Application of novel cyclic peptide compound in anti-mycobacterium medicine

Abstract

The invention discloses a novel cyclic peptide compound. The structure of the novel cyclic peptide compound is shown as a formula (I). The compound has a remarkable inhibition effect on mycobacterium tuberculosis and mycobacterium marinum, is equivalent to a first-line drug isoniazide, and can generate a synergistic or additive effect when being combined with clinically common antibiotics. The invention also discloses application of a pharmaceutical composition containing the compound in preparation of medicines for treating and / or preventing mycobacterium infection diseases.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, and particularly relates to a novel cyclic peptide compound, a composition and use thereof, wherein the compound or the composition has the use of selectively inhibiting or killing Mycobacterium bacteria, and can be used for preventing or treating diseases caused by Mycobacterium bacterial infection. BACKGROUND

[0002] Mycobacterium bacteria are long and slightly curved, sometimes have branches or appear filaments, cause chronic diseases, and are accompanied by granulomas. They are widely distributed in nature, including Mycobacterium tuberculosis, Mycobacterium marinum, Mycobacterium bovis and Mycobacterium paratuberculosis.

[0003] Mycobacterium tuberculosis is the most dangerous one among the Mycobacterium bacteria, and the tuberculosis caused by Mycobacterium tuberculosis is one of the most deadly threats to global human health, and is one of the top ten causes of death. In 2021, the number of deaths worldwide due to tuberculosis reached 1.6 million. The continuous and rapid evolution and spread of drug-resistant pathogens further limit the prevention and control of tuberculosis, and pose a high and increasing risk to public health (WHO. Global tuberculosis report 2022, 2023). Despite great efforts, the first-line anti-tuberculosis drugs currently used in the clinic are still the research results of half a century ago. It is urgent to develop safe and effective new anti-tuberculosis drugs.

[0004] At present, diseases caused by non-tuberculosis Mycobacterium are also increasing. They can invade the lungs, lymph nodes, bones and joints, skin and soft tissues of the host and cause systemic spread, for example, Mycobacterium marinum can cause skin and soft tissue infections and disseminated lesions. Therefore, the development of drugs targeting non-tuberculosis Mycobacterium is also increasingly valued. SUMMARY

[0005] The following only outlines some aspects of the present application and is not limited thereto. These aspects and other parts are more completely described later. All references in the specification are incorporated herein by reference in their entirety. When the disclosure of the specification is different from the cited references, the disclosure of the specification is preferred.

[0006] The present application provides a novel cyclic peptide compound for preventing or treating infectious diseases caused by Mycobacterium, such as tuberculosis, bone tuberculosis, lymph node tuberculosis, lumbar tuberculosis, thoracic tuberculosis, breast tuberculosis, swimming pool granuloma, pulmonary infection, lymph node infection, Buruli ulcer. The compound has significant activity, stable nature, good safety, and can produce significant synergy with commercially available positive drugs, and has good clinical application prospect.

[0007] The present application also provides pharmaceutical compositions comprising these compounds and methods of using these compounds or compositions to treat the above diseases in mammals, especially humans.

[0008] Specifically: In one aspect, the present application aims to provide a stereoisomer, geometric isomer, cis-trans isomer, tautomer, atropisomer, nitroxide, hydrate, solvate, isotopically labeled, metabolite, prodrug, or mixture thereof, or a pharmaceutically acceptable salt or prodrug thereof, of a compound having a structure as shown in formula (I), Wherein: n is independently 0, 1, 2, or 3; L is independently selected from substituted or unsubstituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, biaryl, triaryl, fused heteroaryl, fused biaryl, fused triaryl, wherein the substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, biaryl, triaryl, fused heteroaryl, fused biaryl, fused triaryl can be independently and optionally substituted with one or more substituents selected from deuterium, F, Cl, Br, I, hydroxyl, amino, carboxyl, cyano, nitro, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl, heteroaryloxy, heteroaroyl, heteroarylamino, heteroarylalkoxy, heteroarylalkylamino, heterocyclylalkanoyl, heterocycloalkyl, heterocyclyloxy, heterocyclylamino, heterocyclylacyl, heterocyclylalkoxy, heterocyclylalkylamino, heterocyclylalkanoyl, azidoalkoxy, fused bicyclic group, fused heterobicyclic group, fused bicyclic aliphatic substituent; The amino acids at the positions of AA1-AA7 can be independently and optionally substituted with L or D configuration of natural, unnatural amino acids derived from glycine ; R2 is independently selected from hydrogen or C 1-3 alkyl; X is independently selected from O, S or NR3; R3 alone represents hydrogen, deuterium, halogen, hydroxyl, amino, nitro, cyano, alkyl, haloalkyl, alkoxy, alkylamino, alkylacyl, hydroxyalkoxy, hydroxyalkylamino, hydroxyalkylacyl, haloalkoxy, haloalkylamino, haloalkylacyl, aminoalkoxy, cycloalkyl, cycloalkyloxy, cycloalkylamino, cycloalkylacyl, alkenyl, alkenylalkoxy, alkenylalkylamino, alkenylalkylacyl, alkynyl, alkynylalkoxy, alkynylalkylamino, alkynylalkylacyl, aryl, aryloxy, arylacyl, arylamino, arylalkoxy, arylalkylamino, heteroaryl, heteroaryloxy, heteroarylacyl, heteroarylamino, heteroarylalkoxy, heteroarylalkylamino, heterocyclic alkylacyl, heterocyclic alkyl, heterocyclic alkyloxy, heterocyclic amino, heterocyclic acyl, heterocyclic alkoxy, heterocyclic alkylamino, heterocyclic alkyl, heterocyclic alkyl, heterocyclic alkylamine, heterocyclic alkylalkanes, heterocyclic alkyl. Acyl, azidoalkoxy, fused bicyclic, fused heterobicyclic, fused bicyclic aliphatic, fused heterobicyclic aliphatic, fused bicyclic oxy, fused heterobicyclic oxy, fused bicyclic amino, fused heterobicyclic amino, fused bicyclic alkoxy, fused heterobicyclic alkoxy, fused bicyclic alkylamino, fused heterobicyclic alkylamino, fused heterobicyclic alkylamino, fused heterobicyclic alkylamino, fused bicyclic oxyalkoxy, fused heterobicyclic oxyalkoxy, fused bicyclic amino alkoxy, fused heterobicyclic amino alkoxy, fused bicyclic -C(=O)-, fused bicyclic -C(=O)O-, fused heterobicyclic -C(=O)-, fused heterobicyclic -C(=O)O-, fused bicyclic amino -C(=O)-, fused heterobicyclic amino -C(=O)N(R) 13 )-, Fused heterobicyclic group -C(=O)N(R 13 )-, spirobicycloyl, spirohexacycloyl, spirobicycloyl aliphatic, spirohexacycloyl aliphatic, spirobicycloyloxy, spirohexacycloyloxy, spirobicycloylamino, spirohexacycloylamino, spirobicycloylalkoxy, spirohexacycloylalkoxy, spirobicycloylalkylamino, spirohexacycloylalkylamino, spirobicycloyloxyalkoxy, spirohexacycloyloxyalkoxy, spirobicycloylaminoalkoxy, spirohexacycloylaminoalkoxy, spirohexacycloylaminoalkoxy, spirobicycloyl-C(=O)-, spirobicycloyl-C(=O)O-, spirohexacycloyl-C(=O)-, spirohexacycloyl-C(=O)-, spirohexacycloyl-C(=O)- Bicyclic group -C(=O)O-, spirobicyclic amino-C(=O)-, spirohexacyclic amino-C(=O)-, spirobicyclic -C(=O)N(R4)-, spirohexacyclic -C(=O)N(R4)-, R5R4N-, -C(=O)NR4R5, -OC(=O)NR4R5, -OC(=O)OR4, -N(R4)C(=O)NR4R5, -N(R4)C(=O)OR5, -N(R4)C(=O)-R5, R4R5N-S(=O) t -,R4S(=O) t -,R4S(=O) t N(R5)-, R5R4N-alkyl, R4S(=O)t -alkyl, R5R4N-C(=O)-alkyl, R5R4N-alkoxy, R4S(=O) t -alkoxy, R4R5N-C(=O)-alkoxy, aryl-(CH2) p -G-(CH2) m -, heteroaryl-(CH2) p -G-(CH2) m -, heterocyclyl-(CH2) p -G-(CH2) m -, or cycloalkyl-(CH2) p -G-(CH2) m -, wherein G is O, S, NR6, S(=O), S(=O)2, C(=O), -C(=O)N(R4)-, -OC(=O)N(R4)-, -OC(=O)-, -N(R4)C(=O)N(R4)-, NaOS(=O)2O-, NaOS(=O)2O-, -(R4)N-S(=O) t -, -OS(=O) t -, or -OS(=O) t N(R4)-; t is 1 or 2; p and m are each independently 0, 1, 2, 3 or 4; wherein aryl-(CH2) p -G-(CH2) m -, heteroaryl-(CH2) p -G-(CH2) m -, heterocyclyl-(CH2) p -G-(CH2) m -, or cycloalkyl-(CH2) p -G-(CH2) m - can be substituted by one or more substituents selected from F, Cl, Br, I, alkyl, alkenyl, alkynyl, alkoxy or cyano; -O(CH2) q R7, wherein R7is independently selected from alkylamino, amino, alkyl-C(=O)NH-, heterocyclyl, -(CH2CH2O) m H, glucopyranosyl, NaOS(=O)2O-glucopyranosyl, NaOS(=O)2O-, alkyl-S(=O)2NH, NaOS(=O)2-, (HO)2P(=O)O-, aryl, heterocyclylalkyl, aminoalkyl, -P(=O)R8R9, wherein said heterocyclylalkyl, aminoalkyl and NaOS(=O)2O- are each independently optionally substituted with one or more substituents selected from H, alkyl, amino, halogen or alkoxy, R8and R9are each independently selected from -OR 10 or -NHR11 R 10 are independently H, Na, C 1-6 alkyl; R 11 is H or C 1-8 alkyl, wherein said C 1-8 alkyl is optionally substituted with one or more alkoxycarbonyl groups; q is 0, 1, 2, 3 or 4; each R6may be the same or different, each being independently hydrogen, R5R4NC(=O)-, R5OC(=O)-, R5C(=O)-, R5R4NS(=O)-, R5OS(=O)-, R5S(=O)-, R5R4NS(=O)2-, R5OS(=O)2-, R5S(=O)2-, aliphatic, halogenated aliphatic, hydroxy aliphatic, amino aliphatic, alkoxy aliphatic, alkylamino aliphatic, alkylthio aliphatic, aryl aliphatic, heteroaryl aliphatic, heterocyclyl aliphatic, cycloalkyl aliphatic, aryloxy aliphatic, heterocyclyloxy aliphatic, cycloalkyloxy aliphatic, arylamino aliphatic, heterocyclylamino aliphatic, cycloalkylamino aliphatic, aryl, heteroaryl, heterocyclyl or carbocyclyl; each R5and R4is independently hydrogen, aliphatic, halogenated aliphatic, hydroxy aliphatic, amino aliphatic, alkoxy aliphatic, alkylamino aliphatic, alkylthio aliphatic, aryl aliphatic, heteroaryl aliphatic, heterocyclyl aliphatic, cycloalkyl aliphatic, aryloxy aliphatic, heterocyclyloxy aliphatic, cycloalkyloxy aliphatic, arylamino aliphatic, heterocyclylamino aliphatic, cycloalkylamino aliphatic, aryl, heteroaryl, heterocyclyl or cycloalkyl; when R5and R4are attached to the same nitrogen atom, R5, R4and the nitrogen atom can optionally form a substituted or unsubstituted 3-8 membered ring, a fused bicyclic ring or a spiro bicyclic ring; the heteroatoms involved in the above mentioned heterocyclyl, heteroaryl, fused heterobicyclic, spiro heterobicyclic groups are 1-5 heteroatoms independently selected from N, O, S, Se; The above R3, R4, R5, R6groups can optionally be substituted with one or more of hydroxyl, hydroxymethyl, carboxyl, acetylamino, alkyl (such as methyl, ethyl, propyl), alkoxy (such as methoxy, ethoxy, t-butoxy), alkylamino, cycloalkyl, alkenyl, alkynyl, trifluoromethyl, trifluoroacetyl, thiol, halogen, nitro, amino, azido (-N3), guanidino, cyano, t-butoxycarbonyl (-Boc), carbonyl (-C=O), oxo (=O), thioxo (=S), sulfonyl, aryl, heteroaryl, heterocyclyl.

[0009] The present invention relates to an amino acid sequence of a compound comprising at least one L or D configuration

[0010] In some embodiments, the amino acid sequence of the compound has 1-3 amino acids added or removed, which can be concentrated or dispersed at any position of the amino acid sequence, and the antibacterial activity of the changed amino acid sequence is not significantly reduced, or remains comparable, or is significantly enhanced.

[0011] In another aspect, the present application relates to a pharmaceutical composition comprising the compound disclosed herein.

[0012] In some embodiments, the present application further includes the present application relates to a combination of the compound and one or more drugs for preventing or treating mycobacterium infection.

[0013] In some embodiments, the pharmaceutical composition of the present application further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, solvent or a combination thereof.

[0014] In another aspect, the present application relates to the use of the compound or the pharmaceutical composition disclosed herein for the preparation of a medicament for treating mycobacterium infection, wherein the mycobacterium infection is tuberculosis, bone tuberculosis, lymph node tuberculosis, lumbar tuberculosis, kidney tuberculosis, intestinal tuberculosis, thoracic tuberculosis, breast tuberculosis, swimming pool granuloma, pulmonary infection, lymph node infection, Buruli ulcer.

[0015] The results of biological tests show that the compound provided by the present application can inhibit the growth of mycobacterium.

[0016] Any embodiment of any aspect of the present application can be combined with any other embodiment of the same aspect, unless they conflict with each other. Furthermore, any technical feature of any embodiment of any aspect of the present application can be applied to the technical feature of any other embodiment of the same aspect, unless they conflict with each other.

[0017] The foregoing merely illustrates some aspects of the present application and does not limit the present application to these aspects. These aspects and other aspects will become more apparent to one of ordinary skill in the art from the following detailed description.

[0018] Detailed description of the present application Definitions and general terms Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover all alternatives, modifications, and equivalents, all of which are included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many similar or equivalent methods and materials can be used to practice the invention. The invention is by no means limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ from or contradict this application (including, but not limited to, defined terminology, application of terminology, described techniques, etc.), this application shall prevail.

[0019] It should be further appreciated that certain features of the invention, for clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the invention, for brevity, have been described in a single embodiment, but may also be provided individually or in any suitable sub-combination.

[0020] Unless otherwise stated, all technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. All patents and publications related to this invention are incorporated herein by reference in their entirety.

[0021] Unless otherwise stated, the following definitions shall apply as used herein. For the purposes of this invention, chemical elements are consistent with the CAS edition of the periodic table and the Handbook of Chemistry and Physics, 75th edition, 1994. Furthermore, general principles of organic chemistry can be found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 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.

[0022] Unless otherwise stated or there is a clear conflict in the context, the articles “a,” “an,” and “described” as used herein are intended to include “at least one” or “one or more.” Therefore, these articles as used herein refer to articles for one or more (i.e., at least one) objects. For example, “a component” refers to one or more components, meaning that more than one component may be considered for use or adoption in the implementation of the described embodiments.

[0023] The term "subject" as used herein refers to an animal. Typically the animal is a mammal. A subject, for example, also refers to primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

[0024] The term "patient" as used herein refers to a human (including adults and children) or other animal. In some embodiments, "patient" refers to a human.

[0025] The term "comprising" is a open term, i.e., it includes what the claims recite but not excluding other items.

[0026] "stereoisomers" refer to compounds which have a different spatial arrangement of atoms in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis / trans), atropisomers, and the like.

[0027] "chiral" refers to a molecule which does not superimpose on its mirror image; while "achiral" refers to a molecule which superimposes on its mirror image.

[0028] "enantiomers" refer to two isomers of a compound which are nonsuperimposable mirror images of one another.

[0029] "diastereomers" refer to stereoisomers which have two or more chiral centers and which are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can be separated by high resolution analytical techniques such as electrophoresis and chromatography, e.g., HPLC.

[0030] The stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

[0031] Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of the rotation of plane-polarized light by the compound; (-) or 1 meaning that the compound is levorotatory. A compound, which is (+) or d is dextrorotatory. A specific stereoisomer is an enantiomer; a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur where there has been no stereoselection or stereospecificity in a chemical reaction, and no optical activity in the starting material.

[0032] Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in a racemic or enantiomeric enriched form, e.g., in the (R)-, (S)-, or (R,S)-configurational form. In certain embodiments, each asymmetric atom is at least 50% enantiomeric excess in the (R)- or (S)- configuration, 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.

[0033] Depending on the choice of starting materials and methods, the compounds of the present application can be present in the form of one or more of possible isomers, such as racemates and mixtures of diastereomers (depending on the number of asymmetric carbon atoms), in the form of geometric isomers, such as E or Z isomers, in the form of optical isomers such as (R)- or (S)-enantiomers, as racemates, diastereomeric mixtures, geometric isomers, as pure or substantially pure geometric isomers, as pure or substantially pure optical isomers, or as tautomers. The optical isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents can be in the E or the Z configuration; if the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent can have a cis- or trans-configuration.

[0034] Any mixture of stereoisomers can be separated into their individual components by conventional techniques, such as HPLC or fractional crystallization. The optically active forms of compounds can be obtained by chiral chromatographic processes or by chiral synthesis procedures using optically active reagents.

[0035] Any of the resulting racemates of the end products or intermediates can be resolved into the optical antipodes by methods well known to those skilled in the art, such as, for example, by separation of the resulting diastereomeric salts thereof. The racemates of the products can also be separated by chiral chromatography, such as, for example, high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, the antipodes can be prepared by asymmetric synthesis, for example, as described in Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S. H. Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

[0036] As described herein, the compounds of the present application can optionally be substituted with one or more substituents, such as described herein for the compounds of the general formulae above, or as described in particular examples, subgenera, and classes of compounds encompassed by the present application.

[0037] In general, the term "substituted" means that one or more hydrogen atoms in the given structure are replaced with a substituent as described herein. Unless otherwise indicated, a substituted group can have a substituent at each substitutable position of the group. When more than one position in the general structure can be substituted with one or more substituents selected from a particular group, the substituents can be the same or different at each position.

[0038] The term "unsubstituted" means that the designated group bears no substituents.

[0039] The term "optionally substituted" can be used interchangeably with the term "unsubstituted or substituted," 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, NH2, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylamino, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like.

[0040] Also, it should be noted that the description "each independently" used in the present application is interchangeable with "each independently" and "independently" unless explicitly indicated otherwise, and should be interpreted broadly, i.e., it can mean that the specific options expressed by the same symbol in different groups do not affect each other, or it can mean that the specific options expressed by the same symbol in the same group do not affect each other.

[0041] In various portions of the specification, substituents of the compounds disclosed herein are disclosed by group or range. It is specifically intended that the present application include each and every independent combination of the members of these groups and ranges. For example, it is specifically intended that the term "C1-C6alkyl" include "methyl," "ethyl," "C3alkyl," "C4alkyl," "C5alkyl," and "C6alkyl," each and every independent combination of the members of these groups, and the like. 1-6 "Alkyl" specifically refers to the independently disclosed methyl, ethyl, C3alkyl, C4alkyl, C5alkyl, and C6alkyl.

[0042] In various portions of the specification, linking substituents are described. When the structure clearly requires a linking group, the Markush variable recited for that group should be interpreted as a linking group. For example, if the structure requires a linking group and the Markush group definition recited for that variable recites "alkyl" or "aryl," it should be understood that the "alkyl" or "aryl" represents a linking alkylene group or arylene group, respectively.

[0043] The term "alkyl" or "alkyl group" as used herein means a saturated straight or branched chain monovalent hydrocarbon radical, wherein the alkyl group can be optionally substituted with one or more substituents described herein. Unless otherwise specifically described in detail, alkyl groups contain 1-20 carbon atoms. In one embodiment, alkyl groups contain 1-12 carbon atoms; in another embodiment, alkyl groups contain 3-12 carbon atoms; in another embodiment, alkyl groups contain 1-6 carbon atoms; in yet another embodiment, alkyl groups contain 1-4 carbon atoms.

[0044] Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), t-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-l-butyl (-CH2CH2CH(CH3)2), 2-methyl-l-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, and the like.

[0045] The term "alkoxy" denotes an alkyl group attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specifically indicated, 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 can optionally be substituted by one or more substituents as described herein.

[0046] The term "alkenyl" denotes a straight-chain or branched one valent hydrocarbon group with 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, which is at least one position unsaturated, i.e. one C-C double bond, which is not further substituted. 2"alkenyl" means a straight or branched chain, monovalent hydrocarbon group of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, which contains at least one site of sp2hybridized carbon, i.e., a carbon-carbon double bond, wherein the alkenyl group is independently optionally substituted with one or more substituents described herein, including the positioning of the group as "cis" "trans" or "E / Z", and specific examples include, but are not limited to, ethenyl (-CH=CH2), allyl (-CH2CH=CH2), and the like.

[0047] The term "alkynyl" means a straight or branched chain, monovalent hydrocarbon group of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, which contains at least one site of sp hybridized carbon, i.e., a carbon-carbon triple bond, wherein the alkynyl group is independently optionally substituted with one or more substituents described herein, and specific examples include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), and the like.

[0048] The term "hydroxy-substituted alkyl" means an alkyl group substituted with one or more hydroxy groups, wherein the alkyl group has the meaning described herein. Examples include, but are not limited to, hydroxymethyl, hydroxyethyl, 1,2-dihydroxyethyl, and the like.

[0049] The terms "carbocyclic", "carbocyclyl", "cycloalkyl" mean a monovalent or multivalent, non-aromatic, saturated or partially unsaturated ring, and do not contain heteroatoms, including a monocyclic ring of 3 to 12 carbon atoms or a bicyclic or tricyclic ring of 7 to 12 carbon atoms. Bicyclic carbocycles having 7 to 12 atoms can be bicyclo[4.5], [5.5], [5.6] or [6.6] systems, while bicyclic carbocycles having 9 or 10 atoms can be bicyclo[5.6] or [6.6] systems. Suitable cyclic aliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl groups. Examples of cyclic aliphatic groups further include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1- enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, adamantyl, and the like. Also, the "carbocyclic", "carbocyclyl", "cycloalkyl" groups can be substituted or unsubstituted, wherein the substituents can be, but are not limited to, haloalkyl, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, thiol, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O)-, alkyl-C(=O)-, alkyl-S(=O)-, alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O)2-, carboxyalkoxy, and the like.

[0050] ​The term "cycloalkyloxy" or "carbocyclyloxy" includes an optionally substituted cycloalkyl or carbocyclyl group, as defined herein, attached to an oxygen atom, and linked to the rest of the molecule through the oxygen atom. Examples include, but are not limited to, cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, hydroxysubstituted cyclopropyloxy, and the like.

[0051] The term "cycloalkyloxyaliphatic" means an aliphatic group substituted with one or more cycloalkyloxy groups, wherein the aliphatic group and the cycloalkyloxy group have the meaning as described herein. Examples include, but are not limited to, cyclopropyloxy methyl, cyclopropyloxy ethyl, cyclopentyloxy methyl, cyclopentyloxy ethyl, cyclohexyloxy ethyl, halocyclopropyloxy ethyl, and the like.

[0052] The term "cycloalkylaminoaliphatic" means an aliphatic group substituted with one or more cycloalkylamino groups, wherein the aliphatic group and the cycloalkylamino group have the meaning as described herein. Examples include, but are not limited to, cyclopropylaminomethyl, cyclopropylamino hexyl, cyclopentylaminomethyl, cyclopentylamino ethyl, cyclohexylamino ethyl, halocyclopropylamino ethyl, and the like.

[0053] The term "cycloalkylaliphatic" or "carbocyclylaliphatic" means an aliphatic group which can be substituted with one or more cycloalkyl groups or carbocyclyl groups, wherein the cycloalkyl, or carbocyclyl and the aliphatic group have the meaning as described herein. Examples include, but are not limited to, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopentylmethyl, cyclohexylethyl, and the like.

[0054] The terms "heterocycle", "heterocyclyl", "heteroaliphatic" or "heterocyclic" are used interchangeably herein and mean a monocyclic, bicyclic, or tricyclic ring system in which one or more atoms in the ring system is an independently selected heteroatom, and the ring can be completely saturated or may contain one or more double bonds, but is not aromatic. One or more ring carbon atoms are independently optionally replaced with one or more substituents described herein. In some embodiments, the "heterocycle", "heterocyclyl", "heteroaliphatic" or "heterocyclic" group is a 3-7 membered monocyclic ring (1-6 carbon atoms and 1-3 heteroatoms which are N, O, P, S, wherein S or P are optionally substituted with one or more oxygen atoms to give groups such as SO, SO2, PO, PO2, when the ring is a three membered ring, wherein only one of the heteroatoms is present), or a 7-10 membered bicyclic ring (4-9 carbon atoms and 1-3 heteroatoms which are N, O, P, S, wherein S or P are optionally substituted with one or more oxygen atoms to give groups such as SO, SO2, PO, PO2).

[0055] Heterocyclyl groups can be carbon-based or heteroatom-based. "Heterocyclyl" also includes groups in which a heterocyclyl group is fused to an aryl, phenyl, heteroaryl, C3-C12carbocyclyl or heterocyclyl group. Examples of heterocyclyl groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxazolidinyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, piperidinyl, homopiperidinyl, epoxypropyl, azepanyl, oxepanyl, thiepanyl, 4-methoxy-piperidin-1-yl, 1,2,3,6-tetrahydropyridin-1-yl, oxazepinyl, diazepinyl, thiazepinyl, pyrrolin-1-yl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, dihydropyranyl, tetrahydropyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydrothienyl, pyrazolidinyl imidazolinyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,6-thiadiaza-1,1-dioxo-2-yl, 4-hydroxy-l,4-azaphosphorin-4-oxide-l-yl, 2-hydroxy-l-(piperazin-l-yl)ethanone-4-yl, 2-hydroxy-l-(5,6-dihydro-l,2,4-triazin-l(4H)-yl)ethanone-4-yl, 5,6-dihydro-4H-l,2,4-oxadiazin-4-yl, 2-hydroxy-l-(5,6-dihydropyridin-l(2H)-yl)ethanone-4-yl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 2-methyl-5,6,7,8-tetrahydro-[l.2.4]triazolo[l,5-c]pyrimidin-6-yl, 4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridin-5-yl, 3H-indolyl 2-oxo-5-azabicyclo[2.2.1]heptan-5-yl, 2-oxo-5-azabicyclo[2.2.2]octan-5-yl, quinolizinyl and N-pyridinylurea. Examples of heterocyclyl groups also include 1,1-dioxothiomorpholinyl, and groups in which two carbon atoms of the ring are replaced by oxygen atoms such as pyrimidinedionyl. Also, the heterocyclyl group can be substituted or unsubstituted, where the substituents can be, but are not limited to, haloalkyl, oxo (=0), hydroxy, amino, halogen, cyano, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, thiol, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=0)-, alkyl-C(=0)-, alkyl-S(=0)-, alkyl-S(=0)2-hydroxy-substituted alkyl-S(=0)-, hydroxy-substituted alkyl-S(=0)2-, carboxyalkoxy and the like.

[0056] The term "heterocyclyl aliphatic" means a heterocyclyl substituted aliphatic group, wherein heterocyclyl and aliphatic have the meaning as described herein, such examples include, but are not limited to, pyrrol-2-ylmethyl, piperidin-2-ylethyl, piperazin-2-ylethyl, piperidin-2-ylmethyl and the like.

[0057] The term "heterocyclyloxy" includes an optionally substituted heterocyclyl group, as defined herein, attached to an oxygen atom, wherein the oxygen atom is attached to the remainder of the molecule, such examples include, but are not limited to, pyrrol-2-yloxy, pyrrol-3-yloxy, piperidin-2-yloxy, piperidin-3-yloxy, piperazin-2-yloxy, piperidin-4-yloxy and the like.

[0058] The term "heterocyclylamino" means an amino group substituted with one or two heterocyclyl groups, wherein the nitrogen atom is attached to the remainder of the molecule, and heterocyclyl has the meaning as described herein, such examples include, but are not limited to, pyrrol-2-ylamino, pyrrol-3-ylamino, piperidin-2-ylamino, piperidin-3-ylamino, piperidin-4-ylamino, piperazin-2-ylamino, dipyrryl-2-ylamino and the like.

[0059] The term "heterocyclyloxy aliphatic" means an aliphatic group substituted with one or more heterocyclyloxy groups, wherein aliphatic and heterocyclyloxy have the meaning as described herein, such examples include, but are not limited to, pyrrol-2-yloxymethyl, piperazin-3-yloxyethyl, piperazin-2-yloxyethyl, morpholin-2-yloxymethyl, piperidin-2-yloxyethyl and the like. The term "heterocyclylamino aliphatic" means an aliphatic group substituted with one or more heterocyclylamino groups, wherein aliphatic and heterocyclylamino have the meaning as described herein, such examples include, but are not limited to, pyrrol-2-ylaminomethyl, piperazin-3-ylaminoethyl, piperazin-2-ylaminoethyl, piperidin-2-ylaminoethyl, morpholin-2-ylaminomethyl and the like.

[0060] The term "heteroatom" means one or more O, S, N, P and Se, including any oxidation state of N, S and P; primary, secondary, tertiary amine and quaternary ammonium salt forms; or forms in which the hydrogen on a nitrogen atom in a heterocyclic ring is replaced, for example, N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR (as in N-substituted pyrrolidinyl).

[0061] The term "halogen" means F, Cl, Br or I.

[0062] The term "unsaturated" as used in the present application means that the moiety contains one or more degrees of unsaturation.

[0063] The term "alkoxy" as used herein refers to an alkyl group, as defined herein, attached to the main chain through an oxygen atom ("alkoxy"), such examples include, but are not limited to methoxy, ethoxy, propoxy, butoxy and the like. The alkoxy group can be substituted or unsubstituted, wherein the substituents can be, but are not limited to, hydroxy, amino, halogen, cyano, alkoxy, alkyl, alkenyl, alkynyl, thiol, nitro and the like.

[0064] The term "hydroxy-substituted alkoxy" or "hydroxyalkoxy" means an alkoxy group substituted with one or more hydroxy groups, wherein alkoxy has the meaning as defined herein, such examples include, but are not limited to hydroxymethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxyisopropoxy and the like.

[0065] The term "aminoalkoxy" means an alkoxy group substituted with one or more amino groups, wherein alkoxy has the meaning as defined herein, such examples include, but are not limited to aminomethoxy, 2-aminoethoxy, 2-aminopropoxy, 2-aminoisopropoxy and the like.

[0066] The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" mean that the alkyl, alkenyl or alkoxy group can be substituted with one or more halogen atoms, such examples include, but are not limited to trifluoromethyl, 2-chloro-vinyl, trifluoromethoxy and the like.

[0067] The term "aryl" means monocyclic, bicyclic, and tricyclic carbocyclic ring systems containing 6-14 members in each ring system, wherein at least one ring system is aromatic, wherein each ring system contains 3-7 members, and only one attachment point to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring", such as aromatic ring can include phenyl, naphthyl and anthracene. The aryl group can be substituted or unsubstituted, wherein the substituents can be, but are not limited to, haloalkyl, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, thiol, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O)-, alkyl-C(=O)-, alkyl-S(=O)-, alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O)2-, carboxyalkoxy and the like.

[0068] The term "fluorophenyl" means a phenyl group substituted with one or more fluorine atoms.

[0069] The term "arylaliphatic" means an aliphatic group substituted with one or more aryl groups, wherein aliphatic group and aryl group have the meaning as defined herein, such examples include, but are not limited to phenethyl, phenylmethyl, p-tolylethyl, phenylethenyl and the like.

[0070] The term "aryloxy" or "aryl-oxy" includes an optionally substituted aryl group, as defined herein, attached to an oxygen atom and linked to the remainder of the molecule through the oxygen atom, wherein the aryl group has the meaning as set forth herein, examples of which include, but are not limited to, phenoxy, tolyloxy, ethylphenyloxy and the like.

[0071] The term "arylamino" denotes an amino group substituted by one or two aryl groups, wherein aryl has the meaning as set forth herein, examples of which include, but are not limited to, phenylamino, p-fluorophenylamino, diphenylamino, ditolylamino, di-p-tolylamino and the like.

[0072] The term "aryloxyaliphatic" denotes an aliphatic group substituted by one or more aryl-oxy groups, wherein aryl-oxy and aliphatic have the meaning as set forth herein, examples of which include, but are not limited to, phenoxy-methyl, phenoxy-ethyl, tolyloxy-ethyl, phenoxy-propyl and the like.

[0073] The term "heteroaryloxyaliphatic" denotes an aliphatic group substituted by one or more heteroaryl-oxy groups, wherein heteroaryl-oxy and aliphatic have the meaning as set forth herein, examples of which include, but are not limited to, furanyloxy-methyl, pyrimidinyloxy-ethyl and the like.

[0074] The term "arylaminoaliphatic" denotes an aliphatic group substituted by one or more arylamino groups, wherein arylamino and aliphatic have the meaning as set forth herein, examples of which include, but are not limited to, phenylamino-methyl, phenylamino-ethyl, tolylamino-ethyl, phenylamino-propyl, phenylamino-allyl and the like.

[0075] The term "arylalkyloxy" denotes an alkyloxy group substituted by one or more aryl groups, wherein aryl and alkyloxy have the meaning as set forth herein, examples of which include, but are not limited to, phenylmethyloxy, phenylethyloxy, p-tolylmethyloxy, phenylpropyloxy and the like. And the aryl group can be substituted or unsubstituted, wherein the substituents can be, but are not limited to, haloalkyl, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkyloxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, thiol, nitro, aryloxy, hydroxy-substituted alkyloxy, hydroxy-substituted alkyl-C(=O)-, alkyl-C(=O)-, alkyl-S(=O)-, alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O)2-, carboxyalkyloxy and the like.

[0076] The term "arylalkylamino" means an alkylamino group substituted with one or more aryl groups, where aryl and alkoxy have the meanings described herein, examples of which include, but are not limited to, phenylmethylamino, phenylethylamino, phenylpropylamino, p-tolylmethylamino, and the like.

[0077] The term "heteroaryl" can be used alone or as part of the terms "heteroarylalkyl" or "heteroarylalkoxy" and means a monocyclic, bicyclic, and tricyclic ring system containing from 5 to 14 ring members in which at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring system comprises 3 to 7 ring members and only one point of attachment to the rest of the molecule. The term "heteroaryl" can be used interchangeably with the terms "heteroaromatic" or "heteroaromatic compound". Also, the heteroaryl group can be substituted or unsubstituted, where the substituents can be, but are not limited to, haloalkyl, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, thiol, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O)-, alkyl-C(=O)-, alkyl-S(=O)-, alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O)2-, carboxyalkoxy, and the like.

[0078] Further embodiments are that the heteroaromatic ring includes, but is not limited to, the following monocyclic rings: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methylisoxazol-5-yl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, pyrimidin-5-yl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiatriazol-2-yl, pyrazinyl, pyrazin-2-yl, 1,3,5-triazinyl, benzo[d]thiazol-2-yl, imidazo[l,5-a]pyridin-6-yl; and the following bicyclic rings, but are not limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothiophenyl, benzothiazolyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl).

[0079] The term "heteroaryloxy" includes an optionally substituted heteroaryl group, as defined herein, attached to an oxygen atom and linked to the remainder of the molecule through the oxygen atom, wherein the heteroaryl group has the meaning set out herein, examples of which include, but are not limited to, pyridin-2-yloxy, thiazol-2-yloxy, imidazol-2-yloxy, pyrimidin-2-yloxy and the like.

[0080] The term "carboxyalkoxy" denotes an alkoxy group substituted by one or more carboxy groups, wherein the alkoxy and carboxy groups have the meaning set out herein, examples of which include, but are not limited to, carboxymethoxy, carboxyethoxy and the like.

[0081] The term "alkylthio" includes a C1-C10 straight chain or branched chain alkyl group attached to a divalent sulfur atom. Some examples of which are lower alkylthio groups, C1-C3 alkylthio groups, examples of which include, but are not limited to, methylthio (CH3S-). The term "haloalkylthio" includes a C1-C10 haloalkyl group attached to a divalent sulfur atom. Some examples of which are lower haloalkylthio groups, C1-C3 haloalkylthio groups, examples of which include, but are not limited to, trifluoromethylthio.

[0082] The term "alkylamino", or "alkylamino", includes "N-alkylamino" and "N,N-dialkylamino", wherein the amino group is substituted by one or two alkyl groups, respectively. Some examples of which are lower alkylamino groups, C1-C6 alkyl groups, attached to the nitrogen atom. Further examples of which are lower alkylamino groups, C1-C3 alkyl groups. Suitable alkylamino groups can be monoalkylamino or dialkylamino, examples of which include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino and the like.

[0083] The term "heteroarylamino" denotes an amino group substituted by one or two heteroaryl groups, wherein the heteroaryl groups have the meaning set out herein, examples of which include, but are not limited to, N-thienylamino and the like. Some examples of which are heteroaryl rings on the heteroarylamino group which can be further substituted.

[0084] The term "heteroarylalkyl" denotes an alkyl group substituted by one or more heteroaryl groups, wherein the alkyl and heteroaryl groups have the meaning set out herein, examples of which include, but are not limited to, thien-2-ylethyl, pyridin-4-ylethyl, imidazol-2-ylethyl, furan-2-ylethyl, indol-3-ylethyl and the like.

[0085] The term "heteroarylalkyl" denotes an alkyl group substituted with one or more heteroaryl groups, wherein heteroaryl and alkyl groups have the meaning as described herein, examples of which include, but are not limited to, imidazol-2-ylmethyl, furan-2-ylethyl, indol-3-ylmethyl, and the like.

[0086] The term "heteroarylalkylamino" includes a heteroarylalkyl group containing a nitrogen atom attached to other groups through the nitrogen atom, wherein heteroarylalkyl has the meaning as described herein, examples of which include, but are not limited to, pyridin-2-ylmethylamino, thiazol-2-ylethylamino, imidazol-2-ylethylamino, pyrimidin-2-ylpropylamino, pyrimidin-2-ylmethylamino, and the like.

[0087] The term "heteroarylalkoxy" includes a heteroarylalkyl group containing an oxygen atom attached to other groups through the oxygen atom, wherein heteroarylalkyl has the meaning as described herein, examples of which include, but are not limited to, pyridin-2-ylmethoxy, thiazol-2-ylethoxy, imidazol-2-ylethoxy, pyrimidin-2-ylpropoxy, pyrimidin-2-ylmethoxy, and the like.

[0088] The term "fused bicyclic ring", "fused ring", "fused bicyclic ring group", "fused ring group" denotes a saturated or unsaturated fused ring system, which involves a non-aromatic bicyclic ring system. Such a system can contain independent or conjugated unsaturation, but its core structure does not contain an aromatic or heteroaromatic ring (although aromaticity can exist as a substituent thereon). Each ring in the fused bicyclic ring is either carbocyclic or heteroalicyclic, examples of which include, but are not limited to, hexahydrofuro[3,2-b]furan, 2,3,3a,4,7,6-hexahydro-lH-indene, 7-azabicyclo[2.3.0]heptane, fused bicyclo[3.3.0]octane, fused bicyclo[3.1.0]hexane, l,2,3,4,4a,5,8,8a-octahydronaphthalene, which are included in the system of fused bicyclic ring. And the fused bicyclic ring group can be substituted or unsubstituted, wherein the substituents can be, but are not limited to, haloalkyl, oxo (=0), hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, thiol, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=0)-, alkyl-C(=0)-, alkyl-S(=0)-, alkyl-S(=0)2-, hydroxy-substituted alkyl-S(=0)-, hydroxy-substituted alkyl-S(=0)2-, carboxyalkoxy, and the like.

[0089] The term "fused heterobicyclyl" denotes a saturated or unsaturated fused ring system, involving a non-aromatic bicyclic system. Such systems can contain independent or conjugated unsaturation, but the core structure does not contain an aromatic or heteroaromatic ring (although aromaticity can be present as a substituent thereon). And at least one ring system contains one or more heteroatoms, wherein each ring system contains 3-7 members, i.e., contains 1-6 carbon atoms and 1-3 heteroatoms which are N, O, P, S, wherein S or P are optionally substituted with one or more oxygen atoms to give groups like SO, SO2, PO, PO2, such examples include, but are not limited to hexahydrofuro[3,2-b]furan, 7-azabicyclo[2.3.0]heptane, and the like. And the fused heterobicyclyl group can be substituted or unsubstituted, wherein the substituents can be, but are not limited to, haloalkyl, oxo (=0), hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, thiol, nitro, aryloxy, hydroxy substituted alkoxy, hydroxy substituted alkyl-C(=0)-, alkyl-C(=0)-, alkyl-S(=0)-, alkyl-S(=0)2-, hydroxy substituted alkyl-S(=0)-, hydroxy substituted alkyl-S(=0)2-, carboxy alkoxy, and the like.

[0090] The term "fused bicyclyl aliphatic" denotes an aliphatic group substituted with one or more fused bicyclyl groups, wherein the aliphatic group and the fused bicyclyl group have the meaning as described herein, such examples include, but are not limited to, l,2,3,4,4a,5,8,8a-octahydronaphthylethyl, l,2,3,4,4a,5,8,8a-octahydronaphthylmethyl, l,2,3,4,4a,5,8,8a-octahydronaphthylpropyl, fused bicyclo[3.3.0]octanylmethyl, fused bicyclo[3.1.0]hexanylethyl, and the like.

[0091] The term "fused heterobicyclyl aliphatic" denotes an aliphatic group substituted with one or more fused heterobicyclyl groups, wherein the aliphatic group and the fused heterobicyclyl group have the meaning as described herein, such examples include, but are not limited to, hexahydrofuro[3,2-b]furan-2-ylethyl, hexahydrofuro[3,2-b]furan-2-ylmethyl, 7-azabicyclo[2.3.0]heptan-2-ylmethyl, 7-azabicyclo[2.3.0]heptan-2-ylethyl, 7-azabicyclo[2.3.0]heptan-4-ylmethyl, and the like.

[0092] The term "fused bicyclyloxy" includes optionally substituted fused bicyclyl groups, as defined herein, attached to an oxygen atom and linked to the remainder of the molecule through the oxygen atom. Examples of such include, but are not limited to, l,2,3,4,4a,5,8,8a-octahydronaphthalenyloxy, fused bicyclo[3.3.0]octan-2-yloxy, fused bicyclo[3.1.0]hexan-2-yloxy and the like.

[0093] The term "fused heterobicyclyloxy" includes optionally substituted fused heterobicyclyl groups, as defined herein, attached to an oxygen atom and linked to the remainder of the molecule through the oxygen atom. Examples of such include, but are not limited to, hexahydro-furo[3,2-b]furan-2-yloxy, 7-azabicyclo[2.3.0]heptan-2-yloxy, 7-azabicyclo[2.3.0]heptan-4-yloxy and the like.

[0094] The term "fused bicyclylamino" denotes an amino group substituted by one or two fused bicyclyl groups, wherein fused bicyclyl has the meaning as defined herein. Examples of such include, but are not limited to, l,2,3,4,4a,5,8,8a-octahydronaphthalenylamino, di(l,2,3,4,4a,5,8,8a-octahydronaphthalenyl)amino, fused bicyclo[3.3.0]octanyl-amino, fused bicyclo[3.1.0]hexanyl-amino and the like.

[0095] The term "fused heterobicyclylamino" denotes an amino group substituted by one or two fused heterobicyclyl groups, wherein fused heterobicyclyl has the meaning as defined herein. Examples of such include, but are not limited to, hexahydro-furo[3,2-b]furan-2-ylamino, 7-azabicyclo[2.3.0]heptan-2-ylamino, 7-azabicyclo[2.3.0]heptan-4-ylamino and the like.

[0096] The term "fused bicyclylalkylamino" denotes an alkylamino group substituted by one or more fused bicyclyl groups, wherein fused bicyclyl has the meaning as defined herein. Examples of such include, but are not limited to, l,2,3,4,4a,5,8,8a-octahydronaphthalenylmethylamino, di(l,2,3,4,4a,5,8,8a-octahydronaphthalenyl)methylamino, fused bicyclo[3.3.0]octanyl-methylamino, fused bicyclo[3.1.0]hexanyl-methylamino and the like.

[0097] The term "fused heterobicyclylalkylamino" denotes an alkylamino group substituted by one or more fused heterobicyclyl groups, wherein fused heterobicyclyl has the meaning as defined herein. Examples of such include, but are not limited to, hexahydro-furo[3,2-b]furan-2-ylmethylamino, 7-azabicyclo[2.3.0]heptan-2-ylmethylamino, 7-azabicyclo[2.3.0]heptan-4-ylmethylamino and the like.

[0098] The term "fused bicyclicalkoxy" denotes an alkoxy group which is substituted by one or more fused bicyclic groups, wherein alkoxy and fused bicyclic have the meaning as described in the application, examples of which include, but are not limited to, l,2,3,4,4a,5,8,8a-octahydronaphthalenylmethoxy, l,2,3,4,4a,5,8,8a-octahydronaphthalenylethoxy, fused bicyclo[3.3.0]octaneethoxy, fused bicyclo[3.1.0]hexane-propoxy and the like.

[0099] The term "fused heterobicyclicalkoxy" denotes an alkoxy group which is substituted by one or more fused heterobicyclic groups, wherein alkoxy and fused heterobicyclic have the meaning as described in the application, examples of which include, but are not limited to, hexahydro-furo[3,2-b]furan-2-ylpropoxy, 7-azabicyclo[2.2.1]heptan-2-ylethoxy, 7-azabicyclo[2.3.0]heptan-4-ylpropoxy, hexahydro-furo[3,2-b]furan-2-ylethoxy, 7-azabicyclo[2.3.0]heptan-2-ylpropoxy, 7-azabicyclo[2.3.0]heptan-4-ylethoxy and the like.

[0100] The term "fused bicyclicalkoxy" denotes an alkoxy group which is substituted by one or more fused bicyclic groups, wherein alkoxy and fused bicyclic have the meaning as described in the application, examples of which include, but are not limited to, l,2,3,4,4a,5,8,8a-octahydronaphthalenylmethoxy, l,2,3,4,4a,5,8,8a-octahydronaphthalenylethoxy, fused bicyclo[3.3.0]octaneethoxy, fused bicyclo[3.1.0]hexane-propoxy and the like.

[0101] The term "fused heterobicyclicalkoxy" denotes an alkoxy group which is substituted by one or more fused heterobicyclic groups, wherein alkoxy and fused heterobicyclic have the meaning as described in the application, examples of which include, but are not limited to, hexahydro-furo[3,2-b]furan-2-ylpropoxy, 7-azabicyclo[2.2.1]heptan-2-ylethoxy, 7-azabicyclo[2.3.0]heptan-4-ylpropoxy, hexahydro-furo[3,2-b]furan-2-ylethoxy, 7-azabicyclo[2.3.0]heptan-2-ylpropoxy, 7-azabicyclo[2.3.0]heptan-4-ylethoxy and the like.

[0102] The term "fused bicyclic aminoalkoxy" means an alkoxy group substituted by one or more fused bicyclic amino groups, wherein alkoxy and fused bicyclic amino groups have the meaning as described herein, examples of which include, but are not limited to, l,2,3,4,4a,5,8,8a-octahydronaphthalenylaminoethoxy, l,2,3,4,4a,5,8,8a-octahydronaphthalenylaminopropoxy, di(l,2,3,4,4a,5,8,8a-octahydronaphthalenyl)aminopropoxy, fused bicyclo[3.3.0]octane-2- aminoethoxy, fused bicyclo[3.1.0]hexane-2-aminopropoxy and the like.

[0103] The term "fused heterobicyclic aminoalkoxy" means an alkoxy group substituted by one or more fused heterobicyclic amino groups, wherein alkoxy and fused heterobicyclic amino groups have the meaning as described herein, examples of which include, but are not limited to, 7-azabicyclo[2.2.1]heptan-2-ylaminoethoxy, 7-azabicyclo[2.3.0]heptan-4-ylaminopropoxy, hexahydro-furo[3,2-b]furan-2-ylaminoethoxy, hexahydro-furo[3,2-b]furan-2-ylaminopropoxy, hexahydro-furo[3,2-b]furan-2-ylaminomethoxy and the like.

[0104] The term "spirocyclic group", "spirocycle", "spirobicyclic group", "spirobicycle" means one ring emanates from a special ring carbon of another ring. For example, as described below, a saturated bridged ring system (rings B and B') is referred to as "fused bicyclic", whereas rings A and B share a carbon atom in a two saturated ring system, then referred to as "spirocycle". Each ring within a spirocycle is either carbocyclic or heteroaliphatic. Examples of which include, but are not limited to, 2,7-diazaspiro[4.4]nonan-2-yl, 7-oxo-2-azaspiro[4.5]dec-2-yl, 4-azaspiro[2.4]heptan-5-yl, 4-oxaspiro[2.4]heptan-5-yl, 5-azaspiro[2.4]heptan-5-yl, spiro[2.4]heptanyl, spiro[4.4]nonanyl, 7-hydroxy-5-azaspiro[2.4]heptan-5-yl and the like. And the spirobicyclic group can be substituted or unsubstituted, wherein the substituents can be, but are not limited to, haloalkyl, oxo (=0), hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, thiol, nitro, aryloxy, hydroxy substituted alkoxy, hydroxy substituted alkyl-C(=0)-, alkyl-C(=0)-, alkyl-S(=0)-, alkyl-S(=0)2-, hydroxy substituted alkyl-S(=0)-, hydroxy substituted alkyl-S(=0)2-, carboxy alkoxy and the like.

[0105] The term "spiro bicyclic group" means a ring system in which one ring is fused to another ring through a particular ring atom. For example, as described above, a saturated bridged ring system (rings B and B') is referred to as a "fused bicyclic ring", whereas rings A and B share a carbon atom in a two saturated ring system, and is referred to as a "spirocyclic ring". And at least one ring system contains one or more heteroatoms, wherein each ring system contains 3-7 membered rings, i.e., contains 1-6 carbon atoms and 1-3 heteroatoms which are N, O, P, S, wherein S or P is optionally substituted by one or more oxygen atoms to give groups such as SO, SO2, PO, PO2, such examples include, but are not limited to, 4-azaspiro[2.4]heptan-5-yl, 4-oxaspiro[2.4]heptan-5-yl, 5-azaspiro[2.4]heptan-5-yl, 7-hydroxy-5-azaspiro[2.4]heptan-5-yl, and the like. And the spiro bicyclic group can be substituted or unsubstituted, wherein the substituents can be, but are not limited to, haloalkyl, oxo (=0), hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, thiol, nitro, aryloxy, hydroxy substituted alkoxy, hydroxy substituted alkyl-C(=0)-, alkyl-C(=0)-, alkyl-S(=0)-, alkyl-S(=0)2-, hydroxy substituted alkyl-S(=0)-, hydroxy substituted alkyl-S(=0)2-, carboxy alkoxy, and the like.

[0106] The term "spiro bicyclic group aliphatic" means an aliphatic group substituted by one or more spiro bicyclic groups, wherein the aliphatic group and the spiro bicyclic group have the meaning as described herein, such examples include, but are not limited to, spiro[2.4]heptanemethyl, spiro[2.4]heptaneethyl, spiro[2.4]heptanepropyl, spiro[4.4]nonanemethyl, spiro[4.4]nonaneethyl, 4-azaspiro[2.4]heptan-5-ylmethyl, 4-azaspiro[2.4]heptan-5-ylethyl, 4-oxaspiro[2.4]heptan-5-ylethyl, 5-azaspiro[2.4]heptan-5-ylpropyl, 7-hydroxy-5-azaspiro[2.4]heptan-5-ylpropyl, and the like.

[0107] The term "spiro heterobicyclic group aliphatic" means an aliphatic group substituted by one or more spiro heterobicyclic groups, wherein the aliphatic group and the spiro heterobicyclic group have the meaning as described herein, such examples include, but are not limited to, 4-azaspiro[2.4]heptan-5-ylmethyl, 4-azaspiro[2.4]heptan-5-ylethyl, 4-oxaspiro[2.4]heptan-5-ylethyl, 5-azaspiro[2.4]heptan-5-ylpropyl, 7-hydroxy-5-azaspiro[2.4]heptan-5-ylpropyl, and the like.

[0108] The term "spiro bicyclyloxy" includes optionally substituted spiro bicyclyl groups, as defined herein, attached to an oxygen atom and linked to the remainder of the molecule through the oxygen atom. Examples of such include, but are not limited to, spiro[2.4]heptane-2-oxy, spiro[2.4]heptane-3-oxy, spiro[2.4]heptane-4-oxy, spiro[4.4]nonane-2-oxy, spiro[4.4]nonane-4-oxy, 4-azaspiro[2.4]heptane-5-oxy, and the like.

[0109] The term "spiro heterobicyclyloxy" includes optionally substituted spiro heterobicyclyl groups, as defined herein, attached to an oxygen atom and linked to the remainder of the molecule through the oxygen atom. Examples of such include, but are not limited to, 4-azaspiro[2.4]heptane-5-oxyl, 4-oxaspiro[2.4]heptane-5-oxyl, 5-azaspiro[2.4]heptane-5-oxyl, and the like.

[0110] The term "spiro bicyclylamino" denotes an amino group substituted by one or two spiro bicyclyl groups, wherein spiro bicyclyl has the meaning as defined herein. Examples of such include, but are not limited to, spiro[2.4]heptane-2-amino, spiro[2.4]heptane-3-amino, spiro[2.4]heptane-4-amino, spiro[4.4]nonane-2-amino, spiro[4.4]nonane-4-amino, 4-azaspiro[2.4]heptane-5-amino, and the like.

[0111] The term "spiro heterobicyclylamino" denotes an amino group substituted by one or two spiro heterobicyclyl groups, wherein spiro heterobicyclyl has the meaning as defined herein. Examples of such include, but are not limited to, 4-azaspiro[2.4]heptane-5-ylamino, 4-azaspiro[2.4]heptane-2-ylamino, 4-oxaspiro[2.4]heptane-5-ylamino, 5-azaspiro[2.4]heptane-5-ylamino, and the like.

[0112] The term "spiro bicyclyloxy" includes optionally substituted spiro bicyclyl groups, as defined herein, attached to an oxygen atom and linked to the remainder of the molecule through the oxygen atom. Examples of such include, but are not limited to, spiro[2.4]heptane-2-oxy, spiro[2.4]heptane-3-oxy, spiro[2.4]heptane-4-oxy, spiro[4.4]nonane-2-oxy, spiro[4.4]nonane-4-oxy, 4-azaspiro[2.4]heptane-5-oxy, and the like.

[0113] The term "spiro heterobicyclylalkoxy" means an alkoxy group substituted by one or more spiro heterobicyclyl groups, wherein spiro heterobicyclyl and alkoxy have the meaning as described in the present application, examples of which include, but are not limited to, 4-azaspiro[2.4]heptan-5-ylmethoxy, 4-azaspiro[2.4]heptan-2-ylethoxy, 4-oxaspiro[2.4]heptan-5-ylethoxy, 5-azaspiro[2.4]heptan-5-ylpropoxy and the like.

[0114] The term "spiro bicyclylalkylamino" means an alkylamino group substituted by one or more spiro bicyclyl groups, wherein spiro bicyclyl and alkylamino have the meaning as described in the present application, examples of which include, but are not limited to, spiro[2.4]heptan-2-methylamino, spiro[2.4]heptan-3-ethylamino, spiro[2.4]heptan-4-ethylamino, spiro[4.4]nonan-2-methylamino, spiro[4.4]nonan-4-propylamino, 4-azaspiro[2.4]heptan-5-methylamino and the like.

[0115] The term "spiro heterobicyclylalkylamino" means an alkylamino group substituted by one or more spiro heterobicyclyl groups, wherein spiro heterobicyclyl and alkylamino have the meaning as described in the present application, examples of which include, but are not limited to, 4-azaspiro[2.4]heptan-5-ylmethylamino, 4-azaspiro[2.4]heptan-2-ylethylamino, 4-oxaspiro[2.4]heptan-5-ylethylamino, 5-azaspiro[2.4]heptan-5-ylpropylamino and the like.

[0116] The term "spiro bicyclyloxyalkoxy" means an alkoxy group substituted by one or more spiro bicyclyloxy groups, wherein spiro bicyclyloxy and alkoxy have the meaning as described in the present application, examples of which include, but are not limited to, spiro[2.4]heptan-2- yloxyethoxy, spiro[2.4]heptan-3-yloxypropoxy, spiro[2.4]heptan-4-yloxypropoxy, spiro[4.4]nonan-2-yloxyethoxy, spiro[4.4]nonan-4-yloxypropoxy, 4-azaspiro[2.4]heptan-5-yloxypropoxy and the like.

[0117] The term "spiro heterobicyclyloxyalkoxy" means an alkoxy group substituted by one or more spiro heterobicyclyloxy groups, wherein spiro heterobicyclyloxy and alkoxy have the meaning as described in the present application, examples of which include, but are not limited to, 4-azaspiro[2.4]heptan-5-yloxyethoxy, 4-oxaspiro[2.4]heptan-5-yloxyethoxy, 5-azaspiro[2.4]heptan-5-yloxyethoxy, 4-azaspiro[2.4]heptan-5-yloxypropoxy, 4-oxaspiro[2.4]heptan-5-yloxypropoxy, 5-azaspiro[2.4]heptan-5-yloxypropoxy and the like.

[0118] The term "spiro bicyclic aminoalkoxy" means an alkoxy group substituted with one or more spiro bicyclic amino groups, wherein alkoxy and spiro bicyclic amino groups have the meanings as described herein, examples of which include, but are not limited to, spiro[2.4]heptane-2- aminoethoxy, spiro[2.4]heptane-3-aminopropoxy, spiro[2.4]heptane-4- aminoethoxy, spiro[4.4]nonane-2-aminoethoxy, spiro[4.4]nonane-4- aminopropoxy, 4-azaspiro[2.4]heptane-5-aminopropoxy and the like.

[0119] Unless otherwise stated, the formulae described herein encompass all tautomeric forms (e.g., enantiomeric, diastereomeric, and geometric (or conformational) isomers: for example, R, S configurations about asymmetric centers; (Z), (E) isomers about double bonds; and (Z), (E) conformational isomers about disubstituted olefins. Thus individual stereochemical isomers (or mixtures of stereochemical isomers), for example, enantiomeric, diastereomeric, and geometric (or conformational) isomers, of the compounds of the application, or their salts, are within the scope of the application.

[0120] "Metabolite" refers to a compound formed by metabolism of a specified compound or salt thereof in the body. Metabolites of a compound can be identified using techniques known in the art, and have activities comparable to the specified compound. Such products can be oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like of the specified compound. Accordingly, the application includes metabolites of a compound of the application, including those produced in vivo upon administration of the compound to a mammal.

[0121] The compounds of the present application can contain asymmetric or chiral centers, and thus exist in different stereoisomers. All stereoisomers of the compounds of the present application, including but not limited to, diastereomers, enantiomers, atropisomers, and their mixtures, such as racemates, form part of the present application. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D, L or R, S are used to denote the absolute configuration of the molecule's chiral centers. The prefixes D and L or (+) and (-) are employed to designate the sign of the rotation of plane-polarized light by the compound, with (-) or L designating a levorotatory compound, and (+) or D designating a dextrorotatory compound. Such isomers are basically the same in terms of their chemical structure but differ in their physical properties. A specific stereoisomer can be designated as the enantiomer if its is one of a pair of mirror images that are non-superimposable. A mixture of isomers, typically an enantiomeric mixture, is often referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which can result from chemical reactions that do not have stereoselectivity or stereospecificity. The terms "racemic mixture" and "racemate" refer to an equal mixture of two enantiomeric isomers in which the optical properties are neutral, i.e., the specific rotation is zero.

[0122] As used herein, "pharmaceutically acceptable salts" means organic and inorganic salts of the compounds of the application. Pharmaceutically acceptable salts are well known in the art, as described in detail in S. M. Berge et al., "Pharmaceutical Salts," J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable non-toxic salts of an acid include those derived from inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric, perchloric, and organic acids such as acetic, oxalic, maleic, tartaric, citric, succinic, malonic, salicylic, benzoic, mandelic, methanesulfonic, ethanesulfonic, toluenesulfonic, and isethionic. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, bisulfite, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, sulfocyanate, sulfonate, suberate, succinate, tannate, tartrate, teoclate, toluenesulfonate, undecanoate, valerate, and the like. Salts derived from bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4 alkyl)4 salts. The present application also contemplates the quaternary ammonium salts of any group containing N in the compound. Water or oil-soluble or dispersible products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed by the addition of inorganic or organic acids to a free amine group of the compound, such as hydrochloric, hydrobromic, phosphoric, sulfuric, nitric, C 1-8 sulfonic, and aromatic sulfonic acids.

[0123] Salts of the compounds of the application also include salts of intermediates used in the preparation or purification of a compound of Formula I or a derivative of a compound of Formula I isolated as an enantiomer, but not necessarily a pharmaceutically acceptable salt.

[0124] The term "solvate" as used herein refers to an association or complex of one or more solvent molecules and at least one compound of the present application. 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 the complex that contains water as the solvent.

[0125] When the solvent is water, the term "hydrate" can be used. In some embodiments, one molecule of a compound of the present application can be associated with one molecule of water, such as a monohydrate; in other embodiments, one molecule of a compound of the present application can be associated with more than one molecule of water, such as a dihydrate; and in yet other embodiments, one molecule of a compound of the present application can be associated with less than one molecule of water, such as a hemihydrate. It is noted that the hydrates of the present application retain the biological effectiveness of the compound in its unhydrated form.

[0126] The term "treat" or "treatment" of any disease or disorder, as used herein, means any process that can slow, interrupt, stop, control, or reverse the progression of the disease or disorder, and does not necessarily indicate complete eradication of all the symptoms of the disease or disorder, and includes prophylactic treatment of the symptoms, particularly in a patient susceptible to such disease or disorder. In some embodiments, the term "treat" or "treatment" means to ameliorate the disease or disorder (i.e., to slow or stop or reduce the development of the disease or at least one clinical symptom thereof). In other embodiments, "treat" or "treatment" means to alleviate or ameliorate at least one physical parameter, including those not discernible by the patient. In other embodiments, "treat" or "treatment" means to modulate the disease or disorder physically (e.g., stabilize a discernible symptom), physiologically (e.g., stabilize a physical parameter), or both. In other embodiments, "treat" or "treatment" means to prevent or delay the onset, occurrence or worsening of the disease or disorder.

[0127] The term "therapeutically effective amount" or "therapeutically effective dose" as used herein refers to the amount of a compound of the present application that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc. In one non-limiting embodiment, the term "therapeutically effective amount" refers to the amount of a compound of the present application that, when administered to a subject, is effective to (1) at least partially alleviate, inhibit, prevent and / or ameliorate a Mycobacterium infection. In another embodiment, the term "therapeutically effective amount" refers to the amount of a compound of the present application that, when administered to a cell, or an organ, or a non-cellular biological material, or a medium, is effective to at least partially reduce or inhibit a Mycobacterium infection.

[0128] The terms "administration" and "administering" as used herein refer to the delivery or application of a compound of the application or a prodrug of a compound of the application to an individual in need thereof. It will be appreciated that one of ordinary skill in the art will be able to determine appropriate dosages and administration regimes for a given compound of the application, using dosages and administration regimes known in the art.

[0129] The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. Such term in relation to pharmaceutical compositions includes compositions comprising a combination of active ingredients (one or more) and inert ingredients (one or more) that make up a carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more ingredients, or from dissociation of one or more ingredients, or from other types of reactions or interactions of one or more ingredients. Accordingly, the pharmaceutical compositions of the present application encompass any composition made by admixing a compound of the present application with a pharmaceutically acceptable carrier.

[0130] Substances which can serve as pharmaceutically-acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylate, waxes, polyethylene-polyoxypropylene- block polymers, wool fat, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, phosphate buffer solutions, and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0131] The pharmaceutical compositions of the present application can be orally administered, injected, administered by spray inhalation, administered topically, administered rectally, administered nasally, administered buccally, administered vaginally or administered via an implanted reservoir. They can be in the form of capsules, tablets, pills, powders, granules, and aqueous or oily suspensions or solutions. Oral administration can be in the form of tablets, pills, capsules, dispersible powders, granules, or suspensions, syrups, and elixirs; for topical administration: ointments, gels, medicated gums and the like, or in the form of a sterile injectable solution or suspension for intravenous, subcutaneous, intramuscular, intracerebral, intraventricular, intrathecal, or intraperitoneal administration. The compounds of the present application can also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose, polyvinylpyrrolidone (Povidone). Dispersions can also be prepared in glycerol, liquid, polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0132] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders (for reconstitution into sterile injectable solutions or dispersions). In all cases, the form must be sterile and must be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols, such as glycerol, propylene glycol and liquid polyethylene glycols, suitable mixtures thereof, and vegetable oils.

[0133] The compounds can be administered in a local rather than systemic fashion. For example, the compounds can be injected directly into an organ, often in a dilute solution or suspension. In addition, pharmaceutical compositions containing the compounds of the present application can be used in targeting drug delivery systems, such as liposomes. The liposomes will target the organ and be taken up selectively by that organ. In addition, compositions containing the compounds of the present application can be provided in a rapid release, delayed release, or sustained release formulation.

[0134] For inhalation administration, the compounds of the present application can be in the form of an aerosol, a gas mist, or a powder. The pharmaceutical compositions of the compounds of the present application can be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0135] The compounds of the present application can also be prepared as rectal compositions such as, for example, enemas, rectal gels, rectal foams, rectal aerosols, suppositories, gel suppositories, or retention enemas, containing conventional suppository formulations such as cocoa butter or other glycerides, and synthetic polymers such as polyvinylpyrrolidone, PEG, and the like. In the suppository formulation of the composition, a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides or cocoa butter is optionally first melted.

[0136] The present application discloses a novel class of cyclic peptide compounds, stereoisomers, geometric isomers, tautomers, atropisomers, nitroxides, hydrates, solvates, N-oxides, isotopically-labeled, metabolites, prodrugs, or mixtures thereof, or pharmaceutically acceptable salts or prodrugs thereof, pharmaceutical formulations and compositions thereof, which are useful as prophylactic or therapeutic agents for infectious diseases caused by Mycobacterium bacteria, such as tuberculosis, bone tuberculosis, lymph node tuberculosis, lumbar tuberculosis, thoracic tuberculosis, breast tuberculosis, swimming pool granuloma, pulmonary infection, lymph node infection, Buruli ulcer.

[0137] In one aspect, the present application relates to a stereoisomer, geometric isomer, tautomer, atropisomer, nitroxide, hydrate, solvate, N-oxide, isotopically-labeled, metabolite, prodrug, or mixtures thereof, or pharmaceutically acceptable salts or prodrugs thereof, of a compound of Formula (I), wherein, n is independently 0, 1, 2, or 3; L is independently selected from the group consisting of substituted or unsubstituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, biaryl, triaryl, fused heteroaryl, fused biaryl, fused triaryl, wherein the substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, biaryl, triaryl, fused heteroaryl, fused biaryl, fused triaryl are optionally independently substituted with one or more substituents selected from the group consisting of deuterium, F, Cl, Br, I, hydroxy, amino, carboxy, cyano, nitro, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl, heteroaryloxy, heteroaroyl, heteroarylamino, heteroarylalkoxy, heteroarylalkylamino, heterocyclylalkanoyl, heterocycloalkyl, heterocyclyloxy, heterocyclylamino, heterocyclylacyl, heterocyclylalkoxy, heterocyclylalkylamino, heterocyclylalkanoyl, azidoalkoxy, fused bicyclic group, fused heterobicyclic group, fused bicyclic aliphatic substituent; The amino acid at the position of AA1-AA7may be independently optionally derivatized with a L or D configuration of a natural, non-natural amino acid with a glycine substituted; R2is individually selected from hydrogen or C 1-3 alkyl; X is individually selected from O, S, or NR3; R3is individually hydrogen, deuterium, halogen, hydroxyl, amino, nitro, cyano, alkyl, haloalkyl, alkoxy, alkylamino, alkylacyl, hydroxyalkoxy, hydroxyalkylamino, hydroxyalkylacyl, haloalkoxy, haloalkylamino, haloalkylacyl, aminoalkoxy, cycloalkyl, cycloalkyloxy, cycloalkylamino, cycloalkylacyl, alkenyl, alkenylalkoxy, alkenylalkylamino, alkenylalkylacyl, alkynyl, alkynylalkoxy, alkynylalkylamino, alkynylalkylacyl, aryl, aryloxy, arylacyl, arylamino, arylalkoxy, arylalkylamino, heteroaryl, heteroaryloxy, heteroarylacyl, heteroarylamino, heteroarylalkoxy, heteroarylalkylamino, heterocyclylalkylacyl, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylacyl, heterocyclylalkoxy, heterocyclylalkylamino, heterocyclylalkylacyl, azidoalkoxy, fused bicyclyl, fused heterobicyclyl, fused bicyclyl aliphatic, fused heterobicyclyl aliphatic, fused bicyclyloxy, fused heterobicyclyloxy, fused bicyclylamino, fused heterobicyclylamino, fused bicyclylalkoxy, fused heterobicyclylalkoxy, fused bicyclylalkylamino, fused heterobicyclylalkylamino, fused bicyclyloxyalkoxy, fused heterobicyclyloxyalkoxy, fused bicyclylaminoalkoxy, fused heterobicyclylaminoalkoxy, fused bicyclyl-C(=O)-, fused bicyclyl-C(=O)O-, fused heterobicyclyl-C(=O)-, fused heterobicyclyl-C(=O)O-, fused bicyclylamino-C(=O)-, fused heterobicyclylamino-C(=O)-, fused bicyclyl-C(=O)N(R 13 )-, fused heterobicyclyl-C(=O)N(R 13)-, spiro bicyclic, spiro heterobicyclic, spiro bicyclic aliphatic, spiro heterobicyclic aliphatic, spiro bicyclic oxy, spiro heterobicyclic oxy, spiro bicyclic amino, spiro heterobicyclic amino, spiro bicyclic alkoxy, spiro heterobicyclic alkoxy, spiro bicyclic alkylamino, spiro heterobicyclic alkylamino, spiro bicyclic oxyalkoxy, spiro heterobicyclic oxyalkoxy, spiro bicyclic aminoalkoxy, spiro heterobicyclic aminoalkoxy, spiro bicyclic-C(=O)-, spiro bicyclic-C(=O)O-, spiro heterobicyclic-C(=O)-, spiro heterobicyclic-C(=O)O-, spiro bicyclic amino-C(=O)-, spiro heterobicyclic amino-C(=O)-, spiro bicyclic-C(=O)N(R4)-, spiro heterobicyclic-C(=O)N(R4)-, R5R4N-, -C(=O)NR4R5, -OC(=O)NR4R5, -OC(=O)OR4, -N(R4)C(=O)NR4R5, -N(R4)C(=O)OR5, -N(R4)C(=O)-R5, R4R5N-S(=O) t -, R4S(=O) t -, R4S(=O) t N(R5)-, R5R4N-alkyl, R4S(=O) t -alkyl, R5R4N-C(=O)-alkyl, R5R4N-alkoxy, R4S(=O) t -alkoxy, R4R5N-C(=O)-alkoxy, aryl-(CH2) p -G-(CH2) m -, heteroaryl-(CH2) p -G-(CH2) m -, heterocyclyl-(CH2) p -G-(CH2) m -, or cycloalkyl-(CH2) p -G-(CH2) m -, wherein G is O, S, NR6, S(=O), S(=O)2, C(=O), -C(=O)N(R4)-, -OC(=O)N(R4)-, -OC(=O)-, -N(R4)C(=O)N(R4)-, NaOS(=O)2O-, NaOS(=O)2O-, -(R4)N-S(=O) t -, -OS(=O) t -, or -OS(=O) t N(R4)-; t is 1 or 2; p and m are each independently 0, 1, 2, 3 or 4; wherein aryl-(CH2) p -G-(CH2) m -, heteroaryl-(CH2) p-G-(CH2) m -G-(CH2) p -G-(CH2) m -G-(CH2) p -G-(CH2) m -G-(CH2) q R7, wherein R7is independently selected from alkylamino, amino, alkyl-C(=O)NH-, heterocyclyl, -(CH2CH2O) m H, glucopyranosyl, NaOS(=O)2O-glucopyranosyl, NaOS(=O)2O-, alkyl-S(=O)2NH, NaOS(=O)2-, (HO)2P(=O)O-, aryl, heterocyclylalkyl, aminoalkyl, -P(=O)R8R9, wherein said heterocyclylalkyl, aminoalkyl and NaOS(=O)2O- are each independently optionally substituted with one or more substituents of H, alkyl, amino, halo or alkoxy, and R8and R9are each independently selected from -OR 10 or -NHR 11 ; R 10 are each independently H, Na, C 1-6 alkyl; R 11 is H or C 1-8 alkyl, wherein said C 1-8 alkyl is optionally substituted with one or more alkoxycarbonyl groups; and q is 0, 1, 2, 3 or 4. R6may be the same or different, each independently hydrogen, R5R4NC(=O)-, R5OC(=O)-, R5C(=O)-, R5R4NS(=O)-, R5OS(=O)-, R5S(=O)-, R5R4NS(=O)2-, R5OS(=O)2-, R5S(=O)2-, aliphatic, halogenated aliphatic, hydroxy aliphatic, amino aliphatic, alkoxy aliphatic, alkylamino aliphatic, alkylthio aliphatic, aryl aliphatic, heteroaryl aliphatic, heterocyclyl aliphatic, cycloalkyl aliphatic, aryloxy aliphatic, heterocyclyloxy aliphatic, cycloalkyloxy aliphatic, arylamino aliphatic, heterocyclylamino aliphatic, cycloalkylamino aliphatic, aryl, heteroaryl, heterocyclyl or carbocyclic radical; R5and R4are independently hydrogen, aliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic, heteroarylaliphatic, heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl or cycloalkyl; when R5and R4are attached to the same nitrogen atom, R5, R4and the nitrogen atom can optionally form a substituted or unsubstituted 3-8 membered ring, a fused bicyclic ring or a spiro bicyclic ring; the heteroatoms in the above-mentioned heterocyclyl, heteroaryl, fused heterobicyclic ring, spiro heterobicyclic ring are 1-5 heteroatoms independently selected from N, O, S, Se; The above-mentioned R3, R4, R5, R6groups can be optionally substituted by one or more of hydroxyl, hydroxymethyl, carboxyl, acetylamino, alkyl (such as methyl, ethyl, propyl), alkoxy (such as methoxy, ethoxy, t-butoxy), alkylamino, cycloalkyl, alkenyl, alkynyl, trifluoromethyl, trifluoroacetyl, thiol, halogen, nitro, amino, azido (-N3), guanidino, cyano, t-butoxycarbonyl (-Boc), carbonyl (-C=O), oxo (=O), thioxo (=S), sulfonyl, aryl, heteroaryl, heterocyclyl.

[0138] The present application relates to a compound having an amino acid sequence comprising at least one L or D configuration

[0139] In some embodiments, the amino acid sequence of the compound has 1-3 amino acids added or removed, which can be concentrated or dispersed in any position of the amino acid sequence, and the antibacterial activity of the changed amino acid sequence is not significantly reduced, or remains comparable antibacterial activity, or has significantly enhanced antibacterial activity.

[0140] In some embodiments, the present application relates to one of the following compounds or its stereoisomer, geometric isomer, enantiomer, tautomer, atropisomer, nitroxide, hydrate, solvate, N-oxide, isotopically labeled, metabolite, prodrug, or mixture thereof, or pharmaceutically acceptable salt or its prodrug, but by no means limited to these compounds:

[0141] In some embodiments, the present application relates to a pharmaceutical composition comprising as an active ingredient any one or more of the compounds or several compounds according to any one of the claims of the present application or a pharmaceutically acceptable salt thereof.

[0142] The compounds disclosed herein can contain asymmetric or chiral centers, and thus exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formula (I) are embraced within the scope of this application. This is true even if individual enantiomers or other stereoisomers are disclosd or specifically designated for particular uses. The different stereoisomeric forms are "enantiomers" if they are mirror images of one another, and are "diastereomers" if they are not. The term "stereoisomers" includes both enantiomers and diastereomers. A "racemic mixture" is a mixture of R- and S-enantiomers in equal amounts. A "scalemic mixture" is a mixture of R- and S-enantiomers in unequal amounts. A "non-racemic mixture" is a mixture of R- and S-enantiomers in unequal amounts. A "pure enantiomer" is a mixture of R- and S-enantiomers in a 50:50 ratio. A "pure scalemic mixture" is a mixture of R- and S-enantiomers in a ratio other than 50:50. A "pure diastereomer" is a mixture of diastereomers in a 50:50 ratio. A "pure scalemic mixture" is a mixture of diastereomers in a ratio other than 50:50. A "pure geometric isomer" is a mixture of geometric isomers in a 50:50 ratio. A "pure scalemic mixture" is a mixture of geometric isomers in a ratio other than 50:50. The term "tautomers" refers to structural isomers that exist in equilibrium with each other. The term "tautomer" includes both tautomers and mixtures of tautomers. The term "prodrug" refers to a precursor of a compound of Formula (I) that is converted to the active drug in vivo after administration to a mammal. The term "pharmaceutically acceptable" means that the substance or composition must be compatible chemically and / or toxicologically, with the other ingredients comprising a formulation, and / or the mammal being treated therewith.

[0143] In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not indicated, then all stereoisomers of the structure are intended to be within the scope of the present application and are encompassed by the compounds disclosed herein. When the stereochemistry is indicated by a solid wedge or a dashed line, then the stereochemistry of the structure is explicitly and unambiguously defined.

[0144] The compounds of Formula (I) can exist in different tautomeric forms, and all such tautomers are included within the scope of the present application.

[0145] The compounds of Formula (I) can exist in salt form. In one embodiment, the salt is 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 a formulation, and / or the mammal being treated therewith. In another embodiment, the salt is not necessarily a pharmaceutically acceptable salt, but can be an intermediate for the preparation and / or purification of a compound of Formula (I) and / or for the separation of enantiomeric forms of a compound of Formula (I).

[0146] Pharmaceutically acceptable acid addition salts can be formed with inorganic acids or organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camsylate, chloride / hydrochloride, chlortheophyllonate, citrate, edisylate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate, and trifluoroacetate salts.

[0147] Pharmaceutically acceptable base addition salts can be formed with inorganic or organic bases. For example, salts can be formed with metals or amine bases. Examples of metals used as a pharmaceutically acceptable metal salt can include sodium, potassium, magnesium, calcium, and aluminum. Examples of amine bases can include N,N'-dibenzylethylene-diamine, N-methyl-glucamine, lysine and the like.

[0148] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from 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, with particular suitable salts including ammonium, potassium, sodium, calcium and magnesium salts.

[0149] Organic bases from which salts can be derived include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include, for example, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0150] The pharmaceutically acceptable salts of the present application can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid form of the compound with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting the free base form of the compound with a stoichiometric amount of the appropriate acid. Such reactions typically are carried out in water or in an organic solvent, or in a mixture of the two. Generally, use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where appropriate. Lists of additional suitable salts can be found, e.g., in "Remington's Pharmaceutical Sciences", 20th ed., Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0151] In addition, the compounds disclosed herein, including their salts, can be obtained in the form of their hydrates, or include solvates such as ethanol, DMSO, and the like, used in their crystallization. The compounds disclosed herein can inherently or through design form solvates with pharmaceutically acceptable solvents (including water); thus, the present application is intended to cover both solvated and unsolvated forms of the compounds disclosed herein.

[0152] Any formula given herein is also intended to represent unlabelled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas 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 found in compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl, and 125 I.

[0153] In another aspect, the compounds according to the application include isotopically enriched compounds as defined by the application, for example, those in which a radioisotope is present, such as 3 H, 14 C, and 18 F, or those in which a non-radioactive isotope is present, such as 2 H, and 13 C. Such isotopically enriched compounds are useful in metabolic studies (with 14 C), reaction kinetic studies (with, for example 2 H, or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), or for patient therapy, for example. 18 F-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 described in the Examples and Preparations herein using appropriate isotopically-enriched reagents in place of the non-enriched reagents previously employed.

[0154] Also, the heavier isotope, particularly deuterium (i.e., 2Substitution of H or D) can provide certain therapeutic advantages that result from, for example, increased metabolic stability, increased half-life in vivo, decreased dosage requirements, or improved therapeutic index. It is understood that deuterium in the present application is taken to mean a substituent of a compound of formula (I). The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance of the specified isotope and the natural abundance. If a substituent of a compound of the present application is specified to be deuterium, the compound has an isotopic enrichment factor at each specified deuterium atom of at least 3500 (52.5% deuterium incorporation at each specified 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 present application include those in which the solvent can be isotopically substituted, e.g., D20, acetone-d6, DMSO-d6.

[0155] In another aspect, the present application provides a pharmaceutical composition comprising a compound of the present application. In one embodiment, the pharmaceutical composition of the present application, further comprises a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle or a combination thereof. In another embodiment, the pharmaceutical composition can be in a liquid, solid, semi-solid, gel or spray form.

[0156] Pharmaceutical compositions, formulations and administration of compounds of the present application The present application provides a pharmaceutical composition comprising a compound disclosed herein, e.g., a compound listed in the Examples; and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or a combination thereof.

[0157] The present application provides a method of treating, preventing or ameliorating a disease or a condition comprising administering a safe and effective amount of a combination medicament comprising a compound disclosed herein and one or more therapeutically active agents. In one embodiment, the combination medicament comprises one or more prophylactic or therapeutic agents for treating or preventing tuberculosis, swimmer's granuloma, pulmonary infection, lymph node infection, Buruli ulcer, wherein the active ingredient of the prophylactic or therapeutic agent is different from the compound disclosed herein.

[0158] Medicaments for the prevention or treatment of tuberculosis, swimmer's granuloma, pulmonary infections, lymph node infections, Buruli ulcer include, but are not limited to, isoniazid, rifampin, ethambutol, pyrazinamide, streptomycin, para-aminosalicylic acid, ethionamide, capreomycin, rifalazil, bedaquiline, protomani, triclosan, delamanid, and linezolid, or any combination thereof.

[0159] The dosage of the active ingredients in the compositions of the present application can vary, however, the amount of active ingredient must be such that a suitable dosage will be obtained. The active ingredients can be administered to patients (animals and human) in need of such treatment in dosages that will 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 upon the nature and severity of the disease, the patient's weight, special diets then being followed by a patient, the concurrent or

[0160] It is also recognized that certain compounds of the present application can exist in free form or as a pharmaceutically acceptable derivative thereof. Pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a patient in need is capable of providing directly or indirectly a compound of this application or a metabolite or residue thereof.

[0161] The pharmaceutical or pharmaceutical composition disclosed herein can be prepared and packaged in bulk form, from which a safe and effective amount of the compound of Formula (I) can be withdrawn and administered to a patient in the form of a powder or syrup. Typically, the patient is administered a dosage level of between 0.0001 and 10 mg / kg body weight per day to achieve an effective result. Alternatively, the pharmaceutical composition disclosed herein can be prepared and packaged in unit dosage form, wherein each physically discrete unit contains a safe and effective amount of the compound of Formula (I). When prepared in unit dosage form, the pharmaceutical composition disclosed herein can typically contain, for example, 0.5 mg to 1 g, or 1 mg to 700 mg, or 5 mg to 100 mg of the compound disclosed herein.

[0162] When the pharmaceutical compositions of the present application comprise one or more other active ingredients, the weight ratio of the compound of the present application to the second active ingredient(s) can be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. For example, when the compound of the present application is combined with another agent, the weight ratio of the compound of the present application to the other agent can generally range from about 1000: 1 to about 1 : 1000, such as about 200: 1 to about 1 : 200. Mixtures of the compound of the present application and other active ingredients will generally also fall within the aforementioned range, but in each case, an effective dose of each active ingredient is used.

[0163] As used herein, "pharmaceutically acceptable excipient" means an excipient that is compatible with the dosage form or pharmaceutical composition to which it is administered. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when combined, to avoid interactions that would substantially reduce the efficacy of the disclosed compound of the present application or cause the pharmaceutical composition to be not pharmaceutically acceptable. In addition, each excipient must be pharmaceutically acceptable, e.g., of sufficiently high purity.

[0164] The choice of a suitable pharmaceutically acceptable excipient will depend on the particular dosage form chosen and the particular function desired of the excipient. For example, certain pharmaceutically acceptable excipients can be chosen to aid in the production of a uniform dosage form. Certain pharmaceutically acceptable excipients can be chosen to aid in the production of a stable dosage form. Certain pharmaceutically acceptable excipients can be chosen to aid in the carrying or transport of the disclosed compound of the present application from one organ or portion of the body to another when administered to a patient. Certain pharmaceutically acceptable excipients can be chosen to enhance patient compliance.

[0165] 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, flavorants, 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 can provide more than one function and can provide alternative functions depending on how much of the excipient is present in the formulation and which other excipients are present in the formulation.

[0166] The skilled artisan possesses knowledge and skills in the art to enable them to select an appropriate amount of a suitable pharmaceutically acceptable excipient for use with the application. In addition, there are a number of resources available to the skilled artisan that describe pharmaceutically acceptable excipients and are useful in selecting a suitable pharmaceutically acceptable excipient. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

[0167] Various carriers used to formulate pharmaceutically acceptable compositions and well-known techniques for their preparation are disclosed in Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D. B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York, the contents of each of which are incorporated herein by reference. The use of any conventional carrier medium that is not incompatible with the compounds of the application (e.g., that does not produce any adverse biological effects or other interaction with any other component of the pharmaceutically acceptable composition) is encompassed within the scope of the application.

[0168] The pharmaceutical compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. A description of some of the methods commonly used in the art can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company).

[0169] Thus, in another aspect, the present application relates to a process for preparing a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or a combination thereof, which process comprises mixing the ingredients. Pharmaceutical compositions comprising a compound disclosed herein can be prepared, for example, by mixing at ambient temperature and at atmospheric pressure.

[0170] The compounds disclosed herein are typically formulated into dosage forms suitable for administration to patients by a desired route. For example, dosage forms include those suitable for administration by: (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 lyophilized powders; (3) transdermal administration, such as transdermal patches; (4) rectal administration, such as 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.

[0171] The pharmaceutical compositions provided herein can be provided in compressed tablets, chewable tablets, fast-dissolve tablets, multiple compressed tablets, or enteric-coated tablets, sugar-coated or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a material that resists gastric acid but dissolves or disintegrates in the intestine, thereby preventing the active ingredient from coming into contact with the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, lacquers, ammoniated lacquers and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which can serve to mask an unpleasant taste or odor and can prevent tablet oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate. Film coatings impart the same general properties as sugar coatings. Multiple compressed tablets are compressed tablets prepared over more than one compression cycle, including multi-layer tablets, and compressed coated or dry coated tablets.

[0172] Tablet dosage forms can be prepared from a powder, crystalline or granular active ingredient, 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.

[0173] The pharmaceutical compositions provided herein can be provided in soft or hard capsules, which can be prepared from gelatin, methylcellulose, starch or calcium alginate. The hard gelatin capsules are also known as dry-filled capsules (DFC) and consist of two segments, one of which is inserted into the other, thus completely enclosing 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 shells can contain preservatives to prevent microbial growth. Suitable preservatives are those as described herein, including methyl and propyl parabens, and sorbic acid. The liquid, semisolid and solid dosage forms provided herein can be encapsulated in capsules. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or glyceryl triesters. Capsules containing such solutions can be prepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239 and 4,410,545. The capsules can also employ coatings as known to those skilled in the art, to improve or maintain the dissolution of the active ingredient.

[0174] The pharmaceutical compositions provided herein can be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. Emulsions are two-phase systems, in which one liquid is dispersed in the form of small globules throughout another liquid, which can be either oil-in-water or water-in-oil. Emulsions can include pharmaceutically acceptable non- water liquids and solvents, emulsifying agents, and preservatives. Suspensions can include pharmaceutically acceptable suspending agents and preservatives. Aqueous alcoholic solutions can include pharmaceutically acceptable acetal, such as a di(lower alkyl) acetal of a lower alkyl aldehyde, for example, acetaldehyde diethyl acetal; and water-soluble solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened, aqueous alcoholic solutions. Syrups are concentrated sugar solutions, e.g., in water, and can also contain a preservative. For liquid dosage forms, for example, solutions in polyethylene glycol can be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, such as water, to accurately and conveniently administer the dosage.

[0175] Other useful liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredient provided herein and a secondary diluent mono- or poly-alkylene glycol including: 1,2-dimethoxy methane, diglycol dimethyl ether, triglycol dimethyl ether, tetraglycol dimethyl ether, 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 can further include one or more antioxidants such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and esters and dithioamino acid esters.

[0176] If appropriate, the dosage unit formulations for oral administration can be microencapsulated. They can also be prepared in sustained or modified release compositions, such as by coating or embedding particulate material in polymers, waxes, or the like.

[0177] The oral pharmaceutical compositions provided herein can also be provided in the form of liposomes, micelles, microspheres, or nanosystems. The micellar dosage forms can be prepared by the methods described in U.S. Pat. No. 6,350,458.

[0178] The pharmaceutical compositions provided herein can be provided in non-effervescent or effervescent granules and powders. In the non-effervescent granules or powders, the pharmaceutically acceptable carriers and excipients can include diluents, sweeteners, and wetting agents. In the effervescent granules or powders, the pharmaceutically acceptable carriers and excipients can include organic acids and sources of carbon dioxide.

[0179] Colorants and flavoring agents can be used in all of the above dosage forms.

[0180] The compounds disclosed herein can also be combined with soluble polymers as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamide phenol, or polyoxyethylene polylysine substituted with palmitoyl residues. In addition, the compounds disclosed herein can be combined with biodegradable polymers used in achieving controlled release of drugs, such as polylactic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyortho esters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.

[0181] The pharmaceutical compositions provided herein can be formulated in immediate or modified release dosage forms including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed release formulations.

[0182] The pharmaceutical compositions provided herein can be co-formulated with other active ingredients in a manner that does not impair the desired therapeutic action; or co-administered with substances that supplement the desired action.

[0183] The pharmaceutical compositions provided herein can be administered by injection, infusion or implantation for local or systemic delivery. Parenteral administration as used herein includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration.

[0184] The pharmaceutical compositions provided herein can be formulated into any dosage form suitable for parenteral administration including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems and solid forms suitable for reconstitution or suspension in a liquid prior to injection. Such dosage forms can 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).

[0185] Pharmaceutical compositions intended for parenteral administration can 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 antiseptic agents to prevent growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting and emulsifying agents, complexing agents, sequestering agents, cryoprotective agents, lyoprotective agents, thickening agents, pH adjusting agents, and inert gases.

[0186] Suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic glucose injection, sterile water injection, dextrose and lactated Ringer's injection. Non-aqueous vehicles include, but are not limited to, non-volatile 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 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,N-dimethylacetamide, and dimethyl sulfoxide.

[0187] Suitable antimicrobial agents or preservatives include, but are not limited to, phenol, m-cresol, mercurial agents, benzyl alcohol, chlorobutanol, methyl and propyl parabens, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl- and propyl-parabens, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and dextrose. Suitable buffering agents include, but are not limited to, phosphate and citrate. Suitable antioxidants are those described herein, including bisulfites and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are those described herein, including sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agents include those described herein, including polyoxyethylene sorbitan monolaurate. Polyoxyl 80 and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to, EDTA. Suitable pH modifiers include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including alpha-, beta-, hydroxypropyl-beta-, sulfobutyl ether-beta-, and sulfobutyl ether 7-beta-cyclodextrin CyDex, Lenexa, KS).

[0188] The pharmaceutical compositions provided herein can be formulated for single or multiple dosage administration. The single dosage formulations are packaged in ampules, vials, or syringes. The multiple dosage parenteral formulations must contain antimicrobial agents at bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as is known and practiced in the art.

[0189] In one embodiment, the pharmaceutical composition is provided as a ready-to-use sterile solution. In another embodiment, the pharmaceutical composition is provided as a sterile dry dissolvable product, including a lyophilized powder and a subcutaneous injection tablet, which is reconstituted with a carrier prior to use. In yet another embodiment, the pharmaceutical composition is formulated as a ready-to-use sterile suspension. In still another embodiment, the pharmaceutical composition is formulated as a sterile dry non-dissolvable product that is reconstituted with a carrier prior to use. In still another embodiment, the pharmaceutical composition is formulated as a ready-to-use sterile emulsion.

[0190] The pharmaceutical compositions can be configured as suspensions, solids, semi-solids, or thixotropic liquids for use as implanted depot dosages. In one embodiment, the pharmaceutical composition disclosed herein is dispersed within a solid inner matrix that is surrounded by an outer polymeric membrane that is insoluble in body fluids but allows diffusion of the active ingredients in the pharmaceutical composition therethrough.

[0191] Suitable internal matrices include polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol, and partially hydrolyzed polyvinyl acetate.

[0192] Suitable external polymeric films include polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, chlorobutyl rubber, chlorinated polyethylene, polyvinyl chloride, copolymer of chlorinated ethylene and vinyl acetate, vinylidene dichloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber, halogenated rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / ethyleneoxy ethanol copolymer.

[0193] In another aspect, the pharmaceutical compositions disclosed herein can be formulated in any dosage form suitable for inhalation administration to a patient, such as a dry powder, an aerosol, a suspension, or a solution composition. In one embodiment, the pharmaceutical compositions disclosed herein can be formulated in a dosage form suitable for inhalation administration to a patient with a dry powder. In another embodiment, the pharmaceutical compositions disclosed herein can be formulated in a dosage form suitable for inhalation administration to a patient with a nebulizer. Dry powder compositions for delivery to the lung by inhalation typically comprise a fine powder of the compound disclosed herein and one or more fine powders of pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients 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 can be prepared by, for example, micronization and milling. In general, the compound is reduced in size (e.g., micronized) to a Dv90 (e.g., as measured by laser diffraction) of about 1 to 10 microns. 50 Values (e.g., as measured by laser diffraction) of about 1 to 10 microns.

[0194] Aerosols can be formulated by suspending or dissolving the compounds disclosed herein in a liquefied propellant. Suitable propellants include chlorofluorocarbons, hydrocarbons, and other liquefied gases. Representative propellants include: trichlorofluoromethane (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1,1-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. Aerosols can comprise additional, pharmaceutically acceptable excipients that are useful in MDIs, such as surfactants, lubricants, co-solvents, and other excipients to improve physical stability of the formulation, to improve valve characteristics, to improve solubility, or to improve taste.

[0195] Pharmaceutical compositions suitable for transdermal administration can be prepared as discrete patches intended to remain in intimate contact with the epidermis of the patient for a prolonged period of time. For example, the active ingredient can be delivered from the patch through iontophoresis, as described generally in Pharmaceutical Research, 3(6), 318 (1986).

[0196] Pharmaceutical compositions suitable for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils. For example, ointments, creams and gels can be formulated with water or an oil base and suitable thickening or gelling agents and / or solvents. Such bases and agents include water, and / or oil such as liquid petroleum jelly and petroleum jelly, or solvent such as polyethylene glycol. Thickening agents and gelling agents for use in the formulations include soft paraffin, aluminum stearate, cetyl alcohol, polyethylene glycols, lanolin, beeswax, carboxymethylcellulose and cellulose derivatives, and / or glyceryl monostearate and / or non-ionic emulsifiers.

[0197] Lotions can be formulated with water or an oil base and generally also contain one or more emulsifying, stabilizing, dispersing, suspending or thickening agents.

[0198] Powders for external use can be formed in the presence of any suitable powder base such as talc, lactose or starch. Drops can be formulated with water or non-aqueous bases such as a dispersion, solubilizer, suspending agent or preservative.

[0199] Topical formulations can be administered by applying one or more times a day to the affected area; occlusive dressings over the skin are preferred. Adhesive reservoir bands can be used to achieve continuous or extended delivery.

[0200] Use of the compounds and compositions of the present invention The disclosed compounds or pharmaceutical compositions can be used in the manufacture of a medicament for the treatment, prevention, amelioration, control, or reduction of the effects of an infectious disease caused by a Mycobacterium bacteria.

[0201] In particular, the compounds of the present invention can be used to prevent or treat an infectious disease caused by a Mycobacterium bacteria, including tuberculosis, bone tuberculosis, lymph node tuberculosis, lumbar tuberculosis, thoracic tuberculosis, breast tuberculosis, swimmer's granuloma, pulmonary infection, lymph node infection, Buruli ulcer.

[0202] The compounds or compositions of the present invention can be used, but are in no way limited to, administering to a patient an effective amount of the compounds or compositions of the present invention to prevent, treat, or reduce the effects of a disease caused by a Mycobacterium bacteria.

[0203] The compounds and pharmaceutical compositions of the present invention can be used in the treatment of mammals other than humans, in addition to being useful in the treatment of humans. Examples of other animals include horses, dogs, and cats. In this regard, the compounds of the present invention include pharmaceutically acceptable derivatives thereof.

[0204] Methods of treatment In one embodiment, the 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. The disclosed embodiments of the present invention include methods of treating the diseases mentioned above by 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.

[0205] In one embodiment, the disclosed compounds or pharmaceutical compositions comprising the disclosed compounds can be administered by any appropriate route of administration, including systemic and topical administration. Systemic administration includes oral, parenteral, transdermal, and rectal administration. Typical parenteral administration includes administration by injection or infusion, including intravenous, intramuscular, intradermal, and subcutaneous injection or infusion. Topical administration includes administration to the skin and inhaled, nasal, vaginal, and ocular administration. In one embodiment, the disclosed compounds or pharmaceutical compositions comprising the disclosed compounds can be administered orally. In another embodiment, the disclosed compounds or pharmaceutical compositions comprising the disclosed compounds can be administered inhaled. In yet another embodiment, the disclosed compounds or pharmaceutical compositions comprising the disclosed compounds can be administered intranasally.

[0206] In one embodiment, the disclosed compounds or pharmaceutical compositions comprising the disclosed compounds can be administered at once, or multiple times at specified intervals of time according to a dosing regimen over a specified period of time. For example, once, twice, three times, or four times a day. In one embodiment, once a day. In another embodiment, twice a day. Administration can continue until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. The appropriate dosing regimen of the disclosed compounds or pharmaceutical compositions comprising the disclosed compounds depends on the pharmacokinetic properties of the compound, such as dilution, distribution, and half-life, which can be determined by the skilled artisan. In addition, the appropriate dosing regimen of the disclosed compounds or pharmaceutical compositions comprising the disclosed compounds, including the duration of the regimen, depends on the disease being treated, the severity of the disease 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 like factors within the knowledge and expertise of the skilled artisan. Such skilled artisans will also appreciate that the dosing regimen can require adjustment for an individual patient's response to the regimen, or as the individual patient's needs change over time.

[0207] The disclosed compounds can be administered simultaneously, or before or after, one or more other therapeutic agents. The disclosed compounds can be administered separately, by the same or different routes of administration, or together in the same pharmaceutical composition as the other therapeutic agents.

[0208] For a human individual of about 50-70 kg, the disclosed pharmaceutical compositions and combinations can be in unit dosage form containing from about 1-1000 mg, or about 1-500 mg, or about 1-250 mg, or about 1-150 mg, or about 0.5-100 mg, or about 1-50 mg of active ingredient. The therapeutically effective amount of a compound, pharmaceutical composition, or combination thereof depends on the species of the individual, its body mass, age, and individual condition, the disorder or disease being treated, or the severity of the disorder or disease. A physician, clinician, or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients required to prevent, treat, or inhibit the progress of the disorder or disease.

[0209] The above-cited dosage characteristics have been demonstrated in in vitro and in vivo tests using advantageous mammals, such as mice, rats, dogs, monkeys, or ex vivo organs, tissues, and specimens thereof. The disclosed compounds are used in vitro in the form of a solution, such as an aqueous solution, and in vivo in the form of a suspension or aqueous solution, for example, enterally, parenterally, and especially intravenously.

[0210] In one embodiment, a therapeutically effective dose of a compound of the present application is from about 0.1 mg to about 2,000 mg per day. Pharmaceutical compositions should provide a dose of from about 0.1 mg to about 2,000 mg of the compound. In a particular embodiment, pharmaceutical dosage units are prepared to provide from about 1 mg to about 2,000 mg, from about 10 mg to about 1,000 mg, from about 20 mg to about 500 mg, or from about 25 mg to about 250 mg of the principal active ingredient or a combination of the principal active ingredients in each dosage unit form. In a particular embodiment, pharmaceutical dosage units are prepared to provide about 10 mg, 20 mg, 25 mg, 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg or 2000 mg of the principal active ingredient.

[0211] In addition, a compound of the present application can be administered in a form to provide a prodrug. In the present application, a "prodrug" of a compound of the present application is a functional derivative of a compound of the present application that ultimately releases the compound of the present application in vivo when administered to a patient. The administration of a compound of the present application in the form of a prodrug can be used to achieve one or more of the following: (a) alter the onset of the in vivo effect of the compound; (b) alter the duration of the in vivo effect of the compound; (c) alter the delivery or distribution of the compound in vivo; (d) alter the solubility of the compound in vivo; and (e) overcome side effects or other difficulties associated with the compound. Typical functional derivatives for use in preparing prodrugs include variants of the compound that are cleaved in vivo chemically or enzymatically. Such variants include the preparation of phosphates, amides, esters, thioesters, carbonates, and carbamates, which are well known to those skilled in the art.

[0212] General Synthetic Procedures To illustrate the present application, the following examples are set forth. It should be understood, however, that these examples are included merely to provide a more detailed description of the application, and are not intended to limit the application in any way.

[0213] In general, the compounds of the present application can be prepared by the methods described herein, unless otherwise specified, wherein the substituents are as defined in Formula (I). The following reaction schemes and examples are intended to further illustrate the present application.

[0214] Those skilled in the art will appreciate that the chemical reactions described herein can be performed by using chemically compatible reagents and reaction conditions as described herein or otherwise known to those skilled in the art. The chemistries described herein can be used to prepare many other compounds of the application as appropriate, and other methods for preparing compounds of the application are deemed to be within the scope of the application. For example, the synthesis of those compounds of the application that are not exemplified herein can be successfully performed by a person skilled in the art by using modifications of the methods described herein, such as by appropriately protecting interfering groups, by utilizing other known reagents and reactions, or by making routine modifications of reaction conditions, all as recognized by those skilled in the art. Also, the reactions disclosed herein are recognized to be applicable to other compounds of the application, and the application of such reactions to the preparation of these compounds is deemed to be within the scope of the application.

[0215] Unless otherwise indicated, all temperatures are set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and used without further purification, unless otherwise indicated. General reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyu Chemicals Co. Ltd., Tianjin Fumian Chemical Reagent Factory, Wuhan Xinhua Yuan Science and Technology Development Co. Ltd., Qingdao Tenglong Chemical Reagent Co. Ltd. and Qingdao Haoyang Chemical Factory.

[0216] Ethyl acetate and petroleum ether were used after being dried over anhydrous sodium sulfate.

[0217] Chromatography was performed on silica gel columns. Silica gel (200-300 mesh) was purchased from Qingdao Haoyang Chemical Factory.

[0218] NMR spectra were recorded on a Bruker 400 MHz or 500 MHz or 600 MHz NMR spectrometer in DMSO-d6 or acetone-d6 (in ppm) with TMS (0 ppm) as the reference standard. When multiplets occur, the following abbreviations will be used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants are denoted by (J) and are in Hertz (Hz).

[0219] The following abbreviations will be used throughout the application: mg milligram μM micromole M mole per liter °C degrees Celsius MeOH methanol MeCN acetonitrile mL milliliter rt room temperature AA amino acid A typical synthetic procedure for preparing the compounds disclosed in the present application is shown in the following synthetic scheme 1. Unless otherwise specified, X, L, R3and n described therein have the meanings described in the present application.

[0220] Synthetic scheme 1 All linear and cyclic peptides were synthesized using the method described in the literature (Chem. Commun., 2019, 55, 1104); The cyclic peptide obtained in the previous step (1 eq) was dissolved in an appropriate amount of a mixture of water and acetic acid, and the boronic acid reagent (7 eq), copper acetate (0.43 eq), palladium acetate (0.22 eq) were added to the solution and stirred. The reaction mixture was stirred at 50°C for 7 hours, then the solvent was removed under reduced pressure, dissolved in ethyl acetate and washed with sodium sulfate. The organic layer was collected, dried over anhydrous Na2SO4and evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel to obtain the corresponding target product.

[0221] The compounds, pharmaceutical compositions and uses thereof provided by the present application are further illustrated in conjunction with the following examples. Examples

[0222] Example 1: (Compound 1) White amorphous powder, yield 15%; 1 H NMR (400 MHz, DMSO-d6) δ H10.91 (1H, s), 8.53 (1H, d, J = 7.6 Hz), 8.17 (2H, d, J = 8.7 Hz), 7.97 (2H, t, J = 6.2 Hz), 7.84 (1H, d, J = 4.5 Hz), 7.72 (1H, d, J = 8.5 Hz), 7.55 (1H, d, J = 8.0 Hz), 7.36 (1H, d, J = 8.3 Hz), 7.32 - 7.19 (5H, overlapped), 7.19 - 7.11 (1H, m), 7.05 (1H, t, J = 7.5 Hz), 6.94 (1H, t, J = 7.3 Hz), 6.69 (1H, d, J = 2.4 Hz), 6.66 (1H, dd, J = 8.4, 2.4 Hz), 4.83 (1H, t, J = 5.6 Hz), 4.57 (1H, t, J = 5.5 Hz), 4.50 (1H, m), 4.45 - 4.37 (2H, overlapped), 4.17 (1H, q, J = 5.9 Hz), 4.07 (1H, dd, J = 9.8, 7.4 Hz), 3.90 (1H, m), 3.84 (3H, s), 3.76 (3H, s), 3.70 (2H, m), 3.56 (1H, m), 3.45 (1H, m), 3.17 (1H, dd, J = 13.7, 4.9 Hz), 3.03 (2H, dd, J = 13.7, 7.9 Hz), 2.83 (1H, dd, J = 14.2, 7.2 Hz), 2.73 (1H, dd, J = 13.8, 10.5 Hz), 1.97 (1H, m), 1.71 (1H, m), 1.06 (3H, d, J = 6.7 Hz), 0.68 (9H, q, J = 6.1 Hz), 0.46 (3H, d, J = 6.7 Hz); 13 C NMR (101 MHz, DMSO-de) δ C 172.8, 171.4, 171.0 x 2, 170.7 x 2, 169.1, 160.8, 158.2, 138.0, 135.7, 133.4, 132.5, 129.2 x 2, 128.1 x 2, 127.9, 126.3, 120.8, 118.6, 118.1, 113.8, 110.8, 106.9, 105.0, 98.7, 61.1, 60.7, 59.7, 59.4, 56.2, 55.5, 55.4, 55.2, 54.9 x 2, 48.2, 36.4, 30.4, 29.0, 26.8, 19.1 x 2, 18.2, 17.8, 17.6. HRESIMS m / z 913.4440 [M + H] + (calcd for C 47 H 61 N8O11 + 913.4454).

[0223] Example 2: (Compound 2) White amorphous powder, yield 52%; 1 H NMR (500 MHz, DMSO-d6): δ H 11.23 (1H, s), 8.51 (1H, d, J = 7.7 Hz), 8.21 (1H, d, J = 7.5 Hz), 8.10 (1H, d, J = 9.7 Hz), 7.99 (2H, dd, J = 15.2, 5.7 Hz), 7.92 (1H, d, J = 5.4 Hz), 7.70 - 7.64 (3H, overlapped), 7.57 (1H, d, J = 8.0 Hz), 7.51 (2H, t, J = 7.7 Hz), 7.40 (1H, m), 7.34 (1H, d, J = 8.0 Hz), 7.27 - 7.21 (4H, overlapped), 7.16 (1H, m), 7.09 (1H, m), 6.97 (1H, m), 4.85 (1H, t, J = 5.7 Hz), 4.57 (1H, m), 4.53 - 4.45 (2H, overlapped), 4.37 (1H, m), 4.19 (1H, m), 4.12 (1H, m), 3.85 (1H, m), 3.75 - 3.70 (2H, overlapped), 3.52 - 3.43 (2H, overlapped), 3.21 - 3.11 (3H, overlapped), 2.84 (1H, m), 2.73 (1H, dd, J = 13.8, 10.5 Hz), 2.03 (1H, m), 1.70 (1H, m), 1.09 (3H, d, J = 6.8 Hz), 0.72 - 0.66 (9H, overlapped), 0.46 (3H, d, J = 6.7 Hz); HRESIMS m / z 853.4222 [M + H] + (calcd for C 45 H 57 N8O9 + 853.4243).

[0224] Example 3: (Compound 3) White amorphous powder, yield 38%; 1 H NMR (400 MHz, acetone-d6): δ H10.75 (1H, s), 9.59 (1H, d, J = 8.5 Hz), 9.30 (1H, br s), 9.11 (1H, br s), 8.82 (1H, br s), 8.65 (1H, br s), 8.55 (1H, br s), 7.91 - 7.87 (4H, overlapped), 7.53 (1H, d, J = 8.0 Hz), 7.45 (1H, d, J = 8.2 Hz), 7.38 (2H, d, J = 7.1 Hz), 7.24 (2H, t, J = 7.3 Hz), 7.17 (2H, t, J = 6.9 Hz), 7.05 (1H, t, J = 7.5 Hz), 5.14 (1H, m), 4.86 (1H, m), 4.70 (1H, m), 4.38 (1H, m), 3.91 (1H, d, J = 8.7 Hz), 3.84 (1H, m), 3.83 - 3.75 (2H, overlapped), 3.50 (1H, dd, J = 14.1, 10.8 Hz), 3.40 (1H, dd, J = 14.1, 5.5 Hz), 3.30 - 3.10 (4H, overlapped), 2.83 (1H, m), 2.53 (1H, m), 2.24 (1H, m), 1.76 (1H, m), 1.23 (3H, d, J = 6.4 Hz), 1.03 (3H, d, J = 6.6 Hz), 1.01 (3H, d, J = 6.6 Hz), 0.78 (3H, d, J = 6.6 Hz), 0.42 (3H, d, J = 6.7 Hz); HRESIMS m / z 878.4171 [M+H] + (calcd for C 46 H 56 N9O9 + ,878.4196).

[0225] Example 4: (Compound 4) White amorphous powder, yield 27%; 1 H NMR (400 MHz, DMSO-d6): δ H11.13 (1H, s), 8.53 (1H, d, J = 7.6 Hz), 8.22 (1H, d, J = 7.3 Hz), 8.09 (1H, d, J = 9.8 Hz), 7.98 (2H, dd, J = 9.7, 5.8 Hz), 7.93 (1H, d, J = 5.5 Hz), 7.66 (1H, d, J = 8.3 Hz), 7.60 (2H, d, J = 8.7 Hz), 7.53 (1H, d, J = 7.8 Hz), 7.31 (1H, d, J = 8.0 Hz), 7.27 - 7.20 (4H, overlapped), 7.15 (1H, t, J = 6.8 Hz), 7.06 (3H, t, J = 8.6 Hz), 6.94 (1H, m), 4.87 (1H, t, J = 5.7 Hz), 4.58 - 4.45 (3H, overlapped), 4.38 (1H, m), 4.18 (1H, m), 4.12 (1H, dd, J = 9.6, 7.1 Hz), 3.87 (1H, m), 3.82 (3H, s), 3.72 (2H, dd, J = 8.3, 5.4 Hz), 3.53 - 3.43 (2H, overlapped), 3.21 - 3.13 (2H, overlapped), 3.08 (1H, dd, J = 14.2, 6.6 Hz), 2.85 (1H, m), 2.72 (1H, dd, J = 13.5, 10.8 Hz), 2.02 (1H, m), 1.71 (1H, m), 1.08 (3H, d, J = 6.8 Hz), 0.73 - 0.64 (9H, overlapped), 0.45 (3H, d, J = 6.7 Hz); HRESIMS m / z 883.4330 [M + H] + (calcd for C 46 H 59 N8O 10 + ,883.4349).

[0226] Example 5: (Compound 5) White amorphous powder, yield 43%; 1 H NMR (400 MHz, DMSO-d6): δ H11.18 (1H, s), 8.53 (1H, d, J = 7.6 Hz), 8.22 (1H, d, J = 7.5 Hz), 8.10 (1H, d, J = 9.8 Hz), 7.99 (2H, d, J = 6.0 Hz), 7.94 (1H, d, J = 5.5 Hz), 7.67 (1H, d, J = 8.3 Hz), 7.58 - 7.43 (3H, overlapped), 7.34 - 7.31 (3H, overlapped), 7.29 - 7.20 (4H, overlapped), 7.16 (1H, m), 7.07 (1H, m), 6.96 (1H, m), 4.86 (1H, t, J = 5.7 Hz), 4.57 (1H, m), 4.52 - 4.44 (2H, overlapped), 4.38 (1H, dd, J = 8.1, 6.7 Hz), 4.19 (1H, m), 4.13 (1H, dd, J = 9.8, 7.1 Hz), 3.85 (1H, m), 3.78 - 3.69 (2H, overlapped), 3.53 - 3.44 (2H, overlapped), 3.25 - 3.04 (3H, overlapped), 2.86 (1H, m), 2.73 (1H, dd, J = 13.8, 10.6 Hz), 2.38 (3H, s), 2.03 (1H, m), 1.71 (1H, m), 1.09 (3H, d, J = 6.8 Hz), 0.73 - 0.64 (9H, overlapped), 0.46 (3H, d, J = 6.7 Hz); HRESIMS m / z 867.4390 [M + H] + (calcd for C 46 H 59 N8O9 + ,867.4400).

[0227] Example 6: (Compound 6) White amorphous powder, yield 42%; 1 H NMR (400 MHz, acetone-d6): δ H10.65 (1H, s), 8.04 (1H, d, J = 6.7 Hz), 7.98 (2H, d, J = 8.1 Hz), 7.85 (2H, d, J = 8.2 Hz), 7.68 (1H, d, J = 8.0 Hz), 7.44 (1H, d, J = 8.1 Hz), 7.30 (2H, t, J = 7.2 Hz), 7.26 (2H, d, J = 7.7 Hz), 7.22 - 7.14 (2H, overlapped), 7.08 (1H, t, J = 7.9 Hz), 4.63 - 4.52 (2H, overlapped), 4.45 (1H, m), 4.25 (1H, m), 4.11 - 4.03 (2H, overlapped), 3.92 - 3.79 (2H, overlapped), 3.75 (1H, m), 3.66 (1H, dd, J = 11.3, 5.7 Hz), 3.56 (1H, dd, J = 14.4, 7.9 Hz), 3.46 (1H, m), 3.30 - 3.27 (1H, overlapped), 3.10 (1H, m), 2.24 - 2.12 (2H, overlapped), 2.05 (1H, m), 1.27 (3H, d, J = 6.9 Hz), 0.85 (3H, d, J = 6.7 Hz), 0.77 - 0.63 (9H, overlapped); HRESIMS m / z 921.4107 [M+H] + (calcd for C 46 H 56 F3N8O9 + ,921.4117).

[0228] Example 7: (Compound 7) White amorphous powder, yield 34%; 1 H NMR (400 MHz, DMSO-d6): δ H11.21 (1H, s), 8.52 (1H, d, J = 7.6 Hz), 8.22 (1H, d, J = 7.5 Hz), 8.09 (1H, d, J = 9.7 Hz), 8.00-7.95 (2H, overlapped), 7.93 (1H, d, J = 5.5 Hz), 7.65 (3H, dd, J = 8.5, 7.0 Hz), 7.55 (1H, d, J = 8.0 Hz), 7.44 (2H, d, J = 8.0 Hz), 7.33 (1H, d, J = 8.0 Hz), 7.27-7.20 (4H, overlapped), 7.16 (1H, m), 7.09 (1H, m), 6.98-6.93 (2H, overlapped), 4.59-4.53 (3H, overlapped), 4.49 (1H, m), 4.38 (1H, dd, J = 8.2, 6.7 Hz), 4.19-4.10 (2H, overlapped), 3.85 (1H, m), 3.72 (1H, d, J = 2.5 Hz), 3.48 (1H, d, J = 3.8 Hz), 3.22-3.08 (5H, overlapped), 2.83 (1H, dd, J = 10.7, 3.9 Hz), 2.73 (1H, m), 2.03 (1H, m), 1.69 (1H, m), 1.09 (3H, d, J = 6.7 Hz), 0.73-0.66 (9H, overlapped), 0.46 (3H, d, J = 6.7 Hz); HRESIMS m / z 869.4187 [M+H] + (calcd for C 45 H 57 N8O 10 + ,869.4192).

[0229] Example 8: (Compound 8) White amorphous powder, yield 41%; ESIMS m / z 995.14 [M+H] + .

[0230] Example 9: (Compound 9) White amorphous powder, yield 29%; ESIMS m / z 853.96 [M+H] + .

[0231] Example 10: (Compound 10) White amorphous powder, yield 41 %; 1 H NMR (400 MHz, DMSO-d6): δ H 11.40 (1H, s), 8.53 (1H, d, J = 7.6 Hz), 8.30 - 8.22 (2H, overlapped), 8.12 - 7.95 (6H, overlapped), 7.92 (1H, d, J = 5.5 Hz), 7.86 (1H, m), 7.62 (1H, d, J = 8.2 Hz), 7.59 - 7.52 (3H, overlapped), 7.38 (1H, d, J = 8.1 Hz), 7.28 - 7.20 (4H, overlapped), 7.17 - 7.08 (2H, overlapped), 6.98 (1H, t, J = 7.4 Hz), 4.89 (1H, t, J = 5.7 Hz), 4.70 (1H, m), 4.51 (1H, m), 4.43 (1H, t, J = 5.4 Hz), 4.36 (1H, m), 4.25 - 4.15 (2H, overlapped), 3.82 (1H, m), 3.78 - 3.70 (2H, overlapped), 3.58 - 3.50 (1H, m), 3.45 - 3.39 (1H, overlapped), 3.27 - 3.15 (3H, overlapped), 2.77 - 2.67 (2H, overlapped), 2.07 (1H, m), 1.70 (1H, m), 1.10 (3H, d, J = 6.8 Hz), 0.76 - 0.64 (9H, overlapped), 0.45 (3H, d, J = 6.7 Hz); HRESIMS m / z 903.4388 [M + H] + (calcd for C 49 H 59 N8O9 + ,903.4400).

[0232] Example 11: (Compound 11) White amorphous powder, yield 31 %; 1 H NMR (400 MHz, DMSO-d6): δ H11.63 (1H, s), 8.97 (1H, d, J = 7.5 Hz), 8.66 (1H, d, J = 7.5 Hz), 8.56 (1H, d, J = 9.7 Hz), 8.51 - 8.42 (2H, overlapped), 8.38 (1H, d, J = 5.4 Hz), 8.12 (1H, d, J = 8.3 Hz), 8.04 (2H, d, J = 8.1 Hz), 7.99 (1H, d, J = 7.9 Hz), 7.78 (3H, d, J = 7.9 Hz), 7.72 - 7.65 (4H, overlapped), 7.60 (1H, m), 7.52 (1H, t, J = 7.5 Hz), 7.40 (1H, t, J = 7.5 Hz), 4.97 (2H, overlapped), 4.82 (1H, m), 4.65 (1H, m), 4.58 (1H, dd, J = 9.6, 7.1 Hz), 4.30 (1H, m), 4.22 - 4.15 (2H, overlapped), 3.99 - 3.91 (2H, overlapped), 3.59 (3H, overlapped), 3.27 (1H, dd, J = 10.5, 3.5 Hz), 3.19 (1H, dd, J = 13.6, 10.7 Hz), 3.09 (2H, t, J = 7.6 Hz), 2.49 (1H, m), 2.18 (1H, m), 2.11 - 2.02 (2H, overlapped), 1.80 - 1.71 (6H, overlapped), 1.54 (3H, d, J = 6.8 Hz), 1.33 (3H, d, J = 6.8 Hz), 1.19 - 1.10 (9H, overlapped), 0.92 (3H, d, J = 6.7 Hz); 13 C NMR (100 MHz, DMSO-d6): δ C 172.5, 171.5, 171.0 x 2, 170.8, 170.6, 169.0, 141.7, 137.9, 135.9, 135.8, 130.0, 129.2 x 2, 128.9, 128.6 x 2, 128.1 x 4, 126.3, 121.3, 118.9, 118.5, 111.0, 106.2, 61.1, 60.5, 59.6, 59.0, 56.1, 55.5, 55.2, 54.9, 48.2, 36.5, 34.9, 31.2, 30.9, 30.3, 29.0, 28.4, 26.9, 22.1, 19.3, 19.1, 18.3, 17.8, 17.7, 14.0; HRESIMS m / z 935.4996 [M+H] + (calcd for C 51H 67 N8O9 + ,935.5026).

[0233] Example 12: (Compound 12) White amorphous powder, yield 29%; 1 H NMR (500 MHz, DMSO-d6): δ H 11.32 (1H, s), 8.54 (1H, d, J = 7.4 Hz), 8.26 (1H, d, J = 7.4 Hz), 8.09 (2H, dd, J = 21.8, 7.2 Hz), 8.01 (1H, d, J = 6.3 Hz), 7.93 (1H, d, J = 5.3 Hz), 7.86 - 7.74 (6H, overlapped), 7.69 (1H, d, J = 8.3 Hz), 7.58 (1H, d, J = 8.0 Hz), 7.51 (2H, t, J = 7.7 Hz), 7.42 - 7.35 (2H, overlapped), 7.27 - 7.20 (4H, overlapped), 7.13 (2H, overlapped), 6.99 (1H, t, J = 7.5 Hz), 4.90 (1H, t, J = 5.7 Hz), 4.61 (1H, m), 4.55 - 4.46 (2H, overlapped), 4.39 (1H, m), 4.22 (1H, m), 4.15 (1H, dd, J = 9.6, 7.0 Hz), 3.88 (1H, m), 3.79 - 3.71 (2H, overlapped), 3.57 - 3.44 (2H, overlapped), 3.30 - 3.14 (3H, overlapped), 2.87 (1H, dd, J = 9.6, 4.6 Hz), 2.74 (1H, dd, J = 13.6, 10.7 Hz), 2.04 (1H, m), 1.73 (1H, m), 1.10 (3H, d, J = 6.8 Hz), 0.75 - 0.65 (9H, overlapped), 0.47 (3H, d, J = 6.7 Hz); 13 C NMR (125 MHz, DMSO-d6): δ C172.4, 171.4, 171.0 x 2, 170.8, 170.7, 169.0, 139.6, 138.9, 137.9, 136.0, 135.3, 131.7, 129.2 x 2, 129.0 x 2, 128.9, 128.7 x 2, 128.1 x 2, 127.6, 126.8 x 2, 126.6 x 2, 126.2, 121.6, 119.0, 118.7, 111.1, 107.0, 61.0, 60.6, 59.5, 58.9, 56.1, 55.5, 55.2, 54.9, 48.2, 36.5, 30.3, 29.0, 27.0, 19.3, 19.0, 18.3, 17.7 x 2; HRESIMS m / z 929.4546 [M+H] + (calcd for C 51 H 61 N8O9 + ,929.4556).

[0234] Example 13: (Compound 13) White amorphous powder, yield 22%; 1 H NMR (400 MHz, DMSO-d6): δ H11.34 (1H, s), 8.51 (1H, d, J = 7.7 Hz), 8.20 (1H, d, J = 7.5 Hz), 8.15 (1H, d, J = 4.8 Hz), 8.12 (1H, d, J = 9.7 Hz), 7.96 (1H, d, J = 6.5 Hz), 7.92 - 7.91 (2H, overlapped), 7.80 (2H, d, J = 7.4 Hz), 7.72 - 7.66 (3H, overlapped), 7.61 (1H, d, J = 7.7 Hz), 7.57 (1H, d, J = 8.6 Hz), 7.51 (2H, t, J = 7.6 Hz), 7.40 (1H, t, J = 7.4 Hz), 7.36 (1H, d, J = 8.1 Hz), 7.30 - 7.18 (4H, overlapped), 7.20 - 7.04 (2H, overlapped), 6.98 (1H, t, J = 7.5 Hz), 4.78 (1H, t, J = 5.8 Hz), 4.62 (1H, m), 4.51 (1H, m), 4.44 (1H, t, J = 5.4 Hz), 4.38 (1H, m), 4.24 (1H, m), 4.13 (1H, dd, J = 9.8, 7.1 Hz), 3.83 (1H, m), 3.77 - 7.70 (2H, overlapped), 3.54 - 3.44 (3H, overlapped), 3.29 - 3.13 (2H, overlapped), 2.84 - 2.68 (2H, overlapped), 2.03 (1H, m), 1.69 (1H, m), 1.09 (3H, d, J = 6.8 Hz), 0.76 - 0.61 (9H, overlapped), 0.46 (3H, d, J = 6.7 Hz); 13 C NMR (100 MHz, DMSO-d6): δ C 173.0, 171.9, 171.4 x 2, 171.1, 171.0, 169.4, 141.0, 140.5, 138.4, 136.3, 136.0, 133.6, 129.8, 129.6 x 2, 129.4 x 2, 129.3, 128.5 x 2, 128.1, 127.7, 127.4 x 2, 126.9, 126.6, 126.2, 122.0, 119.5, 119.0, 111.4, 107.2, 61.7, 60.9, 60.1, 59.5, 56.4, 55.7, 55.6, 55.3, 48.5, 36.9, 30.8, 29.4, 27.3, 19.6, 19.5, 18.7, 18.2, 18.0; HRESIMS m / z 929.4550 [M+H] +(calcd for C 51 H 61 N8O9 + ,929.4556).

[0235] Example 14: (Compound 14) White amorphous powder, yield 30%; ESIMS m / z 930.07 [M+H] + .

[0236] Example 15: (Compound 15) White amorphous powder, yield 29%; 1 H NMR (400 MHz, DMSO-d6): δ H 11.38 (1H, s), 8.52 (1H, d, J = 7.6 Hz), 8.24 (1H, d, J = 7.5 Hz), 8.08 (1H, d, J = 9.7 Hz), 8.04 (1H, d, J = 5.1 Hz), 7.99 (1H, d, J = 6.4 Hz), 7.90 (1H, d, J = 5.6 Hz), 7.69 - 7.62 (6H, overlapped), 7.58 (1H, d, J = 8.0 Hz), 7.52 (2H, t, J = 7.6 Hz), 7.44 (1H, m), 7.37 (1H, d, J = 8.0 Hz), 7.28 - 7.19 (4H, overlapped), 7.14 (1H, q, J = 7.9, 7.4 Hz), 6.99 (1H, t, J = 7.5 Hz), 4.88 (1H, t, J = 5.7 Hz), 4.61 (1H, q, J = 7.5, 6.8 Hz), 4.51 (1H, m), 4.47 (1H, t, J = 5.5 Hz), 4.36 (1H, m), 4.20 (1H, t, J = 5.9 Hz), 4.14 (1H, dd, J = 9.7, 6.8 Hz), 3.84 (1H, dt, J = 8.0, 4.2 Hz), 3.78 - 3.68 (2H, m), 3.52 (1H, m), 3.44 (1H, m), 3.24 (1H, m), 3.17 (1H, m), 2.80 (1H, dt, J = 10.7, 4.3 Hz), 2.73 (1H, dd, J = 13.8, 10.5 Hz), 2.04 (1H, m), 1.71 (1H, m), 1.10 (3H, d, J = 6.8 Hz), 0.68 (9H, m), 0.46 (3H, d, J = 6.7 Hz); 13 C NMR (100 MHz, DMSO-d6): δC 172.8, 171.9, 171.4 x 2, 171.3, 171.1, 169.4, 138.4, 136.4, 134.3, 131.3 x 2, 129.6 x 2, 129.2 x 6, 128.5 x 2, 127.3, 126.7, 125.0 x 2, 122.5, 119.6, 119.3, 116.0, 115.7, 111.6, 108.2, 61.5, 60.9, 60.0, 59.3 x 2, 56.5, 56.1, 55.3, 48.6, 36.9, 30.8, 29.5, 27.5, 19.7, 19.5, 18.8, 18.2 x 2; HRESIMS m / z 947.4443 [M+H] + (calcd for C 51 H 60 FN8O9 + ,947.4462).

[0237] Example 16: (Compound 16) White amorphous powder, yield 35%; 1 H NMR (400 MHz, DMSO-d6): δ H11.36 (1H, s), 8.51 (1H, d, J = 7.5 Hz), 8.26 (1H, d, J = 7.5 Hz), 8.13 - 8.07 (2H, overlapped), 8.04 (1H, d, J = 7.0 Hz), 8.00 (2H, d, J = 7.5 Hz), 7.96 - 7.89 (2H, overlapped), 7.87 (2H, d, J = 8.0 Hz), 7.69 (1H, d, J = 8.3 Hz), 7.67 - 7.50 (7H, overlapped), 7.38 (1H, d, J = 8.0 Hz), 7.30 - 7.17 (4H, overlapped), 7.13 (2H, overlapped), 7.00 (1H, t, J = 7.5 Hz), 4.63 (1H, q, J = 6.8 Hz), 4.50 (1H, m), 4.38 (1H, m), 4.21 (1H, q, J = 5.9 Hz), 4.12 (1H, dd, J = 9.7, 6.8 Hz), 3.89 (1H, dt, J = 8.0, 4.2 Hz), 3.75 (2H, overlapped), 3.53 - 3.48 (4H, overlapped), 3.28 (2H, overlapped), 3.15 (1H, dd, J = 13.7, 5.0 Hz), 2.90 (1H, dd, J = 10.8, 3.9 Hz), 2.73 (1H, dd, J = 13.7, 10.5 Hz), 2.01 (1H, m), 1.73 (1H, m), 1.10 (3H, d, J = 6.8 Hz), 0.74 - 0.60 (9H, overlapped), 0.46 (3H, d, J = 6.7 Hz); 13 C NMR (100 MHz, DMSO-d6): δ C 172.9, 171.9, 171.4 x 2, 171.3, 171.2, 169.4, 139.5, 139.4, 138.3, 136.4, 135.8, 134.0, 132.2, 131.3, 130.5 x 2, 129.6 x 2, 129.3, 128.9, 128.7 x 2, 128.5 x 2, 128.3, 127.4, 126.9, 126.7, 126.5, 126.1, 125.7, 122.1, 119.5, 119.2, 111.5, 107.5, 61.4, 61.0, 60.0, 59.4, 56.6, 56.0, 55.6, 55.3, 48.6, 36.9, 30.7, 29.5, 27.4, 19.7, 19.5, 18.7, 18.2 x 2; HRESIMS m / z 979.4684 [M+H] +(calcd for C 55 H 63 N8O9 + ,979.4713)

[0238] Example 17: (Compound 17) white amorphous powder, yield 39%; 1 H NMR (DMSO-d6, 500 MHz): δ H 11.34 (1H, s), 8.51 (1H, d, J = 7.6 Hz), 8.32 (1H, s), 8.13 (1H, d, J = 9.8 Hz), 7.97 (1H, d, J = 6.3 Hz), 7.94 (1H, d, J = 3.9 Hz), 7.90 (1H, m), 7.79 (2H, s), 7.70 (3H, t, J = 8.0 Hz), 7.61-7.58 (5H, overlapped), 7.58-7.49 (3H, overlapped), 7.36 (1H, d, J = 8.0 Hz), 7.26-7.18 (4H, overlapped), 7.15 (2H, m), 7.05 (1H, ddd, J = 8.0, 7.0, 1.0 Hz), 4.83 (1H, s), 4.59 (1H, s), 4.53-4.44 (2H, overlapped), 4.41 (1H, m), 4.12 (1H, s), 4.03 (1H, dd, J = 9.9, 7.5 Hz), 3.88 (1H, s), 3.69 (1H, dd, J = 7.8, 5.2 Hz), 3.64 (1H, s), 3.56 (1H, m), 3.41 (2H, m), 3.16 (1H, dd, J = 13.7, 4.8 Hz), 3.10 (2H, s), 2.72 (1H, dd, J = 13.8, 10.5 Hz), 1.93 (1H, m), 1.70 (1H, m), 1.03 (3H, d, J = 6.8 Hz), 0.66 (9H, dd, J = 20.7, 6.7 Hz), 0.44 (3H, d, J = 6.7 Hz); 13 C NMR (DMSO-d6, 125 MHz): δ C172.5, 171.4, 171.0, 170.9, 170.7 x 2, 169.0, 140.2, 139.9, 137.9, 136.1, 134.8, 132.6, 131.1, 129.9 x 3, 129.2 x 2, 128.8, 128.6 x 2, 128.1 x 2, 127.8, 127.7, 126.6, 126.5, 126.4, 126.3 x 2, 125.8, 121.4, 119.1, 118.6, 111.1, 108.2, 60.9, 60.7, 59.7, 59.3 x 2, 56.1, 55.1, 54.9, 48.2, 36.4, 30.3, 28.9, 26.8, 19.1, 19.0, 18.2, 17.7, 17.5; HRESIMS m / z 979.4694 [M+H] + (calcd for C 55 H 63 N8O9 + ,979.4713).

[0239] Example 18: (Compound 18) White amorphous powder, yield 36%; 1 H NMR (400 MHz, DMSO-d6): δ H11.34 (1H, s), 8.53 (1H, d, J = 7.5 Hz), 8.34 (1H, s), 8.25 (1H, d, J = 7.5 Hz), 8.16 - 7.93 (10H, m), 7.90 (1H, d, J = 5.6 Hz), 7.85 (2H, d, J = 8.1 Hz), 7.68 (1H, d, J = 8.3 Hz), 7.63 - 7.50 (2H, m), 7.38 (1H, d, J = 8.0 Hz), 7.29 - 7.18 (4H, m), 7.19 - 7.07 (2H, m), 6.99 (1H, t, J = 7.6 Hz), 4.89 (1H, s), 4.63 (1H, q, J = 6.7 Hz), 4.57 - 4.45 (1H, m), 4.38 (1H, p, J = 7.0 Hz), 4.22 (1H, q, J = 5.9 Hz), 4.15 (1H, dd, J = 9.8, 6.8 Hz), 3.88 (1H, dt, J = 8.0, 4.2 Hz), 3.76 (2H, dd, J = 8.5, 5.7 Hz), 3.54 (1H, dd, J = 10.8, 5.6 Hz), 3.50 - 3.38 (15H, m), 3.25 (1H, t, J = 8.1 Hz), 3.22 - 3.10 (1H, m), 2.86 (1H, dd, J = 10.9, 4.0 Hz), 2.74 (1H, dd, J = 13.8, 10.4 Hz), 2.12 - 1.99 (1H, m), 1.79 - 1.66 (1H, m), 1.11 (3H, d, J = 6.8 Hz), 0.69 (9H, q, J = 6.4 Hz), 0.47 (3H, d, J = 6.7 Hz); 13 C NMR (100 MHz, DMSO-d6): δ C 172.9, 171.9, 171.4 x 2, 171.3, 171.1, 169.4, 139.1, 138.4, 137.3, 136.4, 135.7, 133.9, 132.8, 132.3, 129.6 x 2, 129.4 x 2, 129.2, 129.0, 128.7 x 2, 128.5 x 2, 128.0, 127.6 x 2, 127.0, 126.7, 125.6, 125.4, 122.1, 119.5, 119.1, 111.5, 107.5, 61.5, 61.0, 60.0, 59.3, 56.5, 56.0, 55.6, 55.4, 48.6, 36.9, 30.8, 29.5, 27.5, 19.7, 19.5, 18.8, 18.2 x 2; HRESIMS m / z 979.4695 [M+H] + (calcd for C 55 H63 N8O9 + 979.4713).

[0240] Example 19: (Compound 19) White amorphous powder, yield 29%; 1 H NMR (500 MHz, DMSO-d6): δ H 11.33 (1H, s), 8.50 (1H, d, J = 7.5 Hz), 8.23 (1H, d, J = 7.5 Hz), 8.11 (1H, d, J = 9.6 Hz), 8.08 (1H, d, J = 5.1 Hz), 7.98 (1H, d, J = 6.4 Hz), 7.92 (1H, d, J = 5.7 Hz), 7.89 (4H, dd, J = 8.5, 7.3 Hz), 7.84 - 7.78 (4H, overlapped), 7.77 - 7.72 (2H, m), 7.67 (1H, d, J = 8.3 Hz), 7.58 (1H, d, J = 8.0 Hz), 7.50 (2H, t, J = 7.7 Hz), 7.42 - 7.39 (1H, m), 7.39 - 7.35 (1H, m), 7.27 - 7.18 (4H, overlapped), 7.18 - 7.13 (1H, m), 7.11 (1H, t, J = 7.3 Hz), 6.98 (1H, t, J = 7.6 Hz), 4.91 (1H, t, J = 5.7 Hz), 4.60 (1H, q, J = 6.7 Hz), 4.56 - 4.51 (1H, m), 4.50 (1H, t, J = 5.5 Hz), 4.42 - 4.32 (1H, m), 4.21 (1H, q, J = 5.9 Hz), 4.13 (1H, dd, J = 9.6, 6.8 Hz), 3.87 (1H, dt, J = 8.0, 4.2 Hz), 3.78 - 3.69 (2H, m), 3.53 (1H, dt, J = 11.3, 5.9 Hz), 3.49 - 3.44 (1H, m), 3.28 - 3.20 (2H, overlapped), 3.15 (1H, dd, J = 13.4, 4.7 Hz), 2.85 (1H, d, J = 6.2 Hz), 2.74 (1H, dd, J = 13.8, 10.3 Hz), 2.05 (1H, m), 1.73 (1H, m), 1.10 (3H, d, J = 6.8 Hz), 0.74 - 0.66 (9H, overlapped), 0.47 (3H, d, J = 6.7 Hz); 13 C NMR (125 MHz, DMSO-d6): δ C ​​172.5, 171.5, 171.1, 171.0, 170.9, 170.7, 169.0, 139.6, 139.3, 138.5, 138.3, 137.9, 136.0, 135.3, 131.8, 129.2x2, 129.1x2, 128.9, 128.7x2, 128.1x2, 127.7, 127.3x2, 127.1x2, 126.7x2, 126.6x2, 126.3, 121.7, 119.0, 118.7, 111.1, 107.1, 61.0, 60.6, 59.6, 59.0, 56.1, 55.6, 55.2, 55.0, 48.2, 36.6, 30.3, 29.0, 27.0, 19.3, 19.1, 18.3, 17.8, 17.8; HRESIMS m / z 1005.4863 [M+H] + (calcd for C 57 H 65 N8O9 + ,1005.4869).

[0241] Example 20: (Compound 20) White amorphous powder, yield 20%; ESIMS m / z 1081.28 [M+H] + .

[0242] Example 21: (Compound 21) White amorphous powder, yield 35%; 1 H NMR (400 MHz, DMSO-d6): δ H11.34 (1H, s), 8.52 (1H, d, J = 7.5 Hz), 8.34 (1H, s), 8.29 (1H, d, J = 7.3 Hz), 8.15 (1H, d, J = 5.0 Hz), 8.10-8.00 (5H, overlapped), 8.00-7.93 (3H, overlapped), 7.87 (3H, d, J = 8.3 Hz), 7.59-7.47 (4H, overlapped), 7.37 (1H, d, J = 8.0 Hz), 7.27-7.17 (4H, overlapped), 7.17-7.08 (2H, overlapped), 6.99 (1H, t, J = 7.5 Hz), 4.86 (1H, t, J = 5.7 Hz), 4.53 (1H, m), 4.41 (1H, m), 4.35 (1H, m), 4.29-4.16 (2H, m), 3.80 (3H, m), 3.60 (1H, m), 3.25 (2H, d, J = 7.4 Hz), 3.17 (1H, dd, J = 13.8, 4.9 Hz), 2.73 (1H, dd, J = 13.8, 10.4 Hz), 2.11 (1H, m), 1.72 (1H, m), 1.09 (3H, d, J = 6.8 Hz), 0.70 (6H, dd, J = 11.1, 5.9 Hz), 0.61 (3H, d, J = 7.3 Hz), 0.47 (3H, d, J = 6.7 Hz); HRESIMS m / z 963.4738 [M+H] (calcd for C + (calcd for C 55 H 63 O8N8 + ,963.4763).

[0243] Example 22: (Compound 22) White amorphous powder, yield 36%; ESIMS m / z 931.07 [M+H] + .

[0244] Example 23: (Compound 23) White amorphous powder, yield 29%; 1 H NMR (400 MHz, DMSO-d6): δ H11.33 (1H, s), 8.53 (1H, d, J = 7.5 Hz), 8.28 (1H, d, J = 7.4 Hz), 8.15 (1H, d, J = 4.9 Hz), 8.09 (1H, d, J = 9.8 Hz), 8.06 (1H, d, J = 6.3 Hz), 7.90 (5H, t, J = 8.2 Hz), 7.82 (4H, dd, J = 11.3, 8.3 Hz), 7.75 (2H, d, J = 7.4 Hz), 7.56 (1H, d, J = 8.4 Hz), 7.51 (3H, t, J = 7.5 Hz), 7.41 (1H, d, J = 7.4 Hz), 7.36 (1H, d, J = 8.0 Hz), 7.29 - 7.18 (4H, overlapped), 7.16 (1H, d, J = 7.0 Hz), 7.11 (1H, m), 6.99 (1H, t, J = 7.5 Hz), 4.87 (1H, t, J = 5.8 Hz), 4.53 (1H, m), 4.44 - 4.30 (2H, overlapped), 4.26 - 4.17 (2H, overlapped), 3.89 - 3.71 (3H, overlapped), 3.60 (1H, dt, J = 11.1, 5.7 Hz), 3.24 (2H, d, J = 7.4 Hz), 3.17 (1H, dd, J = 13.8, 5.0 Hz), 2.74 (1H, dd, J = 13.8, 10.4 Hz), 2.11 (1H, m), 1.73 (1H, m), 1.09 (3H, d, J = 6.8 Hz), 0.71 (9H, dd, J = 12.1, 6.7 Hz), 0.62 (3H, d, J = 7.3 Hz), 0.47 (3H, d, J = 6.7 Hz); HRESIMS m / z 989.4918 [M + H] + (calcd for C 57 H 65 N8O8 + ,989.4920).

[0245] Example 24: (Compound 24) White amorphous powder, yield 37%; ESIMS m / z 979.14 [M + H] + .

[0246] Example 25: (Compound 25) White amorphous powder, yield 34%; ESIMS m / z 947.06 [M + H] + .

[0247] Example 26: (Compound 26) White amorphous powder, yield 29%; ESIMS m / z 1005.17 [M+H] + .

[0248] Example 27: (Compound 27) White amorphous powder, yield 39%; 1 H NMR (400 MHz, DMSO-d6): δ H 11.33 (1H, s), 8.49 (1H, d, J = 7.3 Hz), 8.33 (1H, s), 8.15 (1H, d, J = 4.5 Hz), 8.12 (1H, d, J = 9.7 Hz), 8.08 - 7.92 (8H, overlapped), 7.82 (3H, t, J = 9.2 Hz), 7.75 (1H, d, J = 6.0 Hz), 7.61 - 7.50 (3H, overlapped), 7.38 (1H, d, J = 8.1 Hz), 7.28 - 7.18 (4H, overlapped), 7.18 - 7.07 (2H, overlapped), 6.98 (1H, t, J = 7.5 Hz), 4.57 - 4.45 (2H, overlapped), 4.44 - 4.32 (2H, overlapped), 4.25 (1H, p, J = 6.9 Hz), 4.09 (1H, dd, J = 9.6, 6.4 Hz), 3.88 (1H, dt, J = 7.9, 4.1 Hz), 3.82 (0H, t, J = 6.7 Hz), 3.47 (1H, dd, J = 10.7, 4.4 Hz), 3.35 - 3.28 (1H, m), 3.22 (1H, dd, J = 14.2, 5.6 Hz), 3.09 (1H, dd, J = 13.8, 5.4 Hz), 2.84 (1H, dd, J = 10.8, 3.9 Hz), 2.75 (1H, dd, J = 13.8, 10.0 Hz), 2.07 (1H, m), 1.77 (1H, m), 1.25 (3H, d, J = 7.0 Hz), 1.12 (3H, d, J = 6.9 Hz), 0.72 - 0.64 (9H, overlapped), 0.50 (3H, d, J = 6.7 Hz); 13 C NMR (100 MHz, DMSO-d6): δ C172.8, 172.3, 171.7 x 2, 171.4, 171.0, 169.5, 139.1, 138.2, 137.3, 136.4, 135.5, 133.9, 132.8, 132.4, 129.6 x 2, 129.4, 129.1 x 2, 129.0, 128.7, 128.5 x 2, 128.0, 127.6 x 2, 127.0, 126.7, 126.7, 125.6, 125.4, 122.1, 119.4, 119.1, 111.5, 107.8, 61.0, 59.5, 58.9, 56.5, 55.8, 55.3, 49.0, 48.7, 37.0, 30.3, 29.6, 27.3, 19.7, 19.3, 18.7, 18.5, 18.0, 17.9; HRESIMS m / z 963.4747 [M+H] + (calcd for C 55 H 63 N8O8 + ,963.4763)

[0249] Example 28: (Compound 28) White amorphous powder, yield 36%; ESIMS m / z 931.06 [M+H] + .

[0250] Example 29: (Compound 29) White amorphous powder, yield 53%; 1 H NMR (400 MHz, DMSO-d6) δ H11.31 (1H, s), 8.49 (1H, d, J = 7.3 Hz), 8.15-8.08 (2H, overlapped), 8.05 (1H, d, J = 7.6 Hz), 7.97-7.84 (5H, overlapped), 7.84-7.77 (5H, overlapped), 7.77-7.72 (3H, overlapped), 7.58-7.45 (3H, overlapped), 7.41 (1H, m), 7.37 (1H, m), 7.32-7.18 (4H, overlapped), 7.18-7.13 (1H, m), 7.13-7.08 (1H, m), 6.97 (1H, t, J = 7.5 Hz), 4.53 (1H, dd, J = 10.8, 5.2 Hz), 4.48 (1H, m), 4.44-4.33 (2H, overlapped), 4.24 (1H, m), 4.08 (1H, dd, J = 9.6, 6.5 Hz), 3.87 (1H, m), 3.82 (1H, t, J = 6.7 Hz), 3.47 (1H, m), 3.31 (1H, m), 3.21 (1H, dd, J = 14.2, 5.7 Hz), 3.09 (1H, dd, J = 13.8, 5.4 Hz), 2.84 (1H, m), 2.75 (1H, dd, J = 13.8, 10.0 Hz), 2.06 (1H, m), 1.77 (1H, m), 1.24 (3H, d, J = 6.8 Hz), 1.12 (3H, d, J = 6.9 Hz), 0.68 (9H, dt, J = 6.7, 3.2 Hz), 0.51 (3H, d, J = 6.7 Hz); 13 C NMR (150 MHz, DMSO-d6): δ C 172.8, 172.4, 171.8, 171.7, 171.4, 171.0, 169.6, 140.1, 139.8, 139.0, 138.8, 138.2, 136.5, 135.6, 132.4, 129.7 x 2, 129.6 x 2, 129.1 x 2, 128.6 x 2, 128.1, 127.8 x 2, 127.7, 127.6 x 2, 127.2 x 2, 127.1 x 2, 126.8, 126.1, 122.2, 119.5, 111.5, 107.8, 61.1, 59.6, 59.0, 56.5, 55.8, 55.4, 49.0, 48.8, 37.1, 30.4, 29.6, 27.3, 19.7, 19.4, 18.7, 18.5, 18.0, 17.9; HRESIMS m / z 989.4907 [M+H] +(calcd for C 57 H 65 N8O8 + ,989.4920).

[0251] Example 30: (Compound 30) White amorphous powder, yield 23%; ESIMS m / z 979.13 [M+H] + .

[0252] Example 31: (Compound 31) White amorphous powder, yield 38%; ESIMS m / z 947.06 [M+H] + .

[0253] Example 32: (Compound 32) White amorphous powder, yield 36%; ESIMS m / z 1005.17 [M+H] + .

[0254] Example 33: (Compound 33) White amorphous powder, yield 44%; ESIMS m / z 947.14 [M+H] + .

[0255] Example 34: (Compound 34) White amorphous powder, yield 36%; ESIMS m / z 915.07 [M+H] + .

[0256] Example 35: (Compound 35) White amorphous powder, yield 39%; ESIMS m / z 973.16 [M+H] + .

[0257] Example 36: (Compound 36) White amorphous powder, yield 36%; ESIMS m / z 963.14 [M+H] + .

[0258] Example 37: (Compound 37) White amorphous powder, yield 32%; ESIMS m / z 931.07 [M+H] + .

[0259] Example 38: (Compound 38) White amorphous powder, yield 36%; ESIMS m / z 989.16 [M+H] + .

[0260] Example 39: (Compound 39) Amorphous powder, yield 35%; ESIMS m / z 1040.12 [M+H] + .

[0261] Example 40: (Compound 40) Amorphous powder, yield 32%; ESIMS m / z 1008.06 [M+H] + .

[0262] Example 41: (Compound 41) Amorphous powder, yield 39%; ESIMS m / z 1066.17 [M+H] + .

[0263] Example 42: (Compound 42) White amorphous powder, yield 33%; ESIMS m / z 979.13 [M+H] + .

[0264] Example 43: (Compound 43) White amorphous powder, yield 26%; ESIMS m / z 1005.17 [M+H] + .

[0265] Example 44: (Compound 44) White amorphous powder, yield 37%; ESIMS m / z 1007.19 [M+H] + .

[0266] Example 45: (Compound 45) White amorphous powder, yield 36%; ESIMS m / z 1021.22 [M+H] + .

[0267] Example 46: (Compound 46) White amorphous powder, yield 34%; ESIMS m / z 979.13 [M+H] + .

[0268] Example 47: (Compound 47) White amorphous powder, yield 44%; ESIMS m / z 947.06 [M+H] + .

[0269] Example 48: (Compound 48) White amorphous powder, yield 30%; ESIMS m / z 1005.17 [M+H] + .

[0270] Example 49: (Compound 49) White amorphous powder, yield 39%; ESIMS m / z 969.10 [M+H] + .

[0271] Example 50: (Compound 50) White amorphous powder, yield 29%; ESIMS m / z 937.04 [M+H] + .

[0272] Example 51: (Compound 51) White amorphous powder, yield 32%; ESIMS m / z 995.15 [M+H] + .

[0273] Example 52: (Compound 52) White amorphous powder, yield 59%; 1 H NMR (400 MHz, DMSO-d6): δH 11.34 (1H, s), 9.13 (1H, s), 8.46 (1H, d, J = 7.3 Hz), 8.34 (1H, d, J = 1.8 Hz), 8.24 (1H, d, J = 7.4 Hz), 8.10 - 7.90 (10H, overlapped), 7.85 (3H, d, J = 8.0 Hz), 7.70 (1H, d, J = 8.3 Hz), 7.61 - 7.50 (3H, m), 7.38 (1H, d, J = 8.0 Hz), 7.12 (1H, t, J = 7.4 Hz), 7.03 (2H, d, J = 8.2 Hz), 6.99 (1H, t, J = 7.4 Hz), 6.61 (2H, d, J = 8.2 Hz), 4.89 (1H, s), 4.61 (1H, q, J = 6.7 Hz), 4.46 - 4.32 (2H, m), 4.23 (1H, m), 4.14 (1H, dd, J = 9.7, 6.7 Hz), 3.88 (1H, m), 3.79 (1H, t, J = 6.8 Hz), 3.74 (1H, dd, J = 10.8, 5.9 Hz), 3.55 (1H, dd, J = 10.8, 5.6 Hz), 3.45 (1H, m), 3.25 (2H, m), 3.03 (1H, dd, J = 13.9, 5.0 Hz), 2.86 (1H, dd, J = 10.8, 4.0 Hz), 2.63 (1H, dd, J = 13.9, 10.2 Hz), 2.05 (1H, m), 1.77 (1H, m), 1.11 (3H, d, J = 6.8 Hz), 0.71 (9H, dt, J = 12.9, 6.8 Hz), 0.54 (3H, d, J = 6.7 Hz); 13 C NMR (100 MHz, DMSO-d6): δ C 172.4, 171.4, 171.2, 171.0, 170.9, 170.7, 169.0, 155.8, 138.7, 136.9, 136.0, 135.2, 133.4, 132.4, 131.8, 130.1 x 2, 128.9, 128.7 x 2, 128.6, 128.3, 127.9, 127.6, 127.1 x 2, 126.5, 126.2, 125.2, 124.9, 121.7, 119.0, 118.7, 114.9 x 2, 111.1, 107.1, 61.0, 60.6, 59.4, 58.8, 56.1, 55.6, 55.3, 55.2, 48.2, 35.8, 30.3, 29.1, 27.1, 19.3, 19.1, 18.4, 17.8, 17.7; HRESIMS m / z 995.1444 [M+H] +(calcd for C 55 H 63 N8O 10 + ,995.1470).

[0274] Example 53: (Compound 53) White amorphous powder, yield 32%; ESIMS m / z 963.07 [M+H] + .

[0275] Example 54: (Compound 54) White amorphous powder, yield 44%; 1 H NMR (400 MHz, DMSO-d6): δ H11.32 (1H, s), 9.13 (1H, s), 8.45 (1H, d, J = 7.3 Hz), 8.25 (1H, d, J = 7.4 Hz), 8.06 (2H, t, J = 8.3 Hz), 8.00 (1H, d, J = 6.5 Hz), 7.89 (5H, dd, J = 8.2, 5.6 Hz), 7.81 (4H, dd, J = 8.4, 2.0 Hz), 7.77 - 7.73 (2H, m), 7.70 (1H, d, J = 8.3 Hz), 7.58 (1H, d, J = 8.0 Hz), 7.51 (2H, t, J = 7.6 Hz), 7.39 (2H, dd, J = 16.9, 7.9 Hz), 7.11 (1H, t, J = 7.5 Hz), 7.03 (2H, d, J = 8.2 Hz), 6.98 (1H, t, J = 7.5 Hz), 6.60 (2H, d, J = 8.1 Hz), 4.90 (1H, t, J = 5.7 Hz), 4.60 (1H, q, J = 6.7 Hz), 4.49 (1H, t, J = 5.6 Hz), 4.44 - 4.33 (2H, overlapped), 4.21 (1H, q, J = 6.0 Hz), 4.13 (1H, dd, J = 9.7, 6.8 Hz), 3.87 (1H, m), 3.78 (1H, m), 3.73 (1H, d, J = 5.2 Hz), 3.53 (1H, m), 3.46 (1H, m), 3.22 (1H, m), 3.02 (1H, dd, J = 13.8, 4.9 Hz), 2.90 - 2.83 (1H, m), 2.67 - 2.57 (1H, m), 2.04 (1H, m), 1.75 (1H, m), 1.10 (3H, d, J = 6.8 Hz), 0.72 (5H, t, J = 6.6 Hz), 0.67 (2H, d, J = 6.7 Hz), 0.54 (3H, d, J = 6.7 Hz); HRESIMS m / z 1021.1452 [M + H] + (calcd for C 57 H 65 N8O 10 + ,1021.1850).

[0276] Example 55: (Compound 55) White amorphous powder, yield 33%; ESIMS m / z 979.13 [M + H] + .

[0277] Example 56: (Compound 56) White amorphous powder, yield 34%; ESIMS m / z 947.06 [M+H] + .

[0278] Example 57: (Compound 57) White amorphous powder, yield 29%; ESIMS m / z 1005.18 [M+H] + .

[0279] Example 58: (Compound 58) White amorphous powder, yield 53%; 1 H NMR (500 MHz, DMSO-d6): δ H 11.30 (1H, s), 8.33 (1H, d, J = 1.8 Hz), 8.27 (2H, dd, J = 6.2, 4.0 Hz), 8.09 (1H, d, J = 8.8 Hz), 8.03 (2H, t, J = 7.2 Hz), 8.00 - 7.93 (5H, overlapped), 7.85 - 7.80 (2H, overlapped), 7.62 - 7.49 (4H, overlapped), 7.38 (2H, d, J = 8.3 Hz), 7.25 - 7.20 (4H, overlapped), 7.16 (1H, m), 7.11 (1H, t, J = 7.5 Hz), 7.00 (1H, t, J = 7.0 Hz), 4.91 (1H, t, J = 5.4 Hz), 4.61 - 4.56 (2H, overlapped), 4.43 (1H, m), 4.30 (1H, m), 4.24 (1H, dd, J = 8.7, 6.5 Hz), 4.07 (1H, m), 3.97 (1H, dd, J = 8.6, 4.6 Hz), 3.54 (1H, m), 3.49 (1H, dd, J = 14.6, 6.7 Hz), 3.40 (1H, m), 3.27 (2H, m), 2.85 (2H, qd, J = 13.4, 7.7 Hz), 2.15 - 2.01 (2H, overlapped), 0.75 (6H, dd, J = 13.2, 6.8 Hz), 0.63 (3H, d, J = 6.9 Hz), 0.53 (3H, d, J = 6.9 Hz); HRESIMS m / z 989.4907 [M+H] + (calcd for C 52 H 58 N7O8 + ,989.4920).

[0280] Example 59: (Compound 59) White amorphous powder, yield 40%; ESIMS m / z 934.10 [M+H] + .

[0281] Example 60: (Compound 60) White amorphous powder, yield 31%; 1 H NMR (500 MHz, DMSO-d6): δ H 11.33 (1H, s), 8.75 (1H, d, J = 6.6 Hz), 8.35 (1H, d, J = 1.8 Hz), 8.10 (1H, d, J = 7.8 Hz), 8.04 (2H, d, J = 8.6 Hz), 8.01 - 7.95 (5H, overlapped), 7.93 (2H, d, J = 8.1 Hz), 7.75 (2H, d, J = 8.2 Hz), 7.62 (1H, d, J = 9.5 Hz), 7.59 - 7.52 (3H, overlapped), 7.37 (1H, d, J = 8.1 Hz), 7.31 - 7.20 (6H, overlapped), 7.16 (1H, m), 7.11 (1H, t, J = 7.6 Hz), 6.98 (1H, t, J = 7.5 Hz), 4.85 (1H, t, J = 5.9 Hz), 4.66 (1H, dt, J = 11.0, 5.8 Hz), 4.44 (1H, t, J = 5.6 Hz), 4.40 (1H, m), 4.30 (1H, dd, J = 9.5, 3.9 Hz), 4.19 (1H, m), 4.10 (1H, t, J = 8.4 Hz), 3.84 (1H, dt, J = 7.9, 3.9 Hz), 3.68 (2H, m), 3.63 (2H, m), 3.30 - 3.18 (3H, overlapped), 3.01 (1H, dd, J = 13.7, 5.5 Hz), 2.80 (1H, dd, J = 13.7, 9.8 Hz), 2.57 (1H, m), 2.19 (1H, m), 1.70 (1H, m), 0.71 (3H, d, J = 6.7 Hz), 0.64 (3H, d, J = 6.8 Hz), 0.54 (3H, d, J = 6.7 Hz), 0.49 (3H, d, J = 6.8 Hz); 13 CNMR (125 MHz, DMSO-d6): δ C172.4, 172.2, 171.5, 171.3, 170.7, 170.3, 168.6, 138.9, 138.2, 137.3, 136.4, 135.3, 133.9, 132.8, 132.3, 129.6 x 2, 129.0 x 4, 128.7 x 2, 128.5 x 2, 128.0, 127.5 x 2, 126.9, 126.8, 126.7, 125.6, 125.3, 122.1, 119.4, 119.1, 111.5, 107.7, 61.6, 61.1, 58.2, 57.1, 56.9, 56.6, 56.2, 55.1, 42.6, 36.8, 30.4, 30.2, 28.3, 20.0, 19.2, 19.0, 16.8; HRESIMS m / z 965.4528 [M+H] + (calcd for C 54 H 61 N8O9 + ,965.4556)

[0282] Example 61: (Compound 61) White amorphous powder, yield 36%; ESIMS m / z 991.11 [M+H] + .

[0283] Example 62: (Compound 62) White amorphous powder, yield 32%; ESIMS m / z 979.14 [M+H] + .

[0284] Example 63: (Compound 63) White amorphous powder, yield 37%; ESIMS m / z 979.13 [M+H] + .

[0285] Example 64: (Compound 64) White amorphous powder, yield 30%; ESIMS m / z 979.14 [M+H] + .

[0286] Example 65: (Compound 65) White amorphous powder, yield 29%; ESIMS m / z 1036.05 [M+H] + .

[0287] Example 66: (Compound 66) White amorphous powder, yield 33%; 1 H NMR (DMSO-d6, 400 MHz): δ H 11.22 (1H, s), 8.53 (1H, d, J = 7.6 Hz), 8.25 (1H, d, J = 7.5 Hz), 8.08 (1H, d, J = 9.8 Hz), 8.04 - 7.90 (3H, m), 7.69 (2H, d, J = 8.5 Hz), 7.65 (1H, d, J = 8.5 Hz), 7.55 (1H, d, J = 8.0 Hz), 7.44 (2H, t, J = 7.8 Hz), 7.33 (1H, d, J = 8.0 Hz), 7.27 - 7.18 (5H, overlapped), 7.10 (6H, overlapped), 6.96 (2H, t, J = 7.5 Hz), 4.89 (1H, t, J = 5.8 Hz), 4.56 (1H, m), 4.48 (2H, t, J = 5.5 Hz), 4.37 (1H, t, J = 7.4 Hz), 4.20 - 4.08 (2H, overlapped), 3.84 (1H, m), 3.73 (2H, d, J = 7.1 Hz), 3.48 (1H, dq, J = 15.6, 5.8 Hz), 3.24 - 3.07 (2H, overlapped), 2.85 (1H, m), 2.72 (1H, m), 2.00 (1H, m), 1.70 (1H, m), 1.08 (3H, d, J = 6.8 Hz), 0.68 (9H, dt, J = 10.5, 6.3 Hz), 0.45 (3H, d, J = 6.7 Hz); ESIMS m / z 945.09 [M+H] + .

[0288] Example 67: (Compound 68) White amorphous powder, yield 36%; ESIMS m / z 995.15 [M+H] + .

[0289] Example 68: Anti-mycobacterial test Purpose of the test: to test the growth inhibition effect of the compounds on Mycobacterium tuberculosis and Mycobacterium marinum.

[0290] 1) Test strain: Mycobacterium tuberculosis ATCC 25177 and Mycobacterium marinum.

[0291] 2) Detection method: In the detection plate, 198 μL of diluted 1000 times of Mycobacterium bacteria solution (OD 550 value is about 0.225-0.275), and then 2 μL of prepared compound working solution is added. The detection plate is placed in a 37°C incubator for 10-12 days. Then, 12.5 μL of 7H9+20% Tween 80 medium and 20 μL of Alamar blue solution are added, and the incubation is continued for 24 hours. DMSO is used as a solvent and a growth control. 200 μL of medium is placed in the four corners of the detection plate as a medium control. Rifampicin and isoniazid are used as positive controls, and three parallel tests are performed.

[0292] MIC 90 value: whether the bacteria grow is determined by observing the color change of Alamar blue with the naked eye or by fluorescence detection (Ex / Em, 530 nm / 590 nm), so as to determine the inhibition rate and MIC 90 value.

[0293] Results: Table 1 Inhibitory effect of compounds of the present application on Mycobacterium bacteria Note 1: In the table, in the anti-Mycobacterium tuberculosis activity, “****” indicates that the MIC 90 value is less than or equal to 1 μM, “***” indicates that the MIC 90 value is between 1-15 μM, “**” indicates that the MIC 90 value is between 15-25 μM, “*” indicates that the MIC 90 value is greater than 25 μM; in the anti-Mycobacterium marinum activity, “++++” indicates that the MIC 90 value is between 10-40 μM, “+++” indicates that the MIC 90 value is between 40-80 μM, “++” indicates that the MIC 90 value is between 80-100 μM, “+” indicates that the MIC 90 value is greater than 100 μM. Note 2: The partial cyclic peptide compounds in which L is hydrogen in the preparation process are tested in parallel for control, i.e.

[0294] The compound of the present application shows strong antibacterial activity on the two strains of Mycobacterium bacteria, which is better than the positive drugs (isoniazid and rifampicin) or comparable to the positive drugs to some extent, and the activity against Mycobacterium tuberculosis is significantly better than that of compounds A, B and C. Therefore, the compound of the present application has great potential application prospect in inhibiting the growth of Mycobacterium bacteria.

[0295] Example 69: Other antibacterial activity test Purpose: Test the antibacterial effect of the compound on other pathogenic bacteria, and study whether the compound of the present application is a selective inhibitor of the growth of Mycobacterium bacteria.

[0296] 1) Test strain: Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans, Vibrio vulnificus.

[0297] 2) Detection method: pick the bacteria on the solid culture medium to the culture medium, cultivate in the air-permeable culture bottle at 37°C to the logarithmic growth phase, the density is 1.0×10 7 / milliliter. Before testing activity, dilute it to 1:25 (4×10 5 / milliliter) in the culture medium. Use DMSO to prepare sample solution, and filter with 0.22 μm filter membrane for standby. When testing, add 198 μL culture medium to the first row of 96-well plate, and the volume of bacteria solution in the remaining holes is 100 μL. Add 2 μL of sample solution to be tested to each hole in the first row, and dilute 8 concentrations in equal gradient, then add 100 μL of bacteria solution to each hole. After 60 hours of culture at 32°C, observe from the back of the 96-well plate with the naked eye, and record the concentration of the last row of clear holes, which is the minimum inhibitory concentration MIC 90 . Ciprofloxacin and amphotericin B are used as positive controls, DMSO is used as blank control, and bacteria solution is used as negative control, and three parallel experiments are set.

[0298] MIC 90 Value determination: observe from the back of the 96-well plate with the naked eye, record the clear hole grid to determine whether the bacteria grow, and determine the inhibition effect and MIC 90 value.

[0299] Results: At a concentration of 50 μM, the compounds 1-70 in the present application have no obvious activity on the four strains tested.

[0300] The compound of the present application has strong inhibitory activity on mycobacterium, and is better than the positive drug isoniazid, rifampicin or comparable to the positive drug, and has certain selectivity, and is invalid on other fungi and bacteria. Therefore, the compound of the present application has good potential application prospect in selectively inhibiting the growth of mycobacterium.

[0301] Example 70: Combination drug sensitivity test Test purpose: test the combined effect of the compound and the positive control isoniazid on mycobacterium marinum, and study whether the compound of the present application has the potential of combined application with the positive control.

[0302] Detection method: according to the chessboard method, the MIC of the compound and rifampicin, isoniazid 90 Data is the basis for design, and the chessboard dilution method is used to carry out 7x7 combination of 2*MIC, MIC, 1 / 2*MIC, 1 / 4*MIC, 1 / 8*MIC, 1 / 16*MIC and 1 / 32*MIC of two drugs in the 96-well plate added with bacterial solution, and the 96-well plate is placed in a 32℃ constant temperature incubator, and the results are observed and recorded after 48 hours, and each hole is repeated three times.

[0303] The fractional inhibitory concentration index (FICI) is used to evaluate the combined effect, and the formula is as follows: if the minimum inhibitory concentration of A drug combination is MIC A , the minimum inhibitory concentration of B drug combination is MIC B , and the MIC of the two drugs used alone is A and B respectively. Then, the calculation formula is as follows: FICI = MIC A / A + MIC B / B. The determination of the combined effect is as follows: ① FICI ≤ 0.5, synergistic effect; ② 0.5 < FICI ≤ 1, additive effect; ③ 1 < FICI ≤ 2, irrelevant; ④ FICI > 2, antagonistic effect.

[0304] Results: Table 2 Combined effect of some compounds of the present application and rifampicin or isoniazid on mycobacterium marinum Note: "I" in the table indicates that the FICI value is less than or equal to 0.5, "II" indicates that the FICI value is between 0.5-1, "III" indicates that the FICI value is between 1-2, and "IV" indicates that the FICI value is greater than 2. Table 3 Combined effect of compound 18 of the present application and different positive drugs on mycobacterium marinum Note: "I" in the table means that the FICI value is less than or equal to 0.5, "II" means that the FICI value is between 0.5-1, "III" means that the FICI value is between 1-2, and "IV" means that the FICI value is greater than 2. Table 4 Synergistic effect of compound 19 of the application combined with different positive drugs on Mycobacterium marinum Note: "I" in the table means that the FICI value is less than or equal to 0.5, "II" means that the FICI value is between 0.5-1, "III" means that the FICI value is between 1-2, and "IV" means that the FICI value is greater than 2. Table 5 Synergistic effect of compound 60 of the application combined with different positive drugs on Mycobacterium marinum Note: "I" in the table means that the FICI value is less than or equal to 0.5, "II" means that the FICI value is between 0.5-1, "III" means that the FICI value is between 1-2, and "IV" means that the FICI value is greater than 2.

[0305] After the synergistic effect evaluation, the compound of the application combined with the clinically commonly used anti-tuberculosis drugs can produce more significant synergistic or additive effect. Therefore, the compound of the application has great potential application prospect in the combined use with the clinically commonly used drugs.

[0306] Example 71: Time-kill kinetics study

[0307] The 96-well plate with Middlebrook 7H10 medium was used to perform the kill kinetics determination in 7H9 broth with a volume of 200 μL. The dilutions of the compounds were prepared in DMSO, and 2 μL of the dilutions and 198 μL of the dilutions were added to the 96-well plates containing the Mycobacterium marinum culture solution, and the final concentration of the dilutions was in the range of 2*MIC to 1*MIC. The 96-well plates were incubated at 32°C, and the CFU / mL values (n=3) were counted at 0, 24, 48, and 72 hours by using the enzyme-labeled instrument.

[0308] Results: Table 6 Time-kill kinetics effect of some compounds of the application on Mycobacterium marinum Note: "&" in the table means that the Log 10 (CFU·mL -1 ) value is less than or equal to 4, "&&" means that the Log 10 (CFU·mL -1 ) value is between 4-6, and "&&&" means that the Log 10 (CFU·mL -1between 6-8, "&&&&" means Log 10 (CFU mL -1 between 8-10, "&&&&&" means Log 10 (CFU mL -1 greater than 10.

[0309] Upon time kill kinetics evaluation, the compounds of the present application have a rapid killing effect on M. marinum after early static exposure for up to 24 hours, and have a concentration dependent effect.

[0310] Example 72: Mature biofilm disruption study

[0311] Log phase M. marinum was diluted to 10 5 CFU / mL in 7H10 broth to make working suspensions, which were then dispensed into 12-well plates (2 mL per well). The final test concentrations were 4* MIC, 2* MIC, 1* MIC, 1 / 2* MIC, 1 / 4* MIC and 1 / 8* MIC. All tests were performed in triplicate with rifampicin and isoniazid as control agents, and DMSO was included as a negative control in the culture. All 12-well plates were incubated at 32°C for 48 h, after which the medium was aspirated and the wells were washed 3 times with PBS. The wells were stained with 0.1% crystal violet solution, agitated at 80 rpm for 15 min, and washed 3 times with PBS. Subsequently, 33% acetic acid was added to solubilize the adherent crystal violet, and the absorbance at 600 nm was measured using a microplate reader. The inhibition rate was calculated and the results were analyzed.

[0312] Results: Table 7: Effect of some compounds of the present application on mature biofilm disruption Note: In the table, "^" means the inhibition rate is less than or equal to 20%, "^^" means the inhibition rate is between 20%-40%, "^^^" means the inhibition rate is between 40%-60%, "^^^^" means the inhibition rate is between 60%-80%, and "^^^^^" means the inhibition rate is greater than or equal to 80%.

[0313] Upon biofilm disruption evaluation, the compounds of the present application have a significant biofilm disruption effect, and have a significant concentration dependent effect.

[0314] Example 73: In vivo efficacy study

[0315] M. marinum infection inoculum: M. marinum was cultured as described above. After 7-10 days, the bacteria were collected by centrifugation, washed twice in PBS, and the supernatant enriched with single-cell bacteria was transferred to a new tube. Finally, it was diluted in sterile PBS to a final concentration of 2 x 10 8 cfu / mL.

[0316] Ethical statement and animals: All animal experimental protocols and uses were approved by the Institutional Animal Ethics Committee of the Chinese government. Female BALB / c mice were purchased from Jinan Pengyue Experimental Animal Breeding Co., Ltd. Healthy BALB / c mice (female, 17-20 g) were adapted for 7 days and randomly divided into control group, model group, isoniazid group and compound 18 treatment group, 6 in each group. The animals were raised under standard conditions with a 12-hour day-night cycle. The feed and water were given at will.

[0317] Injection infection: 24 h before the experiment, 100 mg / kg of cyclophosphamide was injected intraperitoneally for immunosuppression. Before modeling, 50 mg / kg of pentobarbital was injected intraperitoneally to induce anesthesia, and then the back hair of the mice was removed with a razor, and 50 μL of the previously prepared bacterial solution was injected subcutaneously into the back of the mice. 1 h after infection, the drug was injected subcutaneously (100 μL), and the blank solvent treatment was used as a negative control. The animals were given 10 mg / kg of compound 18, and 10 mg / kg of isoniazid was used as a reference drug control. All drugs and test compounds were administered subcutaneously for 3 days, 3 times a day. After the administration period, the animals were euthanized, and the main organ tissues (blood, spleen, thymus, tail, skin) of each group were taken out aseptically, and the cytokine (TNF-α, IL-1β) levels were detected by ELISA. The main organ tissues of the mice were aseptically homogenized, and the bacterial CFU was quantitatively determined. The appropriate dilutions of each tissue after grinding were also plated on 7H9 agar without drugs to count the number of bacteria in the culture.

[0318] Statistical analysis: The detected cytokine (TNF-α, IL-1β) levels and the number of colonies obtained by plating were converted, and the Prism software, version 8.0.2 (GraphPad Prism version 8.0.2 for Windows, GraphPad Software, San Diego, California USA) was used to draw the pharmacodynamic effect. Single-factor analysis of variance was used to distinguish the statistical differences in inflammatory factors and tissue CFU between treated and untreated mice.

[0319] Results: Table 8 Effect of some compounds of the present application on reducing CFU in different tissues of animals Note: In the table represents Log 10 (CFU-mL -1 ) value less than or equal to 2, represents Log 10 (CFU-mL -1 ) value between 2-2.5, represents Log 10 (CFU-mL -1 ) value between 2.5-3, represents Log 10 (CFU-mL -1 ) value between 3-3.5, represents Log 10 (CFU-mL -1 ) value between 3.5-4, represents Log 10 (CFU-mL -1 ) value greater than or equal to 4. Table 9 Effect of some compounds of the present application on reducing inflammatory factors in different tissues of animals Note: In the table of TNF-a test, "§" represents pg / mL value less than or equal to 50, "§§" represents pg / mL value between 50-100, "§§§" represents pg / mL value between 100-150, "§§§§" represents pg / mL value between 150-200, "§§§§§" represents pg / mL value greater than or equal to 200; in the table of IL-1 β test, represents pg / mL value less than or equal to 50, represents pg / mL value between 50-100, represents pg / mL value between 100-200, represents pg / mL value greater than or equal to 200.

[0320] After in vivo efficacy study evaluation, the compounds of the present application significantly reduced the incidence of M. marinum infection after 3 days of treatment. The bacterial load of spleen, skin and lung was significantly reduced, and statistically significant differences were observed. The compounds of the present application significantly reduced the inflammation caused by M. marinum infection after 3 days of treatment. The inflammatory factors of spleen, skin were significantly reduced, part of the tissues were comparable to the blank group, and statistically significant differences were observed.

[0321] In summary, the compound of the present application has excellent selective inhibitory activity on mycobacterium growth, can destroy mature biofilm, and has excellent in vivo efficacy when used in combination with a positive drug, and has further research value and broad development prospects.

[0322] Finally, it is to be noted that other ways of implementing the present application are possible. Accordingly, the embodiments of the present application are to be considered as illustrative and not restrictive, and that other modifications or additions can be made thereto without departing from the scope of the present application. All publications or patents cited herein are incorporated by reference.

Claims

1. A novel antibacterial cyclic peptide compound, characterized in that, The term refers to a stereoisomer, geometric isomer, cis-trans isomer, tautomer, trans-isomer, nitrogen oxide, hydrate, solvate, N-oxygen compound, isotope label, metabolite, prodrug, or mixture thereof, or a pharmaceutically acceptable salt or prodrug thereof, of the compound shown in formula (I). in: n can be 0, 1, 2, or 3 independently; L is individually substituted with a substituent selected from substituted or unsubstituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, biaryl, teraryl, fused heteroaryl, fused biaryl, or fused teraryl groups, wherein the substituents on the substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, biaryl, teraryl, fused heteroaryl, fused biaryl, or fused teraryl groups may be independently and optionally substituted with one or more substituents selected from deuterium, F, Cl, Br, I, hydroxyl, amino, carboxyl, cyano, nitro, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, aryl, 5-6 membered heteroaryl, heteroaryloxy, heteroarylacyl, heteroarylamino, heteroarylalkoxy, heteroarylalkylamino, heterocycloalkylacyl, heterocycloalkyl, heterocyclooxyloxy, heterocycloamino, heterocycloacyl, heterocycloalkoxy, heterocycloalkylamino, heterocycloalkylacyl, azide-alkoxy, fused bicyclic, fused heterobicyclic, fused bicyclic aliphatic substituents; The amino acids at positions AA1-AA7 can be independently and optionally replaced by naturally occurring or non-natural amino acids of L or D configuration derived from glycine. replace; X is selected individually from O, S, or NR3; R2 is selected from either hydrogen or C. 1-3 alkyl; R3 alone represents hydrogen, deuterium, halogen, hydroxyl, amino, nitro, cyano, alkyl, haloalkyl, alkoxy, alkylamino, alkylacyl, hydroxyalkoxy, hydroxyalkylamino, hydroxyalkylacyl, haloalkoxy, haloalkylamino, haloalkylacyl, aminoalkoxy, cycloalkyl, cycloalkyloxy, cycloalkylamino, cycloalkylacyl, alkenyl, alkenylalkoxy, alkenylalkylamino, alkenylalkylacyl, alkynyl, alkynylalkoxy, alkynylalkylamino, alkynylalkylacyl, aryl, aryloxy, arylacyl, arylamino, arylalkoxy, arylalkylamino, heteroaryl, heteroaryloxy, heteroarylacyl, heteroarylamino, heteroarylalkoxy, heteroarylalkylamino, heterocyclic alkylacyl, heterocyclic alkyl, heterocyclic alkyloxy, heterocyclic amino, heterocyclic acyl, heterocyclic alkoxy, heterocyclic alkylamino, heterocyclic alkyl, heterocyclic alkyl, heterocyclic alkylamine, heterocyclic alkylalkanes, heterocyclic alkyl. Acyl, azidoalkoxy, fused bicyclic, fused heterobicyclic, fused bicyclic aliphatic, fused heterobicyclic aliphatic, fused bicyclic oxy, fused heterobicyclic oxy, fused bicyclic amino, fused heterobicyclic amino, fused bicyclic alkoxy, fused heterobicyclic alkoxy, fused bicyclic alkylamino, fused heterobicyclic alkylamino, fused heterobicyclic alkylamino, fused heterobicyclic alkylamino, fused bicyclic oxyalkoxy, fused heterobicyclic oxyalkoxy, fused bicyclic amino alkoxy, fused heterobicyclic amino alkoxy, fused bicyclic -C(=O)-, fused bicyclic -C(=O)O-, fused heterobicyclic -C(=O)-, fused heterobicyclic -C(=O)O-, fused bicyclic amino -C(=O)-, fused heterobicyclic amino -C(=O)N(R) 13 )-, Fused heterobicyclic group -C(=O)N(R 13 )-, spirobicycloyl, spirohexacycloyl, spirobicycloyl aliphatic, spirohexacycloyl aliphatic, spirobicycloyloxy, spirohexacycloyloxy, spirobicycloylamino, spirohexacycloylamino, spirobicycloylalkoxy, spirohexacycloylalkoxy, spirobicycloylalkylamino, spirohexacycloylalkylamino, spirobicycloyloxyalkoxy, spirohexacycloyloxyalkoxy, spirobicycloylaminoalkoxy, spirohexacycloylaminoalkoxy, spirohexacycloylaminoalkoxy, spirobicycloyl-C(=O)-, spirobicycloyl-C(=O)O-, spirohexacycloyl-C(=O)-, spirohexacycloyl-C(=O)-, spirohexacycloyl-C(=O)- Bicyclic group -C(=O)O-, spirobicyclic amino-C(=O)-, spirohexacyclic amino-C(=O)-, spirobicyclic -C(=O)N(R4)-, spirohexacyclic -C(=O)N(R4)-, R5R4N-, -C(=O)NR4R5, -OC(=O)NR4R5, -OC(=O)OR4, -N(R4)C(=O)NR4R5, -N(R4)C(=O)OR5, -N(R4)C(=O)-R5, R4R5N-S(=O) t -,R4S(=O) t -,R4S(=O) t N(R5)-, R5R4N-alkyl, R4S(=O) t -alkyl, R5R4N-C(=O)-alkyl, R5R4N-alkoxy, R4S(=O) t -alkoxy, R4R5N-C(=O)-alkoxy, aryl-(CH2) p -G-(CH2) m -, heteroaryl-(CH2) p -G-(CH2) m -, heterocyclic group-(CH2) p -G-(CH2) m - or cycloalkyl-(CH2) p -G-(CH2) m -, where G is O, S, NR6, S(=O), S(=O)2, C(=O), -C(=O)N(R4)-, -OC(=O)N(R4)-, -OC(=O)-, -N(R4)C(=O)N(R4)-, NaOS(=O)2O-, NaOS(=O)2O-, -(R4)NS(=O) t -, -OS (=O) t -, or -OS (=O) t N(R4)-; t is 1 or 2; p and m are each independently 0, 1, 2, 3 or 4; Among them, aryl-(CH2) p -G-(CH2) m -, heteroaryl-(CH2) p -G-(CH2) m -, heterocyclic group-(CH2) p -G-(CH2) m - or cycloalkyl-(CH2) p -G-(CH2) m - It can be substituted by one or more substituents selected from F, Cl, Br, I, alkyl, alkenyl, alkynyl, alkoxy, or cyano; - O(CH2) q R7, wherein R7 is independently selected from alkylamino, amino, alkyl-C(=O)NH-, heterocyclic, -(CH2CH2O). m H, pyranogluyl, NaOS(=O)2O-pyranogluyl, NaOS(=O)2O-, alkyl-S(=O)2NH, NaOS(=O)2-, (HO)2P(=O)O-, aryl, heterocyclic alkyl, aminoalkyl, -P(=O)R8R9, wherein the heterocyclic alkyl, aminoalkyl, and NaOS(=O)2O- are each independently and optionally substituted by one or more substituents selected from H-alkyl, amino, halogen, or alkoxy, and R8 and R9 are each independently selected from -OR 10 or -NHR 11 R 10 H, Na, and C are independent of each other. 1-6 Alkyl; R 11 For H or C 1-8 Alkyl, wherein the C 1-8 The alkyl group is optionally substituted with one or more alkoxycarbonyl groups; q is 0, 1, 2, 3 or 4; Each R6 can be the same or different, and each can be hydrogen independently, R5R4NC(=O)-, R5OC(=O)-, R5C(=O)-, R5R4NS(=O)-, R5OS(=O)-, R5S(=O)-, R5R4NS(=O)2-, R5OS(=O)2-, R5S(=O)2-, aliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic, heteroarylaliphatic, heterocyclicaliphatic, cycloalkylaliphatic, aryloxyaliphatic, heterocyclicoxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclicaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclic or carbocyclic; Each R5 and R4 is independently hydrogen, aliphatic, halogenated aliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic, heteroarylaliphatic, heterocyclic aliphatic, cycloalkylaliphatic, aryloxyaliphatic, heterocyclic oxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclic aminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclic, or cycloalkyl; when R5 and R4 are attached to the same nitrogen atom, R5, R4, and the nitrogen atom can arbitrarily form substituted or unsubstituted 3-8 membered rings, fused bicyclic or spirobicyclic; the heteroatoms in the heterocyclic, heteroaryl, fused heterobicyclic, and spiroheterocyclic groups mentioned above are independently selected from 1-5 heteroatoms from N, O, S, and Se; The R3, R4, R5, and R6 groups mentioned above may be substituted by one or more of the following: hydroxyl, hydroxymethyl, carboxyl, acetamino, alkyl (such as methyl, ethyl, propyl), alkoxy (such as methoxy, ethoxy, tert-butoxy), alkylamino, cycloalkyl, alkenyl, alkynyl, trifluoromethyl, trifluoroacetyl, mercapto, halogen, nitro, amino, azide (-N3), guanidinyl, cyano, tert-butoxycarbonyl (-Boc), carbonyl (-C=O), oxo (=O), thio (=S), sulfonyl, aryl, heteroaryl, and heterocyclic groups.

2. The compound according to claim 1, wherein the amino acid sequence contains at least one L or D configuration.

3. The compound according to claims 1-2, wherein the amino acid sequence has 1-3 amino acids added or removed, the added or removed amino acids may be concentrated or dispersed at any position in the amino acid sequence, and the antibacterial activity of the modified amino acid sequence is not significantly reduced, or maintains considerable antibacterial activity, or has significantly enhanced antibacterial activity.

4. The compound according to claims 1-3, characterized in that, Having one of the following structures or stereoisomers, geometric isomers, cis-trans isomers, tautomers, transisomers, nitrogen oxides, hydrates, solvates, N-oxygen compounds, isotope-labeled substances, metabolites, prodrugs, or mixtures thereof, or pharmaceutically acceptable salts or prodrugs thereof:

5. A pharmaceutical composition, characterized in that, It contains one or more of the compounds or pharmaceutically acceptable salts of any one of claims 1-4 as active ingredients.

6. The pharmaceutical composition according to claim 5, characterized in that, It further includes at least one pharmaceutically acceptable excipient.

7. A compound according to any one of claims 1-4 or a pharmaceutical composition according to any one of claims 5-6, in combination with one or more drugs for the prevention or treatment of mycobacterial infections. Characterized by, The combination drug comprises the compound of the present invention with one or more drugs for the prevention or treatment of mycobacterial infections, specifically rifampin, isoniazid, ethambutol, putomani, bedaquiline, triclosan, streptomycin, pyrazinamide, para-aminosalicylic acid, ethionamide, capreomycin, rifampin, delamani, and linezolid.

8. The compound according to any one of claims 1-4 or the pharmaceutical composition according to any one of claims 5-7, for use in the preparation of an antibacterial drug against mycobacterial infections.

9. The use according to claim 8, wherein the mycobacterium bacteria include Mycobacterium tuberculosis and Mycobacterium marinum.

10. The use according to claim 9, wherein the mycobacterial infection is pulmonary tuberculosis, bone tuberculosis, lymph node tuberculosis, lumbar tuberculosis, renal tuberculosis, intestinal tuberculosis, thoracic tuberculosis, breast tuberculosis, swimming pool granuloma, lung infection, lymph node infection, and Buruli ulcer.

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