CN112574175A - Quinoline compound, preparation method and application thereof - Google Patents

Quinoline compound, preparation method and application thereof Download PDF

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CN112574175A
CN112574175A CN202010661397.4A CN202010661397A CN112574175A CN 112574175 A CN112574175 A CN 112574175A CN 202010661397 A CN202010661397 A CN 202010661397A CN 112574175 A CN112574175 A CN 112574175A
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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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Shanghai Sun Sail Pharmaceutical Science and Technology Co Ltd
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    • 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
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • 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
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    • 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
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    • 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
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Abstract

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

Description

Quinoline compound, preparation method and application thereof
Technical Field
The invention belongs to the fields of pharmacology, medicinal chemistry and pharmacology, and particularly relates to a novel quinoline compound, a preparation method thereof, and application of the quinoline compound in treating related diseases caused by mycobacterium tuberculosis, particularly drug-resistant mycobacterium tuberculosis infection.
Background
Tuberculosis is caused by infection with Mycobacterium tuberculosis (Mtb), one of the oldest diseases in humans. Estimated by the World Health Organization (WHO) in 2017, about 23% of people worldwide (about 17 billion) have latent tubercle bacillus infections, of which 5-10% of the population will develop active tuberculosis during their lifetime. At present, tens of millions of newly-increased people generate active tuberculosis symptoms every year, the annual death number caused by tuberculosis exceeds that of AIDS, and the tuberculosis-induced active tuberculosis killers become world first-class infectious diseases.
At present, a first-line treatment for sensitive tuberculosis adopts a combined treatment strategy of rifampicin, isoniazid, ethambutol and pyrazinamide, although the treatment success rate can reach more than 85%, the treatment period is as long as 6 months, and the treatment side effect is large, for example, the combined treatment of rifampicin and isoniazid may cause serious hepatotoxicity, ethambutol may cause optic nerve damage and the like. Some people fail to receive regular treatment, and some people develop drug-resistant tuberculosis (rifampin-resistant or multidrug-resistant) due to incomplete 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 percent. Drug-resistant tuberculosis, especially multi-drug resistant tuberculosis and widely drug resistant tuberculosis, is a leading cause of death in tuberculosis patients, especially patients with immunodeficiency people, such as AIDS and tuberculosis double-infection patients.
WO2004/011436 discloses a number of diarylquinoline antitubercular compounds, of which Bedaquiline (TMC 207) is a representative compound, which kills mycobacterium tuberculosis by interfering with its ATP synthesis by disrupting the coupling of transmembrane proton transfer to ATP synthesis by acting on the ATP synthase proton pump on the mitochondrial cell membrane of mycobacterium tuberculosis. The united states Food and Drug Administration (FDA) and European Medicines Administration (EMA) approved part of their combination therapy for adult multi-drug resistant tuberculosis at the end of 2012 and in march 2014, respectively. Due to the unique action mechanism, the mycobacterium tuberculosis inhibitor has strong activity of resisting mycobacterium tuberculosis, has no cross drug resistance with other existing tuberculosis drugs, has better bactericidal activity on both replicating types and non-replicating types of the mycobacterium tuberculosis, has better clinical curative effect, and is listed as a first-line drug for treating rifampicin-resistant tuberculosis and multi-drug-resistant tuberculosis by WTO in 2017.
Figure BDA0002578699540000011
However, like most other antitubercular drugs, bedaquiline also has significant disadvantages, such as causing prolongation of QTc intervals in the electrocardiogram, which may lead to serious cardiac safety risks. It is also noteworthy that the mortality rate of the bedaquiline group (12.7%) was higher in the phase 2 trial of clinical trial C208 than in the placebo group (2.5%), but the specific cause was not clear. At present, in a treatment period as long as 18-20 months, patients using the bedaquiline still need to frequently monitor the electrocardio-physiological status and the drug safety reaction, and in addition, the application of the new mechanism drug in tuberculosis patients is limited to a certain extent by the lower bioavailability, obvious hepatotoxicity, drug-induced side effects such as phosphatide disease and the like.
In view of the above, there is an urgent need in the art to develop a new class of quinoline compounds, which has better therapeutic effect and safety than bedaquiline, for treating related diseases caused by mycobacterium tuberculosis, especially drug-resistant mycobacterium tuberculosis infection.
The invention relates to a method for processing a semiconductor chip.
The invention aims to provide a novel anti-tuberculosis compound shown as a structural general formula (I), or an optical isomer and pharmaceutically acceptable inorganic or organic salt thereof;
in a second aspect of the 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 present invention, there is provided the use of the above-mentioned compounds of the present invention, or optical isomers, pharmaceutically acceptable inorganic or organic salts thereof, as active ingredients in the manufacture of medicaments for the treatment of diseases associated with infection by mycobacterium tuberculosis, particularly multidrug-resistant mycobacterium tuberculosis. The compound of the invention also contains pharmaceutically acceptable excipient or carrier, and the compound of the invention with the formula (I) or each optical isomer and pharmaceutically acceptable inorganic or organic salt as active ingredients.
In a first aspect of the present invention, there is provided a compound represented by formula (I), or each optical isomer, or a pharmaceutically acceptable salt thereof:
Figure BDA0002578699540000021
wherein m represents an integer of 0 to 3;
R1represents the following groups:
a) hydrogen or C1-8Alkyl, unsubstituted or substituted with one to three groups independently selected from the group consisting of: halogen, hydroxy, cyano, C1-4Alkyl radical, C1-4An alkoxy group;
b)C3-8cycloalkyl, or said C3-8Cycloalkyl in which one carbon atom is replaced by oxygen, sulfur (sulphoxide or sulphone) or NR8Alternatively, the cycloalkyl is unsubstituted or substituted with one to three groups independently selected from: halogen, hydroxy, halogen substituted or unsubstituted C1-C6Alkyl, halogen substituted or unsubstituted C3-C6Cycloalkyl, halogen substituted or unsubstituted C1-C6Alkoxy, one or two C1-6Alkyl or cycloalkyl substituted or unsubstituted amino, halogen substituted or unsubstituted C1-6An alkylthio group;
R8selected from hydrogen or C1-6An alkyl group; or
c) Alkenyl or alkynyl, said alkenyl or alkynyl being unsubstituted or substituted with: c substituted or unsubstituted with one to three substituents independently selected from cyano, halogen or hydroxy1-6Alkyl, C substituted or unsubstituted by one to three groups independently selected from cyano, halogen or hydroxy3-6A cycloalkyl group;
R2and R3Each independently selected from: hydrogen, C substituted by one to three halogen or unsubstituted1-6Alkyl, C substituted or unsubstituted by one to three groups independently selected from cyano, halogen or hydroxy3-6A cycloalkyl group; or R2And R3Joined to form a 4-8 membered cyclic structure wherein the ring is unsubstituted or substituted with one to three substituents independently selected from cyano, halogen or hydroxy;
R4selected from aryl or heteroaryl, which are unsubstituted or substituted with one to three groups independently selected from: halogen, hydroxy, cyano, halogen substituted or unsubstituted C1-6Alkyl, halogen substituted or unsubstituted C3-6Cycloalkyl, halogen substituted or unsubstituted C1-6Alkoxy, halogen substituted or unsubstituted C1-6Alkylthio, NR9R10Methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl; r9And R10Each independently selected from: hydrogen, halogen substituted or unsubstituted C1-6Alkyl, halogen substituted or unsubstituted C3-6A cycloalkyl group;
R5selected from halogen, cyano, hydroxy, C1-4Alkoxy, or C1-4An alkylthio group;
R6is selected from C1-6Alkyl radical, C1-6Alkoxy, or C1-6An alkylthio group;
R7selected from hydrogen, or C1-6An alkyl group.
In another preferred embodiment, R1Represents C3-6Cycloalkyl, or said C3-6A cycloalkyl group, wherein one carbon atom is replaced by oxygen, is unsubstituted or substituted with one to three groups independently selected from the group consisting of: halogen, halogen substituted or unsubstituted C1-C3An alkyl group.
In another preferred embodiment, R is2And R3Each independently selected from: c substituted by one to three halogens or unsubstituted1-3An alkyl group.
In another preferred embodiment, R is4Selected from naphthyl or heteroaryl, the naphthyl or heteroaryl being unsubstituted or substituted with one to three groups independently selected from: halogen, halogen substituted or unsubstituted C1-4An alkoxy group.
In another preferred embodiment, R is5Selected from halogen or cyano; r6Is selected from C1-3An alkoxy group; r7Selected from hydrogen or C1-3An alkyl group.
The invention provides a compound, or each optical isomer, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following:
Figure BDA0002578699540000031
Figure BDA0002578699540000041
Figure BDA0002578699540000051
Figure BDA0002578699540000061
Figure BDA0002578699540000071
Figure BDA0002578699540000081
in another preferred embodiment, the optical isomer of the compound is in A-1 configuration 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 an active ingredient, a compound provided by the present invention as described above, or each optical isomer, or a pharmaceutically acceptable salt thereof.
In another preferred embodiment, the composition is in an oral dosage form.
In a third aspect of the present invention, there is provided a use of the compound provided by the present invention, or each optical isomer, or a pharmaceutically acceptable salt thereof, as described above, for preparing a composition for inhibiting the growth of Mycobacterium tuberculosis (Mycobacterium tuberculosis).
In a fourth aspect of the invention, there is provided a use of a compound provided by the invention as described above, or each optical isomer, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of an infection.
In another preferred embodiment, the infection is a Mycobacterium tuberculosis infection; more preferably, the infection is a drug-resistant mycobacterium tuberculosis 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 mycobacterium tuberculosis infection of the lung.
In a fifth aspect of the invention, there is provided a process for the preparation of a compound of formula i, said process comprising the steps of:
(1) reacting the compound shown in the formula III with an allyl metal reagent to generate tertiary alcohol;
(2) carrying out dihydroxylation on tertiary alcohol in the presence of an oxidant and then cracking to obtain a compound shown as a formula II; and
(3) reducing a compound shown as a formula II to obtain primary alcohol, activating, and reacting with corresponding amine to generate a compound shown as a formula I;
Figure BDA0002578699540000091
in the formulae, R1、R2、R3、R4、R5、R6、R7M is as defined for formula (I).
In another preferred embodiment, the compound shown in the formula II is reacted with corresponding amine to generate the compound shown in the formula I;
Figure BDA0002578699540000092
therefore, 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, particularly drug-resistant tubercle bacillus infection.
It is to be understood that within the scope of the present invention, the above-described technical features of the present invention and the technical features specifically described below (e.g., examples) may be combined with each other to constitute a new or preferred technical solution. Not to be reiterated herein, but to the extent of space.
Detailed Description
The inventor synthesizes and screens a large number of compounds through extensive research, and finds that the compound shown in the formula (I) has strong inhibitory activity to tubercle bacillus in vitro and in vivo for the first time, and is particularly suitable for preparing medicaments for treating related diseases caused by tubercle bacillus infection. The present invention has been completed based on this finding.
Representative names and structural formulas of the compounds represented by the formula (I) of the present invention are shown in the following table:
Figure BDA0002578699540000101
Figure BDA0002578699540000102
Figure BDA0002578699540000111
Figure BDA0002578699540000121
Figure BDA0002578699540000131
Figure BDA0002578699540000141
Figure BDA0002578699540000151
unless otherwise indicated, the following terms used in the specification and claims have the following meanings:
"alkyl" refers to a saturated aliphatic hydrocarbon group, 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 fused ring group, a 6 to 12 membered aliphatic bridged ring group, or a 6 to 12 membered aliphatic spiro ring group, wherein one or more rings may contain one or more double bonds, but none of the rings have a completely 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- (the R)11May be hydrogen, C1-6Alkyl or C3-6Cycloalkyl groups).
"alkoxy" refers to an alkyl group bonded to the rest of the molecule through an ether oxygen atom. Representative of alkoxy groups are alkoxy groups 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, especially alkoxy groups substituted with one or more halogens.
"hetero" means a non-carbon atom or group containing-O-, -S-, -NR-11- (the R)11Selected from hydrogen, C1-6Alkyl or C3-6Cycloalkyl), -SO-, -SO2-, ═ O, and any combination thereof (e.g., -CONR-, -SO)2NR-, -COO-, -NHCOO-, -NHCONH, and the like); the number of heteroatoms or groups may be 1-6.
"aryl" refers to a group having at least one aromatic ring structure, i.e., an aromatic ring with a conjugated pi-electron system, including carbocyclic aryl, heteroaryl. Substituents at different positions on the aryl group can be connected to form a cyclic structure.
"heteroaryl" refers to a structure in which carbon atoms on the aryl backbone are replaced with a heteroatom or group, including, but not limited to, the following structures: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furyl, N-methylpyrrolyl, N-methylpyridinonyl, 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, quinolyl, isoquinolyl, benzopyrazinyl, benzopyrimidinyl, benzopyrazinone, benzoxazinonyl, benzopyrimidinone, pyridopyrrolyl, pyridofuranyl, pyridothienyl, pyridopyrazolyl, pyridoimidazolyl, pyridothiazolyl, pyridooxazolyl, pyridopyridyl, pyrido-1, 2, 3-triazolyl, pyridopyrazinyl, pyridopyrimidinyl, pyridopyridazinyl, pyridothiazinoyl, pyridooxazinonyl, pyridopyrimidinyl.
"halogen" means fluorine, chlorine, bromine or iodine.
The "pharmaceutically acceptable salt" used herein is not particularly limited as long as it is a pharmaceutically acceptable salt, and includes inorganic salts and organic salts. Specifically, the salt of the compound of the present invention with an acid is exemplified, and examples of an acid suitable for salt formation 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 present 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 nomenclature of the R, S system (the Kane-Engell-Prerogue rule), the configuration of an asymmetric carbon atom is related to the size of the substituent attached to it, and the difference in the size of the substituent may result in the possibility that the R or S of the same asymmetric carbon atom in the same series of compounds may be different, but the orientation of the substituent space of the asymmetric carbon atom is not changed. In the purification and separation process of the last step of the reaction scheme of the present invention, each target compound can be separated into two pairs of diastereomers by a conventional separation method (e.g., column chromatography or preparative thin-layer chromatography), and the two pairs of diastereomers are labeled as compound a and compound B, respectively, according to the order of separation; each pair of diastereomers can be further separated into individual enantiomers by chiral separation methods (e.g., preparative chiral high performance liquid chromatography (chiral-HPLC), and the individual enantiomers are labeled as-1 and-2, respectively, according to the order of separation, four individual isomers have the best a-1 activity, individual B-1 compounds have weaker activity, and a-2 and B-2 have substantially no activity, after multiple in vitro activity tests, the spatial orientation and corresponding isomers of the four individual isomers involved in two key asymmetric carbon atoms are defined as follows, based on the structure of bedaquiline and its site of action and the difference in isomer activities (comparative Chirality,2012,54-69) and the in vitro activity test results of the present invention:
Figure BDA0002578699540000161
process for the preparation of the compounds of the invention
The compounds of the present invention and their various intermediates may 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 combinations thereof with other chemical synthetic methods, and equivalents thereof known to those skilled in the art, with preferred embodiments including, but not limited to, the examples of the present invention.
The following specifically describes the preparation of the compounds of formula (I) according to the invention, but these specific methods do not limit the invention in any way.
The compound having the structure 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, solvent, base, amount of the compound used, reaction temperature, time required for the reaction, etc., are not limited to the following explanation. The compounds of the present invention may also be conveniently prepared by optionally combining various synthetic methods described in the present specification or known in the art, and such combinations may be readily carried out by those skilled in the art to which the present invention pertains.
In the production method of the present invention, the compound represented by the formula (i) can also be produced from the compound (iii) by a five-step reaction comprising the steps of:
in a first step, compound (iii) is reacted with a suitable allylic metal reagent (such as, but not limited to, allylzinc) to form a tertiary alcohol;
secondly, dihydroxylation is carried out under a proper oxidant;
thirdly, cracking the mixture under a proper oxidant to obtain a compound (II);
fourthly, reducing the compound (II) by a proper reducing agent to obtain alcohol;
and fifthly, reacting the primary alcohol in the alcohol obtained in the fourth step with proper amine after proper activation to obtain the target compound (I).
The first reaction step can be carried out in the presence of a suitable catalyst (e.g., without limitation, cubr2S), a suitable solvent (such as, but not limited to, anhydrous THF) and a suitable temperature (e.g., 0-75 ℃).
The oxidizing agent in the above second step includes, but is not limited to, catalytic amounts of potassium osmate 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.
The activation of the primary alcohol in the fifth step above includes, but is not limited to, formation of-OMs with MsCl; the amine used includes, but is not limited to, dimethylamine.
Figure BDA0002578699540000171
Wherein R is1、R2、R3、R4、R5、R6、R7M is as defined herein for formula (I).
The compounds of formula III (also referred to as intermediates III, etc.) used in the present invention can be obtained by the following reaction schemes 1 to 6:
scheme 1:
preparation of intermediate (III)
Figure BDA0002578699540000172
R1、R4、R5、R6、R7M and textThe definitions of formula (I) are the same.
After conversion of the-Cl in the starting material to-CN by a suitable reagent (e.g., sodium cyanide), hydrolysis occurs under suitable conditions (e.g., aqueous sodium hydroxide) to give an acid, which is then reduced by a suitable reducing agent (e.g., a solution of borane dimethylsulfide complex) to a primary alcohol, which is then oxidized by a suitable oxidizing agent (e.g., DMP) to an aldehyde, which is then reacted with a solution containing R4The Grignard reagent is reacted to obtain alcohol, and then the alcohol is oxidized to obtain the key intermediate ketone (IV). Nucleophilic substitution reactions occur under base (e.g., potassium carbonate or sodium hydroxide) conditions at suitable temperatures (e.g., 20-80 ℃) to afford key intermediate (iii).
And (2) a flow scheme:
Figure BDA0002578699540000173
R1、R4、R5、R6、R7m is as defined herein for formula (I).
Starting material R4CO2H is reduced with a suitable reducing agent (e.g., LiAlH4) Reduction to a primary alcohol followed by oxidation to an aldehyde by a suitable oxidant (e.g., manganese dioxide), followed by reaction with 1, 3-propanedithiol to give a dithioacetal, dehydrogenation of the dithioacetal to a carbanion under the action of a suitable base (e.g., butyllithium or lithium diisopropylamide), followed by reaction with a heteroarylmethylene halide to give the compound dithioketal, followed by reaction under suitable oxidation conditions (e.g., [ bis (trifluoroacetoxy) iodonium)]Benzene) to remove the protecting group to give ketone (IV). Nucleophilic substitution reactions occur under base (e.g., potassium carbonate or sodium hydroxide) conditions at suitable temperatures (e.g., 20-80 ℃) to afford key intermediate (iii).
And (3) a flow path:
Figure BDA0002578699540000181
R1、R4、R5、R6、R7m is as defined herein for formula (I).
After conversion of the-Cl in the starting material to-CN by a suitable reagent (e.g., sodium cyanide), Cl is reacted with a suitable metal catalyst (e.g., Ni (dppe))2) Directly reacting with arylboronic acids to give the ketones (IV). Nucleophilic substitution reactions occur under base (e.g., potassium carbonate or sodium hydroxide) conditions at suitable temperatures (e.g., 20-80 ℃) to afford key intermediate (iii).
And (4) a flow chart:
Figure BDA0002578699540000182
R1、R4、R5、R6、R7m and is as defined herein for formula (I).
Starting materials methyl heteroaryl acetate and R4The resulting intermediate is reacted with COCl under suitable base (e.g., LiHMDS) conditions, followed by high temperature removal in a suitable solvent (e.g., dimethyl sulfoxide) to afford ketone (iv). Nucleophilic substitution reactions occur under base (e.g., potassium carbonate or sodium hydroxide) conditions at suitable temperatures (e.g., 20-80 ℃) to afford key intermediate (iii).
And (5) a flow chart:
Figure BDA0002578699540000183
R1、R4、R5、R6、R7m is as defined herein for formula (I).
The starting material allyl alcohol can be synthesized in the literature, the double bond of the allyl alcohol is epoxidized, and the resulting epoxy compound is R-containing1(CH2)mThe nucleophilic reagent of (A) attacks the ring opening 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 reacted with a compound containing R4Reaction of the Grignard reagent with a secondary alcohol, followed by oxidation with a suitable oxidizing agent (e.g., DMP) to give (III).
And (6) a flow path:
Figure BDA0002578699540000184
R1、R4、R5、R6、R7m is as defined herein for formula (I).
The starting compounds are commercially available starting materials or can be prepared according to previously reported synthetic routes. Starting compounds and compounds containing R6Followed by reduction with a suitable reducing agent (e.g., sodium borohydride) to give a primary alcohol, followed by reaction with a suitable chlorinating agent (e.g., thionyl chloride) to give heteroarylmethylene chloride, and a suitable organometallic reagent (e.g., an organozinc reagent) prepared from the heteroarylmethylene chloride with R4CHO reaction, and then oxidation to obtain ketone (IV); nucleophilic substitution reactions occur in the presence of a base (e.g., potassium carbonate or sodium hydroxide) in a suitable single or mixed solvent (e.g., water, acetone, acetonitrile, tetrahydrofuran) and at a suitable temperature (e.g., 20-80 ℃) to afford key intermediate (iii).
The compounds of formula (I) can 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 (such as, but not limited to, NaB (OAc))3) Suitable acids (such as, but not limited to, acetic acid), suitable solvents (such as, but not limited to, 1, 2-dichloroethane), and suitable temperatures (e.g., 0-75 ℃).
Figure BDA0002578699540000191
Wherein R is1、R2、R3、R4、R5、R6、R7M is as defined herein for formula (I).
In one embodiment of the present invention, compound 28 and compound 32 are prepared as follows:
Figure BDA0002578699540000192
compounds 26 and 31 in palladium catalysts (e.g. Pd (PPh)3)4) Coupled with a cyano reagent (e.g., zinc cyanide) and reacted in a suitable solvent (e.g., DMF) and at a suitable temperature (e.g., 0-100 ℃).
Pharmaceutical compositions and methods of administration
The compound of the invention and each optical isomer, pharmaceutically acceptable inorganic or organic salt thereof and a pharmaceutical composition containing the compound as a main active ingredient can be used for treating related diseases caused by mycobacterium tuberculosis, particularly multi-drug resistant mycobacterium tuberculosis infection because the compound has excellent anti-mycobacterium tuberculosis activity.
The compound of the general formula (I) has strong anti-mycobacterium tuberculosis effect. Compared with bedaquiline, the compound has stronger in-vitro bactericidal activity, stronger lung targeting property, lower distribution in brain and smaller potential cardiotoxicity, and the pharmacokinetic property in animals is equivalent to that of the bedaquiline, and the compound can achieve the same bactericidal effect under low administration dosage, so the treatment cost and toxicity are lower, and the treatment compliance of patients is better.
The pharmaceutical composition of the present invention may use a pharmaceutically acceptable excipient or carrier, and the compound of formula (i) of the present invention, or each optical isomer, pharmaceutically acceptable inorganic or organic salt thereof, as an active ingredient.
The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof and 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 composition contains 1-1000mg of a compound of the invention per dose, preferably 5-500mg of a compound of the invention per dose, more preferably 10-200mg of a compound of the invention per dose. The safe and effective amount of the compound is determined according to the age, condition, course of treatment and other specific conditions of a treated subject.
The compound and the pharmaceutically acceptable salt thereof can be prepared into various preparations, wherein the preparation comprises the compound or the pharmaceutically acceptable salt thereof in a safe and effective amount range and 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 age, condition, course of treatment and other specific conditions of a treated subject.
"pharmaceutically acceptable excipient or carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of being blended with the compounds of the present invention and with each other without significantly diminishing the efficacy of the compounds. Examples of pharmaceutically acceptable excipients or carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil etc.), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol etc.), emulsifiers (e.g. tween, etc.)
Figure BDA0002578699540000201
) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
In the present invention, "active ingredient" means a compound represented by the general formula (I), and a pharmaceutically acceptable inorganic or organic salt of the compound of the general formula (I). The compounds of the present invention may contain one or more asymmetric centers and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and individual 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 and 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 a pharmaceutically acceptable acid in a polar protic solvent, such as methanol, ethanol, isopropanol, and the like, to form a pharmaceutically acceptable salt, if 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, or glutamic acid, and the like.
The term "tubercle bacillus caused, in particular caused by infection with multidrug resistant tubercle bacillus", as used herein, refers to a tubercle bacillus caused by drug sensitive tubercle bacillus for clinical tuberculosis, drug resistant tubercle bacillus for one clinical drug, drug resistant tubercle bacillus for multiple clinical drugs, and widely drug resistant tubercle bacillus.
The terms "disease caused by infection with tubercle bacillus" or "tubercle bacillus infectious disease" are used interchangeably and as used herein refer to tuberculosis of the lung, lymphoid tuberculosis, intestinal tuberculosis, bone tuberculosis, tuberculous pleuritis, tuberculous meningitis, and the like.
The compound of the present invention and various crystal forms, pharmaceutically acceptable inorganic or organic salts thereof, and pharmaceutical compositions containing the compound as a main active ingredient can be used for treating diseases related to mycobacterium tuberculosis because the compound has excellent anti-mycobacterium tuberculosis activity. According to the prior art, the compounds of the present invention are useful in the treatment of tuberculosis and other infectious diseases.
When the compounds of the present invention are administered, they 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 compounds, the liquid dosage forms may contain inert diluents commonly employed 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 such materials and the like.
In addition to these inert diluents, the compositions can also contain 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, 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 vehicles include water, ethanol, polyols and suitable mixtures thereof.
The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1 to 1000mg, preferably 10 to 500 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
The main advantages of the invention include:
1. compared with the bedaquiline, the compound has more excellent in-vivo and in-vitro antibacterial activity on mycobacterium tuberculosis (including drug-resistant bacteria).
2. Compared with bedaquiline, the compound of the invention shows better lung targeting and lower brain targeting.
The various specific aspects, features and advantages of the compounds, methods and pharmaceutical compositions described above are set forth in detail in the following description, which makes the present invention clear. It should be understood herein that the detailed description and examples, while indicating specific embodiments, are given by way of illustration only. After reading the description of the present invention, those skilled in the art can make various changes or modifications to the present invention, which also fall within the scope defined by the present application.
The present invention is more specifically explained in the following examples. It should be understood, however, that these examples are for the purpose of illustrating the present invention and are not intended to limit the scope of the present invention in any way. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Parts and percentages are parts and percentages by weight unless otherwise indicated. Examples the organic solvents used in the reactions were all subjected to drying methods known in the art.
1H NMR was recorded using a Varian Mercury 400 or 600 NMR spectrometer with chemical shifts expressed as delta (ppm); MS was measured using Shimadzu LC-MS-2020 Mass spectrometer. The silica gel used for separation is not illustrated to be 200-300 meshes, and the proportions of the eluents are volume ratios.
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 process of the reaction scheme, each target compound can be separated into two pairs of diastereoisomers by a conventional separation method (such as column chromatography or preparative thin layer chromatography), and the two pairs of diastereoisomers are respectively marked as a compound A and a compound B according to the sequence of separation; each pair of diastereoisomers can be further separated into single enantiomers by chiral separation methods (such as preparative chiral high performance liquid chromatography (chiral-HPLC), and the single enantiomers are respectively marked as-1 and-2 according to the sequence of separation, for example, for the compound 1, two pairs of diastereoisomer compounds can be respectively marked as 1A and 1B after conventional separation, two single enantiomers obtained after chiral separation of 1A can be respectively marked as 1A-1 and 1A-2, and two single enantiomers obtained after chiral separation of 1B can be respectively marked as 1B-1 and 1B-2.
The separation method comprises the following steps: the column chromatography was carried out using commercially available ordinary silica gel (200-300 mesh) or commercially available ordinary preparative plates, which were examined by UV-254nm, and the eluent or developing agent was commercially available untreated dichloromethane and methanol, and the ratio was appropriately adjusted depending on the polarity of the compound.
Chiral preparative HPLC conditions: the type of the separation column is a xylonite AD-H column; the detector is a UV detector with the wavelength of 235 nm; temperature: 30 ℃; fluidity: n-hexane: isopropyl alcohol: diethylamine 70: 30: 0.1.
synthetic examples
Preparation of intermediate IV-1
Figure BDA0002578699540000221
The intermediate IV-1 can be prepared according to the following two reaction procedures
Reaction scheme 1:
Figure BDA0002578699540000222
preparation of IV-1-1-1
6-bromo-2-chloroquinoline-3-carbaldehyde (5.0g, 18.52mmol) was dissolved in MeOH (30ml), and fresh sodium methoxide methanol solution (93mmol) was added under ice bath, and the reaction was refluxed for 3 h. TLC, petroleum ether, ethyl acetate 10: 1. Cooling to room temperature after the reaction is finished, pouring the reaction liquid into ice water, separating out a solid, filtering, and drying a filter cake to obtain a light yellow powdery solid: 4.0g, yield: 80 percent. LC-MS (ESI): 266.1[ M + H]+
Preparation of IV-1-1-2
IV-1-1-1 (5.0g, 18.52mmol) was dissolved in MeOH (80ml) and NaBH was added4(1.41g 37mol), and reacted at room temperature for 1 hour. TLC, petroleum ether, ethyl acetate 10: 1. After the reaction is finished, pouring the reaction liquid intoQuenching in ice water, EA extraction, washing the organic phase with saturated salt solution, drying with anhydrous sodium sulfate, and spin-drying. Column chromatography (petroleum ether: ethyl acetate: 5:1) to obtain white powdery solid: 4.5g, yield: 90 percent. LC-MS (ESI): 268.0[ M + H]+
Preparation of IV-1-1-3
IV-1-1-2 (10.1g, 37.67mmol) was dissolved in DCM (400ml) and SOCl was added slowly2(18g 151mol), and 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 spin-dried. Performing column chromatography (petroleum ether: ethyl acetate: 10:1) to obtain a white powdery solid: 8.67g, yield: 80 percent. LC-MS (ESI): 288.0[ M + H]+
Preparation of IV-1-1-4
Zinc powder (2.74g, 41.88mmol), iodine (2 particles) and THF (80ml) are placed in a 250ml three-neck flask, under the protection of argon, LiCl in THF (0.5M, 42ml, 20.94mmol) is added dropwise in ice bath, IV-1-1-3 (4g, 13.96mmol) in THF (40ml) is slowly added dropwise, and the mixture is reacted for 2h in ice bath, TLC, petroleum ether and ethyl acetate are 2: 1. Used directly in the next step.
Preparation of IV-1-1-5
A solution of 3, 5-dimethoxypyridine-4-carbaldehyde (1.98g, 11.87mmol) in THF (40ml) was slowly added to IV-1-1-4 in THF (162ml) and reacted at room temperature overnight. TLC, petroleum ether, ethyl acetate 10: 1. After the reaction is finished, slowly dropwise adding a saturated ammonium chloride solution for quenching, extracting by EA, washing an organic phase by saturated salt water for 2 times, drying by anhydrous sodium sulfate, and spin-drying. Pulping the solid with methyl tert-butyl ether to obtain white powdery solid: 4.65g, yield: 93 percent. LC-MS (ESI): 419.1[ M + H]+
Preparation of IV-1
IV-1-1-5 (4.65g, 11.09mmol) was dissolved in DCM (100ml), and DMP (5.65g, 13.31mmol) was added under ice-bath and reacted at room temperature for 1 h. TLC, petroleum ether, ethyl acetate 10: 1. After the reaction is finished, adding a saturated sodium thiosulfate solution and a sodium bicarbonate solution into the reaction solution in sequence for quenching, stirring at room temperature for 0.5h, extracting EA, washing an organic phase with saturated salt water for 2 times, drying with anhydrous sodium sulfate, and spin-drying.Column chromatography (petroleum ether: ethyl acetate: 50:1) to obtain yellowish powdery solid: 3.6g, yield: 74 percent. LC-MS (ESI):417.5[ M + H]+
1H NMR(400MHz,CDCl3)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:
Figure BDA0002578699540000231
preparation of IV-1-2-1
Dissolving methyl 2- (6-bromo-2-methoxyquinolin-3-yl) acetate (6g, 19.35mmol), which is obtained by reacting methyl 2- (6-bromo-2-chloroquinolin-3-yl) acetate (synthesized according to the publication Angew. chem. int. Ed.2019,58, 3538-3541) with sodium methoxide, in THF (65ml), under the protection of Ar, slowly adding bis (trimethylsilylamino) lithium (23.3ml, 23.21mmol) dropwise at-78 ℃ for about 1h, reacting at-78 ℃ for about 1h, adding a THF (65ml) solution of 2, 6-dimethoxyisonicotinoyl chloride (4.68g, 23.21mmol), maintaining at-78 ℃ during dropwise addition, naturally raising the temperature after addition, reacting overnight, adding saturated ammonium chloride to the reaction solution, quenching, extracting the aqueous phase with EA, washing with saturated water, drying with anhydrous water, spin-drying, a pale yellow powdery solid, 9.06g, yield: 98.6 percent. . LC-MS (ESI): 475.1[ M + H]+
Preparation of IV-1
IV-1-2-1 (9.06g, 19.062mmol) was dissolved in DMSO/H2O (100ml/5ml), reflux reaction at 155 ℃ for 2 h. TLC, petroleum ether, ethyl acetate 10: 1. And cooling to RT, pouring the reaction solution into ice water, standing overnight to precipitate a solid, filtering, washing a filter cake with water, pulping the filter cake with EA, filtering, and drying the filter cake to obtain the product. Light yellow powdery solid: 5.74g, yield: 71.13 percent. LC-MS (ESI) 417.5[ M + H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000232
Taking IV-1-1-3 as a starting material, and preparing an intermediate IV-2 according to the following reaction flow.
Figure BDA0002578699540000233
Preparation of IV-2-1
IV-1-1-3(19g 66.3mmol) was dissolved in DMF (200mL) at room temperature, and NaCN (3.90g 79.6mmol) was added as a solid to react at room temperature. TLC (PE: EA 20:1) detection reaction, adding water to stop the reaction, extracting with ethyl acetate, stirring the aqueous phase with NaClO, combining the organic phases, drying, filtering and evaporating to dryness. And (5) performing column chromatography. Light yellow solid: 11g, yield 60%. LC-MS (ESI) 277.0[ M + H ]]+
Preparation of IV-2-2
Dissolving IV-2-1(10.5g, 37.9mmol) in ethanol (50mL), adding 10% sodium hydroxide aqueous solution (50mL), controlling the temperature at 100 ℃ for reaction overnight, eliminating TLC raw materials, concentrating to remove ethanol, washing an aqueous phase with dichloromethane, discarding a dichloromethane phase, adjusting the pH of the aqueous phase to 4-5, separating out a solid, extracting with ethyl acetate, combining organic phases, drying and concentrating. Light yellow solid: 7.65g, yield 68.2%. LC-MS (ESI) 296.0[ M + H]+
Preparation of IV-2-3
Dissolving IV-2-2(7.4g and 25mmol) in tetrahydrofuran (70mL), adding borane tetrahydrofuran solution, controlling the temperature to carry out reflux reaction overnight, adding a proper amount of ammonium chloride aqueous solution after TLC reaction is finished, filtering, concentrating, and carrying out column chromatography (petroleum ether: ethyl acetate: 5:1-2:1) to obtain colorless jelly: 5.87g, yield 83.4%. LC-MS (ESI) 282.0[ M + H]+
1H NMR(400MHz,CDCl3)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).
Preparation of IV-2-4
Dissolving IV-2-3(5.64g,20mmol) in dichloromethane (60mL), slowly adding DMP (10.2g, 8.5mmol), reacting at room temperature for 1.5h, detecting the reaction completion by TLC (PE: EA ═ 2:1), adding saturated aqueous sodium bicarbonate solution and aqueous sodium thiosulfate solution, stirring for 30min, separating, extracting the aqueous phase with DCM (60mL), combining the organic phases, drying, filtering, evaporating to dryness, and performing column chromatography (petroleum ether: ethyl acetate ═ 50:1-10:1) to obtain a light yellow solid: 3.4g, yield 60%. LC-MS (ESI) 280.0[ M + H]+
Preparation of IV-2-6
Freshly prepared 1-naphthylmagnesium bromide (IV-2-5) (1mol/L,12mmol) was slowly added dropwise to a solution of compound IV-2-4 (3.08g,11mmol) in THF (30mL) in ice bath, and the system was allowed to warm to room temperature and stirred for 30min after dropping. Adding saturated ammonium chloride solution, adding EA, extracting, separating, drying organic phase, rotary steaming, and pulping with small amount of cold methanol. Column chromatography (petroleum ether: ethyl acetate: 20:1-5:1) gave 1.82g, 41.2% of a white solid. LC-MS (ESI) 408.1[ M + H]+
1H NMR(400MHz,CDCl3)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
At room temperature, compound IV-2-6 (1.63g,4mmol) was dissolved in dichloromethane (20mL), DMP (2.03g,4.8mmol) was added, after stirring at room temperature for two hours, the reaction was checked by spotting, and Na was added sequentially2S2O3Saturated solution, NaHCO3The saturated solution was washed with saturated brine, separated, organic phase dried, and column chromatography (petroleum ether: ethyl acetate: 50:1-10:1) was performed to obtain an off-white solid, 1.42g, 88.6%. LC-MS (ESI) 406.1[ M + H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000251
Intermediate IV-3 was prepared from benzofuran-7 carbonitrile starting material according to the following reaction scheme.
Figure BDA0002578699540000252
Preparation of IV-3-1
Benzofuran-7 carbonitrile (4.3g, 30.04mmol) (synthesized according to J.Med.chem.2016,59,7, 3215-3230) was dissolved in MeOH (30ml), NaOH (2.4g, 60.08mmol, H)2O (1.08g, 60.08mmol), was allowed to react overnight at 80 ℃ C. And (3) detecting complete reaction by TLC (thin layer chromatography), petroleum ether and ethyl acetate at 10: 1. Pouring the reaction solution into water, adding EA into the water phase for separating liquid, adding HCl into the water phase for adjusting the pH value to be about 3, extracting the water phase by using EA, combining organic phases, washing by using saturated salt water, drying by using anhydrous sodium sulfate and spin-drying. Yellow powdery solid: 3.392g, yield: 70 percent. LC-MS (ESI) 163.0[ M + H]+
Preparation of IV-3-2
IV-3-1 (2g, 12.34mmol) was dissolved in SOCl2(35ml) and reacted at 30 ℃ for 3.5 h. Cooled to RT, spin dried with DCM and repeated twice, and the product was used directly in the next step. Yellow powdery solid: 2.31 g.
Preparation of IV-3-3
Methyl 2- (6-bromo-2-methoxyquinolin-3-yl) acetate (3.3g, 10.64mmol, 1eq) was dissolved in THF (50ml) with Ar protection and lithium bis (trimethylsilylamino) was slowly added dropwise (13.0ml, 12.77mmol) at-78 deg.C and reacted for about 1h at-78 deg.C. And (3) dropwise adding a THF (45ml) solution of IV-3-2 (2.30g, 12.77mmol), keeping the temperature at-78 ℃ in the dropwise adding process, naturally heating after the dropwise adding process is finished, and reacting overnight. TLC, petroleum ether, ethyl acetate 10: 1. Adding saturated ammonium chloride into the reaction solution, extracting and sterilizing, and adding waterThe phases are extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate and spin-dried. Column chromatography (petroleum ether: ethyl acetate: 10:1) to obtain a light yellow powdery solid: 2.77g, yield: 57 percent. LC-MS (ESI) 454.0[ M + H]+
Preparation of IV-3
IV-3-3 (2.70g, 5.943mmol) was dissolved in DMSO/H2O (30ml/1.5ml), reflux reaction at 155 ℃ for 2 h. TLC, petroleum ether, ethyl acetate 10: 1. Cooling to RT, pouring the reaction solution into ice water, standing overnight to separate out a solid, filtering, washing a filter cake with water, pulping the filter cake with EA, filtering, and drying the filter cake to obtain a light yellow powdery solid: 1.75g, yield: 74 percent.
LC-MS(ESI):396.0[M+H]+
1H NMR(400MHz,DMSO-d6)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
Figure BDA0002578699540000261
The compound 1 is prepared by using the intermediate IV-1 and 2-cyclopropyl ethyl methanesulfonate as starting materials according to the following reaction scheme
Figure BDA0002578699540000262
Preparation of Compound 1-1
Intermediate IV-1 (834mg,2.00mmol), 2-cyclopropylethyl methanesulfonate (966mg,5.46mmol), K2CO3(829mg,6.00mmol), KI (33mg,0.20mmol) were added to acetone (10mL), Ar gas protected, and reacted at 50 ℃ overnight. And (3) detecting a small amount of residual raw materials by TLC, cooling to room temperature, directly stirring and passing through a column (petroleum ether: ethyl acetate: 40: 1-30: 1) to obtain a light yellow solid: 644mg, yield 66%. LC-MS (ESI) 485.1[ M + H]+
Preparation of Compounds 1-2
Reacting CuBr & Me2S (27mg,0.1mmol) is added into a 25mL three-necked flask, a tetrahydrofuran solution (4mL,3.98mmol) of freshly prepared allyl zinc bromide is added dropwise under the protection of Ar gas, the reaction is carried out at room temperature for about 5min, a THF solution (20mL) of 1-1(644mg,1.33mmol) is added dropwise, and the reaction is continued at room temperature for about 20min after the dropwise addition. TLC (petroleum ether: ethyl acetate 10:1) reaction was complete, the reaction was quenched with saturated aqueous ammonium chloride (10mL), water (15mL) was added, EA (2 × 20mL) was extracted 2 times, the organic phase was washed 1 time with saturated brine (20mL), dried and spun dry before being directly dosed to the next step. LC-MS (ESI) 527.2[ M + H]+
Preparation of Compounds 1-3
1-2(702mg,1.33mmol) was dissolved in THF/H2Adding K into O (20mL/4mL)2OsO4·2H2O (24mg,0.05mmol) and NMO (1.558g,13.30mmol) were reacted at room temperature overnight. TLC (petroleum ether: ethyl acetate 10:1) reaction was complete, the reaction was quenched with saturated aqueous sodium thiosulfate (20mL), water (20mL) was added, EA (2 × 20mL) was extracted 2 times, and the organic phase was washed with saturated brine (20mL) 1 time, dried, and spun dry to the next step. LC-MS (ESI) 561.1[ M + H]+
Preparation of Compounds 1-4
Dissolve 1-3(747mg,1.33mmol) in DCM (20mL) and add silica gel-loaded NaIO4(2.66mmol) and reacted at room temperature for about 1 h. TLC (petroleum ether/ethyl acetate 5/1) showed almost complete reaction, filtered and the filtrate was directly sent to the next step. LC-MS (ESI) 528.1[ M + H]+
Preparation of Compounds 1-5
1-4(704mg,1.33mmol) was dissolved in MeOH (10mL) and NaBH added portionwise in an ice bath4(82mg,2.16mmol) and reacted at room temperature for about 1 h. TLC (petroleum ether/ethyl acetate 5/1) reaction was complete, quenched with water (0.5mL) and then spin-dried over column (petroleum ether: ethyl acetate 15: 1-10:1) to give a yellow foamy solid: 555mg 79% (four-step yield). LC-MS (ESI) 531.1[ M + H]+
Preparation of Compounds 1-6
Dissolve 1-5(555mg,1.04mmol) in DCM (20mL), add TEA (527mg,5.22mmol), and ice-washMsCl (357mg,3.13mmol) was added dropwise thereto, and the reaction was carried out at room temperature for about 1h and by TLC (petroleum ether/ethyl acetate: 5/1). Water (20mL) was added and extracted 2 times with DCM (2X 20mL), the organic phase was dried and spun dry for the next step. LC-MS (ESI) 609.1[ M + H]+
Preparation of Compound 1
1-6(634mg,1.04mmol) was dissolved in dimethylamine THF solution (10mL) and the reaction was blocked at 50 ℃ overnight. Column chromatography was performed directly on the sample (dichloromethane: methanol 300: 1-60: 1) to give 1A (169mg) and 1B (119mg)
1A (169mg by manual HPLC to give 1A-1(70mg) and 1A-2(67mg)
LC-MS(ESI):558.2[M+H]+
1H NMR(400MHz,CDCl3)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)；
Resolution of 1B (119mg) by manual HPLC afforded 1B-1(50mg) and 1B-2(45mg)
LC-MS(ESI):558.2[M+H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000271
The intermediates IV-1 and 2- (1-methylcyclopropyl) ethyl-p-toluenesulfonate were used as starting materials to obtain compounds 2A (104mg) and 2B (85mg) using the same reaction scheme as that for the preparation of compound 1.
2A (104mg) was resolved by manual HPLC to give 2A-1(45mg) and 2A-2(39mg)
LC-MS(ESI):572.2[M+H]+
1H NMR(400MHz,CDCl3)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 (85mg) was resolved by manual HPLC to give 2B-1(36mg) and 2B-2(29mg)
LC-MS(ESI):572.3[M+H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000272
The intermediates IV-1 and 3-cyclopropyl propyl p-methyl benzene sulfonate were used as starting materials to obtain compounds 3A (69mg) and 3B (87mg) using the same reaction scheme as that for the preparation of Compound 1
Resolution of 3A (69mg) by manual HPLC afforded 3A-1(22mg) and 3A-2(20mg)
LC-MS(ESI):572.2[M+H]+
1H NMR(400MHz,CDCl3)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 (87mg) by manual HPLC gave 3B-1(27mg) and 3B-2(32mg)
LC-MS(ESI):572.2[M+H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000281
Using intermediates IV-1 and 2- (2, 2-difluorocyclopropyl) ethylmethanesulfonate as starting materials, the same reaction scheme as that used for the preparation of Compound 1 was used to give Compounds 4A (86mg) and 4B (79mg)
Resolution of 4A (86mg) by manual HPLC afforded 4A-1(31mg) and 4A-2(35mg)
LC-MS(ESI):594.2[M+H]+
1H NMR(400MHz,CDCl3)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).
Resolution of 4B (79mg) by manual HPLC afforded 4B-1(29mg) and 4B-2(30mg)
LC-MS(ESI):594.2[M+H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000282
Using intermediates IV-1 and 3, 3-dimethyl-1-bromobutane as starting materials, the same reaction scheme as that used for the preparation of Compound 1 was used to give Compounds 5A (94mg) and 5B (105mg)
Resolution of 5A (94mg) by manual HPLC afforded 5A-1(40mg) and 5A-2(35mg)
LC-MS(ESI):574.2[M+H]+
1H NMR(400MHz,CDCl3)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 (105mg) by manual HPLC gave 5B-1(44mg) and 5B-2(40mg)
LC-MS(ESI):574.2[M+H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000291
Using intermediate IV-1 and bromomethylcyclobutane as starting materials, the same reaction scheme as that for the preparation of Compound 1 was used to give Compounds 6A (86mg) and 6B (96mg)
Resolution of 6A (86mg) by manual HPLC afforded 6A-1(31mg) and 6A-2(35mg)
LC-MS(ESI):558.2[M+H]+
1H NMR(400MHz,CDCl3)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 (96mg) by manual HPLC afforded 6B-1(41mg) and 6B-2(36mg)
LC-MS(ESI):558.2[M+H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000292
Using intermediate IV-1 and (2-cyclobutyl) ethylmethanesulfonate as starting materials, the same reaction scheme as that for the preparation of Compound 1 was employed to give Compounds 7A (104mg) and 7B (104mg)
Resolution of 7A (104mg) by manual HPLC afforded 7A-1(44mg) and 7A-2(38mg)
LC-MS(ESI):572.2[M+H]+
1H NMR(400MHz,CDCl3)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 (104mg) by manual HPLC gave 7B-1(44mg) and 7B-2(36mg)
LC-MS(ESI):572.2[M+H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000301
Using intermediate IV-1 and 2- (3, 3-difluorocyclobutyl) ethyl methanesulfonate as starting materials, the same reaction scheme as that for the preparation of Compound 1 was employed to give Compounds 8A (121mg) and 8B (142mg)
Resolution of 8A (121mg) by manual HPLC afforded 8A-1(55mg) and 8A-2(49mg)
LC-MS(ESI):608.2[M+H]+
1H NMR(400MHz,CDCl3)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 (142mg) by manual HPLC afforded 8B-1(60mg) and 8B-2(54mg)
LC-MS(ESI):608.2[M+H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000302
Using intermediate IV-1 and cyclopentylmethylsulphonate as starting materials, the same reaction scheme was used as that used to prepare Compound 1 to give Compounds 9A (104mg) and 9B (98mg)
The 9A (104mg) was resolved by manual HPLC to give 9A-1(45mg) and 9A-2(42mg)
LC-MS(ESI):572.2[M+H]+
1H NMR(400MHz,CDCl3)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).
The 9B (98mg) was resolved by manual HPLC to give 9B-1(35mg) and 9B-2(33mg)
LC-MS(ESI):572.2[M+H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000303
Using intermediate IV-1 and (3, 3-difluorocyclopentyl) methyl-4-methylbenzenesulfonate as starting materials, the same reaction scheme as that for the preparation of Compound 1 was employed to give Compounds 10A (72mg) and 10B (86mg)
Resolution of 10A (72mg) by manual HPLC afforded 10A-1(28mg) and 10A-2(30mg)
LC-MS(ESI):608.2[M+H]+
1H NMR(400MHz,CDCl3)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).
Resolution of 10B (86mg) by manual HPLC afforded 10B-1(39mg) and 10B-2(42mg)
LC-MS(ESI):608.2[M+H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000311
Using intermediate IV-1 and (4, 4-dimethylcyclohexyl) methyl-4-methylbenzenesulfonate as starting materials, the same reaction scheme as that for the preparation of Compound 1 was employed to obtain Compounds 11A (72mg) and 11B (96mg)
Resolution of 11A (72mg) by manual HPLC afforded 11A-1(29mg) and 11A-2(27mg)
LC-MS(ESI):614.2[M+H]+
1H NMR(400MHz,CDCl3)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)
Resolution of 11B (96mg) by manual HPLC afforded 11B-1(38mg) and 11B-2(31mg)
LC-MS(ESI):614.2[M+H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000312
Using intermediates IV-1 and 2-cyclohexylethylmethanesulfonate as starting materials, the same reaction scheme as that for the preparation of Compound 1 was employed to give Compounds 12A (98mg) and 12B (116mg)
Resolution of 12A (98mg) by manual HPLC afforded 12A-1(36mg) and 12A-2(38mg)
LC-MS(ESI):600.2[M+H]+
1H NMR(400MHz,CDCl3)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).
Resolution of 12B (116mg) by manual HPLC afforded 12B-1(45mg) and 12B-2(52mg)
LC-MS(ESI):600.2[M+H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000321
Using the intermediates IV-1 and (3, 3-difluorocyclohexyl) methylmethanesulfonate as starting materials, the same reaction scheme as that for the preparation of Compound 1 was used to obtain Compounds 13A (98mg) and 13B (121mg)
Resolution of 13A (98mg) by manual HPLC afforded 13A-1(36mg) and 13A-2(30mg)
LC-MS(ESI):622.2[M+H]+
1H NMR(500MHz,CDCl3)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).
Resolution of 13B (121mg) by manual HPLC afforded 13B-1(50mg) and 13B-2(45mg)
LC-MS(ESI):622.2[M+H]+
1H NMR(500MHz,CDCl3)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
Figure BDA0002578699540000322
Using intermediate IV-1 and (4, 4-difluorocyclohexyl) methylmethanesulfonate as starting materials, the same reaction scheme as that for the preparation of Compound 1 was used to obtain Compounds 14A (56mg) and 14B (85mg)
Resolution of 14A (56mg) by manual HPLC afforded 14A-1(16mg) and 14A-2(18mg)
LC-MS(ESI):622.2[M+H]+
1H NMR(400MHz,CDCl3)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 14B (85mg) by manual HPLC afforded 14B-1(31mg) and 14B-2(29mg)
LC-MS(ESI):622.2[M+H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000331
Using intermediate IV-1 and bicyclo [3.1.0] hex-6-ylmethylmethylsulfonate as starting materials, the same reaction scheme as that for the preparation of Compound 1 was used to give Compounds 15A (92mg) and 15B (126mg)
Resolution of 15A (92mg) by manual HPLC afforded 15A-1(40mg) and 15A-2(36mg)
LC-MS(ESI):584.2[M+H]+
1H NMR(600MHz,CDCl3)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).
Resolution of 15B (126mg) by manual HPLC gave 15B-1(45mg) and 15B-2(39mg)
LC-MS(ESI):584.2[M+H]+
1H NMR(600MHz,CDCl3)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
Figure BDA0002578699540000332
Using intermediates IV-1 and 1-bromobut-2-yne as starting materials, the same reaction scheme as for the preparation of Compound 1 was used to give Compounds 16A (102mg) and 16B (116mg)
Resolution of 16A (102mg) by manual HPLC afforded 16A-1(38mg) and 16A-2(36mg)
LC-MS(ESI):542.2[M+H]+
1H NMR(400MHz,CDCl3)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)；
Resolution of 16B (116mg) by manual HPLC afforded 16B-1(47mg) and 16B-2(45mg)
LC-MS(ESI):542.2[M+H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000333
The intermediates IV-1 and 3-cyclopropylprop-2-yn-1-yl (4-methylbenzenesulfonate) were used as starting materials to give compounds 17A (76mg) and 17B (111mg) using the same reaction scheme as for the preparation of Compound 1
Resolution of 17A (76mg) by manual HPLC afforded 17A-1(28mg) and 17A-2(26mg)
LC-MS(ESI):568.2[M+H]+
1H NMR(600MHz,CDCl3)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).
Resolution of 17B (111mg) by manual HPLC afforded 17B-1(39mg) and 17B-2(38mg)
LC-MS(ESI):568.2[M+H]+
1H NMR(600MHz,CDCl3)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
Figure BDA0002578699540000341
The intermediates IV-1 and 4-fluorobut-2-ynyl-1-yl (4-methylbenzenesulfonate) were used as starting materials to give compounds 18A (54mg) and 18B (67mg) using the same reaction scheme as that for the preparation of compound 1
Resolution of 18A (54mg) by manual HPLC afforded 18A-1(14mg) and 18A-2(11mg)
LC-M S(ESI):560.1[M+H]+
1H NMR(400MHz,CDCl3)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 (67mg) by manual HPLC gave 18B-1(18mg) and 18B-2(16mg)
LC-MS(ESI):560.1[M+H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000342
Using intermediate IV-1 and tetrahydropyran-4-methyl methanesulfonate as starting materials, the same reaction scheme as that for the preparation of Compound 1 was employed to give Compounds 19A (165mg) and 19B (186mg)
Resolution of 19A (165mg) by manual HPLC gave 19A-1(64mg) and 19A-2(58mg)
LC-MS(ESI):588.0[M+H]+
1H NMR(400MHz,CDCl3)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 (186mg) by manual HPLC gave 19B-1(75mg) and 19B-2(72mg)
LC-MS(ESI):588.0[M+H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000351
Using intermediate IV-1 and (tetrahydropyran-3-yl) methyl-4-methylbenzenesulfonate as starting materials, the same reaction scheme as that for the preparation of Compound 1 was employed to give Compounds 20A (92mg) and 20B (132mg)
Resolution of 20A (92mg) by manual HPLC afforded 20A-1(32mg) and 20A-2(28mg)
LC-MS(ESI):588.0[M+H]+
1H NMR(400MHz,CDCl3)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 (132mg) by manual HPLC afforded 20B-1(42mg) and 20B-2(33mg)
LC-MS(ESI):588.0[M+H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000352
Using intermediate IV-1 and tert-butyl-4- (bromomethyl) piperidine-1-carboxylic acid ester as starting materials, the same reaction scheme as that for the preparation of Compound 1 was used to prepare a precursor of-Boc protected Compound 21, which was then deprotected with trifluoroacetic acid to give Compounds 21A (41mg) and 21B (66mg)
Resolution of 21A (41mg) by manual HPLC gave 21A-1(12mg) and 21A-2(9mg)
LC-MS(ESI):587.2[M+H]+
1H NMR(400MHz,CDCl3)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 (66mg) by manual HPLC gave 21B-1(20mg) and 21B-2(23mg)
LC-MS(ESI):587.2[M+H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000361
Using intermediates IV-1 and 2-oxetanylethyl (4-methylbenzenesulfonate) as starting materials, the same reaction scheme as that for the preparation of Compound 1 was employed to give Compounds 22A (165mg) and 22B (168mg)
Resolution of 22A (165mg) by manual HPLC afforded 22A-1(60mg) and 22A-2(45mg)
LC-MS(ESI):574.2[M+H]+
1H NMR(400MHz,CDCl3)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).
Resolution of 22B (168mg) by manual HPLC gave 22B-1(55mg) and 22B-2(48mg)
LC-MS(ESI):574.2[M+H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000362
Using intermediates IV-1 and 1-bromocyclohexane as starting materials, the same reaction scheme as for the preparation of Compound 1 was used to give Compounds 23A (121mg) and 23B (146mg)
Resolution of 23A (121mg) by manual HPLC gave 23A-1(40mg) and 23A-2(38mg)
LC-MS(ESI):572.2[M+H]+
1H NMR(600MHz,CDCl3)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 (146mg) by manual HPLC gave 23B-1(37mg) and 23B-2(29mg)
LC-MS(ESI):572.2[M+H]+
1H NMR(600MHz,CDCl3)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
Figure BDA0002578699540000371
Using intermediates IV-1 and 4-bromotetrahydro-2H pyran as starting materials, the same reaction scheme as that used for the preparation of Compound 1 was employed to give Compounds 24A (35mg) and 24B (42mg)
Resolution of 24A (35mg) by manual HPLC afforded 24A-1(8mg) and 24A-2(9mg)
LC-MS(ESI):574.0[M+H]+
1H NMR(400MHz,CDCl3)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 (42mg) by manual HPLC gave 24B-1(11mg) and 24B-2(8mg)
LC-MS(ESI):574.0[M+H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000372
Using intermediates IV-1 and 1- (2-bromoethyl) cyclopropane-1-ol as starting materials, the same reaction scheme as that used to prepare Compound 1 was used to obtain Compounds 25A (58mg) and 25B (63mg)
Resolution of 25A (58mg) by manual HPLC afforded 25A-1(13mg) and 25A-2(15mg)
LC-MS(ESI):574.2[M+H]+
1H NMR(400MHz,CDCl3)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 (63mg) by manual HPLC gave 25B-1(21mg) and 25B-2(22mg)
LC-MS(ESI):574.2[M+H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000373
Figure BDA0002578699540000381
Using intermediate IV-1 and bromomethylcyclohexane as starting materials, the same reaction scheme as that used to prepare Compound 1 was used to give Compounds 26A (220mg) and 26B (176mg)
Chiral HPLC resolution of 26A (220mg) gave 26A-1(83mg) and 26A-2(104mg)
LC-MS(ESI):586.2[M+H]+
1H NMR(400MHz,CDCl3)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 HPLC resolution of 26B (176mg) gave 26B-1(70mg) and 26B-2(80mg)
LC-MS(ESI):586.2[M+H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000382
Compound 26-4(396mg, 0.714mmol) was dissolved in 1, 2-dichloroethane (20ml), methylamine hydrochloride (54mg, 0.786mmol), TEA (360mg, 3.57mmol), AcOH (129mg, 2.142mmol) were added and the reaction stirred, sodium triacetoxyborohydride (756mg, 3.57mmol) was added and the reaction was allowed to proceed overnight at room temperature with TLC monitoring. Water (30ml) was added to the reaction mixture, extraction was carried out with DCM (30 ml. times.2), washing with saturated brine, drying over anhydrous sodium sulfate, filtration and spin-drying for column chromatography to give 27A (55mg) and 27B (60mg)
The 27A (55mg) was resolved by hand to give 27A-1(20mg) and 27A-2(22mg)
LC-MS(ESI):572.2[M+H]+
1H NMR(600MHz,CDCl3)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 (60mg) by manual resolution to give 27B-1(18mg) and 27B-2(24mg)
LC-MS(ESI):572.2[M+H]+
1H NMR(600MHz,CDCl3)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
Figure BDA0002578699540000391
Using Compound 26 and Zn (CN)2Compound 28 was prepared as the starting material according to the following reaction scheme.
Figure BDA0002578699540000392
Preparation of Compound 28
Compound 26(170mg,0.29mmol) is dissolved in DMF (25mL) and stirred, Zn (CN) is added2(24mg, 0.20mmol) and Pd (PPh)3)4(40mg, 0.036mmol), reaction at 90 deg.C overnight, TLC detection of complete reaction, extraction with EA by water for 2 times, drying of organic phase, TLC preparative separation to give 28A (62mg) and 28B (68mg)
The 28A (62mg) was resolved by hand to give 28A-1(23mg) and 28A-2(19mg)
LC-MS(ESI):533.3[M+H]+
1H NMR(400MHz,CDCl3)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).
The 28B (68mg) was resolved by hand to give 28B-1(25mg) and 28B-2(20mg)
LC-MS(ESI):533.3[M+H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000393
Compound 29 was prepared according to the following reaction scheme
Figure BDA0002578699540000394
Preparation of Compound 29-2
Compound 29-1(7.7g,26.18mmol), prepared as described in the European Journal of Organic Chemistry,2011,11, 2057-containing 2061, was dissolved in DCM/MeOH (200mL 10:1) at room temperature and m-CPBA (8g,130.8mmol 85%) was added slowly and reacted overnight. TLC detection (PE: EA: 2: 1). NaHCO3 was added to stop the reaction, EA was extracted twice, the EA phases were combined, dried, rotary evaporated and concentrated. The solid obtained is washed with DCM/PE to give 8.2g of an off-white solid. LC-MS (ESI) 310.0[ M + H ] +
Preparation of Compound 29-3
CuCN (2.974g,33.05mmol) was placed in a 100mL three-necked flask, and a tetrahydrofuran solution of cyclopropylmagnesium bromide (66.1mL,66.10mmol) was added dropwise under Ar gas, and after dropwise addition, the reaction was carried out at room temperature for about 1 hour, and after dropwise addition of a solution of compound 29-2(2.05g,6.61mmol) in THF (dry,20mL), the reaction was continued at room temperature for about 1 hour. The reaction was quenched with saturated aqueous ammonium chloride, dried, filtered and the filtrate was spin-dried 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(648mg,1.84mmol) was dissolved in DCM (15mL), silica gel loaded NaIO4(3.935g,3.68mmol) was added and the reaction was allowed to proceed to completion at rt and TLC (petroleum ether/ethyl acetate 2/1) 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(477mg,1.49mmol) in THF (dry,5mL) was added dropwise to a fresh solution of naphthalen-1-ylmagnesium bromide (4.47mmol) in tetrahydrofuran under ice-bath, the reaction was allowed to proceed for 15min at room temperature for about 1.5h, TLC detected for substantial completion, quenched with saturated aqueous ammonium chloride, dried, filtered under vacuum, and the filtrate was passed through a 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(510mg,1.14mmol) was dissolved in DCM (10mL), DMP (726mg,1.71mmol) was added and reacted for about 1h at rt, TLC checked for completion and directly washed on column (petroleum ether: ethyl acetate ═ 20:1) to give 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 procedures as for Compound 1. To give compounds 29A (56mg) and 29B (64mg)
The manual resolution of 29A (56mg) gave 29A-1(19mg) and 29A-2(23mg)
LC-MS(ESI):519.2[M+H]+
1H NMR(400MHz,CDCl3)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).
The manual resolution of 29B (64mg) gave 29B-1(22mg) and 29B-2(18mg)
LC-MS(ESI):519.2[M+H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000411
The intermediate IV-2 and cyclopropylmethyl bromide were used as starting materials and prepared in the same manner as in Compound 1 to give compounds 30A (50mg) and 30B (60mg)
The 30A (50mg) was resolved manually to give 30A-1(20mg) and 30A-2(18mg)
LC-MS(ESI):533.2[M+H]+
1H NMR(400MHz,CDCl3)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)；
The 30B (60mg) was resolved by hand to give 30B-1(20mg) and 30B-2(24mg)
LC-MS(ESI):533.2[M+H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000412
Using the intermediate IV-2 and cyclopropylethyl (4-methylbenzenesulfonate) as starting materials, preparation was carried out in the same manner as in Compound 1 to give compounds 31A (57mg) and 31B (66mg)
31A (57mg) was resolved by hand to give 31A-1(17mg) and 31A-2(24mg)
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).
The 31B (66mg) was resolved by hand to give 31B-1(25mg) and 31B-2(20mg)
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
Figure BDA0002578699540000413
Figure BDA0002578699540000421
Compound 31 and zinc cyanide were used as starting materials, and they were prepared in the same manner as compound 28 to give compounds 32A (52mg) and 32B (68mg).
The 32A (52mg) was resolved by hand to give 32A-1(11mg) and 32A-2(13mg)
LC-MS(ESI):494.6[M+H]+
1H NMR(400MHz,CDCl3)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).
The 32B (68mg) was resolved by hand to give 32B-1(16mg) and 32B-2(25mg)
LC-MS(ESI):494.6[M+H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000422
Compound 33 is prepared by using compound 33-1 as a starting material and adopting the following reaction scheme
Figure BDA0002578699540000423
Preparation of Compound 33-2
Compound 33-1(2.9g, 7.7mmol) (prepared from 6-bromo-2-methoxy-4-methylquinolin-3-yl) methanol according to the literature Bioorganic and Medicinal Chemistry,2001, 2727-2743) and SO2Cl2Obtained by reaction) was dissolved in DMF (40ml) and stirred, sodium cyanide (377mg, 7.7mmol) was added, the reaction was stirred at room temperature, detection by TLC was incomplete, liquid was separated by adding water (200ml) and ethyl acetate (100ml), washing with water (100ml × 3 times), drying, concentration, and column chromatography was directly concentrated (DCM: petroleum ether ═ 1:1) to obtain 1.03g of a white solid with a yield of 46%. LC-MS (ESI) 291.0[ M + H]+
Preparation of Compound 33-3
Compound 33-2(1.03g, 3.54mmol), 1-naphthalene boronic acid (1.170g, 6.8mmol), {1, 2-bis (diphenylphosphino) ethane } nickel dichloride (180mg,0.34mmol), zinc chloride (927mg,6.8mmol), and water (122mg, 6.8mmol) were dissolved in 1, 4-dioxane (30ml) and stirred under argon protection, heated to 110 ℃ and stirred overnight, the reaction was detected by TLC, and column chromatography was directly concentrated (petroleum ether: DCM ═ 1:1) to give 729mg of a white solid with a yield of 49%. 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 compound 33A (48mg) and 33B (59mg).
The 33A (48mg) was resolved by hand to give 33A-1(15mg) and 33A-2(11mg)
LC-MS(ESI):561.6[M+H]+
1H NMR(400MHz,CDCl3)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).
The manual resolution of 33B (59mg) yielded 33B-1(21mg) and 33B-2(14mg)
LC-MS(ESI):561.6[M+H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000431
Using the intermediate IV-2 and cyclobutylmethanesulfonate as starting materials, the same procedures as those for Compound 1 were carried out to give Compounds 34A (60mg) and 34B (71mg)
The 34A (60mg) was resolved by hand to give 34A-1(18mg) and 34A-2(17mg)
LC-MS(ESI):547.2[M+H]+
1H NMR(400MHz,CDCl3)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).
The manual resolution of 34B (71mg) gave 34B-1(20mg) and 34B-2(35mg)
LC-MS(ESI):547.2[M+H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000441
Using the intermediates IV-2 and 3-chloropropyne as starting materials, preparation was carried out in the same manner as for the compound 1 to give compounds 35A (47mg) and 35B (55mg)
The 35A (47mg) was resolved by hand to give 35A-1(14mg) and 35A-2(11mg)
LC-MS(ESI):517.2[M+H]+
1H 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).
The 35B (55mg) was resolved by hand to give 35B-1(16mg) and 35B-2(18mg)
LC-MS(ESI):517.2[M+H]+
1H 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
Figure BDA0002578699540000442
Using the intermediates IV-2 and 3-cyclopropylprop-2-yn-1-yl (4-methylbenzenesulfonate) as starting materials, preparation was carried out in the same manner as for Compound 1 to give Compounds 36A (53mg) and 36B (67mg).
The 36A (53mg) was resolved by hand to give 36A-1(10mg) and 36A-2(15mg)
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)；
36B (67mg) was resolved by hand to give 36B-1(20mg) and 36B-2(14mg)
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
Figure BDA0002578699540000443
Prepared according to the procedure for compound 29, starting with intermediates 29-2 and 3, 3-dimethyl-but-1-yne, to give 37A (70mg) and 37B (77mg)
The 37A (70mg) was resolved by hand to give 37A-1(33mg) and 37A-2(23mg)
LC-MS(ESI):559.2[M+H]+
1H NMR(400MHz,CD3OD)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).
The 37B (77mg) was resolved by hand to give 37B-1(30mg) and 37B-2(34mg)
LC-MS(ESI):559.2[M+H]+
1H NMR(400MHz,CD3OD)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
Figure BDA0002578699540000451
Using the intermediates IV-2 and 4, 4-dimethylpent-2-en-1-yl (4-methylbenzenesulfonate) as starting materials, preparation was carried out in the same manner as for Compound 1 to give Compounds 38A (51mg) and 38B (66mg).
38A (51mg) was resolved by hand to give 38A-1(8mg) and 38A-2(15mg)
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)；
38B (66mg) was resolved by hand to give 38B-1(12mg) and 38B-2(18mg)
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
Figure BDA0002578699540000452
Using the intermediates IV-2 and but-2-yn-1-ylmethanesulfonate as starting materials, the same procedure as for Compound 1 was carried out to give Compounds 39A (100mg) and 39B (120mg)
The 39A (100mg) was resolved by hand to give 39A-1(45mg) and 39A-2(42mg)
LC-MS(ESI):531.2[M+H]+
1H NMR(400MHz,CD3OD)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).
The 39B (120mg) was resolved by hand to give 39B-1(45mg) and 39B-2(50mg)
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
Figure BDA0002578699540000461
Compound 40 starting with methyl 2- (6-bromo-2-methoxyquinolin-3-yl) acetate and quinoline-5-carbonyl chloride, compounds 40-1 and 40-2 are prepared according to IV-1, reaction scheme 2
Figure BDA0002578699540000462
Then, 40-2 and but-2-yn-1-ylmethanesulfonate were used as starting materials and prepared according to the method for Compound 1, yielding 40A (50mg) and 40B (62 mg).
The 40A (50mg) was resolved by hand to give 40A-1(19mg) and 40A-2(21mg)
LC-MS(ESI):532.2[M+H]+
1H NMR(400MHz,CDCl3)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).
The 40B (62mg) was resolved by hand to give 40B-1(24mg) and 40B-2(29mg)
LC-MS(ESI):532.2[M+H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000463
Using the intermediates IV-3 and 1-bromo-2-butyne as starting materials, the same reaction scheme as for the preparation of Compound 1 was used to give Compounds 41A (73mg) and 41B (70mg)
The 41A (73mg) was resolved by chiral HPLC to give 41A-1(30mg) and 41A-2(25mg)
LC-MS(ESI):521.1[M+H]+
1H NMR(400MHz,CDCl3)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).
The 41B (70mg) was resolved by chiral HPLC to give 41B-1(26mg) and 41B-2(21mg)
LC-MS(ESI):521.1[M+H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000471
Using intermediates IV-2 and 2-cyclopropylethylmethanesulfonate as starting materials, the same reaction scheme as that used for the preparation of Compound 1 was used to give Compounds 42A (83mg) and 42B (87mg)
Resolution of 42A (83mg) by chiral HPLC gave 42A-1(32mg) and 42A-2(31mg)
LC-MS(ESI):537.2[M+H]+
1H NMR(400MHz,CDCl3)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).
Resolution of 42B (87mg) by chiral HPLC gave 42B-1(35mg) and 42B-2(29mg)
LC-MS(ESI):537.2[M+H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000472
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.
Figure BDA0002578699540000481
Compounds 43-1 and 43-2 were prepared according to the procedure of reaction scheme 2, IV-1, 43-3 through 43-6 were prepared according to the procedure for Compound 1, and Compound 43 was prepared according to the procedure for Compound 27 to give pale yellow solids 43A (63mg) and 43B (77mg)
The chiral HPLC resolution of 43A (63mg) gave 43A-1(22mg) and 43A-2(21mg)
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).
The 43B (77mg) was resolved by chiral HPLC to give 43B-1(25mg) and 43B-2(26mg)
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
Figure BDA0002578699540000482
44-2 was prepared according to the procedure of IV-1, starting from methyl 2- (6-bromo-2-methoxyquinolin-3-yl) acetate and 2, 6-diethoxy-4 picolinoyl chloride according to scheme 2.
Figure BDA0002578699540000483
Compound 44 Using intermediate 44-2 and bromomethylcyclohexane as starting materials, the same reaction scheme as that used to prepare Compound 1 was used to give Compounds 44A (83mg) and 44B (77mg)
Chiral HPLC resolution of 44A (83mg) gave 44A-1(32mg) and 44A-2(31mg)
LC-MS(ESI):613.2[M+H]+
1H NMR(400MHz,CDCl3)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).
Chiral HPLC resolution of 44B (77mg) gave 44B-1(38mg) and 44B-2(28mg)
LC-MS(ESI):613.2[M+H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000491
Starting with IV-1-1-3, 45-2 was prepared according to the procedure of reaction scheme 1 of IV-1.
Figure BDA0002578699540000492
The same reaction procedure as for the preparation of Compound 1 was used to obtain Compounds 45A (80mg) and 45B (75mg) using intermediate 45-2 and bromomethylcyclohexane as starting materials
Resolution of 45A (80mg) by chiral HPLC gave 45A-1(32mg) and 45A-2(34mg)
LC-MS(ESI):586.2[M+H]+
1H NMR(400MHz,CDCl3)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).
The chiral HPLC resolution of 45B (75mg) gave 45B-1(23mg) and 45B-2(24mg)
LC-MS(ESI):586.2[M+H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000493
Starting with IV-1-1-3, 46-2 was prepared according to the procedure of reaction scheme 1 of IV-1.
Figure BDA0002578699540000501
The intermediate 46-2 and bromomethylcyclohexane were used as starting materials, and the same reaction procedure as that for the preparation of Compound 1 was employed, to give Compounds 46A (85mg) and 46B (97mg)
Resolution of 46A (85mg) by chiral HPLC gave 46A-1(37mg) and 46A-2(38mg)
LC-MS(ESI):545.2[M+H]+
1H NMR(400MHz,CDCl3)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).
Resolution of 46B (97mg) by chiral HPLC gave 46B-1(34mg) and 46B-2(32mg)
LC-MS(ESI):545.2[M+H]+
1H 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
Figure BDA0002578699540000502
47-2 was prepared according to the procedure of IV-1, starting with methyl 2- (6-bromo-2-methoxyquinolin-3-yl) acetate and 2-chloro-6-methoxy-4-pyridinecarbonyl chloride.
Figure BDA0002578699540000503
Using intermediate 47-2 and bromomethylcyclohexane as starting materials, the same reaction scheme as that used to prepare compound 1 was used to give compounds 47A (75mg) and 47B (87 mg).
Resolution of 47A (75mg) by chiral HPLC gave 47A-1(27mg) and 47A-2(33mg)
LC-MS(ESI):590.2[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 47B (87mg) by chiral HPLC gave 47B-1(29mg) and 47B-2(33mg)
LC-MS(ESI):590.2[M+H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000511
IV-1-1-3 and 1-methyl-2-oxo-4-aldehyde-1, 2-dihydropyridine are used as initial raw materials, and the following reaction process is adopted to prepare a compound 48
Figure BDA0002578699540000512
Preparation of Compound 48-1
1-methyl-2-oxo-4-aldehyde-1, 2-dihydropyridine (1g,7.30mmol) and propanedithiol (869mg,8.03mmol) were dissolved in 30mL of dichloromethane, boron trifluoride ether (2.07g,14.60mmol) was added slowly under ice-bath, and the mixture was allowed to warm to room temperature for 18 h. The reaction was complete by TLC and LC-MS. Adding saturated sodium bicarbonate/dichloromethane for extraction, washing with 1M sodium hydroxide aqueous solution once, washing with water once again, washing the organic phase with saturated salt water, drying with anhydrous sodium sulfate, and spin-drying to obtain light yellow solid: 1.25g, yield: 75 percent. LC-MS (ESI) 228.1[ M + H]+
Preparation of Compound 48-2
48-1(1.25g,5.50mmol) is dissolved in tetrahydrofuran (40mL), Ar is replaced and protected, the temperature is cooled to-78 ℃, LDA (2M,8.25mmol) is slowly added dropwise, the temperature is kept for 1 hour at-78 ℃, then a THF (5mL) solution of IV-1-1-3 is added, and the temperature is raised to room temperature for reaction for 16 hours. The reaction was complete by TLC and LC-MS. Adding saturated NH into the reaction solution4Quenched with Cl, extracted with 50ml × 3 DCM, washed the organic phase with saturated brine, dried over anhydrous sodium sulfate, spun dried, and chromatographed to give a white solid 1.45g, yield: 55 percent of。LC-MS(ESI):478.1[M+H]+
Preparation of Compound 48-3
Dissolve 48-2(1.45g,3.04mmol) in CH3CN/H2O (60mL/20mL), NCS (2.03g,15.19mmol) and AgNO were added3(2.58g,15.19mmol), reaction at room temperature for 10min, TLC and LC-MS to detect completion. The reaction solution was quenched with saturated sodium thiosulfate, and the aqueous phase was extracted with 50ml × 3 DCM, washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and column chromatographed to give 320mg of a yellow solid, yield: 27 percent. LC-MS (ESI) 387.1[ M + H]+
Compounds 48-4 to 48-9 and preparation of Compound 48 the procedure for preparation of Compound 1 was followed to give 48A (65mg) and 48B (73mg) as yellow solids.
Resolution of 48A (65mg) by chiral HPLC gave 48A-1(25mg) and 48A-2(23mg)
LC-MS(ESI):556.2[M+H]+
1H NMR(400MHz,CDCl3)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).
Resolution of 48B (73mg) by chiral HPLC gave 48B-1(30mg) and 48B-2(31mg)
LC-MS(ESI):556.2[M+H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000521
IV-1-1-3 and imidazo [1,2-a ] pyridine-6-carbaldehyde were used as starting materials to give compounds 49A (95mg) and 49B (93mg) by the same reaction scheme as that for the preparation of Compound 48
Resolution of 49A (95mg) by chiral HPLC gave 49A-1(40mg) and 49A-2(35mg)
LC-MS(ESI):565.2[M+H]+
1H NMR(400MHz,CDCl3)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 (93mg) by chiral HPLC gave 49B-1(34mg) and 49B-2(31mg)
LC-MS(ESI):565.2[M+H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000522
Using IV-1-1-3 and imidazo [1,2-a ] pyridine-7-carbaldehyde as starting materials, the same reaction scheme was used as that used to prepare Compound 48, giving Compounds 50A (115mg) and 50B (125mg)
Resolution of 50A (115mg) by chiral HPLC gave 50A-1(48mg) and 50A-2(53mg)
LC-MS(ESI):565.2[M+H]+
1H NMR(400MHz,CDCl3)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 (125mg) by chiral HPLC gave 50B-1(47mg) and 50B-2(54mg)
LC-MS(ESI):565.2[M+H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000531
Using IV-1-1-3 and quinoline-4-carbaldehyde as starting materials, the same reaction scheme as that used to prepare Compound 48 was used to give Compounds 51A (78mg) and 51B (88mg)
Chiral HPLC resolution of 51A (78mg) gave 51A-1(28mg) and 51A-2(32mg)
LC-MS(ESI):576.2[M+H]+
1H NMR(400MHz,CDCl3)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 (88mg) by chiral HPLC gave 51B-1(30mg) and 51B-2(33mg)
LC-MS(ESI):576.2[M+H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000532
Using IV-1-1-3 and 2-methoxyquinoline-4-carbaldehyde as starting materials, the same reaction scheme as that used to prepare Compound 48 was used to obtain Compounds 52A (80mg) and 52B (105mg)
Resolution of 52A (80mg) by chiral HPLC gave 52A-1(32mg) and 52A-2(31mg)
LC-MS(ESI):606.2[M+H]+
1H NMR(400MHz,CDCl3)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 (105mg) by chiral HPLC gave 52B-1(35mg) and 52B-2(38mg)
LC-MS(ESI):606.2[M+H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000541
Using IV-1-1-3 and 6-methoxypyridazin-4-carbaldehyde (synthesized in the same manner as in WO 2014/58747) as starting materials, the same reaction scheme as that for preparing compound 48 was employed to obtain compounds 53A (90mg) and 53B (115mg)
Chiral HPLC resolution of 53A (90mg) gave 53A-1(36mg) and 53A-2(32mg)
LC-MS(ESI):557.2[M+H]+
1H NMR(400MHz,CDCl3)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).
Chiral HPLC resolution of 53B (115mg) gave 53B-1(46mg) and 53B-2(43mg)
LC-MS(ESI):557.2[M+H]+
1H NMR(400MHz,CDCl3)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
Figure BDA0002578699540000542
Starting materials were slightly different (bromine substitution changed to chlorine substitution), and 54A (100mg) and 54B (132mg) were followed using the same reaction scheme as that for the preparation of Compound 1
54A (100mg by manual HPLC to give 54A-1(30mg) and 54A-2(35mg)
LC-MS(ESI):514.2[M+H]+
1H NMR(400MHz,CDCl3)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 (132mg) by manual HPLC gave 54B-1(51mg) and 54B-2(43mg)
LC-MS(ESI):514.2[M+H]+
1H NMR(400MHz,CDCl3)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 test of partial compounds on mycobacterium tuberculosis H37Rv strain
Transferring the tested strain H37Rv into liquid culture medium, culturing at 37 deg.C for 2 weeks, sucking a little culture solution, placing in 4mL liquid culture medium,adding 10-20 sterile glass beads with the diameter of 2-3 mm, oscillating for 20-30S, standing for l 0-20 min, sucking the supernatant of the bacterial suspension, adjusting the turbidity to 1 McLeod unit by using a liquid culture medium, which is equivalent to 1 multiplied by 107CFU/mL is ready for use. Each drug was dissolved in an appropriate amount of DMSO to 1mg/mL and filtered through a 0.22 μm filter. Then diluted with liquid medium to the desired experimental concentration. 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, for a total of 11 concentration gradients. Adding 100 μ L of the above medicinal solution into 96-well microporous plate, adding 100 μ L of 1mg/mL bacterial solution to reach set final concentration, and culturing at 37 deg.C. Three groups of parallel controls were set for the same drug dilution, with the control group containing no drug and the inoculum size set at 100%, 10% and 1%, respectively. After 14 days of incubation at 37 ℃, each colony was observed and the lowest concentration of the colony-free drug group was used as the MIC value of the test compound against the strain. The Minimum Inhibitory Concentration (MIC) of each compound against M.tuberculosis was observed and compared to the MIC results for the control drug Bedaquine (Bedaquinine). The results are shown in Table 1.
TABLE 1 in vitro Activity of Mycobacterium tuberculosis type H37 Rv-Minimum Inhibitory Concentration (MIC)
Figure BDA0002578699540000551
Figure BDA0002578699540000561
As can be seen from Table 1, the in vitro MICs of some of the compounds of the present invention showed significantly better in vitro activity than the control drug Bedaquin. For example, the in vitro activity (MIC) of the compound 1A-1, the compound 4A-1 and the compound 26A-1 is 0.0078 mu g/mL, and the antibacterial activity is 16 times of the in vitro drug effect of a control drug Bedaquin; the in vitro activity (MIC) of the compound 10A-1 and the compound 52A-1 is 0.0156 mu g/mL, and the antibacterial activity of the compounds is 8 times of the in vitro drug effect of a control drug Bedaquin.
The results show that A-1 is most active in all four isomers of the compound, and the other isomers are very weak or completely inactive. Thus only the steric configuration of isomer A-1 and the binding of the target are suitable.
Example 56: in vitro efficacy experiment of part of compounds on drug-resistant mycobacterium tuberculosis strains
Clinical isolates of tested strains (1146-14: streptomycin resistance; 4061-15: isoniazid resistance; 3997-7: rifampicin resistance; B2, MDR-TB; B6, B29 and B53, XDR-TB) mycobacterium tuberculosis are obtained from the pulmonaceae hospital of Shanghai city by the following steps: a. collecting sputum samples of inpatients of tuberculosis in pulmonary hospitals in Shanghai city, treating with alkali, inoculating to improved Roche medium, and culturing for 2 weeks; b. the absolute concentration method is used for measuring drug sensitivity: fresh culture was scraped from the culture medium slant, suspended by grinding with physiological saline to 1 McLeod cell (1mg/mL), diluted to 10-2mg/mL, and 0.1mL was inoculated onto a drug-sensitive medium and observed after four weeks. Reference material: laboratory test protocol for tuberculosis diagnosis, authored by the basic professional committee of the national Antiphthisis Association, the publishing company of Chinese education culture, 2006, 1 month) into a liquid culture medium, culturing at 37 ℃ for 2 weeks, sucking a small amount of culture medium liquid, placing the culture liquid into 4mL of the liquid culture medium, adding 10-20 particles of sterile glass beads with the diameter of 2-3 mm, oscillating for 20-30 seconds, standing for l 0-20 min, sucking supernatant of the bacterial suspension, adjusting the turbidity ratio to 1 McLee unit by using the liquid culture medium, which is equivalent to 1 × 107CFU/mL is ready for use. Each drug was dissolved in an appropriate amount of DMSO to 1mg/mL and filtered through a 0.22 μm filter. Then diluted with liquid medium to the desired experimental concentration. 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, and in 11 concentration gradient tests, 100. mu.L of each of the above-mentioned drug solutions was added to a 96-well microplate, and 100. mu.L of a 1 mg/mL-concentration bacterial solution was added to bring the drug concentration to the set final concentration, and the culture was carried out at 37 ℃. Three groups of parallel controls were set for the same drug dilution, with the control group containing no drug and the inoculum size set at 100%, 10% and 1%, respectively. Observe each drug for tuberculosis of mycobacteriumAnd the MIC results of bedaquin were compared with the MIC results of bedaquin. The results are shown in Table 2.
TABLE 2 in vitro Activity against drug-resistant Mycobacterium tuberculosis-Minimal Inhibitory Concentration (MIC)
Figure BDA0002578699540000571
S is streptomycin, H is isoniazid, R is rifampicin B2, MDR-TB, B53, B29, B6 is XDR-TB.
As can be seen from Table 2, the inventive compound 26A-1 and the control compound Bedaquine (Bedaquinine) showed excellent in vitro antibacterial activity against streptomycin-resistant strains, isoniazid-resistant strains, rifampicin-resistant strains, B2 multi-resistant strains, and B53, B29, B6 wide-range resistant strains, and the in vitro antibacterial activity was comparable to that of the anti-susceptible strains, and the in vitro activity of the inventive compound was also shown to be superior to that of the control Bedaquine. This indicates that the compounds of the present invention, like bedaquiline, can be used for the treatment of diseases caused by drug-resistant tubercle bacillus, especially multi-drug resistant and extensively drug resistant tubercle bacillus.
Example 57: in vivo pharmacokinetic experiments and tissue profiles (Kp) of partial Compounds
Test compounds were formulated as a homogeneous suspension at a final concentration of 2mg/mL using 0.5% CMC-Na in water for oral administration. Orally administered by intragastric administration, the single administration dosage is 20mg/kg, and the administration volume is 10mL/kg., and 0.15mL of blood sample is taken after 15min, 30min, 1h, 2h, 4h, 6h, 10h, 12h and 24h of administration through retrobulbar venous plexus of mice.
Preparing a test article with a final concentration of 0.5mg/mL for intravenous administration, wherein the test article preparation solvent is 5% DMSO + 20% EA + 50% PEG400+ 25% Saline (normal Saline) water solution, and the single administration dose is 2 mg/kg.: blood samples were collected 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 24h after administration.
Selecting CD-1 mice, male, the week age at the beginning of administration is 6-8 weeks, the body weight at the beginning of administration is 20-30g, and the number of marking pen is numbered. Animal weights were measured prior to dosing, and healthy animals of similar weights were selected for inclusion in the experiment without random grouping, with all animals drinking water freely during the experiment.
The plasma is collected and placed in a marked centrifugal tube, the plasma is rapidly separated at 3500 rpm/min, 10min and 4 ℃, and then the plasma is stored below-40 ℃ to be tested. The drug concentration in plasma was measured by LC-MS/MS method and the pharmacokinetic parameters were calculated.
Dissecting after blood sampling 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, and placing the samples in a marked small self-sealing bag to be stored below-40 ℃ for detection. The drug concentration in the tissue is determined by LC-MS/MS method, and the plasma concentration corresponding to the corresponding time point is divided to obtain the Kp value of the tissue distribution.
TABLE 3 results of pharmacokinetic experiments in CD-1 mice
Figure BDA0002578699540000572
TABLE 4 tissue distribution in CD-1 mice
Figure BDA0002578699540000581
As can be seen in Table 3, compound 26A-1 of the present invention exhibited a C comparable to that of the control drug, bedaquiline, after a single oral administrationmaxAnd 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 2 hours and 12 hours, relative to bedaquiline, which means that the partial compounds of the present invention have a greater drug concentration in the lung at the same administered dose; meanwhile, Kp (brain) is lower than that of bedaquiline, and the compound of the invention is probably lower in neurotoxicity. In addition, the in vitro activity of part of the compounds of the invention is obviously higher than that of a contrast medicament, namely the bedaquiline; thus, it is reasonable to assume that some of the compounds of the invention will exhibit greater potency than bedaquiline at the same dose administeredHas in vivo medicinal effect.
Example 58 mouse model of acute infection partial Compounds tested for in vivo efficacy
BALB/c mice, females, weighing approximately 20 grams, were infected with Mycobacterium tuberculosis H37Rv (ATCC strain 27274) by aerosol route using an inhalation exposure system at a dose of approximately 5000 CFU. 5 untreated mice were euthanized on the day of treatment to determine the infection dose. The drugs to be tested were formulated as suspensions using 0.5% w/v carboxymethylcellulose (CMC). Stored at 4 ℃ before use. Control mice were treated with 0.5% CMC only.
Mice were grouped and weighed, 5 mice per group, and gavage was started five days per week, once per day for four weeks. After a 3 day washout period following the last dose, the experimental mice were euthanized, the two lungs were aseptically removed and ground and homogenized in 3mL Hank's Balanced Salt Solution (HBSS). The HBSS solution was ten-fold diluted and cultured on Middlebrook 7H11 agar plates for three weeks, and colony forming units were counted. Results are expressed as mean LogCFU values for each group of mice.
TABLE 5 in vivo efficacy test in H37Rv acutely infected BALB/c female mice
Figure BDA0002578699540000582
a 5 non-dosed mice were euthanized at day 24 post-infection due to a fulminant infection;
b, counting the dosage of the bedaquiline according to free base;
c2 of 5 mice showed negativity;
d 3 of 5 mice showed negativity;
for H37Rv acutely infected BALB/c female mice, none of the mice in both dosing groups of bedaquiline and compound 26A-1 died after dosing was completed. As can be seen from Table 5, the CFU counts in the lungs at the end of the administration of the high dose group of bedaquiline and compound 26A-1 were all 0, indicating complete killing of the tubercle bacillus. The middle dose group obviously reduces the CFU number of the lung, and the detection of the number of the tubercle bacillus in some mice is negative. Although lung CFU was increased in the low dose group (compared to day 0), none of the mice died, indicating that the drug had a good protective effect on the mice.
The data show that the compound has more excellent in-vivo bactericidal activity compared with the bedaquiline, and equivalent or better curative effect can be achieved by using half of the bedaquiline. The compound of the invention can play a better treatment effect at a lower dosage of the compound, and can reduce the side effect of the medicine while reducing the dosage.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (13)

1. A compound of formula (I), or each optical isomer, or a pharmaceutically acceptable salt thereof:
Figure FDA0002578699530000011
wherein m represents an integer of 0 to 3;
R1represents the following groups:
a) hydrogen or C1-8Alkyl, unsubstituted or substituted with one to three groups independently selected from the group consisting of: halogen, hydroxy, cyano, C1-4Alkyl radical, C1-4An alkoxy group;
b)C3-8cycloalkyl, or said C3-8Cycloalkyl in which one carbon atom is replaced by oxygen, sulfur (sulphoxide or sulphone) or NR8Alternatively, the cycloalkyl is unsubstituted or substituted with one to three groups independently selected from: halogen, hydroxy, halogen substituted or unsubstituted C1-C6Alkyl, halogen substituted or unsubstituted C3-C6Cycloalkyl radicalsHalogen substituted or unsubstituted C1-C6Alkoxy, one or two C1-6Alkyl or cycloalkyl substituted or unsubstituted amino, halogen substituted or unsubstituted C1-6An alkylthio group;
R8selected from hydrogen or C1-6An alkyl group;
c) alkenyl or alkynyl, said alkenyl or alkynyl being unsubstituted or substituted with: c substituted or unsubstituted with one to three substituents independently selected from cyano, halogen or hydroxy1-6Alkyl, C substituted or unsubstituted by one to three groups independently selected from cyano, halogen or hydroxy3-6A cycloalkyl group;
R2and R3Each independently selected from: hydrogen, C substituted by one to three halogen or unsubstituted1-6Alkyl, C substituted or unsubstituted by one to three groups independently selected from cyano, halogen or hydroxy3-6A cycloalkyl group; or R2And R3Joined to form a 4-8 membered cyclic structure wherein the ring is unsubstituted or substituted with one to three substituents independently selected from cyano, halogen or hydroxy;
R4selected from aryl or heteroaryl, which are unsubstituted or substituted with one to three groups independently selected from: halogen, hydroxy, cyano, halogen substituted or unsubstituted C1-6Alkyl, halogen substituted or unsubstituted C3-6Cycloalkyl, halogen substituted or unsubstituted C1-6Alkoxy, halogen substituted or unsubstituted C1-6Alkylthio, NR9R10Methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl; r9And R10Each independently selected from: hydrogen, halogen substituted or unsubstituted C1-6Alkyl, halogen substituted or unsubstituted C3-6A cycloalkyl group;
R5selected from halogen, cyano, hydroxy, C1-4Alkoxy, or C1-4An alkylthio group;
R6is selected from C1-6Alkyl radical, C1-6Alkoxy, or C1-6An alkylthio group;
R7selected from hydrogen, or C1-6An alkyl group.
2. The compound of claim 1, wherein R is1Represents C3-6Cycloalkyl, or said C3-6A cycloalkyl group, wherein one carbon atom is replaced by oxygen, is unsubstituted or substituted with one to three groups independently selected from the group consisting of: halogen, halogen substituted or unsubstituted C1-C3An alkyl group.
3. A compound of claim 1 wherein R is2And R3Each independently selected from: c substituted by one to three halogens or unsubstituted1-3An alkyl group.
4. A compound of claim 1 wherein R is4Selected from naphthyl or heteroaryl, the naphthyl or heteroaryl being unsubstituted or substituted with one to three groups independently selected from: halogen, halogen substituted or unsubstituted C1-4An alkoxy group.
5. A compound of claim 1 wherein R is5Selected from halogen or cyano; r6Is selected from C1-3An alkoxy group; r7Selected from hydrogen or C1-3An alkyl group.
6. A compound, or each optical isomer, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
Figure FDA0002578699530000021
Figure FDA0002578699530000031
Figure FDA0002578699530000041
Figure FDA0002578699530000051
Figure FDA0002578699530000061
Figure FDA0002578699530000071
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; the A-1 configuration is preferred.
8. A pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier and, as an active ingredient, a compound according to claim 1, or each optical isomer, or a pharmaceutically acceptable salt thereof.
9. Use of a compound of claim 1, or each of its optical isomers, or a pharmaceutically acceptable salt thereof, for the preparation of a composition for inhibiting the growth of Mycobacterium tuberculosis (Mycobacterium tuberculosis).
10. Use of a compound according to claim 1, or each optical isomer, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of an infection.
11. The use according to claim 10, wherein the infection is a Mycobacterium tuberculosis (Mycobacterium tuberculosis) infection; preferably, the infection is a drug-resistant mycobacterium tuberculosis infection.
12. A process for preparing a compound of formula i, said process comprising the steps of:
(1) reacting the compound shown in the formula III with an allyl metal reagent to generate tertiary alcohol;
(2) carrying out dihydroxylation on tertiary alcohol in the presence of an oxidant and then cracking to obtain a compound shown as a formula II;
(3) reducing a compound shown as a formula II to obtain primary alcohol, activating, and reacting with corresponding amine to generate a compound shown as a formula I;
Figure FDA0002578699530000072
in the formulae, R1、R2、R3、R4、R5、R6、R7M is as defined for formula (I).
13. A process according to claim 12, wherein the compound of formula ii is reacted with the corresponding amine to produce the compound of formula i;
Figure FDA0002578699530000073
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