Antibiotic compounds for treatment of bacterial infections

Abstract

The present invention provides a compound of general formula (I) for use in the prevention and / or treatment of bacterial infections mediated by at least one bacterium selected from the group consisting of Acinetobacter baumannii and the Enterobacteriaceae family such as Escherichia coli and Klebsiella pneumoniae.

Description

Technical Field

[0001] This invention provides compounds for the prevention and / or treatment of bacterial infections selected from Acinetobacter baumannii (…). A. baumannii ) and such as Escherichia coli ( E. coli ) and Klebsiella pneumoniae ( K. pneumoniae This invention provides novel antibiotic compounds that can be used to treat bacterial infections mediated by Acinetobacter baumannii and Enterobacteriaceae. Background Technology

[0002] Around the world, antibiotic resistance is rising to dangerously high levels, threatening our ability to effectively treat and prevent an increasing range of infections. Therefore, there is a need to develop novel antibiotic compounds that can exhibit activity when existing antibiotics are ineffective.

[0003] Although all types of bacteria are considered to have developed some degree of antibiotic resistance, some types are considered to pose a higher risk to human health than others, such as Klebsiella pneumoniae. Klebsiella pneumoniae Acinetobacter baumannii ( Acinetobacter baumannii ) and Escherichia coli ( E. coli Furthermore, there may be a particular need for one or more novel antibiotic compounds that are active in these bacterial species.

[0004] A new class of antibiotic compounds recently developed are FAI inhibitors. These compounds inhibit NADH-dependent enoyl reductase (FabI) ​​from the fatty acid biosynthesis pathway (FAS-II) in type II bacteria, thus providing an alternative for treating bacterial infections when existing antibiotics fail. Advantageously, this FAI mode of action is not expected to introduce any cross-resistance to existing antibiotics. However, while known FAI inhibitor compounds may exhibit high efficacy against some bacterial species, they may be inactive or poorly active against other species, such as Acinetobacter baumannii and Enterobacteriaceae, particularly Gram-negative species like Escherichia coli, Acinetobacter baumannii, and Klebsiella pneumoniae. This may be due to the challenge of penetrating the outer and inner membranes of such Gram-negative bacteria, a challenge that can be further exacerbated by efflux. Therefore, there remains a need for compounds that exhibit antibiotic activity against Acinetobacter baumannii and Enterobacteriaceae species such as Escherichia coli and Klebsiella pneumoniae (especially in the event of failure of existing antibiotics), as well as pharmaceutical compositions containing such compounds. Preferably, such compounds do not induce cross-resistance with existing antibiotics, and advantageously, they produce a low / acceptable incidence of side effects. Furthermore, preferably, such compounds can be used in combination with other antibiotics such as polymyxins and aminoglycosides, for example, to improve efficacy and / or to enable a reduction in the dosage of each individual antibiotic administered, for example, to minimize the risk of side effects.

[0005] One object of the present invention is to solve one or more of the above-mentioned needs. Other potential objects and problems of the present invention will become apparent from the following description of the invention. Summary of the Invention

[0006] The inventors unexpectedly discovered that the compound claimed in this application exhibits antibacterial activity against Acinetobacter baumannii and / or Enterobacteriaceae such as Escherichia coli and Klebsiella pneumoniae, and therefore the compound can be used to treat bacterial infections mediated by said bacteria.

[0007] Therefore, the present invention specifically provides the following: 1. A compound for the prevention and / or treatment of bacterial infections mediated by at least one bacterium selected from the group consisting of Acinetobacter baumannii and Enterobacteriaceae such as Escherichia coli and Klebsiella pneumoniae. The compounds are selected from the group consisting of compounds represented by general formula I and their pharmaceutically acceptable salts. I in, A1 represents A that has the following structure 11 and A 12 The part of the group; A 11 and A 12 ; The line connected to the exocyclic methylene group represents a covalent single bond formed with the nitrogen atom of general formula I; A2 represents methyl; Q1 represents CH2 or NH; Q2 indicates CR 4 R 5 , or CR 4 R 5 -CR 6 R 7 , among which, CR 4 R 5 The group is attached to CO, CR 6 R 7 The group is attached to Q1; Q3 represents O or S; R 1 This indicates a group selected from H or -NH2; R 2 Indicates selection from H, -CH2-O-Ar 1 -CH2-O-Het 1 CH2-NR 9 Ar 1 CH2-NR 9 Het 1 -O-Ar 1 -O-Het 1 -NR 9 R 10 -O-Alk 1 The group, of which Ar 1 This indicates that it can be optionally selected independently by one or more options from -CN, -OC. 1-4 Alkyl group, -O-(CH2) 1-4 -NR 9 R 10 The phenyl group is substituted with a group, or wherein the phenyl group may have two substituents on adjacent ring atoms, such that these adjacent substituents can bond together to form a 5-membered heterocycle having one or two independent heteroatoms selected from N and O, wherein Het 1 This refers to an aromatic heterocycle having 5 or 6 ring atoms (including 1 or 2 heteroatoms independently selected from N, S, and O), or a non-aromatic, partially or fully saturated heterocycle having 6 ring atoms (including 1 heteroatom selected from N and O), wherein Het 1 The group may optionally be selected independently from -C. 1-4 Alkyl, -OC1-4 Alkyl group, -CN, -(CH2) 0-4 The group in -OH is substituted; where R 9 Selected from H and -C 1-4 Alkyl; wherein, R 10 Selected from H, -C 1-4 Alkyl groups and -C(=O)-CH3; wherein, Alk 1 It refers to a straight-chain, branched, cyclic, or combined alkyl group having 1 to 6 carbon atoms, wherein Alk 1 The group may optionally be selected from one or more groups chosen from -OH, -OC 1-4 Alkyl group substitution; R 3 Indicates selection from H, -PO3R 3a 2. -CH2-OPO3R 3a 2 and -CH2-OC(=O)-R 3b group; R 3a This indicates a hydrogen atom or a cation suitable for forming a pharmaceutically acceptable salt, or -CH2-OC(=O)-R 3b Or -CHMe-OC(=O)-R 3b Or -CMe2-OC(=O)-R 3b Or -CH2-OC(=O)-OR 3b Or -CHMe-OC(=O)-OR 3b Or -CMe2-OC(=O)-OR 3b ; R 3b It represents an alkyl group having 1 to 11 carbon atoms, which can be straight-chain, branched, cyclic, or a combination thereof, wherein R 3b The group may optionally be one or more independently selected from -OH and -OC. 1-6 Alkyl group substitution; R 4 Indicates selection from H, C 1-4 Alkyl, -CN and C 1-4 alkylene-F groups; R 5 Indicates selection from C 1-4 Alkyl, C 1-4 alkylene-OH, C 1-4 Alkylene-OR 3 OH, -OPO3R 3a 2 groups; or R 4 and R 5Together they form a cyclic group having 4 to 6 ring members formed by methylene groups and optional oxygen atoms; said cyclic group may optionally contain elements selected from -OH, -OC. 1-4 Substituents of alkyl groups; R 6 Indicates selection from H, -OH, C 1-4 Alkyl, -OPO3R 3a 2 groups; R 7 Indicates selection from H, C 1-4 Alkyl, C 1-4 alkylene-OH, C 1-4 Alkylene-OR 3 C 1-4 Alkyl-F or -CN groups; or R 6 and R 7 Together they form a cyclic group having 4 to 6 ring members formed by methylene groups and optional oxygen atoms; said cyclic group may optionally contain elements selected from -OH, -OC. 1-4 Alkyl substituents.

[0008] 2. The compound used as described in Project 1, wherein the compound is selected from the group consisting of compounds represented by general formulas A, B, C, D, E, F, G, or H. A; or B; or C; or D; or E; or F; or G; or H Q3, R1, R2, R3, R4, R5, R6 and R7 have the same meaning as defined in claim 1 above.

[0009] 3. A compound for use as described in item 1 or 2, wherein the compound is selected from the group of compounds represented by general formula Va, general formula Vb, general formula VI or general formula VII. Va; or Vb; or VI; or VII R1, R2, R3, R4, R5, R6 and R7 have the same meaning as defined in claim 1 above.

[0010] 4. The compound used as described in item 1 or 2, wherein the compound is selected from the group consisting of compounds represented by general formula Xa, general formula Xb, general formula XI or general formula XII. Xa; or Xb; or XI; or XII R1, R2, R3, R4, R5, R6 and R7 have the same meaning as defined in claim 1 above.

[0011] 5. The compound used as described in item 3 or 4, wherein, R 2 Indicates a group selected from -H, -OH, -NH2; and / or R 4 Indicates a group selected from -CN; and / or R 5 Indicates selection from -OH, C 1-4 alkylene-OH groups; and / or R 7 Indicates selection from -CN, -OH, C 1-4 Alkylene-OH groups.

[0012] 6. The compound used as described in Project 5, wherein R 2 Indicates -H, -NH2; and / or

[0013] R 4 Indicates -CN; and / or

[0014] R 5 Indicates selection from -OH, C 1-4 alkylene-OH groups; and / or

[0015] R 7 Indicates selection from -CN, -OH, C 1-4Alkylene-OH groups.

[0016] 7. Compounds used as described in items 4, 5, or 6, wherein, R 1 Indicates -H; R 2 It represents -H or -NH2.

[0017] 8. Compounds used as described in items 3, 4, 5, or 6, wherein, R 1 and R 2 It represents -H.

[0018] 9. The compound used as described in any one of items 3 to 8, wherein, R 5 Represents -CN, -OH, -CH2OH, -CH2OPO3R 3a 2. -OPO3R 3a 2.

[0019] 10. The compound used as described in Item 1, wherein the compound is selected from the following compounds:

[0020] 11. A pharmaceutical composition for the prevention and / or treatment of bacterial infections mediated by at least one bacterium selected from the group consisting of Acinetobacter baumannii and Enterobacteriaceae such as Escherichia coli and Klebsiella pneumoniae, wherein the composition comprises

[0021] Compounds as defined in any of items 1 through 10; and

[0022] Pharmaceutically acceptable excipients.

[0023] 12. The pharmaceutical composition used as described in item 11, further comprising an antibiotic, preferably wherein the antibiotic is selected from the group consisting of polymyxins and aminoglycosides.

[0024] 13. A compound being (R,E)-3-(3-cyano-3-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazaphen-8-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide, and having the following chemical structure: .

[0025] 14. A compound selected from the group consisting of compounds of general formula I and their pharmaceutically acceptable salts. I Where A1 represents a part A with the following structure 12 A 12 ; The line connected to the exocyclic methylene group represents a covalent single bond formed with the nitrogen atom of general formula I; A2 represents methyl; Q1 represents CH2 or NH; Q2 indicates CR 4 R 5 , or CR 4 R 5 -CR 6 R 7 , among which, CR 4 R 5 The group is attached to CO, CR 6 R 7 The group is attached to Q1; Q3 represents O or S; R 1 This indicates a group selected from H or -NH2; R 2 Indicates that it is selected from -CH2-O-Ar 1 -CH2-O-Het 1 CH2-NR 9 Ar 1 and CH2-NR 9 Het 1 , of which Ar 1 This indicates that it can be optionally selected independently by one or more options from -CN, -OC. 1-4 Alkyl group, -O-(CH2) 1-4 -NR 9 R 10 The phenyl group is substituted with a group, or wherein the phenyl group may have two substituents on adjacent ring atoms, such that these adjacent substituents can bond together to form a 5-membered heterocycle having one or two independent heteroatoms selected from N and O, wherein Het 1 This refers to an aromatic heterocycle having 5 or 6 ring atoms (including 1 or 2 heteroatoms independently selected from N, S, and O), or a non-aromatic, partially or fully saturated heterocycle having 6 ring atoms (including 1 heteroatom selected from N and O), wherein Het 1 The group can optionally be selected independently from -C. 1-4 Alkyl, -OC 1-4 Alkyl group, -CN, -(CH2) 0-4 The group in -OH is substituted; where R 9Selected from H and -C 1-4 Alkyl; wherein, R 10 Selected from H, -C 1-4 Alkyl groups and -C(=O)-CH3; R 3 Indicates selection from H, -PO3R 3a 2. -CH2-OPO3R 3a 2 and -CH2-OC(=O)-R 3b group; R 3a This indicates a hydrogen atom or a cation suitable for forming a pharmaceutically acceptable salt, or -CH2-OC(=O)-R 3b Or -CHMe-OC(=O)-R 3b Or -CMe2-OC(=O)-R 3b Or -CH2-OC(=O)-OR 3b Or -CHMe-OC(=O)-OR 3b Or -CMe2-OC(=O)-OR 3b ; R 3b It represents an alkyl group having 1 to 11 carbon atoms, which can be straight-chain, branched, cyclic, or a combination thereof, wherein R 3b The group can optionally be one or more independently selected from -OH and -OC. 1-6 Alkyl group substitution; R 4 Indicates selection from H, C 1-4 Alkyl, -CN and C 1-4 alkylene-F groups; R 5 Indicates selection from H, C 1-4 Alkyl, C 1-4 alkylene-OH, C 1-4 Alkylene-OR 3 OH, -OPO3R 3a 2 groups; or R 4 and R 5 Together they form a cyclic group having 4 to 6 ring members formed by methylene groups and optional oxygen atoms; said cyclic group may optionally contain elements selected from -OH, -OC. 1-4 Substituents of alkyl groups; R 6 Indicates selection from H, -OH, C 1-4 Alkyl, -OPO3R 3a 2 groups; R 7 Indicates selection from H, C 1-4 Alkyl, C 1-4alkylene-OH, C 1-4 Alkylene-OR 3 C 1-4 Alkyl-F or -CN groups; or R 6 and R 7 Together they form a cyclic group having 4 to 6 ring members formed by methylene groups and optional oxygen atoms; said cyclic group may optionally contain elements selected from -OH, -OC. 1-4 Alkyl substituents.

[0026] 15. A compound selected from the group consisting of compounds of general formula I and their pharmaceutically acceptable salts. I Wherein, A1 represents a group A having the following structure 11 The part indicated A 11 ; The line connected to the exocyclic methylene group represents a covalent single bond formed with the nitrogen atom of general formula I; A2 represents methyl; Q1 represents CH2 or NH; Q2 indicates CR 4 R 5 , or CR 4 R 5 -CR 6 R 7 , among which, CR 4 R 5 The group is attached to CO, CR 6 R 7 The group is attached to Q1; Q3 represents O or S; R 1 This indicates a group selected from H or -NH2; R 2 Indicates that it is selected from -CH2-O-Ar 1 -CH2-O-Het 1 CH2-NR 9 Ar 1 CH2-NR 9 Het 1 -O-Ar 1 -O-Het 1 -NR 9 R 10 -O-Alk 1 The group, of which Ar 1 This indicates that it can be optionally selected independently by one or more options from -CN, -OC. 1-4Alkyl group, -O-(CH2) 1-4 -NR 9 R 10 The phenyl group is substituted with a group, or wherein the phenyl group may have two substituents on adjacent ring atoms, such that these adjacent substituents can bond together to form a 5-membered heterocycle having one or two independent heteroatoms selected from N and O, wherein Het 1 This refers to an aromatic heterocycle having 5 or 6 ring atoms (including 1 or 2 heteroatoms independently selected from N, S, and O), or a non-aromatic, partially or fully saturated heterocycle having 6 ring atoms (including 1 heteroatom selected from N and O), wherein Het 1 The group can optionally be selected independently from -C. 1-4 Alkyl, -OC 1-4 Alkyl group, -CN, -(CH2) 0-4 The group in -OH is substituted; where R 9 Selected from H and -C 1-4 Alkyl; wherein, R 10 Selected from H, -C 1-4 Alkyl groups and -C(=O)-CH3; wherein, Alk 1 It refers to a straight-chain, branched, cyclic, or combined alkyl group having 1 to 6 carbon atoms, wherein Alk 1 The group may optionally be selected from one or more groups chosen from -OH, -OC 1-4 Alkyl group substitution; R 3 Indicates selection from H, -PO3R 3a 2. -CH2-OPO3R 3a 2 and -CH2-OC(=O)-R 3b group; R 3a This indicates a hydrogen atom or a cation suitable for forming a pharmaceutically acceptable salt, or -CH2-OC(=O)-R 3b Or -CHMe-OC(=O)-R 3b Or -CMe2-OC(=O)-R 3b Or -CH2-OC(=O)-OR 3b Or -CHMe-OC(=O)-OR 3b Or -CMe2-OC(=O)-OR 3b ; R 3b It represents an alkyl group having 1 to 11 carbon atoms, which can be straight-chain, branched, cyclic, or a combination thereof, wherein R 3b The group can optionally be one or more independently selected from -OH and -OC. 1-6 Alkyl group substitution; R 4 Indicates selection from H, C 1-4 Alkyl, -CN and C 1-4 alkylene-F groups; R 5 Indicates selection from C 1-4 Alkyl, C 1-4 alkylene-OH, C 1-4 Alkylene-OR 3 OH, -OPO3R 3a 2 groups; or R 4 and R 5 Together they form a cyclic group having 4 to 6 ring members formed by methylene groups and optional oxygen atoms; said cyclic group may optionally contain elements selected from -OH, -OC. 1-4 Substituents of alkyl groups; R 6 Indicates selection from H, -OH, C 1-4 Alkyl, -OPO3R 3a 2 groups; R 7 Indicates selection from H, C 1-4 Alkyl, C 1-4 alkylene-OH, C 1-4 Alkylene-OR 3 C 1-4 Alkyl-F or -CN groups; or R 6 and R 7 Together they form a cyclic group having 4 to 6 ring members formed by methylene groups and optional oxygen atoms; said cyclic group may optionally contain elements selected from -OH, -OC. 1-4 Substituents of alkyl groups; Where R 1 If H is the value of R, then R 2 Choose Free - CH2-O-Ar 1 -CH2-O-Het 1 CH2-NR 9 Ar 1 and CH2-NR 9 Het 1 The group formed, and Where R 2 For -NR 9 R 10 Then R 9 and R 10 At least one of them is not H.

[0027] definition

[0028] The following definitions are provided to assist the reader. Unless otherwise defined, all technical terms, symbols, and other scientific or medical terms or specialized terms used herein have the meanings commonly understood by those skilled in the art of chemistry and medicine. In some cases, for clarity and / or ease of reference, terms with their commonly understood meanings are defined herein, and such definitions included herein should not be construed as indicating a material difference from the definitions of terms commonly understood in the art.

[0029] In some embodiments, the term "about" refers to a deviation of ±10% from the stated value. Regarding the use of the word "about" in relation to numbers herein, it should be understood that another embodiment of the invention also includes numbers that are not modified by the presence of the word "about".

[0030] The term “administer” a drug to a patient (and its grammatical equivalent) refers to direct administration, administered by a medical professional to a patient, or possibly self-administered and / or indirect administration, which may be the act of prescribing medication, such as instructing a patient to self-administer the medication or administering the medication to a patient by a physician who has provided a prescription.

[0031] "Dosage" refers to a specific amount of an active agent or therapeutic agent used for administration. These amounts are included in "dosage form," which refers to a single, discrete physical unit suitable for human subjects and other mammals, each unit containing a predetermined amount of active agent, calculated to produce the desired onset, tolerability, and therapeutic effect in combination with one or more suitable pharmaceutical excipients (e.g., a carrier).

[0032] As used in this application, the terms "treatment" and "therapeutic method" refer to a set of hygienic, pharmacological, surgical, and / or physical means used to treat and / or alleviate a disease and / or symptoms, with the aim of addressing a health problem. The terms "treatment" and "therapeutic method" include both preventative and therapeutic approaches, as both aim to maintain and / or restore the health of an individual or animal. Regardless of the source of the symptoms, disease, and disability, the administration of appropriate medication to alleviate and / or treat a health problem should be construed as a form of treatment or therapy within the scope of this application.

[0033] As used herein, “unit dosage form” refers to a physically discrete unit of a therapeutic preparation suitable for the treated subject. However, it should be understood that the total daily dosage of the compositions of this invention will be determined by the attending physician within a reasonable medical judgment. The specific effective dose level for any particular subject or organism will depend on a variety of factors, including the disease being treated and its severity; the activity of the specific active agent used; the specific composition employed; the subject’s age, weight, general health condition, sex, and diet; the timing of administration and the excretion rate of the specific active agent used; the duration of treatment; the drugs and / or adjunctive therapies used in combination with or concurrently with one or more specific compounds used; and similar factors known in the medical field.

[0034] The articles “a” and “an” used in this article refer to one or more (i.e., at least one) of the grammatical objects. For example, “an element” refers to one or more elements.

[0035] The term "comprising" is used to mean "including but not limited to". "Comprising" and "including but not limited to" are used interchangeably. The term "including" has the same meaning as "comprising". The term "consisting of" indicates the presence of one or more of the listed elements, but without any other unmentioned elements. As a preferred embodiment, the term "comprising" is used to include the meaning of "consisting of".

[0036] The term "FabI" is generally accepted in the field to refer to a bacterial enzyme believed to function as an acyl-coarse protein (ACP) reductase in the final step of the four reactions involved in each cycle of bacterial fatty acid biosynthesis. This enzyme is thought to be widely distributed in bacteria and plants.

[0037] The term "enzyme inhibitor" refers to any compound that prevents an enzyme from effectively performing its respective biochemical function. Therefore, a "FabI inhibitor" is any compound that inhibits FabI from performing its biochemical function. The amount of inhibition by any such compound will vary, as described herein and elsewhere.

[0038] The terms "antibiotic agent" or "antimicrobial agent" shall refer to any medicine used to treat, prevent, or otherwise reduce the severity of any bacterial disease or any of its complications (including those arising from and / or any condition, disease, or complication described herein). Antibiotic agents include, for example, cephalosporins, quinolones and fluoroquinolones, penicillins and β-lactamase inhibitors, carbapenems, monocyclic β-lactams, macrolides and lincosamides, glycopeptides, rifampin, oxazolidinones, tetracyclines, aminoglycosides, streptozotocins, sulfonamides, etc. Other antibiotics or antimicrobial agents are disclosed herein and are known to those skilled in the art. In some embodiments, the term "antibiotic agent" does not include formulations that are FAI inhibitors; therefore, in some embodiments, the combination of the present invention will include one formulation that is a FAI inhibitor and another that is not a FAI inhibitor.

[0039] As used herein, the term "medicine" means any substance falling within at least one of the definitions given below: the version of Directive 2001 / 83 / EC of 6 November 2001, Chapter 1, entries 2(a), 2(b) or 3a, of which the version of 16 November 2012 is; or the version of Directive 2001 / 82 / EC of 6 November 2001, Chapter 1, entries 2(a) or 2(b) of which the version of 7 August 2009 is; and Chapter 2 of Regulation (EC) 726 / 2004 of 31 March 2004.

[0040] As used in this article, the term "disease" refers to any disease caused by or related to an organism's infection.

[0041] As used in this article, the term "bacterial disease" refers to any disease caused by or related to a bacterial infection.

[0042] The term "cis" is generally accepted in the art as referring to the arrangement of two atoms or groups around a double bond such that the atoms or groups are on the same side of the double bond. Cis configuration is usually denoted as (Z) configuration.

[0043] The term "trans" is generally accepted in the art as referring to the arrangement of two atoms or groups around a double bond such that the atoms or groups are on opposite sides of the double bond. The trans configuration is usually designated as the (E) configuration.

[0044] The term "therapeutic effect," as is generally accepted in the art, refers to the local or systemic effect caused by a pharmacologically active substance on animals, particularly mammals, and more particularly on humans. Therefore, the term refers to any measurable effect on animals or humans in diagnosing, treating, alleviating, treating, or preventing disease, or in enhancing desired physical or mental development and / or conditions. The phrase "therapeutic effective amount" refers to the amount of such a substance that produces a certain expected local or systemic effect at a reasonable benefit / risk ratio suitable for any treatment. The therapeutically effective amount of the substance will vary depending on the subject being treated and the disease condition, the subject's weight and age, the severity of the disease condition, the method of administration, etc., which can be readily determined by those skilled in the art. For example, certain compositions of the present invention can be administered in sufficient quantities to produce a therapeutic effect at a reasonable benefit / risk ratio suitable for such treatment.

[0045] The term "chirality" refers to a molecule that has a non-overlapping property with its mirror partner, while the term "achirality" refers to a molecule that can be superimposed on its mirror partner. "Prochiral molecules" are molecules that may be transformed into chiral molecules in certain processes.

[0046] The compounds disclosed herein may contain one or more chiral centers and / or double bonds, and thus exist as geometric isomers, enantiomers, or diastereomers. Enantiomers and diastereomers may be designated by the symbols “(+)”, “(-)”, “R”, or “S”, depending on the configuration of the substituents surrounding the stereocarbon atom; however, those skilled in the art will recognize that the structure may implicitly represent one or more chiral centers. Mixtures of enantiomers or diastereomers may be named “(±)” in nomenclature; however, those skilled in the art will recognize that the structure may implicitly represent a chiral center. Geometric isomers arising from the arrangement of substituents around the carbon-carbon double bond or around the cycloalkyl or heterocyclic substituents may also exist in the compounds of the present invention.

[0047] symbol This indicates a key that can be a single key, a double key, or a triple key, as described in this article.

[0048] Substituents surrounding a carbon-carbon double bond are designated as "Z" or "E" structures, where the terms "Z" and "E" are used according to IUPAC standards. Unless otherwise specified, structures describing double bonds include both "E" and "Z" isomers. Substituents surrounding a carbon-carbon double bond may also be referred to as "cis" or "trans," where "cis" indicates the substituent is on the same side of the double bond, and "trans" indicates the substituent is on the opposite side. The arrangement of substituents around the carbon ring may also be referred to as "cis" or "trans." The term "cis" indicates the substituent is on the same side of the ring plane, and the term "trans" indicates the substituent is on opposite sides of the ring plane. Mixtures of compounds with substituents on the same and opposite sides of the ring plane are designated as "cis / trans" or "Z / E."

[0049] As used herein, the term "stereoisomer" encompasses all geometric isomers, enantiomers, or diastereomers. This invention includes various stereoisomers of these compounds and mixtures thereof. Conformational and rotational isomers of the disclosed compounds are also contemplated.

[0050] The term "IC50" is recognized in the art and refers to the effectiveness of a substance in inhibiting a given biological or biochemical process (or components of the process, i.e., enzymes, cells, cell receptors, or microorganisms). IC50 represents the concentration of a drug (e.g., the compounds of the present invention) required to achieve 50% inhibition in vitro.

[0051] The term “MIC” is recognized in the art and refers to the minimum inhibitory concentration, that is, the lowest concentration of an antimicrobial agent that can inhibit the visible growth of microorganisms after overnight incubation, usually expressed as mg / L or μg / mL.

[0052] The term "ED50" is recognized in the art. In some embodiments, ED50 refers to the effective dose of the drug that produces 50% of its maximum response or effect, or alternatively, the dose that produces a predetermined response in 50% of subjects or formulations. The term "LD50" is recognized in the art. In some embodiments, LD50 refers to the drug dose that is lethal to 50% of subjects. The term "therapeutic index" is a recognized term in the art and refers to the therapeutic index of a drug, defined as ED50 / LD50.

[0053] The term "Ki" is generally accepted in the field and refers to the dissociation constant of an enzyme inhibitor complex.

[0054] The term "antimicrobial" is recognized in the art and refers to the ability of compounds disclosed herein to prevent, inhibit, or destroy the growth of microorganisms such as bacteria, fungi, protozoa, and viruses.

[0055] The term "antimicrobial" is generally accepted in the art and refers to the ability of the compounds disclosed herein to prevent, inhibit, or destroy the growth of bacteria or microorganisms.

[0056] The term "microorganism" is generally accepted in the art to refer to a microscopic organism. In some embodiments, the term microorganism applies to bacteria. In other embodiments, the term refers to a pathogenic form of a microscopic organism.

[0057] As used herein, the term "alkyl" refers to a saturated straight-chain / linear or branched or cyclic hydrocarbon. For example, in this document, straight-chain / linear or branched groups having 1-8 or 1-6 carbon atoms are referred to as C1-C8 alkyl or C1-C6 alkyl, respectively, wherein it will be apparent to those skilled in the art that branched or cyclic groups begin with 3 carbon atoms. The term "lower alkyl" as used herein specifically refers to a saturated straight-chain / linear or branched hydrocarbon. For example, straight-chain or branched groups having 1-4 or 1-3 carbon atoms are referred to as C1-C4 alkyl and C1-C3 alkyl, respectively, wherein it will be apparent to those skilled in the art that branched or cyclic groups begin with 3 carbon atoms. Exemplary alkyl and lower alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 3-methyl-2-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, and hexyl.

[0058] Furthermore, the term "alkyl" (or "lower alkyl") includes "substituted alkyl," meaning it should be understood to optionally carry one or more substituents at one or more positions. That is, it also refers to an alkyl moiety having one or more (e.g., two, three, four, five, six, etc.) substituents, each substituting a hydrogen atom on a carbon atom of the hydrocarbon backbone. Such substituents may include, for example, hydroxyl, carbonyl (wherein the carbonyl carries a hydrogen atom, an alkyl group as defined in this paragraph, or another group, such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl-containing groups (wherein the carbonyl carries a hydrogen atom, an alkyl group as defined in this paragraph, or another group, such as thioester, thioacetate, or thiocarbamate), alkoxy, phosphoryl, phosphonate, phosphonite, phosphate, amino, amide, amidine, imine, cyano, nitro, azide, mercapto, alkylthio, sulfate, sulfonate, aminosulfonyl, sulfonamide, sulfonyl, heterocyclic, aralkyl, cycloalkyl, heterocyclic, or aromatic or heteroaromatic moiety. In all instances, the aforementioned groups have more than one valence state, and the other free valences can be saturated with hydrogen atoms, alkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, or heteroaryl groups. Those skilled in the art will further understand that, where appropriate, the substituted portion of the hydrocarbon chain can itself be substituted. For example, substituents in substituted alkyl groups can include substituted and unsubstituted forms of the following groups: amino, azide, imino, amide, phosphoryl (including phosphonates, phosphonites, and phosphates), sulfonyl (including sulfates, sulfonamides, aminosulfonyls, and sulfonates), and silyl, as well as ethers, alkylthio groups, carbonyl (including ketones, aldehydes, carboxylic esters, and esters), nitrile, and isonitriles. For the avoidance of doubt, an alkyl group carrying another alkyl group should not be considered an alkyl group substituted with another alkyl group, but rather a monobranched alkyl group.

[0059] The term "alkylene" is recognized in the art and refers to a group corresponding to the aforementioned alkyl group but having two free valences. Alkylene is sometimes also called alkyldiyl.

[0060] The term "alkenyl" is generally accepted in the art to refer to a group corresponding to the alkyl group described above, but carrying one or more carbon-carbon double bonds. Clearly, the total number of double bonds is limited by the number of carbon atoms in the alkenyl group; to allow at least one double bond, the alkenyl group must have at least two carbon atoms. Apart from this distinction, the definitions and characteristics of alkyl groups described above also apply to alkenyl groups.

[0061] The term "alkynyl" is generally accepted in the art as referring to a group corresponding to the alkyl group described above, but carrying one or more carbon-carbon triple bonds. Clearly, the total number of double bonds is limited by the number of carbon atoms in the alkenyl group; to allow at least one triple bond, the alkynyl group must have at least two carbon atoms. Apart from this distinction, the definitions and characteristics of the alkyl group described above also apply to the alkynyl group.

[0062] The term "aryl" is generally accepted in the art to refer to a 5-, 6-, or 7-membered monocyclic aromatic group that may include 0 to 4 heteroatoms, such as benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. Aromatic groups having heteroatoms in their ring structure may also be called "heteroaryl" or "heteroaromatic hydrocarbons." The aromatic ring may be substituted at one or more ring positions with the aforementioned substituents, such as halogens, azides, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, amino, nitro, mercapto, imino, amide, phosphonate, phosphonite, phosphate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfanilamide, ketone, aldehyde, ester, heterocyclic group, aromatic or heteroaromatic moiety, -CF3, or -CN, etc. The term "aryl" also includes polycyclic systems having two or more rings, wherein two or more carbons are shared with two adjacent rings (the rings are "fused rings"), wherein at least one ring is an aromatic ring, and for example, the other rings may be cycloalkyl, cycloalkenyl, cycloynyl, aryl and / or heterocyclic groups.

[0063] The term “aralkyl” or “arylalkyl” is recognized in the art as referring to an alkyl group that has been substituted with an aryl group (e.g., an aromatic group or a heteroaromatic group).

[0064] The term "carbon ring" is generally accepted in the art as referring to an aromatic or non-aromatic ring in which each atom of the ring is carbon.

[0065] As used herein, the term "cycloalkyl" refers to, for example, a monocyclic saturated or partially unsaturated alkyl or alkenyl group with 3 to 6 or 4 to 6 carbons, referred to herein as, for example, "C6". 3-6 "Cycloalkyl" or "C" 4-6 "Cycloalkyl" and derived from cycloalkanes. Exemplary cycloalkyl groups include, but are not limited to, cyclohexane, cyclohexene, cyclopentane, cyclobutane, cyclopropane, or cyclopentene. As described above, the cycloalkyl group may be substituted with one or more substituents at one or more positions.

[0066] As used herein, the term "halogenated" or "halogen" refers to F, Cl, Br, or I, preferably F. "Halide" refers to the anion corresponding to the halogen.

[0067] The term "amino" as used in this article refers to the general structure -NR a R b Any group of, wherein, unless otherwise specified, R a and R b Independently selected from the group consisting of: H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic, and any other substituents listed above with respect to the range of substituted alkyl groups, except for carbonyl, thiocarbonyl, imino, and substituents therein connected to the remaining molecule by a heteroatom selected from N, O, S, and P. Alternatively, R a and Rb It can represent hydrocarbon groups that form heterocycles together with the nitrogen atoms attached to them.

[0068] As used herein, the term "heteroaryl" refers to a monocyclic aromatic 4- to 6-membered ring system containing one or more heteroatoms (e.g., 1 to 3 heteroatoms, which may be the same or different, such as nitrogen, oxygen, and sulfur). Where possible, the heteroaryl ring may be linked to an adjacent free radical via a carbon or nitrogen atom. Examples of heteroaryl rings include, but are not limited to, furans, benzofurans, thiophenes, pyrroles, thiazoles, oxazoles, isothiazoles, isoxazoles, imidazoles, pyrazoles, triazoles, pyridines, and pyrimidines. The heteroaryl group may be substituted by one or more substituents described for the aryl group. The term "heteroaryl" also includes polycyclic systems having two or more rings, wherein two or more carbons or heteroatoms are shared with two adjacent rings (the rings are "fused rings"), wherein at least one ring is a heteroaryl group as defined above, while the other rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aromatic rings, and / or saturated, unsaturated, or aromatic heterocyclic rings.

[0069] As used herein, the term "heterocycle" refers to a monocycle containing one or more heteroatoms (e.g., 1 to 3 heteroatoms, which may be the same or different, such as nitrogen, oxygen, and sulfur). The remaining ring members are formed by carbon atoms. Heterocycles typically have 4 to 8 ring members, preferably 5 to 6. Unless otherwise specified, heterocycles may be aromatic, partially or fully saturated. Unless otherwise specified, they may contain or not contain the permissible substituents specified herein.

[0070] The term "hydroxyl group" as used in this article refers to the -OH group.

[0071] The term "nitro" is generally accepted in the art as referring to -NO2; the term "thiol" is generally accepted in the art as referring to -SH; and the term "sulfonyl" is generally accepted in the art as referring to -SO2-.

[0072] When the definition of each expression appears multiple times in any structure, it is independent of its definition elsewhere in the same structure.

[0073] The terms "triflyl", "tosyl", "mesyl", and "nonaflyl" are generally accepted in the art and refer to triflyl, p-tosyl, methanesulfonyl, and nonaflyl, respectively. The terms triflate, tosylate, mesylate, and nonaflate are generally accepted in the art and refer to the functional groups of triflate, p-tosyl, methanesulfonate, and nonaflate, respectively, and molecules containing said functional groups.

[0074] The abbreviations Me, Et, Ph, Tf, Nf, Ts, and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutylsulfonyl, p-toluenesulfonyl, and methanesulfonyl, respectively. A more comprehensive list of abbreviations used by ordinary organic chemists in the field is provided in the first issue of each volume of the Journal of Organic Chemistry; this list is usually displayed in a table called the Standard Abbreviation List.

[0075] The term "prodrug" refers to a derivative of an active compound (drug) that undergoes conversion under conditions of use (e.g., in vivo) to release the active drug. Prodrugs are typically (but not necessarily) pharmacologically inactive before being converted into the active drug.

[0076] It should be understood that “substitution” or “being substituted” includes the implicit condition that the substitution is based on the permissible valence states of the substituted atom and the substituent, and that the substitution produces a stable compound, for example, that does not spontaneously undergo transformations such as by rearrangement, cyclization, elimination or other reactions.

[0077] The term "substituted" also considers all permissible substituents of organic compounds. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Exemplary substituents include, for example, those described above, such as those relating to substituted alkyl groups. For a suitable organic compound, permissible substituents may be one or more and may be the same or different. For the purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds that satisfy the heteroatom valence state described herein. In this respect, the term "permissible substituent" means any substituent that can bond to the core molecule without violating general principles of chemical bond formation, such as the maximum number of valence electrons of the atom of interest, and without rendering the compound toxic to the patient (so that unacceptable toxicity would be found even at the lowest dose required to achieve a therapeutic effect).

[0078] For the purposes of this invention, chemical elements are determined according to the periodic table (CAS version, Handbook of Chemistry and Physics, 67th edition, 1986-87, inside cover). Also for the purposes of this invention, the term "hydrocarbon" is intended to include all permissible compounds having at least one hydrogen atom and one carbon atom. In a broad sense, permissible hydrocarbons include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds, whether substituted or unsubstituted.

[0079] The term "pharmaceutically acceptable salt" is recognized in the art as referring to a relatively non-toxic, inorganic or organic acid addition salt or inorganic or organic base addition salt of a compound, including, for example, those contained in the compositions of the present invention, and including those present in other approved pharmaceuticals (which may be approved by any competent authority of the EU, USA, CA, JP, CN, or KR). Pharmaceutically acceptable salts are intended to be included in this invention. Therefore, all references to the compounds of the present invention should be understood as references not only to the compounds themselves, but also to the pharmaceutically acceptable salts of the respective compounds. According to one aspect, a pharmaceutically acceptable salt may be selected from those recognized as pharmaceutically acceptable in the literature at the date of application, particularly those described in J. Med. Chem. 2007, 50, 6665-6672 and references therein. If the compound of the present invention is an acidic compound, particularly a prodrug containing a phosphate group, the compound of the present invention may be provided in the form of a pharmaceutically acceptable salt, wherein the compound forms an anionic moiety, and the counterion is selected from Na, K, Mg, Ca, or the protonated forms of organic bases such as ethanolamine, meglumine, aminobutanetriol (i.e., 2-amino-2-(hydroxymethyl)propane-1,3-diol), and dimethylethanolamine (i.e., 2-(dimethylamino)ethanol). The stoichiometry of the salt is not particularly limited. For example, the salt may be formed from the phosphate prodrug of the present invention (having two acidic protons) in any stoichiometric ratio of 0 to 2 equivalents. Typically, a pharmaceutically acceptable salt is formed such that the net charge of the salt is zero, i.e., the total number of positive charges equals the total number of negative charges.

[0080] The term "treatment" includes any significant effect that leads to improvement of symptoms, diseases, disorders, etc., such as relief, reduction, regulation, or elimination.

[0081] The terms “preventive” or “therapeutic” are recognized in the art as referring to the application of one or more subject compositions to a subject. If the treatment is administered before an undesirable condition (e.g., a disease or other undesirable condition in the subject animal) occurs, the treatment is preventive, i.e., protecting the subject from progressing to the undesirable condition. If the treatment is administered after the undesirable condition has occurred, the treatment is therapeutic (i.e., aimed at reducing, alleviating, or maintaining the existing undesirable condition or its resulting side effects).

[0082] The "patient," "subject," or "subject" in the subject-based approach to treatment can refer to a human or a non-human animal. Non-human animals include companion animals (such as cats and dogs) and animals raised for food (i.e., food animals) such as cattle, pigs, and chickens. Non-human animals are preferably mammals.

[0083] The term "mammal" is known in the art, and exemplary mammals include humans, primates, cattle, pigs, canines, felines, and rodents (e.g., mice and rats).

[0084] The term “bioavailability” is recognized in the art as referring to the form in which a subject, or a portion thereof, is permitted to be absorbed, incorporated into, or otherwise made physiologically available to a subject or patient (to whom it is administered).

[0085] The term "pharmaceutically acceptable carrier" is recognized in the art as a pharmaceutically acceptable material, composition, or delivery vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, relating to the delivery or transport of any subject composition or its components from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of compatibility with the subject composition and its components and will not cause harm to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: (1) sugars, such as dextrose, lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch, and starch derivatives, such as cyclodextrins and modified cyclodextrins, preferably including (2-hydroxypropyl)-β-cyclodextrin and sulfonyl ether-β-cyclodextrin; (3) cellulose and its derivatives, such as microcrystalline cellulose, sodium carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose (HPMC) and cellulose acetate; (4) tragacanth gum powder; (5) malt; (6) gelatin; (7) talc; (8) polymeric excipients for matrix formation, such as polyvinylpyrrolidone (PVP), such as PVP K30, acrylic polymers and copolymers, such as different grades of Eudragit, preferably Eudragit. L100, hydroxypropyl methylcellulose acetate succinate (HPMCAS), other copolymers such as polyethylene glycol copolymers, such as Soluplus; (9) excipients such as cocoa butter and suppository waxes; (10) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (11) glycols such as propylene glycol; (12) polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; (13) esters such as ethyl oleate, glyceryl behenate, and ethyl laurate; (14) agar; (15) buffers such as magnesium hydroxide and aluminum hydroxide; (16) alginic acid; (17) pyrogen-free water; (18) isotonic saline; (19) Ringer's solution; (20) ethanol; (21) phosphate buffer; and (22) other non-toxic and compatible substances for pharmaceutical formulations. The disclosed excipients may perform more than one function. For example, fillers or binders can also be disintegrants, flow aids, anti-adhesion agents, lubricants, sweeteners, etc.

[0086] In this document, the term "solvent" refers to a liquid chemical substance capable of dissolving a substantial amount of another substance of interest ("solute") to produce a transparent, homogeneous solution. The term "substantial amount" is determined by the intended use of the solution, in a manner necessary to achieve the intended use through the amount of solute dissolved. For example, if the compound of the invention is intended to be administered in solution form by injection, the solvent must be able to dissolve the compound in such an amount that the administration of a therapeutic dose is possible.

[0087] The terms “acid” and “base” have their conventional meanings as proton donor and proton acceptor, respectively (i.e., Brønsted acid and base). A “strong base” is any base having a basicity of t-BuOK in tetrahydrofuran or stronger. A “weak acid” is any acid having an acidity of 1 M H₂SO₄ or weaker.

[0088] Unless otherwise specified, all reactions described herein are carried out at reaction temperatures that yield the desired target compounds and provide a reasonable trade-off between reaction rate and selectivity. Typical reaction temperatures for Pd-based coupling and Fe-based cyclization reactions are 80°C to 90°C, while the removal of protecting groups is typically carried out at temperatures from 0°C to room temperature (25°C).

[0089] Unless otherwise specified, all features of the same variable groups as those specified in compounds of Formula I should be understood as being possible, or even preferred, to have more specific meanings and combinations of meanings as embodied in Formulas II to XVI.

[0090] Unless otherwise specified, the term "protecting group" is used herein to characterize a group bound to a functional group to prevent that functional group from participating in the chemical reaction under consideration. Under the conditions of the chemical reaction under consideration, the protecting group must be inert, but must be removable from the compound so that no further transformation occurs in the rest of the molecule. The protecting groups for each functional group are described in "Greene's Protective Groups in Organic Synthesis," Peter G.M. Wuts, Theodora W. Greene, John Wiley & Sons, December 20, 2012.

[0091] Overview

[0092] Surprisingly, the compounds described herein have been found to exhibit antibacterial activity against Gram-negative bacteria, more specifically *Acinetobacter baumannii* and / or Enterobacteriaceae such as *Escherichia coli* and *Klebsiella pneumoniae*. Furthermore, the compounds of this invention have been found to have low MICs (minimum inhibitory concentrations) against Gram-negative bacteria, more specifically *Acinetobacter baumannii* and / or Enterobacteriaceae such as *Escherichia coli* and *Klebsiella pneumoniae*, indicating that the compounds of formula (I) are not only effective against these types of bacteria but also effective at low doses, which minimizes side effects.

[0093] The compounds of the present invention

[0094] The compound of the present invention, which can be used to prevent and / or treat bacterial infections mediated by at least one bacterium selected from the group consisting of Acinetobacter baumannii and Enterobacteriaceae such as Escherichia coli and Klebsiella pneumoniae, is represented by the following general formula I. I in, A1 represents A that has the following structure 11 and A 12 The part of the group; A 11 and A 12 ; The line connected to the exocyclic methylene group represents a covalent single bond formed with the nitrogen atom of general formula I; A2 represents methyl; Q1 represents CH2 or NH; Q2 indicates CR 4 R 5 , or CR 4 R 5 -CR 6 R 7 , among which, CR 4 R 5 The group is attached to CO, CR 6 R 7 The group is attached to Q1; Q3 represents O or S; R 1 This indicates a group selected from H, halogens, or -NH2; R 2 Indicates selection from H, halogens, -CH2-O-Ar 1 -CH2-O-Het 1 CH2-NR 9 Ar 1 CH2-NR 9 Het 1-O-Ar 1 -O-Het 1 -NR 9 R 10 -O-Alk 1 The group, of which Ar 1 This indicates that it can be optionally selected independently by one or more options from -CN, -OC. 1-4 Alkyl group, -O-(CH2) 1-4 -NR 9 R 10 The phenyl group is substituted with a group, or wherein the phenyl group may have two substituents on adjacent ring atoms, such that these adjacent substituents can bond together to form a 5-membered heterocycle having one or two independent heteroatoms selected from N and O, wherein Het 1 This refers to an aromatic heterocycle having 5 or 6 ring atoms (including 1 or 2 heteroatoms independently selected from N, S, and O), or a non-aromatic, partially or fully saturated heterocycle having 6 ring atoms (including 1 heteroatom selected from N and O), wherein Het 1 The group can optionally be selected independently from -C. 1-4 Alkyl, -OC 1-4 Alkyl group, -CN, -(CH2) 0-4 The group in -OH is substituted; where R 9 Selected from H and -C 1-4 Alkyl; wherein, R 10 Selected from H, -C 1-4 Alkyl groups and -C(=O)-CH3; wherein, Alk 1 It refers to a straight-chain, branched, cyclic, or combined alkyl group having 1 to 6 carbon atoms, wherein Alk 1 The group may optionally be selected from one or more groups chosen from -OH, -OC 1-4 Alkyl group substitution; R 3 Indicates selection from H, -PO3R 3a 2. -CH2-OPO3R 3a 2 and -CH2-OC(=O)-R 3b group; R 3a This indicates a hydrogen atom or a cation suitable for forming a pharmaceutically acceptable salt, or -CH2-OC(=O)-R 3b Or -CHMe-OC(=O)-R 3b Or -CMe2-OC(=O)-R 3b Or -CH2-OC(=O)-OR 3b Or -CHMe-OC(=O)-OR 3bOr -CMe2-OC(=O)-OR 3b ; R 3b It represents an alkyl group having 1 to 11 carbon atoms, which can be straight-chain, branched, cyclic, or a combination thereof, wherein R 3b The group may optionally be one or more independently selected from -OH and -OC. 1-6 Alkyl group substitution; R 4 Indicates selection from H, C 1-4 Alkyl, -CN and C 1-4 alkylene-F groups; R 5 Indicates selection from H, C 1-4 Alkyl, C 1-4 alkylene-OH, C 1-4 Alkylene-OR 3 OH, -OPO3R 3a 2 groups; or R 4 and R 5 Together they form a cyclic group having 4 to 6 ring members formed by methylene groups and optional oxygen atoms; said cyclic group may optionally contain elements selected from -OH, -OC. 1-4 Substituents of alkyl groups; R 6 Indicates selection from H, -OH, C 1-4 Alkyl, -OPO3R 3a 2 groups; R 7 Indicates selection from H, C 1-4 Alkyl, C 1-4 alkylene-OH, C 1-4 Alkylene-OR 3 C 1-4 Alkyl-F or -CN groups; or R 6 and R 7 Together they form a cyclic group having 4 to 6 ring members formed by methylene groups and optional oxygen atoms; said cyclic group may optionally contain elements selected from -OH, -OC. 1-4 Substituents of alkyl groups; And its pharmaceutically acceptable salts.

[0095] Variable groups (A2, Q1 to Q3 and R1 to R) 10 The meaning of ) is specifically defined herein (e.g., in the claims and in items 2 to 10 listed in the summary of the invention).

[0096] This invention also relates to (R,E)-3-(3-cyano-3-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide, having the following chemical structure: ;or (R,E)-3-(3-cyano-3-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazaphen-8-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide, which has the following chemical structure: .

[0097] Furthermore, the present invention also relates to compounds represented by general formula I. I Among them, each part is A1, A2, Q1, Q2 and R. 3 The meaning of "is" is specifically defined herein (e.g., in the claims and in items 14 to 16 listed in the summary of the invention).

[0098] The compounds of the present invention may also be pharmaceutically acceptable prodrugs, salts and / or solvates of these formulas (I).

[0099] Unless otherwise expressly stated, this disclosure considers all such compounds falling within the scope of this invention, including cis and trans isomers, R- and S-enantiomers, diastereomers, (d)-isomers, (l)-isomers, racemic mixtures thereof, and other mixtures. However, the carbon-carbon double bond between the pyridine ring and the central amide group must be in the trans configuration, as shown in the formula above. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are intended to be included in this invention.

[0100] For example, if a specific enantiomer of the compound disclosed herein is required, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliaries, wherein the resulting diastereomeric mixture is isolated and the auxiliary groups are cleaved to provide the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), a diastereomeric salt is formed with a suitable optically active acid or base, and the resulting diastereomeric isomer is then resolved by separation crystallization or chromatographic means known in the art, and the pure enantiomer is then recovered.

[0101] Furthermore, the enantiomers and diastereomers of the compounds of the present invention can be synthesized from commercially available starting materials containing asymmetric or stereoisomeric centers, or prepared by preparing racemic mixtures followed by resolution methods well known to those skilled in the art. These resolution methods are exemplified as follows: (1) linking the enantiomer mixture to a chiral auxiliary agent, obtaining a diastereomer mixture by recrystallization or chromatographic separation, and releasing an optically pure product from the auxiliary agent; (2) salting with an optically active resolving agent; (3) direct separation of the optically enantiomer mixture on a chiral liquid chromatography column; or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by known methods (e.g., chiral gas chromatography or crystallization of the compound in a chiral solvent). Stereoselective synthesis is a chemical or enzymatic reaction in which a single reactant forms a heterogeneous mixture of stereoisomers during the generation of a new stereocenter or during the transformation of a pre-existing stereocenter, as is known in the art. Stereoselective synthesis includes enantioselective and diastereoselective conversions. For example, see Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[0102] This invention also includes isotope-labeled compounds of the invention, which, as described herein, differ in that one or more atoms are replaced by atoms having an atomic mass or mass number different from those normally found in nature. Examples of isotopes that may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, respectively. 2 H, 3 H, 13 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. For example, the compounds of the present invention may have one or more deuterium-substituted H atoms.

[0103] Disclosed compounds labeled with certain isotopes (e.g., using...) 3 H and 14 C-labeled compounds can be used for compound and / or substrate tissue distribution analysis. Tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Furthermore, isotopes such as deuterium (i.e., 2Heavier isotope substitutions, such as H), can provide certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirements), and may therefore be preferred in some cases. The isotope-labeled compounds of the present invention can generally be prepared by steps similar to those disclosed, for example, in the embodiments herein, i.e., by replacing non-isotope-labeled reagents with isotope-labeled reagents.

[0104] prodrug

[0105] The prodrug of the present invention comprises at least one prodrug moiety, i.e., a moiety that is cleaved under physiological conditions to release the active substance. Such a prodrug moiety may be composed of a variable group R. 3 All indicated positions are connected to the compounds of the present invention. A suitable prodrug moiety is a methyl phosphate moiety, as described in WO2013 / 190384A1. Other suitable prodrug moieties are phosphate esters or other soluble moieties, as described in "Prodrugs: design and clinical applications" (Rautio et al., Nature Reviews Drug Discovery, 2008, 7, 255). It should be understood that these prodrug moieties may be replaced by other prodrug moieties. According to a preferred embodiment of the invention, the prodrug of the present invention comprises exactly one prodrug moiety.

[0106] Salts, solvates, polymorphs

[0107] The compounds of the present invention can be used in free form or, alternatively, in the form of pharmaceutically acceptable salts. Acid addition salts are particularly suitable. Pharmaceutically acceptable salts that can be used in the present invention are well known to those skilled in the art, for example, as described in SMBerge et al., J. Pharm. Sci., 1977, Vol. 66, No. 1, pp. 1-19; RJ Bastin et al., Org. Proc. Res. Dev., 2000, Vol. 4, pp. 427-435; and Pharmaceutical Salts: Properties, Selection, and Use, 2nd ed., PHStahl and CGWermuth, Wiley-VCH, 2011. Particularly effective salts may be hydrochlorides, such as hydrochloride or dihydrochloride, or fluoroacetates, such as trifluoroacetates.

[0108] The prodrug of the present invention may also be provided in free form or in the form of a pharmaceutically acceptable salt. Suitable salts are pharmaceutically acceptable salts well known to those skilled in the art, such as those described in the above-cited documents.

[0109] The compounds of the present invention can exist in an unsolvated form or in a solvated form with pharmaceutically acceptable solvents such as water and ethanol. The present invention is intended to cover both solvated and unsolvated forms.

[0110] The compounds of the present invention can exist in single crystal or polycrystalline form or polymorphic form. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In yet another embodiment, the compound is crystalline.

[0111] Manufacturing method

[0112] The compounds of the present invention can be prepared using existing organic chemical synthesis methods and procedures and / or the information described below. Starting materials can be purchased (if commercially available) or synthesized using existing organic chemical synthesis methods and procedures and / or the information described in WO2020 / 099341A1, the entire contents of which are incorporated herein by reference. Specifically, the compounds of the present invention can be prepared according to the methods described in the section entitled "Method of Preparation" of WO2020 / 099341A1 (including the sections "Final Step Amide Coupling," "Preparation of the Right-Hand Precursor," "Preparation of the H-NA1A2 Precursor," and "Final Step Heck Coupling").

[0113] Pharmaceutical Composition

[0114] The compounds of the present invention can be included in pharmaceutical compositions together with pharmaceutically acceptable excipients.

[0115] The pharmaceutical compositions of the present invention can be administered in various ways according to their intended use. For example, if the compositions of the present invention are to be administered orally, they can be formulated as tablets, capsules, granules, powders, or syrups. Alternatively, the formulations disclosed herein can be administered parenterally as injections (intravenous, intramuscular, or subcutaneous), drops, or suppositories. For administration via the ocular mucosa, the compositions disclosed herein can be formulated as eye drops or ointments. These formulations can be prepared by conventional methods, and if desired, the compositions can be mixed with any conventional additives, such as excipients, binders, disintegrants, lubricants, corrective agents, solubilizers, suspending agents, emulsifiers, or coating agents. The disclosed excipients can have a variety of functions. For example, fillers or binders can also be disintegrants, flow aids, anti-adhesion agents, lubricants, sweeteners, etc.

[0116] In the formulations disclosed herein, wetting agents, emulsifiers and lubricants (e.g., sodium dodecyl sulfate and magnesium stearate), as well as colorants, release agents, coating agents, sweeteners, flavoring agents and aroma agents, preservatives and antioxidants may be present in the formulated pharmaceutical preparation.

[0117] The subject compositions are suitable for oral, nasal (e.g., inhalation via dry powder or nebulized formulations), topical (including buccal and sublingual), pulmonary (including aerosol administration), rectal, vaginal, aerosol, and / or parenteral (e.g., by injection, such as intravenous, intramuscular, or subcutaneous injection). The formulations can be conveniently presented in unit dosage forms and can be prepared by any method known in the pharmaceutical field. The amount of compound disclosed herein that can be combined with a carrier material to produce a single dose may vary depending on the characteristics of the compound, the subject being treated, and the specific route of administration.

[0118] Methods for preparing these formulations include the step of combining the compositions of the present invention with a carrier and optionally one or more auxiliary components. Generally, the formulations are prepared by uniformly and tightly combining the reagent with a liquid carrier and / or a finely separated solid carrier, and then shaping the product if necessary.

[0119] Suitable formulations for oral administration may be in the following forms: capsules, cachets, pills, tablets, lozenges (using a flavoring base, typically sucrose and gum arabic or tragacanth), powders, granules, or as solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or oil-in-water emulsions, or as elixirs or syrups, or as lozenges (using an inert base, such as gelatin and glycerin, or sucrose and gum arabic), each containing a predetermined amount of the subject composition as the active ingredient. The compositions of the present invention may also be administered as bolus, ointment, or paste.

[0120] In solid dosage forms (capsules, tablets, pills, sugar-coated pills, powders, granules, etc.) intended for oral administration, the subject composition is mixed with one or more pharmaceutically acceptable excipients selected from: (1) fillers or extenders, such as starch, dextrose, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as cellulose (e.g., microcrystalline cellulose, methylcellulose, hydroxypropyl methylcellulose (HPMC), and carboxymethyl cellulose), alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or gum arabic; (3) humectants, such as glycerin; (4) disintegrants, such as croscarmellose sodium, carboxymethyl starch sodium (sodium starch glycolate), croscarmellose (croscarmellose), gellan gum, etc. Xanthan gum, agar, calcium carbonate, potato or cassava starch, alginic acid and sodium alginate, certain silicates (especially calcium silicate), and sodium carbonate; (5) solution retardants, such as paraffin; (6) absorption promoters, such as quaternary ammonium compounds; (7) wetting agents, such as cetyl alcohol and glyceryl monostearate; (8) absorbents, such as kaolin and bentonite; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate and mixtures thereof; (10) colorants; (11) complexing agents, such as cyclodextrin and modified cyclodextrin, preferably including (2-hydroxypropyl)-β-cyclodextrin and sulfobutyl ether-β-cyclodextrin; (12) polymeric excipients for matrix formation, such as polyvinylpyrrolidone (PVP), for example PVP K30, acrylic polymers and copolymers, such as different grades of Eudragit, preferably Eudragit L100, hydroxypropyl methylcellulose acetate succinate (HPMCAS), other copolymers, such as polyethylene glycol copolymers, such as Soluplus; and (13) a carrier, such as sodium citrate or dicalcium phosphate. In the case of capsules, tablets, and pills, the composition may also contain a buffer. Similar types of solid compositions may also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or lactose and high molecular weight polyethylene glycol. The disclosed excipients may be used for a variety of functions. For example, the filler or binder may also be a disintegrant, flow aid, anti-adhesion agent, lubricant, sweetener, etc. More than two excipients may be used according to the invention, wherein the two or more excipients may belong to the same and / or different categories. There are no limitations in this regard.

[0121] Preferred oral formulations

[0122] adhesives

[0123] Adhesives are advantageously used alone or in combination with excipients to increase the particle size of the active component and improve its processability. There are no particular limitations on the adhesive materials that can be used in this invention.

[0124] Suitable binder materials include polyvinylpyrrolidone (PVP), copolyvinylpyrrolidone (1-vinylpyrrolidone-vinyl acetate copolymer), maltodextrin, poloxamer (block copolymers having a first poly(ethylene oxide) block, a second and a central poly(propylene oxide) block, and a third poly(ethylene oxide) block), polyethylene glycol, polyethylene oxide, magnesium aluminosilicate, gelatin, gum arabic, alginate, carbomer (e.g., carbopol), dextrin, glucose binders (purified mixtures of sugars produced by controlled enzymatic hydrolysis of starch), guar gum, hydrogenated vegetable oil, liquid glucose, waxes, starch (pregelatinized starch and regular starch), sodium alginate, and mixtures thereof.

[0125] Povidone and copovidone are preferred.

[0126] The adhesive may be present in a relative amount of 0.5% to 15% by weight, preferably 1% to 12% by weight, and more preferably 4% to 10% by weight.

[0127] diluent

[0128] Diluents are advantageously used to increase the volume of pharmaceutical compositions and facilitate the processing of the compositions. There are no particular limitations on the diluent materials that can be used in this invention.

[0129] Suitable diluent materials include mannitol, isomaltitol, histidine, lactose (including anhydrous or monohydrate forms), calcium phosphate (including dicalcium phosphate and tricalcium phosphate), calcium carbonate, calcium sulfate, sucrose, fructose, maltose, xylitol, sorbitol, maltitol, aluminum silicate, dextrose, starch (pregelatinized starch and regular starch), glucose, glucose binders (purified mixtures of sugars produced by controlled enzymatic hydrolysis of starch), magnesium carbonate, and mixtures thereof.

[0130] Mannitol, xylitol, sorbitol, isomaltitol, and / or histidine are preferred. Mannitol is particularly preferred.

[0131] The diluent may be present in a relative amount without specific limitation. Suitable amounts may be from 2% to 85% by weight, preferably from 8% to 80% by weight, and more preferably from 10% to 50% by weight.

[0132] surfactants

[0133] Surfactants can be advantageously used to enhance the wetting properties of tablets and active ingredients. Surfactants are optional but preferred ingredients. There are no particular limitations on the surfactant materials that can be used in this invention.

[0134] Suitable surfactant materials include sodium dodecyl sulfate, poloxamer, sodium docusate, sorbitan ester, polyethylene oxide, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 (ethoxylated sorbitan esterified with fatty acids, where the number indicates the number of repeating units of polyethylene glycol) and mixtures thereof.

[0135] Sodium dodecyl sulfate is preferred.

[0136] Surfactants can be present in a relative amount without specific limitation. Suitable amounts can be from more than 0% by weight to 7% by weight, preferably from 0.1% by weight to 6.5% by weight, and more preferably from 1% by weight to 6% by weight.

[0137] Disintegrant

[0138] Disintegrants are used to accelerate the disintegration of pharmaceutical compositions, thereby assisting in the dissolution and absorption of the active ingredient. There are no specific limitations on the disintegrant materials that can be used in this invention.

[0139] Suitable disintegrant materials include cross-linked polyvinylpyrrolidone (cross-linked polyvinylpyrrolidone), sodium carboxymethyl starch (sodium starch glycolate), cross-linked sodium carboxymethyl cellulose, gellan gum, xanthan gum, magnesium aluminosilicate, sodium alginate, pregelatinized starch, alginic acid, guar gum, homopolymers and copolymers of (meth)acrylic acid and their salts (such as polacrilin potassium) and mixtures thereof.

[0140] Cross-linked polyvinyl chloride is preferred.

[0141] The disintegrant can be present in a relative amount without specific limitation. Suitable amounts can be from more than 0% by weight to 20% by weight, preferably from 1% by weight to 15% by weight, and more preferably from 2% by weight to 10% by weight.

[0142] Flow aid

[0143] Flow aids advantageously improve the flowability of pharmaceutical compositions, thereby improving their processability. Flow aids are optional but preferred components. There are no specific limitations on the flow aid materials that can be used in this invention.

[0144] Suitable flow aid materials include colloidal silica, magnesium oxide, magnesium silicate, tricalcium phosphate, and mixtures thereof.

[0145] Colloidal silica is preferred.

[0146] The gliding agent can be present in a relative amount without specific limitations. Suitable amounts can be from more than 0% by weight to 5% by weight, preferably from 0.1% by weight to 4% by weight, and more preferably from 0.2% by weight to 1% by weight.

[0147] lubricant

[0148] Lubricants are advantageously used to facilitate tableting, and in particular to prevent tablets from adhering to the tableting machine. Lubricants are optional but preferred ingredients. There are no particular limitations on the lubricant materials that can be used in this invention.

[0149] Suitable lubricant materials include magnesium stearate, sodium stearate fumarate, talc, stearic acid, leucine, poloxamer, polyethylene glycol, glyceryl behenate, glyceryl monostearate, magnesium dodecyl sulfate, sucrose esters of fatty acids, calcium stearate, aluminum stearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, sodium benzoate, zinc stearate, palmitic acid, carnauba wax, sodium dodecyl sulfate, polyoxyethylene monostearate, calcium silicate, and mixtures thereof.

[0150] Lubricants selected from magnesium stearate and sodium stearate fumarate and combinations thereof are preferred.

[0151] The lubricant can be present in a relative amount without specific limitations. Suitable amounts can be from more than 0% by weight to 7% by weight, preferably from 0.1% by weight to 4% by weight, and more preferably from 0.5% by weight to 3.5% by weight.

[0152] Polymers and copolymers for matrix formation

[0153] Suitable matrix-forming polymers and copolymers include polyvinylpyrrolidone (PVP), acrylic polymers and copolymers such as different grades of Eudragit, hydroxypropyl methylcellulose acetate succinate (HPMCAS), and other copolymers such as polyethylene glycol copolymers, such as Soluplus.

[0154] Preferred polymers and copolymers for matrix formation are HPMC AS and Soluplus.

[0155] The polymers and copolymers used for matrix formation can be present in relative amounts without specific limitations. Suitable amounts can be from 0.1 g to 10 g, preferably from 0.2 g to 5 g, and more preferably from 0.3 g to 4 g.

[0156] Complexing agents

[0157] Suitable complexing agents include cyclodextrins and modified cyclodextrins.

[0158] Preferred complexing agents include (2-hydroxypropyl)-β-cyclodextrin and sulfobutyl ether-β-cyclodextrin.

[0159] The complexing agent can be present in a relative amount without specific limitation. Suitable amounts can be from 0.1g to 24g, preferably from 0.1g to 10g, and more preferably from 0.1g to 5g.

[0160] Other types of excipients

[0161] The compositions of the present invention may contain other excipients commonly used in the art.

[0162] Other excipients of this kind may include release rate modifiers, plasticizers, film-forming agents, colorants, anti-sticking agents, and / or pigments for coating the compositions of the present invention. Other types of excipients that may be present include flavoring agents, sweeteners, antioxidants, absorption promoters, and / or bulking agents. The relative amounts of such excipients are not particularly limited and can be determined by those skilled in the art based on common sense and routine procedures.

[0163] Film-forming agents are advantageously used to provide a cohesive coating for the tablets of the present invention. Suitable film-forming agents include isomaltitol, polyvinyl alcohol, polyethylene glycol, maltodextrin, sucrose, xylitol, maltitol, and enteric coating agents (e.g., materials selected from the group consisting of methyl acrylate-methacrylic acid copolymer, polyvinyl acetate-phthalate (PVAP), methyl methacrylate-methacrylic acid copolymer, shellac, sodium alginate, and corn gluten). A combination of film-forming agents comprising polyvinyl alcohol and one or more second agents selected from isomaltitol, maltodextrin, sucrose, xylitol, and maltitol is preferred. A combination of film-forming agents comprising at least polyvinyl alcohol and isomaltitol is particularly preferred.

[0164] Suitable plasticizers include sorbitol, triacetyl triacetate, poloxamer, polyethylene glycol, glycerin, propylene glycol, polyethylene glycol monomethyl ether, tributyl acetylacetonate, triethyl acetylacetonate, castor oil, glyceryl monostearate, diacetylated monoglyceride, dibutyl sebacate, diethyl phthalate, triethyl citrate, and tributyl citrate.

[0165] For each of the above-mentioned excipients, a single substance or a combination of two or more substances belonging to the same category may be used. Clearly, not every member of every category is required.

[0166] The formulations and compositions of the present invention may comprise the disclosed compounds in amorphous particulate form or any crystalline form. There are no particular limitations on particle size. For example, formulations and compositions may comprise micronized crystals of the disclosed compounds. Micronization may be performed alone on the crystals of the compound, or on a mixture of the crystals with some or all of a pharmaceutical excipient or carrier. The average particle size of the micronized crystals of the disclosed compounds may, for example, be from about 5 to about 200 micrometers or from about 10 to about 110 micrometers. The compounds of the present invention may also be present in the form of molecular dispersions within a polymer matrix. In another embodiment, the compounds of the present invention may be complexed with a suitable complexing agent such as cyclodextrin.

[0167] Tablets can be prepared by compression or molding, optionally using one or more excipients. Compressed tablets can be prepared using binders (e.g., gelatin, microcrystalline cellulose, or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium glycolate starch or croscarmellose sodium), surfactants, or dispersants. Molded tablets can be prepared by molding a mixture of a subject composition moistened with an inert liquid diluent in a suitable machine. Tablets and other solid dosage forms, such as sugar-coated pills, capsules, pellets, and granules, can optionally be scored or prepared using coatings and shells (e.g., enteric coatings and other coatings known in the field of pharmaceutical formulation). The disclosed excipients can play more than one role. For example, fillers or binders can also be disintegrants, glidants, anti-adhesion agents, lubricants, sweeteners, etc.

[0168] It should be understood that the disclosed compositions may include the freeze-dried or lyophilized compounds disclosed herein. For example, compositions disclosed herein are compounds in crystalline and / or amorphous powder form. Such forms can be reconfigured for use, for example, in aqueous compositions.

[0169] Orally administered liquid dosage forms include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the subject composition, liquid dosage forms also contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofuranol, fatty acid esters of polyethylene glycol and sorbitan, cyclodextrins, and mixtures thereof.

[0170] In addition to the main composition, the suspension may also contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan ester, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth gum and mixtures thereof.

[0171] Formulations for rectal or vaginal administration may be in the form of suppositories, which can be prepared by mixing a subject composition with one or more suitable non-irritating excipients or carriers (including, for example, cocoa butter, polyethylene glycol, suppository wax, or salicylate), which are solid at room temperature but liquid at body temperature, thereby melting in the body cavity and releasing the active agent. Formulations suitable for vaginal administration also include vaginal suppositories, tampons, creams, gels, pastes, foams, or spray formulations containing suitable carriers known in the art.

[0172] Dosage forms for transdermal application of the subject composition include powders, sprays, ointments, pastes, creams, emulsions, gels, solutions, and patches. The active ingredient may be mixed under aseptic conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0173] In addition to the main composition, ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth gum, cellulose derivatives, polyethylene glycol, silicones, bentonite, silicic acid, talc and zinc oxide or mixtures thereof.

[0174] In addition to the main composition, powders and sprays may also contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. Sprays may also contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0175] Alternatively, the compositions and compounds of the present invention can be administered via aerosol. This is achieved by preparing aqueous aerosols, liposome formulations, or solid particles containing the compound. Non-aqueous suspensions (e.g., fluorocarbon propellants) can be used. Acoustic nebulizers can be used because they minimize the exposure of the reagent to shear forces that could lead to degradation of the compounds contained in the subject composition.

[0176] Typically, aqueous aerosols are manufactured by formulating an aqueous solution or suspension of the subject composition with conventionally pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary depending on the requirements of the specific subject composition, but generally include nonionic surfactants (Tween, pluronics, or polyethylene glycol), harmless proteins (such as serum albumin), sorbitan esters, oleic acid, lecithin, amino acids (such as glycine), buffers, salts, sugars, or sugar alcohols. Aerosols are typically prepared from isotonic solutions.

[0177] It should be noted that the excipients provided as examples may have more than one function. For example, fillers or binders may also be disintegrants, flow aids, anti-adhesion agents, lubricants, sweeteners, etc.

[0178] Pharmaceutical compositions of the present invention suitable for parenteral administration comprise a combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders reconstituted into sterile injectable solutions or dispersions just before use. These compositions may contain antioxidants, buffers, antibacterial agents, solutes that make the formulation isotonic with the blood of the intended recipient, or suspending agents or thickeners. For example, an aqueous composition comprising the disclosed compounds may also contain, for example, dextrose (e.g., about 1% to about 10% by weight of dextrose in water, or about 5% by weight of dextrose (D5W)).

[0179] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters such as ethyl oleate and cyclodextrin. For example, coating materials such as lecithin can be used to maintain the desired particle size in the case of dispersions and to maintain appropriate flowability through the use of surfactants.

[0180] It should be understood that the formulations under consideration, such as oral formulations (e.g., pills or tablets), may be formulated as controlled-release formulations, such as immediate-release formulations, delayed-release formulations, or combinations thereof.

[0181] In some embodiments, the subject compound may be formulated as tablets, pills, capsules, or other suitable ingestible formulations (collectively, “tablets”). In some embodiments, a therapeutic dose may be provided in fewer than 10 tablets. In another example, a therapeutic dose may be provided in 50, 40, 30, 20, 15, 10, 5, or 3 tablets.

[0182] In one embodiment, the disclosed compound is formulated as a tablet, capsule, or aqueous solution or suspension for oral administration. In another embodiment in tablet form, the tablet is formulated such that if the final amount of antimicrobial agent (or multiple antimicrobial agents) provided in 20 tablets is administered together (e.g., over time) at once, it will provide a therapeutically effective dose and / or at least half the effective dose (ED50), for example, a dose in which at least 50% of individuals exhibit a qualitative effect of inhibiting bacterial cell growth or protection (e.g., a statistically significant reduction in infection). In another embodiment, the tablet may be formulated such that the total amount of antimicrobial agent (or multiple antimicrobial agents) provided when 10, 5, 2, or 1 tablet is administered will provide a therapeutically effective dose and / or at least an ED50 dose to the patient (human or non-human mammal). In other embodiments, taking 20, 10, 5, or 2 tablets of the provided antimicrobial agent (or multiple antimicrobial agents) within 24 hours after administration will provide a dosing regimen that, on average, provides an average plasma level of one or more antimicrobial agents having a therapeutically effective dose and / or at least an ED50 concentration (e.g., a concentration that represents 50% of the maximum effect of inhibiting bacterial cell growth). In other embodiments, less than 100, 10, or 5 times the ED50 is provided. In other embodiments, a single-dose tablet (1 to 20 tablets) provides approximately 40 mg to 3000 mg of the compound. These prescribed unit doses also apply to other oral dosage forms.

[0183] Similarly, the compounds disclosed herein can be formulated for parenteral administration, such as for subcutaneous, intramuscular, or intravenous injection. For example, the antimicrobial agents can be provided as sterile solutions or suspensions (hereinafter collectively referred to as "injectable solutions"). In some embodiments, the injectable solutions can be formulated such that the amount of antimicrobial agent (or multiple antimicrobial agents) provided, for example, in a dose of about 0.1 to about 200 cc by bolus or intravenous administration, will provide at least half of the effective dose, or a dose less than 100 times the ED50, or a dose less than 10 or 5 times the ED50. The injectable solutions can be formulated such that the total amount of antimicrobial agent (or multiple antimicrobial agents) provided (after administration) in 100, 50, 25, 10, 5, 2.5, or 1 cc of injection will provide the patient with a therapeutically effective dose and / or an ED50 dose, or less than 100 times the ED50, or less than 10 or 5 times the ED50. In other embodiments, following administration, a total volume of 100 cc, 50, 25, 5, or 2 cc of antimicrobial agent administered via at least two injections within 24 hours will provide a dosing regimen that, on average, delivers an average plasma level of one or more antimicrobial agents having a therapeutically effective dose and / or at least an ED50 concentration, or less than 100 times the ED50, or less than 10 or 5 times the ED50. In other embodiments, a single injection may provide approximately 40 mg to 3000 mg or approximately 100 mg to approximately 1000 mg of antimicrobial agent. In the case of intramuscular administration, the principle of the same amount also applies. However, the upper limit of the unit dose range may be lower, depending on the solubility of the drug compound and the maximum tolerated dose.

[0184] unit dose

[0185] If the pharmaceutical composition of the present invention is administered to a patient orally, a single unit dose of the pharmaceutical composition of the present invention is typically administered once, twice, or three times a day. The daily dose is determined by the physician according to the guidelines described above, taking into account the severity of the infection, the patient's sex, weight, age, and general condition. The preferred daily oral dose ranges from 40 mg to 3000 mg, preferably from 100 mg to 2000 mg. Therefore, a typical unit dose may be between 40 mg and 2000 mg, depending on the intended frequency of administration.

[0186] When administered parenterally (e.g., intravenous or intramuscular), the pharmaceutical compositions of the present invention are typically administered two, three, or more times per day. Preferred daily doses are in the range of 40 mg to 3000 mg, and thus typical unit doses are in the range of 40 mg to 3000 mg, preferably 100 mg to 1000 mg. The upper limit of the specified range depends on its feasibility. For example, in the case of intramuscular administration, the maximum dose for a single injection may be limited due to low solubility and the correspondingly increased volume of the drug solution. In this case, the maximum unit dose is limited by the maximum tolerated dose.

[0187] Drug combination

[0188] This document also contemplates compositions comprising one or more of the disclosed compounds and a second component. The second component in such compositions is typically an antibiotic agent other than the disclosed compounds. Other components may also be present, including FAI inhibitors or other antibiotic agents. In some embodiments, the treatment methods contemplated herein also include administration of another agent such as that described below. For example, a method of treating a bacterial infection is provided, comprising administering the disclosed compounds and further comprising administering an antibiotic or antibacterial agent as described below. The disclosed compounds and second component may be part of the same dosage form or may be formulated into two separate dosage forms. If they are formulated into two separate dosage forms, the dosage form containing the second component may be administered simultaneously with, before, or after the dosage form containing the disclosed compounds.

[0189] Non-limiting examples of antibiotic agents that can be used in the antibacterial compositions of the present invention include polymyxins, cephalosporins, quinolones and fluoroquinolones, penicillins, penicillins and β-lactamase inhibitors, carbapenems, monocyclic β-lactams, macrolides and lincosamine, glycopeptides, rifampin, oxazolidinones, tetracyclines, aminoglycosides, streptozotocins, sulfonamides, etc. Each family includes many members. In a preferred embodiment, the additional antibiotic agent is a polymyxin or an aminoglycoside.

[0190] In a preferred embodiment, the pharmaceutical composition of the present invention further comprises another antibiotic agent. This additional antibiotic agent is preferably selected from the group consisting of polymyxins and aminoglycosides. The combination of the compounds of the present invention with polymyxins and / or aminoglycosides can improve pharmaceutical efficacy in treating bacterial infections mediated by at least one bacterium selected from the group consisting of *Acinetobacter baumannii* and *Enterobacteriaceae* such as *Escherichia coli* and *Klebsiella pneumoniae*. This improved efficacy may be the result of a synergistic effect.

[0191] Polymyxins refer to a class of bacteria such as *Bacillus polymyxa* (…). Paenibacillus polymyxaNonribosomal peptide antibiotics, naturally produced by Gram-positive bacteria, are effective against Gram-negative bacterial infections. A typical example is colistin sodium methanesulfonate, the sodium salt of which is commercially available as polymyxin sodium methanesulfonate (Colistimethat-Natrium). Another typical example is SPR206, which is disclosed, for example, in P. Brown et al., ACS Infect Dis. 2019 Oct 11; 5(10): 1645–1656; doi: 10.1021 / acsinfecdis.9b00217.

[0192] Cephalosporins can be further classified by generation. Non-limiting examples of cephalosporins classified by generation include the following: Examples of cephalosporins: First-generation compounds include cefadroxil, cefazolin, cephahalexin, cephalothin, cephapirin, and cephradine. Second-generation compounds include cefaaclor, cefamandol, cefonicid, cefootetan, cefoxitin, cefoprozil, ceftmetazole, cefouroxime, cefouroxime axetil, and loracarbef. The third generation includes cefdinir, ceftibuten, cefditoren, cefetamet, cefpodoxime, cefprozil, cefuroxime(axetil), cefuroxime(sodium), cefoperazone, cefixime, cefotaxime, cefpodoxime proxetil, ceftazidime, ceftizoxime, and ceftriaxone. The fourth generation includes cefepime.

[0193] Non-limiting examples of quinolones and fluoroquinolones include cinoxacin, ciprofloxacin, enoxacin, gatifloxacin, grepafloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, sparfloxacin, trovafloxacin, oxolinicacid, gemifloxacin, and perfloxacin.

[0194] Non-restrictive examples of penicillins include amoxicillin, ampicillin, bacampicillin, carbenicillin indanyl, mezlocillin, piperacillin, and ticarcillin.

[0195] Non-limiting examples of penicillins and β-lactamase inhibitors include amoxicillin-clavulanic acid, ampicillin-sulbactam, benzylpenicillin, cloxacillin, dicloxacillin, methicillin, oxacillin, penicillin G (benzamine, potassium, procaine), penicillin V, piperacillin-tazobactam, ticarcillin-clavulanic acid, and nafcillin. Non-limiting examples of penicillins include imipenem-cilastatin and meropenem.

[0196] Non-limiting examples of monoamides include aztreonam. Non-limiting examples of macrolides and lincosamides include azithromycin, clarithromycin, clindamycin, irithromycin, erythromycin, lincomycin, and troleandomycin. Non-limiting examples of glycopeptides include teicoplanin and vancomycin. Non-limiting examples of rifampins include rifabutin, rifampin, and rifapentine. Non-limiting examples of oxazolidinones include linezolid. Non-limiting examples of tetracyclines include demeclocycline, doxycycline, methacycline, minocycline, oxytetracycline, tetracycline, and chlortetracycline.

[0197] Non-limiting examples of aminoglycosides include amikacin, arbakacin, gentamicin, kanamycin, sisomicin, neomycin, netilmicin, streptomycin, tobramycin, and paromomycin.

[0198] Non-limiting examples of streptozotocin include quinopristin and dalfopristin.

[0199] Non-limiting examples of sulfonamides include sulfamiron (Mafenide), silver sulfadiazine (Sulfacetamide), sulfadiazine (Sulfadiazine), sulfamethoxazole (Sulfamethoxazole), sulfasalazine (Sulfasalazine), sulfisoxazole (Sulfisoxazole), trimethoprim-sulfamethoxazole (Trimethoprim-Sulfamethoxazole), and sulfamethizole (Sulfamethizole).

[0200] Other non-limiting examples of antibiotics include bacitracin, chloramphenicol, colistimethate, fosfomycin, isoniazid, methenamine, metronidazole, mupirocin, nitrofurantoin, nitrofurazone, novobiocin, polymyxin B, spectinomycin, tobramycin, tigecycline, trimethoprim, colistin, cycloserine, capreomycin, pyrazinamide, para-aminosalicylic acid, and erythromycin ethyl succinate + sulfamethoxazole. ethylsuccinate+sulfisoxazole).

[0201] Therapeutic uses

[0202] Medical indications

[0203] The compounds of the present invention can be used to treat bacterial infections in patients. They are particularly suitable for the prevention and / or treatment of bacterial infections mediated by at least one bacterium selected from the group consisting of Acinetobacter baumannii and Enterobacteriaceae such as Escherichia coli and Klebsiella pneumoniae.

[0204] patient

[0205] The compounds of the present invention can be used to treat bacterial infections in human patients or non-human animals (preferably human and non-human mammals).

[0206] Daily dose

[0207] The dosage of any disclosed compound or composition will vary depending on the patient's symptoms, age and weight, the nature and severity of the condition to be treated or prevented, the route of administration, and the form of the subject composition. Any subject formulation may be administered as a single dose or in multiple doses. The dosage of the composition can be readily determined by techniques known to those skilled in the art or as taught herein.

[0208] In some embodiments, the dose of the subject compound is typically in the range of about 0.01 ng to about 10 g / kg body weight, particularly about 1 ng to about 0.1 g / kg, and more particularly about 100 ng to about 10 mg / kg.

[0209] For any particular composition of the present invention, it may be necessary to determine the effective dose or amount and any possible effects on the timing of formulation administration. This can be achieved through routine experiments as described herein using one or more groups of animals (preferably at least 5 animals per group), or, where appropriate, in human trials. The effectiveness of any subject composition and treatment or prevention method can be assessed by administering the composition and measuring one or more applicable indices to evaluate the effect of administration, and comparing the post-treatment values ​​of these indices with the pre-treatment values ​​of the same indices.

[0210] The precise timing and dosage of any particular subject composition that will produce the most effective therapeutic effect in a given patient will depend on the activity, pharmacokinetics, and bioavailability of the subject composition, the patient's physiological condition (including age, sex, disease type and stage, general physical condition, responsiveness to a given dose and type of drug), and route of administration. The guidelines presented herein can be used to optimize treatment, such as determining the optimal timing and / or amount of administration, which will not require exceeding the standard trial (which consists of monitoring subjects and adjusting dose and / or timing).

[0211] When subjects receive treatment, their health can be monitored by measuring one or more relevant parameters at predetermined intervals during treatment. Treatment can be optimized based on the monitoring results, including composition, dosage, frequency of administration, and formulation. Patients can be periodically reassessed by measuring the same parameters to determine the extent of improvement. Based on these reassessments, the amount of the subject composition administered and the possible timing of administration can be adjusted.

[0212] Treatment can begin with a small dose, less than the optimal dose of the compound. The dose can then be increased gradually until the optimal therapeutic effect is achieved.

[0213] Using a subject composition can reduce the required dosage of any individual agent contained in the composition, because the onset and duration of action of different agents may be complementary.

[0214] The toxicity and therapeutic effects of the subject composition can be determined by standard pharmaceutical procedures in cell cultures or laboratory animals, such as those used to determine LD50 and ED50.

[0215] Data obtained from cell culture analysis and animal studies can be used to determine dosage ranges for human use. The dosage of any subject composition is preferably within a cyclic concentration range that includes an ED50, is less or non-toxic, and / or, when less or non-toxic, statistically significantly reduces infection in at least 50% (e.g., 60%, 70%, 80%, 90%, 100%) of individuals, where less toxicity may, for example, mean non-serious and / or predictable transient toxicity. For example, the dosage of the subject composition can be selected to achieve a reasonable benefit / risk ratio through treatment. The dosage may vary within this range depending on the dosage form and route of administration used. For the compositions of the present invention, the therapeutically effective dose can be initially estimated by cell culture analysis.

[0216] Application frequency

[0217] The compounds and compositions disclosed herein may be administered once or more daily, particularly once daily (qd), twice daily (bid), three times daily (tid), or four times daily (qid).

[0218] Treatment duration

[0219] The compounds and compositions disclosed herein can be administered indefinitely. Advantageously, administration for a period of time is intended to completely eradicate bacterial infection, or at least to the point where the patient's immune system can cope with any remaining pathological bacteria. Typical duration of administration is from 1 day to 2 weeks, particularly 1 to 5 days. In cases of administration by intramuscular injection, typical duration of administration is from 1 to 4 injections, preferably 1 injection. Injections can be given multiple times on the same day, over several consecutive days, or at intervals (without administration during the intervals).

[0220] abbreviation

[0221] The following abbreviations are used in this invention.

[0222]

[0223] The following examples are not intended to limit the scope of the invention, but are merely illustrative of the compounds of the invention and their preparation.

[0224] Example

[0225] General Procedure

[0226] All starting materials and solvents were derived from commercial sources or prepared according to literature citations. All reactions were stirred unless otherwise specified. Organic solutions were typically dried with anhydrous magnesium sulfate or sodium sulfate.

[0227] Column chromatography was performed using the eluent shown on a pre-packed silica column (230 to 400 mesh, 40 to 63 μm). SCX was purchased from Silicycle and treated with 1 M hydrochloric acid before use. Unless otherwise specified, the reaction mixture to be purified was first diluted with MeOH and acidified with a few drops of AcOH. This solution was loaded directly into the SCX and washed with MeOH. The desired material was then eluted by washing with 0.7 M NH3 in methanol.

[0228] Analytical methods

[0229] Analytical LCMS

[0230] Analytical LCMS can be performed using the acidic or basic methods shown below: Method 1a: A Waters X-Select CSH C18, 2.5 μm, 4.6 × 30 mm column was eluted with a gradient of 0.1% formic acid-MeCN solution in 0.1% formic acid aqueous solution. The gradient of 5% to 95% formic acid-MeCN solution was performed at 2.5 mL / min from 0.00 to 3.00 min, followed by rinsing at 4.5 mL / min from 3.01 to 3.5 min. The column was reequilibrated to 5% MeCN from 3.60 to 4.00 min at 2.5 mL / min. The UV spectra of the elution peaks were measured at 254 nm using an Agilent 1260 Infinity or Agilent 1200 VWD. Mass spectra were measured using an Agilent 6120 or Agilent 1956 MSD operating with a positive / negative switch, or an Agilent 6100 MSD operating in either positive or negative mode.

[0231] Method 1b: A Waters X-Select BEH C18, 2.5 μm, 4.6 × 30 mm column was eluted with a gradient of MeCN in 10 mM ammonium bicarbonate aqueous solution. The gradient of 5% to 95% MeCN was carried out at 2.5 mL / min from 0.00 to 3.00 min, followed by rinsing at 4.5 mL / min from 3.01 to 3.5 min. The column was reequilibrated to 5% MeCN from 3.60 to 4.00 min at 2.5 mL / min. The UV spectra of the elution peaks were measured at 254 nm using an Agilent 1260 Infinity or Agilent 1200 VWD. Mass spectra were measured using an Agilent 6120 or Agilent 1956M SD operating with a positive / negative switch, or an Agilent 6100 MSD operating in either positive or negative mode.

[0232] Method 1c: The product was analyzed by UPLC (Acquity and SQD Waters system, Water (HPLC grade) UPLC) ® BEHC18, 50 × 2.1 mm, 1.7 μm (0.1% HCOOH aqueous solution, 0.1% HCOOH acetonitrile solution), 3-minute method, 5% to 95% MeCN / water) for analysis.

[0233] All UPLC-MS analyses were performed on UPLC Acquity and SQD Waters systems. Masslynx software was used to start and analyze experiments using OALogin and automated or manual integration. Details of the methods used are listed below.

[0234]

[0235] Mobile phase description:

[0236] UPLC parameters:

[0237] Mass spectrometry method: Executed based on MS Tune parameters: Routine.ipr, as shown below.

[0238]

[0239] This method is based on the information "MS method: pos_neg_3mn_30v". Number of points per peak: 3.846. Total runtime: 3.0 minutes. MS scan, time 0.00 to 3.00, quality 100.00 to 900.00 ES. + .

[0240] UPLC-MS mass spectrometry recordings were performed on an SQ detector from Acquity Waters (Waters Corporation, Waters Milford, 34 Maple St., Milford, USA), equipped with Empower 2 Pro software, in positive ionization mode. Ionization conditions: capillary 2.25 kV, orifice 160 V, source 100 °C, desolvation 150 °C; gas flow rate → desolvation 500 L / h, orifice 50 L / h.

[0241] Analytical UPLC / MS

[0242] Alternatively, analytical UPLC / MS can be performed using the following acidic or basic methods: Method 2a: A Waters Acquity CSH C18, 1.7 μm, 2.1 × 30 mm column was eluted with a gradient of 0.1% formic acid-MeCN solution in 0.1% formic acid aqueous solution. The gradient was set to start with 5% MeCN and held from 0.0 to 0.11 min. The gradient from 5% to 95% was carried out from 0.11 to 2.15 min, followed by rinsing from 2.15 to 2.56 min. The column was reequilibrated to 5% MeCN from 2.56 to 2.83 min. The UV spectra of the elution peaks were measured using an Acquity PDA, and the mass spectra were recorded using an Acquity QDa detector with ESI positive / negative switches.

[0243] Method 2b: A Waters Acquity BEH C18, 1.7 μm, 2.1 × 30 mm column was used for gradient elution with MeCN in 10 mm of ammonium bicarbonate aqueous solution. The gradient was set to start with 5% MeCN and held from 0.0 to 0.11 min. The gradient from 5% to 95% was carried out from 0.11 to 2.15 min, followed by rinsing from 2.15 to 2.56 min. The column was reequilibrated to 5% MeCN from 2.56 to 2.83 min. The UV spectra of the elution peaks were measured using an Acquity PDA, and the mass spectra were recorded using an Acquity QDa detector with ESI positive / negative switches.

[0244] Preparative HPLC

[0245] Preparative HPLC was performed as follows: a Waters Xselect CSH C18, 5 μm, 19 × 50 mm column was used with a gradient of 0.1% formic acid-MeCN solution in 0.1% aqueous formic acid or a gradient of MeCN in 10 mM ammonium bicarbonate aqueous solution; or a Waters Xbridge BEH C18, 5 μm, 19 × 50 mm column was used with a gradient of MeCN in 10 mM ammonium bicarbonate aqueous solution. Fractions were collected by the following detection methods: single-wavelength ultraviolet light was measured using a variable wavelength detector on a Gilson 215 preparative HPLC or a Varian PrepStar preparative HPLC; single-wavelength mass and ultraviolet light were measured using a Waters FractionLynx LCMS with a ZQ single quadrupole mass spectrometer (with positive and negative ion electrospray ionization) and a dual-wavelength detector.

[0246] Preparative chiral high performance liquid chromatography

[0247] Method 3a: Chiralpak ® IA (Daicel Ltd.) column (2×25 cm), flow rate 13.5 mL / min -1 The sample was eluted with a mixture of heptane + 0.2% TFA and chloroform in a 4:1 ratio (ethanol percentage), and detected by UV at 254 nm. The sample was loaded onto the column using an on-column dilution pump, and chloroform (1.5 mL / min) was pumped during the run. -1 ), yielding 15 mL min - 1. Combined flow rate.

[0248] Method 3b: Chiralpak ® IC (Daicel Ltd.) column (2×25 cm), flow rate 13.5 mL / min -1 The sample was eluted with a mixture of heptane and 0.2% diethylamine in ethanol (ethanol %), and detected at 254 nm using UV spectroscopy. The sample was loaded onto the column using an on-column dilution pump, and chloroform (1.5 mL / min) was pumped during the run. -1 ), yielding 15 mL min - 1. Combined flow rate.

[0249] Analytical chiral high performance liquid chromatography

[0250] Method 4a: Chiralpak ® IA (Daicel Ltd.) column (4.6 mm × 25 mm), flow rate 1 mL / min -1The solution was eluted with a mixture of isohexane, 0.2% TFA, and chloroform in a 4:1 ratio of ethanol (ethanol %) and detected by UV at 254 nm.

[0251] Method 4b: Chiralpak ® IC (Daicel Ltd.) column (4.6 mm × 25 mm), flow rate 1 mL / min -1 The mixture was eluted with an ethanol mixture of isohexane and 0.2% diethylamine (ethanol %) and detected by UV at 254 nm.

[0252] 1 H NMR spectroscopy

[0253] Using residual non-deuterated solvent as a reference, the results were obtained at 400 MHz on a Bruker Avance III spectrometer. 1 HNMR spectrum.

[0254] Example 1. Synthesis of (R,E)-3-(3-cyano-3-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazaphen-8-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide (compound 302)

[0255] Overall synthesis scheme

[0256] Step 1. Ethyl 2-cyano-3-hydroxy-2-methylpropionate (compound 292). A mixture of ethyl 2-cyanopropionate 291 (5.00 g, 39.3 mmol), paraformaldehyde (1.77 g, 59.0 mmol), and triethylamine (6.5 mL, 47.2 mmol) in MeCN (100 mL) was heated to 50 °C and maintained for 3 hours. The reaction mixture was cooled to room temperature, concentrated under vacuum, and the crude product was purified by chromatography (0 to 100% EtOAc / isohexane) to give the desired product 292 as a colorless oil (6.09 g, yield 89%). 1 H NMR (500 MHz, DMSO-d6) δ 5.80 (t, J=5.7 Hz, 1H), 4.20 (q, J=7.1 Hz, 2H), 3.74 (dd, J=10.6, 5.7 Hz, 1H), 3.66 (dd, J=10.6, 5.8 Hz, 1H), 1.44 (s, 3H), 1.23 (t, J=7.1Hz, 3H).

[0257]

[0258] Step 2. Ethyl 3-amino-2-(hydroxymethyl)-2-methylpropionate hydrochloride (compound 293). A mixture of ethyl 2-cyano-3-hydroxy-2-methylpropionate 292 (1.00 g, 6.36 mmol), platinum oxide (0.14 g, 0.64 mmol), and HCl (3.18 mL, 12.7 mmol, 4 M 1,4-dioxane solution) in EtOH (12 mL) was stirred at H2 (5 bar) for ~16 hours. The catalyst was removed by filtration, and the filtrate was concentrated under vacuum. The resulting residue was azeotropically distilled with MeCN (30 mL) to give the desired product 293 as a colorless oil (1.33 g, 95% yield), which could be used directly for the next reaction without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 3H), 5.31 (s, 1H), 4.18–4.01 (m, 2H), 3.60 (d, J=10.9 Hz, 1H), 3.46 (d, J=11.0 Hz, 1H), 3.06 (d, J=13.1 Hz, 1H), 2.94 (d, J=13.1Hz, 1H), 1.20 (t, J=7.1 Hz, 3H), 1.12 (s, 3H).

[0259]

[0260] Step 3. Ethyl 3-((5-bromo-2-nitropyridin-3-yl)amino)-2-(hydroxymethyl)-2-methylpropionate (compound 294). A mixture of ethyl 3-amino-2-(hydroxymethyl)-2-methylpropionate hydrochloride 293 (1.07 g, 5.43 mmol), 5-bromo-3-fluoro-2-nitropyridinium (1.00 g, 4.53 mmol), and TEA (2.52 mL, 18.1 mmol) in EtOH (40 mL) was refluxed and stirred for 2 hours. The reaction mixture was cooled to room temperature, concentrated under vacuum, and the crude product was purified by chromatography (0 to 100% EtOAc / heptane) to give the desired product 294 as a bright yellow gel (1.55 g, 91% yield). t 1.79 min (Method 1a) m / z 362 / 364 (M+H) + (ES + ). 1H NMR (400 MHz, DMSO-d6) δ 8.23 ​​(t, J=6.0 Hz, 1H), 8.04 (d, J=1.9 Hz, 1H), 7.86 (d, J=1.8 Hz, 1H), 5.19 (t, J=5.1 Hz, 1H), 4.12–4.03 (m, 2H), 3.67–3.57 (m, 3H), 3.54 (dd, J=10.7, 5.1 Hz, 1H), 1.16 (t, J=7.1 Hz, 3H), 1.13 (s, 3H).

[0261]

[0262] Step 4. Ethyl 3-((5-bromo-2-nitropyridin-3-yl)amino)-2-formyl-2-methylpropionate (compound 295). Sodium bicarbonate (160 mg, 1.91 mmol) was added to a stirred solution of ethyl 3-((5-bromo-2-nitropyridin-3-yl)amino)-2-(hydroxymethyl)-2-methylpropionate 294 (0.23 g, 0.64 mmol) in DCM (10 mL), followed by fractional addition of Dess Martin Periodinane (350 mg, 0.83 mmol). The reaction mixture was stirred at room temperature for 2 hours, then quenched by adding 2 M Na₂SO₃ solution (40 mL) and further diluted with saturated NaHCO₃ aqueous solution (20 mL) and H₂O (20 mL). The aqueous phase was extracted with DCM (3 × 40 mL) and concentrated under vacuum. The crude product was purified by chromatography (0 to 100% EtOAc / heptane) to give the desired product 295, which was a yellow oil (0.18 g, yield 77%). 1 HNMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.13 (d, J=1.9 Hz, 1H), 8.05 (t, J=6.5 Hz, 1H), 7.90 (d, J=1.8 Hz, 1H), 4.19–4.09 (m, 2H), 3.98–3.83 (m, 2H), 1.36 (s, 3H), 1.16 (t, J=7.1 Hz, 3H).

[0263]

[0264] Step 5. Ethyl 3-((5-bromo-2-nitropyridin-3-yl)amino)-2-((hydroxyimino)methyl)-2-methylpropionate (compound 296). Hydroxylamine hydrochloride (0.68 g, 9.83 mmol), sodium acetate (0.81 g, 9.83 mmol), and water (30 mL) were added to a stirred solution of ethyl 3-((5-bromo-2-nitropyridin-3-yl)amino)-2-formyl-2-methylpropionate 295 (1.18 g, 3.28 mmol) in EtOH (45 mL). The reaction mixture was heated under reflux for 2 hours. The reaction mixture was cooled to room temperature and concentrated under vacuum. The resulting residue was partitioned between EtOAc (25 mL) and water (25 mL). The aqueous phase was extracted with EtOAc (25 mL), the combined organic phases were washed with brine (30 mL), dried using a phase separator, and concentrated under vacuum. The crude product was purified by chromatography (0 to 100% EtOAc / isohexane) to give the desired product 296 as a yellow solid (0.83 g, yield 65%). t 1.90 min (Method 1a) m / z 375 / 377 (M+H) + (ES + ). 1 H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.15 (t, J=6.3 Hz, 1H), 8.10 (d, J=1.9 Hz, 1H), 7.89 (d, J=1.8 Hz, 1H), 7.47 (s, 1H), 4.09 (q, J=7.1 Hz, 2H), 3.86 (dd, J=13.8, 6.6 Hz, 1H), 3.79 (dd, J=13.8, 6.2Hz, 1H), 1.37 (s, 3H), 1.15 (t, J=7.1 Hz, 3H).

[0265]

[0266] Step 6. Ethyl 3-((5-bromo-2-nitropyridin-3-yl)amino)-2-cyano-2-methylpropionate (compound 297). Add Burgess reagent (0.48 g, 2.00 mmol) to a stirred solution of (E)-3-((5-bromo-2-nitropyridin-3-yl)amino)-2-((hydroxyimino)methyl)-2-methylpropionate 296 (0.50 g, 1.33 mmol) in THF (25 mL), and heat the reaction mixture to 50 °C and maintain for approximately 16 hours. Cool the reaction mixture to room temperature and concentrate under vacuum. Place the resulting residue in DCM (100 mL), wash with water (2 × 50 mL) and brine (50 mL), dry using a phase separator, and concentrate under vacuum. The crude product was purified by chromatography (0 to 50% EtOAc / isohexane) to give the target product 297, a yellow oil (0.38 g, 75% yield). t 1.98 min (Method 1a) m / z 357 / 359 (M+H) + (ES + ). 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J=1.9 Hz, 1H), 8.06 (t, J=7.0 Hz, 1H), 7.96 (d, J=1.8Hz, 1H), 4.23–4.16 (m, 2H), 4.15–4.02 (m, 2H), 1.62 (s, 3H), 1.21 (t, J=7.1 Hz, 3H).

[0267]

[0268] Step 7. Ethyl 3-((2-amino-5-bromopyridin-3-yl)amino)-2-cyano-2-methylpropionate (compound 298). A suspension of ethyl 3-((5-bromo-2-nitropyridin-3-yl)amino)-2-cyano-2-methylpropionate 297 (0.38 g, 1.06 mmol), iron powder (0.48 g, 8.47 mmol), and ammonium chloride (0.23 g, 4.23 mmol) in a mixture of EtOH (16 mL) and water (4 mL) was heated to 90 °C and stirred for 30 min. The reaction mixture was cooled to room temperature, dry-loaded onto diatomaceous earth, and purified by chromatography (0 to 50% EtOAc / cyclohexane) to give the desired product 298 as a reddish-brown oil (0.25 g, yield 67%). t 1.17 min (Method 1a) m / z 327 / 329 (M+H) + (ES + ).1 H NMR (400MHz, DMSO-d6) δ 7.35 (d, J=2.0 Hz, 1H), 6.98 (d, J=2.0 Hz, 1H), 5.79 (s, 2H), 5.35 (t, J=6.7 Hz, 1H), 4.22–4.09 (m, 2H), 3.77–3.60 (m, 2H), 1.59 (s, 3H), 1.20 (t, J=7.1 Hz, 3H).

[0269]

[0270] Step 8. Ethyl (R)-3-((2-amino-5-bromopyridin-3-yl)amino)-2-cyano-2-methylpropionate (compound 299). Enantiomer 298 was separated by chiral SFC on a Phenomenex Lux C4 column (10 × 250 mm, 5 μm particle size) using a Waters prep 15 with UV detection via DAD (210–400 nm) at 40 °C and 120 bar. 20% neutral EtOH was used at a flow rate of 15 mL / min. Chirality was arbitrarily specified.

[0271] Through analytical SFC (Waters UPC) 2 A 5 μm Phenomenex Lux C4 column (250 × 4.6 mm, flow rate 4 mL / min) was used as the eluent, and the product was analyzed using 20% ​​EtOH containing 0.3% 7N methanol-ammonia solution. (S)-3-((2-amino-5-bromopyridin-3-yl)amino)-2-cyano-2-methylpropionate ethyl ester (first eluting enantiomeric): R t 2.74 min.

[0272] (R)-3-((2-amino-5-bromopyridin-3-yl)amino)-2-cyano-2-methylpropionate ethyl ester 299 (second eluting enantiomeric): R t 3.98 min.

[0273]

[0274] Step 9. Lithium (R)-3-((2-amino-5-bromopyridin-3-yl)amino)-2-cyano-2-methylpropionate (compound 300). A solution of LiOH (15 mg, 611 μmol) in water (1 mL) was added to a stirred solution of ethyl (R)-3-((2-amino-5-bromopyridin-3-yl)amino)-2-cyano-2-methylpropionate 299 (0.10 g, 306 μmol) in a mixture of THF (4 mL) and MeOH (1 mL). The reaction was stirred at room temperature for 1 hour. The solvent was removed under vacuum, and the solid was azeotropically distilled with MeCN (10 mL). The resulting brown solid 300 (0.12 g, quantitative) was used for the next step of the reaction without further purification. t 0.88 min (Method 1a) m / z 299 / 301 (M+H) + (ES + ). 1 H NMR (400 MHz, DMSO-d6) δ 7.31 (d, J=2.1Hz, 1H), 6.86 (d, J=2.1 Hz, 1H), 5.62 (s, 2H), 5.33 (t, J=6.0 Hz, 1H), 3.29–3.26 (m, 1H), 3.22 (dd, J=12.8, 6.5 Hz, 1H), 1.36 (s, 3H).

[0275]

[0276] Step 10. (R)-8-bromo-3-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazaphen-3-carboxylonitrile (compound 301). DIPEA (160 μL, 916 μmol) was added to a stirred solution of lithium (R)-3-((2-amino-5-bromopyridin-3-yl)amino)-2-cyano-2-methylpropionate 300 (120 mg, 305 μmol) in DMF (2 mL), and the reaction mixture was stirred at room temperature for 5 min. HATU (139 mg, 367 μmol) was then added, and the reaction mixture was stirred for another 1 h. The reaction was quenched with water (30 mL), and the resulting precipitate was collected. The precipitate was azeotropically distilled with MeCN (2 × 10 mL) to give the desired product 301 as a light brown solid (62 mg, 71% yield), which was used in the next reaction without further purification. t 1.44 min (Method 1a) m / z 281 / 283 (M+H) + (ES + ). 1H NMR (400 MHz, DMSO-d6) δ10.51 (s, 1H), 7.79 (d, J=2.1 Hz, 1H), 7.37 (d, J=2.1 Hz, 1H), 6.83 (dd, J=5.8, 3.6 Hz, 1H), 3.62 (dd, J=13.7, 5.9 Hz, 1H), 3.42 (dd, J=13.8, 3.6 Hz, 1H), 1.54 (s, 3H).

[0277]

[0278] Step 11. (R,E)-3-(3-cyano-3-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazaphen-8-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide (compound 302). A mixture of N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide (intermediate 9) (27 mg, 0.12 mmol), (R)-8-bromo-3-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazaphen-3-carboxynitrile 301 (30 mg, 0.11 mmol), and Pd-116 (6 mg, 11 μmol) was purged and purged with nitrogen three times. Then, 1,4-dioxane (2 mL) and DIPEA (37 μL, 0.21 mmol) were added, and the reaction was heated to 90 °C and held for 1 hour. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and the aqueous phase was extracted with DCM (3 × 20 mL). The combined organic phases were washed with brine (1 × 20 mL), dried over MgSO4, and concentrated under vacuum. The crude product was purified by chromatography (0 to 10% MeOH / DCM) to give the desired product 302 as a yellow solid (16 mg, yield 34%). t 2.00 min (Method 1a) m / z 430 (M+H) + (ES + ). 1HNMR (400 MHz, DMSO-d6, 363K) δ 9.94 (s, 1H), 8.06 (d, J=2.0 Hz, 1H), 7.60–7.51 (m, 1H), 7.51–7.38 (m, 3H), 7.33–7.21 (m, 2H), 7.15 (d, J=15.6 Hz, 1H), 6.37 (t, J=3.9 Hz, 1H), 4.84 (s, 2H), 3.62 (dd, J=13.8, 5.7 Hz, 1H), 3.42 (dd, J=13.8, 3.9 Hz, 1H), 3.10 (s, 3H), 2.27 (s, 3H), 1.59 (s, 3H).

[0279] Example 2. Synthesis of (E)-N-methyl-N-((3-methyl-4-((pyridin-3-ylamino)methyl)benzofuran-2-yl)methyl)-3-(4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazaphen-8-yl)acrylamide (compound 312)

[0280] Overall synthesis scheme

[0281] Step 1. Add ethyl 2-bromoacetate (8.40 mL, 76 mmol) to a suspension of 1-(2,6-dihydroxyphenyl)acetone 303 (10.5 g, 69.0 mmol) and potassium carbonate (15.3 g, 110 mmol) in acetone (130 mL). Heat the reaction mixture under reflux for 3 hours, cool to room temperature, and filter. Wash the solid with acetone (100 mL). Combine the washings and filtrate, concentrate under vacuum to give a brown solid. Purify the crude product by chromatography (0 to 10% MeOH in DCM solution) to give compound 304 (12.9 g, 75% yield) as a pale yellow solid.

[0282] R t 2.11 min (Method 1a); m / z 239 [M+H] + (ES + ).

[0283] 1H NMR (400 MHz, DMSO-d6): δ, ppm 11.75 (s, 1H), 7.30 (t, J=8.3 Hz, 1H), 6.51 (ddd, J=17.1, 8.3, 0.9 Hz, 2H), 4.86 (s, 2H), 4.18 (q, J=7.1 Hz, 2H), 2.60 (s, 3H), 1.21 (t, J=7.1 Hz, 3H).

[0284] Step 2. Sodium ethoxide (21% wt% ethanol solution) (18.8 mL, 50.2 mmol) was added to an ethanol solution (700 mL) of ethyl 2-(2-acetyl-3-hydroxyphenoxy)acetate 304 (11.4 g, 47.9 mmol), and the reaction mixture was heated to 75 °C and maintained for 2 hours. After cooling to room temperature, the reaction mixture was slowly poured into a stirred mixture of water (600 mL), ice (600 mL), and concentrated HCl (25 mL). After stirring for 30 minutes, brine (1.1 L) was added, and the mixture was stirred for another 30 minutes. The precipitate was collected by filtration to give ethyl 4-hydroxy-3-methylbenzofuran-2-carboxylate 305 (5.39 g, 50% yield) as a light brown solid.

[0285] R t 2.21 min (Method 1a); m / z 221 [M+H] + (ES + ).

[0286] 1 H NMR (400 MHz, DMSO-d6): δ, ppm 10.35 (s, 1H), 7.30-7.21 (m, 1H), 7.02 (dd, J=8.3, 0.7 Hz, 1H), 6.65 (dd, J=8.0, 0.7 Hz, 1H), 4.32 (q, J=7.1 Hz, 2H), 2.67 (s, 3H), 1.33 (t, J=7.1 Hz, 3H).

[0287] Step 3. At 0 °C, trifluoromethanesulfonic anhydride (2.5 mL, 14.9 mmol) was added dropwise to a suspension of ethyl 4-hydroxy-3-methylbenzofuran-2-carboxylate 305 (2.20 g, 9.90 mmol), DIPEA (2.6 mL, 14.85 mmol), and DMAP (0.24 g, 1.98 mmol) in DCM (50 mL). The mixture was stirred at 0 °C for 1.5 h and then diluted with water (30 mL). The aqueous phase was extracted with DCM (50 mL). The combined organic phases were washed successively with 1 M HCl (2 × 20 mL) and brine (1 × 20 mL), dried through a phase separator, and concentrated under vacuum to give a brown oil. This substance was purified by chromatography (5% to 100% EtOAc / isohexane) to give compound 306 (1.81 g, 52% yield) as a yellow oil.

[0288] R t 2.84 min (Method 1a); m / z 353 [M+H] + (ES + ).

[0289] 1 H NMR (400 MHz, DMSO-d6): δ, ppm 7.86 (dd, J=8.4, 0.7 Hz, 1H), 7.66 (t, J=8.3 Hz, 1H), 7.42 (d, J=8.1 Hz, 1H), 4.38 (q, J=7.1 Hz, 2H), 2.64 (s, 3H), 1.35 (t, J=7.1 Hz, 3H).

[0290] Step 4. Ethyl 3-methyl-4-(((trifluoromethyl)sulfonyl)oxy)benzofuran-2-carboxylate 306 (3.28 g, 9.31 mmol) was dissolved in DMF (50 mL), and nitrogen gas was bubbled through the mixture for 10 minutes. Tetra(triphenylphosphine)palladium (0.75 g, 0.65 mmol) was added, and nitrogen gas was bubbled through the mixture for 10 minutes. Zinc dicyanocyanate (1.31 g, 11.17 mmol) was added, and the mixture was heated to 85 °C and maintained for 16 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc (50 mL) and water (50 mL). The aqueous phase was extracted with EtOAc (3 × 75 mL), washed with water (3 × 100 mL) and brine (1 × 100 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude product was purified by chromatography (0 to 100% EtOAc / isohexane) to give compound 307 (1.7 g, 80% yield) as a white solid.

[0291] Rt 2.31 min (Method 1a); m / z 230 [M+H] + (ES + ).

[0292] 1 H NMR (400 MHz, DMSO-d6): δ, ppm 8.10 (dd, J=8.5, 0.8 Hz, 1H), 7.91 (dd, J=7.5, 0.8 Hz, 1H), 7.69 (dd, J=8.5, 7.5 Hz, 1H), 4.40 (q, J=7.1 Hz, 2H), 2.74 (s, 3H), 1.37 (t, J=7.1 Hz, 3H).

[0293] Step 5. A suspension of ethyl 4-cyano-3-methylbenzofuran-2-carboxylate 307 (300 mg, 1.31 mmol) and Pd / C (70 mg, 0.39 mmol) in MeOH (3 mL) was stirred under hydrogen (5 bar) for 18 hours. The suspension was then filtered through diatomaceous earth and concentrated under vacuum. The crude product was purified by chromatography (0 to 10% DCM solution of 0.7 M ammonia / MeOH) to give compound 308 (260 mg, 84% yield) as a colorless oil.

[0294] R t 1.03 min (Method 1a); m / z 217 [M-NH3] + (ES + ).

[0295] Step 6.

[0296] BrettPhos G3 (82 mg, 0.096 mmol) was added to a degassed solution of 3-bromopyridine (0.2 mL, 1.93 mmol), ethyl 4-(aminomethyl)-3-methylbenzofuran-2-carboxylate 308 (450 mg, 1.93 mmol), and K₂CO₃ (530 mg, 3.86 mmol) in tert-butanol (10 mL). The resulting mixture was heated to 90 °C overnight. The reaction was concentrated under vacuum, and the residue was dissolved in ethyl acetate (40 mL), washed with brine (40 mL), dried, and concentrated under vacuum. The crude product was purified by chromatography (0 to 100% EtOAc / isohexane) to give the subject compound 309 (200 mg, 32% yield).

[0297] R t 1.33 min (Method 1a); m / z 311 [M+H] + (ES+ ); Step 7. Ethyl 3-methyl-4-((pyridin-3-ylamino)methyl)benzofuran-2-carboxylate 309 (250 mg, 0.81 mmol) was dissolved in methylamine (33% ethanol solution) (15 mL, 0.81 mmol), and the mixture was stirred for 18 hours. The reaction mixture was evaporated to dryness, and the residue was stirred in 0.1 N HCl (10 mL). The solid was collected and dried to give the main product 310 (248 mg, 99% yield) as a white solid.

[0298] R t 0.95 min (Method 1a); m / z 296 [M+H] + (ES + ); Step 8. A boranetetrahydrofuran complex (3390 μL, 3.39 mmol) was added to a suspension of N,3-dimethyl-4-((pyridin-3-ylamino)methyl)benzofuran-2-carboxamide 310 (200 mg, 0.68 mmol) in dried THF (10 mL). The mixture was brought to room temperature and then refluxed for 3 hours. The mixture was quenched with methanol (10 mL) while the solution was being refluxed. After the methanol addition was complete, 1 N HCl (1 mL) was added, and the mixture was refluxed for 30 minutes. The mixture was cooled to room temperature and then evaporated to dryness. The residue was dissolved in methanol (3 mL) and loaded onto a SiliaBond. ® Toluenesulfonic acid (SCX) resin (2 g). The column was washed with MeOH (10 mL), and the product was eluted with 10% methanol-ammonia solution (10 mL). After evaporation, the desired product 311 (141 mg, yield 74%) was obtained as a colorless solid.

[0299] R t 1.46 min (Method 1b); m / z 282 [M+H] + (ES + ); Step 9. N-((3-methyl-2-((methylamino)methyl)benzofuran-4-yl)methyl)pyridin-3-amine 311 (67 mg, 0.24 mmol), (E)-3-(4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazaphen-8-yl)acrylate trifluoroacetate 6 (the synthesis of which was previously reported in AFFINIUM PHARMECEUTICALS, INC: WO2007 / 67416, 2007, A2; AURIGENE DISCOVERY TECHNOLOGIES LIMITED: WO2013 / 80222, 2013, A1; Ramnauth Jailall and collaborators, Bioorg. Med. Chem. Lett., 2009, 19, pp. 5359-5362) (110 mg, 0.25 mmol) A suspension of HATU (100 mg, 0.27 mmol) and DIPEA (210 μL, 1.19 mmol) in DMF (2.5 mL) was stirred for 10 minutes. HATU (100 mg, 0.27 mmol) was added in a single addition, and the reaction mixture was stirred for 1 hour. The mixture was diluted with water (3 mL), the solid was collected, and dried. The solid was ground with MeCN (3 mL) to give compound 312 (29 mg, 25% yield) as a pale yellow solid.

[0300] R t 1.22 min (Method 1a); m / z 497 [M+H] + (ES + ).

[0301] 1 H NMR (DMSO-d6): δ, ppm 9.74 (s, 1H), 8.04 (d, J=15.4 Hz, 2H), 7.79 (s, 1H), 7.55-7.36 (m, 3H), 7.24 (s, 2H), 7.14-7.02 (m, 2H), 6.97 (d, J=8.1 Hz, 1H), 6.33 (d, J=5.3 Hz, 1H), 6.04 (s, 1H), 4.87 (s, 2H), 4.60 (s, 2H), 3.44 (s, 2H), 3.18 (s, 3H), 2.95 (s, 1H), 2.70-2.58 (m, 2H), 2.42 (s, 3H).

[0302] Example 3: Preparation Example: The compounds of the present invention were formulated into a solution at a concentration of 10 mg / mL in a 40% Captisol aqueous carrier or a 30% Kleptose carrier (magnetically stirred for 30 minutes at room temperature). This formulation is suitable for use via the IV route.

[0303] The compound of the present invention was formulated as a solid dispersion (20% drug loading) in HPMC AS. The compound and polymer were dissolved in a mixture of dichloromethane and methanol (weight ratio 3:1), with the polymer concentration in the organic phase at 1.4 wt% (batch size 85 mg). The solution was then spray-dried on a Procept 4 M8-Trix spray dryer (process parameters: cyclone S, air velocity 0.35 m). 3 The inlet temperature was 50°C, the feed rate was 6 g / min, the nozzle pressure was 10 L / min, and the air cooling rate was 80 L / min. The recovery rate was 64%. DSC and XRPD analysis confirmed the formation of a solid solution (amorphous physical form, single Tg at 95°C). The formulation was then formulated into tablets or granules for use in the PO route.

[0304] The compounds of the present invention are formulated (at concentrations from 1 mg / mL to 300 mg / mL) as nano- or micro-suspensions in water or oil and stabilized by a polymer (e.g., cellulose, 2-hydroxypropyl ether, or cellulose ether) at a concentration of 0.01% to 10%. The formulation also contains a surfactant, such as polyoxyethylene 20 sorbitan monooleate, at a concentration of 0.01% to 10%. This formulation is suitable for oral administration.

[0305] The compounds of the present invention are formulated (at concentrations from 1 mg / mL to 300 mg / mL) as nano- or micro-suspensions in water or oil. The formulation also comprises 0.01% to 10% of a polymer, such as polyethylene glycol 4000 or α-hydro-o-hydroxy poly(oxy-1,2-ethanediyl) and 0.01% to 10% of a surfactant, such as polyoxyethylene 20 sorbitan monooleate. This formulation is a sustained-release formulation (sustained release over 12 to 72 hours). This formulation is suitable for intramuscular administration.

[0306] The compounds of the present invention are formulated as nano-suspensions or micro-suspensions in water at a concentration of 10 mg / mL. This formulation also contains 10% polyethylene glycol 4000 and 10% polyoxyethylene 20 sorbitan monooleate. This formulation is suitable for intramuscular administration.

[0307] The compounds of the present invention are formulated (at concentrations from 1 mg / mL to 300 mg / mL) as nano- or micro-suspensions in water and combined with the hydrophilic prodrug of the present invention at a ratio of 1:99 to 99:1 (compound: hydrophilic prodrug compound). The composition further comprises 0.01% to 10% of a polymer, such as a copovidone or vinyl acetate polymer having 1-vinyl-2-pyrrolidone, and 0.01% to 10% of a surfactant, such as polyoxyethylene 20 sorbitan monooleate. This formulation is a sustained-release formulation (sustained release for 12 to 72 hours). This formulation is suitable for intramuscular administration.

[0308] The compounds of the present invention are formulated (at concentrations from 1 mg / mL to 300 mg / mL) as solid dispersions, made of microparticles, microspheres, or implants, with a drug loading of 10% to 95%, in PLGA (or other suitable matrices, such as PLA) in an aqueous or oily medium (e.g., sesame oil). The formulation is stabilized by a polymer (such as a copovidone or vinyl acetate polymer having 1-vinyl-2-pyrrolidone) at a concentration of 0.01% to 10%. The formulation also contains a surfactant, polyoxyethylene 20 sorbitan monooleate, at a concentration of 0.01% to 10%. The formulation is a sustained-release formulation (12 to 72 hours, e.g., 24 to 72 hours of sustained release). The formulation is suitable for intramuscular administration.

[0309] The compounds of the present invention are formulated (at concentrations from 1 mg / mL to 300 mg / mL) as hydrogels or oleogels, comprising 0.01% to 50% of a polymer, such as PEG-PLA (polyethylene glycol-polylactic acid) or a polysaccharide. The formulation is a sustained-release formulation (12 to 72 hours, e.g., 24 to 72 hours of sustained release). The formulation is suitable for intramuscular administration.

[0310] The compounds of the present invention are formulated as lipophilic solids or oily prodrugs (at concentrations from 1 mg / mL to 300 mg / mL) using oils (e.g., sesame oil) and cosolvents (e.g., benzyl alcohol and / or ethanol). The formulation is a sustained-release formulation (sustained release over 12 to 72 hours). The formulation is suitable for intramuscular administration.

[0311] Example 4 Antibacterial activity

[0312] The compounds listed in the table were synthesized according to the relevant examples of WO2020 / 099341 (compounds 33, 40, 41, 49, 75, 109, 150, 151, 167, 168, 207, 229, 247, 270, 276, 287, and 290), or according to the method described in Example 1 or 2 herein (compounds 302 and 312). After synthesis, the antibacterial activity of the compounds against Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae was determined using the following test methods: Inhibitory effect of FabI protein: The inhibitory effect of Fabiase from *Acinetobacter baumannii* was tested in the presence or absence of the test compound by measuring the rate of NADH consumption (change in absorbance at 340 nm / min) in a 96-well plate format at 30 °C using an automated plate reader. The test mixture contained 100 mM Tris-HCl (pH 7.25, *Acinetobacter baumannii*), 100 mM ammonium acetate, 0.02% Pluronic F-68 (*Acinetobacter baumannii*), 25 μM crotonyl ACP, 50 μM NADH, 25 pM recombinant Fabiase protein (*Acinetobacter baumannii*), and 7.5% DMSO. The concentrations of the test compounds in a final well volume of 100 μl ranged from 0.17 nM to 10000 nM. Dose-response inhibition assays were performed on each test compound using a 10-point serial dilution series. The IC50 value for each test compound was determined by fitting a logistic S-shaped curve to the inhibitor-response curve.

[0313] MIC: Following the Clinical and Laboratory Standards Institute (CLSI) guidelines for poorly soluble compounds, the broth microdilution minimum inhibitory concentration (MIC) assay was used to test the antimicrobial activity of FAI inhibitors against selected Gram-negative and Gram-positive bacterial species, including susceptible and multidrug-resistant strains of Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae. The test compound was first serially diluted 2-fold in 100% dimethyl sulfoxide (DMSO), and then 100-fold diluted in cationic-regulated Mueller-Hinton broth (CA-MHB) to establish a 10-point test concentration range in 1% DMSO. The final compound concentrations against Staphylococcus aureus ranged from 0.016 µg / ml to 8 µg / ml, and against Gram-negative species from 0.06 µg / ml to 32 µg / ml. Subsequently, 100 µl of the final test medium (test sample in CA-MHB, 1% DMSO) was transferred to the corresponding wells of a sterile, low-binding 96-well polystyrene plate to prepare the MIC test plate. Freshly prepared direct colony suspensions of the test strains were inoculated into the corresponding wells according to CLSI guidelines to achieve a final bacterial density of 5 × 10⁻⁶. 5 CFU / ml. This also includes a growth control (without the test substance) and a negative control (without bacterial inoculum). The entire experimental preparation process was carried out in the dark as much as possible. The MIC test plate was incubated at 35°C for 20 hours. Subsequently, the optical density (OD) at 600 nm was measured using a SpectraMax Plus microplate reader spectrophotometer. 600 To determine bacterial growth, according to OD... 600 The MIC value is defined as the lowest concentration of test substance that results in no visible bacterial growth, based on numerical and in-well visual observation assessments.

[0314] The results are shown in Table 1.

[0315] Table 1

[0316] This invention was completed with government support and is licensed under HHS / ASPR under license number FAIN: IDSEP160030. The government holds certain rights to this invention.

Claims

1. A compound for the prevention and / or treatment of bacterial infections mediated by at least one bacterium selected from the group consisting of Acinetobacter baumannii and Enterobacteriaceae such as Escherichia coli and Klebsiella pneumoniae. in, The compounds are selected from the group consisting of compounds represented by general formula I and their pharmaceutically acceptable salts. I in, A1 represents A that has the following structure 11 and A 12 The part of the group; A 11 ,and A 12 ； The line connected to the exocyclic methylene group represents a covalent single bond formed with the nitrogen atom of general formula I; A2 represents methyl; Q1 represents CH2 or NH; Q2 indicates CR 4 R 5 , or CR 4 R 5 -CR 6 R 7 , among which, CR 4 R 5 The group is attached to CO, CR 6 R 7 The group is attached to Q1; Q3 represents O or S; R 1 This indicates a group selected from H or -NH2; R 2 Indicates selection from H, -CH2-O-Ar 1 -CH2-O-Het 1 CH2-NR 9 Ar 1 CH2-NR 9 Het 1 -O-Ar 1 -O-Het 1 -NR 9 R 10 -O-Alk 1 The group, of which Ar 1 This indicates that it can be optionally selected independently by one or more options from -CN, -OC. 1-4 Alkyl group, -O-(CH2) 1-4 -NR 9 R 10 The phenyl group is substituted with a group, or wherein the phenyl group may have two substituents on adjacent ring atoms, such that these adjacent substituents can bond together to form a 5-membered heterocycle having one or two independent heteroatoms selected from N and O, wherein Het 1 This refers to an aromatic heterocycle having 5 or 6 ring atoms, wherein the ring atoms comprise 1 or 2 heteroatoms independently selected from N, S, and O, or Het 1 This refers to a non-aromatic, partially or fully saturated heterocycle having six ring atoms, wherein each ring atom comprises one heteroatom selected from N and O, wherein Het 1 The group can optionally be selected independently from -C. 1-4 Alkyl, -OC 1-4 Alkyl group, -CN, -(CH2) 0-4 The group in -OH is substituted; where R 9 Selected from H and -C 1-4 Alkyl; wherein, R 10 Selected from H, -C 1-4 Alkyl groups and -C(=O)-CH3; wherein, Alk 1 It refers to a straight-chain, branched, cyclic, or combined alkyl group having 1 to 6 carbon atoms, wherein Alk 1 The group may optionally be selected from one or more groups chosen from -OH, -OC 1-4 Alkyl group substitution; R 3 Indicates selection from H, -PO3R 3a 2. -CH2-OPO3R 3a 2 and -CH2-OC(=O)-R 3b group; R 3a This indicates a hydrogen atom or a cation suitable for forming a pharmaceutically acceptable salt, or -CH2-OC(=O)-R 3b Or -CHMe-OC(=O)-R 3b Or -CMe2-OC(=O)-R 3b Or -CH2-OC(=O)-OR 3b Or -CHMe-OC(=O)-OR 3b Or -CMe2-OC(=O)-OR 3b ; R 3b It represents an alkyl group having 1 to 11 carbon atoms, which can be straight-chain, branched, cyclic, or a combination thereof, wherein R 3b The group can optionally be one or more independently selected from -OH and -OC. 1-6 Alkyl group substitution; R 4 Indicates selection from H, C 1-4 Alkyl, -CN and C 1-4 alkylene-F groups; R 5 Indicates selection from C 1-4 Alkyl, C 1-4 alkylene-OH, C 1-4 Alkylene-OR 3 OH, -OPO3R 3a 2 groups; or R 4 and R 5 Together they form a cyclic group having 4 to 6 ring members formed by methylene groups and optional oxygen atoms; said cyclic group may optionally contain elements selected from -OH, -OC. 1-4 Substituents of alkyl groups; R 6 Indicates selection from H, -OH, C 1-4 Alkyl, -OPO3R 3a 2 groups; R 7 Indicates selection from H, C 1-4 Alkyl, C 1-4 alkylene-OH, C 1-4 Alkylene-OR 3 C 1-4 Alkyl-F or -CN groups; or R 6 and R 7 Together they form a cyclic group having 4 to 6 ring members formed by methylene groups and optional oxygen atoms; said cyclic group may optionally contain elements selected from -OH, -OC. 1-4 Alkyl substituents.

2. The compound used as described in claim 1, wherein, The compound is selected from the group consisting of compounds represented by general formulas A, B, C, D, E, F, G, or H. A； or B； or C； or D； or E； or F； or G； or H Among them, Q 3 R 1 R 2 R 3 R 4 R 5 R 6 and R 7 It has the same meaning as that specified in claim 1 above.

3. The compound used as described in claim 1 or 2, wherein, The compound is selected from the group consisting of compounds represented by general formulas Va, Vb, VI, or VII. And; or Vb; or WE; or VII Among them, R 1 R 2 R 3 R 4 R 5 R 6 and R 7 It has the same meaning as that specified in claim 1 above.

4. The compound used as described in claim 1 or 2, wherein, The compound is selected from the group consisting of compounds represented by general formulas Xa, Xb, XI, or XII. Shah; or Xb; or XI; or XII Among them, R 1 R 2 R 3 R 4 R 5 R 6 and R 7 It has the same meaning as that specified in claim 1 above.

5. The compound used as described in claim 3 or 4, wherein, R 2 Indicates a group selected from -H, -OH, -NH2; and / or R 4 Indicates a group selected from -CN; and / or R 5 Indicates selection from -OH, C 1-4 alkylene-OH groups; and / or R 7 Indicates selection from -CN, -OH, C 1-4 Alkylene-OH groups.

6. The compound for use as described in claim 5, wherein, R 2 Indicates -H, -NH2; and / or R 4 Indicates -CN; and / or R 5 Indicates selection from -OH, C 1-4 alkylene-OH groups; and / or R 7 Indicates selection from -CN, -OH, C 1-4 The alkylene group -OH.

7. The compound used as described in claim 4, 5, or 6, wherein, R 1 Indicates -H; R 2 It represents -H or -NH2.

8. The compound used as described in claim 3, 4, 5 or 6, wherein, R 1 and R 2 It represents -H.

9. The compound for any one of claims 3 to 8, wherein, R 5 represents -CN, -OH, -CH2OH, -CH2OPO3R 3a 2, -OPO3R 3a 2.

10. The compound used as described in claim 1, wherein, The compound is selected from the following compounds:

11. A pharmaceutical composition for the prevention and / or treatment of bacterial infections mediated by at least one bacterium selected from the group consisting of Acinetobacter baumannii and Enterobacteriaceae such as Escherichia coli and Klebsiella pneumoniae, wherein, The composition comprises: The compound as defined in any one of claims 1 to 10; and Pharmaceutically acceptable excipients.

12. The pharmaceutical composition of claim 11, further comprising an antibiotic, preferably wherein, The antibiotics are selected from the group consisting of polymyxins and aminoglycosides.

13. A compound being (R,E)-3-(3-cyano-3-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazaphen-8-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide, and having the following chemical structure: 。 14. A compound selected from the group consisting of compounds of general formula I and their pharmaceutically acceptable salts. I in, A1 represents a part A with the following structure. 12 A 12 ； The line connected to the exocyclic methylene group represents a covalent single bond formed with the nitrogen atom of general formula I; A2 represents methyl; Q1 represents CH2 or NH; Q2 indicates CR 4 R 5 , or CR 4 R 5 -CR 6 R 7 , among which, CR 4 R 5 The group is attached to CO, CR 6 R 7 The group is attached to Q1; Q3 represents O or S; R 1 This indicates a group selected from H or -NH2; R 2 Indicates that it is selected from -CH2-O-Ar 1 -CH2-O-Het 1 CH2-NR 9 Ar 1 and CH2-NR 9 Het 1 The group, of which Ar 1 This indicates that it can be optionally selected independently by one or more options from -CN, -OC. 1-4 Alkyl group, -O-(CH2) 1-4 -NR 9 R 10 The phenyl group is substituted with a group, or wherein the phenyl group may have two substituents on adjacent ring atoms, such that these adjacent substituents can bond together to form a 5-membered heterocycle having one or two independent heteroatoms selected from N and O, wherein Het 1 This refers to an aromatic heterocycle having 5 or 6 ring atoms, wherein the ring atoms comprise 1 or 2 heteroatoms independently selected from N, S, and O, or Het 1 This refers to a non-aromatic, partially or fully saturated heterocycle having six ring atoms, wherein each ring atom comprises one heteroatom selected from N and O, wherein Het 1 The group can optionally be selected independently from -C. 1-4 Alkyl, -OC 1-4 Alkyl group, -CN, -(CH2) 0-4 The group in -OH is substituted; where R 9 Selected from H and -C 1-4 Alkyl; wherein, R 10 Selected from H, -C 1-4 Alkyl groups and -C(=O)-CH3; R 3 Indicates selection from H, -PO3R 3a 2. -CH2-OPO3R 3a 2 and -CH2-OC(=O)-R 3b group; R 3a This indicates a hydrogen atom or a cation suitable for forming a pharmaceutically acceptable salt, or -CH2-OC(=O)-R 3b Or -CHMe-OC(=O)-R 3b Or -CMe2-OC(=O)-R 3b Or -CH2-OC(=O)-OR 3b Or -CHMe-OC(=O)-OR 3b Or -CMe2-OC(=O)-OR 3b ; R 3b It represents an alkyl group having 1 to 11 carbon atoms, which can be straight-chain, branched, cyclic, or a combination thereof, wherein R 3b The group can optionally be one or more independently selected from -OH and -OC. 1-6 Alkyl group substitution; R 4 Indicates selection from H, C 1-4 Alkyl, -CN and C 1-4 alkylene-F groups; R 5 Indicates selection from H, C 1-4 Alkyl, C 1-4 alkylene-OH, C 1-4 Alkylene-OR 3 OH, -OPO3R 3a 2 groups; or R 4 and R 5 Together they form a cyclic group having 4 to 6 ring members formed by methylene groups and optional oxygen atoms; said cyclic group may optionally contain elements selected from -OH, -OC. 1-4 Substituents of alkyl groups; R 6 Indicates selection from H, -OH, C 1-4 Alkyl, -OPO3R 3a 2 groups; R 7 Indicates selection from H, C 1-4 Alkyl, C 1-4 alkylene-OH, C 1-4 Alkylene-OR 3 C 1-4 Alkyl-F or -CN groups; or R 6 and R 7 Together they form a cyclic group having 4 to 6 ring members formed by methylene groups and optional oxygen atoms; said cyclic group may optionally contain elements selected from -OH, -OC. 1-4 Alkyl substituents.

15. A compound selected from the group consisting of compounds of general formula I and their pharmaceutically acceptable salts. I in, A1 represents a group A having the following structure. 11 The part indicated A 11 ； The line connected to the exocyclic methylene group represents a covalent single bond formed with the nitrogen atom of general formula I; A2 represents methyl; Q1 represents CH2 or NH; Q2 indicates CR 4 R 5 , or CR 4 R 5 -CR 6 R 7 , among which, CR 4 R 5 The group is attached to CO, CR 6 R 7 The group is attached to Q1; Q3 represents O or S; R 1 This indicates a group selected from H or -NH2; R 2 Indicates that it is selected from -CH2-O-Ar 1 -CH2-O-Het 1 CH2-NR 9 Ar 1 CH2-NR 9 Het 1 -O-Ar 1 -O-Het 1 -NR 9 R 10 -O-Alk 1 The group, of which Ar 1 This indicates that it can be optionally selected independently by one or more options from -CN, -OC. 1-4 Alkyl group, -O-(CH2) 1-4 -NR 9 R 10 The phenyl group is substituted with a group, or wherein the phenyl group may have two substituents on adjacent ring atoms, such that these adjacent substituents can bond together to form a 5-membered heterocycle having one or two independent heteroatoms selected from N and O, wherein Het 1 This refers to an aromatic heterocycle having 5 or 6 ring atoms, wherein the ring atoms comprise 1 or 2 heteroatoms independently selected from N, S, and O, or Het 1 This refers to a non-aromatic, partially or fully saturated heterocycle having six ring atoms, wherein each ring atom comprises one heteroatom selected from N and O, wherein Het 1 The group can optionally be selected independently from -C. 1-4 Alkyl, -OC 1-4 Alkyl group, -CN, -(CH2) 0-4 The group in -OH is substituted; where R 9 Selected from H and -C 1-4 Alkyl; wherein, R 10 Selected from H, -C 1-4 Alkyl groups and -C(=O)-CH3; wherein, Alk 1 It refers to a straight-chain, branched, cyclic, or combined alkyl group having 1 to 6 carbon atoms, wherein Alk 1 The group may optionally be selected from one or more groups chosen from -OH, -OC 1-4 Alkyl group substitution; R 3 Indicates selection from H, -PO3R 3a 2. -CH2-OPO3R 3a 2 and -CH2-OC(=O)-R 3b group; R 3a This indicates a hydrogen atom or a cation suitable for forming a pharmaceutically acceptable salt, or -CH2-OC(=O)-R 3b Or -CHMe-OC(=O)-R 3b Or -CMe2-OC(=O)-R 3b Or -CH2-OC(=O)-OR 3b Or -CHMe-OC(=O)-OR 3b Or -CMe2-OC(=O)-OR 3b ; R 3b It represents an alkyl group having 1 to 11 carbon atoms, which can be straight-chain, branched, cyclic, or a combination thereof, wherein R 3b The group can optionally be one or more independently selected from -OH and -OC. 1-6 Alkyl group substitution; R 4 Indicates selection from H, C 1-4 Alkyl, -CN and C 1-4 alkylene-F groups; R 5 Indicates selection from C 1-4 Alkyl, C 1-4 alkylene-OH, C 1-4 Alkylene-OR 3 OH, -OPO3R 3a 2 groups; or R 4 and R 5 Together they form a cyclic group having 4 to 6 ring members formed by methylene groups and optional oxygen atoms; said cyclic group may optionally contain elements selected from -OH, -OC. 1-4 Substituents of alkyl groups; R 6 Indicates selection from H, -OH, C 1-4 Alkyl, -OPO3R 3a 2 groups; R 7 Indicates selection from H, C 1-4 Alkyl, C 1-4 alkylene-OH, C 1-4 Alkylene-OR 3 C 1-4 Alkyl-F or -CN groups; Or R 6 and R 7 Together, they form a cyclic group having 4 to 6 ring members formed by methylene groups and optional oxygen atoms; said cyclic group may optionally contain elements selected from -OH, -OC. 1-4 Substituents of alkyl groups; Where R 1 If H is the value of R, then R 2 Choose Free -CH2-O-Ar 1 -CH2-O-Het 1 CH2-NR 9 Ar 1 and CH2-NR 9 Het 1 The group formed, and Where R 2 For -NR 9 R 10 Then R 9 and R 10 At least one of them is not H.

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