CN112574175B - Quinoline compound, preparation method and application thereof - Google Patents

Quinoline compound, preparation method and application thereof Download PDF

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CN112574175B
CN112574175B CN202010661397.4A CN202010661397A CN112574175B CN 112574175 B CN112574175 B CN 112574175B CN 202010661397 A CN202010661397 A CN 202010661397A CN 112574175 B CN112574175 B CN 112574175B
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CN112574175A (en
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赵传生
胡杰
陶志刚
宋海峰
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Chang'ao Pharmaceutical Technology Holdings Ltd
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Nanjing Changao Pharmaceutical Science and Technology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

The invention relates to quinoline compounds, a preparation method and application thereof. In particular, the invention provides a novel quinoline compound, pharmaceutically acceptable salts thereof, a preparation method and application thereof in preparing medicines for treating tubercle bacillus infectious diseases, in particular to medicines for treating infectious diseases caused by drug-resistant tubercle bacillus. The quinoline compound or the pharmaceutically acceptable salt thereof has good anti-tubercle bacillus activity, and particularly has strong activity on drug-resistant tubercle bacillus.

Description

Quinoline compound, preparation method and application thereof
Technical Field
The invention belongs to the fields of pharmacology, pharmaceutical chemistry and pharmacology, and more particularly relates to a novel quinoline compound and a preparation method thereof, and the compound is used for treating related diseases caused by tubercle bacillus, especially drug-resistant tubercle bacillus infection.
Background
Tuberculosis is caused by infection with mycobacterium tuberculosis (Mycobacterium tuberculosis, mtb), one of the oldest diseases in humans. About 23% of people worldwide (about 17 billion) have latent tuberculosis infection estimated by the World Health Organization (WHO) in 2017, of which 5-10% of the population develop active tuberculosis throughout their lifetime. At present, millions of new people have active tuberculosis symptoms each year, and the annual death number caused by tuberculosis exceeds AIDS, so that the tuberculosis becomes a world number-first infectious disease lethal killer.
At present, four-medicine combined treatment strategies of rifampicin, isoniazid, ethambutol and pyrazinamide are adopted for the first-line treatment of sensitive tuberculosis, and although the treatment success rate can reach more than 85%, the treatment period is as long as 6 months, and the treatment side effects are large, for example, if the rifampicin and isoniazid are combined, serious hepatotoxicity is possibly caused, and the ethambutol can cause optic nerve damage and the like. Some people cannot be treated normally, and some people develop drug-resistant tuberculosis (rifampicin resistance or multi-drug resistance) due to incomplete treatment or improper treatment. For drug-resistant tuberculosis, the treatment period is longer, the treatment side effect is larger, and the treatment success rate is only about 55%. Drug resistant tuberculosis, especially multi-drug resistant tuberculosis and extensively drug resistant tuberculosis, are the leading causes of death in tuberculosis patients, especially in patients with immunodeficiency, such as patients with both aids and tuberculosis.
WO 2004/01436 discloses a number of diaryl quinoline antitubercular compounds, of which Bedaquiline (TMC 207) is a representative compound thereof, which kills mycobacterium tuberculosis by disrupting the coupling of transmembrane proton transfer to ATP synthesis by acting on the ATP synthase proton pump on the mitochondrial membrane of mycobacterium tuberculosis, interfering with the synthesis of mycobacterium tuberculosis ATP. The united states Food and Drug Administration (FDA) and European Medicines Administration (EMA) approved their use as part of the adult multi-drug resistant tuberculosis combination therapy at the end of 2012 and in march 2014, respectively. Because of the unique action mechanism, the anti-mycobacterium tuberculosis has strong activity, no cross drug resistance with other existing tuberculosis drugs, and good bactericidal activity on both replication type and non-replication type of the mycobacterium tuberculosis, and good clinical curative effect, the mycobacterium tuberculosis is listed as a first-line drug for treating rifampicin resistance and multi-drug resistance tuberculosis by WTO at the end of 2017.
However, as with most other antitubercular drugs, bedaquiline suffers from significant drawbacks, such as prolonged QTc interval in the electrocardiogram, which may lead to serious cardiac safety risks. It is also notable that the mortality rate of the beraquinoline group (12.7%) found in the phase 2 trial of clinical trial C208 was higher than that of the placebo group (2.5%), but the specific reasons are not clear. At present, patients using the bedaquiline still need to constantly monitor the electrocardiographic physiological condition and the drug safety response in the treatment period of 18-20 months, and in addition, the application of the new mechanism drug in tuberculosis patients is limited to a certain extent due to lower bioavailability, obvious hepatotoxicity, phospholipid diseases caused by the drug and other side effects.
In view of the above, there is an urgent need in the art to develop a new class of quinoline compounds that have better therapeutic effects and safety than bedaquiline for the treatment of tubercle bacillus, especially related diseases caused by drug-resistant tubercle bacillus infections.
Disclosure of Invention
The invention aims to provide novel antituberculous compounds with a structural general formula shown in (I), or optical isomers and pharmaceutically acceptable inorganic or organic salts thereof;
In a second aspect of the present invention, there is provided a process for the preparation of a compound of formula (I), or various optical isomers, pharmaceutically acceptable inorganic or organic salts thereof.
In a third aspect of the invention there is provided the use of a compound of the invention as defined above, or each optical isomer, pharmaceutically acceptable inorganic or organic salt thereof, as an active ingredient in the manufacture of a medicament for the treatment of a disease associated with infection by tubercle bacillus, in particular multidrug-resistant tubercle bacillus. The invention also comprises a pharmacologically acceptable excipient or carrier, and the compound of the formula (I) or each optical isomer and pharmaceutically acceptable inorganic or organic salt thereof as active ingredients.
In a first aspect of the present invention, there is provided a compound of formula (I), or each optical isomer, or pharmaceutically acceptable salt thereof:
wherein m represents an integer of 0 to 3;
R 1 represents the following groups:
a) Hydrogen or C 1-8 Alkyl, alkyl being unsubstituted or substituted with one to three groups independently selected from the group consisting of: halogen, hydroxy, cyano, C 1-4 Alkyl, C 1-4 An alkoxy group;
b)C 3-8 cycloalkyl, or said C 3-8 One carbon atom of cycloalkyl being replaced by oxygen, sulfur (sulfoxide or sulfone) or NR 8 Alternatively, the cycloalkyl is unsubstituted or substituted with one to three groups independently selected from the group consisting of: halogen, hydroxy, halogen substituted or unsubstituted C 1 -C 6 Alkyl, halogen substituted or unsubstituted C 3 -C 6 Cycloalkyl, halogen substituted or unsubstituted C 1 -C 6 Alkoxy, one or two C 1-6 An alkyl or cycloalkyl substituted or unsubstituted amino, a halogen substituted or unsubstituted C 1-6 Alkylthio;
R 8 selected from hydrogen or C 1-6 An alkyl group; or (b)
c) Alkenyl or alkynyl which is unsubstituted or substituted with: c substituted or unsubstituted by one to three groups independently selected from cyano, halogen or hydroxy 1-6 Alkyl, C substituted or unsubstituted by one to three groups independently selected from cyano, halogen or hydroxy 3-6 Cycloalkyl;
R 2 and R is 3 Each independently selected from: hydrogen, C substituted or unsubstituted by one to three halogens 1-6 Alkyl, substituted or unsubstituted by one to three groups independently selected from cyano, halogen or hydroxySubstituted C 3-6 Cycloalkyl; or R is 2 And R is 3 Are linked to form a 4-8 membered cyclic structure wherein the ring is unsubstituted or substituted with one to three groups independently selected from cyano, halogen or hydroxy;
R 4 selected from aryl or heteroaryl, which is unsubstituted or substituted with one to three groups independently selected from the group consisting of: halogen, hydroxy, cyano, halogen substituted or unsubstituted C 1-6 Alkyl, halogen substituted or unsubstituted C 3-6 Cycloalkyl, halogen substituted or unsubstituted C 1-6 Alkoxy, halogen substituted or unsubstituted C 1-6 Alkylthio, NR 9 R 10 Methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl; r is R 9 And R is 10 Each independently selected from: hydrogen, halogen substituted or unsubstituted C 1-6 Alkyl, halogen substituted or unsubstituted C 3-6 Cycloalkyl;
R 5 selected from halogen, cyano, hydroxy, C 1-4 Alkoxy, or C 1-4 Alkylthio;
R 6 selected from C 1-6 Alkyl, C 1-6 Alkoxy, or C 1-6 Alkylthio;
R 7 selected from hydrogen, or C 1-6 An alkyl group.
In another preferred embodiment, R 1 Represents C 3-6 Cycloalkyl, or said C 3-6 A cycloalkyl group wherein one carbon atom is replaced by oxygen, said cycloalkyl group being unsubstituted or substituted with one to three groups independently selected from the group consisting of: halogen, halogen substituted or unsubstituted C 1 -C 3 An alkyl group.
In another preferred embodiment, R is 2 And R is 3 Each independently selected from: c substituted or unsubstituted by one to three halogens 1-3 An alkyl group.
In another preferred embodiment, R is 4 Selected from naphthyl or heteroaryl, which is unsubstituted or substituted with one to three groups independently selected from the group consisting of: halogen, halogen substituted or unsubstituted C 1-4 An alkoxy group.
In another preferred embodiment, R is 5 Selected from halogen or cyano; r is R 6 Selected from C 1-3 An alkoxy group; r is R 7 Selected from hydrogen or C 1-3 An alkyl group.
The present invention provides a compound, or each optical isomer, or pharmaceutically acceptable salt thereof, selected from the group consisting of:
in another preferred embodiment, the optical isomer of the compound is in the a-1 or a-2 configuration; more preferably its A-1 configuration.
In a second aspect of the present invention there is provided a pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier and as active ingredient a compound provided by the present invention as described above, or each optical isomer, or pharmaceutically acceptable salt thereof.
In another preferred embodiment, the composition is in an oral dosage form.
In a third aspect of the invention there is provided the use of a compound provided by the invention as described above, or each optical isomer, or pharmaceutically acceptable salt thereof, for the preparation of a composition for inhibiting the growth of mycobacterium tuberculosis (Mycobacterium tuberculosis).
In a fourth aspect of the invention there is provided the use of a compound provided by the invention as described above, or each optical isomer, or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of infection.
In another preferred embodiment, the infection is a Mycobacterium tuberculosis (Mycobacterium tuberculosis) infection; more preferably, the infection is a drug resistant tubercle bacillus infection.
In another preferred embodiment, the infection is a mycobacterium tuberculosis (Mycobacterium tuberculosis) infection of the lung; more preferably, the infection is a drug resistant tubercle bacillus infection of the lung.
In a fifth aspect of the present invention, there is provided a process for preparing a compound of formula i, said process comprising the steps of:
(1) Reacting a compound shown in a formula III with an allyl metal reagent to generate tertiary alcohol;
(2) The tertiary alcohol is subject to double hydroxylation in the presence of an oxidant and then is subject to pyrolysis to obtain a compound shown in a formula II; and
(3) Reducing the compound shown in the formula II to obtain primary alcohol, activating the primary alcohol, and reacting the primary alcohol with corresponding amine to generate the compound shown in the formula I;
in the formulae, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 M and formula (I) are as defined above.
In another preferred embodiment, the compound of formula II is reacted with a corresponding amine to form a compound of formula I;
accordingly, the invention provides a new quinoline compound which has better curative effect and safety compared with the bedaquiline, and is used for treating related diseases caused by tubercle bacillus, in particular drug-resistant tubercle bacillus infection.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Detailed Description
The inventor synthesizes and screens a large number of compounds through extensive research, and discovers that the compound shown in the formula (I) has strong inhibitory activity on tubercle bacillus in vitro and in vivo for the first time, and is particularly suitable for preparing medicines for treating related diseases caused by tubercle bacillus infection. The present invention has been completed on the basis of this finding.
Representative names of the compounds (or salts thereof) of the formula (I) of the present invention are shown in the following table:
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unless specifically indicated otherwise, the following terms used in the specification and claims have the following meanings:
"alkyl" refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 8 carbon atoms, and also straight and branched chain groups of 1 to 8 carbon atoms. Lower alkyl groups having 1 to 4 carbon atoms are preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl.
"cycloalkyl" refers to a 3-to 8-membered all-carbon monocyclic aliphatic hydrocarbon group, a 4-to 12-membered aliphatic and cyclic group, a 6-to 12-membered aliphatic bridged ring group, or a 6-to 12-membered aliphatic spiro ring group, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi electron system. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexane, cyclohexadiene, and the like; the cycloalkyl backbone may have 1 to 3 carbon atoms replaced by the following heteroatoms or groups: -O-, -S-, -NR 11 - (said R) 11 May be hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl).
"alkoxy" refers to an alkyl group bonded to the remainder of the molecule through an ether oxygen atom. Representative alkoxy groups are those having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy. As used herein, "alkoxy" includes unsubstituted and substituted alkoxy groups, particularly alkoxy groups substituted with one or more halogens.
"hetero" means a non-carbon atom or group comprising-O-, -S-, -NR 11 - (said R) 11 Selected from hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl group, -SO-, -SO 2 -, =o, and any combination thereof (e.g. -CONR-, -SO 2 NR-、-COO--NHCOO-, -NHCONH, etc.; the number of heteroatoms or groups may be from 1 to 6.
"aryl" refers to a group having at least one aromatic ring structure, i.e., an aromatic ring having a conjugated pi electron system, and includes carbocyclic aryl, heteroaryl groups. Substituents at different positions on the aryl group can be connected to form a cyclic structure.
"heteroaryl" refers to a structure in which a carbon atom on the aryl backbone is replaced with a heteroatom or group, heteroaryl including, but not limited to, the following structures: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furyl, N-methylpyrrolidone, N-methylpyrazolyl, N-methylimidazolyl, thiazolyl, oxazolyl, isoxazolyl, 1,2, 4-triazolyl, 1,2, 3-triazolyl, benzofuranyl, benzothienyl, indolyl, benzopyrazolyl, benzimidazolyl, benzisoindolone, benzothiazolyl, benzoxazolyl, benzo-1, 2, 3-triazolyl, quinolinyl, isoquinolinyl, benzopyrazinyl, benzopyrimidinyl, benzopyridazinyl, benzothiazinonyl, benzoxazolonyl, benzopyrimidinyl, pyridofuranyl, pyridothienyl, pyridopyrazolyl, pyridoimidazolyl, pyridothiazolyl, pyridooxazolyl, pyridopyridyl-1, 2, 3-yl, pyridopyrazinyl, pyridopyrimidinyl, pyridoxazinonyl.
"halogen" means fluorine, chlorine, bromine or iodine.
As used herein, "pharmaceutically acceptable salts" means salts which are not particularly limited as long as they are pharmaceutically acceptable, and include inorganic salts and organic salts. Specifically, salts of the compounds of the present invention with acids may be mentioned, and suitable salts-forming acids include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, phosphoric acid, and the like, organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, trifluoroacetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, ethanesulfonic acid, and the like, and acidic amino acids such as aspartic acid, glutamic acid, and the like.
"an integer between 0 and 3" means 0,1,2,3; an "integer between 1 and 3" means 1,2,3.
The compounds of the invention contain at least two asymmetric carbon atoms (optical centers) and thus racemates, diastereomers and individual isomers are included within the scope of the present invention. According to the R, S system naming convention (the kann-english-prasugrel convention), the configuration of an asymmetric carbon atom is related to the size of the substituent to which it is attached, and the difference in the size of the substituent may result in the same asymmetric carbon atom in the same series of compounds having a different R or S, but the spatial orientation of the asymmetric carbon atom substituent is unchanged. In the purification and separation process of the final step of the reaction scheme of the present invention, each target compound may be separated into two pairs of diastereomers by a conventional separation method (e.g., column chromatography or preparative thin layer chromatography), and labeled as compound a and compound B, respectively, according to the order in which they are separated; each pair of diastereomers can be further separated into individual enantiomers by chiral separation methods, such as preparative chiral high performance liquid chromatography (chiral-HPLC), and the four individual enantiomers are labeled-1 and-2, respectively, in the order of the separation, and are subjected to multiple in vitro activity tests, with A-1 being the best active, and individual B-1 compounds having weaker activity, and A-2 and B-2 being essentially inactive, based on the structure of Bedaquinoline and its site of action, and differences in the activity of the isomers (Comprehensive Chirality,2012,54-69), and the results of the in vitro activity test of the present invention, the spatial orientations and corresponding isomers of the four individual isomers involved in two key asymmetric carbon atoms of the present invention are defined as follows:
Process for the preparation of the compounds of the invention
The compounds of the present invention and their various intermediates can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present invention.
The process for preparing the compound of the general formula (I) of the present invention is specifically described below, but these specific processes do not limit the present invention in any way.
The compound of the general formula (I) of the present invention can be produced by the following method, however, the conditions of the method, such as reactants, solvents, bases, amounts of the compounds used, reaction temperature, time required for the reaction, etc., are not limited to the following explanation. The compounds of the present invention may also optionally be conveniently prepared by combining the various synthetic methods described in this specification or known in the art, such combination being readily apparent to those skilled in the art to which the present invention pertains.
In the preparation method of the invention, the compound shown in the formula (I) can be prepared from the compound (III) through five steps of reactions, comprising the following steps:
In a first step, compound (iii) is reacted with a suitable allylic metal reagent (such as, but not limited to, allylic zinc) to form a tertiary alcohol;
secondly, dihydroxylation occurs under a suitable oxidizing agent;
thirdly, cracking under a proper oxidant to obtain a compound (II);
fourth, the compound (II) is reduced by a proper reducing agent to obtain alcohol;
and fifthly, properly activating the primary alcohol in the alcohol obtained in the fourth step and then reacting with proper amine to obtain the target compound (I).
The first step reaction described above may be carried out over a suitable catalyst (such as, but not limited to, cubr. Me 2 S), a suitable solvent (such as, but not limited to, anhydrous THF), and a suitable temperature (e.g., 0-75 ℃).
The oxidizing agents in the second step include, but are not limited to, catalytic amounts of potassium osmium dihydrate and N-methylmorpholine-N-oxide.
The oxidizing agent in the third step includes, but is not limited to, sodium periodate.
The reducing agent in the fourth step includes, but is not limited to, sodium borohydride.
Primary alcohol activation in the fifth step described above includes, but is not limited to, formation of-OMs with MsCl; the amines used include, but are not limited to, dimethylamine.
Wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 M and formula (I) are as defined herein.
The compounds of formula III (which may also be referred to as intermediates III, etc.) used in the present invention can be obtained by the following reaction schemes 1-6:
Scheme 1:
preparation of intermediate (III)
R 1 、R 4 、R 5 、R 6 、R 7 M and formula (I) are as defined herein.
After conversion of-Cl in the starting material to-CN by a suitable reagent (e.g., sodium cyanide), hydrolysis under suitable conditions (e.g., aqueous sodium hydroxide) gives an acid, which is then reduced to a primary alcohol by a suitable reducing agent (e.g., a solution of borane dimethyl sulfide complex), which is then oxidized to an aldehyde by a suitable oxidizing agent (e.g., DMP), which is then reacted with a catalyst containing R 4 The grignard reagent of (C) reacts to obtain alcohol, and then the alcohol is oxidized to obtain key intermediate ketone (IV). Nucleophilic substitution reactions occur under base (e.g., potassium carbonate or sodium hydroxide) at suitable temperatures (e.g., 20-80 ℃) to afford key intermediate (III).
Scheme 2:
R 1 、R 4 、R 5 、R 6 、R 7 m and formula (I) are as defined herein.
Starting material R 4 CO 2 H is reduced with a suitable reducing agent (e.g., liAlH 4 ) Reduction to primary alcohols followed by oxidation to aldehydes by a suitable oxidant (e.g., manganese dioxide) followed by reaction with 1, 3-propanedithiol to give dithioacetals which are hydrocracked under the action of a suitable base (e.g., butyllithium or lithium diisopropylamide) to give carbanions which are then reacted with heteroarylmethylene halides to give the compound dithioketals which are then reacted under suitable oxidation conditions (e.g., [ bis (trifluoroacetoxy) iodo) ]Benzene) to remove the protecting group to obtain ketone (IV). Nucleophilic substitution reactions occur under base (e.g., potassium carbonate or sodium hydroxide) at suitable temperatures (e.g., 20-80 ℃) to afford key intermediate (III).
Scheme 3:
R 1 、R 4 、R 5 、R 6 、R 7 m and formula (I) are as defined herein.
After conversion of-Cl in the starting material to-CN by a suitable reagent (e.g., sodium cyanide), the catalyst is catalyzed by a suitable metal (e.g., ni (dppe) Cl 2 ) Directly reacts with aryl boric acid to obtain ketone (IV). Nucleophilic substitution reactions occur under base (e.g., potassium carbonate or sodium hydroxide) at suitable temperatures (e.g., 20-80 ℃) to afford key intermediate (III).
Scheme 4:
R 1 、R 4 、R 5 、R 6 、R 7 m and formula (I) are as defined herein.
Starting material heteroaryl methyl acetate and R 4 COCl inThe intermediate obtained by reaction under suitable base (e.g., liHMDS) conditions is subsequently removed at high temperature in a suitable solvent (e.g., dimethyl sulfoxide) to give ketone (iv). Nucleophilic substitution reactions occur under base (e.g., potassium carbonate or sodium hydroxide) at suitable temperatures (e.g., 20-80 ℃) to afford key intermediate (III).
Scheme 5:
R 1 、R 4 、R 5 、R 6 、R 7 m and formula (I) are as defined herein.
The starting material allyl alcohol can be synthesized in a literature manner, the double bond of allyl alcohol is epoxidized, and the obtained epoxy compound contains R 1 (CH2) m The ring opening is attacked by nucleophile to give the vicinal diol, which is cleaved in the presence of a suitable oxidizing agent (e.g. sodium periodate) to give the aldehyde, which is then reacted with a reagent containing R 4 The grignard reagent of (c) reacts with the secondary alcohol and is oxidized by a suitable oxidizing agent (e.g., DMP) to give (iii).
Flow 6:
R 1 、R 4 、R 5 、R 6 、R 7 m and formula (I) are as defined herein.
The starting compounds are commercially available starting materials or can be prepared according to reported synthetic routes. Starting compounds and containing R 6 Followed by reduction with a suitable reducing agent (e.g., sodium borohydride) to provide a primary alcohol, followed by reaction with a suitable chlorinating agent (e.g., thionyl chloride) to provide heteroarylmethylene chloride, and a suitable organometallic reagent (e.g., organozinc reagent) prepared from the heteroarylmethylene chloride is reacted with R 4 The CHO reaction and oxidation are carried out to obtain ketone (IV); in the presence of a base (e.g. potassium carbonate or sodium hydroxide) in a suitable solventNucleophilic substitution reactions occur in single or mixed solvents (e.g., water, acetone, acetonitrile, tetrahydrofuran) and at suitable temperatures (e.g., 20-80 ℃) to afford key intermediate (III).
The compounds of formula (I) may also be prepared from compounds of formula (II) and the corresponding amines by reductive amination. The reaction is typically carried out in a suitable reducing agent (e.g., without limitation, naB (OAc)) 3 ) A suitable acid (e.g., without limitation, acetic acid), a suitable solvent (e.g., without limitation, 1, 2-dichloroethane), and a suitable temperature (e.g., 0-75 ℃).
Wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 M and formula (I) are as defined herein.
In one embodiment of the invention, the methods of preparation of compound 28 and compound 32 are as follows:
compound 26 and compound 31 are produced in the presence of a palladium catalyst (e.g., pd (PPh) 3 ) 4 ) Coupling with a cyano reagent (e.g., zinc cyanide) under the action of a suitable solvent (e.g., DMF) and at a suitable temperature (e.g., 0-100 ℃).
Pharmaceutical compositions and methods of administration
Because the compound has excellent anti-tubercle bacillus activity, the compound and optical isomers thereof, pharmaceutically acceptable inorganic or organic salts and the pharmaceutical composition containing the compound as a main active ingredient can be used for treating related diseases caused by tubercle bacillus, in particular multi-drug resistant tubercle bacillus infection.
The compounds of the general formula (I) have strong anti-mycobacterium tuberculosis effect. Compared with the bedaquiline, the compound of the invention has stronger in-vitro bactericidal activity, stronger lung targeting, lower distribution in brain, smaller potential cardiac toxicity, equivalent drug generation property in animal body, and can be expected to achieve the same bactericidal effect under low administration dosage, thus lower treatment cost and toxicity and better treatment compliance of patients.
The pharmaceutical compositions of the present invention may employ pharmaceutically acceptable excipients or carriers, as well as the compounds of formula (i) of the present invention, or individual optical isomers, pharmaceutically acceptable inorganic or organic salts thereof, as active ingredients.
The pharmaceutical compositions of the present invention comprise a safe, effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable excipient or carrier. Wherein "safe, effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical compositions contain 1-1000mg of the compound/dose of the invention, preferably 5-500mg of the compound/dose of the invention, more preferably 10-200mg of the compound/dose of the invention. The safe and effective amount of the compound is determined according to the specific conditions such as age, illness and treatment course of the subject.
The compounds of the present invention and pharmaceutically acceptable salts thereof can be formulated into a variety of formulations comprising a safe and effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable excipient or carrier. Wherein "safe, effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. The safe and effective amount of the compound is determined according to the specific conditions such as age, illness and treatment course of the subject.
"pharmaceutically acceptable excipient or 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 excipients or carrier moietiesCellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talcum, solid lubricant (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyalcohol (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifying agent (such as tween) Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, antioxidants, preservatives, pyrogen-free water and the like.
In the present invention, the term "active ingredient" refers to a compound represented by the general formula (I), and pharmaceutically acceptable inorganic or organic salts of the compound represented by the general formula (I). The compounds of the invention may contain one or more asymmetric centers and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers. Asymmetric centers that may be present depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures, as well as pure or partially pure compounds, are included within the scope of the invention. The present invention is meant to include all such isomeric forms of these compounds.
In addition, the compounds of the present invention may be prepared by reacting the compounds with pharmaceutically acceptable acids in polar protic solvents such as methanol, ethanol, isopropanol, and pharmaceutically acceptable acids to form pharmaceutically acceptable salts, as desired. The pharmaceutically acceptable inorganic or organic acid may be: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid, and the like.
The term "caused by tubercle bacillus, in particular multi-drug resistant tubercle bacillus infection", as used herein, refers to caused by tubercle bacillus sensitive to clinical tubercle drugs, tubercle bacillus resistant to clinical drugs and widely used drugs.
The terms "disease caused by a tuberculous infection" or "tuberculous infectious disease" are used interchangeably and as used herein refer to tuberculosis, lymphoid tuberculosis, intestinal tuberculosis, bone tuberculosis, tuberculous pleurisy, tuberculous meningitis, etc.
Because the compound has excellent anti-tubercle bacillus activity, the compound and various crystal forms, pharmaceutically acceptable inorganic or organic salts thereof and the pharmaceutical composition containing the compound as a main active ingredient can be used for treating diseases related to tubercle bacillus. According to the prior art, the compounds of the present invention are useful in the treatment of tuberculosis and other infectious diseases.
The compounds of the present invention may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically.
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.
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.
Compositions for parenteral 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.
The compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
When a pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically effective dose, and the daily dose is usually 1 to 1000mg, preferably 10 to 500mg, for a human having a body weight of 60 kg. 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 main advantages of the application include:
1. compared with the bedaquiline, the compound of the application has more excellent in-vivo and in-vitro antibacterial activity on mycobacterium tuberculosis (including drug-resistant bacteria).
2. The compounds of the application show better lung targeting and lower brain targeting than bedaquiline.
The details of the various specific aspects, features and advantages of the above-described compounds, methods, pharmaceutical compositions will be set forth in the following description in order to provide a thorough understanding of the present application. It is to be understood that the detailed description and examples, which follow, describe specific embodiments for reference only. After reading the description of the application, those skilled in the art may make various changes or modifications to the application, which also fall within the scope of the application.
The present application is more specifically explained in the following examples. It should be understood, however, that these examples are intended to illustrate the application and are not intended to limit the scope of the application in any way. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Parts and percentages are parts by weight and percentages by weight unless otherwise indicated. The organic solvents used in the examples were all treated by drying methods known in the art.
1 H NMR was recorded on a Varian Mercury 400 or 600 nuclear magnetic resonance apparatus, chemical shifts being expressed as delta (ppm); the MS was measured by using an Shimadzu LC-MS-2020 mass spectrometer. The silica gel for separation is not illustrated as 200-300 meshes, and the ratio of the eluents is volume ratio.
Specific synthetic methods of the above-invented compounds are specifically described below.
Typically, there are (at least) two chiral centers in the compounds of the invention, and thus each compound may comprise (at least) four stereoisomers. In the final purification and separation step of the reaction scheme, each target compound may be separated into two pairs of diastereomers by a conventional separation method (e.g., column chromatography or preparative thin layer chromatography), and labeled as compound a and compound B, respectively, in the order of the separation; each pair of diastereomers may be further separated into individual enantiomers by chiral separation methods, such as preparative chiral high performance liquid chromatography (chiral-HPLC), and are labeled as-1 and-2, respectively, according to the order in which they are separated, for example, for Compound 1, the two pairs of diastereomeric compounds obtained by conventional separation may be labeled as 1A and 1B, respectively, the two individual enantiomers obtained by chiral separation of 1A may be labeled as 1A-1 and 1A-2,1B, respectively, and the two individual enantiomers obtained by chiral separation may be labeled as 1B-1 and 1B-2, respectively.
The separation method comprises the following steps: column chromatography was carried out on commercially available conventional silica gel (200-300 mesh) or commercially available conventional preparation plates, and UV-254nm was used as the detection means, and the eluent or developing agent was commercially available untreated dichloromethane and methanol, with the ratio being appropriately adjusted according to the polarity of the compound.
Chiral preparative HPLC conditions: the model of the separation column is a celluloid AD-H column; a detector, UV detector, wavelength 235nm; temperature: 30 ℃; fluidity: n-hexane: isopropyl alcohol: diethylamine = 70:30:0.1.
synthetic examples
Preparation of intermediate IV-1
Intermediate IV-1 can be prepared according to the following two reaction schemes
Reaction scheme 1:
IV-1-1-1 preparation
6-bromo-2-chloroquinoline-3-carbaldehyde (5.0 g,18.52 mmol) was dissolved in MeOH (30 ml), and a fresh sodium methoxide methanol solution (93 mmol) was added thereto under ice bath, followed by reflux reaction for 3 hours. TLC: petroleum ether: ethyl acetate=10:1. Cooling to room temperature after the reaction is finished, pouring the reaction liquid into ice water, precipitating solid, filtering, and drying a filter cake to obtain light yellow powdery solid: 4.0g, yield: 80%. LC-MS (ESI): 266.1[ M+H ]] +
IV-1-1-2 preparation
IV-1-1-1 (5.0 g,18.52 mmol) was dissolved in MeOH (80 ml) and NaBH was added 4 (1.41 g 37 mol) and allowed to react at room temperature for 1h. TLC: petroleum ether: ethyl acetate=10:1. After the reaction, the reaction solution was poured into ice water to quench, EA was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and dried by spin-drying. Column chromatography (petroleum ether: ethyl acetate=5:1) gives a white powdery solid: 4.5g, yield: 90%. LC-MS (ESI): 268.0[ M+H ] ] +
IV-1-1-3 preparation
IV-1-1-2 (10.1 g,37.67 mmol) was dissolved in DCM (400 ml) and SOCl was slowly added 2 (18 g 151 mol) was reacted at room temperature for 1 hour. TLC: petroleum ether: ethyl acetate=10:1. After the reaction, the reaction solution was poured into ice water to quench, EA was extracted, the organic phase was washed with saturated brine 2 times, dried over anhydrous sodium sulfate, and dried by spin-drying. Column chromatography, (petroleum ether: ethyl acetate=10:1) to give a white powdery solid: 8.67g, yield: 80%. LC-MS (ESI): 288.0[ M+H ]] +
IV-1-1-4 preparation
Zinc powder (2.74 g,41.88 mmol), iodine (2 particles), THF (80 ml) were placed in a 250ml three-necked flask under argon, a solution of LiCl in THF (0.5M, 42ml,20.94 mmol) was added dropwise under ice-bath, a solution of IV-1-1-3 (4 g,13.96 mmol) in THF (40 ml) was slowly added dropwise, the ice-bath reaction was continued for 2h, TLC: petroleum ether: ethyl acetate=2:1. Directly used in the next step.
IV-1-1-5 preparation
A solution of 3, 5-dimethoxypyridine-4-carbaldehyde (1.98 g,11.87 mmol) in THF (40 ml) was slowly added to IV-1-1-4 in THF (162 ml) and reacted overnight at room temperature. TLC: petroleum ether: ethyl acetate=10:1. After the reaction, slowly adding saturated ammonium chloride solution dropwise for quenching, extracting by EA, washing the organic phase with saturated common salt for 2 times, drying by anhydrous sodium sulfate, and spin-drying. Pulping the solid with methyl tertiary butyl ether to obtain white powdery solid: 4.65g, yield: 93%. LC-MS (ESI): 419.1[ M+H ] ] +
IV-1 preparation
IV-1-1-5 (4.65 g,11.09 mmol) was dissolved in DCM (100 ml), DMP (5.65 g,13.31 mmol) was added under ice-bath and reacted at room temperature for 1h. TLC: petroleum ether: ethyl acetate=10:1. And after the reaction is finished, sequentially adding a saturated sodium thiosulfate solution and a sodium bicarbonate solution into the reaction solution for quenching, stirring at room temperature for 0.5h, extracting by EA, washing an organic phase with saturated saline for 2 times, drying by anhydrous sodium sulfate, and spin-drying. Column chromatography (petroleum ether: ethyl acetate=50:1) gives a yellowish powdery solid: 3.6g, yield: 74%. LC-MS (ESI): 417.5[ M+H ]] +
1 H NMR(400MHz,CDCl 3 )δ:7.80(d,J＝2.2Hz,1H),7.74–7.67(m,2H),7.66–7.60(m,1H),6.81(s,2H),4.27–4.22(m,2H),4.00(s,3H),3.94(s,6H).
Reaction scheme 2:
IV-1-2-1 preparation
Methyl 2- (6-bromo-2-methoxyquinolin-3-yl) acetate (6 g,19.35 mmol), which was obtained from methyl 2- (6-bromo-2-chloroquinolin-3-yl) acetate (synthesized according to Angew. Chem. Int. Ed.2019,58, 3538-3541) and sodium methoxide), was dissolved in THF (65 ml), ar protected, and bis (trimethylsilylamino) was slowly added dropwise at-78deg.CLithium (23.3 ml,23.21 mmol), about 1h at-78deg.C, dropwise adding a solution of 2, 6-dimethoxy isonicotinyl chloride (4.68 g,23.21 mmol) in THF (65 ml), maintaining-78deg.C during the dropwise adding, naturally heating after adding, reacting overnight, adding saturated ammonium chloride to the reaction solution for extraction, extracting the water phase with EA, washing with saturated salt, drying with anhydrous sodium sulfate, spinning to obtain a pale yellow powdery solid (9.06 g, yield: 98.6%; LC-MS (ESI): 475.1[ M+H ] ] +
IV-1 preparation
IV-1-2-1 (9.06 g,19.062 mmol) was dissolved in DMSO/H 2 O (100 ml/5 ml), set temperature 155℃reflux reaction for 2h. TLC: petroleum ether: ethyl acetate=10:1. Cooling to RT, pouring the reaction liquid into ice water, standing overnight, precipitating solid, filtering, washing a filter cake with water, pulping the filter cake with EA, filtering, and drying the filter cake to obtain a product. Pale yellow powdery solid: 5.74g, yield: 71.13%. LC-MS (ESI) 417.5[ M+H ]] +
1 H NMR(400MHz,CDCl 3 )δ:7.80(d,J＝2.2Hz,1H),7.74–7.67(m,2H),7.66–7.60(m,1H),6.81(s,2H),4.27–4.22(m,2H),4.00(s,3H),3.94(s,6H).
Preparation of intermediate IV-2
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The intermediate IV-2 is prepared by taking IV-1-1-3 as a starting material according to the following reaction flow.
IV-2-1 preparation
IV-1-1-3 (19 g 66.3 mmol) was dissolved in DMF (200 mL) at room temperature and NaCN (3.90 g 79.6 mmol) solid was added and reacted at room temperature. TLC (PE: ea=20:1) checked the completion of the reaction, quenched by the addition of water, extracted with ethyl acetate, the aqueous phase was stirred with NaClO, the organic phases were combined, dried, filtered and evaporated to dryness. Column chromatography. Pale yellow solid: 11g, 60% yield. LC-MS (ESI): 277.0[ M+H ]] +
IV-2-2 preparation
IV-2-1 (10.5 g 37.9 mmol) was dissolved in ethanol (50 mL), 10% aqueous sodium hydroxide solution (50 mL) was added, the temperature was controlled at 100deg.C for overnight reaction, TLC starting material disappeared, ethanol was concentrated off, aqueous phase was washed with dichloromethane, dichloromethane phase was discarded, aqueous phase was adjusted to pH 4-5, solids were precipitated, ethyl acetate extraction, organic phases were combined, dried, and concentrated. Pale yellow solid: 7.65g, yield 68.2%. LC-MS (ESI): 296.0[ M+H ] ] +
IV-2-3 preparation
IV-2-2 (7.4 g 25 mmol) is dissolved in tetrahydrofuran (70 mL), borane tetrahydrofuran solution is added, temperature control reflux reaction is carried out overnight, an appropriate amount of ammonium chloride aqueous solution is added after TLC reaction is finished, filtration and concentration are carried out, and column chromatography (petroleum ether: ethyl acetate=5:1-2:1) is carried out to obtain colorless gum: 5.87g, yield 83.4%. LC-MS (ESI) 282.0[ M+H ]] +
1 H NMR(400MHz,CDCl 3 )δ7.82(d,J＝2.2Hz,1H),7.75(s,1H),7.70(d,J＝8.9Hz,1H),7.63(dd,J＝8.9,2.2Hz,1H),4.08(s,3H),3.93(t,J＝6.4Hz,2H),2.98(t,J＝6.4Hz,2H).
IV-2-4 preparation
IV-2-3 (5.64 g,20 mmol) was dissolved in dichloromethane (60 mL) and DMP (10.2 g 8.5 mmol) was slowly added, the reaction was carried out at room temperature for 1.5h, TLC (PE: EA=2:1) detected completion, saturated aqueous sodium bicarbonate and aqueous sodium thiosulfate were added, stirred for 30min, the aqueous phase was separated, DCM (60 mL) extracted the aqueous phase, the organic phases were combined, dried, filtered, evaporated to dryness and column chromatographed (petroleum ether: ethyl acetate=50:1-10:1) to give a pale yellow solid: 3.4g, yield 60%. LC-MS (ESI) 280.0[ M+H ]] +
IV-2-6 preparation
Freshly prepared 1-naphthylmagnesium bromide (IV-2-5) (1 mol/L,12 mmol) was slowly added dropwise to a solution of compound IV-2-4 (3.08 g,11 mmol) in THF (30 mL) in ice bath, and the system was allowed to warm to room temperature and stirred for 30min after the dropwise addition. Saturated ammonium chloride solution is added, EA is added for extraction, liquid separation is carried out, the organic phase is dried, rotary evaporation is carried out, and a small amount of cold methanol is used for pulping. Column chromatography (petroleum ether: ethyl acetate=20:1-5:1) gave 1.82g of a white solid, 41.2%. LC-MS (ESI) 408 .1[M+H] +
1 H NMR(400MHz,CDCl 3 )δ8.29(d,J＝8.5Hz,1H),7.91–7.87(m,1H),7.81–7.77(m,2H),7.74(s,1H),7.72(s,1H),7.70(d,J＝3.3Hz,1H),7.63(dd,J＝8.9,2.2Hz,1H),7.56(ddd,J＝8.4,6.8,1.5Hz,1H),7.53–7.45(m,2H),5.83(d,J＝6.9Hz,1H),4.14(s,3H),3.47(dd,J＝14.0,2.9Hz,1H),3.00(dd,J＝14.0,9.2Hz,1H),2.26(s,1H).
Preparation of intermediate IV-2
Compound IV-2-6 (1.63 g,4 mmol) was dissolved in dichloromethane (20 mL) at room temperature, DMP (2.03 g,4.8 mmol) was added, and after stirring at room temperature for two hours, the spot-on-plate detection reaction was completed, na was added in sequence 2 S 2 O 3 Saturated solution of NaHCO 3 Washing the mixture with saturated solution and saturated saline, separating the liquid, drying the organic phase, and performing rotary evaporation column chromatography (petroleum ether: ethyl acetate=50:1-10:1) to obtain off-white solid, 1.42g,88.6%. LC-MS (ESI) 406.1[ M+H ]] +
1 H NMR(400MHz,CDCl 3 )δ8.46(d,J＝8.1Hz,1H),8.37(s,1H),8.05(dd,J＝7.2,1.0Hz,1H),8.02(d,J＝8.3Hz,1H),7.95(t,J＝1.3Hz,1H),7.88(d,J＝7.5Hz,1H),7.69(d,J＝1.3Hz,2H),7.61(ddd,J＝8.5,6.9,1.5Hz,1H),7.57–7.48(m,2H),6.73(s,1H),4.03(s,3H).
Preparation of intermediate IV-3
Starting with benzofuran-7-carbonitrile, intermediate IV-3 was prepared according to the following reaction scheme.
IV-3-1 preparation
Benzofuran-7-carbonitrile (4.3 g,30.04 mmol) (synthesized according to J.Med. Chem.2016,59,7,3215-3230) was dissolved in MeOH (30 ml), and NaOH (2.4 g,60.08mmol, H) was added 2 O (1.08 g,60.08 mmol), set temperature 80℃and reverseShould be overnight. TLC petroleum ether ethyl acetate=10:1 detection reaction was complete. Pouring the reaction solution into water, adding EA into the water phase to separate the water phase, adding HCl to regulate the pH to about 3, extracting the water phase with EA, combining organic phases, washing with saturated saline, drying with anhydrous sodium sulfate, and spin-drying. Yellow powdery solid: 3.392g, yield: 70%. LC-MS (ESI) 163.0[ M+H ]] +
IV-3-2 preparation
IV-3-1 (2 g,12.34 mmol) was dissolved in SOCl 2 (35 ml), reaction was carried out at 30℃for 3.5h. Cooled to RT, dried with DCM and repeated twice, the product was used directly in the next step. Yellow powdery solid: 2.31g.
IV-3-3 preparation
Methyl 2- (6-bromo-2-methoxyquinolin-3-yl) acetate (3.3 g,10.64mmol,1 eq) was dissolved in THF (50 ml), ar protected, lithium bis (trimethylsilylamino) chloride (13.0 ml,12.77 mmol) was slowly added dropwise at-78℃and reacted at-78℃for about 1h. A solution of IV-3-2 (2.30 g,12.77 mmol) in THF (45 ml) was added dropwise, maintained at-78deg.C during the addition, and then heated naturally after the addition, and reacted overnight. TLC: petroleum ether: ethyl acetate=10:1. The reaction solution was quenched with saturated ammonium chloride, the aqueous phase was extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, and dried by spin-drying. Column chromatography (petroleum ether: ethyl acetate=10:1) gives a pale yellow powdered solid: 2.77g, yield: 57%. LC-MS (ESI) 454.0[ M+H ]] +
IV-3 preparation
IV-3-3 (2.70 g,5.943 mmol) was dissolved in DMSO/H 2 O (30 ml/1.5 ml), and reflux reaction was carried out at 155℃for 2 hours. TLC: petroleum ether: ethyl acetate=10:1. Cooling to RT, pouring the reaction liquid into ice water, standing overnight, precipitating solid, filtering, washing a filter cake with water, pulping the filter cake with EA, filtering, and drying the filter cake to obtain light yellow powdery solid: 1.75g, yield: 74%.
LC-MS(ESI):396.0[M+H] +
1 H NMR(400MHz,DMSO-d 6 )δ:8.20(d,J＝2.2Hz,1H),8.15–8.08(m,2H),7.99(dd,J＝7.7,1.3Hz,1H),7.91(dd,J＝7.7,1.3Hz,1H),7.79–7.69(m,2H),7.42(t,J＝7.7Hz,1H),7.14(d,J＝2.2Hz,1H),4.70(s,2H),3.90(s,3H).
Example 1: preparation of Compound 1
Using intermediates iv-1 and 2-cyclopropylethylmethanesulfonate as starting materials, compound 1 was prepared according to the following reaction scheme
Preparation of Compound 1-1
Intermediate IV-1 (834 mg,2.00 mmol), 2-cyclopropylethylmethanesulfonate (966 mg,5.46 mmol), K 2 CO 3 (829 mg,6.00 mmol), KI (33 mg,0.20 mmol) was added to acetone (10 mL), and reacted overnight at 50 ℃. TLC detection of a small amount of starting material left, cooling to room temperature, direct sample application to column (petroleum ether: ethyl acetate=40:1-30:1) to give a pale yellow solid: 644mg, 66% yield. LC-MS (ESI) 485.1[ M+H ]] +
Preparation of Compounds 1-2
CuBr Me 2 S (27 mg,0.1 mmol) was added to a 25mL three-necked flask, a tetrahydrofuran solution (4 mL,3.98 mmol) of freshly prepared allylzinc bromide was added dropwise under Ar protection, the reaction was carried out at room temperature for about 5min, a THF (20 mL) solution of 1-1 (640 mg,1.33 mmol) was added dropwise, and the reaction was continued at room temperature for about 20min. TLC detection (Petroleum ether: ethyl acetate=10:1) was completed, the reaction was quenched with saturated aqueous ammonium chloride (10 mL), water (15 mL), EA (2X 20 mL) was extracted 2 times, the organic phase was washed 1 time with saturated brine (20 mL), dried and spun-dried, and the next step was directly added. LC-MS (ESI): 527.2[ M+H ]] +
Preparation of Compounds 1-3
1-2 (702 mg,1.33 mmol) was dissolved in THF/H 2 O (20 mL/4 mL), K is added to 2 OsO 4 ·2H 2 O (24 mg,0.05 mmol) and NMO (1.5538 g,13.30 mmol) were reacted overnight at room temperature. TLC detection (Petroleum ether: ethyl acetate=10:1) reaction was complete, quenched with saturated aqueous sodium thiosulfate (20 mL)Water (20 mL) was added, EA (2X 20 mL) was extracted 2 times, and the organic phase was washed 1 time with saturated brine (20 mL), dried, and spin-dried directly to the next step. LC-MS (ESI) 561.1[ M+H ]] +
Preparation of Compounds 1-4
1-3 (747 mg,1.33 mmol) was dissolved in DCM (20 mL) and silica gel loaded NaIO 4 (2.66 mmol) and then reacted at room temperature for about 1 hour. TLC detection (petroleum ether/ethyl acetate=5/1) was essentially complete, filtered and the filtrate was taken directly to the next step. LC-MS (ESI) 528.1[ M+H ]] +
Preparation of Compounds 1-5
1-4 (704 mg,1.33 mmol) was dissolved in MeOH (10 mL) and NaBH was added in portions under an ice bath 4 (82 mg,2.16 mmol) was reacted at room temperature for about 1h. TLC detection (petroleum ether/ethyl acetate=5/1) reaction was complete, quenched with water (0.5 mL) and spin-dried over column (petroleum ether: ethyl acetate=15:1-10:1) to give yellow foamy solid: 555mg 79% (four step yield). LC-MS (ESI): 531.1[ M+H ]] +
Preparation of Compounds 1-6
1-5 (555 mg,1.04 mmol) was dissolved in DCM (20 mL), TEA (227 mg,5.22 mmol) was added, msCl (317 mg,3.13 mmol) was added dropwise under ice-bath, the reaction was about 1h at room temperature, and the TLC detection (Petroleum ether/ethyl acetate=5/1) was complete. Water (20 mL) was added and extracted 2 times with DCM (2X 20 mL), the organic phases dried and the mixture was added directly to the next step. LC-MS (ESI): 609.1[ M+H ] ] +
Preparation of Compound 1
1-6 (634 mg,1.04 mmol) was dissolved in dimethylamine THF (10 mL) and the tube was sealed at 50℃overnight. Direct column chromatography (dichloromethane: methanol=300:1-60:1) gave 1A (169 mg) and 1B (119 mg)
1A (169 mg resolved by chiral HPLC gave 1A-1 (70 mg) and 1A-2 (67 mg)
LC-MS(ESI):558.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.22(s,1H),7.89(d,J＝2.2Hz,1H),7.71(d,J＝8.9Hz,1H),7.64(dd,J＝8.9,2.2Hz,1H),7.02–6.03(m,2H),4.10(s,3H),3.98(s,6H),3.66(dd,J＝12.2,3.0Hz,1H),2.18(q,J＝12.8,8.9Hz,1H),1.90(d,J＝9.2Hz,8H),1.57(d,J＝14.8Hz,1H),1.50–1.34(m,2H),0.97–0.80(m,1H),0.67(q,J＝8.3,7.6Hz,1H),0.46–0.30(m,1H),0.20(ttd,J＝13.1,8.9,4.2Hz,2H),-0.31(ddt,J＝23.3,9.3,4.8Hz,2H)；
1B (119 mg) was resolved by chiral HPLC to give 1B-1 (50 mg) and 1B-2 (45 mg)
LC-MS(ESI):558.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:7.94(s,1H),7.76(s,1H),7.55(s,2H),6.20(s,2H),3.89(s,3H),3.75(s,6H),3.65–3.57(m,1H),2.53(t,J＝13.7Hz,1H),2.21(m,8H),1.90(d,J＝12.8Hz,1H),1.62(d,J＝14.4Hz,2H),1.09(d,J＝13.7Hz,1H),0.93–0.74(m,1H),0.60(d,J＝9.9Hz,1H),0.33(dq,J＝8.2,4.2Hz,2H),0.05-0.23(m,2H).
Example 2: preparation of Compound 2
Using intermediates IV-1 and 2- (1-methylcyclopropyl) ethyl p-toluenesulfonate as starting materials, compounds 2A (104 mg) and 2B (85 mg) were obtained using the same reaction scheme as for the preparation of compound 1.
2A (104 mg) was resolved by chiral HPLC to give 2A-1 (45 mg) and 2A-2 (39 mg)
LC-MS(ESI):572.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.17(s,1H),7.87(d,J＝2.2Hz,1H),7.68(s,1H),7.64(d,J＝2.2Hz,1H),6.57(s,2H),4.08(s,3H),3.96(s,6H),2.03(s,1H),1.96(s,6H),1.88(s,2H),1.86–1.76(m,2H),1.52–1.34(m,4H),1.26–1.22(m,3H),0.74(s,4H).
2B (85 mg) resolved by chiral HPLC to give 2B-1 (36 mg) and 2B-2 (29 mg)
LC-MS(ESI):572.3[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.03(s,1H),7.73(d,J＝2.2Hz,1H),7.54(s,1H),7.50(d,J＝2.2Hz,1H),6.43(s,2H),3.94(s,3H),3.82(s,6H),1.89(s,1H),1.82(s,6H),1.74(s,2H),1.72–1.62(m,2H),1.38–1.20(m,4H),1.12–1.08(m,3H),0.60(s,4H).
Example 3: preparation of Compound 3
Using intermediates IV-1 and 3-cyclopropyl-p-methylbenzenesulfonate as starting materials, the same reaction scheme was used as in the preparation of Compound 1 to give Compounds 3A (69 mg) and 3B (87 mg)
Resolution of 3A (69 mg) by chiral HPLC gave 3A-1 (22 mg) and 3A-2 (20 mg)
LC-MS(ESI):572.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.23(s,1H),7.90(d,J＝2.2Hz,1H),7.72(d,J＝8.8Hz,1H),7.65(dd,J＝8.9,2.2Hz,1H),6.56(s,2H),4.11(s,3H),3.97(s,6H),3.60(dd,J＝12.0,3.0Hz,1H),2.21(ddd,J＝26.4,9.4,5.4Hz,1H),1.94(s,9H),1.51–1.40(m,2H),1.25(s,2H),0.96(t,J＝5.5Hz,2H),0.43–0.31(m,1H),0.20(d,J＝7.8Hz,2H),0.14–0.28(m,2H).
Resolution of 3B (87 mg) by chiral HPLC gave 3B-1 (27 mg) and 3B-2 (32 mg)
LC-MS(ESI):572.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.18(s,1H),7.85(d,J＝2.2Hz,1H),7.67(d,J＝8.8Hz,1H),7.60(dd,J＝8.9,2.2Hz,1H),6.51(s,2H),4.06(s,3H),3.92(s,6H),3.55(dd,J＝12.0,3.0Hz,1H),2.16(ddd,J＝26.4,9.4,5.4Hz,1H),1.89(s,9H),1.46–1.35(m,2H),1.20(s,2H),0.91(t,J＝5.5Hz,2H),0.40–0.28(m,1H),0.18(d,J＝7.8Hz,2H),0.15-0.29(m,2H).
Example 4: preparation of Compound 4
Using intermediates IV-1 and 2- (2, 2-difluorocyclopropyl) ethylmethanesulfonate as starting materials, the same reaction scheme was used to prepare Compound 1, affording Compounds 4A (86 mg) and 4B (79 mg)
4A (86 mg) was resolved by chiral HPLC to give 4A-1 (31 mg) and 4A-2 (35 mg)
LC-MS(ESI):594.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.20(s,1H),7.90(s,1H),7.78–7.60(m,2H),6.53(s,2H),4.11(s,3H),3.98(s,6H),3.56(d,J＝11.7Hz,1H),2.36(d,J＝93.4Hz,2H),1.98(s,6H),1.78(d,J＝12.2Hz,2H),1.53(d,J＝10.1Hz,5H),1.27(d,J＝12.0Hz,6H),1.02(dt,J＝24.1,11.9Hz,4H).
4B (79 mg) was resolved by chiral HPLC to give 4B-1 (29 mg) and 4B-2 (30 mg)
LC-MS(ESI):594.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.16(s,1H),7.86(s,1H),7.74–7.56(m,2H),6.49(s,2H),4.07(s,3H),3.98(s,6H),3.52(d,J＝11.7Hz,1H),2.32(d,J＝93.4Hz,2H),1.94(s,6H),1.74(d,J＝12.2Hz,2H),1.49(d,J＝10.1Hz,5H),1.23(d,J＝12.0Hz,6H),0.97(dt,J＝24.1,11.9Hz,4H).
Example 5: preparation of Compound 5
Using intermediates IV-1 and 3, 3-dimethyl-1-bromobutane as starting materials, the same reaction scheme was used as in the preparation of Compound 1 to give Compounds 5A (94 mg) and 5B (105 mg)
Resolution of 5A (94 mg) by chiral HPLC gave 5A-1 (40 mg) and 5A-2 (35 mg)
LC-MS(ESI):574.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.16(s,1H),7.87(s,1H),7.67(d,J＝22.0Hz,2H),6.54(s,2H),4.09(s,3H),3.95(s,6H),3.51(d,J＝11.6Hz,1H),2.32(d,J＝89.8Hz,2H),2.09–1.82(m,6H),1.79–1.53(m,2H),1.27(d,J＝22.7Hz,2H),0.79(d,J＝16.8Hz,2H),0.62(s,9H).
Resolution of 5B (105 mg) by chiral HPLC gave 5B-1 (44 mg) and 5B-2 (40 mg)
LC-MS(ESI):574.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.13(s,1H),7.84(s,1H),7.64(d,J＝22.0Hz,2H),6.51(s,2H),4.06(s,3H),3.92(s,6H),3.49(d,J＝11.6Hz,1H),2.29(d,J＝89.8Hz,2H),2.06–1.79(m,6H),1.76–1.50(m,2H),1.24(d,J＝22.7Hz,2H),0.76(d,J＝16.8Hz,2H),0.59(s,9H).
Example 6: preparation of Compound 6
Using intermediate IV-1 and bromomethylcyclobutane as starting materials, compounds 6A (86 mg) and 6B (96 mg) were obtained using the same reaction scheme as for compound 1
Resolution of 6A (86 mg) by chiral HPLC gave 6A-1 (31 mg) and 6A-2 (35 mg)
LC-MS(ESI):558.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.21(s,1H),7.87(d,J＝2.3Hz,1H),7.73–7.58(m,2H),6.54(s,2H),4.08(s,3H),3.96(s,6H),3.56–3.48(m,1H),2.25(s,1H),2.09–1.80(m,7H),1.73(s,2H),1.54(d,J＝21.9Hz,5H),1.25(d,J＝11.9Hz,3H),0.86(t,J＝6.6Hz,1H).
Resolution of 6B (96 mg) by chiral HPLC gave 6B-1 (41 mg) and 6B-2 (36 mg)
LC-MS(ESI):558.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.16(s,1H),7.82(d,J＝2.3Hz,1H),7.68–7.53(m,2H),6.49(s,2H),4.03(s,3H),3.91(s,6H),3.51–3.43(m,1H),2.20(s,1H),2.04–1.75(m,7H),1.68(s,2H),1.49(d,J＝21.9Hz,5H),1.20(d,J＝11.9Hz,3H),0.81(t,J＝6.6Hz,1H).
Example 7: preparation of Compound 7
Using intermediates IV-1 and (2-cyclobutyl) ethylmethanesulfonate as starting materials, the same reaction scheme as for preparing Compound 1 was employed to give Compounds 7A (104 mg) and 7B (104 mg)
Resolution of 7A (104 mg) by chiral HPLC gave 7A-1 (44 mg) and 7A-2 (38 mg)
LC-MS(ESI):572.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.22(s,1H),7.90(d,J＝2.2Hz,1H),7.72(d,J＝8.8Hz,1H),7.65(dd,J＝8.8,2.2Hz,1H),6.84(m,2H),4.11(s,3H),3.97(s,6H),3.56(dd,J＝12.0,2.9Hz,1H),2.16(m,1H),2.00(m,1H),1.91(s,6H),1.81(m,3H),1.67(m,2H),1.58(m,2H),1.22–1.13(m,2H),1.06-0.94(m,2H),0.89(m,2H).
Resolution of 7B (104 mg) by chiral HPLC gave 7B-1 (44 mg) and 7B-2 (36 mg)
LC-MS(ESI):572.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.18(s,1H),7.86(d,J＝2.2Hz,1H),7.68(d,J＝8.8Hz,1H),7.61(dd,J＝8.8,2.2Hz,1H),6.80(m,2H),4.07(s,3H),3.93(s,6H),3.52(dd,J＝12.0,2.9Hz,1H),2.12(m,1H),1.96(m,1H),1.87(s,6H),1.77(m,3H),1.63(m,2H),1.54(m,2H),1.18–1.09(m,2H),1.02-0.90(m,2H),0.85(m,2H).
Example 8: preparation of Compound 8
Using intermediates IV-1 and 2- (3, 3-difluorocyclobutyl) ethyl methane sulfonate as starting materials, the same reaction scheme as for preparing compound 1 was employed to give compounds 8A (121 mg) and 8B (142 mg)
Resolution of 8A (121 mg) by chiral HPLC gave 8A-1 (55 mg) and 8A-2 (49 mg)
LC-MS(ESI):608.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.23(s,1H),7.90(s,1H),7.80–7.61(m,2H),6.75-6.33(m,2H),4.12(s,3H),3.98(s,6H),3.64–3.51(m,1H),2.50-2.26(m,2H),2.20-2.10(m,1H),1.95-1.72(m,10H),1.64–1.37(m,2H),1.28-1.25(m,2H),1.12-1.00(m,2H).
Resolution of 8B (142 mg) by chiral HPLC gave 8B-1 (60 mg) and 8B-2 (54 mg)
LC-MS(ESI):608.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.20(s,1H),7.87(s,1H),7.87–7.59(m,2H),6.72-6.30(m,2H),4.09(s,3H),3.95(s,6H),3.61–3.49(m,1H),2.47-2.23(m,2H),2.17-2.07(m,1H),1.92-1.69(m,10H),1.61–1.34(m,2H),1.25-1.22(m,2H),1.09-1.00(m,2H).
Example 9: preparation of Compound 9
Using intermediate IV-1 and cyclopentylmethylsulfonate as starting materials, the same reaction scheme as for preparing Compound 1 was used to obtain Compounds 9A (104 mg) and 9B (98 mg)
Resolution of 9A (104 mg) by chiral HPLC gave 9A-1 (45 mg) and 9A-2 (42 mg)
LC-MS(ESI):572.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.16(s,1H),7.89(s,1H),7.66(d,J＝24.9Hz,2H),6.52(s,2H),4.10(s,3H),3.95(s,6H),3.68(s,1H),2.47(s,1H),2.02(s,7H),1.30(d,J＝52.4Hz,10H),0.80(s,3H).
Resolution of 9B (98 mg) by chiral HPLC gave 9B-1 (35 mg) and 9B-2 (33 mg)
LC-MS(ESI):572.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.09(s,1H),7.82(s,1H),7.59(d,J＝24.9Hz,2H),6.47(s,2H),4.03(s,3H),3.88(s,6H),3.61(s,1H),2.40(s,1H),1.95(s,7H),1.23(d,J＝52.4Hz,10H),0.73(s,3H).
Example 10: preparation of Compound 10
Using intermediates IV-1 and (3, 3-difluorocyclopentyl) methyl-4-methylbenzenesulfonate as starting materials, the same reaction scheme was used as in the preparation of Compound 1 to give Compounds 10A (72 mg) and 10B (86 mg)
Resolution of 10A (72 mg) by chiral HPLC gave 10A-1 (28 mg) and 10A-2 (30 mg)
LC-MS(ESI):608.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.22(d,J＝15.2Hz,1H),7.91(d,J＝2.2Hz,1H),7.76–7.63(m,2H),6.53(s,2H),4.15–4.10(m,3H),3.98(s,6H),3.62(m,1H),2.06(m,6H),1.98–1.85(m,3H),1.70(m,4H),1.54(s,3H),1.23–1.01(m,3H).
10B (86 mg) was resolved by chiral HPLC to give 10B-1 (39 mg) and 10B-2 (42 mg)
LC-MS(ESI):608.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.19(d,J＝15.2Hz,1H),7.86(d,J＝2.2Hz,1H),7.71–7.58(m,2H),6.48(s,2H),4.10–4.05(m,3H),3.95(s,6H),3.58(m,1H),2.01(m,6H),1.93–1.80(m,3H),1.66(m,4H),1.50(s,3H),1.19–0.98(m,3H).
Example 11: preparation of Compound 11
Using intermediate IV-1 and (4, 4-dimethylcyclohexyl) methyl-4-methylbenzenesulfonate as starting materials, the same reaction scheme as for preparing Compound 1 was used to give Compounds 11A (72 mg) and 11B (96 mg)
11A (72 mg) was resolved by chiral HPLC to give 11A-1 (29 mg) and 11A-2 (27 mg)
LC-MS(ESI):614.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.211(s,1H),7.882(d,1H),7.689-7.613(dd,2H),6.452(s,2H),4.089(s,3H),3.963(s,6H),3.743-3.707(dd,1H),2.134(t,1H),1.888(s,6H),1.858-1.789(m,2H),1.533-1.496(d,2H),1.436-1.404(m,2H),1.239(d,1H),1.154-1.073(m,4H),0.870-0.796(m,4H),0.703(s,3H),0.681(s,3H),0.649-0.600(m,1H)
11B (96 mg) was resolved by chiral HPLC to give 11B-1 (38 mg) and 11B-2 (31 mg)
LC-MS(ESI):614.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.150s,1H),7.817(d,1H),7.612-7.587(dd,2H),6.423(s,2H),4.012(s,3H),3.903(s,6H),3.721-3.698(dd,1H),2.126(t,1H),1.875(s,6H),1.812-1.768(m,2H),1.501-1.482(d,2H),1.421-1.389(m,2H),1.221(d,1H),1.141-1.012(m,4H),0.836-0.756(m,4H),0.689(s,3H),0.674(s,3H),0.612-0.589(m,1H)
Example 12: preparation of Compound 12
Using intermediates IV-1 and 2-cyclohexylethylmethanesulfonate as starting materials, compounds 12A (98 mg) and 12B (116 mg) were obtained using the same reaction scheme as for the preparation of compound 1
Resolution of 12A (98 mg) by chiral HPLC gave 12A-1 (36 mg) and 12A-2 (38 mg)
LC-MS(ESI):600.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.20(s,1H),7.90(s,1H),7.78–7.60(m,2H),6.53(s,2H),4.11(s,3H),3.98(s,6H),3.56(d,J＝11.7Hz,1H),2.36(d,J＝93.4Hz,2H),1.98(s,6H),1.78(d,J＝12.2Hz,2H),1.53(d,J＝10.1Hz,5H),1.27(d,J＝12.0Hz,6H),1.02(dt,J＝24.1,11.9Hz,4H).
12B (116 mg) was resolved by chiral HPLC to give 12B-1 (45 mg) and 12B-2 (52 mg)
LC-MS(ESI):600.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.05(s,1H),7.85(s,1H),7.68–7.56(m,2H),6.42(s,2H),4.01(s,3H),3.86(s,6H),3.48(d,J＝11.7Hz,1H),2.28(d,J＝93.4Hz,2H),1.90(s,6H),1.70(d,J＝12.2Hz,2H),1.45(d,J＝10.1Hz,5H),1.19(d,J＝12.0Hz,6H),0.98(dt,J＝24.1,11.9Hz,4H).
Example 13: preparation of Compound 13
Using intermediates IV-1 and (3, 3-difluorocyclohexyl) methyl methanesulfonate as starting materials, the same reaction scheme was used to prepare Compound 1 to give Compounds 13A (98 mg) and 13B (121 mg)
Resolution of 13A (98 mg) by chiral HPLC gave 13A-1 (36 mg) and 13A-2 (30 mg)
LC-MS(ESI):622.2[M+H] +
1 H NMR(500MHz,CDCl 3 )δ:8.29(d,J＝33.5Hz,1H),7.93(dd,J＝6.3,2.2Hz,1H),7.75(dd,J＝8.8,4.2Hz,1H),7.69(dt,J＝8.8,2.1Hz,1H),7.06–6.05(m,2H),4.16(d,J＝7.7Hz,3H),4.01(s,6H),2.05–1.84(m,9H),1.79(s,1H),1.76–1.69(m,1H),1.64(d,J＝11.7Hz,2H),1.35–1.20(m,6H),1.16(ddd,J＝14.1,6.8,3.1Hz,3H).
13B (121 mg) was resolved by chiral HPLC to give 13B-1 (50 mg) and 13B-2 (45 mg)
LC-MS(ESI):622.2[M+H] +
1 H NMR(500MHz,CDCl 3 )δ:8.20(d,J＝33.5Hz,1H),7.84(dd,J＝6.3,2.2Hz,1H),7.66(dd,J＝8.8,4.2Hz,1H),7.60(dt,J＝8.8,2.1Hz,1H),6.97–5.96(m,2H),4.07(d,J＝7.7Hz,3H),3.92(s,6H),1.96–1.75(m,9H),1.70(s,1H),1.67–1.60(m,1H),1.55(d,J＝11.7Hz,2H),1.26–1.11(m,6H),1.07(ddd,J＝14.1,6.8,3.1Hz,3H).
Example 14: preparation of Compound 14
Using intermediates IV-1 and (4, 4-difluorocyclohexyl) methyl methanesulfonate as starting materials, compounds 14A (56 mg) and 14B (85 mg) were obtained using the same reaction scheme as for preparation of compound 1
14A (56 mg) was resolved by chiral HPLC to give 14A-1 (16 mg) and 14A-2 (18 mg)
LC-MS(ESI):622.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.22(s,1H),7.90(d,J＝2.2Hz,1H),7.72(d,J＝8.8Hz,1H),7.65(dd,J＝8.8,2.2Hz,1H),6.84(m,2H),4.11(s,3H),3.97(s,6H),3.56(dd,J＝12.0,2.9Hz,1H),2.16(m,1H),2.00(m,1H),1.91(s,6H),1.81(m,3H),1.67(m,2H),1.58(m,2H),1.22–1.13(m,2H),1.06–0.94(m,2H),0.89(m,2H).
14B (85 mg) was resolved by chiral HPLC to give 14B-1 (31 mg) and 14B-2 (29 mg)
LC-MS(ESI):622.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.01(s,1H),7.79(d,J＝2.2Hz,1H),7.61(d,J＝8.8Hz,1H),7.44(dd,J＝8.8,2.2Hz,1H),6.63(m,2H),3.90(s,3H),3.76(s,6H),3.35(dd,J＝12.0,2.9Hz,1H),2.00(m,1H),1.79(m,1H),1.70(s,6H),1.60(m,3H),1.46(m,2H),1.37(m,2H),1.01–0.98(m,2H),0.96–0.82(m,2H),0.73(m,2H).
Example 15: preparation of Compound 15
Using intermediate IV-1 and bicyclo [3.1.0] hexane-6-ylmethyl mesylate as starting materials, compounds 15A (92 mg) and 15B (126 mg) were obtained using the same reaction scheme as for compound 1
Resolution of 15A (92 mg) by chiral HPLC gave 15A-1 (40 mg) and 15A-2 (36 mg)
LC-MS(ESI):584.2[M+H] +
1 H NMR(600MHz,CDCl 3 )δ:8.31(s,1H),7.90(s,1H),7.77–7.59(m,2H),6.53(s,2H)4.12(s,3H),3.97(s,6H),3.71(dt,J＝21.2,8.9Hz,1H),2.50(s,1H),2.12–1.85(m,6H),1.49–1.36(m,3H),1.26(d,J＝17.2Hz,9H),1.04–0.80(m,3H).
15B (126 mg) was resolved by chiral HPLC to give 15B-1 (45 mg) and 15B-2 (39 mg)
LC-MS(ESI):584.2[M+H] +
1 H NMR(600MHz,CDCl 3 )δ:8.26(s,1H),7.85(s,1H),7.72–7.54(m,2H),6.48(s,2H)4.07(s,3H),3.92(s,6H),3.66(dt,J＝21.2,8.9Hz,1H),2.45(s,1H),2.07–1.80(m,6H),1.44–1.31(m,3H),1.21(d,J＝17.2Hz,9H),0.99–0.75(m,3H).
Example 16: preparation of Compound 16
Using intermediates IV-1 and 1-bromobut-2-yne as starting materials, the same reaction scheme was used to prepare Compounds 16A (102 mg) and 16B (116 mg)
16A (102 mg) was resolved by chiral HPLC to give 16A-1 (38 mg) and 16A-2 (36 mg)
LC-MS(ESI):542.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.20(s,1H),7.90(d,J＝2.1Hz,1H),7.71(d,J＝8.8Hz,1H),7.63(dd,J＝8.8,2.2Hz,1H),6.54(s,2H),4.11(s,3H),3.95(s,6H),3.81(dd,J＝11.9,3.8Hz,1H),2.67–2.53(m,1H),2.25–1.98(m,3H),1.97-1.79(m,8H),1.59(dt,J＝14.6,2.9Hz,1H),1.42(t,J＝2.5Hz,4H)；
16B (116 mg) was resolved by chiral HPLC to give 16B-1 (47 mg) and 16B-2 (45 mg)
LC-MS(ESI):542.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.15(s,1H),7.85(d,J＝2.1Hz,1H),7.67(d,J＝8.8Hz,1H),7.58(dd,J＝8.8,2.2Hz,1H),6.49(s,2H),4.06(s,3H),3.90(s,6H),3.76(dd,J＝11.9,3.8Hz,1H),2.62–2.48(m,1H),2.20–1.93(m,3H),1.92-1.75(m,8H),1.54(dt,J＝14.6,2.9Hz,1H),1.37(t,J＝2.5Hz,4H)；
Example 17: preparation of Compound 17
Using intermediates IV-1 and 3-cyclopropylprop-2-yn-1-yl (4-methylbenzenesulfonate) as starting materials, the same reaction scheme as for preparation of Compound 1 was employed to give Compounds 17A (76 mg) and 17B (111 mg)
17A (76 mg) was resolved by chiral HPLC to give 17A-1 (28 mg) and 17A-2 (26 mg)
LC-MS(ESI):568.2[M+H] +
1 H NMR(600MHz,CDCl 3 )δ:8.25(s,1H),7.92(d,J＝2.2Hz,1H),7.73(d,J＝8.8Hz,1H),7.66(dd,J＝8.8,2.2Hz,1H),6.58(s,2H),4.14(s,3H),3.97(s,6H),3.83(dd,J＝11.5,3.9Hz,1H),2.60(dd,J＝16.7,11.6Hz,1H),2.25–2.16(m,1H),2.09(t,J＝8.6Hz,1H),1.96(s,6H),1.36–1.17(m,4H),0.93–0.80(m,3H),0.51–0.40(m,2H).
17B (111 mg) was resolved by chiral HPLC to give 17B-1 (39 mg) and 17B-2 (38 mg)
LC-MS(ESI):568.2[M+H] +
1 H NMR(600MHz,CDCl 3 )δ:8.19(s,1H),7.86(d,J＝2.2Hz,1H),7.68(d,J＝8.8Hz,1H),7.60(dd,J＝8.8,2.2Hz,1H),6.52(s,2H),4.08(s,3H),3.91(s,6H),3.76(dd,J＝11.5,3.9Hz,1H),2.54(dd,J＝16.7,11.6Hz,1H),2.19–2.10(m,1H),2.03(t,J＝8.6Hz,1H),1.90(s,6H),1.30–1.11(m,4H),0.86–0.74(m,3H),0.45–0.34(m,2H).
Example 18: preparation of Compound 18
Using intermediates IV-1 and 4-fluorobut-2-ynyl-1-yl (4-methylbenzenesulfonate) as starting materials, compounds 18A (54 mg) and 18B (67 mg) were obtained using the same reaction scheme as for preparation of compound 1
Resolution of 18A (54 mg) by chiral HPLC gave 18A-1 (14 mg) and 18A-2 (11 mg)
LC-M S(ESI):560.1[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:7.93(s,1H),7.75(t,J＝1.3Hz,1H),7.56(d,J＝2.2Hz,2H),6.17(s,2H),4.79(s,1H),4.67(s,1H),3.94(s,3H),3.74(s,6H),3.13(d,J＝18.4Hz,1H),2.75(s,4H),2.51(s,6H),1.24(s,2H).
Resolution of 18B (67 mg) by chiral HPLC gave 18B-1 (18 mg) and 18B-2 (16 mg)
LC-MS(ESI):560.1[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:7.85(s,1H),7.68(t,J＝1.3Hz,1H),7.48(d,J＝2.2Hz,2H),6.09(s,2H),4.71(s,1H),4.59(s,1H),3.86(s,3H),3.67(s,6H),3.05(d,J＝18.4Hz,1H),2.67(s,4H),2.44(s,6H),1.16(s,2H).
Example 19: preparation of Compound 19
Using intermediate IV-1 and tetrahydropyran-4-methyl methanesulfonate as starting materials, the same reaction scheme was used to prepare Compound 1, affording Compounds 19A (165 mg) and 19B (186 mg)
Resolution of 19A (165 mg) by chiral HPLC gave 19A-1 (64 mg) and 19A-2 (58 mg)
LC-MS(ESI):588.0[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.23(s,1H),7.89(d,J＝2.2Hz,1H),7.74–7.61(m,2H),6.74(s,2H),4.09(s,3H),3.96(s,6H),3.80–3.65(m,4H),3.04(q,J＝10.6Hz,2H),2.25–2.11(m,1H),1.88(d,J＝29.6Hz,9H),1.21–0.78(m,7H).
Resolution of 19B (186 mg) by chiral HPLC gave 19B-1 (75 mg) and 19B-2 (72 mg)
LC-MS(ESI):588.0[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.14(s,1H),7.80(d,J＝2.2Hz,1H),7.65–7.52(m,2H),6.65(s,2H),4.00(s,3H),3.87(s,6H),3.71–3.56(m,4H),2.95(q,J＝10.6Hz,2H),2.16–2.02(m,1H),1.79(d,J＝29.6Hz,9H),1.12–0.69(m,7H).
Example 20: preparation of Compound 20
Using intermediate IV-1 and (tetrahydropyran-3-yl) methyl-4-methylbenzenesulfonate as starting materials, compounds 20A (92 mg) and 20B (132 mg) were obtained using the same reaction scheme as for preparation of compound 1
Resolution of 20A (92 mg) by chiral HPLC gave 20A-1 (32 mg) and 20A-2 (28 mg)
LC-MS(ESI):588.0[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.04(s,1H),7.97(s,1H),7.85(s,1H),7.60(d,J＝2.1Hz,1H),6.57(d,J＝83.3Hz,2H),4.62(s,1H),4.05(s,3H),3.90(d,J＝8.5Hz,6H),3.44(d,J＝11.4Hz,1H),3.06(dt,J＝22.2,11.8Hz,2H),2.45(d,J＝32.0Hz,6H),2.17(d,J＝9.0Hz,2H),1.99(d,J＝13.9Hz,2H),0.80(d,J＝7.0Hz,9H).
Resolution of 20B (132 mg) by chiral HPLC gave 20B-1 (42 mg) and 20B-2 (33 mg)
LC-MS(ESI):588.0[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:7.91(s,1H),7.85(s,1H),7.72(s,1H),7.47(d,J＝2.1Hz,1H),6.44(d,J＝83.3Hz,2H),4.49(s,1H),3.92(s,3H),3.77(d,J＝8.5Hz,6H),3.21(d,J＝11.4Hz,1H),2.93(dt,J＝22.2,11.8Hz,2H),2.32(d,J＝32.0Hz,6H),2.04(d,J＝9.0Hz,2H),1.86(d,J＝13.9Hz,2H),0.67(d,J＝7.0Hz,9H).
Example 21: preparation of Compound 21
Using intermediate IV-1 and tert-butyl-4- (bromomethyl) piperidine-1-carboxylate as starting materials, the same reaction scheme was used to prepare the precursors of Boc-protected compound 21, which was then subjected to trifluoroacetic acid to remove the-Boc protecting groups to afford compounds 21A (41 mg) and 21B (66 mg)
Resolution of 21A (41 mg) by chiral HPLC gave 21A-1 (12 mg) and 21A-2 (9 mg)
LC-MS(ESI):587.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.19(s,1H),7.90(d,J＝2.1Hz,1H),7.73–7.63(m,2H),6.29(s,2H),4.09(s,3H),3.97(s,6H),3.64(dd,J＝12.1,3.0Hz,1H),3.13(t,J＝13.0Hz,2H),2.46(q,J＝12.8Hz,3H),2.27–1.95(m,7H),1.90(t,J＝13.0Hz,2H),1.74(d,J＝14.2Hz,2H),1.48(d,J＝13.9Hz,2H),1.31(s,1H),1.14(s,2H).
Resolution of 21B (66 mg) by chiral HPLC gave 21B-1 (20 mg) and 21B-2 (23 mg)
LC-MS(ESI):587.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.11(s,1H),7.82(d,J＝2.1Hz,1H),7.65–7.55(m,2H),6.21(s,2H),4.01(s,3H),3.89(s,6H),3.56(dd,J＝12.1,3.0Hz,1H),3.05(t,J＝13.0Hz,2H),2.38(q,J＝12.8Hz,3H),2.19–1.87(m,7H),1.82(t,J＝13.0Hz,2H),1.66(d,J＝14.2Hz,2H),1.40(d,J＝13.9Hz,2H),1.23(s,1H),1.06(s,2H).
Example 22: preparation of Compound 22
Using intermediates IV-1 and 2-oxetanylethyl (4-methylbenzenesulfonate) as starting materials, compounds 22A (165 mg) and 22B (168 mg) were obtained using the same reaction scheme as for preparation of compound 1
Resolution of 22A (165 mg) by chiral HPLC gave 22A-1 (60 mg) and 22A-2 (45 mg)
LC-MS(ESI):574.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.29(d,J＝15.7Hz,1H),7.91(t,J＝2.5Hz,1H),7.77–7.63(m,2H),6.96–6.05(m,2H),4.12(s,3H),3.98(s,6H),3.76–3.58(m,2H),3.49(m,2H),3.02(m,1H),2.23–1.98(m,2H),1.92(s,6H),1.79(m,1H),1.58–1.35(m,3H),1.25–1.16(m,2H).
22B (168 mg) was resolved by chiral HPLC to give 22B-1 (55 mg) and 22B-2 (48 mg)
LC-MS(ESI):574.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.20(d,J＝15.7Hz,1H),7.82(t,J＝2.5Hz,1H),7.68–7.54(m,2H),6.87–5.94(m,2H),4.03(s,3H),3.99(s,6H),3.67–3.49(m,2H),3.40(m,2H),2.93(m,1H),2.14–1.89(m,2H),1.83(s,6H),1.70(m,1H),1.49–1.26(m,3H),1.16–1.07(m,2H).
Example 23: preparation of Compound 23
Using intermediates IV-1 and 1-bromocyclohexane as starting materials, compounds 23A (121 mg) and 23B (146 mg) were obtained using the same reaction scheme as for the preparation of compound 1
Resolution of 23A (121 mg) by chiral HPLC gave 23A-1 (40 mg) and 23A-2 (38 mg)
LC-MS(ESI):572.2[M+H] +
1 H NMR(600MHz,CDCl 3 )δ:8.47(s,1H),7.85(d,J＝2.2Hz,1H),7.64(d,J＝8.8Hz,1H),7.57(dd,J＝8.8,2.2Hz,1H),7.00–5.99(m,2H),4.01(s,3H),3.98–3.95(m,1H),3.92(s,6H),3.59–3.54(m,1H),2.51(q,J＝7.1Hz,2H),1.89(d,J＝27.8Hz,6H),1.52(m,2H),1.48–1.30(m,5H),0.95(t,J＝7.2Hz,4H),0.74(m,2H).
Resolution of 23B (146 mg) by chiral HPLC gave 23B-1 (37 mg) and 23B-2 (29 mg)
LC-MS(ESI):572.2[M+H] +
1 H NMR(600MHz,CDCl 3 )δ:8.36(s,1H),7.74(d,J＝2.2Hz,1H),7.53(d,J＝8.8Hz,1H),7.46(dd,J＝8.8,2.2Hz,1H),6.89–5.88(m,2H),3.90(s,3H),3.87–3.85(m,1H),3.81(s,6H),3.48–3.43(m,1H),2.40(q,J＝7.1Hz,2H),1.78(d,J＝27.8Hz,6H),1.41(m,2H),1.37–1.19(m,5H),0.84(t,J＝7.2Hz,4H),0.63(m,2H).
Example 24: preparation of Compound 24
Using intermediates IV-1 and 4-bromotetrahydro-2H pyran as starting materials, compounds 24A (35 mg) and 24B (42 mg) were obtained using the same reaction scheme as for the preparation of compound 1
Resolution of 24A (35 mg) by chiral HPLC gave 24A-1 (8 mg) and 24A-2 (9 mg)
LC-MS(ESI):574.0[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.46(s,1H),7.87(s,1H),7.64(d,J＝8.9Hz,1H),7.58(dd,J＝8.9,2.1Hz,1H),6.81(d,J＝61.6Hz,1H),6.24(s,1H),4.02(s,3H),3.92(s,6H),3.81(d,J＝13.1Hz,1H),3.71–3.56(m,3H),3.08(q,J＝11.4,10.3Hz,2H),2.00(d,J＝10.3Hz,5H),1.86(s,2H),1.32–1.11(m,6H),0.90–0.75(m,2H).
Resolution of 24B (42 mg) by chiral HPLC gave 24B-1 (11 mg) and 24B-2 (8 mg)
LC-MS(ESI):574.0[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.32(s,1H),7.73(s,1H),7.50(d,J＝8.9Hz,1H),7.44(dd,J＝8.9,2.1Hz,1H),6.67(d,J＝61.6Hz,1H),6.10(s,1H),3.88(s,3H),3.78(s,6H),3.67(d,J＝13.1Hz,1H),3.57–3.42(m,3H),2.94(q,J＝11.4,10.3Hz,2H),1.86(d,J＝10.3Hz,5H),1.72(s,2H),1.18–0.88(m,6H),0.76–0.61(m,2H).
Example 25: preparation of Compound 25
Using intermediates IV-1 and 1- (2-bromoethyl) cyclopropan-1-ol as starting materials, compounds 25A (58 mg) and 25B (63 mg) were obtained using the same reaction scheme as for preparation of compound 1
Resolution of 25A (58 mg) by chiral HPLC gave 25A-1 (13 mg) and 25A-2 (15 mg)
LC-MS(ESI):574.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.37(s,1H),7.88(s,1H),7.34(d,J＝0.7Hz,1H),6.41(s,2H),6.26(s,1H),5.58(s,1H),3.91(d,J＝4.2Hz,6H),3.77(d,J＝5.6Hz,1H),3.72(s,3H),3.66–3.54(m,1H),3.11(s,2H),3.04(s,1H),2.59(s,2H),2.43(s,6H),2.34–2.24(m,2H),2.00(s,1H),1.85(d,J＝6.8Hz,2H),1.68(s,1H).
Resolution of 25B (63 mg) by chiral HPLC gave 25B-1 (21 mg) and 25B-2 (22 mg)
LC-MS(ESI):574.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.30(s,1H),7.81(s,1H),7.27(d,J＝0.7Hz,1H),6.33(s,2H),6.19(s,1H),5.51(s,1H),3.84(d,J＝4.2Hz,6H),3.70(d,J＝5.53Hz,1H),3.65(s,3H),3.59–3.47(m,1H),3.04(s,2H),2.97(s,1H),2.52(s,2H),2.38(s,6H),2.27–2.17(m,2H),1.93(s,1H),1.78(d,J＝6.8Hz,2H),1.61(s,1H).
Example 26: preparation of Compound 26
Using intermediate IV-1 and bromomethylcyclohexane as starting materials, compounds 26A (220 mg) and 26B (176 mg) were obtained using the same reaction scheme as for compound 1
Resolution of 26A (220 mg) by chiral HPLC gave 26A-1 (83 mg) and 26A-2 (104 mg)
LC-MS(ESI):586.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.18(s,1H),7.89(d,J＝2.2Hz,1H),7.70(d,J＝8.9Hz,1H),7.63(dd,J＝8.9,2.2Hz,1H),6.28(br,2H),4.10(s,3H),3.96(s,6H),3.74(d,J＝12.0Hz,1H),2.23(br,2H),1.91(s,6H),1.76(s,2H),1.04(s,2H),0.96–0.79(m,7H),0.68(s,3H),0.49(t,J＝10.9Hz,1H).
Resolution of 26B (176 mg) by chiral HPLC gave 26B-1 (70 mg) and 26B-2 (80 mg)
LC-MS(ESI):586.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:7.94(s,1H),7.75(s,1H),7.53(s,2H),6.17(s,2H),3.87(s,3H),3.72(s,6H),3.18(d,J＝5.3Hz,1H),2.57–2.41(m,1H),2.34(t,J＝12.5Hz,1H),2.20(s,6H),1.98–1.70(m,3H),1.58(dt,J＝28.3,10.5Hz,4H),1.42(d,J＝12.1Hz,1H),1.15–0.71(m,7H).
Example 27: preparation of Compound 27
Compound 26-4 (390 mg,0.714 mmol) was dissolved in 1, 2-dichloroethane (20 ml), methylamine hydrochloride (54 mg,0.786 mmol), TEA (360 mg,3.57 mmol) and AcOH (129 mg,2.142 mmol) were added and reacted with stirring, sodium triacetoxyborohydride (751 mg,3.57 mmol) was added and reacted overnight at room temperature, monitored by TLC. The reaction mixture was added with water (30 ml), extracted with DCM (30 ml. Times.2), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by column chromatography to give 27A (55 mg) and 27B (60 mg)
Chiral resolution of 27A (55 mg) gave 27A-1 (20 mg) and 27A-2 (22 mg)
LC-MS(ESI):572.2[M+H] +
1 H NMR(600MHz,CDCl 3 )δ:8.02(s,1H),7.85–7.78(m,1H),7.62(d,J＝8.8Hz,1H),7.59–7.53(m,1H),6.43(s,2H),4.04(s,3H),3.90(s,6H),3.72–3.63(m,1H),2.42–2.36(m,1H),2.22(q,J＝12.5Hz,1H),1.98(s,3H),1.76–1.67(m,2H),1.53(d,J＝13.0Hz,2H),1.20(d,J＝16.2Hz,3H),0.99(t,J＝10.4Hz,1H),0.92–0.74(m,5H),0.63(s,2H),0.43(q,J＝12.2,11.3Hz,1H).
27B (60 mg), chiral resolution yielded 27B-1 (18 mg) and 27B-2 (24 mg)
LC-MS(ESI):572.2[M+H] +
1 H NMR(600MHz,CDCl 3 )δ:7.82(s,1H),7.70–7.68(m,1H),7.53–7.48(m,2H),6.17(s,2H),3.89(s,3H),3.72(s,6H),3.18–3.10(m,1H),2.59–2.46(m,1H),2.34(q,J＝12.5Hz,1H),2.20(s,3H),1.98–1.70(m,2H),1.58-1.42(m,5H),1.15–0.71(m,10H).
Example 28: preparation of Compound 28
Using compound 26 and Zn (CN) 2 Compound 28 was prepared according to the following reaction scheme as starting material.
Preparation of Compound 28
Compound 26 (170 mg,0.29 mmol) was dissolved in DMF (25 mL) and stirred, zn (CN) was added 2 (24 mg,0.20 mmol) and Pd (PPh) 3 ) 4 (40 mg,0.036 mmol) was reacted overnight at 90℃and the reaction was complete by TLC, extracted 2 times with EA, dried by organic phase, and separated by TLC to give 28A (62 mg) and 28B (68 mg))
28A (62 mg) was chiral-resolved to give 28A-1 (23 mg) and 28A-2 (19 mg)
LC-MS(ESI):533.3[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.18(s,1H),7.89(d,J＝2.2Hz,1H),7.70(d,J＝8.9Hz,1H),7.63(dd,J＝8.9,2.2Hz,1H),6.28(br,2H),4.10(s,3H),3.96(s,6H),3.74(d,J＝12.0Hz,1H),2.23(br,2H),1.91(s,6H),1.76(s,2H),1.04(s,2H),0.96–0.79(m,7H),0.68(s,3H),0.49(t,J＝10.9Hz,1H).
Chiral resolution of 28B (68 mg) gave 28B-1 (25 mg) and 28B-2 (20 mg)
LC-MS(ESI):533.3[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:7.95(s,1H),7.73(d,J＝2.2Hz,1H),7.51(s,1H),7.31(s,1H),6.17(br,2H),3.95(s,3H),3.83(s,6H),3.78(d,J＝12.0Hz,1H),2.58-2.47(m,2H),2.01(s,6H),1.96(s,2H),1.75(s,2H),1.58–1.15(m,7H),0.98(s,3H),0.87(s,1H).
Example 29: preparation of Compound 29
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Compound 29 was prepared according to the following reaction scheme
Preparation of Compound 29-2
Compound 29-1 (7.7 g,26.18 mmol) (prepared according to methods of document European Journal of Organic Chemistry,2011,11,2057-2061) was dissolved in DCM/MeOH (200 mL 10:1) at room temperature and m-CPBA (8 g,130.8mmol 85%) was slowly added and reacted overnight. TLC detection (PE: ea=2:1). The reaction was quenched by addition of NaHCO3, extracted twice with EA, and the EA phases were combined, dried and concentrated by rotary evaporation. The resulting solid was washed with DCM/PE system to give 8.2g of an off-white solid. LC-MS (ESI): 310.0[ M+H ] +
Preparation of Compound 29-3
CuCN (2.974 g,33.05 mmol) was placed in a 100mL three-necked flask, a tetrahydrofuran solution (66.1 mL,66.10 mmol) of cyclopropylmagnesium bromide was added dropwise under Ar gas, and after the addition, the reaction was continued at room temperature for about 1 hour, a THF (dry, 20 mL) solution of compound 29-2 (2.05 g,6.61 mmol) was added dropwise. The reaction was quenched with saturated aqueous ammonium chloride, dried, filtered off with suction, and the filtrate was dried by spin-drying over a column (petroleum ether: ethyl acetate=8:1-1:1) to give 648mg of a yellow oil, 28%. LC-MS (ESI): 352.1[ M+H ] +
Preparation of Compound 29-4
Compound 29-3 (488 mg,1.84 mmol) was dissolved in DCM (15 mL) and reacted at room temperature for about 25min after silica gel supported NaIO4 (3.935 g,3.68 mmol) and TLC detection (Petroleum ether/ethyl acetate=2/1) was complete, direct column chromatography (DCM) gave 477mg of a yellow oil, 74%. LC-MS (ESI): 320.0[ M+H ] +
Preparation of Compound 29-5
A solution of compound 29-4 (477 mg,1.49 mmol) in THF (dry, 5 mL) was added dropwise to a solution of freshly prepared naphthalen-1-yl magnesium bromide (4.47 mmol) in tetrahydrofuran under ice-bath, the reaction was allowed to proceed at room temperature for about 1.5h after 15min incubation, the reaction was quenched by TLC with saturated aqueous ammonium chloride, dried, filtered off with suction, and the filtrate was dried over column (petroleum ether: ethyl acetate=40:11-10:1) to give 510mg of a yellow oil, 76%. LC-MS (ESI): 478.1[ M+H ] +
Preparation of Compound 29-6
Compound 29-5 (510 mg,1.14 mmol) was dissolved in DCM (10 mL), DMP (726 mg,1.71 mmol) was added and reacted at room temperature for about 1h, TLC detection was complete and direct column flushing (petroleum ether: ethyl acetate=20:1) gave 440mg of a pale yellow solid, 87%. LC-MS (ESI): 448.1[ M+H ] +
Preparation of Compound 29
Compounds 29-7, 29-8, 29-9, 29-10 and 29 were prepared according to the same method as compound 1. Obtaining compounds 29A (56 mg) and 29B (64 mg)
Chiral resolution of 29A (56 mg) gave 29A-1 (19 mg) and 29A-2 (23 mg)
LC-MS(ESI):519.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.28(d,J＝8.6Hz,1H),8.24(s,1H),7.87(s,1H),7.79(d,J＝7.8Hz,1H),7.56–7.45(m,4H),7.42(t,J＝8.1Hz,2H),7.07(t,J＝7.7Hz,1H),3.55(d,J＝10.2Hz,1H),3.01(dd,J＝20.1,7.5Hz,1H),2.73(s,3H),2.71(s,1H),2.10(s,6H),2.06-2.04(m,1H),1.92-1.90(m,1H),1.04-0.99(m,1H),0.90–0.82(m,1H),0.78-0.74(m,1H),0.50–0.39(m,1H),0.04-0.00(m,1H).
Chiral resolution of 29B (64 mg) gave 29B-1 (22 mg) and 29B-2 (18 mg)
LC-MS(ESI):519.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.02(s,1H),7.87(s,1H),7.53-7.52(m,2H),7.34–7.22(m,6H),6.62(s,1H),3.49(d,J＝10.2Hz,1H),2.85-2.72(m,2H),2.70(s,3H),2.14(s,6H),2.04-1.57(m,3H),1.02-0.27(m,4H)
Example 30: preparation of Compound 30
Prepared in the same manner as compound 1 using intermediate IV-2 and cyclopropylmethyl bromide as starting materials, to give compounds 30A (50 mg) and 30B (60 mg)
Chiral resolution of 30A (50 mg) gave 30A-1 (20 mg) and 30A-2 (18 mg)
LC-MS(ESI):533.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.68(d,J＝8.6Hz,1H),8.34(s,1H),8.14(d,J＝7.0Hz,1H),7.95(d,J＝1.8Hz,1H),7.91(d,J＝7.7Hz,1H),7.77(dd,J＝16.3,8.4Hz,2H),7.65(dd,J＝8.8,2.0Hz,1H),7.52(tt,J＝10.2,7.2Hz,3H),4.61(dd,J＝11.1,2.9Hz,1H),4.28(s,3H),2.07–1.88(m,8H),1.80(d,J＝12.4Hz,1H),1.70–1.57(m,1H),0.89–0.74(m,2H),0.09(dd,J＝9.4,3.9Hz,2H),-0.05–-0.17(m,2H),-0.47(dd,J＝9.3,4.5Hz,1H),-0.67–-0.76(m,1H)；
30B (60 mg) was chiral-resolved to give 30B-1 (20 mg) and 30B-2 (24 mg)
LC-MS(ESI):533.2[M+H] +
1H NMR(400MHz,CDCl 3 )δ8.32(s,1H),8.12(s,1H),7.80–7.69(m,2H),7.69–7.54(m,2H),7.46(s,2H),7.37(s,2H),7.07(s,1H),4.45(s,1H),3.07(s,3H),2.50(dd,J＝64.3,24.3Hz,4H),2.32–1.85(m,9H),0.27(dd,J＝102.8,56.4Hz,4H).
Example 31: preparation of Compound 31
Prepared in the same manner as compound 1 using intermediate IV-2 and cyclopropylethyl (4-methylbenzenesulfonate) as starting materials to give compounds 31A (57 mg) and 31B (66 mg)
Chiral resolution of 31A (57 mg) gave 31A-1 (17 mg) and 31A-2 (24 mg)
LC-MS(ESI):547.2[M+H] +
1H NMR(400MHz,CDCl3)δ:8.76(d,J＝8.2Hz,1H),8.34(s,1H),8.25(d,J＝7.0Hz,1H),7.98(d,J＝13.7Hz,2H),7.83(dd,J＝24.7,8.3Hz,2H),7.71(d,J＝8.5Hz,1H),7.65–7.47(m,3H),4.59(d,J＝10.7Hz,1H),4.32(s,3H),2.52(d,J＝14.1Hz,1H),2.16–1.76(m,10H),1.61(t,J＝12.4Hz,1H),0.83–0.62(m,2H),0.08(m,3H),-0.42(d,J＝33.5Hz,2H).
Chiral resolution of 31B (66 mg) gave 31B-1 (25 mg) and 31B-2 (20 mg)
LC-MS(ESI):547.2[M+H] +
1H NMR(400MHz,CDCl3)δ:8.41(s,1H),7.95(s,1H),7.93(d,J＝6.9Hz,1H),7.85-7.73(m,2H),7.68-7.27(m,5H)7.08(s,1H),4.55(s,1H),3.12(s,3H),2.11-1.52(m,12H),1.01(s,1H),0.76–0.53(m,2H),0.42(d,J＝86.3Hz,4H)
Example 32: preparation of Compound 32
Prepared in the same manner as compound 28 except for using compound 31 and zinc cyanide as raw materials, compounds 32A (52 mg) and 32B (68 mg) were obtained.
Chiral resolution of 32A (52 mg) gave 32A-1 (11 mg) and 32A-2 (13 mg)
LC-MS(ESI):494.6[M+H] +
1H NMR(400MHz,CDCl 3 )δ:8.96(d,J＝8.2Hz,1H),8.54(s,1H),8.45(d,J＝7.0Hz,1H),8.15(d,J＝13.7Hz,2H),7.98(dd,J＝24.7,8.3Hz,2H),7.90(d,J＝8.5Hz,1H),7.85-7.67(m,3H),4.59(d,J＝10.7Hz,1H),4.32(s,3H),2.52(d,J＝14.1Hz,1H),2.16-1.76(m,10H),1.61(t,J＝12.4Hz,1H),0.83–0.62(m,2H),0.54(m,3H),0.42(d,J＝33.5Hz,2H).
Chiral resolution of 32B (68 mg) gave 32B-1 (16 mg) and 32B-2 (25 mg)
LC-MS(ESI):494.6[M+H] +
1H NMR(400MHz,CDCl 3 )δ:8.62(s,1H),8.26(s,1H),8.13(d,J＝6.9Hz,1H),7.95-7.83(m,3H),7.78-7.47(m,4H)7.22(s,1H),4.57(s,1H),3.33(s,3H),2.21-1.82(m,11H),1.71-1.65(s,2H),0.93-0.76(m,2H),0.62(d,J＝85.3Hz,4H)
Example 33: preparation of Compound 33
Using compound 33-1 as a starting material, compound 33 was produced by the following reaction scheme
Preparation of Compound 33-2
Compound 33-1 (2.9 g,7.7 mmol) (prepared from 6-bromo-2-methoxy-4-methylquinolin-3-yl) methanol according to literature Bioorganic and Medicinal Chemistry,2001, 2727-2743) and SO 2 Cl 2 The reaction mixture was dissolved in DMF (40 ml) and stirred, sodium cyanide (377 mg,7.7 mmol) was added, the reaction was stirred at room temperature, TLC was not completed, water (200 ml) and ethyl acetate (100 ml) were added to separate the reaction mixture, washing was performed with water (100 ml. Times.3), drying, concentration was performed, column chromatography was directly concentrated (DCM: petroleum ether=1:1) to obtain 1.03g of a white solid, and the reaction mixture was collectedThe rate was 46%. LC-MS (ESI): 291.0[ M+H ]] +
Preparation of Compound 33-3
Compound 33-2 (1.03 g,3.54 mmol), 1-naphthalene boronic acid (1.170 g,6.8 mmol), {1, 2-bis (diphenylphosphine) ethane } nickel dichloride (180 mg,0.34 mmol), zinc chloride (927 mg,6.8 mmol), water (122 mg,6.8 mmol) were dissolved in 1, 4-dioxane (30 ml) and stirred, argon-protected, heated to 110 ℃ and stirred overnight, TLC detection reaction was complete, and direct concentration column chromatography (petroleum ether: DCM=1:1) gave 729mg of a white solid in 49% yield. LC-MS (ESI) 420.1[ M+H ] ] +
Preparation of Compound 33
Compounds 33-4 to 33-9 and compound 33 were prepared in the same manner as in compound 1, to give compounds 33A (48 mg) and 33B (59 mg).
Chiral resolution of 33A (48 mg) gave 33A-1 (15 mg) and 33A-2 (11 mg)
LC-MS(ESI):561.6[M+H] +
1H NMR(400MHz,CDCl 3 )δ7.84(dd,J＝13.1,7.2Hz,1H),7.74–7.66(m,2H),7.60(dd,J＝8.8,2.2Hz,1H),7.47(m,2H),7.37(t,J＝7.4Hz,2H),7.31(m,2H),3.89(s,3H),3.75–3.64(t,J＝7.2Hz,1H),2.33(d,J＝7.2Hz,3H),2.1(s,3H),3.46(t,J＝7.0Hz,1H),1.88(s,6H),1.75–1.64(m,4H).
Chiral resolution of 33B (59 mg) gave 33B-1 (21 mg) and 33B-2 (14 mg)
LC-MS(ESI):561.6[M+H] +
1H NMR(400MHz,CDCl 3 )δ:7.55(s,1H),7.74–7.66(m,2H),7.40(dd,J＝8.8,2.2Hz,1H),7.23-711(m,6H),3.85(s,3H),3.72–3.61(t,J＝7.1Hz,1H),2.41(d,J＝7.1Hz,3H),2.2(s,3H),3.50(t,J＝7.0Hz,1H),1.92(s,6H),1.80–1.74(m,4H).
Example 34: preparation of Compound 34
Prepared in the same manner as compound 1 using intermediate IV-2 and cyclobutylmethyl methanesulfonate as starting materials, obtaining compounds 34A (60 mg) and 34B (71 mg)
Chiral resolution of 34A (60 mg) gave 34A-1 (18 mg) and 34A-2 (17 mg)
LC-MS(ESI):547.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.28(s,1H),8.09(s,1H),7.77(s,1H),7.65(s,1H),7.44(d,J＝11.6Hz,5H),7.04(s,1H),6.87(s,1H),4.09(s,3H),2.98(s,1H),2.58(s,2H),2.34(s,6H),1.97–1.92(m,2H),1.71–1.65(m,9H).
Chiral resolution of 34B (71 mg) gave 34B-1 (20 mg) and 34B-2 (35 mg)
LC-MS(ESI):547.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.12(s,1H),7.87(s,1H),7.62-7.58(m,2H),7.35(d,J＝11.4Hz,5H),6.87-6.81(m,2H),4.05(s,3H),2.86(s,1H),2.65(s,2H),2.42(s,6H),2.07–1.99(m,2H),1.84–1.75(m,9H).
Example 35: preparation of Compound 35
Prepared in the same manner as compound 1 using intermediate IV-2 and 3-chloropropionine as starting materials to give compounds 35A (47 mg) and 35B (55 mg)
Chiral resolution of 35A (47 mg) gave 35A-1 (14 mg) and 35A-2 (11 mg)
LC-MS(ESI):517.2[M+H] +
1 H NMR(400MHz,DMSO-d6)δ:8.03–7.68(m,5H),7.62–7.27(m,6H),3.43(s,6H),2.91(s,3H),2.47(s,3H),2.14(s,2H),1.57(s,3H).
Chiral resolution of 35B (55 mg) gave 35B-1 (16 mg) and 35B-2 (18 mg)
LC-MS(ESI):517.2[M+H] +
1 H NMR(400MHz,DMSO-d6)δ:7.79–7.58(m,5H),7.54–7.29(m,6H),3.31(s,6H),2.86(s,3H),2.53-2.49(m,3H),2.16(s,2H),1.59(s,3H).
Example 36: preparation of Compound 36
Prepared in the same manner as compound 1 using intermediate iv-2 and 3-cyclopropylprop-2-yn-1-yl (4-methylbenzenesulfonate) as starting materials, to obtain compounds 36A (53 mg) and 36B (67 mg).
Chiral resolution of 36A (53 mg) gave 36A-1 (10 mg) and 36A-2 (15 mg)
LC-MS(ESI):557.2[M+H] +
1H NMR(400MHz,CDCl3)δ:8.66(d,J＝8.0Hz,1H),8.26(s,1H),8.15(d,J＝7.0Hz,1H),7.97(s,1H),7.93(d,J＝7.7Hz,1H),7.85–7.73(m,2H),7.68(d,J＝8.8Hz,1H),7.53(dd,J＝18.0,10.4Hz,3H),4.64(d,J＝8.2Hz,1H),4.29(s,3H),2.76(dd,J＝16.0,12.6Hz,1H),2.45(d,J＝15.1Hz,1H),2.02(d,J＝16.7Hz,1H),1.90(s,1H),1.85(s,6H),1.77(d,J＝12.6Hz,1H),0.73(s,1H),0.35(d,J＝8.6Hz,2H),0.07(m,2H)；
Chiral resolution of 36B (67 mg) gave 36B-1 (20 mg) and 36B-2 (14 mg)
LC-MS(ESI):557.2[M+H] +
1H NMR(400MHz,cdcl3)δ8.32(s,1H),7.87–7.29(m,9H),7.08(s,1H),4.56(s,1H),3.33–2.61(m,8H),2.21(s,10H),1.01(s,1H),0.42(d,J＝86.3Hz,4H)
Example 37: preparation of Compound 37
Prepared by the method of compound 29 using intermediate 29-2 and 3, 3-dimethyl-but-1-yne as starting materials, obtaining 37A (70 mg) and 37B (77 mg)
Chiral resolution of 37A (70 mg) gave 37A-1 (33 mg) and 37A-2 (23 mg)
LC-MS(ESI):559.2[M+H] +
1 H NMR(400MHz,CD 3 OD)δ:8.67(d,J＝8.5Hz,1H),8.58(d,J＝8.3Hz,1H),8.04–7.96(m,2H),7.88(d,J＝7.2Hz,1H),7.82(d,J＝8.3Hz,1H),7.78–7.72(m,2H),7.69(d,J＝13.2Hz,3H),3.95(s,3H),3.92(s,2H),3.14–2.85(m,4H),2.63–2.43(m,2H),1.17(d,J＝9.5Hz,9H),0.99(s,4H).
Chiral resolution of 37B (77 mg) gave 37B-1 (30 mg) and 37B-2 (34 mg)
LC-MS(ESI):559.2[M+H] +
1 H NMR(400MHz,CD 3 OD)δ:8.33(d,J＝8.5Hz,1H),8.21(d,J＝8.2Hz,1H),7.99–7.87(m,2H),7.75(d,J＝7.1Hz,1H),7.72(d,J＝8.2Hz,1H),7.66–7.62(m,2H),7.08(d,J＝13.1Hz,3H),4.45(s,3H),3.82(s,2H),3.21–2.94(m,4H),2.65–2.45(m,2H),1.19(d,J＝9.7Hz,9H),1.03(s,4H).
Example 38: preparation of Compound 38
Prepared in the same manner as compound 1 using intermediate iv-2 and 4, 4-dimethylpent-2-en-1-yl (4-methylbenzenesulfonate) as starting materials, to give compounds 38A (51 mg) and 38B (66 mg).
Chiral resolution of 38A (51 mg) gave 38A-1 (8 mg) and 38A-2 (15 mg)
LC-MS(ESI):573.2[M+H] +
1H NMR(400MHz,CDCl3)δ:8.64(d,J＝8.7Hz,1H),8.29(s,1H),8.15(d,J＝7.3Hz,1H),7.96(d,J＝1.7Hz,1H),7.91(d,J＝8.0Hz,1H),7.79(d,J＝8.0Hz,1H),7.75(d,J＝8.8Hz,1H),7.65(dd,J＝8.9,1.9Hz,1H),7.56(t,J＝7.2Hz,1H),7.53–7.46(m,2H),4.66(dd,J＝11.4,4.2Hz,1H),4.26(s,3H),2.77(dd,J＝16.7,11.5Hz,1H),2.44(d,J＝14.8Hz,1H),1.93(dd,J＝16.9,4.3Hz,2H),1.85(s,6H),1.80–1.73(m,1H),1.67–1.60(m,1H),0.68(s,9H)；
Chiral resolution of 38B (66 mg) gave 38B-1 (12 mg) and 38B-2 (18 mg)
LC-MS(ESI):573.2[M+H] +
1H NMR(400MHz,cdcl3)δ8.38(d,J＝7.9Hz,1H),8.08(s,1H),7.73(d,J＝8.1Hz,1H),7.61(d,J＝7.2Hz,1H),7.53–7.33(m,6H),7.08(t,J＝7.2Hz,1H),4.60(s,1H),3.03(m,5H),2.69(s,2H),2.14(s,8H),0.95(s,9H).
Example 39: preparation of Compound 39
Prepared in the same manner as compound 1 using intermediate IV-2 and but-2-yn-1-ylmethylsulfonate as starting material to obtain compounds 39A (100 mg) and 39B (120 mg)
Chiral resolution of 39A (100 mg) gave 39A-1 (45 mg) and 39A-2 (42 mg)
LC-MS(ESI):531.2[M+H] +
1 H NMR(400MHz,CD 3 OD)δ:8.66(d,J＝8.7Hz,1H),8.28(s,1H),8.15(d,J＝7.3Hz,1H),7.97(d,J＝1.7Hz,1H),7.91(d,J＝8.0Hz,1H),7.76(m,2H),7.65(dd,J＝8.9,1.9Hz,1H),7.56(t,J＝7.2Hz,1H),7.52–7.45(m,2H),4.56(dd,J＝11.2,4.3Hz,1H),4.25(s,3H),2.81(dd,J＝16.7,11.2Hz,1H),2.43(d,J＝14.8Hz,1H),1.93(dd,J＝16.9,4.3Hz,2H),1.85(s,6H),1.80–1.73(m,4H),1.67–1.60(m,1H).
Chiral resolution of 39B (120 mg) gave 39B-1 (45 mg) and 39B-2 (50 mg)
LC-MS(ESI):531.2[M+H] +
1H NMR(400MHz,CDCl3)δ8.41(s,1H),8.14(s,1H),7.98(d,J＝7.2Hz,1H),7.69–7.54(m,5H),7.37(m,2H),7.07(s,1H),4.59(dd,J＝11.3,4.3Hz,1H),4.20(s,3H),2.85(dd,J＝16.7,11.3Hz,1H),2.46(d,J＝14.7Hz,1H),1.95(dd,J＝17.1,4.5Hz,2H),1.88(s,6H),1.83–1.75(m,4H),1.69–1.62(m,1H).
Example 40: preparation of Compound 40
Compound 40 starting from methyl 2- (6-bromo-2-methoxyquinolin-3-yl) acetate and quinoline-5-carbonyl chloride, compounds 40-1 and 40-2 were prepared according to the method of scheme 2 of IV-1
Then, 40A (50 mg) and 40B (62 mg) were obtained by the method of Compound 1 starting from 40-2 and but-2-yn-1-ylmethylsulfonate.
Chiral resolution of 40A (50 mg) gave 40A-1 (19 mg) and 40A-2 (21 mg)
LC-MS(ESI):532.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:9.05(d,J＝8.8Hz,1H),8.95(dd,J＝4.1,1.4Hz,1H),8.26–8.20(m,2H),8.09(d,J＝8.3Hz,1H),7.99(d,J＝2.2Hz,1H),7.78(dt,J＝8.3,3.5Hz,2H),7.69(dd,J＝8.8,2.2Hz,1H),7.49(dd,J＝8.8,4.1Hz,1H),4.47(dd,J＝11.0,4.3Hz,1H),4.30(s,3H),2.82–2.70(m,1H),2.35–2.25(m,1H),2.07(d,J＝17.2Hz,1H),2.10-2.01(m,1H),1.87(s,8H),1.61(s,3H).
Chiral resolution of 40B (62 mg) gave 40B-1 (24 mg) and 40B-2 (29 mg)
LC-MS(ESI):532.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.71(s,1H),8.69(dd,J＝4.0,1.4Hz,1H),8.16–8.09(m,2H),7.97(d,J＝8.2Hz,1H),7.87(d,J＝2.3Hz,1H),7.67(dt,J＝8.2,3.4Hz,2H),7.57-7.46(m,2H),4.43(dd,J＝11.2,4.5Hz,1H),4.27(s,3H),2.87–2.73(m,1H),2.39–2.29(m,1H),2.11-2.05(m,2H),1.95(s,8H),1.73(s,3H).
Example 41: preparation of Compound 41
Using intermediates IV-3 and 1-bromo-2-butyne as starting materials, the same reaction scheme was used to prepare Compounds 41A (73 mg) and 41B (70 mg)
41A (73 mg) was resolved by chiral HPLC to give 41A-1 (30 mg) and 41A-2 (25 mg)
LC-MS(ESI):521.1[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.28(s,1H),7.93(d,J＝2.2Hz,1H),7.72(d,J＝8.8Hz,1H),7.69–7.61(m,3H),7.54(d,J＝7.7Hz,1H),7.28(t,J＝7.6Hz,1H),6.80(d,J＝2.2Hz,1H),4.45(s,1H),4.17(s,3H),2.03(t,J＝23.7Hz,9H),1.38(s,3H),1.25–1.22(m,3H),1.12(dd,J＝5.9,3.4Hz,1H).
41B (70 mg) was resolved by chiral HPLC to give 41B-1 (26 mg) and 41B-2 (21 mg)
LC-MS(ESI):521.1[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:7.95(s,1H),7.76(s,1H),7.65–7.41(m,4H),7.34(d,J＝7.7Hz,1H),7.08(t,J＝7.6Hz,1H),6.63(d,J＝2.2Hz,1H),4.15(s,1H),3.96(s,3H),2.23(t,J＝23.7Hz,9H),1.58(s,3H),1.45–1.32(m,3H),1.22(dd,J＝5.9,3.4Hz,1H).
Example 42: preparation of Compound 42
Using intermediate IV-2 and 2-cyclopropylethylmethanesulfonate as starting materials, the same reaction scheme was used as in the preparation of Compound 1 to give Compounds 42A (83 mg) and 42B (87 mg)
Resolution of 42A (83 mg) by chiral HPLC gave 42A-1 (32 mg) and 42A-2 (31 mg)
LC-MS(ESI):537.2[M+H] +
1H NMR(400MHz,CDCl 3 )δ:8.20(s,1H),7.88(d,J＝2.3Hz,1H),7.74–7.59(m,5H),7.55(dd,J＝7.7,1.3Hz,1H),7.28(t,J＝7.6Hz,1H),7.24(s,2H),6.80(d,J＝2.2Hz,1H),4.34(s,1H),4.13(s,3H),2.22–1.80(m,10H),0.92–0.71(m,2H),0.62(d,J＝14.4Hz,1H),0.32–0.20(m,1H),0.11(t,J＝4.5Hz,1H),-0.36(dq,J＝9.3,4.8Hz,1H),-0.48(dq,J＝9.3,4.7Hz,1H).
42B (87 mg) was resolved by chiral HPLC to give 42B-1 (35 mg) and 42B-2 (29 mg)
LC-MS(ESI):537.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:7.92(s,1H),7.68(d,J＝2.4Hz,1H),7.54–7.39(m,6H),7.08(t,J＝7.6Hz,1H),6.95(s,2H),6.70(d,J＝2.2Hz,1H),4.14(s,1H),3.85(s,3H),2.32–1.95(m,10H),1.12–0.91(m,2H),0.82(d,J＝14.4Hz,1H),0.52–0.30(m,1H),0.21(t,J＝4.5Hz,1H),-0.16(dq,J＝9.3,4.8Hz,1H),-0.28(dq,J＝9.3,4.7Hz,1H).
Example 43: preparation of Compound 43
Compound 43 was prepared according to the following reaction scheme starting from methyl 2- (6-bromo-2-methoxyquinolin-3-yl) acetate and 4, 6-dimethoxy-2-pyridinecarbonyl chloride.
Compounds 43-1 and 43-2 were prepared according to the procedure of scheme 2 of IV-1, 43-3 to 43-6 were prepared according to the procedure of compound 1, and compound 43 was prepared according to the procedure of compound 27 to give pale yellow solids 43A (63 mg) and 43B (77 mg)
Resolution of 43A (63 mg) by chiral HPLC gave 43A-1 (22 mg) and 43A-2 (21 mg)
LC-MS(ESI):586.2[M+H] +
1H NMR(400MHz,CDCl3)δ:8.16(s,1H),7.90(d,J＝2.2Hz,1H),7.71(d,J＝8.8Hz,1H),7.64(dd,J＝8.8,2.2Hz,1H),6.94(d,J＝7.6Hz,2H),4.11(s,3H),3.98(s,3H),3.68(dd,J＝12.4,2.7Hz,1H),2.02(s,2H),1.98(s,6H),1.77(t,J＝12.5Hz,2H),1.67–1.57(m,4H),1.47(t,J＝14.9Hz,5H),0.68(s,3H),0.54–0.40(m,1H).
Resolution of 43B (77 mg) by chiral HPLC gave 43B-1 (25 mg) and 43B-2 (26 mg)
LC-MS(ESI):586.2[M+H] +
1H NMR(400MHz,CDCl3)δ:7.92(s,1H),7.76(s,1H),7.56(s,2H),6.84(d,J＝7.6Hz,2H),3.92(s,3H),3.78(s,3H),3.68(dd,J＝12.3,2.7Hz,1H),2.12(s,2H),1.98(s,6H),1.78(t,J＝12.5Hz,2H),1.67–1.57(m,4H),1.47(t,J＝14.9Hz,5H),0.78(s,3H),0.64–0.50(m,1H).
Example 44: preparation of Compound 44
44-2 was prepared according to scheme 2 of IV-1 starting from methyl 2- (6-bromo-2-methoxyquinolin-3-yl) acetate and 2, 6-diethoxy-4-pyridinecarbonyl chloride.
Compound 44 Using intermediate 44-2 and bromomethylcyclohexane as starting materials, the same reaction scheme as in the preparation of Compound 1 was employed to give Compound 44A (83 mg) and Compound 44B (77 mg)
Resolution of 44A (83 mg) by chiral HPLC gave 44A-1 (32 mg) and 44A-2 (31 mg)
LC-MS(ESI):613.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.20(s,1H),7.89(d,J＝2.2Hz,1H),7.70(d,J＝8.9Hz,1H),7.63(dd,J＝8.8,2.2Hz,1H),6.95–6.03(m,2H)4.35(q,J＝7.1Hz,4H),4.10(s,3H),3.72(d,J＝11.8Hz,1H),2.15(s,1H),1.82(d,J＝51.9Hz,6H),1.62(d,J＝13.1Hz,2H),1.42(t,J＝7.1Hz,9H),1.31(d,J＝8.8Hz,1H),1.25(d,J＝12.1Hz,1H),1.20–1.10(m,1H),1.10–1.01(m,1H),0.99–0.76(m,4H),0.67(s,2H),0.56–0.41(m,1H).
Resolution of 44B (77 mg) by chiral HPLC gave 44B-1 (38 mg) and 44B-2 (28 mg)
LC-MS(ESI):613.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:7.90(s,1H),7.75(s,1H),7.56(s,2H),6.85–6.13(m,2H),4.15(q,J＝7.1Hz,4H),3.91(s,3H),3.72(d,J＝11.7Hz,1H),2.17(s,1H),1.92(d,J＝51.9Hz,6H),1.72(d,J＝13.0Hz,2H),1.52(t,J＝7.1Hz,9H),1.37(d,J＝8.8Hz,1H),1.28(m,2H),1.16–1.09(m,1H),0.99–0.86(m,4H),0.67(s,2H),0.56–0.48(m,1H).
Example 45: preparation of Compound 45
Starting with IV-1-1-3, 45-2 was prepared according to scheme 1 of IV-1.
Using intermediate 45-2 and bromomethylcyclohexane as starting materials, compounds 45A (80 mg) and 45B (75 mg) were obtained using the same reaction scheme as for the preparation of compound 1
Resolution of 45A (80 mg) by chiral HPLC gave 45A-1 (32 mg) and 45A-2 (34 mg)
LC-MS(ESI):586.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.14(s,1H),7.94(s,1H),7.83(d,J＝2.2Hz,1H),7.64(d,J＝8.9Hz,1H),7.56(dd,J＝8.9,2.2Hz,1H),6.31(d,J＝8.2Hz,1H),4.33(s,1H),4.03(d,J＝18.5Hz,3H),3.91(d,J＝17.9Hz,6H),2.40(s,1H),2.14(d,J＝33.4Hz,2H),1.67–1.55(m,3H),1.38(d,J＝9.9Hz,4H),1.33–1.16(m,5H),0.99–0.74(m,6H),0.61(s,2H),0.39(s,1H).
45B (75 mg) was resolved by chiral HPLC to give 45B-1 (23 mg) and 45B-2 (24 mg)
LC-MS(ESI):586.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:7.90(s,1H),7.75(s,1H),7.56(s,2H),7.36(dd,J＝8.9,2.2Hz,1H),6.35(d,J＝8.2Hz,1H),4.08(s,1H),3.85(d,J＝18.5Hz,3H),3.81(d,J＝17.9Hz,6H),2.45(s,1H),2.17(d,J＝33.4Hz,2H),1.67–1.55(m,3H),1.48(d,J＝9.9Hz,4H),1.43–1.26(m,5H),1.09–0.84(m,6H),0.71(s,2H),0.49(s,1H).
Example 46: preparation of Compound 46
Starting with IV-1-1-3, 46-2 was prepared according to scheme 1 of IV-1.
Using intermediate 46-2 and bromomethylcyclohexane as starting materials, compounds 46A (85 mg) and 46B (97 mg) were obtained using the same reaction scheme as for the preparation of compound 1
46A (85 mg) was resolved by chiral HPLC to give 46A-1 (37 mg) and 46A-2 (38 mg)
LC-MS(ESI):545.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.16(s,1H),7.87(d,J＝2.1Hz,1H),7.70(d,J＝8.9Hz,1H),7.63(dd,J＝8.8,2.2Hz,1H),7.09(d,J＝5.0Hz,1H),6.84(d,J＝5.0Hz,1H),4.11(s,3H),2.63–2.47(m,2H),2.32(s,3H),2.05(q,J＝16.8,12.4Hz,6H),1.95–1.81(m,2H),1.64(d,J＝12.4Hz,1H),1.46(d,J＝9.8Hz,3H),1.40–1.21(m,3H),1.03–0.82(m,5H),0.73(q,J＝11.1,9.9Hz,2H),0.55(q,J＝11.9,10.9Hz,1H).
46B (97 mg) was resolved by chiral HPLC to give 46B-1 (34 mg) and 46B-2 (32 mg)
LC-MS(ESI):545.2[M+H] +
1 H NMR(400MHz,CDCl3)δ:7.89(s,1H),7.75(s,1H),7.54(s,2H),7.05(d,J＝5.0Hz,1H),6.82(d,J＝5.0Hz,1H),3.92(s,3H),2.83–2.67(m,2H),2.34(s,3H),2.15(q,J＝16.8,12.4Hz,6H),1.95–1.86(m,2H),1.74(d,J＝12.4Hz,1H),1.56(d,J＝9.8Hz,3H),1.45–1.32(m,3H),1.13–0.92(m,5H),0.79(q,J＝11.1,9.9Hz,2H),0.65(q,J＝11.9,10.9Hz,1H).
Example 47: preparation of Compound 47
47-2 was prepared according to scheme 2 of IV-1 starting from methyl 2- (6-bromo-2-methoxyquinolin-3-yl) acetate and 2-chloro-6-methoxy-4-pyridinecarbonyl chloride.
Using intermediate 47-2 and bromomethylcyclohexane as starting materials, compounds 47A (75 mg) and 47B (87 mg) were obtained using the same reaction scheme as for the preparation of compound 1.
Resolution of 47A (75 mg) by chiral HPLC gave 47A-1 (27 mg) and 47A-2 (33 mg)
LC-MS(ESI):590.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:8.16(s,1H),7.90(d,J＝2.2Hz,1H),7.71(d,J＝8.8Hz,1H),7.64(dd,J＝8.8,2.2Hz,1H),6.94(d,J＝7.6Hz,2H),4.11(s,3H),3.98(s,3H),3.68(dd,J＝12.4,2.7Hz,1H),2.02(s,2H),1.98(s,6H),1.77(t,J＝12.5Hz,2H),1.67–1.57(m,4H),1.47(t,J＝14.9Hz,5H),0.68(s,3H),0.54–0.40(m,1H).
Resolution of 47B (87 mg) by chiral HPLC gave 47B-1 (29 mg) and 47B-2 (33 mg)
LC-MS(ESI):590.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:7.89(s,1H),7.75(s,1H),7.54(s,2H),6.84(d,J＝7.6Hz,2H),3.85(s,3H),3.78(s,3H),3.68(dd,J＝12.4,2.7Hz,1H),2.32(s,2H),2.16(s,6H),1.87(t,J＝12.5Hz,2H),1.77–1.57(m,4H),1.49(t,J＝14.9Hz,5H),0.88(s,3H),0.66–0.52(m,1H).
Example 48: preparation of Compound 48
Using iv-1-1-3 and 1-methyl-2-oxo-4-aldehyde-1, 2-dihydropyridine as starting materials, compound 48 was prepared using the following reaction scheme
Preparation of Compound 48-1
1-methyl-2-oxo-4-formyl-1, 2-dihydropyridine (1 g,7.30 mmol) and malondithiol (869 mg,8.03 mmol) were dissolved in 30mL dichloromethane and boron trifluoride diethyl etherate (2.07 g,14.60 mmol) was slowly added under ice bath and allowed to react at room temperature18h. TLC and LC-MS detection were complete. Saturated sodium bicarbonate/dichloromethane is added for extraction, 1M sodium hydroxide aqueous solution is used for washing once, water is used for washing once again, the organic phase is washed with saturated common salt water, dried by anhydrous sodium sulfate, and the light yellow solid is obtained after spin drying: 1.25g, yield: 75%. LC-MS (ESI): 228.1[ M+H ]] +
Preparation of Compound 48-2
48-1 (1.25 g,5.50 mmol) was dissolved in tetrahydrofuran (40 mL), ar was substituted and protected, cooled to-78 ℃, LDA (2M, 8.25 mmol) was slowly added dropwise, the temperature was kept at-78℃for 1 hour, then IV-1-1-3 in THF (5 mL) was added, and the reaction was carried out at room temperature for 16 hours after the addition. TLC and LC-MS detection were complete. Saturated NH is added into the reaction solution 4 Cl quench, extract the aqueous phase with 50ml×3 DCM, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, spin dry, column chromatography to give 1.45g of white solid, yield: 55%. LC-MS (ESI): 478.1[ M+H ]] +
Preparation of Compound 48-3
48-2 (1.45 g,3.04 mmol) was dissolved in CH 3 CN/H 2 To O (60 mL/20 mL) was added NCS (2.03 g,15.19 mmol) and AgNO 3 (2.58 g,15.19 mmol) was reacted at room temperature for 10min, and the reaction was complete by TLC and LC-MS detection. The reaction mixture was quenched with saturated sodium thiosulfate, the aqueous phase was extracted with 50ml×3 DCM, washed with saturated brine, dried over anhydrous sodium sulfate, and dried by spin-drying to give 320mg of yellow solid by column chromatography, yield: 27%. LC-MS (ESI): 387.1[ M+H ]] +
Compounds 48-4 to 48-9 and preparation of Compound 48 following the procedure for preparation of Compound 1, yellow solid 48A (65 mg) and yellow solid 48B (73 mg) were obtained.
48A (65 mg) was resolved by chiral HPLC to give 48A-1 (25 mg) and 48A-2 (23 mg)
LC-MS(ESI):556.2[M+H] +
1H NMR(400MHz,CDCl 3 )δ:8.18(s,1H),7.93(d,J＝2.1Hz,1H),7.72(d,J＝8.8Hz,1H),7.63(dd,J＝8.8,2.1Hz,1H),7.53(d,J＝6.9Hz,1H),6.53(m,1H),6.48(dd,J＝6.9Hz,1.9Hz,1H),4.11(s,3H),3.71(dd,J＝12.4,2.8Hz,1H),3.45(s,3H),2.02(m,2H),1.98(s,6H),1.71–1.57(m,6H),1.47(m,5H),0.68(s,3H),0.54(m,1H).
48B (73 mg) was resolved by chiral HPLC to give 48B-1 (30 mg) and 48B-2 (31 mg)
LC-MS(ESI):556.2[M+H] +
1H NMR(400MHz,CDCl 3 )δ:7.95(s,1H),7.73(d,J＝2.1Hz,1H),7.52(d,J＝8.8Hz,1H),7.43(m,2H),6.43(m,1H),6.38(dd,J＝6.8Hz,1.9Hz,1H),3.89(s,3H),3.71(dd,J＝12.4,2.8Hz,1H),3.35(s,3H),2.22(m,2H),2.08(s,6H),1.81–1.67(m,6H),1.57(m,5H),0.78(s,3H),0.62(m,1H).
Example 49: preparation of Compound 49
Using IV-1-1-3 and imidazo [1,2-a ] pyridine-6-carbaldehyde as starting materials, compounds 49A (95 mg) and 49B (93 mg) were obtained using the same reaction scheme as for the preparation of compound 48
Resolution of 49A (95 mg) by chiral HPLC gave 49A-1 (40 mg) and 49A-2 (35 mg)
LC-MS(ESI):565.2[M+H] +
1H NMR(400MHz,CDCl 3 )δ:8.90(m,1H),8.18(s,1H),7.93–7.86(m,2H),7.75–7.55(m,5H),4.13(s,3H),3.77(dd,J＝12.5,2.8Hz,1H),2.10(m,2H),1.98(s,6H),1.78(m,2H),1.67–1.45(m,9H),0.69(s,3H),0.54–0.42(m,1H).
Resolution of 49B (93 mg) by chiral HPLC gave 49B-1 (34 mg) and 49B-2 (31 mg)
LC-MS(ESI):565.2[M+H] +
1H NMR(400MHz,CDCl 3 )δ:8.71(m,1H),7.91(s,1H),7.73–7.66(m,2H),7.55–7.38(m,5H),3.88(s,3H),3.79(dd,J＝12.5,2.8Hz,1H),2.31(m,2H),2.10(s,6H),1.88(m,2H),1.77–1.55(m,9H),0.79(s,3H),0.64–0.52(m,1H).
Example 50: preparation of Compound 50
Using IV-1-1-3 and imidazo [1,2-a ] pyridine-7-carbaldehyde as starting materials, compounds 50A (115 mg) and 50B (125 mg) were obtained using the same reaction scheme as for the preparation of compound 48
Resolution of 50A (115 mg) by chiral HPLC gave 50A-1 (48 mg) and 50A-2 (53 mg)
LC-MS(ESI):565.2[M+H] +
1H NMR(400MHz,CDCl 3 )δ:8.54(m,1H),8.18(s,1H),7.93–7.83(m,2H),7.75(d,J＝8.7Hz,1H),7.67(dd,J＝8.7,2.1Hz,1H),7.50(d,J＝1.5Hz,1H),7.41(d,J＝1.0Hz,1H),6.83(m,1H),4.15(s,3H),3.78(dd,J＝12.5,2.8Hz,1H),2.12(m,2H),1.98(s,6H),1.78(m,2H),1.67–1.47(m,9H),0.69(s,3H),0.54–0.42(m,1H).
Resolution of 50B (125 mg) by chiral HPLC gave 50B-1 (47 mg) and 50B-2 (54 mg)
LC-MS(ESI):565.2[M+H] +
1H NMR(400MHz,CDCl 3 )δ:8.24(m,1H),7.93(s,1H),7.73–7.65(m,2H),7.55(d,J＝8.6Hz,1H),7.37(dd,J＝8.7,2.1Hz,1H),7.20(d,J＝1.4Hz,1H),7.11(d,J＝1.0Hz,1H),6.73(m,1H),3.91(s,3H),3.78(dd,J＝12.5,2.8Hz,1H),2.32(m,2H),2.15(s,6H),1.88(m,2H),1.77–1.56(m,9H),0.79(s,3H),0.64–0.52(m,1H).
Example 51: preparation of Compound 51
Using IV-1-1-3 and quinoline-4-carbaldehyde as starting materials, the same reaction scheme was employed as in the preparation of Compound 48 to give Compounds 51A (78 mg) and 51B (88 mg)
Resolution of 51A (78 mg) by chiral HPLC gave 51A-1 (28 mg) and 51A-2 (32 mg)
LC-MS(ESI):576.2[M+H] +
1H NMR(400MHz,CDCl 3 )δ:8.70(s,1H),8.18(s,1H),8.05(d,J＝8.5Hz,1H),7.98(m,2H),7.68(m,3H),7.55(s,1H),7.50(t,J＝7.8Hz,1H),4.11(s,3H),3.71(dd,J＝12.4,2.8Hz,1H),2.02(m,2H),1.98(s,6H),1.70–1.57(m,6H),1.47(m,5H),0.67(s,3H),0.53(m,1H).
Resolution of 51B (88 mg) by chiral HPLC gave 51B-1 (30 mg) and 51B-2 (33 mg)
LC-MS(ESI):576.2[M+H] +
1H NMR(400MHz,CDCl 3 )δ:8.48(s,1H),7.92(s,1H),7.83(d,J＝8.5Hz,1H),7.78–7.68(m,4H),7.55(m,3H),3.89(s,3H),3.71(dd,J＝12.4,2.8Hz,1H),2.15(m,2H),2.05(s,6H),1.77–1.59(m,6H),1.49(m,5H),0.77(s,3H),0.58(m,1H).
Example 52: preparation of Compound 52
Using IV-1-1-3 and 2-methoxyquinoline-4-carbaldehyde as starting materials, the same reaction scheme was employed as in the preparation of Compound 48 to give Compounds 52A (80 mg) and 52B (105 mg)
Resolution of 52A (80 mg) by chiral HPLC gave 52A-1 (32 mg) and 52A-2 (31 mg)
LC-MS(ESI):606.2[M+H] +
1H NMR(400MHz,CDCl 3 )δ:8.72(s,1H),8.16(s,1H),8.03(d,J＝8.5Hz,1H),7.95(m,2H),7.58(m,3H),7.52(s,1H),7.45(t,J＝7.8Hz,1H),4.11(s,3H),3.98(s,3H),3.68(dd,J＝12.4,2.8Hz,1H),2.02(m,2H),1.96(s,6H),1.70–1.57(m,6H),1.47(m,5H),0.69(s,3H),0.55(m,1H).
Resolution of 52B (105 mg) by chiral HPLC gave 52B-1 (35 mg) and 52B-2 (38 mg)
LC-MS(ESI):606.2[M+H] +
1H NMR(400MHz,CDCl 3 )δ:8.52(s,1H),7.93(s,1H),7.78(d,J＝8.5Hz,1H),7.65(m,2H),7.28(m,5H),3.89(s,3H),3.78(s,3H),3.68(dd,J＝12.4,2.8Hz,1H),2.12(m,2H),1.99(s,6H),1.75–1.59(m,6H),1.52(m,5H),0.75(s,3H),0.59(m,1H).
Example 53: preparation of Compound 53
Using IV-1-1-3 and 6-methoxypyridazine-4-aldehyde (synthesized according to the same method as WO 2014/58747) as starting materials, compounds 53A (90 mg) and 53B (115 mg) were obtained using the same reaction scheme as for preparation of compound 48
Resolution of 53A (90 mg) by chiral HPLC gave 53A-1 (36 mg) and 53A-2 (32 mg)
LC-MS(ESI):557.2[M+H] +
1H NMR(400MHz,CDCl 3 )δ:8.78(d,J＝2.0Hz,1H),8.19(s,1H),7.92(d,J＝2.1Hz,1H),7.76–7.63(m,3H),4.11(s,3H),4.01(s,3H),3.67(dd,J＝12.1,2.5Hz,1H),2.02–1.96(m,8H),1.71–1.57(m,6H),1.47(m,5H),0.68(s,3H),0.56(m,1H).
53B (115 mg) was resolved by chiral HPLC to give 53B-1 (46 mg) and 53B-2 (43 mg)
LC-MS(ESI):557.2[M+H] +
1H NMR(400MHz,CDCl 3 )δ:8.58(d,J＝2.1Hz,1H),7.93(s,1H),7.72(d,J＝2.1Hz,1H),7.56–7.43(m,3H),3.89(s,3H),3.78(s,3H),3.67(dd,J＝12.1,2.5Hz,1H),2.18–2.05(m,8H),1.81–1.66(m,6H),1.57(m,5H),0.78(s,3H),0.66(m,1H).
Example 54: preparation of Compound 54
Starting materials were slightly different (bromine substitution to chlorine substitution) and the same reaction scheme as for preparation of Compound 1 was used according to 54A (100 mg) and 54B (132 mg)
54A (100 mg resolved by chiral HPLC gave 54A-1 (30 mg) and 54A-2 (35 mg)
LC-MS(ESI):514.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:7.98(s,1H),7.83(d,J＝2.2Hz,1H),7.68(d,J＝8.9Hz,1H),7.61(dd,J＝8.9,2.2Hz,1H),7.02–6.03(m,2H),4.10(s,3H),3.98(s,6H),3.66(dd,J＝12.2,3.0Hz,1H),2.18(q,J＝12.8,8.9Hz,1H),1.90(d,J＝9.2Hz,8H),1.57(d,J＝14.8Hz,1H),1.50–1.34(m,2H),0.97–0.80(m,1H),0.67(q,J＝8.3,7.6Hz,1H),0.46–0.30(m,1H),0.20(ttd,J＝13.1,8.9,4.2Hz,2H),-0.31(ddt,J＝23.3,9.3,4.8Hz,2H)；
Resolution of 54B (132 mg) by chiral HPLC gave 54B-1 (51 mg) and 54B-2 (43 mg)
LC-MS(ESI):514.2[M+H] +
1 H NMR(400MHz,CDCl 3 )δ:7.85(s,1H),7.70(s,1H),7.54(s,2H),6.20(s,2H),3.89(s,3H),3.75(s,6H),3.65–3.57(m,1H),2.53(t,J＝13.7Hz,1H),2.21(m,8H),1.90(d,J＝12.8Hz,1H),1.62(d,J＝14.4Hz,2H),1.09(d,J＝13.7Hz,1H),0.93–0.74(m,1H),0.60(d,J＝9.9Hz,1H),0.33(dq,J＝8.2,4.2Hz,2H),0.05-0.23(m,2H).
Pharmacological examples
Example 55: in vitro efficacy experiment of partial Compounds on Mycobacterium tuberculosis H37Rv Strain
Transferring the tested strain H37Rv into a liquid culture medium, culturing at 37 ℃ for 2 weeks, absorbing a little of culture bacteria liquid, placing in 4mL of liquid culture medium, adding 10-20 particles of sterile glass beads with the diameter of 2-3 mm, oscillating for 20-30S, standing and precipitating for l 0-20 min, absorbing the bacterial suspension supernatant, adjusting turbidimetry to 1 McO unit by using the liquid culture medium, which is equivalent to 1X 10 7 CFU/mL was ready for use. Each drug was dissolved to 1mg/mL with an appropriate amount of DMSO and filtered through a 0.22 μm filter. And then diluting to the required experimental concentration by using a liquid culture medium. The final concentrations of the test drugs were set as follows: 0.0039. Mu.g/mL, 0.0078. Mu.g/mL, 0.0165. Mu.g/mL, 0.03125. Mu.g/mL, 0.0625. Mu.g/mL, 0.125. Mu.g/mL, 0.25. Mu.g/mL, 0.5. Mu.g/mL, 1. Mu.g/mL, 2. Mu.g/mL, 4. Mu.g/mL, 11 concentration gradients total. Taking 100 mu L of each drug solution, adding the drug solution into a 96-well micro-pore plate, and then adding 100 mu L of bacterial liquid with the concentration of 1mg/mL to ensure that the drug concentration reaches the set final concentration, and culturing at 37 ℃. Three groups of parallel controls are arranged on the same medicine dilution, no medicine is added in the control group, and the inoculation amount is respectively set to be 100%, 10% and 1%. After 14 days of incubation at 37 ℃, the colony growth of each group was observed, and the minimum concentration of the sterile, falling-grown drug group was used as the MIC value of the test compound for the strain. The Minimum Inhibitory Concentration (MIC) of each compound against mycobacterium tuberculosis was observed, while MIC results were compared with those of the control drug Bedaquiline (Bedaquiline). The results are shown in Table 1.
TABLE 1 in vitro Activity of Mycobacterium tuberculosis of H37Rv type-Minimum Inhibitory Concentration (MIC)
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As can be seen from table 1, some of the compounds of the present invention exhibit significantly better in vitro MIC than the control drug bedaquiline. For example, the in vitro activity (MIC) of compound 1A-1, compound 4A-1 and compound 26A-1 was 0.0078 μg/mL, which is 16 times greater than the in vitro potency of the control drug, bedaquiline; the in vitro activity (MIC) of the compound 10A-1 and the compound 52A-1 was 0.0156 mug/mL, and the antibacterial activity was 8 times that of the control drug, bendazole, in vitro.
The results show that the activity of A-1 is strongest among the four isomers of all compounds, and that the other isomers are very weak or completely inactive. Thus only the spatial configuration of isomer a-1 and binding of the target are suitable.
Example 56: in vitro efficacy experiment of partial Compounds on drug-resistant Mycobacterium tuberculosis Strain
The test strains (1146-14: streptomycin resistant; 4061-15: isoniazid resistant; 3997-7: rifampicin resistant; B2, MDR-TB; B6, B29 and B53, XDR-TB) were isolated clinically from Mycobacterium tuberculosis from Shanghai City Lung Hospital, the steps were as follows: a. collecting sputum specimens of tuberculosis patients in Shanghai Lung department hospital, performing alkali treatment, inoculating to an improved Roche culture medium, and culturing for 2 weeks; b. drug sensitivity is measured by an absolute concentration method: fresh cultures were scraped from the slant of the medium, turbidded to 1 McO unit (1 mg/mL) with physiological saline, diluted to 10-2mg/mL, 0.1mL was inoculated on the drug sensitive medium, and the results were observed after four weeks. Reference materials: tuberculosis diagnosis laboratory test procedure, chinese society of anti-tuberculosis basic professional committee editorial, chinese education culture Press, 1 month in 2006) into liquid culture medium, culturing at 37deg.C for 2 weeks, absorbing a little culture broth, placing into 4mL liquid culture medium, adding 10-20 sterilized glass beads with diameter of 2-3 mm, shaking for 20-30S, standing for precipitation l 0-20 min, sucking the supernatant of the bacterial suspension, and regulating the turbidimetry to 1 McO with a liquid culture medium, which is equivalent to 1X 10 7 CFU/mL was ready for use. Each drug was dissolved to 1mg/mL with an appropriate amount of DMSO and filtered through a 0.22 μm filter. And then diluting to the required experimental concentration by using a liquid culture medium. The final concentrations of the test drugs were set as follows: 0.0039 mug/mL, 0.0078 mug/mL, 0.0165 mug/mL, 0.03125 mug/mL, 0.0625 mug/mL, 0.125 mug/mL, 0.25 mug/mL, 0.5 mug/mL, 1 mug/mL, 2 mug/mL, 4 mug/mL, 11 concentration gradient detection, 100 mug of each of the above-mentioned medicine solutions is taken and added into 96-well microplates, and then 100 mug of 1mg/mL concentration bacterial solution is added to make the medicine concentration reach the set final concentration, and the culture is carried out at 37 ℃. Three groups of parallel controls are arranged on the same medicine dilution, no medicine is added in the control group, and the inoculation amount is respectively set to be 100%, 10% and 1%. The Minimum Inhibitory Concentration (MIC) of mycobacterium tuberculosis was observed for each drug and compared to the MIC results of bedaquiline. The results are shown in Table 2.
TABLE 2 in vitro Activity against drug resistant Mycobacterium tuberculosis-Minimum Inhibitory Concentration (MIC)
S is streptomycin, H is isoniazid, R is rifampicin B2 is MDR-TB, B53, B29, B6 is XDR-TB.
As can be seen from Table 2, the compound 26A-1 of the present invention and the control compound Bedaquinine (Bedaquinine) exhibited excellent in vitro antibacterial activity against streptomycin-resistant strains, isoniazid-resistant strains, rifampicin-resistant strains and B2 multi-resistant strains, and B53, B29, and B6-broadly resistant strains, and the in vitro antibacterial activity was comparable to that of the anti-sensitive strain, and also showed that the in vitro activity of the compound of the present invention was superior to that of the control drug Bedaquinine. This shows that the compounds of the present invention, like bedaquiline, are useful in the treatment of diseases caused by drug-resistant tubercle bacillus, especially multi-resistant and broadly resistant tubercle bacillus.
Example 57: in vivo pharmacokinetic experiments and tissue distribution (Kp) of partial compounds
Test compounds were formulated using 0.5% cmc-Na in water as a homogeneous suspension with a final concentration of 2mg/mL for oral administration. The medicine is orally and parenterally administered, the dosage of single administration is 20mg/kg, the administration volume is 10mL/kg., and 0.15mL of blood sample is taken 15min, 30min, 1h, 2h, 4h, 6h, 10h, 12h and 24h after administration through the retrobulbar venous plexus of the mice.
The test sample with the final concentration of 0.5mg/mL is prepared for intravenous administration, the solvent for preparing the test sample is 5% DMSO+20% EA+50% PEG400+25% Saline (physiological saline) water solution, and the single administration dosage is 2mg/kg.: blood samples were collected 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 24h after dosing.
CD-1 mice, males, 6-8 weeks of week old at the beginning of administration, 20-30g of body weight at the beginning of administration, and marker number were selected. Animal body weight was measured prior to dosing and healthy animals with similar body weights were selected for inclusion in the experiment without randomized group, during which time all animals were free to drink water.
After collection, the plasma is placed in a marked centrifuge tube, rapidly separated at 3500 rpm for 10 minutes and at 4 ℃, and then the plasma is placed below-40 ℃ for preservation and measurement. The drug concentration in plasma was determined by LC-MS/MS method and its drug substitution parameters were calculated.
Dissecting after taking blood for 2h and 12h after oral administration, taking liver, lung, kidney, brain and spleen tissue samples, cleaning the surface with physiological saline, wiping the surface with medical gauze, placing the surface in a marked small self-sealing bag, and preserving below-40 ℃ to be tested. The concentration of drug in the tissue was determined by LC-MS/MS, divided by the plasma concentration corresponding to the corresponding time point to obtain the tissue distribution Kp value.
TABLE 3 pharmacokinetic experiment results in CD-1 mice
TABLE 4 tissue distribution in CD-1 mice
As can be seen from the table 3,after a single oral administration, the compound 26A-1 of the present invention showed C comparable to the control drug Beda quinoline max And AUC values, indicating that these compounds have comparable kinetic properties to bedaquiline; also as can be seen from table 4, the partial compounds of the present invention are significantly higher in Kp (lung) than the control drug bedaquiline after both 2 hours and 12 hours, which means that the partial compounds of the present invention have a greater drug concentration in the lung at the same dose administered; while Kp (brain) is lower than bedaquiline, it is shown that the compounds of the invention may have lower neurotoxicity. In addition, as the in vitro activity of part of the compounds is obviously higher than that of the control drug Bedapsone; thus, it is reasonable to consider that at the same dosage administered, some of the compounds of the present invention will exhibit a stronger in vivo efficacy than bedaquiline.
Example 58 mice acute infection model test of in vivo efficacy of partial Compounds
BALB/c mice, females, weighing about 20 g, were infected with Mycobacterium tuberculosis H37Rv (ATCC strain 27274) by aerosol route using an inhalation exposure system at a dose of about 5000CFU. 5 untreated mice were euthanized on the day of treatment to determine the infection dose. The drug to be tested was formulated as a suspension using 0.5% w/v carboxymethylcellulose (CMC). Before use, the mixture is preserved at 4 ℃. Control mice were treated with only 0.5% cmc.
Mice were grouped, weighed, 5 mice per group, and gastric lavage was started, five days a week, once a day, for four weeks. After 3 days of washout following the last dose, the experimental mice were euthanized, both lungs were aseptically removed, ground, and homogenized in 3ml Hank's Balanced Salt Solution (HBSS). After ten-fold dilution of HBSS solution, colony forming units were counted by incubation on Middlebrook 7H11 agar plates for three weeks. Results are expressed as average LogCFU values for each group of mice.
TABLE 5 in vivo efficacy test in H37Rv acute infected BALB/c female mice
a, 5 non-dosed mice were euthanized at 24 days post infection due to the explosive infection;
The dose of the bedaquiline is calculated according to free alkali;
2 out of 5 mice showed negative;
3 out of 5 mice showed negative;
for H37Rv acutely infected BALB/c female mice, none of the mice died after the end of the dosing, both the Bedaquinoline and the compound 26A-1 dosing groups. As can be seen from Table 5, at the end of the administration of the high dose group of Bedaquinoline and Compound 26A-1, the lung CFU numbers were all 0, indicating that the tubercle bacillus had been completely killed. The medium dose group obviously reduces the CFU number of the lung, and the detection of the number of the mycobacterium tuberculosis in part of mice is negative. Although the lung CFU was increased in the low dose group (compared to day 0), none of the mice died, indicating that the drug provided good protection to the mice.
These data indicate that the compounds of the present application have superior in vivo bactericidal activity relative to bedaquiline, and equivalent or superior therapeutic effects can be achieved with half the amount of bedaquiline. The compound can play a better therapeutic effect at a lower dosage, and can reduce the side effect of the medicament while reducing the dosage.
All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.

Claims (14)

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof:
wherein m represents an integer of 0 to 3;
R 1 represents the following groups:
a)C 3-8 cycloalkyl, or said C 3-8 A cycloalkyl group wherein one carbon atom is replaced by oxygen or nitrogen, said cycloalkyl group being unsubstituted or substituted by one to three groups independently selected from the group consisting of: halogen, hydroxy, C 1 -C 6 An alkyl group;
b) Alkynyl, which alkynyl is unsubstituted or substituted with one to three halogens;
R 2 and R is 3 Each independently selected from: hydrogen or C 1-6 An alkyl group;
R 4 selected from pyridine, naphthalene, quinoline, benzofuran, thiophene, pyridazine, imidazopyridine, N-methylpyrrolidone, unsubstituted or substituted respectively with one to three groups independently selected from the group consisting of: halogen, C 1-6 Alkyl, C 1-6 An alkoxy group;
R 5 selected from halogen or cyano;
R 6 selected from C 1-6 An alkoxy group;
R 7 selected from hydrogen or C 1-3 An alkyl group.
2. The compound of claim 1, wherein R 1 Represents C 3-6 Cycloalkyl, or said C 3-6 A cycloalkyl group wherein one carbon atom is replaced by oxygen, said cycloalkyl group being unsubstituted or substituted with one to three groups independently selected from the group consisting of: halogen or C 1 -C 3 An alkyl group.
3. The compound of claim 1, wherein R 2 And R is 3 Are respectively and independently selected from C 1-3 An alkyl group.
4. The compound of claim 1, wherein R 4 Unsubstituted or substituted with one to three groups independently selected from the group consisting of: halogen or C 1-4 An alkoxy group.
5. The compound of claim 1, wherein R 6 Selected from C 1-3 An alkoxy group.
6. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
7. the compound of any one of claims 1-6, wherein the optical isomer of the compound is in the a-1 configuration or the a-2 configuration;
8. the compound of any one of claims 1-6, wherein the optical isomer of the compound is in the a-1 configuration:
9. a pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier and, as active ingredient, a compound of claim 1, or a pharmaceutically acceptable salt thereof.
10. Use of a compound, or a pharmaceutically acceptable salt, as claimed in claim 1, for the preparation of a composition for inhibiting the growth of mycobacterium tuberculosis (Mycobacterium tuberculosis).
11. Use of a compound, or a pharmaceutically acceptable salt, as claimed in claim 1, for the manufacture of a medicament for the treatment of an infection; the infection is a Mycobacterium tuberculosis (Mycobacterium tuberculosis) infection.
12. The use according to claim 11, wherein the infection is a drug resistant tubercle bacillus infection.
13. A process for preparing a compound of formula i, comprising the steps of:
(1) Reacting a compound shown in a formula III with an allyl metal reagent to generate tertiary alcohol;
(2) The tertiary alcohol is subject to double hydroxylation in the presence of an oxidant and then is subject to pyrolysis to obtain a compound shown in a formula II;
(3) Reducing the compound shown in the formula II to obtain primary alcohol, activating the primary alcohol, and reacting the primary alcohol with corresponding amine to generate the compound shown in the formula I;
in the formulae, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 M is as defined in claim 1 for formula (I).
14. The process of claim 13 wherein the compound of formula ii is reacted with a corresponding amine to form the compound of formula i;
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