RU2795229C9 - Mmpl3 inhibitors, compositions based on them and ways of their application - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention generally relates to inhibitors of the mycobacterial membrane protein MmpL3, compositions containing these inhibitors, and methods for their preparation and use. The invention relates to new inhibitors of the mycobacteria MmpL3 membrane protein of formula I.

EFFECT: obtaining new compounds being the inhibitors of the mycobacteria MmpL3 membrane protein that can be used in a method for treating mycobacterial infection.

12 cl, 2 tbl, 35 ex

Description

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

[010] The present invention generally relates to small molecule inhibitors of the mycobacterial membrane protein Large 3 (MmpL3) and their use as therapeutic agents, for example, in the treatment of diseases such as infections.

[020] PRIOR ART

[030] Mycobacteria belong to actinomycetes containing mycolic acids, and the main feature is that the cell wall contains a large amount of lipids, mainly mycolic acid. This is closely related to their staining ability, growth characteristics, pathogenicity and resistance. As a rule, they are painted with difficulty. They are also called acid-fast bacilli if they remain colored or are destroyed when bleached with a powerful bleaching agent, which is hydrochloric acid. This genus of microorganisms is devoid of flagella, has no spores, does not produce endotoxin and exotoxin, and its pathogenicity is associated with bacterial components. There are many types that can be divided into the Mycobacterium tuberculosis complex, nontuberculous mycobacteria, and Mycobacterium leprae .

[040] Mycobacterium tuberculosis ( Mtb ) is a pathogenic bacterium that causes tuberculosis (TB) and is a type of mycobacteria. It is transmitted primarily through the respiratory tract and can cause symptoms such as coughing, chest pain, hemoptysis, and difficulty breathing. Healthy people infected with tuberculosis do not necessarily become ill, except when the body's immunity deteriorates. Tuberculosis is the ninth leading cause of death in the world and is the leading cause of death from single pathogen infection, higher than HIV/AIDS. An estimated 1.3 million people died of TB among HIV-negative people in 2016 (down from 1.7 million in 2000). In terms of HIV-positive people, 374,000 people died from tuberculosis. There were an estimated 10.4 million new cases of TB in 2016, including 90% of adults, 65% of men, 10% of people living with HIV (74% in Africa), and India, Indonesia, China, The Philippines and Pakistan account for 56% of new TB cases.

[050] Mycobacterium tuberculosis ( Mtb ) was discovered in 1882 by the German microbiologist Robert Koch. Under the microscope , Mtb looks like a thin or straight bacillus. Mycobacterium tuberculosis is an obligate aerobic bacterium that grows very slowly. On solid media, the growth period of Mtb is 18-20 hours and the culture period is 8 days to 8 weeks. The colony is rough on most media types. Mtb has a waxy cell wall that is extremely resistant to dry conditions and strong acids and bases and is resistant to many chemical disinfectants. The Mycobacterium tuberculosis complex includes human type, bovine type, mouse type and African type, of which human, bovine and African types are pathogenic.

[060] Mycobacterium bovis is short and thickened, and Mycobacterium avium is pleomorphic. Branching is observed in cells on an old medium. Unlike most gram-positive bacteria, the cell wall of this bacterium is not only a peptidoglycan, but also a specific glycolipid. Due to the effect of glycolipids, the Gram stain is difficult, while the stain for acid-fast bacteria results in a red stain. Bacillus Calmette-Guerin (BCG) is isolated from attenuated Mycobacterium bovis , has the same characteristics as Mycobacterium bovis , is less pathogenic, and grows easily on a glycerin-containing medium.

[070] Mycobacterium smegmatis is an acid-fast strain of mycobacteria that is 3 to 5 µm in length and is rod-shaped and can be fluorescently stained using auramine-O-rhodamine. Because it is "fast growing" and non-pathogenic, it has been used by researchers as a simple model to study other types of mycobacteria. This bacterium has over 2000 genes homologous to Mtb and has the same unique cell wall structure as Mtb and other mycobacteria. Consequently, researchers often use it in the phenotypic screening of drugs for the treatment of tuberculosis.

[080] Mycobacterium marinum is a species of bacteria that exists in sea and fresh water, which are mycobacteria and belong to the same genus as Mycobacterium tuberculosis . It is a non-symbiotic bacterium that can cause the development of opportunistic infections after entering the human body. The bacilli are of medium length or long, often scattered, usually inoculated on solid egg dilution medium at 30° C. for 7 days or more, and the colonies appear smooth to rough. Colonies grown in the dark have no pigment; are light on exposure to light or on short exposure to light, and young colonies are bright yellow. Mycobacterium marinum is most active at 28-32°C and is more difficult to survive above 37°C. Consequently, when it penetrates into the human body, it spreads only in the fascia of the human body and does not penetrate into the internal organs, which have a higher temperature.

[090] Mycobacterium leprae , commonly known as the causative agent of leprosy, can cause leprosy, which is a chronic infectious disease. the morphological structure and method of staining of Mycobacterium leprae were similar to those of Mycobacterium tuberculosis : thin, slightly curved, often in the form of tufts. Both Gram stain and stain using the method for acid-fast bacteria were positive. After treatment, they may have a short rod shape, granule or rosette polymorphism, which may be characteristic of L-type variants. Incomplete cure can lead to relapse. Staining of Mycobacterium leprae using the acid fast method resulted in a red stain and a positive Gram stain. Reproductive capacity is maintained for 7 days in dry conditions. With prolonged exposure to low temperatures, they can survive for several months at -60°C to -13°C and survive for 3 weeks at 0°C.

[100] Encoded in the genome of Mycobacterium , MmpL3 is an integral membrane protein having 12 transmembrane helices, the function of which is to export mycolic acid in the form of trehalose monomycolate (TMM) required for the interstitial or outer membrane. The mycobacterial membrane protein Large 3 (MmpL3) is essential for the survival and pathogenicity of mycobacteria in vivo , thus the MmpL3 membrane protein is a key drug target for Mycobacterium tuberculosis and other mycobacteria. SQ109 has been reported to target the MmpL3 membrane protein from Mycobacterium tuberculosis , and the drug has entered phase II clinical trials. In addition, the compound rimonabant, known as a cannabinoid receptor (CB1) inhibitor, is a new type of diet pill. There are reports that rimonabant has a significant effect against Mycobacterium tuberculosis (H37Rv), and biological studies have demonstrated the targeting of rimonabant to MmpL3.

[110] DESCRIPTION

[120] Provided herein are compounds, or a pharmaceutically acceptable salt, an isotopically enriched analog, a stereoisomer, or a mixture of stereoisomers thereof, that are useful in the treatment and/or prevention of a bacterial infection, such as a mycobacterial infection.

[130] In certain embodiments, compounds are provided that inhibit MmpL3 activity.

[140] In certain embodiments, compounds of Formula I are provided:

I,

I

or a pharmaceutically acceptable salt, solvate, tautomer, isotopically enriched analog, stereoisomer or mixture of stereoisomers thereof,

Where

ring A is a 5-membered heteroaryl, where X ¹ is C or N, X ² , X ³ , X ⁴ and X ⁵ are independently selected from C, N, O and S, with the proviso that no more than one of X ² , X ³ , X ⁴ and X ⁵ is O or S and at least one of X ¹ , X ² , X ³ , X ⁴ and X ⁵ is C;

L ¹ is *-N(R ^1b )CO-, *-CON(R ^1b )-, *-OCO-, *-COO-, *-N(R ^1b )SO ₂ -, *-SO ₂ N( R ^1b )-, *-N(R ^1c )CON(R ^1b )-, *-CO-L ^1a -CO-, *-L ^1a -CO- or alkylene, where optionally one or more of the CH ₂ alkylene groups are substituted a group independently selected from the group consisting of CO, NR ^1b , NR ^1c , O, S, SO, SO ₂ and 5- or 7-membered heterocyclylene;

* denotes a connection point with R ¹ ;

L ^1a is a 5-, 6- or 7-membered heterocyclylene;

each R ^1b is independently H or C _1-3 alkyl;

each R ^1c is independently H or C _1-3 alkyl;

each of m and n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

R ¹ is C _7-15 cycloalkyl optionally substituted with R ^1a in an amount of from one to ten;

each R ^1a is independently selected from halogen, -CN, -NO ₂ , C _1-3 alkyl, C _1-3 haloalkyl, -OR ⁶ , -SR ⁶ , -N(R ⁶ ) ₂ , -C(O)R ⁶ , -C(O)OR ⁶ , -S(O)R ⁶ , -S(O) ₂ R ⁶ , -C(O)N(R ⁶ ) ₂ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)N(R ⁶ ) ₂ , -NHS(O)R ⁶ , -S(O)(NH)R ⁶ , cycloalkyl, aryl, heterocyclyl, heteroaryl or their combinations;

if X ² is C, then R ² is H, halogen, straight or branched alkyl optionally substituted with one to five R ^2a , alkenyl optionally substituted with one to five R ^2a , alkynyl optionally substituted with R ^2a from one to five, cycloalkyl optionally substituted by one to five with R ^2a , aryl optionally substituted by one to five by R ^2a , heterocyclyl optionally substituted by one to five by R ^2a , or heteroaryl, optionally substituted R ^2a in an amount of from one to five,

if X ² is N then R ² is absent or is H, straight or branched alkyl optionally substituted with one to five R ^2a , alkenyl optionally substituted with one to five R ^2a , alkynyl optionally substituted with R ^2a from one to five, cycloalkyl optionally substituted by one to five with R ^2a , aryl optionally substituted by one to five by R ^2a , heterocyclyl optionally substituted by one to five by R ^2a , or heteroaryl, optionally substituted R ^2a in an amount of from one to five,

if X ² is O or S, then R ² is absent;

if X ³ is C, then R ³ is H, halogen, straight or branched alkyl optionally substituted with one to five R ^3a , alkenyl optionally substituted with one to five R ^3a , alkynyl optionally substituted with R ^3a from one to five, cycloalkyl optionally substituted by one to five with R ^3a , aryl optionally substituted by one to five by R ^3a , heterocyclyl optionally substituted by one to five by R ^3a , or heteroaryl, optionally substituted R ^3a in an amount of from one to five,

if X ³ is N then R ³ is absent or is H, straight or branched alkyl optionally substituted with one to five R ^3a , alkenyl optionally substituted with one to five R ^3a , alkynyl optionally substituted with R ^3a from one to five, cycloalkyl optionally substituted by one to five with R ^3a , aryl optionally substituted by one to five by R ^3a , heterocyclyl optionally substituted by one to five by R ^3a , or heteroaryl, optionally substituted R ^3a in an amount of from one to five,

if X ³ is O or S, then R ³ is absent;

if X ⁴ is C, then R ⁴ is H, halogen, straight or branched alkyl optionally substituted with one to five R ^4a , alkenyl optionally substituted with one to five R ^4a , alkynyl optionally substituted with R ^4a from one to five, cycloalkyl optionally substituted by one to five with R ^4a , aryl optionally substituted by one to five by R ^4a , heterocyclyl optionally substituted by one to five by R ^4a , or heteroaryl, optionally substituted R ^4a in an amount of from one to five,

if X ⁴ is N then R ⁴ is absent or is H, straight or branched alkyl optionally substituted with one to five R ^4a , alkenyl optionally substituted with one to five R ^4a , alkynyl optionally substituted with R ^4a from one to five, cycloalkyl optionally substituted by one to five with R ^4a , aryl optionally substituted by one to five by R ^4a , heterocyclyl optionally substituted by one to five by R ^4a , or heteroaryl, optionally substituted R ^4a in an amount of from one to five,

if X ⁴ is O or S, then R ⁴ is absent;

if X ⁵ is C then R ⁵ is H, halogen, straight or branched alkyl optionally substituted with one to five R ^5a , alkenyl optionally substituted with one to five R ^4a , alkynyl optionally substituted with R ^4a from one to five, cycloalkyl optionally substituted by one to five with R ^5a , aryl optionally substituted by one to five by R ^5a , heterocyclyl optionally substituted by one to five by R ^5a , or heteroaryl, optionally substituted R ^5a in an amount of from one to five,

if X ⁵ is N, then R ⁵ is absent or is H, straight or branched alkyl optionally substituted with one to five R ^5a , alkenyl optionally substituted with one to five R ^5a , alkynyl optionally substituted with R ^5a from one to five, cycloalkyl optionally substituted by one to five with R ^5a , aryl optionally substituted by one to five by R ^5a , heterocyclyl optionally substituted by one to five by R ^5a , or heteroaryl, optionally substituted R ^5a in an amount of from one to five,

if X ⁵ is O or S, then R ⁵ is absent;

each R ^2a , R ^3a , R ^4a or R ^5a is independently selected from halogen, C _1-3 alkyl, C _1-3 haloalkyl, -CN, -NO ₂ , -OR ⁶ , -SR ⁶ , -N(R ⁶ ) ₂ , -C(O)R ⁶ , -C(O)OR ⁶ , -S(O)R ⁶ , -S(O) ₂ R ⁶ , -C(O)N(R ⁶ ) ₂ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)N(R ⁶ ) ₂ , -NHS(O)R ⁶ , -S(O)(NH)R ⁶ , cycloalkyl, aryl, heterocyclyl, heteroaryl, or combinations thereof; And

each R ⁶ is independently hydrogen, C _1-3 alkyl, C _1-3 haloalkyl, C _3-6 cycloalkyl, aryl, heteroaryl, or heterocyclyl.

[150] In certain embodiments, a pharmaceutical composition is provided comprising a compound described herein, or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer or mixture of stereoisomers, and a pharmaceutically acceptable carrier.

[160] In certain embodiments, a method is provided for treating or preventing a mycobacterial infection in a subject in need thereof, the method comprising administering to the subject an effective amount of a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, stereoisomer or mixture of stereoisomers.

[170] The present invention also provides compounds and compositions, including pharmaceutical compositions, kits that contain the compounds, and methods of using (or administering) and preparing the compounds. The present invention further provides compounds and compositions based thereon for use in a method of treating a disease, disorder, or condition mediated at least in part by MmpL3 activity. Moreover, the present invention provides for the use of compounds or compositions based on them in the manufacture of a medicinal product for the treatment of bacterial infection.

[180] DETAILED DESCRIPTION

[190] The following description sets forth exemplary embodiments of the present invention. It should be understood, however, that such a description is not intended to limit the scope of the present invention, but rather is provided as a description of exemplary embodiments.

[200] 1. Definitions

[210] As used herein, the following words, expressions, and symbols are generally intended to have the meanings set forth below, except where otherwise indicated in the context in which they are used.

[220] A dash ("-") that is not between two letters or symbols is used to indicate the attachment point of a substituent. For example, -C(O)NH ₂ is attached via a carbon atom. A dash at the beginning or end of a chemical group is used for convenience; chemical groups may be shown with or without one or more dashes without losing their normal meaning. A wavy line or a dashed line drawn through a line in the structure indicates the specified group attachment point. Except where required from a chemical or structural point of view, directionality or stereochemistry is not indicated or implied by the order in which the chemical group is written or named.

[230] The prefix "C _uv " indicates that the next group contains u to v carbon atoms. For example, "C _1-6 alkyl" indicates that the alkyl group contains from 1 to 6 carbon atoms.

[240] Reference to the term "approximately" in relation to a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter as such. In certain embodiments, the term "about" includes the specified amount of ±10%. In other embodiments, the implementation of the term "about" includes the specified number of ±5%. In certain other embodiments, the term "about" includes the specified amount of ±1%. In addition, the term "about X" includes a description of "X". In addition, the singular forms include the corresponding plural forms, unless the context clearly indicates otherwise. Thus, for example, a singular reference to a "compound" includes a plurality of such compounds, and a singular reference to a "method" includes a reference to one or more methods.

.[250] The term "ring A" means a ring containing X ¹ , X ² , X ³ , X ⁴ and X ⁵ defined in this document

.

[260] The term "alkyl" means a straight or branched saturated hydrocarbon chain. In some embodiments, the implementation of the alkyl contains the specified number of carbon atoms. In some embodiments, alkyl has 1 to 20 carbon atoms (i.e., C _1-20 alkyl), 1 to 12 carbon atoms (i.e., C _1-12 alkyl), 1 to 8 carbon atoms (t ie C _1-8 alkyl), 1 to 6 carbon atoms (ie C _1-6 alkyl) or 1 to 4 carbon atoms (ie C _1-4 alkyl). Examples of alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3 -methylpentyl. When an alkyl residue containing a given number of carbon atoms is indicated by a chemical name or defined by a molecular formula, then all positional isomers containing that number of carbon atoms may be covered; thus, for example, the term "butyl" includes n-butyl (i.e. -(CH ₂ ) ₃ CH ₃ ), sec-butyl (i.e. -CH(CH ₃ )CH ₂ CH ₃ ), isobutyl ( ie -CH ₂ CH(CH ₃ ) ₂ ) and tert-butyl (ie -C(CH ₃ ) ₃ ); and the term "propyl" includes n-propyl (ie -(CH ₂ ) ₂ CH ₃ ) and isopropyl (ie -CH(CH ₃ ) ₂ ).

[270] Certain commonly used alternative chemical names may be used. For example, a divalent group such as a divalent "alkyl" group, a divalent "aryl group", etc. may also be referred to as an "alkylene" group, an "arylene" group, respectively. In addition, unless expressly stated otherwise, in cases where combinations of groups are referred to herein as a single moiety, for example, arylalkyl or aralkyl, the last group contains the atom through which the moiety is attached to the rest of the molecule.

[280] The term "alkenyl" means an alkyl group containing at least one carbon-carbon double bond. In some embodiments, the implementation of alkenyl contains the specified number of carbon atoms. In some embodiments, the alkenyl contains 2 to 20 carbon atoms (i.e., C _2-20 alkenyl), 2 to 8 carbon atoms (i.e., C _2-8 alkenyl), 2 to 6 carbon atoms (t i.e. C _2-6 alkenyl) or 2 to 4 carbon atoms (i.e. C _2-4 alkenyl). Examples of alkenyl groups include, for example, ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[290] The term "alkynyl" means an alkyl group containing at least one carbon-carbon triple bond. In some embodiments, the implementation of alkynyl contains the specified number of carbon atoms. In some embodiments, alkynyl contains 2 to 20 carbon atoms (i.e., C _2-20 alkynyl), 2 to 8 carbon atoms (i.e., C _2-8 alkynyl), 2 to 6 carbon atoms (t i.e. C _2-6 alkynyl) or 2 to 4 carbon atoms (i.e. C _2-4 alkynyl). The term "alkynyl" also includes these groups containing one triple bond and one double bond.

[300] The term "alkoxy" means an "alkyl-O-" group. Examples of alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy, n-hexoxy and 1,2-dimethylbutoxy.

[310] The term "alkoxyalkyl" means an "alkyl-O-alkyl" group.

[320] The term "amino" means a group -NR ^y R ^z , where R ^y and R ^z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted as defined herein.

[330] The term "aryl" means an aromatic carbocyclic group containing one ring (eg, monocyclic) or multiple rings (eg, bicyclic or tricyclic), including fused systems. In some embodiments, the aryl contains 6 to 20 ring carbons (i.e., C _6-20 aryl), 6 to 12 ring carbons (i.e., C _6-12 aryl), or 6 to 10 carbon atoms in the ring (ie C _6-10 aryl). Examples of aryl groups include, for example, phenyl, naphthyl, fluorenyl and anthryl. Aryl, however, does not encompass or coincide in any way with heteroaryl, which is defined below. If one or more aryl groups are fused to a heteroaryl, then the resulting ring system is a heteroaryl. If one or more aryl groups are fused to a heterocyclyl, then the resulting ring system is a heterocyclyl.

[340] The term "arylalkyl" or "aralkyl" means an "aryl-alkyl-" group.

[350] The term "cycloalkyl" means a saturated or partially unsaturated cyclic alkyl group containing one ring or multiple rings, including fused, bridged and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., a cyclic group containing at least one double bond) and carbocyclic fused ring systems containing at least one sp ³ carbon atom (i.e., at least one non-aromatic ring ). In some embodiments, cycloalkyl has 3 to 20 ring carbons (i.e., C _3-20 cycloalkyl), 3 to 12 ring carbons (i.e., C _3-12 cycloalkyl), 3 to 10 ring carbons (i.e. C _3-10 cycloalkyl), 3 to 8 ring carbons (i.e. C _3-8 cycloalkyl), or 3 to 6 ring carbons (i.e. C _3-6 cycloalkyl). monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Polycyclic cycloalkyl means a cycloalkyl containing at least two rings, which may be a fused, bridged or spiro ring system. Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. The term "spirocycloalkyl" means a polycyclic cycloalkyl group where at least two rings are bonded together via one common atom, eg spiro[2.5]octanyl, spiro[4.5]decanyl or spiro[5.5]undecanyl. Spirocycloalkyl may contain fused rings in the ring system, but not bridged rings. The term "fused cycloalkyl" means a polycyclic cycloalkyl group, where at least two rings are linked together through two common atoms, where two common atoms are connected through a covalent bond. The fused cycloalkyl does not contain any spiro or bridged rings in the ring system. The term "bridged cycloalkyl" means a polycyclic cycloalkyl that contains a bridge - an alkylene (such as a C _1-4 alkylene) group that connects two atoms "at the head of the bridge". Non-limiting examples of bridged cycloalkyl include bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbornyl, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. bridged cycloalkyl may contain fused and/or spiro rings in the ring system. In addition, the term "cycloalkyl" is intended to encompass any non-aromatic ring that can be fused to an aryl ring, regardless of where it attaches to the rest of the molecule.

[360] The term "cycloalkylalkyl" means a "cycloalkyl-alkyl-" group.

[370] The term "imino" means the group -C(NR ^y )R ^z , where each of R ^y and R ^z independently represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein.

[380] The term "halogen" or "halo" means atoms occupying group VIIA of the periodic table of the elements, such as fluorine, chlorine, bromine or iodine.

[390] The term "haloalkyl" means a straight or branched alkyl group as defined above, wherein one or more (eg, 1 to 6, 1 to 5, or 1 to 3) hydrogen atoms are replaced by a halogen atom. For example, if a residue is substituted by more than one halogen atom, this may be indicated by a prefix corresponding to the number of attached halogen moieties. Dihaloalkyl and trihaloalkyl mean alkyl substituted with two ("di") or three ("tri") halogen groups, which may, but need not, be the same halogen. Examples of haloalkyl include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[400] The term "haloalkoxy" means an alkoxy group as defined above, wherein one or more (eg, 1 to 6, 1 to 5, or 1 to 3) hydrogen atoms has been replaced by a halogen atom.

[410] The term "hydroxyalkyl" means an alkyl group as defined above, wherein one or more (eg, 1 to 6, 1 to 5, or 1 to 3) hydrogen atoms has been replaced by a hydroxy group.

[420] The term "heteroalkyl" means an alkyl group in which each of one or more, but not all, carbon atoms (and any associated hydrogen atoms) is independently replaced by the same or different group containing a heteroatom, provided that the point of attachment to the remainder molecule is provided by a carbon atom. The term "heteroalkyl" includes a straight or branched saturated chain containing carbon and heteroatoms. By way of example, 1, 2, or 3 carbon atoms may be independently substituted with the same or different heteroatom containing groups. Groups containing a heteroatom include, without limitation -NR ^y -, -O-, -S-, -S(O)-, -S(O) ₂ - and the like, where R ^y represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein. Examples of heteroalkyl groups include, for example, ethers (for example, -CH ₂ OCH ₃ , -CH(CH ₃ )OCH ₃ , -CH ₂ CH ₂ OCH ₃ , -CH ₂ CH ₂ OCH ₂ CH ₂ OCH ₃ , etc. .), thioethers (for example, -CH ₂ SCH ₃ , -CH(CH ₃ )SCH ₃ , -CH ₂ CH ₂ SCH ₃ , -CH ₂ CH ₂ SCH ₂ CH ₂ SCH ₃ , etc.), sulfones (for example, -CH ₂ S(O) ₂ CH ₃ , -CH(CH ₃ )S(O) ₂ CH ₃ , -CH ₂ CH ₂ S(O) ₂ CH ₃ , -CH ₂ CH ₂ S(O) ₂ CH ₂ CH ₂ OCH ₃ , etc.) and amines (for example, -CH ₂ NR ^y CH ₃ , -CH (CH ₃ )NR ^y CH ₃ , -CH ₂ CH ₂ NR ^y CH ₃ , -CH ₂ CH ₂ NR ^y CH ₂ CH ₂ NR ^y CH ₃ etc., where R ^y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined in this document). In some embodiments, heteroalkyl contains 1 to 10 carbon atoms (C _1-10 heteroalkyl), 1 to 8 carbon atoms (C _1-8 heteroalkyl), or 1 to 4 carbon atoms (C _1-4 heteroalkyl); and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[430] The term "heteroalkylene" means a divalent alkyl group (i.e., alkylene) in which each of one or more (e.g., one to five or one to three) carbon atoms (and any associated hydrogen atoms) is independently substituted the same or different group containing a heteroatom. "Heteroalkylene" groups must contain at least one carbon atom and at least one group containing a heteroatom in the chain. The point of attachment of the heteroalkylene to the rest of the molecule can be provided by a carbon atom or a heteroatom. The term "heteroalkylene" includes a straight or branched saturated chain containing carbon and heteroatoms. By way of example, 1, 2, or 3 carbon atoms may be independently substituted with the same or different heteroatom containing groups. Groups containing a heteroatom include, without limitation -NR ^y -, -O-, -S-, -S(O)-, -S(O) ₂ - and the like, where R ^y represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein. Examples of heteroalkylene groups include, for example, -CH ₂ OCH ₂ -, -CH(CH ₃ )OCH ₂ -, -CH ₂ CH ₂ OCH ₂ -, -CH ₂ CH ₂ OCH ₂ CH ₂ OCH ₂ -, -CH ₂ SCH ₂ -, -CH (CH ₃ )SCH ₂ -, -CH ₂ CH ₂ SCH ₂ -, -CH ₂ CH ₂ SCH ₂ CH ₂ SCH ₂ -, -CH ₂ S (O) ₂ CH ₂ -, -CH ( CH ₃ )S(O) ₂ CH ₂ -, -CH ₂ CH ₂ S(O) ₂ CH ₂ -, -CH ₂ CH ₂ S(O) ₂ CH ₂ CH ₂ OCH ₂ -, -CH ₂ NR ^y CH ₂ -, -CH(CH ₃ )NR ^y CH ₂ -, -CH ₂ CH ₂ NR ^y CH ₂ -, -CH ₂ CH ₂ NR ^y CH ₂ CH ₂ NR ^y CH ₂ - etc., where R ^y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein). In some embodiments, heteroalkylene contains 1 to 10 carbon atoms (C _1-10 heteroalkylene), 1 to 8 carbon atoms (C _1-8 heteroalkylene), or 1 to 4 carbon atoms (C _1-4 heteroalkylene); and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[440] The term "heteroaryl" means an aromatic group containing one ring, multiple rings, or multiple fused rings, with one or more heteroatoms in the ring independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl contains from 1 to 20 ring carbon atoms (i.e. C_1-20heteroaryl), 3 to 12 ring carbons (i.e. C_3-12heteroaryl) or 3 to 8 ring carbons (i.e. C_3-8heteroaryl) as well as 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms or 1 ring heteroatom independently selected from nitrogen, oxygen and sulfur . In certain cases, heteroaryl contains 5-10 membered ring systems, 5-7 membered ring systems or 5-6 membered ring systems, each of which independently contains from 1 to 4 heteroatoms in the ring, from 1 to 3 heteroatoms in the ring, 1 to 2 ring heteroatoms or 1 ring heteroatom independently selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, for example, acridinyl, benzimidazolyl, benzothiazolyl, benzdolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, phenazinil, phthalazinil, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl and triazinyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl where heteroaryl can be linked via any of the rings of the condensed system. Any aromatic ring characterized by the presence of one or more fused rings containing at least one heteroatom is considered to be heteroaryl regardless of where it is attached to the rest of the molecule (ie via any of the fused rings). Heteroaryl does not encompass and is not the same as aryl as defined above.

[450] The term "heteroarylalkyl" means a "heteroaryl-alkyl-" group.

[460] The term "heterocyclyl" means a saturated or partially unsaturated cyclic alkyl group containing one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur. The term "heterocyclyl" includes heterocycloalkenyl groups (ie, a heterocyclyl group containing at least one double bond), bridged heterocyclyl groups, fused heterocyclyl groups, and spiro-heterocyclyl groups. The heterocyclyl may be a single ring or multiple rings, where the multiple rings may be fused, bridged, or spiro rings, and may also contain one or more (e.g., 1 to 3) oxo-(=O) or N-oxide ( -O-) fragments. Any non-aromatic ring containing at least one heteroatom is considered to be a heterocyclyl regardless of the site of attachment (ie, may be attached via a carbon atom or a heteroatom). In addition, the term "heterocyclyl" is intended to encompass any non-aromatic ring containing at least one heteroatom, where the ring can be fused to an aryl or heteroaryl ring, regardless of where it attaches to the rest of the molecule. As used herein, heterocyclyl has 2 to 20 ring carbons (i.e. C_2-20heterocyclyl), 2 to 12 ring carbons (i.e. C_2-12heterocyclyl), 2 to 10 ring carbons (i.e. C_2-10heterocyclyl), 2 to 8 ring carbons (i.e. C_2-8heterocyclyl), 3 to 12 ring carbons (i.e. C_3-12heterocyclyl), 3 to 8 ring carbons (i.e. C_3-8heterocyclyl) or 3 to 6 ring carbons (i.e. C_3-6heterocyclyl); it contains from 1 to 5 heteroatoms in the ring, from 1 to 4 heteroatoms in the ring, from 1 to 3 heteroatoms in the ring, from 1 to 2 heteroatoms in the ring or 1 heteroatom in the ring, independently selected from nitrogen, sulfur or oxygen. In certain instances, heterocyclyl includes a 3-10 membered heterocyclyl containing a total of 3-10 ring atoms, a 5-7 membered heterocyclyl containing a total of 5-7 ring atoms, or a 5- or 6-membered heterocyclyl containing total 5 or 6 ring atoms. Examples of heterocyclyl groups include, for example, azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxynyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3] dithianil, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazoli dinyl, oxiranil, oxetanil, phenothiazinil, phenoxazinil, piperidinil, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiophenyl (i.e. thienyl), tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl and 1,1-dioc co-thiomorpholinyl . The term "heterocyclyl" also includes "spiroheterocyclyl" wherein at least two rings are bonded together via one common atom. Examples of spiroheterocyclyl rings include, for example, bicyclic and tricyclic ring systems such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl . Examples of fused heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl may be linked via any of the rings of the condensed system. Heterocyclylene means a divalent heterocyclyl group.

[470] The term "heterocyclylalkyl" means a "heterocyclyl-alkyl-" group.

[480] The term "oxime" means a -CR ^y (=NOH) group, where R ^y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted as defined herein.

[490] The terms "optional" or "optional" mean that the event or circumstance described thereafter may or may not occur, and that the description includes cases where the specified event or circumstance occurs and cases where it does not occur. In addition, the term "optionally substituted" means the designated atom or group, where any one or more (for example, 1 to 5 or 1 to 3) hydrogen atoms on the designated atom or group may or may not be substituted by a moiety other than from hydrogen.

[500] In certain embodiments, the term "substituted" includes any of the above alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, wherein one or more (e.g., 1 to 5 or 1 to 3) atoms hydrogen are independently substituted by halogen, cyano, nitro, azido, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR ^g R ^h , -NR ^g C(=O)R ^h , -NR ^g C(=O)NR ^g R ^h , -NR ^g C(=O)OR ^h , -NR ^g S(=O) _1-2 R ^h , -C(=O)R ^g , -C(=O) OR ^g , -OC(=O)OR ^g , -OC(=O)R ^g , -C(=O)NR ^g R ^h , -OC(=O)NR ^g R ^h , -OR ^g , -SR ^g , -S(=O)R ^g , -S(=O) ₂ R ^g , -OS(=O) _1-2 R ^g , -S(=O) _1-2 OR ^g , -NR ^g S(= O) _1-2 NR ^g R ^h , =NSO ₂ R ^g , =NOR ^g , -S(=O) _1-2 NR ^g R ^h , -SF ₅ , -SCF ₃ or -OCF ₃ . In certain embodiments, the term "substituted" also means any of the above groups, where one or more (for example, from 1 to 5 or from 1 to 3) hydrogen atoms are replaced by -C(=O)R ^g , -C(=O) OR ^g , -C(=O)NR ^g R ^h , -CH ₂ SO ₂ R ^g or -CH ₂ SO ₂ NR ^g R ^h . As stated above, R ^g and R ^h are the same or different and are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and/or heteroarylalkyl. In certain embodiments, “substituted” means any of the above groups wherein one or more (e.g., 1 to 5 or 1 to 3) hydrogen atoms is replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, atom halogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl and/or heteroarylalkyl, or two of R ^g and R ^h and R ⁱ are taken together with the atoms to which they are attached to form a heterocyclyl ring optionally substituted with oxo, halogen or alkyl, optionally substituted with oxo, halogen, amino, hydroxyl or alkoxy.

[510] It is contemplated that polymers or similar structures of indeterminate length, obtained by describing substituents with additional substituents added ad infinitum (e.g., substituted aryl containing substituted alkyl, which is itself substituted by substituted aryl group, which is further substituted by substituted heteroalkyl group, etc.) are not included in this document. Unless otherwise indicated, the maximum number of serial substitutions in the compounds described in this document is three. For example, serial substitutions of substituted aryl groups with two other substituted aryl groups are limited to the structure ((substituted aryl) substituted aryl) substituted aryl. Likewise, the above definitions are not intended to include invalid substitution patterns (eg, methyl substituted with 5 fluorine atoms, or heteroaryl groups containing two adjacent ring oxygen atoms). Such invalid substitution patterns are well known to the person skilled in the art. When used to modify a chemical group, the term "substituted" may describe other chemical groups as defined herein.

[520] In certain embodiments, the expression "one or more" as used herein means a number from one to five. In certain embodiments, the expression "one or more" as used herein means a number from one to three.

[530] It is also contemplated that any compound or structure provided herein is the unlabeled form as well as the isotopically labeled form of the compounds. Such forms of the compounds may also be referred to as "isotope-enriched analogues". isotopically labeled compounds have the structures depicted herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that may be included in the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl, ¹²³ I, and ¹²⁵ I, respectively. A variety of isotopically labeled compounds of the present invention are provided, for example, compounds in which radioactive isotopes such as ³ H, ¹³ C and ¹⁴ C are incorporated. Such isotopically labeled compounds may be useful in metabolism studies, reaction kinetics studies, detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or in the treatment of subjects with radioactive agents.

[540] The term "isotopically enriched analogs" includes "deuterated analogs" of the compounds described herein, where one or more hydrogen atoms are replaced by a deuterium atom, for example, a hydrogen atom at a carbon atom. Such compounds may exhibit increased metabolic stability and thus are useful for increasing the half-life of any compound when administered to a mammal, in particular a human. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. sci. 5(12):524-527 (1984). Such compounds are synthesized by methods well known in the art, for example by using starting materials in which one or more hydrogen atoms are replaced by a deuterium atom.

[550] The deuterium-labeled or substituted therapeutic compounds of the present invention have improved distribution, metabolism, and excretion (ADME) DMPK (metabolism and drug pharmacokinetics) properties. Substitution with heavier isotopes, such as deuterium, may provide certain therapeutic benefits due to higher metabolic stability, such as increased in vivo half-life, reduced dose required, and/or improved therapeutic index. ^{The 18} F, ³ H, ¹¹ C labeled compound may be suitable for PET or SPECT or other imaging studies. the isotopically labeled compounds of the present invention can generally be prepared by following the procedures disclosed in the Schemes or in the examples and preparation methods described below by substituting a commonly available isotopically labeled reagent for a non-isotopically labeled reagent.

[560] The concentration of such a heavier isotope, in particular deuterium, can be expressed by an isotopic enrichment factor. In the compounds of the present invention, any atom not explicitly designated as a particular isotope is intended to be any stable isotope of that atom. Unless otherwise indicated, when an atom is represented by its name or letter designation such as H, C, O, or N, the atom is to be understood to be characterized by its natural isotopic composition. For example, if a position is specifically designated as "H" or "hydrogen", then the position is understood to contain hydrogen in its natural isotopic composition. Accordingly, in the compounds of the present invention, any atom specifically designated as deuterium (D) is intended to be deuterium.

[570] In many cases, the compounds of the present invention have the ability to form salts of acids and/or bases as a result of the presence of amino groups, and/or carboxyl groups, or similar groups.

[580] Also contemplated are a pharmaceutically acceptable salt, an isotopically enriched analog, a deuterated analog, a stereoisomer, and a mixture of stereoisomers of the compounds described herein. The term "pharmaceutically acceptable" or "physiologically acceptable" means compounds, salts, compositions, dosage forms, and other materials that are useful in the preparation of a pharmaceutical composition that is suitable for pharmaceutical use in veterinary or human medicine.

[590] The term "pharmaceutically acceptable salt" of a given compound means salts that retain the biological efficacy and properties of the given compound and that are not biologically or otherwise undesirable. The term "pharmaceutically acceptable salts" or "physiologically acceptable salts" includes, for example, inorganic acid salts and organic acid salts. In addition, if the compounds described herein are obtained as an acid addition salt, then the free base can be obtained by increasing the basicity of the acid salt solution. Conversely, if the product is a free base, then an addition salt, in particular a pharmaceutically acceptable addition salt, can be prepared by dissolving the free base in a suitable organic solvent and treating the solution with an acid in accordance with conventional procedures for preparing acid addition salts from basic compounds. One skilled in the art will recognize a variety of synthetic methodologies that can be used to prepare non-toxic, pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include, for example, acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium and magnesium salts. Salts derived from organic bases include, without limitation, salts of primary, secondary, and tertiary amines such as alkylamines (i.e. NH ₂ (alkyl)), dialkylamines (i.e. HN(alkyl) ₂ ), trialkylamines (i.e. e. N(alkyl) ₃ ), substituted alkylamines (i.e. NH ₂ (substituted alkyl)), di(substituted alkyl) amines (i.e. HN(substituted alkyl) ₂ ), tri(substituted alkyl) amines ( i.e. N(substituted alkyl) ₃ ), alkenylamines (i.e. NH ₂ (alkenyl)), dialkenylamines (i.e. HN(alkenyl) ₂ ), trialkenylamines (i.e. N(alkenyl) ₃ ) , substituted alkenylamines (i.e. NH ₂ (substituted alkenyl)), di(substituted alkenyl)amines (i.e. HN(substituted alkenyl) ₂ ), tri(substituted alkenyl)amines (i.e. N(substituted alkenyl ) ₃ , mono-, di- or tricycloalkylamines (i.e. NH ₂ (cycloalkyl), HN(cycloalkyl) ₂ , N(cycloalkyl) ₃ ), mono-, di- or triarylamines (i.e. NH ₂ (aryl ), HN(aryl) ₂ , N(aryl) ₃ ) or mixed amines, etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl )amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[600] Some of the compounds exist as tautomers. The tautomers are in equilibrium with each other. For example, amide-containing compounds may exist in equilibrium with imido acid tautomers. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium among the tautomers, one of ordinary skill in the art will appreciate that the compounds include tautomers. Thus, amide-containing compounds are intended to include their imidoacid tautomers. Similarly, imidoacid-containing compounds are intended to include their amide tautomers.

[610] The term "stereoisomer" means a compound formed from the same atoms linked through the same bonds, but having different spatial structures that are not interchangeable. The present invention contemplates a variety of stereoisomers and mixtures thereof, and these include the following.

[620] Stereoisomers include enantiomers, diastereomers, and other forms of stereoisomers that can be defined in terms of absolute stereochemistry as ( R )- or ( S )-, or as (D)- or (L)- in the case of amino acids. The present invention is intended to include all possible such isomers, as well as their racemic and optically pure forms. Optically active (+)- and (-)-, ( R )- and ( S )-, or (D)- and (L)-isomers can be obtained using chiral synthons or chiral reagents, or isolated using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). Stereoisomers also include geometric isomers when the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry. Unless otherwise indicated, such compounds are intended to include geometric isomers, both E- and Z-.

[630] "Enantiomers" are two stereoisomers whose molecules are non-superimposable mirror images of each other. "Diastereomers" are stereoisomers that contain at least two asymmetric atoms, but which are not mirror images of each other.

[640] The relative centers of the compounds depicted herein are indicated graphically using the "thick bond" style (bold or parallel lines), and the absolute stereochemistry is depicted using wedge bonds (bold or parallel lines).

[650] The term "solvate" means a complex formed by combining a compound described herein, or a salt or crystalline form thereof, and a solvent. As used herein, the term "solvate" includes a hydrate ( i.e. , a solvate if the solvent is water).

[660] 2. Connections

[670] Provided herein are compounds that inhibit MmpL3 activity, which may also be referred to as small molecule MmpL3 inhibitors, MmpL3 mycobacterial membrane protein inhibitors, or small molecule inhibitors of mycobacterial MmpL3 membrane protein, and these names are used interchangeably.

[680] In certain embodiments, a compound of Formula I is provided:

I,

I

or a pharmaceutically acceptable salt, solvate, tautomer, isotopically enriched analogue, stereoisomer or mixture of stereoisomers thereof,

Where

ring A is a 5-membered heteroaryl, where X ¹ is C or N, X ² , X ³ , X ⁴ and X ⁵ are independently selected from C, N, O and S, with the proviso that no more than one of X ² , X ³ , X ⁴ and X ⁵ is O or S and at least one of X ¹ , X ² , X ³ , X ⁴ and X ⁵ is C;

L ¹ is *-N(R ^1b )CO-, *-CON(R ^1b )-, *-OCO-, *-COO-, *-N(R ^1b )SO ₂ -, *-SO ₂ N( R ^1b )-, *-N(R ^1c )CON(R ^1b )-, *-CO-L ^1a -CO-, *-L ^1a -CO- or alkylene, where optionally one or more of the CH ₂ alkylene groups are substituted a group independently selected from the group consisting of CO, NR ^1b , NR ^1c , O, S, SO, SO ₂ and 5-, 6- or 7-membered heterocyclylene;

* denotes a connection point with R ¹ ;

L ^1a is a 5-, 6- or 7-membered heterocyclylene;

each R ^1b is independently H or C _1-3 alkyl;

each R ^1c is independently H or C _1-3 alkyl;

each of m and n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

R ¹ is C _7-15 cycloalkyl optionally substituted with R ^1a in an amount of one to ten;

each R ^1a is independently selected from halogen, -CN, -NO ₂ , C _1-3 alkyl, C _1-3 haloalkyl, -OR ⁶ , -SR ⁶ , -N(R ⁶ ) ₂ , -C(O)R ⁶ , -C(O)OR ⁶ , -S(O)R ⁶ , -S(O) ₂ R ⁶ , -C(O)N(R ⁶ ) ₂ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)N(R ⁶ ) ₂ , -NHS(O)R ⁶ , -S(O)(NH)R ⁶ , cycloalkyl, aryl, heterocyclyl, heteroaryl or their combinations;

if X ² is C, then R ² is H, halogen, straight or branched alkyl optionally substituted with one to five R ^2a , alkenyl optionally substituted with one to five R ^2a , alkynyl optionally substituted with R ^2a from one to five, cycloalkyl optionally substituted by one to five with R ^2a , aryl optionally substituted by one to five by R ^2a , heterocyclyl optionally substituted by one to five by R ^2a , or heteroaryl, optionally substituted R ^2a in an amount of from one to five,

if X ² is N, then R ² is absent or is H, straight or branched alkyl optionally substituted with one to five R ^2a , alkenyl optionally substituted with one to five R ^2a , alkynyl optionally substituted with R ^2a from one to five, cycloalkyl optionally substituted by one to five with R ^2a , aryl optionally substituted by one to five by R ^2a , heterocyclyl optionally substituted by one to five by R ^2a , or heteroaryl, optionally substituted R ^2a in an amount of from one to five,

if X ² is O or S, then R ² is absent;

if X ³ is C then R ³ is H, halogen, straight or branched alkyl optionally substituted with one to five R ^3a , alkenyl optionally substituted with one to five R ^3a , alkynyl optionally substituted with R ^3a from one to five, cycloalkyl optionally substituted by one to five with R ^3a , aryl optionally substituted by one to five by R ^3a , heterocyclyl optionally substituted by one to five by R ^3a , or heteroaryl, optionally substituted R ^3a in an amount of from one to five,

if X ³ is N then R ³ is absent or is H, straight or branched alkyl optionally substituted with one to five R ^3a , alkenyl optionally substituted with one to five R ^3a , alkynyl optionally substituted with R ^3a from one to five, cycloalkyl optionally substituted by one to five with R ^3a , aryl optionally substituted by one to five by R ^3a , heterocyclyl optionally substituted by one to five by R ^3a , or heteroaryl, optionally substituted R ^3a in an amount of from one to five,

if X ³ is O or S, then R ³ is absent;

if X ⁴ is C, then R ⁴ is H, halogen, straight or branched alkyl optionally substituted with one to five R ^4a , alkenyl optionally substituted with one to five R ^4a , alkynyl optionally substituted with R ^4a from one to five, cycloalkyl optionally substituted by one to five with R ^4a , aryl optionally substituted by one to five by R ^4a , heterocyclyl optionally substituted by one to five by R ^4a , or heteroaryl, optionally substituted R ^4a in an amount of from one to five,

if X ⁴ is N then R ⁴ is absent or is H, straight or branched alkyl optionally substituted with one to five R ^4a , alkenyl optionally substituted with one to five R ^4a , alkynyl optionally substituted with R ^4a from one to five, cycloalkyl optionally substituted by one to five with R ^4a , aryl optionally substituted by one to five by R ^4a , heterocyclyl optionally substituted by one to five by R ^4a , or heteroaryl, optionally substituted R ^4a in an amount of from one to five,

if X ⁴ is O or S, then R ⁴ is absent;

if X ⁵ is C, then R ⁵ is H, halogen, straight or branched alkyl optionally substituted with one to five R ^5a , alkenyl optionally substituted with one to five R ^5a , alkynyl optionally substituted with R ^5a from one to five, cycloalkyl optionally substituted by one to five with R ^5a , aryl optionally substituted by one to five by R ^5a , heterocyclyl optionally substituted by one to five by R ^5a , or heteroaryl, optionally substituted R ^5a in an amount of from one to five,

if X ⁵ is N then R ⁵ is absent or is H, straight or branched alkyl optionally substituted with one to five R ^5a , alkenyl optionally substituted with one to five R ^5a , alkynyl optionally substituted with R ^5a from one to five, cycloalkyl optionally substituted by one to five with R ^5a , aryl optionally substituted by one to five by R ^5a , heterocyclyl optionally substituted by one to five by R ^5a , or heteroaryl, optionally substituted R ^5a in an amount of from one to five,

if X ⁵ is O or S, then R ⁵ is absent;

each R ^2a , R ^3a , R ^4a or R ^5a is independently selected from halogen, C _1-3 alkyl, C _1-3 haloalkyl, -CN, -NO ₂ , -OR ⁶ , -SR ⁶ , -N(R ⁶ ) ₂ , -C(O)R ⁶ , -C(O)OR ⁶ , -S(O)R ⁶ , -S(O) ₂ R ⁶ , -C(O)N(R ⁶ ) ₂ , -NR ⁶ C(O)R ⁶ , -NR ⁶ C(O)OR ⁶ , -NR ⁶ C(O)N(R ⁶ ) ₂ , -NHS(O)R ⁶ , -S(O)(NH)R ⁶ , cycloalkyl, aryl, heterocyclyl, heteroaryl, or combinations thereof; And

each R ⁶ is independently hydrogen, C _1-3 alkyl, C _1-3 haloalkyl, C _3-6 cycloalkyl, aryl, heteroaryl, or heterocyclyl.

[690] In certain embodiments, Ring A is pyrrole, imidazole, triazole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, or thiadiazole.

[700] In certain embodiments, a compound of formula

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or

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or a pharmaceutically acceptable salt, solvate, tautomer, isotopically enriched analogue, stereoisomer or mixture of stereoisomers thereof.

[710] In certain embodiments, at least one of R ² , R ³ , R ⁴ or R ⁵ is cycloalkyl optionally substituted with one to five R ^5a , aryl optionally substituted with one to five R ^5a , heterocyclyl optionally substituted with one to five R ^5a , or heteroaryl optionally substituted with one to five R ^5a . In certain embodiments, at least one of R ² , R ³ , R ⁴ or R ⁵ is aryl optionally substituted with one to five R ^5a . In certain embodiments, at least one of R ² , R ³ , R ⁴ or R ⁵ is phenyl optionally substituted with one to five R ^5a . In certain embodiments, at least one of R ² , R ³ , R ^{4 ,} or R ⁵ is heteroaryl optionally substituted with one to five R ^5a . In certain embodiments, at least one of R ² , R ³ , R ⁴ or R ⁵ is a 5-membered heteroaryl optionally substituted with one to five R ^5a . In certain embodiments, at least one of R ² , R ³ , R ⁴ or R ⁵ is a 6-membered heteroaryl optionally substituted with one to five R ^5a . In certain embodiments, at least one of R ² , R ³ , R ⁴ , or R ⁵ is pyridyl optionally substituted with one to five R ^5a . In certain embodiments, at least one of R ² , R ³ , R ^{4 ,} or R ⁵ is substituted aryl or substituted heteroaryl.

[720] In certain embodiments, at least one of R ³ or R ⁴ is optionally substituted aryl or optionally substituted heteroaryl. In certain embodiments, at least one of R ² and R ⁵ is independently absent, is H, halogen, straight or branched C _1-3 alkyl optionally substituted with one to five R ^2a , or C _3-6 cycloalkyl, optionally substituted R ^2a in an amount of from one to five.

[730] In certain embodiments, R ³ is phenyl optionally substituted with one to two R ^3a . In certain embodiments, R ³ is pyridyl optionally substituted with one to two R ^4a . In certain embodiments, R ^3a is independently halogen, CN, methyl, methoxy, or trifluoromethyl. In certain embodiments, R ^3a is chlorine. In certain embodiments, R ³ is 4-chlorophenyl or 2,4-dichlorophenyl.

[740] In certain embodiments, R ⁴ is phenyl optionally substituted with one to two R ^4a . In certain embodiments, R ⁴ is pyridyl optionally substituted with one to two R ^4a . In certain embodiments, R ^4a is independently halogen, CN, methyl, methoxy, or trifluoromethyl. In certain embodiments, R ^4a is chlorine. In certain embodiments, R ⁴ is 4-chlorophenyl or 2,4-dichlorophenyl.

[750] In certain embodiments, L ¹ is *-(CH ₂ ) _m -N(R ^1b )CO-, *-(CH ₂ ) _m -CON(R ^1b )-, *-(CH ₂ ) _n - OCO-, *-(CH ₂ ) _n -COO-, *-(CH ₂ ) _m -N(R ^1b )SO ₂ -, *-(CH ₂ ) _m -SO ₂ N(R ^1b )- or *- (CH ₂ ) _n -N(R ^1c )CON(R ^1b )-.

[760] In certain embodiments, L ¹ is alkylene, where optionally one or more of the CH ₂ groups of the alkylene is substituted with a group independently selected from CO, NR ^1b , NR ^1c , O, S, SO, SO ₂ and 5-, 6 - or 7-membered heterocyclylene. In some embodiments, two adjacent CH ₂ alkylene groups are together substituted with -N(R ^1b )CO-, -CON(R ^1b )-, -N(R ^1b )SO ₂ - or SO ₂ N(R ^1b )-. In some embodiments, the three adjacent CH ₂ alkylene groups are together substituted with -N(R ^1c )CON(R ^1b )-. In some embodiments, the three adjacent CH ₂ alkylene groups are together substituted with -N(R ^1b )-N(R ^1b )-(CO)-. In additional embodiments, the first CH ₂ alkylene group is substituted with a group independently selected from CO, NR ^1b , NR ^1c , O, S, SO, SO ₂ and 5-, 6-, or 7-membered heterocyclylene, and two or three of the following adjacent groups The CH ₂ alkylene is substituted with a group independently selected from -N(R ^1b )CO-, -CON(R ^1b )-, -N(R ^1b )SO ₂ -, SO ₂ N(R ^1b )- or -N(R ^1b )-N(R ^1b )-(CO)-.

или

. [770] In some embodiments, one CH ₂ alkylene group is substituted with a piperazinyl ring. In some embodiments, two adjacent CH ₂ alkylene groups are substituted together

or

.

. [780] In some embodiments, three adjacent CH ₂ alkylene groups are together substituted

.

[790] In certain embodiments, L ¹ is *-N(R ^1b )CO-, *-(CH ₂ ) _k -N(R ^1b )CO-, *-(CH ₂ ) _n -N(R ^1c ) -(CH ₂ ) _k -N(R ^1b )CO-, *-(CH ₂ ) _n -(O(CH ₂ ) _m ) _p -O(CH ₂ ) _k -N(R ^1b )CO-, *- (CH ₂ ) _m -CO-L ^1a -CO-, *-(CH ₂ ) _m -L ^1a -CO-, *-(CH ₂ ) _n -NHCONH-(CH ₂ ) _m -, *-(CH ₂ ) _n -N(R ^1c )-(CH ₂ ) _k -N(R ^1b )-(CH ₂ ) _m -, *-(CH ₂ ) _n -CON(R ^1b )-(CH ₂ ) _m -, * -(CH ₂ ) _p -N(R ^1c )-(CH ₂ ) _n -CON(R ^1b )-(CH ₂ ) _m -, *-(CH ₂ ) _p -N(R ^1c )-(CH ₂ ) _n -SO ₂ N(R ^1b )-(CH ₂ ) _m -, *-(CH ₂ ) _n -SO ₂ N(R ^1b )-(CH ₂ ) _m - or *-(CH ₂ ) _n -OCO- ; Where

* denotes a connection point with R ¹ ;

L ^1a is a 5-, 6- or 7-membered heterocyclylene;

R ^1b is H or C _1-3 alkyl;

R ^1c is H or C _1-3 alkyl;

k is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; And

each of m, n, and p is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[800] In certain embodiments, L ¹ is *-N(R ^1b )CO-, *-(CH ₂ ) _k -N(R ^1b )CO-, *-(CH ₂ ) _n -N(R ^1c ) -(CH ₂ ) _k -N(R ^1b )CO-, *-(CH ₂ ) _n -(O(CH ₂ ) _m ) _p -O(CH ₂ ) _k -N(R ^1b )CO-, *- (CH ₂ ) _m -CO-L ^1a -CO-, *-(CH ₂ ) _m -L ^1a -CO-, *-(CH ₂ ) _n -NHCONH-(CH ₂ ) _m -, *-(CH ₂ ) _n -N(R ^1c )-(CH ₂ ) _k -N(R ^1b )-(CH ₂ ) _m -, *-(CH ₂ ) _n -CON(R ^1b )-(CH ₂ ) _m -, * -(CH ₂ ) _p -N(R ^1c )-(CH ₂ ) _n -CON(R ^1b )-(CH ₂ ) _m -, *-(CH ₂ ) _p -N(R ^1c )-(CH ₂ ) _n -SO ₂ N(R ^1b )-(CH ₂ ) _m -, *-(CH ₂ ) _n -SO ₂ N(R ^1b )-(CH ₂ ) _m -, *-(CH ₂ ) _n -OCO- , *-(CH ₂ ) _n -L ^1a -(CH ₂ ) _m -, *-N(R ^1c )-(CH ₂ ) _n -N(R ^1b )-(CH ₂ ) _m - or *-N( R ^1c )-(CO)-(CH ₂ ) _n -N(R ^1b )-N(R ^1b )-(CO)-; Where

* denotes a connection point with R ¹ ;

L ^1a is a 5-, 6- or 7-membered heterocyclylene;

R ^1b is H or C _1-3 alkyl;

R ^1c is H or C _1-3 alkyl;

k is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; And

each of m, n, and p is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[810] In certain embodiments, L ¹ is alkylene, where optionally one or more of the CH ₂ groups of the alkylene is substituted with a group independently selected from CO, NR ^1b , NR ^1c , O, S, SO, SO ₂ and 5- or 6 -membered heterocyclylene such as *-(CH ₂ ) _k -N(R ^1b )CO-, *-(CH ₂ ) _n -N(R ^1c )-(CH ₂ ) _k -N(R ^1b )CO-, *-(CH ₂ ) _n -(O(CH ₂ ) _m ) _p -O(CH ₂ ) _k -N(R ^1b )CO-, *-(CH ₂ ) _m -CO-L ^1a -CO-, * -(CH ₂ ) _m -L ^1a -CO-, *-(CH ₂ ) _n -NHCONH-(CH ₂ ) _m -, *-(CH ₂ ) _n -N(R ^1c )-(CH ₂ ) _k - N(R ^1b )-(CH ₂ ) _m -, *-(CH ₂ ) _n -CON(R ^1b )-(CH ₂ ) _m -, *-(CH ₂ ) _p -N(R ^1c )-(CH ₂ ) _n -CON(R ^1b )-(CH ₂ ) _m -, *-(CH ₂ ) _p -N(R ^1c )-(CH ₂ ) _n -SO ₂ N(R ^1b )-(CH ₂ ) _m - or *-(CH ₂ ) _n -SO ₂ N(R ^1b )-(CH ₂ ) _m -. In certain embodiments, L ¹ is C _1-20 alkylene, where optionally one to ten CH ₂ C _1-20 alkylene groups are substituted with a group independently selected from CO, NR ^1b , NR ^1c , O, S, SO, SO ₂ and 5- or 6-membered heterocyclylene.

[820] In certain embodiments, L ¹ is *-N(R ^1b )CO-.

[830] In certain embodiments, L ¹ is *-(CH ₂ ) _k -N(R ^1b )CO-.

[840] In certain embodiments, L ¹ is *-(CH ₂ ) _n -N(R ^1c )-(CH ₂ ) _k -N(R ^1b )CO-.

[850] In certain embodiments, L ¹ is *-(CH ₂ ) _n -(O(CH ₂ ) _m ) _p -O(CH ₂ ) _k -N(R ^1b )CO-.

[860] In certain embodiments, L ¹ is *-(CH ₂ ) _n -CO-L ^1a -CO-. In certain embodiments, L ^1a is piperazine.

[870] In certain embodiments, L ¹ is *-(CH ₂ ) _m -L ^1a -CO-. In certain embodiments, L ^1a is piperazine.

[880] In certain embodiments, L ¹ is *-(CH ₂ ) _n -NHCONH-(CH ₂ ) _m -.

[890] In certain embodiments, L ¹ is *-(CH ₂ ) _n -N(R ^1c )-(CH ₂ ) _k -N(R ^1b )-(CH ₂ ) _m -.

[900] In certain embodiments, L ¹ is *-(CH ₂ ) _n -CON(R ^1b )-(CH ₂ ) _m -.

[910] In certain embodiments, L ¹ is *-N(R ^1c )-(CH ₂ ) _n -CON(R ^1b )-(CH ₂ ) _m -.

[920] In certain embodiments, L ¹ is *-(CH ₂ ) _n -N(R ^1c )-(CH ₂ ) _n -SO ₂ N(R ^1b )-(CH ₂ ) _m -.

[930] In certain embodiments, L ¹ is *-(CH ₂ ) _n -SO ₂ N(R ^1b )-(CH ₂ ) _m -.

[940] In certain embodiments, L ¹ is *-(CH ₂ ) _n -N(R ^1c )-(CH ₂ ) _n -N(R ^1b )SO ₂ -(CH ₂ ) _m -.

[950] In certain embodiments, L ¹ is *-(CH ₂ ) _n -N(R ^1b )SO ₂ -(CH ₂ ) _m -.

[960] In certain embodiments, L ¹ is *-(CH ₂ ) _n -OCO-.

[970] In certain embodiments, L ¹ is *-(CH ₂ ) _n -L ^1a -(CH ₂ ) _m -.

[980] In certain embodiments, L ¹ is *-N(R ^1c )-(CH ₂ ) _n -N(R ^1b )-(CH ₂ ) _m -.

[990] In certain embodiments, L1 is *-N(R ^1c )-(CO)-(CH ₂ ) _n -N(R ^1b )-N(R ^1b )-(CO)-.

[1000] In certain embodiments, L ¹ is selected from *-NHCONH-, *-NHCONHCH ₂ -, *-CH ₂ NHCONHCH ₂ -, *-(CH ₂ ) ₂ NHCONHCH ₂ -, *-(CH ₂ ) ₃ NHCONHCH ₂ -, *-(CH ₂ ) ₄ NHCONHCH ₂ -, *-(CH ₂ ) ₅ NHCONHCH ₂ -, *-(CH ₂ ) ₆ NHCONHCH ₂ -, *-NHCH ₂ NHCO-, *-NH(CH ₂ ) ₂ NHCO-, *-NH(CH ₂ ) ₃ NHCO-, *-NH(CH ₂ ) ₄ NHCO-, *-NH(CH ₂ ) ₅ NHCO-, *-NH(CH ₂ ) ₆ NHCO-, *-NH (CH ₂ ) ₇ NHCO-, *-CH ₂ NHCH ₂ NHCO-, *-CH ₂ NH(CH ₂ ) ₂ NHCO-, *-CH ₂ NH(CH ₂ ) ₃ NHCO-, *-CH ₂ NH(CH ₂ ) ₄ NHCO-, *-CH ₂ NH (CH ₂ ) ₅ NHCO-, *-CH ₂ NH (CH ₂ ) ₆ NHCO-, *-CH ₂ NH (CH ₂ ) ₇ NHCO-, *-CH ₂ NHCO -, *-(CH ₂ ) ₂ NHCO-, *-(CH ₂ ) ₃ NHCO-, *-(CH ₂ ) ₄ NHCO-, *-(CH ₂ ) ₅ NHCO-, *-(CH ₂ ) ₆ NHCO -, *-(CH ₂ ) ₇ NHCO-, *-(CH ₂ ) ₈ NHCO-, *-NHCO-, *-O(CH ₂ ) ₂ NHCO-, *-CH ₂ NHCO-, *-CH ₂ O (CH ₂ ) ₂ NHCO-, *-(CH ₂ ) ₂ O(CH ₂ ) ₂ NHCO-, *-(CH ₂ ) ₃ O(CH ₂ ) ₂ NHCO-, *-O(CH ₂ ) ₂ O( CH ₂ ) ₂ NHCO-, *-CH ₂ O(CH ₂ ) ₂ O(CH ₂ ) ₂ NHCO-, *-(CH ₂ ) ₂ O(CH ₂ ) ₂ O(CH ₂ ) ₂ NHCO-, *- (CH ₂ ) ₃ O(CH ₂ ) ₂ O(CH ₂ ) ₂ NHCO-, *-O(CH ₂ ) ₃ NHCO-, *-NH(CH ₂ ) ₂ NHCH ₂ -, *-NH(CH ₂ ) ₄ NHCH ₂ -, *-NH(CH ₂ ) ₂ SO ₂ NHCH ₂ -, *-OC(O)-, *-CH ₂ O(CH ₂ ) ₃ NHCO-, *-CH ₂ NH(CH ₂ ) ₂ NHCH ₂ -, * -CH ₂ NH (CH ₂ ) ₄ NHCH ₂ -, * -CH ₂ NH (CH ₂ ) ₂ SO ₂ NHCH ₂ -, * -CH ₂ OC (O) -,

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And

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[1010] In certain embodiments, R ¹ is a polycyclic C _7-15 cycloalkyl optionally substituted with one to ten R ^1a . In certain embodiments, R ¹ is a bridged C _7-15 cycloalkyl optionally substituted with one to ten R ^1a . In certain embodiments, R ¹ is an unsubstituted bridged C _7-15 cycloalkyl.

[1020] In certain embodiments, R ¹ is optionally substituted with R ^1a in an amount of one to ten, R ^1a in an amount of 1 to 9, R ^1a in an amount of 1 to 8, R ^1a in an amount of 1 to 7, R ^1a in 1 to 6 R ^1a 1 to 5 R ^1a 1 to 4 R 1a 1 to 3 or R ^{1a 1} to 2 or 1, 2, 3, 4 , 5, 6, 7, 8, 9 or 10 R ^1a .

[1030] In certain embodiments, R ¹ is adamantyl optionally substituted with R ^1a in an amount of one to ten, R ^1a in an amount of 1 to 9, R ^1a in an amount of 1 to 8, R ^1a in an amount of 1 to 7 , R ^1a in an amount of 1 to 6, R ^1a in an amount of 1 to 5, R ^1a in an amount of 1 to 4, R ^1a in an amount of 1 to 3 or R ^1a in an amount of 1 to 2, or 1, 2 , 3, 4, 5, 6, 7, 8, 9 or 10 R ^1a .

[1040] In certain embodiments, R ¹ is 1-adamantyl, 2-adamantyl, 3-adamantyl, 4-adamantyl, 5-adamantyl, 6-adamantyl, 7-adamantyl, 8-adamantyl, 9-adamantyl, or 10-adamantyl , each of which is optionally substituted with 1 to 10 R ^1a , 1 to 9 R ^1a , 1 to 8 R ^1a , 1 to 7 R ^1a , 1 to 6 R ^1a , R ^1a in an amount of 1 to 5, R ^1a in an amount of 1 to 4, R ^1a in an amount of 1 to 3 or R ^1a in an amount of 1 to 2, or 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 R ^1a .

[1050] In certain embodiments, R ¹ is bicyclo[2.2.1]heptyl optionally substituted with one to ten R ^1a , 1 to 9 R ^1a , ¹ to 8 R 1a, R ^1a in an amount of 1 to 7, R ^1a in an amount of 1 to 6, R ^1a in an amount of 1 to 5, R ^1a in an amount of 1 to 4, R ^1a in an amount of 1 to 3 or R ^1a in an amount of 1 to 2, or 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 R ^1a . In certain embodiments, R ¹ is 1-bicyclo[2.2.1]heptyl, 2-bicyclo[2.2.1]heptyl, 3-bicyclo[2.2.1]heptyl, 4-bicyclo[2.2.1]heptyl, 5- bicyclo[2.2.1]heptyl, 6-bicyclo[2.2.1]heptyl, or 7-bicyclo[2.2.1]heptyl, each of which is optionally substituted with one to ten R ^1a , 1 to 9 R ^1a , R ^1a in the amount of 1 to 8, R ^1a in the amount of 1 to 7, R ^1a in the amount of 1 to 6, R ^1a in the amount of 1 to 5, R ^1a in the amount of 1 to 4, R ^1a in the amount of 1 to 3 or R ^1a in an amount of 1 to 2, or 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 R ^1a . In certain embodiments, R ¹ is 1,7,7-trimethylbicyclo[2.2.1]heptane. In certain embodiments, R ¹ is methyl.

[1060] In certain instances, R ¹ is a bridged C _7-15 cycloalkyl, where the bridged C _7-15 cycloalkyl is a substituted adamantyl or a substituted bicyclo[2.2.1]heptyl. In certain instances, R ¹ is a bridged C _7-15 cycloalkyl, where the bridged C _7-15 cycloalkyl is unsubstituted adamantyl or unsubstituted bicyclo[2.2.1]heptyl.

[1070] In certain embodiments, R ¹ is selected from

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or

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[1080] In certain embodiments, R ¹ is selected from

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[1090] In certain embodiments, a compound of formula selected from:

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или

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or

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or a pharmaceutically acceptable salt, tautomer, isotopically enriched analogue, stereoisomer or mixture of stereoisomers thereof,

Where

R ¹ is a bridged C _7-15 cycloalkyl optionally substituted with one to ten R ^1a ;

each R ^1a is independently selected from halo, C _1-3 alkyl, C _1-3 alkoxy, and C _1-3 haloalkyl;

L ¹ is *-N(R ^1b )CO-, *-(CH ₂ ) _k -N(R ^1b )CO-, *-(CH ₂ ) _n -N(R ^1c )-(CH ₂ ) _k - N(R ^1b )CO-, *-(CH ₂ ) _n -(O(CH ₂ ) _m ) _p -O(CH ₂ ) _k -N(R ^1b )CO-, *-(CH ₂ ) _m -CO -L ^1a -CO-, *-(CH ₂ ) _m -L ^1a -CO-, *-(CH ₂ ) _n -NHCONH-(CH ₂ ) _m -, *-(CH ₂ ) _n -N(R ^1c )-(CH ₂ ) _k -N(R ^1b )-(CH ₂ ) _m -, *-(CH ₂ ) _n -CON(R ^1b )-(CH ₂ ) _m -, *-(CH ₂ ) _p - N(R ^1c )-(CH ₂ ) _n -CON(R ^1b )-(CH ₂ ) _m -, *-(CH ₂ ) _p -N(R ^1c )-(CH ₂ ) _n -SO ₂ N(R ^1b )-(CH ₂ ) _m -, *-(CH ₂ ) _n -SO ₂ N(R ^1b )-(CH ₂ ) _m -, *-(CH ₂ ) _p -N(R ^1c )-(CH ₂ ) _n -N(R ^1b )SO ₂ -(CH ₂ ) _m -, *-(CH ₂ ) _n -N(R ^1b )SO ₂ -(CH ₂ ) _m -, or *-(CH ₂ ) _n - OCO-, *-(CH ₂ ) _n -L ^1a -(CH ₂ ) _m -, *-N(R ^1c )-(CH ₂ ) _n -N(R ^1b )-(CH ₂ ) _m - or *- N(R ^1c )-(CO)-(CH ₂ ) _n -N(R ^1b )-N(R ^1b )-(CO)-;

* denotes a connection point with R ¹ ;

L ^1a is a 5- or 6-membered heterocyclylene;

R ^1b is H or C _1-3 alkyl;

R ^1c is H or C _1-3 alkyl;

k is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

each of m, n and p is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

R ² is absent or is H, halogen, straight or branched alkyl optionally substituted with one to five R ^2a , or cycloalkyl optionally substituted with one to five R ^2a ;

R ³ is straight or branched alkyl optionally substituted with one to five R ^3a , cycloalkyl optionally substituted with one to five R ^3a , aryl optionally substituted with one to five R ^3a , heterocyclyl optionally substituted R ^3a in an amount of one to five, or heteroaryl optionally substituted with R ^3a in an amount of one to five;

R ⁴ is straight or branched alkyl optionally substituted with one to five R ^4a , cycloalkyl optionally substituted with one to five R ^4a , aryl optionally substituted with one to five R ^4a , heterocyclyl optionally substituted R ^4a in an amount of one to five, or heteroaryl optionally substituted with R ^4a in an amount of one to five;

with the proviso that at least one of R ³ or R ⁴ is optionally substituted aryl or optionally substituted heteroaryl; And

each R ^2a , R ^3a or R ^4a is independently selected from halo, -CN, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, C _3-6 cycloalkyl, phenyl, 3-6 membered heterocyclyl and 5-6 membered heteroaryl.

[1100] In certain embodiments, if R ² is present, it is H, C _1-3 alkyl, or C _3-6 cycloalkyl.

[1110] In certain embodiments, if R ⁵ is present, it is H, C _1-3 alkyl, or C _3-6 cycloalkyl.

[1120] In certain embodiments, R ³ is phenyl optionally substituted with one to two R ^3a . In certain embodiments, R ³ is pyridyl optionally substituted with one to two R ^4a . In certain embodiments, R ^3a is independently halogen, CN, methyl, methoxy, or trifluoromethyl. In certain embodiments, R ^3a is chlorine. In certain embodiments, R ³ is 4-chlorophenyl or 2,4-dichlorophenyl.

[1130] In certain embodiments, R ⁴ is phenyl optionally substituted with one to two R ^4a . In certain embodiments, R ⁴ is pyridyl optionally substituted with one to two R ^4a . In certain embodiments, R ^4a is independently halogen, CN, methyl, methoxy, or trifluoromethyl. In certain embodiments, R ^4a is chlorine. In certain embodiments, R ⁴ is 4-chlorophenyl or 2,4-dichlorophenyl.

[1140] In certain embodiments, each R ^2a , R ^3a or R ^4a is independently selected from halo, -CN, C _1-3 alkyl, C _1-3 alkoxy, and C _1-3 haloalkyl.

[1150] In certain embodiments, a compound of Formula II is provided:

II,

II,

or a pharmaceutically acceptable salt, tautomer, isotopically enriched analogue, stereoisomer or mixture of stereoisomers thereof,

Where

X ¹ , X ² , X ³ , X ⁴ , X ⁵ , R ¹ , R ² , R ³ , R ⁵ , R ^4a and L ¹ are defined herein,

Z is CR ^4a or N;

q is 0, 1, 2 or 3; And

L ⁴ is a bond or CH ₂ .

[1160] In certain embodiments, a compound of formula III is provided:

III,

III,

or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer or mixture of stereoisomers thereof,

Where

X ¹ , X ² , X ³ , X ⁴ , X ⁵ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^4a and L ¹ are defined herein,

each R ^3b and R ^3c is independently H or R ^3a ; And

each R ^4b and R ^4c is independently H or R ^4a .

[1170] In certain embodiments, at least one of R ^3b , R ^3c , R ^4b and R ^4c is selected from F, Cl, CN, methyl, methoxy, or trifluoromethyl. In certain embodiments, at least two of R ^3b , R ^3c , R ^4b and R ^4c are selected from F, Cl, CN, methyl, methoxy, or trifluoromethyl. In certain embodiments, at least three of R ^3b , R ^3c , R ^4b and R ^4c are selected from F, Cl, CN, methyl, methoxy, or trifluoromethyl. In certain embodiments, R ^3c is H, and R ^3b , R ^4b and R ^4c are selected from F, Cl, CN, methyl, methoxy, or trifluoromethyl. In certain embodiments, R ^3c is H and R ^3b , R ^4b and R ^4c are Cl.

[1180] In certain embodiments, a compound represented by Formula I-C is provided:

I-C,

ic,

or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer or mixture of stereoisomers thereof, wherein L ³ is *-(CH ₂ ) _n -, *-(CH ₂ ) _n -N(R ^1c )-(CH ₂ ) _k - or *-(CH ₂ ) _n -(O(CH ₂ ) _m ) _p -O(CH ₂ ) _k -, and each of m, n, k, p, X ¹ , X ² , X ³ , X ⁴ , X ⁵ , R ¹ , R ^1b , R ^1c , R ² , R ³ , R ⁴ and R ⁵ are defined herein.

[1190] In certain embodiments, a compound represented by Formula II-C is provided:

II-C,

II-C,

or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, or a mixture of stereoisomers, wherein each of m, n, X ¹ , X ² , X ³ , X 4 , X ⁵ , R ¹ , R ² , R ^{3 ,} R ⁴ and R ⁵ is defined in this document.

[1200] In certain embodiments, a compound represented by formula III-C is provided:

III-C,

III-C,

or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, or a mixture of stereoisomers, wherein each of k, n, X ¹ , X ² , X ³ , X 4 , X ⁵ , R ^1b , R ^1c , ^{R 1 ,} R ² , R ³ , R ⁴ and R ⁵ are defined herein.

[1210] In certain embodiments, a compound represented by Formula IV-C is provided:

IV-C,

IV-C,

or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, or mixture of stereoisomers thereof, wherein s and t are independently 0, 1, or 2, and each of X ¹ , X 2 , X ³ , X ⁴ , X ^{5 ,} R ¹ , R ² , R ³ , R ⁴ and R ⁵ is defined in this document. In certain embodiments, each of s and t is 1.

[1220] In certain embodiments, a compound represented by formula V-C is provided:

V-C,

VC,

or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer or mixture of stereoisomers thereof, wherein ^{L 4} is CO or SO ₂ and each of m, n, X ¹ , X ² , X 3 , X ⁴ , X ⁵ , R ^1b , R ¹ , R ² , R ³ , R ⁴ and R ⁵ are defined herein.

[1230] In certain embodiments, a compound represented by formula VI-C is provided:

VI-C,

VI-C,

or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer or mixture of stereoisomers thereof, wherein L ⁴ is CO or SO ₂ and each of m, X ¹ , X ^{2 ,} X 3 , X ⁴ , X ⁵ , R ^1b , R ¹ , R ² , R ³ , R ⁴ and R ⁵ is defined in this document.

[1240] In certain embodiments, a compound represented by Formula VII-C is provided:

VII-C,

VII-C,

or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, or a mixture of stereoisomers, wherein each of m, n, s, t, X ¹ , X ² , X 3 , X ⁴ , X ⁵ , R ¹ , R ^{2 ,} R ³ , R ⁴ and R ⁵ are defined herein.

[1250] In certain embodiments, a compound represented by Formula VIII-C is provided:

VIII-C,

VIII-C,

or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, or a mixture of stereoisomers, wherein each of m, n, X ¹ , X ² , X ³ , X 4 , X ⁵ , R ^1b , R ^1c , ^{R 1 ,} R ² , R ³ , R ⁴ and R ⁵ are defined herein.

[1260] In certain embodiments, a compound represented by Formula IX-C is provided:

IX-C,

IX-C,

or a pharmaceutically acceptable salt thereof, an isotopically enriched analog, a stereoisomer, or a mixture of stereoisomers, wherein each of n, X ¹ , X ² , X ³ , X ⁴ , X 5 , R ^1c , R ¹ , R ^{2 ,} R ³ , R ⁴ and R ⁵ is defined in this document.

[1270] In certain embodiments, provided herein is a compound represented by any one or more of formulas I-C-IX-C, including any two, any three, any four, any five, any six, any seven, any eight, or all of the formulas I-C-IX-C described in this document.

[1280] In certain embodiments, a compound of the formula is provided:

,

,

or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer or mixture of stereoisomers thereof, wherein X ^5a is N or CH, u and v are each independently 0, 1, 2, 3, 4 or 5, R ² is H, C _1-3 alkyl or C _3-6 cycloalkyl, each of L ¹ , R ¹ , R ² , R ^3a and R ^4a is defined in this document.

[1290] A connection is provided, selected from

,

,

,

,

,

,

,

,

,

,

,or

,

or a pharmaceutically acceptable salt, isotopically enriched analogue, stereoisomer or mixture of stereoisomers thereof, wherein X ^5a is N or CH, R ² is H, C _1-3 alkyl or C _3-6 cycloalkyl, each of k, m, n, s, t, R ¹ , R ^3b , R ^3c , R ^4b and R ^4c is defined herein.

[1300] In certain embodiments, provided herein is a compound selected from Table 1 below, or a pharmaceutically acceptable salt, solvate, tautomer, isotopically enriched analog, stereoisomer, or mixture of stereoisomers thereof. In certain embodiments, provided herein is a compound selected from the Examples section herein, or a pharmaceutically acceptable salt, solvate, tautomer, isotopically enriched analogue, stereoisomer, or mixture of stereoisomers thereof.

Table 1

3. Methods and ways of application

[1310] In certain embodiments, the compounds described herein are used in the treatment of a disease or condition, such as an infection.

[1320] "Treatment" or "treatment" is an approach to obtaining favorable or desirable results, including clinical results. Beneficial or desirable clinical results may include one or more of the following: a) suppression of the disease or condition (eg, reduction in the severity of one or more symptoms associated with the disease or condition and/or reduction in the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or slowing the deterioration or progression of the disease or condition, and/or preventing or slowing the spread (e.g., metastases) of the disease or condition) ; and/or c) alleviating the disease, namely, causing regression of clinical symptoms (e.g., alleviating the status of the disease, providing partial or complete remission of the disease or condition, enhancing the effect of another drug, slowing the progression of the disease, improving the quality of life and/or prolonging life.

[1330] The term "prevention" or "prevention" refers to any treatment of a disease or condition that prevents the development of clinical symptoms of the disease or condition. In some embodiments, the compounds may be administered to a subject (including a human) at risk of developing or having a family history of a disease or condition.

[1340] The term “subject” means an animal, such as a mammal (including a human), that has been or will be the subject of treatment, observation, or experiment. The methods described herein may be useful in human and/or veterinary therapeutic applications. In some embodiments, the subject is a mammal. In certain embodiments, the subject is a human.

[1350] The term "therapeutically effective amount" or "effective amount" of a compound described herein (which may be presented in the form of its pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, or mixture of stereoisomers) means an amount sufficient to effect treatment in administration to a subject, to provide a therapeutic effect, such as reducing the intensity of symptoms or slowing the progression of the disease. For example, a therapeutically effective amount may be an amount sufficient to reduce the severity of a symptom of the disease or condition described herein. The therapeutically effective amount may vary depending on the subject and the disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the route of administration, which can be readily determined by one of ordinary skill in the art.

[1360] In some embodiments, a compound described herein is provided for preventing and/or treating an infection caused by a microorganism expressing mycobacterium large 3 membrane proteins (MmpL3) or a disease caused by such an infection. In some embodiments, a compound described herein is provided for the prevention and/or treatment of a mycobacterial infection or disease associated with an infection. In some embodiments, the mycobacterial infection includes, without limitation, Mycobacterium tuberculosis infection, Mycobacterium leprae infection, Mycobacterium ulcerans infection, Mycobacterium abscessus infection, Mycobacterium bovis infection, and Mycobacterium marine infection.

[1370] In some embodiments, the disease includes, without limitation, tuberculosis due to Mycobacterium tuberculosis infection, leprosy due to Mycobacterium leprae , Buruli ulcer due to Mycobacterium ulcerans , infectious disease due to infection caused by Mycobacterium abscessus , infectious disease due to infection caused by Mycobacterium bovis , or an infectious disease caused by an infection caused by Mycobacterium marine .

[1380] In some embodiments, provided herein are methods of treating or preventing an infection caused by a microorganism expressing mycobacterial large 3 membrane proteins (MmpL3) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein. In a further aspect of the present invention, there is also provided a method for treating or preventing a mycobacterial infection or a disease caused by an infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound described herein.

[1390] In some embodiments, mycobacterial infections include, without limitation, infection caused byMycobacterium tuberculosis, an infection causedMycobacterium leprae, an infection causedMycobacterium ulcerans, an infection causedMycobacterium abscessus, an infection causedMycobacterium bovisor an infection caused byMycobacterium marine. In some embodiments, the disease is leprosy due toMycobacterium leprae, Buruli ulcer due toMycobacterium ulcerans, infectious diseases caused by an infection caused byMycobacterium abscessus, an infection causedMycobacterium bovis, and infectious diseases caused by infection caused byMycobacterium marine.

[1400] In some embodiments, provided herein is the use of a compound described herein in a method of treating an infection caused by a microorganism expressing Mycobacterium large 3 membrane proteins (MmpL3) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound described herein.

[1410] In some embodiments, provided herein is the use of a compound described herein for the manufacture of a medicament for the treatment of an infection caused by a microorganism expressing Mycobacterium large 3 membrane proteins (MmpL3) in a subject.

[1420] In some embodiments, the microorganism is a mycobacterium. In some embodiments, mycobacterial infections include, but are not limited to, infection caused byMycobacterium tuberculosis, an infection causedMycobacterium leprae, an infection causedMycobacterium ulcerans, an infection causedMycobacterium abscessus, an infection causedMycobacterium bovisor an infection caused byMycobacterium marine. In some embodiments, the disease is leprosy due toMycobacterium leprae, Buruli ulcer due toMycobacterium ulcerans, infectious diseases caused by an infection caused byMycobacterium abscessus,Mycobacterium bovis, and infectious diseases caused by infection caused byMycobacterium marine.

[1430] In some embodiments, the microorganism is Mycobacterium tuberculosis .

[1440] In some embodiments, the subject is suffering from tuberculosis or leprosy.

[1450] In some embodiments, the subject is a human.

[1460] The methods or routes of application described herein can be applied to cell populations in vivo or ex vivo . The term " in vivo " means within the body of a living individual, such as within the body of an animal or human. In this context, the methods described herein can be used as a therapy in an individual. The term " ex vivo " means outside the body of a living individual. Examples of ex vivo cell populations include cell cultures and in vitro biological samples, including biological fluid or tissue samples obtained from individuals. Such samples can be obtained using methods well known in the art. Illustrative body fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this context, the compounds and compositions described herein can be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein can be used ex vivo to determine the activity of a compound of the present invention in relation to a given indication, cell type, individual, and other parameters. The information obtained from such applications may be used for experimental purposes or in clinical practice to establish in vivo treatment protocols. Other ex vivo uses for which the compounds and compositions described herein may be suitable are described below or will be apparent to those skilled in the art.

[1470] Administration of one or more of the compounds described herein can result in at least a 10% reduction (e.g., at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or even 100% reduction in relation to an infection described herein, a disease caused by an infection, or a symptom of a disease, such as , for example, the magnitude of the bacterial load in the subject.

4. Sets

[1480] Also provided herein are kits that contain a compound of the present invention (including a pharmaceutically acceptable salt, an isotopically enriched analogue, a stereoisomer, or a mixture of stereoisomers of a compound) and suitable packaging. In some embodiments, the implementation of the kit further contains instructions for use. In one aspect, the kit contains a compound of the present invention, as well as a label and/or instructions for use of the compounds in the treatment of indications, including the diseases or conditions described herein.

[1490] This document also provides finished products that include the connection described in this document, in a suitable container. The container may be a vial, a vial, an ampoule, a pre-filled syringe, and an intravenous solution bag.

5. Pharmaceutical compositions and routes of administration

[1500] The compounds provided herein are usually administered in the form of pharmaceutical compositions. Thus, this document also provides pharmaceutical compositions that contain one or more of the compounds described herein (which may be in the form of their pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers) and one or more pharmaceutically acceptable carrier vehicles. selected from carriers, excipients and excipients. Suitable pharmaceutically acceptable carriers may include, for example, inert solid diluents and excipients, diluents including sterile aqueous solution and various organic solvents, penetration enhancers, solubilizers, and adjuvants. Such compositions are prepared by a process well known in the art of pharmacy. See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA. ^17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. ^3rd Ed. (GS Banker and CT Rhodes, Eds.). Compositions may contain from about 0.1% to about 90% of the compound disclosed herein, based on the total weight of the composition.

[1510] Pharmaceutical compositions can be administered either as a single dose or as multiple doses. A pharmaceutical composition containing the compounds described herein can be prepared for a suitable route of administration (including, but not limited to, intranasal administration, inhalation administration, topical administration, oral administration, oral administration, rectal administration, intrapleural administration, intraperitoneal administration, vaginal administration, intramuscular administration, subcutaneous administration, transdermal administration, epidural administration, intrathecal administration and intravenous administration). Suitable formulations include spray formulations, patches, tablets, capsules, dragees, lozenges, powders, granules, powders or liquid preparations (eg suspensions, solutions, emulsions or syrups).

[1520] One route of administration is parenteral administration, eg, by injection. Forms in which the pharmaceutical compositions described herein may be included for administration by injection include, for example, aqueous or oily suspensions or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as tinctures, mannitol , dextrose or sterile aqueous solution, as well as similar pharmaceutical carriers.

[1530] Oral administration may be another route of administration for the compounds described herein. The introduction can be by means of, for example, enteric-coated capsules or tablets. In the manufacture of pharmaceutical compositions that include at least one compound described herein, the active ingredient is usually diluted with an excipient and/or enclosed in such a carrier, which may be presented in the form of a capsule, sachet, paper or other container. If the excipient functions as a diluent, it may be in the form of a solid, semi-solid or liquid material which acts as an auxiliary carrier, vehicle or medium for the active ingredient. Thus, the compositions can be presented in the form of tablets, pills, powders, lozenges, sachets, cachets, tinctures, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, not more than 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions and packaged sterile powders.

[1540] Some examples of suitable excipients include, for example, lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum arabic, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup and methylcellulose. The formulations may further include lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl and propylhydroxybenzoates; sweeteners and flavors.

[1550] Compositions that contain at least one compound described herein can be formulated to provide rapid, delayed or delayed release of the active ingredient after administration to a subject, using procedures known in the art. Delivery systems for controlled release of an oral drug include osmotic pump systems and dissolution systems containing polymer coated reservoirs or drug-polymer matrix formulations. Another formulation for use in the methods disclosed herein uses transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or intermittent infusion of the compounds described herein in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceuticals are well known in the art. Such patches can be designed for continuous, pulsatile delivery of pharmaceuticals or on-demand delivery of pharmaceuticals.

[1560] To obtain solid compositions such as tablets, the main active ingredient can be mixed with a pharmaceutical excipient to form a solid preformulated composition containing a homogeneous mixture of the compound described herein. By referring to these preformulated compositions as being homogeneous, the active ingredient can be evenly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[1570] Tablets or pills based on the compounds described herein may be coated or otherwise formulated to provide a long-acting advantage or to protect against acidic conditions in the stomach. For example, a tablet or pill may contain an internal and external dose component, with the second present in the form of a shell around the first. The two components can be separated by an enteric layer, prevents disintegration in the stomach, and allows the inner component to pass intact into the duodenum or delay its release. A variety of materials can be used for such enteric layers or coatings, including a variety of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[1580] Compositions for inhalation or insufflation may contain solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, the compositions are administered by inhalation through the mouth or nose to provide a local or systemic effect. In other embodiments, the implementation of the composition in pharmaceutically acceptable solvents can be sprayed by the use of inert gases. Nebulized solutions may be inhaled directly from a nebulizing device, or the nebulizing device may be attached to an inhalation mask or ventilator in positive pressure intermittent ventilation mode. Solution, suspension or powder formulations may be administered, preferably orally or intranasally, from devices that deliver the formulation in a suitable manner.

[1590] In some embodiments, the implementation of the pharmaceutical composition further comprises one or more additional drugs for the treatment or prevention of infection caused by a microorganism.

6. Dosing

[1600] The specific dosage level of a compound of the present disclosure may depend on a variety of factors, including potency of the particular compound used, age, body weight, general health, sex, diet, time of administration, route of administration, and rate of elimination, drug combination and the severity of the particular disease being treated. For example, the dose may be expressed in milligrams of a compound described herein per kilogram of the subject's body weight (mg/kg). Doses ranging from about 0.1 mg/kg to 150 mg/kg may be suitable. In some embodiments, a dose of about 0.1 mg/kg to 100 mg/kg may be appropriate. In other embodiments, a dose of about 0.5 mg/kg to 60 mg/kg may be appropriate. In some embodiments, a dose of from about 0.0001 mg to about 100 mg per kg of body weight per day, from about 0.001 mg to about 50 mg of the compound per kg of body weight, or from about 0.01 mg to about 10 mg of the compound per day. kg body weight may be appropriate. The total daily dose can be administered once a day or administered twice, three times, four times or more times during the day in divided doses.

7. Synthesis of compounds

[1610] Connections can be obtained using the methods disclosed in this document, and their standard modifications, which will be apparent in view of the description given in this document and methods widely known in the art. traditional and well-known synthesis methods may be applied in addition to the teachings presented herein. Synthesis of typical compounds described in this document can be carried out as described in the following examples. Where available, reagents and starting materials may be purchased from commercial sources such as Sigma Aldrich or other chemical suppliers.

[1620] It should be understood that while typical or preferred process conditions (e.g., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.) are given, others can also be used. method conditions, unless otherwise indicated. Optimum reaction conditions may vary depending on the specific reactants or solvent employed, but such conditions can be determined by one of ordinary skill in the art through routine optimization procedures.

[1630] In addition, traditional protecting groups may be required to prevent certain functional groups from entering into undesirable reactions. Suitable protecting groups for a variety of functional groups, as well as suitable conditions for introducing and removing a protecting group for particular functional groups, are well known in the art. For example, a number of protecting groups are described in Wuts, P. G. M., Greene, T. W. and Greene, T. W. (2006). Greene's protective groups in organic synthesis. Hoboken, N.J., Wiley-Interscience, as well as in the literature cited in this source.

[1640] In addition, the compounds of the present invention may contain one or more chiral centers. Accordingly, if desired, such compounds may be prepared or isolated as pure stereoisomers, for example as single enantiomers or diastereomers, or as mixtures enriched in stereoisomers. All such stereoisomers (and enriched mixtures) are included within the scope of the present invention unless otherwise indicated. Pure stereoisomers (or enriched mixtures) can be obtained using, for example, optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be isolated using, for example, chiral column chromatography, chiral separation aids, and the like.

[1650] Suitable starting materials are well known compounds or can be obtained using known procedures or modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Others may be obtained by following the procedures or modifications thereof described in standard reference books such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989) organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5 ^th Edition, 2001) and Larock's Comprehensive Organic Transformations ( VCH Publishers Inc., 1989).

[1660] Intermediates and products can be isolated from reaction mixtures and purified using conventional methods such as extraction, evaporation, precipitation, filtration, crystallization, and chromatography. Intermediates can also be used directly in the next reaction without purification or separation.

¹ H NMR proton nuclear magnetic resonance calc. calculated conc. concentrated DCM dichloromethane DIPEA diisopropylethylamine DMA dimethylacetamide DMAP dimethylaminopyridine DMF dimethylformamide DMSO dimethyl sulfoxide EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide equiv. equivalent ESI electrospray ionization EtOAc ethyl acetate EtOH ethanol EtONa or EA sodium ethoxide HOAc or AcOH acetic acid HOBT 1-hydroxybenzotriazole HPLC high performance liquid chromatography HRMS high resolution mass spectrometry LC liquid chromatography LC-MS liquid chromatography with mass spectrometry LRMS low resolution mass spectrometry M molar ml milliliter MeOH methanol min. minute mmol millimole NMM N-methylmorpholine TEA triethylamine THF tetrahydrofuran TLC thin layer chromatography TMS tetramethylsilane TsOH p-toluenesulfonic acid

General synthesis

[1670] In certain embodiments, a method for preparing a compound of the present invention is provided. In certain embodiments, compounds can be prepared according to general schemes I-VI using starting materials and reagents that can be purchased or obtained using methods known to a person skilled in the art. In schemes I-VI, m, n, X ¹ , X ² , X ³ , X ⁴ , X ⁵ , R ¹ , R ^1b , R ² , R ³ , R ⁴ and R ⁵ are defined herein.

Scheme I

In the scheme, IL ³ is *-(CH ₂ ) _n -, *-(CH ₂ ) _n -N(R ^1c )-(CH ₂ ) _k - or *-(CH ₂ ) _n -(O(CH ₂ ) _m ) _p -O(CH ₂ ) _k -, and *, n, k, p and R ^1c are defined herein. Compound IA reacts with compound IB under amide coupling reaction conditions to give compound IC. Amide coupling reaction conditions are generally known in the art and typically include a coupling reagent, for example, carbodiimides such as N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC) and 1- ethyl 3-(3'-dimethylaminopropyl)carbodiimide (EDCI). Carbodiimides can be used in combination with additives such as DMAP or HOBt. Common amide coupling reagents also include, but are not limited to, phosphorus oxychloride (POCl ₃ ), 2-propanephosphonic anhydride (T3P), carbonyldiimidazole (CDI), 2-chloro-4,6-dimethoxy-1,2,5-triazine ( CDMT). Amide coupling reagents also include aminium and phosphonium based reagents such as hexafluorophosphate N-oxide N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]- N-methylmethanaminium (HATU), N-[(1H-benzotriazol-1-yl)(dimethylamino)methylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HBTU), and benzotriazol-1-yl-N-hydroxy-tris(pyrrolidino) hexafluorophosphate )phosphonium (PyBOP). Amide coupling reaction conditions may include a solvent such as DMF, THF, DCM, acetone, DMA, EtOAc, acetonitrile, or a mixture thereof, and may also include an organic base such as pyridine, TEA, DIPEA, DMAP, NMM, or a mixture thereof. Coupling reaction conditions may include temperatures ranging from -10° C. to room temperature.

Scheme II

[1690] In Scheme II, compound II-A reacts with compound II-B in the presence of triphosgene to give compound II-C. The reaction is generally carried out in a solvent such as THF or DCM in the presence of an organic base such as TEA or DIPEA and under cooling conditions such as an ice bath.

Scheme III

[1700] In scheme III, compound III-A reacts with compound III-B under reductive amination conditions to give compound III-C. Reductive amination conditions are generally known in the art and typically include a solvent such as MeOH, EtOH, DCM, THF or dioxane, a reducing agent such as NaBH ₄ , NaBH ₃ CN or NaBH(OCOCH ₃ ) ₃ , and optionally Lewis acids such as Ti(iPrO) ₄ or ZnCl ₂ ; and a molecular sieve.

Scheme IV

[1710] In Scheme IV, s and t are independently 0, 1, or 2. Compound IV-A reacts with compound IV-B in the presence of triphosgene to give compound IV-C. The reaction is typically carried out in a solvent such as DCM in the presence of an organic base such as TEA or DIPEA and at a temperature in the range from about -10°C to about 40°C or from about 0°C to about 25°C.

Scheme V

[1720] In the scheme, VL ⁴ is CO or SO ₂ and LG is a leaving group such as halo. The VA compound is reacted with the VB compound to form the VC compound. The reaction is generally carried out in a solvent such as anhydrous CH ₃ CN in the presence of a base such as K ₂ CO ₃ under heating conditions such as reflux.

Scheme VI

[1730] In Scheme VI, L ⁴ is CO or SO ₂ . Compound VI-A reacts with compound VI-B to form compound VI-C. The reaction is generally carried out in a solvent such as MeOH under heating conditions, eg reflux.

Scheme VII

[170] In scheme VII, compound III-A is reacted with compound VII-B to give compound VII-C, where m is 1. In additional embodiments, compound III-A can be converted to compound III-AA and compound III- AA reacts with compound VII-B to give compound VII-C, where m is 2. The reaction is generally carried out under reductive amination conditions to give compound VII-C. Reductive amination conditions are generally known in the art and typically include a solvent such as MeOH, EtOH, DCM, THF or dioxane, a reducing agent such as NaBH ₄ , NaBH ₃ CN or NaBH(OCOCH ₃ ) ₃ , and optionally Lewis acids such as Ti(iPrO) ₄ or ZnCl ₂ ; and a molecular sieve.

Scheme VIII

[1750] In Scheme VIII, compound III-AA reacts with compound VIII-B to give compound VIII-C. The reaction is generally carried out under reductive amination conditions to give compound VIII-C. Reductive amination conditions are generally known in the art and typically include a solvent such as MeOH, EtOH, DCM, THF, or dioxane, a reducing agent such as NaBH ₄ , NaBH ₃ CN, or NaBH(OCOCH ₃ ) ₃ , and optional Lewis acids such as Ti(iPrO) ₄ or ZnCl ₂ and a molecular sieve.

Scheme IX

[1760] In Scheme IX, compound IX-A reacts with compound IX-B to give compound IX-C. The reaction is generally carried out in a solvent such as EtOH with or without heating, for example at room temperature or under reflux.

EXAMPLES

[1770] The following examples are included to demonstrate specific embodiments of the present invention. It will be appreciated by those skilled in the art that the techniques disclosed in the examples that follow are those that work properly in the practice of the present invention, and which can thus be considered as the basis for particular ways of practicing it. However, in light of the present invention, those skilled in the art will appreciate that many changes can be made to the specific embodiments that are disclosed and still obtain similar or similar results without departing from the spirit and scope of the present invention.

[1780] General Experimental Methods

[1790] All solvents used were commercially available and were used without further purification. The reactions were generally carried out using anhydrous solvents under an inert nitrogen atmosphere.

NMR spectroscopy

[1800] In accordance with the present invention, ¹ H NMR spectrum was measured using a nuclear magnetic resonance spectrometer type Bruker-500 MHz using 0.1% TMS in CD ₃ OD as a solvent, where CD ₃ OD (δ = 3, 31 ppm) is used as an internal standard; 0.1% TMS in CDCl ₃ as solvent, where CDCl ₃ (δ = 7.26 ppm) is used as an internal standard; or 0.03% TMS in DMSO-d ₆ as solvent, where DMSO-d ₆ (δ = 2.50 ppm) is used as an internal standard. LRMS spectra were determined using an AB Triple 4600 mass spectrometer, HPLC preparations were determined using an instrument of the SHIMADZU LC-20AP type, and HPLC purity was determined using a SHIMADZU LC-30AP or Waters 1525 instrument. Unless otherwise indicated, all reactions were performed in the atmosphere of air; and after reactions were performed, TLC or LC-MS was performed. Representative chemical shifts (δ) are reported in parts per million using traditional abbreviations for major peaks: eg s: singlet; d: doublet; t: triplet; q: quartet; dd: doublet of doublets; dt: doublet of triplets; br: wide signal.

[1810] Solvents and Reagents

[1820] Unless otherwise indicated, the solvent used to carry out the reactions, such as DCM, DMF, anhydrous EtOH, anhydrous MeOH, was purchased from the Sinopharm Group; HPLC grade materials were prepared using CH ₃ CN and deionized water; and other reagents were used directly in the form in which they were purchased from the manufacturers.

Example 1 Preparation of Compound 43

Stage 1

[1830] To a solution of diethyl oxalate (11.7 g, 80.1 mmol) in EtOH (100 ml) was added dropwise a solution of sodium ethoxide (36.3 g, 20% w/w, 106.8 mmol) under a nitrogen atmosphere. After stirring at room temperature for 10 min. 4'-chloropropiophenone (9 g, 53.4 mmol, dissolved in 100 ml EtOH) was added. The reaction mixture was stirred for 24 hours at room temperature. After the starting material was consumed, the reaction mixture was quenched with ice water and the pH of the solution was adjusted to 3-4 with 1 M HCl (aq.). The mixture was extracted with dichloromethane, washed with brine, dried over anhydrous Na ₂ SO ₄ . The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give SIAIS40611A in 76.9% yield as a yellow solid (11.0 g). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.28 (t, J = 7.2 Hz, 3H), 1.43 (d, J = 7.1 Hz, 3H), 4.25 (q, J = 7.2 Hz, 2H), 4.98 (q, J = 7.1 Hz, 1H), 7.47 (d, J = 8.3 Hz, 2H), 7.91 (d, J = 8 .6 Hz, 2H).

[1840] Stage 2

[1850] To a solution of SIAIS40611A (1.4 g, 5.21 mmol) in acetic acid (14 mL) was added 2,4-dichlorophenylhydrazine hydrochloride (1.13 g, 5.31 mmol) at room temperature under a nitrogen atmosphere. The mixture was then heated under reflux at 130° C. for 3 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved with 50 ml of ethyl acetate and washed successively with aqueous phosphoric acid (0.5 m, 30 ml×3), saturated aqueous NaHCO ₃ and brine. This was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give compound SIAIS40611B (as a yellow solid, 2.0 g, yield = 93.9%) without further purification.

Stage 3

To a solution of SIAIS40611B (1.3 g, 3.17 mmol) in EtOH/THF (7 ml/13 ml) was added an aqueous solution of NaOH (1.2 g, 31.7 mmol, 6 ml). The mixture was heated under reflux at 75°C for 2.5 hours, then cooled to room temperature and concentrated in vacuo. The residue was dissolved with 50 ml H ₂ O and the pH of the solution was adjusted to 2-3 with 1M HCl (aq.). The resulting was extracted with EA (50 ml × 2) and the organic phase was washed with 50 ml of saline. This was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give SIAIS40611C (as a yellow solid, 1.1 g, yield = 91.6%) which was used without further purification.

Stage 4

[1870] Oxalyl chloride (0.33 g, 2.62 mmol) was added to a solution of SIAIS40611C (0.5 g, 1.31 mmol) in 8 ml DCM. One drop of DMF was added to catalyze the reaction, and the mixture was stirred at room temperature for 18 hours. Concentrated in vacuo to give SIAIS40611D as a pale yellow solid (0.52 g, yield = 99.2%) which was used without further purification.

Stage 5

[1890] Cooled a solution of 2-adamantanamine hydrochloride (0.32 g, 1.69 mmol) and TEA (0.46 g, 4.55 mmol) in 10 ml DCM in an ice water bath under nitrogen atmosphere and then added dropwise solution of SIAIS40611D (0.52 g, 1.30 mmol) in 10 ml of DCM. After stirring at room temperature for 21 hours, the mixture was heated under reflux at 45°C for another 8 hours. The mixture was cooled to room temperature and quenched with 20 ml of water. The organic layer was separated and the aqueous layer was extracted with DCM (30 ml x 2). The organic phase was then combined, washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to give compound 43 as a white solid (0.33 g, yield = 50.0%). ¹ H NMR (400 MHz, DMSO-d6) δ 1.54 (d, J = 12.5 Hz, 2H), 1.67 (br. s., 2H), 1.79 (br. s., 8H ), 1.91 (br. s., 2H), 2.21 (s, 3H), 4.02 (d, J = 6.36 Hz, 1H), 7.19 (d, J = 8.1 Hz, 2H), 7.37-7.49 (m, 3H), 7.51-7.59 (m, 1H), 7.72 (d, J = 11.5 Hz, 2H); calc. by HRMS (ESI) value for C ₂₇ H ₂₇ Cl ₃ N ₃ O ⁺ [M+H] ⁺ , 514.1214; the detected value is 514.1209.

Example 2 Get SIAIS40612A

[1900] Heated a solution of SIAIS40611A (2.5 g, 9.3 mmol) and 2,4-difluorophenylhydrazine hydrochloride (1.68 g, 9.3 mmol) in 8 ml of acetic acid to 130°C and refluxed at for 3 hours under nitrogen atmosphere. The mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was dissolved in 50 ml of EA, washed successively with saturated aqueous NaHCO ₃ (30 ml × 2) and brine. Dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to give SIAIS40612A as a white solid (2.0 g, yield = 57.1%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.41 (t, J = 7.1 Hz, 3H) 2.30 (s, 3H), 4.44 (q, J = 7.1 Hz, 2H) , 6.71-6.81 (m, 1H), 6.91 (t, J = 7.8 Hz, 1H), 7.06 (d, J = 8.3 Hz, 2H), 7.30 ( d, J = 8.6 Hz, 2H), 7.41-7.45 (m, 1H).

Example 3: Get SIAIS40614A

[1910] Heated a solution of SIAIS40611A (2.0 g, 7.4 mmol) and 2,4-dimethylphenylhydrazine hydrochloride (1.28 g, 7.4 mmol) in 15 ml of acetic acid to 130℃ and refluxed for 5 hours under nitrogen atmosphere. The mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was dissolved in 50 ml of EA, washed successively with saturated aqueous NaHCO ₃ (30 ml × 2) and brine. Dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to give SIAIS40614A as a white solid (2.0 g, yield = 72.8%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.40 (t, J = 7.1 Hz, 3H), 1.84 (s, 3H), 2.28 (s, 3H), 2.33 (s , 3H), 4.42 (q, J = 7.1 Hz, 2H), 6.89-6.97 (m, 2H), 7.02 (d, J = 8.6 Hz, 2H), 7 .07 (d, J = 7.8 Hz, 1H), 7.22-7.26 (m, 2H).

Example 4 Preparation of Compound 17

Stage 1

[1920] Refluxed a solution of 2-adamantanone (10.0 g, 66.57 mmol), ethylenediamine (25 ml) and TsOH (1.3 g, 6.66 mmol) in 100 ml of toluene at 130°C in for 8 hours, at the same time the water was separated. The mixture was then cooled to room temperature and concentrated in vacuo. The obtained residue was dissolved in 50 ml of methanol and cooled in an ice-water bath, NaBH ₄ (5.0 g, 130 mmol) was added thereto in 3 portions, and reaction was carried out for 4 hours. The reaction mixture was quenched with water (100 ml) and the methanol was removed. The aqueous phase was extracted with EA (200 ml x 3) and the organic phase was combined, washed with 50 ml brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to give SIAIS40616A as a light yellow oil (10.5 g, yield = 81.4%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.45 (s, 3H), 1.48 (s, 2H), 1.72-1.63 (m, 4H), 1.78-1.72 ( m, 1H), 1.86-1.78 (m, 5H), 1.93 (d, J = 12.2 Hz, 2H), 2.67-2.60 (m, 2H), 2.68 (s, 1H), 2.78 (dd, J = 6.5, 5.2 Hz, 2H).

Stage 2

[1930] A solution of SIAIS40611B (0.50 g, 1.22 mmol), SIAIS40616A (0.95 g, 4.88 mmol), MgCl ₂ (0.58 g, 6.10 mmol) in 25 ml was heated under nitrogen atmosphere CH ₃ CN was heated to 90°C and kept for 8 hours. After the starting material was consumed, the mixture was cooled to room temperature and quenched with 30 ml of water. The aqueous phase was extracted with EA (50 ml x 3). The combined organic phase was washed with 50 ml of brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography to give compound 17 as a yellow solid (0.52 g, yield = 76.5%). ¹ H NMR (400 MHz, DMSO- d 6) δ 1.50 (d, J = 12.9 Hz, 2H), 1.79-1.71 (m, 8H), 2.15-2.01 ( m, 4H), 2.22 (s, 3H), 2.88-2.91 (m, 1H), 3.06 (t, J = 6.5 Hz, 2H), 3.30-3.31 (m, 1H), 3.62 (t, J = 6.3 Hz, 2H), 7.24-7.15 (m, 2H), 7.46-7.39 (m, 2H), 7, 56 (dd, J =8.5, 2.3Hz, 1H), 7.70 (d, J =8.5Hz, 1H), 7.75 (d, J =2.3Hz, 1H), 8.54 (t, J = 5.9 Hz, 1H), 8.87 (s, 2H). Calc. using HRMS (ESI) value for C ₂₉ H ₃₂ Cl ₃ N ₄ O ⁺ [M + H] ⁺ 557.1636; the detected value is 557.1649.

Example 5 Preparation of Compound 76

[1940] Heated a solution of SIAIS40612A (0.30 g, 0.80 mmol), SIAIS40616A (0.78 g, 4.0 mmol), MgCl ₂ (0.30 g, 3.2 mmol) in 16 ml CH ₃ CN up to 90°C and kept for 4 hours in a nitrogen atmosphere. After the starting material was consumed, the mixture was cooled to room temperature and quenched with 30 ml of water. The aqueous phase was extracted with EA (50 ml x 3). The combined organic phase was washed with 50 ml of brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography to give compound 76 as a white solid (0.30 g, yield = 71.4%). ¹ H NMR (400 MHz, DMSO- d 6) δ 1.34 (d, J =11.7 Hz, 2H), 1.60-1.64 (m, 5H), 1.71-1.82 ( m, 5H), 1.93-2.04 (m, 2H), 2.21 (s, 3H), 2.71-2.82 (m, 3H), 3.31-3.34 (m, 2H), 7.13-7.28 (m, 3H), 7.33-7.52 (m, 3H), 7.60-7.74 (m, 1H), 8.23 (br. s. , 1H). Calc. using HRMS (ESI) value for C ₂₉ H ₃₂ ClF ₂ N ₄ O ⁺ [M + H] ⁺ : 525.2227; detected value: 525.2236.

Example 6 Preparation of Compound 77

[1950] Heated a solution of SIAIS40614A (0.60 g, 1.63 mmol), SIAIS40616A (1.26 g, 6.52 mmol), MgCl ₂ (0.77 g, 8.15 mmol) in 25 ml CH ₃ CN up to 90°C and kept for 10 hours in a nitrogen atmosphere. After the starting material was consumed, the mixture was cooled to room temperature and quenched with 30 ml of water. The aqueous phase was extracted with EA (50 ml x 3). The combined organic phase was washed with 50 ml of brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography, washed 2 times with dilute aqueous HCl to give compound 77 as a white solid (0.78 g, yield = 92.8%). ¹ H NMR (400 MHz, DMSO- d 6) δ 1.50 (d, J = 12.8 Hz, 2H), 1.68 (d, J = 17.9 Hz, 4H), 1.79 (d , J = 11.2 Hz, 4H), 1.85 (s, 3H), 2.10 (d, J = 17.6 Hz, 4H), 2.23 (d, J = 7.6 Hz, 6H ), 3.07 (t, J = 6.3 Hz, 2H), 3.31-3.33 (m, 1H), 3.63 (t, J = 6.2 Hz, 2H), 7.22 -6.96 (m, 5H), 7.42-7.34 (m, 2H), 8.52 (t, J = 5.9 Hz, 1H), 9.02 (s, 2H). Calc. using HRMS (ESI) value for C ₃₁ H ₃₈ ClN ₄ O ⁺ [M + H] ⁺ 517.2729; detected value: 517.2730.

Example 7 Preparation of Compound 74

Stage 1

[1960] N -methylethanediamine (0.15 g, 2.0 mmol) was added to a solution of 2-adamantanone (0.20 g, 1.33 mmol) in 8 ml of methanol. After stirring for 15 min. acetic acid (0.34 ml) and NaBH ₃ CN (0.25 g, 4.0 mmol) were added at room temperature and the reaction was carried out overnight. The mixture was quenched with 10 ml of water and extracted with EA (25 ml x 2). The organic phase was combined, washed with 50 ml brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give SIAIS1300077 as crude product (0.24 g, yield = 86%). ¹ H NMR (500 MHz, CD ₃ OD) δ 3.11-3.04 (m, 2H), 2.95 (dd, J = 6.8, 5.2 Hz, 2H), 2.89 (d , J = 2.4 Hz, 1H), 2.68 (s, 3H), 2.10-2.02 (m, 2H), 2.02-1.92 (m, 4H), 1.93- 1.78 (m, 6H), 1.70-1.58 (m, 2H). ¹³ C NMR (126 MHz, CD ₃ OD) δ 61.97, 48.49, 42.49, 37.38, 37.05, 32.68, 31.37, 30.54, 27.63, 27, 46. Calc. using HRMS (ESI) value for C ₁₃ H ₂₅ N ₂ ⁺ [M + H] ⁺ : 209.2012; detected value: 209.2015.

Stage 2

[1970] To a solution of SIAIS1300077 (23 mg, 0.11 mmol) and SIAIS40611C (41 mg, 0.11 mmol) in 2 ml of DMF were added successively EDCI (32 mg, 0.17 mmol), HOBT (15 mg, 0.11 mmol) 11 mmol) and DIPEA (18 μl, 0.11 mmol) and reacted overnight. The mixture was quenched with 0.2 ml of water, purified by preparative HPLC to give compound 74 as a white powder (32 mg, yield = 49%). ¹ H NMR (500 MHz, CD ₃ OD) δ 7.71-7.43 (m, 3H), 7.39 (d, J = 8.5 Hz, 2H), 7.22 (d, J = 8 .0 Hz, 2H), 3.99 (d, J = 57.1 Hz, 2H), 3.60-3.39 (m, 3H), 3.35 (s, 1.5H, NCH ₃ ), 3.17 (s, 1.5H, NCH ₃ ), 2.23 (s, 1H), 2.19 (s, 3H), 2.07-1.78 (m, 8H), 1.72 (s , 2H), 1.54 (s, 3H). Calc. using HRMS (ESI) value for C ₃₀ H ₃₄ Cl ₃ N ₄ O [M + H] ⁺ : 571.1793; detected value: 571.1799.

Example 8 Preparation of Compound 18

Stage 1

[1980] To a solution of 2-adamantanone (0.20 g, 1.33 mmol) in 8 ml of methanol was added 1,3-diaminopropane (0.30 g, 4.0 mmol) and stirred for 15 minutes. at room temperature. Acetic acid (0.34 ml) and NaBH ₃ CN (0.25 g, 4.0 mmol) were added and the reaction was carried out overnight. The mixture was quenched with 10 ml water and extracted with EA (25 ml×2), then the organic phase was combined and washed with 50 ml brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Salt formation with HCl solution and washing with EA gave SIAIS1300079 as crude product (0.22 g, yield = 67%).

Stage 2

To a solution of SIAIS1300079 (27 mg, 0.11 mmol) and SIAIS40611C (41 mg, 0.11 mmol) in 2 ml of DMF, EDCI (32 mg, 0.17 mmol), HOBT (15 mg, 0.11 mmol) were added successively and DIPEA (18 μl, 0.11 mmol) and reacted overnight. The mixture was quenched with 0.2 ml of water, purified by preparative HPLC to give compound 18 as a white powder (16 mg, yield = 25%). ¹ H NMR (500 MHz, CD ₃ OD) δ 7.61 (d, J = 2.2 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.48 (dd, J = 8.5, 2.2 Hz, 1H), 7.42-7.38 (m, 2H), 7.24-7.20 (m, 2H), 3.74-3.67 (m, 1H), 3.60-3.57 (m, 1H), 3.54 (t, J = 6.2 Hz, 2H), 3.44 (s, 1H), 3.14 (t, J = 7 .1 Hz, 2H), 2.34 (s, 3H), 2.22 (d, J = 8.3 Hz, 2H), 2.14-2.00 (m, 6H), 1.96 (d , J = 6.4 Hz, 2H), 1.88 (d, J = 13.1 Hz, 4H), 1.79 (d, J = 13.7 Hz, 2H). Calc. using HRMS (ESI) mass/charge value for C ₃₀ H ₃₄ Cl ₃ N ₄ O [M + H] ⁺ : 571.1793; detected value: 571.1785.

Example 9 Preparation of Compound 19

Stage 1

[2000] To a solution of 2-adamantanone (0.20 g, 1.33 mmol) in 8 ml of methanol was added 1,4-diaminobutane (0.35 g, 4.0 mmol) and stirred for 15 minutes. at room temperature. Acetic acid (0.34 ml) and NaBH ₃ CN (0.25 g, 4.0 mmol) were added and the reaction was carried out overnight. The mixture was quenched with 10 ml water and extracted with EA (25 ml×2), then the organic phase was combined and washed with 50 ml brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Salt formation with HCl solution and washing with EA gave SIAIS1300081 as crude product (0.32 g, yield = 93%).

Stage 2

[2010] To a solution of SIAIS1300081 (27 mg, 0.11 mmol) and SIAIS40611C (41 mg, 0.11 mmol) in 2 ml of DMF, EDCI (32 mg, 0.17 mmol), HOBT (15 mg, 11 mmol) and DIPEA (18 μl, 0.11 mmol) and reacted overnight. The mixture was quenched with 0.2 ml of water, purified by preparative HPLC to give compound 19 as a white powder (16 mg, yield = 24%). ¹ H NMR (500 MHz, CD ₃ OD) δ 7.62 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.50 (dd, J = 8.5, 2.3 Hz, 1H), 7.46-7.37 (m, 2H), 7.30-7.16 (m, 2H), 3.47 (t, J = 6, 2 Hz, 2H), 3.42 (s, 1H), 3.20-3.09 (m, 2H), 2.35 (s, 3H), 2.06-1.92 (m, 7H), 1.91-1.71 (m, 11H). Calc. using HRMS (ESI) mass/charge value for C ₃₁ H ₃₆ Cl ₃ N ₄ O [M + H] ⁺ : 585.1949; detected value: 585.1953.

Example 10 Preparation of Compound 52

[2020] EDCI (32 mg, 0.17 mmol), HOBT (15 mg , 0.11 mmol) and DIPEA (18 μl, 0.11 mmol) and reacted overnight. The mixture was quenched with 0.2 ml of water, purified by preparative HPLC to give compound 52 as a white powder (40 mg, yield = 72%). ¹ H NMR (500 MHz, CD ₃ OD) δ 7.60 (d, J = 2.2 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.48 (dd, J = 8.4, 2.2 Hz, 1H), 7.42-7.36 (m, 2H), 7.26-7.15 (m, 2H), 2.30 (s, 3H), 2 .17 (d, J = 2.9 Hz, 6H), 2.16-2.08 (m, 3H), 1.78 (d, J = 2.9 Hz, 6H). Calc. using HRMS (ESI) mass/charge value for C ₂₇ H ₂₇ Cl ₃ N ₃ O ⁺ [M + H] ⁺ : 514.1214; detected value: 514.1220.

Example 11 Preparation of Compound 163

Stage 1

[2030] Cool a solution of 1-adamantanamine hydrochloride (1.0 g, 5.3 mmol) in 8 ml DCM to 0°C, add chloroacetyl chloride (0.90 g, 8.0 mmol) and DIPEA (1, 36 g, 1.76 ml). The reaction was carried out at room temperature overnight and the mixture was quenched with 20 ml of water. The aqueous phase was extracted with DCM (25 ml×2) and the combined organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography to give a white solid (0.91 g, yield = 75%).

Stage 2

[2040] The product of step 1 was dissolved in 8 ml of methanol, NaN ₃ (0.50 g, 7.7 mmol) was added thereto and the mixture was heated under reflux for 24 hours. The mixture was concentrated in vacuo and the resulting residue was purified by silica gel column chromatography, SIAIS1300091 was obtained as a white solid (0.77 g, yield = 82%). ¹ H NMR (500 MHz, CDCl ₃ ) δ 5.93 (s, 1H), 3.88 (s, 2H), 2.11 (s, 3H), 2.03 (s, 6H), 1.72 (s, 6H). ¹³ C NMR (126 MHz, CDCl ₃ ) δ 165.28, 53.17, 52.25, 41.47, 36.24, 29.40. Calc. using HRMS (ESI) mass/charge value for C ₁₂ H ₁₉ N ₄ O ⁺ [M + H] ⁺ : 235.1553; detected value: 235.1549.

Stage 3

[2050] To a solution of SIAIS1300091 (0.50 g, 2.1 mmol) in 20 ml THF was added LiAlH ₄ (0.41 g, 10.7 mmol) and the mixture was refluxed for 24 hours. The reaction mixture was successively quenched with 0.41 ml H ₂ O, 0.41 ml 15% NaOH (aq) and 1.2 ml H ₂ O. The mixture was filtered and the solution concentrated in vacuo to give SIAIS1300101 (0.47 g, yield = 95%), which was used without further purification.

Stage 4

[2060] To a solution of SIAIS1300101 (27 mg, 0.11 mmol) and SIAIS40611C (41 mg, 0.11 mmol) in 2 mL of DMF, EDCI (32 mg, 0.17 mmol), HOBT (15 mg, 0. 11 mmol) and DIPEA (18 µl, 0.11 mmol). The reaction was carried out overnight and the mixture was quenched with 0.2 ml of water, then directly purified using preparative HPLC. Compound 163 was obtained as a white powder (23 mg, yield = 36%). ¹ H NMR (500 MHz, CD ₃ OD) δ 7.62 (d, J = 2.2 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.49 (dd, J = 8.5, 2.3 Hz, 1H), 7.43-7.34 (m, 2H), 7.28-7.17 (m, 2H), 3.72-3.68 (m, 2H), 3.58 (dd, J = 5.5, 4.0 Hz, 2H), 2.35 (s, 3H), 2.24 (s, 3H), 1.96 (d, J = 2 .9 Hz, 6H), 1.83 (d, J = 12.7 Hz, 3H), 1.75 (d, J = 12.8 Hz, 3H). Calc. using HRMS (ESI) mass/charge value for C ₂₉ H ₃₂ Cl ₃ N ₄ O ⁺ [M + H] ⁺ : 557.1636; detected value: 557.1631.

Example 12 Preparation of Compound 23

Stage 1

[2070] A solution of memantine-HCl (1.0 g, 4.6 mmol) in 8 ml DCM was cooled to 0°C, chloroacetyl chloride (0.78 g, 7.0 mmol) and DIPEA (1.18 g, 1.52 ml). The reaction was carried out at room temperature overnight and the mixture was quenched with 20 ml of water. The aqueous phase was extracted with DCM (25 ml×2) and the organic phase was combined, washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel column chromatography to give a white solid (0.98 g, yield = 83%).

Stage 2

[2080] The product of step 1 was dissolved in 8 ml of methanol, NaN ₃ (0.50 g, 7.7 mmol) was added thereto and heated under reflux for 24 hours. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography to give SIAIS1300093 as a white solid (0.81 g, yield = 80%). ¹ H NMR (500 MHz, CDCl ₃ ) δ 5.95 (s, 1H), 3.88 (s, 2H), 2.18 (p, J = 3.2 Hz, 1H), 1.92-1 .81 (m, 2H), 1.75-1.63 (m, 4H), 1.45-1.40 (m, 2H), 1.39-1.29 (m, 2H), 1.24 -1.13 (m, 2H), 0.88 (s, 6H). ¹³ C NMR (126 MHz, CDCl ₃ ) δ 165.37, 53.83, 53.17, 50.49, 47.43, 42.55, 39.99, 32.44, 30.09, 30.00 . Calc. using HRMS (ESI) mass/charge value for C ₁₄ H ₂₃ N ₄ O ⁺ [M + H] ⁺ : 263.1866; detected value: 263.1863.

Stage 3

To a solution of SIAIS1300091 (0.50 g, 1.9 mmol) in 20 ml THF was added LiAlH ₄ (0.41 g, 10.7 mmol) and the mixture was refluxed for 24 hours. The reaction mixture was successively quenched with 0.41 ml H ₂ O, 0.41 ml 15% NaOH (aq), 1.2 ml H ₂ O. The mixture was then filtered and the solution concentrated in vacuo to give SIAIS1300103 (0.44 g , yield = 89%), which was used without further purification.

Stage 4

[2100] To a solution of SIAIS1300103 (28 mg, 0.11 mmol) and SIAIS40611C (41 mg, 0.11 mmol) in 2 mL of DMF, EDCI (32 mg, 0.17 mmol), HOBT (15 mg, 0. 11 mmol) and DIPEA (18 µl, 0.11 mmol). The reaction was carried out overnight and the mixture was quenched with 0.2 ml of water, then directly purified using preparative HPLC. Compound 23 was obtained as a white powder (20 mg, yield = 30%). ¹ H NMR (500 MHz, CD ₃ OD) δ 7.60 (d, J = 2.2 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.46 (dd, J = 8.5, 2.3 Hz, 1H), 7.42-7.35 (m, 2H), 7.27-7.12 (m, 2H), 3.66 (dd, J = 5, 5, 3.8 Hz, 2H), 3.23 (t, J = 6.1 Hz, 2H), 2.33 (s, 3H), 1.78 (d, J = 3.2 Hz, 2H) , 1.66-1.49 (m, 4H), 1.43 (d, J = 3.0 Hz, 4H), 1.35-1.16 (m, 3H), 0.94 (s, 6H ). Calc. using HRMS (ESI) mass/charge value for C ₃₁ H ₃₆ Cl ₃ N ₄ O ⁺ [M + H] ⁺ : 585.1949; detected value: 585.1941.

Example 13 Preparation of Compound 54

[2110] To a solution of 2-(1-adamantyl)ethanamine (20 mg, 0.11 mmol) and SIAIS40611C (41 mg, 0.11 mmol) in 2 mL of DMF was added successively EDCI (32 mg, 0.17 mmol), HOBT (15 mg, 0.11 mmol) and DIPEA (18 µl, 0.11 mmol). The reaction was carried out overnight and the mixture was quenched with water (0.2 ml) and directly purified using preparative HPLC. Compound 54 was obtained as a white powder (24 mg, yield = 40%). ¹ H NMR (500 MHz, CD ₃ OD) δ 7.57 (d, J = 2.3 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.44 (dd, J = 8.5, 2.3 Hz, 1H), 7.42-7.33 (m, 2H), 7.24-7.14 (m, 2H), 3.63-3.58 (m, 1H), 3.42-3.36 (m, 2H), 2.30 (s, 3H), 2.00-1.48 (m, 17H). Calc. using HRMS (ESI) mass/charge value for C ₂₉ H ₃₁ Cl ₃ N ₃ O ⁺ [M + H] ⁺ : 542.1527; detected value: 542.1531.

Example 14 Get SIAIS1300172

Stage 1

[2120] To a solution of SIAIS40611C (2.0 g, 5.2 mmol) in 25 ml of methanol was added 10 drops of H ₂ SO ₄ (conc.) and the mixture was heated under reflux at 70°C for 12 hours until the solution became transparent. The reaction mixture was quenched with 50 ml of water and the aqueous phase was extracted with DCM (50 ml x 2). The organic phase was combined, washed successively with saturated NaHCO ₃ solution and brine, evaporated in vacuo to give a crude product which was used in the next step without further purification.

Stage 2

[2130] The above product was dissolved in 25 ml of THF and cooled to 0°C, LiAlH ₄ (0.20 g, 5.2 mmol) was added thereto in portions. The solution was warmed naturally to room temperature and kept for 1 hour, after which it was quenched with 0.20 ml H ₂ O, 0.20 ml 15% NaOH (aq.), 0.6 ml H ₂ O. The mixture was filtered and evaporated in vacuo to give a crude product which was used in the next step without further purification.

Stage 3

[2140] The product of step 2 was dissolved in 50 ml of DCM, activated MnO ₂ (4.5 g, 52 mmol) was added thereto and stirred for 12 hours at room temperature. After the starting material was consumed, the mixture was filtered, concentrated in vacuo and purified by silica gel column chromatography to give SIAIS1300172 as a white solid (1.26 g, yield = 66%). ¹ H NMR (500 MHz, CDCl ₃ ) δ 10.06 (s, 1H), 7.38 (dd, J = 1.9, 0.6 Hz, 1H), 7.35-7.21 (m, 4H), 7.08-6.94 (m, 2H), 2.28 (s, 3H). Calc. using HRMS (ESI) mass/charge value for C ₁₇ H ₁₂ Cl ₃ N ₂ O ⁺ [M + H] ⁺ : 365.0010; detected value: 365.0015.

Example 15 Preparation of Compound 164

[2150] To a solution of 2-adamantanone (25 mg, 0.16 mmol) and 1,3-diaminopropane (12 mg, 0.16 mmol) in 1 mL of methanol was added 3Å molecular sieves (25 mg). After stirring for 1 hour, SIAIS1300172 (20 mg, 0.055 mmol) was added to the solution and stirred for an additional 15 minutes, then cooled to 0°C. NaBH ₃ CN (30 mg, 0.49 mmol) and ZnCl ₂ (33 mg, 0.24 mmol) were added sequentially. The solution was kept at 0°C for 2 hours and warmed to room temperature overnight. The reaction mixture was quenched with 10 ml of water and the aqueous phase was extracted with EA (10 ml x 2). The organic phase was combined, washed with brine and evaporated in vacuo. The resulting residue was purified by preparative HPLC to give compound 164 as a white solid (7.3 mg, yield = 21%). ¹ H NMR (500 MHz, CD ₃ OD) δ 7.47 (d, J = 2.1 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 7.34 (dd, J = 8.5, 2.2 Hz, 1H), 7.26 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 8.1 Hz, 2H), 4.30 ( s, 2H), 3.33 (s, 1H), 3.22 (d, J = 6.9 Hz, 2H), 3.10 (t, J = 8.0 Hz, 2H), 2.22 ( q, J = 8.4, 7.8 Hz, 2H), 2.11 (s, 2H), 2.07 (s, 3H), 1.99-1.92 (m, 2H), 1.88 (d, J = 12.4 Hz, 2H), 1.86-1.79 (m, 2H), 1.79-1.69 (m, 4H), 1.64 (d, J = 13.6 Hz, 2H). ¹³ C NMR (126 MHz, CD ₃ OD) δ 144.87, 144.09, 137.45, 137.18, 136.16, 134.07, 132.62, 132.17, 131.07, 129, 93, 129.30, 128.81, 116.07, 64.72, 45.73, 43.95, 43.81, 38.04, 37.75, 31.16, 30.50, 28.35, 28.06, 23.87, 8.32. Calc. using HRMS (ESI) mass/charge value for C ₃₀ H ₃₆ Cl ₃ N ₄ ⁺ [M + H] ⁺ : 557.2000; detected value: 557.1995.

Example 16 Preparation of Compound 165

[2160] SIAIS1300077 (17 mg, 0.082 mmol) was added to a solution of SIAIS1300172 (20 mg, 0.055 mmol) in 1 mL of methanol, and the mixture was stirred for 15 minutes. and then cooled to 0°C. NaBH ₃ CN (30 mg, 0.49 mmol) and ZnCl ₂ (33 mg, 0.24 mmol) were added successively and the reaction medium was kept at 0° C. for 2 hours, after which it was warmed to room temperature. The reaction was carried out overnight and then the reaction mixture was quenched with 10 ml of water. The aqueous phase was extracted with EA (10 ml x 2) and the organic phase was combined, washed with brine and evaporated in vacuo. The resulting residue was purified by preparative HPLC to give compound 165 as a white solid (23 mg, yield = 67%). ¹ H NMR (500 MHz, CD ₃ OD) δ 7.61 (dd, J = 5.3, 2.3 Hz, 2H), 7.46 (dt, J = 8.5, 2.1 Hz, 1H ), 7.38 (dd, J = 8.6, 2.3 Hz, 2H), 7.25-7.16 (m, 2H), 4.60 (s, 2H), 3.65 (s, 2H), 3.50 (s, 1H), 3.32-3.29 (m, 2H), 3.11-3.00 (m, 3H), 2.22 (s, 5H), 2.08 (d, J = 14.2 Hz, 2H), 1.98 (d, J = 12.8 Hz, 2H), 1.91 (s, 2H), 1.82 (s, 4H), 1.73 (d, J = 13.8 Hz, 2H). ¹³ C NMR (126 MHz, CD ₃ OD) δ 144.40, 142.78, 137.33, 137.24, 136.23, 134.11, 132.80, 132.32, 131.01, 129, 90, 129.29, 128.61, 117.97, 65.72, 52.46, 52.22, 41.56, 37.99, 37.67, 31.25, 30.48, 28.29, 28.02, 8.80. Calc. using HRMS (ESI) mass/charge value for C ₃₀ H ₃₆ Cl ₃ N ₄ ⁺ [M + H] ⁺ : 557.2000; detected value: 557.2000.

Example 17 Preparation of Compound 166

[2170] To a solution of 2-adamantanone (42 mg, 0.28 mmol) and ethylenediamine (16 mg, 0.28 mmol) in 1 mL of methanol was added 3Å molecular sieves (25 mg) and stirred for 1 hour. SIAIS1300172 (20 mg, 0.055 mmol) was added and the mixture was stirred for an additional 15 minutes. After cooling to 0°C, NaBH ₃ CN (30 mg, 0.49 mmol) and ZnCl ₂ (33 mg, 0.24 mmol) were added sequentially. The solution was kept at 0°C for 2 hours and warmed to room temperature. Stirred overnight, the reaction mixture was quenched with 10 ml of water and the aqueous phase was extracted with EA (10 ml × 2). The organic phase was combined, washed with brine and evaporated in vacuo. The resulting residue was purified by preparative HPLC to give compound 166 as a white solid (8.5 mg, yield = 25%). ¹ H NMR (500 MHz, CD ₃ OD) δ 7.59 (d, J = 2.3 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.45 (dd, J = 8.4, 2.2 Hz, 1H), 7.41-7.33 (m, 2H), 7.23-7.14 (m, 2H), 4.47 (s, 2H), 3 .68 (t, J = 6.9 Hz, 2H), 3.54-3.50 (m, 2H), 3.49 (s, 1H), 2.22 (s, 2H), 2.19 ( s, 3H), 2.12-1.71 (m, 12H). Calc. using HRMS (ESI) mass/charge value for C ₂₉ H ₃₄ Cl ₃ N ₄ ⁺ [M + H] ⁺ , 543.1844; detected value: 543.1838.

Example 18 Preparation of Compound 167

[2180] To a solution of 2-adamantanone (25 mg, 0.16 mmol) and 1,4-diaminobutane (9.7 mg, 0.11 mmol) in 1 mL of methanol was added 3Å molecular sieves (25 mg). After stirring for 1 hour, SIAIS1300172 (20 mg, 0.055 mmol) was added, stirred for an additional 15 minutes. and then cooled to 0°C. NaBH ₃ CN (30 mg, 0.49 mmol) and ZnCl ₂ (33 mg, 0.24 mmol) were successively added to the solution at 0°C and kept for 2 hours. The solution was warmed to room temperature and stirred overnight. The reaction mixture was quenched with 10 ml of water and extracted with EA (10 ml x 2). The organic phase was combined, washed with brine and evaporated in vacuo. The resulting residue was purified by preparative HPLC to give compound 167 as a white solid (6.1 mg, yield = 17%). ¹ H NMR (500 MHz, CD ₃ OD) δ 7.59 (d, J = 2.0 Hz, 1H), 7.50-7.43 (m, 2H), 7.42-7.34 (m , 2H), 7.26-7.12 (m, 2H), 4.37 (s, 2H), 3.41 (s, 1H), 3.25 (s, 2H), 3.10 (s, 2H), 2.19 (s, 2H), 2.16 (s, 3H), 2.05-1.71 (m, 16H). Calc. using HRMS (ESI) mass/charge value for C ₃₁ H ₃₈ Cl ₃ N ₄ ⁺ [M + H] ⁺ : 571.2157; detected value: 571.2154.

Example 19 Get SIAIS230018

Stage 1

[2190] Mix SIAIS40611C (0.50 g, 1.31 mmol) with 2 ml SOCl₂ and carried out the reaction at 60°C for 2 hours. After completion of the reaction, excess SOCl₂ removed in vacuo. The resulting solid was dissolved in 5 ml DCM and cooled to 0°C, then added dropwise 5 ml of NH₃H₂O (water). The mixture was warmed to room temperature and the reaction was carried out for another 1 hour. The mixture was separated and the aqueous phase was extracted with DCM (20 ml x 2). The organic phase was combined, washed with brine and dried over anhydrous Na₂SO₄. The solution was filtered and concentrated in vacuo to give SIAIS1300073 as a white solid (0.45 g, yield = 90%).

Stage 2

[2200] Ph ₃ PO (1.5 mg, 0.005 mmol) and TEA (0.16 g, 1.56 mmol) were added to a solution of SIAIS1300073 (0.20 g, 0.52 mmol) in 5 ml CH ₃ CN. The mixture was cooled to 0° C. and oxalyl chloride (0.13 g, 1.04 mmol) was added dropwise. The solution was warmed to room temperature and stirred for an additional 20 minutes, then concentrated in vacuo. The residue was purified by silica gel column chromatography to give SIAIS230022 as a colorless oil (0.16 g, yield = 84%). ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.36 (d, J = 2.1 Hz, 1H), 7.27-7.18 (m, 4H), 7.04-6.92 (m, 2H), 2.18(s, 3H). ¹³ C NMR (126 MHz, CDCl ₃ ) δ 142.22, 136.65, 135.66, 135.27, 132.74, 130.51, 130.45, 130.32, 129.20, 128.07 , 127.76, 126.05, 121.01, 113.17, 8.81.

Stage 3

A solution of SIAIS230022 (0.28 g, 0.76 mmol) in 10 ml THF was cooled to 0° C. and LiAlH ₄ (58 mg, 1.52 mmol) was added in portions. The reaction was carried out overnight. The reaction mixture was quenched with 58 μl H ₂ O, 58 μl 15% NaOH (aq.), 0.17 ml H ₂ O. The mixture was filtered and the solution was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to give SIAIS230018 as a white solid (0.22 g, yield = 80%). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.48 (s, 3H), 7.77 (dd, J = 1.8, 0.8 Hz, 1H), 7.58 (d, J = 1.8 Hz, 2H), 7.52-7.40 (m, 2H), 7.26-7.12 (m, 2H), 4.12 (d, J = 5.4 Hz, 2H), 2.09 (s, 3H). ¹³ C NMR (126 MHz, DMSO- d ₆ ) δ 145.88, 141.56, 135.93, 134.71, 133.58, 131.82, 131.67, 130.86, 129.73, 128 .85, 128.45, 127.55, 113.80, 34.58, 7.92. Calc. using HRMS (ESI) mass/charge value for C ₁₇ H ₁₅ Cl ₃ N ₃ ⁺ [M + H] ⁺ : 366.0326; detected value: 366.0321.

Example 20 Preparation of Compound 10

[2220] TEA (69 mg, 0.68 mmol) was added to a solution of SIAIS230018 (25 mg, 0.068 mmol) and 1-adamantanamine hydrochloride (26 mg, 0.136 mmol) in 2 mL of THF. The mixture was cooled to 0°C and triphosgene (20 mg, 0.068 mmol) was added to the solution. The reaction was carried out overnight and the mixture was purified using silica gel column chromatography to give compound 10 as a white solid (9.2 mg, yield = 25%). ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.40 (d, J = 2.2 Hz, 1H), 7.29-7.21 (m, 4H), 7.04 (d, J = 8, 5 Hz, 2H), 4.81 (t, J = 5.2 Hz, 1H), 4.40 (d, J = 5.2 Hz, 2H), 4.35 (s, 1H), 2.08 (s, 3H), 2.07-1.59 (m, 15H). Calc. using HRMS (ESI) mass/charge value for C ₂₈ H ₃₀ Cl ₃ N ₄ O ⁺ [M + H] ⁺ : 543.1480; detected value: 543.1478.

Example 21 Preparation of Compound 11

TEA (69 mg, 0.68 mmol) was added to a solution of SIAIS230018 (25 mg, 0.068 mmol) and 1-adamantanemethylamine (23 mg, 0.136 mmol) in 2 ml THF. The mixture was cooled to 0°C and triphosgene (20 mg, 0.068 mmol) was added to the solution. The resultant was stirred overnight and the mixture was purified by silica gel column chromatography to give compound 11 as a white solid (11.7 mg, yield = 31%). ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.41 (d, J = 2.2 Hz, 1H), 7.34-7.19 (m, 4H), 7.12-7.01 (m, 2H), 4.98 (t, J = 5.3 Hz, 1H), 4.76 (s, 1H), 4.44 (d, J = 5.1 Hz, 2H), 2.88 (d, J = 6.0 Hz, 2H), 2.09 (d, J = 1.5 Hz, 3H), 1.99-1.52 (m, 15H). Calc. using HRMS (ESI) mass/charge value for C ₂₉ H ₃₂ Cl ₃ N ₄ O ⁺ [M + H] ⁺ : 557.1636; detected value: 557.1628.

Example 22 Preparation of Compound 12

[2240] TEA (69 mg, 0.68 mmol) was added to a solution of SIAIS230018 (25 mg, 0.068 mmol) and 2-(1-adamantyl)ethanamine (24 mg, 0.136 mmol) in 2 mL of THF. The mixture was cooled to 0°C and triphosgene (20 mg, 0.068 mmol) was added to the solution. The resultant was stirred overnight and the mixture was purified by silica gel column chromatography to give compound 12 as a white solid (9.7 mg, yield = 25%). ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.41 (d, J = 2.2 Hz, 1H), 7.34-7.19 (m, 4H), 7.10-7.00 (m, 2H), 4.93 (t, J = 5.3 Hz, 1H), 4.48 (s, 1H), 4.44 (d, J = 5.2 Hz, 2H), 3.25-3, 14 (m, 2H), 2.09 (s, 3H), 2.01-1.40 (m, 17H). Calc. using HRMS (ESI) mass/charge value for C ₃₀ H ₃₄ Cl ₃ N ₄ O ⁺ [M + H] ⁺ : 571.1793; detected value: 571.1792.

Example 23 Get SIAIS230032

[2250] A solution of SIAIS230018 (50 mg, 0.14 mmol) in 2 ml THF was cooled to 0°C, TEA (44 mg, 0.34 mmol), acrylyl chloride (19 mg, 0.20 mmol) were added sequentially. The reaction was carried out overnight and the solution was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to give SIAIS230032 as a white solid (50 mg, yield = 87%). ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.34 (d, J = 2.1 Hz, 1H), 7.25-7.15 (m, 4H), 7.03-6.95 (m, 2H), 6.27 (dd, J = 17.0, 1.5 Hz, 1H), 6.25 (s, 1H), 6.09 (dd, J = 17.0, 10.3 Hz, 1H ), 5.60 (dd, J = 10.3, 1.4 Hz, 1H), 4.55 (d, J = 5.1 Hz, 2H), 2.02 (s, 3H). Calc. using HRMS (ESI) mass/charge value for C ₂₀ H ₁₇ Cl ₃ N ₃ O ⁺ [M + H] ⁺ : 420.0432; detected value: 420.0429.

Example 24 Preparation of Compound 168

Stage 1

[2260] A solution of SIAIS230018 (50 mg, 0.14 mmol) in 2 ml THF was cooled to 0°C and TEA (44 mg, 0.34 mmol) and 2-chloroethanesulfonyl chloride (24 mg, 0.15 mmol) were added sequentially. The reaction was carried out overnight and the solution was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to give SIAIS230033 as a white solid (37 mg, yield = 59%). ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.34 (d, J = 2.2 Hz, 1H), 7.23-7.19 (m, 4H), 7.15 (d, J = 8, 5 Hz, 1H), 7.00-6.95 (m, 2H), 6.48 (dd, J = 16.5, 10.0 Hz, 1H), 6.22 (d, J = 16.6 Hz, 1H), 5.87 (d, J = 9.9 Hz, 1H), 4.22 (d, J = 5.5 Hz, 2H), 2.02 (s, 3H). ¹³ C NMR (126 MHz, CDCl ₃ ) δ 147.79, 142.23, 136.12, 135.70, 135.62, 134.75, 132.91, 130.58, 130.51, 130.27 , 128.91, 127.90, 127.61, 126.86, 113.66, 39.54, 8.23. Calc. using HRMS (ESI) mass/charge value for C ₁₉ H ₁₇ Cl ₃ N ₃ O ₂ S ⁺ [M + H] ⁺ : 456.0102; detected value: 456.0095.

Stage 2

Memantine (8.1 mg, 0.045 mmol) was added to a solution of SIAIS230033 (10 mg, 0.022 mmol) in 1 ml of methanol. The mixture was heated under reflux for 24 hours and then purified using preparative HPLC. Compound 168 was obtained as a white solid (8.6 mg, yield = 58%). ¹ H NMR (500 MHz, CD ₃ OD) δ 7.65-7.57 (m, 1H), 7.46 (dd, J = 3.5, 2.1 Hz, 2H), 7.36 (d , J = 8.5 Hz, 2H), 7.17 (d, J = 8.5 Hz, 2H), 4.42 (s, 2H), 3.44 (d, J = 1.2 Hz, 4H ), 2.29-2.21 (m, 1H), 2.14 (s, 3H), 1.70 (s, 2H), 1.58-1.44 (m, 4H), 1.46- 1.33 (m, 4H), 1.33-1.13 (m, 2H), 0.92 (s, 6H). Calc. using HRMS (ESI) mass/charge value for C ₃₁ H ₃₈ Cl ₃ N ₄ O ₂ S ⁺ [M + H] ⁺ : 635.1776; detected value: 635.1770.

Example 25 Preparation of Compound 169

Stage 1

[2280] Cool a solution of SIAIS230018 (100 mg, 0.27 mmol) in 5 ml THF to 0°C. DIPEA (87 mg, 0.68 mmol) and chloroacetyl chloride (46 mg, 0.41 mmol) were added sequentially to the solution. The reaction was carried out overnight and the solution was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to give SIAIS230029 as a white solid (0.11 g, yield = 91%). ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.35 (d, J = 2.1 Hz, 1H), 7.26-7.15 (m, 4H), 7.10 (s, 1H), 7 .03-6.93 (m, 2H), 4.52 (d, J = 5.1 Hz, 2H), 4.04 (s, 2H), 2.02 (s, 3H). Calc. using HRMS (ESI) mass/charge value for C ₁₉ H ₁₆ Cl ₄ N ₃ O ⁺ [M + H] ⁺ : 442.0042; detected value: 442.0032.

Stage 2

[2290] Memantine (8.1 mg, 0.045 mmol) and K ₂ CO ₃ (4.7 mg, 0.035 mmol) were added to a solution of SIAIS230029 (10 mg, 0.023 mmol) in 1 ml CH ₃ CN. The mixture was heated under reflux for 24 hours and purified using preparative HPLC. Compound 169 was obtained as a white solid (12 mg, yield = 85%). ¹ H NMR (500 MHz, CD ₃ OD) δ 7.57 (d, J = 2.0 Hz, 1H), 7.49-7.40 (m, 2H), 7.40-7.32 (m , 2H), 7.21-7.03 (m, 2H), 4.56 (s, 2H), 3.79 (s, 2H), 2.32-2.21 (m, 1H), 2, 11 (s, 3H), 1.76 (d, J = 3.2 Hz, 2H), 1.64-1.45 (m, 4H), 1.42 (d, J = 3.0 Hz, 4H ), 1.35-1.13 (m, 2H), 0.93 (s, 6H). Calc. using HRMS (ESI) mass/charge value for C ₃₁ H ₃₆ Cl ₃ N ₄ O ⁺ [M + H] ⁺ : 585.1949; discovered value: 585.1950.

Example 26 Preparation of Compound 170

Stage 1

[2300] Cool a solution of SIAIS40611D (0.52 g, 1.31 mmol) in 15 ml DCM to 0°C. 1-Boc-piperazine (0.24 g, 1.3 mmol) and TEA (0.14 g, 1.4 mmol) were added thereto. The mixture was allowed to react overnight and then purified by silica gel column chromatography to give SIAIS1300147 as a white solid (0.67 g, yield = 94%). ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.38 (d, J = 2.2 Hz, 1H), 7.25-7.21 (m, 2H), 7.19-7.17 (m, 1H), 7.09 (d, J = 8.5 Hz, 1H), 7.05-6.95 (m, 2H), 3.73 (dt, J = 20.5, 5.1 Hz, 4H ), 3.44 (dt, J = 24.1, 5.1 Hz, 4H), 2.14 (s, 3H), 1.41 (s, 9H). Calc. using HRMS (ESI) mass/charge value for C ₂₆ H ₂₈ Cl ₃ N ₄ O ₃ ⁺ [M + H] ⁺ : 549.1222; detected value: 549.1222.

Stage 2

[2310] SIAIS1300147 (0.20 g, 0.36 mmol) was dissolved in a solution of DCM/TFA (1 ml/1 ml) and reacted overnight. The solution was concentrated in vacuo and purified by reverse phase column to give SIAIS1300163 as a white solid (0.13 g, yield = 79%). ¹ H NMR (500 MHz, CD ₃ OD) δ 7.63 (d, J = 2.0 Hz, 1H), 7.47-7.42 (m, 2H), 7.41-7.37 (m , 2H), 7.22-7.18 (m, 2H), 4.09 (d, J = 63.8 Hz, 4H), 3.36-3.32 (m, 4H), 2.19 ( s, 3H). Calc. using HRMS (ESI) mass/charge value for C ₂₁ H ₂₀ Cl ₃ N ₄ O ⁺ [M + H] ⁺ : 449.0697; detected value: 449.0703.

Stage 3

[2320] Cool a solution of 1-adamantanecarbonyl chloride (12 mg, 0.067 mmol) in 2 ml DCM to 0°C. SIAIS1300163 (20 mg, 0.044 mmol) and TEA (14 mg, 0.134 mmol) were added thereto, and the solution was warmed naturally to room temperature. The mixture was allowed to react for 12 hours and the solvent was removed in vacuo. The resulting residue was purified by silica gel column chromatography to give compound 170 as a white solid (8.6 mg, yield = 32%). ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.39 (d, J = 2.3 Hz, 1H), 7.28-7.21 (m, 3H), 7.11 (d, J = 8, 5 Hz, 1H), 7.06-6.95 (m, 2H), 3.79 (d, J = 5.6 Hz, 2H), 3.74 (s, 4H), 3.66 (t, J = 5.2 Hz, 2H), 2.14 (s, 3H), 1.99 (s, 3H), 1.94 (d, J = 2.8 Hz, 6H), 1.73-1, 63(m, 6H). Calc. using HRMS (ESI) mass/charge value for C ₃₂ H ₃₄ Cl ₃ N ₄ O ₂ ⁺ [M + H] ⁺ : 611.1742; detected value: 611.1734.

Example 27 Preparation of Compound 171

[2330] SIAIS40611C (0.13 g, 0.34 mmol), (±)-isoborneol (0.05 g, 0.32 mmol), DMAP (10 mg) and EDCI (0.068 g, 0.35 mmol) were added sequentially ) to 3 ml THF and the mixture was stirred at room temperature for 12 hours. After consumption of the starting material, the reaction mixture was quenched with 5 ml of water and the aqueous phase was extracted with EA (10 ml × 3). The organic phase was combined, washed with brine and dried over anhydrous Na ₂ SO ₄ . The solution was filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to give compound 171 as a white solid (0.10 g, yield = 60%). ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.38 (d, J = 2.2 Hz, 1H), 7.32 (t, J = 5.8 Hz, 1H), 7.31-7.28 (m, 3H), 7.07-7.05 (m, 2H), 5.00 (dd, J = 7.5, 4.3 Hz, 1H), 2.30 (s, 3H), 1, 97 (dd, J = 10.1, 5.9 Hz, 1H), 1.79 (q, J = 4.2 Hz, 1H), 1.76-1.70 (m, 1H), 1.69 (s, 1H), 1.65-1.58 (m, 1H), 1.28-1.23 (m, 1H), 1.18-1.12 (m, 1H), 1.10 (s , 3H), 0.99 (s, 3H), 0.88 (s, 4H). Calc. using HRMS (ESI) mass/charge value for C ₂₇ H ₂₈ Cl ₃ N ₂ O ₂ [M+H] ⁺ : 517.1216; detected value: 517.1209.

Example 28 Preparation of Compound 172

[2340] Connection 172 was obtained in accordance with the procedure similar to that described in example 27, using (-)-borneol as starting material (white solid, yield = 50%). ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.38 (d, J = 2.2 Hz, 1H), 7.36-7.34 (m, 1H), 7.32-7.28 (m, 3H), 7.09-7.05 (m, 2H), 5.22 (ddd, J = 9.9, 3.4, 2.2 Hz, 1H), 2.54-2.47 (m, 1H), 2.33 (s, 3H), 2.17-2.11 (m, 1H), 1.83-1.76 (m, 1H), 1.74 (t, J = 4.5 Hz , 1H), 1.43-1.38 (m, 1H), 1.35-1.29 (m, 1H), 1.20 (dd, J = 13.9, 3.5 Hz, 1H), 0.98 (s, 3H), 0.95 (s, 3H), 0.92 (s, 3H). Calc. using HRMS (ESI) mass/charge value for C ₂₇ H ₂₈ Cl ₃ N ₂ O ₂ ⁺ [M+H] ⁺ : 517.1216; detected value: 517.1212.

Example 29 Preparation of Compound 173

[2350] Connection 173 was obtained in accordance with a procedure similar to that described in example 27, using (+)-borneol as a starting material. (white solid, yield = 65%). ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.38 (d, J = 2.2 Hz, 1H), 7.37-7.34 (m, 1H), 7.29 (td, J = 6, 9, 3.4 Hz, 3H), 7.07 (d, J = 8.4 Hz, 2H), 5.31-5.09 (m, 1H), 2.54-2.47 (m, 1H ), 2.33 (s, 3H), 2.17-2.11 (m, 1H), 1.83-1.76 (m, 1H), 1.74 (t, J = 4.4 Hz, 1H), 1.43-1.38 (m, 1H), 1.35-1.30 (m, 1H), 1.20 (dd, J = 13.8, 3.5 Hz, 1H), 0 .98 (s, 3H), 0.95 (s, 3H), 0.92 (s, 3H). Calc. using HRMS (ESI) mass/charge value for C ₂₇ H ₂₈ Cl ₃ N ₂ O ₂ ⁺ [M+H] ⁺ : 517.1216; detected value: 517.1207.

Example 30 Preparation of Compound 174

[2360] Compound 174 was obtained in accordance with a procedure similar to that described in example 16. (white solid, yield = 70%), ¹ H NMR (500 MHz, CD ₃ OD) δ 7.58 (d, J = 8, 6 Hz, 2H), 7.44 (dd, J = 8.7, 2.2 Hz, 1H), 7.38 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 8.2 Hz, 2H), 4.52 (s, 2H), 4.04 (s, 2H), 3.85 (s, 4H), 3.55-3.30 (m, 3H), 2, 43 (s, 2H), 2.20 (s, 3H), 2.25-2.15 (m, 2H), 2.06 (d, J = 12.9 Hz, 2H), 1.94 (d , J = 11.4 Hz, 2H), 1.86 (d, J = 15.1 Hz, 4H), 1.74 (d, J = 13.6 Hz, 2H). Calc. using HRMS (ESI) mass/charge value for C ₃₁ H ₃₆ Cl ₃ N ₄ ⁺ [M+H] ⁺ : 569.2000; detected value: 569.2078.

Example 31 Preparation of Compound 175

[2370] Connection 175 was obtained in accordance with the procedure similar to that described in example 16, using 1-(((3r,5r,7r)-adamantan-1-yl)methyl)piperazine as starting material instead of the specified one. ¹ H NMR (500 MHz, CD ₃ OD) δ 7.60 (s, 1H), 7.55 (dd, J = 14.4, 8.5 Hz, 1H), 7.44 (d, J = 8 .5 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.3 Hz, 2H), 4.42 (d, J = 30.7 Hz, 2H), 3.90-3.70 (br, s, 4H), 3.70-3.30 (br, s, 4H), 2.96 (s, 2H), 2.20 (s, 3H), 2.04 (s, 3H), 1.85-1.70 (m, 12H). Calc. using HRMS (ESI) mass/charge value for C ₃₂ H ₃₈ Cl ₃ N ₄ ⁺ [M+H] ⁺ : 583.2157; detected value: 583.2215.

Example 32 Preparation of Compound 178

[2380] Step 1: Dissolve (methoxymethyl)triphenylphosphonium chloride (200 mg, 0.58 mmol) in 8 ml anhydrous THF and cool to -78°C. To this was added dropwise a solution of 1 M LHMDS in THF (0.84 ml, 0.84 mmol). Warmed to 0° C. naturally, then SIAS292180 (212 mg, 0.58 mmol) was added and the reaction was carried out overnight. The reaction mixture was quenched with water and the organic phase was extracted with DCM (20 ml x 3). The organic solution was evaporated and the residue was purified by silica gel column chromatography.

The above product was dissolved in acetone and hydrolysed with 6 M HCl (aq) for 4 hours to give compound SIAIS292180 as a white solid (0.13 g, yield = 58%). Calc. using MS (ESI) mass/charge value for C ₁₈ H ₁₄ Cl ₃ N ₂ O ⁺ [M+H] ⁺ : 379.02; detected value: 379.14.

[2390] Step 2. Compound 178 was prepared according to a procedure similar to that described in Example 16 using N1-((1r,3r,5r,7r)-adamantan-2-yl)-N2-benzylethane-1,2- diamine as starting material instead of the specified one and followed by hydrogenation in MeOH solution at 60°C for 24 h. ¹ H NMR (500 MHz, CD ₃ OD) δ 7.62 (s, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 7.38 (d, J = 7.8 Hz, 2H), 7.22 (d, J = 7.9 Hz, 2H), 4.56 (s, 2H), 3.82 (s, 2H), 3.41 (s, 1H), 3.04 (s, 2H), 2.97 (s, 2H), 2.41 (s, 2H), 2.20 (s, 3H), 2.00 (d, J = 13.3 Hz, 3H), 1.88 (d, J = 17.5 Hz, 3H), 1.78(s, 4H), 1.67(s, 2H). Calc. using HRMS (ESI) mass/charge value for C ₃₀ H ₃₆ Cl ₃ N ₄ ⁺ [M+H] ⁺ : 557.2000; detected value: 557.1998.

Example 33 Preparation of Compound 179

[2400] Step 1. SIAIS292173 was prepared according to a similar procedure to SIAIS1300093 using hydrazine hydrate instead of NaN ₃ using EtOH as a solvent, and the reaction was carried out at room temperature.

Step 2 Compound 179 was prepared using a procedure similar to that described in Example 13. ¹ H NMR (500 MHz, CD ₃ OD) δ 7.56 (s, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.44 (d, J = 8.3 Hz, 1H), 7.37 (d, J = 8.2 Hz, 2H), 7.20 (d, J = 8.2 Hz, 2H), 3.44 (s, 2H), 2.32 (s, 3H), 2.13-1.97 (m, 9H), 1.72 (d, J = 2.9 Hz, 6H). Calc. using HRMS (ESI) mass/charge value for C ₂₉ H ₃₁ Cl ₃ N ₅ O ₂ ⁺ [M+H] ⁺ : 586.1538; detected value: 586.1540.

Biological Activity Test Example 1

[2420] The microplate method using resazurin was used to measure the MIC (minimum inhibitory concentration) of small molecule MmpL3 inhibitors against Mycobacterium smegmatis .

[2430] The experiment was carried out in accordance with the methods described in the literature (SQ109 targets MmpL3, a membrane transporter of trehalose monomycolate involved in mycolic acid donation to the cell wall core of Mycobacterium tuberculosis . [J] Antimicrobial Agents and Chemotherapy, 2012, 4 (56) 1797-1809).

[2440] (1) Preparation of liquid inoculum: A strain of Mycobacterium smegmatis (mc ² 155) was grown in 7H9 liquid medium (7H9 agar, 50% glycerol, 0.05% Tween 80, and 10.05% ADS) at a ratio of 1: 100 on a sterile work table, oscillated at 37°C, 220 rpm. After reaching an OD ₆₀₀ value of 1.0, cells were centrifuged at 8000 rpm for 10 min and harvested by adding 1 ml of 50% glycerol (sterilized) and 1 ml of 7H9 liquid medium on a sterile worktable. The strains were frozen at -80°C after packaging in parts. The liquid inoculum was a strain of Mycobacterium smegmatis (mc ² 155) grown to OD ₆₀₀ = 1.0 and kept fresh by refreshing every three weeks.

[2450] (2) Activation of the liquid inoculum: the liquid inoculum was inoculated into 5 ml of 7H9 liquid medium at a ratio of 1:100 on a sterile worktable and oscillated at 37°C, 220 rpm until an OD value of ₆₀₀ was reached. which was 0.5 (logarithmic growth phase). The OD ₆₀₀ of cultured bacteria was adjusted to 0.15 with 7H9 liquid medium and then diluted 100-fold for use.

[2460] (3) Dilution of the rimonabant positive control compound: rimonabant was used as a positive control during the experiment. Rimonabant is a cannabinoid type I (CB1) receptor inhibitor, a new type of weight loss drug that has entered the market. Studies have shown that rimonabant is also an inhibitor of MmpL3 and has a significant inhibitory effect on Mycobacterium tuberculosis (H37Rv). Rimonabant was prepared in the following gradient dilutions: 543.9024392 µg/mL, 271.9512196 µg/mL, 135.9756098 µg/mL, 67.98780492 µg/mL, 33.99390246 µg/mL, 16.99695123 mcg/ml, 8 .498475615 µg/ml, 4.249237808 µg/ml, 2.124618904 µg/ml, 1.062309452 µg/ml, 0.531154726 µg/ml, 0.265577363 µg/ml. Typically, the sixth dilution gradient was guaranteed to be the minimum inhibitory concentration of the compound against wild-type strains. The MIC of rimonabant against the M. smegmatis strain is 16.99695123 µg/mL.

[2470] (4) Dilution of small molecule inhibitors of Mycobacterium MmpL3 membrane protein: Compounds were diluted according to a 2-fold dilution gradient. Gradient dilutions for each small molecular weight compound are given as the following list. Compound 17 gradient dilutions were 380.48 μg/mL, 190.24 μg/mL, 95.12 μg/mL, 47.56 μg/mL, 23.78 μg/mL, 11.89 μg/mL, 5.945 μg /ml, 2.9725 µg/ml, 1.48625 µg/ml, 0.743125 µg/ml, 0.3715625 µg/ml, 0.18578125 µg/ml; compound 76 gradient dilutions were 468.288 µg/mL, 234.144 µg/mL, 117.072 µg/mL, 58.536 µg/mL, 29.268 µg/mL, 14.634 µg/mL, 7.317 µg/mL, 3.6585 m kg/ml, 1, 82925 µg/ml, 0.914625 µg/ml, 0.4573125 µg/ml, 0.22865625 µg/ml; gradient dilutions of compound 77 were 331.52 µg/ml, 165.76 µg/ml, 82.88 µg/ml, 41.44 µg/ml, 20.72 µg/ml, 10.36 µg/ml, 5, 18 µg/ml, 2.59 µg/ml, 1.295 µg/ml, 0.6475 µg/ml, 0.32375 µg/ml, 0.161875 µg/ml; compound 74 gradient dilutions were 107.32 µg/ml, 53.66 µg/ml, 26.83 µg/ml, 13.415 µg/ml, 6.7075 µg/ml, 3.35375 µg/ml, 1.676875 µg /ml, 0.8384375 µg/ml, 0.41921875 µg/ml, 0.209609375 µg/ml; compound 18 gradient dilutions were 97.56 µg/mL, 48.78 µg/mL, 24.39 µg/mL, 12.195 µg/mL, 6.0975 µg/mL, 3.04875 µg/mL, 1.524375 µg /ml, 0.7621875 µg/ml, 0.38109375 µg/ml, 0.190546875 µg/ml; compound 19 gradient dilutions were 107.32 µg/mL, 53.66 µg/mL, 26.83 µg/mL, 13.415 µg/mL, 6.7075 µg/mL, 3.35375 µg/mL, 1.676875 µg /ml, 0.8384375 µg/ml, 0.41921875 µg/ml, 0.209609375 µg/ml; compound 163 gradient dilutions were 117.0732 µg/mL, 58.5366 µg/mL, 29.2683 µg/mL, 14.6341 µg/mL, 7.3171 µg/mL, 3.6585 µg/mL, 1, 8293 µg/ml, 0.9146 µg/ml, 0.4573 µg/ml, 0.2287 µg/ml, 0.1143 µg/ml, 0.0572 µg/ml; compound 23 gradient dilutions were 117.0732 µg/ml, 58.5366 µg/ml, 29.2683 µg/ml, 14.6341 µg/ml, 7.3171 µg/ml, 3.6585 µg/ml, 1, 8293 µg/ml, 0.9146 µg/ml, 0.4573 µg/ml, 0.2287 µg/ml, 0.1143 µg/ml, 0.0572 µg/ml; compound 164 gradient dilutions were 207.3171 µg/mL, 103.6585 µg/mL, 51.8293 µg/mL, 25.9146 µg/mL, 12.9573 µg/mL, 6.4787 µg/mL, 3, 2393 µg/ml, 1.6197 µg/ml, 0.8098 µg/ml, 0.4049 µg/ml, 0.2025 µg/ml, 0.1012 µg/ml; compound 165 gradient dilutions were 231.7073 µg/mL, 115.8537 µg/mL, 57.9268 µg/mL, 28.9634 µg/mL, 14.4817 µg/mL, 7.2409 µg/mL, 3, 6204 µg/ml, 1.8102 µg/ml, 0.9051 µg/ml, 0.4526 µg/ml, 0.2263 µg/ml, 0.1131 µg/ml; compound 10 gradient dilutions were 170.7317 µg/mL, 85.3659 µg/mL, 42.6829 µg/mL, 21.3415 µg/mL, 10.6707 µg/mL, 5.3354 µg/mL, 2, 6677 µg/ml, 1.3338 µg/ml, 0.6669 µg/ml, 0.3335 µg/ml, 0.1667 µg/ml, 0.0834 µg/ml; compound 11 gradient dilutions were 134.1463 µg/mL, 67.0732 µg/mL, 33.5366 µg/mL, 16.7683 µg/mL, 8.3841 µg/mL, 4.1921 µg/mL, 2, 0960 µg/ml, 1.0480 µg/ml, 0.5240 µg/ml, 0.2620 µg/ml, 0.1310 µg/ml, 0.0655 µg/ml; compound 12 gradient dilutions were 121.9512 µg/mL, 60.9756 µg/mL, 30.4878 µg/mL, 15.2439 µg/mL, 7.6220 µg/mL, 3.8110 µg/mL, 1, 9055 µg/ml, 0.9527 µg/ml, 0.4764 µg/ml, 0.2382 µg/ml, 0.1191 µg/ml, 0.0595 µg/ml; compound 171 gradient dilutions were 200.0000 µg/mL, 100.0000 µg/mL, 50.0000 µg/mL, 25.0000 µg/mL, 12.5000 µg/mL, 6.2500 µg/mL, 3, 1250 µg/ml, 1.5625 µg/ml, 0.7813 µg/ml, 0.3906 µg/ml, 0.1953 µg/ml, 0.0977 µg/ml; compound 172 gradient dilutions were 337.8049 µg/mL, 168.9024 µg/mL, 84.4512 µg/mL, 42.2256 µg/mL, 21.1128 µg/mL, 10.5564 µg/mL, 5, 2782 µg/ml, 2.6391 µg/ml, 1.3196 µg/ml, 0.6598 µg/ml, 0.3299 µg/ml, 0.1649 µg/ml; compound 173 gradient dilutions were 231.7073 µg/mL, 115.8537 µg/mL, 57.9268 µg/mL, 28.9634 µg/mL, 14.4817 µg/mL, 7.2409 µg/mL, 3, 6204 µg/ml, 1.8102 µg/ml, 0.9051 µg/ml, 0.4526 µg/ml, 0.2263 µg/ml, 0.1131 µg/ml; compound 166 gradient dilutions were 243.9024 µg/mL, 121.9512 µg/mL, 60.9756 µg/mL, 30.4878 µg/mL, 15.2439 µg/mL, 7.6220 µg/mL, 3, 8110 µg/ml, 1.9055 µg/ml, 0.9527 µg/ml, 0.4764 µg/ml, 0.2382 µg/ml, 0.1191 µg/ml; gradient dilutions of compound 167 were 268.2927 µg/ml, 134.1463 µg/ml, 67.0732 µg/ml, 33.5366 µg/ml, 16.7683 µg/ml, 8.3841 µg/ml, 4, 1921 µg/ml, 2.0960 µg/ml, 1.0480 µg/ml, 0.5240 µg/ml, 0.2620 µg/ml, 0.1310 µg/ml; compound 169 gradient dilutions were 243.9024 µg/mL, 121.9512 µg/mL, 60.9756 µg/mL, 30.4878 µg/mL, 15.2439 µg/mL, 7.6220 µg/mL, 3, 8110 µg/ml, 1.9055 µg/ml, 0.9527 µg/ml, 0.4764 µg/ml, 0.2382 µg/ml, 0.1191 µg/ml; compound 168 gradient dilutions were 341.4634 µg/mL, 170.7317 µg/mL, 85.3659 µg/mL, 42.6829 µg/mL, 21.3415 µg/mL, 10.6707 µg/mL, 5, 3354 µg/ml, 2.6677 µg/ml, 1.3338 µg/ml, 0.6669 µg/ml, 0.3335 µg/ml, 0.1667 µg/ml; compound 170 gradient dilutions were 292.6829 µg/mL, 146.3415 µg/mL, 73.1707 µg/mL, 36.5854 µg/mL, 18.2927 µg/mL, 9.1463 µg/mL, 4, 5732 µg/ml, 2.2866 µg/ml, 1.1433 µg/ml, 0.5716 µg/ml, 0.2858 µg/ml, 0.1429 µg/ml.

[2480] (5) Add 40 µl of 7H9 liquid medium (containing Tween-80 and ADS) to 96-well plates. Three replicates were set for each gradient. 2 µl of compounds with various gradients and 40 µl of diluted cultured bacteria (mc ² 155) were added and mixed by gentle shaking. The plates were incubated in an incubator at 37°C for 48 hours.

[2490] (6) Added 0.02% (w/v) resazurin solution to the wells on a sterile worktable and continued to incubate the plates in the incubator for 4 hours. Bacterial growth was observed under an inverted microscope. The MIC was defined as the lowest concentration of a compound that stopped bacterial growth. Resazurin was pink when bacterial growth was stopped and blue when growth continued.

Biological Activity Test Example 2

[2500] The resazurin microplate method was used to measure the MICs of small molecule MmpL3 inhibitors against Mycobacterium bovis BCG strain and Mycobacterium tuberculosis H37Ra strain.

[250] (1) Preparation of liquid inoculum: BCG strain and H37Ra strain were grown in 7H9 liquid medium (7H9 agar, 50% glycerol, 0.05% Tween 80 and 10.05% ADS) at a ratio of 1:100 on sterile desktop, oscillated at 37°C, 110 rpm. After reaching an OD ₆₀₀ value of 1.0, the cells were centrifuged at 8000 rpm. within 10 min. and harvested by adding 1 ml of 50% glycerol (sterilized) and 1 ml of 7H9 liquid medium on a sterile worktable. The strains were frozen at -80°C after packaging in parts. The liquid inoculum was a strain grown to OD ₆₀₀ =1.0 and kept fresh by refreshing every three weeks.

[2520] (2) Activation of liquid inoculum: The liquid inoculum was inoculated into 5 ml of 7H9 liquid medium at a ratio of 1:100 on a sterile worktable and oscillated at 37°C, 110 rpm until an OD of ₆₀₀ was reached. which was 0.5 (logarithmic growth phase). The OD ₆₀₀ of cultured bacteria was adjusted to 0.15 with 7H9 liquid medium and then diluted 100-fold for use.

[2530] (3) Dilution of the rimonabant positive control compound: rimonabant was used as a positive control during the experiment. Rimonabant is a cannabinoid type I (CB1) receptor inhibitor, a new type of weight loss drug that has entered the market. Studies have shown that rimonabant is also an inhibitor of MmpL3 and has a significant inhibitory effect on Mycobacterium tuberculosis (H37Rv). Rimonabant was prepared in the following gradient dilutions: 543.9024392 µg/mL, 271.9512196 µg/mL, 135.9756098 µg/mL, 67.98780492 µg/mL, 33.99390246 µg/mL, 16.99695123 mcg/ml, 8 .498475615 µg/ml, 4.249237808 µg/ml, 2.124618904 µg/ml, 1.062309452 µg/ml, 0.531154726 µg/ml, 0.265577363 µg/ml. Typically, the sixth dilution gradient was guaranteed to be the minimum inhibitory concentration of the compound against wild-type strains. The MICs of rimonabant against the BCG strain and the H37Ra strain were 33.99390246 μg/mL and 16.99695123 μg/mL, respectively.

[2540] (4) Dilution of small molecule inhibitors of Mycobacterium MmpL3 membrane protein: Compounds were diluted according to a 2-fold dilution gradient. Gradient dilutions for each small molecular weight compound are given as the following list. Compound 17 gradient dilutions were 380.48 μg/mL, 190.24 μg/mL, 95.12 μg/mL, 47.56 μg/mL, 23.78 μg/mL, 11.89 μg/mL, 5.945 μg /ml, 2.9725 µg/ml, 1.48625 µg/ml, 0.743125 µg/ml, 0.3715625 µg/ml, 0.18578125 µg/ml; compound 76 gradient dilutions were 468.288 µg/mL, 234.144 µg/mL, 117.072 µg/mL, 58.536 µg/mL, 29.268 µg/mL, 14.634 µg/mL, 7.317 µg/mL, 3.6585 m kg/ml, 1, 82925 µg/ml, 0.914625 µg/ml, 0.4573125 µg/ml, 0.22865625 µg/ml; gradient dilutions of compound 77 were 331.52 µg/ml, 165.76 µg/ml, 82.88 µg/ml, 41.44 µg/ml, 20.72 µg/ml, 10.36 µg/ml, 5, 18 µg/ml, 2.59 µg/ml, 1.295 µg/ml, 0.6475 µg/ml, 0.32375 µg/ml, 0.161875 µg/ml; compound 74 gradient dilutions were 107.32 µg/ml, 53.66 µg/ml, 26.83 µg/ml, 13.415 µg/ml, 6.7075 µg/ml, 3.35375 µg/ml, 1.676875 µg /ml, 0.8384375 µg/ml, 0.41921875 µg/ml, 0.209609375 µg/ml; compound 18 gradient dilutions were 97.56 µg/mL, 48.78 µg/mL, 24.39 µg/mL, 12.195 µg/mL, 6.0975 µg/mL, 3.04875 µg/mL, 1.524375 µg /ml, 0.7621875 µg/ml, 0.38109375 µg/ml, 0.190546875 µg/ml; compound 19 gradient dilutions were 107.32 µg/mL, 53.66 µg/mL, 26.83 µg/mL, 13.415 µg/mL, 6.7075 µg/mL, 3.35375 µg/mL, 1.676875 µg /ml, 0.8384375 µg/ml, 0.41921875 µg/ml, 0.209609375 µg/ml; compound 163 gradient dilutions were 117.0732 µg/mL, 58.5366 µg/mL, 29.2683 µg/mL, 14.6341 µg/mL, 7.3171 µg/mL, 3.6585 µg/mL, 1, 8293 µg/ml, 0.9146 µg/ml, 0.4573 µg/ml, 0.2287 µg/ml, 0.1143 µg/ml, 0.0572 µg/ml; compound 23 gradient dilutions were 117.0732 µg/ml, 58.5366 µg/ml, 29.2683 µg/ml, 14.6341 µg/ml, 7.3171 µg/ml, 3.6585 µg/ml, 1, 8293 µg/ml, 0.9146 µg/ml, 0.4573 µg/ml, 0.2287 µg/ml, 0.1143 µg/ml, 0.0572 µg/ml; compound 164 gradient dilutions were 207.3171 µg/mL, 103.6585 µg/mL, 51.8293 µg/mL, 25.9146 µg/mL, 12.9573 µg/mL, 6.4787 µg/mL, 3, 2393 µg/ml, 1.6197 µg/ml, 0.8098 µg/ml, 0.4049 µg/ml, 0.2025 µg/ml, 0.1012 µg/ml; compound 165 gradient dilutions were 231.7073 µg/mL, 115.8537 µg/mL, 57.9268 µg/mL, 28.9634 µg/mL, 14.4817 µg/mL, 7.2409 µg/mL, 3, 6204 µg/ml, 1.8102 µg/ml, 0.9051 µg/ml, 0.4526 µg/ml, 0.2263 µg/ml, 0.1131 µg/ml; compound 10 gradient dilutions were 170.7317 µg/mL, 85.3659 µg/mL, 42.6829 µg/mL, 21.3415 µg/mL, 10.6707 µg/mL, 5.3354 µg/mL, 2, 6677 µg/ml, 1.3338 µg/ml, 0.6669 µg/ml, 0.3335 µg/ml, 0.1667 µg/ml, 0.0834 µg/ml; compound 11 gradient dilutions were 134.1463 µg/mL, 67.0732 µg/mL, 33.5366 µg/mL, 16.7683 µg/mL, 8.3841 µg/mL, 4.1921 µg/mL, 2, 0960 µg/ml, 1.0480 µg/ml, 0.5240 µg/ml, 0.2620 µg/ml, 0.1310 µg/ml, 0.0655 µg/ml; compound 12 gradient dilutions were 121.9512 µg/mL, 60.9756 µg/mL, 30.4878 µg/mL, 15.2439 µg/mL, 7.6220 µg/mL, 3.8110 µg/mL, 1, 9055 µg/ml, 0.9527 µg/ml, 0.4764 µg/ml, 0.2382 µg/ml, 0.1191 µg/ml, 0.0595 µg/ml; compound 171 gradient dilutions were 200.0000 µg/mL, 100.0000 µg/mL, 50.0000 µg/mL, 25.0000 µg/mL, 12.5000 µg/mL, 6.2500 µg/mL, 3, 1250 µg/ml, 1.5625 µg/ml, 0.7813 µg/ml, 0.3906 µg/ml, 0.1953 µg/ml, 0.0977 µg/ml; compound 172 gradient dilutions were 337.8049 µg/mL, 168.9024 µg/mL, 84.4512 µg/mL, 42.2256 µg/mL, 21.1128 µg/mL, 10.5564 µg/mL, 5, 2782 µg/ml, 2.6391 µg/ml, 1.3196 µg/ml, 0.6598 µg/ml, 0.3299 µg/ml, 0.1649 µg/ml; compound 173 gradient dilutions were 231.7073 µg/mL, 115.8537 µg/mL, 57.9268 µg/mL, 28.9634 µg/mL, 14.4817 µg/mL, 7.2409 µg/mL, 3, 6204 µg/ml, 1.8102 µg/ml, 0.9051 µg/ml, 0.4526 µg/ml, 0.2263 µg/ml, 0.1131 µg/ml; compound 166 gradient dilutions were 243.9024 µg/mL, 121.9512 µg/mL, 60.9756 µg/mL, 30.4878 µg/mL, 15.2439 µg/mL, 7.6220 µg/mL, 3, 8110 µg/ml, 1.9055 µg/ml, 0.9527 µg/ml, 0.4764 µg/ml, 0.2382 µg/ml, 0.1191 µg/ml; gradient dilutions of compound 167 were 268.2927 µg/ml, 134.1463 µg/ml, 67.0732 µg/ml, 33.5366 µg/ml, 16.7683 µg/ml, 8.3841 µg/ml, 4, 1921 µg/ml, 2.0960 µg/ml, 1.0480 µg/ml, 0.5240 µg/ml, 0.2620 µg/ml, 0.1310 µg/ml; compound 169 gradient dilutions were 243.9024 µg/mL, 121.9512 µg/mL, 60.9756 µg/mL, 30.4878 µg/mL, 15.2439 µg/mL, 7.6220 µg/mL, 3, 8110 µg/ml, 1.9055 µg/ml, 0.9527 µg/ml, 0.4764 µg/ml, 0.2382 µg/ml, 0.1191 µg/ml; compound 168 gradient dilutions were 341.4634 µg/mL, 170.7317 µg/mL, 85.3659 µg/mL, 42.6829 µg/mL, 21.3415 µg/mL, 10.6707 µg/mL, 5, 3354 µg/ml, 2.6677 µg/ml, 1.3338 µg/ml, 0.6669 µg/ml, 0.3335 µg/ml, 0.1667 µg/ml; compound 170 gradient dilutions were 292.6829 µg/mL, 146.3415 µg/mL, 73.1707 µg/mL, 36.5854 µg/mL, 18.2927 µg/mL, 9.1463 µg/mL, 4, 5732 µg/ml, 2.2866 µg/ml, 1.1433 µg/ml, 0.5716 µg/ml, 0.2858 µg/ml, 0.1429 µg/ml.

[2550] (5) Added 40 µl of 7H9 liquid medium (containing Tween-80 and ADS) to 96-well plates. Three replicates were set for each gradient. 2 µl of compounds with various gradients and 40 µl of diluted cultured bacteria (BCG strain or H37Ra strain) were added and mixed by gentle shaking. The plates were incubated in an incubator at 37°C for 168 hours.

[2560] (6) Added 0.02% (w/v) resazurin solution to the wells on a sterile worktable and continued to incubate the plates in the incubator for 4 hours. Bacterial growth was observed under an inverted microscope. The MIC was defined as the lowest concentration of a compound that stopped bacterial growth. Resazurin was pink when bacterial growth was stopped and blue when growth continued.

[2570] MIC results for small molecule MmpL3 inhibitors against Mycobacterium smegmatis , Mycobacterium bovis BCG, and Mycobacterium tuberculosis H37Ra are shown in Table 2.

table 2

[2580] The data in Table 2 showed that against strains of M. smegmatis, BCG and H37Ra, all of compounds 17 ', 76 ', 77 ', 74' , 18 ', 19 ', 163 and 23 had an appropriate inhibitory effect. Among them, Compound 76 and Compound 23 are superior to other compounds in a broad spectrum of antimicrobial activity and can be used as potential drugs for Mycobacterium.beta. infection.

[2590] Unless otherwise indicated, all technical and scientific terms used in this document have the same meanings that are usually understood by a person of ordinary skill in the field of technology to which the present invention pertains.

[2600] The present invention illustratively described herein can be practiced in an appropriate manner in the absence of any element or elements, limitation or limitations not specifically disclosed herein. Thus, for example, the terms "providing", "including", "comprising", etc. should be interpreted broadly and without limitation. In addition, the terms and expressions used herein are used as descriptive, not limiting terms, and such terms and expressions are not intended to exclude any equivalents to the items or parts shown and described, but various modifications are possible within the scope of the claimed invention.

[2610] All publications, patent applications, patents and other references mentioned in this document are expressly incorporated herein by reference in their entirety to the same extent as if each of them were incorporated by reference individually . In the event of a conflict, the present description, including definitions, will take precedence.

[2620] It should be understood that while the present invention has been described in conjunction with the embodiments described above, the above description and examples are intended to be illustrative and not intended to limit the scope of the present invention. The present invention is not limited to the embodiments shown and described above, but may be varied within the scope of the claims. Other aspects, advantages and modifications within the scope of the present invention will be apparent to those skilled in the art to which the present invention pertains.

Claims (49)

1. Compound of formula I:

or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof, Where formula I is

; X ¹ , X ² and X ³ are C; X ⁴ and X ⁵ are N; L ¹ is *-(CH ₂ ) _n -N(R ^1c )-(CH ₂ ) _k -N(R ^1b )CO-, *-(CH ₂ ) _m -CO-L ^1a -CO-, *- (CH ₂ ) _n -NHCONH-(CH ₂ ) _m -, *-(CH ₂ ) _n -N(R ^1c )-(CH ₂ ) _k -N(R ^1b )-(CH ₂ ) _m -, *- (CH ₂ ) _p -N(R ^1c )-(CH ₂ ) _n -CON(R ^1b )-(CH ₂ ) _m -, *-(CH ₂ ) _p -N(R ^1c )-(CH ₂ ) _n -SO ₂ N(R ^1b )-(CH ₂ ) _m - or *-(CH ₂ ) _n -OCO-; * denotes a connection point with R ¹ ; L ^1a is a 5- or 6-membered heterocyclylene; where the heteroatoms are nitrogen and the number of heteroatoms is two; each R ^1b is independently H or C _1-3 alkyl; each R ^1c is independently H or C _1-3 alkyl; k is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; And each of m, n and p is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; R ¹ is adamantyl substituted with one to five R ^1a , bicyclo[2.2.1]heptyl substituted with one to five R ^1a , or unsubstituted adamantyl; each R ^1a is independently C _1-3 alkyl; R ² is C _1-3 alkyl; each R ^3b and R ^3c is independently H or R ^3a ; And each R ^4b and R ^4c is independently H or R ^4a ; R ^3a and R ^4a are independently selected from halo and C _1-3 alkyl; R ⁵ is missing. 2. A compound of formula I-C, II-C, III-C, IV-C, V-C and VIII-C, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof:

or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof, wherein L ³ is *-(CH ₂ ) _n -N(R ^1c )-(CH ₂ ) _k -, L ⁴ is SO ₂ , s and t are independently 0, 1, or 2, and each of m, n, k, p, X ¹ , X ² , X ³ , X ⁴ , X ⁵ , R ^1b , R ^1c , R ¹ , R ² , R ³ , R ⁴ and R ⁵ are defined in paragraph 1 . 3. A compound of formula VI-C, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof,

where L ⁴ is SO ₂ , each of m, X ¹ , X ² , X ³ , X ⁴ , X ⁵ , R ^1b , R ^1c , R ¹ , R ² , R ³ , R ⁴ and R ⁵ are defined in paragraph 1. 4. The compound according to claim 1, where L ¹ is selected from *-NHCONH-, *-NHCONHCH ₂ -, *-CH ₂ NHCONHCH ₂ -, *-(CH ₂ ) ₂ NHCONHCH ₂ -, *-(CH ₂ ) ₃ NHCONHCH ₂ -, *-(CH ₂ ) ₄ NHCONHCH ₂ -, *-(CH ₂ ) ₅ NHCONHCH ₂ -, *-(CH ₂ ) ₆ NHCONHCH ₂ -, *-NHCH ₂ NHCO-, *-NH(CH ₂ ) ₂ NHCO-, *-NH(CH ₂ ) ₃ NHCO-, *-NH(CH ₂ ) ₄ NHCO-, *-NH(CH ₂ ) ₅ NHCO-, *-NH(CH ₂ ) ₆ NHCO-, * -NH(CH ₂ ) ₇ NHCO-, *-CH ₂ NHCH ₂ NHCO-, *-CH ₂ NH(CH ₂ ) ₂ NHCO-, *-CH ₂ NH(CH ₂ ) ₃ NHCO-, *-CH ₂ NH (CH ₂ ) ₄ NHCO-, *-CH ₂ NH(CH ₂ ) ₅ NHCO-, *-CH ₂ NH(CH ₂ ) ₆ NHCO-, *-CH ₂ NH(CH ₂ ) ₇ NHCO-, *-NH (CH ₂ ) ₂ NHCH ₂ -, *-NH(CH ₂ ) ₄ NHCH ₂ -, *-NH(CH ₂ ) ₂ SO ₂ NHCH ₂ -, *-OC(O)-, *-CH ₂ NH(CH ₂ ) ₂ NHCH ₂ -, * -CH ₂ NH (CH ₂ ) ₄ NHCH ₂ -, * -CH ₂ NH (CH ₂ ) ₂ SO ₂ NHCH ₂ -, * -CH ₂ OC (O) -,

5. Connection according to any one of paragraphs. 1-4, where R ¹ is selected from:

6. A compound, or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof, wherein the compound is selected from any of the following compounds:

7. A method for inhibiting the membrane protein of mycobacteria Large 3 in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of paragraphs. 1-6. 8. A method of treating a mycobacterial infection in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of paragraphs. 1-6, wherein the mycobacterial infection is Mycobacterium tuberculosis infection, Mycobacterium leprae infection, Mycobacterium ulcerans infection, Mycobacterium abscessus infection, Mycobacterium bovis infection, or Mycobacterium marinum infection. 9. A method of treating a disease caused by a mycobacterial infection in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of paragraphs. 1-6, wherein the disease caused by mycobacterial infection is tuberculosis caused by infection caused by Mycobacterium tuberculosis , leprosy caused by Mycobacterium leprae , Buruli ulcer caused by Mycobacterium ulcerans , infectious disease caused by Mycobacterium abscessus , infectious disease caused by infection caused by Mycobacterium bovis , or an infectious disease caused by an infection caused by Mycobacterium marinum . 10. The use of a compound according to any one of paragraphs. 1-6 in the manufacture of a medicinal product for the prevention or treatment of mycobacterial infection or disease caused by mycobacterial infection. 11. Use according to claim 10, wherein the mycobacterial infection is Mycobacterium tuberculosis infection, Mycobacterium leprae infection, Mycobacterium ulcerans infection, Mycobacterium abscessus infection, Mycobacterium bovis infection, or Mycobacterium marinum infection. 12. Use according to claim 10, wherein the disease caused by mycobacterial infection is tuberculosis caused by infection caused by Mycobacterium tuberculosis , leprosy caused by Mycobacterium leprae , Buruli ulcer caused by Mycobacterium ulcerans , infectious disease caused by Mycobacterium abscessus , infectious disease caused by an infection caused by Mycobacterium bovis or an infectious disease caused by an infection caused by Mycobacterium marinum .