CN111148734B - Pyrrole-2-formamide compound and preparation method and application thereof - Google Patents

Pyrrole-2-formamide compound and preparation method and application thereof Download PDF

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CN111148734B
CN111148734B CN201880056468.9A CN201880056468A CN111148734B CN 111148734 B CN111148734 B CN 111148734B CN 201880056468 A CN201880056468 A CN 201880056468A CN 111148734 B CN111148734 B CN 111148734B
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halo
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CN111148734A (en
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黄海洪
张东峰
高永鑫
林紫云
赵红义
高猛
马辰
李燕
盛莉
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    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/402—1-aryl substituted, e.g. piretanide
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention discloses a pyrrole-2-formamide compound, a preparation method thereof, a pharmaceutical composition and application thereof in preparing medicaments for treating or preventing infectious diseases caused by mycobacterium tuberculosis. In particular, the invention relates to compounds of formula (I), pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising the compounds of the invention, wherein R is 1 And R 2 As described in the specification. The present invention aims to prepare new compounds with activity against mycobacterium tuberculosis as potential new drugs, while being useful for overcoming the problems associated with drug resistance against mycobacterium tuberculosis.

Description

Pyrrole-2-formamide compound and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines. In particular to a pyrrole-2-formamide compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition and application thereof in preparing medicaments for treating and/or preventing infectious diseases caused by mycobacterium tuberculosis.
Background
Tuberculosis (TB) is a chronic fatal disease caused by mycobacterium tuberculosis, is a major infectious disease which endangers human health and causes human death, and is one of the main causes of death worldwide like AIDS. Estimated by the World Health Organization (WHO) (Global tubocullosis report 2015): 960 ten thousand people worldwide have tuberculosis (540 million men, 320 million women and 100 million children), 150 million deaths (110 million aids virus negative patients and 40 million aids virus positive patients) in 2014, and cases of death include 89 million men, 48 million women and 14 million children.
Chemotherapy is the primary means of tuberculosis treatment. The streptomycin is used in 1944, a new era of antituberculosis drug treatment is created, with the successive appearance of isoniazid, rifampicin and pyrazinamide, the treatment course for treating tuberculosis is shortened to 6 months, and the 'short-range chemotherapy era' is entered. Nevertheless, long-term drug combination therapy causes adverse reactions to patients, and is difficult to adhere to regular medication, and in addition, most of the drugs are born in the fifties and sixties of the last century, and long-term, wide-range and irregular use causes development of drug-resistant bacteria to become more serious, and multi-drug-resistant tuberculosis (MDR-TB), wide-range drug-resistant tuberculosis (XDR-TB) and total drug-resistant tuberculosis (TDR-TB) appear. In the face of drug-resistant tuberculosis, a second-line or even a third-line antitubercular drug which is expensive and has high toxicity needs to be used.
In view of the above, there is still a need in the art to research and develop antitubercular drugs with novel structure, stronger antitubercular activity, lower toxic and side effects and excellent pharmacokinetic properties.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a safe and effective anti-tuberculosis and drug-resistant tuberculosis pyrrole-2-formamide compound with a novel structure. The inventor finds that the compounds have strong in vivo and in vitro anti-mycobacterium tuberculosis activity, thereby providing a compound which has a novel structure and strong anti-mycobacterium tuberculosis activity and can be used for treating tuberculosis. The present invention has been completed based on the above findings.
In order to solve the technical problem, the invention provides the following technical scheme:
the first aspect of the technical scheme of the invention provides a compound shown in a general formula (I) or a pharmaceutically acceptable salt thereof,
Figure GPA0000285329380000021
wherein the content of the first and second substances,
R 1 is composed of
Figure GPA0000285329380000022
m is 1,2 or 3; n is 1 and 2;
R 3 represents one or more substituents, which are the same or different and are each independently selected from the following groups: H. f, cl, br, = O, = S, hydroxy, amino, nitro, cyano, trifluoromethyl, C 1 -C 3 Alkyl, halo C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkoxy radical, C 1 -C 3 Alkylamino or halogeno C 1 -C 3 Alkylamino, and when m is 1, R 3 Is not a hydroxyl group;
R 4 represents one or more substituents, which are the same or different and are each independently selected from the following groups: H. f, cl, br, = O, = S, hydroxy, amino, nitro, cyano, trifluoromethyl, C 1 -C 3 Alkyl, halo C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkoxy radical, C 1 -C 3 Alkylamino or halogeno C 1 -C 3 An alkylamino group;
R 5 represents one or more substituents, which are the same or different and are each independently selected from the following groups: H. f, cl, br, = O, = S, hydroxy, amino, nitro, cyano, trifluoromethyl, C 1 -C 3 Alkyl, halo C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkoxy radical, C 1 -C 3 Alkylamino or halogeno C 1 -C 3 An alkylamino group;
R 2 is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted 5-10 membered heteroaryl;
R 2 the substituted or unsubstituted 5-to 10-membered heteroaryl group in (1) contains at least one heteroatom selected from the group consisting of N, O and S;
R 2 wherein said substituents may independently be optionally selected from the group consisting of: F. cl, br, hydroxyl, amino, nitro, cyano, carboxyl, C 1 -C 3 Alkyl, halo C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkoxy or C 1 -C 3 An alkylamino group.
In some aspects, the compound of formula I is selected from compounds of formula (I-A):
Figure GPA0000285329380000031
wherein the content of the first and second substances,
R 3 represents one or more substituents, which are the same or different and are each independently selected from the following groups: H. f, cl, br, = O, = S, amino, nitro, cyano, trifluoromethyl, C 1 -C 3 Alkyl, halo C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkoxy radical, C 1 -C 3 Alkylamino or halogeno C 1 -C 3 An alkylamino group.
R 2 Is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted quinolyl, substituted or unsubstituted 5-6 membered heteroaryl;
R 2 the substituted or unsubstituted 5-6 membered heteroaryl group in (1) contains at least one heteroatom selected from N, O and S;
R 2 wherein said substituents may independently be optionally selected from the group consisting of: F. cl, br, hydroxyl, amino, nitro, cyano, carboxyl, C 1 -C 3 Alkyl, halo C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkoxy or C 1 -C 3 An alkylamino group.
In some aspects, the compound of formula I is selected from compounds of formula (I-B):
Figure GPA0000285329380000032
wherein the content of the first and second substances,
R 3 represents one or more substituents, which are the same or different and are each independently selected from the following groups: H. f, cl, br, = O, = S, hydroxy, amino, nitro, cyano, trifluoromethyl, C 1 -C 3 Alkyl, halo C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkoxy radical, C 1 -C 3 Alkylamino or halogeno C 1 -C 3 An alkylamino group.
R 2 Is a substituted or unsubstituted phenyl, substituted or unsubstitutedSubstituted naphthyl, substituted or unsubstituted quinolyl, substituted or unsubstituted 5-6 membered heteroaryl;
R 2 the substituted or unsubstituted 5-6 membered heteroaryl group in (1) contains at least one heteroatom selected from N, O and S;
R 2 wherein said substituents may be independently optionally selected from the group consisting of: F. cl, br, hydroxyl, amino, nitro, cyano, carboxyl, C 1 -C 3 Alkyl, halo C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkoxy or C 1 -C 3 An alkylamino group.
In some aspects, the compound of formula I is selected from compounds of formula (I-C):
Figure GPA0000285329380000041
wherein the content of the first and second substances,
R 3 represents one or more substituents, which are identical or different and are each independently selected from the following groups: H. f, cl, br, = O, = S, hydroxy, amino, nitro, cyano, trifluoromethyl, C 1 -C 3 Alkyl, halo C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkoxy radical, C 1 -C 3 Alkylamino or halogeno C 1 -C 3 An alkylamino group.
R 2 Is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted quinolyl, substituted or unsubstituted 5-6 membered heteroaryl;
R 2 the substituted or unsubstituted 5-6 membered heteroaryl group in (1) contains at least one heteroatom selected from N, O and S;
R 2 wherein said substituents may be independently optionally selected from the group consisting of: F. cl, br, hydroxyl, amino, nitro, cyano, carboxyl, C 1 -C 3 Alkyl, halo C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkoxy orC 1 -C 3 An alkylamino group.
In some aspects, the compound of formula I is selected from compounds of formula (I-D):
Figure GPA0000285329380000042
wherein the content of the first and second substances,
R 4 represents one or more substituents, which are identical or different and are each independently selected from the following groups: H. f, cl, br, = O, = S, hydroxyl, amino, nitro, cyano, trifluoromethyl, C 1 -C 3 Alkyl, halo C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkoxy radical, C 1 -C 3 Alkylamino or halogeno C 1 -C 3 An alkylamino group.
R2 is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted quinolyl, substituted or unsubstituted 5-6 membered heteroaryl;
R 2 the substituted or unsubstituted 5-6 membered heteroaryl group in (1) contains at least one heteroatom selected from N, O and S;
R 2 wherein said substituents may independently be optionally selected from the group consisting of: F. cl, br, hydroxyl, amino, nitro, cyano, carboxyl, C 1 -C 3 Alkyl, halo C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkoxy or C 1 -C 3 An alkylamino group.
In some aspects, the compound of formula I is selected from compounds of formula (I-E):
Figure GPA0000285329380000051
wherein the content of the first and second substances,
R 5 represents one or more substituents, which are the same or different and are each independently selected from the following groups: H. f, cl, br, = O, = S, hydroxyl, amino, nitro, cyanoAlkyl, trifluoromethyl, C 1 -C 3 Alkyl, halo C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkoxy radical, C 1 -C 3 Alkylamino or halogeno C 1 -C 3 An alkylamino group.
R 2 Is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted quinolyl, substituted or unsubstituted 5-6 membered heteroaryl;
R 2 the substituted or unsubstituted 5-6 membered heteroaryl group in (1) contains at least one heteroatom selected from N, O and S;
R 2 wherein said substituents may independently be optionally selected from the group consisting of: F. cl, br, hydroxyl, amino, nitro, cyano, carboxyl, C 1 -C 3 Alkyl, halo C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkoxy or C 1 -C 3 An alkylamino group.
In some aspects, the compound of formula I is selected from compounds of formula (I-F):
Figure GPA0000285329380000052
wherein, the first and the second end of the pipe are connected with each other,
R 2 is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted quinolyl, substituted or unsubstituted 5-6 membered heteroaryl;
R 2 the substituted or unsubstituted 5-6 membered heteroaryl group in (1) contains at least one heteroatom selected from N, O and S;
R 2 wherein said substituents may independently be optionally selected from the group consisting of: F. cl, br, hydroxyl, amino, nitro, cyano, carboxyl, C 1 -C 3 Alkyl, halo C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkoxy or C 1 -C 3 An alkylamino group.
In some aspects, the compound of formula I is selected from compounds of formula (I-G):
Figure GPA0000285329380000053
wherein the content of the first and second substances,
R 2 is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted quinolyl, substituted or unsubstituted 5-6 membered heteroaryl;
R 2 the substituted or unsubstituted 5-6 membered heteroaryl group in (1) contains at least one heteroatom selected from N, O and S;
R 2 wherein said substituents may independently be optionally selected from the group consisting of: F. cl, br, hydroxyl, amino, nitro, cyano, carboxyl, C 1 -C 3 Alkyl, halo C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkoxy or C 1 -C 3 An alkylamino group.
In some aspects, the compound of formula I is selected from compounds of formula (I-H):
Figure GPA0000285329380000061
wherein the content of the first and second substances,
R 2 is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted quinolyl, substituted or unsubstituted 5-6 membered heteroaryl;
R 2 the substituted or unsubstituted 5-6 membered heteroaryl group in (1) contains at least one heteroatom selected from N, O and S;
R 2 wherein said substituents may be independently optionally selected from the group consisting of: F. cl, br, hydroxyl, amino, nitro, cyano, carboxyl, C 1 -C 3 Alkyl, halo C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkoxy or C 1 -C 3 An alkylamino group.
The compounds and pharmaceutically acceptable salts according to any one of the first aspect of the invention,
Figure GPA0000285329380000062
wherein, the first and the second end of the pipe are connected with each other,
R 2 is composed of
Figure GPA0000285329380000063
Figure GPA0000285329380000064
Figure GPA0000285329380000071
The compounds according to any one of the first aspect of the invention and pharmaceutically acceptable salts thereof,
Figure GPA0000285329380000072
wherein, the first and the second end of the pipe are connected with each other,
R 1 is composed of
Figure GPA0000285329380000073
Figure GPA0000285329380000074
R 2 Is composed of
Figure GPA0000285329380000075
Figure GPA0000285329380000076
A compound according to any one of the first aspect of the invention, which is a subject compound of the invention (represented by the structural formula or described by systematic name) or a pharmaceutically acceptable salt thereof, prepared in the examples.
Figure GPA0000285329380000081
Figure GPA0000285329380000091
Figure GPA0000285329380000101
Figure GPA0000285329380000111
Figure GPA0000285329380000121
Figure GPA0000285329380000131
The pharmaceutically acceptable salts described in the present invention are salts of the compounds of the present invention with an acid selected from the group consisting of: hydrochloric acid, p-toluenesulfonic acid, tartaric acid, maleic acid, lactic acid, methanesulfonic acid, sulfuric acid, phosphoric acid, citric acid, acetic acid or trifluoroacetic acid. Preferably hydrochloric acid, p-toluenesulfonic acid or trifluoroacetic acid.
A second aspect of the present invention provides a process for preparing a compound according to any one of the first aspect of the present invention, which comprises the following six synthetic modes:
in a first mode
Figure GPA0000285329380000132
Compound A in (Boc) 2 Adding DMAP as a catalyst in the presence of O under basic conditions (such as triethylamine or N, N-diisopropylethylamine) and reacting in a polar solvent (such as dichloromethane) for 3 hours to obtain a compound I-1;
compounds I-1 and R 2 The substituted boronic acid is catalyzed by a metal-containing palladium catalyst (e.g., bis- (triphenylphosphine) palladium dichloride), under basic conditions (e.g., sodium carbonate, potassium carbonate, or cesium carbonate) and a polar solvent (e.g., dioxane and water) in an inert gas (Ar or N) 2 ) Reacting for 2-6 hours at 60-80 ℃ under protection to obtain a compound I-2;
reacting the compound I-2 with a polar solvent (such as ethanol and water) under alkaline conditions (such as lithium hydroxide or sodium hydroxide) at 60-80 ℃ for 2-4 hours to obtain a compound I-3;
reacting the compound I-3 with amine under the action of a condensing agent (such as EDCI and HOBt) and in a polar solvent (such as dichloromethane or N, N-dimethylformamide) under basic conditions (such as N, N-diisopropylethylamine or triethylamine) at room temperature for 6-12 hours to obtain a compound shown in the general formula I;
mode two
Figure GPA0000285329380000133
Reacting the compound A in a polar solvent (such as ethanol and water) under an alkaline condition (such as lithium hydroxide or sodium hydroxide) at 60-80 ℃ for 2-4 hours to obtain a compound I-4;
compound I-4 and compound containing R 1 Under the action of a condensing agent (such as EDCI and HOBt), in a polar solvent (such as dichloromethane or N, N-dimethylformamide) under basic conditions (such as N, N-diisopropylethylamine or triethylamine) at room temperature for 6-12 hours to obtain a compound I-5;
compound I-5 is in (Boc) 2 Adding catalyst DMAP in the presence of O under basic conditions (such as triethylamine or N, N-diisopropylethylamine), and reacting in a polar solvent (such as dichloromethane) for 3 hours to obtain a compound I-6;
compounds I-6 and R 2 The substituted boronic acids are catalyzed by a metal-containing palladium catalyst (e.g., bis- (triphenylphosphine) palladium dichloride) under basic conditions (e.g., sodium carbonate, potassium carbonate, or cesium carbonate) and a polar solvent (e.g., dioxane and water)Inert gas (Ar or N) 2 ) Reacting for 2-6 hours at 60-80 ℃ under protection to obtain a compound I-7;
the compound I-7 is reacted in a polar solvent (e.g. dichloromethane) in the presence of trifluoroacetic acid for 2 hours to obtain the compound represented by the general formula I.
Mode III
Figure GPA0000285329380000141
Reacting the compound A in a polar solvent (such as ethanol and water) under alkaline conditions (such as lithium hydroxide or sodium hydroxide) at 60-80 ℃ for 2-4 hours to obtain a compound I-4;
compound I-4 and compounds containing R 1 Under the action of condensing agents EDCI and HOBt, and under basic conditions (such as N, N-diisopropylethylamine or triethylamine), reacting in a polar solvent (such as dichloromethane or N, N-dimethylformamide) at room temperature for 6-12 hours to obtain a compound I-5;
adding a catalyst NaH into the compound I-5 in the presence of Sem-Cl, and reacting in a polar solvent (such as N, N-dimethylformamide) for 3-4 hours to obtain a compound I-8;
compounds I-8 and R 2 The substituted boronic acids are catalyzed by a metal-containing palladium catalyst (e.g., tetrakis- (triphenylphosphine) palladium), under basic conditions (e.g., sodium, potassium, or cesium carbonate) and in a polar solvent (e.g., ethanol/toluene) in an inert gas (Ar or N) 2 ) Reacting for 2-6 hours at 80-90 ℃ under protection to obtain a compound I-9;
the compound I-9 reacts in a polar solvent in the presence of tetrabutylammonium fluoride (TBAF) (1 mol/L THF) to remove a Sem protecting group, and a compound shown in the general formula I is obtained.
Mode IV
Figure GPA0000285329380000142
Compound B with NIS In a Lewis acid (e.g. In (OTf) 3 ) Under the action of (2), reacting at 0-room temperatureCompound C should be obtained. Reacting the compound C in a polar solvent (such as ethanol and water) under an alkaline condition (such as lithium hydroxide or sodium hydroxide) at 60-80 ℃ for 2-4 hours to obtain a compound I-10;
compound I-10 and compounds containing R 1 Under the action of a condensing agent (such as EDCI and HOBt), in a polar solvent (such as dichloromethane or N, N-dimethylformamide) under basic conditions (such as N, N-diisopropylethylamine or triethylamine) at room temperature for 6-12 hours to obtain a compound I-11;
compound I-11 is described in (Boc) 2 Adding catalyst DMAP in the presence of O under basic conditions (such as triethylamine or N, N-diisopropylethylamine), and reacting in a polar solvent (such as dichloromethane) for 3 hours to obtain a compound I-12;
compounds I-12 and R 2 The substituted boronic acid is catalyzed by a metal-containing palladium catalyst (e.g., bis- (triphenylphosphine) palladium dichloride), under basic conditions (e.g., sodium carbonate, potassium carbonate, or cesium carbonate) and a polar solvent (e.g., dioxane and water) in an inert gas (Ar or N) 2 ) Reacting for 2-6 hours at 60-80 ℃ under protection to obtain a compound I-13;
compound I-13 is reacted in a polar solvent (e.g., dichloromethane) in the presence of trifluoroacetic acid for 2 hours to provide the compound of formula I.
Mode five
Figure GPA0000285329380000151
Compound B with NIS In the presence of a Lewis acid (e.g. In (OTf) 3 ) Under the action of (1), reacting at 0-room temperature to obtain a compound C. Reacting the compound C in a polar solvent (such as ethanol and water) under an alkaline condition (such as lithium hydroxide or sodium hydroxide) at 60-80 ℃ for 2-4 hours to obtain a compound I-10;
compound I-10 and compounds containing R 1 In a polar solvent (e.g. dichloromethane or N, N-dimethylformamide) under basic conditions (e.g. N, N-diisopropylethylamine or triethylamine) with the aid of condensing agents (e.g. EDCI and HOBt)Reacting at room temperature for 6-12 hours to obtain a compound I-11;
compound I-11 is reacted in a polar solvent (e.g., N-dimethylformamide) for 3 to 4 hours in the presence of Sem-Cl with the addition of a base NaH to give compound I-14;
compounds I-14 and R 2 The substituted boronic acids are catalyzed by a metal-containing palladium catalyst (e.g., tetrakis- (triphenylphosphine) palladium), in a polar solvent (e.g., ethanol/toluene) under basic conditions (e.g., sodium carbonate, potassium carbonate, or cesium carbonate) in an inert gas (Ar or N) 2 ) Reacting for 2-6 hours at 80-90 ℃ under the protection to obtain a compound I-15;
and reacting the compound I-15 in a polar solvent in the presence of tetrabutylammonium fluoride (TBAF) (1 mol/L THF) to remove a Sem protecting group, thereby obtaining the compound shown in the general formula I.
Mode six
Figure GPA0000285329380000152
Compound B in (Boc) 2 Adding catalyst DMAP in the presence of O under basic conditions (such as triethylamine or N, N-diisopropylethylamine), and reacting in a polar solvent (such as dichloromethane) for 3 hours to obtain a compound I-16;
compound I-16 is reacted with pinacolborane in the presence of a metal-containing catalyst (e.g., methoxy (cyclooctadiene) iridium dimer), under basic conditions (e.g., 4' -di-t-butylpyridinium) and a nonpolar solvent (e.g., N-hexane) in the presence of an inert gas (Ar or N) 2 ) Under protection, the mixture is kept at room temperature for 2 to 8 hours to obtain a compound I-17;
compound I-17 is catalyzed with a bromide in a metal-containing palladium catalyst (e.g., tetrakis- (triphenylphosphine) palladium), under basic conditions (e.g., sodium carbonate, potassium carbonate, or cesium carbonate) and in a polar solvent (e.g., ethanol/toluene, dioxane/water) in an inert gas (Ar or N) 2 ) Reacting for 2-8 hours at 80-90 ℃ under the protection to obtain a compound I-18;
reacting the compound I-18 in a polar solvent (such as ethanol and water) under alkaline conditions (such as lithium hydroxide or sodium hydroxide) at 60-80 ℃ for 2-4 hours to obtain a compound I-19;
the compound I-19 reacts with amine under the action of condensing agent (such as EDCI and HOBt) and under alkaline condition (such as N, N-diisopropylethylamine or triethylamine) and polar solvent (such as dichloromethane or N, N-dimethylformamide) at room temperature for 6-12 hours to obtain the compound shown in the general formula I.
In a third aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of the first aspect of the present invention and pharmaceutically acceptable salts thereof, and optionally one or more pharmaceutically acceptable excipients.
The present invention relates to a pharmaceutical composition comprising the compound of the present invention as an active ingredient. The pharmaceutical composition may be prepared according to methods well known in the art. The compounds of the invention may be formulated into any dosage form suitable for human or animal use by combining them with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants.
The compounds of the present invention or pharmaceutical compositions containing them may be administered in unit dosage form by enteral or parenteral routes, such as oral, intravenous, intramuscular, subcutaneous, nasal, oromucosal, ophthalmic, pulmonary and respiratory, dermal, vaginal, rectal and the like.
The dosage form for administration may be a liquid, solid or semi-solid dosage form. The liquid dosage forms can be solution (including true solution and colloidal solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion, liniment, etc.; the solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.; semisolid dosage forms can be ointments, gels, pastes, and the like.
The compound can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle delivery systems.
For tableting the compound of the present invention, a wide variety of excipients known in the art may be used, including diluents, binders, wetting agents, disintegrants, lubricants, and solubilizers. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the humectant can be water, ethanol, isopropanol, etc.; the binder can be starch slurry, dextrin, syrup, mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and cosolvent may be talc, silica, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.
The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.
To encapsulate the administration unit, the active ingredient of the compound of the present invention may be mixed with a diluent and a cosolvent, and the mixture may be directly placed in a hard capsule or soft capsule. Or preparing the effective component of the compound of the invention into granules or pellets with a diluent, an adhesive and a disintegrating agent, and then placing the granules or pellets into hard capsules or soft capsules. The diluents, binders, wetting agents, disintegrants, and cosolvents used to prepare the compound tablets of the present invention can also be used to prepare capsules of the compounds of the present invention.
For preparing the compound of the present invention into injection, water, ethanol, isopropanol, propylene glycol or their mixture can be used as solvent, and appropriate amount of solubilizer, cosolvent, pH regulator, and osmotic pressure regulator commonly used in the art can be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-beta-cyclodextrin, etc.; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, mannitol and glucose can be added as proppant for preparing lyophilized powder for injection.
In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired.
For administration purposes, to enhance the therapeutic effect, the medicaments or pharmaceutical compositions of the invention may be administered by any known method of administration.
The compounds or compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic agents. When the compound of the present invention is used in a synergistic manner with other therapeutic agents, the dosage thereof should be adjusted according to the actual circumstances.
The fourth aspect of the present invention provides the use of the compound of any one of the first aspect of the present invention and its pharmaceutically acceptable salt, or the pharmaceutical composition of the third aspect of the present invention in the preparation of a medicament for the treatment and prevention of infectious diseases caused by bacteria, in particular, infectious diseases caused by mycobacterium tuberculosis.
Any aspect of the invention or any one of the aspects having features is equally applicable to any other aspect or any one of the other aspects as long as they are not mutually inconsistent, although appropriate modifications to the respective features may be made as necessary when applicable to each other. In the present invention, for example, reference to "any of the first aspects of the invention" means any sub-aspect of the first aspects of the invention, and in other respects similarly referred to, has similar meaning.
Detailed description of the invention:
various aspects and features of the disclosure are described further below.
All documents cited herein are incorporated herein by reference in their entirety and to the extent they do not conform to the teachings of the present invention, the statements made therein shall control. Further, the various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and even though such terms and phrases are intended to be described or explained in greater detail herein, reference is made to the term and phrase as being inconsistent with the known meaning and meaning as is accorded to such meaning throughout this disclosure. The following are definitions of various terms used herein, which apply to the terms used throughout this application unless otherwise indicated in specific instances.
The term "substituted" means that any one or more hydrogen atoms on a particular atom in a given structure is replaced with a particular substituent, provided that the valency of the particular atom is normal and the resulting compound is stable after the substitution. Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently. Wherein the substituent may be, but is not limited to, hydrogen, deuterium, oxo (= O), halogen, cyano, nitro, hydroxy, mercapto, amino (-NH) 2 ) Arylamine, aminoalkyl, alkyl, alkylthio, hydroxyalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C (= O) R a 、-OR b 、-COOR b 、-SO 2 R b 、-NR c R d 、-CONR c R d 、-SO 2 NR c R d 、-C(NR c R d ) (ii) a Wherein R is a 、R b 、R c And R d Each independently is hydrogen, cyano, amino, alkylamino, arylamino, alkylthio, alkoxy, aryloxy, hydroxy, mercapto, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylsulfonyl, aminosulfonyl, hydroxyalkyl, aminoalkyl, aminoalkylacyl, or alkanoyl.
The carbon atom content of each hydrocarbon-containing moiety is indicated by a prefix designating the minimum and maximum number of carbon atoms in that moiety. C i -C j Denotes a moiety having an integer "i" (inclusive of i) to an integer "j" (inclusive of j) carbon atoms. Thus, for example, C 1 -C 3 Alkyl means alkyl having 1 to 3 (including 1 and 3) carbon atoms, especially methyl, ethyl and C 3 An alkyl group.
As used herein, the term "alkyl" refers to an alkyl group having the specified number of carbon atoms, which is a straight or branched chain alkyl group, and which may include subgroups thereof, for example, with reference to "C 1 -C 3 When "alkyl", it may also include C 1 -C 2 Alkyl radical, C 2 -C 3 Alkyl represents a sub-range of groups, and specific groups such as methyl, ethyl, n-propyl, isopropyl. The terms "alkoxy" and "alkylamino" are used in their conventional expressions to refer to an alkyl group attached to the remainder of the molecule through an oxygen atom or an amine group, respectively, wherein the alkyl group is as described herein. Alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, n-propoxy, and the like. Alkylamino groups include, but are not limited to, methylamino, ethylamino, isopropylamino, n-propylamino, and the like.
The term "haloalkyl" denotes an alkyl group substituted with one or more halogen atoms, including, but not limited to, trifluoromethyl, difluoromethyl, and the like.
As used herein, the terms "halo", "halogen atom", "halo", and the like, denote fluorine, chlorine, bromine, or iodine, and particularly denote chlorine, bromine, or iodine.
As used herein, the term "heteroaryl" refers herein to an aromatic group having from 1 to 3 heteroatoms as ring atoms, the remaining ring atoms being carbon, wherein the heteroatoms include oxygen, sulfur, and nitrogen. For example, "5-10 membered heteroaryl" includes 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl and 10 membered heteroaryl. Wherein 5-membered heteroaryl includes, but is not limited to, imidazolyl, furyl, thienyl, triazolyl, tetrazolyl, pyrazolyl (e.g., 2-pyrazolyl), thiazolyl, oxazolyl, isoxazolyl. 6-membered heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3, 5-triazinyl. 9-membered heteroaryl groups include, but are not limited to, indolyl, purinyl, benzothienyl, benzofuranyl, pyridoimidazolyl. 10-membered heteroaryl groups include, but are not limited to, quinolinyl, isoquinolinyl. In embodiments, the heteroaryl is pyridyl, pyrimidinyl, furanyl, thienyl, quinolinyl.
As used herein, the term "ring" refers to a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl. The so-called ring includes condensed rings. The number of atoms in the ring is generally defined as the number of ring members, e.g., "3-6 membered ring" means 3-6 atoms arranged around the ring.
As described herein, the substituent R x The ring system formed on the ring having one bond to the center representing one or more identical or different substituents R x Substitutions may be made at any substitutable position on the ring. For example, formula a represents the A or B ring optionally substituted by one or more R x And (4) substitution.
Figure GPA0000285329380000181
As used herein, the term "effective amount" refers to an amount of a drug that achieves the desired treatment of a disease or disorder described herein in a subject.
As used herein, the term "pharmaceutically acceptable" when describing a "pharmaceutically acceptable salt" means that the salt is not only physiologically acceptable to the subject, but may also refer to a synthetic substance of pharmaceutical value, e.g., a salt formed as an intermediate in order to effect chiral resolution, which salt may play a role in achieving the end product of the invention, although such intermediate salt may not be directly administered to the subject.
As described herein, the term "pharmaceutical composition", which may also be a "composition", may be used to effect treatment of a disease or condition described herein in a subject, particularly a mammal.
"treatment" of a disease includes:
(1) Preventing the disease, i.e., causing the clinical symptoms of the disease not to occur in a mammal exposed to or susceptible to the disease but who does not experience or exhibit symptoms of the disease,
(2) Inhibiting the disease, i.e., preventing or reducing the progression of the disease or its clinical symptoms,
(3) Alleviating the disease, i.e., causing the recovery of the disease or its clinical symptoms.
"therapeutically effective amount" refers to the amount of a compound that is sufficient to effect treatment of a disease when administered to a mammal for the treatment of the disease. The therapeutically effective amount will vary depending upon the compound, the disease to be treated and its severity, as well as the age, weight, sex, etc., of the mammal. A therapeutically effective amount may also refer to any amount of the compound sufficient to achieve a desired beneficial effect, including preventing, inhibiting, or ameliorating a disease as described in (1) - (3) above. For example, the amount of the compound may be between 0.1 and 250mg/kg, or preferably, 0.5 and 100mg/kg, or more preferably, 1 and 50mg/kg, or even more preferably, 2 and 20mg/kg. Preferably, the amount of the compound is administered to the mammal twice daily. More preferably, the amount of the compound is administered to the mammal once daily. More preferably, the amount of the compound is administered to the mammal once weekly or once biweekly.
As used herein, the term "disease and/or disorder" refers to a physical condition of the subject that is associated with the disease and/or disorder of the present invention. For example, the disease and/or disorder of the present invention refers to a mycobacterium tuberculosis infectious disease.
As used herein, the term "subject" can refer to a patient or other animal, particularly a mammal, such as a human, dog, monkey, cow, horse, etc., that receives a compound of formula I of the invention or a pharmaceutical composition thereof to treat a disease or condition described herein.
Advantageous technical effects
The inventor finds that most of the compounds in the invention have good in vitro anti-tuberculosis activity, and particularly the compounds 4, 7, 9, 10, 15, 23, 25, 37, 41, 42, 44, 46, 47, 48, 49, 50, 55, 57, 58, 59, 63, 64 and 76 show strong in vitro anti-mycobacterium tuberculosis activity (MIC < 0.016. Mu.g/mL), and the activity is far stronger than that of the first-line anti-tuberculosis drugs isoniazid and rifampicin. The safety evaluation result shows that the compound has low Vero cytotoxicity, low cardiotoxicity risk and good safety. In addition, the compound shows good antibacterial activity on MDR-TB and XDR-TB, and has strong in-vivo anti-tuberculosis activity. The invention provides pyrrole-2-formamide-containing compounds with novel structures, strong activity and low toxicity, which can be used for treating infectious diseases caused by bacteria, particularly for treating and preventing infectious diseases caused by mycobacterium tuberculosis, have good antibacterial activity on sensitive mycobacterium tuberculosis and drug-resistant mycobacterium tuberculosis, and can be used for preventing and treating diseases caused by infection of sensitive or drug-resistant mycobacterium tuberculosis.
Detailed Description
The present invention will be described in detail by the following examples, but is not intended to limit the present invention in any way. Having described the invention in detail and having disclosed specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.
For all of the following examples, standard procedures and purification methods known to those skilled in the art may be used. Unless otherwise indicated, all temperatures are expressed in degrees Celsius. The structure of the compounds is determined by nuclear magnetic resonance spectroscopy (NMR) and/or Mass Spectrometry (MS).
Preparation examples section
The structure of the compound is shown by nuclear magnetic resonance hydrogen spectrum ( 1 H NMR) or Mass Spectrometry (MS). Nuclear magnetic resonance hydrogen spectral shifts (δ) are given in units of parts per million (ppm). NMR spectra were determined using a Mercury-400 or Brucker-500 NMR spectrometer using deuterated chloroform (CDCl) 3 ) Or deuterated dimethyl sulfoxide (DMSO-d) 6 ) As a solvent, tetramethylsilane (TMS) was used as an internal standard.
The electronic balance used was a Sartorius BSA323S type electronic balance.
The column chromatography generally uses 200-300 mesh or 300-400 mesh silica gel as a carrier.
The anhydrous solvents were all processed by standard methods. Other reagents were all commercially available analytical grade.
The invention employs the following abbreviations:
DCM is dichloromethane.
MeOH is methanol.
EA is ethyl acetate.
PE is petroleum ether.
THF is tetrahydrofuran.
TFA is trifluoroacetic acid.
Et 3 N is triethylamine.
DIPEA is N, N-diisopropylethylamine.
DMF is N, N-dimethylformamide.
HATU is 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate.
EDCI is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride.
HOBt is 1-hydroxybenzotriazole.
Pd(Ph 3 P) 2 Cl 2 Is bis (triphenylphosphine) palladium dichloride.
Pd(Ph 3 P) 4 Is tetrakis (triphenylphosphine) palladium.
(Boc) 2 O is di-tert-butyl dicarbonate.
DMAP is 4-dimethylaminopyridine.
In(OTf) 3 Is indium trifluoromethanesulfonate.
NIS is N-iodosuccinimide.
Sem-Cl is 2- (trimethylsilyl) ethoxymethyl chloride.
Dtbpy is 4,4' -di-tert-butylbipyridine.
[Ir(OMe)(COD)] 2 Is methoxy (cyclooctadiene) iridium dimer.
PinBH is pinacolborane.
TBAF is tetrabutylammonium fluoride.
Preparation example
1 preparation of intermediate I-3-1
Figure GPA0000285329380000201
First step preparation of 1- (tert-butyl) -2-methyl-4-bromo-1H-pyrrole-1, 2-dicarboxylate
In a 100mL reaction flask, compound A (4.08g, 20mmol) was dissolved in DCM (60 mL) and added (Boc) 2 O(5.24g，24mmol)、Et 3 N (4 mL,28.9 mmol) and DMAP (0.4 g,3.2 mmol) were reacted at room temperature overnight. The reaction mixture was washed twice with 1N hydrochloric acid solution (20 mL), washed with saturated brine (20 mL), and the organic phase was dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (EA: PE = 1-5%) to obtain 5.8g of a white solid with a yield of 95.4%.
Second step preparation of 1- (tert-butyl) -2-methyl-4- (2, 4-dichlorophenyl) -1H-pyrrole-1, 2-dicarboxylate
A100 mL reaction flask was charged with Compound I-1 (2.5g, 5.8mmol), 2, 4-dichlorophenylboronic acid (2.3mmol, 7.5mmol), sodium carbonate (1.3g, 12.2mmol), and bis (triphenylphosphine) palladium dichloride (140 mg), and dioxane (35 mL) and water (5.5 mL) were injected under argon, and heated at 60 ℃ for 3 hours. Cooling, adding water (40 mL) to precipitate solid, filtering, washing with water and pumping, washing twice with n-hexane, and drying to obtain off-white solid 2.64g with yield of 85.2%.
The third step is the preparation of 4- (2, 4-dichlorophenyl) -1H-pyrrole-2-carboxylic acid
A100 mL reaction flask was charged with compound I-2-1 (3.7g, 10mmol) and sodium hydroxide (0.8g, 20mmol), ethanol (20 mL) and water (20 mL) were added, the mixture was heated at 60 ℃ for 3 hours, cooled, and a 1N aqueous hydrochloric acid solution (40 mL) was added dropwise thereto to adjust the pH to 3 to 4, whereby a white solid was precipitated, and the resulting mixture was filtered, washed with water and dried by suction, washed twice with N-hexane, and dried to obtain intermediate I-3-1 as a white solid (2.43 g, yield 95%). 1 H NMR(400MHz，DMSO-d 6 )δ：12.46(s，1H)，12.07(s，1H)，7.59-7.56(m，2H)，7.37-7.35(m，2H)，7.06(s，1H).
2 preparation of intermediate I-6-1
Figure GPA0000285329380000211
First step preparation of N- (adamantan-2-yl) -4-bromo-1H-pyrrole-2-carboxamide
Adding the compound A (2.04g, 10mmol) and sodium hydroxide (0.8g, 20mmol) into a 100mL reaction bottle, adding ethanol (20 mL) and water (20 mL), heating at 60 ℃ for 3 hours, cooling, dropwise adding 1N hydrochloric acid aqueous solution (40 mL), adjusting the pH to 3-4 to separate out a white solid, filtering, washing with water, draining, washing twice with N-hexane, drying to obtain 1.8g of a white-like solid, wherein the yield is 95% and the white-like solid is directly used for the next reaction without further purification.
In a 100mL reaction flask, compound I-4 (1.88g, 10mmol) and 2-adamantanamine (1.87g, 12.4mmol) were dissolved in DMF (30 mL), EDCI (1.06g, 11mmol) and HOBt (1.34g, 11mmol) were added, and DIPEA (3.87g, 30mmol) was added dropwise under ice bath, followed by reaction at room temperature overnight. Water (20 mL) was added in an ice bath to precipitate a white solid, which was filtered, washed with water and then pumped to dryness, washed twice with n-hexane and dried to obtain an off-white solid, 2.64g, yield 85.2%.
Second preparation of tert-butyl-2- (adamantan-2-yl) -carbamoyl-4-bromo-1H-pyrrole-1-carboxylate
In a 100mL reaction flask, compound I-5-1 (2.5g, 7.8mmol) was dissolved in DCM (30 mL) and added (Boc) 2 O(2.1g，9.36mmol)、Et 3 N (2.36g, 23.4mmol) and DMAP (100mg, 0.78mmol) were reacted at room temperature overnight. The reaction mixture was washed twice with 1N aqueous hydrochloric acid (20 mL), washed with saturated brine (20 mL), and the organic phase was dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (EA: PE = 1-5%) to obtain intermediate I-6-1 as a white solid (3.01 g, yield 93.8%). LC-MS: [ M + H ]] + 423.13
3 preparation of intermediate I-6-2
Figure GPA0000285329380000212
First step preparation of 4-bromo-N- (4, 4-dimethylcyclohexyl) -1H-pyrrole-2-carboxamide
Compound A (2.1g, 10mmol) and sodium hydroxide (0.8g, 20mmol) were charged into a 100mL reaction flask, ethanol (20 mL) and water (20 mL) were added, heating was carried out at 60 ℃ for 3 hours, cooling was carried out, a 1N aqueous hydrochloric acid solution (40 mL) was added dropwise, the pH was adjusted to 3-4, a white solid was precipitated, filtration was carried out, washing with water and draining, washing was carried out twice with N-hexane, drying was carried out to obtain 1.8g of an off-white solid, yield 95%. I-4 was used without purification in the next step, in a 100mL reaction flask, compound I-4 (1.88g, 10mmol) and 4, 4-dimethylcyclohexylamine (1.27g, 10mmol) were dissolved in DMF (30 mL), EDCI-4 (1.06g, 110mmol) was added dropwise, DIPEA (3.8730mmol), reaction was carried out at room temperature, water (20 mL) was added, washing was carried out twice with water, filtering was carried out, and drying was carried out twice with N-hexane (2.10mmol) to obtain a white solid, drying was carried out to obtain a dry solid.
Second preparation of tert-butyl-4-bromo-2- (4, 4-dimethylcyclohexyl) -carbamoyl-1H-pyrrole-1-carboxylate
In a 100mL reaction flask, compound I-5-2 (4.6 g,15.4 mmol) was dissolved in DCM (160 mL) and Et was added separately 3 N (2.34g, 23.1mmol) and DMAP (188mg, 1.54mmol) were reacted at room temperature overnight. Washed twice with 1N aqueous hydrochloric acid (20 mL), washed with saturated brine (20 mL), and the organic phase was dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (EA: PE = 1-5%) to obtain intermediate I-6-2 as a white solid (4.72 g, yield 76.9%). LC-MS: [ M + H ]] + 399.12.
Preparation of 4 intermediate I-6-3
Figure GPA0000285329380000221
First step preparation of N- (adamantan-1-yl) -4-bromo-1H-pyrrole-2-carboxamide
In a 100mL reaction flask, compound I-4 (5g, 26.3mmol) and 1-amantadine (2.55g, 17mmol) were dissolved in DMF (30 mL), EDCI (2.59g, 13.58mmol) and HOBt (1.66g, 13.58mmol) were added, and DIPEA (7g, 54.32mmol) was added dropwise over ice and reacted at room temperature overnight. And was supplemented with EDCI (1.3g, 6.79mmol) and DIPEA (1.76g, 13.58mmol). Water (120 mL) was added in an ice bath to precipitate a white solid, which was filtered, washed with water and pumped to dryness, washed twice with n-hexane and dried to obtain an off-white solid (5 g) in 99% yield.
Second preparation of tert-butyl-2- (adamantan-1-yl) -carbamoyl-4-bromo-1H-pyrrole-1-carboxylate
In a 250mL reaction flask, compound I-5-3 (5g, 16mmol) was dissolved in DCM (100 mL) and added portionwise (Boc) under ice-bath conditions 2 O(4.19g，19.2mmol)、Et 3 N (4.86g, 48mmol) and DMAP (195mg, 1.6 mmol) were reacted at room temperature overnight. Concentrating, stirring and washing with n-hexane overnight, filtering, and infrared drying to obtain intermediate I-6-3,6.08g, with a yield of 89.8%. 1 H NMR(400MHz，DMSO-d 6 )δ：7.74(s，1H)，7.36(d，J＝1.6Hz，1H)，6.49(d，J＝1.6Hz，1H)，1.99-1.96(m，9H)，1.59(brs，1H)，1.47(s，9H).
5 preparation of intermediate I-6-4
Figure GPA0000285329380000222
First step preparation of N-cyclooctyl-4-bromo-1H-pyrrole-2-carboxamide
In a 100mL reaction flask, compound I-4 (1g, 5.26mmol) and cyclooctylamine (0.67g, 5.26mmol) were dissolved in DMF (6 mL), EDCI (1g, 5.26mmol) and HOBt (0.64g, 5.26mmol) were added, DIPEA (2.72g, 21mmol) was added dropwise over ice, and the mixture was reacted at room temperature overnight. Cyclooctylamine (0.20g, 1.58mmol) and EDCI (0.30g, 1.58mmol) were further added. The mixture was extracted twice with ethyl acetate and water, washed successively with 2N HCl (15 mL), saturated sodium bicarbonate solution and saturated brine (20 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated to give 1.7g, and stirred with N-hexane overnight and dried to give 1.423g, with a yield of 90.0%.
Second step preparation of tert-butyl-2- (cyclooctan-1-yl) -carbamoyl-4-bromo-1H-pyrrole-1-carboxylate
In a 100mL reaction flask, compound I-5-4 (1.41g, 4.72mmol) was dissolved in DCM (28 mL) and portionwise incubated under ice bath conditionsMetered addition (Boc) 2 O(1.24g，5.66mmol)、Et 3 N (1.43g, 14.16mmol) and DMAP (58mg, 0.472mmol) were reacted at room temperature overnight. Concentrating, stirring with n-hexane overnight, and drying to obtain intermediate I-6-4,1.63g, with yield 86.0%. 1 H NMR(400MHz，DMSO-d 6 )δ：8.28(d，J＝5.6Hz，1H)，7.42(s，1H)，6.51(s，1H)，3.86(brs，1H)，1.73-1.49(m，23H).
Preparation of 6 intermediate I-6-5
Figure GPA0000285329380000231
First step preparation of 4-bromo-N- ((1S, 2S,3S, 5R) -2, 6-trimethylbicyclo [3.1] heptan-3-yl) -1H-pyrrole-2-carboxamide
In a 50mL reaction flask, compound I-4 (1g, 5.26mmol) and isobornylamine (1.21g, 7.89mmol) were dissolved in DMF (9 mL), EDCI (1.51g, 7.89mmol) and HOBt (0.64g, 5.26mmol) were added, and DIPEA (2.72g, 21mmol) was added dropwise under ice bath, followed by reaction at room temperature for 5.5 hours. The mixture was extracted twice with ethyl acetate and water, and washed successively with 2N HCl (15 mL), saturated sodium bicarbonate solution and saturated brine (20 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated to 872mg, yield 51%. Second step preparation of 4-bromo-2- ((1S, 2S,3S, 5R) -2, 6-trimethylbicyclo [3.1] heptan-3-yl) carbamoyl-1H-pyrrole-1-carboxylic acid ester
In a 50mL reaction flask, compound I-5-5 (765mg, 2.35mmol) was dissolved in DCM (14 mL) and (Boc) was added 2 O(615mg，2.82mmol)、Et 3 N (713mg, 7.05mmol) and DMAP (29mg, 0.235mmol) were reacted at room temperature overnight. Concentrating, stirring and washing with n-hexane overnight, and drying to obtain intermediate I-6-5, 723mg, and yield 72%. LC-MS: [ M + H ]] + 425.14.
Preparation of 7 intermediate I-8-1
Figure GPA0000285329380000232
Preparation of N- (adamantan-1-yl) -4-bromo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole-2-carboxamide
In a 250mL reaction flask, compound I-5-3 (198mg, 0.613mmol) was dissolved in DMF (5 mL), naH was added, sem-Cl (123mg, 0.736 mmol) was added, and the reaction was allowed to proceed overnight at room temperature. Concentration, extraction with ethyl acetate and water twice, washing with saturated brine (20 mL), drying the organic phase over anhydrous sodium sulfate, and concentration gave intermediate I-8-1, 199mg, 72.0% yield. 1 H NMR(400MHz，DMSO-d 6 )δ：7.32(s，1H)，7.16(d，J＝2.0Hz，1H)，6.78(d，J＝1.6Hz，1H)，5.55(s，2H)，3.39(t，J＝8.0Hz，2H)，1.97(s，9H)，1.59(s，6H)，0.75(J＝7.6Hz，2H)，-0.09(s，9H).
Preparation of 8 intermediate I-8-2
Figure GPA0000285329380000233
Preparation of 4-bromo-N-cyclooctyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole-2-carboxamide
In a 100mL reaction flask, compound I-5-4 (1g, 3.34mmol) was dissolved in DMF (30 mL), naH (96mg, 4.01mmol) was added, reaction was carried out at room temperature for 0.5h, sem-Cl (668mg, 4.01mmol) was added, and stirring was carried out overnight. Concentration, extraction with ethyl acetate and water twice, washing with saturated brine (20 mL), drying the organic phase with anhydrous sodium sulfate, concentration to obtain intermediate I-8-2,1.8g, yield 99%. 1 H NMR(400MHz，DMSO-d 6 )δ：8.00(d，J＝8.0Hz，1H)，7.29(d，J＝2.0Hz，1H)，6.93(d，J＝2.0Hz，1H)，5.70(s，2H)，3.99-3.95(m，1H)，3.49(t，J＝7.6Hz，2H)，1.77-1.53(m，14H)，0.85(J＝7.6Hz，2H)，-0.01(s，9H).
9 preparation of intermediate I-8-3
Figure GPA0000285329380000241
Preparation of 4-bromo-N- ((1S, 2S,3S, 5R) -2, 6-trimethylbicyclo [3.1.1] heptan-3-yl) -1 ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole-2-carboxamide
Compound I-5-5 (320mg, 0.98mmol) was dissolved in DMF (10 mL) in a 100mL reaction flask, naH (28mg, 1.18mmol) was added, the reaction was carried out at room temperature for 0.5h, sem-Cl (197mg, 1.18mmol) was added, and the mixture was stirred for 2 hours. Extracted twice with ethyl acetate and water, washed with saturated brine (20 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated to give intermediate I-8-3, 545mg, 99% yield. LC-MS: [ M + H ]] + 455.17.
Preparation of 10 intermediate I-8-4
Figure GPA0000285329380000242
Preparation of N- (adamantan-2-yl) -4-bromo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole-2-carboxamide
A50 mL single-neck flask was charged with I-5-1 (1.3 g, 4.04mmol), 20mL DMF, naH (194mg, 4.84mmol) was added, and the reaction was carried out at room temperature for 0.5h, sem-Cl (0.859mL, 4.84mmol) was added, and the reaction was carried out at room temperature overnight. EA/water extraction, aqueous extraction three times, organic phase combination, saturated salt water washing once, na 2 SO 4 Drying, filtering and concentrating the crude product, and separating by silica gel (300-400 mesh) column chromatography 5% EA/PE to obtain intermediate I-8-4,1.26g white solid with yield of 70%. 1 H NMR(400MHz，DMSO-d 6 )δ：7.70(d，J＝6.8Hz，1H)，7.26(d，J＝2.0Hz，1H)，6.98(d，J＝2.0Hz，1H)，5.60(s，2H)，3.97-3.95(m，1H)，3.44(t，J＝2.0Hz，2H)，2.07-2.04(m，2H)，1.90-1.70(m，10H)，1.51-1.47(m，2H)，0.79(t，J＝8.0Hz，2H)，-0.06(s，9H).
Preparation of 11 intermediate I-12-1
Figure GPA0000285329380000243
First step preparation of methyl 4-iodo-1H-pyrrole-2-carboxylate
In a 250mL reaction flask, compound B (2.5g, 20mmol) was dissolved In 60mL of anhydrous acetonitrile, and NIS (4.95g, 22mmol), in (OTf) were added 3 (1.12g，2mmol)。Stirred at 0 ℃ for 5 hours, then moved to room temperature and stirred for 1 hour. Extracting with ethyl acetate and water twice, washing with saturated saline solution (20 mL), drying the organic phase with anhydrous sodium sulfate, concentrating, washing with n-hexane, and infrared drying to obtain 5.23g. The crude yield was 99%.
Second step preparation of 4-iodo-1H-pyrrole-2-carboxylic acid
A250 mL reaction flask was charged with Compound C (5.23g, 21mmol) and sodium hydroxide (1.54g, 42mmol), and then heated at 60 ℃ for 4.5 hours with ethanol (50 mL) and water (50 mL). Cooling, concentrating to half of the original volume, adding 1N hydrochloric acid aqueous solution (40 mL) in batches under ice bath condition, adjusting pH to 3-4 to precipitate white solid, filtering, washing with water, draining, and drying to obtain 3.89g with yield of 78.8%.
Third step preparation of 4-iodo-N- ((1R) -9-methyl-9-azabicyclo [3.3.1] nonan-3-yl) -1H-pyrrole-2-carboxamide
In a 100mL reaction flask, compound I-10 (1.63g, 6.86mmol) and tolperiside (1.06g, 6.86mmol) were dissolved in DMF (10 mL), EDCI (1.31g, 6.86mmol) and HOBt (837mg, 6.86mmol) were added, DIPEA (3.61g, 27mmol) was added dropwise in ice bath, and the reaction was carried out at room temperature overnight. Water (20 mL) was added to precipitate a white solid, which was filtered, washed with water and then dried, washed twice with n-hexane and dried to give an off-white solid (2.22 g) in 86.8% yield.
Preparation of tert-butyl 2 ((tert-butyloxycarbonyl) (1R) -9-methyl-9-azabicyclo [3.3.1] nonane-3-acylcarbamoyl) -4-iodo-1H-pyrrole-1-carboxylate in the fourth step
In a 50mL reaction flask, compound I-11-1 (400mg, 1.07mmol) was dissolved in DCM (6 mL) and (Boc) was added 2 O(560mg，2.4mmol)、Et 3 N (325mg, 3.21mmol) and DMAP (13mg, 0.107mmol) were reacted at room temperature overnight. Concentration and column chromatography (MeOH: DCM = 5%) gave 553mg of white solid in 90.1% yield. LC-MS: [ M + H ]] + 574.18.
Preparation of intermediate 12, I-14-1
Figure GPA0000285329380000251
Preparation of 4-iodo-N- ((1R) -9-methyl-9-azabicyclo [3.3.1] nonan-3-yl ] -1 ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrole-2-carboxamide
In a 100mL reaction flask, compound I-11-1 (1g, 3.34mmol) was dissolved in DMF (30 mL), naH (96mg, 4.008mmol) was added, reaction was carried out at room temperature for 0.5h, sem-Cl (668mg, 4.008mmol) was added, and stirring was carried out overnight. Concentrated, extracted twice with ethyl acetate and water, washed with saturated brine (20 mL), and the organic phase dried over anhydrous sodium sulfate and concentrated to give 1.8g, 99% yield. 1 H NMR(400MHz，DMSO-d 6 )δ：8.13(brs，1H)，7.27(d，J＝2.0Hz，1H)，6.98(d，J＝1.6Hz，1H)，5.64(s，2H)，3.55(brs，2H)，3.42(t，J＝8.0Hz，2H)，2.77(brs，3H)，2.73(s，3H)，2.33(brs，2H)，2.05(brs，2H)，1.73(t，J＝7.5Hz，2H)，1.38(brs，2H)，0.77(J＝8.0Hz，2H)，-0.70(s，9H).
Preparation of 13 intermediate I-18-1
Figure GPA0000285329380000252
First step preparation of 1- (tert-butyl) -2-methyl-1H-pyrrole-1, 2-dicarboxylate
A50 mL single-neck flask was charged with Compound B (1g, 8mmol), 30mL of DCM, and tert-butyl dicarbonate (2.2mL, 9.6 mmol), triethylamine (1.33mL, 9.6 mmol), and DMAP (98mg, 0.8mmol) and reacted at room temperature for 1 hour. Extracting with ethyl acetate/water, extracting water layer for three times, mixing organic phases, washing with saturated salt water once, and extracting with Na 2 SO 4 Drying, filtering, concentrating the crude product, washing with 10mL of n-hexane, filtering and drying to obtain 1.5g of light yellow solid with the yield of 83.3%.
Second step preparation of 1- (tert-butyl) -2-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxoborane-2-yl) -1H-pyrrole-1, 2-dicarboxylate
5mL of n-hexane was added to a 50mL two-necked flask and [ Ir (OMe) (COD) was added under nitrogen protection] 2 (18mg, 0.03mmol) and (7mg, 0.03mmol) by dropwise addition of a solution of PinBH (0.2mL, 1.78mmol) in 2mL of n-hexane, the solution became darker in color, and after dropwise addition of I-16 (200 mg,0.89 mmol) in 2mL of n-hexane at room temperature for 7h. Concentration and column chromatography of the crude product on silica gel (300-400 mesh) 5% EA/PE separation gave 175mg of a white solid with a yield of 56%.
Third step preparation of 4- (pyridin-2-yl) -1H-pyrrole-2-carboxylic acid methyl ester
A50 mL single-necked flask was charged with I-17 (300mg, 0.85mmol), 2-bromopyridine (0.12mL, 1.28mmol), pd (PPh) 3 ) 4 (100mg，0.09mmol)，Na 2 CO 3 (272mg, 2.55mmol), 15mL dioxane, 10mL water, under nitrogen at 80 ℃ for 7h. EA/water extraction, aqueous extraction three times, organic phase combination, saturated salt water washing once, na 2 SO 4 Drying, filtering and concentrating the crude product, subjecting to silica gel (300-400 mesh) column chromatography, and separating by 40% EA/PE elution to obtain 103mg of oily liquid with a yield of 60%. 1 H NMR(400MHz，DMSO-d 6 )δ：8.48(d，J＝4.8Hz，1H)，7.72(d，J＝3.2Hz，2H)，7.66(d，J＝1.6Hz，1H)，7.35(d，J＝1.6Hz，1H)，7.17-7.13(m，1H)，3.80(s，3H).
14 preparation of intermediate I-18-2
Figure GPA0000285329380000261
Preparation of methyl 4- (pyrimidin-5-yl) -1H-pyrrole-2-carboxylate
To a 50mL single-necked flask were added I-17 (300mg, 0.85mmol), 5-bromopyrimidine (200mg, 1.28mmol), pd (PPh) 3 ) 4 (100mg，0.09mmol)，Na 2 CO 3 (272mg, 2.55mmol), 15mL dioxane, 10mL water, under nitrogen protection at 80 ℃ for 12h. EA/water extraction, water layer extraction three times, organic phase combination, saturated salt water washing once, na 2 SO 4 Drying, filtration and concentration the crude product obtained was subjected to silica gel (300-400 mesh) column chromatography and isolated by 70% EA/PE elution to give 145mg of a pale yellow solid with a yield of 84.3%. 1 H NMR(400MHz，DMSO-d 6 )δ：12.34(s，1H)，9.11(s，2H)，8.97(s，1H)，7.77(dd，J＝2.8，1.6Hz，1H)，7.41(t，J＝2.0Hz，1H)，3.81(s，3H).
15 preparation of intermediate I-18-3
Figure GPA0000285329380000262
Preparation of methyl 4- (6-methylpyridin-3-yl) -1H-pyrrole-2-carboxylate
A50 mL single-necked flask was charged with I-17 (300mg, 0.85mmol), 6-methyl-3-bromopyridine (221mg, 1.28mmol), pd (PPh) 3 ) 4 (100mg，0.09mmol)，Na 2 CO 3 (272mg, 2.55mmol), 15mL dioxane, 10mL water, under nitrogen at 80 ℃ for 3h. EA/water extraction, aqueous extraction three times, organic phase combination, saturated salt water washing once, na 2 SO 4 Drying, filtering and concentrating to obtain crude product, performing silica gel (300-400 mesh) column chromatography, and separating by 20% -30% EA/PE elution to obtain 120mg of light yellow solid with yield of 59%. 1 H NMR(400MHz，DMSO-d 6 )δ：12.17(s，1H)，8.76(s，1H)，7.95(dd，J＝8.0，1.6Hz，1H)，7.61(s，1H)，7.26-7.23(m，2H)，3.79(s，3H)，2.45(s，3H).
Preparation of 16 intermediate I-18-4
Figure GPA0000285329380000263
Preparation of methyl 4- (2-fluoropyrimidin-5-yl) -1H-pyrrole-2-carboxylate
To a 50mL single-neck bottle were added I-17 (300mg, 0.85mmol), 2-fluoro-5-bromopyrimidine (227mg, 1.28mmol), pd (PPh) 3 ) 4 (100mg，0.09mmol)，Na 2 CO 3 (272mg, 2.55mmol), 15mL dioxane, 10mL water, under nitrogen at 80 ℃ for 6h. EA/water extraction, water layer extraction three times, organic phase combination, saturated salt water washing once, na 2 SO 4 Drying, filtering and concentrating the crude product, subjecting to silica gel (300-400 mesh) column chromatography, and separating by 20% EA/PE elution to obtain 100mg of off-white solid with a yield of 53%. 1 H NMR(400MHz，DMSO-d 6 )δ：12.33(s，1H)，9.09(s，2H)，7.75(dd，J＝3.2，1.6Hz，1H)，7.41(dd，J＝2.4，1.6Hz，1H)，3.80(s，3H).
17 preparation of intermediate I-18-5
Figure GPA0000285329380000271
Preparation of 4- (6-fluoro-2-methylpyridin-3-yl) -1H-pyrrole-2-carboxylic acid methyl ester
To a 50mL single-necked flask were added I-17 (300mg, 0.85mmol), 6-fluoro-2-methyl-3-bromopyridine (243mg, 1.28mmol), pd (PPh) 3 ) 4 (100mg，0.09mmol)，Na 2 CO 3 (272mg, 2.55mmol), 15mL dioxane, 10mL water, under nitrogen at 80 ℃ for 3h. EA/water extraction, aqueous extraction three times, organic phase combination, saturated salt water washing once, na 2 SO 4 Drying, filtering and concentrating the crude product, subjecting to silica gel (300-400 mesh) column chromatography, and separating by 20% EA/PE elution to obtain 50mg of off-white solid with a yield of 25%. 1 H NMR(400MHz，DMSO-d 6 )δ：12.23(s，1H)，7.92(t，J＝8.4Hz，1H)，7.31(t，J＝1.6Hz，1H)，7.03(t，J＝1.6Hz，1H)，6.98(dd，J＝8.4，3.6Hz，1H)，3.79(s，3H)，2.49(s，3H).
Example 1
Figure GPA0000285329380000272
4- (3, 5-dichlorophenyl) -N- (4, 4-dimethylcyclohexyl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000273
By a similar operation as in the preparation of intermediate I-3-1, intermediate I-3-2 (180mg, 0.67mmol) was obtained, which was placed in a reaction flask and added with compound 4, 4-dimethylcyclohexylamine (118mg, 0.93mmol) and HATU (353mg, 0.93mmol), DMF (5 mL) was added, DIPEA (240mg, 1.86mmol) was added dropwise under ice bath,the reaction was carried out at room temperature for 3 hours. Water (5 mL) and ethyl acetate (15 mL) were added under ice-bath, and the organic phase was washed with 1N HCl solution, saturated sodium bicarbonate solution and saturated brine, respectively, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (EA in PE = 2-6%) to obtain compound 1 as an off-white solid (60 mg, yield 25%). 1 H NMR(400MHz，DMSO-d 6 )δ11.76(s，1H)，7.79-7.70(m，1H)，7.62-7.48(m，3H)，7.36-7.22(m，2H)，3.78-3.56(m，1H)，1.79-1.08(m，8H)，0.95(s，3H)，0.93(s，3H).
Example 2
Figure GPA0000285329380000281
4- (2, 4-dichlorophenyl) -N- (4, 4-dimethylcyclohexyl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000282
Using 4, 4-dimethylcyclohexylamine hydrochloride (450mg, 2.75mmol) as a starting material, the similar procedure as in example 1 was followed to give compound 2 as an off-white solid, 420mg, 42% yield. 1 H NMR(400MHz，CDCl 3 )δ9.61(s，1H)，7.44(d，J＝2.0Hz，1H)，7.35(d，J＝8.4Hz，1H)，7.26-7.25(m，1H)，7.22(dd，J＝2.0，8.4Hz，1H)，6.79(dd，J＝1.2，2.8Hz，1H)，5.78(d，J＝7.2Hz，1H)，3.95-3.81(m，1H)，1.88-1.84(m，2H)，1.44-1.33(m，6H)，0.93(s，6H).
Example 3
Figure GPA0000285329380000283
4- (2, 4-difluorophenyl) -N- (4, 4-dimethylcyclohexyl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000284
Using 4, 4-dimethylcyclohexylamine (62mg, 0.49mmol) as a starting material, the similar procedures as in example 1 were carried out to give compound 3 as an off-white solid in 60mg at a yield of 37%. 1 H NMR(500MHz，CDCl 3 )δ9.78(s，1H)，7.64-7.52(m，1H)，6.97-6.85(m，2H)，6.56(s，2H)，5.74(d，J＝5.5Hz，1H)，3.89(brs，1H)，1.93-1.79(m，2H)，1.51-1.30(m，6H)，0.94(s，6H).
Example 4
Figure GPA0000285329380000285
N- (adamantan-2-yl) -4-phenyl-1H-pyrrole-2-carboxamide
Figure GPA0000285329380000291
A50 mL reaction flask was charged with Compound I-6-1 (300mg, 0.71mmol), phenylboronic acid (130mg, 1.06mmol), sodium carbonate (226mg, 2.13mmol), and bis (triphenylphosphine) palladium dichloride (50mg, 0.07mmol) and, under argon, dioxane (8 mL) and water (2 mL) were injected and heated at 60 ℃ for 3 hours. After cooling, water (10 mL) and EA (20 mL) were added, and the organic phase was treated with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a brown solid. The above solid was dissolved in DCM (3 mL), added TFA (3 mL), stirred at room temperature for 2 hours, concentrated, and column chromatographed (EA in PE = 2-6%) to give compound 4 as an off-white solid 90mg, yield 40%. 1 H NMR(400MHz，DMSO-d 6 )δ11.62(s，1H)，7.64-7.52(m，2H)，7.42-7.28(m，5H)，7.14(t，J＝7.2Hz，1H)，4.08-4.01(m，1H)，2.18-2.06(m，2H)，1.94(brs，2H)，1.88-1.76(m，6H)，1.73(s，2H)，1.59-1.49(m，2H).
Example 5
Figure GPA0000285329380000292
N- (adamantan-2-yl) -4- (2, 4-dichlorophenyl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000293
Using 2-adamantanamine hydrochloride (55mg, 0.29mmol) as a starting material, the similar procedure as in example 1 was carried out to give compound 5 as an off-white solid (54 mg, yield 47%). 1 H NMR(400MHz，DMSO-d 6 )δ11.82(s，1H)，7.82-7.59(m，2H)，7.47(d，J＝6.8Hz，1H)，7.42(dd，J＝2.0，8.4Hz，1H)，7.38(brs，1H)，7.36-7.35(m，1H)，4.07-4.05(m，1H)，2.12-2.09(m，2H)，1.94-1.72(m，10H)，1.55-1.52(m，2H).
Example 6
Figure GPA0000285329380000294
N- (adamantan-2-yl) -4- (2-chlorophenyl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000295
Using 2-chlorobenzeneboronic acid (166mg, 1.06mmol) as a starting material and following the procedure similar to example 4, compound 6 was obtained in the form of an off-white solid (60 mg, 24% yield). 1 H NMR(400MHz，DMSO-d 6 )δ11.77(s，1H)，7.58(dd，J＝7.8，1.6Hz，1H)，7.47(dd，J＝8.0，1.2Hz，2H)，7.40-7.36(m，1H)，7.36-7.30(m，2H)，7.25-7.19(m，1H)，4.07-4.05(m，1H)，2.16-2.05(m，2H)，1.94(brs，2H)，1.89-1.76(m，6H)，1.72(brs，2H)，1.57-1.49(m，2H).
Example 7
Figure GPA0000285329380000301
N- (adamantan-2-yl) -4- (2, 4-difluorophenyl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000302
Using 2-adamantanamine hydrochloride (50mg, 0.27mmol) as a starting material, the similar procedure as in example 1 was followed to give compound 7 as an off-white solid in a yield of 30mg and 31%. 1 H NMR(400MHz，CDCl 3 )δ9.68(s，1H)，7.55-7.46(m，1H)，7.29(brs，1H)，6.93-6.83(m，3H)，6.26(s，1H)，4.25-4.23(m，1H)，2.05(brs，2H)，1.95-1.83(m，6H)，1.79(brs，2H)，1.76-1.67(m，2H)。
Example 8
Figure GPA0000285329380000303
N- (adamantan-2-yl) -4- (4-chlorophenyl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000304
Using 4-chlorobenzeneboronic acid (234mg, 1.5 mmol) as a starting material and through the similar procedure as in example 4, compound 8 was obtained in the form of an off-white solid (80 mg) with a yield of 23%. 1 H NMR(400MHz，CDCl 3 )δ9.58(s，1H)，7.46-7.38(m，2H)，7.34-7.28(m，2H)，7.16(dd，J＝1.6，2.8Hz，1H)，6.77(dd，J＝1.6，2.4Hz，1H)，6.23(d，J＝6.4Hz，1H)，4.23-4.21(m，1H)，2.03(brs，2H)，1.94-1.82(m，6H)，1.77(brs，2H)，1.75-1.67(m，2H)，1.64(brs，2H)。
Example 9
Figure GPA0000285329380000305
N- (adamantan-2-yl) -4- (4-fluorophenyl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000311
Using 4-fluorophenylboronic acid (210mg, 1.5 mmol) as a starting material and through the similar procedures as in example 4, compound 9 was obtained as an off-white solid (30 mg, yield 8.9%). 1 H NMR(400MHz，DMSO-d 6 )δ11.63(s，1H)，7.64-7.56(m，2H)，7.42-7.22(m，3H)，7.23-7.03(m，2H)，4.07-4.02(m，1H)，2.15-2.06(m，2H)，1.93(brs，2H)，1.89-1.76(m，6H)，1.73(brs，2H)，1.58-1.50(m，2H)。
Example 10
Figure GPA0000285329380000312
N- (adamantan-2-yl) -4- (2-fluorophenyl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000313
Using 2-fluorophenylboronic acid (104mg, 0.75mmol) as a starting material and through the similar procedures as in example 4, compound 10 was obtained as an off-white solid (30 mg, 18% yield). 1 H NMR(400MHz，DMSO-d 6 )δ11.75(s，1H)，7.74-7.65(m，1H)，7.52-7.41(m，2H)，7.34-7.28(m，1H)，7.25-7.15(m，3H)，4.12-4.02(m，1H)，2.17-2.07(m，2H)，1.95(brs，2H)，1.89-1.76(m，6H)，1.73(brs，2H)，1.59-1.48(m，2H)。
Example 11
Figure GPA0000285329380000314
N- (adamantan-2-yl) -4- (2, 4-dimethoxyphenyl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000315
Using 2, 4-dimethoxyphenylboronic acid (129mg, 0.7 mmol) as a starting material, the same procedures used in example 4 were repeated to give compound 11 as an off-white solid in a yield of 35mg (19%). 1 H NMR(500MHz，DMSO-d 6 )δ11.45(s，1H)，7.50(d，J＝8.5Hz，1H)，7.37-7.30(m，2H)，7.25(s，1H)，6.59(s，1H)，6.54(d，J＝8.5Hz，1H)，4.05(s，1H)，3.84(s，3H)，3.77(s，3H)，2.15-2.07(m，2H)，1.93(brs，2H)，1.89-1.77(m，6H)，1.73(brs，2H)，1.58-1.49(m，2H)。
Example 12
Figure GPA0000285329380000321
N- (adamantan-2-yl) -4- (2, 4-bis-trifluoromethylphenyl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000322
Using 2, 4-bis (trifluoromethyl) phenylboronic acid (183mg, 0.7 mmol) as a starting material and the similar procedure as in example 4, compound 12 was obtained as an off-white solid (40 mg, 19% yield). 1 H NMR(400MHz，DMSO-d 6 )δ11.93(s，1H)，8.05-8.04(m，2H)，7.79(d，J＝8.4Hz，1H)，7.52(d，J＝7.2Hz，1H)，7.24(s，1H)，7.13(brs，1H)，4.11-4.03(m，1H)，2.14-2.06(m，2H)，1.95(brs，2H)，1.89-1.76(m，6H)，1.72(brs，2H)，1.57-1.46(m，2H)。
Example 13
Figure GPA0000285329380000323
N- (adamantan-2-yl) -4- (2, 4-dimethylphenyl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000324
Using 2, 4-dimethoxyphenylboronic acid (106mg, 0.7 mmol) as a starting material and by a similar procedure as in example 4, compound 13 was obtained as an off-white solid (60 mg, yield 37%). 1 H NMR(400MHz，CDCl 3 )δ9.90(s，1H)，7.23(d，J＝8.0Hz，1H)，7.16-6.93(m，3H)，6.66(s，1H)，6.41-6.21(m，1H)，4.25(brs，1H)，2.38(s，3H)，2.34(s，3H)，2.18-1.62(m，14H)。
Example 14
Figure GPA0000285329380000325
N- (adamantan-2-yl) -4- (2-fluoro-4-methoxyphenyl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000331
Using 2-fluoro-4-methoxyphenylboronic acid (211mg, 1.24mmol) as a starting material and following the procedure analogous to that described in example 4, compound 14 was obtained as an off-white solid in 70mg, 27% yield. 1 H NMR(500MHz，DMSO-d 6 )δ11.93(s，1H)，7.88(t，J＝8.0Hz，1H)，7.78(d，J＝8.5Hz，1H)，7.71(d，J＝12.0Hz，1H)，7.58-7.50(m，2H)，7.45(brs，1H)，4.09-4.02(m，1H)，3.86(s，3H)，2.17-2.07(m，2H)，1.95(brs，2H)，1.90-1.76(m，6H)，1.73(brs，2H)，1.59-1.50(m，2H)。
Example 15
Figure GPA0000285329380000332
N- (adamantan-2-yl) -4- (4-fluoro-2-methoxyphenyl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000333
Using 2-adamantanamine hydrochloride (50mg, 0.27mmol) as a starting material, the procedure similar to that in example 1 was carried out to give compound 15 in the form of a white powdery solid (65 mg, 33% yield). 1 H NMR(400MHz，CDCl 3 )δ9.57(s，1H)，7.46-7.40(m，1H)，7.37(brs，1H)，6.87(brs，1H)，6.75-6.59(m，2H)，6.31-6.23(m，1H)，4.27-4.19(m，1H)，3.89(s，3H)，2.04(brs，2H)，1.95-1.81(m，8H)，1.78(brs，2H)，1.76-1.65(m，2H)。
Example 16
Figure GPA0000285329380000334
N- (adamantan-2-yl) -4- (2-fluoro-4-hydroxyphenyl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000335
Using 2-fluoro-4-hydroxyphenylboronic acid (117mg, 0.75mmol) as a starting material, through the similar procedure as in example 4, compound 16 was obtained in the form of a white powdery solid (35 mg, yield 20%). 1 H NMR(400MHz，DMSO-d 6 )δ13.09(s，1H)，11.93(s，1H)，7.83(t，J＝8.0Hz，1H)，7.75(dd，J＝1.6，8.0Hz，1H)，7.66(dd，J＝1.6，12.0Hz，1H)，7.56-7.48(m，2H)，7.46-7.41(m，1H)，4.06-4.04(m，1H)，2.13-2.10(m，2H)，1.94-1.72(m，10H)，1.55-1.52(m，2H)。
Example 17
Figure GPA0000285329380000341
4- (2, 4-dichlorophenyl) -N- (5-hydroxyadamantan-2-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000342
In a 100mL reaction flask, compound I-3-1 (100mg, 0.4 mmol) and 4-aminoadamantan-1-ol (66mg, 0.4 mmol) were dissolved in DMF (5 mL), EDCI (82mg, 0.43mmol) and HOBt (60mg, 0.43mmol) were added, DIPEA (151mg, 1.2mmol) was added dropwise under ice bath, and the reaction was carried out overnight at room temperature. Water (5 mL) and ethyl acetate (15 mL) were added under ice-bath, and the organic phase was washed with 1N HCl solution, saturated sodium bicarbonate solution and saturated brine, respectively, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (MeOH in DCM = 1-4%) to obtain an off-white solid 20mg in 12% yield. 1 H NMR(400MHz，DMSO-d 6 )δ11.83(s，1H)，7.62(d，J＝2.4Hz，1H)，7.55(d，J＝8.4Hz，1H)，7.45-7.41(m，2H)，7.39-7.38(m，1H)，7.34(dd，J＝1.6，2.8Hz，1H)，4.45(s，1H)，3.99-3.94(m，1H)，2.06-1.97(m，5H)，1.74-1.71(m，2H)，1.65-1.62(m，4H)，1.36-1.33(m，2H).
Example 18
Figure GPA0000285329380000343
4- (2, 4-difluorophenyl) -N- (5-hydroxyadamantan-2-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000344
Column chromatography (EA in PE = 30-60%) using 4-aminoadamantan-1-ol (123mg, 0.74mmol) as the starting material and the similar procedure as in example 17 gave compound 18 as a white powdery solid, 30mg, yield 11%. 1 H NMR(400MHz，DMSO-d 6 )δ11.77(s，1H)，7.76-7.66(m，1H)，7.46-7.38(m，2H)，7.29-7.18(m，2H)，7.14-7.07(m，1H)，4.47(s，1H)，4.01-3.92(m，1H)，2.13-1.93(m，5H)，1.80-1.56(m，6H)，1.40-1.30(m，2H)。
Example 19
Figure GPA0000285329380000345
4- (2, 4-dichlorophenyl) -N-cyclohexyl-1H-pyrrole-2-carboxamide
Figure GPA0000285329380000351
Column chromatography (EA in PE = 2-7%) using cyclohexylamine (55mg, 0.55mmol) as the starting material, using the similar procedure as in example 17, gave compound 19 as a white powdery solid in 104mg with a yield of 62%.1H NMR (400MHz, DMSO-d) 6 )δ11.75(s，1H)，7.85(d，J＝8.0Hz，1H)，7.61(d，J＝2.4Hz，1H)，7.55(d，J＝8.8Hz，1H)，7.41(dd，J＝2.4，8.4Hz，1H)，7.32-7.26(m，1H)，7.24(brs，1H)，3.81-3.65(m，1H)，1.90-1.54(m，5H)，1.39-1.06(m，5H).
Example 20
Figure GPA0000285329380000352
4- (2, 4-dichlorophenyl) -N-cycloheptyl-1H-pyrrole-2-carboxamide
Figure GPA0000285329380000353
Column chromatography (EA in PE = 2-7%) using cycloheptylamine (68mg, 0.6 mmol) as the starting material and using the similar procedure as in example 17 gave compound 20 as a white powdery solid at 60mg in 28% yield. 1 H NMR(400MHz，CDCl 3 )δ9.85(s，1H)，7.43(s，1H)，7.35(d，J＝8.0Hz，1H)，7.33-7.18(m，2H)，6.79(s，1H)，5.91(brs，1H)，4.13(brs，1H)，2.12-1.87(m，2H)，1.76-1.46(m，10H)。
Example 21
Figure GPA0000285329380000354
4- (2, 4-dichlorophenyl) -N-cyclooctyl-1H-pyrrole-2-carboxamide
Figure GPA0000285329380000355
Column chromatography (EA in PE = 2-7%) using cyclooctylamine (76mg, 0.6 mmol) as the starting material and the similar procedure as in example 17 gave compound 21 as a white powdery solid, 90mg, yield 54%. 1 H NMR(400MHz，DMSO-d 6 )δ11.72(s，1H)，7.86(d，J＝8.4Hz，1H)，7.61(d，J＝2.4Hz，1H)，7.55(d，J＝8.4Hz，1H)，7.41(dd，J＝2.4，8.4Hz，1H)，7.31-7.28(m，1H)，7.20(t，J＝2.0Hz，1H)，4.05-3.91(m，1H)，1.81-1.42(m，14H)。
Example 22
Figure GPA0000285329380000361
N- (adamantan-2-yl) -4- (3-fluoropyridin-4-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000362
Using (3-fluoropyridin-4-yl) boronic acid (210mg, 1.5 mmol) as a starting material and the similar procedure in example 4, compound 22 was obtained in the form of a white powdery solid (40 mg, yield 12%). 1 H NMR(400MHz，DMSO-d 6 )δ12.06(s，1H)，8.51(d，J＝3.2Hz，1H)，8.33(d，J＝4.8Hz，1H)，7.72(dd，J＝5.2，6.8Hz，1H)，7.61-7.51(m，3H)，4.12-3.98(m，1H)，2.19-2.04(m，2H)，2.04-1.68(m，10H)，1.63-1.46(m，2H)。
Example 23
Figure GPA0000285329380000363
N- (adamantan-2-yl) -4- (2, 6-difluoropyridin-3-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000364
Using (2, 6-difluoropyridin-3-yl) boronic acid (110mg, 0.75mmol) as a starting material and through the similar procedures as in example 4, compound 23 was obtained as a white powdery solid at 25mg in 14% yield. 1 H NMR(400MHz，DMSO-d 6 )δ11.89(s，1H)，8.43-8.36(m，1H)，7.50(d，J＝7.2Hz，1H)，7.47-7.44(m，1H)，7.40-7.36(m，1H)，7.16(dd，J＝2.4，8.0Hz，1H)，4.10-4.02(m，1H)，2.17-2.05(m，2H)，1.94(brs，2H)，1.90-1.75(m，6H)，1.73(brs，2H)，1.59-1.49(m，2H)。
Example 24
Figure GPA0000285329380000365
N- (adamantan-2-yl) -4- (pyridin-3-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000366
Using pyridin-3-ylboronic acid (92mg, 0.75mmol) as a starting material and through the similar procedure as in example 4, compound 24 was obtained in the form of a white powdery solid (30 mg, yield 19%). 1 H NMR(400MHz，DMSO-d 6 )δ11.78(s，1H)，8.84(d，J＝1.6Hz，1H)，8.33(dd，J＝1.6，4.8Hz，1H)，7.90(dt，J＝2.0，8.0Hz，1H)，7.49-7.40(m，2H)，7.39(d，J＝7.2Hz，1H)，7.33(dd，J＝4.8，8.0Hz，1H)，4.09-4.01(m，1H)，2.19-2.06(m，2H)，1.94(brs，2H)，1.89-1.76(m，6H)，1.73(m，2H)，1.61-1.50(m，2H)。
Example 25
Figure GPA0000285329380000371
N- (adamantan-2-yl) -4- (3-chloropyridin-4-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000372
Using (3-chloropyridin-4-yl) boronic acid (236mg, 1.5mmol) as a starting material and through the similar procedure as in example 4, compound 25 was obtained in the form of a white powdery solid (40 mg) with a yield of 11%. 1 H NMR(400MHz，DMSO-d 6 )δ12.05(s，1H)，8.58(s，1H)，8.43(d，J＝5.2Hz，1H)，7.68-7.62(m，2H)，7.62-7.58(m，1H)，7.54(d，J＝7.0Hz，1H)，4.10-4.02(m，1H)，2.16-2.05(m，2H)，1.95(brs，2H)，1.88-1.77(m，6H)，1.73(brs，2H)，1.58-1.48(m，2H)。
Example 26
Figure GPA0000285329380000373
N- (adamantan-2-yl) -4- (pyridin-4-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000374
Using pyridin-4-ylboronic acid (92mg, 0.75mmol) as a starting material and through the similar procedure as in example 4, compound 26 was obtained in the form of a white powdery solid (20 mg, yield 12%). 1 H NMR(400MHz，DMSO-d 6 )δ11.97(s，1H)，8.48(s，2H)，7.89-7.24(m，5H)，4.01(brs，1H)，2.31-1.44(m，14H)。
Example 27
Figure GPA0000285329380000381
N- (adamantan-2-yl) -4- (3-methoxy-pyridin-4-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000382
Using (3-methoxypyridin-4-yl) boronic acid (114mg, 0.75mmol) as a starting material and the similar procedure in example 4, compound 27 was obtained as a white powdery solid in an amount of 10mg with a yield of 6%. 1 H NMR(400MHz，DMSO-d 6 )δ11.93(s，1H)，7.85(t，J＝8.0Hz，1H)，7.77(dd，J＝1.6，8.4Hz，1H)，7.70(dd，J＝1.6，12.1Hz，1H)，7.57-7.50(m，2H)，7.46-7.42(m，1H)，4.09-4.01(m，1H)，3.86(s，3H)，2.17-2.06(m，2H)，1.94(brs，2H)，1.89-1.76(m，6H)，1.72(brs，2H)，1.59-1.50(m，2H)。
Example 28
Figure GPA0000285329380000383
4- (3-Chloropyridin-4-yl) -N- (4, 4-dimethylcyclohexyl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000384
Using (3-chloropyridin-4-yl) boronic acid (236mg, 1.5mmol) as a starting material and through the similar procedure as in example 4, compound 28 was obtained in the form of a white powdery solid (80 mg) with a yield of 24%. 1 H NMR(400MHz，DMSO-d 6 )δ11.96(s，1H)，8.58(s，1H)，8.41(d，J＝5.2Hz，1H)，7.94(d，J＝8.4Hz，1H)，7.60-7.58(m，2H)，7.44(d，J＝2.0Hz，1H)，3.86-3.65(m，1H)，1.79-1.17(m，8H)，0.95(s，3H)，0.93(s，3H).
Example 29
Figure GPA0000285329380000385
N- (adamantan-2-yl) -4- (quinolin-3-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000386
Using quinoline-3-boronic acid pinacol ester (90mg, 0.35mmol) as a starting material and through the similar procedures as in example 4, compound 29 was obtained as a pale yellow powder with 20mg of solid in a yield of 23%. 1 H NMR(400MHz，DMSO-d 6 )δ11.85(s，1H)，9.23(d，J＝2.4Hz，1H)，8.43(d，J＝2.4Hz，1H)，7.97(d，J＝8.0Hz，1H)，7.91(d，J＝7.6Hz，1H)，7.69-7.63(m，2H)，7.63-7.54(m，2H)，7.46(d，J＝6.8Hz，1H)，4.11-4.04(m，1H)，2.19-2.09(m，2H)，1.96(brs，2H)，1.91-1.78(m，6H)，1.74(brs，2H)，1.61-1.52(m，2H)。
Example 30
Figure GPA0000285329380000391
N- (adamantan-2-yl) -4- (2-methoxypyrimidin-5-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000392
A50 mL single-neck flask was charged with I-18-4 (90mg, 0.41mmol), naOH (163mg, 4.1mmol), 20mL MeOH, and 5mL H 2 O, reacting at 90 ℃ for 2h. Adjusting pH to weak acidity with 1N HCl, EA/water extraction, water layer extraction three times, combining organic phases, washing with saturated salt solution once, na 2 SO 4 Dried, filtered and concentrated for the next step. To the product of the above step was added 20mL of DMF, EDCI (157 mg)0.82 mmol), 2-adamantanamine hydrochloride (77mg, 0.41mmol), HOBt (50mg, 0.41mmol), DIPEA (0.29mL, 1.64mmol), at room temperature overnight. EA/water extraction, water layer extraction three times, organic phase combination, saturated salt water washing once, na 2 SO 4 Drying, filtering and concentrating the crude product, subjecting to silica gel (300-400 mesh) column chromatography, and separating by 70% EA/PE elution to obtain compound 30 as off-white solid 60mg with a two-step yield of 42%. m.p.:245-247 ℃. 1 H NMR(400MHz，DMSO-d 6 )δ11.79(s，1H)，8.82(s，2H)，7.46(dd，J＝2.8，1.6Hz，1H)，7.40-7.37(m，2H)，4.06-4.04(m，1H)，3.91(s，3H)，2.10(d，J＝12.4Hz，2H)，1.93-1.73(m，10H)，1.54(d，J＝12.8Hz，2H).
Example 31
Figure GPA0000285329380000393
N- (adamantan-2-yl) -4- (pyrimidin-5-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000394
Using intermediate I-18-2 (145mg, 0.72mmol) as a starting material, the similar procedure as in example 30 was conducted to give compound 31 as a white powdery solid in a yield of 100 mg. 1 H NMR(400MHz，DMSO-d 6 )δ11.93(s，1H)，9.03(s，2H)，8.95(s，1H)，7.62(dd，J＝2.8，1.6Hz，1H)，7.53-7.52(m，1H)，7.40(d，J＝7.2Hz，1H)，4.07-4.02(m，1H)，2.11(d，J＝12.8Hz，2H)，1.99-1.73(m，10H)，1.55(d，J＝12.4Hz，2H).
Example 32
Figure GPA0000285329380000401
N- (adamantan-2-yl) -4- (pyridin-2-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000402
Using intermediate I-18-1 (103mg, 0.50mmol) as a starting material, through the similar procedures as in example 30, compound 32 was obtained in the form of a white powdery solid (40 mg, yield 25%). 1 H NMR(400MHz，DMSO-d 6 )δ11.72(s，1H)，8.47(d，J＝4.0Hz，1H)，7.71(t，J＝7.6Hz，1H)，7.63(d，J＝8.0Hz，1H)，7.57(s，1H)，7.51(s，2H)，7.12-7.10(m，1H)，4.05(s，1H)，2.13(d，J＝12.8Hz，2H)，1.94-1.73(m，10H)，1.53(d，J＝12.8Hz，2H).
Example 33
Figure GPA0000285329380000403
N- (adamantan-2-yl) -4- (2-fluoro-pyridin-3-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000404
To a 50mL single-necked flask were added I-6-1 (100mg, 0.24mmol), 2-fluoro-3-pyridineboronic acid (50mg, 0.35mmol), pd (PPh) 3 ) 4 (27mg，0.02mmol)，Na 2 CO 3 (75mg, 0.72mmol), 20mL dioxane, 5mL water, under nitrogen at 80 ℃ reaction overnight. EA/water extraction, water layer extraction three times, organic phase combination, saturated salt water washing once, na 2 SO 4 Drying, filtering and concentrating the crude product, subjecting to silica gel (300-400 mesh) column chromatography, and separating by 10% EA/PE elution to obtain compound 33 as an off-white solid (10 mg, yield 12.5%). m.p.:216-218 ℃. 1 H NMR(500MHz，DMSO-d 6 )δ11.88(s，1H)，8.21(t，J＝8.5Hz，1H)，8.01(s，1H)，7.50(s，2H)，7.40-7.36(m，2H)，4.06(s，1H)，2.11(d，J＝12.5Hz，2H)，1.95-1.73(m，10H)，1.54(d，J＝12.0Hz，2H).
Example 34
Figure GPA0000285329380000405
N- (adamantan-2-yl) -4- (6-fluoro-pyridin-3-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000406
The similar procedure used in example 33 was repeated except for using intermediate I-6-1 (128mg, 0.30mmol) and 4-fluoro-3-pyridineboronic acid (72mg, 0.51mmol) as starting materials to give compound 34 as an off-white solid in a yield of 30% m.p. of 213-215 ℃. 1 H NMR(400MHz，DMSO-d 6 )δ11.79(s，1H)，8.46(d，J＝2.4Hz，1H)，8.15(td，J＝8.4，2.8Hz，1H)，7.48-7.47(m，1H)，7.44-7.43(m，1H)，7.38(d，J＝7.2Hz，1H)，7.16(dd，J＝8.4，2.8Hz，1H)，4.06-4.04(m，1H)，2.12-2.09(m，2H)，1.99-1.73(m，10H)，1.56-1.53(m，2H).
Example 35
Figure GPA0000285329380000411
N- (adamantan-2-yl) -4- (6-chloro-pyridin-3-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000412
A50 mL single-necked flask was charged with I-8-4 (90mg, 0.20mmol), 20mL dioxane, 5mL water, 4-chloro-3-pyridineboronic acid (47mg, 0.30mmol), pd (PPh) 3 ) 4 (23mg，0.02mmol)，Na 2 CO 3 (63mg, 0.60mmol). Reacting at 80 ℃ under the protection of nitrogen, gradually changing the solution into a black opaque solution, and reacting for 6 hours. EA/water extraction, aqueous extraction three times, organic phase combination, saturated salt water washing once, na 2 SO 4 Drying, filtering and concentrating the crude product, separating by silica gel (300-400 mesh) column chromatography 5% -10% EA/PE to obtain 35mg oily liquid, placing in a 50mL single-neck bottle, adding 10mL TBAF (1.0M in THF), and reacting at 70 deg.C for 3h. EA/water extraction, water layer extraction three times, organic phase combination, saturated salt water washing once, na 2 SO 4 Drying, filtering and concentrating the resulting crude product, subjecting to silica gel (300-400 mesh) column chromatography, and isolating by 25% EA/PE elution to give compound 35, off-white solid 15mg, two-step yield 21.1%. m.p.: is > 250 ℃. 1 H NMR(500MHz，DMSO-d 6 )δ11.84(s，1H)，8.66(s，1H)，8.03(d，J＝8.0Hz，1H)，7.53(s，1H)，7.47(s，2H)，7.39(d，J＝7.5Hz，1H)，4.05(s，1H)，2.10(d，J＝13.5Hz，2H)，1.93-1.73(m，10H)，1.55(d，J＝12.5Hz，2H).
Example 36
Figure GPA0000285329380000413
N- (adamantan-2-yl) -4- (3-chloro-pyridin-3-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000414
Using intermediate I-6-1 (100mg, 0.24mmol) and 2-chloro-3-pyridineboronic acid (56mg, 0.35mmol) as starting materials, the similar procedure to that in example 33 was followed to give compound 36 as an off-white solid in a yield of 10mg (12%). m.p.:225-227 ℃. 1 H NMR(400MHz，DMSO-d 6 )δ11.88(s，1H)，8.25(dd，J＝4.4，1.6Hz，1H)，8.02(dd，J＝8.0，2.0Hz，1H)，7.49(d，J＝7.2Hz，1H)，7.45-7.42(m，3H)，4.07-4.05(m，1H)，2.11(d，J＝12.4Hz，2H)，1.94-1.72(m，10H)，1.54(d，J＝12.4Hz，2H).
Example 37
Figure GPA0000285329380000421
N- (adamantan-2-yl) -4- (2-methoxy-pyridin-3-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000422
Using compound I-8-4 (200mg, 0.44mmol), 2-methoxy-3-pyridineboronic acid (135mg, 0.88mmol) as a starting material, the similar procedure as in example 35 was carried out to give compound 37 as an off-white solid in a yield of 65mg, 42%. m.p.:194 to 196 ℃ is adopted. 1 H NMR(500MHz，DMSO-d 6 )δ11.66(s，1H)，7.97(dd，J＝14.0，5.5Hz，2H)，7.49-7.40(m，3H)，7.02-7.00(m，1H)，4.06(s，1H)，3.97(s，3H)，2.11(d，J＝12.5Hz，2H)，1.94-1.73(m，10H)，1.54(d，J＝12.5Hz，2H).
Example 38
Figure GPA0000285329380000423
N- (adamantan-2-yl) -4- (6-methoxy-pyridin-3-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000424
Using intermediate I-6-1 (200mg, 0.47mmol) and 4-methoxy-3-pyridineboronic acid (108mg, 0.71mmol) as starting materials, the similar procedure as in example 33 was carried out to give compound 38 as an off-white solid in a yield of 30 mg. m.p.:211-213 ℃. 1 H NMR(500MHz，DMSO-d 6 )δ11.66(s，1H)，8.40(s，1H)，7.89(d，J＝8.5Hz，1H)，7.37-7.34(m，3H)，6.80(d，J＝8.5Hz，1H)，4.05(s，1H)，3.85(s，3H)，2.11(d，J＝12.5Hz，2H)，1.93-1.73(m，10H)，1.54(d，J＝12.5Hz，2H).
Example 39
Figure GPA0000285329380000425
N- (adamantan-2-yl) -4- (6-methyl-pyridin-3-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000426
Using intermediate I-18-3 (100mg, 0.46mmol) as a starting material, the similar procedures as in example 30 were carried out to give compound 39 as an off-white solid in a yield of 70mg in two steps of 48%. m.p.:151-153 ℃. 1 H NMR(400MHz，DMSO-d 6 )δ11.71(s，1H)，8.70(s，1H)，7.83(dd，J＝8.0，2.0Hz，1H)，7.42-7.38(m，3H)，7.20(d，J＝8.0Hz，1H)，4.06-4.02(m，1H)，2.44(s，3H)，2.11(d，J＝12.8Hz，2H)，1.93-1.73(m，10H)，1.54(d，J＝12.4Hz，2H).
Example 40
Figure GPA0000285329380000431
N- (adamantan-2-yl) -4- (2-methyl-6-fluoro-pyridin-3-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000432
Using intermediate I-18-5 (100mg, 0.43mmol) as a starting material, the similar procedure as in example 30 was carried out to give compound 40 as an off-white solid in a yield of 40mg in two steps of 26%. m.p.:203-205 ℃. 1 H NMR(400MHz，DMSO-d 6 )δ11.78(s，1H)，7.90(t，J＝8.4Hz，1H)，7.41(d，J＝6.8Hz，1H)，7.23-7.22(m，1H)，7.16-7.14(m，1H)，6.99(dd，J＝8.4，3.6Hz，1H)，4.06-4.05(m，1H)，2.54(s，3H)，2.10(d，J＝13.2Hz，2H)，1.94-1.72(m，10H)，1.53(d，J＝12.4Hz，2H).
EXAMPLE 41
Figure GPA0000285329380000433
N- (adamantan-1-yl) -4- (2, 4-difluorophenyl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000434
A100 mL reaction flask was charged with compound I-6-3 (200mg, 0.472mmol), compound 2, 4-difluorophenylboronic acid (133mg, 0.84mmol), 2M sodium carbonate (300mg, 2.832mmol) dissolved in water (1.4 mL) and tetrakis (triphenylphosphine) palladium (28mg, 0.0236 mmol) and under argon, injected with ethanol (6 mL) and toluene (3 mL) and heated at 90 ℃ for 3.5 h. After cooling, water (10 mL) and ethyl acetate (20 mL) were added, and the organic phase was treated with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (EA: PE = 10%) to obtain compound 41 as an off-white solid (128 mg) with a yield of 76.2%. m.p.:182 to 184 ℃. 1 H NMR(400MHz，DMSO-d 6 )δ11.68(s，1H)，7.68-7.62(m，1H)，7.27-7.21(m，3H)，7.08(dt，J＝8.8，2.4Hz，1H)，2.06(s，9H)，1.66(s，6H).
Example 42
Figure GPA0000285329380000435
N- (adamantan-1-yl) -4- (2, 6-difluoropyridin-3-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000441
Using 2, 6-difluoro-3-pyridineboronic acid (133mg, 0.84mmol) as a starting material, the similar procedure used in example 41 was followed to give compound 42 as an off-white solid in a yield of 100mg (59%). m.p.: is > 250 ℃. 1 H NMR(500MHz，CDCl 3 )δ9.71(s，1H)，8.03-7.98(m，1H)，7.30(s，1H)，6.85(d，J＝7.5Hz，1H)，6.78(s，1H)，5.63(s，1H)，2.13(s，9H)，1.73(s，6H).
Example 43
Figure GPA0000285329380000442
N- (adamantan-1-yl) -4- (2, 4-dichlorophenyl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000443
Using 2, 4-dichlorophenylboronic acid (68mg, 0.354mmol) as a starting material, the similar procedure as in example 41 was followed to give compound 43 as a yellow solid in 78mg at a yield of 84.9%. 1 H NMR(500MHz，DMSO-d 6 )δ11.67(s，1H)，7.64(s，1H)，7.58(d，J＝8.5Hz，1H)，7.44(d，J＝8.5Hz，1H)，7.32(s，1H)，7.27(d，J＝6.5Hz，2H)，2.09(s，9H)，1.69(s，6H).
Example 44
Figure GPA0000285329380000444
N- (adamantan-1-yl) -4-phenyl-1H-pyrrole-2-carboxamide
Figure GPA0000285329380000445
Using phenylboronic acid (115mg, 0.945mmol) as a starting material and through a similar procedure as in example 41, compound 44 was obtained in a yield of 21.2% as an off-white solid (32 mg). 1 H NMR(500MHz，DMSO-d 6 )δ11.45(s，1H)，7.54(d，J＝7.5Hz，2H)，7.33-7.30(m，3H)，7.21(s，1H)，7.15-7.13(m，2H)，2.06(s，9H)，1.66(s，6H).
Example 45
Figure GPA0000285329380000446
N- (adamantan-1-yl) -4- (4-chlorophenyl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000451
Using 4-chlorobenzeneboronic acid (148mg, 0.945mmol) as a starting material and through the similar procedure as in example 41, compound 45 was obtained in a yield of 71% as a yellow solid (119 mg). 1 H NMR(500MHz，DMSO-d 6 )δ11.52(s，1H)，7.55(d，J＝7.5Hz，2H)，7.37-7.34(m，3H)，7.22(s，1H)，7.15(s，1H)，2.06(s，9H)，1.66(s，6H).
Example 46
Figure GPA0000285329380000452
N- (adamantan-1-yl) -4- (4-fluoro-2-methoxyphenyl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000453
Using 2-methoxy-4-fluorobenzeneboronic acid (161mg, 0.945mmol) as a starting material and through a similar procedure to that in example 41, compound 46 was obtained as an off-white solid (43 mg, yield 25%). 1 H NMR(500MHz，DMSO-d 6 )δ11.37(s，1H)，7.50(t，J＝7.5Hz，1H)，7.27(s，1H)，7.22(s，1H)，7.14(s，1H)，6.92(d，J＝11.5Hz，1H)，6.78(t，J＝7.5Hz，1H)，3.86(s，3H)，2.06(s，9H)，1.66(s，6H).
Example 47
Figure GPA0000285329380000454
N- (adamantan-1-yl) -4- (4-fluorophenyl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000455
Using 4-fluorophenylboronic acid (198mg, 1.42mmol) as a starting material and through the similar procedures to those in example 41, compound 47 is obtained as an off-white solid (80 mg, yield 33%). 1 H NMR(400MHz，DMSO-d 6 )δ11.46(s，1H)，7.57-7.54(m，2H)，7.28-7.27(m，1H)，7.18-7.12(m，4H)，2.06(s，9H)，1.66(s，6H).
Example 48
Figure GPA0000285329380000461
N- (adamantan-1-yl) -4- (2-fluorophenyl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000462
Using 2-fluorophenylboronic acid (198mg, 1.42mmol) as a starting material, the similar procedure to that in example 41 was employed to give compound 48 in the form of an off-white solid (114 mg, yield 47%). 1 H NMR(400MHz，DMSO-d 6 )δ11.58(s，1H)，7.66-7.62(m，1H)，7.29-7.25(m，3H)，7.21-7.18(m，3H)，2.07(s，9H)，1.66(s，6H).
Example 49
Figure GPA0000285329380000463
N- (adamantan-1-yl) -4- (2-chlorophenyl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000464
Using 2-chlorobenzeneboronic acid (222mg, 1.42mmol) as a starting material and through the similar procedure as in example 41, compound 49 was obtained as an off-white solid (93 mg, yield 37%). 1 H NMR(400MHz，DMSO-d 6 )δ11.58(s，1H)，7.53(dd，J＝8.0，1.6Hz，1H)，7.46(dd，J＝8.0，1.2Hz，1H)，7.33(td，J＝7.6，1.2Hz，1H)，7.27-7.26(m，1H)，7.23-7.21(m，3H)，2.06(s，9H)，1.66(s，6H).
Example 50
Figure GPA0000285329380000465
N- (adamantan-1-yl) -4- (2-methoxypyridin-3-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000466
Using 2-methoxy-3-pyridineboronic acid (54mg, 0.354mmol) as a starting material and through the similar procedures as in example 35, compound 50 was obtained as an off-white solid (90 mg, yield 91%). 1 H NMR(500MHz，DMSO-d 6 )δ11.50(s，1H)，7.97(d，J＝3.5Hz，1H)，7.88(d，J＝7.5Hz，1H)，7.39(s，1H)，7.32(s，1H)，7.18(s，1H)，7.01-6.99(m，1H)，3.96(s，3H)，2.07(s，9H)，1.66(s，6H).
Example 51
Figure GPA0000285329380000471
N- (adamantan-1-yl) -4- (3-pyridyl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000472
Starting from 3-pyridineboronic acid (41mg, 0.33mmol), the procedure analogous to that described in example 35 was followed,compound 51 was obtained as an off-white solid, 94mg, yield 56%. 1 H NMR(500MHz，DMSO-d 6 )δ11.61(s，1H)，8.80(s，1H)，8.33(d，J＝4.0Hz，1H)，7.90(d，J＝8.0Hz，1H)，7.43(s，1H)，7.33(dd，J＝7.5，5.0Hz，1H)，7.28(s，1H)，7.18(s，1H)，2.07(s，9H)，1.66(s，6H).
Example 52
Figure GPA0000285329380000473
N- (adamantan-1-yl) -4- (3-fluoropyridin-4-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000474
Using 3-fluoro-4-pyridineboronic acid (93mg, 0.66mmol) as a starting material, the similar procedure as in example 35 was followed to give compound 52 as an off-white solid (48 mg, yield 32.2%). 1 H NMR(400MHz，DMSO-d 6 )δ11.88(s，1H)，8.50(d，J＝3.2Hz，1H)，8.33(dd，J＝5.2，1.2Hz，1H)，7.66(dd，J＝6.8，4.8Hz，1H)，7.51-7.49(m，1H)，7.42-7.42(m，1H)，7.35(s，1H)，2.07(s，9H)，1.67(s，6H).
Example 53
Figure GPA0000285329380000475
N- (adamantan-1-yl) -4- (3-chloropyridin-4-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000476
Using 3-chloro-4-pyridineboronic acid (236mg, 1.5mmol) as a starting material and through the similar procedures as in example 35, compound 53 was obtained in the form of an off-white solid (54 mg) with a yield of 15.2%. 1 H NMR(500MHz，DMSO-d 6 )δ11.89(s，1H)，8.57(s，1H)，8.42(d，J＝5.0Hz，1H)，7.59(d，J＝5.5Hz，2H)，7.45(s，1H)，7.34(s，1H)，2.07(s，9H)，1.66(s，6H).
Example 54
Figure GPA0000285329380000481
N- (adamantan-1-yl) -4- (6-methoxypyridin-3-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000482
Using 6-methoxy-3-pyridineboronic acid (161mg, 1.05mmol) as a starting material, the similar procedure as in example 35 was followed to give compound 54 as an off-white solid in 34mg with a yield of 13.8%. 1 H NMR(400MHz，DMSO-d 6 )δ11.49(s，1H)，8.35(d，J＝2.4Hz，1H)，7.85(dd，J＝8.8，2.4Hz，1H)，7.29-7.28(m，1H)，7.16-7.15(m，2H)，6.80(d，J＝8.4Hz，1H)，3.84(s，3H)，2.06(s，9H)，1.66(s，6H).
Example 55
Figure GPA0000285329380000483
N-cyclooctyl-4- (2, 4-difluorophenyl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000484
Using the procedure similar to that in example 41 and starting from the compound 2, 4-difluorophenylboronic acid (178mg, 1.125mmol), compound 55 was obtained in 78% yield as a yellow solid. 1 H NMR(500MHz，DMSO-d 6 )δ11.66(s，1H)，7.85(d，J＝7.5Hz，1H)，7.68-7.63(m，1H)，7.25-7.22(m，3H)，7.09(t，J＝8.0Hz，1H)，3.99(brs，1H)，1.75-1.51(m，14H).
Example 56
Figure GPA0000285329380000485
N-cyclooctyl-4- (2, 6-difluoropyridin-3-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000486
Using 2, 6-difluoro-3-pyridineboronic acid (179mg, 1.125mmol) as a starting material, the similar procedures used in example 41 were followed to give compound 56 as a pale yellow solid, 36mg, 14% yield. 1 H NMR(400MHz，DMSO-d 6 )δ11.80(s，1H)，8.38-8.32(m，1H)，7.90(d，J＝8.0Hz，1H)，7.38(s，1H)，7.29(d，J＝2.0Hz，1H)，7.19(dd，J＝8.4，2.8Hz，1H)，4.00(brs，1H)，1.75-1.50(m，14H).
Example 57
Figure GPA0000285329380000491
N-cyclooctyl-4- (4-fluorophenyl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000492
Using 4-fluorophenylboronic acid (157mg, 1.125mmol) as a starting material and through the similar procedures as in example 41, compound 57 was obtained as an off-white solid in 68mg with a yield of 29%. 1 H NMR(400MHz，DMSO-d 6 )δ11.53(s，1H)，7.75(d，J＝7.5Hz，1H)，7.55(brs，2H)，7.29(s，1H)，7.17-7.14(m，3H)，3.98(brs，1H)，1.75-1.51(m，14H).
Example 58
Figure GPA0000285329380000493
N-cyclooctyl-4- (2-fluorophenyl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000494
Using 2-fluorophenylboronic acid (157mg, 1.125mmol) as a starting material and through the similar procedures as in example 41, compound 58 is obtained as an off-white solid (98 mg, yield 42%). 1 H NMR(500MHz，DMSO-d 6 )δ11.66(s，1H)，7.86(d，J＝8.0Hz，1H)，7.64(s，1H)，7.29(brs，2H)，7.19(brs，3H)，3.99(brs，1H)，1.75-1.51(m，14H).
Example 59
Figure GPA0000285329380000495
N-cyclooctyl-4- (4-fluoro-2-methoxyphenyl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000501
Using 2-methoxy-4-fluorophenylboronic acid (191mg, 1.125mmol) as a starting material and the similar procedure as in example 41, compound 59 was obtained as an off-white solid (186 mg, yield 72%). 1 H NMR(500MHz，DMSO-d 6 )δ11.44(s，1H)，7.75(s，1H)，7.50-7.47(m，1H)，7.27(s，1H)，7.22(s，1H)，6.92(d，J＝7.2Hz，1H)，6.78(d，J＝5.2Hz，1H)，3.99(brs，1H)，3.86(s，3H)，1.73-1.53(m，14H).
Example 60
Figure GPA0000285329380000502
N-cyclooctyl-4- (2-chlorophenyl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000503
Using 2-chlorobenzeneboronic acid (176mg, 1.125mmol) as a starting material and the similar procedure as in example 41, compound 60 was obtained as an off-white solid (207 mg, 83% yield). 1 H NMR(400MHz，DMSO-d 6 )δ11.65(s，1H)，7.84(d，J＝8.0Hz，1H)，7.53(dd，J＝8.0，1.6Hz，1H)，7.46(dd，J＝8.0，0.8Hz，1H)，7.32(dt，J＝7.6，0.8Hz，1H)，7.26-7.21(m，3H)，3.99(brs，1H)，1.75-1.50(m，14H).
Example 61
Figure GPA0000285329380000504
N-cyclooctyl-4- (4-chlorophenyl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000505
Using 4-chlorobenzeneboronic acid (176mg, 113mmol) as a starting material and through the similar procedure as in example 41, compound 61 was obtained in the form of an off-white solid (91 mg, yield 37%). 1 H NMR(400MHz，DMSO-d 6 )δ11.60(s，1H)，7.77(d，J＝8.4Hz，1H)，7.56-7.54(m，2H)，7.38-7.35(m，3H)，7.22-7.21(m，1H)，3.99(brs，1H)，1.73-1.50(m，14H).
Example 62
Figure GPA0000285329380000506
N-cyclooctyl-4- (2, 4-dichlorophenyl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000511
Using 2, 4-dichlorophenylboronic acid (215mg, 113mmol) as a starting material, the procedure similar to that described in example 41 was followed to give compound 62 as an off-white solid in a yield of 65mg (41%). 1 H NMR(400MHz，DMSO-d 6 )δ11.72(s，1H)，7.85(d，J＝8.0Hz，1H)，7.61(d，J＝2.0Hz，1H)，7.55(d，J＝8.4Hz，1H)，7.41(dd，J＝8.4，2.4Hz，1H)，7.29-7.28(m，1H)，7.24-7.23(m，1H)，4.00-3.97(m，1H)，1.74-1.49(m，14H).
Example 63
Figure GPA0000285329380000512
N-cyclooctyl-4-phenyl-1H-pyrrole-2-carboxamide
Figure GPA0000285329380000513
Using phenylboronic acid (137mg, 1.125mmol) as a starting material and the similar procedure as in example 41, compound 63 was obtained as an off-white solid in 100mg with a yield of 45%. 1 H NMR(400MHz，DMSO-d 6 )δ11.53(s，1H)，7.77(d，J＝8.4Hz，1H)，7.54(d，J＝7.6Hz，2H)，7.34-7.30(m，3H)，7.22-7.21(m，1H)，7.13(t，J＝7.2Hz，1H)，3.97(brs，1H)，1.76-1.50(m，14H).
Example 64
Figure GPA0000285329380000514
N-cyclooctyl-4- (2-methoxypyridin-3-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000515
Using 2-methoxy-3-pyridineboronic acid (64mg, 0.419mmol) as a starting material and through a similar procedure as in example 35, compound 64 was obtained as an off-white solid of 77mg in a yield of 72%. 1 H NMR(500MHz，DMSO-d 6 )δ11.57(s，1H)，7.98(d，J＝3.0Hz，1H)，7.87(d，J＝7.0Hz，1H)，7.80(d，J＝8.0Hz，1H)，7.40(s，1H)，7.32(s，1H)，7.02-7.00(m，1H)，3.96(brs，4H)，1.75-1.51(m，14H).
Example 65
Figure GPA0000285329380000521
N-cyclooctyl-4- (pyridin-3-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000522
Using 3-pyridineboronic acid (86mg, 0.699mmol) as a starting material, the similar procedure as in example 35 was followed to give compound 65 as an off-white solid (22 mg, 15.8% yield). 1 H NMR(400MHz，DMSO-d 6 )δ11.69(s，1H)，8.80(d，J＝2.0Hz，1H)，8.34(dd，J＝4.4，1.2Hz，1H)，7.91-7.88(m，1H)，7.81(d，J＝8.0Hz，1H)，7.45-7.44(m，1H)，7.33(dddd，J＝4.8，0.8Hz，1H)，7.28-7.27(m，1H)，3.99(s，1H)，1.76-1.50(m，14H).
Example 66
Figure GPA0000285329380000523
N-cyclooctyl-4- (3-fluoropyridin-4-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000524
Using 3-fluoro-4-pyridine boric acid (94mg, 0.67mmol) as raw materialThe procedure was similar to that in example 35 to give compound 66 as an off-white solid in 81mg, yield 55.1%. 1 H NMR(400MHz，DMSO-d 6 )δ11.97(s，1H)，8.50(d，J＝3.2Hz，1H)，8.34(dd，J＝5.2，0.8Hz，1H)，7.97(d，J＝8.4Hz，1H)，7.66(dd，J＝6.8，1.2Hz，1H)，7.53-7.52(m，1H)，7.42(s，1H)，4.01-3.96(m，1H)，1.76-1.50(m，14H).
Example 67
Figure GPA0000285329380000525
N-cyclooctyl-4- (3-chloropyridin-4-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000526
Using 3-chloro-4-pyridineboronic acid (220mg, 1.3972 mmol) as a starting material, the similar procedure as in example 35 was carried out to give compound 67 as an off-white solid in a yield of 71mg (23%). 1 H NMR(500MHz，DMSO-d 6 )δ11.97(s，1H)，8.57(s，1H)，8.42(d，J＝5.0Hz，1H)，7.95(d，J＝8.0Hz，1H)，7.60-7.59(m，2H)，7.46(s，1H)，3.99(brs，1H)，1.76-1.51(m，14H).
Example 68
Figure GPA0000285329380000531
N-cyclooctyl-4- (6-methoxypyridin-3-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000532
Using 6-methoxy-3-pyridineboronic acid (143mg, 0.932mmol) as a starting material and the similar procedure as in example 35, the compound 68 was obtained as an off-white solid (123 mg) with a yield of 60.5%. 1 H NMR(400MHz，DMSO-d 6 )δ11.56(s，1H)，8.35(d，J＝2.0Hz，1H)，7.85(dd，J＝8.8，2.4Hz，1H)，7.77(d，J＝8.0Hz，1H)，7.31-7.29(m，1H)，7.16-7.15(m，1H)，6.80(d，J＝8.8Hz，1H)，4.06-3.95(m，1H)，3.85(s，3H)，1.75-1.50(m，14H).
Example 69
Figure GPA0000285329380000533
4- (2, 4-difluorophenyl) -N- ((1S, 2S,3S, 5R) -2, 6-trimethylbicyclo [3.1] heptan-3-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000534
Using the procedure similar to that in example 41, starting from the compound 2, 4-difluorophenylboronic acid (67mg, 0.423mmol), compound 69 was obtained in the form of a yellow solid 40mg with a yield of 39%. 1 H NMR(500MHz，DMSO-d 6 )δ11.69(s，1H)，7.96(d，J＝8.5Hz，1H)，7.69-7.65(m，1H)，7.27-7.23(m，3H)，7.09(t，J＝8.0Hz，1H)，4.37-4.30(m，1H)，2.41-2.36(m，2H)，2.05-2.02(m，1H)，1.94(s，1H)，1.81(s，1H)，1.69-1.65(m，1H)，1.26-1.19(m，4H)，1.06-1.02(m，6H).
Example 70
Figure GPA0000285329380000535
4- (2, 6-Difluoropyridin-3-yl) -N- ((1S, 2S,3S, 5R) -2, 6-trimethylbicyclo [3.1.1] heptan-3-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000536
With 2, 6-difluoro-3-pyridineboronic acid (1)39mg, 0.878mmol) as a starting material in the similar manner to the procedure in example 35 was carried out to give compound 70 as an off-white solid in an amount of 45mg and a yield of 29.1%. 1 H NMR(400MHz，DMSO-d 6 )δ11.83(s，1H)，8.40-8.34(m，1H)，8.02(d，J＝8.8Hz，1H)，7.40(s，1H)，7.31(s，1H)，7.20(dd，J＝8.0，2.4Hz，1H)，4.37-4.30(m，1H)，2.44-2.36(m，2H)，2.07-2.02(m，1H)，1.94(s，1H)，1.81(t，J＝5.2Hz，1H)，1.69-164(m，1H)，1.23-1.18(m，4H)，1.06-1.04(m，6H).
Example 71
Figure GPA0000285329380000541
4- (2-methoxypyridin-3-yl) -N- ((1S, 2S,3S, 5R) -2, 6-trimethylbicyclo [3.1] heptan-3-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000542
Using 2-methoxy-3-pyridineboronic acid (56mg, 0.37mmol) as a starting material, the similar procedure as in example 35 was followed to give compound 71 as an off-white solid (33 mg, yield 37.8%). 1 H NMR(400MHz，DMSO-d 6 )δ11.59(s，1H)，7.99(d，J＝3.6Hz，1H)，7.94-7.88(m，2H)，7.41(s，1H)，7.34(s，1H)，7.01(t，J＝6.0Hz，1H)，4.33(brs，1H)，3.97(s，3H)，2.50-2.38(m，2H)，2.06-2.02(m，1H)，1.94(s，1H)，1.81(s，1H)，1.69-1.65(m，1H)，1.23-1.19(m，4H)，1.06-1.04(m，6H).
Example 72
Figure GPA0000285329380000543
4- (2, 4-difluorophenyl) -N- ((1R) -9-methyl-9-azabicyclo [3.3.1] nonan-3-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000544
A25 mL reaction flask was charged with compound I-12-1 (200mg, 0.42mmol), compound 3, 4-difluorophenylboronic acid (99mg, 0.63mmol), 2M sodium carbonate (267mg, 2.52mmol) dissolved in water (1.3 mL) and tetrakis (triphenylphosphine) palladium (97mg, 0.084 mmol) under argon and heated at 90 ℃ for 4 hours with ethanol (6 mL) and toluene (3 mL). After cooling, water (10 mL) and ethyl acetate (20 mL) were added, and the organic phase was treated with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (MeOH: DCM = 5%) to give compound 72-1 as a yellow oil 117mg, yield 59.8%. Compound 72-1 was dissolved in 2mL of DCM and 1mL of TFA. After stirring at room temperature for 3 hours, quenching with saturated sodium bicarbonate, adding water (10 mL) and DCM (20 mL), treating the organic phase with saturated brine, drying over anhydrous sodium sulfate, concentrating, and column chromatography (MeOH (1% nh3. H2O) in DCM = 2%) gave compound 72 as an off-white solid 41mg with a yield of 60%. 1 H NMR(400MHz，DMSO-d 6 )δ11.72(s，1H)，7.76(d，J＝8.4Hz，1H)，7.69-7.63(m，1H)，7.28-7.24(m，2H)，7.23-7.21(m，1H)，7.09(td，J＝8.4，2.4Hz，1H)，4.34-4.23(m，1H)，2.97(d，J＝11.2Hz，2H)，2.41(s，3H)，2.21-2.14(m，2H)，2.05-1.99(m，1H)，1.95-1.86(m，2H)，1.48-1.37(m，3H)，0.92(d，J＝12.8Hz，2H).
Example 73
Figure GPA0000285329380000551
4- (2-Difluoropyridin-3-yl) -N- ((1R) -9-methyl-9-azabicyclo [3.3.1] nonan-3-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000552
A25 mL reaction flask was charged with Compound I-14-1 (100mg, 0.2mmol), compound 2, 6-difluoro-3-pyridineboronic acid (48mg, 0.3mmol), and 2MSodium carbonate (127mg, 1.2mmol) was dissolved in water (0.6 mL) and tetrakis (triphenylphosphine) palladium (46mg, 0.04mmol), and under argon, ethanol (6 mL) and toluene (3 mL) were injected and heated at 90 ℃ for 4 hours. After cooling, water (10 mL) and ethyl acetate (20 mL) were added for extraction, and the organic phase was treated with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography (MeOH: DCM = 2%) to obtain compound 73-1 as a yellow solid (110 mg) which was used directly in the next step. Compound 73-1 was dissolved in 6mL of LTBAF (1 mol/LTHF solution) and heated to reflux at 80 ℃. Concentration and column chromatography (MeOH: DCM = 2%) gave compound 73 as an off-white solid, 20mg, 28% yield. 1 H NMR(400MHz，DMSO-d 6 )δ11.86(s，1H)，8.39-8.32(m，1H)，7.82(d，J＝8.4Hz，1H)，7.39(s，1H)，7.26(s，1H)，7.20(d，J＝8.4Hz，1H)，4.33-4.25(m，1H)，2.98(d，J＝8.8Hz，2H)，2.41(s，3H)，2.22-2.14(m，2H)，2.02-1.88(m，3H)，1.48-1.38(m，3H)，0.93(d，J＝12.4Hz，2H).
Example 74
Figure GPA0000285329380000553
4- (2-methoxypyridin-3-yl) -N- ((1R) -9-methyl-9-azabicyclo [3.3.1] nonan-3-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000554
Using 2-methoxy-3-pyridineboronic acid (100mg, 0.65mmol) as a starting material and through the similar procedures as in example 73, compound 74 was obtained as an off-white solid (32 mg, yield 26.6%). 1 H NMR(400MHz，DMSO-d 6 )δ11.66(s，1H)，7.98(dd，J＝4.8，2.0Hz，1H)，7.87(dd，J＝7.2，1.6Hz，1H)，7.77(d，J＝8.4Hz，1H)，7.39(dd，J＝2.8，1.6Hz，1H)，7.30(s，1H)，7.01(dd，J＝7.6，4.8Hz，1H)，4.33-4.25(m，1H)，3.97(s，3H)，2.98(d，J＝10.4Hz，2H)，2.41(s，3H)，2.20-2.14(m，2H)，2.06-2.03(m，1H)，1.94-1.87(m，2H)，1.48-1.37(m，3H)，0.94(d，J＝12.4Hz，2H).
Example 75
Figure GPA0000285329380000561
N- (adamantan-1-yl) -4- (2-methoxy-5-fluoropyridin-3-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000562
Using I-19-6 (50mg, 0.21mmol) as a starting material, the procedure similar to that in example 30 was carried out to give compound 75 as a pale yellow solid in an yield of 64.9% at 50 mg. 1 H NMR(400MHz，DMSO-d 6 )δ11.62(s，1H)，7.93(d，J＝2.8Hz，1H)，7.81(dd，J＝9.6，3.2Hz，1H)，7.46(dd，J＝2.8，1.6Hz，1H)，7.37(t，J＝1.6Hz，1H)，7.14(s，1H)，3.96(s，3H)，2.07(s，9H)，1.66(s，6H).
Example 76
Figure GPA0000285329380000563
N- (adamantan-2-yl) -4- (2-methoxy-5-fluoropyridin-3-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000564
Using I-19-6 (50mg, 0.21mmol) as a starting material, the similar procedure as in example 30 was carried out to give compound 76 as an off-white solid, 52mg, yield 67.5%. 1 H NMR(400MHz，DMSO-d 6 )δ11.78(s，1H)，7.94(d，J＝2.8Hz，1H)，7.90(dd，J＝9.6，3.2Hz，1H)，7.55(t，J＝1.6Hz，1H)，7.50(dd，J＝2.8，1.6Hz，1H)，7.35(d，J＝7.2Hz，1H)，4.07-4.05(m，1H)，3.97(s，3H)，2.11(d，J＝12.0Hz，2H)，1.94-1.72(m，10H)，1.54(d，J＝12.4Hz，2H).
Example 77
Figure GPA0000285329380000565
N- (adamantan-1-yl) -4- (2-amino-5-fluoropyridin-3-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000566
Using I-19-7 (50mg, 0.23mmol) as a starting material, the procedure described in example 30 was repeated to give 77 as a yellow solid in a yield of 49mg of 60.5%. 1 H NMR(500MHz，DMSO-d 6 )δ11.62(s，1H)，7.79(s，1H)，7.38(d，J＝9.5Hz，1H)，7.20(s，2H)，7.14(s，1H)，5.55(s，2H)，2.06(s，9H)，1.66(s，6H).
Example 78
Figure GPA0000285329380000571
N- (adamantan-2-yl) -4- (2-amino-5-fluoropyridin-3-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000572
Using I-19-7 (50mg, 0.23mmol) as a starting material, the similar procedures as in example 30 were carried out to give compound 78 as an off-white solid in 46mg at a yield of 56.8%. 1 H NMR(400MHz，DMSO-d 6 )δ11.79(s，1H)，7.80(d，J＝3.2Hz，1H)，7.45-7.41(m，2H)，7.30-7.26(m，2H)，5.57(s，2H)，4.06-4.04(m，1H)，2.10(d，J＝12.4Hz，2H)，1.99-1.73(m，10H)，1.54(d，J＝12.4Hz，2H).
Example 79
Figure GPA0000285329380000573
N-cyclooctyl-4- (2-methoxy-5-fluoropyridin-3-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000574
Using I-19-6 (50mg, 0.21mmol) as a starting material, the similar procedure to that in example 30 was carried out to give compound 79 as a white solid (51 mg, yield 70.8%). 1 H NMR(500MHz，DMSO-d 6 )δ11.69(s，1H)，7.94(d，J＝3.5Hz，1H)，7.81-7.77(m，2H)，7.46(dd，J＝3.5，2.0Hz，1H)，7.37(t，J＝3.0Hz，1H)，4.01-3.96(m，4H)，1.74-1.50(m，14H).
Example 80
Figure GPA0000285329380000575
N-cyclooctyl-4- (5-fluoropyridin-3-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000581
Using 5-fluoropyridine-3-boronic acid (124mg, 0.88mmol) as a starting material and through the similar procedures as in example 35, compound 80 was obtained as a pale yellow solid (44 mg, yield 23.8%). 1 H NMR(400MHz，DMSO-d 6 )δ11.78(s，1H)，8.68(s，1H)，8.32(d，J＝2.8Hz，1H)，7.85-7.78(m，2H)，7.55(dd，J＝2.4，1.2Hz，1H)，7.31(t，J＝2.0Hz，1H)，4.02-3.96(m，1H)，1.76-1.50(m，14H).
Example 81
Figure GPA0000285329380000582
N-cyclooctyl-4- (6-cyanopyridin-3-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000583
Using 5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2-cyanopyridine (145mg, 0.63mmol) as a starting material, the similar procedure as in example 35 was carried out to give compound 81 as an off-white solid in a yield of 29mg (21.4%). 1 H NMR(500MHz，DMSO-d 6 )δ11.94(s，1H)，8.97(s，1H)，8.11(d，J＝8.0Hz，1H)，7.96(d，J＝8.0Hz，1H)，7.85(d，J＝8.0Hz，1H)，7.68(s，1H)，7.38(s，1H)，3.99(brs，1H)，1.7-1.51(m，14H).
Example 82
Figure GPA0000285329380000584
N-cyclooctyl-4- (furan-2-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000585
Using furan-2-boronic acid (80mg, 0.71mmol) as a starting material and through the similar procedure as in example 35, compound 82 was obtained in a yield of 49.4% as an off-white solid. 1 H NMR(400MHz，DMSO-d 6 )δ11.56(s，1H)，7.83(d，J＝8.0Hz，1H)，7.53(d，J＝1.6Hz，1H)，7.12(dd，J＝2.8，1.6Hz，1H)，7.06(t，J＝2.4Hz，1H)，6.46(dd，J＝3.2，1.6Hz，1H)，6.37(d，J＝3.2Hz，1H)，3.98-3.96(m，1H)，1.74-1.49(m，14H).
Example 83
Figure GPA0000285329380000591
N-cyclooctyl-4- (thien-2-yl) -1H-pyrrole-2-carboxamide
Figure GPA0000285329380000592
Using thiophene-2-boronic acid (89mg, 0.699mmol) as a starting material and through a similar procedure as in example 35, compound 83 is obtained as an off-white solid (26 mg, 18.4% yield). 1 H NMR(400MHz，DMSO-d 6 )δ11.55(s，1H)，7.84(d，J＝8.0Hz，1H)，7.27(d，J＝5.2Hz，1H)，7.16(s，1H)，7.10(d，J＝3.6Hz，1H)，7.04(s，1H)，7.00(dd，J＝4.8，3.6Hz，1H)，4.00-3.94(m，1H)，1.74-1.50(m，14H).
Biological activity assay
Experimental example 1 in vitro anti-tuberculosis Activity test
The determination method comprises the following steps: in vitro anti-tubercular activity was determined by the Microplate Alamar Blue Assay (MABA) method.
The experimental principle is as follows: alamar Blue added to the medium can act as a redox indicator, changing the color from Blue to red, reflecting the consumption of oxygen molecules by the microorganism under study. The color change of Alamar Blue can be determined photometrically and has an emission wavelength of 590nm.
The experimental method comprises the following steps: sterile 96-well plates (Falcon 3072; becton Dickinson, lincoln Park, n.j.), test compounds were dissolved in DMSO to make a primary solution with a concentration of 5mg/mL, 199 μ L of 7H9 medium and 1 μ L of the primary solution of the compound were added to the highest concentration well, mixed well, and diluted 2-fold sequentially to the remaining wells, with the final concentration of the compound: 25. 12.5, 6.25, 3.125, 1.56, 0.78, 0.39, 0.2, 0.1, 0.05, 0.025, 0.016 mug/mL. Selecting Mycobacterium tuberculosis H 37 R v Culturing for 2-3 weeks to obtain bacterial suspension, inoculating into 7H9 medium containing 0.05% Tween80 and 10% ADC, culturing at 37 deg.C for 1-2 weeks, and growing to turbidity of McFarland 1 (corresponding to 10%) 7 CFU/mL), diluting at 1: 20, adding 100 μ L of each well, and adjusting the final concentration of the bacterial liquid to 10 6 CFU/mL. Each plate was equipped with 2 growth control wells without antimicrobial, and the 96-well plate was incubated at 37 ℃. Growth control wells were added 7 days later20 μ L of 10 Xamar Blue and 5% Tween80 μ L of a mixture, incubated at 37 ℃ for 24 hours, if the color changes from Blue to pink, the above amounts of Alamar Blue and Tween80 mixture were added to the wells of each test drug, the color of each well was recorded after incubation at 37 ℃ for 24 hours, 590nm fluorescence was measured using a microplate reader, and MIC was calculated 90 。
TABLE 1 in vitro anti-Mycobacterium tuberculosis Activity of some of the Compounds of the invention
Figure GPA0000285329380000593
Figure GPA0000285329380000601
As can be seen from the data in Table 1, most of the compounds of the present invention have good in vitro anti-tubercular bacillus activity, especially compounds 4, 7, 9, 10, 15, 23, 25, 37, 41, 42, 44, 46, 47, 48, 49, 50, 55, 57, 58, 59, 63, 64 and 76 show strong in vitro anti-tubercular bacillus activity (MIC < 0.016. Mu.g/mL), and the activity is much stronger than that of the first-line anti-tubercular drugs isoniazid and rifampicin.
Experimental example 2 cytotoxicity test
The determination method comprises the following steps: MTT method
The experimental principle is as follows: the cell activity is measured by reducing 3- (4, 5-dimethylthiazol-2-yl) -2, 5-diphenyltetrazolium bromide (trade name: thiazole blue)/MTT [3- (4, 5-dimethylthiazol-2-yl) -2, 5-diphenyltetrazolium bromide ] in an oxidation state into a hardly soluble blue methyl tympanites (formazan) compound through an intramitochondrial dehydrogenase (such as succinate dehydrogenase), and the conversion is positively related to the number of living cells by color development after dissolving the compound in DMSO.
The experimental method comprises the following steps: 1. preparation of cell suspension. And digesting the Vero cells cultured to the logarithmic phase for 2-3 min by using 0.25% pancreatin, removing the digestive juice, adding a proper amount of culture solution, uniformly mixing, taking 20 mu L, counting under a microscope by using a blood cell counter, and preparing cell suspension with a proper concentration for later use. With PBS (phosphate) simultaneouslybuffered solution) was prepared into 5g/L MTT solution, which was filter sterilized and kept ready for use. 2. Medicine preparation and cytotoxicity detection. The test drug was dissolved in DMSO, diluted 50-fold with medium to the highest concentration tested, and then serially diluted 1: 3 in 96-well plates with 6 concentrations of each compound, with a maximum concentration of 64 μ g/mL, 6 parallel wells per concentration, 50 μ L/well in medium. The prepared cell suspension was inoculated into a 96-well plate at a cell concentration of 4X 10 at 50. Mu.L/well 5 one/mL. Meanwhile, a cell control hole without medicine and a culture medium blank control hole are arranged. After 48 hours of incubation, 10. Mu.L/well of MTT was added and incubation was continued for 4 hours. Taking out the culture plate, carefully discarding the culture medium in the wells, adding DMSO (100 μ L) into each well, shaking until the nail tympanites particles are completely dissolved, and measuring the Optical Density (OD) at 570nm by using an enzyme linked immunosorbent assay (ELISA) detector 570 ). 3. And (6) data processing. Percent (%) cell inhibition = [ (cell control OD) 570 Value-additive medicine OD 570 Value)/(cell control OD 570 Value-blank OD 570 Value)]X100%. Dose-response curve fitting was performed using origin7.0 software to calculate the concentration (IC) at which each compound inhibited 50% of cells 50 )。
TABLE 2 cytotoxicity of some of the compounds of the invention
Compound (I) IC 50 (μg/mL) Compound (I) IC 50 (μg/mL)
Compound 1 27.91 Compound 45 ＞64
Compound 2 ＞64 Compound 46 ＞64
Compound 5 44.09 Compound 47 25.35
Compound 6 ＞64 Compound 48 35.81
Compound 10 21.228 Compound 49 ＞64
Compound 11 ＞64 Compound 50 ＞64
Compound 14 ＞64 Compound 51 40.09
Compound 15 22.05 Compound 52 ＞64
Compound 16 ＞64 Compound 53 ＞64
Compound 22 45.73 Compound 54 ＞64
Compound 25 58.67 Compound 56 30.44
Compound 26 44.67 Compound 57 36.8
Compound 27 58.81 Compound 58 33.66
Compound 28 ＞64 Compound 59 ＞64
Compound 29 ＞64 Compound 60 ＞64
Compound 31 ＞64 Compound 61 ＞64
Compound 32 47.3 Compound 62 31.76
Compound 33 ＞64 Compound 63 41.64
Compound 34 35.15 Compound 64 ＞64
Compound 40 27.72 Compound 65 28.55
Compound 41 62.75 Compound 66 ＞64
Compound 42 ＞64 Compound 67 ＞64
Compound 43 ＞64 Compound 80 ＞64
Compound 44 27.91 Compound 82 ＞64
As can be seen from the data in Table 2, the compound of the present invention having a strong antitubercular activity has low cytotoxicity and high safety.
Experimental example 3 Activity test against drug-resistant Mycobacterium tuberculosis
TABLE 3, compound 2,5 and 25 Activity against drug-resistant Mycobacterium tuberculosis
Figure GPA0000285329380000611
Figure GPA0000285329380000621
Note: 12611 strain is a clinically separated drug-resistant strain simultaneously resistant to rifampicin and isoniazid
14231 strain is clinically isolated drug-resistant strain simultaneously resistant to rifampicin, isoniazid, ethambutol, levofloxacin and streptomycin
As can be seen from the data in Table 3, the compound of the present invention has strong inhibitory activity against multidrug-resistant strains and broad-spectrum drug-resistant strains, and particularly, the compound 25 has strong in vitro anti-Mycobacterium tuberculosis activity.
EXAMPLE 4 Compound Pair hERG K + Channel inhibitory Activity assay
The CHO/hERG cell test is adopted, the cells are firstly subjected to subculture, and the culture medium: f-12 (Ham)/Glutamax, 10% FBS, 1X Penicillin/Streptomyces (100U/ml),30. Mu.g/ml Blasticidin S HCl (Stock: 10 mg/ml), 400. Mu.g/ml Hygromycin B (Stock: 50 mg/ml), for patch clamp recordings 1-3 days after cell passage. Ion channel current recording: CHO/hERG cells cultured for 1-3 days were first rinsed 2 times with extracellular fluid and 2mL of extracellular fluid was added for the experiment. The recording electrode is controlled by an electrode controller through a two-step method, and is subjected to thermal polishing treatment by an electrode polishing instrument before use, so that the caliber of the tip of the microelectrode is about 1 mu M, and the impedance is 3-5M omega after filling the electrode internal liquid. Electrode internal solution (mM): KCl 130, mgCl 2 1, EGTA 5, ATP-Mg 5, HEPES 10 (pH 7.2), external electrode solution (mM): naCl 137, caCl 2 1.8，KCl 4，MgCl 2 1,glucose 5, HEPES 10 (pH 7.4). An EPC-9 patch clamp amplifier is adopted to collect current signals, a HEKA Pulse software sampling program is adopted to collect the current signals, and the sampling frequency of the current signals is 10KHz through 3KHz low-pass Bessel filtering (low-pass Bessel filter) of the patch clamp amplifier. Pulse v8.64 was applied in voltage clamp mode for stimulation delivery and signal acquisition. When hERG current was recorded, cells were clamped at-70 mV, depolarized from-70 mV to +50mV (duration 2 seconds), then repolarized from +50mV to-40 mV to induce a tail current in hERG potassium current (Itail), and the magnitude of the tail current was measured at each repolarization to-40 mV. According to the inhibition rate of the compounds with different concentrations on the magnitude of the hERG potassium current tail current amplitude, calculating the IC of the inhibition effect of different compounds on the hERG potassium current tail current 50 。
TABLE 4 hERG K of Compounds + Channel inhibitory Activity
Compound (I) IC 50 (μM)
Compound 23 ＞30
Compound 41 ＞30
Compound 42 ＞30
Compound 46 23.3
Compound 52 ＞10
Compound 55 ＞10
Compound 56 ＞10
Compound 66 ＞10
As can be seen from the data in Table 4, the inhibitory activity of the test compounds on hERGK + channels is greater than 10 μ M, and the inhibitory effect is weak, which indicates that the compounds of the present invention have low risk of cardiotoxicity.
Example 5 in vivo antitubercular Activity assay of Compounds
And (3) taking the CFU value of the lung of the mouse as a main evaluation index, and investigating the in vivo anti-tuberculosis activity of the target compound. Balb/c mice are infected with mycobacterium tuberculosis H in aerosol mode 37 Rv, drug treatment (100 mg/kg) 10 days after infection, once a day, 5 times a week, three weeks after administration, dissection, lung homogenization, serial dilution, culture on 7H11 agar plates, incubation for four weeks at 37 ℃, and determination of CFU values.
TABLE 5 in vivo antitubercular Activity of the Compounds
Compound (I) Dosage (mg/kg) Mouse body weight (g) Log 10 CFU
Blank control group 20.93±0.73 6.44±0.34
Compound 23 100 21.22±0.60 4.56±0.12
As can be seen from the data in Table 5, compound 23 of the present invention has a reduction of about 2 Log compared to the blank control 10 CFU value shows stronger in vivo anti-tuberculosis activity.
In the description of the specification, reference to the description of "one embodiment," "some embodiments," "an example," "a specific example" or "some examples" or the like means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims (16)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
Figure FDA0003888190070000011
wherein the content of the first and second substances,
R 1 is composed of
Figure FDA0003888190070000012
m is 1,2 or 3; n is 1 and 2;
when m is 1, R 3 Is ethyl, C 3 An alkyl group; when m is 2 or 3, R 3 Is H;
R 4 represents one or more substituents, which are the same or different and are each independently selected from the following groups: h or a hydroxyl group;
R 5 is H;
R 2 is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted 5-10 membered heteroaryl;
R 2 the substituted or unsubstituted 5-to 10-membered heteroaryl group in (1) contains at least one heteroatom selected from the group consisting of N, O and S;
R 2 wherein said substituents are independently optionally selected from the group consisting of: F. cl, br, hydroxy, amino, cyano, C 1 -C 3 Alkyl, halo C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkoxy radicalOr C 1 -C 3 An alkylamino group.
2. The compound according to claim 1, which is represented by the general formula (I-a):
Figure FDA0003888190070000013
wherein the content of the first and second substances,
R 3 is ethyl, C 3 An alkyl group;
R 2 is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted quinolyl, substituted or unsubstituted 5-6 membered heteroaryl;
R 2 the substituted or unsubstituted 5-6 membered heteroaryl group in (1) contains at least one heteroatom selected from N, O and S;
R 2 wherein said substituents are independently optionally selected from the group consisting of: F. cl, br, hydroxy, amino, cyano, C 1 -C 3 Alkyl, halo C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkoxy or C 1 -C 3 An alkylamino group.
3. The compound according to claim 1, which is represented by the general formula (I-B):
Figure FDA0003888190070000021
wherein the content of the first and second substances,
R 3 is H
R 2 Is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted quinolyl, substituted or unsubstituted 5-6 membered heteroaryl;
R 2 the substituted or unsubstituted 5-to 6-membered heteroaryl group in (1) contains at least one member selected from the group consisting of N, O and SA heteroatom;
R 2 wherein said substituents are independently optionally selected from the group consisting of: F. cl, br, hydroxy, amino, cyano, C 1 -C 3 Alkyl, halo C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkoxy or C 1 -C 3 An alkylamino group.
4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is represented by the general formula (I-C):
Figure FDA0003888190070000022
wherein the content of the first and second substances,
R 3 is H;
R 2 is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted quinolyl, substituted or unsubstituted 5-6 membered heteroaryl;
R 2 the substituted or unsubstituted 5-6 membered heteroaryl group in (1) contains at least one heteroatom selected from N, O and S;
R 2 wherein said substituents are independently optionally selected from the group consisting of: F. cl, br, hydroxy, amino, cyano, C 1 -C 3 Alkyl, halo C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkoxy or C 1 -C 3 An alkylamino group.
5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is represented by the general formula (I-D):
Figure FDA0003888190070000023
wherein the content of the first and second substances,
R 4 represents one or more substituents, whichIdentical or different and each independently selected from the following groups: h or hydroxy;
R 2 is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted quinolyl, substituted or unsubstituted 5-6 membered heteroaryl;
R 2 the substituted or unsubstituted 5-6 membered heteroaryl group in (1) contains at least one heteroatom selected from N, O and S;
R 2 wherein said substituents are independently optionally selected from the group consisting of: F. cl, br, hydroxy, amino, cyano, C 1 -C 3 Alkyl, halo C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkoxy or C 1 -C 3 An alkylamino group.
6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is represented by general formula (I-E):
Figure FDA0003888190070000031
wherein, the first and the second end of the pipe are connected with each other,
R 5 is H;
R 2 is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted quinolyl, substituted or unsubstituted 5-6 membered heteroaryl;
R 2 the substituted or unsubstituted 5-6 membered heteroaryl group in (1) contains at least one heteroatom selected from N, O and S;
R 2 wherein said substituents are independently optionally selected from the group consisting of: F. cl, br, hydroxy, amino, cyano, C 1 -C 3 Alkyl, halo C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkoxy or C 1 -C 3 An alkylamino group.
7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is represented by the general formula (I-F):
Figure FDA0003888190070000032
R 2 is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted quinolyl, substituted or unsubstituted 5-6 membered heteroaryl;
R 2 the substituted or unsubstituted 5-6 membered heteroaryl group in (1) contains at least one heteroatom selected from N, O and S;
R 2 wherein said substituents are independently optionally selected from the group consisting of: F. cl, br, hydroxy, amino, cyano, C 1 -C 3 Alkyl, halo C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkoxy or C 1 -C 3 An alkylamino group.
8. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is represented by the general formula (I-G):
Figure FDA0003888190070000033
R 2 is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted quinolyl, substituted or unsubstituted 5-6 membered heteroaryl;
R 2 the substituted or unsubstituted 5-6 membered heteroaryl group in (1) contains at least one heteroatom selected from N, O and S;
R 2 wherein said substituents are independently optionally selected from the group consisting of: F. cl, br, hydroxy, amino, cyano, C 1 -C 3 Alkyl, halo C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkoxy or C 1 -C 3 An alkylamino group.
9. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, represented by the general formula (I-H):
Figure FDA0003888190070000041
R 2 is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted quinolyl, substituted or unsubstituted 5-6 membered heteroaryl;
R 2 the substituted or unsubstituted 5-6 membered heteroaryl group in (1) contains at least one heteroatom selected from N, O and S;
R 2 wherein said substituents are independently optionally selected from the group consisting of: F. cl, br, hydroxy, amino, cyano, C 1 -C 3 Alkyl, halo C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy, halo C 1 -C 3 Alkoxy or C 1 -C 3 An alkylamino group.
10. A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R is 2 Is composed of
Figure FDA0003888190070000042
Figure FDA0003888190070000043
Figure FDA0003888190070000051
11. A compound as shown in formula (I) or a pharmaceutically acceptable salt thereof,
Figure FDA0003888190070000052
wherein the content of the first and second substances,
R 1 is composed of
Figure FDA0003888190070000053
Figure FDA0003888190070000054
R 2 Is composed of
Figure FDA0003888190070000055
Figure FDA0003888190070000056
12. A compound according to claim 11, or a pharmaceutically acceptable salt thereof, selected from the following compounds:
Figure FDA0003888190070000061
Figure FDA0003888190070000071
Figure FDA0003888190070000081
Figure FDA0003888190070000091
Figure FDA0003888190070000101
Figure FDA0003888190070000111
13. a process for the preparation of a compound according to any one of claims 1 to 12, comprising the steps of:
(1)
Figure FDA0003888190070000112
protecting the A with Boc to obtain I-1, performing coupling reaction with corresponding boric acid to obtain I-2, removing Boc protecting group and hydrolyzing to obtain I-3, and finally condensing with amine to obtain a product shown in formula I;
or (2)
Figure FDA0003888190070000113
Hydrolyzing the raw material A, condensing with amine to obtain an I-5 intermediate, carrying out Boc protection to obtain an I-6 intermediate, coupling with boric acid, and removing a Boc protecting group to obtain a compound shown in a formula I;
or (3)
Figure FDA0003888190070000114
Hydrolyzing the raw material A, condensing with amine to obtain an I-5 intermediate, carrying out Sem protection to obtain an I-8 intermediate, coupling with boric acid, and removing a Sem protecting group to obtain a compound shown in a formula I;
or (4)
Figure FDA0003888190070000121
Reacting the raw material B with NIS to obtain a compound C, hydrolyzing, condensing with amine to obtain an I-11 intermediate, carrying out Boc protection to obtain an I-12 intermediate, coupling with boric acid, and removing a Boc protecting group to obtain a compound shown in a formula I; or (5)
Figure FDA0003888190070000122
Reacting the raw material B with NIS to obtain a compound C, hydrolyzing, condensing with amine to obtain an I-11 intermediate, carrying out Sem protection to obtain an I-14 intermediate, coupling with boric acid, and removing a Sem protecting group to obtain a compound shown in a formula I; or (6)
Figure FDA0003888190070000123
Protecting the raw material B with Boc to obtain I-16, performing coupling reaction with corresponding boric acid ester to obtain I-17, coupling with bromo-compound to obtain intermediate I-18, hydrolyzing to obtain I-19, and finally condensing with amine to obtain a product shown in formula I;
wherein R is 1 And R 2 As defined in any one of claims 1 to 12.
14. A pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.
15. Use of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, for the manufacture of a medicament for the treatment and/or prophylaxis of infectious diseases caused by bacteria.
16. Use according to claim 15, characterized in that said bacteria are selected from the group consisting of Mycobacterium tuberculosis.
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