CN111393435A

CN111393435A - Azaindole amide compound and preparation method and application thereof

Info

Publication number: CN111393435A
Application number: CN202010179599.5A
Authority: CN
Inventors: 邵长伦
Original assignee: Qingdao Ji'ao Pharmaceutical Technology Co ltd
Current assignee: Qingdao Ji'ao Pharmaceutical Technology Co ltd
Priority date: 2020-03-16
Filing date: 2020-03-16
Publication date: 2020-07-10
Also published as: CN112679497B; CN112679497A

Abstract

The invention discloses an azaindoleamide compound, a composition thereof, a preparation method and application thereof. The compounds or compositions of the invention have the effect of inhibiting the growth of mycobacteria or reducing the bacterial load activity of the mycobacteria, and can be used to treat tuberculosis or mycobacterial infections.

Description

Azaindole amide compound and preparation method and application thereof

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to azaindoleamide compounds, a composition, a preparation method and an application thereof, wherein the compounds or the composition have the application of inhibiting the growth of mycobacteria or reducing the bacterial load of the mycobacteria, and can be used for treating tuberculosis or mycobacterial infection.

Background

Tuberculosis (TB) causes 130 million deaths and 1000 million new cases each year, still one of the ten leading causes of death worldwide (World Health organization. global Tuberculosis Report 2018; WHO, 2018.). The current treatment strategy for drug-sensitive mycobacterium tuberculosis (Mtb) infection is a 6-month treatment regimen involving the first 2 months of combined use of 4 drugs including isoniazid, rifampin, pyrazinamide and ethambutol and the last 4 months of maintenance of isoniazid and rifampin. The treatment scheme is clinically applied for nearly 40 years, so that a plurality of drug-resistant patients appear, and the wide multi-drug resistant tuberculosis is rising year by year. For the last 50 years, Delamanid (Delamanid) and Bedaquiline (Bedaquiline) were the only two approved new drugs for the treatment of tuberculosis. However, both drugs still pose safety risks. Therefore, the development of new action mechanisms of drugs for treating tuberculosis is urgent.

The DprE1 enzyme (decaprenylphosphinyl- β -D-ribose-2' -epimerase) is a new target of anti-tuberculosis drugs, and the inhibition of the DprE1 enzyme can block the synthesis of araban which is an essential component of the cell wall of Mycobacterium tuberculosis, thereby killing bacteria and playing a role in treating tuberculosis or mycobacterial infection.

In recent years, some small molecule DprE1 enzyme inhibitors have been disclosed in documents (J.Med.chem.2013,56,23,9701-.

Summary of The Invention

The following is a summary of some aspects of the invention only and is not intended to be limiting. These aspects and others are described more fully below. All references in this specification are incorporated herein by reference in their entirety. When the disclosure of the present specification differs from the cited documents, the disclosure of the present specification controls.

The invention provides a compound with DprE1 enzyme activity inhibition, has the functions of inhibiting the growth of mycobacteria or reducing the bacterial load of the mycobacteria, and can be used for treating tuberculosis or mycobacterial infection.

The invention also provides processes for the preparation of these compounds, pharmaceutical compositions containing these compounds and methods of using these compounds or compositions in the treatment of the above-mentioned diseases in mammals, especially humans.

Specifically, the method comprises the following steps:

in one aspect, the invention relates to a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof of a compound of formula (I),

wherein:

R¹represents hydrogen, deuterium, halogen, cyano, C_1-6Alkyl or C_1-6An alkoxy group;

R²represents hydrogen, deuterium, halogen, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Haloalkoxy or C_1-6An alkoxy group;

R³represents hydrogen, deuterium, halogen, hydroxy, amino, cyano, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Alkylamino, 3-8 membered cycloalkyl or 3-8 membered heterocyclyl;

R⁴represents hydrogen, deuterium or C_1-6An alkyl group;

R⁵represents hydrogen, deuterium, halogen, C_1-6Alkyl or C_1-6An alkoxy group;

R^aand R^bEach independently represents hydrogen, deuterium, halogen or C_1-6An alkyl group; or R^a、R^bTogether with the carbon atom to which they are jointly attached form C_3-8Cycloalkanes or 3-8 membered heterocycles;

x represents CR^xOr N; y represents CR^YOr N; z represents CR^ZOr N;

R^X、R^Yand R^ZEach independently represents hydrogen, deuterium, halogen, cyano, amino, hydroxy, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylamino or C_1-6A haloalkoxy group;

n is 0, 1,2 or 3.

In some embodiments, R¹Represents hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy or n-butyloxy.

In some embodiments, R²Represents hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy, ethoxy, isopropoxy, tert-butoxy or n-butyloxy.

In some embodiments, R³Represents hydrogen, deuterium, fluorine, chlorine, hydroxyl, amino, cyano, difluoromethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, n-butyloxy, methylamino, ethylamino, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, pyrrolidinyl or tetrahydrofuranyl.

In some embodiments, R⁴Represents hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl.

In some embodiments, R⁵Represents hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, n-butyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy or n-butyloxy.

In some embodiments, R^aAnd R^bEach independently represents hydrogen, deuterium, fluorine, methyl, ethyl, n-propyl or isopropyl; or R^a、R^bAnd together with the carbon atom to which they are commonly attached form a cyclopropane, cyclobutane, cyclopentane, cyclohexane, oxetane or azetidine.

In some embodiments, R^X、R^YAnd R^ZEach independently represents hydrogen, deuterium, fluorine, chlorine, cyano, amino, hydroxyl, methyl, ethyl, isopropyl, n-butyl, tert-butyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, n-butyloxy, methylamino, dimethylamino, amino, nitro, cyano, amino, hydroxy, methyl, trifluoromethyl, cyano, amino, nitro, amino,ethylamino, diethylamino, 2,2, 2-trifluoroethoxy, difluoromethoxy or trifluoromethoxy.

In another aspect, the present invention comprises a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a solvate, a hydrate, a metabolite, an ester, a pharmaceutically acceptable salt, or a prodrug thereof, of a compound of one of the following, but is in no way limited to:

in another aspect, the present invention relates to a pharmaceutical composition comprising any of the compounds disclosed herein.

In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle, or combination thereof.

In other embodiments, the pharmaceutical composition of the present invention further comprises another drug for treating tuberculosis or mycobacterial infection, said drug being rifampin, isoniazid, pyrazinamide, ethambutol, ciprofloxacin, levofloxacin, gatifloxacin, streptomycin, kanamycin, amikacin, capreomycin, erythromycin, enramycin, rifabutin, clarithromycin, linezolid, thiosemicarbazide, thioridazine, or any combination thereof.

In one aspect, the invention relates to the use of a compound or composition disclosed herein for the preparation of a medicament for the treatment of tuberculosis or mycobacterial infection.

In another aspect, the invention relates to the use of a compound or pharmaceutical composition according to the invention in the manufacture of a medicament for inhibiting the growth of, or reducing the bacterial load of, a mycobacterium.

In another aspect, the invention relates to the use of a compound or composition disclosed herein in the manufacture of a medicament for inhibiting the DprE1 enzyme.

In another aspect, the invention relates to methods for the preparation, isolation and purification of compounds encompassed by formula (I).

Biological test results show that the compound provided by the invention can be used as a better DprE1 enzyme inhibitor and can better inhibit the growth of mycobacteria.

Any embodiment of any aspect of the invention may be combined with other embodiments, as long as they do not contradict. Furthermore, in any embodiment of any aspect of the invention, any feature may be applicable to that feature in other embodiments, so long as they do not contradict.

The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting. These and other aspects will be more fully described below.

Detailed description of the invention

Definitions and general terms

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.

It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and the handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry can be found in the descriptions of "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and Jerry March, John Wiley & Sons, New York:2007, the entire contents of which are incorporated herein by reference.

The articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, as used herein, the articles refer to articles of one or more than one (i.e., at least one) object. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in embodiments of the described embodiments.

The term "subject" as used herein refers to an animal. Typically the animal is a mammal. Subjects, e.g., also primates (e.g., humans, males or females), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.

The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.

"stereoisomers" refers to compounds having the same chemical structure but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.

"chiral" is a molecule having the property of not overlapping its mirror image; and "achiral" refers to a molecule that can overlap with its mirror image.

"enantiomer" refers to two isomers of a compound that are not overlapping but are in mirror image relationship to each other.

Diastereoisomers have different physical properties, such as melting point, boiling point, spectroscopic properties and reactivity.

The stereochemical definitions and rules used in the present invention generally follow the general definitions of S.P. Parker, Ed., McGraw-Hilldictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; andEliel, E.and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of a molecule with respect to one or more of its chiral centers, the prefixes D and l or (+) and (-) are symbols used to designate the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is levorotatory, and the compound prefixed (+) or D is dextrorotatory.

Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.

Depending on the choice of starting materials and methods, the compounds of the invention may exist as one of the possible isomers or as mixtures thereof, for example as racemates and diastereomeric mixtures (depending on the number of asymmetric carbon atoms). Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.

Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.

The racemates of any of the resulting end products or intermediates can be resolved into the optical Enantiomers by methods known to those skilled in the art, e.g., by separation of the diastereomeric salts thereof so obtained the racemic products can also be separated by chiral chromatography, e.g., high performance liquid chromatography (HP L C) using a chiral adsorbent^ndEd.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tablesof Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of NotreDame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A PracticalApproach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。

The compounds of the invention may be optionally substituted with one or more substituents, as described herein, in compounds of the general formula above, or as specifically exemplified, sub-classes, and classes of compounds encompassed by the invention.

In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Unless otherwise indicated, a substituted group may have one substituent 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.

The term "unsubstituted" means that the specified group bears no substituents.

The term "optionally substituted with … …" is used interchangeably with the term "unsubstituted or substituted with … …", i.e., the structure is unsubstituted or substituted with one or more substituents described herein. Substituents described herein include, but are not limited to, D, F, Cl, Br, I, N₃、CN、NO₂、OH、SH、NH₂Alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylamino, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like.

In addition, unless otherwise explicitly indicated, the descriptions of the terms "… independently" and "… independently" and "… independently" used in the present invention are interchangeable and should be understood in a broad sense to mean that the specific items expressed between the same symbols do not affect each other in different groups or that the specific items expressed between the same symbols in the same groups do not affect each other.

In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the present invention include each of these groups in both the variety and scopeEach independent sub-combination of members. For example, the term "C_1-6Alkyl "means in particular independently disclosed methyl, ethyl, C₃Alkyl radical, C₄Alkyl radical, C₅Alkyl and C₆An alkyl group.

In each of the parts of the invention, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.

The term "alkyl" or "alkyl group" as used herein, denotes a saturated straight or branched chain monovalent hydrocarbon radical, wherein the alkyl group may be optionally substituted with one or more substituents as described herein. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In one embodiment, the alkyl group contains 1 to 12 carbon atoms; in another embodiment, the alkyl group contains 3 to 12 carbon atoms; in another embodiment, the alkyl group contains 1 to 6 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 4 carbon atoms.

Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)₃) Ethyl group (Et, -CH)₂CH₃) N-propyl (n-Pr, -CH)₂CH₂CH₃) Isopropyl group (i-Pr, -CH (CH)₃)₂) N-butyl (n-Bu, -CH)₂CH₂CH₂CH₃) Isobutyl (i-Bu, -CH)₂CH(CH₃)₂) Sec-butyl (s-Bu, -CH (CH)₃)CH₂CH₃) Tert-butyl (t-Bu, -C (CH)₃)₃) N-pentyl (-CH)₂CH₂CH₂CH₂CH₃) 2-pentyl (-CH (CH)₃)CH₂CH₂CH₃) 3-pentyl (-CH (CH)₂CH₃)₂) 2-methyl-2-butyl (-C (CH)₃)₂CH₂CH₃)，3-Methyl-2-butyl (-CH (CH)₃)CH(CH₃)₂) 3-methyl-1-butyl (-CH)₂CH₂CH(CH₃)₂) 2-methyl-1-butyl (-CH)₂CH(CH₃)CH₂CH₃) N-hexyl (-CH)₂CH₂CH₂CH₂CH₂CH₃) 2-hexyl (-CH (CH)₃)CH₂CH₂CH₂CH₃) 3-hexyl (-CH (CH)₂CH₃)(CH₂CH₂CH₃) 2-methyl-2-pentyl (-C (CH))₃)₂CH₂CH₂CH₃) 3-methyl-2-pentyl (-CH (CH)₃)CH(CH₃)CH₂CH₃) 4-methyl-2-pentyl (-CH (CH)₃)CH₂CH(CH₃)₂) 3-methyl-3-pentyl (-C (CH)₃)(CH₂CH₃)₂) 2-methyl-3-pentyl (-CH (CH)₂CH₃)CH(CH₃)₂) 2, 3-dimethyl-2-butyl (-C (CH)₃)₂CH(CH₃)₂) 3, 3-dimethyl-2-butyl (-CH (CH)₃)C(CH₃)₃) N-heptyl, n-octyl, and the like.

The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein.

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH)₃) Ethoxy (EtO, -OCH)₂CH₃) 1-propoxy (n-PrO, n-propoxy, -OCH)₂CH₂CH₃) 2-propoxy (i-PrO, i-propoxy, -OCH (CH)₃)₂) 1-butoxy (n-BuO, n-butoxy, -OCH)₂CH₂CH₂CH₃) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH)₂CH(CH₃)₂) 2-butoxy (s-BuO, s-butoxy, -OCH (CH)₃)CH₂CH₃) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH)₃)₃) 1-pentyloxy (n-pentyloxy, -OCH)₂CH₂CH₂CH₂CH₃) 2-pentyloxy (-OCH (CH)₃)CH₂CH₂CH₃) 3-pentyloxy (-OCH (CH))₂CH₃)₂) 2-methyl-2-butoxy (-OC (CH))₃)₂CH₂CH₃) 3-methyl-2-butoxy (-OCH (CH)₃)CH(CH₃)₂) 3-methyl-l-butoxy (-OCH)₂CH₂CH(CH₃)₂) 2-methyl-l-butoxy (-OCH)₂CH(CH₃)CH₂CH₃) And so on.

The term "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" in which the amino groups are each independently substituted with one or two alkyl groups; the alkyl group has the meaning described in the present invention. In some of these embodiments, the alkylamino group is one or two C_1-6The alkyl group is attached to a nitrogen atom to form a lower alkylamino group. In other embodiments, the alkylamino group is one or two C_1-4To the nitrogen atom to form an alkylamino group. Suitable alkylamino groups can be monoalkylamino or dialkylamino, and such examples include, but are not limited to, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, and the like.

The term "haloalkyl" or "haloalkoxy" means an alkyl or alkoxy group substituted with one or more halogen atoms, wherein the alkyl or alkoxy group has the meaning as described herein, examples of which include, but are not limited to, trifluoromethyl, difluoromethyl, 2,2, 2-trifluoroethyl, 2,2,3, 3-tetrafluoropropyl, difluoromethoxy, trifluoromethoxy, 2,2, 2-trifluoroethoxy, and the like.

The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic cyclic hydrocarbon radical containing from 3 to 12 carbon atoms. In one embodiment, cycloalkyl groups contain 7 to 12 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3 to 8 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3 to 6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. The cycloalkyl groups may be independently unsubstituted or substituted with one or more substituents described herein.

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a saturated or partially unsaturated, non-aromatic, monovalent or polyvalent, monocyclic, bicyclic, or tricyclic ring containing from 3 to 12 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise indicated, a heterocyclyl group may be attached to other groups in the molecule through a carbon atom, may be attached to other groups in the molecule through a nitrogen atom, and-CH₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaxanyl, homopiperazinyl, homopiperidinyl, diazepanyl, oxepanyl, thiepanyl, oxazepanyl, thiazepanyl, oxazepanyl, and pyrrolidinyl

Radical diaza

Radical, sulfur nitrogen hetero

Yl, 2-oxa-5-azabicyclo [2.2.1]Hept-5-yl. In heterocyclic radicals of-CH₂Examples of-groups substituted by-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl and pyrimidinedione. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, sulfolane group, 1-dioxothiomorpholinyl group. The heterocyclyl group may be optionally substituted with one or more substituents as described herein.

The term "halogen" or "halogen atom" means a fluorine atom (F), chlorine atom (Cl), bromine atom (Br) or iodine atom (I).

The term "cyano" or "CN" denotes a cyano structure, which group may be attached to another group.

The terms "amino" and "hydroxy" each represent the group-NH₂and-OH.

The term "protecting group" or "PG" refers to a substituent that, when reacted with other functional groups, is generally used to block or protect a particular functionality. For example, "amino protecting group" means a substituent attached to an amino group to block or protect the functionality of the amino group in a compound, and suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, "hydroxyl protecting group" refers to the functionality of a substituent of a hydroxyl group to block or protect the hydroxyl group, and suitable protecting groups include acetyl and silyl groups. "carboxy protecting group" refers to the functionality of a substituent of a carboxy group to block or protect the carboxy group, and typical carboxy protecting groups include-CH₂CH₂SO₂Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General descriptions of protecting groups can be found in the literature: greene, Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005.

The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C)₁-C₂₄) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following: T.Higuchi and V.Stella, Pro-drugs as Novel delivery systems, Vol.14of the A.C.S.Symphosium Series, Edward B.Roche, ed., Bioredeployers in Drug designs, American Pharmaceutical Association and PergammonPress, 1987, J.Rautio et al, Prodrug: Design and Clinical Applications, Nature review delivery, 2008,7,255 and 270, S.J.Hecker et al, Prodrugs of pharmaceuticals and phosphates, Journal of chemical Chemistry,2008,51,2328 and 2345.

"metabolite" refers to the product of a particular compound or salt thereof obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are in the fieldAs is well known, such as in the literature: berge et al, descriptive acceptable salts in detail in J. pharmaceutical Sciences,1977,66:1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids formed by reaction with amino groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or those obtained by other methods described in the literature above, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, malates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, stearates, thiocyanates, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N⁺(C_1-4Alkyl radical)₄A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C_1-8Sulfonates and aromatic sulfonates.

"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association of solvent molecules that is water.

When the solvent is water, the term "hydrate" may be used. In some embodiments, a molecule of a compound of the present invention may be associated with a molecule of water, such as a monohydrate; in other embodiments, one molecule of the compound of the present invention may be associated with more than one molecule of water, such as a dihydrate, and in still other embodiments, one molecule of the compound of the present invention may be associated with less than one molecule of water, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the biological effectiveness of the compound in its non-hydrated form.

The term "therapeutically effective amount" or "therapeutically effective dose" as used herein refers to an amount of a compound of the invention that is capable of eliciting a biological or medical response in an individual. Such as reducing or inhibiting the activity of an enzyme or protein associated with mycobacterial infection or tuberculosis, ameliorating the symptoms of mycobacterial infection or tuberculosis, or slowing or delaying the progression of mycobacterial infection or tuberculosis.

The terms "administration" and "administering" of a compound as used herein shall be understood as providing a compound of the invention or a prodrug of a compound of the invention to a subject in need thereof. It will be appreciated that those skilled in the art will treat patients currently suffering from this disorder by administering an effective amount of a compound of the invention.

The term "inhibition" as used herein includes a decrease in the baseline activity of a biological activity or process.

The term "treating" as used herein includes reducing or inhibiting the activity of an enzyme or protein associated with a mycobacterial infection or tuberculosis in a subject, ameliorating one or more symptoms of a mycobacterial infection or tuberculosis in a subject, or slowing or delaying the progression of a mycobacterial infection or tuberculosis in a subject. The term "treating" also includes inhibiting bacterial growth, replication, or reducing the bacterial load of a mycobacterium in a subject.

The term "mycobacterial infection" as used herein includes infection by one or more of the species of the Mycobacterium tuberculosis (Mycobacterium tuberculosis) complex, such as Mycobacterium tuberculosis (Mycobacterium tuberculosis), Mycobacterium bovis (Mycobacterium bovis), Mycobacterium africanum (Mycobacterium africanum), Mycobacterium cassiae (Mycobacterium canetti), Mycobacterium caprine (Mycobacterium caprae), Mycobacterium microti (Mycobacterium micoti) or Mycobacterium marinum (Mycobacterium pinipedii). In some embodiments, the mycobacterium infection is a mycobacterium tuberculosis infection.

The term "non-drug resistant tuberculosis" includes diseases caused by infection with one or more species of the mycobacterium tuberculosis complex, which does not exhibit bacterial resistance to standard tuberculosis treatment.

The term "composition" as used herein refers to a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. The meaning of such terms in relation to pharmaceutical compositions includes products comprising the active ingredient(s) and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from mixing, complexation or aggregation of any two or more of the ingredients, or from decomposition of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention include any composition prepared by admixing a compound of the present invention and a pharmaceutically acceptable carrier.

Description of the Compounds of the invention

The invention discloses a compound with DprE1 enzyme activity inhibition, which has the functions of inhibiting the growth of mycobacteria or reducing the bacterial load of the mycobacteria and can be used for treating tuberculosis or mycobacterial infection.

Specifically, the method comprises the following steps:

wherein:

R³represents hydrogen, deuterium, halogen, hydroxy, amino, cyano, C_1-6A halogenated alkyl group,C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Alkylamino, 3-8 membered cycloalkyl or 3-8 membered heterocyclyl;

R⁴represents hydrogen, deuterium or C_1-6An alkyl group;

x represents CR^xOr N; y represents CR^YOr N; z represents CR^ZOr N;

n is 0, 1,2 or 3.

At one endIn some embodiments, R⁴Represents hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl.

In some embodiments, R⁵Represents hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, butyl, methoxy, ethoxy, isopropoxy, tert-butoxy or n-butyloxy.

In some embodiments, R^aAnd R^bEach independently represents hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl; or R^a、R^bAnd together with the carbon atom to which they are commonly attached form a cyclopropane, cyclobutane, cyclopentane, cyclohexane, oxetane or azetidine.

In some embodiments, R^X、R^YAnd R^ZEach independently represents hydrogen, deuterium, fluorine, chlorine, cyano, amino, hydroxyl, methyl, ethyl, isopropyl, n-butyl, tert-butyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, n-butyloxy, methylamino, dimethylamino, ethylamino, diethylamino, 2,2, 2-trifluoroethoxy, difluoromethoxy, or trifluoromethoxy.

in another aspect, the invention relates to a pharmaceutical composition comprising a compound disclosed herein.

In other embodiments, the pharmaceutical composition of the present invention further comprises other drugs for treating tuberculosis or mycobacterial infection, which are rifampicin, isoniazid, pyrazinamide, ethambutol, quinolones (e.g., ciprofloxacin, levofloxacin, and gatifloxacin), aminoglycosides (e.g., streptomycin, kanamycin, and amikacin), polypeptides (e.g., capreomycin, erythromycin, and enramycin), rifabutin, clarithromycin, linezolid, thiosemicarbazide, thioridazine, or any combination thereof.

In another aspect, the invention relates to the use of a compound or pharmaceutical composition disclosed herein for the manufacture of a medicament for inhibiting the growth of, or reducing the bacterial load of, a mycobacterium.

Stereoisomers, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of formula (I) are included within the scope of the present invention unless otherwise indicated.

The compounds of the present disclosure may contain asymmetric or chiral centers and thus may exist in different stereoisomeric forms. The present invention contemplates that all stereoisomeric forms of the compounds of formula (I), including but not limited to diastereomers, enantiomers, atropisomers and geometric (or conformational) isomers, and mixtures thereof, such as racemic mixtures, are integral to the invention.

In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not specified, then all stereoisomers of that structure are contemplated as within this invention and are included as disclosed compounds in this invention. When stereochemistry is indicated by a solid wedge (solid wedge) or dashed line representing a particular configuration, then the stereoisomers of the structure are so well-defined and defined.

The compounds of formula (I) may exist in different tautomeric forms and all such tautomers are included within the scope of the invention.

The compounds of formula (I) may be present in the form of salts. In one embodiment, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be compatible chemically and/or toxicologically with the other ingredients comprising the formulation and/or the mammal being treated therewith. In another embodiment, the salts need not be pharmaceutically acceptable salts and may be intermediates useful in the preparation and/or purification of compounds of formula (I) and/or in the isolation of enantiomers of compounds of formula (I).

Pharmaceutically acceptable acid addition salts may be formed from the disclosed compounds of the invention by the action of an inorganic or organic acid, for example, acetate, aspartate, benzoate, benzenesulfonate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorotheyl salt, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/biphosphate/dihydrogen phosphate, phosphate, Polysilonolactates, propionates, stearates, succinates, sulfosalicylates, tartrates, tosylates and trifluoroacetates.

Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, and the like.

Pharmaceutically acceptable base addition salts may be formed from the disclosed compounds by reaction with an inorganic or organic base.

Inorganic bases from which salts can be derived include, for example, ammonium salts and metals of groups I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

Organic bases from which salts can be derived include primary, secondary and tertiary amines, and substituted amines include naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Some organic amines include, for example, isopropylamine, benzathine (benzathine), choline salts (cholinate), diethanolamine, diethylamine, lysine, meglumine (meglumine), piperazine, and tromethamine.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate base (e.g., Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are usually carried out in water or an organic solvent or a mixture of both. Generally, where appropriate, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. In, for example, "Remington's Pharmaceutical Sciences", 20 th edition, Mack Publishing Company, Easton, Pa., (1985); and "handbook of pharmaceutically acceptable salts: properties, Selection and application (Handbook of pharmaceutical salts: Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) may find some additional lists of suitable salts.

In addition, the compounds disclosed herein, including their salts, may also be obtained in the form of their hydrates or in the form of solvents containing them (e.g., ethanol, DMSO, etc.), for their crystallization. The compounds disclosed herein may form solvates with pharmaceutically acceptable solvents (including water), either inherently or by design; thus, the present invention is intended to include both solvated and unsolvated forms of the disclosed compounds.

Any formulae given herein are also intended to represent the non-isotopically enriched forms as well as the isotopically enriched forms of these compounds. Isotopically enriched compounds have the structure depicted by the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as²H、³H、¹¹C、¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、¹⁸F、³¹P、³²P、³⁵S、³⁶Cl and¹²⁵I。

in another aspect, the compounds of the invention include isotopically enriched compounds as defined herein, e.g. wherein a radioisotope, e.g. is present³H、¹⁴C and¹⁸those compounds of F, or in which a non-radioactive isotope is present, e.g.²H and¹³those of C. The isotopically enriched compounds can be used for metabolic studies (use)¹⁴C) Reaction kinetics study (using, for example²H or³H) Detection or imaging techniques such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) including drug or substrate tissue distribution determination, or may be used in radiotherapy of a patient.¹⁸F-enriched compounds are particularly desirable for PET or SPECT studies. Isotopically enriched compounds of formula (I) can be prepared by conventional techniques known to those skilled in the art or by the procedures and examples described in the present specification using a suitable isotopically labelled reagent in place of the original used unlabelled reagent.

In addition, heavier isotopes are, in particular, deuterium (i.e.,²the substitution of H or D) may provide certain therapeutic advantages which result fromHigher metabolic stability. For example, increased in vivo half-life or decreased dosage requirements or improved therapeutic index. It is to be understood that deuterium in the present invention is to be considered as a substituent of the compound of formula (I). The concentration of such heavier isotopes, particularly deuterium, can be defined by isotopic enrichment factors. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic and natural abundance of a given isotope. If a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, e.g. D₂O, acetone-d₆、DMSO-d₆Those solvates of (a).

In another aspect, the invention relates to intermediates for the preparation of compounds of formula (I).

In another aspect, the invention relates to methods for the preparation, isolation and purification of compounds of formula (I).

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention. In one embodiment, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle or combination thereof. In another embodiment, the pharmaceutical composition may be in a liquid, solid, semi-solid, gel, or spray dosage form.

Pharmaceutical compositions, formulations and administration of the compounds of the invention

The present invention provides a pharmaceutical composition comprising a compound disclosed herein, for example, as set forth in the examples; and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or combination thereof.

The present invention provides methods of treating, preventing or ameliorating a disease or condition comprising administering a safe and effective amount of a combination comprising a compound of the present disclosure and one or more therapeutically active agents. Wherein the combination comprises one or more additional drugs for the treatment of tuberculosis or mycobacterial infection.

The other drugs for treating tuberculosis or mycobacterial infection are rifampicin, isoniazid, pyrazinamide, ethambutol, quinolones (e.g., ciprofloxacin, levofloxacin, and gatifloxacin), aminoglycosides (e.g., streptomycin, kanamycin, and amikacin), polypeptides (e.g., capreomycin, erythromycin, and enramycin), rifabutin, clarithromycin, linezolid, thiosemicarbazide, thioridazine, or any combination thereof.

The amount of compound in the pharmaceutical compositions disclosed herein is that amount which is effective to detect the inhibition of the biological sample. The dosage of the active ingredient in the composition of the present invention may vary, however, the amount of the active ingredient must be such that a suitable dosage form is obtained. The active ingredient may be administered to patients (animals and humans) in need of such treatment at dosages that provide optimal pharmaceutical efficacy. The selected dosage depends on the desired therapeutic effect, on the route of administration and on the duration of the treatment. The dosage will vary from patient to patient depending on the nature and severity of the disease, the weight of the patient, the particular diet of the patient, the concurrent use of drugs, and other factors that will be recognized by those skilled in the art. The dosage range is generally about 0.5mg to 1.0g per patient per day and may be administered in a single dose or in multiple doses. In one embodiment, the dosage range is from about 0.5mg to 500mg per patient per day; from about 0.5mg to 200mg per patient per day in another embodiment; and in yet another embodiment from about 5mg to 100mg per patient per day.

It will also be appreciated that certain compounds of the invention may be present in free form and used in therapy, or if appropriate in the form of a pharmaceutically acceptable derivative thereof. Pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any additional adduct or derivative that upon administration to a patient in need thereof provides, directly or indirectly, a compound of the present invention or a metabolite or residue thereof.

The medicaments or pharmaceutical compositions disclosed herein may be prepared and packaged in bulk (bulk) form, wherein a safe and effective amount of the compound of formula (I) may be extracted and then administered to a patient in the form of a powder or syrup. Typically, the administration to the patient is at a dosage level of between 0.0001 and 10mg/kg body weight per day. Alternatively, the pharmaceutical compositions disclosed herein can be prepared and packaged in unit dosage forms, wherein each physically discrete unit contains a safe and effective amount of a compound of formula (I). When prepared in unit dosage form, the disclosed pharmaceutical compositions can generally contain, for example, from 0.5mg to 1g, or from 1mg to 700mg, or from 5mg to 100mg of the disclosed compounds.

When the pharmaceutical composition of the invention contains one or more other active ingredients in addition to the compound of the invention, the compound weight ratio of the compound of the invention to the second active ingredient may vary and depends on the effective dose of each ingredient. Generally, an effective dose of each is used. Thus, for example, when a compound of the present invention is mixed with another pharmaceutical agent, the weight ratio of the compound of the present invention to the other pharmaceutical agent typically ranges from about 1000: 1 to about 1: 1000, e.g., from about 200: 1 to about 1: 200. Mixtures of the compounds of the invention with other active ingredients are generally also within the above-mentioned ranges, but in each case an effective dose of each active ingredient should be used.

As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, mixture or vehicle, which is compatible with the dosage form or pharmaceutical composition to be administered. Each excipient, when mixed, must be compatible with the other ingredients of the pharmaceutical composition to avoid interactions that would substantially reduce the efficacy of the disclosed compounds and which would result in a pharmaceutical composition that is not pharmaceutically acceptable when administered to a patient. Furthermore, each excipient must be pharmaceutically acceptable, e.g., of sufficiently high purity.

Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form selected. In addition, pharmaceutically acceptable excipients may be selected for their specific function in the composition. For example, certain pharmaceutically acceptable excipients may be selected to aid in the production of a uniform dosage form. Certain pharmaceutically acceptable excipients may be selected to aid in the production of stable dosage forms. Certain pharmaceutically acceptable excipients may be selected to facilitate carrying or transporting the disclosed compounds from one organ or portion of the body to another organ or portion of the body when administered to a patient. Certain pharmaceutically acceptable excipients may be selected that enhance patient compliance.

Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants and buffers. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may provide more than one function, and provide alternative functions, depending on how many such excipients are present in the formulation and those other excipients are present in the formulation.

Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing L approved), and The Handbook of Pharmaceutical Excipients (The American Pharmaceutical Association and The Pharmaceutical Press).

Various carriers for The preparation of incompatible pharmaceutically acceptable compositions and known techniques for their preparation are disclosed in Remington, The Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy, &lTtTtranslation = L "&gTtL &lTt/T &gTtippincott Williams & Wilkins, Philadelphia, and Encyclopedia of pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan,1988-1999, Mardecekker, New York, The contents of each of which are incorporated herein by reference.

The pharmaceutical compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. Some commonly used methods in the art are described in Remington's Pharmaceutical Sciences (Mack publishing company).

Thus, in another aspect, the invention relates to a process for preparing a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or combination thereof, which process comprises admixing the ingredients. Pharmaceutical compositions comprising the disclosed compounds may be prepared by mixing, for example, at ambient temperature and atmospheric pressure.

The compounds disclosed herein are generally formulated in a dosage form suitable for administration to a patient by a desired route. For example, dosage forms include those suitable for the following routes of administration: (1) oral administration, such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets and cachets; (2) parenteral administration, such as sterile solutions, suspensions, and reconstituted powders; (3) transdermal administration, such as transdermal patches; (4) rectal administration, e.g., suppositories; (5) inhalation, such as aerosols, solutions, and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams and gels.

In one embodiment, the compounds disclosed herein may be formulated in oral dosage forms. In another embodiment, the compounds disclosed herein may be formulated in an inhalation dosage form. In another embodiment, the compounds disclosed herein can be formulated for nasal administration. In yet another embodiment, the compounds disclosed herein can be formulated for transdermal administration. In yet another embodiment, the compounds disclosed herein may be formulated for topical administration.

The pharmaceutical compositions provided by the present invention may be provided as compressed tablets, milled tablets, chewable lozenges, fast-dissolving tablets, double-compressed tablets, or enteric-coated, sugar-coated or film-coated tablets. Enteric coated tablets are compressed tablets coated with a substance that is resistant to the action of gastric acid but dissolves or disintegrates in the intestine, thereby preventing the active ingredient from contacting the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which can help to mask unpleasant tastes or odors and prevent oxidation of the tablet. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble substance. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings are endowed with the same general characteristics as sugar coatings. A tabletted tablet is a compressed tablet prepared over more than one compression cycle, including a multi-layer tablet, and a press-coated or dry-coated tablet.

Tablet dosage forms may be prepared from the active ingredient in powder, crystalline or granular form, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled release polymers, lubricants, diluents and/or colorants. Flavoring and sweetening agents are particularly useful in forming chewable tablets and lozenges.

The pharmaceutical composition provided by the present invention may be provided in soft or hard capsules, which may be prepared from gelatin, methylcellulose, starch or calcium alginate. The hard gelatin capsules, also known as Dry Fill Capsules (DFC), consist of two segments, one inserted into the other, thus completely encapsulating the active ingredient. Soft Elastic Capsules (SEC) are soft, spherical shells, such as gelatin shells, which are plasticized by the addition of glycerol, sorbitol or similar polyols. The soft gelatin shell may contain a preservative to prevent microbial growth. Suitable preservatives are those as described herein, including methyl and propyl parabens, and sorbic acid. The liquid, semi-solid and solid dosage forms provided by the present invention may be encapsulated in a capsule. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions may be as described in U.S. patent nos.4,328,245; 4,409,239 and 4,410,545. The capsules may also be coated as known to those skilled in the art to improve or maintain dissolution of the active ingredient.

The pharmaceutical compositions provided herein may be provided in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs and syrups. Emulsions are two-phase systems in which one liquid is dispersed throughout another in the form of globules, which can be either oil-in-water or water-in-oil. Emulsions may include pharmaceutically acceptable non-aqueous liquids and solvents, emulsifiers and preservatives. Suspensions may include a pharmaceutically acceptable suspending agent and a preservative. The aqueous alcoholic solution may comprise pharmaceutically acceptable acetals, such as di (lower alkyl) acetals of lower alkyl aldehydes, e.g. acetaldehyde diethyl acetal; and water-soluble solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened, hydroalcoholic solutions. Syrups are concentrated aqueous solutions of sugars, such as sucrose, and may also contain preservatives. For liquid dosage forms, for example, a solution in polyethylene glycol may be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, such as water, for precise and convenient administration.

Other useful liquid and semi-solid dosage forms include, but are not limited to, those comprising the active ingredients provided herein and a secondary mono-or poly-alkylene glycol, including: 1, 2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, where 350, 550, 750 refer to the approximate average molecular weight of the polyethylene glycol. These formulations may further include one or more antioxidants, such as Butylated Hydroxytoluene (BHT), Butylated Hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.

Dosage unit formulations for oral administration may be microencapsulated, where appropriate. They may also be prepared as extended or sustained release compositions, for example by coating or embedding the particulate material in a polymer, wax or the like.

The oral pharmaceutical composition provided by the invention can also be provided in the form of liposome, micelle, microsphere or nano system. Micellar dosage forms can be prepared using the methods described in U.S. Pat. No.6,350,458.

The pharmaceutical compositions provided herein can be provided as non-effervescent or effervescent granules and powders for reconstitution into liquid dosage forms. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders may include diluents, sweeteners and wetting agents. Pharmaceutically acceptable carriers and excipients used in effervescent granules or powders may include organic acids and sources of carbon dioxide.

Coloring and flavoring agents may be used in all of the above dosage forms.

The disclosed compounds may also be conjugated to soluble polymers as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol or polyoxyethylene polylysine substituted with palmitoyl residues. In addition, the disclosed compounds may be combined with a class of biodegradable polymers used in achieving controlled release of a drug, such as polylactic acid, poly-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphipathic block copolymers of hydrogels.

The pharmaceutical compositions provided by the present invention may be formulated into immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed release forms.

The pharmaceutical compositions provided by the present invention may be co-formulated with other active ingredients that do not impair the intended therapeutic effect, or with substances that supplement the intended effect.

The pharmaceutical compositions provided by the present invention may be administered parenterally by injection, infusion or implantation for local or systemic administration. Parenteral administration as used herein includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.

The pharmaceutical compositions provided herein can be formulated in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems and solid forms suitable for solution or suspension in a liquid prior to injection. Such dosage forms may be prepared according to conventional methods known to those skilled in The art of pharmaceutical Science (see Remington: The Science and Practice of Pharmacy, supra).

Pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives to inhibit microbial growth, stabilizers, solubility enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, thickening agents, pH adjusting agents, and inert gases.

Suitable aqueous carriers include, but are not limited to: water, saline, normal saline or Phosphate Buffered Saline (PBS), sodium chloride injection, Ringers injection, isotonic glucose injection, sterile water injection, dextrose and lactated Ringers injection. Non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and the medium chain triglycerides of coconut oil, and palm seed oil. Water-miscible vehicles include, but are not limited to, ethanol, 1, 3-butanediol, liquid polyethylene glycols (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerol, N-methyl-2-pyrrolidone, N-dimethylacetamide, and dimethylsulfoxide.

Suitable antimicrobial or preservative agents include, but are not limited to, phenol, cresol, mercuric, benzyl alcohol, chlorobutanol, methyl and propyl parabens, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl and propyl parabens, and sorbic acid suitable isotonicity agents include, but are not limited to, sodium chloride, glycerol, and glucose suitable buffering agents include, but are not limited to, phosphates and citrates suitable antioxidants are those as described herein including bisulfite and sodium metabisulfite suitable local anesthetics include, but are not limited to, procaine hydrochloride suitable suspending agents and dispersing agents are those as described herein including sodium carboxymethylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone suitable emulsifiers include those described herein including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monoleate 80, and triethanolamine oleate suitable sequestering or chelating agents include, but are not limited to, edta suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid suitable complexing agents include, cyclodextrin 35-3632-sulfobutyl cyclodextrin, 3632-sulfocyclodextrin, and sulfobutyl cyclodextrin-3632-sulfocyclodextrin

,CyDex,Lenexa,KS)。

The pharmaceutical compositions provided herein may be formulated for single or multiple dose administration. The single dose formulations are packaged in ampoules, vials or syringes. The multi-dose parenteral formulation must contain a bacteriostatic or fungistatic concentration of the antimicrobial agent. All parenteral formulations must be sterile, as is known and practiced in the art.

In one embodiment, the pharmaceutical composition is provided as a ready-to-use sterile solution. In another embodiment, the pharmaceutical compositions are provided as sterile dried soluble products, including lyophilized powders and subcutaneous injection tablets, which are reconstituted with a carrier prior to use. In yet another embodiment, the pharmaceutical composition is formulated as a ready-to-use sterile suspension. In yet another embodiment, the pharmaceutical composition is formulated as a sterile, dry, insoluble product that is reconstituted with a carrier prior to use. In yet another embodiment, the pharmaceutical composition is formulated as a sterile emulsion ready for use.

The pharmaceutical composition may be formulated as a suspension, solid, semi-solid, or thixotropic liquid for depot administration for implantation. In one embodiment, the disclosed pharmaceutical compositions are dispersed in a solid internal matrix surrounded by an outer polymeric membrane that is insoluble in body fluids but allows diffusion therethrough of the active ingredient in the pharmaceutical composition.

Suitable internal matrices include polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, silicone carbonate copolymers, hydrogels of hydrophilic polymers such as esters of acrylic and methacrylic acid, collagen, crosslinked polyvinyl alcohol, and partially hydrolyzed polyvinyl acetate of the class of copolymers.

Suitable outer polymeric films include polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, neoprene, chlorinated polyethylene, polyvinyl chloride, copolymers of chlorinated ethylene and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomers polyethylene terephthalate, butyl rubber chlorohydrin rubber, ethylene/vinyl alcohol copolymers, ethylene/vinyl acetate/vinyl alcohol terpolymers, and ethylene/ethyleneoxyethanol copolymers.

In another aspect, the disclosed pharmaceutical compositions may be formulated in any dosage form suitable for administration to a patient by inhalation, such as a dry powder, aerosol, suspension, or solution composition. In one embodiment, the pharmaceutical compositions disclosed herein can be formulated to be suitable for useA dosage form for inhalation administration of the dry powder to a patient. In yet another embodiment, the disclosed pharmaceutical compositions may be formulated in a dosage form suitable for inhalation administration to a patient via a nebulizer. Dry powder compositions for delivery to the lung by inhalation typically comprise a finely powdered compound disclosed herein and one or more finely powdered pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients that are particularly suitable for use as dry powders are known to those skilled in the art and include lactose, starch, mannitol, and mono-, di-and polysaccharides. Fine powders may be prepared, for example, by micronization and milling. Generally, the size-reduced (e.g., micronized) compound may pass through a D of about 1 to 10 microns₅₀Values (e.g., measured by laser diffraction).

Aerosols can be formulated by suspending or dissolving the disclosed compounds in a liquefied propellant. Suitable propellants include chlorinated hydrocarbons, hydrocarbons and other liquefied gases. Representative propellants include: trichlorofluoromethane (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1-difluoroethane (HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoropropane (HFA-227a), perfluoropropane, perfluorobutane, perfluoropentane, butane, isobutane and pentane. Aerosols comprising the compounds disclosed herein are typically administered to a patient via a Metered Dose Inhaler (MDI). Such devices are known to those skilled in the art

The aerosol may contain additional pharmaceutically acceptable excipients that may be used by MDIs, such as surfactants, lubricants, co-solvents, and other excipients, to improve the physical stability of the formulation, to improve valve characteristics, to improve solubility, or to improve taste.

Pharmaceutical compositions suitable for transdermal administration may be prepared as discrete patches intended to remain in intimate contact with the epidermis of the patient for an extended period of time. For example, the active ingredient may be delivered from a patch agent by iontophoresis, as generally described in Pharmaceutical Research,3(6),318 (1986).

Pharmaceutical compositions suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. For example, ointments, creams and gels may be formulated with a water or oil base, and suitable thickeners and/or gelling agents and/or solvents. Such bases may include, water, and/or oils such as liquid paraffin and vegetable oils (e.g., peanut oil or castor oil), or solvents such as polyethylene glycol. Thickeners and gelling agents used according to the nature of the base include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycol, lanolin, beeswax, carbopol and cellulose derivatives, and/or glyceryl monostearate and/or non-ionic emulsifiers.

Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents or thickening agents.

Powders for external use may be formed in the presence of any suitable powder base, for example talc, lactose or starch. Drops may be formulated with an aqueous or non-aqueous base containing one or more dispersing agents, solubilising agents, suspending agents or preservatives.

Topical formulations may be administered by application to the affected area one or more times per day; an occlusive dressing covering the skin is preferably used. Adhesive depot systems allow for continuous or extended administration.

Use of the Compounds and compositions of the invention

The compounds or pharmaceutical compositions disclosed in the present invention may be used for the preparation of a medicament for the treatment of tuberculosis or mycobacterial infections.

In addition to being beneficial for human therapy, the compounds and pharmaceutical compositions of the present invention may also find application in veterinary therapy for pets, animals of the introduced species and mammals in farm animals. Examples of other animals include horses, dogs, and cats. Herein, the compound of the present invention includes pharmaceutically acceptable derivatives thereof.

Method of treatment

In one embodiment, the presently disclosed methods of treatment comprise administering to a patient in need thereof a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention. Various embodiments of the present disclosure include methods of treating the above-mentioned diseases by administering to a patient in need thereof a safe and effective amount of a disclosed compound or a pharmaceutical composition comprising a disclosed compound.

In one embodiment, the disclosed compounds or pharmaceutical compositions comprising the disclosed compounds may be administered by any suitable route of administration, including systemic and topical administration. Systemic administration includes oral, parenteral, transdermal and rectal administration. Typical parenteral administration refers to administration by injection or infusion, including intravenous, intramuscular, and subcutaneous injection or infusion. Topical administration includes application to the skin and intraocular, otic, intravaginal, inhalation, and intranasal administration. In one embodiment, a disclosed compound or a pharmaceutical composition comprising a disclosed compound may be administered orally. In another embodiment, a disclosed compound or a pharmaceutical composition comprising a disclosed compound may be administered by inhalation. In yet another embodiment, the presently disclosed compounds or compositions comprising the presently disclosed compounds may be administered intranasally.

In one embodiment, a disclosed compound or a pharmaceutical composition comprising a disclosed compound may be administered once or several times at different time intervals over a specified period of time according to a dosing regimen. For example, once, twice, three times or four times daily. In one embodiment, the administration is once daily. In yet another embodiment, the administration is twice daily. The administration may be carried out until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely. Suitable dosing regimens for the disclosed compounds or pharmaceutical compositions comprising the disclosed compounds depend on the pharmacokinetic properties of the compound, such as dilution, distribution and half-life, which can be determined by the skilled person. In addition, suitable dosing regimens for the compounds or pharmaceutical compositions comprising the disclosed compounds, including the duration of the regimen, will depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient being treated, the nature of concurrent therapy, the desired therapeutic effect, and other factors within the knowledge and experience of the skilled artisan. Such a skilled artisan will also appreciate that adjustments to the subject's response to the dosage regimen, or the need for changes in the subject's patient over time, may be required.

The compounds disclosed herein may be administered simultaneously, or before or after, one or more other therapeutic agents. The compounds of the invention may be administered separately from the other therapeutic agents, by the same or different routes of administration, or together with them in pharmaceutical compositions.

For an individual of about 50-70kg, the disclosed pharmaceutical compositions and combinations may be in unit dosage form containing from about 1-1000mg, or from about 1-500mg, or from about 1-250mg, or from about 1-150mg, or from about 0.5-100mg, or from about 1-50mg of the active ingredient. The therapeutically effective amount of the compound, pharmaceutical composition or combination thereof will depend on the species, weight, age and condition of the individual, the disease (disorder) or illness (disease) being treated, or the severity thereof. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient to prevent, treat or inhibit the progression of the disease (disorder) or condition (disease).

The above cited dose profiles have been demonstrated in vitro and in vivo tests using beneficial mammals (e.g., mice, rats, dogs, monkeys) or isolated organs, tissues and specimens thereof. The compounds disclosed herein are used in vitro in the form of solutions, e.g. aqueous solutions, and also enterally, parenterally, especially intravenously, in vivo, e.g. in the form of suspensions or aqueous solutions.

In one embodiment, a therapeutically effective dose of a compound of the present disclosure is from about 0.1mg to about 2,000mg per day. The pharmaceutical composition thereof should provide a dose of the compound of about 0.1mg to about 2,000 mg. In a particular embodiment, the pharmaceutical dosage unit form is prepared to provide from about 1mg to about 2,000mg, from about 10mg to about 1,000mg, from about 20mg to about 500mg, or from about 25mg to about 250mg of the principal active ingredient or a combination of principal ingredients per dosage unit form. In a particular embodiment, the pharmaceutical dosage unit form is prepared to provide about 10mg, 20mg, 25mg, 50mg, 100mg, 250mg,500mg, 1000mg or 2000mg of the primary active ingredient.

In addition, the compounds disclosed herein may be administered in the form of a prodrug. In the present invention, a "prodrug" of a disclosed compound is a functional derivative that, when administered to a patient, is ultimately released in vivo. When administering the compounds disclosed herein in the form of a prodrug, one skilled in the art can practice one or more of the following: (a) altering the in vivo onset time of the compound; (b) altering the duration of action of the compound in vivo; (c) altering the in vivo delivery or distribution of the compound; (d) altering the in vivo solubility of the compound; and (e) overcoming side effects or other difficulties faced by the compounds. Typical functional derivatives useful for preparing prodrugs comprise variants of the compounds which are cleaved in vivo either chemically or enzymatically. These variants, which involve the preparation of phosphates, amides, esters, thioesters, carbonates and carbamates, are well known to those skilled in the art.

General synthetic procedure

To illustrate the invention, the following examples are set forth. It is to be understood that the invention is not limited to these embodiments, but is provided as a means of practicing the invention.

In general, the compounds of the present invention may be prepared by the methods described herein, wherein the substituents are as defined in formula (I), unless otherwise indicated. The following reaction schemes and examples serve to further illustrate the context of the invention.

Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.

The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin Haojian Yunyu chemical Co., Ltd, Tianjin Shucheng chemical reagent factory, Wuhan Xin Huayuan scientific and technological development Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaolingyi factory.

The anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained through reflux drying of metal sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, petroleum ether, N-hexane, N, N-dimethylacetamide and N, N-dimethylformamide were used as they were previously dried over anhydrous sodium sulfate.

The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. The glassware was dried.

The column chromatography is performed using a silica gel column. Silica gel (300 and 400 meshes) was purchased from Qingdao oceanic chemical plants.

NMR spectra were recorded using a Bruker 400MHz or 600MHz NMR spectrometer, CDC1₃、DMSO-d₆、CD₃OD or acetone-d₆TMS (0ppm) or chloroform (7.26ppm) was used as a reference standard for the solvent (in ppm). When multiple peaks occur, the following abbreviations will be used: s (singleton), d (doublet), t (triplet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets). Coupling constants are expressed in hertz (Hz).

Low resolution Mass Spectrometry (MS) data were determined using Agilent 6120 quadrupole HP L C-M (column model: Zorbax SB-C18, 2.1x30mm, 3.5 μ M, 6min, flow rate 0.6M L/min. mobile phase 5% -95% (CH with 0.1% formic acid)₃CN) in (H containing 0.1% formic acid)₂O) by electrospray ionization (ESI) at 210nm/254nm, with UV detection.

The purity of the compound was measured by high performance liquid chromatography (HP L C), using Agilent 1260HP L C (column model: Agilent zorbax Eclipse Plus C18), and detecting with a DAD detector, and finally calculating by area normalization to obtain the purity of the compound.

The following acronyms are used throughout the invention:

CDCl₃deuterated chloroform

DMF N, N-dimethylformamide

DMSO-d₆Deuterated dimethyl sulfoxide

g

h hours

min for

mmol millimole

M mol per liter

DEG C

m L, ml

Microgram/ml

mg/ml

Microliter of

DCM dichloromethane

RT, RT, r.t. Room temperature

rpm rotation per minute

Rt Retention time

Typical synthetic procedures for preparing the disclosed compounds of the invention are shown in the following synthetic schemes. Wherein M represents a leaving group including, but not limited to, a halogen atom, methylsulfonyloxy, and the like; w represents an alkyl group including, but not limited to, methyl, ethyl, isopropyl, tert-butyl. Unless otherwise indicated, R¹、R²、R³、R⁴、R⁵、、R^a、R^bX, Y, Z and n have the definitions as described herein.

Synthetic schemes

The compounds comprised by formula (I) can be prepared by the following procedure:

the compound (1-C) is obtained by the substitution reaction of the compound (1-A) and the compound (1-B) in a solvent under the alkaline condition. The base includes, but is not limited to, potassium carbonate and the like. The reaction is carried out in a solvent inert to the reaction, including but not limited to DMF and the like.

Compound (1-D) is obtained by deprotecting compound (1-C) under basic conditions. The base includes, but is not limited to, lithium hydroxide and the like. The reaction is carried out in a solvent inert to the reaction, including but not limited to methanol and the like.

The compound of the general formula (I) is obtained by carrying out condensation reaction on a compound (1-D) and a compound (1-E) in an alkaline environment under the action of a condensing agent. The condensing agent includes, but is not limited to, 1-propylphosphoric anhydride. The base includes, but is not limited to, triethylamine and the like. The reaction is carried out in a solvent inert to the reaction; including but not limited to DCM and the like.

The compounds, pharmaceutical compositions and uses thereof provided by the present invention are further illustrated below in connection with the examples.

Examples

EXAMPLE 1N- (cyanomethyl) -1- ((6-methoxy-5-methylpyrimidin-4-yl) methyl) -6-methyl-1H-pyrrolo [3,2-b ] pyridine-3-carboxamide

First step Ethyl 1- ((6-methoxy-5-methylpyrimidin-4-yl) methyl) -6-methyl-1H-pyrrolo [3,2-b ] pyridine-3-carboxylate

Under nitrogen protection, 4- (chloromethyl) -6-methoxy-5-methylpyrimidine (1.0g,5.79mmol) (see synthesis of intermediate 44 of patent 201480046182.4), ethyl 6-methyl-1H-pyrrolo [3,2-b ] pyridine-3-carboxylate (1.4g,6.9mmol) (see synthesis of intermediate 6 of patent 201480046182.4) and potassium carbonate (2.4g,17mmol) in DMF (20m L) were stirred at room temperature overnight, quenched with water (50m L), extracted with dichloromethane (50m L× 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (DCM: methanol ═ 50:1) to give the title compound 0.8g as a pink solid in 40% yield.

¹H NMR(600MHz,CDCl₃)8.61(s,1H),8.54(d,J＝1.5Hz,1H),7.99(s,1H),7.51(d,J＝0.9Hz,1H),5.33(s,2H),4.46(q,J＝7.1Hz,2H),4.03(s,3H),2.47(s,3H),2.19(s,3H),1.43(t,J＝7.1Hz,3H).

Second step 1- ((6-methoxy-5-methylpyrimidin-4-yl) methyl) -6-methyl-1H-pyrrolo [3,2-b ] pyridine-3-carboxylic acid

Lithium hydroxide monohydrate (493mg, 11.75mmol) was added to a methanol/water (20M L, 1:1) solution of ethyl 1- ((6-methoxy-5-methylpyrimidin-4-yl) methyl) -6-methyl-1H-pyrrolo [3,2-b ] pyridine-3-carboxylate (0.8g, 2.35mmol) at room temperature, the reaction was stirred at room temperature until completion, most of the organic solvent was removed under reduced pressure, the residue was weakly acidic with 1M hydrochloric acid, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (DCM: methanol ═ 20:1) to obtain 0.7g of the objective compound as a pale yellow solid in 95% yield.

MS(ES-API,pos.ion)m/z:313.3[M+H]⁺

The third step is N- (cyanomethyl) -1- ((6-methoxy-5-methylpyrimidin-4-yl) methyl) -6-methyl-1H-pyrrolo [3,2-b ] pyridine-3-carboxamide

Triethylamine (0.48m L, 3.46mmol) and 1-propylphosphoric anhydride (1.03m L, 1.73mmol, 50% EA solvent) were added to a solution of 1- ((6-methoxy-5-methylpyrimidin-4-yl) methyl) -6-methyl-1H-pyrrolo [3,2-b ] pyridine-3-carboxylic acid (0.27g,0.86mmol) in dichloromethane (20m L) at room temperature, after stirring for 5 minutes at room temperature, aminoacetonitrile hydrochloride (160mg,1.73mmol) was added, stirring was continued overnight, the system was diluted with water (30m L), dichloromethane (10m L× 2) was extracted, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM: MeOH ═ 50:1) to give 25mg of the title compound as a white solid in 8.2% yield.

MS(ES-API,pos.ion)m/z:351.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)9.03(s,1H),8.38(d,J＝11.3Hz,2H),8.24(s,1H),7.78(s,1H),5.66(s,2H),4.46(d,J＝5.4Hz,2H),3.93(s,3H),2.40(s,3H),2.24(s,3H).

EXAMPLE 2N- (2-cyanoethyl) -1- ((6-methoxy-5-methylpyrimidin-4-yl) methyl) -6-methyl-1H-pyrrolo [3,2-b ] pyridine-3-carboxamide

Triethylamine (0.80m L, 5.78mmol) and 1-propylphosphoric anhydride (1.62m L, 2.88mmol, 50% EA solvent) were added to a solution of 1- ((6-methoxy-5-methylpyrimidin-4-yl) methyl) -6-methyl-1H-pyrrolo [3,2-b ] pyridine-3-carboxylic acid (0.45g, 1.44mmol) in dichloromethane (30m L) at room temperature, after stirring for 5 minutes at room temperature, 3-aminopropionitrile (202mg, 2.88mmol) was added, stirring was continued overnight, the system was diluted with water (30m L), dichloromethane (10m L× 2) was extracted, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM: MeOH ═ 50:1) to give 300mg of the title compound as a white solid in 57% yield.

MS(ES-API，pos.ion)m/z:365.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)8.92(t,J＝6.0Hz,1H),8.42(s,1H),8.36(s,1H),8.18(s,1H),7.77(s,1H),5.65(s,2H),3.94(s,3H),3.66(q,J＝6.3Hz,2H),2.83(t,J＝6.5Hz,2H),2.41(s,3H),2.25(s,3H).

Biological activity assay

Test example 1 Mycobacterium tuberculosis (Mtb) Minimum Inhibitory Concentration (MIC) assay

Test method 1

1) Compound preparation: DMSO was added to a 96-well plate containing the test compound to a final concentration of 5 mg/ml. Standing at room temperature for 0.5-1h, and blowing and sucking with a pipette to dissolve completely.

2) Compound dilution, compound final detection concentration of 50 ug/ml and 10ug/ml, no parallel, 5mg/ml mother liquor diluted 5 times to obtain 1mg/ml compound working solution, Rifampicin final test concentration (ug/ml) of 0.04, 0.02, 0.01, 0.005 ug/ml, Isoniazide final test concentration (ug/ml) of 0.1, 0.05, 0.025, 0.0125 ug/ml, 100 × positive control working solution.

3) Preparing a detection plate: mu.l of each of 5mg/ml and 1mg/ml compound working solutions was added to the test plate. DMSO was added to the remaining two wells as solvent and growth control. Mu.l of culture medium was placed in the wells around the plate as a control.

4) Inoculation: the assay plates were inoculated with 198ul of 1000-fold dilutions of H37Ra (e.g., pre-frozen at-80 ℃ C., OD550 of about 0.225 to 0.275).

5) Culturing: culturing in 37 deg.C incubator for 10-12 days. After the culture, 12.5ul of 7H9+ 20% Tween 80 medium and 20ul of Alamar blue were added, and the culture was continued for 24 hours.

6) And (4) judging a result: whether the bacteria grow is judged by visual observation of the Alamar blue color change or by fluorescence detection (Ex/Em,530nm/590 nm).

The results of the Mtb inhibitory activity of the compounds of the present invention are shown in table 1.

2) Test results

TABLE 1 test results for Mtb inhibitory Activity of the Compounds of the present invention

Numbering	MIC(μg/ml)
		Example 1	0.625
Example 2	0.1953

And (4) conclusion: the compound has better inhibitory activity to Mtb.

Pharmacokinetic evaluation

1. Test method

SD rats were weighed after fasting overnight for 15 hours and randomly grouped according to body weight, test compound formulation vehicle was 5% DMSO + 5% Solutol + 90% saline. for the intravenously administered test group, the test animals were given a dose of 1mg/kg, for the orally administered test group, 5mg/kg, and then venous blood (about 0.2m L) was taken at time points of 0, 0.083 (intravenous only group), 0.25, 0.5, 1.0, 2.0, 5.0, 7.0, and 24 hours and placed in an EDTAK₂In an anticoagulation tube, centrifuge at 11000rpm for 2 minutes, collect plasma, and store at-20 ℃ or-70 ℃ until L C/MS/MS analysis is performed, determine the drug concentration in plasma at each time point, calculate pharmacokinetic parameters according to drug concentration-time curve.

The pharmacokinetic properties of the compounds of the invention were tested by the above tests and the pharmacokinetic parameters are shown in table 2.

2. Test results

TABLE 2 pharmacokinetic Activity of the Compounds of the invention

And (4) conclusion: as shown in Table 2, the compound of the invention has high blood concentration and exposure water average in rats after oral administration, long half-life period, high bioavailability and good pharmacokinetic characteristic.

Finally, it should be noted that there are other ways of implementing the invention. Accordingly, the embodiments of the present invention will be described by way of illustration, but not limitation to the description of the present invention, and modifications made within the scope of the present invention or equivalents added to the claims are possible. All publications or patents cited herein are incorporated by reference.

Claims

1. A compound which is a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof,

wherein:

R⁴represents hydrogen, deuterium or C_1-6An alkyl group;

x represents CR^xOr N; y represents CR^YOr N; z represents CR^ZOr N;

n is 0, 1,2 or 3.

2. The compound of claim 1, wherein R is¹Represents hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, n-propyl, isopropylN-butyl, t-butyl, methoxy, ethoxy, isopropoxy, t-butoxy or n-butyloxy.

3. The compound of claim 1, wherein R is²Represents hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy, ethoxy, isopropoxy, tert-butoxy or n-butyloxy.

4. The compound of claim 1, wherein R is³Represents hydrogen, deuterium, fluorine, chlorine, hydroxyl, amino, cyano, difluoromethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, n-butyloxy, methylamino, ethylamino, difluoromethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, pyrrolidinyl or tetrahydrofuranyl.

5. The compound of claim 1, wherein R is⁴Represents hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl.

6. The compound of claim 1, wherein R is⁵Represents hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, n-butyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy or n-butyloxy.

7. The compound of claim 1, wherein R is^aAnd R^bEach independently is hydrogen, deuterium, fluoro, chloro, methyl, ethyl, n-propyl or isopropyl; or R^a、R^bAnd together with the carbon atom to which they are commonly attached form a cyclopropane, cyclobutane, cyclopentane, cyclohexane, oxetane or azetidine.

8. The compound of claim 1Wherein said R is^X、R^YAnd R^ZEach independently represents hydrogen, deuterium, fluorine, chlorine, cyano, amino, hydroxyl, methyl, ethyl, isopropyl, n-butyl, tert-butyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, tert-butoxy, n-butyloxy, methylamino, dimethylamino, ethylamino, diethylamino, 2,2, 2-trifluoroethoxy, difluoromethoxy, or trifluoromethoxy.

9. The compound of claim 1, having the structure of one of:

10. a pharmaceutical composition comprising a compound of any one of claims 1-9.

11. The pharmaceutical composition of claim 10, further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle, or combination thereof.

12. The pharmaceutical composition of claim 11, further comprising an additional drug for the treatment of tuberculosis or mycobacterial infection, said drug being rifampin, isoniazid, pyrazinamide, ethambutol, ciprofloxacin, levofloxacin, gatifloxacin, streptomycin, kanamycin, amikacin, capreomycin, erythromycin, enramycin, rifabutin, clarithromycin, linezolid, thiosemicarbazide, thioridazine, or any combination thereof.

13. Use of a compound according to any one of claims 1 to 9 or a pharmaceutical composition according to any one of claims 10 to 12 in the manufacture of a medicament for the treatment of tuberculosis or mycobacterial infections in a mammal.

14. Use of a compound according to any one of claims 1 to 9 or a pharmaceutical composition according to any one of claims 10 to 12 in the manufacture of a medicament for inhibiting the growth of or reducing the bacterial load of a mycobacterium.

15. Use of a compound of any one of claims 1-9 or a pharmaceutical composition of any one of claims 10-12 in the manufacture of a medicament for inhibiting DprE 1.