the purchased amine compound (1.0 eq to 3.0 eq) were dissolved in dichloromethane and stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (3.0 eq) was then added to the reaction system and stirred at room temperature overnight. After the reaction was complete as monitored by TLC, H2O was added to the reaction system, and the mixture was extracted with EtOAc. The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography or Prep-TLC to obtain compounds 16-48 to 16-51 and 16-55 of the present invention.

[0576] Preparation of 16-48D and 16-49D.

[0577] 16-48 to 16-49 were dissolved in ether, cooled to 0°C with an ice-water bath, and HCl / Et2O (2 eq) solution was slowly added to the reaction system with a syringe. The mixture was stirred for 10 minutes, filtered, washed with ether, and dried to obtain 16-48D and 16-49D of the present invention.

[0578] 16-48: white solid, 61.3 mg, ESI [M+H] + =332.0.

[0579] 1 H NMR(400MHz, CDCl3)δ7.10(s,1H),7.04(s,1H),4.99(s,1H),3.75(s,3H) ,3.98–3.31(m,7H),3.21–3.11(m,1H),2.54–2.44(m,1H),1.32(d,J=7.0H z,3H),1.29(d,J=6.9Hz,3H),1.28(d,J=6.9Hz,3H),1.15–1.03(m,1H),0. 66–0.55(m,1H),0.54–0.44(m,1H),0.29–0.20(m,1H),0.21–0.12(m,1H).

[0580] 16-48D: white solid, 372.6 mg, ESI [M+H] + =332.0.

[0581] 1 H NMR(400MHz,d6-DMSO)δ10.53(brs,0.5H),10.31(brs,0.5H),8.30(s,1H),7.22( d,J=0.8Hz,1H),7.10(d,J=1.5Hz,1H),4.30–4.09(m,6H),3.78–3.62(m,4H),3.3 2–3.24(m,2H),1.20(d,J=6.9Hz,3H),1.16(dd,J=6.8,1.9Hz,6H),1.06–0.98(m, 1H),0.55–0.48(m,1H),0.36–0.28(m,1H),0.20–0.13(m,1H),0.10–0.03(m,1H).

[0582] 16-49: colorless oil, 31.2 mg, ESI [M+H] + =346.1.

[0583] 1H NMR (400MHz, CDCl3) δ7.08(s,1H),7.02(s,1H),4.97(s,1H),3.94–3.45( m,8H),3.21–3.11(m,1H),3.06–2.84(m,2H),2.73–2.56(m,2H),2.54–2.4 4(m,1H),1.32(d,J=7.0Hz,3H),1.30–1.26(m,6H),1.15–1.03(m,1H),0. 65–0.55(m,1H),0.53–0.42(m,1H),0.28–0.21(m,1H),0.21–0.12(m,1H).

[0584] 16-49D: white solid, 111.5 mg, ESI [M+H] + =346.1.

[0585] 1 H NMR(400MHz,d6-DMSO)δ10.51(brs,0.5H),10.39(brs,0.5H),8.28(d,J=3.4Hz,1H),7.26–7.19(m,1H),7.15–7.06(m,1H),4.2 1(dd,J=18.9,5.8Hz,2H),4.16–4.07(m,1H),4.03–3.94(m,1H),3.91–3.82(m,1H),3.77–3.69(m,1H),3.60(s,3H),3.44–3.37( m,1H),3.32–3.24(m,1H),3.04–2.94(m,1H),2.84(d,J=7.9Hz,1H),2.72(d,J=7.7Hz,1H),1.20(d,J=6.9Hz,3H),1.16(d,J=6. 8Hz,7H),1.15(d,J=6.8Hz,7H),1.06–0.98(m,1H),0.55–0.47(m,1H),0.35–0.27(m,1H),0.20–0.12(m,1H),0.10–0.03(m,1H).

[0586] 16-50: colorless oil, 7 mg, ESI[M+H] + =290.2.

[0587] 1H NMR(400MHz,DMSO)δ8.07(s,1H),7.10(s,1H),6.99(s,1H),5.95–5.65(m,1H), 4.42–4.25(m,1H),3.96–3.76(m,3H),3.30–3.21(m,1H),3.19–3.13(m,1H),2. 48–2.43(m,1H),1.18(d,J=6.9Hz,3H),1.14(d,J=6.8Hz,6H),1.06–0.94(m,1H ),0.55–0.44(m,1H),0.35–0.22(m,1H),0.19–0.09(m,1H),0.10–0.01(m,1H).

[0588] 16-51: colorless oil, 14 mg, ESI [M+H] + =362.1.

[0589] 1 H NMR(400MHz,d6-DMSO)δ7.78(s,1H),6.94(d,J=1.8Hz,1H),6.83(d,J=1.8Hz,1H),4 .16–4.09(m,1H),4.06(s,2H),3.63(s,3H),3.46–3.40(m,4H),3.28–3.21(m,1H),2 .87–2.79(m,2H),1.17(d,J=6.9Hz,3H),1.13(d,J=2.3Hz,3H),1.11(d,J=2.3Hz,3H ),1.02–0.94(m,1H),0.52–0.43(m,1H),0.34–0.26(m,1H),0.16–0.10(m,1H),0.08– 0.01(m,1H).

[0590] 16-55: white solid, 35.4 mg, ESI [M+H] + =320.0.

[0591] 1H NMR (400MHz, CDCl3) δ13.21(s,1H),7.38(d,J=15.8Hz,1H),7.28(d,J=14.3Hz,1 H),5.23(s,1H),4.51–4.30(m,2H),3.81(d,J=2.2Hz,3H),3.77–3.54(m,2H),3.2 1–3.08(m,1H),3.01(s,3H),2.53–2.39(m,1H),1.33–1.23(m,9H),1.12–1.02(m, 1H),0.65–0.55(m,1H),0.55–0.42(m,1H),0.29–0.19(m,1H),0.18–0.07(m,1H).

[0592] Example 18, compounds 16-52 to 16-54 of the present invention

[0593] 1. Preparation of intermediate compound C

[0594] NBS (1.75 g, 9.83 mmol) was added portionwise to a solution of compound C-1 (2.00 g, 9.79 mmol) in acetonitrile (20 mL) at 0°C and stirred at 0°C for 30 minutes. After completion of the reaction as monitored by TLC, H2O (30 mL) was added to the reaction system and extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / petroleum ether (v / v) = 1 / 200 to 1 / 50) and monitored by TLC (dichloromethane / petroleum ether (v / v) = 1 / 20). Fractions with Rf = 0.4 to 0.5 were collected to obtain compound C-2 (1.14 g, 41.1% yield) as a yellow oil. ESI [M+H] + =283.1.

[0595] At 0°C, NaH (161.5 mg, 60%, 4.04 mmol) was added portionwise to a solution of compound C-2 (1.04 g, 3.67 mmol) in dry tetrahydrofuran (12 mL). After stirring for 30 minutes, TIPSCl (778.34 mg, 4.04 mmol) was added. The reaction system was warmed to room temperature and stirred for 3 hours. After completion of the reaction as monitored by TLC, H2O (20 mL) was added to the reaction system, and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (n-heptane) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 50). Fractions with Rf = 0.5-0.6 were collected to obtain compound C (1.35 g, 83.7% yield) as a white solid. ESI [M+H] + =439.3.

[0596] 2. Preparation of 16-52 to 16-54 of the present invention

[0597] At room temperature, compound C (1.0 eq), the corresponding amine compound (2.0-3 eq), Pd2(dba)3 (0.5 eq), t-BuONa (1.5 eq) or t-BuOK (1.5 eq), and XPhos (0.5 eq) were dissolved in toluene. The reaction system was purged with nitrogen three times, protected by nitrogen, and stirred at 90°C overnight. After completion of the reaction as monitored by TLC, the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography or Prep-TLC to obtain the intermediate compound. The intermediate compound was deprotected with TBAF and purified by silica gel column chromatography or Prep-TLC to obtain the target compounds 16-52 to 16-54.

[0598] 16-52: pale yellow oil, 94.3 mg, ESI [M+H] + =318.1.

[0599] 1H NMR(400MHz,d6-DMSO)δ7.22(s,1H),6.21(d,J=2.5Hz,1H),6.10(d,J=2.5Hz,1H),3.97– 3.93(m,2H),3.78–3.73(m,2H),3.66(s,3H),3.61–3.54(m,2H),3.26–3.20(m,1H),2.45 –2.40(m,1H),1.16(d,J=6.9Hz,3H),1.12(d,J=2.4Hz,3H),1.11(d,J=2.4Hz,3H),1.02– 0.96(m,1H),0.51–0.43(m,1H),0.33–0.25(m,1H),0.17–0.10(m,1H),0.09–0.02(m,1H).

[0600] 16-53: yellow oil, 94.1 mg, ESI [M+H] + =332.0.

[0601] 1 H NMR(400MHz,d6-DMSO)δ7.14(s,1H),6.16(d,J=2.7Hz,1H),6.04(d,J=2.7Hz,1H),3.88–3.82( m,2H),3.60(s,3H),3.39–3.28(m,2H),3.28–3.18(m,1H),2.94–2.83(m,1H),2.69(d,J=7.8Hz ,2H),2.45–2.36(m,1H),1.15(d,J=6.9Hz,3H),1.11(d,J=2.2Hz,3H),1.10(d,J=2.2Hz,3H),1 .01–0.93(m,1H),0.50–0.43(m,1H),0.32–0.24(m,1H),0.16–0.09(m,1H),0.09–0.01(m,1H).

[0602] 16-54: yellow oil, 36.2 mg, ESI [M+H] + =374.3.

[0603] 1H NMR(400MHz,d6-DMSO)δ7.12(s,1H),6.15(d,J=2.7Hz,1H),6.04(d,J=2.8Hz,1H),3.87–3.81( m,2H),3.40–3.30(m,2H),3.28–3.18(m,1H),2.90–2.80(m,1H),2.56(d,J=7.6Hz,2H),2.46–2 .35(m,1H),1.39(s,9H),1.15(d,J=6.9Hz,3H),1.11(d,J=6.8Hz,3H),1.10(d,J=6.8Hz,3H),1 .01–0.93(m,1H),0.49–0.41(m,1H),0.32–0.23(m,1H),0.16–0.09(m,1H),0.08–0.01(m,1H).

[0604] Example 19. Preparation of compounds 16-56 to 16-65 of the present invention

[0605] 1. Preparation of 16-56 to 16-60 of the present invention

[0606] At room temperature, compound A (5.0 g, 12.09 mmol) was dissolved in dry tetrahydrofuran (50 mL). The system was purged with argon three times, and the reaction system was protected by argon. The reaction system was cooled to -60°C using a dry ice-ethanol bath. n-Butyl lithium (7.25 mL, 2.5 mol / L in THF, 18.13 mmol) was slowly added to the reaction system via syringe, and stirred at -60°C for 1 hour. A solution of tert-butyl 2-formylpyrrolidine-1-carboxylate (2.89 g, 14.51 mmol) in tetrahydrofuran (5 mL) was slowly added to the reaction system via syringe, and the temperature was naturally increased and stirred for 3 hours. After the reaction is complete, the reaction system is slowly poured into a saturated ammonium chloride solution and extracted with ethyl acetate (3×10 mL). The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0-12%), monitored by TLC (ethyl acetate / petroleum ether (V / V) = 1 / 8), and the Rf = 0.4-0.5 fraction is collected to obtain a crude product 16-56-1 (4.84 g).

[0607] At room temperature, PCC (6.972 g, 32.35 mmol) was added in batches to a solution of crude product 16-56-1 (4.84 g) and silica gel (8 g) in dichloromethane (50 mL), and stirred at room temperature for 5 hours. After the reaction was completed by TLC, the mixture was filtered, and the filter cake was washed with dichloromethane (50 mL). The filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0-4%) to obtain a white solid 16-56-2 (3.949 g, two-step yield 61.4%).

[0608] In an ice-water bath at 0°C, TBAF (0.2 mL, 1 mol / L in THF, 0.2 mmol) was added to a solution of compound 56-2 (100 mg, 0.188 mmol) in dry THF (3 mL) via syringe and stirred at 0°C for 5 minutes. After the reaction was complete as monitored by TLC, saturated brine was added to the reaction system and extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0-20%) to afford 16-56 (24.2 mg, 34.3% yield) as a white solid. ESI [M+Na] + =398.0.

[0609] 1 H NMR(400MHz,CD3OD)δ7.78(s,1H),7.75(s,1H),5.39–5.28(m,1H),3.67–3.48(m, 3H),3.41–3.37(m,1H),2.51–2.34(m,1H),2.01–1.82(m,3H),1.30–1.27(m,21H).

[0610] TFA (8.147 g, 71.45 mmol) was added to a solution of 16-56-2 (3.8 g, 7.145 mmol) in dichloromethane (20 mL) in an ice-water bath at 0°C and stirred at 0°C for 1 hour. After completion of the reaction as monitored by TLC, the mixture was concentrated under reduced pressure, basified with saturated sodium bicarbonate (10 mL), and extracted with dichloromethane (3 × 10 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (V / V) = 0-10%) and monitored by TLC (methanol / dichloromethane (V / V) = 1 / 10). Fractions with Rf = 0.6-0.7 were collected to obtain 16-57 (1.8 g, 91.5% yield) as a white solid. ESI [M+H] + =276.3

[0611] 1H NMR(400MHz,CD3OD)δ7.76(s,2H),4.90–4.86(m,1H),3.43–3.24(m,3H),3.17–3.04(m,1H),2.57 –2.41(m,1H),2.10–1.96(m,1H),1.92–1.76(m,2H),1.29(d,J=6.8Hz,6H),1.28(d,J=6.8Hz,6H).

[0612] At room temperature, 16-57 (600 mg, 2.179 mmol) and aqueous formaldehyde (2 mL) were dissolved in methanol (3 mL) and stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (1.85 g, 8.73 mmol) was then added to the reaction system and stirred at room temperature overnight. After the reaction was complete as monitored by TLC, H₂O (20 mL) was added to the reaction system and extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-10%) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10). Fractions with Rf = 0.6-0.7 were collected to obtain 16-58 (400 mg, 63.4% yield) as a white solid. ESI [M+H] + =290.3

[0613] 1 H NMR (400MHz, CD3OD) δ7.76(s,2H),4.40–4.23(m,1H),3.42–3.35(m,2H),3.32–3.23(m,1H),2.78–2.66( m,1H),2.56(s,3H),2.55–2.43(m,1H),2.11–1.80(m,3H),1.30(d,J=3.1Hz,6H),1.28(d,J=3.1Hz,6H).

[0614] Sodium borohydride (13 mg, 0.344 mmol) was added portionwise to a solution of 16-58 (50 mg, 0.173 mmol) in methanol (3 mL) in an ice-water bath at 0°C. The mixture was stirred at 0°C for 1 hour. After completion of the reaction as monitored by TLC, H₂O (20 mL) was added to the reaction system, and the mixture was extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (V / V) = 0-10%), monitored by TLC (methanol / dichloromethane (V / V) = 1 / 10). Fractions with Rf = 0.6-0.7 were collected to afford 16-59 (13.9 mg, 27.6% yield) as a white solid. ESI [M+H] + =292.4

[0615] 1 H NMR(400MHz,CD3OD)δ7.09(s,2H),4.98–4.93(m,1H),3.57–3.28(m,4H),3.03–2.55(m ,4H),2.16–2.05(m,1H),1.97–1.86(m,2H),1.78–1.67(m,1H),1.25(d,J=6.9Hz,12H).

[0616] The preparation of 16-60 was carried out using 16-57 as the starting material. After sodium borohydride reduction, the yellow solid 16-60 was purified and obtained, 9.4 mg. ESI [M+H] + =278.3

[0617] 1 H NMR(400MHz,CD3OD)δ7.11(s,2H),4.90–4.85(m,1H),3.75–3.64(m,1H),3.4 1–3.37(m,1H),3.32–3.15(m,3H),2.09–1.79(m,4H),1.26(d,J=6.9Hz,12H).

[0618] 2. Preparation of 16-61 to 16-65 of the present invention

[0619] At room temperature, TIPSCl (1.2 eq) was slowly added to a dry dichloromethane solution of 16-57 (1.0 eq) and triethylamine (4.0 eq) and stirred at room temperature for 1 hour. After the reaction was complete as monitored by TLC, the reaction system was cooled to 0°C with an ice-water bath, and R5Br (1.2 eq) was slowly added to the reaction system with a syringe. The mixture was stirred at 0°C for 5 hours. After the reaction was complete as monitored by TLC, the mixture was extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain intermediates 16-61-2 to 16-65-2.

[0620] TBAF (1.0 eq) was added to a dry THF solution of 16-61-2 to 16-65-2 (1.0 eq) using a syringe at 0°C in an ice-water bath, and stirred at 0°C for 5 minutes. After the reaction was complete as monitored by TLC, saturated brine was added to the reaction system, extracted with EtOAc, and the combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography or Prep-TLC to obtain 16-61 to 16-65 of the present invention.

[0621] 16-61: yellow solid, 10.3 mg, ESI [M+H] + =360.0.

[0622] 1 H NMR(400MHz,CD3OD)δ7.75(s,2H),4.49–4.38(m,1H),3.89–3.77(m,1H),3.58–3.44(m,1H),3.43–3.24(m,3H),2.81–2.59(m,2H) ,2.46–2.29(m,1H),2.03–1.74(m,3H),1.28(d,J=6.8Hz,6H),1.27(d,J=6.8Hz,6H),1.08(d,J=6.9Hz,3H),1.05(d,J=6.9Hz,3H).

[0623] 16-62: yellow solid, 26.1 mg, ESI [M+H] + =374.0.

[0624] 1H NMR (400MHz, CD3OD) δ7.74(s,2H),4.65–4.44(m,1H),3.54–3.36(m,3H),3.31–3.24(m,1H),2.76–2.61( m,2H),2.47–2.31(m,1H),2.05–1.75(m,3H),1.28(d,J=6.8Hz,6H),1.27(d,J=6.8Hz,6H),1.14(s,9H).

[0625] 16-63: yellow solid, 26.3 mg, ESI [M+H] + =358.8.

[0626] 1 H NMR (400MHz, CD3OD) δ7.77(s,2H),4.48–4.33(m,1H),3.94–3.79(m,1H),3.61–3.48(m,1H),3.41–3.35(m,2H),3.32–3.26(m,1H),2.76–2.61(m, 1H),2.46–2.29(m,1H),2.27–2.08(m,1H),2.00–1.88(m,2H),1.89–1.74 (m,1H),1.28(d,J=6.8Hz,6H),1.28(d,J=6.8Hz,6H),1.02–0.86(m,4H).

[0627] 16-64: yellow oil, 87.9 mg, ESI [M+H] + =348.0.

[0628] 1 H NMR (400MHz, CD3OD) δ7.76(s,2H),4.51(dd,J=9.3,6.8Hz,1H),3.69(s,3H),3.61(d,J=16.8Hz,1H),3.41(d,J=16.9Hz,1H),3.39–3 .36(m,1H),3.32–3.28(m,1H),2.84–2.76(m,1H),2.45–2.34(m,1H),2.01–1.88(m,2H),1.87–1.76(m,1H),1.28(d,J=6.8Hz,12H).

[0629] 16-65: yellow oil, 69.0 mg, ESI [M+H] + =376.0.

[0630] 1H NMR (400MHz, CD3OD) δ7.76(s,2H),5.06–4.98(m,1H),4.56–4.50(m,1H),3.59–3.38(m,2H),3.37–3.27(m,3H),2.87–2.78(m,1H) ),2.45–2.33(m,1H),2.01–1.87(m,2H),1.87–1.76(m,1H),1.28(d,J=6.8Hz,12H),1.23(d,J=9.4Hz,3H),1.22(d,J=9.4Hz,3H).

[0631] Example 20. Preparation of compounds 16-66 to 16-78 of the present invention

[0632] 1. Preparation of 16-66 of the present invention

[0633] At room temperature, compound A (9.5 g, 22.97 mmol) was dissolved in dry tetrahydrofuran (100 mL). The reaction system was purged with argon three times, and the atmosphere was protected with argon. The reaction system was cooled to -60°C using a dry ice-ethanol bath. n-Butyl lithium (11.0 mL, 2.5 mol / L in THF, 27.5 mmol) was slowly added to the reaction system via syringe and stirred at -60°C for 1 hour. A solution of tert-butyl 3-formylpyrrolidine-1-carboxylate (5.5 g, 27.6 mmol) in tetrahydrofuran (10 mL) was slowly added to the reaction system via syringe and stirred at naturally elevated temperature for 5 hours. After the reaction was complete, the reaction system was slowly poured into a saturated ammonium chloride solution and extracted with ethyl acetate (3×10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / dichloromethane (V / V) = 0-15%) and monitored by TLC (ethyl acetate / petroleum ether (V / V) = 1 / 5). The Rf = 0.5-0.6 fraction was collected to obtain a light yellow solid 16-66-1 (10.807 g, yield 88.1%).

[0634] PCC (21.82 g, 101.22 mmol) was added in batches to a solution of compound 66-1 (10.807 g, 20.24 mmol) and silica gel (15 g) in dichloromethane (100 mL) in an ice-water bath at 0°C. The mixture was stirred at room temperature for 3.5 hours. After the reaction was complete as detected by TLC, the mixture was filtered off with suction, and the filter cake was washed with dichloromethane (100 mL). The filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0-9%) and monitored by TLC (ethyl acetate / petroleum ether (V / V) = 1 / 10). The fraction with Rf = 0.6-0.7 was collected to obtain 16-66-2 (10.14 g, yield 94.2%) as a white solid.

[0635] TFA (20.88 g, 183.13 mmol) was added to a solution of 16-66-2 (9.738 g, 18.31 mmol) in dichloromethane (100 mL) at room temperature and stirred at room temperature for 3 hours. After completion of the reaction as monitored by TLC, the mixture was concentrated under reduced pressure, basified with saturated sodium bicarbonate (100 mL), and extracted with dichloromethane (3×10 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-10%) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10). Fractions with Rf = 0.6-0.7 were collected to obtain 16-66-3 (6.9 g, 99.1% yield) as a white solid.

[0636] In an ice-water bath at 0°C, TBAF (0.9 mL, 1 mol / L in THF, 0.9 mmol) was added to a solution of 16-66-2 (469 mg, 0.882 mmol) in dry THF (5 mL) via syringe and stirred at 0°C for 5 minutes. After completion of the reaction as monitored by TLC, saturated brine was added to the reaction system and extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0-20%) to afford 16-66-2 (318 mg, 96.0% yield) as a white solid. ESI [M+Na] + =398.0

[0637] 1H NMR(400MHz,CD3OD)δ7.76(s,2H),4.24–4.11(m,1H),3.69–3.55(m,2H),3.53–3.42(m,2H),3.42–3.35 (m,1H),3.34–3.29(m,1H),2.32–2.21(m,1H),2.21–2.06(m,1H),1.50(s,9H),1.29(d,J=6.9Hz,12H).

[0638] 2. Preparation of 16-67 to 16-74 and 16-78 of the present invention

[0639] In an ice-water bath at 0°C, slowly add R6Br (1.2 eq) to a solution of 16-66-3 (1.0 eq) and triethylamine (2.0 eq) in dry dichloromethane using a syringe and stir at 0°C for 1 hour. After the reaction is complete, extract with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography or Prep-TLC to obtain intermediates 16-67-1 to 16-74-1.

[0640] In an ice-water bath at 0°C, TBAF (1.0 eq) was added to a dry THF solution of 16-67-1 to 16-74-1 (1.0 eq) using a syringe. The mixture was stirred at 0°C for 5 minutes. After the reaction was complete as monitored by TLC, saturated brine was added to the reaction system, and the mixture was extracted with EtOAc. The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography or Prep-TLC to obtain the target compound.

[0641] During the preparation of 16-72, 16-78 was isolated.

[0642] 16-67: white solid, 105.2 mg, ESI [M+H] + =348.0.

[0643] 1 H NMR (400MHz, CD3OD) δ7.74(s,2H),4.16–4.05(m,1H),3.75(s,3H),3.44(d,J=5.8Hz,2H),3.41–3.36(m,1H),3.34–3.28(m,1H ),3.19(t,J=9.0Hz,1H),3.04–2.96(m,1H),2.91–2.83(m,1H),2.69–2.59(m,1H),2.29–2.09(m,2H),1.28(d,J=6.9Hz,12H).

[0644] 16-68: white solid, 115.1 mg, ESI [M+H] + =376.0.

[0645] 1 H NMR (400MHz, CD3OD) δ7.74(s,2H),5.12–5.02(m,1H),4.16–4.05(m,1H),3.39(d,J=6.5Hz,2H),3.38–3.35(m,1H),3.33–3.29(m,1H), 3.19(t,J=9.0Hz,1H),3.03–2.96(m,1H),2.90–2.82(m,1H),2.64(dd,J=16.5,7.7Hz,1H),2.27–2.10(m,2H),1.28(d,J=6.8Hz,18H).

[0646] 16-69: white solid, 120.5 mg, ESI [M+H] + =360.0.

[0647] 1 H NMR (400MHz, CD3OD) δ7.74(s,2H),4.14–4.03(m,1H),3.69–3.50(m,1H),3.42–3.36(m,1H),3.41–3.36(m,1H),3.33–3.27(m,1H),3.20–3.12 (m,1H),3.02–2.93(m,1H),2.81–2.66(m,2H),2.56(dd,J=16.6,7.9Hz,1H),2.26–2.08(m,2H),1.28(d,J=6.9Hz,12H),1.12(d,J=6.9Hz,6H).

[0648] 16-70: light yellow solid, 123.4 mg, ESI [M+H] + =346.0.

[0649] 1H NMR(400MHz,CD3OD)δ7.74(s,2H),4.16–4.02(m,1H),3.60–3.46(m,1H), 3.41–3.35(m,2H),3.34–3.29(m,1H),3.18–3.10(m,1H),3.00–2.92(m,1H),2.82–2.73(m,1H),2.61– 2.53(m,1H),2.50(q,J=7.4Hz,2H),2.26–2.07(m,2H),1.28(d,J=6.9Hz,12H),1.08(t,J=7.3Hz,3H).

[0650] 16-71: light yellow solid, 105.0 mg, ESI [M+H] + =361.0.

[0651] 1 H NMR (400MHz, CD3OD) δ7.73(s,2H),4.16–4.04(m,1H),3.55–3.43(m,2H),3.43–3.36(m,1H),3.34–3.26(m,1H),3.16(t,J=9.0Hz, 1H),3.10(s,3H),3.00–2.90(m,4H),2.86–2.78(m,1H),2.63(dd,J=16.2,7.8Hz,1H),2.26–2.09(m,2H),1.28(d,J=6.9Hz,12H).

[0652] 16-72: white solid, 66.9 mg, ESI [M+H] + =358.0.

[0653] 1 H NMR (400MHz, CD3OD) δ7.73(s,2H),4.14–4.04(m,1H),3.75–3.59(m,1H),3.41–3.35(m,2H),3.33–3.29(m,1H),3.18–3.10(m,1 H),3.00–2.91(m,1H),2.84–2.76(m,1H),2.59(q,J=7.6Hz,1H),2.27–2.07(m,3H),1.28(d,J=6.9Hz,12H),1.03–0.92(m,4H).

[0654] 16-73: white solid, 120.0 mg, ESI [M+H] + =332.0.

[0655] 1H NMR (400MHz, CD3OD) δ7.74(s,2H),4.14–4.03(m,1H),3.58–3.35(m,3H),3.33–3.28(m,1H),3.19–3.10(m,1H),3.00–2.91(m,1 H),2.83–2.75(m,1H),2.58(dd,J=16.5,7.8Hz,1H),2.27–2.17(m,1H),2.15(s,3H),2.14–2.04(m,1H),1.28(d,J=6.9Hz,12H).

[0656] 16-74: white solid, 60.5 mg, ESI [M+H] + =374.0.

[0657] 1 H NMR (400MHz, CD3OD) δ7.74(s,2H),4.14–4.05(m,1H),3.75–3.65(m,1H),3.42–3.35(m,2H),3.33–3.27(m,1H),3.23–3.14 (m,1H),3.05–2.96(m,1H),2.80–2.71(m,1H),2.60–2.49(m,1H),2.26–2.08(m,2H),1.28(d,J=6.9Hz,12H),1.19(s,9H).

[0658] 16-78: yellow solid, 13 mg, ESI [M+H] + =440.0.

[0659] 1 H NMR (400MHz, CD3OD) δ7.60(s,2H),5.89(s,1H),5.56(s,1H),3.63(s,4H),3.40–3.36(m,1H),3.32–3.29(m,1H),2.82(t ,J=7.1Hz,2H),2.70(t,J=7.2Hz,2H),2.25–2.17(m,2H),1.26(d,J=6.9Hz,12H),0.96–0.90(m,4H),0.86–0.80(m,4H).

[0660] 3. Preparation of 16-75 to 16-77 of the present invention

[0661] In an ice-water bath at 0°C, R7Cl (1.5 eq) was slowly added to a solution of compound 66-3 (1.0 eq) and triethylamine (2.0 eq) in dry dichloromethane using a syringe and stirred at 0°C for 1 hour. After the reaction was complete, the mixture was extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography or Prep-TLC to obtain intermediates 16-75-1 to 16-77-1.

[0662] TBAF (1.0 eq) was added to a dry THF solution of 16-75-1 to 16-77-1 (1.0 eq) using a syringe at 0°C in an ice-water bath, and stirred at 0°C for 5 minutes. After the reaction was complete as monitored by TLC, saturated brine was added to the reaction system, extracted with EtOAc, and the combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography or Prep-TLC to obtain 16-75 to 16-77 of the present invention.

[0663] 16-75: white solid, 174.8 mg, ESI [M+H] + =362.0.

[0664] 1 H NMR (400MHz, CD3OD) δ7.76(s,2H),4.96–4.88(m,1H),4.26–4.13(m,1H),3.72–3.61(m,2H),3.50(t,J=7.0H z,2H),3.41–3.36(m,1H),3.33–3.28(m,1H),2.33–2.23(m,1H),2.21–2.07(m,1H),1.29(d,J=6.8Hz,18H).

[0665] 16-76: white solid, 160.6 mg, ESI [M+H] + =360.0.

[0666] 1 H NMR(400MHz,CD3OD)δ7.77(s,2H),4.31–4.06(m,1H),4.02–3.47(m,4H),3.42–3.36 (m,1H),3.34–3.29(m,1H),2.37–1.93(m,21H),1.30(s,9H),1.29(d,J=6.9Hz,12H).

[0667] 16-77: white solid, 279.8 mg, ESI [M+H] + =346.0.

[0668] 1 H NMR(400MHz,CD3OD)δ7.78(d,J=3.7Hz,2H),4.34–4.16(m,1H),3.98–3.78(m,1H),3.77–3.67(m,2H),3.59–3.48(m,1H) ,3.42–3.37(m,1H),3.33–3.27(m,1H),2.88–2.78(m,1H),2.41–2.03(m,2H),1.29(d,J=6.9Hz,12H),1.19–1.12(m,6H).

[0669] Example 21. Preparation of compounds 16-79 to 16-93 of the present invention

[0670] 1. Preparation of 16-79 and 16-80 of the present invention

[0671] CDI (5.31 g, 32.75 mmol) was added portionwise to a solution of 16-79-1 (5.78 g, 25.21 mmol) in dry dichloromethane (150 mL) at room temperature. The mixture was stirred at room temperature for 1 hour. N,O-Dimethylhydroxylamine hydrochloride (2.95 g, 30.24 mmol) was added to the reaction system and stirred at room temperature for 4 hours. After the reaction was completed as monitored by LC-MS, the system was extracted with dichloromethane (3×15 mL) in sequence, and the organic phases were combined and washed with hydrochloric acid (20 mL, 2 M), saturated sodium bicarbonate (50 mL), and saturated brine (50 mL) in sequence, and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0-30%), monitored by TLC (ethyl acetate / petroleum ether (V / V) = 1 / 3), and the Rf = 0.5-0.6 portion was collected to obtain a light colorless oily crude product 16-79-2 (6.16 g, yield 89.7%).

[0672] At room temperature, compound A (6.2 g, 15.0 mmol) was dissolved in dry tetrahydrofuran (100 mL). The system was replaced with argon three times, and the reaction system was protected by argon. The reaction system was cooled to -60°C using a dry ice ethanol bath. n-Butyl lithium (9.0 mL, 2.5 mol / L in THF, 22.5 mmol) was slowly added to the reaction system via syringe and stirred at -60°C for 1 hour. A solution of crude compound 79-2 (4.9 g, 18.0 mmol) in tetrahydrofuran (10 mL) was slowly added to the reaction system via syringe and stirred at naturally elevated temperature for 4 hours. After the reaction was complete, the reaction system was slowly poured into a saturated ammonium chloride solution and extracted with ethyl acetate (3×15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0-25%), monitored by TLC (ethyl acetate / petroleum ether (V / V) = 1 / 5), and the Rf = 0.4-0.5 fraction was collected to obtain 16-79-3 (2.523 g, yield 30.8%) as a white solid.

[0673] In an ice-water bath at 0°C, TBAF (0.4 mL, 1 mol / L in THF, 0.4 mmol) was added to a solution of 16-79-3 (200 mg, 0.366 mmol) in dry THF (5 mL) via syringe and stirred at 0°C for 5 minutes. After the reaction was complete as monitored by TLC, saturated brine was added to the reaction system and extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0-12%) to afford 16-79 (119 mg, 83.5% yield) as a white solid. ESI [M+Na] + =412.0

[0674] 1 H NMR(400MHz,CD3OD)δ7.69(s,2H),5.65–5.57(m,1H),3.99–3.86(m,1H),3.43–3.36(m,1H),3.34–3.28(m,1 H),2.23–1.83(m,2H),1.81–1.60(m,2H),1.57–1.34(m,12H),1.29(d,J=7.0Hz,6H),1.27(d,J=6.9Hz,6H).

[0675] TFA (4.66 g, 40.87 mmol) was added to a solution of 16-79-3 (2.232 g, 4.09 mmol) in dichloromethane (50 mL) at room temperature and stirred at room temperature for 5 hours. After completion of the reaction as monitored by TLC, the mixture was concentrated under reduced pressure, basified with saturated sodium bicarbonate (50 mL), extracted with dichloromethane (3×10 mL), and the combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-10%) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10). Fractions with Rf = 0.6-0.7 were collected to obtain the crude product 16-80-1 (1.964 g) as a white solid.

[0676] In an ice-water bath at 0°C, TBAF (0.5 mL, 1 mol / L in THF, 0.5 mmol) was added to a solution of 16-80-1 (200 mg, 0.449 mmol) in dry THF (5 mL) via syringe and stirred at 0°C for 5 minutes. After the reaction was complete as monitored by TLC, saturated brine was added to the reaction system and extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by Prep-TLC (methanol / dichloromethane (V / V) = 1 / 10) to afford 16-80 (29 mg, 22.3% yield) as a white solid. ESI [M+Na] + =312.0

[0677] 1 H NMR(400MHz,CD3OD)δ7.73(s,2H),4.81(dd,J=12.2,3.0Hz,1H),3.45–3.36(m,2H),3.13–2.98(m,1H),2.25–2.1 6(m,1H),2.01–1.77(m,3H),1.75–1.61(m,1H),1.60–1.45(m,1H),1.29(d,J=6.8Hz,6H),1.28(d,J=6.9Hz,6H).

[0678] 2. Preparation of compounds 16-82 to 16-84 of the present invention

[0679] In an ice-water bath at 0°C, slowly add compound R8Cl (1.5 eq) to a solution of 16-80-1 (1.0 eq) and triethylamine (2.0 eq) in dry dichloromethane using a syringe and stir at 0°C for 1 hour. After the reaction is complete, extract with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography or Prep-TLC to obtain intermediates 16-82-1 to 16-83-1.

[0680] TBAF (1.0 eq) was added to a dry THF solution of intermediates 16-82-1 to 16-83-1 (1.0 eq) using a syringe at 0°C in an ice-water bath, and the mixture was stirred at 0°C for 5 minutes. After the reaction was complete as monitored by TLC, saturated brine was added to the reaction system, and the mixture was extracted with EtOAc. The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography or Prep-TLC to obtain 16-82 to 16-83 of the present invention.

[0681] During the preparation of 16-83, 16-84 was isolated.

[0682] 16-82: white solid, 92 mg, ESI [M+H] + =360.0.

[0683] 1 H NMR(400MHz,CD3OD)δ7.69(s,2H),6.07–6.01(m,1H),4.02–3.93(m,1H),3 .51–3.39(m,1H),3.39–3.36(m,1H),3.32–3.26(m,1H),3.08–2.97(m,1H) ,2.24–2.14(m,1H),1.91–1.76(m,2H),1.73–1.51(m,3H),1.28(d,J=6.8H z, 6H), 1.27 (d, J = 6.8Hz, 6H), 1.16 (d, J = 6.7Hz, 3H), 1.10 (d, J = 6.8Hz, 3H).

[0684] 16-83: white solid, 80 mg, ESI [M+H] + =374.0.

[0685] 1H NMR(400MHz,CD3OD)δ7.66(s,2H),5.95(dd,J=5.5,2.9Hz,1H),4.22–4.08(m,1H),3.43–3.35(m,2H),3.33–3 .26(m,1H),2.23–2.08(m,1H),1.92–1.51(m,5H),1.29(s,9H),1.28(d,J=1.7Hz,6H),1.27(d,J=1.6Hz,36H).

[0686] 16-84: white solid, 25 mg, ESI [M+H] + =458.4.

[0687] 1 H NMR(400MHz,CD3OD)δ7.74(s,2H),5.96–5.90(m,1H),4.19–4.09(m,1H),3.03–2.89(m,2H),2.23–2 .11(m,1H),1.90–1.67(m,4H),1.65–1.52(m,1H),1.45(s,9H),1.26(s,9H),1.25(d,J=7.1Hz,12H).

[0688] 3. Preparation of compounds 16-85 to 16-90 of the present invention

[0689] In an ice-water bath at 0°C, slowly add compound R9Br (1.2 eq) to a solution of 16-80-1 (1.0 eq) and triethylamine (2.0 eq) in dry dichloromethane using a syringe and stir at 0°C for 1 hour. After the reaction is complete, extract with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography or Prep-TLC to obtain intermediates 16-85-1 to 16-90-1.

[0690] TBAF (1.0 eq) was added to a dry THF solution of 16-85-1 to 16-90-1 (1.0 eq) using a syringe at 0°C in an ice-water bath, and the mixture was stirred at 0°C for 5 minutes. After the reaction was complete as monitored by TLC, saturated brine was added to the reaction system, and the mixture was extracted with EtOAc. The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography or Prep-TLC to obtain 16-85 to 16-90 of the present invention.

[0691] 16-85: yellow solid, 59 mg, ESI [M+H] + =374.0.

[0692] 1 H NMR (400MHz, CD3OD) δ7.84(s,2H),4.42–4.29(m,1H),3.55–3.45(m,1H),3.42–3.35(m,2H),3.32–3.27(m,1H),3.13–3.04(m,1H),2.72–2 .55(m,2H),1.93–1.76(m,2H),1.75–1.61(m,3H),1.57–1.45(m,1H),1.28(d,J=6.9Hz,12H),0.98(d,J=6.9Hz,3H),0.93(d,J=6.9Hz,3H).

[0693] 16-86: gray solid, 4.0 mg, ESI [M+H] + =360.0.

[0694] 16-87: white solid, 56 mg, ESI [M+H] + =375.0.

[0695] 1 H NMR(400MHz,CD3OD)δ7.80(s,2H),4.43–4.32(m,1H),3.56–3.46(m,1H),3.41–3.27(m,2H),3.24–3.15(m,1H),3.14–3.11(m,1H) ,3.09(s,3H),2.90(s,3H),2.72–2.60(m,1H),1.96–1.84(m,1H),1.82–1.42(m,5H),1.29(d,J=6.8Hz,6H),1.28(d,J=6.8Hz,6H).

[0696] 16-88: white solid, 89 mg, ESI [M+H] + =372.0.

[0697] 1 H NMR(400MHz,CD3OD)δ7.86(s,2H),4.36–4.25(m,1H),3.66–3.50(m,1H),3.43–3.35(m,2H),3.34–3.28(m,1H),3.15–3.04(m,1H),2.6 5–2.50(m,1H),2.25–2.14(m,1H),1.95–1.85(m,1H),1.85–1.63(m,4H),1.57–1.44(m,1H),1.28(d,J=6.9Hz,12H),1.01–0.77(m,4H).

[0698] 16-89: yellow solid, 31 mg, ESI [M+H] + =346.0.

[0699] 1 H NMR(400MHz,CD3OD)δ7.85(s,2H),4.35–4.22(m,1H),3.53–3.37(m,2H),3.33–3.18(m,2H),3.15–3.04(m,1H),2 .62–2.48(m,1H),2.08(s,3H),1.96–1.84(m,1H),1.84–1.61(m,4H),1.57–1.46(m,1H),1.28(d,J=6.9Hz,12H).

[0700] 16-90: yellow solid, 88 mg, ESI [M+H] + =388.0.

[0701] 1 H NMR(400MHz,CD3OD)δ7.83(s,2H),4.56–4.43(m,1H),3.65–3.54(m,1H),3.39–3.27(m,3H),3.14–3.03 (m,1H),2.77–2.61(m,1H),1.93–1.60(m,5H),1.57–1.45(m,1H),1.28(d,J=6.9Hz,12H),1.01(s,9H).

[0702] Example 22. Preparation of compounds 16-94 to 16-100 of the present invention

[0703] 1. Preparation of 16-94 to 16-96, 16-99 and 16-99 of the present invention

[0704] At room temperature, compound A (5.8 g, 14.03 mmol) was dissolved in dry tetrahydrofuran (100 mL). The reaction system was purged with argon three times, and the atmosphere was protected with argon. The reaction system was cooled to -60°C using a dry ice-ethanol bath. n-Butyl lithium (11.0 mL, 2.5 mol / L in THF, 27.5 mmol) was slowly added to the reaction system via syringe and stirred at -60°C for 1 hour. A solution of tert-butyl 4-formylpiperidine-1-carboxylate (3.0 g, 14.07 mmol) in tetrahydrofuran (10 mL) was slowly added to the reaction system via syringe and stirred at naturally elevated temperature for 5 hours. After the reaction was complete, the reaction system was slowly poured into a saturated ammonium chloride solution and extracted with ethyl acetate (3×10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane / ethyl acetate (V / V) = 0-15%) and monitored by TLC (ethyl acetate / petroleum ether (V / V) = 1 / 5). The Rf = 0.5-0.6 fraction was collected to obtain 16-94-1 (3.7 g, yield 48.1%) as a light yellow solid.

[0705] At room temperature, PCC (21.82 g, 67.55 mmol) was added in batches to 16-94-1 (3.7 g, 6.75 mmol) and silica gel (10 g) in dichloromethane (50 mL), and stirred at room temperature overnight. After the reaction was completed by TLC, it was filtered and the filter cake was washed with dichloromethane (100 mL). The filtrate was concentrated to give the crude product (ethyl acetate / petroleum ether (V / V) = 0-20%), monitored by TLC (ethyl acetate / petroleum ether (V / V) = 1 / 8), and the Rf = 0.5-0.6 portion was collected to give a gray solid 16-94-2 (3.49 g, yield 94.7%).

[0706] In an ice-water bath at 0°C, TBAF (0.4 mL, 1 mol / L in THF, 0.4 mmol) was added via syringe to a solution of compound 94-2 (184 mg, 0.337 mmol) in dry THF (5 mL). The mixture was stirred at 0°C for 5 minutes. After completion of the reaction as monitored by TLC, saturated brine was added to the reaction system, and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0-20%) to afford 16-94 (82 mg, 62.5% yield) as a white solid. ESI [M+Na] + =412.3.

[0707] 1H NMR(400MHz,CD3OD)δ7.74(s,2H),4.20–4.09(m,2H),3.70–3.57(m,1H),3.42–3.36(m,1H),3.34–3.27 (m,1H),3.12–2.89(m,2H),1.91–1.76(m,2H),1.69–1.56(m,2H),1.50(s,9H),1.29(d,J=6.9Hz,12H).

[0708] TFA (20.88 g, 183.13 mmol) was added to a solution of 16-94-2 (2.99 g, 5.48 mmol) in dichloromethane (100 mL) at room temperature and stirred at room temperature for 3 hours. After completion of the reaction as monitored by TLC, the mixture was concentrated under reduced pressure, basified with saturated sodium bicarbonate (100 mL), and extracted with dichloromethane (3×10 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0-10%) and monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10). Fractions with Rf = 0.6-0.7 were collected to obtain 16-95-1 (2.1 g, 86.0% yield) as a white solid.

[0709] 16-95-1 was deprotected by TBAF to give 118.9 mg of white solid 16-95. ESI [M+H] + =290.4.

[0710] 1 H NMR(400MHz,CD3OD)δ7.76(s,2H),3.88–3.74(m,1H),3.54–3.43(m,2H),3.42–3.29(m ,2H),3.28–3.18(m,2H),2.14–2.03(m,2H),2.01–1.85(m,2H),1.29(d,J=6.8Hz,12H).

[0711] Dissolve 16-95-1 (300 mg, 0.673 mmol) and paraformaldehyde (101.1 mg, 3.37 mmol) in methanol (3 mL) at room temperature and stir at room temperature for 1 hour. Then, add sodium triacetoxyborohydride (570.5 mg, 2.69 mmol) to the reaction system and stir at room temperature overnight. After the reaction is complete as monitored by TLC, add H2O (20 mL) to the reaction system and extract with EtOAc (3 × 10 mL). The combined organic phases are washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product 16-96-1, which is used directly in the next step without purification.

[0712] In an ice-water bath at 0°C, TBAF (0.9 mL, 1 mol / L in THF, 0.9 mmol) was added to a solution of 16-96-1 in dry THF (5 mL) via syringe and stirred at 0°C for 5 minutes. After the reaction was complete as monitored by TLC, saturated brine was added to the reaction system and extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0-20%) to afford 16-96 (47.2 mg, 23.1% yield over two steps) as a white solid. ESI [M+H] + =304.2.

[0713] 1 H NMR (400MHz, CD3OD) δ7.72(s,2H),3.54–3.25(m,3H),3.14–3.00(m,2H),2.41(s,3H),2.39–2.31(m,2H),1.97–1.71(m,4H),1.28(d,J=6.9Hz,12H).

[0714] 16-100 was collected during the preparation of 16-94 to 16-96 as a white solid, 115 mg. ESI [M+H] + =362.4.

[0715] 1 H NMR (400MHz, CD3OD) δ7.04(s,2H),3.47–3.21(m,4H),2.85–2.69(m,2H),2.69(s,3H),2.20–2.07(m,1H),2.05–1.92(m,1H),1.92–1.79(m,2H), 1.74–1.63(m,1H),1.60–1.43(m,2H),1.41–1.28(m,3H),1.25(d,J=6.7 Hz, 6H), 1.24 (d, J = 6.6Hz, 6H), 1.12–1.00 (m, 1H), 0.90 (t, J = 7.1Hz, 3H).

[0716] 16-96 was reduced with sodium borohydride to give 16-99 as a white solid, 106.8 mg, ESI [M+H] + =306.4.

[0717] 1H NMR (400MHz, CD3OD) δ6.99 (s, 2H), 4.28 (d, J = 7.5Hz, 1H), 3.40–3.27 (m, 2H), 3.19–3.08 (m, 1H), 3.06–2.97 (m, 1H) ,2.44(s,3H),2.41–2.17(m,2H),2.16–1.99(m,1H),1.77–1.59(m,1H),1.53–1.27(m,3H),1.24(d,J=6.9Hz,12H).

[0718] 2. Preparation of 16-97 of the present invention

[0719] In an ice-water bath at 0°C, pivaloyl chloride (81.2 mg, 0.673 mmol) was slowly added via syringe to a solution of 16-95-1 (200 mg, 0.449 mmol) and triethylamine (90.8 mg, 0.897 mmol) in dry dichloromethane (5 mL). The reaction was stirred at 0°C for 1 hour. After completion of the reaction, the mixture was extracted with dichloromethane (3 × 5 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0-20%) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2). Fractions with Rf = 0.6-0.7 were collected to obtain 16-97-1 (188 mg, 79.0% yield) as a white solid.

[0720] In an ice-water bath at 0°C, TBAF (0.4 mL, 1 mol / L in THF, 0.4 mmol) was added to a solution of 16-97-1 (188 mg, 0.355 mmol) in dry THF (3 mL) via syringe and stirred at 0°C for 5 minutes. After completion of the reaction as monitored by TLC, saturated brine was added to the reaction system and extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0-35%), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2). Fractions with Rf = 0.4-0.5 were collected to obtain 16-97 (71 mg, 53.5% yield) as a white solid. ESI [M+H] + =374.3

[0721] 1H NMR(400MHz,CD3OD)δ7.75(s,2H),4.52–4.40(m,2H),3.79–3.66(m,1H),3.42–3.36(m,1H),3.34–3.27(m ,1H),3.16(t,J=12.6Hz,2H),1.97–1.86(m,2H),1.75–1.58(m,2H),1.32(s,9H),1.29(d,J=6.9Hz,12H).

[0722] Example 23. Preparation of Compound 16-101 of the Invention

[0723] At room temperature, compound C (870 mg, 1.98 mmol) was dissolved in dry tetrahydrofuran (10 mL). The system was purged with argon three times, and the reaction system was protected with argon. The reaction system was cooled to -60°C using a dry ice-ethanol bath. n-Butyl lithium (1.6 mL, 2.5 mol / L in THF, 3.96 mmol) was slowly added to the reaction system via syringe and stirred at -60°C for 1 hour. A solution of pivalaldehyde (340.95 mg, 3.96 mmol) in tetrahydrofuran (2 mL) was slowly added to the reaction system via syringe and stirred at -60°C for 5 hours. After the reaction was complete, the reaction system was slowly poured into a saturated ammonium chloride solution at 0°C and extracted with ethyl acetate (3×10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0-6%) and monitored by TLC (ethyl acetate / petroleum ether (V / V) = 1 / 6). The fraction with Rf = 0.7-0.8 was collected to obtain a light yellow intermediate 16-101-1 (840 mg, yield 95.0%).

[0724] In an ice-water bath at 0°C, TBAF (1.8 mL, 1 mol / L in THF) was added to a solution of 16-101-1 (840 mg, 1.88 mmol) in dry THF (5 mL) via syringe and stirred at 0°C for 5 minutes. After the reaction was complete as monitored by TLC, saturated brine was added to the reaction system and extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0-8%), monitored by TLC (ethyl acetate / petroleum ether (V / V) = 1 / 6), and fractions with Rf = 0.5-0.6 were collected to obtain 16-101 (474 ​​mg, 86.8% yield) as a white solid. ESI [M-OH] + =272.9.

[0725] 1 H NMR (400MHz, CD3OD) δ7.08(dd,J=12.5,2.0Hz,1H),6.99(dd,J=8.4,2.0Hz,1H),4.29(s,1H),3.33–3.23(m,1H),2.58–2.42(m,1H),1.30(d,J =6.9Hz,3H),1.26–1.21(m,6H),1.13–1.00(m,1H),0.91(s,9H),0.61– 0.50(m,1H),0.42–0.30(m,1H),0.25–0.16(m,1H),0.16–0.06(m,1H).

[0726] Example 24. Preparation of 16-102 to 16-105 of the present invention

[0727] The preparation of 16-102 and 16-104 of the present invention is similar to 16-101 in Example 13.

[0728] Intermediates 16-102-1 and 16-104-1 are reacted with NaH and iodomethane to generate 16-103-1 and 16-105-1, which are then deprotected by TBAF to obtain 16-103 and 16-105 of the present invention.

[0729] 16-102: white solid, 87 mg, ESI[M-OH] + =272.9.

[0730] 1 H NMR(400MHz,CD3OD)δ7.12(s,1H),7.03(s,1H),4.89–4.86(m,1H),4.83–4.80(m ,1H),4.79–4.72(m,1H),4.64–4.56(m,1H),4.47–4.39(m,1H),3.32–3.25(m,1H) ,2.56–2.44(m,1H),1.29(d,J=6.9Hz,3H),1.24(d,J=6.9Hz,6H),1.14–1.01(m, 1H),0.62–0.50(m,1H),0.43–0.32(m,1H),0.27–0.16(m,1H),0.16–0.06(m,1H).

[0731] 16-103: white solid, 123 mg, ESI [M-OMe] + =272.9.

[0732] 1H NMR(400MHz,CD3OD)δ7.08(s,1H),6.97(s,1H),4.84–4.77(m,1H),4.77–4.6 9(m,1H),4.59–4.52(m,1H),4.47–4.36(m,2H),3.32–3.26(m,1H),3.24(s,3H ),2.58–2.42(m,1H),1.33–1.27(m,3H),1.27–1.20(m,6H),1.14–1.00(m,1H) ,0.64–0.52(m,1H),0.45–0.34(m,1H),0.26–0.17(m,1H),0.15–0.06(m,1H).

[0733] 16-104: white solid, 57 mg, ESI[M-OH] + =300.8.

[0734] 1 H NMR(400MHz,CD3OD)δ7.08(s,1H),7.00(s,1H),4.24(d,J=7.7Hz,1H),4.05–3.97(m, 1H),3.92–3.85(m,1H),3.54–3.38(m,2H),3.32–3.26(m,1H),2.61–2.46(m,1H),2.0 3–1.90(m,1H),1.87–1.74(m,1H),1.50–1.36(m,1H),1.33–1.16(m,11H),1.13–1.02 (m,1H),0.62–0.52(m,1H),0.42–0.31(m,1H),0.24–0.16(m,1H),0.16–0.07(m,1H).

[0735] 16-105: white solid, 180 mg, ESI [M-OMe] + =300.9.

[0736] 1H NMR(400MHz,d6-DMSO)δ6.20(t,J=2.3Hz,1H),6.10(d,J=1.8Hz,1H),3.15(dd,J=11.4,3.4Hz, 1H),3.05(dd,J=11.5,3.6Hz,1H),2.98(dd,J=7.8,1.3Hz,1H),2.63–2.54(m,1H),2.50–2.43( m,1H),2.36(s,3H),1.78–1.62(m,1H),1.12(d,J=13.4Hz,1H),1.07–0.90(m,1H),0.67–0.19( m,13H),-0.18–-0.34(m,1H),-0.36–-0.51(m,1H),-0.58–-0.67(m,1H),-0.67–-0.79(m,1H).

[0737] Example 25. Preparation of Compounds 16-106 and 16-107 of the Invention

[0738] 1. Preparation of 16-106 of the present invention

[0739] At room temperature, compound C (400 mg, 0.91 mmol), propane-2-thiol (138.8 mg, 1.82 mmol), Pd2(dba)3 (83.52 mg, 0.091 mmol), DIPA (184 mg, 1.82 mmol), and Xantphos (52.8 mg, 0.091 mmol) were dissolved in 1,4-dioxane (7 mL). The reaction system was purged with argon three times, protected by argon, and stirred at 100°C overnight. After completion of the reaction, as monitored by TLC (n-heptane), the reaction was concentrated under reduced pressure to obtain the crude product. The crude product was purified by Biotage (petroleum ether) and monitored by TLC (petroleum ether). The fraction with Rf = 0.5 was collected to obtain the crude product 16-106-1 (325 mg, 82.1% yield) as a colorless oil.

[0740] In an ice-water bath at 0°C, TBAF (0.24 mL, 1 mol / L in THF, 0.24 mmol) was added to a solution of compound 106-1 (103 mg, 0.24 mmol) in dry THF (5 mL) via syringe and stirred at 0°C for 5 minutes. After the reaction was complete as monitored by TLC, saturated brine was added to the reaction system and extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by Prep-TLC to obtain 16-106 (34 mg, 50.9% yield) as a colorless oil. ESI [M+H] +=278.8

[0741] 1 H NMR (400MHz, CD3OD) δ7.23(d,J=2.2Hz,1H),7.11(d,J=2.2Hz,1H),3.32–3.23(m,1H),3.20–3.05(m,1H),2.57–2.37(m,1H),1.29(d, J=6.9Hz,3H),1.23(d,J=6.7Hz,12H),1.12–0.97(m,1H),0.64–0.53(m,1H),0.46–0.34(m,1H),0.26–0.16(m,1H),0.16–0.06(m,1H).

[0742] 2. Preparation of 16-107 of the present invention

[0743] 16-106-1 (222 mg, 0.51 mmol) and NaIO4 (330.7 mg, 1.53 mmol) were dissolved in methanol (8 mL) at room temperature and stirred overnight. After the reaction was complete, as monitored by TLC (n-heptane), the mixture was filtered, the filter cake washed with methanol, and the filtrate concentrated under reduced pressure to yield the crude product. The crude product was dissolved in dry THF (3 mL), cooled to 0°C with an ice-water bath, and TBAF (0.5 mL, 1 mol / L in THF, 0.5 mmol) was added to the system via syringe. The mixture was stirred at 0°C for 5 minutes. After the reaction was complete, as monitored by TLC, saturated brine was added to the reaction system, and the mixture was extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to yield the crude product. The crude product was purified by Prep-TLC (petroleum ether / ethyl acetate) to yield 16-107 (~5 mg, ~3.3% yield over two steps) as a white solid. ESI[M+H] + =294.8

[0744] 1 H NMR (400MHz, CD3OD) δ7.46(dd,J=10.4,2.1Hz,1H),7.34(dd,J=6.7,2.2Hz,1H),3.32–3.24(m,1H),3.00–2.87(m,1H) ,2.63–2.49(m,1H),1.41–1.09(m,16H),0.69–0.57(m,1H),0.48–0.37(m,1H),0.31–0.21(m,1H),0.16–0.06(m,1H).

[0745] Example 26. Preparation of compounds 16-109 to 16-112 of the present invention

[0746] 1. Preparation of 16-109 and 16-111 of the present invention

[0747] At room temperature, 1-methylcyclopropane-1-carboxylic acid (5.0 g, 49.9 mmol) and N,O-dimethylhydroxylamine hydrochloride (9.74 g, 99.9 mmol) were dissolved in CH2Cl2 (100 mL). The reaction system was cooled to 0°C using an ice-water bath. CDI (32.4 g, 199.76 mmol) was added portionwise to the reaction system and stirred at room temperature overnight. After completion of the reaction as monitored by TLC, H2O (100 mL) was added to the reaction system. The mixture was extracted with CH2Cl2 (3 × 50 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 3) to afford 16-109-1 (4.712 g, 58.4% yield) as a white solid. ESI [M+H] + =144.2

[0748] At room temperature, compound A (2.0 g, 4.84 mmol) was dissolved in dry tetrahydrofuran (20 mL). The system was replaced with argon three times, and the reaction system was protected with argon. The reaction system was cooled to -60°C using a dry ice ethanol bath. n-Butyl lithium (2.9 mL, 2.5 mol / L in THF, 7.25 mmol) was slowly added to the reaction system via syringe and stirred at -60°C for 1 hour. A solution of 109-1 (912.4 mg, 5.8 mmol) in tetrahydrofuran (2 mL) was slowly added to the reaction system via syringe and stirred at -60°C for 5 hours. After the reaction is complete, the reaction system is slowly poured into a saturated ammonium chloride solution at 0°C, extracted with ethyl acetate (3×10 mL), the organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0-6%), monitored by TLC (ethyl acetate / petroleum ether (V / V) = 1 / 6), and the Rf = 0.7-0.8 portion is collected to obtain a light yellow intermediate 16-109-2 (1.37 g, yield 67.9%).

[0749] TBAF (0.9 mL, 1 mol / L in THF) was added to a solution of compound 109-2 (360 mg, 0.86 mmol) in dry THF (5 mL) via syringe in an ice-water bath at 0°C. The mixture was stirred at 0°C for 5 minutes. After completion of the reaction as monitored by TLC, saturated brine was added to the reaction system, and the mixture was extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether) and monitored by TLC (ethyl acetate / petroleum ether) to obtain 16-109 (111 mg, 49.6% yield) as a white solid.

[0750] 1 H NMR (400MHz, CD3OD) δ7.68(s,2H),3.40–3.31(m,2H),1.48(s,3H),1.28(d,J=6.9Hz,12H),1.16(q,J=4.0Hz,2H),0.82(q,J=4.1Hz,2H).

[0751] At room temperature, 16-109-2 (450 mg, 1.08 mmol) was dissolved in MeOH (15 mL). The reaction system was cooled to 0°C using an ice-water bath. NaBH4 (61.6 mg, 1.62 mmol) was added portionwise to the reaction system and stirred at 0°C for 1 hour. After the reaction was complete as monitored by TLC, H2O (50 mL) was added to the reaction system and extracted with EtOAc (3 × 10 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain 16-111-1 (277 mg, 61.3% yield) as a colorless oil. ESI [M+H] + =416.8

[0752] In an ice-water bath at 0°C, TBAF (0.7 mL, 1 mol / L in THF) was added to a solution of 16-111-1 (277 mg, 0.66 mmol) in dry THF (5 mL) via syringe and stirred at 0°C for 5 minutes. After the reaction was complete as monitored by TLC, saturated brine was added to the reaction system and extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether) and monitored by TLC (ethyl acetate / petroleum ether) to obtain 16-111 (105 mg, 60.6% yield) as a white solid. ESI [M-OH] + =244.9

[0753] 1H NMR (400MHz, CD3OD) δ7.05 (s, 2H), 4.15 (s, 1H), 3.43–3.26 (m, 2H), 1.25 (d, J = 6. 9Hz,12H),0.99(s,3H),0.70–0.53(m,1H),0.41–0.31(m,1H),0.29–0.20(m,1H).

[0754] 2. Preparation of 16-110 and 16-112 of the present invention

[0755] The preparation methods of compounds 16-110 and 16-112 of the present invention are similar to those of compounds 16-109 and 16-111 of the present invention.

[0756] 16-110: white solid, 85 mg, ESI [M+H] + =274.8.

[0757] 1 H NMR (400MHz, CD3OD) δ7.62(s,2H),3.39–3.27(m,2H),2.72–2.60(m,2H),2.24–2.02(m,3H),1.87–1.73(m,1H),1.64(s,3H),1.26(d,J=6.9Hz,12H).

[0758] 16-112: white solid, 165 mg, ESI [M+H] + =258.9.

[0759] 1 H NMR(400MHz,d6-DMSO)δ6.98(s,2H),4.43(s,1H),3.44–3.25(m,2H),2.41–2.18(m,2H),2.03–1.82( m,1H),1.80–1.67(m,1H),1.68–1.54(m,1H),1.53–1.37(m,1H),1.23(d,J=6.9Hz,12H),1.03(s,3H).

[0760] Example 27. Preparation of compounds 16-117 to 16-119 of the present invention

[0761] Compound 3,5-diisopropyl-4-((triisopropylsilyl)oxy)benzoic acid and R 10 OH was condensed by DCC to give 16-117-1 to 16-119-1, and then deprotected by TBAF to give the corresponding 16-117 to 16-119.

[0762] 16-117: white solid, 348 mg, ESI [M+H] + =236.9.

[0763] 1 H NMR (400MHz, CD3OD) δ7.75 (s, 2H), 3.90 (s, 3H), 3.44–3.22 (m, 2H), 1.27 (d, J = 6.9Hz, 12H).

[0764] 16-118: white solid, 186 mg, ESI [M+H] + =250.9.

[0765] 1 H NMR (400MHz, CD3OD) δ7.78 (s, 2H), 7.51–7.18 (m, 5H), 5.36 (s, 2H), 3.43–3.22 (m, 2H), 1.26 (d, J = 6.9Hz, 12H).

[0766] 16-119: white solid, 60 mg, ESI [M+H] + =312.9.

[0767] 1 H NMR (400MHz, CD3OD) δ7.75 (s, 2H), 4.36 (q, J = 7.1Hz, 2H), 3.43–3.22 (m, 2H), 1.41 (t, J = 7.1Hz, 3H), 1.27 (d, J = 6.9Hz, 12H).

[0768] The beneficial effects of the present invention are demonstrated by the following test examples.

[0769] The beneficial effects of the present invention are demonstrated by the following test examples.

[0770] Test Example 1: Determination of anesthetic / analgesic pharmacological data of the compounds prepared in the present invention

[0771] 1. Experimental Methods

[0772] The anesthetic effect (minimum anesthetic effective dose) of the compound prepared in the examples of the present invention after injection into the rat tail vein was tested. The specific method is as follows:

[0773] SD rats were selected and administered via the tail vein (dosage rate 0.02 ml / s, dosing volume 0.6 ml / rat) to determine whether the compound causes loss of the righting reflex using a sequential method. The test compound dose started at 1 mg / kg, and the actual dose was calculated based on the body weight of each animal before the experiment. The subsequent dose was increased or decreased based on the experimental animal's response (whether the righting reflex was lost). The minimum dose that caused the first loss of the righting reflex was determined as the minimum anesthetic effective dose.

[0774] Before testing the compounds of the present invention, a baseline must be established in rats. Prior to administration, a crocodile clip is first applied to the rat's tail at one-third of the site to assess any pain responses (e.g., avoidance, tail licking, screaming, etc.). Once the compound is injected into the rat's tail vein, and once it is confirmed that the compound has an anesthetic effect (loss of righting reflex lasting 30 seconds), the compound is tested for response to a noxious stimulus (approximately 30 seconds after clamping the middle and outer thirds of the rat's tail). If the rat does not respond within 30 seconds, the compound is considered to have an analgesic effect. One minute after the compound has lost its anesthetic effect (loss of righting reflex does not last 30 seconds), a noxious stimulus (approximately 30 seconds after clamping the middle and outer thirds of the rat's tail) is administered. If the rat does not respond within 30 seconds, the compound is considered to have an analgesic effect. If the compound does not last 30 seconds, the compound is considered to have no analgesic effect.

[0775] 2. Experimental Results

[0776] Table 1. Anesthetic / analgesic effects of the compounds of the present invention

[0777] The above test results show that the compound of the present invention has an anesthetic effect with a short onset of anesthesia, and also has an analgesic effect. The compound of the present invention has a large therapeutic index and is safe to use.

[0778] In summary, the present invention provides a substituted phenol derivative that not only has sedative, hypnotic, and / or anesthetic effects, but also has analgesic effects, can control status epilepticus, and has good safety when used. Therefore, the derivative provided by the present invention has broad application prospects in the preparation of drugs that have sedative, hypnotic, and / or anesthetic effects, analgesic effects, and can control status epilepticus, providing a new option for the clinical preparation of drugs that have both analgesic and sedative, hypnotic, and / or anesthetic effects and can control status epilepticus.

Claims

1. A compound represented by formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or a deuterated derivative thereof: in, R is selected from hydrogen, COR a 、COCH(NH2)R a 、COOR h1 、(CH2COO) v R h1 、(CH2CO) v R h1 ,PO(OR h1 )(OR h2 ) or CH2OPO(OR h1 )(OR h2 );R a Selected from hydrogen, C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, aryl or heteroaryl; R h1 , R h2 are each independently selected from hydrogen, C 1-4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, aryl or heteroaryl; v is an integer selected from 1 to 2; R 11 , R 12 , R 21 , R 22 Each independently selected from hydrogen, halogen, hydroxyl, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, NR h3 R h4 ; X is selected from N or CR 4 ; R 1 , R 2 , R 4 Each independently selected from hydrogen, halogen, hydroxyl, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, NR h3 R h4 ; or R 1 , R 2 , R 4 Any two of them form = R 5 , and the remaining one is selected from hydrogen, halogen, hydroxyl, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, NR h3 R h4 ; R h3 , R h4 are each independently selected from hydrogen, C 1～4 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group; R 5 Selected from CHR 6 NR 6 ; R 6 Selected from C 1～4 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group; U is selected from None, CR 7 R 8 , C2~C 10 Alkylene, C2~C 10 Alkenylene, C2~C 10 Alkynylidene, NR 7 、O、S(O)、S、S(O)R 7 R 8 , 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, aryl, heteroaryl; in this case, R 33 of For single key Or U from CR 7 , then connect R 33 of Double bond The carbon atoms in the main chain of the alkylene, alkenylene, and alkynylene groups in U may be replaced by one or more heteroatoms selected from O, S, or N; R 7 , R 8 Each independently selected from hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Alkoxy, hydroxyl, mercapto, 3- to 6-membered heterocyclic group, 3- to 6-membered cycloalkyl, NR d1 R d2 、C(O)R d1 ; or R 7 , R 8 Formation = R 9 ; R 9 Selected from O, S, NR d3 , CR d3 R d31 , 3- to 6-membered heterocyclic group, 3- to 6-membered cycloalkyl group; R d3 , R d31 Selected from hydrogen, hydroxyl, C 1～4 Alkyl, C 1～4 Alkoxy, (CH2) m C(O)R d4 ; R 33 Selected from hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Alkoxy, hydroxyl, mercapto, NR d1 R d2 、C(O)R d1 , OR d1 , by s R 3’ substituted 3- to 8-membered heterocyclic group, substituted by s R 3’ Substituted 3- to 8-membered cycloalkyl, substituted by s R 3’ Substituted 5- to 10-membered aromatic group, substituted by s R 3’ Substituted 5- to 10-membered heteroaryl; s is an integer selected from 0 to 8, each R 3’ are each independently selected from hydrogen, C 1～8 Alkyl, halogenated C 1～4 Alkyl, C 2～8 Alkenyl, C 2～8 Alkynyl, hydroxyl, carboxyl, cyano, nitro, 3-6 membered heterocyclic group, 3-6 membered cycloalkyl group, 5-10 membered aryl group, 5-10 membered heteroaryl group, tert-butyloxycarbonyl group, (CR a1 R a2 ) n1 COR b , (CR a1 R a2 ) n1 COOR b1 、O(CR a1 R a2 ) n1 COR b , (CR a1 R a2 ) n1 NR c1 R c2 , (CR a1 R a2 ) n1 OR b1 , (CR a1 R a2 ) n1 CO(CR a3 R a4 ) n2 NR c1 R c2 , (CR a1 R a2 ) n1 CO(CR a3 R a4 ) n2 COOR b1 , (CR a1 R a2 ) n1 CO(CR a3 R a4 ) n2 CONR c1 R c2 ; n1 is selected from 0, 1, 2; n2 is selected from 0, 1, 2; R a1 , R a2 , R a3 , R a4 are each independently selected from hydrogen, halogen, C 1～8 Alkyl, C 2～8 Alkenyl, C 2～8 Alkynyl, 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, 5- to 10-membered aryl, 5- to 10-membered heteroaryl, CN, OR f , SR f or NR d1 R d2 ; or R a1 and R a2 Together with the carbon atom to which it is attached, it forms a 3-6 membered ring structure, wherein the ring structure contains 0 or 1 heteroatom selected from N, O, and S; R b1 Selected from hydrogen, C 1～4 Alkyl, C 1～4 Alkoxy, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, aryl or heteroaryl; R b Selected from hydrogen, C 1～4 Alkyl, C 1～4 Alkoxy, C 2～4 Alkenyl, C 2～4 Alkynyl, NR d1 R d2 , 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, aryl or heteroaryl; R c1 , R c2 are each independently selected from hydrogen, C 1～4 Alkyl, (CR a1 R a2 ) n1 COR b ; R d1 , R d2 are each independently selected from hydrogen, OR f , C 1～4 Alkyl, C 1～4 Alkoxy, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, benzyl, S(O)(O)R f 、S(O)R f 、(CH2) m C(O)R d4 ; or R d1 and R d2 Together with the carbon atom to which it is attached, it forms a 3-6 membered ring structure, wherein the ring structure contains 0 or 1 heteroatom selected from N, O, and S; The above R, R 1 , R 2 , R 3’ , R 4 , R 6 , R 7 , R 8 , R 9 , R 11 , R 12 , R 21 , R 22 , R a1 , R a2 , R a3 , R a4 , R b , R b1 , R c1 , R c2 , R d1 , R d2 The alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl in U is unsubstituted or optionally substituted by one or two or more of the following groups: halogen, hydroxyl, C 1～4 Alkyl, C 1～4 Alkoxy, halogenated C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, CN, NO2, OR f , SR f NR d1 R d2 , COR i 、(CH2) m COOR f 、(CH2) m COR f ,OCOR i ,CONR d1 R d2 NR d1 COR i NR d1 S02R i or SO2R i ; R f is selected from hydrogen, 3-6 membered cycloalkyl, C 1～4 Alkyl or halogenated C 1～4 alkyl; R i Selected from hydrogen, C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclic group; R d4 Selected from hydroxyl, C 1～4 Alkoxy; m is selected from 0, 1, 2, 3, 4.

2. The compound according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The structure of the compound is shown in Formula IA: in, R is selected from hydrogen, COR a 、COCH(NH2)R a 、COOR h1 、(CH2COO) v R h1 、(CH2CO) v R h1 ,PO(OR h1 )(OR h2 ) or CH2OPO(OR h1 )(OR h2 );R a Selected from hydrogen, C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, aryl or heteroaryl; R h1 , R h2 are each independently selected from hydrogen, C 1-4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, aryl or heteroaryl; v is an integer selected from 1 to 2; R 11 , R 12 , R 21 , R 22 Each independently selected from hydrogen, halogen, hydroxyl, C 1～4 Alkyl, C 2～4 alkenyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, NR h3 R h4 ; X is selected from N or CR 4 ; R 1 , R 2 , R 4 Each independently selected from hydrogen, halogen, hydroxyl, C 1～4 Alkyl, C 2～4 alkenyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, NR h3 R h4 ; or R 1 , R 2 , R 4 Any two of them form = R 5 , and the remaining one is selected from hydrogen, halogen, hydroxyl, C 1～4 Alkyl, C 2～4 alkenyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, NR h3 R h4 ; R h3 , R h4 are each independently selected from hydrogen, C 1～4 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group; R 5 Selected from CHR 6 NR 6 ; R 6 Selected from C 1～4 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group; U is selected from None, CR 7 R 8 , C2~C 10 Alkylene, C2~C 10 Alkenylene, C2~C 10 Alkynylidene, NR 7 、O、S(O)、S、S(O)R 7 R 8 , 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, aryl, heteroaryl; the carbon atoms in the main chain of the alkylene, alkenylene, alkynylene in U may be replaced by one or more heteroatoms selected from O, S or N; R 7 , R 8 Each independently selected from hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Alkoxy, hydroxyl, mercapto, 3- to 6-membered heterocyclic group, 3- to 6-membered cycloalkyl, NR d1 R d2 、C(O)R d1 ; or R 7 , R 8 Formation = R 9 ; R 3 Selected from hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Alkoxy, hydroxyl, mercapto, 3- to 6-membered heterocyclic group, 3- to 6-membered cycloalkyl, NR d1 R d2 、C(O)R d1 , OR d1 ; R 9 Selected from O, S, NR d3 , CR d3 R d31 , 3- to 6-membered heterocyclic group, 3- to 6-membered cycloalkyl group; R d3 , R d31 Selected from hydrogen, hydroxyl, C 1～4 Alkyl, C 1～4 Alkoxy, (CH2) m C(O)R d4 ; The above R, R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 11 , R 12 , R 21 , R 22 The alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl in U is unsubstituted or optionally substituted by one or two or more of the following groups: halogen, hydroxyl, C 1～4 Alkyl, C 1～4 Alkoxy, halogenated C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, CN, NO2, OR f , SR f NR d1 R d2 , COR i 、(CH2) m COOR f 、(CH2) m COR f ,OCOR i ,CONR d1 R d2 NR d1 COR i NR d1 S02R i or SO2R i ; R d1 , R d2 are each independently selected from hydrogen, OR f , C 1～4 Alkyl, C 1～4 Alkoxy, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, benzyl, S(O)(O)R f 、S(O)R f 、(CH2) m C(O)R d4 ; or R d1 and R d2 Together with the carbon atom to which it is attached, it forms a 3-6 membered ring structure, wherein the ring structure contains 0 or 1 heteroatom selected from N, O, and S; R f is selected from hydrogen, 3-6 membered cycloalkyl, C 1～4 Alkyl or halogenated C 1～4 alkyl; R i Selected from hydrogen, C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclic group; R d4 Selected from hydroxyl, C 1～4 Alkoxy; m is selected from 0, 1, 2, 3, 4.

3. The compound according to claim 2, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The structure of the compound is shown in Formula IIA: in, R 11 , R 12 ,X,R 1 , R 2 , R 3 , U as shown in claim 2.

4. The compound according to claim 3, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: X is selected from N or CR 4 ; R 1 , R 2 , R 4 Each independently selected from hydrogen, halogen, hydroxyl, C 1～4 Alkyl, C 2～4 alkenyl, 3-6 membered cycloalkyl, aziridinyl, oxirane, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, NR h3 R h4 ; or R 1 , R 2 , R 4 Any two of them form = R 5 , and the remaining one is selected from hydrogen, halogen, hydroxyl, C 1～4 Alkyl, C 2～4 alkenyl, 3-6 membered cycloalkyl, aziridinyl, oxirane, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, NR h3 R h4 ; R h3 , R h4 are each independently selected from hydrogen, C 1～4 Alkyl, 3-6 membered cycloalkyl, aziridine, oxirane, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, R 5 Selected from CHR 6 NR 6 ; R 6 Selected from C 1～4 Alkyl, 3-6 membered cycloalkyl, aziridine, oxirane, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, U is selected from None, CR 7 R 8 , C2~C 10 Alkylene, C2~C 10 Alkenylene, C2~C 10 Alkynylidene, NR 7 、O、S(O)、S、S(O)R 7 R 8 , 3-6 membered cycloalkyl, aziridine, oxirane, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, Phenyl, pyridyl; the carbon atoms in the main chain of the alkylene, alkenylene, alkynylene in U may be replaced by one or 1, 2, 3, 4, or 5 heteroatoms selected from O, S or N; R 7 , R 8 Each independently selected from hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Alkoxy, hydroxy, mercapto, aziridinyl, oxetanyl, azetidinyl, oxirane, tetrahydrofuranyl, tetrahydropyranyl, 3-6 membered cycloalkyl, NR d1 R d2 、C(O)R d1 ; or R 7 , R 8 Formation = R 9 ; R 3 Selected from hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Alkoxy, hydroxy, mercapto, aziridinyl, oxetanyl, azetidinyl, oxirane, tetrahydrofuranyl, tetrahydropyranyl, 3-6 membered cycloalkyl, NR d1 R d2 、C(O)R d1 , OR d1 ; R 9 Selected from O, S, NR d3 , CR d3 R d31 , aziridine, oxirane, azetidinyl, oxetane, Tetrahydrofuranyl, tetrahydropyranyl, 3-6 membered cycloalkyl; R d3 , R d31 Selected from hydrogen, hydroxyl, C 1～4 Alkyl, C 1～4 Alkoxy, (CH2) m C(O)R d4 ; The above R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy, cycloalkyl, aziridinyl, oxirane, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, Phenyl and pyridyl are unsubstituted or optionally substituted by one or two or more of the following groups: halogen, hydroxyl, C 1～4 Alkyl, C 1～4 Alkoxy, halogenated C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3- to 6-membered cycloalkyl, aziridinyl, oxirane, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, CN, NO2, OR f , SR f , NR d1 R d2 , COR i , (CH2) m COOR f , (CH2) m COR f , OCOR i , CONR d1 R d2 , NR d1 COR i , NR d1 SO2R i or SO2R i ; R d1 , R d2 are each independently selected from hydrogen, OR f , C 1～4 Alkyl, C 1～4 Alkoxy, 3-6 membered cycloalkyl, aziridine, oxirane, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, Benzyl, S(O)(O)R f 、S(O)R f 、(CH2) m C(O)R d4 ; or R d1 and R d2 3-6 membered cycloalkyl, aziridine, oxirane, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, R f is selected from hydrogen, 3-6 membered cycloalkyl, C 1～4 Alkyl or halogenated C 1～4 alkyl; R i Selected from hydrogen, C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3- to 6-membered cycloalkyl, aziridinyl, oxirane, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, R d4 Selected from hydroxyl, C 1～4 Alkoxy; m is selected from 0, 1, 2, 3, 4.

5. The compound according to claim 4, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The structure of the compound is shown in Formula IVA: in, X, R 1 , R 2 As shown in claim 4.

6. The compound according to claim 4, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The structure of the compound is shown in Formula VA: in, X, R 1 , R 2 , R 3 , R 7 , R 8 As shown in claim 4.

7. The compound according to claim 6, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The structure of the compound is shown in Formula VIA1 or Formula VIA2: in, m1 is selected from 0, 1, 2; m2 is selected from 0, 1, 2; R 10 Selected from hydrogen, C 1～4 alkyl; R 7 , R 8 As shown in claim 6.

8. The compound according to claim 6, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The structure of the compound is shown in Formula VIIA1 or Formula VIIA2: in, m3 is selected from 0, 1, 2; m4 is selected from 0, 1, 2; R 3 As shown in claim 6.

9. The compound according to claim 6, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The structure of the compound is shown in Formula VIIIA1 or Formula VIIIA2: in, R' is selected from hydrogen, C 1～4 alkyl; R 7 , R 8 As shown in claim 6.

10. The compound according to claim 6, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The structure of the compound is shown in Formula IXA1 or Formula IXA2: in, R 3 As shown in claim 6.

11. The compound according to claim 6, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The structure of the compound is shown in Formula XA1 or Formula XA2: in, R 7 , R 8 , R d1 , R d2 As shown in claim 6.

12. The compound according to claim 6, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The structure of the compound is shown in Formula XIA1 or Formula XIA2: in, R 3 , R d3 As shown in claim 6.

13. The compound according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The structure of the compound is shown in Formula IB: in, R is selected from hydrogen, COR a 、COCH(NH2)R a 、COOR h1 、(CH2COO) v R h1 、(CH2CO) v R h1 ,PO(OR h1 )(OR h2 ) or CH2OPO(OR h1 )(OR h2 );R a For hydrogen, C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, 5- to 10-membered aryl or 5- to 10-membered heteroaryl; R h1 , R h2 are each independently selected from hydrogen, C 1-4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 5-10 membered aryl or 5-10 membered heteroaryl; v is an integer selected from 1 to 2; R 1 , R 2 , R 11 , R 12 , R 21 , R 22 are independently selected from hydrogen, halogen, hydroxyl, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl or 3- to 6-membered cycloalkyl; U is selected from None, CR 7 R 8 , C2~C 10 Alkylene, C2~C 10 Alkenylene, C2~C 10 Alkynylidene, NR 7 、O、S(O)、S、S(O)R 7 R 8 , 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, 5-10 membered aryl, 5-10 membered heteroaryl, in which case the For single key Or U selected from CR 7 , at this time, the connection of ring A Double bond The carbon atoms in the main chain of the alkylene, alkenylene, and alkynylene groups in U may be replaced by one or more heteroatoms selected from O, S, or N; R 7 , R 8 Each independently selected from hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Alkoxy, hydroxyl, mercapto, 3- to 6-membered heterocyclic group, 3- to 6-membered cycloalkyl, NR d1 R d2 ; or R 7 , R 8 Formation = R 9 ; R 9 Selected from O, S, NR d3 , 3- to 6-membered heterocyclic group, 3- to 6-membered cycloalkyl group; R d3 Selected from hydrogen, hydroxyl, C 1～4 Alkyl, C 1～4 Alkoxy, (CH2) m C(O)R d4 ; Ring A is selected from 3- to 8-membered heterocyclic groups, 3- to 8-membered cycloalkyl groups, 5- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups; R 3’ is a substituent on ring A, s is the number of substituents, s is an integer selected from 0 to 8, each R 3’ are each independently selected from hydrogen, C 1～8 Alkyl, halogenated C 1～4 Alkyl, C 2～8 Alkenyl, C 2～8 Alkynyl, hydroxyl, carboxyl, cyano, nitro, 3-6 membered heterocyclic group, 3-6 membered cycloalkyl group, 5-10 membered aryl group, 5-10 membered heteroaryl group, tert-butyloxycarbonyl group, (CR a1 R a2 ) n1 COR b , (CR a1 R a2 ) n1 COOR b1 、O(CR a1 R a2 ) n1 COR b , (CR a1 R a2 ) n1 NR c1 R c2 , (CR a1 R a2 ) n1 OR b1 , (CR a1 R a2 ) n1 CO(CR a3 R a4 ) n2 NR c1 R c2 , (CR a1 R a2 ) n1 CO(CR a3 R a4 ) n2 COOR b1 , (CR a1 R a2 ) n1 CO(CR a3 R a4 ) n2 CONR c1 R c2 ; n1 is selected from 0, 1, 2; n2 is selected from 0, 1, 2; R a1 , R a2 , R a3 , R a4 are each independently selected from hydrogen, halogen, C 1～8 Alkyl, C 2～8 Alkenyl, C 2～8 Alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, 5- to 10-membered aryl, 5- to 10-membered heteroaryl, CN, OR f , SR f or NR d1 R d2 ; or R a1 and R a2 Together with the carbon atom to which it is attached, it forms a 3-6 membered ring structure, wherein the ring structure contains 0 or 1 heteroatom selected from N, O, and S; R b1 Selected from hydrogen, C 1～4 Alkyl, C 1～4 Alkoxy, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, aryl or heteroaryl; R b Selected from hydrogen, C 1～4 Alkyl, C 1～4 Alkoxy, C 2～4 Alkenyl, C 2～4 Alkynyl, NR d1 R d2 , 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, aryl or heteroaryl; R c1 , R c2 are each independently selected from hydrogen, C 1～4 Alkyl, (CR a1 R a2 ) n1 COR b ; R d1 , R d2 are each independently selected from hydrogen, OR f , C 1～4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group; or R d1 and R d2 Together with the carbon atom to which it is attached, it forms a 3-6 membered ring structure, wherein the ring structure contains 0 or 1 heteroatom selected from N, O, and S; The above R, R 1 , R 2 , R 11 , R 12 , R 21 , R 22 , R 7 , R 8 , R 9 , R 3’ , R a1 , R a2 , R a3 , R a4 , R b , R b1 , R c1 , R c2 , R d1 , R d2 The alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl in U is unsubstituted or optionally substituted by one or more of the following groups: halogen, C 1～4 Alkyl, C 1～4 Alkoxy, halogenated C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, CN, NO2, OR f , SR f NR d1 R d2 , COR i 、COOR f ,OCOR i ,CONR d1 R d2 NR d1 COR i NR d1 S02R i or SO2R i ; R f Selected from hydrogen, C 1～4 Alkyl or halogenated C 1～4 alkyl; R i Selected from hydrogen, C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclic group; R d4 Selected from hydroxyl, C 1～4 Alkoxy; m is selected from 0, 1, and 2.

14. The compound according to claim 13, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The structure of the compound is shown in Formula IIB: in, m5 is selected from 0, 1, 2, 3, 4; m6 is selected from 0, 1, 2, 3, 4; R 3’ is a substituent at any position on the ring; For single key When X is selected from CR d5 or N; Key When X is selected from C; Y is selected from N or CR d5 ; and X and Y are not C at the same time; R d5 Selected from hydrogen, C 1～4 alkyl; R, R 1 , R 2 , R 11 , R 12 ,U,R 3’ As shown in claim 13.

15. The compound according to claim 14, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The structure of the compound is shown in Formula IIaB: in, R, R 1 , R 2 , R 11 , R 12 ,U,R 3’ , X, Y, m5, m6 as shown in claim 14.

16. The compound according to claim 15, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: U is selected from None, CR 7 R 8 , C2~C 10 Alkylene, C2~C 10 Alkenylene, C2~C 10 Alkynylidene, NR 7 、O、S(O)、S、S(O)R 7 R 8 , 3-6 membered cycloalkyl, oxirane, aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, Phenyl, pyridyl, thienyl, furanyl, pyrimidinyl, imidazolyl, at this time For single key Or U selected from CR 7 ,at this time Double bond The carbon atoms in the main chain of the alkylene, alkenylene, and alkynylene groups in U may be replaced by one or more heteroatoms selected from O, S, or N; R 7 , R 8 Each independently selected from hydrogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl, C 1～6 Alkoxy, hydroxy, mercapto, oxirane, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, 3-6 membered cycloalkyl, NR d1 R d2 ; or R 7 , R 8 Formation = R 9 ; R 9 Selected from O, S, NR d3 , oxirane, aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, 3-6 membered cycloalkyl; R d3 Selected from hydrogen, hydroxyl, C 1～4 Alkyl, C 1～4 Alkoxy, (CH2) m C(O)R d4 ; For single key When X is selected from CR d5 or N; Key When X is selected from C; Y is selected from N or CR d5 ; and X and Y are not C at the same time; R d5 Selected from hydrogen, C 1～4 alkyl; m5 is selected from 0, 1, 2, 3, 4; m6 is selected from 0, 1, 2, 3, 4; R 3’ is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, halogenated C 1～4 Alkyl, C 2～8 Alkenyl, C 2～8 Alkynyl, hydroxyl, carboxyl, cyano, nitro, oxirane, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, Phenyl, pyridyl, thienyl, furyl, pyrimidyl, imidazolyl, 3-6 membered cycloalkyl, tert-butyloxycarbonyl, (CR a1 R a2 ) n1 COR b , (CR a1 R a2 ) n1 COOR b1 、O(CR a1 R a2 ) n1 COR b , (CR a1 R a2 ) n1 NR c1 R c2 , (CR a1 R a2 ) n1 OR b1 , (CR a1 R a2 ) n1 CO(CR a3 R a4 ) n2 NR c1 R c2 , (CR a1 R a2 ) n1 CO(CR a3 R a4 ) n2 COOR b1 , (CR a1 R a2 ) n1 CO(CR a3 R a4 ) n2 CONR c1 R c2 ; n1 is selected from 0, 1, 2; n2 is selected from 0, 1, 2; R a1 , R a2 , R a3 , R a4 are each independently selected from hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, C 2～6 Alkenyl, C 2～6 Alkynyl, 3-6 membered cycloalkyl, oxirane, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, Phenyl, pyridyl, thienyl, furanyl, pyrimidinyl, imidazolyl, CN, OR f , SR f or NR d1 R d2 ; or R a1 and R a2 Together with the carbon atom to which it is attached, it forms oxirane, aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, Phenyl, pyridyl, thienyl, furanyl, pyrimidinyl, imidazolyl; R b1 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, C 1～4 Alkoxy, 3- to 6-membered cycloalkyl, oxirane, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, Phenyl, pyridyl, thienyl, furanyl, pyrimidinyl, imidazolyl; R b is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, C 1～4 Alkoxy, C 2～4 Alkenyl, C 2～4 Alkynyl, NR d1 R d2 , 3-6 membered cycloalkyl, oxirane, aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, Phenyl, pyridyl, thienyl, furanyl, pyrimidinyl, imidazolyl; R c1 , R c2 are each independently selected from hydrogen, C 1～4 Alkyl, (CR a1 R a2 ) n1 COR b ; R d1 , R d2 are each independently selected from hydrogen, OR f , C 1～4 Alkyl, 3-6 membered cycloalkyl, oxirane, aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, or R d1 and R d2 Together with the carbon atom to which it is attached, it forms an aziridine group, an azetidinyl group, a tetrahydropyranyl group, a pyrrolidinyl group, a piperidinyl group, Pyridyl, pyrimidinyl, imidazolyl; The above R, R 1 , R 2 , R 11 , R 12 , R 7 , R 8 , R 9 , R 3’ , R a1 , R a2 , R a3 , R a4 , R b , R b1 , R c1 , R c2 , R d1 , R d2 , alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy, cycloalkyl, oxirane, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, Phenyl, pyridyl, thienyl, furanyl, pyrimidinyl, imidazole are unsubstituted or optionally substituted by one or more of the following groups: halogen, C 1～4 Alkyl, C 1～4 Alkoxy, halogenated C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3-6 membered cycloalkyl, oxirane, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, CN, NO2, OR f , SR f , NR d1 R d2 , COR i , COOR f , OCOR i , CONR d1 R d2 , NR d1 COR i , NR d1 , SO2R i or SO2R i ; R f Selected from hydrogen, C 1～4 Alkyl or halogenated C 1～4 alkyl; R i Selected from hydrogen, C 1～4 Alkyl, C 2～4 Alkenyl, C 2～4 Alkynyl, 3-6 membered cycloalkyl, oxirane, aziridine, nitrogen Heterocyclobutane, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, R d4 Selected from hydroxyl, C 1～4 Alkoxy; m is selected from 0, 1, and 2.

17. The compound according to claim 16, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The structure of the compound is shown in Formula IIIB: in, R, R 1 , R 2 , R 11 , R 12 ,U,R 3’ , m5, m6 as shown in claim 16.

18. The compound according to claim 16, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The structure of the compound is shown in Formula IVB: in, R, R 1 , R 2 , R 11 , R 12 ,U,R 3’ , m5, m6 as shown in claim 16.

19. The compound according to claim 18, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The structure of the compound is shown in Formula VB1 or Formula VB2: in, R, U, R 3’ , m5, m6 as shown in claim 18.

20. The compound according to claim 19, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The structure of the compound is shown in Formula VIB1 or Formula VIB2: in, R, R 7 , R 3’ , m5, m6 as shown in claim 19.

21. The compound according to claim 19, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The structure of the compound is shown in Formula VIIB1 or Formula VIIB2: in, R, R 7 , R 8 , R 3’ , m5, m6 as shown in claim 19.

22. The compound according to claim 21, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The structure of the compound is shown in Formula VIIIB1 or Formula VIIIB2: in, R, R 3’ , m5, m6 as shown in claim 21.

23. The compound according to claim 17, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The structure of the compound is shown in Formula XB: in, R 7 , R 8 , R 3’ , m5, m6 as shown in claim 17.

24. The compound according to claim 17, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The structure of the compound is shown in Formula XIB: in, m5, m6, R 3’ As shown in claim 17.

25. The compound according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite, or its deuterated derivative, characterized in that: The structure of the compound is selected from:

26. The compound according to any one of claims 1 to 25, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or a deuterated derivative thereof, characterized in that: The pharmaceutically acceptable salt is acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate, carbonate, bisulfate, sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrochloride, hydrobromide, hydroiodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, teasulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, dihydroxynaphthoate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate, xinafoate, methanesulfonate or p-toluenesulfonate.

27. A drug, characterized in that: It is a preparation prepared with the compound described in any one of claims 1 to 26, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite, or its deuterated derivative as the active ingredient, and pharmaceutically acceptable excipients.

28. Use of the compound according to any one of claims 1 to 26, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite, or its deuterated derivative in the preparation of a drug having both analgesic and sedative, hypnotic and / or anesthetic effects and / or capable of controlling status epilepticus.

Images