CN109761906B - Substituted imidazole formate derivative and application thereof - Google Patents

Substituted imidazole formate derivative and application thereof Download PDF

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CN109761906B
CN109761906B CN201910157801.1A CN201910157801A CN109761906B CN 109761906 B CN109761906 B CN 109761906B CN 201910157801 A CN201910157801 A CN 201910157801A CN 109761906 B CN109761906 B CN 109761906B
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CN109761906A (en
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马海军
王昌华
解振彪
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Chengdu Mabeisan Pharmaceutical Technology Co ltd
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract

The invention discloses a compound 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, which is a substituted imidazole formate derivative with a novel structure, and belongs to the field of pharmaceutical chemistry. The invention also discloses application of the substituted imidazole or pyrrole formate derivatives in preparing medicaments with sedative, hypnotic and/or anesthetic effects and in preparing medicaments capable of controlling status epilepticus. The compound has good inhibition effect on the central nervous system, and provides a new choice for clinically screening and/or preparing medicines with sedative, hypnotic and/or anesthetic effects and for controlling epileptic status.

Description

Substituted imidazole formate derivative and application thereof
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a substituted imidazole formate derivative and application thereof.
Background
The imidazole derivative etomidate, the chemical name of which is R- (+) -1- (1-phenethyl) -1-hydro-imidazole-5-ethyl formate, is a hypnotic intravenous general anesthetic, has a large safety range, and is one of the common drugs for anesthesia induction. The clinical application of the imidazole derivative has been 30 years old (Br J Anaesth.1976;48 (3): 213-6.PubMed:1259887;Arch Int Pharmacodyn Ther.1975;214 (1): 92-132.PubMed:1156027;Acad Emerg Med.2006;13 (4): 378-83.PubMed: 16531603). Etomidate is a non-barbital intravenous sedative, has the action intensity of 4 times of barbital sodium and 12 times of thiobarbital sodium respectively, is quick in general anesthesia induction, quick in recovery after administration, free from sleepiness, dizziness and other adverse reactions after recovery of patients, and has a certain anti-vomiting effect, so that the etomidate is widely applied. The structural formula is shown in the following figure, and the molecular formula C 14 H 16 N 2 O 2 Molecular weight 244.29. The imidazole derivative is insoluble in water and unstable in neutral solution.
The first to begin with etomidate in the last 70 th century in the yansen pharmacy. As the most major developer, janssen PA et al reported in one of the study reports published in 1965 that recorded the major process of etomidate synthesis and described the passage of how etomidate was screened from 42 similar compounds. Among the 11 compounds with defined anesthetic action etomidate showed the best safety in rats (i.e. highest therapeutic index TI). In addition, researchers have found that etomidate is stereoselective in sedative hypnotic effect, with the drug in the R configuration being ten times more potent than the drug in the S configuration (J Med chem.1965;8:220-3.PubMed:14332665; anesthesiology.1998;88 (3): 708-17.PubMed: 9523815). The imidazole derivative has outstanding advantages, such as larger treatment window and smaller inhibition to circulatory system in the existing general anesthetic, and is especially suitable for the elderly, coronary heart disease and hypertension patients and critical patients. Standard drugs, once anesthesia-induced, are also used as drugs for total intravenous anesthesia.
However, since the eighties of the last century, some drawbacks of etomidate (such as slightly poorer awakening quality than the other general anesthetic drug propofol), especially adverse effects on adrenocortical function, have been increasingly observed with long-term clinical use. It has been reported that etomidate inhibits the synthesis of adrenocortical hormone, thereby reducing survival in critically ill patients (Lancet.1983; 1 (8339): 1434.PubMed:6134189;Crit Care.2007;11 (3): 145.PubMed: 1761749; anesthesiology.2011;114 (3): 695-707.PubMed: 21263301). Even some studies have shown that use of etomidate in a single rapid sequential induction increases mortality in hospitalized patients (Crit Care med.2012;40 (11): 2945-53.PubMed:22971586;Anesth Analg.2013;117 (6): 1329-37.Pubmed: 24257383); many researchers speculate that this high mortality occurs in association with etomidate inhibition of adrenocortical hormone synthesis (Cochrane Database Syst Rev.2015;1: CD010225.PubMed: 25568981). Meanwhile, the other general intravenous anesthetic propofol commonly used in clinic at present has the disadvantage of obviously reducing blood pressure in the anesthesia induction process (Crit Care.2015; 19:45.PubMed:25887642) except for small treatment window, and cardiovascular adverse events are often increased. Therefore, a new compound is designed, so that the compound can not only keep the excellent characteristics of etomidate circulation stability, but also has very important clinical significance and wide application prospect without inhibiting synthesis of adrenocortical hormone.
The literature suggests that etomidate inhibits the synthesis site of adrenocortical hormone mainly by 11-beta hydroxylase and cholesterol side chain lyase, which are key enzymes in the pathways of adrenocortical synthesis of corticosterone, cortisol and the like. (N Engl J Med.1984;310 (22): 1415-21.PubMed: 6325910). Atucha et al (Bioorg Med Chem Lett.2009;19 (15): 4284-7.PubMed: 19497738) found that the esteric side chain of etomidate can affect not only GABA receptors (the primary site of the anesthetic effect of etomidate) but also the synthesis of adrenocortical hormone. In addition, etomidate, the major product of etomidate metabolism, was found to have little 11-beta hydroxylase inhibiting effect compared to etomidate (Anesthesiology. 2016;125 (5): 943-951.PubMed: 27541316). If the inhibition of adrenocortical function by the compound itself is reduced or eliminated by modification of the etomidate structure and the metabolite of the compound is also not affecting adrenocortical function, the inhibition of adrenocortical function by the drug can be reduced or eliminated. Subsequent studies based on etomidate structure have focused on how to reduce or eliminate the inhibition of adrenocortical function, in addition to retaining the advantages of etomidate in clinical use.
WO 2009/146024A1 discloses an etomidate analogue with improved pharmacokinetic and pharmacodynamic properties and its use as an anaesthetic and discloses that the compound may be MOC- (R) -etomidate.
WO 2011/005969A2 discloses an etomidate analogue with improved pharmacokinetic and pharmacodynamic properties and its use as an anaesthetic and discloses that the compound may be MOC-carboetomidate.
CN201380014062 discloses that an analogue of medetomidine and etomidate can be obtained with improved pharmacokinetic and pharmacodynamic properties, and that the compound may be cyclopropyl MOC-medetomidate.
Although scientists follow-up studies based on etomidate structure have focused on how to reduce or eliminate the inhibition of adrenocortical function in addition to retaining the advantages of etomidate for clinical use. And etomidate analogs such as dimethylmethoxycarbonyl metomidate (DMMM) and cyclopropyl methoxycarbonyl metomidate (CPMM) have been discovered sequentially, compounds that retain the unique advantages of etomidate (e.g., high potency, safety) while eliminating its inhibitory effect on adrenocortical function have not yet been sought.
Therefore, a new compound is designed, so that the compound can not only keep the excellent characteristics of etomidate circulation stability, but also has very important clinical significance and wide application prospect without inhibiting synthesis of adrenocortical hormone.
Meanwhile, there is also a need for safer imidazole derivatives in clinic for preparing medicaments with sedative, hypnotic and/or anesthetic actions and medicaments for controlling status epilepticus.
Disclosure of Invention
In order to solve the problems, the invention provides a novel substituted imidazole formate derivative and application thereof.
The present invention provides a compound of 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:
x is selected from O, S or NR 30 Wherein R is 30 Selected from hydrogen, deuterium or C 1-8 An alkyl group;
R 1 each independently selected from deuterium, halogen, -CN, -NO 2 、-OR 32 、-C(O)R 32 、-CO 2 R 32 、-CON(R 32 ) 2 、-N(R 32 ) 2 、-OC(O)R 32 、-SO 2 R 32 Substituted or unsubstituted 3-to 8-membered heterocyclic group, substituted or unsubstituted C 1-8 Alkyl, substituted or unsubstituted C 2-8 Alkenyl, substituted or unsubstituted C 2-8 Alkynyl;
wherein R is 32 Each independently selected from hydrogen, deuterium, substituted or unsubstituted C 1-8 Alkyl, substituted or unsubstituted C 2-8 Alkenyl, substituted or unsubstituted C 2-8 Alkynyl, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; the substituent is deuterium, cyano, hydroxyl, carboxyl, halogen, 3-8 membered cycloalkyl or halogen or deuterated thereof, 3-8 membered heterocyclic group or halogen or deuterated thereof, aryl or halogen or deuterated thereof, heteroaryl or halogen or deuterated thereof;
n is an integer of 0 to 5;
R 2 selected from hydrogen, deuterium, halogen, C 1-8 Alkyl or halo or deuterated, C 1-8 Alkoxy or halo or deutero, C 2-8 Alkenyl or halo or deuterated, C 2-8 Alkynyl or halo or deuterated thereof, 3-to 8-membered heterocyclyl or halo or deuterated thereof;
R 3 and R is 4 Each independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted C 1-8 An alkyl group; the substituent is deuterium, halogen and C 1-8 Alkyl or halo or deuterated, C 1-8 Alkoxy or halo or deuterated thereof, 3-8 membered cycloalkyl or halo or deuterated thereof, 3-8 membered heterocyclyl or halo or deuterated thereof, aryl or halo or deuterated thereof, heteroaryl or halo or deuterated thereof;
L 1 and L 2 Each independently selected from the group consisting of unsubstituted, substituted, and unsubstituted C 1-8 An alkylene group; the substituent is deuterium, cyano, hydroxy, carboxyl, halogen, C 1-8 Alkyl or halo or deuterated, C 2-8 Alkenyl or halo or deuterated, C 2-8 Alkynyl or halo or deuterated, C 1-8 Alkoxy or halo or deuterated thereof, 3-8 membered cycloalkyl or halo or deuterated thereof, 3-8 membered heterocyclyl or halo or deuterated thereof, aryl or halo or deuterated thereof, heteroaryl or halo or deuterated thereof;
R 5 selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C 1-8 Alkyl, -OR 33 、-SR 33 、-OC(O)R 33 、-CO 2 R 33 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, aryl, heteroaryl, -N (R) 33 ) 2 、-C(O)R 33 、-C(S)R 33 、-S(O)R 33 、-CON(R 33 ) 2 、-SO 2 R 33 、-SR 33 、-CR 33 R 40 Substituted or unsubstituted C 2-8 Alkenyl, substituted or unsubstituted C 2-8 Alkynyl;
wherein R is 33 And R is 40 Each independently selected from hydrogen, deuterium, C 1-8 Alkoxy, methylsulfonyl, substituted or unsubstituted C 1-8 Alkyl, substituted or unsubstituted C 2-8 Alkenyl, substituted or unsubstituted C 2-8 Alkynyl, allenyl, -L 31 -COO-L 32 Substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -S-C 1-8 An alkyl group; l (L) 31 Selected from substituted or unsubstituted C 1-8 An alkylene group; l (L) 32 Selected from substituted or unsubstituted C 1-8 An alkyl group;
r is as described above 5 、R 33 And R is 40 Wherein the substituents are deuterium, cyano, hydroxy, carboxyl, halogen, C 1-4 Alkyl or halo or deuterated, C 2-4 Alkenyl or halo or deuterated, C 1-4 Alkoxy or halo or deuterated thereof, 3-8 membered cycloalkyl or halo or deuterated thereof, 3-8 membered heterocyclyl or halo or deuterated thereof, aryl or halo or deuterated thereof, heteroaryl or halo or deuterated thereof, -S-C 1-4 Alkyl, =r 55 、C 2～8 Alkenyl or C 2～8 Alkynyl; wherein R is 55 Selected from O, S, NR 66 Or CR (CR) 66 R 67 ，R 66 、R 67 Each independently selected from hydrogen, deuterium, halogen, C 1-4 Alkyl or halo or deuterated thereof;
the A ring is selected from 0 to 4R 34 Substituted 3-8 membered saturated cycloalkyl, 3-8 membered unsaturated cycloalkyl, 3-8 membered saturated heterocyclyl, 3-8 membered unsaturated heterocyclyl, 5-12 membered saturated or unsaturated bridged cycloalkyl, 5-12 membered saturated or unsaturated bridged heterocyclyl, 5-12 membered saturated or unsaturated spirocycloalkyl, 5-12 membered saturated or unsaturated spiroheterocyclyl, 4-12 membered saturated or unsaturated fused ring alkyl, 4-12 membered saturated or unsaturated fused ring heterocyclyl;
wherein R is 34 Each independently selected from deuterium, halogen, cyano, isocyano, isothiocyano, allenyl, nitro, C 1-8 Alkyl or halo or deuterated, C 2-8 Alkenyl or halo or deuterated, C 2-8 Alkynyl or halo or deuterated, C 1-8 Alkoxy group、C 1-8 Alkylthio, -OC (O) R 35 、-C(O)R 35 、-S(O)R 35 、-C(O)N(R 35 ) 2 、-L 33 -R 36 Or=r 37 ；
L 33 Selected from C 1-4 An alkylene group; r is R 36 Selected from cyano, nitro, -OC (O) R 35 、-C(O)R 35 、-S(O)R 35 、-C(O)N(R 35 ) 2 ；R 35 Each independently selected from C 1-4 Alkyl or halo or deuterated thereof; r is R 37 Selected from O, S, N (R) 38 )、CR 38 R 39 、C 1-8 Alkyl or C 2-8 Alkenyl groups; r is R 38 、R 39 Each independently selected from hydrogen, halogen or C 1-8 An alkyl group;
R 5 h, L of a shape of H, L 2 If not, the A ring is not 3-6 membered saturated heterocyclic group;
ring A is substituted by 0R 34 In the case of substituted 3-membered saturated carbocycles, if L 1 And L 2 If not, R 5 Not hydrogen, ethoxy; if L 1 L is none, L 2 Is methylene, then R 5 Not methoxy; if L 1 Is methylene, L 2 Is free of or methylene, R 5 Not methoxy;
ring A is substituted by 0R 34 In the case of substituted 4-to 6-membered saturated heterocyclic groups, if L 2 If not, R 5 Is not H; if R is 5 Is H, then L 2 And not none.
Further, the method comprises the steps of,
x is selected from O, S or NR 30 Wherein R is 30 Selected from hydrogen, deuterium or C 1-4 An alkyl group;
R 1 each independently selected from deuterium, halogen, -CN, -NO 2 、-OR 32 、-C(O)R 32 、-CO 2 R 32 、-CON(R 32 ) 2 、-N(R 32 ) 2 、-OC(O)R 32 Substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 2-4 Alkenyl, substituted or unsubstituted C 2-4 Alkynyl;
wherein R is 32 Each independently selected from hydrogen, deuterium, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 2-4 Alkenyl, substituted or unsubstituted C 2-4 Alkynyl, substituted or unsubstituted 3-to 6-membered cycloalkyl, substituted or unsubstituted 3-to 6-membered heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; the substituent is deuterium, cyano, hydroxy, carboxyl and halogen;
n is an integer of 0 to 4;
R 2 selected from hydrogen, deuterium, halogen, C 1-4 Alkyl or halo or deuterated, C 1-4 Alkoxy or halo or deutero, C 2-4 Alkenyl or halo or deuterated, C 2-4 Alkynyl or halo or deuterated thereof;
R 3 and R is 4 Each independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted C 1-4 An alkyl group; the substituent is deuterium, halogen and C 1-4 Alkoxy or halo or deuterated thereof, 3-to 4-membered cycloalkyl or halo or deuterated thereof, 3-to 4-membered heterocyclyl or halo or deuterated thereof;
L 1 and L 2 Each independently selected from the group consisting of unsubstituted, substituted, and unsubstituted C 1-6 An alkylene group; the substituent is deuterium, halogen and C 1-4 Alkyl or halo or deuterated, C 2-4 Alkenyl or halo or deuterated, C 2-4 Alkynyl or halo or deuterated, C 1-4 Alkoxy or halo or deuterated thereof, 3-to 4-membered cycloalkyl or halo or deuterated thereof, 3-to 4-membered heterocyclyl or halo or deuterated thereof;
R 5 selected from hydrogen, deuterium, halogen, cyano, -OR 33 、-SR 33 、-OC(O)R 33 Cycloalkyl of 3-8 members, heterocyclyl of 3-8 members, aryl, heteroaryl, -C (O) R 33 、-C(S)R 33 、-S(O)R 33 、-CON(R 33 ) 2 、-SO 2 R 33 、-SR 33 、-CR 33 R 40 、C 2-4 Alkenyl, C 2-4 Alkynyl;
wherein R is 33 And R is 40 Each independently selected from hydrogen, deuterium, C 1-4 Alkoxy radicalRadicals, substituted or unsubstituted C 1～8 Alkyl, substituted or unsubstituted C 2-8 Alkenyl, substituted or unsubstituted C 2-8 Alkynyl, allenyl, -L 31 -COO-L 32 Substituted or unsubstituted 3-to 4-membered cycloalkyl, substituted or unsubstituted 3-to 8-membered heterocyclyl, -S-C 1-6 An alkyl group; l (L) 31 Selected from substituted or unsubstituted C 1-4 An alkylene group; l (L) 32 Selected from substituted or unsubstituted C 1-4 An alkyl group;
r is as described above 5 、R 33 And R is 40 Wherein the substituents are deuterium, cyano, hydroxy, carboxyl, halogen, C 1-4 Alkyl or halo or deuterated, C 2-4 Alkenyl or halo or deuterated, C 1-4 Alkoxy or halo or deuterated thereof, 3-to 8-membered cycloalkyl or halo or deuterated thereof, 3-to 8-membered heterocyclyl or halo or deuterated thereof, -S-C 1-4 Alkyl, =r 55 、C 2～8 Alkenyl or C 2～8 Alkynyl; wherein R is 55 Selected from O, S, NR 66 Or CR (CR) 66 R 67 ，R 66 、R 67 Each independently selected from hydrogen, deuterium, halogen, C 1-4 Alkyl or halo or deuterated thereof;
the A ring is selected from 0 to 4R 34 Substituted 3-8 membered saturated cycloalkyl, 3-8 membered unsaturated cycloalkyl, 3-8 membered saturated heterocyclyl, 3-8 membered unsaturated heterocyclyl, 5-12 membered saturated or unsaturated bridged cycloalkyl, 5-12 membered saturated or unsaturated bridged heterocyclyl, 5-12 membered saturated or unsaturated spirocycloalkyl, 5-12 membered saturated or unsaturated spiroheterocyclyl, 4-12 membered saturated or unsaturated fused ring alkyl, 4-12 membered saturated or unsaturated fused ring heterocyclyl;
Wherein R is 34 Each independently selected from deuterium, halogen, cyano, isocyano, isothiocyano, allenyl, C 1-6 Alkyl or halo or deuterated, C 2-6 Alkenyl or halo or deuterated, C 2-6 Alkynyl or halo or deuterated, C 1-4 Alkoxy, C 1-4 Alkylthio, -C (O) R 35 、-S(O)R 35 、-C(O)N(R 35 ) 2 、-L 33 -R 36 Or=r 37 ；
L 33 Selected from C 1-4 An alkylene group; r is R 36 Selected from cyano, nitro, -OC (O) R 35 、-C(O)R 35 、-S(O)R 35 、-C(O)N(R 35 ) 2 ；R 35 Each independently selected from C 1-4 Alkyl or halo or deuterated thereof; r is R 37 Selected from O, S, N (R) 38 )、CR 38 R 39 、C 1-6 Alkyl or C 2-8 Alkenyl groups; r is R 38 、R 39 Each independently selected from hydrogen, halogen or C 1-8 An alkyl group.
Further, the compound is shown as a formula II:
x is selected from O, S or NR 30 Wherein R is 30 Selected from hydrogen, deuterium or C 1-4 An alkyl group;
R 3 and R is 4 Each independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted C 1-4 An alkyl group; the substituent is deuterium, halogen and C 1-4 Alkoxy or halo or deuterated thereof, 3-to 4-membered cycloalkyl or halo or deuterated thereof, 3-to 4-membered heterocyclyl or halo or deuterated thereof;
L 1 and L 2 Each independently selected from the group consisting of unsubstituted, substituted, and unsubstituted C 1-6 An alkylene group; the substituent is deuterium, halogen and C 1-4 Alkyl or halo or deuterated, C 2-4 Alkenyl or halo or deuterated, C 2-4 Alkynyl or halo or deuterated, C 1-4 Alkoxy or halo or deuterated thereof, 3-to 4-membered cycloalkyl or halo or deuterated thereof, 3-to 4-membered heterocyclyl or halo or deuterated thereof;
R 5 Selected from hydrogen, deuterium, halogen, cyano, -OR 33 、-SR 33 、-OC(O)R 33 Cycloalkyl of 3-8 members, heterocyclyl of 3-8 members, aryl, heteroaryl, -C (O) R 33 、-C(S)R 33 、-S(O)R 33 、-CON(R 33 ) 2 、-SO 2 R 33 、-SR 33 、-CR 33 R 40 、C 2-4 Alkenyl, C 2-4 Alkynyl;
wherein R is 33 And R is 40 Each independently selected from hydrogen, deuterium, C 1-4 Alkoxy, substituted or unsubstituted C 1～8 Alkyl, substituted or unsubstituted C 2-8 Alkenyl, allenyl, substituted or unsubstituted C 2-8 Alkynyl, -L 31 -COO-L 32 Substituted or unsubstituted 3-to 4-membered cycloalkyl, substituted or unsubstituted 3-to 8-membered heterocyclyl, -S-C 1-6 An alkyl group; l (L) 31 Selected from substituted or unsubstituted C 1-4 An alkylene group; l (L) 32 Selected from substituted or unsubstituted C 1-4 An alkyl group;
r is as described above 5 、R 33 And R is 40 Wherein the substituents are deuterium, cyano, hydroxy, carboxyl, halogen, C 1-4 Alkyl or halo or deuterated, C 2-4 Alkenyl or halo or deuterated, C 1-4 Alkoxy or halo or deuterated thereof, 3-to 8-membered cycloalkyl or halo or deuterated thereof, 3-to 8-membered heterocyclyl or halo or deuterated thereof, -S-C 1-4 Alkyl, =r 55 、C 2～8 Alkenyl or C 2～8 Alkynyl; wherein R is 55 Selected from O, S, NR 66 Or CR (CR) 66 R 67 ，R 66 、R 67 Each independently selected from hydrogen, deuterium, halogen, C 1-4 Alkyl or halo or deuterated thereof;
the A ring is selected from 0 to 4R 34 Substituted 3-8 membered saturated cycloalkyl, 3-8 membered unsaturated cycloalkyl, 3-8 membered saturated heterocyclyl, 3-8 membered unsaturated heterocyclyl, 5-12 membered saturated or unsaturated bridged cycloalkyl, 5-12 membered saturated or unsaturated bridged heterocyclyl, 5-12 membered saturated or unsaturated spirocycloalkyl, 5-12 membered saturated or unsaturated spiroheterocyclyl, 4-12 membered saturated or unsaturated fused ring alkyl, 4-12 membered saturated or unsaturated fused ring heterocyclyl;
Wherein R is 34 Each independently selected from deuterium, halogen, cyano, isocyano, isothiocyano, allenyl, C 1-5 Alkyl or halo or deuterated, C 2-5 Alkenyl or halo or deuterated thereof,C 2-6 Alkynyl or halo or deuterated, C 1-4 Alkoxy, C 1-4 Alkylthio, -C (O) R 35 、-S(O)R 35 、-C(O)N(R 35 ) 2 、-L 33 -R 36 Or=r 37 ；
L 33 Selected from C 1-4 An alkylene group; r is R 36 Selected from cyano, nitro, -OC (O) R 35 、-C(O)R 35 、-S(O)R 35 、-C(O)N(R 35 ) 2 ；R 35 Each independently selected from C 1-4 Alkyl or halo or deuterated thereof; r is R 37 Selected from O, S, N (R) 38 )、CR 38 R 39 、C 1-6 Alkyl or C 2-8 Alkenyl groups; r is R 38 、R 39 Each independently selected from hydrogen, halogen or C 1-8 An alkyl group.
Further, the compound is shown as a formula IIA:
in the method, in the process of the invention,
x is selected from O, S or NR 30 Wherein R is 30 Selected from hydrogen, deuterium or C 1-4 An alkyl group;
z is selected from O or S;
R 3 and R is 4 Each independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted C 1-4 An alkyl group; the substituent is deuterium, halogen and C 1-4 Alkoxy or halo or deuterated thereof, 3-to 4-membered cycloalkyl or halo or deuterated thereof, 3-to 4-membered heterocyclyl or halo or deuterated thereof;
L 1 and L 2 Each independently selected from the group consisting of unsubstituted, substituted, and unsubstituted C 1-6 An alkylene group; the substituent is deuterium, halogen and C 1-4 Alkyl or halo or deuterated, C 2-4 Alkenyl or halo or deuterated, C 2-4 Alkynyl or halo or deuterated, C 1-4 Alkoxy or halo or deuterated thereof, 3-to 4-membered cycloalkyl or halo or deuterated thereof, 3-to 4-membered heterocyclyl or halo or deuterated thereof;
R 33 selected from hydrogen, deuterium, C 1-4 Alkoxy, substituted or unsubstituted C 1～8 Alkyl, substituted or unsubstituted C 2-8 Alkenyl, allenyl, substituted or unsubstituted C 2-8 Alkynyl, -L 31 -COO-L 32 Substituted or unsubstituted 3-to 4-membered cycloalkyl, substituted or unsubstituted 3-to 8-membered heterocyclyl, -S-C 1-6 An alkyl group; l (L) 31 Selected from substituted or unsubstituted C 1-4 An alkylene group; l (L) 32 Selected from substituted or unsubstituted C 1-4 An alkyl group; the substituent is deuterium, cyano, hydroxy, carboxyl, halogen, C 1-4 Alkyl or halo or deuterated, C 2-4 Alkenyl or halo or deuterated, C 1-4 Alkoxy or halo or deuterated thereof, 3-to 8-membered cycloalkyl or halo or deuterated thereof, 3-to 8-membered heterocyclyl or halo or deuterated thereof, -S-C 1-4 Alkyl, =r 55 、C 2～8 Alkenyl or C 2～8 Alkynyl; wherein R is 55 Selected from O, S, NR 66 Or CR (CR) 66 R 67 ，R 66 、R 67 Each independently selected from hydrogen, deuterium, halogen, C 1-4 Alkyl or halo or deuterated thereof;
the A ring is selected from 0 to 4R 34 Substituted 3-8 membered saturated cycloalkyl, 3-8 membered unsaturated cycloalkyl, 3-8 membered saturated heterocyclyl, 3-8 membered unsaturated heterocyclyl, 5-12 membered saturated or unsaturated bridged cycloalkyl, 5-12 membered saturated or unsaturated bridged heterocyclyl, 5-12 membered saturated or unsaturated spirocycloalkyl, 5-12 membered saturated or unsaturated spiroheterocyclyl, 4-12 membered saturated or unsaturated fused ring alkyl, 4-12 membered saturated or unsaturated fused ring heterocyclyl;
R 34 Selected from deuterium, halogen, cyano, isocyano, isothiocyano, allenyl, C 1-5 Alkyl or halo or deuterated, C 2-5 Alkenyl or halo or deuterated, C 2-6 Alkynyl or halo or deuterated, C 1-4 Alkoxy, C 1-4 Alkylthio, -C (O) R 35 、-S(O)R 35 、-C(O)N(R 35 ) 2 、-L 33 -R 36 Or=r 37 ；
L 33 Selected from C 1-4 An alkylene group; r is R 36 Selected from cyano, nitro, -OC (O) R 35 、-C(O)R 35 、-S(O)R 35 、-C(O)N(R 35 ) 2 ；R 35 Each independently selected from C 1-4 Alkyl or halo or deuterated thereof; r is R 37 Selected from O, S, N (R) 38 )、CR 38 R 39 、C 1-6 Alkyl or C 2-8 Alkenyl groups; r is R 38 、R 39 Each independently selected from hydrogen, halogen or C 1-8 An alkyl group;
or the compound is shown as a formula IIB:
in the method, in the process of the invention,
x is selected from O, S or NR 30 Wherein R is 30 Selected from hydrogen, deuterium or C 1-4 An alkyl group;
R 3 and R is 4 Each independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted C 1-4 An alkyl group; the substituent is deuterium, halogen and C 1-4 Alkoxy or halo or deuterated thereof, 3-to 4-membered cycloalkyl or halo or deuterated thereof, 3-to 4-membered heterocyclyl or halo or deuterated thereof;
L 1 and L 2 Each independently selected from the group consisting of unsubstituted, substituted, and unsubstituted C 1-6 An alkylene group; the substituent is deuterium, halogen and C 1-4 Alkyl or halo or deuterated, C 2-4 Alkenyl or halo or deuterated, C 2-4 Alkynyl or halo or deuterated, C 1-4 Alkoxy or halo or deuterated thereof, 3-to 4-membered cycloalkyl or halo or deuterated thereof, 3-to 4-membered heterocyclyl or halo or deuterated thereof;
R 33 Selected from hydrogen, deuterium, C 1-4 Alkoxy, substituted or unsubstituted C 1～8 Alkyl group,Substituted or unsubstituted C 2-8 Alkenyl, allenyl, substituted or unsubstituted C 2-8 Alkynyl, -L 31 -COO-L 32 Substituted or unsubstituted 3-to 4-membered cycloalkyl, substituted or unsubstituted 3-to 8-membered heterocyclyl, -S-C 1-6 An alkyl group; l (L) 31 Selected from substituted or unsubstituted C 1-4 An alkylene group; l (L) 32 Selected from substituted or unsubstituted C 1-4 An alkyl group; the substituent is deuterium, cyano, hydroxy, carboxyl, halogen, C 1-4 Alkyl or halo or deuterated, C 2-4 Alkenyl or halo or deuterated, C 1-4 Alkoxy or halo or deuterated thereof, 3-to 8-membered cycloalkyl or halo or deuterated thereof, 3-to 8-membered heterocyclyl or halo or deuterated thereof, -S-C 1-4 Alkyl, =r 55 、C 2～8 Alkenyl or C 2～8 Alkynyl; wherein R is 55 Selected from O, S, NR 66 Or CR (CR) 66 R 67 ，R 66 、R 67 Each independently selected from hydrogen, deuterium, halogen, C 1-4 Alkyl or halo or deuterated thereof;
the A ring is selected from 0 to 4R 34 Substituted 3-8 membered saturated cycloalkyl, 3-8 membered unsaturated cycloalkyl, 3-8 membered saturated heterocyclyl, 3-8 membered unsaturated heterocyclyl, 5-12 membered saturated or unsaturated bridged cycloalkyl, 5-12 membered saturated or unsaturated bridged heterocyclyl, 5-12 membered saturated or unsaturated spirocycloalkyl, 5-12 membered saturated or unsaturated spiroheterocyclyl, 4-12 membered saturated or unsaturated fused ring alkyl, 4-12 membered saturated or unsaturated fused ring heterocyclyl;
R 34 Selected from deuterium, halogen, cyano, isocyano, isothiocyano, allenyl, C 1-5 Alkyl or halo or deuterated, C 2-5 Alkenyl or halo or deuterated, C 2-6 Alkynyl or halo or deuterated, C 1-4 Alkoxy, C 1-4 Alkylthio, -C (O) R 35 、-S(O)R 35 、-C(O)N(R 35 ) 2 、-L 33 -R 36 Or=r 37 ；
L 33 Selected from C 1-4 An alkylene group; r is R 36 Selected from cyano, nitro, -OC (O) R 35 、-C(O)R 35 、-S(O)R 35 、-C(O)N(R 35 ) 2 ；R 35 Each independently selected from C 1-4 Alkyl or halo or deuterated thereof; r is R 37 Selected from O, S, N (R) 38 )、CR 38 R 39 、C 1-6 Alkyl or C 2-8 Alkenyl groups; r is R 38 、R 39 Each independently selected from hydrogen, halogen or C 1-8 An alkyl group;
or the compound is shown as a formula IIC:
in the method, in the process of the invention,
x is selected from O, S or NR 30 Wherein R is 30 Selected from hydrogen, deuterium or C 1-4 An alkyl group;
R 3 and R is 4 Each independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted C 1-4 An alkyl group; the substituent is deuterium, halogen and C 1-4 Alkoxy or halo or deuterated thereof, 3-to 4-membered cycloalkyl or halo or deuterated thereof, 3-to 4-membered heterocyclyl or halo or deuterated thereof;
L 1 selected from the group consisting of unsubstituted, substituted or unsubstituted C 1-6 An alkylene group; the substituent is deuterium, halogen and C 1-4 Alkyl or halo or deuterated, C 2-4 Alkenyl or halo or deuterated, C 2-4 Alkynyl or halo or deuterated, C 1-4 Alkoxy or halo or deuterated thereof, 3-to 4-membered cycloalkyl or halo or deuterated thereof, 3-to 4-membered heterocyclyl or halo or deuterated thereof;
The A ring is selected from 0 to 4R 34 Substituted 3-8 membered saturated cycloalkyl, 3-8 membered unsaturated cycloalkyl, 3-8 membered saturated heterocyclyl, 3-8 membered unsaturated heterocyclyl, 5-12 membered saturated or unsaturated bridged cycloalkyl, 5-12 membered saturated or unsaturated bridged heterocyclyl, 5-12 membered saturated or unsaturated spirocycloalkyl, 5-12 membered saturated or unsaturated spiroheterocyclyl, 4-12 membered saturated or unsaturated fused ring alkyl, 4-12 membered saturated or unsaturated fused ring heterocyclyl;
R 34 selected from deuteriumHalogen, cyano, isocyano, isothiocyano, allenyl, C 1-5 Alkyl or halo or deuterated, C 2-5 Alkenyl or halo or deuterated, C 2-6 Alkynyl or halo or deuterated, C 1-4 Alkoxy, C 1-4 Alkylthio, -C (O) R 35 、-S(O)R 35 、-C(O)N(R 35 ) 2 、-L 33 -R 36 Or=r 37 ；
L 33 Selected from C 1-4 An alkylene group; r is R 36 Selected from cyano, nitro, -OC (O) R 35 、-C(O)R 35 、-S(O)R 35 、-C(O)N(R 35 ) 2 ；R 35 Each independently selected from C 1-4 Alkyl or halo or deuterated thereof; r is R 37 Selected from O, S, N (R) 38 )、CR 38 R 39 、C 1-6 Alkyl or C 2-8 Alkenyl groups; r is R 38 、R 39 Each independently selected from hydrogen, halogen or C 1-8 An alkyl group.
Further, the method comprises the steps of,
in the compound IIA, the compound is a compound,
x is selected from O or S;
z is selected from O or S;
R 3 、R 4 each independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted C 1～4 An alkyl group; the substituent of the alkyl is deuterium and halogen;
L 1 and L 2 Each independently selected from the group consisting of unsubstituted, substituted, and unsubstituted C 1～6 An alkylene group; the substituent of the alkylene is deuterium and halogen;
R 33 selected from hydrogen, deuterium, substituted or unsubstituted C 1～4 Alkyl, C 1 ～ 4 Alkoxy, substituted or unsubstituted C 2 ～ 4 Alkynyl, substituted or unsubstituted C 2 ～ 4 Alkenyl, allenyl; the substituent of the alkyl is halogen; the substituent of the alkynyl is C 1～4 Alkyl, C 2 ～ 4 Alkenyl groups; the substituent of the alkenyl is C 1～4 Alkyl, halogen;
the A ring is selected from 0 to 3R 34 Substituted 4-10 membered saturated cycloalkyl, 5-10 membered unsaturated cycloalkyl, 4-10 membered saturated heterocyclyl, 5-10 membered unsaturated heterocyclyl, 5-10 membered saturated bridged cycloalkane; the heteroatom of the saturated heterocyclic group is N, O, S, and the number of the heteroatom is 1; the heteroatom of the unsaturated heterocyclic group is O, N, S, and the number of the heteroatom is 1;
R 34 selected from deuterium, halogen, C 1～4 Alkyl, C 2 ～ 4 Alkenyl, C 2 ～ 4 Alkynyl, C 1-4 An alkoxy group;
or, in the compound IIB,
x is selected from O or S;
R 3 、R 4 each independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted C 1～4 An alkyl group; the substituent of the alkyl is deuterium and halogen;
L 1 and L 2 Each independently selected from the group consisting of unsubstituted, substituted, and unsubstituted C 1～6 An alkylene group; the substituent of the alkylene is deuterium, halogen and C 2～4 Alkynyl, C 2-4 Alkenyl, C 1-4 An alkoxy group;
R 33 Selected from hydrogen, deuterium, substituted or unsubstituted C 1～6 Alkyl, C 1 ～ 4 Alkoxy, substituted or unsubstituted C 2 ～ 4 Alkynyl, substituted or unsubstituted C 2 ～ 6 Alkenyl groups; the substituent of the alkyl is halogen; the substituent of the alkynyl is C 1～4 Alkyl, C 2 ～ 4 Alkenyl groups; the substituent of the alkenyl is C 1～4 Alkyl, halogen;
the A ring is selected from 0 to 3R 34 Substituted 4-10 membered saturated cycloalkyl, 5-10 membered unsaturated cycloalkyl, 4-10 membered unsaturated heterocyclyl, 5-10 membered saturated bridged cycloalkane; the heteroatom of the unsaturated heterocyclic group is N, O, S, and the number of the heteroatom is 1;
R 34 selected from deuterium, halogen, C 1～4 Alkyl, C 2 ～ 4 Alkenyl, C 2 ～ 4 Alkynyl, C 1-4 An alkoxy group;
or, in the compound IIC,
x is selected from O or S;
R 3 、R 4 each independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted C 1～4 An alkyl group; the substituent of the alkyl is deuterium and halogen;
L 1 selected from the group consisting of unsubstituted, substituted or unsubstituted C 1～6 An alkylene group; the substituent of the alkylene is deuterium, halogen and C 2～4 Alkynyl, C 2-4 Alkenyl, C 1-4 An alkoxy group;
the A ring is selected from 0 to 3R 34 Substituted 4-10 membered saturated cycloalkyl, 5-10 membered unsaturated cycloalkyl, 4-10 membered unsaturated heterocyclyl, 6-10 membered heterospirocyclic; the hetero atom of the heterocyclic group is N, O, S, and the number of the hetero atom is 1; the hetero atom of the hetero spiro group is N, O, S, and the number of the hetero atoms is 1;
R 34 Selected from substituted or unsubstituted C 1～4 Alkyl, cyano, isocyano, isothiocyano, allenyl, C 2～5 Alkynyl, =r 37 、C 1～4 Alkylthio, C 2～5 Alkenyl groups; the substitution of the alkyl group is halogen;
R 37 selected from O, S, CR 38 R 39 、C 2～6 Alkenyl groups;
R 38 、R 39 each independently selected from hydrogen, C 1～6 Alkyl, halogen.
Further, the method comprises the steps of,
in the compound IIA, the compound is a compound,
x is selected from O or S;
z is selected from O or S;
R 3 、R 4 each independently selected from hydrogen, halogen, substituted C 1～4 An alkyl group; the substituent of the alkyl is halogen;
L 1 and L 2 Each independently selected from none, C 1～6 An alkylene group;
R 33 selected from hydrogen, C 1～4 Alkyl, C 1 ～ 4 Alkoxy, substituted or unsubstituted C 2 ～ 4 Alkynyl, C 2 ～ 4 Alkenyl, allenyl; the substituent of the alkynyl is C 2 ～ 4 Alkenyl groups;
the A ring is selected from 0 to 3R 34 Substituted 4-8 membered saturated cycloalkyl, 5-8 membered unsaturated cycloalkyl, 4-6 membered saturated heterocyclyl, 5-8 membered unsaturated heterocyclyl, 5-8 membered saturated bridged cycloalkane; the heteroatom of the saturated heterocyclic group is N, O, S, and the number of the heteroatom is 1; the heteroatom of the unsaturated heterocyclic group is O, N, S, and the number of the heteroatom is 1;
R 34 selected from C 1～4 Alkyl, C 2 ～ 4 Alkenyl, C 2 ～ 4 Alkynyl;
or, in the compound IIB,
x is selected from O or S;
R 3 、R 4 each independently selected from hydrogen, halogen, substituted C 1～4 An alkyl group; the substituent of the alkyl is halogen;
L 1 and L 2 Each independently selected from the group consisting of unsubstituted, substituted, and unsubstituted C 1～6 An alkylene group; the substituent of the alkylene is C 2～4 Alkynyl;
R 33 selected from substituted or unsubstituted C 1～6 Alkyl, C 3～6 Alkenyl, C 1 ～ 4 An alkoxy group; the substituent of the alkyl is halogen;
the A ring is selected from 0 to 3R 34 Substituted 4-8 membered saturated cycloalkyl, 5-8 membered unsaturated cycloalkyl, 4-6 membered unsaturated heterocyclyl, 5-8 membered saturated bridged cycloalkane; the heteroatom of the unsaturated heterocyclic group is N, O, S, and the number of the heteroatom is 1;
R 34 selected from C 1～4 An alkoxy group;
or, in the compound IIC,
x is selected from O or S;
R 3 、R 4 each independently selected from hydrogen, halogen;
L 1 selected from the group consisting of unsubstituted, substituted or unsubstituted C 1～6 An alkylene group; the substituent of the alkylene is C 2～4 Alkynyl;
the A ring is selected from 0 to 3R 34 Substituted 4-8 membered saturated cycloalkyl, 5-8 membered unsaturated cycloalkyl, 4-6 membered unsaturated heterocyclyl, 6-8 membered saturated spiroheterocyclyl; the heteroatom of the unsaturated heterocyclic group is N, O, S, and the number of the heteroatom is 1; the heteroatom of the saturated spiro heterocyclic group is N, O, S, and the number of the heteroatom is 1;
R 34 selected from substituted or unsubstituted C 1～4 Alkyl, cyano, isocyano, isothiocyano, allenyl, C 2～4 Alkynyl, =r 37 、C 1～4 Alkylthio, C 2～5 Alkenyl groups; the substitution of the alkyl group is halogen;
R 37 selected from O, S, CR 38 R 39 、C 2～5 Alkenyl groups;
R 38 、R 39 each independently selected from hydrogen, C 1～4 Alkyl, halogen.
Further, the method comprises the steps of,
in the compound IIA, the compound is a compound,
x is selected from O or S;
z is selected from O or S;
R 3 、R 4 each independently selected from hydrogen, halogen, substituted methyl; the substituent of the methyl is halogen;
L 1 and L 2 Each independently selected from the group consisting of no, methylene;
R 33 selected from hydrogen, methyl, C 1 ～ 2 Alkoxy, vinyl, propyienyl, substituted or unsubstituted C 2 ～ 3 Alkynyl; the substituent of the alkynyl is vinyl;
the A ring is selected from 0 to 1R 34 Substituted 4-6 membered saturated cycloalkyl, 5-7 membered unsaturated cycloalkyl, 4 membered saturated heterocyclyl, 5-7 membered unsaturated heterocyclyl, 5-membered saturated bridged cycloalkyl; the heteroatom of the saturated heterocyclic group is N, and the number of the heteroatom is 1; the heteroatom of the unsaturated heterocyclic group is O, and the number of the heteroatom is 1;
R 34 selected from ethyl, vinyl, ethynyl;
or, in the compound IIB,
x is selected from O or S;
R 3 、R 4 each independently selected from hydrogen, halogen, substituted methyl; the substituent of the methyl is halogen;
L 1 and L 2 Each independently selected from the group consisting of unsubstituted, substituted or unsubstituted methylene; the substituent of the methylene is C 2～3 Alkynyl;
R 33 selected from substituted or unsubstituted C 1～3 Alkyl, C 3 Alkenyl groups; the substituent of the alkyl is halogen;
the A ring is selected from 0 to 1R 34 Substituted 4-6 membered saturated cycloalkyl, 5-6 membered unsaturated cycloalkyl, 5-membered unsaturated heterocyclyl, 5-membered saturated bridged cycloalkyl; the heteroatom of the unsaturated heterocyclic group is O, and the number of the heteroatom is 1;
R 34 selected from C 2 An alkoxy group;
or, in the compound IIC,
x is selected from O or S;
R 3 、R 4 each independently selected from hydrogen, halogen;
L 1 selected from the group consisting of an unsubstituted, substituted or unsubstituted methylene group; the substituent of the methylene is C 2～3 Alkynyl;
the A ring is selected from 0 to 2R 34 Substituted 4-6 membered saturated cycloalkyl, 5 membered unsaturated heterocyclyl, 6 membered saturated spiroheterocyclyl; the heteroatom of the unsaturated heterocyclic group is O, and the number of the heteroatom is 1; the heteroatom of the saturated spiro heterocyclic group is O, and the number of the heteroatom is 1;
R 34 selected from substituted or unsubstituted C 1～2 Alkyl, cyano, isocyano, isothiocyano, allenyl, C 2～3 Alkynyl, =r 37 Methylthio, vinyl; the substitution of the alkyl group is halogen;
R 37 selected from O, S, CR 38 R 39 Vinyl;
R 38 、R 39 each independently selected from hydrogen, C 1～2 Alkyl, halogen.
Further, the compound is:
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The invention also provides the use of the aforementioned compound, 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 the manufacture of a medicament having sedative, hypnotic and/or anesthetic effects, and/or useful for controlling status epilepticus; wherein the anesthesia is general anesthesia.
The invention also provides a medicine which is a preparation prepared from the compound, or a stereoisomer, or a pharmaceutically acceptable salt, or a solvate, or a prodrug, or a metabolite, or a deuterated derivative of the compound, or the stereoisomer, or the pharmaceutically acceptable salt, or the solvate, or the prodrug, or the metabolite, or the deuterated derivative of the prodrug, and pharmaceutically acceptable auxiliary materials.
The invention relates to a drug with sedation, which is a drug for effectively helping sleep and effectively improving sleep. Can avoid serious harm of insomnia to human body, treat insomnia and improve sleep quality.
The invention relates to a drug with hypnotic effect, which is a drug capable of inducing drowsiness and promoting sleep. I.e. has an inhibitory effect on the central nervous system, a small dose causes sedation, and an excess leads to general anesthesia.
The term "drug with anesthesia" as used herein refers to a reversible inhibition of central and/or peripheral nervous system functions, which is characterized by a loss of sensation, particularly pain, resulting from the drug.
Preferably, the anesthesia is general anesthesia.
The general anesthesia is abbreviated as general anesthesia, and refers to temporary inhibition of central nervous system after anesthetic enters the body, and clinical manifestations of the general anesthesia are loss of mind, loss of general pain, forgetfulness, reflex inhibition and skeletal muscle relaxation.
The use of a compound as defined above, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, for the manufacture of a medicament capable of controlling status epilepticus.
The invention relates to a status epilepticus, which means that consciousness between epileptic continuous seizures is not completely recovered and frequently recurred, or the seizure is not stopped by itself after more than 30 minutes. If the epileptic seizure is not treated in time, irreversible brain damage can be caused by hyperthermia, circulatory failure or neuronal excitotoxic damage, and the disability rate and the death rate are high, so that the epileptic status is a common emergency in the department of medicine.
The invention provides a medicine which is a preparation prepared from the compound, or a stereoisomer, or a pharmaceutically acceptable salt, or a solvate, or a prodrug, or a metabolite, or a deuterated derivative thereof, and pharmaceutically acceptable auxiliary materials.
The compounds and derivatives provided in the present invention may be named according to IUPAC (international union of pure and applied chemistry) or CAS (chemical abstract service, columbus, OH) naming system.
Definition of terms used in connection with the present invention: unless otherwise indicated, the initial definitions provided for groups or terms herein apply to the groups or terms throughout the specification; for terms not specifically defined herein, the meanings that one skilled in the art can impart based on the disclosure and the context.
"substituted" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
The structures of the compounds in the invention all refer to structures which can exist stably.
"deuterium" refers to an isotope of hydrogen (H), also known as deuterium, with the elemental symbol typically D or 2H.
The substituent "-C (O) R" in the present invention 32 "has the structural formula:
substituent "-CO" in the present invention 2 R 32 "has the structural formula:
substituent "-CON (R) in the present invention 32 ) 2 "has the structural formula:
substituent "-N in the present invention(R 32 ) 2 "has the structural formula:
substituent "-OC (O) R in the present invention 32 "has the structural formula:
substituent "-SO" in the present invention 2 R 32 "has the structural formula:
the substituent "-C (S) R" in the present invention 33 "has the structural formula:
in the present invention, the substituent "-S (O) R 33 "has the structural formula:
substituent "-CR" in the present invention 33 R 40 "has the structural formula:
substituent "-OR" in the present invention 33 "has the structural formula:
the minimum and maximum values of the carbon atom content in the hydrocarbon group are represented by prefixes, for example, prefixes (C a ～ b ) Alkyl indicates any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, C 1 ～ 8 Alkyl refers to alkyl groups containing 1 to 8 carbon atoms. C (C) 1 ～ 8 Alkyl refers to a straight or branched hydrocarbon chain containing one to eight carbon atoms.
"alkyl" is a hydrocarbon radical containing few hydrogen atoms in the alkane molecule, e.g. methyl-CH 3 ethyl-CH 3 CH 2 Etc.
"alkylene" refers to a hydrocarbon group of alkane molecules with a reduced number of two hydrogen atoms, e.g. methylene-CH 2 -, ethylene-CH 2 CH 2 -and the like. "C 1-8 Alkylene "refers to a straight or branched hydrocarbon chain containing one to eight carbon atoms.
"substituted or unsubstituted C 1-8 Alkyl "means C 1-8 The alkyl group may be substituted or unsubstituted.
In the present invention, 3-8 membered cycloalkyl means 3-8 membered saturated cycloalkyl and 3-8 membered unsaturated cycloalkyl, and cycloalkyl in the present invention means monocyclic cycloalkyl.
In the present invention, 3-8 membered saturated cycloalkyl means a monocyclic cycloalkyl group consisting of 3 to 8 carbon atoms, wherein there is no double bond in the cycloalkyl group. For example:
in the present invention, 3-to 8-membered unsaturated cycloalkyl means a monocyclic cycloalkyl group consisting of 3 to 8 carbon atoms, wherein the cycloalkyl group contains a double bond. For example:
etc.
In the present invention, 3-8 membered heterocyclic group means 3-8 membered saturated heterocyclic group and 3-8 membered unsaturated heterocyclic group, and heterocyclic groups in the present invention mean monocyclic heterocyclic group.
In the present invention, a 3-to 8-membered saturated heterocyclic group means a saturated monocyclic heterocyclic group having no double bond, wherein the heterocyclic group carries at least one nitrogen atom selected from O, S or a substituent, and the remaining ring atoms are carbon. For example:
etc.
In the present invention, a 3-to 8-membered unsaturated heterocyclic group means an unsaturated monocyclic heterocyclic group having a double bond, wherein the heterocyclic group carries at least one nitrogen atom selected from O, S or a substituent, and the remaining ring atoms are carbon. For example:
etc.
In the present invention, a 5-to 12-membered saturated or unsaturated bridged cycloalkyl group means a bridged cycloalkyl group consisting of 5 to 12 carbon atoms; wherein, the bridged cycloalkyl has no double bond or has double bond.
In the present invention, a 5-to 12-membered saturated or unsaturated bridged heterocyclic group means a bridged heterocyclic group having no double bond or containing a double bond, wherein the bridged heterocyclic group carries at least one nitrogen atom selected from O, S or substitution, and the remaining ring atoms are carbon.
In the present invention, a 5-to 12-membered saturated or unsaturated spirocycloalkyl group means a spirocycloalkyl group consisting of 5 to 12 carbon atoms, wherein there is no double bond or a double bond in the spirocycloalkyl group.
In the invention, the 5-12 membered saturated or unsaturated spiroheterocyclic group refers to a spiroheterocyclic group without double bonds or containing double bonds, wherein at least one nitrogen atom selected from O, S or substituted nitrogen atoms is carried in the spiroheterocyclic group, and the rest ring atoms are carbon.
In the present invention, a 4-to 12-membered saturated or unsaturated condensed ring alkyl group means a condensed ring alkyl group consisting of 4 to 12 carbon atoms, wherein the condensed ring alkyl group has no double bond or has a double bond.
In the present invention, the 4-12 membered saturated or unsaturated fused heterocyclic group means a fused heterocyclic group having no double bond or containing double bond, wherein at least one nitrogen atom selected from O, S or substitution is carried in the fused heterocyclic group, and the remaining ring atoms are carbon.
In the present invention, bridged cycloalkyl, bridged heterocyclyl, spirocycloalkyl, spiroheterocyclyl, fused-ring alkyl, fused-ring heterocyclyl include both bicyclic and polycyclic rings (e.g., tricyclic, tetracyclic, pentacyclic, etc.).
"alkynyl" refers to an aliphatic hydrocarbon group having one carbon-carbon triple bond. The alkynyl group may be straight or branched. Having a definition of the number of carbon atoms before alkynyl (e.g. C 2-8 Alkynyl), for example, the term "C 2-8 Alkynyl "refers to straight or branched chain alkynyl groups having 2 to 8 carbon atoms.
"alkenyl" refers to an aliphatic hydrocarbon group having one carbon-carbon double bond. The alkenyl group may be straight or branched. Having a limit on the number of carbon atoms before the alkenyl group (e.g. C 2-8 Alkenyl), for example, the term "C 2-8 Alkenyl "refers to straight or branched alkenyl groups having 2 to 8 carbon atoms.
Halogen is fluorine, chlorine, bromine or iodine.
"aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, such as phenyl and naphthyl. The aryl ring may be fused to other cyclic groups (including saturated and unsaturated rings) but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, while the point of attachment to the parent must be at a carbon atom on the ring with a conjugated pi-electron system. Aryl groups may be substituted or unsubstituted.
"heteroaryl" refers to a heteroaromatic group containing one to more heteroatoms. Heteroatoms as referred to herein include oxygen, sulfur and nitrogen. Such as furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring. Heteroaryl groups may be optionally substituted or unsubstituted.
"cycloalkyl" refers to a saturated or unsaturated cyclic hydrocarbon substituent;the cyclic hydrocarbon may be a single ring or multiple rings. For example, "C 3-8 Cycloalkyl "refers to cycloalkyl groups having 3 to 8 carbon atoms.
"heterocyclyl" refers to a saturated or unsaturated cyclic hydrocarbon substituent; the cyclic hydrocarbon may be monocyclic or polycyclic and carries at least one cycloalkyl group selected from O, S or a substituted nitrogen atom, the remaining ring atoms being carbon, e.g. "C 3-8 The heterocyclic group means a heterocyclic group having 3 to 8 carbon atoms and a hetero atom in total.
One carbon atom of the "A ring" in the compounds of the invention being attached to L 1 And L 2 Directly connected. For example:
etc.
The A ring is none or is covered with' 0-4R 34 Substituted "0-4R 34 Substituted 3-7 membered saturated cycloalkyl, 3-12 membered unsaturated cycloalkyl, 3-12 membered saturated heterocyclic group, 3-12 membered unsaturated heterocyclic group, 5-10 membered saturated bridged cycloalkyl, 6-12 membered saturated spirocycloalkyl, 6-12 membered saturated spiroheterocyclic group; wherein R is 34 Each independently selected from deuterium, halogen, cyano, isocyano, isothiocyano, allenyl, nitro, C 1-8 Alkyl or halo or deuterated, C 2-8 Alkenyl or halo or deuterated, C 2-8 Alkynyl or halo or deuterated, C 1-8 Alkoxy, C 1-8 Alkylthio, -OC (O) R 35 、-C(O)R 35 、-S(O)R 35 、-C(O)N(R 35 ) 2 、-L 33 -R 36 Or=r 37 。
Here, with "substituent R 34 "the carbon atom attached is not L 1 Or L 2 Directly linked carbon atoms. For example:
etc.
“C 1-4 Alkyl or halo or deuterated "means C 1-4 Alkyl, C substituted by halogen or deuterium 1-4 An alkyl group. Other terms are similarly defined with respect to "or halo or deuterated thereof".
Among all the compounds of the present invention, each chiral carbon atom (chiral center) may optionally be in the R configuration or S configuration, or a mixture of R and S configurations.
"pharmaceutically acceptable carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulphate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g. tween ) Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, antioxidants, preservatives, pyrogen-free water and the like.
The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention with pharmaceutically acceptable inorganic and organic acids, suitable for contact with the tissues of a subject (e.g., a human) without undue adverse side effects. Among the preferred mineral acids include (but are not limited to): hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, and sulfuric acid; preferred organic acids include (but are not limited to): formic acid, acetic acid, propionic acid, succinic acid, naphthalene disulfonic acid (1, 5), asiatic acid, oxalic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, valeric acid, diethyl acetic acid, malonic acid, succinic acid, fumaric acid, pimelic acid, adipic acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, p-toluenesulfonic acid, citric acid, and amino acids.
The term "pharmaceutically acceptable solvate" refers to a solvate of a compound of the invention with a pharmaceutically acceptable solvent, wherein the pharmaceutically acceptable solvent includes (but is not limited to): water, ethanol, methanol, isopropanol, propylene glycol, tetrahydrofuran, and dichloromethane.
As used herein, the term "pharmaceutically acceptable stereoisomer" refers to a chiral carbon atom referred to in the compounds of the invention that can be in the R configuration, or in the S configuration, or a combination thereof.
The compounds of the invention or compositions and methods of use thereof:
the compounds of the present invention and various crystalline forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, as well as pharmaceutical compositions containing the compounds of the present invention as the primary active ingredient, are useful in the administration of sedation, hypnosis and/or general anesthesia. The compounds of the present invention are also useful in the control of status epilepticus and the like.
The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
Modes of use of the compounds or pharmaceutical compositions of the present invention include (but are not limited to): intragastric, enteral, parenteral (intravenous, intramuscular or subcutaneous), oral and various topical administration.
Compositions for parenteral (intravenous, intramuscular, subcutaneous) injection may comprise physiologically acceptable sterile aqueous or anhydrous 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.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.
Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.
Dosage forms of the compounds of the present invention for topical administration 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 which may be required if necessary.
In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-agar or mixtures of these substances, and the like.
The compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
When used in pharmaceutical compositions, a safe and effective amount of a compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically safe and effective dosage.
When a pharmaceutical composition is used, a safe and effective amount of a compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is pharmaceutically effective, and for a human of 60 kg body weight, the daily dosage is usually 1 to 2000 mg, preferably 5 to 500 mg. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.
The room temperature is 25+/-5 ℃.
The "overnight" according to the invention is 12.+ -. 1 hour.
The "1N HCl" of the invention is 1mol/L HCl.
The invention provides a compound shown in a formula I, which is a substituted imidazole or pyrrole formate derivative with a novel structure, has a good inhibition effect on a central nervous system, can be used for preparing medicines with sedative, hypnotic and/or anesthetic effects, can be used for preparing medicines capable of controlling epileptic persistance, and provides a new choice for clinically screening and/or preparing medicines with sedative, hypnotic and/or anesthetic effects, epileptic persistance control and the like.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Drawings
FIG. 1 shows the effect (measured value) of the compounds of the invention on Mean Arterial Pressure (MAP).
FIG. 2 shows the effect (rate of change) of the compounds of the invention on Mean Arterial Pressure (MAP).
FIG. 3 shows the effect (measured value) of the compounds of the invention on Heart Rate (HR).
FIG. 4 shows the effect (rate of change) of the compounds of the invention on Heart Rate (HR).
Detailed Description
The materials and equipment used in the embodiments of the present invention are all known products and are obtained by purchasing commercially available products.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. Delta.) of 10 -6 Units of (ppm) are given. NMR was performed using a (Bruker Avance III) nuclear magnetic resonance apparatus, in which the solvent was deuterated dimethyl sulfoxide (d) 6 -DMSO) or deuterated chloroform (CDCl) 3 ) The internal standard is Tetramethylsilane (TMS).
LCMS was measured (Agilent LCMS 1260-6110) (ESI), column: waters X-Bridge C18 (50mm X4.6mm X3.5 μm). Column temperature is 40 ℃; the flow rate is 2.0mL/min; mobile phase from 95% [ water+0.05% TFA over 3 minutes]And 5% [ CH ] 3 CN+0.05％TFA]Gradient to 0% [ water+0.05% TFA]And 100% [ CH ] 3 CN+0.05％TFA]Under this condition for 1 minute, and thenGradient to 95% over 0.05 min [ water+0.05% TFA]And 5% [ CH ] 3 CN+0.05％TFA]This condition was maintained for an additional 0.7 minutes.
1) Medicinal materials and reagents
The thin layer chromatography silica gel plate is HSGF254 silica gel plate of Ministry of Chemicals, ministry of tobacco, and has a thickness of 1mm.
Thin Layer Chromatography (TLC) was developed using a smoke table Jiang You silica gel, a product of the company limited, with a specification of 0.2±0.03mm.
The column layer is generally carried by silica gel of 100-200 mesh or 200-300 mesh of solar desiccant Co., ltd., shandong Wisea.
2) Main instrument
JA2003N electronic balance (Shanghai bleb instruments, inc.);
98-2 magnetic stirrer (Shanghai Sele instruments Co., ltd.);
contact voltage regulator (Zhejiang day positive electric machine Co., ltd.);
temperature controller (Shanghai position, electric appliance Co., ltd.);
ZF-2 three-purpose ultraviolet instrument (Shanghai Anting electronic instruments works);
R-201 rotary evaporator (Shanghai Shen Shun Biotechnology Co., ltd.);
W201D thermostatic water bath (Shanghai Shen Shun Biotechnology Co., ltd.);
SHB-III circulating water vacuum pump (Zhengzhou Hui Cheng Co., ltd.);
SHB-B95 mobile water pump (Zhengzhou Hui Cheng Kong trade Co., ltd.);
a cryo-cooling circulation pump (incorporated by reference, inc.);
rotary vane vacuum pump (a company of forever vacuum equipment, in the ocean);
ultraviolet high-pressure mercury lamp (Beijing Tianmai constant glow source electric Co., ltd.).
General operation a:
1H-imidazole-5-carboxylic acid, 4-fluoro-1H-imidazole-5-carboxylic acid, 2-fluoro-1H-imidazole-5-carboxylic acid, 4-chloro-1H-imidazole-5-carboxylic acid, 2, 4-dichloro-1H-imidazole-5-carboxylic acid, 4-trifluoromethyl-1H-imidazole-5-carboxylic acid were dissolved in methylene chloride (2 mL/mmol of imidazole carboxylic acid) (1 eq), DCC (1.5 eq) and DMAP (1.5 eq) at room temperature, stirred for 5 minutes at room temperature, and the corresponding alcohol (1.5 eq) was slowly added to the reaction system using a syringe, and stirred overnight at room temperature. After the TLC monitoring system is completely reacted, removing a solvent through reduced pressure concentration, adding methyl tertiary butyl ether, stirring, carrying out suction filtration, washing a filter cake by using the methyl tertiary butyl ether, concentrating the filtrate under reduced pressure to obtain a crude product, purifying the crude product through silica gel column chromatography (one of the ratio of ethyl acetate to petroleum ether (v/v) =1/1-1/6), monitoring the TLC (one of the ratio of ethyl acetate to petroleum ether (v/v) =1/1-1/6), and collecting a certain part of Rf=0.3-0.7 to obtain a 2-position, 4-position or 2, 4-position substituted 1H-imidazole-5-formate intermediate.
At the temperature of 0 ℃ in ice water bath, the 2,4 or 2, 4-substituted 1H-imidazole-5-formate intermediate (1 eq), S-phenethyl alcohol (1.5 eq) and PPh obtained in the last step are prepared 3 (1.5 eq) was dissolved in THF (10 mL/mmol of the substituted imidazole formate) solution, and then DEAD (1.5 eq) was slowly added dropwise to the above reaction system with a syringe, slowly warmed to room temperature after the dropwise addition was completed, and stirring was continued overnight. After completion of the reaction by TLC, saturated brine (10 mL) was added to the reaction system, extracted with ethyl acetate (3×10 mL), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered off with suction, concentrated under reduced pressure to give a crude product, which was purified by preparative TLC (ethyl acetate/petroleum ether (v/v) =1/1) and some fraction of rf=0.3 to 0.7 was collected to give the objective compound.
EXAMPLE 1 preparation of Compound 1 of the present invention
1. Preparation of 3- (hydroymethyl) cyclic-1-carbonifile (1-1)
3-Methylenecyclobutylcarbonitrile (5.59 g,60 mmol) was dissolved in THF (150 mL) and the system was cooled to dryness in an ice-water bathAt 0deg.C, 9-BBN (0.5M/THF, 144mL,72 mmol) was added dropwise to the system at a rate of 2mL/min, and the temperature was controlled below 0deg.C, stirring was continued at this temperature for 1 hour, the system was warmed naturally to room temperature, and the reaction was continued for 4 hours. Sodium perborate (24.54 g,300 mmol) in H 2 A solution of O (200 mL) was added dropwise to the system at a rate of 5mL/min and stirred at room temperature for 12 hours. After the reaction was completed by TLC, it was filtered under suction, the cake was washed with ethyl acetate (3X 50 mL), the filtrate was extracted with ethyl acetate (3X 50 mL), the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered under suction, and concentrated under reduced pressure to give Compound 1-1 (4.41 g, 66%) as a colorless oil, which was used in the next reaction without purification. ESI [ M+H ]] + ＝112.1
2. Preparation of (3-cyanobutyl) methyl 1H-imidozole-5-carboxylate (1-2)
1H-imidazole-5-carboxylic acid (112 mg,1.0 mmol), DCC (309 mg,1.5 mmol) and DMAP (183 mg,1.5 mmol) were dissolved in dichloromethane (2 mL) at room temperature, stirred at room temperature for 5 min, 1-1 (167 mg,1.5 mmol) was slowly added to the reaction by syringe, and stirred at room temperature overnight. The reaction was monitored by TLC to completion, the solvent was removed by concentrating under reduced pressure, methyl tert-butyl ether (5 mL) was added, stirred, filtered off with suction, the filter cake was washed with methyl tert-butyl ether, the filtrate was concentrated under reduced pressure to give the crude product, which was purified by preparative TLC (ethyl acetate/petroleum ether (v/v) =1/1) and the fraction of rf=0.4 to 0.6 was collected to give compound 1-2 (161 mg, yield 78%) as a colourless oil. ESI [ M+H ] ] + ＝206.1
3. Preparation of target Compound 1
1-2 (160 mg,0.78 mmol), S-phenethyl alcohol (143 mg,1.17 mmol) and PPh were incubated in an ice water bath at 0deg.C 3 (307 mg,1.17 mmol) was dissolved in THF (8 mL) and then DEA was injected with a syringeD (204 mg,1.17 mmol) was slowly added dropwise to the reaction system, and after the completion of the dropwise addition, the mixture was slowly warmed to room temperature and stirred overnight. After completion of the reaction by TLC, saturated brine (10 mL) was added to the reaction system, extracted with ethyl acetate (3×10 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered off with suction, concentrated under reduced pressure to give a crude product, which was purified by preparative TLC (ethyl acetate/petroleum ether (v/v) =1/1) and a fraction of rf=0.4 to 0.5 was collected to give the objective compound 1 (82 mg, yield 34%). ESI [ M+H ]] + ＝310.3
1 H NMR(400MHz,CDCl 3 )δ7.87–7.75(m,2H),7.41–7.27(m,3H),7.22–7.12(m,2H),6.38–6.26(m,1H),4.28–4.14(m,2H),3.17–2.87(m,1H),2.80–2.63(m,1H),2.56–2.43(m,2H),2.33–2.15(m,2H),1.88(d,J＝7.1Hz,3H).
The following compounds 2 to 39 were prepared analogously to example 1, compound 1 and according to the general procedure a, using 1H-imidazole-5-carboxylic acid to condense with the corresponding tetracyclic alcohol to give the 1H-imidazole-5-carboxylic acid ester intermediate, which was then reacted with S-phenylethanol.
Compound 2:210mg, ESI [ M+H ]] + ＝296.2
1 H NMR(400MHz,CDCl 3 )δ7.84(s,1H),7.79(s,1H),7.35(dt,J＝13.7,6.9Hz,3H),7.17(d,J＝7.1Hz,2H),6.28(q,J＝7.1Hz,1H),5.08(t,J＝7.4Hz,1H),2.98–2.71(m,3H),2.64–2.47(m,2H),1.88(d,J＝7.1Hz,3H).
Compound 3:171mg, ESI [ M+H ]] + ＝343.3
1 H NMR(400MHz,CDCl 3 )δ7.89–7.75(m,2H),7.42–7.29(m,3H),7.23–7.14(m,2H),6.43–6.31(m,1H),4.32–4.12(m,2H),3.69(s,3H),3.18–2.98(m,1H),2.70–2.57(m,1H),2.47–2.27(m,2H),2.19–2.01(m,2H),1.87(d,J＝7.1Hz,3H).
Compound 4:10mg, ESI [ M+H ]] + ＝313.3
1 H NMR(400MHz,CDCl 3 )δ9.79(s,1H),7.88(s,1H),7.82(s,1H),7.42–7.29(m,3H),7.24–7.14(m,2H),6.45–6.28(m,1H),4.35–4.19(m,2H),3.25–3.05(m,1H),2.77–2.57(m,1H),2.49–2.33(m,2H),2.33–2.17(m,1H),2.15–1.96(m,1H),1.88(d,J＝6.5Hz,3H).
Compound 5:23mg, ESI [ M+H ]] + ＝299.2
1 H NMR(400MHz,CDCl 3 )δ9.77(s,1H),8.00(s,1H),7.85(s,1H),7.38–7.34(m,3H),7.26–7.20(m,2H),6.37–6.35(m,1H),,5.27–5.11(m,1H),3.02–2.84(m,1H),2.65–2.62(m,2H),2.41–2.38(m,2H),1.89(d,J＝7.0Hz,3H).
Compound 6:37mg, ESI [ M+H ]] + ＝327.3
1 H NMR(400MHz,CDCl 3 )δ7.86(d,J＝5.7Hz,1H),7.81(d,J＝4.6Hz,1H),7.41–7.28(m,3H),7.23–7.15(m,2H),6.44–6.32(m,1H),4.33–4.21(m,1H),4.20–4.07(m,1H),3.28–3.10(m,1H),2.69–2.54(m,1H),2.42–2.31(m,1H),2.31–2.20(m,1H),2.09(s,3H),2.06–1.94(m,2H),1.90–1.83(m,3H).
Compound 7:16mg, ESI [ M+H ] ] + ＝313.3
1 H NMR(400MHz,CDCl 3 )δ7.80(d,J＝4.6Hz,1H),7.75(d,J＝4.3Hz,1H),7.42–7.30(m,3H),7.20–7.17(m,2H),6.39–6.25(m,1H),5.16–5.07(m,1H),2.99–2.93(m,1H),2.64–2.60(m,2H),2.36–2.31(m,2H),2.15(s,3H),1.87(d,J＝7.1Hz,3H).
Compound 8:43mg, ESI [ M+H ]] + ＝309.3
1 H NMR(400MHz,CDCl 3 )δ7.91–7.81(m,2H),7.40–7.29(m,3H),7.23–7.16(m,2H),6.42–6.35(m,1H),4.32–4.12(m,2H),3.10–2.52(m,2H),2.47–2.36(m,1H),2.31–2.22(m,1H),2.19(d,J＝2.4Hz,1H),2.17–2.08(m,1H),2.03–1.92(m,1H),1.89–1.87(m,3H).
Compound 9:164mg, ESI [ M+H ]] + ＝295.3
1 H NMR(400MHz,CDCl 3 )δ7.83(s,1H),7.78(s,1H),7.35(dt,J＝13.7,6.9Hz,3H),7.19(d,J＝7.2Hz,2H),6.33(d,J＝7.1Hz,1H),5.01(t,J＝7.4Hz,1H),2.90–2.63(m,3H),2.40–2.23(m,2H),2.20(d,J＝2.2Hz,1H),1.88(d,J＝7.1Hz,3H).
Compound 10:48mg, ESI [ M+H ]] + ＝329.3
1 H NMR(400MHz,CDCl 3 )δ7.86–7.80(m,2H),7.42–7.29(m,3H),7.23–7.16(m,2H),6.45–6.30(m,1H),4.32–4.10(m,2H),3.41–3.28(m,5H),2.68–2.42(m,2H),2.20–2.07(m,1H),1.91(t,J＝7.5Hz,2H),1.87(d,J＝7.1Hz,3H),1.66–1.54(m,1H).
Compound 11:164mg, ESI [ M+H ]] + ＝315.3
1 H NMR(400MHz,CDCl 3 )δ7.79(s,1H),7.74(s,1H),7.34–7.26(m,3H),7.19–7.17(m,2H),6.34(q,J＝7.0Hz,1H),5.10–4.90(m,1H),3.38(d,J＝6.1Hz,2H),3.35(s,2H),2.63–2.42(m,2H),2.31–2.11(m,1H),1.95–1.91(m,2H),1.85(d,J＝7.1Hz,3H).
Compound 12:55mg, ESI [ M+H ]] + ＝315.3
1 H NMR(400MHz,CDCl 3 )δ7.81(s,1H),7.76(s,1H),7.41–7.31(m,3H),7.25–7.20(m,2H),6.37(d,J＝7.1Hz,1H),4.28–4.13(m,2H),3.81–3.77(m,1H),3.37(s,3H),2.41–2.18(m,3H),1.88(d,J＝7.1Hz,3H),1.78–1.70(m,2H).
Compound 13:200mg, ESI [ M+H ]] + ＝301.3
1 H NMR(400MHz,CDCl 3 )δ7.78(s,1H),7.72(s,1H),7.35–7.25(m,3H),7.17–7.16(m,2H),6.31(q,J＝7.1Hz,1H),4.79–4.75(m,1H),3.63–3.59(m,1H),3.25(s,3H),2.85–2.76(m,2H),2.13–2.05(m,2H),1.85(d,J＝7.1Hz,3H).
Compound 14:132mg, ESI [ M+H ]] + ＝297.3
1 H NMR(400MHz,CDCl 3 )δ7.81(s,1H),7.80(s,1H),7.41–7.28(m,3H),7.23–7.14(m,2H),6.37(q,6.7Hz,1H),4.85–4.73(m,2H),4.35–4.18(m,2H),2.89–2.75(m,2H),2.74–2.59(m,1H),2.53–2.39(m,2H),1.88(d,J＝7.1Hz,3H).
Compound 15:10mg, ESI [ M+H ]] + ＝299.2
1 H NMR(400MHz,CDCl 3 )δ7.85(s,2H),7.41–7.30(m,3H),7.23–7.15(m,2H),6.35(q,J＝6.9Hz,1H),5.40–5.29(m,1H),2.94–2.81(m,2H),2.78(s,2H),2.72–2.57(m,2H),1.88(d,J＝7.1Hz,3H).
Compound 16:164mg, ESI [ M+H ]] + ＝353.2
1 H NMR(400MHz,CDCl 3 )δ7.80(s,1H),7.77(s,1H),7.34–7.26(m,3H),7.23–7.21(m,2H),6.34(q,J＝7.2Hz,1H),3.70(s,3H),3.14–3.10(m,1H),2.98–2.85(m,2H),2.79–2.65(m,2H),2.64(s,1H),1.87(d,J＝7.1Hz,3H).
Compound 17:18mg, ESI [ M+H ]] + ＝313.3
1 H NMR(400MHz,CDCl 3 )δ7.93(s,1H),7.86(s,1H),7.41–7.29(m,3H),7.23–7.13(m,2H),6.40(q,J＝7.0Hz,1H),4.50(q,J＝12.0Hz,2H),3.80(s,2H),2.94(t,J＝3.1Hz,1H),1.88(d,J＝7.1Hz,3H),1.81–1.73(m,2H),1.56–1.44(m,2H).
Compound 18:129mg, ESI [ M+H ]] + ＝355.2
1 H NMR(400MHz,CDCl 3 )δ7.79(s,1H),7.71(s,1H),7.36–7.31(m,3H),7.21–7.19(m,2H),6.32(q,J＝7.0Hz,1H),6.15(dd,J＝17.2,10.8Hz,1H),5.27(dd,J＝21.6,14.1Hz,2H),3.72(s,3H),2.89–2.82(m,1H),2.78–2.61(m,4H),1.86(d,J＝7.1Hz,3H).
Compound 19:45mg, ESI [ M+H ]] + ＝357.3
1 H NMR(400MHz,CDCl 3 )δ7.81(s,1H),7.80(s,1H),7.35–7.30(m,3H),7.19–7.17(m,2H),6.32(q,J＝7.0Hz,1H),4.70–4.62(m,1H),3.06–2.99(m,2H),2.64(d,J＝4.0Hz,3H),1.87(d,J＝7.1Hz,3H).
Compound 20:90mg, ESI [ M+H ]] + ＝315.3
1 H NMR(400MHz,CDCl 3 )δ7.82(s,1H),7.81(s,1H),7.39–7.28(m,3H),7.22–7.15(m,2H),6.35(q,J＝6.9Hz,1H),4.79(p,J＝7.4Hz,1H),3.70(p,J＝7.0Hz,1H),3.42(q,J＝7.0Hz,2H),2.91–2.72(m,2H),2.18–2.07(m,2H),1.87(d,J＝7.1Hz,3H),1.21(t,J＝7.0Hz,3H).
Compound 21:40mg, ESI [ M+H ]] + ＝329.3
1 H NMR(400MHz,CDCl 3 )δ7.80(s,1H),7.77(s,1H),7.34–7.29(m,3H),7.19–7.17(m,2H),6.33(q,J＝7.1Hz,1H),4.78–4.74(m,1H),3.76–3.73(m,1H),3.63–3.57(m,1H),2.89–2.72(m,2H),2.21–2.07(m,2H),1.86(d,J＝7.1Hz,3H),1.15(d,J＝6.1Hz,6H).
Compound 22:15mg, ESI [ M+H ]] + ＝327.3
1 H NMR(400MHz,CDCl 3 )δ7.87(s,1H),7.82(s,1H),7.42–7.28(m,3H),7.23–7.11(m,2H),6.36(q,J＝7.0Hz,1H),6.01–5.84(m,1H),5.32–5.24(m,1H),5.22–5.16(m,1H),4.79(p,J＝7.3Hz,1H),3.96–3.86(m,2H),3.75(p,J＝7.1Hz,1H),2.90–2.75(m,2H),2.21–2.10(m,2H),1.87(d,J＝7.1Hz,3H).
Compound 23:22mg, ESI [ M+H ]] + ＝317.2
1 H NMR(400MHz,CDCl 3 )δ7.79(s,1H),7.76(s,1H),7.39–7.28(m,3H),7.23–7.15(m,2H),6.28(q,J＝7.1Hz,1H),4.80–4.70(m,1H),2.90–2.69(m,2H),2.63–2.57(m,1H),2.18–2.04(m,5H),1.82(d,J＝7.1Hz,3H).
Compound 24:24mg, ESI [ M+H ]] + ＝317.3
1 H NMR(400MHz,CDCl 3 )δ7.77(s,1H),7.73(s,1H),7.37–7.28(m,3H),7.21–7.15(m,2H),6.25(q,J＝7.1Hz,1H),4.17–3.99(m,2H),3.25(s,3H),2.67–2.45(m,2H),2.35–2.15(m,2H),1.82(d,J＝7.1Hz,3H).
Compound 25:31mg, ESI [ M+H ]] + ＝333.2
1 H NMR(400MHz,CDCl 3 )δ7.75(s,1H),7.73(s,1H),7.38–7.27(m,3H),7.22–7.14(m,2H),6.22(q,J＝7.1Hz,1H),3.81–3.74(m,1H),2.63–2.59(m,3H),2.09(s,3H),2.08–1.94(m,2H),1.80(d,J＝7.1Hz,3H).
Compound 26:13mg, ESI [ M+H ]] + ＝315.1
1 H NMR(400MHz,CDCl 3 )δ7.91(s,1H),7.83(s,1H),7.45–7.26(m,3H),7.22–7.16(m,2H),6.30(q,J＝7.2Hz,1H),5.05–5.00(m,1H),2.87–2.62(m,3H),2.36–2.23(m,2H),1.90(d,J＝7.1Hz,3H).
Compound 27:24mg, ESI [ M+H ]] + ＝301.0
1 H NMR(400MHz,CDCl 3 )δ7.82(s,1H),7.81(s,1H),7.37–7.25(m,3H),7.21–7.13(m,2H),6.34(q,J＝7.1Hz,1H),4.23–4.09(m,1H),2.32–2.17(m,1H),1.98–1.71(m,7H),0.98–0.85(m,3H).
Compound 28:33mg, ESI [ M+H ]] + ＝283.2
1 H NMR(400MHz,CDCl 3 )δ7.82(s,1H),7.81(s,1H),7.39–7.28(m,3H),7.21–7.14(m,2H),6.35(q,J＝7.1Hz,1H),5.23–5.09(m,1H),4.92(s,2H),3.18–2.97(m,2H),2.93–2.78(m,2H),1.87(d,J＝7.1Hz,3H).
Compound 29:24mg, ESI [ M+H ]] + ＝299.2
1 H NMR(400MHz,CDCl 3 )δ7.81(s,1H),7.77(s,1H),7.37–7.27(m,3H),7.23–7.15(m,2H),6.37(q,J＝7.1Hz,1H),4.90(s,2H),4.23–4.09(m,1H),3.10–2.90(m,2H),2.88–2.71(m,2H),1.86(d,J＝7.1Hz,3H).
Compound 30:42mg, ESI [ M+H ]] + ＝285.0
1 H NMR(400MHz,CDCl 3 )δ7.82(s,2H),7.43–7.28(m,3H),7.25–7.16(m,2H),6.31(q,J＝7.1Hz,1H),6.11–6.08(m,1H),2.78–2.71(m,2H),2.29–2.24(m,2H),1.88(d,J＝7.1Hz,3H).
Compound 31:11mg, ESI [ M+H ]] + ＝359.3
1 H NMR(400MHz,CDCl 3 )δ7.81(s,2H),7.39–7.27(m,3H),7.23–7.15(m,2H),6.34(q,J＝7.1Hz,1H),5.07–4.95(m,1H),3.49–3.36(m,4H),2.81–2.66(m,2H),2.32–2.22(m,2H),1.87(d,J＝7.1Hz,3H),1.20(q,J＝7.0Hz,6H).
Compound 32:12mg, ESI [ M+H ]] + ＝311.0
1 H NMR(400MHz,CDCl 3 )δ7.82(s,1H),7.81(s,1H),7.39–7.28(m,3H),7.21–7.14(m,2H),6.35(q,J＝7.1Hz,1H),5.23–5.09(m,2H),3.18–2.97(m,2H),2.93–2.78(m,2H),2.07–1.98(m,2H),1.87(d,J＝7.1Hz,3H),0.83–0.76(m,3H).
Compound 33:49mg, ESI [ M+H ]] + ＝301.2
1 H NMR(400MHz,CDCl 3 )δ7.82(s,2H),7.42–7.28(m,3H),7.21–7.14(m,2H),6.32(q,J＝7.1Hz,1H),5.14–4.93(m,1H),2.77–2.71(m,2H),2.29–2.23(m,2H),1.87(d,J＝7.1Hz,3H).
Compound 34:37mg, ESI [ M+H ]] + ＝327.0
1 H NMR(400MHz,CDCl 3 )δ7.87(s,1H),7.82(s,1H),7.42–7.24(m,3H),7.22–7.15(m,2H),6.28(q,J＝7.1Hz,1H),6.10–6.07(m,1H),1.96–1.70(m,7H),1.35(s,6H).
Compound 35:50mg, ESI [ M+H ]] + ＝327.2
1 H NMR(400MHz,CDCl 3 )δ7.91(s,1H),7.81(s,1H),7.43–7.25(m,3H),7.23–7.15(m,2H),6.30(q,J＝7.2Hz,1H),6.12–6.10(m,1H),1.97–1.71(m,7H),1.70–1.63(m,4H),0.91–0.82(m,6H).
Compound 36:79mg, ESI [ M+H ]] + ＝329.3
1 H NMR(400MHz,CDCl 3 )δ7.81(s,1H),7.79(s,1H),7.36–7.26(m,3H),7.18–7.15(m,2H),6.31(q,J＝7.1Hz,1H),5.09–5.01(m,1H),3.70(s,3H),2.83–2.74(m,1H),2.72–2.62(m,2H),2.49–2.44(m,2H),1.85(d,J＝7.1Hz,3H).
Compound 37:11mg, ESI [ M+H ]] + ＝330.0
1 H NMR(400MHz,CDCl 3 )δ7.69(s,1H),7.35–7.26(m,4H),7.24–7.16(m,2H),6.43(q,J＝7.2Hz,1H),4.55–4.41(m,4H),3.75(s,3H),3.61–3.30(m,1H),1.88(d,J＝7.1Hz,3H).
Compound 38:65mg, ESI [ M+H ]] + ＝329.3
1 H NMR(400MHz,CDCl 3 )δ7.86(s,1H),7.82(s,1H),7.44–7.26(m,3H),7.23–7.16(m,2H),6.34(q,J＝6.8Hz,1H),5.38–5.31(m,1H),3.72(s,3H),3.19–3.12(m,1H),2.76–2.70(m,2H),2.47–2.38(m,2H),1.90(d,J＝7.1Hz,3H).
Compound 39:77mg, ESI [ M+H ]] + ＝345.0
1 H NMR(400MHz,CDCl 3 )δ7.90(s,1H),7.77(s,1H),7.43–7.26(m,3H),7.23–7.14(m,2H),6.30(q,J＝7.2Hz,1H),5.00–4.95(m,1H),3.70(s,3H),2.88–2.23(m,5H),1.89(d,J＝7.1Hz,3H).
EXAMPLE 2 preparation of Compound 40 of the present invention
Preparation of Compound 40 Compound 1 was prepared according to the general procedure A.
The intermediate compound 40-1 was obtained by condensation reaction of 1H-imidazole-5-carboxylic acid and methyl 2-cyclopentanone carboxylate, and then reacted with S-phenethyl alcohol to obtain the objective compound 40 (24 mg). ESI [ M+H ]] + ＝341.2
1 H NMR(400MHz,CDCl 3 )δ7.97(s,1H),7.88(s,1H),7.41–7.29(m,3H),7.25–7.16(m,2H),6.31(q,J＝7.2Hz,1H),3.59(s,3H),2.73–2.61(m,4H),2.04–1.94(m,2H),1.90(d,J＝7.1Hz,3H).
The following compounds 41 to 51 were prepared analogously to example 2, compound 40, according to the general procedure A, using 1H-imidazole-5-carboxylic acid to condense with the corresponding five-membered ring alcohol to give the 1H-imidazole-5-carboxylic acid ester intermediate, which was then reacted with S-phenylethanol.
Compound 41:77mg, ESI [ M+H ]] + ＝325.4
1 H NMR(400MHz,CDCl 3 )δ7.90(s,1H),7.88(s,1H),7.40–7.28(m,3H),7.18–7.16(m,2H),6.26(q,J＝7.1Hz,1H),2.53–2.37(m,4H),2.35(s,3H),1.90(d,J＝7.1Hz,3H),1.86–1.79(m,2H).
Compound 42:28mg, ESI [ M+H ]] + ＝335.2
1 H NMR(400MHz,CDCl 3 )δ7.92(s,1H),7.82(s,1H),7.43–7.26(m,3H),7.25–7.14(m,2H),6.35(q,J＝7.1Hz,1H),2.80–2.61(m,5H),1.91–1.79(m,5H).
Compound 43:22mg, ESI [ M+H ]] + ＝349.4
1 H NMR(400MHz,CDCl 3 )δ7.90(s,1H),7.81(s,1H),7.42–7.26(m,3H),7.24–7.16(m,2H),6.34(q,J＝7.2Hz,1H),2.73–2.61(m,4H),2.07–1.76(m,8H).
Compound 44:20mg, ESI [ M+H ]] + ＝349.0
1 H NMR(400MHz,CDCl 3 )δ7.93(s,1H),7.83(s,1H),7.47–7.29(m,3H),7.26–7.16(m,2H),6.32(q,J＝7.2Hz,1H),6.05–5.92(m,1H),5.07–4.98(m,2H),2.72–2.60(m,4H),2.02–1.78(m,5H).
Compound 45:18mg, ESI [ M+H ]] + ＝361.1
1 H NMR(400MHz,CDCl 3 )δ7.94(s,1H),7.83(s,1H),7.46–7.29(m,3H),7.26–7.16(m,2H),6.32(q,J＝7.1Hz,1H),5.90–5.77(m,1H),5.72–5.58(m,2H),2.60–2.36(m,4H),1.92–1.78(m,5H).
Compound 46:14mg, ESI [ M+H ]] + ＝327.2
1 H NMR(400MHz,CDCl 3 )δ7.92(s,1H),7.83(s,1H),7.45–7.29(m,3H),7.25–7.16(m,2H),6.31(q,J＝7.2Hz,1H),4.04(s,2H),3.03(s,3H),2.77–2.41(m,4H),1.92–1.74(m,5H).
Compound 47:50mg, ESI [ M+H ]] + ＝311.0
1 H NMR(400MHz,CDCl 3 )δ8.17(s,1H),7.91(s,1H),7.83(s,1H),7.44–7.29(m,3H),7.25–7.16(m,2H),6.31(q,J＝7.2Hz,1H),2.63–2.36(m,4H),1.95–1.74(m,5H).
Compound 48:41mg, ESI [ M+H ]] + ＝341.4
1 H NMR(400MHz,CDCl 3 )δ7.91(s,1H),7.88(s,1H),7.43–7.28(m,3H),7.24–7.16(m,2H),6.27(d,J＝7.1Hz,1H),2.55–2.32(m,4H),1.90–1.75(m,5H),1.56(s,3H).
Compound 49:23mg, ESI [ M+H ]] + ＝327.0
Compound 50:40mg, ESI [ M+H ]] + ＝311.2
1 H NMR(400MHz,CDCl 3 )δ7.92(s,1H),7.89(s,1H),7.44–7.30(m,3H),7.26–7.14(m,2H),6.27(q,J＝7.1Hz,1H),5.30–5.20(m,1H),2.79–2.25(m,4H),1.91(d,J＝7.1Hz,3H),1.70(s,6H).
Compound 51:44mg, ESI [ M+H ]] + ＝339.2
1 H NMR(400MHz,CDCl 3 )δ7.90(s,1H),7.88(s,1H),7.44–7.30(m,3H),7.25–7.15(m,2H),6.28(q,J＝7.1Hz,1H),5.29–5.16(m,1H),2.53–2.25(m,4H),2.11–2.02(m,4H),1.11–0.85(m,6H).
EXAMPLE 3 preparation of Compound 52 of the present invention
Compound 52 was prepared analogously to compound 1 by the method of general procedure a.
The intermediate compound 52-1 was obtained by condensation reaction of 1H-imidazole-5-carboxylic acid with ethyl 2-cyclohexanone formate, and then reacted with S-phenethyl alcohol to obtain the objective compound 52 (215 mg). ESI [ M+H ]] + ＝369.4
1 H NMR(400MHz,CDCl 3 )δ7.90(s,1H),7.88(s,1H),7.44–7.30(m,3H),7.27–7.20(m,2H),6.36(q,J＝6.6Hz,1H),4.19–3.90(m,2H),2.44(t,J＝6.0Hz,2H),2.32–2.24(m,2H),1.89(d,J＝7.1Hz,3H),1.83–1.73(m,2H),1.73–1.64(m,2H),0.99(t,J＝7.1Hz,3H).
The following compounds 53 to 73 were prepared analogously to example 3 compound 52 by the general procedure a, condensing 1H-imidazole-5-carboxylic acid with the corresponding hexacyclic alcohol to give the 1H-imidazole-5-carboxylic acid ester intermediate, and reacting with S-phenylethanol.
Compound 53:215mg, ESI [ M+H ]] + ＝339.3
1 H NMR(400MHz,CDCl 3 )δ7.91(s,1H),7.91(s,1H),7.40–7.28(m,3H),7.22–7.14(m,2H),6.30(q,J＝7.2Hz,1H),2.45–2.21(m,4H),2.09(s,3H),1.90(d,J＝7.1Hz,3H),1.80–1.57(m,4H).
Compound 54:47mg, ESI [ M+H ]] + ＝351.4
1 H NMR(400MHz,CDCl 3 )δ7.83(s,1H),7.76(s,1H),7.42–7.31(m,3H),7.30–7.25(m,2H),6.46–6.38(m,1H),6.07–5.92(m,1H),2.82–2.71(m,1H),2.53–2.26(m,5H),2.16–2.07(m,1H),2.04–1.99(m,1H),1.93–1.86(m,3H),1.76–1.64(m,2H).
Compound 55:14mg, ESI [ M+H ]] + ＝363.2
1H NMR(400MHz,CDCl 3 )δ7.95(s,1H),7.94(s,1H),7.41–7.28(m,3H),7.25–7.14(m,2H),6.32(q,J＝7.2Hz,1H),2.45–2.20(m,4H),2.01(s,3H),1.90(d,J＝7.1Hz,3H),1.80–1.55(m,4H).
Compound 56:11mg, ESI [ M+H ]] + ＝363.1
1H NMR(400MHz,CDCl 3 )δ7.96(s,1H),7.94(s,1H),7.43–7.28(m,3H),7.27–7.14(m,2H),6.32(q,J＝7.2Hz,1H),6.01–5.95(m,1H),5.15–5.03(m,2H),2.45–2.20(m,4H),1.90(d,J＝7.1Hz,3H),1.80–1.55(m,4H).
Compound 57:22mg, ESI [ M+H ]] + ＝375.1
1H NMR(400MHz,CDCl 3 )δ7.93(s,1H),7.92(s,1H),7.43–7.28(m,3H),7.24–7.14(m,2H),6.33(q,J＝7.2Hz,1H),5.92–5.75(m,1H),5.73–5.58(m,2H),2.46–2.20(m,4H),1.90(d,J＝7.1Hz,3H),1.83–1.55(m,4H).
Compound 58:19mg, ESI [ M+H ]] + ＝341.1
1H NMR(400MHz,CDCl 3 )δ7.92(s,1H),7.90(s,1H),7.40–7.28(m,3H),7.22–7.14(m,2H),6.30(q,J＝7.2Hz,1H),4.04(s,2H),3.46(s,3H),2.44–2.20(m,4H),1.90(d,J＝7.1Hz,3H),1.80–1.55(m,4H).
Compound 59:40mg, ESI [ M+H ]] + ＝401.5
1 H NMR(400MHz,CDCl 3 )δ7.93–7.66(m,2H),7.47–7.28(m,3H),7.26–7.06(m,2H),6.50–6.07(m,1H),4.65–4.10(m,2H),3.83–3.61(m,2H),3.56–3.30(m,2H),2.87–2.51(m,1H),2.51–1.97(m,4H),1.98–1.76(m,3H),1.73–1.50(m,2H),1.54–1.30(m,2H),1.29–1.09(m,6H).
Compound 60:23mg, ESI [ M+H ]] + ＝425.4
1H NMR(400MHz,CDCl 3 )δ7.95–7.58(m,2H),7.45–7.29(m,3H),7.25–7.03(m,2H),6.52–6.26(m,1H),6.14–5.81(m,1H),3.85–3.62(m,1H),3.59–3.13(m,3H),2.55–2.39(m,1H),2.18–1.41(m,12H),1.28–1.14(m,6H)
Compound 61:34mg, ESI [ M+H ]] + ＝439.4
1 H NMR(400MHz,CDCl 3 )δ7.89(s,1H),7.77(s,1H),7.44–7.33(m,3H),7.32–7.27(m,2H),6.52–6.37(m,1H),6.07–5.93(m,1H),3.77–3.68(m,4H),2.76–2.67(m,1H),2.62–2.40(m,3H),2.09–2.02(m,3H),1.94–1.79(m,6H),1.74–1.62(m,2H),1.30–1.16(m,6H).
Compound 62:42mg, ESI [ M+H ]] + ＝351.2
1 H NMR(400MHz,CDCl 3 )δ7.81(s,1H),7.78(s,1H),7.45–7.25(m,5H),6.46–6.38(m,1H),6.21–5.62(m,3H),2.51–2.16(m,4H),1.93–1.86(m,3H),1.82–1.61(m,4H).
Compound 63:25mg, ESI [ M+H ]] + ＝327.3
1 H NMR(400MHz,CDCl 3 )δ7.89(s,1H),7.79(s,1H),7.43–7.29(m,3H),7.24–7.16(m,2H),6.38(q,J＝7.6Hz,1H),4.63–4.49(m,1H),4.32–4.16(m,1H),2.80–2.64(m,1H),2.50–2.40(m,1H),2.39–2.26(m,1H),2.24–2.05(m,2H),1.98–1.91(m,1H),1.88(d,J＝7.1Hz,3H),1.77–1.57(m,2H),1.57–1.37(m,1H).
Compound 64:59mg, ESI [ M+H ]] + ＝351.3
1 H NMR(400MHz,CDCl 3 )δ7.81(d,J＝5.6Hz,1H),7.75(s,1H),7.43–7.31(m,3H),7.30–7.21(m,2H),6.46–6.36(m,1H),6.07–5.91(m,1H),2.81–2.71(m,1H),2.52–2.26(m,5H),2.18–2.07(m,1H),2.07–1.96(m,1H),1.93–1.84(m,3H),1.79–1.61(m,2H).
Compound 65:47mg, ESI [ M+H ]] + ＝365.2
1 H NMR(400MHz,CDCl 3 )δ7.77(s,1H),7.73(s,1H),7.42–7.30(m,3H),7.29–7.26(m,2H),6.42(q,J＝7.3Hz,1H),6.04–5.85(m,1H),2.78–2.61(m,1H),2.50–2.23(m,3H),2.15–1.96(m,2H),1.91–1.86(m,3H),1.86–1.80(m,3H),1.77–1.61(m,3H).
Compound 66:29mg, ESI [ M+H ]] + ＝325.3
1 H NMR(400MHz,CDCl 3 )δ8.19(t,J＝2.1Hz,1H),7.94(s,1H),7.89(s,1H),7.41–7.29(m,3H),7.21–7.19(m,2H),6.31(q,J＝7.0Hz,1H),2.65(td,J＝6.6,2.1Hz,2H),2.45(t,J＝6.6Hz,2H),1.90(d,J＝7.1Hz,3H),1.88-1.85(m,2H),1.81–1.72(m,2H).
Compound 67:213mg, ESI [ M+H ]] + ＝355.3
1 H NMR(400MHz,CDCl 3 )δ7.89(s,1H),7.86(s,1H),7.40–7.29(m,3H),7.26–7.20(m,2H),6.35(q,J＝6.9Hz,1H),3.50(s,3H),2.48–2.39(m,2H),2.33–2.24(m,2H),1.89(d,J＝7.1Hz,3H),1.81–1.73(m,2H),1.73–1.64(m,2H).
Compound 68:14mg, ESI [ M+H ]] + ＝365.1
1H NMR(400MHz,CDCl 3 )δ7.86(s,1H),7.84(s,1H),7.42–7.29(m,3H),7.29–7.21(m,2H),6.34(q,J＝6.9Hz,1H),5.16–5.01(m,1H),3.44(s,3H),2.58–2.34(m,3H),2.33–2.24(m,2H),1.86(d,J＝7.1Hz,3H),1.80–1.73(m,2H),1.72–1.64(m,2H).
Compound 69:12mg, ESI [ M+H ]] + ＝379.1
1H NMR(400MHz,CDCl 3 )δ7.89(s,1H),7.86(s,1H),7.42–7.29(m,3H),7.27–7.20(m,2H),6.35(q,J＝6.9Hz,1H),5.17–4.94(m,1H),3.45(s,3H),2.48–2.24(m,4H),2.01(s,3H),1.89(d,J＝7.1Hz,3H),1.81–1.64(m,4H).
Compound 70:66mg, ESI [ M+H ]] + ＝343.0
1H NMR(400MHz,CDCl 3 )δ7.88(s,1H),7.78(s,1H),7.43–7.29(m,3H),7.24–7.16(m,2H),6.36(q,J＝7.6Hz,1H),4.51–4.07(m,2H),2.70–2.54(m,1H),2.40–2.16(m,2H),2.14–1.95(m,2H),1.88–1.81(m,4H),1.78–1.37(m,3H).
Compound 71:54mg, ESI [ M+H ]] + ＝341.1
1H NMR(400MHz,CDCl 3 )δ8.24(s,1H),7.92(s,1H),7.87(s,1H),7.43–7.29(m,3H),7.25–7.14(m,2H),6.30(q,J＝7.0Hz,1H),2.65–2.40(m,4H),1.88(d,J＝7.1Hz,3H),1.86–1.84(m,2H),1.80–1.70(m,2H).
Compound 72:13mg，ESI[M+H] + ＝357.2
1 H NMR(400MHz,DMSO-d 6 )δ8.30(s,1H),7.70(d,J＝0.9Hz,1H),7.36-7.31(m,2H),7.29-7.24(m,1H),7.18-7.14(m,2H),6.23(q,J＝7.2Hz,1H),4.96(br s,1H),3.65-3.59(m,3H),2.49-2.42(m,1H),1.85(d,J＝7.2Hz,3H),1.77-1.62(m,8H).
Compound 73:11mg, ESI [ M+H ]] + ＝357.2
1 H NMR(400MHz,DMSO-d 6 )δ8.30(d,J＝0.6Hz,1H),7.66(d,J＝0.9Hz,1H),7.37-7.30(m,2H),7.29-7.23(m,1H),7.20-7.13(m,2H),6.22(q,J＝7.1Hz,1H),4.81-4.65(m,1H),3.60(s,3H),2.40-2.29(m,1H),1.96-1.87(m,4H),1.84(d,J＝7.3Hz,3H),1.56-1.38(m,4H).
EXAMPLE 4 preparation of Compound 74 of the invention
Preparation of Compound 74 Compound 1 was prepared according to the general procedure A.
The 1H-imidazole-5-carboxylic acid was subjected to condensation reaction with ethyl 2-cycloheptanonecarboxylate to give compound 74-1, which was then reacted with S-phenethyl alcohol to give the objective compound 74 (159 mg). ESI [ M+H ]] + ＝383.2
1 H NMR(400MHz,CDCl 3 )7.85(s,1H),7.78(s,1H),7.39–7.29(m,3H),7.25–7.17(m,2H),6.35(q,J＝7.1Hz,1H),4.12–3.86(m,2H),2.58–2.26(m,4H),1.87(d,J＝7.1Hz,3H),1.83–1.50(m,6H),0.95(t,J＝7.1Hz,3H).
The following compounds 75 to 81 were prepared analogously to example 4, 74, by following the general procedure a, using 1H-imidazole-5-carboxylic acid to condense with the corresponding alcohol to give the 1H-imidazole-5-carboxylic acid ester intermediate, which was then reacted with S-phenylethanol.
Compound 75:35mg, ESI [ M+H ]] + ＝353.4
1 H NMR(400MHz,CDCl 3 )δ7.91(s,1H),7.89(s,1H),7.43–7.30(m,3H),7.19(d,J＝6.9Hz,2H),6.29(q,J＝7.1Hz,1H),2.66–2.57(m,2H),2.25(t,J＝5.6Hz,2H),2.17(s,3H),1.91(d,J＝7.1Hz,3H),1.77–1.62(m,4H),1.55–1.48(m,2H).
Compound 76:212mg, ESI [ M+H ]] + ＝369.3
1H NMR(400MHz,CDCl 3 )δ7.87(s,2H),7.42–7.29(m,3H),7.26–7.18(m,2H),6.36(q,J＝7.0Hz,1H),3.51(s,3H),2.62–2.37(m,4H),1.89(d,J＝7.1Hz,3H),1.85–1.59(m,6H).
Compound 77:215mg, ESI [ M+H ]] + ＝339.0
1H NMR(400MHz,CDCl 3 )δ8.20(s,1H),7.94(s,1H),7.91(s,1H),7.43–7.28(m,3H),7.25–
7.15(m,2H),6.33(q,J＝7.1Hz,1H),2.67–2.55(m,4H),1.90(d,J＝7.1Hz,3H),1.81–1.49(m,6H).
Compound 78:33mg, ESI [ M+H ]] + ＝369.1
1H NMR(400MHz,CDCl 3 )δ7.92(s,1H),7.88(s,1H),7.44–7.30(m,3H),7.26–7.15(m,2H),6.28(q,J＝7.1Hz,1H),2.68–2.14(m,4H),1.91(d,J＝7.1Hz,3H),1.77–1.62(m,4H),1.58–1.42(m,5H).
Compound 79:56mg, ESI [ M+H ]] + ＝355.2
Compound 80:18mg, ESI [ M+H ]] + ＝341.0
1H NMR(400MHz,CDCl 3 )δ7.92(s,1H),7.86(s,1H),7.44–7.26(m,3H),7.23–7.14(m,2H),6.44–6.32(m,1H),3.68(s,3H),2.36(s,6H),1.85(d,J＝7.1Hz,3H).
Compound 81:25mg, ESI [ M+H ]] + ＝313.0
1H NMR(400MHz,CDCl 3 )δ7.91(s,1H),7.89(s,1H),7.45–7.27(m,3H),7.25–7.13(m,2H),6.45–6.31(m,1H),3.55(s,3H),2.36(s,6H),1.85(d,J＝7.1Hz,3H).
EXAMPLE 5 preparation of Compound A1 of the present invention
1. Preparation of Ethyl 4-amino-1H-imidozole-5-carboxylate (A1-1)
5-amino-1H-imidazole-4-carboxamide (3.0 g,23.8 mmol), ethanol (30 mL) and methanesulfonic acid (6 mL) were added sequentially to a 200mL lock tube at room temperature, and reacted at 120℃for 10 hours. The reaction solution was concentrated and then was treated with saturated NaHCO 3 The aqueous solution of (2) was adjusted to ph=8, extracted with ethyl acetate (3×150 mL), washed with saturated brine (100 mL), dried, suction-filtered, and the filtrate was concentrated to give white solid A1-1 (3.0 g, yield 81%).
2. Preparation of 4-fluoro-1H-imidazole-5-carboxylic acid ethyl ester (A1-2)
A1-1 (250 mg,1.61 mmol) was dissolved in 40% HBF at-10deg.C in an ice salt bath 4 Adding NaNO into 2 (117 mg,1.69 mmol) in water (0.15 mL) was reacted under irradiation of a mercury lamp (254 nm) for 2 hours. After completion of the reaction, ph=7 was adjusted with 1N NaOH in water in ice-water bath, the aqueous layer was extracted with ethyl acetate (3×10 mL), the organic phases were combined, washed with saturated brine, dried, filtered with suction, concentrated under reduced pressure to give the crude product, which was isolated by column chromatography (ethyl acetate/petroleum ether (v/v) =1/1), monitored by TLC (ethyl acetate/petroleum ether (v/v) =1/1), and rf=0.4 to 0.5 fractions were collected to give compound A1-2 as a colorless oil (100 mg, yield 39%).
3. Preparation of 4-fluoro-1H-imidazole-5-carboxylic acid (A1-3)
NaOH (50 mg,1.26 mmol) was added to a solution of A1-2 (100 mg,0.63 mmol) in ethanol/water (5 mL, v/v=1/1) at room temperature and reacted at room temperature for 5 hours. After completion of the reaction, the mixture was concentrated, cooled, pH was adjusted to 5 with 1N HCl, extracted with ethyl acetate (3X 5 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and suction-filteredConcentration gave compound A1-3 as a grey solid (74 mg, overall yield 90%). ESI [ M+H ]] + ＝131.0
4. Preparation of (3-methylethan-3-yl) methyl 4-fluoro-1H-imidozole-5-carboxylate (A1-4)
A1-3 (74 mg,0.57 mmol), DCC (173 mg,0.84 mmol) and DMAP (103 mg,0.84 mmol) were dissolved in dichloromethane (5 mL) at room temperature and stirred for 5 min at room temperature, and (3-methylxetan-3-yl) methanol (86 mg,0.84 mmol) was slowly added to the reaction by syringe and stirred at room temperature overnight. The reaction was completed by TLC monitoring system, the solvent was removed by vacuum concentration, methyl tert-butyl ether was added and stirred, suction filtration was performed, the filter cake was washed with methyl tert-butyl ether, the filtrate was 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) =1/3), TLC (ethyl acetate/petroleum ether (v/v) =1/1) monitoring was performed, rf=0.5 to 0.6 fraction was collected to give colorless oily compound A1-4 (109 mg, yield 89%). ESI [ M+H ] ] + ＝215.1
5. Preparation of target Compound A1
A1-4 (109 mg,0.51 mmol), S-phenethyl alcohol (94 mg,0.77 mmol) and PPh were incubated in an ice-water bath at 0deg.C 3 (202 mg,0.77 mmol) was dissolved in THF (10 mL), and DEAD (230 mg,1.32 mmol) was slowly added dropwise to the reaction system via syringe, and the mixture was slowly warmed to room temperature and stirred for 5 hours after the dropwise addition. After completion of the reaction by TLC, saturated brine (10 mL) was added to the reaction system, extracted with ethyl acetate (3×10 mL), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, suction-filtered, and concentrated under reduced pressure to give a crude product, which was purified by preparative TLC (ethyl acetate/petroleum ether (v/v) =1/1) and a fraction of rf=0.4 to 0.6 was collected to give compound A1 (109 mg, yield 67%) as a colorless oil. ESI [ M+H ]] + ＝319.0
1H NMR(400MHz,CDCl 3 )δ7.39–7.28(m,4H),7.23–7.15(m,2H),6.23(q,J＝7.1Hz,1H),4.81–4.74(m,1H),3.63–3.58(m,1H),3.25(s,3H),2.90–2.69(m,2H),2.18–2.04(m,2H),1.83(d,J＝7.1Hz,3H).
The following compounds A2 to A52 were prepared analogously to example 5, compound A1, according to the general procedure A, by condensing 4-fluoro-1H-imidazole-5-carboxylic acid with the corresponding alcohol to give the 4-fluoro-1H-imidazole-5-carboxylic acid ester intermediate, which was then reacted with S-phenethyl alcohol.
Compound A2:105mg, ESI [ M+H ]] + ＝357.0
1H NMR(400MHz,CDCl 3 )δ7.45(s,1H),7.40–7.28(m,3H),7.23–7.11(m,2H),6.19(q,J＝7.0Hz,1H),2.44–2.20(m,4H),2.10(s,3H),1.87(d,J＝7.1Hz,3H),1.79–1.69(m,2H),1.69–1.61(m,2H).
Compound A3:64mg, ESI [ M+H ]] + ＝343.0
1 H NMR(400MHz,CDCl 3 )δ7.45(d,J＝1.2Hz,1H),7.41–7.29(m,3H),7.22–7.16(m,2H),6.16(q,J＝7.0Hz,1H),2.55–2.27(m,7H),1.87(d,J＝7.1Hz,3H),1.85–1.76(m,2H).
Compound A4:87mg, ESI [ M+H ]] + ＝359.0
1H NMR(400MHz,CDCl 3 )δ7.40(s,1H),7.39–7.29(m,3H),7.25–7.19(m,2H),6.21(q,J＝7.0Hz,1H),3.58(s,3H),2.77–2.49(m,4H),2.07–1.92(m,2H),1.86(d,J＝7.1Hz,3H).
Compound A5:87mg, ESI [ M+H ]] + ＝373.0
1H NMR(400MHz,CDCl 3 )δ7.40–7.29(m,4H),7.26–7.21(m,2H),6.24(q,J＝7.1Hz,1H),3.52(s,3H),2.47–2.35(m,2H),2.32–2.22(m,2H),1.86(d,J＝7.1Hz,3H),1.80–1.72(m,2H),1.72–1.63(m,2H).
Compound A6:100mg, ESI [ M+H ] ] + ＝387.0
1H NMR(400MHz,CDCl 3 )δ7.45–7.29(m,4H),7.27–7.21(m,2H),6.23(q,J＝7.1Hz,1H),3.52(s,3H),2.62–2.35(m,4H),1.88(d,J＝7.1Hz,3H),1.85–1.58(m,6H).
Compound A7:22mg of the total of two or more of the components,ESI[M+H] + ＝331.0
1 H NMR(400MHz,CDCl 3 )δ7.43–7.27(m,4H),7.25–7.20(m,2H),6.23(q,J＝7.1Hz,1H),5.19–5.07(m,1H),3.00–2.93(m,1H),2.65–2.60(m,2H),2.38–2.30(m,2H),2.14(s,3H),1.88(d,J＝7.1Hz,3H).
compound A8:41mg, ESI [ M+H ]] + ＝327.0
1 H NMR(400MHz,CDCl 3 )δ7.45–7.28(m,4H),7.27–7.21(m,2H),6.24(q,J＝7.1Hz,1H),4.35–4.10(m,2H),3.11–2.52(m,2H),2.47–2.22(m,2H),2.20–1.92(m,3H),1.89–1.87(m,3H).
Compound A9:45mg, ESI [ M+H ]] + ＝347.0
1 H NMR(400MHz,CDCl 3 )δ7.45–7.27(m,4H),7.27–7.21(m,2H),6.24(q,J＝7.1Hz,1H),4.35–4.10(m,2H),3.42–3.40(m,1H),3.33–3.28(m,4H),2.69–2.42(m,2H),2.23–2.07(m,1H),1.88(t,J＝7.5Hz,2H),1.87(d,J＝7.1Hz,3H),1.68–1.54(m,1H).
Compound a10:50mg, ESI [ M+H ]] + ＝333.0
1 H NMR(400MHz,CDCl 3 )δ7.46–7.29(m,4H),7.27–7.21(m,2H),6.24(q,J＝7.1Hz,1H),4.29–4.11(m,2H),3.85–3.74(m,1H),3.35(s,3H),2.45–2.16(m,3H),1.88(d,J＝7.1Hz,3H),1.80–1.70(m,2H).
Compound a11:20mg, ESI [ M+H ]] + ＝443.0
1 H NMR(400MHz,CDCl 3 )δ7.45–7.29(m,4H),7.27–7.21(m,2H),6.25(q,J＝7.1Hz,1H),6.16–5.80(m,1H),3.85–3.60(m,1H),3.58–3.11(m,3H),2.56–2.38(m,1H),2.19–1.37(m,12H),1.29–1.10(m,6H).
Compound a12:22mg, ESI [ M+H ]] + ＝301.0
1 H NMR(400MHz,CDCl 3 )δ7.45–7.29(m,4H),7.27–7.21(m,2H),6.24(q,J＝7.1Hz,1H),5.25–5.11(m,1H),4.93(s,2H),3.20–2.94(m,2H),2.96–2.71(m,2H),1.88(d,J＝7.1Hz,3H).
Compound a13:28mg, ESI [ M+H ]] + ＝345.0
1 H NMR(400MHz,CDCl 3 )δ7.45–7.29(m,4H),7.27–7.21(m,2H),6.24(q,J＝7.1Hz,1H),4.67–4.45(m,1H),4.34–4.15(m,1H),2.81–2.60(m,1H),2.55–2.26(m,2H),2.23–1.91(m,3H),1.87(d,J＝7.1Hz,3H),1.78–1.37(m,3H).
Compound a14:27mg, ESI [ M+H ]] + ＝343.0
1 H NMR(400MHz,CDCl 3 )δ8.20(t,J＝2.1Hz,1H),7.46(s,1H),7.41–7.28(m,3H),7.27–7.21(m,2H),6.24(q,J＝7.1Hz,1H),2.68–2.64(m,2H),2.46(t,J＝6.6Hz,2H),1.88(d,J＝7.1Hz,3H),1.88–1.72(m,4H).
Compound a15:80mg, ESI [ M+H ]] + ＝333.2
1 H NMR(400MHz,CDCl 3 )δ7.45(s,1H),7.40–7.28(m,3H),7.27–7.21(m,2H),6.24(q,J＝7.1Hz,1H),4.87–4.74(m,1H),3.75–3.70(m,1H),3.41(q,J＝7.0Hz,2H),2.89–2.74(m,2H),2.16–2.09(m,2H),1.86(d,J＝7.1Hz,3H),1.20(t,J＝7.0Hz,3H).
Compound a16:35mg, ESI [ M+H ]] + ＝347.0
1 H NMR(400MHz,CDCl 3 )δ7.44(s,1H),7.41–7.28(m,3H),7.26–7.21(m,2H),6.24(q,J＝7.1Hz,1H),4.80–4.73(m,1H),3.76–3.59(m,2H),2.88–2.72(m,2H),2.20–2.07(m,2H),1.86(d,J＝7.1Hz,3H),1.16(d,J＝6.1Hz,6H).
Compound a17:28mg, ESI [ M+H ]] + ＝335.2
1 H NMR(400MHz,CDCl 3 )δ7.42(s,1H),7.40–7.28(m,3H),7.27–7.21(m,2H),6.24(q,J＝7.1Hz,1H),6.05–5.84(m,1H),5.35–5.24(m,1H),5.23–5.15(m,1H),4.81–4.77(m 1H),3.96–3.81(m,2H),3.77–3.73(m,1H),2.90–2.75(m,2H),2.21–2.06(m,2H),1.87(d,J＝7.1Hz,3H).
Compound a18:10mg, ESI [ M+H ]] + ＝377.0
1 H NMR(400MHz,CDCl 3 )δ7.43(s,1H),7.41–7.28(m,3H),7.26–7.21(m,2H),6.22(q,J＝7.1Hz,1H),5.14–4.93(m,1H),3.45–3.43(m,4H),2.76–2.72(m,2H),2.27–2.24(m,2H),1.87(d,J＝7.1Hz,3H),1.21(q,J＝7.0Hz,6H).
Compound a19:11mg, ESI [ M+H ]] + ＝373.2
Compound a20:9mg, ESI [ M+H ]] + ＝337.2
Compound a21:12mg, ESI [ M+H ]] + ＝313.0
1 H NMR(400MHz,CDCl 3 )δ7.45(s,1H),7.40–7.28(m,3H),7.27–7.21(m,2H),6.24(q,J＝7.1Hz,1H),5.25–5.09(m,1H),4.98(s,2H),3.10–2.70(m,4H),1.88(d,J＝7.1Hz,3H).
Compound a22:13mg, ESI [ M+H ]] + ＝315.0
1 H NMR(400MHz,CDCl 3 )δ7.44(s,1H),7.41–7.28(m,3H),7.27–7.19(m,2H),6.25(q,J＝7.1Hz,1H),5.29–4.93(m,2H),3.10–2.66(m,4H),2.53–2.38(m,3H),1.86(d,J＝7.1Hz,3H).
Compound a23:12mg, ESI [ M+H ]] + ＝327.0
1 H NMR(400MHz,CDCl 3 )δ7.45(s,1H),7.40–7.29(m,3H),7.27–7.20(m,2H),6.26(q,J＝7.1Hz,1H),5.02–4.99(m,1H),2.90–2.63(m,3H),2.43–2.13(m,5H),1.88(d,J＝7.1Hz,3H).
Compound a24:14mg, ESI [ M+H ]] + ＝315.2
1 H NMR(400MHz,CDCl 3 )δ7.45(s,1H),7.42–7.28(m,3H),7.27–7.21(m,2H),6.24(q,J＝7.1Hz,1H),6.16–6.14(m,1H),5.28–4.95(m,3H),2.90–2.63(m,3H),2.40–2.23(m,2H),1.87(d,J＝7.1Hz,3H).
Compound a25:80mg, ESI [ M+H ]] + ＝373.0
1H NMR(400MHz,CDCl 3 )δ7.42(s,1H),7.41–7.27(m,3H),7.22–7.11(m,2H),6.20(q,J＝7.0Hz,1H),2.42–2.20(m,4H),2.09(s,3H),1.86(d,J＝7.1Hz,3H),1.78–1.61(m,4H).
Compound a26:12mg, ESI [ M+H ]] + ＝361.0
1 H NMR(400MHz,CDCl 3 )δ7.45(s,1H),7.42–7.28(m,3H),7.27–7.21(m,2H),6.24(q,J＝7.1Hz,1H),4.92–4.78(m,4H),3.59(s,3H),1.86(d,J＝7.1Hz,3H).
Compound a27:12mg, ESI [ M+H ]] + ＝389.1
1 H NMR(400MHz,CDCl 3 )δ7.45(s,1H),7.40–7.28(m,3H),7.26–7.21(m,2H),6.20(q,J＝7.1Hz,1H),4.86–4.54(m,4H),3.52(s,3H),2.62–2.37(m,4H),1.89(d,J＝7.1Hz,3H).
Compound a28:50mg, ESI [ M+H ]] + ＝389.0
1H NMR(400MHz,CDCl 3 )δ7.44–7.28(m,4H),7.26–7.21(m,2H),6.20(q,J＝7.1Hz,1H),3.51(s,3H),2.30–2.09(m,4H),1.85(d,J＝7.1Hz,3H),1.81–1.59(m,4H).
Compound a29:13mg, ESI [ M+H ]] + ＝347.0
1 H NMR(400MHz,CDCl 3 )δ7.45(s,1H),7.40–7.28(m,3H),7.27–7.23(m,2H),6.21(q,J＝7.1Hz,1H),4.85–4.66(m,4H),3.80(s,2H),3.29(s,3H),1.86(d,J＝7.1Hz,3H).
Compound a30:15mg, ESI [ M+H ]] + ＝333.2
1 H NMR(400MHz,CDCl 3 )δ7.44(s,1H),7.41–7.27(m,3H),7.25–7.22(m,2H),6.25(q,J＝7.1Hz,1H),4.90–4.71(m,4H),3.54(s,3H),1.88(d,J＝7.1Hz,3H).
Compound a31:16mg, ESI [ M+H ]] + ＝361.0
1 H NMR(400MHz,CDCl 3 )δ7.45(s,1H),7.40–7.27(m,3H),7.26–7.22(m,2H),6.20(q,J＝7.1Hz,1H),4.95–4.70(m,4H),3.74–3.59(m,1H),1.86(d,J＝7.1Hz,3H),1.15(d,J＝6.1Hz,6H).
Compound a32:22mg, ESI [ M+H ]] + ＝345.0
1 H NMR(400MHz,CDCl 3 )δ7.42(s,1H),7.40–7.28(m,3H),7.27–7.24(m,2H),6.21(q,J＝7.1Hz,1H),4.91–4.70(m,4H),2.11(s,3H),1.86(d,J＝7.1Hz,3H).
Compound a33:28mg, ESI [ M+H ]] + ＝373.0
1 H NMR(400MHz,CDCl 3 )δ7.45(s,1H),7.39–7.28(m,3H),7.26–7.21(m,2H),6.19(q,J＝7.1Hz,1H),4.80–4.16(m,4H),2.60–2.35(m,4H),2.15(s,3H),1.86(d,J＝7.1Hz,3H).
Compound a34:33mg, ESI [ M+H ]] + ＝359.0
1 H NMR(400MHz,CDCl 3 )δ7.45–7.28(m,4H),7.25–7.21(m,2H),6.17(q,J＝7.0Hz,1H),2.52–2.30(m,7H),1.85(d,J＝7.1Hz,3H),1.83–1.74(m,2H).
Compound a35:31mg, ESI [ M+H ]] + ＝361.0
1 H NMR(400MHz,CDCl 3 )δ7.44(s,1H),7.43–7.26(m,3H),7.24–7.21(m,2H),6.20(q,J＝7.1Hz,1H),3.61(s,2H),3.29(s,3H),2.52–2.30(m,4H),1.85(d,J＝7.1Hz,3H),1.83–1.74(m,2H).
Compound a36:9mg, ESI [ M+H ]] + ＝331.0
1 H NMR(400MHz,CDCl 3 )δ7.45(s,1H),7.42–7.31(m,3H),7.26–7.21(m,2H),6.17(q,J＝7.0Hz,1H),3.56(s,3H),2.51–2.31(m,4H),1.88(d,J＝7.1Hz,3H),1.84–1.71(m,2H).
Compound a37:16mg, ESI [ M+H ]] + ＝359.0
1 H NMR(400MHz,CDCl 3 )δ7.45–7.31(m,4H),7.25–7.20(m,2H),6.18(q,J＝7.0Hz,1H),3.74–3.61(m,1H),2.51–2.31(m,4H),1.88(d,J＝7.1Hz,3H),1.84–1.71(m,2H),1.16(d,J＝6.0Hz,6H).
Compound a38:28mg, ESI [ M+H ]] + ＝371.0
1 H NMR(400MHz,CDCl 3 )δ7.45(s,1H),7.43–7.28(m,3H),7.27–7.21(m,2H),6.20(q,J＝7.1Hz,1H),5.53–5.04(m,4H),1.91(d,J＝7.1Hz,3H).
Compound a39:33mg, ESI [ M+H ]] + ＝328.0
H NMR(400MHz,CDCl 3 )δ7.45(s,1H),7.41–7.25(m,3H),7.22–7.19(m,2H),6.24(q,J＝7.1Hz,1H),5.21–4.85(m,4H),1.88(d,J＝7.1Hz,3H).
Compound a40:18mg, ESI [ M+H ]] + ＝329.0
H NMR(400MHz,CDCl 3 )δ7.40(s,1H),7.38–7.25(m,3H),7.22–7.19(m,2H),6.22(q,J＝7.1Hz,1H),5.29–4.78(m,7H),1.87(d,J＝7.1Hz,3H).
Compound a41:22mg, ESI [ M+H ] ] + ＝327.1
H NMR(400MHz,CDCl 3 )δ7.44(s,1H),7.40–7.25(m,3H),7.23–7.19(m,2H),6.21(q,J＝7.1Hz,1H),4.88–4.65(m,4H),2.85(s,1H),1.88(d,J＝7.1Hz,3H).
Compound a42:17mg, ESI [ M+H ]] + ＝341.0
H NMR(400MHz,CDCl 3 )δ7.43(s,1H),7.41–7.24(m,3H),7.22–7.18(m,2H),6.24(q,J＝7.1Hz,1H),4.93–4.79(m,4H),2.16–1.92(m,3H),1.88(d,J＝7.1Hz,3H).
Compound a43:32mg, ESI [ M+H ]] + ＝341.0
H NMR(400MHz,CDCl 3 )δ7.43(s,1H),7.40–7.24(m,3H),7.21–7.19(m,2H),6.23(q,J＝7.1Hz,1H),5.35–5.00(m,3H),4.90–4.75(m,4H),1.88(d,J＝7.1Hz,3H).
Compound a44:17mg, ESI [ M+H ]] + ＝360.0
H NMR(400MHz,CDCl 3 )δ7.44(s,1H),7.43–7.25(m,3H),7.22–7.18(m,2H),6.26(q,J＝7.1Hz,1H),4.92–4.79(m,4H),1.88(d,J＝7.1Hz,3H).
Compound a45:34mg, ESI [ M+H ]] + ＝363.0
1 H NMR(400MHz,CDCl 3 )δ7.44(s,1H),7.41–7.28(m,3H),7.26–7.21(m,2H),6.24(q,J＝7.1Hz,1H),3.77–3.59(m,3H),2.71–2.54(m,2H),2.18–2.07(m,2H),1.85(d,J＝7.1Hz,3H),1.15(d,J＝6.1Hz,6H).
Compound a46:26mg, ESI [ M+H ]] + ＝338.0
1 H NMR(400MHz,CDCl 3 )δ7.45(s,1H),7.43–7.28(m,3H),7.25–7.21(m,2H),6.14(q,J＝7.0Hz,1H),5.35–4.99(m,3H),2.52–2.30(m,4H),1.85(d,J＝7.1Hz,3H),1.83–1.74(m,2H).
Compound a47:28mg, ESI [ M+H ]] + ＝358.0
1 H NMR(400MHz,CDCl 3 )δ7.44(s,1H),7.42–7.31(m,3H),7.19(d,J＝6.8Hz,2H),6.16(q,J＝7.0Hz,1H),2.55–2.30(m,4H),1.86(d,J＝7.1Hz,3H),1.84–1.74(m,2H).
Compound a48:36mg, ESI [ M+H ]] + ＝335.0
1 H NMR(400MHz,CDCl 3 )δ7.39–7.29(m,4H),7.23–7.17(m,2H),6.25(q,J＝7.0Hz,1H),4.19–4.00(m,2H),3.24(s,3H),2.64–2.49(m,2H),2.39–2.20(m,2H),1.81(d,J＝7.1Hz,3H).
Compound a49:30mg, ESI [ M+H ]] + ＝327.2
1 H NMR(400MHz,CDCl 3 )δ7.44–7.30(m,4H),7.25–7.17(m,2H),6.20(q,J＝7.0Hz,1H),5.25–4.99(m,3H),2.50–2.30(m,4H),1.87(d,J＝7.1Hz,3H),1.84–1.74(m,2H).
Compound a50:28mg, ESI [ M+H ]] + ＝347.0
1 H NMR(400MHz,CDCl 3 )δ7.45(s,1H),7.40–7.28(m,3H),7.27–7.21(m,2H),6.24(q,J＝7.1Hz,1H),5.15–5.00(m,1H),3.69(s,3H),2.84–2.74(m,1H),2.70–2.58(m,2H),2.47–2.35(m,2H),1.87(d,J＝7.1Hz,3H).
Compound a51:21mg, ESI [ M+H ]] + ＝363.0
1 H NMR(400MHz,CDCl 3 )δ7.44(s,1H),7.41–7.27(m,3H),7.25–7.21(m,2H),6.22(q,J＝7.1Hz,1H),4.88–4.62(m,1H),3.68(s,3H),2.90–2.75(m,1H),2.60–2.13(m,4H),1.87(d,J＝7.1Hz,3H).
Compound a52:12mg, ESI [ M+H ]] + ＝375.2
1 H NMR(400MHz,CDCl 3 )δ7.45(s,1H),7.40–7.28(m,3H),7.27–7.21(m,2H),6.24(q,J＝7.1Hz,1H),5.10–4.82(m,1H),3.67(s,3H),2.50–1.94(m,5H),1.86(d,J＝7.1Hz,3H),1.74–1.32(m,4H).
The following compounds A53-A56 were prepared analogously to example 5, compound A1, according to the general procedure A, using 2-fluoro-1H-imidazole-5-carboxylic acid to condense with the corresponding alcohol to give the 2-fluoro-1H-imidazole-5-carboxylic acid ester intermediate, which was then reacted with S-phenethyl alcohol.
Compounds of formula (I)A53：26mg，ESI[M+H] + ＝319.0
1H NMR(400MHz,CDCl 3 )δ7.42–7.28(m,4H),7.23–7.15(m,2H),6.18(q,J＝7.1Hz,1H),4.80–4.73(m,1H),3.60–3.55(m,1H),3.28(s,3H),2.95–2.64(m,2H),2.16–2.01(m,2H),1.86(d,J＝7.1Hz,3H).
Compound a54:80mg, ESI [ M+H ]] + ＝357.0
1H NMR(400MHz,CDCl 3 )δ7.45–7.28(m,4H),7.25–7.11(m,2H),6.17(q,J＝7.0Hz,1H),2.46–2.19(m,4H),2.12(s,3H),1.86(d,J＝7.1Hz,3H),1.78–1.60(m,4H).
Compound a55:55mg, ESI [ M+H ]] + ＝343.0
1 H NMR(400MHz,CDCl 3 )δ7.47–7.30(m,4H),7.26–7.09(m,2H),6.18(q,J＝7.1Hz,1H),2.57–2.24(m,7H),1.88(d,J＝7.1Hz,3H),1.88–1.66(m,2H).
Compound a56:66mg, ESI [ M+H ]] + ＝359.0
1H NMR(400MHz,CDCl 3 )δ7.42–7.29(m,4H),7.27–7.15(m,2H),6.20(q,J＝7.0Hz,1H),3.56(s,3H),2.79–2.40(m,4H),2.05–1.83(m,2H),1.86(d,J＝7.1Hz,3H).
EXAMPLE 6 preparation of Compound A57 of the invention
1. Preparation of Ethyl 4-chloro-1H-imidozole-5-carboxylate (A57-1) and Ethyl 2, 4-dichloro-1H-imidozole-5-carboxylate (A62-1)
1H-imidazole-5-carboxylic acid ethyl ester (1 eq) and NCS (2 eq) were dissolved in acetonitrile (10 mL/mmol) solution and stirred at reflux for 3 hours. The reaction was monitored by TLC to completion, the reaction was cooled to room temperature, water was added, extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure to give a crude colorless oil, which was isolated by column chromatography (ethyl acetate/petroleum ether (v/v) =1/100), monitored by TLC (ethyl acetate/petroleum ether (v/v) =1/30), and collected to give intermediates a57-1, a57-1A and a62-1.
2. Preparation of target Compound A57
LiOH.H was then added at room temperature 2 O (2 eq) was added to a solution of Compound A57-1 (1 eq) in methanol/tetrahydrofuran/water (10 mL/mmol of Compound A57-1, V/V/V=1/1/1.5) and reacted at room temperature for 3 hours. After completion of the reaction, the mixture was concentrated, cooled, adjusted to pH 5 with 1N HCl, extracted with ethyl acetate (3X 20 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and concentrated to give Compound A57-2 as a white solid. A57-2 was condensed with the compound (1S, 3S) -3-methoxyycyclobatan-1-ol to give the carboxylate intermediate A57-3, which was then prepared with S-phenylethanol according to the general procedure A, purified by TLC (ethyl acetate/petroleum ether (v/v) =1/3) and the fraction having Rf=0.4 to 0.5 was collected to give the colorless oily compound A57 (42 mg). ESI [ M+H ]] + ＝335.0
1H NMR(400MHz,CDCl 3 )δ7.83(s,1H),7.40–7.28(m,3H),7.21–7.11(m,2H),6.66–6.52(m,1H),4.83–4.72(m,1H),3.65–3.55(m,1H),3.26(s,3H),2.87–2.64(m,2H),2.17–2.04(m,2H),1.82(d,J＝7.1Hz,3H).
The following compounds A58 to A61 were prepared analogously to example 6, compound A57, according to the general procedure A, using 4-chloro-1H-imidazole-5-carboxylic acid to condense with the corresponding alcohol to give the 4-chloro-1H-imidazole-5-carboxylic acid ester intermediate, which was then reacted with S-phenethyl alcohol.
Compound a58:99mg, ESI [ M+H ]] + ＝373.0
1H NMR(400MHz,CDCl 3 )δ7.83(s,1H),7.40–7.28(m,3H),7.21–7.11(m,2H),6.66–6.52(m,1H),2.41–2.27(m,4H),2.16(s,3H),2.03–2.01(d,J＝7.1Hz,3H),1.80–1.71(m,2H),1.71–1.61(m,2H).
Compound a59:35mg, ESI [ M+H ]] + ＝359.0
1H NMR(400MHz,CDCl 3 )δ7.82(s,1H),7.41–7.28(m,3H),7.22–7.12(m,2H),6.54(q,J＝7.0Hz,1H),2.66–2.30(m,7H),2.02(d,J＝7.1Hz,3H),1.92–1.79(m,2H).
Compound a60:54mg, ESI [ M+H ]] + ＝375.0
1H NMR(400MHz,CDCl 3 )δ7.90(s,1H),7.40–7.28(m,3H),7.24–7.15(m,2H),6.69–6.58(m,1H),3.66(s,3H),2.77–2.61(m,4H),2.03–1.94(m,5H).
Compound a61:22mg, ESI [ M+H ]] + ＝389.0
1H NMR(400MHz,CDCl 3 )δ7.86(s,1H),7.44–7.15(m,5H),6.58(q,J＝7.1Hz,1H),3.55(s,3H),2.48–2.35(m,2H),2.35–2.20(m,2H),1.88(d,J＝7.1Hz,3H),1.85–1.60(m,4H).
EXAMPLE 7 preparation of Compound A62 of the present invention
The synthesis method of compound a62 is the same as that of compound a 57.
A62-1 was hydrolyzed with lithium hydroxide, and carboxylic acid was condensed with 2-acetylcyclohexanone, followed by S-phenethyl alcohol to give the objective compound A62 (210 mg) according to the general procedure A for the compound A57 of example 6. ESI [ M+Na ]] + ＝428.9
1H NMR(400MHz,CDCl 3 )δ7.39–7.27(m,3H),7.22–7.15(m,2H),6.68–6.52(m,1H),2.42–2.26(m,4H),2.17(s,3H),2.01(d,J＝7.2Hz,3H),1.80–1.61(m,4H).
The following compounds A63 to A65 were prepared analogously to example 7, compound A62, according to the general procedure A, by condensing 2, 4-dichloro-1H-imidazole-5-carboxylic acid with the corresponding alcohol to give the 2, 4-dichloro-1H-imidazole-5-carboxylic acid ester intermediate, which was then reacted with S-phenylethanol.
Compound a63:59mg, ESI [ M+Na ]] + ＝414.9
1H NMR(400MHz,CDCl 3 )δ7.41–7.27(m,3H),7.22–7.12(m,2H),6.48(q,J＝7.0Hz,1H),2.63–2.41(m,2H),2.38(t,J＝7.9Hz,2H),2.31(t,J＝2.1Hz,3H),2.01(d,J＝7.1Hz,3H),1.91–1.78(m,2H).
Compound a64:196mg, ESI [ M+Na ]] + ＝430.9
1H NMR(400MHz,CDCl 3 )δ7.41–7.27(m,3H),7.25–7.17(m,2H),6.62(q,J＝7.1Hz,1H),3.65(s,3H),2.76–2.51(m,4H),2.23–2.06(m,2H),2.00(d,J＝7.2Hz,3H).
Compound a65:101mg, ESI [ M+H ]] + ＝444.9
1H NMR(400MHz,CDCl 3 )δ7.41–7.17(m,5H),6.60(q,J＝7.1Hz,1H),3.65(s,3H),3.56(s,3H),2.49–2.28(m,4H),1.86(d,J＝7.1Hz,3H),1.86–1.63(m,4H).
EXAMPLE 8 preparation of Compound A66 of the present invention
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1. Preparation of Ethyl 4- (trifluoromethyl) -1H-imidozole-5-carboxylate (A66-1)
Ethyl 2-chloro-4, 4-trifluoroacetoacetate (4.89 g,22.4 mmol), water (0.8 mL), and formamide (10.1 g,224 mmol) were added sequentially to a 100mL lock tube at room temperature and reacted at 150℃for 2 hours. After the reaction is completed, the reaction solution is cooled by dilute NaHCO 3 The aqueous solution of (2) was adjusted to ph=8, extracted with ethyl acetate (3×150 mL), washed with saturated brine (100 mL), dried, suction filtered, and the filtrate was concentrated to give a white solid a66-1 (1.9 g, yield 41%). ESI [ M+H ] ] + ＝209.1
2. Preparation of target Compound A66
LiOH.H was then added at room temperature 2 O (2 eq) was added to methanol/tetrahydrofuran/water (10 mL/mmol of Compound A) of Compound A66-1 (1 eq)66-1, V/v=1/1/1.5) solution, for 3 hours at room temperature. After the reaction was completed, the mixture was concentrated, cooled, pH was adjusted to 5 with 1N HCl, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered off with suction, and concentrated to give Compound A66-2 as a white solid. A66-2 was condensed with the compound (1S, 3S) -3-methoxyycyclobatan-1-ol according to general procedure A to give the carboxylate intermediate A66-3, which was then reacted with S-phenylethanol to give the colorless oily compound A66 (45 mg) by preparative TLC purification (ethyl acetate/petroleum ether (v/v) =1/3) and collecting the fraction having Rf=0.4 to 0.5. ESI [ M+H ]] + ＝369.1
1H NMR(400MHz,CDCl 3 )δ7.68(s,1H),7.41–7.29(m,3H),7.21–7.12(m,2H),6.30(q,J＝7.0Hz,1H),4.80(p,J＝7.3Hz,1H),3.67–3.56(m,1H),3.25(s,3H),2.90–2.66(m,2H),2.19–2.04(m,2H),1.89(d,J＝7.1Hz,3H).
The following compounds A67 and A68 were prepared as assimilates A66 according to general procedure A, condensing 2-trifluoromethyl-1H-imidazole-5-carboxylic acid with the corresponding alcohol to give 2-trifluoromethyl-1H-imidazole-5-carboxylic acid ester intermediate, which was then reacted with S-phenethyl alcohol.
Compound a67:62mg, ESI [ M+H ]] + ＝423.0
1H NMR(400MHz,CDCl 3 )δ7.66(s,1H),7.44–7.31(m,3H),7.30–7.22(m,2H),6.43–6.33(m,1H),3.52(s,3H),2.49–2.39(m,2H),2.36–2.19(m,2H),1.91(d,J＝6.6Hz,3H),1.82–1.73(m,2H),1.74–1.65(m,2H).
Compound a68:29mg, ESI [ M+H ]] + ＝393.0
1H NMR(400MHz,CDCl 3 )δ7.68(s,1H),7.45–7.23(m,5H),6.30(q,J＝7.1Hz,1H),2.63–
2.31(m,7H),2.01(d,J＝7.1Hz,3H),1.92–1.79(m,2H).
The beneficial effects of the invention are illustrated by way of experimental examples:
experimental example 1 evaluation of general anesthesia action of the Compound of the invention Using disappearance of rat Innovative reflection as a criterion
Adult male SD rats with body weights ranging from 250 to 300 grams were selected for the trial. The above examples were combinedThe compound and control drug etomidate, CPMM, were dissolved in dimethyl sulfoxide (DMSO), and the blank group was given an equal volume of DMSO. Determination of ED of the general anesthetic action of the Compounds of the invention Using the sequential method (Up-and-Down method) with loss of eversion as a criterion 50 . The rats were dosed intravenously at the time of the test, each rat at a dosing volume of 0.6ml and a dosing rate of 0.1 ml/sec. The disappearance of the rat eversion reflex (lor) was used as an indicator of the onset of the general anesthetic effect for 30 seconds. The results are shown in Table 1.
TABLE 1 ED of general anesthesia of the inventive Compounds with disappearance of rat anti-normal reflection as a determination index 50
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Remarks: * Numerals in brackets indicate 95% confidence limits (mg/kg);
a represents the measured ED 50 In the range of 0.01-0.10mg/kg (including 0.01 and 0.10 mg/kg);
b represents the measured ED 50 In the range of 0.10-0.50mg/kg (excluding 0.10mg/kg, including 0.50 mg/kg);
c represents the measured ED 50 In the range of 0.50-1.00mg/kg (excluding 0.50mg/kg, including 1.00 mg/kg).
The results show that: the compounds of the invention can produce definite, transient general anesthetic action as do the control etomidate, CPMM. And the compounds of the invention exhibit the same or better potency as etomidate, CPMM.
Experimental example 2ED so that the rat eversion and the reflection disappear 50 Dose comparison of the pharmacological Effect of the Compounds of the invention
Adult male SD rats with body weights ranging from 250 to 300 grams were selected for the trial (n=8). The compounds of the above examples and the control drug etomidate, CPMM were dissolved in dimethyl sulfoxide (DMSO),the blank control group was given an equal volume of DMSO. 2ED with disappearance of orthotopic reflection in rats 50 The dose was tested. The rats were dosed intravenously at the time of the test, each rat at a dosing volume of 0.6ml and a dosing rate of 0.1ml/s. The time at which the loss of the eversion reflex (lor) was taken as the time at which the anesthetic effect started to be produced. The results are shown in Table 2.
TABLE 2 disappearance of 2ED with substantial rat eversion and specular reflection 50 Dose comparison of the pharmacological Effect of the Compounds of the invention
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Remarks: a represents the measured ED 50 In the range of 0.01-0.10mg/kg (including 0.01 and 0.10 mg/kg);
b represents the measured ED 50 In the range of 0.10-0.50mg/kg (excluding 0.10mg/kg, including 0.50 mg/kg);
c represents the measured ED 50 In the range of 0.50-1.00mg/kg (excluding 0.50mg/kg, including 1.00 mg/kg).
The results show that: the compound of the invention has the characteristics of quick response and quick recovery as compared with etomidate and CPMM. The duration of the pharmacological action can meet the time requirements of rapid induction of general anesthesia and the time requirements of diagnostic examination, short-term invasive examination or operation. In the experiment, the types and incidence of adverse reactions of the compounds of the invention are less than those of the control etomidate and CPMM.
Experimental example 3 in vitro cell assay to determine the effect of the compounds of the invention on adrenocortical function
Cell culture is performed by selecting H295R cell lines, incubating the cultured cells with the vehicle DMSO, etomidate, CPMM, etomidate metabolite etomidate, and a compound of the invention, and then determining the presence or absence of inhibition of adrenocortical function by the compound of the invention by measuring cortisol and corticosterone secreted by the cells in the supernatant of the cultured cells using HPLC-MS/MS method.
TABLE 3 cell assay to test the effect of the compounds of the invention on adrenocortical function
The results show that: the compounds of the invention meet the design requirements (see Table 3), and no inhibition of adrenocortical function is observed in the test.
Experimental example 4 determination of the Effect of the Compounds of the invention on the circulation function of rats Using the Small animal implantable physiological Signal telemetry System
Determination of the compounds of the invention according to the sequential method (Up-and-Down method) ED with loss of rat specular reflection as an indicator of anesthesia 50 Administration of 2ED 50 Dose (n=6), changes in heart rate and blood pressure of rats during and within 30 minutes after administration were observed using DSI (Data Science International, inc.) implanted physiological signal telemetry system, and the effect of the compounds of the present invention on circulatory function of rats was judged using Mean Arterial Pressure (MAP) and Heart Rate (HR) as representative indicators.
The main test instrument equipment is as follows:
DSI (Data Science International, inc.) implanted physiological signal telemetry systems for small animals include implants (model HD-S21, DSI corporation, usa), receiver boards (model RPC-1, DSI corporation, usa), signal converters (model DEM, DSI corporation, usa), perfusate gels (model, DSI corporation, usa), fibrin films (DSI corporation, usa), and the like.
Small animal breathing machine (model: HX-101E, manufacturer: chengdu Telechtin technology Co., ltd.); electronic balance (model: ME215S, manufacturer: sartorius, germany).
Firstly, establishing an animal model, placing a left ventricle catheter, an abdominal aorta catheter and placing an electrocardiosignal. Signals can be collected to begin the test at least one week after the post-operative stabilization.
The drug administration process comprises the following steps: loading rats into a holderIn the device, tail vein is exposed, 20G indwelling needle is placed into tail vein of rat, 0.2mL heparin is given, then extension tube with pre-pumped medicine is connected, adhesive tape is stuck to fix extension tube on tail vein, rat taking out fixer is put back into rearing cage and put on signal receiver together. After data acquisition begins, the rats are quietly adapted for 30 minutes and then calculated as 2ED 50 Dosing, dosing at a constant speed, observing and recording pharmacological effects, adverse reactions, behavior and the like of rats after dosing.
The administration is of a compound of the invention, etomidate (ETO) and Propofol (PRO)
And (3) data acquisition: after the software is completed to set the parameters for data acquisition, the power supply of the implant is turned on, and the data acquisition can be started. The experimental data recording frequency was set to 15 seconds once for this experiment. Data acquisition was recorded for 30 minutes before and after rat dosing. And (5) ending data acquisition and stopping the test. The experimental results are shown in fig. 1, 2, 3 and 4.
The 0min on the abscissa in the figure represents the end of dosing, and all test animals had lost the eversion specular reflection 1min after the end of dosing; the time for recovery of the eversion of each compound or drug is PRO:645s (10.75 min); ETO:440s (7.33 min); compound 7:110s (1.83 min); compound 8:129s (2.15 min); compound 11:225s (3.75 min); compound 12:254s (4.23 min); compound 15:193s (3.22 min); compound 16:167s (2.78 min); compound 17:327s (5.45 min); compound 18:273s (4.55 min); compound 27:126s (2.10 min); compound 28:435s (7.25 min); compound 29:255s (4.25 min); compound 45:200s (3.33 min).
The results show that: the compounds of the present invention showed little inhibitory effect on circulatory function as the control etomidate, whereas the control propofol showed significant inhibition of circulatory function (see figures 1, 2, 3, 4).
Experimental example 5 pharmacological Effect of the Compound of the invention on sustained infusion into rats
Adult male SD rats with body weights ranging from 250 to 300 grams were selected for continuous infusion experiments. The compound of the invention and a control drug etomidate and CPMM are prepared into fat emulsion before the test, and are continuously infused through the tail vein of a rat at 2 times MIR (minimum infusion speed), so that the disappearance of the eversion and the positive reflection begin to be maintained for 1 hour, and the recovery time and the complete recovery time of experimental animals after the infusion is stopped are recorded. The results are shown in Table 4.
TABLE 4 pharmacological effects of continuous infusion of the compounds of the invention into rats
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The results show that: the compound of the invention has recovery time which is equal to that of single intravenous injection 2ED after continuous infusion for 1 hour under 2 times MIR condition 50 There was no significant prolongation after the dose and the recovery time was significantly shorter than etomidate. The types and incidence of adverse reactions are also significantly better than etomidate and CPMM.
In summary, the invention discloses an etomidate derivative with a novel structure, which has a better central nervous system inhibition effect, can generate sedative, hypnotic and/or general anesthesia effects and control status epilepticus, and provides a new choice for clinically screening and/or preparing medicines with sedative, hypnotic and/or general anesthesia effects and medicines for controlling status epilepticus.

Claims (10)

1. A compound of formula II, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof:
x is selected from O or S;
R 3 and R is 4 Each independently selected from hydrogen, halogen, substituted or unsubstituted C 1-4 An alkyl group; the substituent is halogen;
L 1 selected from substituted or unsubstituted C 1 An alkylene group; the substituent is C 2-4 Alkynyl;
L 2 selected from unsubstituted and non-substituted C 1 An alkylene group;
R 5 selected from hydrogen, -OR 33 ；
Wherein R is 33 Selected from unsubstituted C 1～8 An alkyl group;
the A ring is selected from 0 to 4R 34 Substituted 4-8 membered saturated cycloalkyl;
wherein R is 34 Each independently selected from cyano, isocyano, isothiocyano, allenyl, C 1-5 Alkyl or halo, C 2-5 Alkenyl, C 2-6 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio or =r 37 ；
R 37 Selected from O, S, CR 38 R 39 Or C 2-8 Alkenyl groups; r is R 38 、R 39 Each independently selected from hydrogen, halogen or C 1-8 An alkyl group.
2. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, wherein: the compound is one of the following compounds:
3. a compound, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, characterized in that:
the compound is shown as a formula IIB:
in the method, in the process of the invention,
x is selected from O;
R 3 and R is 4 Each independently selected from hydrogen;
L 1 selected from none;
L 2 selected from unsubstituted and non-substituted C 1 An alkylene group;
R 33 selected from unsubstituted C 1 Alkyl, C 3 Alkyl, unsubstituted C 3 Alkenyl groups;
the A ring is selected from 0 to 1R 34 Substituted 4-membered saturated cycloalkyl;
R 34 selected from C 2 An alkoxy group;
or the compound is shown as a formula IIC:
in the method, in the process of the invention,
x is selected from O;
R 3 and R is 4 Each independently selected from hydrogen;
L 1 selected from none;
the A ring is selected from 0 to 2R 34 Substituted 4-membered saturated cycloalkyl;
R 34 selected from C 2 Alkynyl or =r 37 ；
R 37 Selected from CR 38 R 39 ；R 38 、R 39 Each independently selected from hydrogen.
4. A compound according to claim 3, a pharmaceutically acceptable salt thereof or a deuterated derivative thereof, wherein: the compound is as follows:
5. a compound of formula IIA, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof:
in the method, in the process of the invention,
x is selected from O or S;
z is selected from O or S;
R 3 and R is 4 Each independently selected from hydrogen, halogen, substituted methyl; the substituent of the methyl is halogen;
L 1 selected from unsubstituted C 1 An alkylene group;
L 2 selected from unsubstituted and non-substituted C 1 An alkylene group;
R 33 selected from hydrogen, methyl, vinyl, allenyl, substituted or unsubstituted C 2 ～ 3 Alkynyl; the substituent of the alkynyl is vinyl;
the A ring is selected from 4-6 membered saturated cycloalkyl.
6. The compound of claim 5, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, wherein: the compound is as follows:
7. A compound, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, characterized in that: the compound is as follows:
8. a compound, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, characterized in that: the compound is as follows:
9. use of a compound as claimed in any one of claims 1 to 8, a pharmaceutically acceptable salt thereof, or a deuterated derivative thereof, in the manufacture of a medicament having sedative, hypnotic and/or anaesthetic effects, and/or useful for controlling status epilepticus; wherein the anesthesia is general anesthesia.
10. A medicament, characterized in that: a formulation prepared from a compound according to any one of claims 1 to 8, a pharmaceutically acceptable salt or deuterated derivative thereof, and pharmaceutically acceptable excipients.
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