2-Amino-N-(oxo-aryl-λ6-thionyl)acetamide compounds and their therapeutic uses

Abstract

This invention generally relates to the field of therapeutic compounds. More specifically, this invention relates to 2-amino- N -(oxo-aryl-λ) 6 (-Thionyl)acetamide compounds (referred to herein as ANOSA compounds), said compounds In particular Inhibition (e.g., selective inhibition) of bacterial aminoacyl-tRNA synthetases (aaRS) (e.g., bacterial leucyl-tRNA synthetase, LeuRS). The present invention also relates to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions in vitro and in vivo to inhibit (e.g., selectively inhibit) bacterial aminoacyl-tRNA synthetases; to treat conditions improved by inhibition (e.g., selective inhibition) of bacterial aminoacyl-tRNA synthetases; to treat bacterial infections; and so on.

Description

Related applications

[0001] This application relates to UK (GB) patent application No. 2317786.8, filed on 21 November 2023, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0002] This invention generally relates to the field of therapeutic compounds. More specifically, this invention relates to 2-amino- N -(oxo-aryl-λ) 6 -Thionyl)acetamide compounds (referred to as ANOSA compounds in this article), their especially Inhibition (e.g., selective inhibition) of bacterial aminoacyl-tRNA synthetases (aaRS) (e.g., bacterial leucyl-tRNA synthetase, LeuRS). The present invention also relates to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions in vitro and in vivo to inhibit (e.g., selectively inhibit) bacterial aminoacyl-tRNA synthetases; to treat conditions improved by inhibition (e.g., selective inhibition) of bacterial aminoacyl-tRNA synthetases; to treat bacterial infections; and so on. Background Technology

[0003] This document cites numerous publications to more fully describe and disclose the invention and the prior art to which it pertains. Each of these references is incorporated herein by reference in its entirety as if each individual reference were specifically and individually designated as incorporated by reference.

[0004] Throughout the entire specification including the appended claims, unless the context otherwise requires, the word “comprise” and its variations (such as “comprises” and “comprising”) shall be understood to implicitly include the indicated integer or step or group of steps, but not exclude any other integer or step or group of steps.

[0005] It must be noted that, unless the context clearly indicates otherwise, the singular forms “a / an” and “the” as used in this specification and the appended claims include a plural of the referred objects. Thus, for example, a reference to “drug carrier” includes a mixture of two or more such carriers, etc.

[0006] A range is typically expressed herein as from “about” a particular value and / or to “about” another particular value. When such a range is expressed, another embodiment includes from said one particular value and / or to said other particular value. Similarly, when a value is expressed as an approximation using the antecedent “about”, it will be understood that said particular value forms another embodiment.

[0007] This disclosure includes information that can be used to understand the invention. It is not an admission that any information provided herein is prior art or related to the currently claimed invention, nor is it an admission that any publication specifically or implicitly referenced is prior art.

[0008] Bacterial aminoacyl-tRNA synthetase Currently used antimicrobial drugs are generally susceptible to resistance, prompting the search for novel chemotherapeutic drugs that can slow down or completely halt the development of resistance. This can be achieved by targeting functional bacterial proteins, whose mutations lead to reduced bacterial adaptability.

[0009] Bacterial enzymes known as aminoacyl-tRNA synthetases (aaRS) have been identified as molecular targets for drug development. See, for example, Gadakh et al., 2012; Vondenhoff et al., 2011; and Pham et al., 2014.

[0010] Aminoacyl-tRNA synthetases (aaRS) are enzymes in the aminoacyl-tRNA synthetase family that catalyze the addition of protein amino acids to their homologous tRNAs. The resulting aminoacyl-tRNA participates in the translation of messenger RNA into proteins at the ribosome. The aaRS mechanism is as follows: it binds ATP and the corresponding amino acid to form an aminoacyl-adenosine intermediate, releasing inorganic pyrophosphate (PPi). The adenosine-aaRS complex binds to the appropriate tRNA molecule, and the amino acid is transferred from the aminoacyl-AMP to the 2'-OH or 3'-OH of the last 3'-terminal tRNA nucleotide.

[0011] This mechanism can be summarized by the following reaction series: Amino acid + ATP → aminoacyl-AMP + PPi Aminoacyl-AMP + tRNA → Aminoacyl-tRNA + AMP There are two classes of aminoacyl-tRNA synthases (aaRS): "Class I" (with two highly conserved sequence motifs that are aminoacylated at the 2'-OH of the terminal adenosine nucleotide of the tRNA) and "Class II" (with three highly conserved sequence motifs that are aminoacylated at the 3'-OH of the terminal adenosine nucleotide of the tRNA). Known aminoacyl-tRNA synthetases include: alanyl-tRNA synthetase; arginyl-tRNA synthetase; aspartyl-tRNA synthetase; glucoyl-tRNA synthetase; glycyl-tRNA synthetase; histyl-RNA synthetase; isoleucyl-tRNA synthetase; leucyl-tRNA synthetase; lysyl-tRNA synthetase; methionyl-tRNA synthetase; phenylalanyl-tRNA synthetase; serinel-tRNA synthetase; threonyl-tRNA synthetase; tryptophanyl-tRNA synthetase; tyrosyl-tRNA synthetase; and valine-tRNA synthetase.

[0012] Bacterial aminoacyl-tRNA synthases (aaRS) possess a variety of characteristics that make them promising targets for broad-spectrum antimicrobial drugs; they are essential for survival, present in all bacterial pathogens, and in many cases, their structures differ sufficiently from their eukaryotic counterparts to allow for selective targeting (e.g., see Hurdle et al., 2005; Ochsner et al., 2007). Furthermore, these enzymes have been chemically and clinically validated as useful targets for antimicrobial chemotherapy.

[0013] However, despite the potential of this range of targets, to date only one aaRS inhibitor with a relatively limited indication has been approved for the treatment of bacterial infections. Specifically, mupirocin (also known as Bactroban and Centany; as shown below) is an isoleucyl-tRNA synthetase inhibitor that has been approved for use as a topical agent in the nasal cavity. Staphylococcus aureus For the clearance and treatment of superficial skin infections (e.g., see Laupland et al., 2003).

[0014] Several inhibitors have been developed targeting other bacterial tRNA synthases; however, none of these inhibitors have been approved for medical use to date.

[0015] The inventors have identified a novel class of small molecule inhibitors of bacterial aminoacyl-tRNA synthetase (specifically, bacterial leucyl-tRNA synthetase) that can be used to treat a variety of diseases, including bacterial infections.

[0016] Known compounds Jirgensons et al., 2016, described certain N-acyl-arylsulfonamide derivatives of the following formula as aminoacyl-tRNA synthetase inhibitors, which can... especially Used to treat bacterial infections.

[0017] Finn et al., 2018, described certain 2-amino-N-(arylsulfinyl)-acetamide compounds of the following formula as inhibitors of bacterial aminoacyl-tRNA synthetase. These inhibitors can... especially Used to treat bacterial infections.

[0018] Edmund et al., 2021, described certain 2-amino-N-(amino-oxo-aryl-λ6-thionyl)acetamide compounds of the following formula as inhibitors of bacterial aminoacyl-tRNA synthetase. These inhibitors can... especially Used to treat bacterial infections.

[0019] Compared to these known compounds, the aminoacyl-tRNA synthetase inhibitors described herein have the following formula: .

[0020] In other words, unlike the compounds described by Edmund et al. 2021, the compounds described herein additionally contain a substituted acyl group, -NR. N C(=O)Y. Summary of the Invention

[0021] One aspect of the present invention relates to certain 2-amino- N -(oxo-aryl-λ) 6 (-Thionyl)acetamide compounds (referred to herein as ANOSA compounds), as described herein.

[0022] Another aspect of the invention relates to a composition (e.g., a pharmaceutical composition) comprising an ANOSA compound as described herein and a pharmaceutically acceptable carrier or diluent.

[0023] Another aspect of the invention relates to a method for preparing a composition (e.g., a pharmaceutical composition) comprising the step of mixing an ANOSA compound as described herein with a pharmaceutically acceptable carrier or diluent.

[0024] Another aspect of the invention relates to a method for inhibiting (e.g., selectively inhibiting) bacterial aminoacyl-tRNA synthetases (aaRS) (e.g., bacterial leucyl-tRNA synthetase, LeuRS, etc.) in vitro or in vivo, comprising contacting the synthetase with an effective amount of an ANOSA compound as described herein.

[0025] Another aspect of the present invention relates to a exist A method for inhibiting (e.g., selectively inhibiting) the function of bacterial aminoacyl-tRNA synthetases (aaRS) (e.g., bacterial leucyl-tRNA synthetase, LeuRS, etc.) in cells in vitro or in vivo, comprising contacting said cells with an effective amount of an ANOSA compound as described herein.

[0026] Another aspect of the invention relates to an ANOSA compound as described herein, used in a method of treating a human or animal body by means of therapy, for example, in a method of treating a condition (e.g., a disease) as described herein.

[0027] Another aspect of the invention relates to the use of the ANOSA compound as described herein in the manufacture of a medicine, for example in a treatment method, such as in a method of treating a condition (e.g., a disease) as described herein.

[0028] Another aspect of the invention relates to a treatment method, such as a method of treating a condition (e.g., disease) as described herein, comprising administering to a subject requiring treatment a therapeutically effective amount of a compound as described herein, preferably in the form of a pharmaceutical composition.

[0029] In one embodiment, the treatment is for a condition in a human or animal body that is improved by inhibiting (e.g., selectively inhibiting) bacterial aminoacyl-tRNA synthetases (aaRS) (e.g., bacterial leucyl-tRNA synthetase, LeuRS).

[0030] In one implementation, the treatment is a treatment for a bacterial infection.

[0031] Another aspect of the invention relates to a kit comprising (a) an ANOSA compound as described herein, preferably provided as a pharmaceutical composition and in a suitable container and / or having suitable packaging; and (b) instructions for use, such as written instructions on how to administer the compound.

[0032] Another aspect of the present invention relates to a synthesis method as described herein or a method comprising the synthesis method described herein. get ANOSA compounds.

[0033] Another aspect of the present invention relates to a synthesis method as described herein or a method comprising the synthesis method described herein. get ANOSA compounds.

[0034] Another aspect of the invention relates to novel intermediates as described herein, which are suitable for use in the synthetic methods described herein.

[0035] Another aspect of the invention relates to the use of such a novel intermediate as described herein in the synthetic methods described herein.

[0036] Those skilled in the art will understand that features and preferred embodiments of one aspect of the invention will also relate to other aspects of the invention. Detailed Implementation

[0037] compound One aspect of the present invention relates to certain compounds that can be conveniently described as 2-amino- N -(oxo-aryl-λ) 6 (-Thionyl)acetamide compounds. A simple example of such compounds is 2-amino- N -(acetamido-oxo-phenyl-λ) 6 -Thionyl)-acetamide, as shown below.

[0038] Another simple example of such compounds is 2-amino- N -(oxo-phenyl-urea-λ) 6 -Thionyl)acetamide, as shown below.

[0039] Therefore, one aspect of the present invention relates to compounds of the following formula and their pharmaceutically acceptable salts, hydrates and solvates, wherein -A, -R N -Y, -R 1 and -R 2 As defined herein (for convenience, it will be referred to herein as "2-amino-N-(oxo-aryl-λ")), 6 -Thionyl)acetamide compounds or "ANOSA compounds": Left-hand group, AS(=O)(NR) N C(=O)Y)=NH- can be conveniently considered as an arylsulfonylimide amide moiety. The right-hand group, -C(=O)-CR 1 R 2 -NH2 can be conveniently regarded as an α-amino acid residue.

[0040] Some embodiments of the present invention include the following: (1) A compound selected from compounds of the following formula and their pharmaceutically acceptable salts, hydrates and solvates: in: -Y is independent of -NR UA R UB or -R P ; -R UA Independently -H or -R UUA ; -R UUA Independently: -R U1 -R U2 -R U3 -R U4 -R U5 -L U -R U2 -L U -R U3 -L U -R U4 -C(=O)-R U4 -L U -R U5 or -C(=O)-R U5 ; -R U1 For linear or branched saturated C 1-6 Alkyl group, and optionally with one or more groups -R UU2 replace; Each -R U2 For saturated C 3-6 Cycloalkyl, and optionally with one or more groups -R UU1 and one or more groups -R UU2 replace; Each -R U3 Non-aromatic C 3-8 Heterocyclic group, and optionally with one or more groups -R UU1 and one or more groups -R UU2 replace; Each -R U4 Independently phenyl or naphthyl, and optionally with one or more -R groups UU1 and one or more groups -R UU2 replace; Each -R U5 C 5-10Heteroaryl, and optionally with one or more groups -R UU1 and one or more groups -R UU2 replace; Each -L U - is the saturated C for linear or branched chains. 1-4 Alkylene, and optionally with a alkylene group selected from -OH, -OR UL -NH2, -NHR UL and -NR UL 2-group substitution; Each -R UL Independently for linear or branched saturated C 1-4 alkyl; Each -R UU1 Selected independently from: -R UU , -L UU -OH, -L UU -OR UU , -L UU -NH2, -L UU -NHR UU -L UU -N(R UU )2 and -L UU -R UM ; Each -R UU2 Selected independently from: -F, -Cl, -Br, -I, -OH, -OR UU , -CF3, -CHF2, -OCF3, -OCHF2, -NH2、-NHR UU -N(R) UU )2、-R UM , -C(=O)OH, -C(=O)OR UU -OC(=O)R UU , -C(=O)NH2、-C(=O)NHR UU -C(=O)N(R) UU )2、-C(=O)R UM , -NHC(=O)R UU -NR UN C(=O)R UU , -NHC(=O)NH2、-NHC(=O)NHR UU-NHC(=O)N(R) UU )2、-NHC(=O)R UM , -NR UN C(=O)NH2、-NR UN C(=O)NHR UU -NR UN C(=O)N(R UU 2. -NR UN C(=O)R UM , -NHC(=O)OR UU -NR UN C(=O)OR UU , -OC(=O)NH2、-OC(=O)NHR UU -OC(=O)N(R) UU )2、-OC(=O)R UM , -NHC(=NH)NH2、 -C(=O)R UU , -S(=O)NH2、-S(=O)NHR UU -S(=O)N(R) UU )2、-S(=O)R UM , -S(=O)2NH2、-S(=O)2NHR UU -S(=O)2N(R) UU )2、-S(=O)2R UM , -NHS(=O)R UU -NR UN S(=O)R UU , -NHS(=O)2R UU -NR UN S(=O)2R UU , -S(=O)R UU -S(=O)2R UU , -SH、-SR UU -CN and -NO2; in: Each -L UU - is the saturated C for linear or branched chains. 1-4 Alkylene; Each -R UU Independently for linear or branched saturated C1-4 Alkyl, phenyl, or -CH2-phenyl, wherein each phenyl group is optionally substituted with one or more groups selected from -F, -Cl, -Br, -Me, -OH, -OMe, -CF3, and -OCF3; Each -R UN For linear or branched saturated C 1-4 alkyl; Each -R UM Independently substituted with aza-butane, pyrrolidine, piperidin, piperazine, morpholine, aza-heptane, or diaza-heptane, and: Optionally, it may be replaced with one or more groups selected from the following: -R UMM -C(=O)R UMM -C(=O)OR UMM and -S(=O)2R UMM ; Each of -R UMM Independently for linear or branched saturated C 1-4 Alkyl, phenyl, or -CH2-phenyl, wherein each phenyl group is optionally substituted with one or more groups selected from -F, -Cl, -Br, -Me, -OH, -OMe, -CF3, and -OCF3; -R UB Independently -H or -R UUB ; -R UUB Independently for linear or branched saturated C 1-4 alkyl; -R P Independently: -R P1 -R P2 -R P3 -R P4 -R P5 -L P -R P2 -L P -R P3 -L P -R P4 or -L P -R P5 ; -R P1 For linear or branched saturated C 1-6 Alkyl group, and optionally with one or more groups -R PP2 replace; Each -R P2 For saturated C 3-6 Cycloalkyl, and optionally with one or more groups -R PP1 and one or more groups -RPP2 replace; Each -R P3 Non-aromatic C 3-8 Heterocyclic group, and optionally with one or more groups -R PP1 and one or more groups -R PP2 replace; Each -R P4 Independently phenyl or naphthyl, and optionally with one or more -R groups PP1 and one or more groups -R PP2 replace; Each -R P5 C 5-10 Heteroaryl, and optionally with one or more groups -R PP1 and one or more groups -R PP2 replace; Each -L P - is the saturated C for linear or branched chains. 1-4 Alkylene, and optionally with a alkylene group selected from -OH, -OR PL -NH2, -NHR PL and -NR PL 2-group substitution; Each -R PL Independently for linear or branched saturated C 1-4 alkyl; Each -R PP1 Selected independently from: -R PP , -L PP -OH, -L PP -OR PP , -L PP -NH2, -L PP -NHR PP -L PP -N(R PP )2 and -L PP -R PM ; Each -R PP2 Selected independently from: -F, -Cl, -Br, -I, -OH, -OR PP , -CF3, -CHF2, -OCF3, -OCHF2, -NH2、-NHR PP -N(R) PP )2、-R PM , -C(=O)OH、-C(=O)OR PP 、-OC(=O)R PP 、 -C(=O)NH2、-C(=O)NHR PP 、-C(=O)N(R PP )2、-C(=O)R PM 、 -NHC(=O)R PP 、-NR PN C(=O)R PP 、 -NHC(=O)NH2、-NHC(=O)NHR PP 、-NHC(=O)N(R PP )2、-NHC(=O)R PM 、 -NR PN C(=O)NH2、-NR PN C(=O)NHR PP 、-NR PN C(=O)N(R PP )2、 -NR PN C(=O)R PM 、 -NHC(=O)OR PP 、-NR PN C(=O)OR PP 、 -OC(=O)NH2、-OC(=O)NHR PP 、-OC(=O)N(R PP )2、-OC(=O)R PM 、 -NHC(=NH)NH2、 -C(=O)R PP 、 -S(=O)NH2、-S(=O)NHR PP 、-S(=O)N(R PP )2、-S(=O)R PM 、 -S(=O)2NH2、-S(=O)2NHR PP 、-S(=O)2N(R PP )2、-S(=O)2R PM 、 -NHS(=O)R PP 、-NR PN S(=O)R PP 、 -NHS(=O)2RPP -NR PN S(=O)2R PP , -S(=O)R PP -S(=O)2R PP , -SH、-SR PP -CN and -NO2; in: Each -L PP - is the saturated C for linear or branched chains. 1-4 Alkylene; Each -R PP Independently for linear or branched saturated C 1-4 Alkyl, phenyl, or -CH2-phenyl, wherein each phenyl group is optionally substituted with one or more groups selected from -F, -Cl, -Br, -Me, -OH, -OMe, -CF3, and -OCF3; Each -R PN For linear or branched saturated C 1-4 alkyl; Each -R PM Independently substituted with aza-butane, pyrrolidine, piperidin, piperazine, morpholine, aza-heptane, or diaza-heptane, and: Optionally, it may be replaced with one or more groups selected from the following: -R PMM -C(=O)R PMM -C(=O)OR PMM and -S(=O)2R PMM ; Each of -R PMM Independently for linear or branched saturated C 1-4 Alkyl, phenyl, or -CH2-phenyl, wherein each phenyl group is optionally substituted with one or more groups selected from -F, -Cl, -Br, -Me, -OH, -OMe, -CF3, and -OCF3; -R N Independently -H or -R NN ; -R NN Independently for linear or branched saturated C 1-4 alkyl; And among them: -A is independent of -A C or -A H ; -A C Independently phenyl or naphthyl, and optionally with one or more substituents -R X replace; -AH Independently for C 5-12 Heteroaryl, and optionally with one or more substituents -R X replace; in: Each -R X Selected independently from: -R XX -R XXU -R XXV , -F, -Cl, -Br, -I, -OH, -OR XX , -L XX -OH, -L XX -OR XX , -CF3, -CHF2, -OCF3, -OCHF2, -NH2、-NHR XX -NR XX 2. -R XM , -L XX -NH2, -L XX -NHR XX -L XX -NR XX 2. -L XX -R XM , -C(=O)OH, -C(=O)OR XX -OC(=O)R XX , -C(=O)NH2、-C(=O)NHR XX -C(=O)NR XX 2. -C(=O)R XM , -NHC(=O)R XX -NR XN C(=O)R XX , -NHC(=O)NH2、-NHC(=O)NHR XX -NHC(=O)NR XX 2. -NHC(=O)R XM , -NR XN C(=O)NH2、-NR XN C(=O)NHR XX -NR XN C(=O)NR XX 2. -NR XNC(=O)R XM , -NHC(=O)OR XX -NR XN C(=O)OR XX , -OC(=O)NH2、-OC(=O)NHR XX -OC(=O)NR XX 2. -OC(=O)R XM , -NHC(=NH)NH2、 -C(=O)R XX , -S(=O)NH2、-S(=O)NHR XX -S(=O)NR XX 2. -S(=O)R XM , -S(=O)2NH2、-S(=O)2NHR XX -S(=O)2NR XX 2. -S(=O)2R XM , -NHS(=O)R XX -NR XN S(=O)R XX , -NHS(=O)2R XX -NR XN S(=O)2R XX , -S(=O)R XX -S(=O)2R XX , -SH、-SR XX -CN and -NO2; In addition, two adjacent groups -R X If they exist, they can be formed together: -O-CH2-O-, -O-CH2CH2-O-, -CH2-CH2-O-, -CH2-CH2CH2-O-, -CH2-O-CH2-, or -CH2-CH2-O-CH2-; in: Each -L XX - is the saturated C for linear or branched chains. 1-4 Alkylene; Each -R XX Independently for linear or branched saturated C 1-4Alkyl, phenyl, or -CH2-phenyl, wherein each phenyl group is optionally substituted with one or more groups selected from -F, -Cl, -Br, -Me, -OH, -OMe, -CF3, and -OCF3; Each -R XXU C can be independently linear or branched. 2-4 alkenyl; Each -R XXV C can be independently linear or branched. 2-4 alkynyl group; Each -R XN For linear or branched saturated C 1-4 alkyl; Each -R XM Independently substituted with aza-butane, pyrrolidine, piperidin, piperazine, morpholine, aza-heptane, or diaza-heptane, and: Optionally, it may be replaced with one or more groups selected from the following: -R XMM -C(=O)R XMM -C(=O)OR XMM and -S(=O)2R XMM ; Each of -R XMM Independently for linear or branched saturated C 1-4 Alkyl, phenyl, or -CH2-phenyl, wherein each phenyl group is optionally substituted with one or more groups selected from -F, -Cl, -Br, -Me, -OH, -OMe, -CF3, and -OCF3; -R 1 Independently -H or -R 11 ; -R 11 Independently for -R 11A or -R 11B ; -R 11A Independently: -R A1 -R A2 -R A3 -R A4 -R A5 -L A -R A2 -L A -R A3 -L A -R A4 or -L A -R A5 ; -R A1 For linear or branched saturated C 1-6Alkyl group, and optionally with one or more groups -R AA2 replace; Each -R A2 For saturated C 3-6 Cycloalkyl, and optionally with one or more groups -R AA1 and one or more groups -R AA2 replace; Each -R A3 Non-aromatic C 3-7 Heterocyclic group, and optionally with one or more groups -R AA1 and one or more groups -R AA2 replace; Each -R A4 Independently phenyl or naphthyl, and optionally with one or more -R groups AA1 and one or more groups -R AA2 replace; Each -R A5 C 5-10 Heteroaryl, and optionally with one or more groups -R AA1 and one or more groups -R AA2 replace; Each -L A - is the saturated C for linear or branched chains. 1-4 Alkylene; Each -R AA1 Selected independently from: -R AA , -L AA -OH, -L AA -OR AA , -L AA -NH2, -L AA -NHR AA -L AA -N(R AA )2 and -L AA -R AM ; Each -R AA2 Selected independently from: -F, -Cl, -Br, -I, -OH, -OR AA , -CF3, -CHF2, -OCF3, -OCHF2, -NH2、-NHR AA -N(R) AA )2、-R AM , -C(=O)OH, -C(=O)ORAA 、-OC(=O)R AA 、 -C(=O)NH2、-C(=O)NHR AA 、-C(=O)N(R AA )2、-C(=O)R AM 、 -NHC(=O)R AA 、-NR AN C(=O)R AA 、 -NHC(=O)NH2、-NHC(=O)NHR AA 、-NHC(=O)N(R AA )2、-NHC(=O)R AM 、 -NR AN C(=O)NH2、-NR AN C(=O)NHR AA 、-NR AN C(=O)N(R AA )2、 -NR AN C(=O)R AM 、 -NHC(=O)OR AA 、-NR AN C(=O)OR AA 、 -OC(=O)NH2、-OC(=O)NHR AA ,-OC(=O)N(R AA )2、-OC(=O)R AM 、 -NHC(=NH)NH2, -C(=O)R AA 、 -S(=O)NH2、-S(=O)NHR AA 、-S(=O)N(R AA )2、-S(=O)R AM 、 -S(=O)2NH2、-S(=O)2NHR AA 、-S(=O)2N(R AA )2、-S(=O)2R AM 、 -NHS(=O)R AA 、-NR AN S(=O)R AA 、 -NHS(=O)2R AA 、-NRAN S(=O)2R AA , -S(=O)R AA -S(=O)2R AA , -SH、-SR AA -CN and -NO2; in: Each -L AA - is the saturated C for linear or branched chains. 1-4 Alkylene; Each -R AA Independently for linear or branched saturated C 1-4 Alkyl, phenyl, or -CH2-phenyl, wherein each phenyl group is optionally substituted with one or more groups selected from -F, -Cl, -Br, -Me, -OH, -OMe, -CF3, and -OCF3; Each -R AN For linear or branched saturated C 1-4 alkyl; Each -R AM Independently substituted with aza-butane, pyrrolidine, piperidin, piperazine, morpholine, aza-heptane, or diaza-heptane, and: Optionally, it may be replaced with one or more groups selected from the following: -R AMM -C(=O)R AMM -C(=O)OR AMM and -S(=O)2R AMM ; Each of -R AMM Independently for linear or branched saturated C 1-4 Alkyl, phenyl, or -CH2-phenyl, wherein each phenyl group is optionally substituted with one or more groups selected from -F, -Cl, -Br, -Me, -OH, -OMe, -CF3, and -OCF3; -R 11B Selected independently from: -F, -Cl, -Br, -I, -OH, -OR BB , -CF3, -CHF2, -OCF3, -OCHF2, -NH2、-NHR BB -NR BB 2. -R BM , -C(=O)OH, -C(=O)OR BB -OC(=O)R BB , -C(=O)NH2、-C(=O)NHR BB 、-C(=O)NR BB 2、-C(=O)R BM 、 -NHC(=O)R BB 、-NR BN C(=O)R BB 、 -NHC(=O)NH2、-NHC(=O)NHR BB 、-NHC(=O)NR BB 2、-NHC(=O)R BM 、 -NR BN C(=O)NH2、-NR BN C(=O)NHR BB 、-NR BN C(=O)NR BB 2、-NR BN C(=O)R BM 、 -NHC(=O)OR BB 、-NR BN C(=O)OR BB 、 -OC(=O)NH2、-OC(=O)NHR BB 、-OC(=O)NR BB 2、-OC(=O)R BM 、 -NHC(=NH)NH2、 -C(=O)R BB 、 -S(=O)NH2、-S(=O)NHR BB 、-S(=O)NR BB 2、-S(=O)R BM 、 -S(=O)2NH2、-S(=O)2NHR BB 、-S(=O)2NR BB 2、-S(=O)2R BM 、 -NHS(=O)R BB 、-NR BN S(=O)R BB 、 -NHS(=O)2R BB 、-NR BN S(=O)2R BB 、 -S(=O)R BB 、-S(=O)2RBB , -SH、-SR BB -CN and -NO2; in: Each -R BB Independently for linear or branched saturated C 1-4 Alkyl, phenyl, or -CH2-phenyl, wherein each phenyl group is optionally substituted with one or more groups selected from -F, -Cl, -Br, -Me, -OH, -OMe, -CF3, and -OCF3; Each -R BN For linear or branched saturated C 1-4 alkyl; Each -R BM Independently substituted with aza-butane, pyrrolidine, piperidin, piperazine, morpholine, aza-heptane, or diaza-heptane, and: Optionally, it may be replaced with one or more groups selected from the following: -R BMM -C(=O)R BMM -C(=O)OR BMM and -S(=O)2R BMM ; Each of -R BMM Independently for linear or branched saturated C 1-4 Alkyl, phenyl, or -CH2-phenyl, wherein each phenyl group is optionally substituted with one or more groups selected from -F, -Cl, -Br, -Me, -OH, -OMe, -CF3, and -OCF3; -R 2 Independently -H or -R 22 ; -R 22 Independently for -R 22C or -R 22D ; -R 22C Independently: -R C1 -R C2 -R C3 -R C4 -R C5 -L C -R C2 -L C -R C3 -L C -R C4 or -L C -R C5 ; -R C1 For linear or branched saturated C 1-6Alkyl group, and optionally with one or more groups -R CC2 replace; Each -R C2 For saturated C 3-6 Cycloalkyl, and optionally with one or more groups -R CC1 and one or more groups -R CC2 replace; Each -R C3 Non-aromatic C 3-7 Heterocyclic group, and optionally with one or more groups -R CC1 and one or more groups -R CC2 replace; Each -R C4 Independently phenyl or naphthyl, and optionally with one or more -R groups CC1 and one or more groups -R CC2 replace; Each -R C5 C 5-10 Heteroaryl, and optionally with one or more groups -R CC1 and one or more groups -R CC2 replace; Each -L C - is the saturated C for linear or branched chains. 1-4 Alkylene; Each -R CC1 Selected independently from: -R CC , -L CC -OH, -L CC -OR CC , -L CC -NH2, -L CC -NHR CC -L CC -N(R CC )2 and -L CC -R CM ; Each -R CC2 Selected independently from: -F, -Cl, -Br, -I, -OH, -OR CC , -CF3, -CHF2, -OCF3, -OCHF2, -NH2、-NHR CC -N(R) CC )2、-R CM , -C(=O)OH, -C(=O)ORCC 、-OC(=O)R CC 、 -C(=O)NH2、-C(=O)NHR CC 、-C(=O)N(R CC )2、-C(=O)R CM 、 -NHC(=O)R CC 、-NR CN C(=O)R CC 、 -NHC(=O)NH2、-NHC(=O)NHR CC 、-NHC(=O)N(R CC )2、-NHC(=O)R CM 、 -NR CN C(=O)NH2、-NR CN C(=O)NHR CC 、-NR CN C(=O)N(R CC )2、 -NR CN C(=O)R CM 、 -NHC(=O)OR CC 、-NR CN C(=O)OR CC 、 -OC(=O)NH2、-OC(=O)NHR CC ,-OC(=O)N(R CC )2、-OC(=O)R CM 、 -NHC(=NH)NH2, -C(=O)R CC 、 -S(=O)NH2、-S(=O)NHR CC 、-S(=O)N(R CC )2、-S(=O)R CM 、 -S(=O)2NH2、-S(=O)2NHR CC 、-S(=O)2N(R CC )2、-S(=O)2R CM 、 -NHS(=O)R CC 、-NR CN S(=O)R CC 、 -NHS(=O)2R CC 、-NRCN S(=O)2R CC , -S(=O)R CC -S(=O)2R CC , -SH、-SR CC -CN and -NO2; in: Each -L CC - is the saturated C for linear or branched chains. 1-4 Alkylene; Each -R CC Independently for linear or branched saturated C 1-4 Alkyl, phenyl, or -CH2-phenyl, wherein each phenyl group is optionally substituted with one or more groups selected from -F, -Cl, -Br, -Me, -OH, -OMe, -CF3, and -OCF3; Each -R CN For linear or branched saturated C 1-4 alkyl; Each -R CM Independently substituted with aza-butane, pyrrolidine, piperidin, piperazine, morpholine, aza-heptane, or diaza-heptane, and: Optionally, it may be replaced with one or more groups selected from the following: -R CMM -C(=O)R CMM -C(=O)OR CMM and -S(=O)2R CMM ; Each of -R CMM Independently for linear or branched saturated C 1-4 Alkyl, phenyl, or -CH2-phenyl, wherein each phenyl group is optionally substituted with one or more groups selected from -F, -Cl, -Br, -Me, -OH, -OMe, -CF3, and -OCF3; -R 22D Selected independently from: -F, -Cl, -Br, -I, -OH, -OR DD , -CF3, -CHF2, -OCF3, -OCHF2, -NH2、-NHR DD -NR DD 2. -R DM , -C(=O)OH, -C(=O)OR DD -OC(=O)R DD , -C(=O)NH2、-C(=O)NHR DD 、-C(=O)NR DD 2、-C(=O)R DM 、 -NHC(=O)R DD 、-NR DN C(=O)R DD 、 -NHC(=O)NH2、-NHC(=O)NHR DD 、-NHC(=O)NR DD 2、-NHC(=O)R DM 、 -NR DN C(=O)NH2、-NR DN C(=O)NHR DD 、-NR DN C(=O)NR DD 2、-NR DN C(=O)R DM 、 -NHC(=O)OR DD 、-NR DN C(=O)OR DD 、 -OC(=O)NH2、-OC(=O)NHR DD 、-OC(=O)NR DD 2、-OC(=O)R DM 、 -NHC(=NH)NH2、 -C(=O)R DD 、 -S(=O)NH2、-S(=O)NHR DD 、-S(=O)NR DD 2、-S(=O)R DM 、 -S(=O)2NH2、-S(=O)2NHR DD 、-S(=O)2NR DD 2、-S(=O)2R DM 、 -NHS(=O)R DD 、-NR DN S(=O)R DD 、 -NHS(=O)2R DD 、-NR DN S(=O)2R DD 、 -S(=O)R DD 、-S(=O)2RDD , -SH、-SR DD -CN and -NO2; in: Each -R DD Independently for linear or branched saturated C 1-4 Alkyl, phenyl, or -CH2-phenyl, wherein each phenyl group is optionally substituted with one or more groups selected from -F, -Cl, -Br, -Me, -OH, -OMe, -CF3, and -OCF3; Each -R DN For linear or branched saturated C 1-4 alkyl; Each -R DM Independently substituted with aza-butane, pyrrolidine, piperidin, piperazine, morpholine, aza-heptane, or diaza-heptane, and: Optionally, it may be replaced with one or more groups selected from the following: -R DMM -C(=O)R DMM -C(=O)OR DMM and -S(=O)2R DMM ; Each of -R DMM Independently for linear or branched saturated C 1-4 Alkyl, phenyl, or -CH2-phenyl, wherein each phenyl group is optionally substituted with one or more groups selected from -F, -Cl, -Br, -Me, -OH, -OMe, -CF3, and -OCF3; or -R 1 and -R 2 Together with the carbon atoms they are attached to, they form saturated carbon. 3-6 cycloalkyl or non-aromatic C 3-7 Heterocyclic group, and optionally with one or more groups -R CC2 replace.

[0041] For convenience, the table below lists the various groups mentioned above.

[0042] To avoid ambiguity, it should be noted that -S(=O)(NR) N The -NH2 group attached to the carbon atom in the (C(=O)Y))=NH-C(=O)-C(NH2)< bond is... Unmodified (e.g., unsubstituted; unprotected; etc.). However, it may be protonated, i.e., form -NH3. + .

[0043] In addition, to avoid ambiguity, Not Meaning -S(=O)(NR) N (C(=O)Y))=NH-C(=O)-C(NH2)<bond any Part of forming a ring.

[0044] In addition, to avoid ambiguity, Not It refers to -A and -R 1 Together, or -A and -R 2 Together, they form part of a ring. For example, Not Meaning in addition Connect -A and -R 1 In addition to -S(=O)(NR) N (C(=O)Y))=NH-C(=O)-C(NH2)(R 2 Besides the )-key. Similarly, Not Meaning in addition Connect -A and -R 2 In addition to -S(=O)(NR) N (C(=O)Y))=NH-C(=O)-C(NH2)(R 1 In addition to the - key. However, in some embodiments as described herein, -R 1 and -R 2 Together with the carbon atoms they are attached to, they can form a ring.

[0045] Similarly, to avoid ambiguity, Not It refers to -A and -R N Together, or -A and -Y together, they form part of a ring. Similarly, to avoid ambiguity, Not Meaning -R 1 and -R N Combined, or -R 1 Together with -Y, they form part of a ring. Similarly, to avoid ambiguity, Not Meaning -R 2 and -R N Combined, or -R 2 It combines with -Y to form part of a ring.

[0046] Furthermore, to avoid ambiguity, when a given substituent is described as "optionally replaced by one or more groups XXX and one or more groups YYY" (e.g., where XXX and YYY are respectively: -R UU1 and -R UU2 ;-R PP1 and -R PP2 ;-R AA1 and -R AA2; or -R CC1 and -R CC2 When the substituent is: (i) unsubstituted, (ii) substituted with one or more groups XXX, (iii) substituted with one or more groups YYY, or (iv) substituted with one or more of each of groups XXX and YYY.

[0047] It should be noted that these compounds have at least one chiral center; specifically, the sulfur atom forming part of the sulfonylimide amide group is marked with an asterisk (*) in the following formula. Unless otherwise specified, the sulfur atom at this position can be ( R )or( S ) configuration.

[0048] It should also be noted that, according to -R 1 and -R 2 The nature of the group means that the compound may have a secondary chiral center; specifically, -R 1 and -R 2 The carbon atom to which it is attached is marked with a hash symbol (#) in the following formula. Unless otherwise specified, the carbon atom at this position can be ( R )or( S ) configuration.

[0049] To avoid ambiguity, unless otherwise stated, references to one or more compounds without specifying one or two chiral centers are intended to cover all possible configurations. For example, the following formula (without mention of stereochemistry): The aim is to cover all four diastereomers: , and .

[0050] Similarly, the following formula (without mentioning the stereochemistry of the sulfur atom): The aim is to cover two diastereomers: and .

[0051] It should be noted that, according to -R NDue to the nature of the sulfonylimide amide bond, tautomerism may occur, as shown below. This article primarily describes these compounds in one tautomer form. However, unless otherwise stated, references to one or more compounds having one tautomer form are intended to cover both tautomer forms.

[0052] It should be noted that, in principle, stereoisomers around the S=N double bond (e.g., cis, trans, E, Z) are possible, for example, as shown below. This document primarily describes such compounds by one configuration. However, unless otherwise stated, references to one or more compounds having one configuration are intended to encompass both configurations.

[0053] In addition, to avoid ambiguity: Such as "C" 9-10 "Miscellaneous aromatics", "C" 3-7 The subscript "C" in terms such as "heterocyclic group" x-y "" refers to the number of ring atoms, which can be carbon atoms or heteroatoms (e.g., N, O, S, as the case may be). For example, pyridyl is an example of a C6 heteroaryl, and piperidinyl is an example of a C6 heterocyclic group.

[0054] All compounds named in this article were drawn using Chemaxon Marvin Sketch version 19.24 or Perkin Elmer ChemDraw Professional version 19.1.

[0055] Group -Y (2) Based on the compound in (1), where -Y is -NR UA R UB .

[0056] (3) Based on the compound in (1), where -Y is -R P .

[0057] Group -R UA (4) A compound based on any one of (1) to (3), wherein -R UA If it exists, it is -H.

[0058] (5) A compound based on any one of (1) to (3), wherein -R UA If it exists, then -R UUA .

[0059] Group -R UUA (6) A compound based on any one of (1) to (5), wherein -R UUA If it exists, it is independent as follows: -R U1 -R U2 -R U4 -R U5 -L U -R U2 -L U -R U4 -C(=O)-R U4 or -L U -R U5 .

[0060] (7) A compound based on any one of (1) to (5), wherein -R UUA If it exists, it is independent as follows: -R U1 -R U2 -R U4 -L U -R U4 or -C(=O)-R U4 .

[0061] (8) A compound based on any one of (1) to (5), wherein -R UUA If it exists, it is independent as follows: -R U1 -R U4 or -L U -R U4 .

[0062] (9) A compound based on any one of (1) to (5), wherein -R UUA If it exists, then -R U1 .

[0063] (10) A compound according to any one of (1) to (5), wherein -R UUA If it exists, then -R U2 .

[0064] (11) A compound based on any one of (1) to (5), wherein -R UUA If it exists, then -R U3 .

[0065] (12) A compound based on any one of (1) to (5), wherein -R UUA If it exists, then -R U4 .

[0066] (13) A compound based on any one of (1) to (5), wherein -RUUA If it exists, then -R U5 .

[0067] (14) A compound based on any one of (1) to (5), wherein -R UUA If it exists, then -L U -R U2 .

[0068] (15) A compound according to any one of (1) to (5), wherein -R UUA If it exists, then -L U -R U3 .

[0069] (16) A compound according to any one of (1) to (5), wherein -R UUA If it exists, then -L U -R U4 .

[0070] (17) A compound based on any one of (1) to (5), wherein -R UUA If it exists, then it is -C(=O)-R U4 .

[0071] (18) A compound based on any one of (1) to (5), wherein -R UUA If it exists, then -L U -R U5 .

[0072] (19) A compound based on any one of (1) to (5), wherein -R UUA If it exists, then it is -C(=O)-R U5 .

[0073] Group -R U1 (20) A compound according to any one of (1) to (19), wherein -R U1 If present, they are independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, -tBu, - just pentyl, - Zhong pentyl or - different pentyl; and optionally with one or more groups -R UU2 replace.

[0074] (21) A compound according to any one of (1) to (19), wherein -R U1 If present, it is independently -Me, -Et, -nPr, -nBu, or - just pentyl; and optionally with one or more groups -R UU2replace.

[0075] (22) A compound according to any one of (1) to (19), wherein -R U1 If present, it is independently -Me, -Et, or -nPr; and optionally with one or more groups -R. UU2 replace.

[0076] (23) A compound according to any one of (1) to (19), wherein -R U1 If present, it is independently -Me, -Et, -nPr, -nBu, or - just pentyl; and with a group -R UU2 replace.

[0077] (24) A compound according to any one of (1) to (19), wherein -R U1 If present, it is independently -Me, -Et, or -nPr; and is accompanied by a group -R. UU2 replace.

[0078] (25) A compound according to any one of (1) to (19), wherein -R U1 If present, it is -Et; and optionally with one or more groups -R UU2 replace.

[0079] (26) A compound according to any one of (1) to (19), wherein -R U1 If present, it is -nPr; and optionally with one or more groups -R. UU2 replace.

[0080] (27) A compound according to any one of (1) to (19), wherein -R U1 If present, it is -Me; and optionally with one or more groups -R. UU2 replace.

[0081] (28) A compound according to any one of (1) to (19), wherein -R U1 If present, it can be -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu independently.

[0082] (29) A compound according to any one of (1) to (19), wherein -R U1 If present, it is independently -Me, -Et, or -nPr.

[0083] (30) A compound according to any one of (1) to (19), wherein -R U1 If it exists, it will be -Me.

[0084] (31) A compound according to any one of (1) to (19), wherein -R U1 If it exists, it is -Et.

[0085] (32) A compound according to any one of (1) to (19), wherein -R U1 If it exists, it is -nPr.

[0086] Group -R U2 (33) A compound according to any one of (1) to (32), wherein each -R U2 If present, it is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and optionally with one or more groups -R UU1 and one or more groups -R UU2 replace.

[0087] (34) A compound according to any one of (1) to (32), wherein each -R U2 If present, it is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0088] (35) A compound according to any one of (1) to (32), wherein each -R U2 If present, it is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and is represented by a group -R. UU2 replace.

[0089] (36) A compound according to any one of (1) to (32), wherein each -R U2 If present, it is independently a cyclohexyl group.

[0090] Group -R U3 (37) A compound according to any one of (1) to (36), wherein each -R U3 If present, it is independently an oxetane, tetrahydrofuranyl, tetrahydropyranyl, dioxane, azirane, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azirane-heptane, or diazirane-heptane, and optionally with one or more -R groups. UU1 and one or more groups -R UU2 Replace; or -R U3 If it exists, then (3a) S ,6a R )-2-oxohexahydro-1 H -thieno[3,4- d Imidazole group.

[0091] (38) A compound according to any one of (1) to (36), wherein each -RU3 If present, it is independently tetrahydrofuranyl, tetrahydropyranyl, dioxyl, pyrrolidinyl, piperidinyl, piperazineyl, or morpholinyl, and optionally with one or more -R groups. UU1 and one or more groups -R UU2 Replace; or -R U3 If it exists, then (3a) S ,6a R )-2-oxohexahydro-1 H -thieno[3,4- d Imidazole group.

[0092] (39) A compound according to any one of (1) to (36), wherein each -R U3 If present, it is independently piperidinyl, piperazineyl, or morpholinyl, and optionally with one or more -R groups. UU1 and one or more groups -R UU2 Replace; or -R U3 If it exists, then (3a) S ,6a R )-2-oxohexahydro-1 H -thieno[3,4- d Imidazole group.

[0093] (40) A compound according to any one of (1) to (36), wherein each -R U3 If present, it is independently pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; or -R U3 If it exists, then (3a) S ,6a R )-2-oxohexahydro-1 H -thieno[3,4- d Imidazole group.

[0094] (41) A compound according to any one of (1) to (36), wherein each -R U3 If present, it is a pyrrolidinyl group.

[0095] (42) A compound according to any one of (1) to (36), wherein each -R U3 If it exists, then (3a) S ,6a R )-2-oxohexahydro-1 H -thieno[3,4- d Imidazole group.

[0096] Group (3a) S ,6a R )-2-oxohexahydro-1 H -thieno[3,4-d The imidazole group is a group in compounds having the following structure: .

[0097] To avoid ambiguity, this group is intended to be composed of "non-aromatic C 3-8 The definition of "heterocyclic group" covers, for example, groups such as -R U3 The quoted text.

[0098] Group -R U4 (43) A compound according to any one of (1) to (42), wherein each -R U4 If present, it is phenyl, and optionally with one or more -R groups. UU1 and one or more groups -R UU2 replace.

[0099] (44) A compound according to any one of (1) to (42), wherein each -R U4 If present, it is phenyl, and is represented by one or more -R groups. UU2 replace.

[0100] (45) A compound according to any one of (1) to (42), wherein each -R U4 If present, it is phenyl, and represented by a -R group. UU2 replace.

[0101] (46) A compound according to any one of (1) to (42), wherein each -R U4 If present, it is phenyl, and represented by two groups -R. UU2 replace.

[0102] (47) A compound according to any one of (1) to (42), wherein each -R U4 If present, it is phenyl.

[0103] Group -R U5 (48) A compound according to any one of (1) to (47), wherein each -R U5 If present, it is independently furanyl, thiopheneyl, pyrroleyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, tetrazolyl, pyridinyl, pyridinyl, pyrazinyl, indolyl, benzimidazolyl, indazoleyl, benzofuranyl, benzothiopheneyl, benzoxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, quinolinyl, isoquinolinyl, cenolinyl, quinoxalolinyl, quinazolinyl, or phthalazinyl, and optionally with one or more groups -R UU1 and one or more groups -R UU2 replace.

[0104] (49) A compound according to any one of (1) to (47), wherein each -R U5 If present, it is independently furanyl, thiopheneyl, pyrroleyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, and optionally with one or more -R groups. UU1 and one or more groups -R UU2 replace.

[0105] (50) A compound according to any one of (1) to (47), wherein each -R U5 If present, it is independently furanyl, thiopheneyl, pyrroleyl, imidazoleyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, or tetrazolyl, and optionally with one or more -R groups. UU1 and one or more groups -R UU2 replace.

[0106] (51) A compound according to any one of (1) to (47), wherein each -R U5 If present, it is independently pyridinyl, pyridinyl, pyrimidinyl, or pyrazinyl, and optionally with one or more -R groups. UU1 and one or more groups -R UU2 replace.

[0107] (52) According to any one of (1) to (47), wherein each -R U5 If present, it is independently furanyl, thiophene, pyrrole, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, tetrazolyl, pyridinyl, pyridinyl, pyrimidinyl, or pyrazinyl.

[0108] (53) A compound according to any one of (1) to (47), wherein each -R U5 If present, they are independently furanyl, thiophene, pyrrole, imidazole, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, tetrazolyl.

[0109] (54) A compound according to any one of (1) to (47), wherein each -R U5 If present, it is independently thienyl, thiazolyl, tetrazolyl, pyridinyl, or pyrimidinyl.

[0110] (55) A compound according to any one of (1) to (47), wherein each -R U5 If present, it is independently pyridinyl, pyridinyl, pyrimidinyl, or pyrazinyl.

[0111] (56) A compound according to any one of (1) to (47), wherein each -R U5 If present, it is independently pyridinyl or pyrimidinyl.

[0112] (57) A compound according to any one of (1) to (47), wherein each -R U5 If present, it is independently thienyl, thiazolyl, or tetrazolyl.

[0113] group -L U - (58) A compound according to any one of (1) to (57), wherein each -L U -If present, it is independently -CH2CH2CH2-, -CH2CH2-, -CH(CH3)CH2-, -CH(CH3)-, or -CH2-, and optionally one selected from -OH, -OR UL -NH2, -NHR UL and -NR UL 2. Substitution of the group.

[0114] (59) A compound according to any one of (1) to (57), wherein each -L U -If present, it is independently -CH2CH2 or -CH2-, and optionally with a choice of -OH, -OR UL -NH2, -NHR UL and -NR UL 2. Substitution of the group.

[0115] (60) A compound according to any one of (1) to (57), wherein each -L U -If present, it is independently -CH2CH2 or -CH2-, and optionally uses a selection from -NH2, -NHR. UL and -NR UL 2. Substitution of the group.

[0116] (61) A compound according to any one of (1) to (57), wherein each -L U -If present, it is independently -CH2CH2CH2-, -CH2CH2-, -CH(CH3)CH2-, -CH(CH3)- or -CH2-, and is replaced by -NH2.

[0117] (62) A compound according to any one of (1) to (57), wherein each -L U -If present, it is independently -CH2CH2 or -CH2-, and is replaced by -NH2.

[0118] (63) A compound according to any one of (1) to (57), wherein each -L U -If present, it is independently -CH2CH2CH2-, -CH2CH2-, -CH(CH3)CH2-, -CH(CH3)-, or -CH2-.

[0119] (64) According to any one of (1) to (57), wherein each -L U -If present, it is independently -CH2CH2 or -CH2-.

[0120] (65) A compound according to any one of (1) to (57), wherein each -L U -If it exists, it is -CH2CH2-.

[0121] (66) A compound according to any one of (1) to (57), wherein each -L U -If it exists, it is -CH2-.

[0122] Group -R UU1 (67) A compound according to any one of (1) to (66), wherein each -R UU1 If it exists, it is independently -R. UU -L UU -OH or -L UU -OR UU .

[0123] (68) A compound according to any one of (1) to (66), wherein each -R UU1 If it exists, then -R UU .

[0124] Group -R UU2 (69) A compound according to any one of (1) to (68), wherein each -R UU2 If it exists, select independently from: -F, -Cl, -Br, -I, -OH, -OR UU , -CF3, -CHF2, -OCF3, -OCHF2, -NH2、-NHR UU -N(R) UU )2、-R UM , -C(=O)OH, -C(=O)OR UU -OC(=O)R UU , -C(=O)NH2、-C(=O)NHR UU -C(=O)N(R) UU )2、-C(=O)R UM , -NHC(=O)R UU -NR UN C(=O)R UU , -NHC(=O)NH2、-NHC(=O)NHR UU -NHC(=O)N(R) UU )2、-NHC(=O)R UM , -NR UN C(=O)NH2、-NR UN C(=O)NHR UU -NR UN C(=O)N(R UU 2. -NR UN C(=O)R UM , -NHC(=O)OR UU -NR UN C(=O)OR UU , -OC(=O)NH2、-OC(=O)NHR UU -OC(=O)N(R) UU )2、-OC(=O)R UM , -C(=O)R UU , -SH、-SR UU -CN and -NO2.

[0125] (70) A compound according to any one of (1) to (68), wherein each -R UU2 If it exists, select independently from: -F, -Cl, -OH, -OR UU , -CF3, -CHF2, -NH2、-NHR UU -N(R) UU )2、-R UM , -C(=O)OH, -C(=O)OR UU -OC(=O)R UU , -C(=O)NH2、-C(=O)NHRUU -C(=O)N(R) UU )2、-C(=O)R UM , -NHC(=O)R UU -NR UN C(=O)R UU , -C(=O)R UU and -CN.

[0126] (71) A compound according to any one of (1) to (68), wherein each -R UU2 If it exists, select independently from: -OH, -OR UU , -NH2、-NHR UU -N(R) UU 2. -C(=O)OH, -C(=O)OR UU , -C(=O)NH2、-C(=O)NHR UU -C(=O)N(R) UU 2. -NHC(=O)R UU -NR UN C(=O)R UU and -CN.

[0127] (72) According to any one of (1) to (68), wherein each -R UU2 If it exists, select independently from: -OH, -NH2, -NHR UU -N(R) UU )2、-C(=O)OH、-NHC(=O)R UU and -CN.

[0128] (73) A compound according to any one of (1) to (68), wherein each -R UU2 If it exists, select independently from: -OH, -OR UU -NH2, -NHR UU -N(R) UU )2 and -C(=O)OH.

[0129] (74) A compound according to any one of (1) to (68), wherein each -R UU2 If it exists, select independently from: -ORUU -NH2 and -C(=O)OH.

[0130] Group -R UL (75) A compound according to any one of (1) to (74), wherein each -R UL If present, it can be -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu independently.

[0131] (76) A compound according to any one of (1) to (74), wherein each -R UL If present, it can be -Me, -Et, -nPr, or -iPr independently.

[0132] (77) A compound according to any one of (1) to (74), wherein each -R UL If present, it is either -Me or -Et.

[0133] (78) A compound according to any one of (1) to (74), wherein each -R UL If it exists, it will be -Me.

[0134] Group -R UU (79) A compound according to any one of (1) to (78), wherein each -R UU If it exists, it is independently a linear or branched saturated C. 1-4 Alkyl, phenyl, or -CH2-phenyl.

[0135] (80) A compound according to any one of (1) to (78), wherein each -R UU If it exists, it is independently a linear or branched saturated C. 1-4 alkyl.

[0136] (81) A compound according to any one of (1) to (78), wherein each -R UU If present, it can be -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu independently.

[0137] (82) A compound according to any one of (1) to (78), wherein each -R UU If present, it is independently -Me, -Et, -nPr, or -iPr.

[0138] (83) A compound according to any one of (1) to (78), wherein each -R UU If present, it is either -Me or -Et.

[0139] (84) A compound according to any one of (1) to (78), wherein each -R UU If it exists, it will be -Me.

[0140] Group -R UN (85) A compound according to any one of (1) to (84), wherein each -R UN If present, it can be -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu independently.

[0141] (86) A compound according to any one of (1) to (84), wherein each -R UN If present, it is independently -Me, -Et, -nPr, or -iPr.

[0142] (87) A compound according to any one of (1) to (84), wherein each -R UN If present, it is either -Me or -Et.

[0143] (88) A compound according to any one of (1) to (84), wherein each -R UN If it exists, it will be -Me.

[0144] Group -R UM (89) A compound according to any one of (1) to (88), wherein each -R UM If present, it is independently of aza-butane, pyrrolidine, piperidin, piperazine, or morpholine, and: Optionally, it may be replaced with one or more groups selected from the following: -R UMM -C(=O)R UMM -C(=O)OR UMM and -S(=O)2R UMM .

[0145] (90) A compound according to any one of (1) to (88), wherein each -R UM If present, it is independently of aza-butane, pyrrolidine, piperidine, piperazine, or morpholine.

[0146] (91) A compound according to any one of (1) to (88), wherein each -R UM If present, it is independently pyrrolidine or piperidine.

[0147] group -L UU - (92) A compound according to any one of (1) to (91), wherein each -L UU-If present, it is independently -CH2CH2CH2-, -CH2CH2-, -CH(CH3)CH2-, -CH(CH3)-, or -CH2-.

[0148] (93) A compound according to any one of (1) to (91), wherein each -L UU -If present, it is independently -CH2CH2 or -CH2-.

[0149] (94) A compound according to any one of (1) to (91), wherein each -L UU -If it exists, it is -CH2CH2-.

[0150] (95) A compound according to any one of (1) to (91), wherein each -L UU -If it exists, it is -CH2-.

[0151] Group -R UMM (96) A compound according to any one of (1) to (95), wherein each -R UMM If it exists, it is independently a linear or branched saturated C. 1-4 Alkyl, phenyl, or -CH2-phenyl.

[0152] (97) A compound according to any one of (1) to (95), wherein each -R UMM If it exists, it is independently a linear or branched saturated C. 1-4 alkyl.

[0153] (98) A compound according to any one of (1) to (95), wherein each -R UMM If present, it can be -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu independently.

[0154] (99) A compound according to any one of (1) to (95), wherein each -R UMM If present, it is independently -Me, -Et, -nPr, or -iPr.

[0155] (100) A compound according to any one of (1) to (95), wherein each -R UMM If present, it is either -Me or -Et.

[0156] (101) A compound according to any one of (1) to (95), wherein each -R UMM If it exists, it will be -Me.

[0157] Group -R UB (102) A compound according to any one of (1) to (101), wherein -R UB If it exists, it is -H.

[0158] (103) A compound according to any one of (1) to (101), wherein -R UB If it exists, then -R UUB .

[0159] Group -R UUB (104) According to any one of (1) to (103), wherein each -R UUB If present, it can be -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu independently.

[0160] (105) According to any one of (1) to (103), wherein each -R UUB If present, it is independently -Me, -Et, -nPr, or -iPr.

[0161] (106) According to any one of (1) to (103), wherein each -R UUB If present, it is either -Me or -Et.

[0162] (107) According to any one of (1) to (103), wherein each -R UUB If it exists, it will be -Me.

[0163] Group -R P (108) A compound according to any one of (1) to (107), wherein -R P If it exists, it is independent as follows: -R P1 -R P2 -R P3 -R P4 -L P -R P3 -L P -R P4 or -L P -R P5 .

[0164] (109) A compound according to any one of (1) to (107), wherein -R P If it exists, it is independent as follows: -R P1 -R P2 -L P -R P3 -L P-R P4 or -L P -R P5 .

[0165] (110) A compound according to any one of (1) to (107), wherein -R P If it exists, it is independent as follows: -R P1 -L P -R P4 or -L P -R P5 .

[0166] (111) According to any one of (1) to (107), the compound wherein -R P If it exists, then -R P1 .

[0167] (112) According to any one of (1) to (107), the compound wherein -R P If it exists, then -R P2 .

[0168] (113) According to any one of (1) to (107), the compound wherein -R P If it exists, then -R P3 .

[0169] (114) According to any one of (1) to (107), the compound wherein -R P If it exists, then -R P4 .

[0170] (115) According to any one of (1) to (107), the compound wherein -R P If it exists, then -R P5 .

[0171] (116) A compound according to any one of (1) to (107), wherein -R P If it exists, then -L P -R P2 .

[0172] (117) A compound according to any one of (1) to (107), wherein -R P If it exists, then -L P -R P3 .

[0173] (118) A compound according to any one of (1) to (107), wherein -R P If it exists, then -L P -R P4 .

[0174] (119) According to any one of (1) to (107), the compound wherein -R P If it exists, then -L P -R P5 .

[0175] Group -R P1 (120) A compound according to any one of (1) to (119), wherein -R P1 If present, they are independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, -tBu, - just pentyl, - Zhong pentyl or - different pentyl; and optionally with one or more groups -R PP2 replace.

[0176] (121) According to any one of (1) to (119), the compound wherein -R P1 If present, it is independently -Me, -Et, -nPr, -nBu, or - just pentyl; and optionally with one or more groups -R PP2 replace.

[0177] (122) According to any one of (1) to (119), the compound wherein -R P1 If present, it is independently -Me, -Et, or -nPr; and optionally with one or more groups -R. PP2 replace.

[0178] (123) According to any one of (1) to (119), the compound wherein -R P1 If present, it is independently -Me, -Et, -nPr, -nBu, or - just pentyl; and with one or two groups -R PP2 replace.

[0179] (124) According to any one of (1) to (119), the compound wherein -R P1 If present, it is independently -Me, -Et, or -nPr; and with one or two groups -R. PP2 replace.

[0180] (125) A compound according to any one of (1) to (119), wherein -R P1 If present, it is -Et; and optionally with one or more groups -R PP2 replace.

[0181] (126) According to any one of (1) to (119), the compound wherein -R P1 If present, it is -nPr; and optionally with one or more groups -R. PP2 replace.

[0182] (127) According to any one of (1) to (119), the compound wherein -R P1 If present, it is -Me; and optionally with one or more groups -R. PP2 replace.

[0183] (128) According to any one of (1) to (119), the compound wherein -R P1 If present, it can be -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu independently.

[0184] (129) A compound according to any one of (1) to (119), wherein -R P1 If present, it is independently -Me, -Et, or -nPr.

[0185] (130) A compound according to any one of (1) to (119), wherein -R P1 If it exists, it is -Et.

[0186] (131) According to any one of (1) to (119), the compound wherein -R P1 If it exists, it is -nPr.

[0187] (132) According to any one of (1) to (119), the compound wherein -R P1 If it exists, it will be -Me.

[0188] (133) According to any one of (1) to (119), the compound wherein -R P1 If present, select groups from the following structural formulas: Where R P1R -H or C 1-4 Alkyl group, which is optionally represented by a group R PP2 replace.

[0189] (134) According to any one of (1) to (119), the compound wherein -R P1 If present, select groups from the following structural formulas: Where R P1R It is -Me or -Et and uses a group RPP2 replace.

[0190] Group -R P2 (135) According to any one of (1) to (134), wherein each -R P2 If present, it is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and optionally with one or more groups -R PP1 and one or more groups -R PP2 replace.

[0191] (136) According to any one of (1) to (134), wherein each -R P2 If present, it is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0192] (137) According to any one of (1) to (134), wherein each -R P2 If present, it is independently cyclopropyl, and is represented by a group R. PP2 replace.

[0193] (138) According to any one of (1) to (134), wherein each -R P2 If present, it is independently cyclopropyl.

[0194] Group -R P3 (139) According to any one of (1) to (138), wherein each -R P3 If present, it is independently an oxetane, tetrahydrofuranyl, tetrahydropyranyl, dioxane, azirane, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azirane-heptane, or diazirane-heptane, and optionally with one or more -R groups. PP1 and one or more groups -R PP2 Replace; or -R P3 If it exists, then (3a) S ,6a R )-2-oxohexahydro-1 H -thieno[3,4- d Imidazole group.

[0195] (140) According to any one of (1) to (138), wherein each -R P3 If present, it is independently tetrahydrofuranyl, tetrahydropyranyl, dioxyl, pyrrolidinyl, piperidinyl, piperazineyl, or morpholinyl, and optionally with one or more -R groups. PP1 and one or more groups -R PP2 Replace; or -R P3If it exists, then (3a) S ,6a R )-2-oxohexahydro-1 H -thieno[3,4- d Imidazole group.

[0196] (141) According to any one of (1) to (138), wherein each -R P3 If present, it is independently pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, and optionally with one or more -R groups. PP1 and one or more groups -R PP2 Replace; or -R P3 If it exists, then (3a) S ,6a R )-2-oxohexahydro-1 H -thieno[3,4- d Imidazole group.

[0197] (142) According to any one of (1) to (138), wherein each -R P3 If present, it is independently pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; or -R P3 If it exists, then (3a) S ,6a R )-2-oxohexahydro-1 H -thieno[3,4- d Imidazole group.

[0198] (143) According to any one of (1) to (138), wherein each -R P3 If present, it is a pyrrolidinyl group.

[0199] (144) According to any one of (1) to (138), wherein each -R P3 If it exists, then (3a) S ,6a R )-2-oxohexahydro-1 H -thieno[3,4- d Imidazole group.

[0200] Group (3a) S ,6a R )-2-oxohexahydro-1 H -thieno[3,4- d The imidazole group is a group in compounds having the following structure: .

[0201] To avoid ambiguity, this group is intended to be composed of "non-aromatic C 3-8The definition of "heterocyclic group" covers, for example, groups such as -R P3 The quoted text.

[0202] Group -R P4 (145) According to any one of (1) to (144), wherein each -R P4 If present, it is phenyl, and optionally with one or more -R groups. PP1 and one or more groups -R PP2 replace.

[0203] (146) According to any one of (1) to (144), wherein each -R P4 If present, it is phenyl, and is represented by one or more -R groups. PP2 replace.

[0204] (147) According to any one of (1) to (144), wherein each -R P4 If present, it is phenyl, and represented by a -R group. PP2 replace.

[0205] (148) A compound according to any one of (1) to (144), wherein each -R P4 If present, it is phenyl, and represented by two groups -R. PP2 replace.

[0206] (149) According to any one of (1) to (144), wherein each -R P4 If present, it is phenyl.

[0207] Group -R P5 (150) According to any one of (1) to (149), wherein each -R P5 If present, it is independently furanyl, thiopheneyl, pyrroleyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, tetrazolyl, pyridinyl, pyridinyl, pyrazinyl, indolyl, benzimidazolyl, indazoleyl, benzofuranyl, benzothiopheneyl, benzoxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, quinolinyl, isoquinolinyl, cenolinyl, quinoxalolinyl, quinazolinyl, or phthalazinyl, and optionally with one or more groups -R PP1 and one or more groups -R PP2 replace.

[0208] (151) According to any one of (1) to (149), wherein each -R P5If present, it is independently furanyl, thiopheneyl, pyrroleyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, and optionally with one or more -R groups. PP1 and one or more groups -R PP2 replace.

[0209] (152) According to any one of (1) to (149), wherein each -R P5 If it exists, it is independent as follows: (a) pyridinyl, pyridinyl, pyrimidinyl, or pyrazinyl, and optionally with one or more -R groups PP1 and one or more groups -R PP2 Replace; or (b) Thiophene, thiazolyl or tetrazolium.

[0210] (153) According to any one of (1) to (149), wherein each -R P5 If present, it is independently furanyl, thiopheneyl, pyrroleyl, imidazoleyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, or tetrazolyl, and optionally with one or more -R groups. PP1 and one or more groups -R PP2 replace.

[0211] (154) According to any one of (1) to (149), wherein each -R P5 If present, it is independently pyridinyl, pyridinyl, pyrimidinyl, or pyrazinyl, and optionally with one or more -R groups. PP1 and one or more groups -R PP2 replace.

[0212] (155) According to any one of (1) to (149), wherein each -R P5 If present, it is independently thienyl, thiazolyl, tetrazolyl, pyridinyl, or pyrimidinyl.

[0213] (156) According to any one of (1) to (149), wherein each -R P5 If present, it is independently pyridinyl, pyridinyl, pyrimidinyl, or pyrazinyl.

[0214] (157) According to any one of (1) to (149), wherein each -R P5 If present, it is independently thienyl, thiazolyl, or tetrazolyl.

[0215] (158) According to any one of (1) to (149), wherein each -RP5 If present, independently, optionally with one or more groups R PP1 and one or more groups R PP2 Substituted thiazole group.

[0216] (159) According to any one of (1) to (149), wherein each -R P5 If present, independently, optionally with one or more groups R PP1 and one or more groups R PP2 Substituted pyridinyl group.

[0217] group -L P - (160) According to any one of (1) to (159), wherein each -L P -If present, it is independently -CH2CH2CH2-, -CH2CH2-, -CH(CH3)CH2-, -CH(CH3)-, or -CH2-, and optionally one selected from -OH, -OR PL -NH2, -NHR PL and -NR PL 2. Substitution of the group.

[0218] (161) According to any one of (1) to (159), wherein each -L P -If present, it is independently -CH2CH2 or -CH2-, and optionally with a choice of -OH, -OR PL -NH2, -NHR PL and -NR PL 2. Substitution of the group.

[0219] (162) According to any one of (1) to (159), wherein each -L P -If present, it is independently -CH2CH2 or -CH2-, and optionally uses a selection from -NH2, -NHR. PL and -NR PL 2. Substitution of the group.

[0220] (163) According to any one of (1) to (159), wherein each -L P -If present, it is independently -CH2CH2CH2-, -CH2CH2-, -CH(CH3)CH2-, -CH(CH3)- or -CH2-, and is replaced by -NH2.

[0221] (164) According to any one of (1) to (159), wherein each -L P-If present, it is independently -CH2CH2 or -CH2-, and is replaced by -NH2.

[0222] (165) According to any one of (1) to (159), wherein each -L P -If present, it is independently -CH2CH2CH2-, -CH2CH2-, -CH(CH3)CH2-, -CH(CH3)-, or -CH2-.

[0223] (166) According to any one of (1) to (159), wherein each -L P -If present, it is independently -CH2CH2- or -CH2-.

[0224] (167) According to any one of (1) to (159), wherein each -L P -If it exists, it is -CH2CH2-.

[0225] (168) According to any one of (1) to (159), wherein each -L P -If it exists, it is -CH2-.

[0226] Group -R PP1 (169) According to any one of (1) to (168), wherein each -R PP1 If it exists, it is independently -R. PP -L PP -OH or -L PP -OR PP .

[0227] (170) According to any one of (1) to (168), wherein each -R PP1 If it exists, then -R PP .

[0228] Group -R PP2 (171) According to any one of (1) to (170), wherein each -R PP2 If it exists, select independently from: -F, -Cl, -Br, -I, -OH, -OR PP , -CF3, -CHF2, -OCF3, -OCHF2, -NH2、-NHR PP -N(R) PP )2、-R PM , -C(=O)OH, -C(=O)OR PP -OC(=O)R PP , -C(=O)NH2、-C(=O)NHR PP -C(=O)N(R) PP )2、-C(=O)R PM , -NHC(=O)R PP -NR PN C(=O)R PP , -NHC(=O)NH2、-NHC(=O)NHR PP -NHC(=O)N(R) PP )2、-NHC(=O)R PM , -NR PN C(=O)NH2、-NR PN C(=O)NHR PP -NR PN C(=O)N(R PP 2. -NR PN C(=O)R PM , -NHC(=O)OR PP -NR PN C(=O)OR PP , -OC(=O)NH2、-OC(=O)NHR PP -OC(=O)N(R) PP )2、-OC(=O)R PM , -C(=O)R PP , -SH、-SR PP -CN and -NO2.

[0229] (172) According to any one of (1) to (170), wherein each -R PP2 If it exists, select independently from: -F, -Cl, -OH, -OR PP , -CF3, -CHF2, -NH2、-NHR PP -N(R) PP )2、-R PM , -C(=O)OH, -C(=O)ORPP -OC(=O)R PP , -C(=O)NH2、-C(=O)NHR PP -C(=O)N(R) PP )2、-C(=O)R PM , -NHC(=O)R PP -NR PN C(=O)R PP , -C(=O)R PP and -CN.

[0230] (173) According to any one of (1) to (170), wherein each -R PP2 If it exists, select independently from: -OH, -OR PP , -NH2、-NHR PP -N(R) PP 2. -C(=O)OH, -C(=O)OR PP , -C(=O)NH2、-C(=O)NHR PP -C(=O)N(R) PP 2. -NHC(=O)R PP -NR PN C(=O)R PP and -CN.

[0231] (174) According to any one of (1) to (170), wherein each -R PP2 If it exists, select independently from: -OH, -NH2, -NHR PP -N(R) PP )2 and -C(=O)OH.

[0232] (175) According to any one of (1) to (170), wherein each -R PP2 If it exists, select independently from: -OH, -NH2 and -C(=O)OH.

[0233] (176) According to any one of (1) to (170), wherein each -R PP2 If it exists, select independently from: -OH and -NH2.

[0234] Group -R PL (177) According to any one of (1) to (176), wherein each -R PL If present, it can be -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu independently.

[0235] (178) According to any one of (1) to (176), wherein each -R PL If present, it is independently -Me, -Et, -nPr, or -iPr.

[0236] (179) According to any one of (1) to (176), wherein each -R PL If present, it is either -Me or -Et.

[0237] (180) According to any one of (1) to (176), wherein each -R PL If it exists, it will be -Me.

[0238] Group -R PP (181) According to any one of (1) to (180), wherein each -R PP If it exists, it is independently a linear or branched saturated C. 1-4 Alkyl, phenyl, or -CH2-phenyl.

[0239] (182) According to any one of (1) to (180), wherein each -R PP If it exists, it is independently a linear or branched saturated C. 1-4 alkyl.

[0240] (183) According to any one of (1) to (180), wherein each -R PP If present, it can be -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu independently.

[0241] (184) According to any one of (1) to (180), wherein each -R PP If present, it is independently -Me, -Et, -nPr, or -iPr.

[0242] (185) According to any one of (1) to (180), wherein each -R PP If present, it is either -Me or -Et.

[0243] (186) According to any one of (1) to (180), wherein each -R PP If it exists, it will be -Me.

[0244] Group -R PN (187) According to any one of (1) to (186), wherein each -R PN If present, it can be -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu independently.

[0245] (188) According to any one of (1) to (186), wherein each -R PN If present, it is independently -Me, -Et, -nPr, or -iPr.

[0246] (189) According to any one of (1) to (186), wherein each -R PN If present, it is either -Me or -Et.

[0247] (190) According to any one of (1) to (186), wherein each -R PN If it exists, it will be -Me.

[0248] Group -R PM (191) According to any one of (1) to (190), the compound wherein each -R PM If present, it is independently of aza-butane, pyrrolidine, piperidin, piperazine, or morpholine, and: Optionally, it may be replaced with one or more groups selected from the following: -R PMM -C(=O)R PMM -C(=O)OR PMM and -S(=O)2R PMM .

[0249] (192) According to any one of (1) to (190), the compound wherein each -R PM If present, it is independently of aza-butane, pyrrolidine, piperidine, piperazine, or morpholine.

[0250] (193) According to any one of (1) to (190), the compound wherein each -R PM If present, it is independently pyrrolidine or piperidine.

[0251] group -L PP - (194) According to any one of (1) to (193), the compound wherein each -L PP -If present, it is independently -CH2CH2CH2-, -CH2CH2-, -CH(CH3)CH2-, -CH(CH3)-, or -CH2-.

[0252] (195) According to any one of (1) to (193), the compound wherein each -L PP -If present, it is independently -CH2CH2 or -CH2-.

[0253] (196) According to any one of (1) to (193), the compound wherein each -L PP -If it exists, it is -CH2CH2-.

[0254] (197) According to any one of (1) to (193), the compound wherein each -L PP -If it exists, it is -CH2-.

[0255] Group -R PMM (198) According to any one of (1) to (197), the compound wherein each -R PMM If it exists, it is independently a linear or branched saturated C. 1-4 Alkyl, phenyl, or -CH2-phenyl.

[0256] (199) According to any one of (1) to (197), wherein each -R PMM If it exists, it is independently a linear or branched saturated C. 1-4 alkyl.

[0257] (200) According to any one of (1) to (197), wherein each -R PMM If present, it can be -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu independently.

[0258] (201) According to any one of (1) to (197), wherein each -R PMM If present, it is independently -Me, -Et, -nPr, or -iPr.

[0259] (202) According to any one of (1) to (197), wherein each -R PMM If it exists, it is independently -Me or -Et. (203) According to any one of (1) to (197), wherein each -R PMM If it exists, it will be -Me.

[0260] Group -R N (204) A compound according to any one of (1) to (203), wherein -R N It is -H.

[0261] (205) A compound according to any one of (1) to (203), wherein -R N -R NN .

[0262] Group -R NN (206) According to any one of (1) to (205), wherein each -R NN If present, it can be -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu independently.

[0263] (207) According to any one of (1) to (205), wherein each -R NN If present, it is independently -Me, -Et, -nPr, or -iPr.

[0264] (208) According to any one of (1) to (205), wherein each -R NN If present, it is either -Me or -Et.

[0265] (209) A compound according to any one of (1) to (205), wherein each -R NN If it exists, it will be -Me.

[0266] Group -A (210) A compound according to any one of (1) to (209), wherein -A is -A C .

[0267] (211) A compound based on any one of (1) to (209), wherein -A is -A H .

[0268] Group -A C (212) According to any one of (1) to (211), the compound in which -A C If present, it is phenyl or naphthyl, and optionally with one, two, or three substituents -R. X replace.

[0269] (213) According to any one of (1) to (211), the compound in which -A CIf present, it is phenyl, and optionally with one or more substituents -R X replace.

[0270] (214) According to any one of (1) to (211), the compound wherein -A C If present, it is phenyl, and optionally with one, two, or three substituents -R. X replace.

[0271] (215) According to any one of (1) to (211), the compound in which -A C If it exists, select independently from: , , , , , , , , , , , , , and , Each of -R X1 -R X2 -R X3 -R X4 and -R X5 Independently, such as -R X Defined.

[0272] (216) According to any one of (1) to (211), the compound wherein -A C If it exists, select independently from: , , , , , , , , and , Each of -R X1 -R X2 -R X3 -R X4 and -RX5 Independently, such as -R X Defined.

[0273] (217) According to any one of (1) to (211), the compound in which -A C If it exists, select independently from: , , and , Each of -R X1 -R X2 and -R X3 Independently, such as -R X Defined.

[0274] (218) According to any one of (1) to (211), the compound in which -A C If it exists, select independently from: , and , Each of -R X1 -R X2 and -R X3 Independently, such as -R X Defined.

[0275] (219) According to any one of (1) to (211), the compound wherein -A C If it exists: , Where -R X1 Independently, such as -R X Defined.

[0276] (220) According to any one of (1) to (211), the compound wherein -A C If it exists: , Where -R X2 Independently, such as -R X Defined.

[0277] (221) According to any one of (1) to (211), the compound in which -A C If it exists: , Where -R X3 Independently, such as -R X Defined.

[0278] (222) According to any one of (1) to (211), the compound in which -A C If present, it is phenyl.

[0279] (223) According to any one of (1) to (211), the compound in which -A C If present, it is naphthyl, and optionally with one or more substituents -R X replace.

[0280] (224) According to any one of (1) to (211), the compound wherein -A C If present, it is naphthyl, and optionally with one, two, or three substituents -R X replace.

[0281] (225) According to any one of (1) to (211), the compound in which -A C If present, it is naphthyl.

[0282] (226) According to any one of (1) to (211), the compound wherein -A C If present, it is naphth-1-yl, and optionally with one or more substituents -R X replace.

[0283] (227) According to any one of (1) to (211), the compound in which -A C If present, it is naphth-2-yl, and optionally with one or more substituents -R X replace.

[0284] (228) According to any one of (1) to (211), the compound wherein -A C If present, it is naphth-1-yl.

[0285] (229) According to any one of (1) to (211), the compound in which -A C If present, it is naphth-2-yl.

[0286] Group -A H (230) According to any one of (1) to (229), the compound wherein -A H If it exists, then it is C. 5-10 Heteroaryl, and optionally with one or more substituents -R X replace.

[0287] (231) According to any one of (1) to (229), the compound in which -A HIf it exists, then it is C. 5-10 Heteroaryl, and optionally with one, two or three substituents -R X replace.

[0288] (232) According to any one of (1) to (229), the compound in which -A H If it exists, then it is C. 5-6 heteroaryl or C 9-10 Heteroaryl, and optionally with one or more substituents -R X replace.

[0289] (233) According to any one of (1) to (229), the compound in which -A H If present, it is furanyl, thiophene, pyrrole, pyrazolyl, imidazole, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridinyl, indolyl, benzimidazolyl, indazole, benzofuranyl, benzothiophene, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, thiophenepyridinyl, thiophenethiophene, quinolinyl, isoquinolinyl, cenolinyl, quinazolinyl, quinoxolinyl, phthalazinyl, or benzopyranyl, and optionally with one or more substituents -R X replace.

[0290] (234) According to any one of (1) to (229), the compound in which -A H If present, it is furanyl, thiophene, pyrrole, pyrazolyl, imidazole, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzimidazolyl, inzolyl, benzofuranyl, benzothiophene, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, quinolinyl, isoquinolinyl, cenolinyl, quinazolinyl, quinoxalolinyl, phthalazinyl, or benzopyranyl, and optionally with one or more substituents -R X replace.

[0291] (235) According to any one of (1) to (229), the compound wherein -A H If present, it is thienyl, thiazolyl, or thienothienyl, and optionally with one or more substituents -R X replace.

[0292] Monocyclic groups: (236) According to any one of (1) to (229), the compound in which -A HIf present, it is furanyl, thiopheneyl, pyrroleyl, pyrazolyl, imidazoleyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, and optionally with one or more substituents -R X replace.

[0293] (237) According to any one of (1) to (229), the compound in which -A H If present, it is pyridyl, thiophene, or thiazolyl, and optionally with one or more substituents -R X replace.

[0294] (238) According to any one of (1) to (229), the compound in which -A H If present, it is a thiophene group, and optionally with one or more substituents -R X replace.

[0295] (239) According to any one of (1) to (229), the compound in which -A H If it exists, select independently from: , , , , , , , , , , , , and , Each of -R X2 -R X3 -R X4 and -R X5 Independently, such as -R X Defined.

[0296] (240) According to any one of (1) to (229), the compound wherein -A H If it exists, select independently from: , and , Each of -R X3 -R X4 and -R X5 Independently, such as -R X Defined.

[0297] (241) According to any one of (1) to (229), the compound in which -A H If it exists, select independently from: , , , , , , and , Each of -R X2 -R X3 -R X4 and -R X5 Independently, such as -R X Defined.

[0298] (242) According to any one of (1) to (229), the compound in which -A H If present, it is thiophene-2-yl, and optionally with one or more substituents -R X replace.

[0299] (243) According to any one of (1) to (229), the compound in which -A H If it exists, select independently from: , , and , Each of -R X3 -R X4 and -R X5 Independently, such as -R X Defined.

[0300] (244) According to any one of (1) to (229), the compound in which -A H If it exists, select independently from: , and , Each of -R X3 and -R X4 Independently, such as -R X Defined.

[0301] (245) According to any one of (1) to (229), the compound in which -A H If it exists, select independently from: and , Each of -R X3 and -R X4 Independently, such as -R X Defined.

[0302] (246) According to any one of (1) to (229), the compound in which -A H If it exists: , Where -R X4 Independently, such as -R X Defined.

[0303] (247) According to any one of (1) to (229), the compound in which -A H If present, it is thiophene-3-yl, and optionally with one or more substituents -R X replace.

[0304] (248) According to any one of (1) to (229), the compound in which -A H If it exists, select independently from: , , and , Each of -R X2 -R X4 and -R X5 Independently, such as -R X Defined.

[0305] (249) According to any one of (1) to (229), the compound in which -A H If it exists: Where -R X5 For example -R X Defined.

[0306] (250) According to any one of (1) to (229), the compound wherein -A H If present, it is a thiazolyl group, and optionally with one or more substituents -R X replace.

[0307] (251) According to any one of (1) to (229), the compound in which -A H If it exists, select independently from: , , , , , , , , , , and , Each of -R X2 -R X4 and -R X5 Independently, such as -R X Defined.

[0308] (252) According to any one of (1) to (229), the compound in which -A H If present, it is thiazol-2-yl, and optionally with one or more substituents -R X replace.

[0309] (253) According to any one of (1) to (229), the compound in which -A H If it exists, select independently from: , , and , Each of -R X4 and -R X5 Independently, such as -R X Defined.

[0310] (254) According to any one of (1) to (229), the compound in which -A H If present, it is thiazol-4-yl, and optionally with one or more substituents -R X replace.

[0311] (255) According to any one of (1) to (229), the compound wherein -A H If it exists, select independently from: , , and , Each of -R X2 and -R X5 Independently, such as -R X Defined.

[0312] (256) According to any one of (1) to (229), the compound in which -A H If present, it is thiazol-5-yl, and optionally with one or more substituents -R X replace.

[0313] (257) According to any one of (1) to (229), the compound wherein -A H If it exists, select independently from: , , and , Each of -R X2 and -R X4 Independently, such as -R X Defined.

[0314] (258) According to any one of (1) to (229), the compound wherein -A H If present, it is independently pyrazolyl or imidazole, and optionally with one or more substituents -R X replace.

[0315] (259) According to any one of (1) to (229), the compound wherein -A H If present, it is a pyrazolyl group, and optionally with one or more substituents -R X replace.

[0316] (260) According to any one of (1) to (229), the compound wherein -A H If present, it is independently 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, or pyrazol-1-yl, and optionally with one or more substituents -R X replace.

[0317] (261) According to any one of (1) to (229), the compound in which -A H If present, it is 1H-pyrazole-3-yl, and optionally with one or more substituents -R X replace.

[0318] (262) According to any one of (1) to (229), the compound in which -A H If present, it is an imidazole group, and optionally with one or more substituents -R X replace.

[0319] (263) According to any one of (1) to (229), the compound in which -A H If present, it is independently 1H-imidazol-2-yl, 1H-imidazol-5-yl, 1H-imidazol-4-yl, or imidazol-1-yl, and optionally with one or more substituents -R Xreplace.

[0320] (264) According to any one of (1) to (229), the compound in which -A H If present, it is pyridyl, and optionally with one or more substituents -R X replace.

[0321] (265) According to any one of (1) to (229), the compound in which -A H If present, it is pyridin-2-yl, and optionally with one or more substituents -R X replace.

[0322] (266) According to any one of (1) to (229), the compound in which -A H If present, it is pyridin-3-yl, and optionally with one or more substituents -R X replace.

[0323] (267) According to any one of (1) to (229), the compound in which -A H If present, it is pyridin-4-yl, and optionally with one or more substituents -R X replace.

[0324] Fused bicyclic groups: (268) According to any one of (1) to (229), the compound in which -A H If present, it is indolyl, benzimidazolyl, indazolyl, benzofuranyl, benzothiophenyl, benzooxazolyl, benzoisooxazolyl, benzothiazolyl, benzoisothiazolyl, thienylpyridyl, thienylthienyl, quinolinyl, isoquinolinyl, cenolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, or benzopyranyl, and optionally with one or more substituents -R X replace.

[0325] (269) According to any one of (1) to (229), the compound in which -A H If present, it is indolyl, benzimidazolyl, indazolyl, benzofuranyl, benzothiophenyl, benzooxazolyl, benzoisooxazolyl, benzothiazolyl, benzoisothiazolyl, quinolinyl, isoquinolinyl, cenolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, or benzopyranyl, and optionally with one or more substituents -R X replace.

[0326] (270) According to any one of (1) to (229), the compound wherein -AH If present, it is indolyl, benzimidazolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl, and optionally with one or more substituents -R X replace.

[0327] (271) According to any one of (1) to (229), the compound in which -A H If present, it is benzofuranyl, benzothiophenyl, quinolinyl, or isoquinolinyl, and optionally with one or more substituents -R X replace.

[0328] (272) According to any one of (1) to (229), the compound in which -A H If present, it is benzofuranyl or benzothiopheneyl, and optionally with one or more substituents -R X replace.

[0329] (273) According to any one of (1) to (229), the compound in which -A H If present, it is benzothiophene group, and optionally with one or more substituents -R X replace.

[0330] (274) According to any one of (1) to (229), the compound in which -A H If present, it is benzothiophene-2-yl, and optionally with one or more substituents -R X replace.

[0331] (275) According to any one of (1) to (229), the compound in which -A H If present, it is benzothiophene-3-yl, and optionally with one or more substituents -R X replace.

[0332] (276) According to any one of (1) to (229), the compound in which -A H If present, it is benzothiazolyl, and optionally with one or more substituents -R X replace.

[0333] (277) According to any one of (1) to (229), the compound in which -A H If present, it is 1,2-benzothiazol-3-yl, and optionally with one or more substituents -R X replace.

[0334] (278) According to any one of (1) to (229), the compound in which -A H If present, it is 1,3-benzothiazol-2-yl, and optionally with one or more substituents -R X replace.

[0335] (279) According to any one of (1) to (229), the compound in which -A H If present, it is thienenopyridyl, and optionally with one or more substituents -R X replace.

[0336] (280) According to any one of (1) to (229), the compound wherein -A H If present, it is thieneno[3,2-b]pyridyl, and optionally with one or more substituents -R X replace.

[0337] (281) According to any one of (1) to (229), the compound in which -A H If present, it is thieneno[3,2-b]pyridin-2-yl, and optionally with one or more substituents -R X replace.

[0338] (282) According to any one of (1) to (229), the compound in which -A H If present, it is thieno[3,2-b]pyridin-3-yl, and optionally with one or more substituents -R X replace.

[0339] (283) According to any one of (1) to (229), the compound in which -A H If present, it is thienenoylthienyl, and optionally with one or more substituents -R X replace.

[0340] (284) According to any one of (1) to (229), the compound in which -A H If present, it is thieneno[3,2-b]thienyl, and optionally with one or more substituents -R X replace.

[0341] (285) According to any one of (1) to (229), the compound in which -A H If present, it is thieneno[3,2-b]thien-5-yl, and optionally with one or more substituents -R X replace.

[0342] (286) According to any one of (1) to (229), the compound wherein -A H If present, it is thieneno[3,2-b]thien-6-yl, and optionally with one or more substituents -R X replace.

[0343] (287) According to any one of (1) to (229), the compound in which -A H If present, it is quinolinyl, and optionally with one or more substituents -R X replace.

[0344] (288) According to any one of (1) to (229), the compound in which -A H If present, it is quinoline-7-yl, and optionally with one or more substituents -R X replace.

[0345] Group -R X (289) According to any one of (1) to (288), wherein each -R X If it exists, select independently from: -R XX , -F, -Cl, -Br, -I, -OH, -OR XX , -L XX -OH, -L XX -OR XX , -CF3, -CHF2, -OCF3, -OCHF2, -NH2、-NHR XX -NR XX 2. -R XM , -L XX -NH2, -L XX -NHR XX -L XX -NR XX 2. -L XX -R XM , -C(=O)OH, -C(=O)OR XX -OC(=O)R XX , -C(=O)NH2、-C(=O)NHR XX -C(=O)NRXX 2、-C(=O)R XM 、 -NHC(=O)R XX 、-NR XN C(=O)R XX 、 -NHC(=O)NH2、-NHC(=O)NHR XX 、-NHC(=O)NR XX 2、-NHC(=O)R XM 、 -NR XN C(=O)NH2、-NR XN C(=O)NHR XX 、-NR XN C(=O)NR XX 2、-NR XN C(=O)R XM 、 -NHC(=O)OR XX 、-NR XN C(=O)OR XX 、 -OC(=O)NH2、-OC(=O)NHR XX 、-OC(=O)NR XX 2、-OC(=O)R XM 、 -NHC(=NH)NH2、 -C(=O)R XX 、 -S(=O)NH2、-S(=O)NHR XX 、-S(=O)NR XX 2、-S(=O)R XM 、 -S(=O)2NH2、-S(=O)2NHR XX 、-S(=O)2NR XX 2、-S(=O)2R XM 、 -NHS(=O)R XX 、-NR XN S(=O)R XX 、 -NHS(=O)2R XX 、-NR XN S(=O)2R XX 、 -S(=O)R XX 、-S(=O)2R XX 、 -SH、-SR XX-CN and -NO2; In addition, two adjacent groups -R X If they exist, they can be formed together: -O-CH2-O-, -O-CH2CH2-O-, -CH2-CH2-O-, -CH2-CH2CH2-O-, -CH2-O-CH2- or -CH2-CH2-O-CH2-.

[0346] (290) According to any one of (1) to (288), wherein each -R X If it exists, select independently from: -R XX -R XXU -R XXV , -F, -Cl, -Br, -I, -OH, -OR XX , -CF3, -CHF2, -OCF3, -OCHF2, -NH2、-NHR XX -NR XX 2. -R XM , -C(=O)OH, -C(=O)OR XX -OC(=O)R XX , -C(=O)NH2、-C(=O)NHR XX -C(=O)NR XX 2. -C(=O)R XM , -NHC(=O)R XX -NR XN C(=O)R XX , -C(=O)R XX , -S(=O)NH2、-S(=O)NHR XX -S(=O)NR XX 2. -S(=O)R XM , -S(=O)2NH2、-S(=O)2NHR XX -S(=O)2NR XX 2. -S(=O)2R XM , -NHS(=O)R XX -NR XN S(=O)R XX , -NHS(=O)2R XX -NR XN S(=O)2R XX , -S(=O)R XX -S(=O)2R XX , -SR XX -CN and -NO2.

[0347] (291) According to any one of (1) to (288), wherein each -R X If it exists, select independently from: -R XX -R XXU -R XXV , -F, -Cl, -Br, -I, -OH, -OR XX , -CF3, -CHF2, -OCF3, -OCHF2, -NH2、-NHR XX -NR XX 2. -R XM , -C(=O)OH, -C(=O)OR XX -OC(=O)R XX , -SR XX -CN and -NO2.

[0348] (292) According to any one of (1) to (288), wherein each -R X If it exists, select independently from: -R XX -R XXU , -F, -Cl, -Br -OH, -OR XX , -CF3, -CHF2, -OCF3, -OCHF2, -C(=O)NH2、-C(=O)NHR XX -C(=O)NR XX 2. -C(=O)R XM , -C(=O)R XX and -CN; In addition, two adjacent groups -R X If they exist, they can be formed together: -O-CH2-O- or -CH2-CH2-O-.

[0349] (293) According to any one of (1) to (288), wherein each -R X If it exists, select independently from: -R XX , -F, -Cl, -Br, -I, -OH, -OR XX , -CF3, -CHF2, -OCF3, -OCHF2, -NH2、-NHR XX -NR XX 2. -R XM and -CN.

[0350] (294) According to any one of (1) to (288), wherein each -R X If it exists, select independently from: -R XX , -F, -Cl, -Br, -I, -OH, -OR XX , -CF3, -CHF2, -OCF3, and -OCHF2.

[0351] (295) According to any one of (1) to (288), wherein each -R X If it exists, select independently from: -R XX , -F, -Cl, -Br and -I.

[0352] (296) According to any one of (1) to (288), wherein each -R X If it exists, select independently from: -F and -Cl.

[0353] (297) According to any one of (1) to (288), wherein each -R X If present, it is -Cl.

[0354] -A and -R X Some preferred combinations (298) According to any one of (1) to (288), the compound wherein -A H If it exists: , Where -R X4 It is -Cl.

[0355] (299) According to any one of (1) to (288), the compound in which -A C If it exists: , Where -R X2 It is -Cl.

[0356] group -L XX - (300) According to any one of (1) to (299), wherein each -L XX -If present, it is independently -CH2CH2CH2-, -CH2CH2-, -CH(CH3)CH2-, -CH(CH3)-, or -CH2-.

[0357] (301) According to any one of (1) to (299), wherein each -L XX -If present, it is independently -CH2CH2- or -CH2-.

[0358] (302) According to any one of (1) to (299), wherein each -L XX -If it exists, it is -CH2-.

[0359] Group -R XX (303) A compound according to any one of (1) to (302), wherein each -R XX If it exists, it is independently a linear or branched saturated C. 1-4 Alkyl, phenyl, or -CH2-phenyl.

[0360] (304) A compound according to any one of (1) to (302), wherein each -R XX If it exists, it is a linear or branched saturation C. 1-4 alkyl.

[0361] (305) A compound according to any one of (1) to (302), wherein each -R XX If it exists, it will be -Me.

[0362] Group -R XXU (306) A compound according to any one of (1) to (305), wherein each -R XXU If present, it is independently -CH=CH2 or -CH2-CH=CH2.

[0363] (307) A compound according to any one of (1) to (305), wherein each -R XXU If it exists, it is -CH=CH2.

[0364] Group -R XXV (308) A compound according to any one of (1) to (307), wherein each -R XXV If present, it is independently -CH≡CH or -CH2-C≡CH.

[0365] (309) A compound according to any one of (1) to (307), wherein each -R XXV If it exists, it is -CH≡CH.

[0366] Group -R XN (310) A compound according to any one of (1) to (309), wherein each -R XN If present, it is independently -Me, -Et, -nPr, or -iPr.

[0367] (311) According to any one of (1) to (309), wherein each -R XN If it exists, it will be -Me.

[0368] Group -R XM (312) According to any one of (1) to (311), wherein each -R XM If present, it is independently pyrrolidine, piperidinium, piperazine, or morpholine, and: Optionally, it may be replaced with one or more groups selected from the following: -R XMM -C(=O)R XMM -C(=O)OR XMM and -S(=O)2R XMM .

[0369] (313) A compound according to any one of (1) to (311), wherein each -R XM If present, it is independently pyrrolidine, piperidine, piperazine, or morpholine.

[0370] Group -R XMM (314) According to any one of (1) to (313), wherein each -R XMM If it exists, it is independently a linear or branched saturated C. 1-4 Alkyl, phenyl, or -CH2-phenyl.

[0371] (315) A compound according to any one of (1) to (313), wherein each -R XMM If it exists, it is a linear or branched saturation C. 1-4 alkyl.

[0372] (316) According to any one of (1) to (313), wherein each -R XMM If it exists, it will be -Me.

[0373] Group -R 1 (317) A compound according to any one of (1) to (316), wherein -R 1 -R 11 .

[0374] (318) A compound according to any one of (1) to (316), wherein -R 1 It is -H.

[0375] Group -R 11 (319) A compound according to any one of (1) to (318), wherein -R 11 If it exists, then -R 11A .

[0376] (320) A compound according to any one of (1) to (318), wherein -R 11 If it exists, then -R 11B .

[0377] Group -R 11A (321) A compound according to any one of (1) to (320), wherein -R 11A If it exists, it is independently -R. A1 -R A4 -L A -R A2 -L A -R A4 or -L A -R A5 .

[0378] (322) A compound according to any one of (1) to (320), wherein -R 11A If it exists, it is independently -R. A1 -L A -R A2 -L A -R A4 or -L A -R A5 .

[0379] (323) A compound according to any one of (1) to (320), wherein -R 11A If it exists, it is independently -R. A1 or -L A -R A2 .

[0380] (324) A compound according to any one of (1) to (320), wherein -R 11A If it exists, then -R A1 .

[0381] (325) A compound according to any one of (1) to (320), wherein -R 11A If it exists, then -L A -R A2 .

[0382] (326) A compound according to any one of (1) to (320), wherein -R 11A If it exists, then -L A -R A4 .

[0383] (327) A compound according to any one of (1) to (320), wherein -R 11A If it exists, then -L A -R A5 .

[0384] Group -R A1 (328) A compound according to any one of (1) to (327), wherein -R A1 If present, it is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu; and optionally with one or more groups -R AA2 replace.

[0385] (329) A compound according to any one of (1) to (327), wherein -R A1 If present, it is -iBu; and optionally with one or more groups -R AA2 replace.

[0386] (330) A compound according to any one of (1) to (327), wherein -R A1 If present, it is -sBu; and optionally with one or more groups -R. AA2 replace.

[0387] (331) According to any one of (1) to (327), the compound wherein -R A1If present, it is -iPr; and optionally with one or more groups -R. AA2 replace.

[0388] (332) According to any one of (1) to (327), the compound wherein -R A1 If present, it is -Me; and optionally with one or more groups -R. AA2 replace.

[0389] (333) According to any one of (1) to (327), the compound wherein -R A1 If present, it can be -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu independently.

[0390] (334) According to any one of (1) to (327), the compound wherein -R A1 If present, it is independently -iPr, -iBu, or -sBu.

[0391] (335) According to any one of (1) to (327), the compound wherein -R A1 If it exists, it is -iBu.

[0392] (336) According to any one of (1) to (327), the compound wherein -R A1 If it exists, it is -sBu.

[0393] (337) A compound according to any one of (1) to (327), wherein -R A1 If it exists, it is -iPr.

[0394] (338) A compound according to any one of (1) to (327), wherein -R A1 If it exists, it will be -Me.

[0395] Group -R A2 (339) A compound according to any one of (1) to (338), wherein each -R A2 If present, it is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and optionally with one or more groups -R AA1 and one or more groups -R AA2 replace.

[0396] (340) According to any one of (1) to (338), wherein each -R A2 If present, it is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0397] (341) According to any one of (1) to (338), wherein each -R A2 If present, it is independently cyclopropyl.

[0398] Group -R A3 (342) According to any one of (1) to (341), wherein each -R A3 If present, it is independently an oxetane, tetrahydrofuranyl, tetrahydropyranyl, dioxane, azirane, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azirane-heptane, or diazirane-heptane, and optionally with one or more -R groups. AA1 and one or more groups -R AA2 replace.

[0399] (343) According to any one of (1) to (341), wherein each -R A3 If present, it is independently tetrahydrofuranyl, tetrahydropyranyl, dioxyl, pyrrolidinyl, piperidinyl, piperazineyl, or morpholinyl, and optionally with one or more -R groups. AA1 and one or more groups -R AA2 replace.

[0400] (344) According to any one of (1) to (341), wherein each -R A3 If present, it is independently tetrahydrofuranyl, tetrahydropyranyl, or dioxane, and optionally with one or more -R groups. AA1 and one or more groups -R AA2 replace.

[0401] (345) According to any one of (1) to (341), wherein each -R A3 If present, it is independently pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, and optionally with one or more -R groups. AA1 and one or more groups -R AA2 replace.

[0402] (346) According to any one of (1) to (341), wherein each -R A3 If present, it is independently tetrahydrofuranyl, tetrahydropyranyl, dioxyl, pyrrolidinyl, piperidinyl, piperazineyl, or morpholinyl.

[0403] (347) According to any one of (1) to (341), wherein each -R A3 If present, it is independently tetrahydrofuranyl, tetrahydropyranyl, or dioxane.

[0404] (348) According to any one of (1) to (341), wherein each -R A3 If present, it is independently pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl.

[0405] Group -R A4 (349) According to any one of (1) to (348), wherein each -R A4 If present, it is phenyl, and optionally with one or more -R groups. AA1 and one or more groups -R AA2 replace.

[0406] (350) According to any one of (1) to (348), wherein each -R A4 If present, it is phenyl.

[0407] Group -R A5 (351) According to any one of (1) to (350), wherein each -R A5 If present, it is independently furanyl, thiopheneyl, pyrroleyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyridinyl, indolyl, benzimidazolyl, indazoleyl, benzofuranyl, benzothiopheneyl, benzoxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, quinolinyl, isoquinolinyl, cenolinyl, quinoxalolinyl, quinazolinyl, or phthalazinyl, and optionally with one or more groups -R AA1 and one or more groups -R AA2 replace.

[0408] (352) According to any one of (1) to (350), wherein each -R A5 If present, it is independently furanyl, thiopheneyl, pyrroleyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyridinyl, pyrimidinyl, or pyrazinyl, and optionally with one or more -R groups. AA1 and one or more groups -R AA2 replace.

[0409] (353) According to any one of (1) to (350), wherein each -R A5 If present, it is independently furanyl, thiopheneyl, pyrroleyl, imidazoleyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, or isothiazolyl, and optionally with one or more -R groups. AA1 and one or more groups -R AA2 replace.

[0410] (354) According to any one of (1) to (350), wherein each -R A5 If present, it is independently pyridinyl, pyridinyl, pyrimidinyl, or pyrazinyl, and optionally with one or more -R groups. AA1 and one or more groups -R AA2 replace.

[0411] (355) A compound according to any one of (1) to (350), wherein each -R A5 If present, it is independently imidazole or indole, and optionally with one or more -R groups. AA1 and one or more groups -R AA2 replace.

[0412] (356) According to any one of (1) to (350), wherein each -R A5 If present, it is independently furanyl, thiopheneyl, pyrroleyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyridinyl, pyrimidinyl, or pyrazinyl.

[0413] (357) According to any one of (1) to (350), wherein each -R A5 If present, it is independently furanyl, thiopheneyl, pyrroleyl, imidazoleyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, or isothiazolyl.

[0414] (358) According to any one of (1) to (350), wherein each -R A5 If present, it is independently pyridinyl, pyridinyl, pyrimidinyl, or pyrazinyl.

[0415] (359) A compound according to any one of (1) to (350), wherein each -R A5 If present, it is independently an imidazole group or an indole group.

[0416] group -L A - (360) According to any one of (1) to (359), wherein each -L A -If present, it is independently -CH2CH2CH2-, -CH2CH2-, -CH(CH3)CH2-, -CH(CH3)-, or -CH2-.

[0417] (361) According to any one of (1) to (359), wherein each -L A -If present, it is independently -CH2CH2 or -CH2-.

[0418] (362) According to any one of (1) to (359), wherein each -L A -If it exists, it is -CH2-.

[0419] Group -R AA1 (363) According to any one of (1) to (362), wherein each -R AA1 If it exists, then -R AA .

[0420] Group -R AA2 (364) According to any one of (1) to (363), wherein each -R AA2 If it exists, select independently from: -F, -Cl, -Br, -I, -OH, -OR AA , -OCF3, -NH2、-NHR AA -N(R) AA )2、-R AM , -C(=O)OH, -C(=O)OR AA -OC(=O)R AA , -C(=O)NH2、-C(=O)NHR AA -C(=O)N(R) AA )2、-C(=O)R AM , -NHC(=O)R AA -NR AN C(=O)R AA , -C(=O)R AA , -S(=O)NH2、-S(=O)NHR AA -S(=O)N(R) AA )2、-S(=O)R AM , -S(=O)2NH2、-S(=O)2NHR AA -S(=O)2N(R) AA )2、-S(=O)2R AM , -NHS(=O)R AA -NR AN S(=O)R AA , -NHS(=O)2R AA-NR AN S(=O)2R AA , -S(=O)R AA -S(=O)2R AA , -SH、-SR AA -CN and -NO2.

[0421] (365) According to any one of (1) to (363), wherein each -R AA2 If it exists, select independently from: -F, -Cl, -Br, -I, -OH, -OR AA , -OCF3, -NH2、-NHR AA -N(R) AA )2、-R AM and -CN.

[0422] (366) According to any one of (1) to (363), wherein each -R AA2 If it exists, select independently from: -F, -Cl, -Br, -I, -OH, -OR AA and -OCF3.

[0423] (367) According to any one of (1) to (363), wherein each -R AA2 If it exists, select independently from: -OH, -OR AA , -NH2、-NHR AA -N(R) AA )2、-R AM , -C(=O)OH, -C(=O)OR AA , -C(=O)NH2、-C(=O)NHR AA -C(=O)N(R) AA )2、-C(=O)R AM , -NHC(=NH)NH2、 -SH and -SR AA .

[0424] (368) According to any one of (1) to (363), wherein each -RAA2 If it exists, select independently from: -OH、 -NH2、 -C(=O)OH、 -C(=O)NH2、 -NHC(=NH)NH2、 -SH and -SMe.

[0425] group -L AA - (369) According to any one of (1) to (368), wherein each -L AA -If present, it is independently -CH2CH2CH2-, -CH2CH2-, -CH(CH3)CH2-, -CH(CH3)-, or -CH2-.

[0426] (370) According to any one of (1) to (368), wherein each -L AA -If present, it is independently -CH2CH2 or -CH2-.

[0427] Group -R AA (371) According to any one of (1) to (370), wherein each -R AA If it exists, it is independently a linear or branched saturated C. 1-4 Alkyl, phenyl, or -CH2-phenyl.

[0428] (372) According to any one of (1) to (370), wherein each -R AA If it exists, it is a linear or branched saturation C. 1-4 alkyl.

[0429] (373) According to any one of (1) to (370), wherein each -R AA If it exists, it will be -Me.

[0430] Group -R AN (374) According to any one of (1) to (373), wherein each -R AN If present, it is independently -Me, -Et, -nPr, or -iPr.

[0431] (375) According to any one of (1) to (373), wherein each -R AN If it exists, it will be -Me.

[0432] Group -R AM (376) According to any one of (1) to (375), wherein each -R AM If present, it is independently pyrrolidine, piperidinium, piperazine, or morpholine, and: Optionally, it may be replaced with one or more groups selected from the following: -R AMM -C(=O)R AMM -C(=O)OR AMM and -S(=O)2R AMM .

[0433] (377) According to any one of (1) to (375), wherein each -R AM If present, it is independently pyrrolidine, piperidine, piperazine, or morpholine.

[0434] Group -R AMM (378) According to any one of (1) to (377), wherein each -R AMM If it exists, it is independently a linear or branched saturated C. 1-4 Alkyl, phenyl, or -CH2-phenyl.

[0435] (379) According to any one of (1) to (377), wherein each -R AMM If it exists, it is a linear or branched saturation C. 1-4 alkyl.

[0436] (380) According to any one of (1) to (377), wherein each -R AMM If it exists, it will be -Me.

[0437] Group -R 11A : Some specific groups (381) A compound according to any one of (1) to (320), wherein -R 11A If it exists, select independently from: -CH3 (e.g., as in alanine), -CH2CH(CH3)2 (e.g., as in leucine), -CH(CH3)CH2CH3 (e.g., as in isoleucine), -CH2CH2-S-CH3 (e.g., as in methionine), -CH2-(phenyl) (e.g., as in phenylalanine), -CH2-(1H-indol-3-yl) (e.g., as in tryptophan), -CH(CH3)2 (e.g., as in valine), -CH2-C(=O)NH2 (e.g., as in asparagine), -CH2-SH (e.g., as in cysteine), -CH2CH2-C(=O)NH2 (e.g., as in glutamine), -CH2-OH (e.g., in serine), -CH(OH)CH3 (e.g., as in threonine), -CH2-(4-hydroxy-phenyl) (e.g., as in tyrosine), -CH2CH2CH2-NH-C(=NH)-NH2 (e.g., in arginine), -CH2-(1H-imidazol-4-yl) (e.g., as in histidine), -CH2CH2CH2CH2-NH2 (e.g., as in lysine), -CH2-C(=O)OH (e.g., as in aspartic acid), and -CH2CH2-C(=O)OH (e.g., as in glutamic acid).

[0438] (382) According to any one of (1) to (320), the compound wherein -R 11A If it exists, select independently from: -CH2CH(CH3)2 (e.g., as in leucine), -CH(CH3)CH2CH3 (e.g., as in isoleucine), -CH(CH3)2 (e.g., as in valine).

[0439] (383) A compound according to any one of (1) to (320), wherein -R 11A If present, it is -CH2CH(CH3)2 (e.g., as in leucine).

[0440] (384) According to any one of (1) to (320), the compound wherein -R 11A If present, it is -CH(CH3)CH2CH3 (e.g., as in isoleucine).

[0441] (385) A compound according to any one of (1) to (320), wherein -R 11A If present, it is -CH(CH3)2 (e.g., as in valine).

[0442] Group -R 11B (386) A compound according to any one of (1) to (385), wherein -R 11B If it exists, select independently from: -F, -Cl, -Br, -I, -OH, -OR BB , -OCF3, -NH2、-NHR BB -NR BB 2. -R BM , -C(=O)OH, -C(=O)OR BB -OC(=O)R BB , -C(=O)NH2、-C(=O)NHR BB -C(=O)NR BB 2. -C(=O)R BM , -NHC(=O)R BB -NR BN C(=O)R BB , -C(=O)R BB , -S(=O)NH2、-S(=O)NHR BB -S(=O)NR BB 2. -S(=O)R BM , -S(=O)2NH2、-S(=O)2NHR BB -S(=O)2NR BB 2. -S(=O)2R BM , -NHS(=O)R BB -NR BN S(=O)R BB , -NHS(=O)2R BB -NR BN S(=O)2R BB , -S(=O)R BB -S(=O)2R BB , -SR BB -CN and -NO2.

[0443] (387) A compound according to any one of (1) to (385), wherein each -R 11B If it exists, select independently from: -F, -Cl, -Br, -I, -OH, -OR BB , -OCF3, -NH2、-NHR BB -NR BB 2. -R BM , -SR BB and -CN.

[0444] (388) A compound according to any one of (1) to (385), wherein each -R 11B If it exists, select independently from: -F, -Cl, -Br, -I, -OH, -OR BB , -OCF3 and -SR BB .

[0445] (389) A compound according to any one of (1) to (385), wherein each -R 11B If it exists, select independently from: -F, -Cl, -Br, -I, -OH, -OR BB and -OCF3.

[0446] Group -R BB (390) According to any one of (1) to (389), wherein each -R BB If it exists, it is independently a linear or branched saturated C. 1-4 Alkyl, phenyl, or -CH2-phenyl.

[0447] (391) According to any one of (1) to (389), wherein each -R BB If it exists, it is a linear or branched saturation C. 1-4 alkyl.

[0448] (392) According to any one of (1) to (389), wherein each -R BB If it exists, it will be -Me.

[0449] Group -R BN (393) According to any one of (1) to (392), wherein each -R BN If present, it is independently -Me, -Et, -nPr, or -iPr.

[0450] (394) According to any one of (1) to (392), wherein each -R BN If it exists, it will be -Me.

[0451] Group -R BM (395) According to any one of (1) to (394), wherein each -R BM If present, it is independently pyrrolidine, piperidinium, piperazine, or morpholine, and: Optionally, it may be replaced with one or more groups selected from the following: -R BMM -C(=O)R BMM -C(=O)OR BMM and -S(=O)2R BMM .

[0452] (396) According to any one of (1) to (394), wherein each -R BM If present, it is independently pyrrolidine, piperidine, piperazine, or morpholine.

[0453] Group -R BMM (397) According to any one of (1) to (396), wherein each -R BMM If it exists, it is independently a linear or branched saturated C. 1-4 Alkyl, phenyl, or -CH2-phenyl.

[0454] (398) According to any one of (1) to (396), wherein each -R BMM If it exists, it is a linear or branched saturation C. 1-4 alkyl.

[0455] (399) According to any one of (1) to (396), wherein each -R BMM If it exists, it will be -Me.

[0456] Group -R 2 (400) A compound according to any one of (1) to (399), wherein -R 2 It is -H.

[0457] (401) A compound according to any one of (1) to (399), wherein -R 2 -R 22 .

[0458] Group -R 22 (402) A compound according to any one of (1) to (401), wherein -R 22 If it exists, then -R 22C .

[0459] (403) A compound according to any one of (1) to (401), wherein -R 22 If it exists, then -R 22D .

[0460] Group -R 22C (404) A compound according to any one of (1) to (403), wherein -R 22C If it exists, it is independently -R. C1 -R C4 -L C -R C4 or -L C -R C5 .

[0461] (405) A compound according to any one of (1) to (403), wherein -R 22C If it exists, it is independently -R. C1 -L C -R C4 or -L C -R C5 .

[0462] (406) A compound according to any one of (1) to (403), wherein -R 22C If it exists, it is independently -R. C1 or -L C -R C4 .

[0463] (407) A compound according to any one of (1) to (403), wherein -R 22C If it exists, then -R C1 .

[0464] (408) A compound according to any one of (1) to (403), wherein -R 22C If it exists, then -L C -R C4 .

[0465] (409) A compound according to any one of (1) to (403), wherein -R 22C If it exists, then -L C -R C5 .

[0466] Group -R C1 (410) A compound according to any one of (1) to (409), wherein -R C1 If present, it is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu; and optionally with one or more groups -R CC2 replace.

[0467] (411) A compound according to any one of (1) to (409), wherein -R C1 If present, it is independently -Me; and optionally with one or more groups -R. CC2 replace.

[0468] (412) A compound according to any one of (1) to (409), wherein -R C1 If present, it is independently -iPr; and optionally with one or more groups -R. CC2 replace.

[0469] (413) A compound according to any one of (1) to (409), wherein -R C1 If present, it is independently -iBu; and optionally with one or more groups -R. CC2 replace.

[0470] (414) A compound according to any one of (1) to (409), wherein -R C1 If present, it can be -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu independently.

[0471] (415) A compound according to any one of (1) to (409), wherein -R C1 If it exists, it is independently -Me.

[0472] (416) A compound according to any one of (1) to (409), wherein -R C1 If it exists, it is independently -iPr.

[0473] (417) A compound according to any one of (1) to (409), wherein -R C1 If it exists, it is independently -iBu.

[0474] Group -R C2 (418) A compound according to any one of (1) to (417), wherein each -R C2 If present, it is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and optionally with one or more groups -R CC1 and one or more groups -RCC2 replace.

[0475] (419) According to any one of (1) to (417), wherein each -R C2 If present, it is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0476] Group -R C3 (420) According to any one of (1) to (419), wherein each -R C3 If present, it is independently an oxetane, tetrahydrofuranyl, tetrahydropyranyl, dioxane, azirane, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azirane-heptane, or diazirane-heptane, and optionally with one or more -R groups. CC1 and one or more groups -R CC2 replace.

[0477] (421) According to any one of (1) to (419), wherein each -R C3 If present, it is independently tetrahydrofuranyl, tetrahydropyranyl, dioxyl, pyrrolidinyl, piperidinyl, piperazineyl, or morpholinyl, and optionally with one or more -R groups. CC1 and one or more groups -R CC2 replace.

[0478] (422) According to any one of (1) to (419), wherein each -R C3 If present, it is independently tetrahydrofuranyl, tetrahydropyranyl, or dioxane, and optionally with one or more -R groups. CC1 and one or more groups -R CC2 replace.

[0479] (423) According to any one of (1) to (419), wherein each -R C3 If present, it is independently pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, and optionally with one or more -R groups. CC1 and one or more groups -R CC2 replace.

[0480] (424) According to any one of (1) to (419), wherein each -R C3 If present, it is independently tetrahydrofuranyl, tetrahydropyranyl, dioxyl, pyrrolidinyl, piperidinyl, piperazineyl, or morpholinyl.

[0481] (425) According to any one of (1) to (419), wherein each -R C3If present, it is independently tetrahydrofuranyl, tetrahydropyranyl, or dioxane.

[0482] (426) According to any one of (1) to (419), wherein each -R C3 If present, it is independently pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl.

[0483] Group -R C4 (427) A compound according to any one of (1) to (426), wherein each -R C4 If present, it is phenyl, and optionally with one or more -R groups. CC1 and one or more groups -R CC2 replace.

[0484] (428) A compound according to any one of (1) to (426), wherein each -R C4 If present, it is phenyl.

[0485] Group -R C5 (429) A compound according to any one of (1) to (428), wherein each -R C5 If present, it is independently furanyl, thiopheneyl, pyrroleyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyridinyl, indolyl, benzimidazolyl, indazoleyl, benzofuranyl, benzothiopheneyl, benzoxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, quinolinyl, isoquinolinyl, cenolinyl, quinoxalolinyl, quinazolinyl, or phthalazinyl, and optionally with one or more groups -R CC1 and one or more groups -R CC2 replace.

[0486] (430) A compound according to any one of (1) to (428), wherein each -R C5 If present, it is independently furanyl, thiopheneyl, pyrroleyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyridinyl, pyrimidinyl, or pyrazinyl, and optionally with one or more -R groups. CC1 and one or more groups -R CC2 replace.

[0487] (431) A compound according to any one of (1) to (428), wherein each -R C5 If present, it is independently furanyl, thiopheneyl, pyrroleyl, imidazoleyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, or isothiazolyl, and optionally with one or more -R groups. CC1and one or more groups -R CC2 replace.

[0488] (432) According to any one of (1) to (428), wherein each -R C5 If present, it is independently pyridinyl, pyridinyl, pyrimidinyl, or pyrazinyl, and optionally with one or more -R groups. CC1 and one or more groups -R CC2 replace.

[0489] (433) According to any one of (1) to (428), wherein each -R C5 If present, it is independently imidazole or indole, and optionally with one or more -R groups. CC1 and one or more groups -R CC2 replace.

[0490] (434) According to any one of (1) to (428), wherein each -R C5 If present, it is independently furanyl, thiopheneyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl.

[0491] (435) According to any one of (1) to (428), wherein each -R C5 If present, it is independently furanyl, thiopheneyl, pyrroleyl, imidazoleyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, or isothiazolyl.

[0492] (436) According to any one of (1) to (428), wherein each -R C5 If present, it is independently pyridinyl, pyridinyl, pyrimidinyl, or pyrazinyl.

[0493] (437) According to any one of (1) to (428), wherein each -R C5 If present, it is independently an imidazole group or an indole group.

[0494] group -L C - (438) According to any one of (1) to (437), wherein each -L C -If present, it is independently -CH2CH2CH2-, -CH2CH2-, -CH(CH3)CH2-, -CH(CH3)-, or -CH2-.

[0495] (439) According to any one of (1) to (437), wherein each -L C-If present, it is independently -CH2CH2 or -CH2-.

[0496] (440) According to any one of (1) to (437), wherein each -L C -If it exists, it is -CH2-.

[0497] Group -R CC1 (441) A compound according to any one of (1) to (440), wherein each -R CC1 If it exists, then -R CC .

[0498] Group -R CC2 (442) According to any one of (1) to (441), wherein each -R CC2 If it exists, select independently from: -F, -Cl, -Br, -I, -OH, -OR CC , -OCF3, -NH2、-NHR CC -N(R) CC )2、-R CM , -C(=O)OH, -C(=O)OR CC -OC(=O)R CC , -C(=O)NH2、-C(=O)NHR CC -C(=O)N(R) CC )2、-C(=O)R CM , -NHC(=O)R CC -NR CN C(=O)R CC , -C(=O)R CC , -S(=O)NH2、-S(=O)NHR CC -S(=O)N(R) CC )2、-S(=O)R CM , -S(=O)2NH2、-S(=O)2NHR CC -S(=O)2N(R) CC )2、-S(=O)2R CM , -NHS(=O)R CC -NR CN S(=O)RCC , -NHS(=O)2R CC -NR CN S(=O)2R CC , -S(=O)R CC -S(=O)2R CC , -SH、-SR CC -CN and -NO2.

[0499] (443) Compounds according to any one of (1) to (441), wherein each -R CC2 If it exists, select independently from: -F, -Cl, -Br, -I, -OH, -OR CC , -OCF3, -NH2、-NHR CC -N(R) CC )2、-R CM and -CN.

[0500] (444) A compound according to any one of (1) to (441), wherein each -R CC2 If it exists, select independently from: -F, -Cl, -Br, -I, -OH, -OR CC and -OCF3.

[0501] (445) According to any one of (1) to (441), wherein each -R CC2 If it exists, select independently from: -OH, -OR CC , -NH2、-NHR CC -N(R) CC )2、-R CM , -C(=O)OH, -C(=O)OR CC , -C(=O)NH2、-C(=O)NHR CC -C(=O)N(R) CC )2、-C(=O)R CM , -NHC(=NH)NH2、 -SH and -SR CC .

[0502] (446) According to any one of (1) to (441), wherein each -R CC2 If it exists, select independently from: -OH、 -NH2、 -C(=O)OH、 -C(=O)NH2、 -NHC(=NH)NH2、 -SH and -SMe.

[0503] group -L CC - (447) According to any one of (1) to (446), wherein each -L CC -If present, it is independently -CH2CH2CH2-, -CH2CH2-, -CH(CH3)CH2-, -CH(CH3)-, or -CH2-.

[0504] (448) According to any one of (1) to (446), wherein each -L CC -If present, it is independently -CH2CH2 or -CH2-.

[0505] (449) A compound according to any one of (1) to (446), wherein each -L CC -If it exists, it is -CH2-.

[0506] Group -R CC (450) A compound according to any one of (1) to (449), wherein each -R CC If it exists, it is independently a linear or branched saturated C. 1-4 Alkyl, phenyl, or -CH2-phenyl.

[0507] (451) According to any one of (1) to (449), wherein each -R CC If it exists, it is a linear or branched saturation C. 1-4 alkyl.

[0508] (452) According to any one of (1) to (449), wherein each -R CC If it exists, it will be -Me.

[0509] Group -R CN (453) According to any one of (1) to (452), wherein each -R CN If present, it is independently -Me, -Et, -nPr, or -iPr.

[0510] (454) According to any one of (1) to (452), wherein each -R CN If it exists, it will be -Me.

[0511] Group -R CM (455) According to any one of (1) to (454), wherein each -R CM If present, it is independently pyrrolidine, piperidinium, piperazine, or morpholine, and: Optionally, it may be replaced with one or more groups selected from the following: -R CMM -C(=O)R CMM -C(=O)OR CMM and -S(=O)2R CMM .

[0512] (456) According to any one of (1) to (454), wherein each -R CM If present, it is independently pyrrolidine, piperidine, piperazine, or morpholine.

[0513] Group -R CMM (457) According to any one of (1) to (456), wherein each -R CMM If it exists, it is independently a linear or branched saturated C. 1-4 Alkyl, phenyl, or -CH2-phenyl.

[0514] (458) A compound according to any one of (1) to (456), wherein each -R CMM If it exists, it is a linear or branched saturation C. 1-4 alkyl.

[0515] (459) According to any one of (1) to (456), wherein each -R CMM If it exists, it will be -Me.

[0516] Group -R 22C : Some specific groups (460) A compound according to any one of (1) to (403), wherein -R 22C If it exists, select independently from: -CH3 (e.g., as in alanine), -CH2CH(CH3)2 (e.g., as in leucine), -CH(CH3)CH2CH3 (e.g., as in isoleucine), -CH2CH2-S-CH3 (e.g., as in methionine), -CH2-(phenyl) (e.g., as in phenylalanine), -CH2-(1H-indol-3-yl) (e.g., as in tryptophan), -CH(CH3)2 (e.g., as in valine), -CH2-C(=O)NH2 (e.g., as in asparagine), -CH2-SH (e.g., as in cysteine), -CH2CH2-C(=O)NH2 (e.g., as in glutamine), -CH2-OH (e.g., in serine), -CH(OH)CH3 (e.g., as in threonine), -CH2-(4-hydroxy-phenyl) (e.g., as in tyrosine), -CH2CH2CH2-NH-C(=NH)-NH2 (e.g., in arginine), -CH2-(1H-imidazol-4-yl) (e.g., as in histidine), -CH2CH2CH2CH2-NH2 (e.g., as in lysine), -CH2-C(=O)OH (e.g., as in aspartic acid), and -CH2CH2-C(=O)OH (e.g., as in glutamic acid).

[0517] Group -R 22D (461) According to any one of (1) to (460), the compound wherein -R 22D If it exists, select independently from: -F, -Cl, -Br, -I, -OH, -OR DD , -OCF3, -NH2、-NHR DD -NR DD 2. -R DM , -C(=O)OH, -C(=O)OR DD -OC(=O)R DD , -C(=O)NH2、-C(=O)NHR DD -C(=O)NR DD 2. -C(=O)R DM , -NHC(=O)R DD -NRDN C(=O)R DD , -C(=O)R DD , -S(=O)NH2、-S(=O)NHR DD -S(=O)NR DD 2. -S(=O)R DM , -S(=O)2NH2、-S(=O)2NHR DD -S(=O)2NR DD 2. -S(=O)2R DM , -NHS(=O)R DD -NR DN S(=O)R DD , -NHS(=O)2R DD -NR DN S(=O)2R DD , -S(=O)R DD -S(=O)2R DD , -SR DD -CN and -NO2.

[0518] (462) According to any one of (1) to (460), wherein each -R 22D If it exists, select independently from: -F, -Cl, -Br, -I, -OH, -OR DD , -OCF3, -NH2、-NHR DD -NR DD 2. -R DM , -SR DD and -CN.

[0519] (463) According to any one of (1) to (460), wherein each -R 22D If it exists, select independently from: -F, -Cl, -Br, -I, -OH, -OR DD , -OCF3 and -SR DD .

[0520] (464) According to any one of (1) to (460), wherein each -R 22D If it exists, select independently from: -F, -Cl, -Br, -I, -OH, -OR DD and -OCF3.

[0521] Group -R DD (465) According to any one of (1) to (464), wherein each -R DD If it exists, it is independently a linear or branched saturated C. 1-4 Alkyl, phenyl, or -CH2-phenyl.

[0522] (466) According to any one of (1) to (464), wherein each -R DD If it exists, it is a linear or branched saturation C. 1-4 alkyl.

[0523] (467) According to any one of (1) to (464), wherein each -R DD If it exists, it will be -Me.

[0524] Group -R DN (468) According to any one of (1) to (467), wherein each -R DN If present, it is independently -Me, -Et, -nPr, or -iPr.

[0525] (469) According to any one of (1) to (467), wherein each -R DN If it exists, it will be -Me.

[0526] Group -R DM (470) According to any one of (1) to (469), wherein each -R DM If present, it is independently pyrrolidine, piperidinium, piperazine, or morpholine, and: Optionally, it may be replaced with one or more groups selected from the following: -R DMM -C(=O)R DMM -C(=O)OR DMM and -S(=O)2R DMM .

[0527] (471) According to any one of (1) to (469), wherein each -R DMIf present, it is independently pyrrolidine, piperidine, piperazine, or morpholine.

[0528] Group -R DMM (472) According to any one of (1) to (471), wherein each -R DMM If it exists, it is independently a linear or branched saturated C. 1-4 Alkyl, phenyl, or -CH2-phenyl.

[0529] (473) Compounds according to any one of (1) to (471), wherein each -R DMM If it exists, it is a linear or branched saturation C. 1-4 alkyl.

[0530] (474) According to any one of (1) to (471), wherein each -R DMM If it exists, it will be -Me.

[0531] Group R 1 and R 2 Put together (475) A compound according to any one of (1) to (474), wherein -R 1 and -R 2 Together with the carbon atoms they are attached to, they form saturated carbon. 3-6 cycloalkyl or non-aromatic C 3-7 Heterocyclic group, and optionally with one or more groups -R CC2 replace.

[0532] (476) According to any one of (1) to (474), the compound wherein -R 1 and -R 2 Together with the carbon atoms they are attached to, they form saturated carbon. 3-6 Cycloalkyl, and optionally with one or more groups -R CC2 replace.

[0533] (477) A compound according to any one of (1) to (474), wherein -R 1 and -R 2 Together with the carbon atoms to which they are attached, they form saturated C5 cycloalkyl groups, and optionally with one or more -R groups. CC2 replace.

[0534] Optional substituents -R CC2 It can be defined, for example, as above.

[0535] R 1 and R 2 Some preferred combinations (478) According to any one of (1) to (477), the compound, wherein: -R1 Independently -CH(CH3)CH2CH3, -CH2CH(CH3)2, or -CH(CH3)2; and -R 2 It is -H.

[0536] (479) According to any one of (1) to (477), the compound, wherein: -R 1 Independently -CH(CH3)CH2CH3 or -CH2CH(CH3)2; and -R 2 It is -H.

[0537] (480) According to any one of (1) to (477), the compound wherein: -R 1 It is -CH2CH(CH3)2; and -R 2 It is -H.

[0538] Chiral center (481) A compound according to any one of (1) to (480), wherein the sulfur atom forming a portion of the sulfonylimide amide group is in the configuration shown in the following structural formula: .

[0539] (482) A compound according to any one of (1) to (480), wherein the sulfur atom forming a portion of the sulfonylimide amide group is in the configuration shown in the following structural formula: .

[0540] (483) According to any one of (1) to (482), the compound wherein -R 1 and -R 2 The bonded carbon atom (i.e., marked with a hash symbol (#) in the following formula) is in ( S ) configuration.

[0541] (484) A compound according to any one of (1) to (482), wherein -R 1 and -R 2 The carbon atom that is attached (i.e., marked with a hash symbol (#) in the above formula) is in ( R ) configuration.

[0542] (485) According to any one of (1) to (482), where R 2It is a compound with -H, and is selected from compounds of the following formula, as well as their pharmaceutically acceptable salts, hydrates, and solvates: .

[0543] (486) According to any one of (1) to (480), the compound, wherein: The sulfur atom forming part of the sulfonylimide amide group (i.e., marked with an asterisk (*) in the following formula) is in the configuration shown in (481); and -R 1 and -R 2 The bonded carbon atom (i.e., marked with a hash symbol (#) in the following formula) is in ( S ) configuration.

[0544] (487) According to any one of (1) to (480), the compound, wherein: The sulfur atom that forms part of the sulfonylimide amide group (i.e., marked with an asterisk (*) in the above formula) is in the configuration shown in (481); and -R 1 and -R 2 The carbon atom that is attached (i.e., marked with a hash symbol (#) in the above formula) is in ( R ) configuration.

[0545] (488) According to any one of (1) to (480), the compound, wherein: The sulfur atom forming part of the sulfonylimide amide group (i.e., marked with an asterisk (*) in the above formula) is in the configuration shown in (482); and -R 1 and -R 2 The carbon atom that is attached (i.e., marked with a hash symbol (#) in the above formula) is in ( S ) configuration.

[0546] (489) According to any one of (1) to (480), the compound, wherein: The sulfur atom forming part of the sulfonylimide amide group (i.e., marked with an asterisk (*) in the above formula) is in the configuration shown in (482); and -R 1 and -R 2 The carbon atom that is attached (i.e., marked with a hash symbol (#) in the above formula) is in ( R ) configuration.

[0547] Some preferred combinations (490) According to any one of (1) to (316), the compound, wherein: -R 1 Independently -CH(CH3)CH2CH3, -CH2CH(CH3)2, or -CH(CH3)2; -R 2 It is -H; and -R 1 and -R 2 The attached carbon atom is in ( S ) configuration.

[0548] (491) According to any one of (1) to (316), the compound, wherein: -R 1 Independently, it is -CH(CH3)CH2CH3 or -CH2CH(CH3)2; -R 2 It is -H; and -R 1 and -R 2 The attached carbon atom is in ( S ) configuration.

[0549] (492) According to any one of (1) to (316), the compound, wherein: -R 1 It is -CH2CH(CH3)2; -R 2 It is -H; and -R 1 and -R 2 The attached carbon atom is in ( S ) configuration.

[0550] Some specific compounds (493) According to (1), the compounds are selected from compounds of the following formula, and their pharmaceutically acceptable salts, hydrates and solvates:

[0551] (494) The compounds according to (493) are selected from ANOSA-001 to ANOSA-068, as well as pharmaceutically acceptable salts, hydrates and solvates.

[0552] combination It should be understood that certain features of the invention described in the context of individual embodiments for clarity may also be provided in combination with individual embodiments. Conversely, various features of the invention described in the context of individual embodiments for brevity may also be provided individually or in any suitable sub-combination. This relates to variables (e.g., -A, -R). N -R 1 -R 2 All combinations of embodiments of the chemical groups represented by (e.g., ...) are specifically covered by the present invention and disclosed herein, as each combination is individually and explicitly disclosed, to the extent that such combinations cover compounds as stable compounds (i.e., compounds whose biological activity can be isolated, characterized, and tested). Furthermore, all sub-combinations of the chemical groups listed in embodiments describing these variables are also specifically covered by the present invention and disclosed herein, as each such sub-combination of the chemical groups is individually and explicitly disclosed herein.

[0553] Basically purified form One aspect of the present invention relates to a purified form of ANOSA compounds.

[0554] In one embodiment, the compound is in a substantially purified form and / or a substantially contaminant-free form.

[0555] In one embodiment, the compound is in a substantially purified form with a purity of at least 50% by weight, for example at least 60% by weight, for example at least 70% by weight, for example at least 80% by weight, for example at least 90% by weight, for example at least 95% by weight, for example at least 97% by weight, for example at least 98% by weight, for example at least 99% by weight.

[0556] Unless otherwise stated, substantially purified form refers to a compound in any stereoisomer or enantiomeric form. For example, in one embodiment, substantially purified form refers to a mixture of stereoisomers, i.e., purified relative to other compounds. In one embodiment, substantially purified form refers to a single stereoisomer, such as an optically pure stereoisomer. In one embodiment, substantially purified form refers to a mixture of enantiomers. In one embodiment, substantially purified form refers to an equimolar mixture of enantiomers (i.e., a racemic mixture, a racemic mixture). In one embodiment, substantially purified form refers to a single enantiomer, such as an optically pure enantiomer.

[0557] In one embodiment, the compound is in a substantially contaminant-free form, wherein the contaminant comprises no more than 50% by weight, for example no more than 40% by weight, for example no more than 30% by weight, for example no more than 20% by weight, for example no more than 10% by weight, for example no more than 5% by weight, for example no more than 3% by weight, for example no more than 2% by weight, for example no more than 1% by weight.

[0558] Unless otherwise stated, a contaminant refers to a compound other than a stereoisomer or enantiomer. In one embodiment, a contaminant refers to other compounds and other stereoisomers. In another embodiment, a contaminant refers to other compounds and other enantiomers.

[0559] In one embodiment, the compound is in a substantially purified form with an optical purity of at least 60% (i.e., in molar terms, 60% of the compound is the desired stereoisomer or enantiomer and 40% is the undesired stereoisomer or enantiomer), for example at least 70%, for example at least 80%, for example at least 90%, for example at least 95%, for example at least 97%, for example at least 98%, for example at least 99%.

[0560] Isomers Certain compounds may exist in one or more specific geometric, optical, enantiomeric, diastereomeric, stereoisomeric, tautomeric, conformational, or terminal isomeric forms, including but not limited to cis and trans; E- and Z-forms; c-, t-, and r-forms; introverted and extroverted forms; R-, S-, and mesoforms; D- and L-forms; d- and l-forms; (+) and (-) forms; ketol, enol, and enolate forms; cis and trans forms; synclinal and anticline forms; α- and β-forms; axial and apical forms; boat, chair, torsional, envelope, and half-chair forms, and combinations thereof, collectively referred to below as “isomers” (or “isomeric forms”).

[0561] It should be noted that, except as discussed below regarding tautomerism, the term "isomer" as used herein specifically excludes structural (or constructive) isomers (i.e., isomers with different atomic connections, not just different spatial positions of atoms). For example, a reference to methoxy-OCH3 should not be interpreted as a reference to its structural isomer hydroxymethyl-CH2OH. Similarly, a reference to ortho-chlorophenyl should not be interpreted as a reference to its structural isomer meta-chlorophenyl. However, a reference to a class of structures is likely to include structural isomers within the scope of said class (e.g., C...). 1-3 Alkyl groups include n-propyl and isopropyl; butyl groups include n-butyl, isobutyl, sec-butyl, and tert-butyl; methoxyphenyl groups include o-methoxyphenyl, m-methoxyphenyl, and p-methoxyphenyl.

[0562] The above exclusions do not involve tautomer forms, such as ketone, enol, and enolate forms, such as in the following tautomer pairs: ketone / enol (described below), imine / enamine, amide / imino alcohol, amidine / amidinium, nitroso / oxime, thionone / enthiol, N-nitroso / hydroxyazo, and nitro / isonitroso.

[0563] For example, 1H-pyridin-2-one-3-yl and 2-hydroxy-pyridin-3-yl (shown below) are tautomers of each other. This article mentions one in order to cover both.

[0564] It should be noted that the term "isomer" specifically includes compounds having one or more isotopic substitutions. For example, H can be any isotopic form, including... 1 H, 2 H (D) and 3 H (T); C can be any isotopic form, including 12 C 13 C and 14 C and O can be in any isotopic form, including 16 O and 18 O; S can be any isotopic form, including 32 S, 33 S, 34 S, 35 S and 36 S; etc.

[0565] For example, while this article mentions non-deuterated compounds, it also aims to cover the corresponding deuterated compounds. In a specific instance, R in compound ANOSA-003... 1 and R 2 The H atom of the substituent at the position can be replaced by a D atom.

[0566] Unless otherwise stated, references to a particular compound include all such isomers, including mixtures thereof (e.g., racemic mixtures). Methods for preparing (e.g., asymmetric synthesis) and separating (e.g., fractional crystallization and chromatographic methods) such isomers are known in the art or readily available by modifying the methods taught herein or known methods in a known manner.

[0567] Salt Preparing, purifying, and / or treating the corresponding salts of compounds, such as pharmaceutically acceptable salts, may be convenient or desirable. Examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, “Pharmaceutically Acceptable Salts”. J. Pharm. Sci. Volume 66, pages 1-19.

[0568] For example, if the compound is an anion or has a functional group that can be an anion (e.g., -COOH can be -COO). - If so, then salts can be formed from suitable cations. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions, such as Na+. + and K + Alkaline earth metal ions, such as Ca 2+ and Mg 2+ ; and other cations, such as Al 3+ Examples of suitable organic cations include, but are not limited to, ammonium ions (i.e., NH4+). + ) and substituted ammonium ions (e.g., NH3R) + NH2R2 + NHR3 + NR4 + Some suitable examples of substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids such as lysine and arginine. A common example of a quaternary ammonium ion is N(CH3)4. + .

[0569] If the compound is a cation or has a functional group that can be a cation (e.g., -NH2 can be -NH3). + If a salt can be formed from a suitable anion, then such anion can be used. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfurous acid, nitric acid, nitrous acid, phosphoric acid, and phosphorous acid.

[0570] Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetoxybenzoic acid, acetic acid, ascorbic acid, aspartic acid, benzoic acid, camphorsulfonic acid, cinnamic acid, citric acid, edemaic acid, ethanesulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, glucoheponic acid, gluconic acid, glutamic acid, glycolic acid, hydroxymaleic acid, hydroxynaphthoic acid, hydroxyethanesulfonic acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, mesylic acid, mucoic acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, pantothenic acid, phenylacetic acid, benzenesulfonic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, toluenesulfonic acid, and valeric acid. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid and carboxymethyl cellulose.

[0571] Unless otherwise stated, references to a particular compound also include its salt form.

[0572] hydrates and solvates Preparing, purifying, and / or treating the corresponding solvates of compounds may be convenient or desirable. As used herein in a conventional sense, the term "solvate" refers to a complex of a solute (e.g., a compound, a salt of a compound) and a solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, such as a hemihydrate, monohydrate, sesquihydrate, dihydrate, trihydrate, etc.

[0573] Unless otherwise stated, references to a particular compound also include its solvate and hydrate forms.

[0574] Chemical protection forms The preparation, purification, and / or treatment of compounds in their chemically protected form may be convenient or desirable. The term "chemically protected form" is used herein in its conventional chemical sense and refers to a compound in which one or more reactive functional groups are protected from unwanted chemical reactions under specific conditions (e.g., pH, temperature, radiation, solvent, etc.). In practice, well-known chemical methods are used to reversibly render functional groups non-reactive, which would otherwise be reactive under specific conditions. In a chemically protected form, one or more reactive functional groups are in the form of a protected or protecting group (also called a masking or shielding group or a blocked or closed group). By protecting the reactive functional group, reactions involving other unprotected reactive functional groups can be carried out without affecting the protected group; typically, the protecting group can be removed in subsequent steps without substantially affecting the rest of the molecule. See, for example... Protective Groups in Organic Synthesis (T. Greene and P. Wuts; 4th edition; John Wiley and Sons, 2006).

[0575] Various methods of “protection,” “closure,” or “masking” are widely used and well-known in organic synthesis. For example, a compound having two non-equivalent reactive functional groups that would be reactive under certain conditions can be derivatized such that one of the functional groups is “protected” and therefore not reactive under certain conditions; thus protected, the compound can be used as a reactant that effectively has only one reactive functional group. After the desired reaction (involving the other functional group) is completed, the protected group may be “deprotected,” restoring it to its original functional group.

[0576] For example, the hydroxyl group can be protected as an ether (-OR) or an ester (-OC(=O)R), for example, protected as: tert-butyl ether; benzyl, diphenylmethyl (diphenylmethyl) or triphenylmethyl (triphenylmethyl) ether; trimethylsilyl or tert-butyldimethylsilyl ether; or acetyl ester (-OC(=O)CH3, -OAc).

[0577] For example, the amino group can be protected as an amide (-NRCO-R) or a carbamate (-NRCO-OR), for example, as: formamide (-NHCO-CH3); benzyloxyamide (-NHCO-OCH2C6H5, -NH-Cbz); tert-butoxyamide (-NHCO-OC(CH3)3, -NH-Boc); 2-biphenyl-2-propoxyamide (-NHCO-OC(CH3)2C6H4C6H5, -NH-Bpo) c) 9-fluorenylmethoxyamide (-NH-Fmoc), 6-nitroveratroloxyamide (-NH-Nvoc), 2-trimethylsilylethoxyamide (-NH-Teoc), 2,2,2-trichloroethoxyamide (-NH-Troc), allyloxyamide (-NH-Alloc), 2(-phenylsulfonyl)ethoxyamide (-NH-Psec); or, under suitable conditions (e.g., cyclic amines), protected as a nitroxide radical (>NO●).

[0578] prodrug The preparation, purification, and / or processing of compounds in prodrug form may be convenient or desirable. As used herein, the term "prodrug" refers to a compound that, when metabolized (e.g., in vivo), produces the desired active compound. Typically, prodrugs are inactive or less active than the desired active compound, but provide advantageous processing, administration, or metabolic properties.

[0579] For example, some prodrugs are esters of the active compound (e.g., physiologically acceptable metabolically unstable esters). During metabolism, the ester group (-C(=O)OR) is cleaved to produce the active drug. The ester can be formed by, for example, esterification of any carboxylic acid group (-C(=O)OH) in the parent compound with, where appropriate, pre-protection of any other reactive groups present in the parent compound, followed by deprotection if needed.

[0580] In addition, some prodrugs are enzymatically activated to produce active compounds, or are compounds that produce active compounds upon further chemical reactions (e.g., as in ADEPT, GDEPT, LIDEPT, etc.). For example, a prodrug can be a sugar derivative or other glycoside conjugate, or it can be an amino acid ester derivative.

[0581] Chemical synthesis This article describes methods for the chemical synthesis of ANOSA compounds. These and / or other well-known methods may be modified and / or adapted in known ways to provide alternative or improved methods for the synthesis of ANOSA compounds.

[0582] Composition One aspect of the present invention relates to a composition (e.g., a pharmaceutical composition) comprising an ANOSA compound as described herein and a pharmaceutically acceptable carrier, diluent, or excipient.

[0583] Another aspect of the invention relates to a method for preparing a composition (e.g., a pharmaceutical composition) comprising mixing an ANOSA compound as described herein with a pharmaceutically acceptable carrier, diluent, or excipient.

[0584] use The ANOSA compounds described herein can be used to treat conditions (e.g., diseases) that are improved by inhibiting (e.g., selectively inhibiting) bacterial aminoacyl-tRNA synthetases (aaRS) (e.g., bacterial leucyl-tRNA synthetase, LeuRS; etc.).

[0585] Selective In one embodiment, inhibition of bacterial aminoacyl-tRNA synthetase (aaRS) is, for example, relative to... Breastfeeding thing Aminoacyl-tRNA synthetase (aaRS), for example, the corresponding mammal Aminoacyl-tRNA synthetase is selectively inhibited.

[0586] In one embodiment, inhibition of bacterial aminoacyl-tRNA synthetase (aaRS) is, for example, relative to... Humans Aminoacyl-tRNA synthetase (aaRS), for example, the corresponding Humans Aminoacyl-tRNA synthetase is selectively inhibited.

[0587] For example, in one implementation, with Humans Compared to leucyl-tRNA synthetase (LeuRS), the ANOSA compound selectively inhibits bacterial leucyl-tRNA synthetase (LeuRS).

[0588] In methods for inhibiting bacterial aminoacyl-tRNA synthetase One aspect of the invention relates to a method for inhibiting (e.g., selectively inhibiting) bacterial aminoacyl-tRNA synthetases (aaRS) (e.g., bacterial leucyl-tRNA synthetase, LeuRS, etc.) in vitro or in vivo, comprising contacting the synthetase with an effective amount of an ANOSA compound as described herein.

[0589] One aspect of the invention relates to a method for inhibiting (e.g., selectively inhibiting) the function of bacterial aminoacyl-tRNA synthetases (aaRS) (e.g., bacterial leucyl-tRNA synthetase, LeuRS, etc.) in cells (e.g., bacterial cells) in vitro or in vivo, comprising contacting said cells with an effective amount of an ANOSA compound as described herein.

[0590] Those skilled in the art can readily determine whether a candidate compound inhibits bacterial aminoacyl-tRNA synthetases (e.g., bacterial leucyl-tRNA synthetase, etc.). For example, suitable assays are described herein or are known in the art.

[0591] In one embodiment, the method is performed in vitro.

[0592] In one implementation, the method is performed in vivo.

[0593] In one embodiment, the ANOSA compound is provided in the form of a pharmaceutically acceptable composition.

[0594] One aspect of the invention relates to a method for inhibiting bacterial aminoacyl-tRNA synthetases (e.g., bacterial leucyl-tRNA synthetase, etc.) in cells (e.g., bacterial cells) in vitro or in vivo, comprising contacting said cells with an effective amount of an ANOSA compound as described herein.

[0595] For example, cell samples can be grown in vitro, a compound can be brought into contact with the cells, and the effect of the compound on those cells can be observed. As an example of "effect," the morphological state of the cells (e.g., alive or dead, etc.) can be determined. When a compound is found to have an effect on cells, it can be used as a prognostic or diagnostic biomarker for the efficacy of the compound in methods for treating patients carrying the same cell type.

[0596] Uses in treatment Another aspect of the invention relates to an ANOSA compound as described herein, used in a method of treating a human or animal body by means of therapy, for example, in a method of treating a condition (e.g., a disease) as described herein.

[0597] Uses in pharmaceutical manufacturing Another aspect of the invention relates to the use of the ANOSA compound as described herein in the manufacture of a medicine, for example in a treatment method, such as in a method of treating a condition (e.g., a disease) as described herein.

[0598] In one embodiment, the drug comprises an ANOSA compound.

[0599] Treatment Another aspect of the invention relates to a treatment method, such as a method of treating a condition (e.g., disease) as described herein, comprising administering to a subject requiring treatment a therapeutically effective amount of a compound as described herein, preferably in the form of a pharmaceutical composition.

[0600] The condition treated – a condition improved by inhibiting bacterial aminoacyl-tRNA synthetase. In one embodiment (e.g., use in a treatment method, use in the manufacture of a medicament, treatment method), the treatment is to treat a condition (e.g., a disease) that can be improved by inhibiting (e.g., selectively inhibiting) bacterial aminoacyl-tRNA synthetase (e.g., bacterial leucyl-tRNA synthetase, etc.).

[0601] The condition being treated - bacterial infection In one implementation (e.g., use in a treatment method, use in the manufacture of a drug, treatment method), the treatment is the treatment of a bacterial infection.

[0602] In one implementation, the bacteria are Gram-positive bacteria (i.e., a bacterial infection is an infection with Gram-positive bacteria; a bacterial infection is a Gram-positive bacterial infection; etc.).

[0603] In one implementation, the bacteria are Gram-negative bacteria.

[0604] In one implementation, the bacteria are aerobic bacteria.

[0605] In one implementation, the bacteria are anaerobic bacteria.

[0606] In one implementation, the bacteria are intracellular bacteria.

[0607] In one implementation scheme, the bacteria are: Staphylococci For example Staphylococcus aureus; Enterococci For example Enterococcus faecalis; Streptococci For example Streptococcus pneumoniae; Haemophilus ,For example Haemophilus influenzae (H. influenza); Moraxella ,For example Moraxella catarrhalis ; Klebsiella ,For example Klebsiella pneumoniae ; Acinetobacter ,For example Acinetobacter baumanii ; Pseudomonas ,For example Pseudomonas aeruginosa ; Proteus ,For example Proteus mirabilis ; Neisseria ,For example Neisseria gonorrhoeae ; Clostridium (genus Clostridium) ,For example Clostridium difficile; Campylobacter, For example Campylobacter jejuni; Salmonella For example Salmonella typhi; Shigella For example Shigella flexneri; Enterobacter ,For example Enterobacter cloacae; Citrobacter ,For example Citrobacter freundii; Francisella For example F. tularensis; Yersinia ,For example Yersinia pestis (Yersinia pestis); Burkholderia, for example Burkholderia nasalis (B.) pseudomallei); Morganella ,For example Morganella morganii; Stenotrophomonas ,For example Stenotrophomonas maltophilia; Serratia ,For example Serratia marcescens; or Escherichia ,For example Escherichia coli .

[0608] In one implementation scheme, the bacteria are: Mycobacteria ,For example Mycobacterium tuberculosis .

[0609] In one implementation scheme, the bacteria are: Chlamydia For example Chlamydia trachomatis ; Rickettsiae, For example Rickettsia prowazekii; or Mycoplasma For example Mycoplasma pneumoniae (M. pneumoniae).

[0610] Infection type / site The infection may be related to specific sites, organs, etc.

[0611] In one implementation scheme, infection is: Central nervous system infection; External ear infection; Middle ear infections, including acute otitis media; Cranial sinus infection; Eye infection; Oral infections, including infections of the teeth, gums, or mucous membranes; Upper respiratory tract infection; Lower respiratory tract infection; Urogenital tract infection; Urinary tract infection; Intra-abdominal infection; Gastrointestinal infection; Gynecological infection; septicemia; Bone or joint infection; Infection of the skin or skin structure; Bacterial endocarditis; Wound infection; or Burn infection.

[0612] prevention Treatment can be preventative, such as antimicrobial prophylaxis during surgery, and antimicrobial prophylaxis in immunosuppressed patients, including those undergoing cancer chemotherapy or organ transplants.

[0613] treat As used herein in the context of treating a condition, the term "treatment" generally refers to the treatment of humans or animals (e.g., in veterinary applications) to achieve desired therapeutic effects, such as inhibiting the progression of the condition, and includes a reduction in the rate of progression, cessation of the rate of progression, alleviation of symptoms, improvement of the condition, and cure of the condition. It also includes treatment as a preventative measure (i.e., prevention). For example, the term "treatment" is used with patients who have not yet developed the condition but are at risk of developing it.

[0614] For example, treatment for bacterial infections includes preventing bacterial infections, reducing the incidence of bacterial infections, and relieving the symptoms of bacterial infections.

[0615] As used herein, the term "therapeutic effective amount" refers to the amount of a compound or material, composition, or dosage form containing the compound that, when administered according to the desired treatment regimen, effectively produces some desired therapeutic effect commensurate with a reasonable benefit / risk ratio.

[0616] Combination therapy The term "treatment" includes combination therapies and treatments, where two or more treatments or treatments are combined, for example, sequentially or simultaneously. For instance, the compounds described herein can also be used in combination therapies, such as in combination with other agents.

[0617] One aspect of the invention relates to compounds as described herein and one or more (e.g., 1, 2, 3, 4) wait Other treatments, such as combinations of other antibacterial agents.

[0618] The specific combination will be determined by the physician, who will use their common sense and known dosing regimens to select the dosage.

[0619] The agent (i.e., the ANOSA compound described herein, plus one or more other agents) can be administered simultaneously or sequentially, and can be administered via individually varied dosing regimens and different routes. For example, when administered sequentially, the agent can be administered at closely spaced intervals (e.g., within a time period of 5-10 minutes) or at longer intervals (e.g., between 1, 2, 3, 4 or more hours, or even longer time periods as needed), with precise dosing regimens proportionate to the characteristics of the therapeutic agent.

[0620] The agents (i.e., the compounds described herein, together with one or more other agents) may be formulated together into a single dosage form, or alternatively, the individual agents may be formulated separately and presented together as a kit, optionally with their instructions for use.

[0621] Other uses The ANOSA compounds described in this article can also be used as cell culture additives to inhibit bacterial aminoacyl-tRNA synthetases (e.g., bacterial leucyl-tRNA synthetase, etc.).

[0622] The ANOSA compounds described herein can also be used as part of an in vitro assay, for example, to determine whether a candidate host may benefit from treatment with the compounds discussed.

[0623] The ANOSA compounds described herein can also be used, for example, as standards in assays to identify other active compounds, other bacterial aminoacyl-tRNA synthetase inhibitors, etc.

[0624] Reagent test kit One aspect of the invention relates to a kit comprising (a) an ANOSA compound as described herein, or a composition comprising an ANOSA compound as described herein, preferably provided, for example, in a suitable container and / or having suitable packaging; and (b) instructions for use, such as written instructions on how to administer the compound or composition.

[0625] The written instructions may also include a list of indications for which the active ingredient is suitable for treatment.

[0626] Application route ANOSA compounds or pharmaceutical compositions containing ANOSA compounds may be administered to subjects via any convenient route of administration, whether systemic / peripheral or local (i.e., at the desired site of action).

[0627] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, for example, by patches, plasters, etc.); transmucosal (including, for example, by patches, plasters, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or blowing therapy, using, for example, via aerosols, such as through the mouth or nose); rectal (e.g., by suppositories or enemas); vaginal (e.g., by vaginal suppositories); parenteral, such as by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, intracardiac, intrasheath, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intra-articular, subarachnoid, and intrasternal; and by implantation of, for example, subcutaneous or intramuscular storage devices or repositories.

[0628] Subject / Patient Subjects / patients may be chordates, vertebrates, mammals, placental mammals, marsupials (e.g., kangaroos, wombats), rodents (e.g., guinea pigs, hamsters, rats, mice), murines (e.g., mice), rabbits (e.g., rabbits), birds (e.g., birds), canines (e.g., dogs), felines (e.g., cats), equines (e.g., horses), pigs (e.g., domestic pigs), sheep (e.g., sheep), cattle (e.g., dairy cows), primates, apes (e.g., monkeys or apes), monkeys (e.g., marmosets, baboons), apes (e.g., gorillas, chimpanzees, orangutans, gibbons), or humans.

[0629] Furthermore, the subject / patient can be in any developmental stage, such as a fetus.

[0630] In a preferred embodiment, the subject / patient is a human.

[0631] preparation Although ANOSA compounds can be administered alone, they are preferably presented as pharmaceutical formulations (e.g., compositions, formulations, drugs) comprising at least one ANOSA compound as described herein, together with one or more other pharmaceutically acceptable ingredients known to those skilled in the art, including but not limited to pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, antioxidants, lubricants, stabilizers, solubilizers, surfactants (e.g., wetting agents), masking agents, colorants, flavoring agents, and sweeteners. The formulation may further comprise other active agents, such as other therapeutic or preventative agents.

[0632] Therefore, the present invention further provides pharmaceutical compositions as defined above, and methods for preparing pharmaceutical compositions, the method comprising mixing at least one ANOSA compound as described herein with one or more other pharmaceutically acceptable ingredients known to those skilled in the art, such as carriers, diluents, excipients, etc. If formulated as discrete units (e.g., tablets, etc.), each unit contains a predetermined amount (dosage) of the compound.

[0633] As used herein, the term "pharmaceutically acceptable" refers to compounds, ingredients, materials, compositions, dosage forms, etc., that are suitable for use in contact with the tissues of the subjects in question (e.g., humans) to the extent of reasonable medical judgment without excessive toxicity, irritation, allergic reactions, or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio. Each carrier, diluent, excipient, etc., must also be "acceptable" in the sense of compatibility with other components of the formulation.

[0634] Suitable carriers, diluents, excipients, etc., can be found in standard drug catalogs, for example... Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, Pa., 1990; and Handbook of Pharmaceutical Excipients , 5th edition, 2005.

[0635] Formulations can be prepared by any method well known in the pharmaceutical field. Such methods involve the step of associating a compound with a carrier that constitutes one or more auxiliary components. Generally, formulations are prepared by homogeneously and tightly associating a compound with a carrier (e.g., a liquid carrier, a finely divided solid carrier, etc.), and then shaping the product if necessary.

[0636] Formulations can be prepared to provide rapid or slow release; immediate, delayed, timed or sustained release; or combinations thereof.

[0637] The formulation may suitably be in the form of a liquid, solution (e.g., aqueous, non-aqueous), suspension (e.g., aqueous, non-aqueous), emulsion (e.g., oil-in-water, water-in-oil), elixir, syrup, medicated sugar, mouthwash, drops, tablet (including, for example, coated tablets), granules, powder, lozenges, tablets, capsules (including, for example, hard and soft gelatin capsules), flat capsules, pills, ampoules, large pills, suppositories, vaginal suppositories, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, mists, or aerosols.

[0638] The formulation may be suitably provided as a patch, adhesive tape, bandage, dressing, etc., impregnated with one or more compounds and optionally one or more other pharmaceutically acceptable ingredients, including, for example, penetration, permeation, and absorption enhancers. The formulation may also be suitably provided in the form of a storage or stock.

[0639] The compound can be dissolved, suspended in, or mixed with one or more other pharmaceutically acceptable ingredients. The compound can be present in liposomes or other microparticles designed to target the compound to, for example, blood components or one or more organs.

[0640] Preparations suitable for oral administration (e.g., by ingestion) include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, pharmaceutical sugars, tablets, granules, powders, capsules, flat capsules, pills, ampoules, and large pills.

[0641] Suitable buccal formulations include mouthwashes, lozenges, tablets, patches, adhesive tapes, storage containers, and storage containers. Lozenges typically contain compounds in a flavoring matrix (usually sucrose and gum arabic or astragalus gum). Tablets typically contain compounds in an inert matrix such as gelatin and glycerin or sucrose and gum arabic. Mouthwashes typically contain compounds in a suitable liquid carrier.

[0642] Preparations suitable for sublingual administration include tablets, lozenges, tablets, capsules, and pills.

[0643] Preparations suitable for oral administration via mucosal application include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), mouthwashes, lozenges, tablets, as well as patches, adhesive tapes, storage products, and storage products.

[0644] Preparations suitable for non-oral administration via mucosal application include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), suppositories, vaginal suppositories, gels, pastes, ointments, creams, lotions, oils, as well as patches, adhesive tapes, storage products, and storage products.

[0645] Preparations suitable for transdermal application include gels, pastes, ointments, creams, lotions, and oils, as well as patches, adhesive tapes, bandages, dressings, storage products, and storage products.

[0646] Tablets can be produced by conventional methods, such as compression or molding, optionally with one or more excipients. Compressed tablets can be prepared by compressing a compound in a free-flowing form (such as powder or granules) in a suitable machine, said compound optionally mixed with: one or more binders (e.g., povidone, gelatin, gum arabic, sorbitol, astragalus gum, hydroxypropyl methylcellulose); fillers or diluents (e.g., lactose, microcrystalline cellulose, dicalcium phosphate); lubricants (e.g., magnesium stearate, talc, silica); disintegrants (e.g., sodium starch glycolate, crospovidone, crospovidone carboxymethyl cellulose); surfactants or dispersants or wetting agents (e.g., sodium lauryl sulfate); preservatives (e.g., methylparaben, propylparaben, sorbic acid); flavoring agents, taste enhancers, and sweeteners. Molded tablets can be prepared by molding a mixture of powdered compounds wetted with an inert liquid diluent in a suitable machine. The tablets may optionally be coated or scored and may be formulated to provide a slow or controlled release of the compounds therein, using, for example, different proportions of hydroxypropyl methylcellulose to provide the desired release profile. The tablets may optionally have a coating, such as an enteric coating, to influence release, to provide release in the intestinal portion other than the stomach.

[0647] Ointments are typically prepared from compounds and paraffin or water-miscible ointment bases.

[0648] Creams are typically prepared from a compound and an oil-in-water cream base. If desired, the aqueous phase of the cream base may contain, for example, at least about 30% w / w polyols, i.e., alcohols having two or more hydroxyl groups, such as propylene glycol, 1,3-butanediol, mannitol, sorbitol, glycerin, and polyethylene glycol, and mixtures thereof. Topical formulations may desirably include compounds that enhance the absorption or penetration of the compound through the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogues.

[0649] Emulsions are typically prepared from compounds and an oil phase, which optionally contains only an emulsifier (also called an emulsion), or may contain at least one emulsifier with fats or oils, or a mixture of both. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. Oils and fats are also preferably included. In summary, emulsifiers with or without stabilizers constitute so-called emulsified waxes, and the waxes, together with oils and / or fats, constitute a so-called emulsified ointment matrix, which forms the oily dispersed phase of a cream formulation.

[0650] Suitable emulsifiers and emulsion stabilizers include Tween 60, Span 80, cetearyl alcohol, myristicin, monostearate, and sodium lauryl sulfate. The choice of suitable oil or fat for the formulation is based on achieving the desired cosmetic properties, as the solubility of compounds in most oils suitable for pharmaceutical emulsion formulations can be very low. Therefore, the cream should preferably be a non-greasy, non-staining, and washable product with a suitable consistency to prevent leakage from tubes or other containers. Straight-chain or branched, mono- or dialkyl esters can be used, such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, or blends of branched esters known as Crodamol CAP, with the last three being preferred esters. Depending on the desired properties, these substances can be used alone or in combination. Alternatively, high-melting-point lipids such as nephrite and / or liquid paraffin or other mineral oils can be used.

[0651] Suitable intranasal formulations with a liquid carrier include, for example, nasal sprays, nasal drops, or aerosols administered via a nebulizer, including aqueous or oil solutions of the compound.

[0652] When the carrier is solid, formulations suitable for intranasal administration include, for example, those presented as coarse powder having a particle size in the range of, for example, about 20 micrometers to about 500 micrometers, which are administered by nasal inhalation, i.e., rapidly inhaled through the nasal cavity from a powder container near the nose.

[0653] Formulations suitable for pulmonary administration (e.g., by inhalation or inhalation therapy) include those presented as aerosol sprays from pressurized packages, using suitable propellants such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gases.

[0654] Formulations suitable for ocular administration include eye drops, in which the compound is dissolved or suspended in a suitable carrier, particularly an aqueous solvent of the compound.

[0655] Preparations suitable for rectal administration may be presented as suppositories with a suitable matrix comprising, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, such as cocoa butter or salicylates; or as solutions or suspensions for enema treatment.

[0656] Preparations suitable for vaginal administration may be presented as vaginal suppositories, tampons, creams, gels, pastes, foams or sprays, and in addition to the active compound, contain a suitable carrier as known in the art.

[0657] Formulations suitable for parenteral administration (e.g., by injection) include aqueous or non-aqueous, isotonic, pyrogen-free, sterile liquids (e.g., solutions, suspensions) in which the compound is dissolved, suspended, or otherwise provided (e.g., in liposomes or other microparticles). Such liquids may additionally contain other pharmaceutically acceptable ingredients, such as antioxidants, buffers, preservatives, stabilizers, antibacterial agents, suspending agents, thickeners, and solutes that make the formulation isotonic with the intended recipient's blood (or other relevant bodily fluids). Examples of excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, etc. Examples of isotonic carriers suitable for use in such formulations include sodium chloride injection, Ringer's solution, or lactated Ringer's injection. Typically, the concentration of the compound in the liquid is from about 1 ng / mL to about 10 μg / mL, for example, from about 10 ng / mL to about 1 μg / mL. Formulations can be presented in single-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored under lyophilized (freeze-dried) conditions, requiring only the addition of a sterile liquid carrier, such as water for injection, just before use. Temporary injectable solutions and suspensions can be prepared from sterile powders, granules, and tablets.

[0658] dose Those skilled in the art will understand that the appropriate dosage of ANOSA compounds and compositions containing ANOSA compounds can vary from patient to patient. Determining the optimal dosage will generally involve balancing the level of therapeutic benefit with any risks or adverse side effects. The selected dosage level will depend on a variety of factors, including but not limited to the activity of the specific ANOSA compound, route of administration, time of administration, excretion rate of the ANOSA compound, duration of treatment, other drugs, compounds and / or materials used in combination, severity of the condition, and the patient's species, sex, age, weight, disease, general health condition, and medical history. The amount and route of administration of the ANOSA compound will ultimately be determined by a physician, veterinarian, or clinician, but generally a dosage will be chosen to achieve a local concentration at the site of action to achieve the desired effect without causing substantial or harmful side effects.

[0659] Throughout the treatment, a single dose may be administered continuously or intermittently (e.g., divided into doses at appropriate time intervals). Methods for determining the most effective manner of administration and dosage are well known to those skilled in the art and will vary depending on the formulation used for treatment, the purpose of treatment, the target cells being treated, and the subject being treated. Single or multiple administrations may be performed according to the dosage level and pattern selected by the treating physician, veterinarian, or clinician.

[0660] Typically, the appropriate dose of an ANOSA compound is in the range of approximately 0.1 mg to approximately 5000 mg per kilogram of body weight per day (more typically approximately 10 mg to approximately 3000 mg). When the compound is a salt, ester, amide, prodrug, etc., the dosage is calculated based on the parent compound, and therefore the actual weight to be used is increased proportionally.

[0661] General Chemical Synthesis The chemical synthesis methods for ANOSA compounds are described herein and can be prepared using techniques known in the art. These and / or other well-known methods can be modified and / or adapted to facilitate the synthesis of other compounds described herein.

[0662] In the following general scheme, when specific reaction conditions such as temperature, reaction duration, acid, base, reagent, solvent, and coupling agent are mentioned, it should be understood that other reaction conditions such as temperature, reaction duration, acid, base, reagent, solvent, and coupling agent may also be used, and therefore these conditions are also included within the scope of this disclosure.

[0663] General Scheme 1 The scheme shown in the figure above illustrates one of several possible methods for synthesizing the acylated sulfonylimide amide derivative of formula (D). The desired sulfonylimide amide derivative (A) was prepared using a procedure that is part of an earlier patent disclosure published by Edmund et al. in 2021.

[0664] By using this method, a suitable sulfonylimide amide of formula (A) reacts with an acid or its activated form of formula (B) in the presence of a base and an acid activator known in the art to give an acylated sulfonylimide amide of formula (C). If desired, the individual stereoisomers (enantiomers and diastereomers) of the derivative of formula (C) can be separated by applying suitable separation methods known in the art. The product (C) or its isomers can be deprotected using TFA or HCl to give the acylsulfonylimide amide derivative of formula (D).

[0665] General Scheme 1.2 General Option 2 Synthesis of 2,2,2-trifluoroacetate of 4-chlorothiophene-2-sulfonylimide amide, Int-B-4.23 Step 1: Dissolve 4-chlorothiophene-2-sulfonamide, Int-B-2.23 (2.0 g, 10.1 mmol, 1 equivalent) in anhydrous THF (150 mL). Cool the solution to 0 °C, slowly add 60% NaH (1.21 g, 30.4 mmol, 3 equivalent), and stir the mixture at room temperature for 30 min. Then, add TBDMS-Cl (1.83 g, 12.1 mmol, 1.2 equivalent), and stir the mixture at room temperature until complete (8–16 h). After completion, slightly evaporate the mixture; add water and extract three times with EtOAc. Wash the combined organic phases with brine and dry with anhydrous Na2SO4. After solvent evaporation, use the crude TBS protected product Int-B-3.23 for the next step.

[0666] Step 2: Under an Ar atmosphere, triethylamine (2.81 mL, 20.2 mmol, 2 equivalents) was added to a stirred suspension of Ph3PCl2 (5.05 g, 15.2 mmol, 1.5 equivalents) in anhydrous CHCl3 (20 mL). The mixture was stirred for 10 min, and then a suspension of Int-B-3.23 (10.1 mmol, 1 equivalent) in anhydrous CHCl3 (10 mL) was added to the reaction mixture at 0 °C. The mixture was stirred at 0 °C for 30 min (a clear solution formed after about 5 min), and then the reaction mixture was cooled to -78 °C and bubbled with gaseous NH3 at -78 °C for 5 min. The mixture was stirred at -78 °C for 30 min, and then heated to room temperature. The solvent, excess NH3, and Et3N were removed under reduced pressure to obtain a crude residue, which was dissolved in acetonitrile (about 10 mL) and cooled to 0 °C. 2,2,2-Trifluoroacetic acid (4.65 mL, 60.7 mmol, 6 equivalents) was added, and the mixture was stirred at room temperature for 5 min to 1 h (conversion determined by UPLC / MS). The solvent was removed under reduced pressure to obtain an oily residue, which was purified by reversed-phase chromatography (C18 silica, gradient 98% to 0%: 0.01% TFA in H2O / ACN) and direct-phase chromatography (EtOAc: PE = 1:1) to obtain 1.8 g (57%) of pure Int-B-4.23 as a white solid.

[0667] Prepare the following intermediates in Table 1 according to the procedure described in Int-B-4.23:

[0668] synthesis(( S )-1-((( S )-Amino(3-chlorophenyl)(oxo)-λ 6 -thionyl)amino)-4-methyl-1-oxo tert-butyl pentyl-2-yl)carbamate Int-A-4,3-Fr-1 and (( S )-1-((( R )-Amino(3-chlorophenyl)(oxo)-λ 6 -Asia (thioalkyl)amino)-4-methyl-1-oxopent-2-yl)carbamic acid Uncle Butyl ester Int-A-4.3-Fr-2 Dissolve 3-chlorobenzenesulfonylimide amide 2,2,2-trifluoroacetate Int-A-3.3 (780 mg, 2.6 mmol, 1 equivalent) in anhydrous DMF (15 mL). Cool the solution to 0 °C and slowly add 60% NaH (307.2 mg, 7.7 mmol, 3 equivalents). Stir the mixture for 10–15 min, then add… N -Boc- L-Leucine-OSu (840.6 mg, 2.6 mmol, 1 equivalent) was added and the mixture was stirred at room temperature until complete (8–16 h). After completion, the mixture was quenched with water and extracted three times with EtOAc. The combined organic phases were washed with brine and dried over anhydrous Na2SO4. After solvent evaporation, the crude residue was purified by column chromatography (EtOAc:PE 1:2 to EtOAc) or reversed-phase chromatography (C18 silica, gradient 98% to 0%: H2O / ACN) to obtain 550 mg (53%) of rac-Int-A-4.3 in the form of a mixture of two diastereomers. The diastereomers were separated using chiral preparative HPLC: CHIRALPAK IC (250 x 30 mm, 5 μm), mobile phase: heptane-IPA-DCM (65-15-20), flow rate: 20 mL / min, yielding 254 mg of [the product / product / concentration]. S,S- Isomer (Int-A-4.3-Fr-1), retention time: 13.3 min; and 263 mg S,R- Isomer (Int-A-4.3-Fr-2), retention time: 37.3 min.

[0669] Prepare the following intermediates in Table 2 according to the procedures described in Int-A-4.3-Fr-1 and Int-A-4.3-Fr-2:

[0670] synthesis(( S )-1-((( S )-(4-chlorothiophene-2-yl)(oxo)(ureo)-λ 6 -thionyl)amino)-4-methyl 1-O-1-oxopentan-2-yl)carbamic acid Uncle Triethylamine butyl acetate Int-C-6.0-2 Triethylamine (0.27 mL, 1.9 mmol, 4 equivalents) and TMSNCO (0.13 mL, 0.97 mmol, 2 equivalents) were added to a solution of Int-B-5.23-Fr-2 (200 mg, 0.48 mmol, 1 equivalent) in dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 5 h. Incomplete conversion of Int-B-5.23-Fr-2 was detected by UPLC / MS. A second portion of triethylamine (0.27 mL, 1.9 mmol, 4 equivalents) and TMSNCO (0.13 mL, 0.97 mmol, 2 equivalents) was added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with MeOH (0.5 mL), and the solvent was removed under reduced pressure. The crude residue was purified by reversed-phase chromatography (C18 silica, gradient 98% to 0%: H2O / ACN) to obtain 195 mg (72%) of Int-C-6.0-2 as a white amorphous solid.

[0671] Prepare the following intermediates in Table 3 according to the procedure described in Int-C-6.0-2:

[0672] synthesis(( S )-1-((( R )-(4-chlorothiophene-2-yl)(3-ethylureo)(oxo)-λ 6 -thionyl)amino)- 4-Methyl-1-oxopent-2-yl)carbamic acid Uncle Triethylamine butyl acetate Int-C-6.7-1 Triethylamine (0.14 mL, 0.98 mmol, 4 equivalents) and EtNCO (0.040 mL, 0.49 mmol, 2 equivalents) were added to a solution of Int-B-5.23-Fr-1 (100 mg, 0.24 mmol, 1 equivalent) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with MeOH (0.5 mL), and the solvent was removed under reduced pressure. The crude residue was purified by reversed-phase chromatography (C18 silica, gradient 98% to 0%: H2O / ACN) to give 82 mg (70%) of Int-C-6.7-1 as a colorless oil.

[0673] Prepare the following intermediates in Table 4 according to the procedure described in Int-C-6.7-1:

[0674] synthesis(( S )-1-((( R )-acetamido(3-chlorophenyl)(oxo)-λ 6 -thionyl)amino)-4-methyl-1- oxopent-2-yl)carbamate Uncle Butyl ester Int-D-6.0-1 60% NaH (70 mg, 1.7 mmol, 3 equivalents) was slowly added to a solution of Int-A-4.3-Fr-1 (236 mg, 0.58 mmol, 1 equivalent) in THF (10 mL). Acetyl chloride (0.06 mL, 0.87 mmol, 1.5 equivalents) was then added, and the reaction mixture was stirred at room temperature for 1 h, followed by quenching with MeOH (0.5 mL). The solvent was removed under reduced pressure. The crude residue was purified by reversed-phase chromatography (C18 silica, gradient 98% to 0%: H2O / ACN) to obtain 211 mg (81%) of Int-D-6.0-1 as a colorless oil.

[0675] Prepare the following intermediates in Table 5 according to the procedure described in Int-D-6.0-1:

[0676] synthesis(( S )-1-((( R )-(4-chlorothiophene-2-yl)(oxo)(5-((3a) S 4 S ,6a R )-2-oxohexahydro-1H- Thiophene[3,4-d]imidazol-4-yl)pentamido)-λ 6 -Thionyl)amino)-4-methyl-1-oxopent-2-yl)amino Formic acid Uncle Butyl ester Int-D-6.1-1 Add EDCI to a stirred solution of acid Int-X1 (48.5 mg, 0.20 mmol, 1 equivalent) in DMF (20 mL). . HCl (45.6 mg, 0.24 mmol, 1.2 equivalents) and HOBT (29.5 mg, 0.22 mmol, 1.1 equivalents) were added, followed by the addition of Int-B-5.23-Fr-1 (81.3 mg, 0.20 mmol, 1 equivalent). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure, and the residue was purified by reversed-phase chromatography (C18 silica, gradient 98% to 0%: H2O / ACN) to give 63 mg (50%) of Int-D-6.1-1 as a colorless oil.

[0677] Prepare the following intermediates in Table 6 according to the procedure described in Int-D-6.1-1:

[0678] synthesis( S )-2-amino- N -(( S )-(4-chlorothiophene-2-yl)(oxo)(ureo)-λ 6 -thionyl)-4-methyl 2,2,2-Trifluoroacetate of pentylamide ANOSA-003-2 TFA (0.4 mL, approximately 10 eq) was added to a solution of Int-C-6.0-2 (195 mg, 0.35 mmol, 1 equivalent) in DCM (15 mL), and the mixture was stirred at room temperature for 30 min to 2 h (conversion determined by UPLC / MS). After complete conversion of the starting material, the reaction mixture was concentrated under reduced pressure, and the product was purified by reversed-phase chromatography (C18 silica, gradient 98% to 0%: 0.01% TFA in H2O / ACN) to obtain 87 mg (53%) of ANOSA-003-2 as a white amorphous solid.

[0679] Prepare the following intermediates listed in Table 7 according to the procedure described in ANOSA-003-2:

[0680] synthesis( S )- N -(( S )-acetamido(3-chlorophenyl)(oxo)-λ 6 (-thionyl)-2-amino-4-methylpentane Amide ANOSA-004-2 TFA (0.2 mL, approximately 10 eq) was added to a solution of Int-D-6.0-2 (287 mg, 0.64 mmol, 1 equivalent) in DCM (15 mL), and the mixture was stirred at room temperature for 30 min to 2 h (conversion determined by UPLC / MS). After complete conversion of the starting material, the reaction mixture was concentrated under reduced pressure, and the product was purified by reversed-phase chromatography (C18 silica, gradient 98% to 0%: H2O / ACN) to obtain 138 mg (62%) of ANOSA-004-2 as a white amorphous solid.

[0681] Note: Using a gradient of 98% to 0%: 0.01% TFA in H2O / ACN yields the final product in the form of TFA salt.

[0682] Prepare the following intermediates in Table 8 according to the procedure described in ANOSA-004-2:

[0683] Synthesis of 2-(4-acetamidophenyl)acetic acid (Int-W1) Acetic anhydride (0.74 g, 7.27 mmol) was added to a solution of 2-(4-aminophenyl)acetic acid (0.50 g, 3.30 mmol) in acetonitrile (8.0 mL), and the reaction mixture was stirred at room temperature for 8 h. After the reaction was indicated by TLC to be complete, the reaction mixture was concentrated under vacuum. The crude product was purified by column chromatography (82% ethyl acetate / hexane) to give the title compound (0.32 g, 50.07%) as a white solid. LCMS ESI (m / z): 194.0 (M+H). 1 H NMR (400 MHz, DMSO-d6) δ12.11 (s, 1H), 9.88 (s, 1H), 7.49 (d, J = 8.4 Hz, 2H), 7.15 (d,J = 8.4 Hz, 2H), 3.48 (s, 2H), 2.02 (s, 3H).

[0684] Synthesis of (R)-2,3-bis((tert-butoxycarbonyl)amino)propionic acid (Int-W2) At 0 °C, a solution of sodium hydroxide (0.12 g, 1.47 mmol) and (R)-3-amino-2-((tert-butoxycarbonyl)amino)propionic acid (0.20 g, 0.98 mmol) in water (1 mL) was added to Boc anhydride (0.32 g, 2.94 mmol) in 2 mL of 1,4-dioxane, and the reaction mixture was stirred at room temperature for 3 h. After TLC indicated the reaction was complete, the reaction mixture was diluted with 10% sodium hydroxide solution (10 mL) and washed with diethyl ether (3 x 10 mL). The aqueous layer was acidified to pH 2 with dilute HCl (10 mL) and extracted with diethyl ether (3 x 20 mL). The combined organic layers were washed with water (30 mL), dried over sodium sulfate, and concentrated under vacuum to give the title compound (0.25 g, 86.66%) as a white solid. LCMS ESI (m / z): 305.8, (M +1).

[0685] The following intermediates (Int-W3 to W5; in Synthesis Table 9) were prepared using a similar reaction scheme as shown in Int-W2:

[0686] Synthesis of (S)-3-((tert-butoxycarbonyl)amino)-2-((tert-butyldimethylsilyl)oxy)propionic acid (Int- W6) Step-1: Prepare it using similar reaction conditions as shown in Int-W2. LCMS ESI (m / z): 206.0 (M+1) Step 2: TEA (0.20 mL, 1.46 mmol) was added to a solution of (S)-3-((tert-butyloxycarbonyl)amino)-2-hydroxypropionic acid (0.10 g, 0.48 mmol) in THF (2 mL) at 0 °C and stirred for 30 min. TBDMS-Cl (0.11 g, 0.73 mmol) was added at 0 °C and the reaction mixture was stirred at 70 °C for 2 h. After TLC indicated the reaction was complete, the reaction mixture was poured into water and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over Na2SO4 and evaporated under vacuum to give the title compound, which was used directly in the next step (0.31 g crude product).

[0687] Synthesis of 2-(thiazol-2-yl)acetic acid (Int-W7) Step 1: NaBH4 (0.166 g, 4.41 mmol) was added to a solution of thiazolium-2-carboxaldehyde (1.0 g, 8.83 mmol) in MeOH (10.0 mL) at 0 °C, and the reaction mixture was stirred for another 30 min. After the reaction was indicated by TLC to be complete, the reaction mixture was poured into water and extracted with DCM (3 x 25 mL). The combined organic layers were dried over Na2SO4 and evaporated under vacuum to give the title compound (0.75 g, 74.25%) as a white solid. LCMS ESI (m / z): 116.34 (M+H).

[0688] Step 2: Thiazol-2-ylmethanol (0.5 g, 4.34 mmol) was added to a solution of thionyl chloride (0.63 mL, 8.68 mmol) in DCM (6 mL), and the reaction mixture was stirred at 40 °C for 1 h. The reaction mixture was cooled to room temperature and concentrated under vacuum to give the title compound (0.535 g, 92.08%) as a brown solid. It was immediately used for the next step without further purification. LCMS ESI (m / z): 134.2, 136.2 (M&M+2).

[0689] Step 3: 2-(chloromethyl)thiazole (0.4 g, 2.99 mmol) and trimethylcyanosilane (0.75 mL, 5.98 mmol) were added to TBAF solution (8.98 mL, 8.98 mmol, 1 M in THF), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated and treated with saturated sodium bicarbonate aqueous solution (10 mL). The product was extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, and evaporated under vacuum. The crude product was purified by column chromatography (35% ethyl acetate / hexane) to give the title compound (0.085 g, 22.91%) as a brown viscous solid. LCMS ESI (m / z): 125.2 (M+1).

[0690] Step 4: KOH (0.074 g, 1.32 mmol) was added to a solution of 2-(thiazolyl-2-yl)acetonitrile (0.055 g, 0.44 mmol) in dioxane:water (0.5:0.5 mL), and the reaction mixture was heated at 100 °C for 2 h. The reaction mixture was concentrated under vacuum and treated with water (10 mL). It was acidified with 1N HCl (pH ~2), the resulting solid was filtered, and washed with water and hexane. The solid was dried under vacuum to give the title compound (0.033 g, 52.38%) as a yellow solid. LCMSESI (m / z): 143.99 (M+1) Synthesis of 2-(3-acetamidophenyl)acetic acid (Int-W8) Step 1: Et3N (0.8 mL, 6.05 mmol) was added to a solution of methyl 2-(3-aminophenyl)acetate (0.50 g, 3.02 mmol) in THF (5.00 mL) at 0 °C, followed by the addition of acetyl chloride (0.28 mL, 3.93 mmol), and the mixture was stirred at room temperature for 1 h. After the reaction was indicated by TLC to be complete, the reaction mixture was concentrated under vacuum to give the title compound (0.6 g, 95.66%) as a viscous solid. LCMS ESI (m / z): 208.28 (M+1).

[0691] Step 2: LiOH·H2O (0.06 g, 1.44 mmol) was added to a solution of 2-(3-acetamidophenyl) acetate (0.6 g, 0.28 mmol) in EtOH:H2O (0.5:0.2 mL), and the mixture was stirred at 60 °C for 2 h. After the reaction was indicated by TLC to be complete, the reaction mixture was concentrated and then poured into a 1 N HCl aqueous solution (pH ~4). The product was extracted with ethyl acetate (2 x 30 mL). The combined organic layers were dried over Na2SO4 and evaporated under vacuum to give the title compound (0.23 g, 41.11%) as a white solid. LCMS ESI (m / z): 194.23 (M+H).

[0692] Synthesis of ((S)-1-(((S)-amino(5-chlorothiophene-3-yl)(oxo)-λ6-thionyl)amino)-4-methyl- 1-Oxopent-2-yl)tert-butyl carbamate &((S)-1-(((R)-amino(5-chlorothiophene-3-yl)(oxo)-λ6-thione 4-Methyl-1-oxopent-2-yl)carbamate tert-butyl ester (Int-B-5.52-Fr-1 & Int-B-5.52-Fr-2) Step 1: NCS (17.52 g, 131.43 mmol) was added to a solution of 2,3-dibromothiophene (30 g, 124.48 mmol) in AcOH (300 mL) at room temperature and stirred at 110 °C for 2 h. After TLC indicated the reaction was complete, the reaction mixture was poured into an aqueous sodium hydroxide solution and extracted with ethyl acetate (3 x 500 mL). The combined organic layers were dried over Na₂SO₄ and evaporated under vacuum (47.5 g crude product). ¹H NMR (400 MHz, CDCl₃) δ 6.79 (s, ¹H).

[0693] Step 2: Zinc powder (55.35 g, 846.00 mmol) was added to a stirred solution of 2,3-dibromo-5-chlorothiophene (Int-B-2.12-A1) (47.5 g, 172.10 mmol) in AcOH (375 mL) at room temperature and stirred at 110 °C for 16 h. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth. The filtrate was poured into a saturated sodium bicarbonate solution and extracted with ethyl acetate (3 x 500 mL). The combined organic layers were dried over Na2SO4 and evaporated under vacuum. The crude product was used for the next step (28 g, crude product). ¹H NMR (400 MHz, CDCl3) δ 7.04 (d, J = 1.6, 1H), 6.87 (d, J = 1.2, 1H).

[0694] Step 3: Add benzyl mercaptan (1.1 mL, 10.12 mmol) and DIPEA (3.49 mL, 20.20 mmol) to a stirred solution of 4-bromo-2-chlorothiophene (Int-B-2.12-A2) (2.0 g, 10.12 mmol) in dioxane (20 mL). Purge the reaction mixture with N2 for 30 min. Add Xantphos (0.59 g, 1.01 mmol) and Pd2dba3 (0.46 g, 0.50 mmol) to the reaction mixture and heat at 120 °C for 16 h. After TLC indicated the reaction was complete, filter the reaction mixture through diatomaceous earth. Pour the filtrate into water and extract with ethyl acetate (3 x 100 mL). Dry the combined organic layers with Na2SO4 and evaporate under vacuum. The crude product was purified by silica gel column chromatography (0.4% ethyl acetate / hexane) to give 4-(benzylthio)-2-chlorothiophene (1.7 g, 70.83%). ¹H NMR (400 MHz, CDCl₃), δ 7.31–7.22 (m, 5H), 6.83 (d, J = 1.2, 1H), 6.77 (d, J = 1.6, 1H).

[0695] Step 4: N-chlorosuccinimide (2.82 g, 21.25 mmol) was added to a stirred solution of 4-(benzylthio)-2-chlorothiophene (Int-B-2.12-A3) (1.7 g, 7.06 mmol) in acetic acid (34 mL)-water (3.4 mL) and stirred at room temperature for 1 h. After the reaction was indicated by TLC to be complete, the reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and evaporated under vacuum. The crude product was used for the next step (2.5 g crude product).

[0696] Step 5: Ammonia gas was blown into THF (10 mL) at -78°C and added to a solution of 5-chlorothiophene-3-sulfonyl chloride (Int-B-2.12-A4) (2.5 g, 10.41 mmol) in THF (15 mL). The reaction mixture was stirred for another 30 min. After TLC indicated the reaction was complete, the reaction mixture was allowed to reach room temperature and evaporated under vacuum. The crude product was purified by silica gel column chromatography (35% ethyl acetate / hexane) to give 5-chlorothiophene-3-sulfonamide (1.0 g, 45.45%). LCMS ESI (m / z): 196.0 (M-1) Step 6: NaH (60% in mineral oil) (3.69 g, 92.33 mmol) was added to a solution of 5-chlorothiophene-3-sulfonamide (Int-B-2.12) (3.65 g, 18.46 mmol) in THF (50 mL) at 0 °C, and the mixture was stirred for another 1 h. TBDMS-Cl (5.56 g, 36.93 mmol) in THF (50 mL) was added, and the reaction mixture was stirred for 1 h. After TLC indicated the reaction was complete, the reaction mixture was poured into water (80 mL) and extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, and evaporated under vacuum to give N-(tert-butyldimethylsilyl)-5-chlorothiophene-3-sulfonamide (7.3 g crude product) as a colorless liquid.

[0697] Step 7: Add hexachloroethane (5.15 g, 21.83 mmol) to a solution of triphenylphosphine (5.2 g, 19.84 mmol) in chloroform (50 mL) and stir at 70 °C for 12 h. Add DIPEA (8.06 mL, 46.80 mmol) and stir further for 30 min. Add N-(tert-butyldimethylsilyl)-5-chlorothiophene-3-sulfonamide (7.3 g, 23.40 mmol) dropwise to a solution of N-chlorothiophene-3-sulfonamide (7.3 g, 23.40 mmol) in chloroform (7 mL) at 0 °C and stir the reaction mixture for 30 min. Purge the reaction mixture with ammonia for 30 min. After TLC indicates completion, pour the reaction mixture into water (120 mL) and extract with DCM (3 x 120 mL). Dry the combined organic layers with Na₂SO₄ and evaporate under vacuum. The crude product was purified by silica gel column chromatography (17% ethyl acetate / hexane) to obtain N-(tert-butyldimethylsilyl)-5-chlorothiophene-3-sulfonamide (2.8 g, 35.41% after two steps) as a white solid. LCMS ESI (m / z): 311.44, 313.46 (M&M+2).

[0698] Step 8: 4M HCl (2 mL) in dioxane was added to a solution of N-(tert-butyldimethylsilyl)-5-chlorothiophene-3-sulfonamide (Int-B-3.12) (2.8 g, 9.00 mmol) in DCM (15 mL), and the mixture was stirred at room temperature for 1 h. After the reaction was complete, the reaction mixture was evaporated under vacuum and ground into a crude product with n-pentane and diethyl ether to give 5-chlorothiophene-3-sulfonamide hydrochloride as a white solid. LCMS ESI (m / z): 197.3, 199.3 (M&M+2). (2.4 g, quantitative).

[0699] Step 9: Add NaH (60% in mineral oil) (2.44 g, 61.22 mmol) to a solution of 5-chlorothiophene-3-sulfonamide hydrochloride (Int-B-4.12) (2.4 g, 12.24 mmol) in DMF (20 mL) and stir at 0 °C for 1 h. Add (tert-butoxycarbonyl)-L-leucine 2,5-dioxopyrrolidine-1-yl ester (4.42 g, 13.46 mmol) in DMF (10 mL) and stir the resulting reaction mixture at 0 °C for 1 h. After TLC indicated the reaction was complete, pour the reaction mixture into water (80 mL) and extract with ethyl acetate: THF (9:1) (3 x 80 mL). Dry the combined organic layers with Na₂SO₄ and evaporate under vacuum. The crude product was purified by silica gel column chromatography (27% ethyl acetate / hexane) to obtain Int-B-5.52 (2.6 g, 51.79%) as a yellow viscous solid. LCMS ESI (m / z): 410.6, 412.9 (M&M+2).

[0700] In addition, diastereomers were separated by chiral preparative HPLC (chiral preparative HPLC: CHIRAKPAK IA 250 x 5 mm 5 μm, mobile phase: A = liquid CO2, B = 0.1% DEA in IPA: MTBE (70:30), A:B = 70:30), yielding isomer-1 (Int-B-5.52-Fr-1): retention time: 7.20 min and isomer-2 (Int-B-5.52-Fr-2): retention time: 10.25 min.

[0701] Synthesis of ((S)-1-(((S)-amino(oxo)(thieno[3,2-b]thieno-3-yl)-λ6-thionyl)amine tert-butyl carbamate (S)-1-((R)-amino(oxo)(thieno[3,2-b]) Thiophene-3-yl)-λ6-thionyl)amino)-4-methyl-1-oxopent-2-yl)tert-butyl carbamate (Int-B-5.40-) Fr-1&Int-B-5.40-Fr-2) Step 1: Diisopropylaminolithium (2M in THF) (62 mL, 123.96 mmol) was added to a solution of 3,4-dibromothiophene (15 g, 62.00 mmol) in THF (150 mL) at -78 °C and stirred for 2 h at -78 °C. DMF (5.77 mL, 74.38 mmol) was added dropwise to the reaction mixture, and the mixture was stirred for another 1 h at room temperature. After the reaction was complete as indicated by TLC, the reaction mixture was poured into NH4Cl solution (500 mL) and extracted with ethyl acetate (500 mL). The organic layer was dried over Na2SO4 and evaporated under vacuum. The crude product was purified by silica gel column chromatography to give 3,4-dibromothiophene-2-carboxaldehyde (Int-Y4-A1) (11 g, 65%). 1H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.46 (s, 1H).

[0702] Step 2: Add ethyl mercaptoacetate (6 g, 48.88 mmol), potassium carbonate (17 g, 123.9 mmol), and 18-crown ether-6 (1 g, 4.03 mmol) to a solution of 3,4-dibromothiophene-2-carboxaldehyde (Int-Y4-A1) (11 g, 40.74 mmol) in DMF (110 mL). Heat the reaction mixture at 70 °C for 2 h. After the reaction is complete as indicated by LCMS, pour the reaction mixture into ice-cold water (200 mL). Filter the solid and wash with water. Dry the residue under vacuum to give 6-bromothiophene[3,2-b]thiophene-2-carboxylate (Int-Y4-A2) (12.5 g, quantified). 1H NMR (400 MHz, DMSO-d6) δ8.31 (s, 1H), 8.12 (s, 1H), 4.33 (q, J=7.1 Hz, 1H), 1.32 (t, J=6.8 Hz, 3H).

[0703] Step 3: Lithium hydroxide monohydrate (5.4 g, 129.26 mmol) was added to a solution of ethyl 6-bromothieno[3,2-b]thiophene-2-carboxylate (Int-Y4-A2) (12.5 g, 42.94 mmol) in THF:water (1:1) (120 mL), and the reaction mixture was heated at 70 °C for 3 h. After TLC indicated the reaction was complete, the reaction mixture was poured into water (200 mL) and acidified with 1N HCl (pH ~4). The resulting solid was filtered and dried under vacuum to give 6-bromothieno[3,2-b]thiophene-2-carboxylic acid (Int-Y4-A3) (8.6, 76%). ¹H NMR (400 MHz, DMSO-d6) δ 13.54 (s, 1H), 8.21 (s, 1H), 8.08 (s, 1H).

[0704] Step 4: Potassium carbonate (0.33 g, 2.45 mmol) and silver acetate (0.27 g, 1.63 mmol) were added to a degassed solution of 6-bromothieno[3,2-b]thiophene-2-carboxylic acid (Int-Y4-A3) (4.3 g, 16.34 mmol) in N-methyl-2-pyrrolidone (45 mL). The reaction mixture was heated at 120 °C for 3 h. After the reaction was indicated by TLC to be complete, the reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were washed with brine (4 x 200 mL), dried over Na2SO4, and evaporated under vacuum. The crude product was purified by silica gel column chromatography to give 3-bromothieno[3,2-b]thiophene (Int-Y4-A4) (3 g, 41.89%). 1H NMR (400 MHz, DMSO-d6) δ 7.82 (s, 1H), 7.79 (d, J=5.1 Hz, 1H), 7.56 (d, J=5.1 Hz, 1H).

[0705] Step 5: Add xantphos (0.95 g, 1.64 mmol), Pd2dba3 (0.75 g, 0.82 mmol), and benzyl mercaptan (2.04 g, 16.43 mmol) to a degassed solution of 3-bromothieno[3,2-b]thiophene (Int-Y4-A4) (3.6 g, 16.43 mmol) and DIPEA (4.25 g, 32.86 mmol) in dioxane (36 mL) and heat at 100 °C for 3 h. After TLC indicated the reaction was complete, filter the reaction mixture through diatomaceous earth and pour the filtrate into water (100 mL). Extract the product with ethyl acetate (2 x 100 mL). Wash the combined organic layers with brine (2 x 200 mL), dry to Na2SO4, and evaporate under vacuum. The crude product was subjected to silica gel column chromatography to give the title compound (Int-Y4-A5) (3.4 g, 78.86%). ¹H NMR (400 MHz, DMSO-d6) δ 7.71 (d, J=5.2, 1H), 7.53 (s, 1H), 7.46 (d, J=5.2 Hz, 1H), 7.29–7.21 (m, 5H), 4.23 (s, 2H) Step 6: N-chlorosuccinimide (5.18 g, 38.87 mmol) was added fractionally to a stirred solution of 3-(benzylthio)thieno[3,2-b]thiophene (Int-Y4-A5) (3.4 g, 12.95 mmol) in acetic acid (68 mL) and water (6.8 mL) at room temperature. The reaction mixture was stirred for 2 h. After the reaction was indicated by TLC to be complete, the reaction mixture was evaporated under vacuum and then partitioned between water (150 mL) and ethyl acetate (150 mL). The organic layer was washed with water (150 mL), dried over Na2SO4, and evaporated under vacuum. The crude product was purified by silica gel column chromatography to give the title compound (Int-Y4) (2.9 g, 93.75%).

[0706] Step 7: Thiophene[3,2-b]thiophene-3-sulfonyl chloride (Int-Y4) in 10 mL of THF was added to a freshly prepared saturated ammonia solution of THF (20 mL) at -78 °C. After the reaction was indicated by TLC, the reaction mixture was evaporated to dryness and the crude product was purified by silica gel column chromatography to give the title compound (Int-B-2.40) (2 g, 75%). LCMS ESI (m / z): 218.2 (MH).

[0707] Step 8: Thiophene[3,2-b]thiophene-3-sulfonamide (Int-B-2.40) (2.7 g, 12.31 mmol) and TEA (6.85 mL, 49.24 mmol) in THF (20 mL) solution was added to TBDMS-Cl (5.56 g, 36.93 mmol) in 7 mL of THF at 0 °C. The reaction mixture was stirred at 70 °C for 3 h. After the reaction was indicated by TLC to be complete, the reaction mixture was poured into water (150 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with brine, dried over Na2SO4 and evaporated under vacuum to give N-(tert-butyldimethylsilyl)thiophene[3,2-b]thiophene-3-sulfonamide (7.8 g crude).

[0708] Step 9: Add hexachloroethane (7.83 g, 33.16 mmol) to a solution of triphenylphosphine (7.91 g, 30.15 mmol) in chloroform (50 mL) and stir at 70 °C for 12 h to obtain fresh PPh3Cl2. Add DIPEA (6.87 mL, 40.2 mmol) and stir the reaction mixture for 30 min. Add dropwise a solution of N-(tert-butyldimethylsilyl)thiopheno[3,2-b]thiophene-3-sulfonamide (15.8 g, 50.64 mmol) in chloroform (10 mL) at 0 °C. Stir the resulting reaction mixture at 0 °C for 30 min. Blow ammonia gas at 0 °C for 30 min. After the reaction is complete as indicated by TLC, pour the reaction mixture into water (150 mL) and extract with DCM (3 x 150 mL). Dry the combined organic layers with Na2SO4 and evaporate under vacuum. The crude product was purified by silica gel column chromatography (17% ethyl acetate / hexane) to obtain N-(tert-butyldimethylsilyl)thieno[3,2-b]thieno-3-sulfonamide (Int-3.40) (1.0 g, 25 %). LCMS ESI (m / z): 333.5, 334.5 (M&M+2).

[0709] Step 10: A solution of N-(tert-butyldimethylsilyl)thieno[3,2-b]thieno-3-sulfonamide (Int-3.40) (1 g, 3.01 mmol) in 1,4-dioxane (2 mL) was added with 4 M HCl (2 mL) in dioxane and stirred at room temperature for 2 h. After the reaction was complete, the reaction mixture was evaporated under vacuum and ground with n-pentane and diethyl ether to give thieno[3,2-b]thieno-3-sulfonamide hydrochloride (Int-4.40) (0.91 g, quantitative). LCMS ESI (m / z): 219.2 (M +1).

[0710] Step 11: NaH (60% in mineral oil) (0.49 g, 12.36 mmol) was added to a solution of thieno[3,2-b]thiophene-3-sulfonamide hydrochloride (Int-4.40) (0.9 g, 4.12 mmol) in DMF (5 mL) and stirred at 0 °C for 30 min. A solution of (tert-butoxycarbonyl)-L-leucine 2,5-dioxopyrrolidine-1-yl ester (1.48 g, 4.53 mmol) in DMF (5 mL) was added to the reaction mixture and stirred for 2 h. After TLC indicated the reaction was complete, the reaction mixture was poured into water (60 mL) and extracted with ethyl acetate (3 x 60 mL). The combined organic layers were dried over Na₂SO₄ and evaporated under vacuum. The crude product was purified by silica gel column chromatography (38% ethyl acetate / hexane) to obtain Int-5.40 (0.88 g, 51.76%) as a yellow viscous solid. LCMS ESI (m / z): 432.8 (M+1).

[0711] In addition, diastereomers were separated by chiral preparative HPLC (YMC CHIRALART CELLULOSE-SC, 250 x 20 mm, S-5 μm, mobile phase: A = n-heptane, B = IPA: acetonitrile (70:30), A:B = 90:10) to obtain isomer-1 (Int-5.40-Fr-1): retention time: 8.90 min and isomer-2 (Int-5.40-Fr-2): retention time 23.76 min.

[0712] Synthesis of ((S)-1-(((R)-(4-chlorothiophene-2-yl)(oxo)(2-(thiophene-2-yl)acetamyl)-λ6-thionite Alkyl)amino)-4-methyl-1-oxopent-2-yl)tert-butyl carbamate &((S)-1-(((S)-(4-chlorothiophen-2-yl) (oxo)(2-(thiophen-2-yl)acetamyl)-λ6-thionyl)amino)-4-methyl-1-oxopent-2-yl)carbamic acid tert-butyl ester (Int-B-6.1-Fr-1 & Int-B-6.1-Fr-2) Step 1: EDC·HCl (0.20 g, 1.06 mmol) and DMAP (0.13 g, 1.06 mmol) were added to a solution of 2-(thiophene-2-yl)acetic acid (0.08 g, 0.56 mmol) in DCM (2.5 mL) at 0 °C and stirred for 10 min. Int-B-5.23 (0.23 g, 0.56 mmol) was added to the reaction mixture and stirred at room temperature for 1 h. After the reaction was indicated by TLC, the reaction mixture was poured into water (30 mL) and extracted with DCM (3 x 25 mL). The combined organic layers were dried over Na2SO4 and evaporated under vacuum. The crude product was purified by rapid column chromatography (20% MeOH / DCM) to give the title compound (0.18 g, 61.72%) in the form of a mixture of isomers.

[0713] In addition, diastereomers were separated by chiral preparative HPLC (column: CHIRALPAK IG 250X20 mm 5μm, mobile phase: A=liquid CO2, B=0.1% DEA in IPA:MTBE (70:30), A:B = 55:45) to obtain isomer-1 (Int-B-6.1-Fr-1): retention time: 1.91 min & isomer-2 (Int-B-6.1-Fr-2): retention time: 4.60 min.

[0714] The following intermediates were prepared using the precursors shown in Table 10 below, following the procedure described in Int-B-6.1. The isomers were separated by chiral preparative HPLC purification according to the specifications shown in the "Analytical Data" table for each intermediate:

[0715] Synthesis of ((R)-4-(((R)-N'-((tert-butoxycarbonyl)-L-leucine)-4-chlorothiophene)-2-sulfonylimide 4-oxobutane-1,3-dimethyl)dicarbamate di-tert-butyl ester (Int-B-) 6.29-Fr-1) DIPEA (0.16 mL, 0.94 mmol), EDC.HCl (0.20 g, 1.06 mmol), and HOBt (0.06 g, 0.47 mmol) were added to a solution of (R)-2,4-bis((tert-butoxycarbonyl)amino)butyric acid (Int-W3) (0.1 g, 0.31 mmol) in DMF (1 mL) and stirred for 15 min. Int-B-5.23-Fr-1 (0.13 g, 0.31 mmol) was added to the reaction mixture and stirred at room temperature for 4 h. After the reaction was indicated by TLC, the reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3 x 25 mL). The combined organic layers were dried over Na2SO4 and evaporated under vacuum. The crude product was purified by reversed-phase column chromatography (water:acetonitrile, 9:1) to give the title compound (0.1 g, 40.34%) as a viscous solid. LCMS ESI (m / z): 710.3, 712.2 (M&M+2).

[0716] The following intermediates were prepared using the precursors shown in Table 11 below, according to the procedure described in Int-B-6.29-Fr-1:

[0717] Synthesis of ((S)-1-(((R)-((R)-2-((tert-butoxycarbonyl)amino)-3-hydroxypropamido)(4-chlorothiophene- 2-yl)(oxo)-λ6-thionyl)amino)-4-methyl-1-oxopent-2-yl)carbamate tert-butyl ester (Int-B-6.38-) Fr-1) HATU (0.14 g, 0.36 mmol) and DIPEA (0.12 mL, 0.72 mmol) were added to a solution of (tert-butoxycarbonyl)-D-serine (0.07 g, 0.36 mmol) in DMF (0.5 mL) at 0 °C and stirred for 10 min. Int-B-5.23-Fr-1 (0.10 g, 0.24 mmol) was added to the reaction mixture and stirred further at room temperature for 2 h. After TLC indicated the completion of the reaction, the reaction mixture was poured into water (10 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were dried over Na2SO4 and evaporated under vacuum. The crude product was purified by column chromatography (30% MeOH / DCM) to give the title compound (0.09 g, 62.09%) as a white solid. LCMS ESI (m / z): 497.9 (M-Boc).

[0718] The following intermediates were prepared using the intermediates shown in Table 12 below, according to the procedure described in Int-B-6.38-Fr-1:

[0719] Synthesis of ((S)-1-(((R)-(4-chlorothiophene-2-yl)(2-(3,4-dihydroxyphenyl)acetamyl)(oxo)-λ 6-Thionyl)amino)-4-methyl-1-oxopent-2-yl)tert-butyl carbamate (Int-B-6,42-Fr-1) TEA (0.16 mL, 1.097 mmol) and Int-B-5.23-Fr-1 (0.15 g, 0.365 mmol) were added to a solution of 2-(3,4-dihydroxyphenyl)acetic acid (0.095 g, 0.548 mmol) in acetonitrile (3.0 mL) at 0 °C and stirred for 10 min. T3P (50% ethyl acetate solution) (0.46 mL, 0.731 mmol) was added to the reaction mixture, and the mixture was stirred further at room temperature for 1 h. After TLC indicated the reaction was complete, the reaction mixture was poured into water and extracted with DCM (3 x 25 mL). The combined organic layers were dried over Na2SO4 and evaporated under vacuum. The crude product was purified by column chromatography (6% MeOH / DCM) to give the title compound (0.035 g, 17.50%) as a grayish-white solid. LCMS ESI (m / z): 504.8 (M-56).

[0720] Synthesis of ((S)-1-(((R)-benzamido(4-chlorothiophene-2-yl)(oxo)-λ6-thionyl)amino)-4- methyl-1-oxopent-2-yl) tert-butyl carbamate & ((S)-1-(((S)-benzamido(4-chlorothiophene-2-yl)(oxy 4-methyl-1-oxopent-2-yl)-λ6-thionyl)amino)-4-methyl-1-oxopent-2-yl)tert-butyl carbamate (Int-B-6,43-Fr-1& Int-B-6.43-Fr-2) NaH (60% mineral oil) (0.07 g, 1.82 mmol) was added to a solution of Int-B-5.23 (0.25 g, 0.60 mmol) in THF (1.5 mL) at 0 °C and stirred for 10 min. Then, benzoyl chloride (0.13 g, 0.91 mmol) in THF (1 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. After TLC indicated the reaction was complete, the reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over Na₂SO₄ and evaporated under vacuum. The crude product was purified by column chromatography (5% MeOH / DCM) to give a mixture of isomers (0.27 g, 86.26%). LCMS ESI (m / z): 514.3, 516.3 (M&M+2).

[0721] In addition, diastereomers were separated by chiral preparative HPLC (column: CHIRALPAK IG 250X20 mm 5μm, mobile phase: A=liquid CO2, B=0.1% DEA in IPA:MTBE (70:30), A:B = 60:40), yielding isomer-1 (Int-B-6.43-Fr-1): retention time: 1.91 min & isomer-2 (Int-B-6.43-Fr-2): retention time: 4.60 min.

[0722] Following the procedures described above for Int-B-6.43-Fr-1 and Fr-2, the following intermediates were prepared using the precursors shown in Table 13 below. The isomers were then separated by chiral preparative HPLC purification according to the specifications shown in the table:

[0723] Synthesis of ((S)-1-(((R)-acetamido(5-chlorothiophen-3-yl)(oxo)-λ6-thionyl)amino)-4-methyl tert-butyl carbamate (Int-B-6.48-Fr-1) TEA (0.06 mL, 0.45 mmol) was added to a solution of Int-B-5.52-Fr-1 (0.06 g, 0.15 mmol) in THF (1.0 mL) at 0 °C and stirred for 30 min. Acetic anhydride (0.01 mL, 0.10 mmol) was added, and the mixture was stirred for 1 hr at room temperature. After TLC indicated completion, the reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over Na₂SO₄ and evaporated under vacuum. The crude product was purified by reversed-phase column chromatography (water:acetonitrile, 8:2) to give the title compound as a white solid (0.045 g, 68.18%). LCMS ESI (m / z): 452.0, 454.1 (M&M+2). The following intermediates were prepared using the precursors shown in Table 14 below, according to the procedure described in Int-B-6.48-Fr-1:

[0724] Synthesis of ((S)-1-(((R)-(4-chlorocyclopentan-1,4-dien-1-yl)(oxo)(ureo)-λ6-thionyl)amine 4-Methyl-1-oxopentan-2-yl)carbamate tert-butyl ester (Int-B-6.50-Fr-1) TEA (0.30 mL, 2.19 mmol) was added to a solution of Int-B-5.52-Fr-1 (0.15 g, 0.36 mmol) in DCM (1.5 mL) at 0 °C and stirred for 30 min. TMS-NCO (0.14 mL, 1.09 mmol) was added to the reaction mixture and stirred at room temperature for 16 h. After TLC indicated completion, the reaction mixture was poured into water and extracted with DCM (3 x 10 mL). The combined organic layers were dried over Na₂SO₄ and evaporated under vacuum. The crude product was purified by reversed-phase chromatography (water:acetonitrile, 7:3) to give the title compound (0.10 g, 61.81%) as a white solid. LCMS ESI (m / z): 453.9, 455.0 (M&M+2) The following intermediates were prepared using the precursors shown in the following synthesis table 15, according to the procedure described in Int-B-6.50:

[0725] Synthesis of (2S)-N-(N-(L-leucyl)-5-chlorothiophene-3-sulfonyl)-2-amino-4-methylpentanamide Dihydrochloride (Int-B-6.52) 5-Chlorothiophene-3-sulfonamide hydrochloride (Int-B-4.12) (0.2 g, 1.01 mmol) was added to a suspension of 60% NaH (0.12 g, 3.0 mmol) in DMF (3.0 mL) at 0 °C and stirred for 1 h at the same temperature. (tert-Butoxycarbonyl)-L-leucine 2,5-dioxopyrrolidine-1-yl ester (0.66 g, 2.00 mmol) was added to the reaction mixture and stirred for 1 h at room temperature. After TLC indicated the reaction was complete, the reaction mixture was poured into water and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were dried over Na₂SO₄ and evaporated under vacuum. The crude product was purified by silica gel column chromatography (30% ethyl acetate / hexane) to give the title compound (0.15 g, 23.69%) as a white solid. LCMS ESI (m / z): 623.6, 625.5 (M&M+2).

[0726] Synthesis of (S)-2-amino-N-((R)-(2-amino-2-methylpropionamide)(4-chlorothiophene-2-yl)(oxo)-λ6- (thionyl)-4-methylpentanamide bis(2,2,2-trifluoroacetate) (ANOSA-041-1) & (S)-2-amino-N-((S)-(2- (amino-2-methylpropionamide)(4-chlorothiophene-2-yl)(oxo)-λ6-thionyl)-4-methylpentanamide bis(2,2,2-tri) Fluoroacetate (ANOSA-041-2) A solution of Int-B-6.6-Fr-1 (75 mg, 0.12 mmol) in 1,4-dioxane (1 mL) was added with 4 M HCl (1 mL) in dioxane, and the reaction mixture was stirred at room temperature for 2 h. After TLC indicated the completion of the reaction, the reaction mixture was concentrated under vacuum and then ground with n-pentane and diethyl ether to give the title compound in the form of hydrochloride, which was further purified by reversed-phase preparative HPLC (column: SUNFIRE Prep C18 OBD, 19 x 250 mm, 5 μm, mobile phase: A = 0.05% TFA aqueous solution, B = acetonitrile + 10% MTBE, A:B = 84:16) to give the title compound in the form of TFA salt (21 mg, 28.47%).

[0727] ¹H NMR (400 MHz, DMSO-d⁶) δ 7.89 (br s, 6H), 7.77 (s, 1H), 7.47 (d, J = 1.2 Hz, 1H), 3.55–3.52 (m, 1H), 1.76–1.73 (m, 1H), 1.64–1.60 (m, 1H), 1.48–1.42 (m, 1H), 1.34 (d, J = 5.6 Hz, 6H), 0.86 (d, J = 6.4 Hz, 6H). LCMS: 395.8, 397.8 (M&M+2). Purity at 210 nm: 95.76%. Similarly, treating Int-B-6.6-Fr-2 with 4N HCl as a deprotecting agent yielded ANOSA-041-2.

[0728] ¹H NMR (400 MHz, DMSO-d⁶) δ 7.91 (br s, 3H), 7.85 (br s, 3H), 7.76 (d, J = 1.6 Hz, 1H), 7.46 (s, 1H), 3.54 (br s, 1H), 1.76–1.71 (m, 1H), 1.68–1.61 (m, 1H), 1.51–1.46 (m, 1H), 1.35 (s, 3H), 1.33 (s, 3H), 0.87 (t, J = 6.0 Hz, 6H). LCMS: 395.8, 397.8 (M&M+2). Purity at 210 nm: 100.0%. Synthesis of (S)-2-amino-N-((R)-(4-chlorothiophene-2-yl)(oxo)(2-(thiophene-2-yl)acetamido)-λ 6-Thionyl)-4-methylpentanamide hydrochloride &(S)-2-amino-N-((S)-(4-chlorothiophene-2-yl)(oxo)(2-(thiophene-2-yl)(oxo)(thiophene-2-yl)(oxo) Pheno-2-yl)acetamyl)-λ6-thionyl)-4-methylpentanamide hydrochloride (ANOSA-029-1 & ANOSA-029-2) A solution of Int-B-6.1-Fr-1 (0.08 g, 0.14 mmol) in 1,4-dioxane (1 mL) was added with 4 M HCl (1 mL) in dioxane and stirred at room temperature for 1 h. After the reaction was indicated by TLC, the reaction mixture was concentrated under reduced pressure and then ground with n-pentane and diethyl ether to give the title compound as a white solid, which was further purified by reversed-phase preparative HPLC (column: SUNFIRE Prep C18 OBD, 19 x 250 mm, 5 μm, mobile phase: A = 0.01% HCl aqueous solution, B = acetonitrile, A:B = 62:38) to give the title compound in hydrochloride form (12 mg, 18.46%).

[0729] 1H NMR (400 MHz, DMSO-d6) δ 7.90 (br s, 3H), 7.79 (d, J = 1.2 Hz,1H), 7.47 (d, J = 1.2 Hz, 1H), 7.32 (d, J = 5.2 Hz, 1H), 6.92 – 6.90 (m, 1H),6.85 (s, 1H), 3.65 (s, 2H),3.52-3.50(m, 1H), 1.77-1.73 (m, 1H), 1.67-1.62 (m,1H), 1.48-1.43 (m, 1H), 0.88-086 (dd, J = 6.4, 2.0 Hz, 6H). LCMS: 434.8, 436.8(M+, M+1).

[0730] Similarly, Int-B-6.1-Fr-2 was reacted with 4M HCl in dioxane, followed by reversed-phase preparative HPLC (column: SUNFIRE Prep C18 OBD, 19 x 250 mm, 5 μm; mobile phase: A = 0.01% HCl aqueous solution, B = acetonitrile, A:B = 62:38) to give the title compound (12 mg, 25%) in hydrochloride form.

[0731] 1H NMR (400 MHz, DMSO-d6) δ 7.90 (br s, 3H), 7.79 (s, 1H), 7.46 (s,1H), 7.32 (d, J = 5.2 Hz, 1H), 6.92-6.90 (m, 1H), 6.85 (s, 1H), 3.65 (s, 2H), 1.76-1.72 (m, 1H), 1.68-1.62 (m, 1H), 1.50 – 1.43 (m, 1H), 0.87 (t, J = 10.8, 5.2 Hz, 6H). LCMS: 434.7, 436.8 (M&M+2).

[0732] Synthesis of (R)-N-((R)-N-(L-leucyl)-4-chlorothiophene-2-sulfonyl)-2,5-diaminopentanamide Trihydrochloride (ANOSA-056-1) A solution of Int-B-6.15-Fr-1 (0.085 g, 0.11 mmol) in DCM (1 mL) was added to triisopropylsilane (0.4 mL), dioxane, and 4M HCl (0.8 mL), and stirred at room temperature for 2 h. After the reaction was indicated by TLC, the reaction mixture was concentrated under reduced pressure and then ground with n-pentane and diethyl ether to give the title compound as a white solid. This solid was further purified by reversed-phase preparative HPLC (column: YMC-PACK ODS-AQ Prep C18-S, 250 X 20 mm S-5 μm, 12 nm; mobile phase: A = 0.01% HCl aqueous solution, B = acetonitrile, A: B = 87:13) to give the title compound as an HCl salt (0.017, 27.41%).

[0733] 1 H NMR (400 MHz, DMSO-d6) δ 8.05-7.96 (br s, 9H), 7.78 (d, J = 1.6 Hz, 1H), 7.53 (d, J = 1.6 Hz, 1H), 3.57 (br s, 2H), 2.78 (br s, 2H), 1.82 – 1.76(m, 2H), 1.70-1.65 (m, 3H), 1.62-1.59 (m, 1H), 1.52 – 1.45 (m, 1H), 0.87 (d, J = 6.0 Hz, 6H). LCMS ESI (m / z): 424.1, 426.1 (M&M+2). Purity at 210 nm: 100% The following compounds shown in Table 16 were prepared using HCl as a deprotecting agent, following the procedure described for compounds ANOSA-029-1&2 or ANOSA-056-1:

[0734] Biological methods Study on 1-enzyme inhibition The aminoacylation reaction catalyzed by aminoacyl-tRNA synthetase (aaRS) proceeds in two steps. First, aaRS activates its homologous amino acid using ATP; second, the activated amino acid is loaded onto its corresponding tRNA. This reaction can be summarized as follows: aaRS + aa + ATP = aaRS-aa-AMP + PPi aaRS-aa-AMP + tRNA = aa-tRN + AMP + aaRS Wherein: aaRS, aminoacyl-tRNA synthetase; aa, amino acid; aaRS-aa-AMP, enzyme that binds to aminoacyl-adenosine monophosphate; AMP, adenosine monophosphate; aa-tRNA, aminoacyl-tRNA; PPi, inorganic pyrophosphate.

[0735] Leucyl-tRNA synthetase Determination of IC 50 The activity of pathogenic aaRS was monitored by measuring AMP production using the commercial kit AMP-Glo ​​(Promega, Madison, USA).

[0736] The ligand stock solution was prepared in 100% DMSO at a concentration of 10 mM. An assay buffer consisting of 100 mM TrisHCl (pH 7.6), 40 mM MgCl, 20 mM KCl, and 150 mM NaCl was prepared in dH₂O. An enzyme solution containing 72.95 μM LeuRS was prepared in the assay buffer to provide a final assay concentration of 20 nM and a stock concentration of 50 nM for 1:2.5 dilution in the assay. A substrate solution was also prepared in an assay buffer containing 50 mM L-leucine, 10 mM ATP, and 100 mg / mL tRNA. A final assay concentration of 500 μM L-leucine, 16.7 μM ATP, and 0.5 mg / mL tRNA, and a stock concentration of 833.33 μM L-leucine, 27.83 μM ATP, and 0.83 mg / mL tRNA were used for 1:1.66 dilution in the assay.

[0737] In 384-well plate format, ten-point concentration-response curves were generated for each compound using the highest concentration of 10 μM. The known inhibitor LeuAMS was used as a positive control for the LeuRS assay. 100% DMSO was used as a negative control. IC50 50 It is calculated based on nonlinear regression analysis.

[0738] The data is summarized in the table below.

[0739] Symbol explanation: A<100 nM; 100 nM ≤ B<500 nM; 500 nM ≤ C<2 μM; 2 μM ≤ D<10 μM; 10 μM ≤ E.

[0740] (*) Mixture of diastereomers Study 2 - Antibacterial activity The minimum inhibitory concentration (MIC) was determined using the broth microdilution method according to the Clinical Laboratory Standards Association (CLSI) guidelines. For the test, a 5 mg / mL DMSO solution was prepared by dissolving the solid in DMSO. A 5 mg / mL stock solution of the standard antibiotic was prepared according to the CLSI guidelines. After preparing the DMSO stock solution, 38.4 μL of the stock solution was added to 1461.6 μL of MH medium to prepare working solutions in MH medium. 100 μL of these working solutions was transferred to the wells in the third column of a 96-well assay plate. All wells of the assay plate, except the wells in the third column, were pre-filled with 50 μL of MH medium. After adding the compound and antibiotic, 50 μL was transferred from the third column to the fourth column, then from the fourth column to the fifth column, and so on. In this manner, the compound and antibiotic were inoculated into the 96-well assay plate at consecutive 2-fold dilutions, starting with the highest concentration of 256 μg / mL or 64 μg / mL.

[0741] MIC values ​​are determined by visually inspecting bacterial growth within the 96-well plate. The column with no visible bacterial growth in the first well is designated as the MIC value for the compound or antibiotic tested in that particular row. ATCC strains are used as reference strains; the MIC values ​​for these strains to standard antibiotics are known. The assay is considered valid when the MIC value of the standard antibiotic falls within the CLSI-specified range for ATCC strain testing.

[0742] The data is summarized in the table below.

[0743] Symbol explanation: A = E. coli ATCC 25922 B = E. coli BAA-2469 C = Klebsiella pneumoniae ATCC 700603 D = E. coli BW25113 E = Klebsiella pneumoniae ATCC 43816 F = Pseudomonas aeruginosa ATCC 27853 G = Acinetobacter baumannii B1931 Research 3 - Human Cell Viability To assess the potential non-specific cytotoxicity of the compound against the human hepatocyte cell line (HepG2 ATCC HB-8065), HepG2 cells were seeded at a concentration of 15,000 cells per well in 100 μL of MEM growth medium containing 1% NEAA and 1% sodium pyruvate. Border wells were filled with 100 μL of sterile PBS. After two days of cell culture, the compound was added. A compound dilution was prepared in pure DMSO in 96-well V-type plates. Growth medium was aspirated from five plates and replaced with 98.7 μL of fresh growth medium. 1.28 μL of the compound prepared in the V-type plates (78.1x dilution) was transferred to test plates using a multichannel pipette. The final DMSO concentration per well was 1.28%. In control wells, 1.28 μL of DMSO was added to 98.7 μL of medium. All tests were performed repeatedly. Cells were incubated with the compound for 24 hours, and cell viability was assessed by measuring ATP levels. ATP levels were measured by adding 50 μL of CellTiter-Glo reagent to each well, followed by 5 minutes of incubation, and then luminescence was measured using a SpectraMax i3. The potential effect of the test compounds on cell viability was determined by comparing the signals obtained in the presence of different concentrations of the compounds with those obtained in the presence of DMSO alone. The potential effect was then calculated and expressed as IC50. 50 Value (μg / mL) is expressed.

[0744] The data is summarized in the table below.

[0745] The principles, preferred embodiments, and modes of operation of the present invention have been described above. However, the invention should not be construed as limited to the specific embodiments discussed. Rather, the above embodiments should be considered illustrative rather than restrictive. It should be understood that those skilled in the art can make changes to those embodiments without departing from the scope of the invention.

[0746] References This document cites numerous publications to more fully describe and disclose the invention and the prior art to which it pertains. Full citations of these references are provided below.

[0747] Each of these references is incorporated in full by reference to this disclosure as if each individual reference were specifically and individually indicated to be incorporated by reference.

[0748]

Claims

1. A compound selected from compounds of the following formula, and their pharmaceutically acceptable salts, hydrates, and solvates: in: -Y is independent of -NR UA R UB or -R P ; -R UA Independently -H or -R UUA ; -R UUA Independently: -R U1 、 -R U2 、 -R U3 、 -R U4 、 -R U5 、 -L U -R U2 、 -L U -R U3 、 -L U -R U4 、 -C(=O)-R U4 、 -L U -R U5 or -C(=O)-R U5 ; -R U1 For linear or branched saturated C 1-6 Alkyl group, and optionally with one or more groups -R UU2 replace; Each -R U2 For saturated C 3-6 Cycloalkyl, and optionally with one or more groups -R UU1 and one or more groups -R UU2 replace; Each -R U3 Non-aromatic C 3-8 Heterocyclic group, and optionally with one or more groups -R UU1 and one or more groups -R UU2 replace; Each -R U4 Independently phenyl or naphthyl, and optionally with one or more -R groups UU1 and one or more groups -R UU2 replace; Each -R U5 C 5-10 Heteroaryl, and optionally with one or more groups -R UU1 and one or more groups -R UU2 replace; Each -L U - is the saturated C for linear or branched chains. 1-4 Alkylene, and optionally with a alkylene group selected from -OH, -OR UL -NH2, -NHR UL and -NR UL 2-group substitution; Each -R UL Independently for linear or branched saturated C 1-4 alkyl; Each -R UU1 Selected independently from: -R UU 、 -L UU -OH、-L UU -OR UU 、 -L UU -NH2, -L UU -NHR UU -L UU -N(R UU )2 and -L UU -R UM ; Each -R UU2 Selected independently from: -F, -Cl, -Br, -I, -OH、-OR UU 、 -CF3, -CHF2, -OCF3, -OCHF2, -NH2, -NHR UU -N(R) UU )2、-R UM 、 -C(=O)OH、-C(=O)OR UU 、-OC(=O)R UU 、 -C(=O)NH2、-C(=O)NHR UU 、-C(=O)N(R UU )2、-C(=O)R UM 、 -NHC(=O)R UU 、-NR UN C(=O)R UU 、 -NHC(=O)NH2、-NHC(=O)NHR UU 、-NHC(=O)N(R UU )2、-NHC(=O)R UM 、 -NR UN C(=O)NH2、-NR UN C(=O)NHR UU 、-NR UN C(=O)N(R UU )2、 -NR UN C(=O)R UM 、 -NHC(=O)OR UU 、-NR UN C(=O)OR UU 、 -OC(=O)NH2, -OC(=O)NHR UU -OC(=O)N(R UU )2、-OC(=O)R UM 、 -NHC(=NH)NH2、 -C(=O)R UU 、 -S(=O)NH2、-S(=O)NHR UU ,-S(=O)N(R UU )2、-S(=O)R UM 、 -S(=O)2NH2、-S(=O)2NHR UU 、-S(=O)2N(R UU )2、-S(=O)2R UM 、 -NHS(=O)R UU 、-NR UN S(=O)R UU 、 -NHS(=O)2R UU 、-NR UN S(=O)2R UU 、 -S(=O)R UU 、-S(=O)2R UU 、 -SH、-SR UU -CN and -NO2; in: Each -L UU - is the saturated C for linear or branched chains. 1-4 Alkylene; Each -R UU Independently for linear or branched saturated C 1-4 Alkyl, phenyl, or -CH2-phenyl, wherein each phenyl group is optionally substituted with one or more groups selected from -F, -Cl, -Br, -Me, -OH, -OMe, -CF3, and -OCF3; Each -R UN For linear or branched saturated C 1-4 alkyl; Each -R UM Independently substituted with aza-butane, pyrrolidine, piperidin, piperazine, morpholine, aza-heptane, or diaza-heptane, and: Optionally, it may be replaced with one or more groups selected from the following: -R UMM 、 -C(=O)R UMM 、 -C(=O)OR UMM 和 -S(=O)2R UMM ; Each of -R UMM Independently for linear or branched saturated C 1-4 Alkyl, phenyl, or -CH2-phenyl, wherein each phenyl group is optionally substituted with one or more groups selected from -F, -Cl, -Br, -Me, -OH, -OMe, -CF3, and -OCF3; -R UB Independently -H or -R UUB ; -R UUB Independently for linear or branched saturated C 1-4 alkyl; -R P Independently: -R P1 -R P2 -R P3 -R P4 -R P5 -L P -R P2 -L P -R P3 -L P -R P4 or -L P -R P5 ; -R P1 For linear or branched saturated C 1-6 Alkyl group, and optionally with one or more groups -R PP2 replace; Each -R P2 For saturated C 3-6 Cycloalkyl, and optionally with one or more groups -R PP1 and one or more groups -R PP2 replace; Each -R P3 Non-aromatic C 3-8 Heterocyclic group, and optionally with one or more groups -R PP1 and one or more groups -R PP2 replace; Each -R P4 Independently phenyl or naphthyl, and optionally with one or more -R groups PP1 and one or more groups -R PP2 replace; Each -R P5 C 5-10 Heteroaryl, and optionally with one or more groups -R PP1 and one or more groups -R PP2 replace; Each -L P - is the saturated C for linear or branched chains. 1-4 Alkylene, and optionally with a alkylene group selected from -OH, -OR PL -NH2, -NHR PL and -NR PL 2-group substitution; Each -R PL Independently linear or branched saturated C 1-4 alkyl; Each -R PP1 Selected independently from: -R PP 、 -L PP -OH、-L PP -OR PP 、 -L PP -NH2, -L PP -NHR PP -L PP -N(R PP )2 and -L PP -R PM ; Each -R PP2 Selected independently from: -F, -Cl, -Br, -I, -OH、-OR PP 、 -CF3, -CHF2, -OCF3, -OCHF2, -NH2, -NHR PP -N(R) PP )2、-R PM 、 -C(=O)OH、-C(=O)OR PP 、-OC(=O)R PP 、 -C(=O)NH2、-C(=O)NHR PP 、-C(=O)N(R PP )2、-C(=O)R PM 、 -NHC(=O)R PP 、-NR PN C(=O)R PP 、 -NHC(=O)NH2、-NHC(=O)NHR PP 、-NHC(=O)N(R PP )2、-NHC(=O)R PM 、 -NR PN C(=O)NH2、-NR PN C(=O)NHR PP 、-NR PN C(=O)N(R PP )2、 -NR PN C(=O)R PM 、 -NHC(=O)OR PP 、-NR PN C(=O)OR PP 、 -OC(=O)NH2, -OC(=O)NHR PP -OC(=O)N(R PP )2、-OC(=O)R PM 、 -NHC(=NH)NH2、 -C(=O)R PP 、 -S(=O)NH2、-S(=O)NHR PP ,-S(=O)N(R PP )2、-S(=O)R PM 、 -S(=O)2NH2、-S(=O)2NHR PP 、-S(=O)2N(R PP )2、-S(=O)2R PM 、 -NHS(=O)R PP 、-NR PN S(=O)R PP 、 -NHS(=O)2R PP 、-NR PN S(=O)2R PP 、 -S(=O)R PP 、-S(=O)2R PP 、 -SH、-SR PP -CN and -NO2; in: Each -L PP - is the saturated C for linear or branched chains. 1-4 Alkylene; Each -R PP Independently for linear or branched saturated C 1-4 Alkyl, phenyl, or -CH2-phenyl, wherein each phenyl group is optionally substituted with one or more groups selected from -F, -Cl, -Br, -Me, -OH, -OMe, -CF3, and -OCF3; Each -R PN For linear or branched saturated C 1-4 alkyl; Each -R PM Independently substituted with aza-butane, pyrrolidine, piperidin, piperazine, morpholine, aza-heptane, or diaza-heptane, and: Optionally, it may be replaced with one or more groups selected from the following: -R PMM 、 -C(=O)R PMM 、 -C(=O)OR PMM and -S(=O)2R PMM ; Each of -R PMM Independently for linear or branched saturated C 1-4 Alkyl, phenyl, or -CH2-phenyl, wherein each phenyl group is optionally substituted with one or more groups selected from -F, -Cl, -Br, -Me, -OH, -OMe, -CF3, and -OCF3; -R N Independently -H or -R NN ; -R NN Independently for linear or branched saturated C 1-4 alkyl; And among them: -A is independent of -A C or -A H ; -A C Independently phenyl or naphthyl, and optionally with one or more substituents -R X replace; -A H Independently for C 5-12 Heteroaryl, and optionally with one or more substituents -R X replace; in: Each -R X Selected independently from: -R XX 、-R XXU 、-R XXV 、 -F, -Cl, -Br, -I, -OH、-OR XX 、 -L XX -OH、-L XX -OR XX 、 -CF3, -CHF2, -OCF3, -OCHF2, -NH2, -NHR XX 、-NR XX 2.-R XM 、 -L XX -NH2, -L XX -NHR XX -L XX -NR XX 2.-L XX -R XM 、 -C(=O)OH、-C(=O)OR XX 、-OC(=O)R XX 、 -C(=O)NH2、-C(=O)NHR XX 、-C(=O)NR XX 2、-C(=O)R XM 、 -NHC(=O)R XX 、-NR XN C(=O)R XX 、 -NHC(=O)NH2、-NHC(=O)NHR XX 、-NHC(=O)NR XX 2、-NHC(=O)R XM 、 -NR XN C(=O)NH2、-NR XN C(=O)NHR XX 、-NR XN C(=O)NR XX 2、-NR XN C(=O)R XM 、 -NHC(=O)OR XX 、-NR XN C(=O)OR XX 、 -OC(=O)NH2, -OC(=O)NHR XX -OC(=O)NR XX 2、-OC(=O)R XM 、 -NHC(=NH)NH2、 -C(=O)R XX 、 -S(=O)NH2、-S(=O)NHR XX 、-S(=O)NR XX 2、-S(=O)R XM 、 -S(=O)2NH2、-S(=O)2NHR XX 、-S(=O)2NR XX 2、-S(=O)2R XM 、 -NHS(=O)R XX 、-NR XN S(=O)R XX 、 -NHS(=O)2R XX 、-NR XN S(=O)2R XX 、 -S(=O)R XX 、-S(=O)2R XX 、 -SH、-SR XX -CN and -NO2; In addition, two adjacent groups -R X If they exist, they can be formed together: -O-CH2-O-, -O-CH2CH2-O-, -CH2-CH2-O-, -CH2-CH2CH2-O-, -CH2-O-CH2- or -CH2-CH2-O-CH2-; in: Each -L XX - is the saturated C for linear or branched chains. 1-4 Alkylene; Each -R XX Independently for linear or branched saturated C 1-4 Alkyl, phenyl, or -CH2-phenyl, wherein each phenyl group is optionally substituted with one or more groups selected from -F, -Cl, -Br, -Me, -OH, -OMe, -CF3, and -OCF3; Each -R XXU C can be independently linear or branched. 2-4 alkenyl; Each -R XXV C can be independently linear or branched. 2-4 alkynyl group; Each -R XN For linear or branched saturated C 1-4 alkyl; Each -R XM Independently substituted with aza-butane, pyrrolidine, piperidin, piperazine, morpholine, aza-heptane, or diaza-heptane, and: Optionally, it may be replaced with one or more groups selected from the following: -R XMM 、 -C(=O)R XMM 、 -C(=O)OR XMM and -S(=O)2R XMM ; Each of -R XMM Independently for linear or branched saturated C 1-4 Alkyl, phenyl, or -CH2-phenyl, wherein each phenyl group is optionally substituted with one or more groups selected from -F, -Cl, -Br, -Me, -OH, -OMe, -CF3, and -OCF3; -R 1 Independently -H or -R 11 ; -R 11 Independently for -R 11A or -R 11B ; -R 11A Independently: -R A1 -R A2 -R A3 -R A4 -R A5 -L A -R A2 -L A -R A3 -L A -R A4 or -L A -R A5 ; -R A1 For linear or branched saturated C 1-6 Alkyl group, and optionally with one or more groups -R AA2 replace; Each -R A2 For saturated C 3-6 Cycloalkyl, and optionally with one or more groups -R AA1 and one or more groups -R AA2 replace; Each -R A3 Non-aromatic C 3-7 Heterocyclic group, and optionally with one or more groups -R AA1 and one or more groups -R AA2 replace; Each -R A4 Independently phenyl or naphthyl, and optionally with one or more -R groups AA1 and one or more groups -R AA2 replace; Each -R A5 C 5-10 Heteroaryl, and optionally with one or more groups -R AA1 and one or more groups -R AA2 replace; Each -L A - is the saturated C for linear or branched chains. 1-4 Alkylene; Each -R AA1 Selected independently from: -R AA 、 -L AA -OH、-L AA -OR AA 、 -L AA -NH2, -L AA -NHR AA -L AA -N(R AA )2 and -L AA -R AM ; Each -R AA2 Selected independently from: -F, -Cl, -Br, -I, -OH、-OR AA 、 -CF3, -CHF2, -OCF3, -OCHF2, -NH2, -NHR AA -N(R) AA )2、-R AM 、 -C(=O)OH、-C(=O)OR AA 、-OC(=O)R AA 、 -C(=O)NH2、-C(=O)NHR AA 、-C(=O)N(R AA )2、-C(=O)R AM 、 -NHC(=O)R AA 、-NR AN C(=O)R AA 、 -NHC(=O)NH2、-NHC(=O)NHR AA 、-NHC(=O)N(R AA )2、-NHC(=O)R AM 、 -NR AN C(=O)NH2、-NR AN C(=O)NHR AA 、-NR AN C(=O)N(R AA )2、 -NR AN C(=O)R AM 、 -NHC(=O)OR AA 、-NR AN C(=O)OR AA 、 -OC(=O)NH2, -OC(=O)NHR AA -OC(=O)N(R AA )2、-OC(=O)R AM 、 -NHC(=NH)NH2、 -C(=O)R AA 、 -S(=O)NH2、-S(=O)NHR AA ,-S(=O)N(R AA )2、-S(=O)R AM 、 -S(=O)2NH2、-S(=O)2NHR AA 、-S(=O)2N(R AA )2、-S(=O)2R AM 、 -NHS(=O)R AA 、-NR AN S(=O)R AA 、 -NHS(=O)2R AA 、-NR AN S(=O)2R AA 、 -S(=O)R AA 、-S(=O)2R AA 、 -SH、-SR AA -CN and -NO2; in: Each -L AA - is the saturated C for linear or branched chains. 1-4 Alkylene; Each -R AA Independently for linear or branched saturated C 1-4 Alkyl, phenyl, or -CH2-phenyl, wherein each phenyl group is optionally substituted with one or more groups selected from -F, -Cl, -Br, -Me, -OH, -OMe, -CF3, and -OCF3; Each -R AN For linear or branched saturated C 1-4 alkyl; Each -R AM Independently substituted with aza-butane, pyrrolidine, piperidin, piperazine, morpholine, aza-heptane, or diaza-heptane, and: Optionally, it may be replaced with one or more groups selected from the following: -R AMM 、 -C(=O)R AMM 、 -C(=O)OR AMM 和 -S(=O)2R AMM ; Each of -R AMM Independently for linear or branched saturated C 1-4 Alkyl, phenyl, or -CH2-phenyl, wherein each phenyl group is optionally substituted with one or more groups selected from -F, -Cl, -Br, -Me, -OH, -OMe, -CF3, and -OCF3; -R 11B Selected independently from: -F, -Cl, -Br, -I, -OH、-OR BB 、 -CF3, -CHF2, -OCF3, -OCHF2, -NH2, -NHR BB 、-NR BB 2.-R BM 、 -C(=O)OH、-C(=O)OR BB 、-OC(=O)R BB 、 -C(=O)NH2、-C(=O)NHR BB 、-C(=O)NR BB 2、-C(=O)R BM 、 -NHC(=O)R BB 、-NR BN C(=O)R BB 、 -NHC(=O)NH2、-NHC(=O)NHR BB 、-NHC(=O)NR BB 2、-NHC(=O)R BM 、 -NR BN C(=O)NH2、-NR BN C(=O)NHR BB 、-NR BN C(=O)NR BB 2、-NR BN C(=O)R BM 、 -NHC(=O)OR BB 、-NR BN C(=O)OR BB 、 -OC(=O)NH2, -OC(=O)NHR BB -OC(=O)NR BB 2、-OC(=O)R BM 、 -NHC(=NH)NH2、 -C(=O)R BB 、 -S(=O)NH2、-S(=O)NHR BB 、-S(=O)NR BB 2、-S(=O)R BM 、 -S(=O)2NH2、-S(=O)2NHR BB 、-S(=O)2NR BB 2、-S(=O)2R BM 、 -NHS(=O)R BB 、-NR BN S(=O)R BB 、 -NHS(=O)2R BB 、-NR BN S(=O)2R BB 、 -S(=O)R BB 、-S(=O)2R BB 、 -SH、-SR BB -CN and -NO2; in: Each -R BB Independently for linear or branched saturated C 1-4 Alkyl, phenyl, or -CH2-phenyl, wherein each phenyl group is optionally substituted with one or more groups selected from -F, -Cl, -Br, -Me, -OH, -OMe, -CF3, and -OCF3; Each -R BN For linear or branched saturated C 1-4 alkyl; Each -R BM Independently substituted with aza-butane, pyrrolidine, piperidin, piperazine, morpholine, aza-heptane, or diaza-heptane, and: Optionally, it may be replaced with one or more groups selected from the following: -R BMM 、 -C(=O)R BMM 、 -C(=O)OR BMM and -S(=O)2R BMM ; Each of -R BMM Independently for linear or branched saturated C 1-4 Alkyl, phenyl, or -CH2-phenyl, wherein each phenyl group is optionally substituted with one or more groups selected from -F, -Cl, -Br, -Me, -OH, -OMe, -CF3, and -OCF3; -R 2 Independently -H or -R 22 ; -R 22 Independently for -R 22C or -R 22D ; -R 22C Independently: -R C1 -R C2 -R C3 -R C4 -R C5 -L C -R C2 -L C -R C3 -L C -R C4 or -L C -R C5 ; -R C1 For linear or branched saturated C 1-6 Alkyl group, and optionally with one or more groups -R CC2 replace; Each -R C2 For saturated C 3-6 Cycloalkyl, and optionally with one or more groups -R CC1 and one or more groups -R CC2 replace; Each -R C3 Non-aromatic C 3-7 Heterocyclic group, and optionally with one or more groups -R CC1 and one or more groups -R CC2 replace; Each -R C4 Independently phenyl or naphthyl, and optionally with one or more -R groups CC1 and one or more groups -R CC2 replace; Each -R C5 C 5-10 Heteroaryl, and optionally with one or more groups -R CC1 and one or more groups -R CC2 replace; Each -L C - is the saturated C for linear or branched chains. 1-4 Alkylene; Each -R CC1 Selected independently from: -R CC 、 -L CC -OH、-L CC -OR CC 、 -L CC -NH2, -L CC -NHR CC -L CC -N(R CC )2 and -L CC -R CM ; Each -R CC2 Selected independently from: -F, -Cl, -Br, -I, -OH、-OR CC 、 -CF3, -CHF2, -OCF3, -OCHF2, -NH2, -NHR CC -N(R) CC )2、-R CM 、 -C(=O)OH、-C(=O)OR CC 、-OC(=O)R CC 、 -C(=O)NH2、-C(=O)NHR CC 、-C(=O)N(R CC )2、-C(=O)R CM 、 -NHC(=O)R CC 、-NR CN C(=O)R CC 、 -NHC(=O)NH2、-NHC(=O)NHR CC 、-NHC(=O)N(R CC )2、-NHC(=O)R CM 、 -NR CN C(=O)NH2、-NR CN C(=O)NHR CC 、-NR CN C(=O)N(R CC )2、 -NR CN C(=O)R CM 、 -NHC(=O)OR CC 、-NR CN C(=O)OR CC 、 -OC(=O)NH2, -OC(=O)NHR CC -OC(=O)N(R CC )2、-OC(=O)R CM 、 -NHC(=NH)NH2、 -C(=O)R CC 、 -S(=O)NH2、-S(=O)NHR CC ,-S(=O)N(R CC )2、-S(=O)R CM 、 -S(=O)2NH2、-S(=O)2NHR CC 、-S(=O)2N(R CC )2、-S(=O)2R CM 、 -NHS(=O)R CC 、-NR CN S(=O)R CC 、 -NHS(=O)2R CC 、-NR CN S(=O)2R CC 、 -S(=O)R CC 、-S(=O)2R CC 、 -SH、-SR CC -CN and -NO2; in: Each -L CC - is the saturated C for linear or branched chains. 1-4 Alkylene; Each -R CC Independently for linear or branched saturated C 1-4 Alkyl, phenyl, or -CH2-phenyl, wherein each phenyl group is optionally substituted with one or more groups selected from -F, -Cl, -Br, -Me, -OH, -OMe, -CF3, and -OCF3; Each -R CN For linear or branched saturated C 1-4 alkyl; Each -R CM Independently substituted with aza-butane, pyrrolidine, piperidin, piperazine, morpholine, aza-heptane, or diaza-heptane, and: Optionally, it may be replaced with one or more groups selected from the following: -R CMM 、 -C(=O)R CMM 、 -C(=O)OR CMM and -S(=O)2R CMM ; Each of -R CMM Independently for linear or branched saturated C 1-4 Alkyl, phenyl, or -CH2-phenyl, wherein each phenyl group is optionally substituted with one or more groups selected from -F, -Cl, -Br, -Me, -OH, -OMe, -CF3, and -OCF3; -R 22D Selected independently from: -F, -Cl, -Br, -I, -OH、-OR DD 、 -CF3, -CHF2, -OCF3, -OCHF2, -NH2, -NHR DD 、-NR DD 2.-R DM 、 -C(=O)OH、-C(=O)OR DD 、-OC(=O)R DD 、 -C(=O)NH2、-C(=O)NHR DD 、-C(=O)NR DD 2、-C(=O)R DM 、 -NHC(=O)R DD 、-NR DN C(=O)R DD 、 -NHC(=O)NH2、-NHC(=O)NHR DD 、-NHC(=O)NR DD 2、-NHC(=O)R DM 、 -NR DN C(=O)NH2、-NR DN C(=O)NHR DD 、-NR DN C(=O)NR DD 2、-NR DN C(=O)R DM 、 -NHC(=O)OR DD 、-NR DN C(=O)OR DD 、 -OC(=O)NH2, -OC(=O)NHR DD -OC(=O)NR DD 2、-OC(=O)R DM 、 -NHC(=NH)NH2、 -C(=O)R DD 、 -S(=O)NH2、-S(=O)NHR DD 、-S(=O)NR DD 2、-S(=O)R DM 、 -S(=O)2NH2、-S(=O)2NHR DD 、-S(=O)2NR DD 2、-S(=O)2R DM 、 -NHS(=O)R DD 、-NR DN S(=O)R DD 、 -NHS(=O)2R DD 、-NR DN S(=O)2R DD 、 -S(=O)R DD 、-S(=O)2R DD 、 -SH、-SR DD -CN and -NO2; in: Each -R DD Independently for linear or branched saturated C 1-4 Alkyl, phenyl, or -CH2-phenyl, wherein each phenyl group is optionally substituted with one or more groups selected from -F, -Cl, -Br, -Me, -OH, -OMe, -CF3, and -OCF3; Each -R DN For linear or branched saturated C 1-4 alkyl; Each -R DM Independently substituted with aza-butane, pyrrolidine, piperidin, piperazine, morpholine, aza-heptane, or diaza-heptane, and: Optionally, it may be replaced with one or more groups selected from the following: -R DMM 、 -C(=O)R DMM 、 -C(=O)OR DMM 和 -S(=O)2R DMM ; Each of -R DMM Independently for linear or branched saturated C 1-4 Alkyl, phenyl, or -CH2-phenyl, wherein each phenyl group is optionally substituted with one or more groups selected from -F, -Cl, -Br, -Me, -OH, -OMe, -CF3, and -OCF3; or -R 1 and -R 2 Together with the carbon atoms they are attached to, they form saturated carbon. 3-6 cycloalkyl or non-aromatic C 3-7 Heterocyclic group, and optionally with one or more groups -R CC2 replace.

2. The compound according to claim 1, wherein -R UA -R UUA .

3. The compound according to claim 1 or 2, wherein -R UUA Independently: -R U1 -R U2 -R U4 -L U -R U4 or -C(=O)-R U4 .

4. The compound according to any one of claims 1 to 3, wherein -R U1 Independently -Me, -Et, or -nPr; and optionally with one or more groups -R UU2 replace.

5. The compound according to any one of claims 1 to 4, wherein each -R U2 It is an independent cyclohexyl group.

6. The compound according to any one of claims 1 to 5, wherein each -R U4 It is a phenyl group.

7. The compound according to any one of claims 1 to 6, wherein each -L U - is -CH2-.

8. The compound according to any one of claims 1 to 7, wherein each -R UU2 Selected independently from: -OR UU , -NH2, and -C(=O)OH.

9. The compound according to claim 1, wherein -R UA It is -H.

10. The compound according to any one of claims 1 to 9, wherein -R UB It is -H.

11. The compound according to any one of claims 1 to 10, wherein -R P Independently: -R P1 -R P2 -L P -R P3 -L P -R P4 or -L P -R P5 .

12. The compound according to any one of claims 1 to 11, wherein -R P1 Independently for -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, -tBu, - just pentyl, - Zhong pentyl or - different pentyl; and optionally with one or more groups -R PP2 replace.

13. The compound according to any one of claims 1 to 12, wherein -R P1 Independently -Me, -Et, or -nPr; and with one or two groups -R PP2 replace.

14. The compound according to any one of claims 1 to 13, wherein -R P1 Groups selected from the following structural formulas: Where R P1R It is -Me or -Et and uses a group R PP2 replace.

15. The compound according to any one of claims 1 to 14, wherein each -R P5 Independently: (a) pyridinyl, pyridinyl, pyrimidinyl, or pyrazinyl, and optionally with one or more -R groups PP1 and one or more groups -R PP2 Replace; or (b) Thiophene, thiazolyl or tetrazolium.

16. The compound according to any one of claims 1 to 15, wherein each -R P5 Independently, optionally using one or more groups R PP1 and one or more groups R PP2 Substituted thiazole group.

17. The compound according to any one of claims 1 to 16, wherein each -R P5 Independently, optionally using one or more groups R PP1 and one or more groups R PP2 Substituted pyridinyl group.

18. The compound according to any one of claims 1 to 17, wherein each -R P2 Independently cyclopropyl, and with a group R PP2 replace.

19. The compound according to any one of claims 1 to 18, wherein each -R P3 It is independently pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; or -R P3 For (3a) S ,6a R )-2-oxohexahydro-1 H -thieno[3,4- d Imidazole group.

20. The compound according to any one of claims 1 to 19, wherein each -R P4 It is phenyl, and is enclosed in one or more groups -R PP2 replace.

21. The compound according to any one of claims 1 to 17, wherein -R P -R P1 or -L P -R P5 .

22. The compound according to any one of claims 1 to 21, wherein -L P - Independently, it is -CH2CH2- or -CH2-.

23. The compound according to any one of claims 1 to 22, wherein -L P - is -CH2-.

24. The compound according to any one of claims 1 to 23, wherein each -R PP2 Selected independently from: -OH、-OR PP 、 -NH2, -NHR PP -N(R) PP 2. -C(=O)OH、-C(=O)OR PP 、 -C(=O)NH2, -C(=O)NHR PP -C(=O)N(R PP 2. -NHC(=O)R PP -NR PN C(=O)R PP and -CN.

25. The compound according to any one of claims 1 to 24, wherein each -R PP2 Selected independently from: -OH, -NH2, -NHR PP -N(R) PP )2 and -C(=O)OH.

26. The compound according to any one of claims 1 to 25, wherein each -R PP2 Selected independently from: -OH, -NH2 and -C(=O)OH.

27. The compound according to any one of claims 1 to 26, wherein each -R PP For -Me.

28. The compound according to any one of claims 1 to 10, wherein -Y is -NR. UA R UB .

29. The compound according to any one of claims 1 and 11 to 27, wherein -Y is -R P .

30. The compound according to any one of claims 1 to 29, wherein -R N It is -H.

31. The compound according to any one of claims 1 to 30, wherein -A H It is thienyl, thiazolyl, or thienothienyl, and optionally with one or more substituents -R X replace.

32. The compound according to any one of claims 1 to 31, wherein -A H It is thiophene-2-yl or thiophene-3-yl, and optionally with one or more substituents -R X replace.

33. The compound according to any one of claims 1 to 31, wherein -A H It is thiazol-2-yl and optionally with one or more substituents -R X replace.

34. The compound according to any one of claims 1 to 31, wherein -A H It is thiophene-thiophene group and optionally with one or more substituents -R X replace.

35. The compound according to any one of claims 1 to 34, wherein -A C It is phenyl and optionally substituent with one or more -R groups X replace.

36. The compound according to any one of claims 1 to 34, wherein -A C for: ， Where -R X2 It is -Cl.

37. The compound according to any one of claims 1 to 31, 35 and 36, wherein -A H for: ， Where -R X4 It is -Cl.

38. The compound according to any one of claims 1 to 35, wherein each -R X It can be -Cl or -F.

39. The compound according to any one of claims 1 to 34 and 37, wherein -A is -A H .

40. The compound according to any one of claims 1 to 30, 35, 36 and 38, wherein -A is -A C .

41. The compound according to any one of claims 1 to 40, wherein: -R 1 It is -CH2CH(CH3)2; and -R 2 It is -H.

42. The compound according to any one of claims 1 to 41, wherein R 2 It is a compound with -H, and is selected from compounds of the following formula, as well as their pharmaceutically acceptable salts, hydrates, and solvates: 。 43. The compound according to any one of claims 1 to 42, wherein the sulfur atom forming a portion of the sulfonylimide amide group is in the configuration shown in the following structural formula: 。 44. The compound according to any one of claims 1 to 42, wherein the sulfur atom forming a portion of the sulfonylimide amide group is in the configuration shown in the following structural formula: 。 45. The compound according to claim 1, wherein the compound is selected from any one of ANOSA-001 to ANOSA-087, and its pharmaceutically acceptable salts, hydrates and solvates.

46. ​​A pharmaceutical composition comprising the compound of any one of claims 1 to 45 and a pharmaceutically acceptable carrier or diluent.

47. A method for preparing a pharmaceutical composition, comprising the step of mixing the compound of any one of claims 1 to 45 with a pharmaceutically acceptable carrier or diluent.

48. A method for inhibiting bacterial aminoacyl-tRNA synthetase in vitro or in vivo, comprising contacting the synthetase with an effective amount of the compound according to any one of claims 1 to 45.

49. A method for inhibiting bacterial aminoacyl-tRNA synthetase in cells in vitro or in vivo, comprising contacting the cells with an effective amount of the compound according to any one of claims 1 to 45.

50. The compound according to any one of claims 1 to 45, used in a method of treating a human or animal body by means of therapy.

51. The compound according to any one of claims 1 to 45, in a method of treating a condition in a human or animal body that is improved by inhibiting bacterial aminoacyl-tRNA synthetase.

52. Use of the compound according to any one of claims 1 to 45, for the manufacture of a medicament for treating a condition in a human or animal body that is improved by inhibiting bacterial aminoacyl-tRNA synthetase.

53. A method of treating a condition in a human or animal body that is improved by inhibiting bacterial aminoacyl-tRNA synthetase, comprising administering to a subject requiring treatment a therapeutically effective amount of the compound of any one of claims 1 to 45.

54. The compound according to any one of claims 1 to 45, in a method of treating bacterial infection.

55. Use of the compound according to any one of claims 1 to 45, for the manufacture of a medicament for treating bacterial infections.

56. A method of treating a disease in a human or animal body, comprising administering to a subject requiring treatment a therapeutically effective amount of the compound of any one of claims 1 to 45, wherein the disease is a bacterial infection.

57. The compound used according to claim 54, the use according to claim 55, or the method according to claim 56, wherein the bacteria is a Gram-positive bacterium.

58. The compound used according to claim 54, the use according to claim 55, or the method according to claim 56, wherein the bacteria is a Gram-negative bacterium.

59. The compound used according to claim 54, the use according to claim 55, or the method according to claim 56, wherein the bacteria are aerobic bacteria.

60. The compound used according to claim 54, the use according to claim 55, or the method according to claim 56, wherein the bacteria are anaerobic bacteria.

61. The compound used according to claim 54, the use according to claim 55, or the method according to claim 56, wherein the bacteria are intracellular bacteria.

62. The compound used according to claim 54, the use according to claim 55, or the method according to claim 56, wherein the bacteria is: Staphylococcus spp. For example Staphylococcus aureus; Enterococcus spp. For example Enterococcus faecalis; Streptococcus spp. For example Streptococcus pneumoniae; Haemophilus spp. ,For example Haemophilus influenzae; Moraxella ,For example Moraxella catarrhalis ; Klebsiella ,For example Klebsiella pneumoniae ; Acinetobacter ,For example Acinetobacter baumannii ; Pseudomonas ,For example Pseudomonas aeruginosa ; Proteus ,For example Proteus mirabilis ; Neisseria ,For example Neisseria gonorrhoeae ; Clostridium ,For example Clostridium difficile; Campylobacter, For example Campylobacter jejuni; Salmonella ,For example Salmonella typhi; Shigella genus, For example Shigella flexneri; Enterobacteriaceae ,For example Enterobacter cloacae; Citrobacter spp. ,For example Citrobacter freundii; Serratia ,For example Serratia marcescens; or Escherichia coli ,For example E. coli .

63. The compound used according to any one of claims 54 and 57 to 62, the use according to any one of claims 55 and 57 to 62, or the method according to any one of claims 56 to 62, wherein the infection is: Central nervous system infection; External ear infection; Middle ear infections, including acute otitis media; Cranial sinus infection; Eye infection; Oral infections, including infections of the teeth, gums, or mucous membranes; Upper respiratory tract infection; Lower respiratory tract infection; Urogenital tract infection; Urinary tract infection; Intra-abdominal infection; Gastrointestinal infection; Gynecological infection; septicemia, Bone or joint infection Infection of the skin or skin structure; Bacterial endocarditis; or Burn infection.

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