antimalarial drugs

Abstract

The present invention provides a method of treating malaria, comprising administering to a subject in need of such treatment a compound of formula (I) or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined herein. The present invention further provides the use of a compound of formula (I) as defined herein for inhibiting the activity of plasmepsin X, plasmepsin IX or plasmepsin X and IX, for treating a malaria parasite infection, and for treating malaria. Also provided are methods of treatment further comprising administering one or more additional antimalarial compounds. [Formula 1] TIFF2024545498000356.tif52134

Description

[Technical Field]

[0001] The present invention relates to compounds represented by formula (I) or pharmaceutically acceptable salts thereof that are useful for the treatment of malaria parasitic infections. More specifically, the present invention relates to compounds represented by formula (I) or pharmaceutically acceptable salts thereof that are useful for the treatment of malaria parasitic infections, and in particular for the treatment of malaria. [Background technology]

[0002] Malaria is a major human disease, infecting hundreds of millions of people and causing over 450,000 deaths annually. The most deadly form of malaria is caused by Plasmodium falciparum. This protozoan parasite is responsible for almost all malaria deaths, most of which occur in Africa. Plasmodium falciparum has a complex life cycle that begins in the body of the Anopheles mosquito vector, into which sporozoites are injected into the human host during blood feeding. These sporozoites migrate to the liver and invade liver cells, where they grow and form thousands of hepatic merozoites. These hepatic merozoites then leave the liver cells and enter the bloodstream, where they invade red blood cells and initiate the parasite's asexual reproduction cycle, which causes the symptoms of malaria. The parasite grows within the protected niche of red blood cells, forming 16–32 merozoites. These merozoites, upon maturation, emerge from the host cell and invade new red blood cells. Some of these parasites differentiate to form germ cells, the sexual form of the parasite. These can be taken up by mosquitoes, where male and female gametes are formed, fuse, and differentiate on the extracellular matrix of the mosquito's midgut to form zygosporangia. Sporozoites are formed within the zygosporangia, and upon emerging from there, they migrate to the salivary glands and are delivered to the next host during blood feeding for the permanence and survival of the parasite.

[0003] Another form of malaria is recurrent malaria caused by Plasmodium vivax, which is a serious pathological condition and can cause the disease's prototype, sometimes leading to death, and is mainly a concern outside of Africa. Plasmodium knowlesi is a zoonotic parasite found in Southeast Asia, usually infecting cynomolgus macaques, but has been shown to infect humans in Borneo, Malaysia.

[0004] Artemisinin, in combination with partner drugs, is a staple in the treatment and control of malaria. However, the increasing threat of drug resistance to artemisinin-based combination therapy (ACT) makes the development of novel antimalarial drugs with new targets that inhibit multiple stages in the parasite's life cycle an urgent priority in the field of malaria control. Such novel antimalarial drugs (e.g., monotherapy or ACT partner drugs) could represent a step towards malaria eradication because they are less likely to contain existing resistance mutations within the parasite population.

[0005] Currently, aspartate proteases are major targets for drug development: HIV aspartate protease has been successfully targeted with drugs used in clinical settings; inhibitors targeting human renin, BACE1, and γ-secretase have already been clinically developed or are in clinical development. In the field of antimalarial drugs, plasmepsin X and plasmepsin IX (PMX and PMIX), aspartate proteases of Plasmodium falciparum, have been identified as potential targets because inhibitors prevent the parasite from escaping from and entering host cells, and prevent the maturation of certain roptree and microname proteins necessary for this process (Pino P, Caldelari R, Mukherjee B, Vahokoski J, Klages N, Maco B, et al. A multistage antimalarial targets the plasmepsins IX and X essential for invasion and egress. Science. 2017;358(6362):522-8). [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Pino P, Caldelari R, Mukherjee B, Vahokoski J, Klages N, Maco B, et al. A multistage antimalarial targets the plasmepsins IX and X essential for invasion and egress. Science. 2017;358(6362):522-8 [Overview of the project] [Means for solving the problem]

[0007] The present invention relates to formula (I): [ka]

[0008] [In the formula, A, X, V, Y, Z, R a , R b , R 3 , R 4 , R 12 , R 13 , R 15 m and p are explained below. The target compounds are those represented by [the formula shown].

[0009] Furthermore, this specification also describes a method for treating malaria parasite infection, comprising administering a compound represented by formula (I) or a pharmaceutically acceptable salt thereof to a person in need of treatment for malaria parasite infection. Furthermore, this specification also describes a method for treating malaria parasite infection, comprising administering a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier to a person in need of treatment for malaria parasite infection.

[0010] Furthermore, this specification describes a method for treating malaria, comprising administering a compound represented by formula (I) or a pharmaceutically acceptable salt thereof to a person in need of treatment for malaria.

[0011] The present invention further provides the use of a composition (including pharmaceutical compositions) for the treatment of malaria, wherein the composition comprises one or more compounds of the present invention (e.g., one of the compounds of the present invention) or a tautomer thereof, or a pharmaceutically acceptable salt or solvate of said compound and / or said tautomer, optionally together with one or more additional therapeutic agents, optionally in an optionally acceptable (e.g., pharmaceutically acceptable) carrier or diluent.

[0012] Furthermore, the present invention provides a method of using a pharmaceutical composition for treating malaria parasitic infection, for treating malaria, for inhibiting plasmepsin X, or for doubly inhibiting plasmepsin X and plasmepsin IX, wherein the pharmaceutical composition comprises one or more of the compounds in free form or in the form of pharmaceutically acceptable salts together with one or more conventional pharmaceutical excipients. Methods of using a combination of the compounds or salts of the present invention together with one or more additional pharmaceutically active agents are also provided.

[0013] The present invention further provides a method for inhibiting plasmmepsin X or a method for doubly inhibiting the activity of plasmmepsin X and plasmmepsin IX, and a method for treating, preventing, improving, and / or delaying the onset of a disease or disorder (e.g., malaria) in which inhibition of plasmmepsin X and / or plasmmepsin IX has or may have a therapeutic effect.

[0014] The present invention further provides a method for inhibiting Plasmodium falciparum aspartate protease. The present invention further provides a method for inhibiting the growth of Plasmodium falciparum by inhibiting plasmmepsin X. The present invention further provides a method for inhibiting the growth of Plasmodium falciparum by inhibiting both PMX and plasmmepsin IX.

[0015] The present invention further provides a method for treating malaria by inhibiting plasmmepsin X. The present invention further provides a method for treating malaria by inhibiting both PMX and plasmmepsin IX.

[0016] These embodiments and other embodiments of the present invention are described in detail below or will be apparent to those skilled in the art, and such embodiments are included within the scope of the present invention. [Modes for carrying out the invention]

[0017] Described herein is structural formula (I): [Chemical Formula]

[0018] [wherein A is a straight-chain or branched-chain saturated or unsaturated (C3-C 10 ) alkylene, phenyl(C3-C 10 ) alkylene or cycloalkyl(C3-C 10 ) alkylene, wherein one or more additional -CH2- groups in A may independently be replaced by a substructure selected from the group consisting of O, S, NR, CONR, NRCO, SO2 and SO2NR, and wherein one or more of the hydrogens along A may be replaced by a group independently selected from hydroxyl, halogen and C 1-3 haloalkyl; X is a bond, C(R 14 )2, O, S, SO, SO2 or NH; Y is CR 9 or N, where when Y is N, Z is CR 11 and V is CR 10 ; V is CR 10 or N, where when V is N, Z is CR 11 and Y is CR 9 ; Z is CR 11 or N, where when Z is N, V is CR 10 and Y is CR 9 ; R is hydrogen, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkyl OH, COC1-C6 alkyl or COOC1-C6 alkyl; R aThis includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylC3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkyl N(R 7 )(R 8 ) or R b When combined with, it forms a C3-C6 cycloalkyl or heterocycloalkyl, where the C3-C6 cycloalkyl or heterocycloalkyl is unsubstituted or halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6alkyl, C1-C6 alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1-C6alkylCOOC1-C6alkyl, C3-C6 cycloalkyl, C1-C6 alkylC3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6alkylO haloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 It is substituted with one or two substituents selected from the group consisting of ); R b This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylC3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R 7 )(R8 ), N(R 7 )(R 8 ) or C1-C6 alkyl N(R 7 )(R 8 ) or R a When combined with, it forms a C3-C6 cycloalkyl or heterocycloalkyl, where the C3-C6 cycloalkyl or heterocycloalkyl is unsubstituted or halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6alkyl, C1-C6 alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1-C6alkylCOOC1-C6alkyl, C3-C6 cycloalkyl, C1-C6 alkylC3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6alkylO haloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 It is substituted with 1 to 3 substituents selected from the group consisting of ); R 3 This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R) 7 )(R 8 ), N(R 7 )(R 8 ), C1-C6 alkyl N(R 7 )(R 8 ), C1-C6 alkyl (OCH2CH2) n N(R 7 )(R 8 ) or C1-C6 alkyl O halo C1-C6 alkyl, or R 4 When combined with other elements, it forms a C3-C6 cycloalkyl or C3-C6 heterocycloalkyl group; R 4This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R) 7 )(R 8 ), N(R 7 )(R 8 ), C1-C6 alkyl N(R 7 )(R 8 ), C1-C6 alkyl (OCH2CH2) n N(R 7 )(R 8 ) or C1-C6 alkyl O halo C1-C6 alkyl, or R 3 When combined with other elements, it forms a C3-C6 cycloalkyl or C3-C6 heterocycloalkyl group; R 7 These are hydrogen, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, COC1-C6 alkyl, or COOC1-C6 alkyl; R 8 These are hydrogen, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, COC1-C6 alkyl, or COOC1-C6 alkyl; R 9 This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R) 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkyl N(R 7 )(R 8 ) and; R 10is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkyl OC1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkyl OH, CON(R 7 )(R 8 )、N(R 7 )(R 8 ) or C1-C6 alkyl N(R 7 )(R 8 ); R 11 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkyl OC1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkyl OH, CON(R 7 )(R 8 )、N(R 7 )(R 8 ) or C1-C6 alkyl N(R 7 )(R 8 ); R 12 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkyl OC1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkyl OH, CON(R 7 )(R 8 )、N(R 7 )(R 8 ) or C1-C6 alkyl N(R 7 )(R 8 ); R 13 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkyl OC1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkyl OH, CON(R 7 )(R 8 )、N(R 7 )(R 8 ) or C1-C6 alkyl N(R 7 )(R 8 ); R 14 Each of these is present in the following forms: hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R) 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 Independently selected from the group consisting of; R 15 This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R) 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkyl N(R 7 )(R 8 ) and; R 16 Each of these is present in the following forms: hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R) 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 Independently selected from the group consisting of; m is either 0 or 1; n is 1, 2, 3 or 4; and, p is either 0 or 1. It is a compound that has [a certain characteristic].

[0019] In the embodiments described herein, X is bonded, C(R 14)2, O, S, SO, SO2 or NH. In certain embodiments described herein, X is a bond. In certain embodiments, X is C(R 14 )2, and here, R 14 This will be discussed in more detail below. In certain embodiments, X is a bond, CH2, CH(CH3), C(CH3)2, O, CH(OCH3), SO2, or CF2. In other embodiments, X is CH2, O, S, SO, SO2, or NH. In certain embodiments, X is CH2. In embodiments described herein, X is O. In certain embodiments described herein, X is S. In certain embodiments described herein, X is SO. In other embodiments described herein, X is SO2. In certain embodiments described herein, X is NH.

[0020] In the embodiments described herein, Y is CR 9 Or N. In a particular embodiment, Y is CR 9 And here, R 9 This will be discussed in detail below. In certain embodiments, Y is N. In certain embodiments, Y is CH. In certain embodiments, if Y is N, then Z is CR. 11 And V is CR 10 That is the case.

[0021] In the embodiments described herein, V is CR 10 Or N. In a particular embodiment, V is CR 10 And here, R 10 This will be discussed in detail below. In certain embodiments, V is N. In certain embodiments, V is CH. In certain embodiments, if V is N, then Z is CR. 11 And Y is CR 9 That is the case.

[0022] In the embodiments described herein, Z is CR 11 Or N. In certain embodiments, Z is CR11 And here, R 11 This will be discussed in detail below. In certain embodiments, Z is CH. In certain embodiments, Z is N. In certain embodiments, if Z is N, then V is CR. 10 And Y is CR 9 That is the case.

[0023] In certain embodiments, X is O, Y and V are each CH, and Z is N. In certain embodiments, X is O, Y and Z are each CH, and V is N. In certain embodiments, X is O, and V, Y and Z are all CH at the same time.

[0024] In the compounds described herein, R a This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylC3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkyl N(R 7 )(R 8 ) or R bWhen combined with, it forms a C3-C6 cycloalkyl or heterocycloalkyl, where the C3-C6 cycloalkyl or heterocycloalkyl is unsubstituted or halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6alkyl, C1-C6 alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1-C6alkylCOOC1-C6alkyl, C3-C6 cycloalkyl, C1-C6 alkylC3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6alkylO haloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 It is substituted with one or two substituents selected from the group consisting of ).

[0025] In certain embodiments described herein, R a It is hydrogen.

[0026] In a particular embodiment, R a These are halogens. Suitable examples of halogens include chlorine, bromine, fluorine, and iodine.

[0027] In a particular embodiment, R a This is CN.

[0028] In a particular embodiment, R a It is OH.

[0029] In a particular embodiment, R a It is a C1-C6 alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy.

[0030] In a particular embodiment, R a It is a C1-C6 alkyl group.

[0031] In a particular embodiment, R a It is a C1-C6 alkylCOOH group.

[0032] In a particular embodiment, R a COOH is.

[0033] In a particular embodiment, R a This is an oxo group.

[0034] In a particular embodiment, R a It is a COOC1-C6 alkyl group.

[0035] In a particular embodiment, R a It is a C1-C6 alkyl COOC1-C6 alkyl.

[0036] In a particular embodiment, R a These are C3-C6 cycloalkyl groups. Suitable examples of cycloalkyl groups, but not limited to, include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0037] In a particular embodiment, R a These are C1-C6 alkyl and C3-C6 cycloalkyl groups. Appropriate examples of cycloalkyl groups, though not limited to these, include: [ka]

[0038] These are some examples.

[0039] In a particular embodiment, R aR is a C1-C6 alkyl group. Examples of C1-C6 alkyl groups, though not limited to them, include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In a particular embodiment, R a It is methyl.

[0040] In a particular embodiment, R a This is a C1-C6 alkyl O halo C1-C6 alkyl. Appropriate examples of C1-C6 alkyl O halo C1-C6 alkyl are, but are not limited to, [ka]

[0041] These are some examples.

[0042] In a particular embodiment, R a These are halo-C1-C6 alkyl groups. Suitable examples of halo-alkyl groups, but not limited to, include fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl.

[0043] In a particular embodiment, R a The compound is a C1-C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol.

[0044] In a particular embodiment, R aCON(R 7 )(R 8 ) In certain embodiments, R a N(R) 7 )(R 8 ) In certain embodiments, R a C1-C6 alkylN(R 7 )(R 8 ) and here, R 7 and R 8 This will be explained in detail below.

[0045] In certain embodiments, the compounds described herein are of formula (II): [ka]

[0046] It is represented as follows.

[0047] In a particular embodiment, R a R b Together with these, they form a C3-C6 cycloalkyl or heterocycloalkyl, where the C3-C6 cycloalkyl or heterocycloalkyl is unsubstituted or halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylC3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 It is substituted with one or two substituents selected from the group consisting of ).

[0048] In a particular embodiment, R a R bTogether with these, they form a C3-C6 cycloalkyl, where the cycloalkyl is unsubstituted or halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylC3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 It is substituted with one or two substituents selected from the group consisting of ).

[0049] Appropriate examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0050] In certain embodiments, the cycloalkyl is not substituted. In certain embodiments, the heterocycloalkyl is halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylC3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 It is substituted with one or two substituents selected from the group consisting of ).

[0051] In certain embodiments, the cycloalkyl is a halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylC3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 It is substituted with one substituent selected from the group consisting of ).

[0052] In certain embodiments, the cycloalkyl is a halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylC3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 It is substituted with two substituents selected from the group consisting of ).

[0053] In certain embodiments, the cycloalkyl group is substituted with an OH group.

[0054] In a particular embodiment, R a R bTogether with these, they form a heterocycloalkyl, where the heterocycloalkyl is either unsubstituted or halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylC3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 It is substituted with one or two substituents selected from the group consisting of ).

[0055] Non-limiting examples of monocyclic heterocycloalkyl groups include piperidyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, β-lactam, γ-lactam, δ-lactam, β-lactone, γ-lactone, δ-lactone, and pyrrolidinone, as well as their oxides. Non-limiting examples of heterocycloalkyl groups include, but are not limited to, [ka]

[0056] These are some examples.

[0057] A non-limiting example of a bicyclic heterocycloalkyl group is, but is not limited to, [ka]

[0058] These are some examples.

[0059] In a particular embodiment, R aR b Together with, [ka]

[0060] It forms.

[0061] In certain embodiments, the heterocycloalkyl is not substituted. In certain embodiments, the heterocycloalkyl is halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylC3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 It is substituted with one or two substituents selected from the group consisting of ).

[0062] In certain embodiments, the heterocycloalkyl is a halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylC3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 It is substituted with one substituent selected from the group consisting of ).

[0063] In certain embodiments, the heterocycloalkyl is a halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylC3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 It is substituted with two substituents selected from the group consisting of ).

[0064] In certain embodiments, the heterocycloalkyl group is substituted with two substituents selected from the group consisting of C1-C6 alkyl groups.

[0065] In the compounds described herein, R b This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylC3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkyl N(R 7 )(R 8 ) or R aWhen combined with, it forms a C3-C6 cycloalkyl or heterocycloalkyl, where the C3-C6 cycloalkyl or heterocycloalkyl is unsubstituted or halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6alkyl, C1-C6 alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1-C6alkylCOOC1-C6alkyl, C3-C6 cycloalkyl, C1-C6 alkylC3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6alkylO haloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 It is substituted with one or two substituents selected from the group consisting of ).

[0066] In certain embodiments described herein, R b It is hydrogen.

[0067] In a particular embodiment, R b These are halogens. Suitable examples of halogens include chlorine, bromine, fluorine, and iodine.

[0068] In a particular embodiment, R b This is CN.

[0069] In a particular embodiment, R b It is OH.

[0070] In a particular embodiment, R b It is a C1-C6 alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy.

[0071] In a particular embodiment, R b It is a C1-C6 alkyl group.

[0072] In a particular embodiment, R b It is a C1-C6 alkylCOOH group.

[0073] In a particular embodiment, R b COOH is.

[0074] In a particular embodiment, R b This is an oxo group.

[0075] In a particular embodiment, R b It is a COOC1-C6 alkyl group.

[0076] In a particular embodiment, R b It is a C1-C6 alkyl COOC1-C6 alkyl.

[0077] In a particular embodiment, R b These are C3-C6 cycloalkyl groups. Suitable examples of cycloalkyl groups, but not limited to, include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0078] In a particular embodiment, R b These are C1-C6 alkyl and C3-C6 cycloalkyl groups. Appropriate examples of cycloalkyl groups, though not limited to these, include: [ka]

[0079] These are some examples.

[0080] In a particular embodiment, R bR is a C1-C6 alkyl group. Examples of C1-C6 alkyl groups, though not limited to them, include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In a particular embodiment, R b It is methyl.

[0081] In a particular embodiment, R b This is a C1-C6 alkyl O halo C1-C6 alkyl. Appropriate examples of C1-C6 alkyl O halo C1-C6 alkyl are, but are not limited to, [ka]

[0082] These are some examples.

[0083] In a particular embodiment, R b These are halo-C1-C6 alkyl groups. Suitable examples of halo-alkyl groups, but not limited to, include fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl.

[0084] In a particular embodiment, R b The compound is a C1-C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol.

[0085] In a particular embodiment, R bCON(R 7 )(R 8 ) In certain embodiments, R b N(R) 7 )(R 8 ) In certain embodiments, R b C1-C6 alkylN(R 7 )(R 8 ) and here, R 7 and R 8 This will be explained in detail below.

[0086] In a particular embodiment, R b R a Together with these, they form a cycloalkyl or heterocycloalkyl, where the cycloalkyl or heterocycloalkyl is unsubstituted or halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylC3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 It is substituted with one or two substituents selected from the group consisting of ).

[0087] In a particular embodiment, R b R aTogether with, they form a cycloalkyl, where the cycloalkyl is unsubstituted or halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylC3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 It is substituted with one or two substituents selected from the group consisting of ).

[0088] Appropriate examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0089] In certain embodiments, the cycloalkyl is not substituted. In certain embodiments, the heterocycloalkyl is halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylC3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 It is substituted with one or two substituents selected from the group consisting of ).

[0090] In certain embodiments, the cycloalkyl is a halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylC3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 It is substituted with one substituent selected from the group consisting of ).

[0091] In certain embodiments, the cycloalkyl is a halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylC3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 It is substituted with two substituents selected from the group consisting of ).

[0092] In certain embodiments, the cycloalkyl group is substituted with an OH group.

[0093] In a particular embodiment, R b R aTogether with these, they form a heterocycloalkyl, where the heterocycloalkyl is either unsubstituted or halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylC3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 It is substituted with one or two substituents selected from the group consisting of ).

[0094] Non-limiting examples of monocyclic heterocycloalkyl groups include piperidyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, β-lactam, γ-lactam, δ-lactam, β-lactone, γ-lactone, δ-lactone, and pyrrolidinone, as well as their oxides. Non-limiting examples of heterocycloalkyl groups include, but are not limited to, [ka]

[0095] These are some examples.

[0096] A non-limiting example of a bicyclic heterocycloalkyl group is, but is not limited to, [ka]

[0097] These are some examples.

[0098] In a particular embodiment, R bR a Together with, [ka]

[0099] It forms.

[0100] In certain embodiments, the cycloalkyl or heterocycloalkyl is not substituted. In certain embodiments, the cycloalkyl or heterocycloalkyl is halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylC3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 ) are substituted with one or two substituents selected from the group consisting of ). In certain embodiments, the cycloalkyl or heterocycloalkyl is substituted with halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylC3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8) is substituted with one substituent selected from the group consisting of ). In a particular embodiment, the cycloalkyl or heterocycloalkyl is substituted with halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylC3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 It is substituted with two substituents selected from the group consisting of ).

[0101] In certain embodiments, the heterocycloalkyl is substituted with two substituents selected from the group consisting of C1-C6 alkyl groups. In certain embodiments, the cycloalkyl is substituted with two substituents selected from the group consisting of C1-C6 alkyl groups. In certain embodiments, the cycloalkyl is unsubstituted.

[0102] In the embodiments described herein, R 3 This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R) 7 )(R 8 ), N(R 7 )(R 8 ), C1-C6 alkyl N(R 7 )(R 8 ), C1-C6 alkyl (OCH2CH2) n N(R 7 )(R 8 ) or C1-C6 alkyl O halo C1-C6 alkyl, or R 4When combined with other elements, it forms a C3-C6 cycloalkyl or C3-C6 heterocycloalkyl group.

[0103] In certain embodiments of the compounds described herein, R 3 This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R) 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkyl N(R 7 )(R 8 ) or R 4 When combined with, it forms a C3-C6 cycloalkyl or C3-C6 heterocycloalkyl. In certain embodiments, R 3 is hydrogen. In a particular embodiment, R 3 is a halogen. Suitable halogens include fluorine, chlorine, bromine, and iodine. In certain embodiments, R 3 is CN. In a particular embodiment, R 3 It is OH.

[0104] In a particular embodiment, R 3 R is a C1-C6 alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. In certain embodiments, R 3 is a C1-C6 alkyl group. In certain embodiments, R 3 is COOH. In a particular embodiment, R 3 is a C1-C6 alkylCOOH. In certain embodiments, R 3 R is a C3-C6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 3R is a C1-C6 alkyl group. Examples of C1-C6 alkyl groups, though not limited to them, include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In a particular embodiment, R 3 is a halo-C1-C6 alkyl group. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 3 R is a C1-C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol. In certain embodiments, R 3 CON(R 7 )(R 8 ) is. N(R 7 )(R 8 Appropriate examples of ) include, but are not limited to, CONH2 and CON(CH3)2. In certain embodiments, R 3 N(R) 7 )(R 8 ) is. N(R 7 )(R 8 Appropriate examples of ) include, but are not limited to, NH2 and N(CH3)2. In certain embodiments, R 3 C1-C6 alkylN(R 7 )(R 8 ) is C1-C6 alkyl N(R 7 )(R 8 Appropriate examples of ) include, but are not limited to, [ka]

[0105] These include R. 7 and R 8 This will be discussed in more detail below.

[0106] In a particular embodiment, R 3 This is a C1-C6 alkyl O halo C1-C6 alkyl. Appropriate examples of haloalkyls are, but are not limited to, [ka]

[0107] These are some examples.

[0108] In a particular embodiment, R 3 is C1-C6 alkyl (OCH2CH2) n N(R 7 )(R 8 ) is R 7 , R 8 The terms and n will be discussed in detail below. C1-C6 alkyl(OCH2CH2) n N(R 7 )(R 8 Appropriate examples of ) include, but are not limited to, [ka]

[0109] These are some examples.

[0110] With respect to the compounds described herein, n is 1, 2, 3, or 4. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4.

[0111] In a particular embodiment, R 3 R 4Together with it, it forms a C3-C6 cycloalkyl or C3-C6 heterocycloalkyl. In certain embodiments, R 3 R 4 Together with these, they form a C3-C6 cycloalkyl group. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 3 R 4 Together with these, they form C3-C6 heterocycloalkyls. Suitable examples of heterocycloalkyls, but not limited to, include piperidyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, β-lactam, γ-lactam, δ-lactam, β-lactone, γ-lactone, δ-lactone, and pyrrolidinone, as well as their oxides.

[0112] In a particular embodiment, R 3 hydrogen, fluorine, methyl, ethyl, OH, methoxy, [ka]

[0113] That is the case.

[0114] In a particular embodiment, R 3 is hydrogen, methyl, ethyl or [ka]

[0115] That is the case.

[0116] In a particular embodiment, R 3 R 4 Together with it, it forms oxetanyl.

[0117] In certain embodiments described herein, R 4This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R) 7 )(R 8 ), N(R 7 )(R 8 ), C1-C6 alkyl N(R 7 )(R 8 ), C1-C6 alkyl (OCH2CH2) n N(R 7 )(R 8 ) or C1-C6 alkyl O halo C1-C6 alkyl, or R 3 When combined with, it forms a C3-C6 cycloalkyl or C3-C6 heterocycloalkyl. In certain embodiments of the compounds described herein, R 4 This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R) 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkyl N(R 7 )(R 8 ) or R 3 When combined with, it forms a C3-C6 cycloalkyl or C3-C6 heterocycloalkyl. In certain embodiments, R 4 is hydrogen. In a particular embodiment, R 4 is a halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R 4 is CN. In a particular embodiment, R 4 It is OH.

[0118] In a particular embodiment, R 4R is a C1-C6 alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. In certain embodiments, R 4 is a C1-C6 alkyl group. In certain embodiments, R 4 is COOH. In a particular embodiment, R 4 is a C1-C6 alkylCOOH. In certain embodiments, R 4 R is a C3-C6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 4 R is a C1-C6 alkyl group. Examples of C1-C6 alkyl groups, though not limited to them, include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In a particular embodiment, R 4 is a halo-C1-C6 alkyl group. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 4 R is a C1-C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol. In certain embodiments, R 4 CON(R 7 )(R 8 ) is. N(R 7 )(R8 Appropriate examples of ) include, but are not limited to, CONH2 and CON(CH3)2. In certain embodiments, R 4 N(R) 7 )(R 8 ) is. N(R 7 )(R 8 Appropriate examples of ) include, but are not limited to, NH2 and N(CH3)2. In certain embodiments, R 4 C1-C6 alkylN(R 7 )(R 8 ) is C1-C6 alkyl N(R 7 )(R 8 Appropriate examples of ) include, but are not limited to, [ka]

[0119] These include R. 7 and R 8 This will be discussed in more detail below.

[0120] In a particular embodiment, R 4 This is a C1-C6 alkyl O halo C1-C6 alkyl. Appropriate examples of haloalkyls are, but are not limited to, [ka]

[0121] These are some examples.

[0122] In a particular embodiment, R 4 is C1-C6 alkyl (OCH2CH2) n N(R 7 )(R 8 ) is R 7 , R 8 This is discussed in detail below, and n is discussed above. C1-C6 alkyl(OCH2CH2) n N(R 7 )(R 8Appropriate examples of ) include, but are not limited to, [ka]

[0123] These are some examples.

[0124] In a particular embodiment, R 4 R 3 Together with it, it forms a C3-C6 cycloalkyl or C3-C6 heterocycloalkyl. In certain embodiments, R 4 R 3 Together with these, they form a C3-C6 cycloalkyl group. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 4 R 3 Together with these, they form C3-C6 heterocycloalkyls. Suitable examples of heterocycloalkyls, but not limited to, include piperidyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, β-lactam, γ-lactam, δ-lactam, β-lactone, γ-lactone, δ-lactone, and pyrrolidinone, as well as their oxides.

[0125] In a particular embodiment, R 4 is hydrogen or methyl. In certain embodiments, R 4 is hydrogen, methyl, ethyl or [ka]

[0126] In a particular embodiment, R 4 R 3 Together with it, it forms oxetanyl. In certain embodiments, R 3 and R 4 Both are hydrogen, methyl, or ethyl.

[0127] In a particular embodiment, R 3 is hydrogen, and R 4 It is hydrogen.

[0128] In a particular embodiment, R 3 and R 4 Both are halogens, where the halogen is selected from fluorine, chlorine, bromine, and iodine. In a particular embodiment, R 3 and R 4 Both are fluorine.

[0129] In the embodiments described herein, R 5 This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylC3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkyl N(R 7 )(R 8 )

[0130] In certain embodiments described herein, R 5 It is hydrogen.

[0131] In a particular embodiment, R 5 These are halogens. Suitable examples of halogens include chlorine, bromine, fluorine, and iodine.

[0132] In a particular embodiment, R 5 This is CN.

[0133] In a particular embodiment, R 5 It is OH.

[0134] In a particular embodiment, R 5 It is a C1-C6 alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy.

[0135] In a particular embodiment, R 5 It is a C1-C6 alkyl group.

[0136] In a particular embodiment, R 5 It is a C1-C6 alkylCOOH group.

[0137] In a particular embodiment, R 5 COOH is.

[0138] In a particular embodiment, R 5 This is an oxo group.

[0139] In a particular embodiment, R 5 It is a COOC1-C6 alkyl group.

[0140] In a particular embodiment, R 5 It is a C1-C6 alkyl COOC1-C6 alkyl.

[0141] In a particular embodiment, R 5 These are C3-C6 cycloalkyl groups. Suitable examples of cycloalkyl groups, but not limited to, include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0142] In a particular embodiment, R 5 These are C1-C6 alkyl and C3-C6 cycloalkyl groups. Appropriate examples of cycloalkyl groups, though not limited to these, include: [ka]

[0143] These are some examples.

[0144] In a particular embodiment, R 5 R is a C1-C6 alkyl group. Examples of C1-C6 alkyl groups, though not limited to them, include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In a particular embodiment, R 5 It is methyl.

[0145] In a particular embodiment, R 5 This is a C1-C6 alkyl O halo C1-C6 alkyl. Appropriate examples of C1-C6 alkyl O halo C1-C6 alkyl are, but are not limited to, [ka]

[0146] These are some examples.

[0147] In a particular embodiment, R 5 These are halo-C1-C6 alkyl groups. Suitable examples of halo-alkyl groups, but not limited to, include fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl.

[0148] In a particular embodiment, R 5 The compound is a C1-C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol.

[0149] In a particular embodiment, R 5 CON(R 7 )(R 8 ) In certain embodiments, R 1 N(R) 7 )(R 8 ) In certain embodiments, R 5 C1-C6 alkylN(R 7 )(R 8 ) and here, R 7 and R 8 This will be explained in detail below.

[0150] In a particular embodiment, R 5 These are hydrogen, methyl, ethyl, or t-butyl.

[0151] In the embodiments described herein, R 6 This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylC3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkyl N(R 7 )(R 8 )

[0152] In certain embodiments described herein, R 6 It is hydrogen.

[0153] In a particular embodiment, R 6 These are halogens. Suitable examples of halogens include chlorine, bromine, fluorine, and iodine.

[0154] In a particular embodiment, R 6 This is CN.

[0155] In a particular embodiment, R 6 It is OH.

[0156] In a particular embodiment, R 6 It is a C1-C6 alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy.

[0157] In a particular embodiment, R 6 It is a C1-C6 alkyl group.

[0158] In a particular embodiment, R 6 It is a C1-C6 alkylCOOH group.

[0159] In a particular embodiment, R 6 COOH is.

[0160] In a particular embodiment, R 6 This is an oxo group.

[0161] In a particular embodiment, R 6 It is a COOC1-C6 alkyl group.

[0162] In a particular embodiment, R 6 It is a C1-C6 alkyl COOC1-C6 alkyl.

[0163] In a particular embodiment, R 6 These are C3-C6 cycloalkyl groups. Suitable examples of cycloalkyl groups, but not limited to, include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0164] In a particular embodiment, R 6 These are C1-C6 alkyl and C3-C6 cycloalkyl groups. Appropriate examples of cycloalkyl groups, though not limited to these, include: [ka]

[0165] These are some examples.

[0166] In a particular embodiment, R 6 R is a C1-C6 alkyl group. Examples of C1-C6 alkyl groups, though not limited to them, include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In a particular embodiment, R 6 It is methyl.

[0167] In a particular embodiment, R 6 This is a C1-C6 alkyl O halo C1-C6 alkyl. Appropriate examples of C1-C6 alkyl O halo C1-C6 alkyl are, but are not limited to, [ka]

[0168] These are some examples.

[0169] In a particular embodiment, R 6 These are halo-C1-C6 alkyl groups. Suitable examples of halo-alkyl groups, but not limited to, include fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl.

[0170] In a particular embodiment, R 6 The compound is a C1-C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol.

[0171] In a particular embodiment, R 6 CON(R 7 )(R 8 ) In certain embodiments, R 1 N(R) 7 )(R 8 ) In certain embodiments, R 6 C1-C6 alkylN(R 7 )(R 8 ) and here, R 7 and R 8 This will be explained in detail below.

[0172] In a particular embodiment, R 6 These are hydrogen, methyl, ethyl, or t-butyl.

[0173] In the embodiments described herein, R 7 R is hydrogen, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, COC1-C6 alkyl, or COOC1-C6 alkyl. In certain embodiments, R 7 These are hydrogen, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, or C1-C6 alkylOH.

[0174] In a particular embodiment, R 7 is hydrogen. In a particular embodiment, R 7 is a C1-C6 alkylCOOH. In certain embodiments, R 7 is COOH. In a particular embodiment, R 7R is a C3-C6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 7 R is a C1-C6 alkyl group. Examples of C1-C6 alkyl groups, though not limited to them, include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In a particular embodiment, R 7 is a halo-C1-C6 alkyl group. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 7 The compound is a C1-C6 alkyl OH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol.

[0175] In a particular embodiment, R 7 is a COC1-C6 alkyl group. Suitable examples, but not limited to, include COCH3. In certain embodiments, R 7 This is a COOC1-C6 alkyl group. Suitable examples, though not limited to them, include COOCH3.

[0176] In the embodiments described herein, R 8R is hydrogen, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, COC1-C6 alkyl, or COOC1-C6 alkyl. In certain embodiments, R 8 These are hydrogen, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, or C1-C6 alkylOH.

[0177] In a particular embodiment, R 8 is hydrogen. In a particular embodiment, R 8 is a C1-C6 alkylCOOH. In certain embodiments, R 8 is COOH. In a particular embodiment, R 8 R is a C3-C6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 8 R is a C1-C6 alkyl group. Examples of C1-C6 alkyl groups, though not limited to them, include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In a particular embodiment, R 8 is a halo-C1-C6 alkyl group. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 8The compound is a C1-C6 alkyl OH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol.

[0178] In a particular embodiment, R 8 is a COC1-C6 alkyl group. Suitable examples, but not limited to, include COCH3. In certain embodiments, R 8 This is a COOC1-C6 alkyl group. Suitable examples, though not limited to them, include COOCH3.

[0179] In the embodiments described herein, R 9 This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R) 7 )(R 8 ) and N(R 7 )(R 8 ) In certain embodiments, R 9 is hydrogen. In a particular embodiment, R 9 is a halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R 9 is CN. In a particular embodiment, R 9 It is OH.

[0180] In a particular embodiment, R 9 R is a C1-C6 alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. In certain embodiments, R 9 is a C1-C6 alkyl group. In certain embodiments, R 9 is COOH. In a particular embodiment, R 9 is a C1-C6 alkylCOOH. In certain embodiments, R 9R is a C3-C6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 9 R is a C1-C6 alkyl group. Examples of C1-C6 alkyl groups, though not limited to them, include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In a particular embodiment, R 9 is a halo-C1-C6 alkyl group. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 9 R is a C1-C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol. In certain embodiments, R 9 CON(R 7 )(R 8 ) In certain embodiments, R 9 N(R) 7 )(R 8 ) In certain embodiments, R 9 C1-C6 alkylN(R 7 )(R 8 )

[0181] With respect to the compounds described herein, R 10This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R) 7 )(R 8 ) and N(R 7 )(R 8 ) In certain embodiments, R 10 is hydrogen. In a particular embodiment, R 10 is a halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R 10 is CN. In a particular embodiment, R 10 It is OH.

[0182] In a particular embodiment, R 10 R is a C1-C6 alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. In certain embodiments, R 10 is a C1-C6 alkyl group. In certain embodiments, R 10 is COOH. In a particular embodiment, R 10 is a C1-C6 alkylCOOH. In certain embodiments, R 10 R is a C3-C6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 10R is a C1-C6 alkyl group. Examples of C1-C6 alkyl groups, though not limited to them, include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In a particular embodiment, R 10 is a halo-C1-C6 alkyl group. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 10 R is a C1-C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol. In certain embodiments, R 10 CON(R 7 )(R 8 ) In certain embodiments, R 10 N(R) 7 )(R 8 ) In certain embodiments, R 10 C1-C6 alkylN(R 7 )(R 8 )

[0183] In the embodiments described herein, R 11 This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R) 7 )(R 8) and N(R 7 )(R 8 ) In certain embodiments, R 11 is hydrogen. In a particular embodiment, R 11 is a halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R 11 is CN. In a particular embodiment, R 11 It is OH.

[0184] In a particular embodiment, R 11 R is a C1-C6 alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. In certain embodiments, R 11 is a C1-C6 alkyl group. In certain embodiments, R 11 is COOH. In a particular embodiment, R 11 is a C1-C6 alkylCOOH. In certain embodiments, R 11 R is a C3-C6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 11 R is a C1-C6 alkyl group. Examples of C1-C6 alkyl groups, though not limited to them, include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In a particular embodiment, R 11is a halo-C1-C6 alkyl group. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 11 R is a C1-C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol. In certain embodiments, R 11 CON(R 7 )(R 8 ) In certain embodiments, R 11 N(R) 7 )(R 8 ) In certain embodiments, R 11 C1-C6 alkylN(R 7 )(R 8 )

[0185] In the embodiments described herein, R 12 This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R) 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkyl N(R 7 )(R 8 ) In certain embodiments, R 12 is hydrogen. In a particular embodiment, R 12 is a halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R 12 is CN. In a particular embodiment, R 12 It is OH.

[0186] In a particular embodiment, R 12is a C1-C6 alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. In certain embodiments, R 12 is a C1-C6 alkyl group. In certain embodiments, R 12 is COOH. In a particular embodiment, R 12 is a C1-C6 alkylCOOH. In certain embodiments, R 12 R is a C3-C6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 12 R is a C1-C6 alkyl group. Examples of C1-C6 alkyl groups, though not limited to them, include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In a particular embodiment, R 12 is a halo-C1-C6 alkyl group. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 12 R is a C1-C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol. In certain embodiments, R 12 CON(R 7 )(R 8 ) In certain embodiments, R12 N(R) 7 )(R 8 ) In certain embodiments, R 12 C1-C6 alkylN(R 7 )(R 8 )

[0187] In a particular embodiment, R 12 is hydrogen, methyl, ethyl, methoxy, OH or [ka]

[0188] That is the case.

[0189] In a particular embodiment, R 12 is hydrogen or [ka]

[0190] That is In the embodiments described herein, R 13 This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R) 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkyl N(R 7 )(R 8 ) In certain embodiments, R 13 is hydrogen. In a particular embodiment, R 13 is a halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R 13 is CN. In a particular embodiment, R 13 It is OH.

[0191] In a particular embodiment, R 13is a C1-C6 alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. In certain embodiments, R 13 is a C1-C6 alkyl group. In certain embodiments, R 13 is COOH. In a particular embodiment, R 13 is a C1-C6 alkylCOOH. In certain embodiments, R 13 R is a C3-C6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 13 R is a C1-C6 alkyl group. Examples of C1-C6 alkyl groups, though not limited to them, include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In a particular embodiment, R 13 is a halo-C1-C6 alkyl group. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 13 R is a C1-C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol. In certain embodiments, R 13 CON(R 7 )(R 8 ) In certain embodiments, R13 N(R) 7 )(R 8 ) In certain embodiments, R 13 C1-C6 alkylN(R 7 )(R 8 )

[0192] In a particular embodiment, R 13 is hydrogen, methyl, ethyl, methoxy, OH or [ka]

[0193] That is the case.

[0194] In a particular embodiment, R 13 is hydrogen or [ka]

[0195] That is the case.

[0196] In a particular embodiment, R 12 and R 13 These are independently selected from the group consisting of hydrogen and C1-C6 alkyl, C1-C6 alkyl, and C1-C6 alkyl.

[0197] In certain embodiments described herein, R 14 Each of these is present in the following forms: hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R) 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkyl N(R 7 )(R 8 In a particular embodiment, R is independently selected from the group consisting of ). 14 is hydrogen. In a particular embodiment, R14 is a halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R 14 is CN. In a particular embodiment, R 14 It is OH.

[0198] In a particular embodiment, R 14 is a C1-C6 alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. In certain embodiments, R 14 is a C1-C6 alkyl group. In certain embodiments, R 14 is COOH. In a particular embodiment, R 14 is a C1-C6 alkylCOOH. In certain embodiments, R 14 R is a C3-C6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 14 R is a C1-C6 alkyl group. Examples of C1-C6 alkyl groups, though not limited to them, include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In a particular embodiment, R 14 is a halo-C1-C6 alkyl group. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R14 R is a C1-C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol. In certain embodiments, R 14 CON(R 7 )(R 8 ) In certain embodiments, R 14 N(R) 7 )(R 8 ) In certain embodiments, R 14 C1-C6 alkylN(R 7 )(R 8 )

[0199] In a particular embodiment, X is C(R 14 )If R 14 The element is independently selected from the group consisting of hydrogen, halogen, OH, C1-C6alkylOH, C1-C6alkylalkoxy, C1-C6alkylOC1-C6alkyl, and C1-C6alkyl.

[0200] In a particular embodiment, R 14 is hydrogen, methyl, ethyl, methoxy, OH or [ka]

[0201] That is the case.

[0202] In the embodiments described herein, R 15 This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R) 7 )(R 8 ) and N(R 7 )(R 8 ) In certain embodiments, R 15 is hydrogen. In a particular embodiment, R 15is a halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R 15 is CN. In a particular embodiment, R 15 It is OH.

[0203] In a particular embodiment, R 15 R is a C1-C6 alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. In certain embodiments, R 15 is a C1-C6 alkyl group. In certain embodiments, R 15 is COOH. In a particular embodiment, R 15 is a C1-C6 alkylCOOH. In certain embodiments, R 15 R is a C3-C6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 15 R is a C1-C6 alkyl group. Examples of C1-C6 alkyl groups, though not limited to them, include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In a particular embodiment, R 15 It is ethyl.

[0204] In a particular embodiment, R 15is a halo-C1-C6 alkyl group. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 15 R is a C1-C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol. In certain embodiments, R 15 CON(R 7 )(R 8 ) In certain embodiments, R 15 N(R) 7 )(R 8 ) In certain embodiments, R 15 C1-C6 alkylN(R 7 )(R 8 )

[0205] In a particular embodiment, R 15 It is either methyl or ethyl.

[0206] In the embodiments described herein, R 16 This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R) 7 )(R 8 ) and N(R 7 )(R 8 ) In certain embodiments, R 16 is hydrogen. In a particular embodiment, R 16 is a halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R 16 is CN. In a particular embodiment, R 16 It is OH.

[0207] In a particular embodiment, R 16R is a C1-C6 alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. In certain embodiments, R 16 is a C1-C6 alkyl group. In certain embodiments, R 16 is COOH. In a particular embodiment, R 16 is a C1-C6 alkylCOOH. In certain embodiments, R 16 R is a C3-C6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 16 R is a C1-C6 alkyl group. Examples of C1-C6 alkyl groups, though not limited to them, include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In a particular embodiment, R 16 is a halo-C1-C6 alkyl group. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 16 R is a C1-C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol. In certain embodiments, R 16 CON(R 7 )(R 8 ) In certain embodiments, R16 N(R) 7 )(R 8 ) In certain embodiments, R 16 C1-C6 alkylN(R 7 )(R 8 )

[0208] In the embodiments of the compounds described herein, m is either 0 or 1. In certain embodiments, m is 0. In certain embodiments, m is 1.

[0209] In the embodiments of the compounds described herein, p is 0 or 1. In certain embodiments, p is 0. In certain embodiments, p is 1.

[0210] In the embodiments described herein, A is a linear or branched saturated or unsaturated (C3-C) group containing at least one -CH2- group. 10 ) Alkylene, phenyl (C3-C 10 ) Alkylene or cycloalkyl (C3-C 10 ) is an alkylene, where one or more further -CH2- groups in A may be independently replaced by substructures selected from the group consisting of O, S, NR, CONR, NRCO, SO2 and SO2NR, and where one or more hydrogens along A are hydroxyl, halogen and C 1-3 It can be replaced with a group independently selected from the haloalkyl group. In certain embodiments, A is a linear or branched saturated or unsaturated (C3-C3) group. 10 ) Alkylene or cycloalkyl (C3-C 10 ) is an alkylene, where one or more -CH2- groups in A may be independently replaced by substructures selected from the group consisting of O, S, and NH. In certain embodiments, A always has at least one -CH2- group.

[0211] In certain embodiments, A is a linear (C3-C 10 ) is an alkylene. Linear (C3-C 10 Examples of alkylenes include, [ka]

[0212] These are some examples.

[0213] In a particular embodiment, A is a branched chain (C3-C 10 ) is alkylene. Appropriate branched chain (C3-C 10 ) This does not limit the definition of alkylene, [ka]

[0214] These are some examples.

[0215] In a particular embodiment, A is saturated (C3-C 10 ) These are alkylenes. For example, [ka]

[0216] These are some examples.

[0217] In certain embodiments, A is unsaturated (C3-C 10 ) is alkylene. Appropriate unsaturated (C3-C 10 )As alkylene, the saturated (C3-C 10 )In any of the alkylenes, hydrogen has been removed, and there is one or more double or triple covalent bonds between adjacent carbon atoms. Unsaturated (C3-C 10 Examples of alkylenes are not limited to these, but [ka]

[0218] These are some examples.

[0219] In another embodiment, A is a linear cycloalkyl (C3-C10 ) is an alkylene. Appropriate linear cycloalkyl (C3-C 10 )As an alkylene, the two carbon atoms in the chain are (C3-C 10 )Cycloalkyl (C3-C) contained in cycloalkyl 10 Examples include alkylenes. Linear cycloalkyl (C3-C 10 Examples of alkylenes are not limited to these, but [ka]

[0220] These are some examples.

[0221] In certain embodiments, A is a branched cycloalkyl (C3-C 10 ) is alkylene. Appropriate branched chain cycloalkyl (C3-C 10 )As an alkylene, the two carbon atoms in the chain are (C3-C 10 ) Branched chains (C3-C) contained in cycloalkyls 10 Examples include alkylenes. Cycloalkyl (C3-C 10 Examples of alkylenes are not limited to these, but [ka]

[0222] These are some examples.

[0223] In certain embodiments, A is a saturated cycloalkyl (C3-C 10 ) is alkylene. Saturated cycloalkyl (C3-C 10 Examples of alkylenes are not limited to these, but [ka]

[0224] These are some examples.

[0225] In certain embodiments, A is an unsaturated cycloalkyl (C3-C10 ) is alkylene. Unsaturated cyclo(C3-C 10 Examples of alkylenes are not limited to these, but [ka]

[0226] These are some examples.

[0227] In certain embodiments, A is an unsaturated or saturated phenyl (C3-C3) 10 ) is alkylene. Unsaturated and saturated phenyl (C3-C 10 Examples of alkylenes are not limited to these, but [ka]

[0228] These are some examples.

[0229] In another embodiment, one or more -CH2- groups in A may be independently replaced with substructures selected from the group consisting of O, S, NR, CONR, NRCO, SO2, and SO2NR. In another embodiment, one or more -CH2- groups in A may be independently replaced with substructures selected from the group consisting of O, S, and NH. In another embodiment, one or more -CH2- groups in A may be independently replaced with O. In another embodiment, one or more -CH2- groups in A may be independently replaced with S. In another embodiment, one or more -CH2- groups in A may be independently replaced with NR. In another embodiment, one or more -CH2- groups in A may be independently replaced with CONR. In another embodiment, one or more -CH2- groups in A may be independently replaced with NRCO. In another embodiment, one or more -CH2- groups in A may be independently replaced with SO2. In another embodiment, one or more -CH2- groups in A may be independently replaced with SO2NR. R will be explained in more detail below.

[0230] In the embodiments described herein, R is hydrogen, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkylOH, COC1-C6 alkyl, or COOC1-C6 alkyl. In certain embodiments, R is hydrogen, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, halo-C1-C6 alkyl, or C1-C6 alkylOH.

[0231] In certain embodiments, R is hydrogen. In certain embodiments, R is a C1-C6 alkylCOOH. In certain embodiments, R is a COOH. In certain embodiments, R is a C3-C6 cycloalkyl. Suitable examples of cycloalkyls, but not limited to, include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R is a C1-C6 alkyl. Examples of C1-C6 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In certain embodiments, R is a halo-C1-C6 alkyl group. Suitable examples of halo-alkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R is a C1-C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol.

[0232] In certain embodiments, R is a COC1-C6 alkyl group. Suitable examples, but not limited to, include COCH3.

[0233] Examples of such embodiments include, but are not limited to, [ka]

[0234] These are some examples.

[0235] In a particular embodiment, A is [ka]

[0236] That is the case.

[0237] In certain embodiments, one or more of the hydrogen atoms along A are hydroxyl, halogen, and C 1-3 It can be replaced with a group independently selected from the haloalkyl group. Examples of suitable halogens include chlorine, bromine, fluorine, and iodine. In certain embodiments, A is [ka]

[0238] That is the case.

[0239] Further described herein is structural formula (III): [ka]

[0240] [During the ceremony, A is a linear or branched saturated or unsaturated (C3-C) group containing at least one -CH2- group. 10 ) Alkylene, phenyl (C3-C 10 ) Alkylene or cycloalkyl (C3-C 10 ) is an alkylene, where one or more further -CH2- groups in A may be independently replaced by substructures selected from the group consisting of O, S, NR, CONR, NRCO, SO2 and SO2NR, and where one or more hydrogens along A are hydroxyl, halogen and C 1-3 It can be replaced with a group independently selected from the haloalkyl group; Q is C(R 16 )2, O, S, SO, SO2 or NH; X is a bond, C(R 14 )2, O, S, SO, SO2 or NH; Y is CR 9 Or N, where if Y is N, then Z is CR 11 And V is CR 10 and; V is CR 10 Or N, where if V is N, then Z is CR 11 And Y is CR 9 and; Z is CR 11 Or N, where if Z is N, then V is CR 10 And Y is CR 9 and; R is hydrogen, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, COC1-C6 alkyl, or COOC1-C6 alkyl; R 1This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylC3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkyl N(R 7 )(R 8 ) and; R 2 This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylC3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkyl N(R 7 )(R 8 ) and; R 3 This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R) 7 )(R 8 ), N(R 7 )(R 8 ), C1-C6 alkyl N(R 7 )(R 8 ), C1-C6 alkyl (OCH2CH2) n N(R 7 )(R 8) or is C1-C6 alkyl O halo C1-C6 alkyl, or, R 4 when combined with, forms C3-C6 cycloalkyl or C3-C6 heterocycloalkyl; R 4 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkyl OC1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkyl OH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ), C1-C6 alkyl N(R 7 )(R 8 ), C1-C6 alkyl (OCH2CH2) n N(R 7 )(R 8 ) or is C1-C6 alkyl O halo C1-C6 alkyl, or, R 3 when combined with, forms C3-C6 cycloalkyl or C3-C6 heterocycloalkyl; R 5 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkyl OC1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkyl OH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkyl N(R 7 )(R 8 ); R 6 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkyl OC1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkyl OH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkyl N(R 7 )(R8 ) and; R 7 These are hydrogen, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, COC1-C6 alkyl, or COOC1-C6 alkyl; R 8 These are hydrogen, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, COC1-C6 alkyl, or COOC1-C6 alkyl; R 9 This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R) 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkyl N(R 7 )(R 8 ) and; R 10 This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R) 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkyl N(R 7 )(R 8 ) and; R 11 This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R) 7 )(R 8 ), N(R 7 )(R 8) or C1-C6 alkyl N(R 7 )(R 8 ) and; R 12 This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R) 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkyl N(R 7 )(R 8 ) and; R 13 This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R) 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkyl N(R 7 )(R 8 ) and; R 14 Each of these is present in the following forms: hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R) 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 Independently selected from the group consisting of; R 15 This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R) 7 )(R8 ), N(R 7 )(R 8 ) or C1-C6 alkyl N(R 7 )(R 8 ); R 16 each occurrence of which is independently selected from the group consisting of hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkyl OC1-C6 alkyl, C1-C6 alkyl COOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkyl OH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkyl N(R 7 )(R 8 ); l is 0 or 1; m is 0 or 1; n is 1, 2, 3 or 4; and, p is 0 or 1〕 is a compound having.

[0241] In the embodiments described herein, Q is C(R 16 )2, O, S, SO, SO2 or NH. In certain embodiments, Q is C(R 16 )2, where R 16This will be discussed in more detail below. In certain embodiments, Q is CH2, CH(CH3), C(CH3)2, O, CH(OCH3), SO2, or CF2. In other embodiments, Q is CH2, O, S, SO, SO2, or NH. In certain embodiments, Q is CH2. In certain embodiments described herein, Q is O. In certain embodiments described herein, Q is S. In other embodiments described herein, Q is SO. In other embodiments described herein, Q is SO2. In certain embodiments described herein, Q is NH. In other embodiments described herein, Q is O or SO2. In yet another embodiment described herein, Q is O or CH2.

[0242] In the embodiments described herein, X is bonded, C(R 14 )2, O, S, SO, SO2 or NH. In certain embodiments described herein, X is a bond. In certain embodiments, X is C(R 14 )2, and here, R 14 This will be discussed in more detail below. In certain embodiments, X is a bond, CH2, CH(CH3), C(CH3)2, O, CH(OCH3), SO2, or CF2. In other embodiments, X is CH2, O, S, SO, SO2, or NH. In certain embodiments, X is CH2. In embodiments described herein, X is O. In certain embodiments described herein, X is S. In certain embodiments described herein, X is SO. In other embodiments described herein, X is SO2. In certain embodiments described herein, X is NH.

[0243] In the embodiments described herein, Y is CR 9 Or N. In a particular embodiment, Y is CR 9 And here, R 9This will be discussed in detail below. In certain embodiments, Y is N. In certain embodiments, Y is CH. In certain embodiments, if Y is N, then Z is CR. 11 And V is CR 10 That is the case.

[0244] In the embodiments described herein, V is CR 10 Or N. In a particular embodiment, V is CR 10 And here, R 10 This will be discussed in detail below. In certain embodiments, V is N. In certain embodiments, V is CH. In certain embodiments, if V is N, then Z is CR. 11 And Y is CR 9 That is the case.

[0245] In the embodiments described herein, Z is CR 11 Or N. In certain embodiments, Z is CR 11 And here, R 11 This will be discussed in detail below. In certain embodiments, Z is CH. In certain embodiments, Z is N. In certain embodiments, if Z is N, then V is CR. 10 And Y is CR 9 That is the case.

[0246] In certain embodiments, X is O, Y and V are each CH, and Z is N. In certain embodiments, X is O, Y and Z are each CH, and V is N. In certain embodiments, X is O, and V, Y and Z are all CH at the same time.

[0247] In certain embodiments, X is a bond, Y and V are CH, respectively, and Z is N.

[0248] Further described herein is structural formula (IIIA): [ka]

[0249] [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 15 A and Q are as described herein. The compound is represented by R. Embodiments of the present invention are R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 15 This is achieved when A and Q are as described in Formula III. Another embodiment of Formula IIIA is R 3 and R 4 This is achieved when both are hydrogen, methyl, ethyl, or halogen. Another embodiment of formula IIIA is R 3 and R 4 This is realized when both are halogens selected from chlorine and fluorine. Another embodiment of formula IIIA is realized when Q is CH2, CH(CH3), C(CH3)2, O, CH(OCH3), SO2, or CF2. In another embodiment described herein, Q in formula IIIA is O or SO2. In yet another embodiment described herein, Q in formula IIIIA is O or CH2. Another embodiment of formula IIIA is a linear or branched saturated or unsaturated (C3-C) group containing at least one -CH2- group. 10 ) is an alkylene, where one or more further -CH2- groups in A may be independently replaced by substructures selected from the group consisting of O, S, NR, CONR, NRCO, SO2 and SO2NR, and where one or more hydrogens along A may be hydroxyl, halogen and C 1-3 This is achieved when the group can be replaced by a group independently selected from the haloalkyl group.

[0250] Furthermore, the structural formula (IIIB): [ka]

[0251] [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 15 A and Q are as described herein. The compound is represented by R. Embodiments of the present invention are R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 15 This is achieved when A and Q are as described in Formula III. Another embodiment of Formula IIIB is R 3 and R 4 This is achieved when both are hydrogen, methyl, ethyl, or halogen. Another embodiment of formula IIIB is R 3 and R 4 This is realized when both are halogens selected from chlorine and fluorine. Another embodiment of formula IIIB is realized when Q is CH2, CH(CH3), C(CH3)2, O, CH(OCH3), SO2, or CF2. In another embodiment described herein, Q in formula IIIB is O or SO2. In yet another embodiment described herein, Q in formula IIIIB is O or CH2. Another embodiment of formula IIIB is a linear or branched saturated or unsaturated (C3-C) group containing at least one -CH2- group. 10 ) is an alkylene, where one or more further -CH2- groups in A may be independently replaced by substructures selected from the group consisting of O, S, NR, CONR, NRCO, SO2 and SO2NR, and where one or more hydrogens along A may be hydroxyl, halogen and C 1-3This is achieved when the group can be replaced by a group independently selected from the haloalkyl group.

[0252] Specific embodiments include: Formulas IV-VI: [ka]

[0253] It is expressed as follows.

[0254] In the embodiments described herein, R 1 This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylC3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkyl N(R 7 )(R 8 )

[0255] In certain embodiments described herein, R 1 It is hydrogen.

[0256] In a particular embodiment, R 1 These are halogens. Suitable examples of halogens include chlorine, bromine, fluorine, and iodine.

[0257] In a particular embodiment, R 1 This is CN.

[0258] In a particular embodiment, R 1 It is OH.

[0259] In a particular embodiment, R 1It is a C1-C6 alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy.

[0260] In a particular embodiment, R 1 It is a C1-C6 alkyl group.

[0261] In a particular embodiment, R 1 It is a C1-C6 alkylCOOH group.

[0262] In a particular embodiment, R 1 COOH is.

[0263] In a particular embodiment, R 1 This is an oxo group.

[0264] In a particular embodiment, R 1 It is a COOC1-C6 alkyl group.

[0265] In a particular embodiment, R 1 It is a C1-C6 alkyl COOC1-C6 alkyl.

[0266] In a particular embodiment, R 1 These are C3-C6 cycloalkyl groups. Suitable examples of cycloalkyl groups, but not limited to, include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0267] In a particular embodiment, R 1 These are C1-C6 alkyl and C3-C6 cycloalkyl groups. Appropriate examples of cycloalkyl groups, though not limited to these, include: [ka]

[0268] These are some examples.

[0269] In a particular embodiment, R1 The C1-C6 alkyl group is a C1-C6 alkyl group. Examples of C1-C6 alkyl groups, though not limited to them, include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl.

[0270] In a particular embodiment, R 1 This is a C1-C6 alkyl O halo C1-C6 alkyl. Appropriate examples of C1-C6 alkyl O halo C1-C6 alkyl are, but are not limited to, [ka]

[0271] These are some examples.

[0272] In a particular embodiment, R 1 These are halo-C1-C6 alkyl groups. Suitable examples of halo-alkyl groups, but not limited to, include fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl.

[0273] In a particular embodiment, R 1 The compound is a C1-C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol.

[0274] In a particular embodiment, R 1 CON(R 7 )(R8 ) In certain embodiments, R 1 N(R) 7 )(R 8 ) In certain embodiments, R 1 C1-C6 alkylN(R 7 )(R 8 ) and here, R 7 and R 8 This will be explained in detail below.

[0275] In a particular embodiment, R 1 These are hydrogen, bromine, fluorine, chlorine, methyl, OH, halogen, CN oxo, methoxymethyl, COOCH2CH3, or trifluoromethyl.

[0276] In the embodiments described herein, R 2 This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylC3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkyl N(R 7 )(R 8 )

[0277] In certain embodiments described herein, R 2 It is hydrogen.

[0278] In a particular embodiment, R 2 These are halogens. Suitable examples of halogens include chlorine, bromine, fluorine, and iodine.

[0279] In a particular embodiment, R 2 This is CN.

[0280] In a particular embodiment, R 2 It is OH.

[0281] In a particular embodiment, R 2 It is a C1-C6 alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy.

[0282] In a particular embodiment, R 2 It is a C1-C6 alkyl group.

[0283] In a particular embodiment, R 2 It is a C1-C6 alkylCOOH group.

[0284] In a particular embodiment, R 2 COOH is.

[0285] In a particular embodiment, R 2 This is an oxo group.

[0286] In a particular embodiment, R 2 It is a COOC1-C6 alkyl group.

[0287] In a particular embodiment, R 2 It is a C1-C6 alkyl COOC1-C6 alkyl.

[0288] In a particular embodiment, R 2 These are C3-C6 cycloalkyl groups. Suitable examples of cycloalkyl groups, but not limited to, include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0289] In a particular embodiment, R 2 These are C1-C6 alkyl and C3-C6 cycloalkyl groups. Appropriate examples of cycloalkyl groups, though not limited to these, include: [ka]

[0290] These are some examples.

[0291] In a particular embodiment, R 2 The C1-C6 alkyl group is a C1-C6 alkyl group. Examples of C1-C6 alkyl groups, though not limited to them, include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl.

[0292] In a particular embodiment, R 2 This is a C1-C6 alkyl O halo C1-C6 alkyl. Appropriate examples of C1-C6 alkyl O halo C1-C6 alkyl are, but are not limited to, [ka]

[0293] These are some examples.

[0294] In a particular embodiment, R 2 These are halo-C1-C6 alkyl groups. Suitable examples of halo-alkyl groups, but not limited to, include fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl.

[0295] In a particular embodiment, R 2The compound is a C1-C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol.

[0296] In a particular embodiment, R 2 CON(R 7 )(R 8 ) In certain embodiments, R 1 N(R) 7 )(R 8 ) In certain embodiments, R 2 C1-C6 alkylN(R 7 )(R 8 ) and here, R 7 and R 8 This will be explained in detail below.

[0297] In a particular embodiment, R 2 These are hydrogen, bromine, fluorine, chlorine, methyl, OH, halogen, CN oxo, methoxymethyl, COOCH2CH3, or trifluoromethyl.

[0298] In a particular embodiment, R 1 and R 2 Both are hydrogen. In a particular embodiment, R 1 is OH, and R 2 It is hydrogen.

[0299] In the embodiments described herein, R 3 This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R) 7 )(R 8 ), N(R 7 )(R 8 ), C1-C6 alkyl N(R 7 )(R 8 ), C1-C6 alkyl (OCH2CH2) n N(R 7 )(R8 ) or C1-C6 alkyl O halo C1-C6 alkyl, or R 4 When combined with other elements, it forms a C3-C6 cycloalkyl or C3-C6 heterocycloalkyl group.

[0300] In certain embodiments of the compounds described herein, R 3 This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R) 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkyl N(R 7 )(R 8 ) or R 4 When combined with, it forms a C3-C6 cycloalkyl or C3-C6 heterocycloalkyl. In certain embodiments, R 3 is hydrogen. In a particular embodiment, R 3 is a halogen. Suitable halogens include fluorine, chlorine, bromine, and iodine. In certain embodiments, R 3 is CN. In a particular embodiment, R 3 It is OH.

[0301] In a particular embodiment, R 3 R is a C1-C6 alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. In certain embodiments, R 3 is a C1-C6 alkyl group. In certain embodiments, R 3 is COOH. In a particular embodiment, R 3 is a C1-C6 alkylCOOH. In certain embodiments, R 3R is a C3-C6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 3 R is a C1-C6 alkyl group. Examples of C1-C6 alkyl groups, though not limited to them, include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In a particular embodiment, R 3 is a halo-C1-C6 alkyl group. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 3 R is a C1-C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol. In certain embodiments, R 3 CON(R 7 )(R 8 ) is. N(R 7 )(R 8 Appropriate examples of ) include, but are not limited to, CONH2 and CON(CH3)2. In certain embodiments, R 3 N(R) 7 )(R 8 ) is. N(R 7 )(R 8 Appropriate examples of ) include, but are not limited to, NH2 and N(CH3)2. In certain embodiments, R 3C1-C6 alkylN(R 7 )(R 8 ) is C1-C6 alkyl N(R 7 )(R 8 Appropriate examples of ) include, but are not limited to, [ka]

[0302] These include R. 7 and R 8 This will be discussed in more detail below.

[0303] In a particular embodiment, R 3 This is a C1-C6 alkyl O halo C1-C6 alkyl. Appropriate examples of haloalkyls are, but are not limited to, [ka]

[0304] These are some examples.

[0305] In a particular embodiment, R 3 is C1-C6 alkyl (OCH2CH2) n N(R 7 )(R 8 ) is R 7 , R 8 The terms and n will be discussed in detail below. C1-C6 alkyl(OCH2CH2) n N(R 7 )(R 8 Appropriate examples of ) include, but are not limited to, [ka]

[0306] These are some examples.

[0307] With respect to the compounds described herein, n is 1, 2, 3, or 4. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4.

[0308] In a particular embodiment, R 3 R 4 Together with it, it forms a C3-C6 cycloalkyl or C3-C6 heterocycloalkyl. In certain embodiments, R 3 R 4 Together with these, they form a C3-C6 cycloalkyl group. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 3 R 4 Together with these, they form C3-C6 heterocycloalkyls. Suitable examples of heterocycloalkyls, but not limited to, include piperidyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, β-lactam, γ-lactam, δ-lactam, β-lactone, γ-lactone, δ-lactone, and pyrrolidinone, as well as their oxides.

[0309] In a particular embodiment, R 3 hydrogen, fluorine, methyl, ethyl, OH, methoxy, [ka]

[0310] That is the case.

[0311] In a particular embodiment, R 3 is hydrogen, methyl, ethyl or [ka]

[0312] That is the case.

[0313] In a particular embodiment, R 3 R 4 Together with it, it forms oxetanyl.

[0314] In certain embodiments described herein, R 4 This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R) 7 )(R 8 ), N(R 7 )(R 8 ), C1-C6 alkyl N(R 7 )(R 8 ), C1-C6 alkyl (OCH2CH2) n N(R 7 )(R 8 ) or C1-C6 alkyl O halo C1-C6 alkyl, or R 3 When combined with, it forms a C3-C6 cycloalkyl or C3-C6 heterocycloalkyl. In certain embodiments of the compounds described herein, R 4 This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R) 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkyl N(R 7 )(R 8 ) or R 3 When combined with, it forms a C3-C6 cycloalkyl or C3-C6 heterocycloalkyl. In certain embodiments, R 4 is hydrogen. In a particular embodiment, R 4is a halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R 4 is CN. In a particular embodiment, R 4 It is OH.

[0315] In a particular embodiment, R 4 R is a C1-C6 alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. In certain embodiments, R 4 is a C1-C6 alkyl group. In certain embodiments, R 4 is COOH. In a particular embodiment, R 4 is a C1-C6 alkylCOOH. In certain embodiments, R 4 R is a C3-C6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 4 R is a C1-C6 alkyl group. Examples of C1-C6 alkyl groups, though not limited to them, include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In a particular embodiment, R 4 is a halo-C1-C6 alkyl group. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 4R is a C1-C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol. In certain embodiments, R 4 CON(R 7 )(R 8 ) is. N(R 7 )(R 8 Appropriate examples of ) include, but are not limited to, CONH2 and CON(CH3)2. In certain embodiments, R 4 N(R) 7 )(R 8 ) is. N(R 7 )(R 8 Appropriate examples of ) include, but are not limited to, NH2 and N(CH3)2. In certain embodiments, R 4 C1-C6 alkylN(R 7 )(R 8 ) is C1-C6 alkyl N(R 7 )(R 8 Appropriate examples of ) include, but are not limited to, [ka]

[0316] These include R. 7 and R 8 This will be discussed in more detail below.

[0317] In a particular embodiment, R 4 This is a C1-C6 alkyl O halo C1-C6 alkyl. Appropriate examples of haloalkyls are, but are not limited to, [ka]

[0318] These are some examples.

[0319] In a particular embodiment, R 4 is C1-C6 alkyl (OCH2CH2) n N(R7 )(R 8 ) is R 7 , R 8 This is discussed in detail below, and n is discussed above. C1-C6 alkyl(OCH2CH2) n N(R 7 )(R 8 Appropriate examples of ) include, but are not limited to, [ka]

[0320] These are some examples.

[0321] In a particular embodiment, R 4 R 3 Together with it, it forms a C3-C6 cycloalkyl or C3-C6 heterocycloalkyl. In certain embodiments, R 4 R 3 Together with these, they form a C3-C6 cycloalkyl group. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 4 R 3 Together with these, they form C3-C6 heterocycloalkyls. Suitable examples of heterocycloalkyls, but not limited to, include piperidyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, β-lactam, γ-lactam, δ-lactam, β-lactone, γ-lactone, δ-lactone, and pyrrolidinone, as well as their oxides.

[0322] In a particular embodiment, R 4 is hydrogen or methyl. In certain embodiments, R 4 is hydrogen, methyl, ethyl or [ka]

[0323] In a particular embodiment, R 4 R 3 Together with it, it forms oxetanyl. In certain embodiments, R 3 and R 4 Both are hydrogen, methyl, or ethyl.

[0324] In a particular embodiment, R 3 is hydrogen, and R 4 It is hydrogen.

[0325] In the embodiments described herein, R 5 This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylC3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkyl N(R 7 )(R 8 )

[0326] In certain embodiments described herein, R 5 It is hydrogen.

[0327] In a particular embodiment, R 5 These are halogens. Suitable examples of halogens include chlorine, bromine, fluorine, and iodine.

[0328] In a particular embodiment, R 5 This is CN.

[0329] In a particular embodiment, R 5 It is OH.

[0330] In a particular embodiment, R 5 It is a C1-C6 alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy.

[0331] In a particular embodiment, R 5 It is a C1-C6 alkyl group.

[0332] In a particular embodiment, R 5 It is a C1-C6 alkylCOOH group.

[0333] In a particular embodiment, R 5 COOH is.

[0334] In a particular embodiment, R 5 This is an oxo group.

[0335] In a particular embodiment, R 5 It is a COOC1-C6 alkyl group.

[0336] In a particular embodiment, R 5 It is a C1-C6 alkyl COOC1-C6 alkyl.

[0337] In a particular embodiment, R 5 These are C3-C6 cycloalkyl groups. Suitable examples of cycloalkyl groups, but not limited to, include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0338] In a particular embodiment, R 5 These are C1-C6 alkyl and C3-C6 cycloalkyl groups. Appropriate examples of cycloalkyl groups, though not limited to these, include: [ka]

[0339] These are some examples.

[0340] In a particular embodiment, R 5 R is a C1-C6 alkyl group. Examples of C1-C6 alkyl groups, though not limited to them, include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In a particular embodiment, R 5 It is methyl.

[0341] In a particular embodiment, R 5 This is a C1-C6 alkyl O halo C1-C6 alkyl. Appropriate examples of C1-C6 alkyl O halo C1-C6 alkyl are, but are not limited to, [ka]

[0342] These are some examples.

[0343] In a particular embodiment, R 5 These are halo-C1-C6 alkyl groups. Suitable examples of halo-alkyl groups, but not limited to, include fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl.

[0344] In a particular embodiment, R 5 The compound is a C1-C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol.

[0345] In a particular embodiment, R 5 CON(R 7 )(R 8 ) In certain embodiments, R 1 N(R) 7 )(R 8 ) In certain embodiments, R 5 C1-C6 alkylN(R 7 )(R 8 ) and here, R 7 and R 8 This will be explained in detail below.

[0346] In a particular embodiment, R 5 These are hydrogen, methyl, ethyl, or t-butyl.

[0347] In the embodiments described herein, R 6 This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, oxo, COOC1-C6 alkyl, C1-C6 alkylCOOC1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkylC3-C6 cycloalkyl, C1-C6 alkyl, -C1-C6 alkylO haloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkyl N(R 7 )(R 8 )

[0348] In certain embodiments described herein, R 6 It is hydrogen.

[0349] In a particular embodiment, R 6 These are halogens. Suitable examples of halogens include chlorine, bromine, fluorine, and iodine.

[0350] In a particular embodiment, R 6This is CN.

[0351] In a particular embodiment, R 6 It is OH.

[0352] In a particular embodiment, R 6 It is a C1-C6 alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy.

[0353] In a particular embodiment, R 6 It is a C1-C6 alkyl group.

[0354] In a particular embodiment, R 6 It is a C1-C6 alkylCOOH group.

[0355] In a particular embodiment, R 6 COOH is.

[0356] In a particular embodiment, R 6 This is an oxo group.

[0357] In a particular embodiment, R 6 It is a COOC1-C6 alkyl group.

[0358] In a particular embodiment, R 6 It is a C1-C6 alkyl COOC1-C6 alkyl.

[0359] In a particular embodiment, R 6 These are C3-C6 cycloalkyl groups. Suitable examples of cycloalkyl groups, but not limited to, include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0360] In a particular embodiment, R 6 These are C1-C6 alkyl and C3-C6 cycloalkyl groups. Appropriate examples of cycloalkyl groups, though not limited to these, include: [ka]

[0361] These are some examples.

[0362] In a particular embodiment, R 6 R is a C1-C6 alkyl group. Examples of C1-C6 alkyl groups, though not limited to them, include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In a particular embodiment, R 6 It is methyl.

[0363] In a particular embodiment, R 6 This is a C1-C6 alkyl O halo C1-C6 alkyl. Appropriate examples of C1-C6 alkyl O halo C1-C6 alkyl are, but are not limited to, [ka]

[0364] These are some examples.

[0365] In a particular embodiment, R 6 These are halo-C1-C6 alkyl groups. Suitable examples of halo-alkyl groups, but not limited to, include fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl.

[0366] In a particular embodiment, R 6The compound is a C1-C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol.

[0367] In a particular embodiment, R 6 CON(R 7 )(R 8 ) In certain embodiments, R 1 N(R) 7 )(R 8 ) In certain embodiments, R 6 C1-C6 alkylN(R 7 )(R 8 ) and here, R 7 and R 8 This will be explained in detail below.

[0368] In a particular embodiment, R 6 These are hydrogen, methyl, ethyl, or t-butyl.

[0369] In the embodiments described herein, R 7 R is hydrogen, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, COC1-C6 alkyl, or COOC1-C6 alkyl. In certain embodiments, R 7 These are hydrogen, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, or C1-C6 alkylOH.

[0370] In a particular embodiment, R 7 is hydrogen. In a particular embodiment, R 7 is a C1-C6 alkylCOOH. In certain embodiments, R 7 is COOH. In a particular embodiment, R 7 R is a C3-C6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R7 R is a C1-C6 alkyl group. Examples of C1-C6 alkyl groups, though not limited to them, include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In a particular embodiment, R 7 is a halo-C1-C6 alkyl group. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 7 The compound is a C1-C6 alkyl OH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol.

[0371] In a particular embodiment, R 7 is a COC1-C6 alkyl group. Suitable examples, but not limited to, include COCH3. In certain embodiments, R 7 This is a COOC1-C6 alkyl group. Suitable examples, though not limited to them, include COOCH3.

[0372] In the embodiments described herein, R 8 R is hydrogen, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, COC1-C6 alkyl, or COOC1-C6 alkyl. In certain embodiments, R 8These are hydrogen, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, or C1-C6 alkylOH.

[0373] In a particular embodiment, R 8 is hydrogen. In a particular embodiment, R 8 is a C1-C6 alkylCOOH. In certain embodiments, R 8 is COOH. In a particular embodiment, R 8 R is a C3-C6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 8 R is a C1-C6 alkyl group. Examples of C1-C6 alkyl groups, though not limited to them, include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In a particular embodiment, R 8 is a halo-C1-C6 alkyl group. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 8 The compound is a C1-C6 alkyl OH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol.

[0374] In a particular embodiment, R 8is a COC1-C6 alkyl group. Suitable examples, but not limited to, include COCH3. In certain embodiments, R 8 This is a COOC1-C6 alkyl group. Suitable examples, though not limited to them, include COOCH3.

[0375] In the embodiments described herein, R 9 This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R) 7 )(R 8 ) and N(R 7 )(R 8 ) In certain embodiments, R 9 is hydrogen. In a particular embodiment, R 9 It is a halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine.

[0376] In a particular embodiment, R 9 is CN. In a particular embodiment, R 9 It is OH.

[0377] In a particular embodiment, R 9 R is a C1-C6 alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. In certain embodiments, R 9 is a C1-C6 alkyl group. In certain embodiments, R 9 is COOH. In a particular embodiment, R 9 is a C1-C6 alkylCOOH. In certain embodiments, R 9 R is a C3-C6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 9R is a C1-C6 alkyl group. Examples of C1-C6 alkyl groups, though not limited to them, include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In a particular embodiment, R 9 is a halo-C1-C6 alkyl group. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 9 R is a C1-C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol. In certain embodiments, R 9 CON(R 7 )(R 8 ) In certain embodiments, R 9 N(R) 7 )(R 8 ) In certain embodiments, R 9 C1-C6 alkylN(R 7 )(R 8 )

[0378] With respect to the compounds described herein, R 10 This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R) 7 )(R 8) and N(R 7 )(R 8 ) In certain embodiments, R 10 is hydrogen. In a particular embodiment, R 10 is a halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R 10 is CN. In a particular embodiment, R 10 It is OH.

[0379] In a particular embodiment, R 10 R is a C1-C6 alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. In certain embodiments, R 10 is a C1-C6 alkyl group. In certain embodiments, R 10 is COOH. In a particular embodiment, R 10 is a C1-C6 alkylCOOH. In certain embodiments, R 10 R is a C3-C6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 10 R is a C1-C6 alkyl group. Examples of C1-C6 alkyl groups, though not limited to them, include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In a particular embodiment, R 10is a halo-C1-C6 alkyl group. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 10 R is a C1-C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol. In certain embodiments, R 10 CON(R 7 )(R 8 ) In certain embodiments, R 10 N(R) 7 )(R 8 ) In certain embodiments, R 10 C1-C6 alkylN(R 7 )(R 8 )

[0380] In the embodiments described herein, R 11 This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R) 7 )(R 8 ) and N(R 7 )(R 8 ) In certain embodiments, R 11 is hydrogen. In a particular embodiment, R 11 is a halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R 11 is CN. In a particular embodiment, R 11 It is OH.

[0381] In a particular embodiment, R 11 R is a C1-C6 alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. In certain embodiments, R11 is a C1-C6 alkyl group. In certain embodiments, R 11 is COOH. In a particular embodiment, R 11 is a C1-C6 alkylCOOH. In certain embodiments, R 11 R is a C3-C6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 11 R is a C1-C6 alkyl group. Examples of C1-C6 alkyl groups, though not limited to them, include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In a particular embodiment, R 11 is a halo-C1-C6 alkyl group. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 11 R is a C1-C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol. In certain embodiments, R 11 CON(R 7 )(R 8 ) In certain embodiments, R 11 N(R) 7 )(R 8 ) In certain embodiments, R 11 C1-C6 alkylN(R 7)(R 8 )

[0382] In the embodiments described herein, R 12 This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R) 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkyl N(R 7 )(R 8 ) In certain embodiments, R 12 is hydrogen. In a particular embodiment, R 12 is a halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R 12 is CN. In a particular embodiment, R 12 It is OH.

[0383] In a particular embodiment, R 12 is a C1-C6 alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. In certain embodiments, R 12 is a C1-C6 alkyl group. In certain embodiments, R 12 is COOH. In a particular embodiment, R 12 is a C1-C6 alkylCOOH. In certain embodiments, R 12 R is a C3-C6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 12R is a C1-C6 alkyl group. Examples of C1-C6 alkyl groups, though not limited to them, include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In a particular embodiment, R 12 is a halo-C1-C6 alkyl group. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 12 R is a C1-C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol. In certain embodiments, R 12 CON(R 7 )(R 8 ) In certain embodiments, R 12 N(R) 7 )(R 8 ) In certain embodiments, R 12 C1-C6 alkylN(R 7 )(R 8 )

[0384] In a particular embodiment, R 12 is hydrogen, methyl, ethyl, methoxy, OH or [ka]

[0385] That is the case.

[0386] In a particular embodiment, R 12 is hydrogen or [ka]

[0387] That is the case.

[0388] In the embodiments described herein, R 13 This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R) 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkyl N(R 7 )(R 8 ) In certain embodiments, R 13 is hydrogen. In a particular embodiment, R 13 is a halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R 13 is CN. In a particular embodiment, R 13 It is OH.

[0389] In a particular embodiment, R 13 is a C1-C6 alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. In certain embodiments, R 13 is a C1-C6 alkyl group. In certain embodiments, R 13 is COOH. In a particular embodiment, R 13 is a C1-C6 alkylCOOH. In certain embodiments, R 13R is a C3-C6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 13 R is a C1-C6 alkyl group. Examples of C1-C6 alkyl groups, though not limited to them, include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In a particular embodiment, R 13 is a halo-C1-C6 alkyl group. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 13 R is a C1-C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol. In certain embodiments, R 13 CON(R 7 )(R 8 ) In certain embodiments, R 13 N(R) 7 )(R 8 ) In certain embodiments, R 13 C1-C6 alkylN(R 7 )(R 8 )

[0390] In a particular embodiment, R 13 is hydrogen, methyl, ethyl, methoxy, OH or [ka]

[0391] That is the case.

[0392] In a particular embodiment, R 13 is hydrogen or [ka]

[0393] That is the case.

[0394] In a particular embodiment, R 12 and R 13 These are independently selected from the group consisting of hydrogen and C1-C6 alkyl, C1-C6 alkyl, and C1-C6 alkyl.

[0395] In certain embodiments described herein, R 14 Each of these is present in the following forms: hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R) 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkyl N(R 7 )(R 8 In a particular embodiment, R is independently selected from the group consisting of ). 14 is hydrogen. In a particular embodiment, R 14 is a halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R 14 is CN. In a particular embodiment, R 14 It is OH.

[0396] In a particular embodiment, R 14is a C1-C6 alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. In certain embodiments, R 14 is a C1-C6 alkyl group. In certain embodiments, R 14 is COOH. In a particular embodiment, R 14 is a C1-C6 alkylCOOH. In certain embodiments, R 14 R is a C3-C6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 14 R is a C1-C6 alkyl group. Examples of C1-C6 alkyl groups, though not limited to them, include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In a particular embodiment, R 14 is a halo-C1-C6 alkyl group. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 14 R is a C1-C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol. In certain embodiments, R 14 CON(R 7 )(R 8 ) In certain embodiments, R14 N(R) 7 )(R 8 ) In certain embodiments, R 14 C1-C6 alkylN(R 7 )(R 8 )

[0397] In a particular embodiment, X is C(R 14 )If R 14 The element is independently selected from the group consisting of hydrogen, halogen, OH, C1-C6alkylOH, C1-C6alkylalkoxy, C1-C6alkylOC1-C6alkyl, and C1-C6alkyl.

[0398] In a particular embodiment, R 14 is hydrogen, methyl, ethyl, methoxy, OH or [ka]

[0399] That is the case.

[0400] In the embodiments described herein, R 15 This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R) 7 )(R 8 ) and N(R 7 )(R 8 ) In certain embodiments, R 15 is hydrogen. In a particular embodiment, R 15 is a halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R 15 is CN. In a particular embodiment, R 15 It is OH.

[0401] In a particular embodiment, R 15R is a C1-C6 alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. In certain embodiments, R 15 is a C1-C6 alkyl group. In certain embodiments, R 15 is COOH. In a particular embodiment, R 15 is a C1-C6 alkylCOOH. In certain embodiments, R 15 R is a C3-C6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 15 R is a C1-C6 alkyl group. Examples of C1-C6 alkyl groups, though not limited to them, include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In a particular embodiment, R 15 It is ethyl.

[0402] In a particular embodiment, R 15 is a halo-C1-C6 alkyl group. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 15 R is a C1-C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol. In certain embodiments, R15 CON(R 7 )(R 8 ) In certain embodiments, R 15 N(R) 7 )(R 8 ) In certain embodiments, R 15 C1-C6 alkylN(R 7 )(R 8 )

[0403] In a particular embodiment, R 15 It is either methyl or ethyl.

[0404] In the embodiments described herein, R 16 This includes hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R) 7 )(R 8 ) and N(R 7 )(R 8 ) In certain embodiments, R 16 is hydrogen. In a particular embodiment, R 16 is a halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R 16 is CN. In a particular embodiment, R 16 It is OH.

[0405] In a particular embodiment, R 16 R is a C1-C6 alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. In certain embodiments, R 16 is a C1-C6 alkyl group. In certain embodiments, R 16 is COOH. In a particular embodiment, R 16 is a C1-C6 alkylCOOH. In certain embodiments, R 16These are C3-C6 cycloalkyl groups. Suitable examples of cycloalkyl groups, but not limited to, include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0406] In a particular embodiment, R 16 R is a C1-C6 alkyl group. Examples of C1-C6 alkyl groups, though not limited to them, include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In a particular embodiment, R 16 is a halo-C1-C6 alkyl group. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 16 R is a C1-C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol. In certain embodiments, R 16 CON(R 7 )(R 8 ) In certain embodiments, R 16 N(R) 7 )(R 8 ) In certain embodiments, R 16 C1-C6 alkylN(R 7 )(R 8 )

[0407] In embodiments of the compounds described herein, l is either 0 or 1. In certain embodiments, l is 0. In certain embodiments, l is 1.

[0408] In the embodiments of the compounds described herein, m is either 0 or 1. In certain embodiments, m is 0. In certain embodiments, m is 1.

[0409] In the embodiments of the compounds described herein, p is 0 or 1. In certain embodiments, p is 0. In certain embodiments, p is 1.

[0410] In certain embodiments, m and p are 1, and X is O.

[0411] In certain embodiments, m and p are 1, and X is CH2.

[0412] In a particular embodiment, m is 0, p is 1, and X is 0.

[0413] In certain embodiments, m and p are 1, and X is SO2.

[0414] In a particular embodiment, m is 0, p is 1, and X is C(R 14 )2, and here, R 14 Each of these elements is independently selected from the group consisting of hydrogen, halogens, OH, C1-C6 alkoxy, and C1-C6 alkyl.

[0415] In a particular embodiment, m is 1, and X is C(R 14 )2, and here, R 14 Each of these elements is independently selected from the group consisting of hydrogen, halogens, OH, C1-C6 alkoxy, and C1-C6 alkyl.

[0416] For example, in a particular embodiment of formula (I), as shown in formula (VII), l is 0; m is 1; p is 1; X is 0; V, Y, and Z are CH; and Q is CH2. [ka]

[0417] For example, in a particular embodiment of formula (I), l, m, and p are 1, as shown in formula (VIII); X is O; V, Y, and Z are CH; and Q is O. [ka]

[0418] In the embodiments described herein, A is a linear or branched saturated or unsaturated (C3-C) group containing at least one -CH2- group. 10 ) Alkylene, phenyl (C3-C 10 ) Alkylene or cycloalkyl (C3-C 10 ) is an alkylene, where one or more further -CH2- groups in A may be independently replaced by substructures selected from the group consisting of O, S, NR, CONR, NRCO, SO2 and SO2NR, and where one or more hydrogens along A are hydroxyl, halogen and C 1-3 It can be replaced with a group independently selected from the haloalkyl group. In certain embodiments, A is a linear or branched saturated or unsaturated (C3-C3) group. 10 ) Alkylene or cycloalkyl (C3-C 10 ) is an alkylene, where one or more -CH2- groups in A may be independently replaced by substructures selected from the group consisting of O, S, and NH. In certain embodiments, A always has at least one -CH2- group.

[0419] In certain embodiments, A is a linear (C3-C 10 ) is an alkylene. Linear (C3-C 10Examples of alkylenes include, [ka]

[0420] These are some examples.

[0421] In a particular embodiment, A is a branched chain (C3-C 10 ) is alkylene. Appropriate branched chain (C3-C 10 ) This does not limit the definition of alkylene, [ka]

[0422] These are some examples.

[0423] In a particular embodiment, A is saturated (C3-C 10 ) These are alkylenes. For example, [ka]

[0424] These are some examples.

[0425] In certain embodiments, A is unsaturated (C3-C 10 ) is alkylene. Appropriate unsaturated (C3-C 10 )As alkylene, the saturated (C3-C 10 )In any of the alkylenes, hydrogen has been removed, and there is one or more double or triple covalent bonds between adjacent carbon atoms. Unsaturated (C3-C 10 Examples of alkylenes are not limited to these, but [ka]

[0426] These are some examples.

[0427] In another embodiment, A is a linear cycloalkyl (C3-C 10 ) is an alkylene. Appropriate linear cycloalkyl (C3-C 10 )As an alkylene, the two carbon atoms in the chain are (C3-C 10 )Cycloalkyl (C3-C) contained in cycloalkyl 10 Examples include alkylenes. Linear cycloalkyl (C3-C 10 Examples of alkylenes are not limited to these, but [ka]

[0428] These are some examples.

[0429] In certain embodiments, A is a branched cycloalkyl (C3-C 10 ) is alkylene. Appropriate branched chain cycloalkyl (C3-C 10 )As an alkylene, the two carbon atoms in the chain are (C3-C 10 ) Branched chains (C3-C) contained in cycloalkyls 10 Examples include alkylenes. Cycloalkyl (C3-C 10 Examples of alkylenes are not limited to these, but [ka]

[0430] These are some examples.

[0431] In certain embodiments, A is a saturated cycloalkyl (C3-C 10 ) is alkylene. Saturated cycloalkyl (C3-C 10 Examples of alkylenes are not limited to these, but [ka]

[0432] These are some examples.

[0433] In certain embodiments, A is an unsaturated cycloalkyl (C3-C 10 ) is alkylene. Unsaturated cyclo(C3-C 10 Examples of alkylenes are not limited to these, but [ka]

[0434] These are some examples.

[0435] In certain embodiments, A is an unsaturated or saturated phenyl (C3-C3) 10 ) is alkylene. Unsaturated and saturated phenyl (C3-C 10 Examples of alkylenes are not limited to these, but [ka]

[0436] These are some examples.

[0437] In another embodiment, one or more -CH2- groups in A may be independently replaced with substructures selected from the group consisting of O, S, NR, CONR, NRCO, SO2, and SO2NR. In another embodiment, one or more -CH2- groups in A may be independently replaced with substructures selected from the group consisting of O, S, and NH. In another embodiment, one or more -CH2- groups in A may be independently replaced with O. In another embodiment, one or more -CH2- groups in A may be independently replaced with S. In another embodiment, one or more -CH2- groups in A may be independently replaced with NR. In another embodiment, one or more -CH2- groups in A may be independently replaced with CONR. In another embodiment, one or more -CH2- groups in A may be independently replaced with NRCO. In another embodiment, one or more -CH2- groups in A may be independently replaced with SO2. In another embodiment, one or more -CH2- groups in A may be independently replaced with SO2NR. R will be explained in more detail below.

[0438] In the embodiments described herein, R is hydrogen, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkylOH, COC1-C6 alkyl, or COOC1-C6 alkyl. In certain embodiments, R is hydrogen, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, halo-C1-C6 alkyl, or C1-C6 alkylOH.

[0439] In certain embodiments, R is hydrogen. In certain embodiments, R is a C1-C6 alkylCOOH. In certain embodiments, R is a COOH. In certain embodiments, R is a C3-C6 cycloalkyl. Suitable examples of cycloalkyls, but not limited to, include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R is a C1-C6 alkyl. Examples of C1-C6 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In certain embodiments, R is a halo-C1-C6 alkyl group. Suitable examples of halo-alkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R is a C1-C6 alkyl OH group. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol.

[0440] In certain embodiments, R is a COC1-C6 alkyl group. Suitable examples, but not limited to, include COCH3.

[0441] Examples of such embodiments include, but are not limited to, [ka]

[0442] These are some examples.

[0443] In a particular embodiment, A is [ka]

[0444] That is the case.

[0445] In certain embodiments, one or more of the hydrogen atoms along A are hydroxyl, halogen, and C 1-3 It can be replaced with a group independently selected from the haloalkyl group. Examples of suitable halogens include chlorine, bromine, fluorine, and iodine. In certain embodiments, A is [ka]

[0446] That is the case.

[0447] In each of the various embodiments of the present invention, it is understood that each variable part (including each of formulas (I) to (VIII) and those of their various embodiments) in the compounds used in the methods herein is selected independently of the other parts unless otherwise indicated.

[0448] In each of the various embodiments of the present invention, the compounds described herein, encompassing each of formulas (I) to (VIII) and the compounds in their various embodiments, may exist in various forms, for example, in the form of any solvates, hydrates, stereoisomers and tautomers of the compound and any pharmaceutically acceptable salt thereof.

[0449] In certain embodiments, the compounds described herein include the following compounds: [ka] TIFF0007868149000085.tif234135TIFF0007868149000086.tif235133TIFF0007868149000087.tif203135 TIFF0007868149000088.tif197133TIFF0007868149000089.tif190134TIFF0007868149000090.tif161134

[0450] In certain embodiments, the compounds described herein include the following compounds or pharmaceutically acceptable salts thereof: [ka] TIFF0007868149000092.tif236135TIFF0007868149000093.tif237134TIFF0007868149000094.tif234134 TIFF0007868149000095.tif214134TIFF0007868149000096.tif236134TIFF0007868149000097.tif208135

[0451] Definitions and abbreviations: The terms used herein have their usual meanings, and the meanings of such terms are independent of each instance. Nevertheless, and unless otherwise indicated, the following definitions apply throughout this specification and the claims. Chemical names, common names and chemical structures may be used interchangeably to describe the same structure. These definitions apply whether the term is used alone or in combination with other terms, unless otherwise indicated. Accordingly, the definition of “alkyl” applies to “alkyl” and “alkyl” parts such as “hydroxyalkyl,” “haloalkyl,” “arylalkyl,” “alkylaryl,” and “alkoxy.”

[0452] In the various embodiments of the invention described herein, it should be understood that any variable parts not explicitly defined in relation to such embodiments are as defined in formula (I).

[0453] In the various embodiments described herein, each variable part is selected independently of the remaining variable parts, unless otherwise indicated.

[0454] "Drug resistance" in relation to malaria parasite strains refers to Plasmodium species that no longer show susceptibility to at least one previously effective drug; they have developed the ability to withstand attack by at least one previously effective drug. Drug-resistant strains can pass on their resistance to their offspring. This resistance may result from random gene mutations in bacterial cells that alter susceptibility to a single drug or a variety of drugs.

[0455] The term "patient" includes both humans and non-human animals. Non-human animals include research animals and companion animals such as mice, rats, primates, monkeys, chimpanzees, apes, dogs, and domestic cats.

[0456] "Pharmaceutical composition" (or "pharmaceutically acceptable composition") means a composition suitable for administration to a patient. Such a composition may contain the neat compound (or a plurality of compounds) or mixture thereof, or salts, solvates, prodrugs, isomers or tautomers thereof, and one or more pharmaceutically acceptable carriers or diluents. The term "pharmaceutical composition" is intended to encompass both bulk compositions and individual dose units, comprising one or more (e.g., two) pharmaceutically active agents (e.g., compounds of the present invention and additional agents selected from the list of additional agents described herein) and any pharmaceutically inert excipients. The bulk composition and each individual dose unit may contain a fixed amount of the aforementioned "two or more pharmaceutically active agents." The bulk composition is material that has not yet been formed into individual dose units. Exemplary dose units are oral dose units such as tablets and pills. Similarly, the methods described herein for treating a patient by administering the pharmaceutical compositions of the present invention are intended to encompass the administration of the bulk compositions and individual dose units.

[0457] "Halogen" and "halo" refer to fluorine, chlorine, bromine, or iodine. Fluorine, chlorine, and bromine are preferred.

[0458] "Alkylene" means a divalent hydrocarbon chain radical having the specified number of carbon atoms, either by itself or as part of other substituents. For example, -(C1-C5)alkylene includes, for example, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH(CH3)CH2-, or -CH2CH2CH2CH2CH2-. Straight-chain alkylene means a divalent straight-chain hydrocarbon chain radical having the specified number of carbon atoms. Branched-chain alkylene means a divalent branched-chain hydrocarbon chain radical having the specified number of carbon atoms. Saturated alkylene means a divalent saturated hydrocarbon chain radical having the specified number of carbon atoms. Unsaturated alkylene means a divalent hydrocarbon chain radical having the specified number of carbon atoms and having one or more double or triple covalent bonds in its chain. Cycloalkylene means a divalent hydrocarbon chain radical having the specified number of carbon atoms and having a cycloalkyl moiety in its chain.

[0459] "Alkyl" refers to an aliphatic hydrocarbon group that can be linear or branched and contains about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups (e.g., methyl, ethyl, or propyl) are bonded to a linear alkyl chain. "Lower alkyl" refers to a group that has about 1 to about 6 carbon atoms in the chain, which can be linear or branched. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, and t-butyl.

[0460] "Haloalkyl" refers to an alkyl group as defined above, in which one or more hydrogen atoms on the alkyl group are replaced by the halo group defined above.

[0461] "Aryl" means an aromatic monocyclic or polycyclic ring system containing about 6 to about 14 carbon atoms (preferably about 6 to about 10 carbon atoms). The aryl group can be substituted with one or more "ring system substituents" as defined herein, which may be the same or different. Non-limiting examples of suitable aryl groups include phenyl and naphthyl. "Monocyclic aryl" means phenyl.

[0462] "Cycloalkyl" refers to a non-aromatic monocyclic or polycyclic ring system containing about 3 to about 12 carbon atoms (preferably about 3 to about 10 carbon atoms). A preferred cycloalkyl ring contains about 5 to about 10 ring atoms. The cycloalkyl can be substituted with one or more substituents, which may be the same or different, as described herein. Monocyclic cycloalkyl indicates a monocyclic version of the cycloalkyl moiety described herein. Non-limiting examples of suitable monocyclic cycloalkyl include cyclopropyl, cyclopentyl, cyclohexyl, and cycloheptyl. Polycyclic cycloalkyl indicates a polycyclic ring containing a non-aromatic ring (this includes a bicyclic ring). Non-limiting examples of suitable polycyclic cycloalkyl include 1-decalinyl, norbornyl, and adamantyl. In certain embodiments, the non-aromatic ring is condensed with an aromatic ring.

[0463] "Heterocycloalkyl" (or "heterocyclyl") means a non-aromatic saturated or partially saturated monocyclic or polycyclic ring system containing about 3 to about 10 ring atoms (preferably about 5 to about 10 ring atoms), wherein one or more atoms in the ring system are elements other than carbon (e.g., nitrogen, oxygen, or sulfur), either alone or in combination. There are no adjacent oxygen and / or sulfur atoms in the ring system. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefixes aza, oxa, or thia preceding the heterocyclyl root name mean that at least one nitrogen, oxygen, or sulfur atom is present as a ring atom, respectively. Any -NH in the heterocyclyl ring can exist in a protected state, for example, as a -N(Boc) group, -N(CBz) group, -N(Tos) group, etc.; such protection is also considered part of the present invention. The heterocyclyl can be substituted with one or more substituents, which may be the same or different, as described herein. The nitrogen or sulfur atom of the heterocyclyl can be oxidized to the corresponding N-oxide, S-oxide, or S,S-dioxide. Thus, the term “oxide” means the corresponding N-oxide, S-oxide, or S,S-dioxide when it appears in the definition of the variable part in the general structure described herein. “Heterocyclyl” further encompasses a ring in which =O is replaced by two available hydrogens on the same carbon atom (i.e., a heterocyclyl encompasses a ring having a carbonyl group within its ring). Such =O groups may be referred to herein as “oxo.” An example of such a part is pyrrolidinone (or pyrrolidone): [ka]

[0464] Where used herein, the term “monocyclic heterocycloalkyl” refers to the monocyclic version of the heterocycloalkyl moiety described herein and encompasses 4-7 member monocyclic heterocycloalkyl groups containing 1-4 ring heteroatoms (where the ring heteroatoms are independently selected from the group consisting of N, N-oxide, O, S, S-oxide, S(O), and S(O)2). The bonding site to the parent moiety is any available ring carbon or ring heteroatom. Non-limiting examples of monocyclic heterocycloalkyl groups include piperidyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, β-lactam, γ-lactam, δ-lactam, β-lactone, γ-lactone, δ-lactone, and pyrrolidinone and their oxides. Non-limiting examples of monocyclic heterocycloalkyl groups include substructures: [ka]

[0465] These include, for example, bicyclic heterocycloalkyl groups. Non-exclusive examples of polycyclic heterocycloalkyl groups include bicyclic heterocycloalkyl groups. Specific examples, though not limited to, include, [ka]

[0466] These are some examples.

[0467] "Alkoxy" refers to an alkyl-O-group, as previously described. Suitable non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. The bond to the parent moiety is via an ether oxygen.

[0468] The term "substituted" means that one or more hydrogen atoms on a specified atom are replaced with those selected from the group shown, provided that the substitution does not exceed the normal valence of the specified atom under existing circumstances and that the substitution results in a stable compound. Combinations of substituents and / or variable parts are permitted only if such combinations result in a stable compound. A "stable compound" or "stable structure" means a compound that is strong enough to withstand isolation from the reaction mixture to a usable degree of purity and formulation into an effective therapeutic agent.

[0469] The term "may be substituted" means optional substitution by a specified group, radical, or substructure.

[0470] If the variable part appears two or more times within the base (for example, -N(R 8 )R in 2 8 ), or if a variable part appears more than once in the structure described herein, the variable part may be the same or different.

[0471] The solid line—in general, indicates a bond that is a mixture of possible isomers (e.g., a mixture containing (R)-stereochemistry and (S)-stereochemistry), or one of those possible isomers. For example, [ka]

[0472] teeth, [ka]

[0473] This means that it includes either one or both of the above.

[0474] The wavy lines ~~ used herein, which are shown intersecting with lines representing chemical bonds, indicate the bonding points to the rest of the compound. Lines drawn within a ring system, for example, [ka]

[0475] This indicates that the shown line (bond) can bond to any of the substitutable ring atoms.

[0476] "Oxo" is defined as an oxygen atom double-bonded to a ring carbon of a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, or another ring as described herein, for example, [ka]

[0477] That is the case.

[0478] In this specification, if multiple oxygen atoms and / or sulfur atoms are present in a ring system, no adjacent oxygen atoms and / or sulfur atoms may be present in that ring system.

[0479] As is well known in this art, a bond drawn from a specific atom where no substructure is depicted at the end of the bond indicates a methyl group bonded to that atom through that bond, unless otherwise indicated. For example, [ka]

[0480] teeth, [ka]

[0481] It represents.

[0482] In another embodiment, compounds useful in the method of the present invention and / or compositions containing them useful in the method exist in isolated and / or purified forms. The terms “purified,” “in a purified form,” or “in an isolated and purified form” with respect to a compound refer to the physical state of the compound after it has been isolated from a synthetic process (e.g., from a reaction mixture) or from a natural source or a combination thereof. Accordingly, the terms “purified,” “in a purified form,” or “in an isolated and purified form” with respect to a compound refer to the physical state of the compound (or its tautomers or stereoisomers, or pharmaceutically acceptable salts or solvates of the compound, its stereoisomers, or its tautomers) after being obtained from one or more purification processes described herein or one or more purification processes well known to those skilled in the art (e.g., chromatography, recrystallization), and / or being of sufficient purity for in vivo use or pharmaceutically use and / or being characterized by standard analytical techniques described herein or analytical techniques well known to those skilled in the art.

[0483] It should be understood that carbon and heteroatoms whose valence is not satisfied in the text, schemes, examples, and tables herein are presumed to have a sufficient number of hydrogen atoms to satisfy their valence.

[0484] When a functional group in a compound is said to be "protected," this means that the group is in a modified form to prevent undesirable side reactions at the protected site when the compound is subjected to a reaction. Appropriate protecting groups will be recognized by those skilled in the art by referring to standard textbooks such as, for example, "TW Greene et al., Protective Groups in Organic Synthesis (1991), Wiley, New York."

[0485] Another embodiment provides prodrugs and / or solvates of the compounds of the present invention. For a discussion of prodrugs, see "T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987)". 14 This information is provided in “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the ACS Symposium Series and “Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press.” The term “prodrug” means a compound (e.g., a drug precursor) that is converted in vivo to produce the compound of the present invention or a pharmaceutically acceptable salt, hydrate, or solvate of the compound. Such conversion can occur by various mechanisms (e.g., by metabolic or chemical processes), for example, by hydrolysis in the blood. Discussions regarding the use of prodrugs are provided in “T. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the ACS Symposium Series” and “Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.”

[0486] For example, if a compound useful in the method of the present invention or a pharmaceutically acceptable salt thereof contains a carboxylic acid functional group, the prodrug may have hydrogen atoms of the acid group such as (C1-C8) alkyl, (C2-C 12) Alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having 4-9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having 5-10 carbon atoms, alkoxycarbonyloxymethyl having 3-6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having 4-7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having 5-8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having 3-9 carbon atoms, having 4-10 carbon atoms The product may contain esters formed by substituting groups such as 1-(N-(alkoxycarbonyl)amino)ethyl, 3-phthalidyl, 4-crotonolactonyl, γ-butyrolacton-4-yl, di-N,N-(C1-C2)alkylamino(C2-C3)alkyl (e.g., β-dimethylaminoethyl), carbamoyl-(C1-C2)alkyl, N,N-di(C1-C2)alkylcarbamoyl-(C1-C2)alkyl, and piperidino-, pyrrolidino-, or morpholino(C2-C3)alkyl.

[0487] Similarly, if the compound used in the method of the present invention contains an alcohol functional group, the prodrug can be formed by replacing the hydrogen atoms of the alcohol group with a group such as (C1-C6)alkanoyloxymethyl, 1-((C1-C6)alkanoyloxy)ethyl, 1-methyl-1-((C1-C6)alkanoyloxy)ethyl, (C1-C6)alkoxycarbonyloxymethyl, N-(C1-C6)alkoxycarbonylaminomethyl, succinoyl, (C1-C6)alkanoyl, α-amino(C1-C4)alkanyl, arylacyl and α-aminoacyl or α-aminoacyl-α-aminoacyl [wherein each α-aminoacyl group is independently selected from natural L-amino acids, P(O)(OH)2, -P(O)(O(C1-C6)alkyl)2 or glycosyl (a radical obtained by removing the hydroxyl group from the hemiacetal form of a carbohydrate)].

[0488] If the compound used in the method of the present invention contains an amine functional group, the prodrug removes the hydrogen atoms in the amine group, for example, R-carbonyl, RO-carbonyl, NRR'-carbonyl [where R and R' are independently (C1-C 10 )alkyl, (C3-C7)cycloalkyl, benzyl, or R-carbonyl is natural α-aminoacyl or natural aminoacyl], -C(OH)C(O)OY 1 [Here, Y 1 [is H, (C1-C6) alkyl or benzyl], -C(OY 2 )Y 3 [Here, Y 2 is (C1-C4) alkyl, and Y 3 [These are (C1-C6)alkyl, carboxy(C1-C6)alkyl, amino(C1-C4)alkyl, or mono-N- or di-N,N-(C1-C6)alkylaminoalkyl], -C(Y 4 )Y 5 [Here, Y 4 is H or methyl, and Y 5 This can be formed by substituting a group such as mono-N- or di-N,N-(C1-C6)alkylamino, morpholino, piperidine-1-yl, or pyrrolidine-1-yl.

[0489] One or more compounds used in the methods of the present invention may exist in a non-solvated form and in a solvated form with a pharmaceutically acceptable solvent such as water or ethanol, and the present invention is intended to encompass both solvated and non-solvated forms. “Solvated product” means the physical association of the compound of the present invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding (including hydrogen bonding). In certain examples, for example, if one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvated product can be isolated. “Solvated product” encompasses both solution phases and isolateable solvated products. Non-limiting examples of suitable solvated products include ethanolates and methanelates. “Hydrate” is a solvated product in which the solvent molecule is H2O.

[0490] One or more compounds used in the method of the present invention can be converted into solvates. The preparation of solvates is generally known. For example, "M. Caira et al, J. Pharmaceutical Sci., 1993, 3, 601-611" describes the preparation of antifungal fluconazole solvates in ethyl acetate and from water. Similar preparations of solvates, semi-solvates, hydrates, etc., are described by "EC van Tonder et al, AAPS PharmSciTech., 5(1), article 12 (2004)" and "AL Bingham et al, Chem. Commun., 603-604 (2001)". A typical, non-limiting process involves dissolving the compound of the present invention in a desired amount of a desired solvent (organic or water or a mixture thereof) at a temperature above ambient temperature, and cooling the solution at a rate sufficient to form crystals, which are then isolated by standard methods. Analytical techniques (e.g., IR spectroscopy) can be used to demonstrate the presence of a solvent (or water) within the crystal as a solvate (or hydrate).

[0491] "Effective dose" or "therapeutic effective dose" is intended to represent the amount of compound or composition used in the method of the present invention that is effective in inhibiting the disease or enzyme activity described above, and therefore effective in producing the desired therapeutic, ameliorative, inhibitory, or preventive effect.

[0492] In another embodiment, pharmaceutically acceptable salts of compounds used in the methods of the present invention are provided. Accordingly, in this specification, references to compounds used in the methods of the present invention are understood to also include references to their salts unless otherwise indicated. The term “salt” (singular or plural), as used herein, refers to acidic salts formed using inorganic and / or organic acids, and basic salts formed using inorganic and / or organic bases. Furthermore, if the compounds of the present invention contain both a basic moiety (e.g., pyridine or imidazole) and an acidic moiety (e.g., carboxylic acid), zwitterions ("internal salts") may be formed, and these are included in the term “salt” (singular or plural) as used herein. Pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable) salts are preferred, but other salts are also useful. Salts of compounds used in the method of the present invention can be formed, for example, by reacting the compound of the present invention with a specific amount (e.g., equivalent) of acid or base in a medium (e.g., a medium in which the salt precipitates) or an aqueous medium, and then freeze-drying.

[0493] Typical acid addition salts include acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, and toluenesulfonate (also known as tosylate).

[0494] Furthermore, acids generally considered suitable for forming pharmaceutically useful salts from basic pharmaceutical compounds include, for example, "P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH" and "S. Berge et al, Journal of Pharmaceutical Sciences (1977)." 66(1) 1-19, P. Gould, International J. of Pharmaceutics (1986) 33 This is discussed in "201-217," "Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York," and "The Orange Book (Food & Drug Administration, Washington, DC on their website)." These disclosures are incorporated herein by reference.

[0495] Typical basic salts include ammonium salts, alkali metal salts such as sodium salts, lithium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, salts with organic bases (e.g., organic amines) such as salts with dicyclohexylamine and t-butylamine, and salts with amino acids such as salts with arginine and lysine. Basic nitrogen-containing groups can be quaternized using agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, and dibutyl sulfate), long-chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides, and iodides), and aralkyl halides (e.g., benzyl bromide and phenethyl bromide).

[0496] All such acidic and basic salts are intended to be pharmaceutically acceptable salts within the scope of the present invention, and all acidic and basic salts are considered equivalent to the free form of the corresponding compound with respect to the purposes of the present invention.

[0497] Another embodiment provides pharmaceutically acceptable esters of compounds used in the method of the present invention. Such esters include the following groups: (1) Carboxylic acid esters obtained by esterification of a hydroxyl group [wherein the non-carbonyl portion of the carboxylic acid portion of the ester group is a linear alkyl or branched alkyl (e.g., acetyl, n-propyl, t-butyl or n-butyl), an alkoxyalkyl (e.g., methoxymethyl), an aralkyl (e.g., benzyl), an aryloxyalkyl (e.g., phenoxymethyl), an aryl (e.g., halogen, C 1-4 Alkyl or C 1-4 (1) Selected from alkoxy or amino, e.g., phenyl); (2) Sulfonic acid esters, e.g., alkylsulfonyl or aralkylsulfonyl (e.g., methanesulfonyl); (3) Amino acid esters (e.g., L-valyl or L-isoleucine); (4) Phosphate esters; and (5) Mono-, di- or triphosphate esters. The phosphate ester is, for example, C 1-20 By alcohol or its reactive derivative, or by 2,3-di(C 6-24 It can be further esterified by acylglycerol.

[0498] As described herein, in other embodiments, tautomers of the compounds of the present invention used in the methods herein are provided, as well as salts, solvates, esters, and prodrugs of said tautomers. It should be understood that all tautomer forms of such compounds are within the range of compounds used in the methods of the present invention. For example, all keto-enol and imine-enamine forms of said compounds are included in the present invention, if present.

[0499] The compounds used in the methods of the present invention may contain chiral or asymmetric centers and, therefore, may exist in various stereoisomers. All stereoisomers of the compounds used in the methods of the present invention, as well as mixtures thereof (this includes racemic mixtures), are intended to form part of the present invention. Furthermore, the present invention encompasses the use of all geometric and positional isomers. For example, if the compounds used in the methods of the present invention contain double bonds or fused rings, both cis and trans forms, (E) and (Z) forms, and mixtures thereof are included within the scope of the present invention.

[0500] In another embodiment, a diastereomer mixture and individual enantiomers of the compounds used in the method of the present invention are provided. The diastereomer mixture can be separated into its individual diastereomers based on their physicochemical differences by methods well known to those skilled in the art, for example, by chromatography and / or fractional crystallization. The enantiomers can be separated by converting the enantiomer mixture into a diastereomer mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary agent, e.g., a chiral alcohol or moscherate), separating the diastereomers, and converting the individual diastereomers (e.g., by hydrolysis) to the corresponding pure enantiomers. Furthermore, some of the compounds used in the method of the present invention may be atropisomers (e.g., substituted biaryls) and are considered part of the present invention. The enantiomers can also be separated using a chiral HPLC column.

[0501] All stereoisomers (e.g., geometric isomers, optical isomers, etc.) of the compounds used in the methods of the present invention (this includes salts, solvates, esters, and prodrugs of the compounds, as well as salts, solvates, and esters of the prodrugs), such as isomers that may exist due to chiral carbons on various substituents, such as enantiomers (which may exist even in the absence of chiral carbons), rotomers, atropisomers, and diastereomers, are intended as embodiments within the scope of the present invention, as are positional isomers (e.g., 4-pyridyl and 3-pyridyl). (For example, if the compounds of the present invention contain a double bond or a fused ring, both cis and trans forms, as well as mixtures thereof, are included within the scope of the present invention. Furthermore, for example, all keto-enol and imine-enamine forms of the compounds are included in the methods of the present invention.)

[0502] The individual stereoisomers of the compounds of the present invention may, for example, substantially contain no other isomers, or may be mixed as a racemic compound, or may be mixed with all other stereoisomers or other selected stereoisomers. The chiral centers of the present invention may have S or R configurations as defined by the "IUPAC 1974 Recommendations". The use of terms such as "salt," "solvate," "ester," and "prodrug" is intended to apply similarly to salts, solvates, esters, and prodrugs of enantiomers, stereoisomers, rotational isomers, tautomers, positional isomers, racemic compounds, or prodrugs of the compounds of the present invention.

[0503] Another embodiment provides isotope-labeled compounds used in the method of the present invention. Such compounds are identical to those described herein, except that one or more atoms are replaced by atoms having atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, 2 H, 3 H,13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Examples include Cl.

[0504] The present invention provides specific isotope-labeled compounds (for example, 3 H and 14 Compounds labeled with 1C are useful in tissue distribution assays of compounds and / or substrates. Tritiation (i.e., 3 H) Isotopes and carbon-14 (i.e., 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Furthermore, deuterium (i.e., 2 Substitution with heavier isotopes, such as H), can result in certain therapeutic benefits arising from greater metabolic stability (e.g., extended in vivo half-life or reduced required dose), and may therefore be preferable in certain situations. The isotope-labeled compounds of the present invention can generally be prepared by replacing an unlabeled reagent with a suitable isotope-labeled reagent according to a method similar to that disclosed in the scheme and / or examples below.

[0505] In the compounds used in the methods of the present invention, the atoms may exhibit the abundance of their natural isotopes, or one or more of the atoms may be artificially enriched with specific isotopes having the same atomic number but different atomic masses or mass numbers from those primarily found in nature. The present invention is intended to encompass all appropriate isotopic variations of the compounds of the present invention. For example, different isotopic forms of hydrogen (H) include protium ( 1 H) and deuterium ( 2Examples include H). The presence of deuterium in the compounds of the present invention is indicated by "D". Protium is the dominant hydrogen isotope found in nature. Enriching with deuterium may result in specific therapeutic advantages (e.g., extension of in vivo half-life or reduction of required dose) or provide compounds useful as standards for characterizing biological samples. The isotope-enriched compounds of the present invention can be prepared without excessive experimentation by conventional techniques well known to those skilled in the art, or by processes similar to those described herein in the schemes and examples using appropriate isotope-enriched reagents and / or intermediates.

[0506] Polymorphs of the compounds used in the methods of the present invention, as well as polymorphs of salts, solvates, esters, and prodrugs of the compounds of the present invention, are intended to be included in the present invention.

[0507] Treatment method The present invention relates to a method for treating malaria parasitic infection, wherein the method comprises administering a compound described herein or a pharmaceutically acceptable salt thereof to a subject in need of such treatment. More specifically, the method of the present invention comprises administering a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition further comprising a pharmaceutically acceptable carrier or excipient.

[0508] The present invention provides a method for treating malaria infection or malaria or inhibiting plasmmepsin X, the method comprising administering a therapeutically effective amount of a specific compound or a pharmaceutically acceptable salt thereof to a subject in need of such treatment, wherein the compound has structural formula (I) as described in the "Summary of the Invention". In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical composition together with a pharmaceutically acceptable carrier. Furthermore, various embodiments of these methods, as described below, are also provided herein.

[0509] The present invention further relates to the use of compounds represented by formula (I)-(VIII) or pharmaceutically acceptable salts thereof for inhibiting plasmmepsin X activity, for treating malaria parasitic infections, or for treating malaria. The present invention further relates to the use of compounds represented by formula (I)-(VIII) or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals for inhibiting plasmmepsin X activity, in the manufacture of pharmaceuticals for treating malaria parasitic infections, or in the manufacture of pharmaceuticals for treating malaria. Compounds represented by formula (I)-(VIII) or pharmaceutically acceptable salts thereof described in any embodiment of the present invention herein are useful for any of the above uses.

[0510] The present invention provides a method for treating malaria infection or malaria or inhibiting plasmmepsin IX, the method comprising administering a therapeutically effective amount of a specific compound or a pharmaceutically acceptable salt thereof to a subject in need of such treatment, wherein the compound has structural formula (I) as described in the "Summary of the Invention". In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical composition together with a pharmaceutically acceptable carrier. Furthermore, various embodiments of these methods, as described below, are also provided herein.

[0511] The present invention further relates to the use of compounds represented by formula (I)-(VIII) or pharmaceutically acceptable salts thereof for inhibiting plasmmepsin IX activity, for treating malaria parasitic infections, or for treating malaria. The present invention further relates to the use of compounds represented by formula (I)-(VIII) or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals for inhibiting plasmmepsin IX activity, in the manufacture of pharmaceuticals for treating malaria parasitic infections, or in the manufacture of pharmaceuticals for treating malaria. Compounds represented by formula (I)-(VIII) or pharmaceutically acceptable salts thereof described in any embodiment of the present invention herein are useful for any of the above uses.

[0512] The present invention provides methods for treating malaria infection or malaria or inhibiting plasmepsin X and plasmepsin IX, the methods comprising administering a therapeutically effective amount of a specific compound or a pharmaceutically acceptable salt thereof to a subject in need of such treatment, wherein the compound has structural formula (I) as described in the "Summary of the Invention". In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical composition together with a pharmaceutically acceptable carrier. Furthermore, various embodiments of these methods, as described below, are also provided herein.

[0513] The present invention further relates to the use of compounds represented by formula (I)-(VIII) or pharmaceutically acceptable salts thereof for inhibiting the activity of plasmmepsin X and plasmmepsin IX, for treating malaria parasitic infections, or for treating malaria. The present invention further relates to the use of compounds represented by formula (I)-(VIII) or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals for inhibiting the activity of plasmmepsin X and plasmmepsin IX, in the manufacture of pharmaceuticals for treating malaria parasitic infections, or in the manufacture of pharmaceuticals for treating malaria. Compounds represented by formula (I)-(VIII) or pharmaceutically acceptable salts thereof described in any embodiment of the present invention herein are useful for any of the above uses.

[0514] The methods of the present invention are useful for treating malaria in that they suppress the onset, development, or progression of the condition; improve the symptoms of the condition; induce regression of the condition; treat the condition; or otherwise improve the general health of a person who has or is at risk of having the condition. Accordingly, in accordance with the subject matter now disclosed, the terms “treat,” “treating,” and their grammatical variations, as well as the phrase “method of treating,” are intended to encompass any desired therapeutic intervention (which includes, but is not limited to, methods of treating an existing infection in a person with an infection, for example, in a person exposed to the parasites disclosed herein).

[0515] Embodiments of the present invention further include one or more compounds represented by formulas (I)-(VIII) or pharmaceutically acceptable salts thereof for use in (i) the following, (ii) as a pharmaceutically or composition for the following, or (iii) in the preparation of a pharmaceutically acceptable compound for the following: (a) treatment (e.g., treatment of the human body); (b) medical treatment; (c) inhibition of the growth of parasites / malaria parasites; (d) treatment or prevention of infections caused by Plasmodium species; (e) reduction of the progression, onset or severity of pathological symptoms associated with malaria parasitic infection and / or reduction of the likelihood of severe malaria parasitic infection; or (f) treatment, prevention, or delay of the onset, severity or progression of diseases associated with malaria parasites (this includes, but is not limited to, malaria).

[0516] Accordingly, another embodiment provides a method for treating malaria or a malaria parasite infection, wherein the method comprises administering a combination comprising a specific amount of at least one compound represented by formula (I)-(VIII) or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof and an effective amount of one or more additional agents described below. In a particular embodiment, described herein is a method for treating malaria or a malaria parasite infection, wherein the method comprises administering a combination comprising a specific amount of at least one compound represented by formula (I)-(VIII) or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof and an effective amount of one or more additional antimalarial agents. In certain embodiments, methods for treating malaria by inhibiting plasmepsin X, plasmepsin IX, and at least one other mechanism, comprising administering a combination comprising a specific amount of at least one compound represented by formula (I)-(VIII) or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof and an effective amount of one or more additional antimalarial agents, wherein the additional antimalarial agents act through a mechanism different from the inhibition of plasmepsin IX or plasmepsin X. The pharmacological properties of the compounds represented by formula (I)-(VIII) or pharmaceutically acceptable salts thereof can be confirmed by several pharmacological assays. Specific assays are illustrated herein.

[0517] Dosage and administration In another embodiment, appropriate dosages and forms of administration of the compound used in the method of the present invention are provided. An appropriate dosage for administering the compound used in the method of the present invention to a patient can be readily determined by those skilled in the art, e.g., a physician, pharmacist, or other expert, and may vary depending on the patient's health, age, weight, frequency of administration, concomitant use with other active ingredients, and / or the indication for which the compound is administered. The dosage may be in the range of about 0.001 to 500 mg / kg body weight / day of the compound of the present invention. In one embodiment, the dosage is about 0.01 to about 25 mg / kg body weight / day of the compound of the present invention or a pharmaceutically acceptable salt or solvate of the compound. In another embodiment, the amount of the active compound in a unit dose of the formulation can be varied or adjusted, depending on the specific use, to about 1 mg to about 100 mg, in a specific embodiment to about 1 mg to about 50 mg, and in a specific embodiment to about 1 mg to about 25 mg. In another embodiment, a typical recommended daily dose regimen for oral administration may range from approximately 1 mg / day to approximately 500 mg / day in 2 to 4 divided doses, and in specific embodiments, from 1 mg / day to 200 mg / day.

[0518] As discussed above, the dosage and frequency of the compounds and / or pharmaceutically acceptable salts of the present invention should be adjusted according to the judgment of the attending clinician, taking into account factors such as the patient's age, condition and size, and the severity of the symptoms being treated.

[0519] Liquid formulations include solutions, suspensions, and emulsions. Examples include aqueous solutions or water-propylene glycol solutions for parenteral injection, or the addition of sweeteners and opacifiers to oral solutions, oral suspensions, and oral emulsions. Liquid formulations may also include solutions for intranasal administration.

[0520] Aerosol formulations suitable for inhalation include solutions and solid powders, which can be combined with pharmaceutically acceptable carriers such as inert compressed gases (e.g., nitrogen).

[0521] Furthermore, the term also includes solid formulations that are intended to be converted into liquid formulations for either oral or parenteral administration immediately before use. Such liquid formulations include solutions, suspensions, and emulsions.

[0522] Another embodiment provides the use of a composition comprising a compound represented by formula (I)-(VIII) or a pharmaceutically acceptable salt thereof, formulated for transdermal delivery. The transdermal composition may take the form of a cream, lotion, aerosol and / or emulsion, and may be incorporated into a matrix-type or reservoir-type transdermal patch, which are conventional in the art for this purpose.

[0523] Another embodiment provides the use of a composition containing a compound represented by formula (I)-(VIII) or a pharmaceutically acceptable salt thereof, formulated for subcutaneous delivery. Another embodiment provides the use of a composition suitable for oral delivery. In some embodiments, a pharmaceutical formulation containing one or more compounds represented by formula (I)-(VIII) or a pharmaceutically acceptable salt thereof may be advantageously prepared into unit dose forms. In such forms, the formulation is divided into appropriately sized unit doses containing an appropriate amount of the active ingredient (e.g., an effective amount to achieve the desired objective). The aforementioned alternatives are each considered to be encompassed in various embodiments of the present invention.

[0524] When used in combination with one or more additional therapeutic agents ("combination therapy"), the compounds used in the method of the present invention, i.e., the compounds represented by formulas (I)-(VIII), may be administered together or sequentially. When administered sequentially, the compounds of the present invention may be administered before or after the one or more additional therapeutic agents, as determined by the art or the patient's preference.

[0525] When formulated as a fixed dose, such combination product shall use a compound represented by formula (I)-(VIII) or a pharmaceutically acceptable salt thereof within the dosage range described herein, and any other pharmaceutically active agent or treatment within the dosage range thereof.

[0526] Combination therapy Another embodiment provides a therapeutic method using a pharmaceutically acceptable composition comprising the compounds of the present invention as a neat chemical or optionally further comprising additional components. Such compositions are intended for preparation and use in monotherapy or combination therapy. To prepare a pharmaceutically acceptable composition from the compounds of the present invention, an inert and pharmaceutically acceptable carrier may be either solid or liquid. Solid formulations include powders, tablets, dispersible granules, capsules, cachets, and suppositories. Powders and tablets may consist of about 5 to about 95% of the active ingredient. Suitable solid carriers are known in the art and include, for example, magnesium carbonate, magnesium stearate, talc, sugar, or lactose. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods for preparing various compositions can be found in "A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pennsylvania".

[0527] Some non-exclusive examples of useful adjunctive drugs and activators in combination therapy for the treatment of malaria include: Coartem® (Novartis International AG, Basel, Switzerland; artemether + lumefantrine), Eurartesim® (Sigma-Tau Pharmaceuticals, Inc., Rome, Italy; dihydroartemisinin-piperaquine), Pyramax® (Shin Poong Pharmaceutical Co., Ltd., Seoul, Korea; pyronarizine-artesunate), ASAQ Winthrop® (Sanofi SA (Gentilly, France) / DNDi (Geneva, Switzerland); artesunate + amodiaquine), ASMQ (Cipla Limited (Mumbai, India) / DNDi; artesunate + mefloquine), SPAQ-CO TM (Guilin Pharmaceutical Co., Ltd. (Shanghai); Amodiaquine + Sulfadoxine, Pyrimethamine), Artesun® (Guilin Pharmaceutical; Artesunate), Artemether, Artesunate, Dihydroartemisinin, Lumefantrine, Amodiaquine, Mefloquine, Piperaquine, Quinine, Chloroquine, Atovaquone and Proguanil and Sulfadoxine-Pyrimethamine, Tafenoquine (Glaxosmithkline), OZ439 / PQP (Sanofi), OZ439 / FQ (Sanofi), KAE609 (Novartis), KAF156 (Novartis), DSM265 (NIH / Takeda), and MK-4815 (Merck & Co., Inc., Powles et al., Antimicrobial Agents and Chemotherapy 56(5): 2414-2419 (2012)). The selection of such additional active ingredients is determined by the attending physician or other healthcare provider, depending on the existing disease or disorder to be treated.

[0528] Accordingly, the present invention further provides a method for using a compound represented by formula (I)-(VIII) or a pharmaceutically acceptable salt thereof to inhibit plasmomepsin X, plasmomepsin IX, or plasmomepsin X and plasmomepsin IX, for treating malaria infection, or for treating malaria, wherein the method further comprises administering one or more additional antimalarial agents to a subject in need of such inhibition or treatment. In some embodiments, the one or more additional antimalarial agents are selected from the group consisting of: artemether, lumefantrine, dihydroartemisinin, piperaquine, pyronarizine, artesunate, amodiaquine, mefloquine, sulfadoxine, pyrimethamine, lumefantrine, quinine, chloroquine, atovaquone, and proguanil. [Examples]

[0529] Examples The meanings of the abbreviations used in the examples are shown below. [Table 1] TIFF0007868149000108.tif248170TIFF0007868149000109.tif193160

[0530] The meanings of abbreviations in nuclear magnetic resonance spectroscopy are as follows: s = single line, d = double line, dd = double line of double lines, dt = triple line of double lines, ddd = double line of double lines, Sept = seven-line, t = triple line, m = multiple lines, br = broad line, brs = broad single line, q = quadruple line, J = coupling constant, and Hz = Hertz.

[0531] Several methods for preparing the compounds of this disclosure are described in the following schemes and examples. Starting materials and intermediates were commercially purchased from common catalog sources or prepared using known methods or as otherwise illustrated. Several routes applicable in many cases to the compound represented by formula (I) are described in the following schemes. In some cases, the order in which the reaction steps in the scheme are carried out can be altered to expedite the reaction or to avoid undesirable reaction products.

[0532] Scheme 1 [ka]

[0533] The compound represented by formula S-2 is prepared from S-1 by macrolactamization using an amide coupling reagent.

[0534] Scheme 2 [ka]

[0535] The intermediate compound represented by formula S-4 is prepared from S-3 after a ring-closing metathesis (RCM) reaction using second-generation catalysts such as Grubbs catalysts, Zhan catalysts, and Hoveyda / Grubbs catalysts. The double bond in S-4 can be reduced, for example, under hydrogenation conditions to produce the product represented by formula S-5.

[0536] Scheme 3 [ka]

[0537] The intermediate compound represented by formula S-7 is prepared from S-6, where X is a halogen (e.g., Cl, Br, and I), after an intramolecular cross-coupling reaction catalyzed by a transition metal (e.g., Heck reaction). The double bond formed in S-7 can be reduced, for example, under hydrogenation conditions, to obtain the product represented by formula S-8.

[0538] Scheme 4 [ka]

[0539] The product represented by formula S-10 is prepared from S-9, where X is a halogen (e.g., Cl, Br, and I), after an intramolecular cross-coupling reaction catalyzed by a transition metal (e.g., a palladium-catalyzed CO coupling reaction).

[0540] Scheme 5 [ka]

[0541] The product represented by formula S-12 is an intramolecular S between the alcohol and X (where X is a leaving group such as Cl, Br, I, OMs, OTs, or OTf) from S-11. N The product is prepared after two reactions. The product represented by formula S-12 can also be prepared from the S-11 diol after dehydration using an acid or other dehydrating agent.

[0542] Scheme 6 [ka]

[0543] The product represented by formula S-12 is prepared from intermediate S-13 or S-14 after intramolecular reductive etherification under conditions such as TMSOTf and Et3SiH.

[0544] Reactions sensitive to moisture or air were carried out in a glove box or under nitrogen or argon conditions using anhydrous solvents and reagents. The progress of the reactions was confirmed by analytical thin-layer chromatography (TLC) using E. Merck pre-coated TLC plates (silica gel 60F-254, 0.25 mm thick) or by liquid chromatography-mass spectrometry (LC / MS).

[0545] Typically, the analytical LC-MS system used was an Agilent 1100 series HPLC with an autosampler, used in cation detection mode for electrospray ionization of Waters ZQ. TM The platform consisted of a column, typically a "Waters Xterra MS C18, 3.0 × 50 mm, 5 μm" or a "Waters Acquity UPLC® BEH C18 1.0 × 50 mm, 1.7 μm". The flow rate was 1 mL / min, and the injection volume was 10 μL. UV detection was in the range of 210–400 nm. The mobile phase consisted of solvent A (water + 0.05% TFA) and solvent B (MeCN + 0.05% TFA), with the gradient as follows: 100% solvent A for 0.7 minutes, changing to 100% solvent B over 3.75 minutes, maintaining for 1.1 minutes, and then returning to 100% solvent A over 0.2 minutes.

[0546] Preparative HPLC purification was typically performed using either a mass spectrometry-directed system or a non-mass-guided system. These were usually LC-MS systems (which consist of the following: Waters ZQ). TMThe single quad MS system (electrospray ionization), Waters 2525 Gradient Pump, Waters 2767 Injector / Collector, and Waters 996 PDA Detector were used. The MS conditions were as follows: 150-750amu, Positive Electrospray, Collection Triggered by MS, and performed on a Waters Chromatography Workstation consisting of a Waters SUNFIRE® C-18 5 micron, 30 mm (id) × 100 mm column. The mobile phase consisted of a mixture of acetonitrile (10-100%) in water containing 0.1% TFA. The flow rate was maintained at 50 mL / min, the injection volume was 1800 μL, and the UV detection range was 210-400 nm. The alternative preparative HPLC system used was a Gilson Workstation (which consists of: Gilson GX-281 Injector / Collector, Gilson UV / VIS-155 Detector, Gilson 333 and 334 Pumps, and a Phenomenex Gemini-NX C-18 5 micron, 50 mm (id) × 250 mm column, or a Waters XBridge). TM C-18 5 micron OBD TM The column size was 30 mm (id) × 250 mm. The mobile phase consisted of a mixture of acetonitrile (0-75%) in water containing 5 mmol (NH4)HCO3. The flow rate was Waters Xbridge. TMFor column chromatography, the flow rate was maintained at 50 mL / min, and for Phenomenex Gemini columns, it was maintained at 90 mL / min. The injection volume was in the range of 1000–8000 μL, and the UV detection range was 210–400 nm. The mobile phase gradient was optimized for each individual compound. Reactions performed using microwave irradiation were typically carried out using an Emrys Optimizer (Personal Chemistry) or Initiator (Biotage). Solution concentration was performed under reduced pressure using a rotary evaporator. Flash chromatography was typically performed using silica gel (32–63 μM, 60 Å pore size) in pre-packed cartridges of the sizes listed, using one of the following: Biotage® Flash Chromatography apparatus (Dyax Corp.), ISCO CombiFlash® Rf apparatus, or ISCO CombiFlash® Companion XL. 1¹H NMR spectra were obtained in CDCl3 solution using a 500 MHz spectrometer unless otherwise indicated. Chemical shifts are reported in parts per million (ppm). Tetramethylsilane (TMS) was used as an internal reference in CDCl3 solution, and the residual CH3OH peak or TMS was used as an internal reference in CD3OD solution. Coupling constants (J) are reported in Hertz (Hz). Chiral analytical chromatography was most commonly performed using one of the following columns: CHIRALPAK® AS column (250 × 4.6 mm), CHIRALPAK® AD column (250 × 4.6 mm), CHIRALCEL® OD column (250 × 4.6 mm), CHIRALCEL® IA column (250 × 4.6 mm), or CHIRALCEL® OJ column (250 × 4.6 mm) (Daicel Chemical Industries, Ltd.), with either ethanol in hexane (%Et / Hex) or isopropanol in heptane (%IPA / Hep) in the stated proportions (%) as the constant solvent system. Chiral preparative chromatography was performed using one of the following columns: CHIRALPAK AS column (20×250mm), CHIRALPAK AD column (20×250mm), CHIRALCEL® OD column (20×250mm), CHIRALCEL® IA column (20×250mm), or CHIRALCEL® OJ column (20×250mm) (Daicel Chemical Industries, Ltd.), in a desired fixed-composition solvent system certified for chiral analytical chromatography, or under supercritical fluid (SFC) conditions.

[0547] It is understood that a chiral center in a compound can exist in either an "S" configuration, an "R" configuration, or a mixture of both. Within a molecule, each bond drawn linearly from the chiral center can encompass both the (R) and (S) stereoisomers, as well as mixtures thereof.

[0548] Intermediate 1 Preparation of intermediates 1-2 [ka]

[0549] DBU (21.72 mL, 144 mmol) and diphenylphosphinyl were added to a mixture of methyl (S)-4-hydroxychroman-6-carboxylate (INT1-1) (10 g, 48.0 mmol) in THF (80 mL). Then, azide (35.0 g, 144 mmol) was added under N2 conditions. The mixture was stirred at 50°C for 12 hours. The mixture was quenched with water (100 mL) and extracted with SiO2 (3 × 100 mL). The organic layer was washed with brine (80 mL), dehydrated with Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, eluent 15% SiO2 / petroleum ether gradient @ 50 mL / min) to obtain methyl (R)-4-azidochroman-6-carboxylate (INT1-2).

[0550] MS (ESI) m / z 234.0(M+H + ) 1 ¹H NMR (500 MHz, chloroform-d) δ 7.93-7.96 (m, 2H), 6.91 (d, J=8.5 Hz, 1H), 4.65 (t, J=3.5 Hz, 1H), 4.29-4.35 (m, 2H), 3.90 (s, 3H), 2.14-2.26 (m, 1H), 2.06-2.12 (m, 1H) Preparation of intermediates 1-3 [ka]

[0551] Pd-C (2.510 g, 4.72 mmol) was added under an N2 atmosphere to a solution of methyl (R)-4-azidochroman-6-carboxylate (INT1-2) (11 g, 47.2 mmol) dissolved in THF (200 mL). The mixture was degassed and refilled with H2 (3 times). The resulting mixture was stirred at 25°C for 12 hours under an H2 (15 psi) atmosphere. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to obtain methyl (R)-4-aminochroman-6-carboxylate (INT1-3).

[0552] MS (ESI) m / z: 191.1 (M-17+H + ) Preparation of Intermediate 1 [ka]

[0553] Sodium hydride (3.77 g, 94 mmol) was added in small amounts at 0°C to a solution of N,N-bis-Boc-thiourea (16.94 g, 61.3 mmol) dissolved in THF (250 mL) under N2. After 1 hour at this temperature, 2,2,2-trifluoroacetic anhydride (8.82 mL, 61.3 mmol) was added dropwise. The mixture was stirred at 0°C for 1 hour. A solution of methyl (R)-4-aminochroman-6-carboxylate (INT1-3) (9.77 g, 47.1 mmol) dissolved in THF (50 mL) was added dropwise at 0°C. The mixture was stirred at 0°C for 2 hours. The mixture was quenched with water (80 mL) and extracted with SiO2 (3 × 50 mL). The organic layer was washed with brine (40 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, eluent 20% siRNA / petroleum ether gradient @ 50 mL / min) to obtain methyl (R)-4-(3-(tert-butoxycarbonyl)thioureide)chroman-6-carboxylate (INT-1).

[0554] MS (ESI) m / z 367.1 (M+H + ) 1 ¹H NMR (500 MHz, chloroform-d) δ 8.01 (d, J=1.5 Hz, 1H), 7.96 (s, 1H), 7.89 (dd, J=2.0, 9.0 Hz, 1H), 6.89 (d, J=9.0 Hz, 1H), 4.34-4.41 (m, 1H), 4.19-4.26 (m, 1H), 3.88 (s, 3H), 2.25-2.40 (m, 2H), 1.47 (s, 9H) Intermediate 2 Preparation of intermediate 2-2 [ka]

[0555] Penta-4-enoic acid (INT2-1) (40 g, 400 mmol), EDCI (92 g, 479 mmol), 1H-benzo[d][1,2,3]triazole-1-ol (64.8 g, 479 mmol), and N-ethyl-N-isopropylpropan-2-amine (279 mL, 1598 mmol) were dissolved in DCM (400 mL). N,O-dimethylhydroxylamine hydrochloride (54.6 g, 559 mmol) was added to this solution. The reaction mixture was stirred at 25°C for 12 hours under an N2 atmosphere. LCMS showed the desired mass. The mixture was quenched with water (300 mL) and extracted with DCM (3 × 100 mL). The organic layer was washed with brine (100 mL), dehydrated with Na2SO4, filtered, concentrated under reduced pressure, and the crude product was purified by flash silica gel chromatography (ISCO®; 220 g Agela Silica Flash Column, eluent 8% ethyl acetate / petroleum ether gradient @ 50 mL / min) to obtain N-methoxy-N-methylpenta-4-enamide (INT2-2).

[0556] MS (ESI) m / z 144.1 (M+H) + 1¹H NMR (500 MHz, chloroform-d) δ 5.83-5.92 (m, 1H), 4.94-5.10 (m, 2H), 3.68 (s, 3H), 3.18 (s, 3H), 2.50-2.56 (m, 2H), 2.35-2.42 (m, 2H) Preparation of intermediates 2-3 [ka]

[0557] N-methoxy-N-methylpenta-4-enamide (INT2-2) (20 g, 140 mmol) was dissolved in THF (200 mL) and ethylmagnesium bromide (69.8 mL, 210 mmol) was added dropwise at 0°C under an N2 atmosphere. The reaction mixture was stirred at 25°C for 1 hour under an N2 atmosphere. TLC showed new spots. The mixture was quenched with saturated aqueous solution NH4Cl (100 mL) and water (100 mL) and extracted with siRNA (3 × 100 mL). The organic layer was washed with brine (50 mL), dehydrated with Na2SO4, filtered, concentrated under reduced pressure, and the crude product was purified by flash silica gel chromatography (ISCO®; 120 g Agela Silica Flash Column, eluent 5% ethyl acetate / petroleum ether gradient @ 40 mL / min) to obtain hepta-6-en-3-one (INT2-3).

[0558] 1 ¹H NMR (500 MHz, chloroform-d) δ 5.78-5.83 (m, 1H), 4.92-5.07 (m, 2H), 2.48-2.54 (m, 2H), 2.43 (q, J = 7.0 Hz, 2H), 2.29-2.37 (m, 2H), 1.06 (t, J = 7.0 Hz, 3H) Preparation of intermediates 2-4 [ka]

[0559] To a solution of hepta-6-en-3-one (INT2-3) (10 g, 89 mmol) dissolved in THF (100 mL), (R)-2-methylpropane-2-sulfinamide (12.97 g, 107 mmol) was added, followed by the addition of Ti(EtO)4 (37.5 mL, 178 mmol). The reaction mixture was then stirred at 75°C for 12 hours under an N2 atmosphere. TLC showed new spots. The final mixture was cooled to room temperature, then diluted with DCM (200 mL), stirred for 15 minutes, then dissolved in ice-cold saturated sodium bicarbonate aqueous solution (50 mL) and Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (ISCO®; 120g Agela Silica Flash Column, eluent 8% ethyl acetate / petroleum ether gradient @ 40mL / min) to obtain (R,E)-N-(hepta-6-ene-3-ylidene)-2-methylpropane-2-sulfinamide (INT2-4).

[0560] MS (ESI) m / z 216.2 (M+H) + 1 ¹H NMR (500 MHz, chloroform-d) δ 5.73-5.88 (m, 1H), 4.94-5.10 (m, 2H), 2.64-2.87 (m, 2H), 2.31-2.58 (m, 4H), 1.22 (s, 9H), 1.05-1.20 (m, 3H) Preparation of intermediates 2-5 [ka]

[0561] Diisopropylamine (19.64 mL, 139 mmol) was dissolved in anhydrous THF (40 mL), and butyllithium (55.7 mL, 139 mmol) was added dropwise under an N2 atmosphere at -78°C. The reaction mixture was stirred at 0°C for 30 minutes to obtain LDA. Methyl acetate (7.48 mL, 93 mmol) and Ti(OiPr)3Cl (116 mL, 116 mmol) were added to anhydrous THF (90 mL). Then, LDA (76 mL, 93 mmol) was added dropwise to the mixture at -78°C. After 1 hour, a solution of (R,E)-N-(hepta-6-ene-3-ylidene)-2-methylpropane-2-sulfinamide (INT2-4) (10 g, 46.4 mmol) dissolved in anhydrous THF (20 mL) was added dropwise, and the mixture was stirred at -78°C for 3 hours. There was no change in color, and it remained yellow. LC-MS showed the major DP mass. The mixture was quenched with ice-cold semi-saturated aqueous ammonium chloride (60 mL). The slurry was diluted with ELISA (200 mL), then filtered, and washed with ELISA and water. The organic layer was washed with brine (50 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 120g Agela Silica Flash Column, eluent 25% ethyl acetate / petroleum ether gradient @ 40mL / min) to obtain methyl 3-(((R)-tert-butylsulfinyl)amino)-3-ethylhepta-6-enoate (INT2-5).

[0562] MS (ESI) m / z 290.1 ​​(M+H) + 1H NMR (500 MHz, chloroform-d) δ 5.76-5.82 (m, 1H), 5.01-5.05 (m, 1H), 4.97 (dd, J = 1.0, 10.0 Hz, 1H), 4.63 (br d, J = 17.0 Hz, 1H), 3.68 (s, 3H), 2.72 (dd, J = 5.0, 16.0 Hz, 1H), 2.52 (dd, J = 2.5, 16.0 Hz, 1H), 2.07-2.13 (m, 1H), 1.82-1.91 (m, 1H), 1.76-1.81 (m, 1H), 1.71-1.75 (m, 1H), 1.26 (t, J = 7.0 Hz, 2H), 1.24 (s, 9H), 0.87-0.95 (m, 3H) Preparation of intermediates 2-6 [ka]

[0563] Methyl 3-(((R)-tert-butylsulfinyl)amino)-3-ethylhepta-6-enoate (INT2-5) (12g, 41.5 mmol) was separated using an SFC column DAIEL CHIRALPAK AD (250mm × 50mm, 10um) under the conditions 0.1% NH3H2O ​​IPA, start B 15, end B 15, gradient, time (min) 100% B, retention time (min), flow rate (mL / min) 200, injection 200) and a column DAIEL CHIRALPAK AD (250mm × 50mm, 10um) under the conditions 0.1% NH3H2O ​​IPA, start B 12, end B 12, gradient, time (min) 100% B, retention time (min), flow rate (mL / min) 200, injection 240). (R)-3-(((R)-tert-butylsulfinyl)amino)-3-ethylhepta-6-enoate (INT2-6_P1, desired) (tR=1.978 min, UV=220 nm) and methyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-ethylhepta-6-enoate (INT2-6_P2) (tR=2.132 min, UV=220 nm) were obtained.

[0564] MS (ESI) m / z 290.1 ​​(M+H) + INT2-6_P1 : 1 H NMR (500 MHz, chloroform-d) δ 5.79 (tdd, J = 6.56, 10.32, 16.99 Hz, 1H), 4.93-5.09 (m, 2H), 3.62-3.73 (m, 3H), 2.72 (d, J = 15.87 Hz, 1H), 2.52 (d, J = 15.87 Hz, 1H), 2.48 (s, 1H), 2.00-2.09 (m, 2H), 1.76-1.88 (m, 2H), 1.68-1.74 (m, 2H), 1.23 (s, 9H), 0.86-0.95 (m, 3H). INT2-6_P2: 1 H NMR (500 MHz, chloroform-d) δ 5.71-5.87 (m, 1H), 4.94-5.07 (m, 2H), 3.65-3.73 (m, 3H), 2.72 (d, J = 16.02 Hz, 1H), 2.52 (d, J = 16.02 Hz, 1H), 2.00-2.14 (m, 2H), 1.83-1.91 (m, 1H), 1.74-1.80 (m, 1H), 1.67-1.74 (m, 2H), 1.20-1.25 (m, 8H), 0.83-0.89 (m, 3H). Preparation of intermediates 2-7 [ka]

[0565] A solution of methyl (R)-3-(((R)-tert-butylsulfinyl)amino)-3-ethylhepta-6-enoate (INT2-6_P1) (20 g, 69.1 mmol) dissolved in HCl-dioxane (4N) (100 mL) and MeOH (200 mL) was stirred at 25°C for 2 hours. LC-MS indicated that the reaction was complete. The solvent was evaporated under reduced pressure to obtain the product methyl (R)-3-amino-3-ethylhepta-6-enoate hydrochloride (INT2-7).

[0566] MS (ESI) m / z 186.3 (M+H) + 1 H NMR (500 MHz, メタノール-d4) δ 5.80-5.87 (m, 1H), 5.07-5.15 (m, 1H), 5.02-5.04 (m, 1H), 3.73 (s, 3H), 2.71-2.79 (m, 2H), 2.07-2.18 (m, 2H), 1.75-1.85 (m, 4H), 0.99 (t, J = 7.6 Hz, 3H) Preparation of intermediates 2-8

change

[0567] DMB-BOC-thiourea (5 g, 15.32 mmol), methyl (R)-3-amino-3-ethylhepta-6-enoate hydrochloride (INT2-7) (3.74 g, 16.85 mmol), and EDC (7.34 g, 38.3 mmol) were dissolved in acetonitrile (100 mL), to which DIEA (12.04 mL, 68.9 mmol) was added. The reaction mixture was stirred at 15 °C for 12 hours under an N2 atmosphere. LC-MS showed the desired mass and some ring-opening byproduct esters. The temperature was then raised to 50 °C and stirred at 50 °C for 2 hours. LC-MS showed only the mass of the desired product. The mixture was concentrated under reduced pressure. The crude product was dissolved in HCl (100 mL) and water (100 mL), and the layers were separated. The aqueous layer was extracted with HCl (2 × 50 mL). The organic layers were combined, washed with brine (100 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column (ISCO®; 80 g Agela Silica Flash Column, eluent 15% ethyl acetate / petroleum ether gradient @ 30 mL / min) to obtain tert-butyl (R,E)-(4-(buta-3-en-1-yl)-1-(2,4-dimethoxybenzyl)-4-ethyl-6-oxotetrahydropyrimidine-2(1H)-ylidene)carbamate (INT2-8).

[0568] MS (ESI) m / z 390.1 (M+H-56) + 1 H NMR (400 MHz, chloroform-d) δ 9.92 (br s, 1H), 7.10 (br d, J = 8.8 Hz, 1H), 6.33-6.50 (m, 2H), 5.63-5.83 (m, 1H), 5.09 (s, 2H), 4.96-5.06 (m, 2H), 3.78 (dd, J = 1.6, 4.4 Hz, 6H), 2.61 (s, 2H), 1.98-2.12 (m, 2H), 1.59-1.70 (m, 4H), 1.49 (s, 9H), 0.92 (t, J = 7.6 Hz, 3H) Preparation of intermediates 2-9 [ka]

[0569] A solution of tert-butyl (R,E)-(4-(buta-3-en-1-yl)-1-(2,4-dimethoxybenzyl)-4-ethyl-6-oxotetrahydropyrimidine-2(1H)-ylidene)carbamate (INT2-8) (1.0 g, 2.244 mmol) dissolved in TFA (10 mL) was stirred at 60°C for 16 hours. LC-MS showed the desired mass. The mixture was concentrated under reduced pressure. The residue was partitioned between petroleum ether / ethyl (v / v=4:1, 10 mL) and water (10 mL). LC-MS showed that the product was present only in the aqueous phase and was fairly pure. (R)-6-(buta-3-en-1-yl)-6-ethyl-2-iminotetrahydropyrimidine-4(1H)-one (INT2-9) in water (10 mL) was used directly in the next step.

[0570] MS (ESI) m / z 196.0 (M+H) + Preparation of Intermediate 2 [ka]

[0571] (R)-6-(buta-3-en-1-yl)-6-ethyl-2-iminotetrahydropyrimidine-4(1H)-one (INT2-9) (438 mg, 2.243 mmol) was dissolved in water (10 mL) and THF (3 mL). NaHCO3 (942 mg, 11.22 mmol) and (BOC)2O (1.042 mL, 4.49 mmol) were added in small amounts at 0°C. The reaction mixture was stirred at 25°C for 16 hours. LC-MS showed the desired mass. The mixture was extracted with ELISA (3 × 10 mL). The organic layer was washed with brine (10 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column (ISCO®; 12 g Agela Silica Flash Column, eluent 20% EE (EtOAC / EtOH=3:1) / petroleum ether gradient @ 30 mL / min) to obtain tert-butyl (R,E)-(4-(buta-3-en-1-yl)-4-ethyl-6-oxotetrahydropyrimidine-2(1H)-ylidene)carbamate (intermediate 2).

[0572] MS (ESI) m / z 296.2 (M+H) + 1 ¹H NMR (400 MHz, chloroform-d) δ 9.37 (br s, 1H), 5.74-5.81 (m, 1H), 4.90-5.17 (m, 2H), 2.59 (s, 2H), 2.07-2.10 (m, 2H), 1.62-1.78 (m, 4H), 1.51 (s, 9H), 0.97 (t, J = 7.2 Hz, 3H) Example 1 [ka]

[0573] (1R,5R,15R,16R)-5-ethyl-15-hydroxy-3-imino-9-methyl-23-oxa-2,4,17-triazahexacyclo[17.6.2.22,5.210,13.012,16.022,26]henthriaconta-10,12,19,21,26,28-hexaene-18,31-dione Preparation of Compounds 1-2 [ka]

[0574] Trifluoromethanesulfonic acid (503 mg, 3.35 mmol) and N-bromosuccinimide (596 mg, 3.35 mmol) were added at 0°C to a solution of (1R,2R)-1-amino-2,3-dihydro-1H-inden-2-ol (1-1) (500 mg, 3.35 mmol) dissolved in DCM (10 mL). The reaction product was stirred at 18°C ​​for 1 hour under an N2 atmosphere. The mixture was quenched at 0°C with saturated sodium bicarbonate solution (10 mL), extracted with DCM (1 × 10 mL), and then extracted with ethyl acetate (3 × 10 mL). The organic layer was washed with brine (10 mL), dehydrated with Na2SO4, filtered, concentrated under reduced pressure, and the crude product was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, eluent 10% MeOH / DCM (with 1% ammonium hydroxide added), gradient @ 50 mL / min) to obtain (1R,2R)-1-amino-6-bromo-2,3-dihydro-1H-inden-2-ol (1-2).

[0575] MS (ESI) m / z: 228.1, 230.1(M+H + ) 1 H NMR (400 MHz, methanol-d4) δ 7.50 (s, 1H), 7.33 (dd, J=1.6, 8.0 Hz, 1H), 7.10 (d, J=8.0 Hz, 1H), 4.10 (q, J=6.8 Hz, 1H), 4.01-4.05 (m, 1H), 3.15 (dd, J=6.8, 15.6 Hz, 1H), 2.68 (dd, J=7.2, 15.6 Hz, 1H) Preparation of Compounds 1-3 [ka]

[0576] (R)-4-((R,E)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxo-4-(penta-4-en-1-yl)tetrahydropyrimidine-1(2H)-yl)chroman-6-carboxylic acid (1-2) (96 mg, 0.198 mmol), EDC (189 mg, 0.989 mmol), 1H-benzo[d][1,2,3]triazole-1-ol (134 mg, 0.989 mmol), and (1R,2R)-1-amino-6-bromo-2,3-dihydro-1H-inden-2-ol (45.1 mg, 0.198 mmol) were dissolved in THF (5 mL), to which DIEA (0.276 mL, 1.582 mmol) was added. The reaction mixture was stirred at 18 °C for 2 hours. The mixture was quenched with water (5 mL) and extracted with ethyl acetate (3 × 5 mL). The organic layer was washed with brine (5 mL), dehydrated with Na₂SO₄, filtered, concentrated under reduced pressure, and the crude product was purified by prep-TLC (petroleum ether / ethyl acetate = 1:1) to obtain tert-butyl ((R,E)-1-((R)-6-(((1R,2R)-6-bromo-2-hydroxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)croman-4-yl)-4-ethyl-6-oxo-4-(penta-4-en-1-yl)tetrahydropyrimidine-2(1H)-ylidene)carbamate (1-3).

[0577] MS (ESI) m / z: 695.1, 697.1 (M+H + ) Preparation of Compounds 1-4A, 1-4B, and 1-4C [ka]

[0578] To a solution prepared by dissolving tert-butyl ((R,E)-1-((R)-6-((1R,2R)-6-bromo-2-hydroxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)croman-4-yl)-4-ethyl-6-oxo-4-(penta-4-en-1-yl)tetrahydropyrimidine-2(1H)-ylidene)carbamate (1-3) (100 mg, 0.144 mmol) in dioxane (1.5 mL), chloro[tri(o-tolyl)phosphine][2-(2'-amino-1,1'-biphenyl)]palladium(II) (8.83 mg, 0.014 mmol) and N,N-dicyclohexylmethylamine (140 mg, 0.719 mmol) were added in a glove box at 25°C. The reaction mixture was stirred at 70°C for 16 hours. The mixture was quenched with water (3 mL) and extracted with toluene (3 × 5 mL).The organic layer was washed with brine (5 mL), dehydrated with Na2SO4, filtered, concentrated under reduced pressure, and the crude product was purified by back-preparative HPLC (instrument ED; Method Column Boston Prime C18 150×30 mm, 5 μm; conditions Water (0.04% NH3H2O ​​+ 10 mM NH4HCO3)-ACN Start B 65; End B 95 Gradient Time (min) 10; 100% B Retention time (min) 2 Flow rate (mL / min) 25; Injection 5) to obtain the following: tert-butyl ((4aR,8R,12E,18R,18aR,28E)-8-ethyl-18-hydroxy-6,20-dioxo-4,4a,7,8,9,10,11,17,18,18a,19,20-dodecahydro-3H,6H-1,21-(epiethane[1,2]diylidene)-8,5-(epiminomethano)-14,16-ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclononadesine-28-ylidene)carbamate(1-4A);tert-butyl ((4aR,8R,12Z,18R,18aR,28E)-8-ethyl-18-hydroxy-6,20-dioxo-4,4a,7,8,9,10,11,17,18,18a,19,20-dodecahydro-3H,6H-1,21-(epiethane[1,2]diylidene)-8,5-(epiminomethano)-14,16-ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclononadesine-28-ylidene)carbamate(1-4B); and tert-butyl ((4aR,8R,17R,17aR,E)-8-ethyl-17-hydroxy-12-methylene-6,19-dioxo-4,4a,6,7,8,9,10,11,12,16,17,17a,18,19-tetradecahydro-3H-1,20-(epiethane[1,2]diylidene)-8,5-(epiminomethano)-13,15-ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclooctadecine-27-ylidene)carbamate(1-4C).

[0579] MS (ESI) m / z: 486.2 (M+H + ) 1-4A: 1H NMR (500 MHz, クロロホルム-d) δ 10.09 (s, 1H), 7.93 (dd, J=1.5, 8.50 Hz, 1H), 7.21-7.26 (m, 2H), 7.14 (d, J=8.0 Hz, 1H), 6.91-6.98 (m, 2H), 6.42-6.54 (m, 3H), 5.82-5.92 (m, 1H), 5.25 (t, J=5.5 Hz, 1H), 4.94 (s, 1H), 4.40-4.50 (m, 2H), 4.25-4.35 (m, 1H), 3.34 (dd, J=8.0, 15.5 Hz, 1H), 2.99-3.05 (m, 1H), 2.67-2.86 (m, 2H), 2.57 (d, J=13.5 Hz, 1H), 2.40 (d, J=15.5 Hz, 1H), 2.07 (s, 2H), 1.82 (d, J=11.0 Hz, 2H), 1.62-1.67 (m, 4H), 1.49 (s, 9H), 0.96 (t, J=7.5 Hz, 3H) 1-4B: 1H NMR (500 MHz, クロロホルム-d) δ 10.13 (s, 1H), 7.90 (dd, J=2.0, 8.50 Hz, 1H), 7.37 (s, 1H), 7.25 (d, J=7.5 Hz, 1H), 7.17 (s, 1H), 7.12 (d, J=7.5 Hz, 1H), 6.96 (d, J=8.50 Hz, 1H), 6.41-6.48 (m, 2H), 6.26 (dd, J=7. 0, 9.0 Hz, 1H), 5.60-5.70 (m, 1H), 5.34 (t, J=6.5 Hz, 1H), 4.60 (s, 1H), 4.46-4.54 (m, 1H), 4.42 (td, J=4.0, 11.0 Hz, 1H), 4.21 (dt, J=2.5, 11.0 Hz, 1H), 3.34 (dd, J=7.5, 16.0 Hz, 1H), 2.97 (dd, J=7.5, 16.0 Hz, 1H), 2.60-2.72 (m, 2H), 2.49-2.53 (m, 2H), 2.22-2.30 (m, 1H), 2.13-2.18 (m, 1H), 2.03-2.12 (m, 2H), 1.72-1.82 (m, 4H), 1.49 (s, 9H), 1.00 (t, J=7.5 Hz, 3H) 1-4C: 11H NMR (500 MHz, chloroform-d) δ 10.04 (s, 1H), 7.81 (dd, J = 2.0, 8.5 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 6.99 - 7.16 (m, 2H), 6.91 (d, J = 8.50 Hz, 1H), 6.38 - 6.50 (m, 2H), 5.44 (s, 1H), 5.31 (t, J = 6.5 Hz, 1H), 5.13 (s, 1H), 4.41 - 4.57 (m, 2H), 4.36 (s, 1H), 4.23 (dt, J = 2.0, 11.50 Hz, 1H), 3.34 (dd, J = 8.0, 16.0 Hz, 1H), 2.98 (dd, J = 8.0, 16.0 Hz, 1H), 2.69 - 2.79 (m, 1H), 2.59 - 2.63 (m, 1H), 2.45 - 2.52 (m, 2H), 1.93 - 2.09 (m, 2H), 1.86 (d, J = 12.0 Hz, 2H), 1.53 - 1.65 (m, 4H), 1.45 (s, 9H), 0.98 (t, J = 7.5 Hz, 3H) Preparation of compounds 1-5

Chem.

[0580] To a solution of tert-butyl ((4aR,8R,17R,17aR,E)-8-ethyl-17-hydroxy-12-methylene-6,19-dioxo-4,4a,6,7,8,9,10,11,12,16,17,17a,18,19-tetradecahydro-3H-1,20-(epiethane[1,2]diylidene)-8,5-(epiminomethano)-13,15-ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclooctadecine-27-ylidene)carbamate (1-4C) (10 mg, 0.016 mmol) dissolved in MeOH (2 mL), Pd-C (1.731 mg, 3.25 μmol) was added under an N2 atmosphere. The mixture was degassed and refilled with H2 (3 times). The resulting mixture was stirred at 25°C for 12 hours under H2 (15 psi). The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to obtain tert-butyl ((4aR,8R,17R,17aR,E)-8-ethyl-17-hydroxy-12-methyl-6,19-dioxo-4,4a,6,7,8,9,10,11,12,16,17,17a,18,19-tetradecahydro-3H-1,20-(epiethane[1,2]diylidene)-8,5-(epiminomethano)-13,15-ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclooctadecine-27-ylidene)carbamate (1-5).

[0581] MS (ESI) m / z: 617.3 (M+H + ) Preparation of Example 1 [ka]

[0582] To a solution of tert-butyl((4aR,8R,17R,17aR,E)-8-ethyl-17-hydroxy-12-methyl-6,19-dioxo-4,4a,6,7,8,9,10,11,12,16,17,17a,18,19-tetradecahydro-3H-1,20-(epiethane[1,2]diylidene)-8,5-(epiminomethano)-13,15-ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclooctadecine-27-ylidene)carbamate (1-5) (8 mg, 0.013 mmol) dissolved in DCM (3 mL), zinc(II) bromide (29.2 mg, 0.130 mmol) was added at 22°C under an N2 atmosphere. The mixture was stirred at 22°C for 16 hours. The mixture was cooled, and the solvent was evaporated under reduced pressure to obtain the crude product. The residue was purified by back-preparative HPLC (instrument: EJ Method Column Boston Green ODS 150×30mm, 5um Conditions: Water (TFA)-ACN Start B 22 End B 52 Gradient Time (min) 10 100% B retention time (min) 2 Flow rate (mL / min) 25 Injection 1) to obtain Example 1.

[0583] MS (ESI) m / z: 517.2 (M+H + ) 1H NMR (500 MHz, メタノール-d4) δ 8.49 (d, J=9.0 Hz, 1H), 7.72 (dd, J=2.0, 8.5 Hz, 1H), 7.39 (d, J=1.0 Hz, 1H), 7.19-7.24 (m, 1H), 7.14-7.19 (m, 1H), 6.91-6.96 (m, 2H), 5.30-5.39 (m, 2H), 4.38-4.53 (m, 2H), 4.13-4.15 (m, 1H), 3.18-3.29 (m, 1H), 2.75-2.94 (m, 3H), 2.61-2.72 (m, 2H), 2.20-2.30 (m, 1H), 1.74-1.85 (m, 3H), 1.58-1.68 (m, 2H), 1.50-1.57 (m, 1H), 1.31 (d, J=7.0 Hz, 3H), 1.24-1.29 (m, 1H), 1.11-1.20 (m, 1H), 0.97 (t, J=7.5 Hz, 3H) Example 2

change

[0584] (1R,5R,16R,17R)-5-ethyl-16-hydroxy-3-imino-24-oxa-2,4,18-triazahexacyclo[18.6.2.22,5.211,14.013,17.023,27]dotriaconta-11,13,20,22,27,29-hexaene-19,32-dione Preparation of Compound 2-1

change

[0585] To a solution of tert-butyl ((4aR,8R,12E,18R,18aR,28E)-8-ethyl-18-hydroxy-6,20-dioxo-4,4a,7,8,9,10,11,17,18,18a,19,20-dodecahydro-3H,6H-1,21-(epiethane[1,2]diylidene)-8,5-(epiminomethano)-14,16-ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclononadesine-28-ylidene)carbamate (2-1) (13 mg, 0.021 mmol) dissolved in MeOH (4 mL), Pd-C (2.250 mg, 4.23 μmol) was added under an N2 atmosphere. The mixture was degassed and refilled with H2 (3 times). The resulting mixture was stirred at 20°C for 2 hours under H2 (15 psi). The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to obtain tert-butyl ((4aR,8R,18R,18aR,E)-8-ethyl-18-hydroxy-6,20-dioxo-4,4a,7,8,9,10,11,12,13,17,18,18a,19,20-tetradecahydro-3H,6H-1,21-(epiethane[1,2]diylidene)-8,5-(epiminomethano)-14,16-ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclononadecin-28-ylidene)carbamate (2-1).

[0586] MS (ESI) m / z: 617.2 (M+H + ) Preparation of Example 2 [ka]

[0587] To a solution of tert-butyl ((4aR,8R,18R,18aR,E)-8-ethyl-18-hydroxy-6,20-dioxo-4,4a,7,8,9,10,11,12,13,17,18,18a,19,20-tetradecahydro-3H,6H-1,21-(epiethane[1,2]diylidene)-8,5-(epiminomethano)-14,16-ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclononadesine-28-ylidene)carbamate (2-1) (13 mg, 0.021 mmol) dissolved in DCM (3 mL), zinc(II) bromide (47.5 mg, 0.211 mmol) was added under an N2 atmosphere. The mixture was stirred at 22°C for 16 hours. The mixture was concentrated under reduced pressure to obtain the crude product. The residue was then subjected to back-preparative HPLC (instrument: EJ; Method Column: Boston Green ODS 150×30mm, 5um, conditions: water (TFA)-ACN; Start: B 22; End: B 52; Gradient: Time (min) 10; 100% B; Retention time (min) 2; Flow rate (mL / min) 25; Purification by injection 1) yielded (4aR,8R,18R,18aR)-8-ethyl-18-hydroxy-28-imino-4,4a,8,9,10,11,12,13,17,18,18a,19-dodecahydro-3H,6H-1,21-(epiethane[1,2]diylidene)-8,5-(epiminomethano)-14,16-ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclononadesine-6,20(7H)-dione (Example 2).

[0588] MS (ESI) m / z: 517.2 (M+H + ) 11H NMR (500 MHz, methanol-d4) δ 7.76 (dd, J = 2.0, 8.5 Hz, 1H), 7.46 (d, J = 1.5 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 6.99 - 7.06 (m, 2H), 6.93 (d, J = 8.5 Hz, 1H), 5.21 (t, J = 7.5 Hz, 1H), 5.07 (d, J = 5.5 Hz, 1H), 4.54 - 4.62 (m, 1H), 4.38 - 4.49 (m, 1H), 4.09 - 4.19 (m, 1H), 3.23 - 3.28 (m, 1H), 2.90 (d, J = 16.5 Hz, 1H), 2.79 (dd, J = 6.0, 16.0 Hz, 1H), 2.62 - 2.74 (m, 2H), 2.50 - 2.61 (m, 2H), 2.20 - 2.34 (m, 1H), 1.81 (s, 1H), 1.62 - 1.76 (m, 3H), 1.49 (t, J = 11.5 Hz, 1H), 1.12 - 1.44 (m, 6H), 0.95 (t, J = 7.5 Hz, 3H) Example 3A

Chem.

[0589] (1R,5R,17S)-5-ethyl-3-imino-15,15-dimethyl-14,24-dioxa-2,4,18-triazahexacyclo[18.6.2.22,5.210,13.012,17.023,27]dotriaconta-10,12,20,22,27,29-hexaene-19,32-dione Preparation of compound 3-2

Chem.

[0590] Penta-4-enoic acid (40 g, 400 mmol), EDC (92 g, 479 mmol), 1H-benzo[d][1,2,3]triazole-1-ol (3-1) (64.8 g, 479 mmol), and N-ethyl-N-isopropylpropan-2-amine (279 mL, 1598 mmol) were dissolved in DCM (400 mL), to which N,O-dimethylhydroxylamine hydrochloride (54.6 g, 559 mmol) was added. The reaction product was stirred under an N2 atmosphere at 25°C for 12 hours. The mixture was quenched with water (300 mL) and extracted with DCM (3 × 100 mL). The organic layer was washed with brine (100 mL), dehydrated with Na2SO4, filtered, concentrated under reduced pressure, and the crude product was purified by flash silica gel chromatography (ISCO®; 220 g Agela Silica Flash Column, eluent 8% ethyl acetate / petroleum ether gradient @ 50 mL / min) to obtain N-methoxy-N-methylpenta-4-enamide (3-2).

[0591] MS (ESI) m / z 144.1 (M+H + ) 1 ¹H NMR (500 MHz, chloroform-d) δ 5.83-5.92 (m, 1H), 4.94-5.10 (m, 2H), 3.68 (s, 3H), 3.18 (s, 3H), 2.50-2.56 (m, 2H), 2.35-2.42 (m, 2H) Preparation of Compound 3-3 [ka]

[0592] N-methoxy-N-methylpenta-4-enamide (3-2) (20 g, 140 mmol) was dissolved in THF (200 mL) and ethylmagnesium bromide (69.8 mL, 210 mmol) was added dropwise at 0°C under an N2 atmosphere. The reaction mixture was stirred at 25°C for 1 hour under an N2 atmosphere. The mixture was quenched with saturated aqueous solution NH4Cl (100 mL) and water (100 mL) and extracted with siRNA (3 × 100 mL). The organic layer was washed with brine (50 mL), dehydrated with Na2SO4, filtered, concentrated under reduced pressure, and the crude product was purified by flash silica gel chromatography (ISCO®; 120 g Agela Silica Flash Column, eluent 5% ethyl acetate / petroleum ether gradient @ 40 mL / min) to obtain hepta-6-en-3-one (3-3).

[0593] 1 ¹H NMR (500 MHz, chloroform-d) δ 5.78-5.83 (m, 1H), 4.92-5.07 (m, 2H), 2.48-2.54 (m, 2H), 2.43 (q, J=7.0 Hz, 2H), 2.29-2.37 (m, 2H), 1.06 (t, J=7.0 Hz, 3H) Preparation of Compounds 3-4 [ka]

[0594] To a solution of hepta-6-en-3-one (3-3) (10 g, 89 mmol) dissolved in THF (100 mL), (R)-2-methylpropan-2-sulfinamide (12.97 g, 107 mmol) was added. Ti(EtO)4 (37.5 mL, 178 mmol) was also added, and the reaction mixture was stirred at 75°C for 12 hours under an N2 atmosphere. The mixture was cooled to room temperature, diluted with DCM (200 mL), and stirred for 15 minutes. Ice-cold saturated sodium bicarbonate aqueous solution (50 mL) and Na2SO4 were added, the mixture was filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (ISCO®; 120g Agela Silica Flash Column, eluent 8% ethyl acetate / petroleum ether gradient @ 40mL / min) to obtain (R,E)-N-(hepta-6-ene-3-ylidene)-2-methylpropane-2-sulfinamide (3-4).

[0595] MS (ESI) m / z 216.2(M+H + ) 1 ¹H NMR (500 MHz, chloroform-d) δ 5.73-5.88 (m, 1H), 4.94-5.10 (m, 2H), 2.64-2.87 (m, 2H), 2.31-2.58 (m, 4H), 1.22 (s, 9H), 1.05-1.20 (m, 3H) Preparation of Compounds 3-5 [ka]

[0596] Diisopropylamine (19.64 mL, 139 mmol) was dissolved in anhydrous THF (40 mL), and butyllithium (55.7 mL, 139 mmol) was added dropwise under an N2 atmosphere at -78°C. The reaction mixture was stirred at 0°C for 30 minutes to produce LDA. The obtained LDA (76 mL, 93 mmol) was added dropwise to a mixture of ethyl acetate (7.48 mL, 93 mmol) and Ti(OiPr)3Cl (116 mL, 116 mmol) in anhydrous THF (90 mL) at -78°C. After 1 hour, a solution of (R,E)-N-(hepta-6-ene-3-ylidene)-2-methylpropane-2-sulfinamide (3-4) (10 g, 46.4 mmol) dissolved in anhydrous THF (20 mL) was added dropwise, and the mixture was stirred at -78°C for 3 hours. The mixture was quenched with ice-cold semi-saturated aqueous solution of ammonium chloride (60 mL). The slurry was diluted with ethyl acetate (200 mL), filtered, and washed with ethyl acetate and water. The organic layer was washed with brine (50 mL), dehydrated with Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 120 g Agela Silica Flash Column, eluent 25% ethyl acetate / petroleum ether gradient @ 40 mL / min) to obtain methyl 3-(((R)-tert-butylsulfinyl)amino)-3-ethylhepta-6-enoate (3-5).

[0597] MS (ESI) m / z 290.1 ​​(M+H + ) 1H NMR (500 MHz, chloroform-d) δ 5.76-5.82 (m, 1H), 5.01-5.05 (m, 1H), 4.97 (dd, J=1.0, 10.0 Hz, 1H), 4.63 (br d, J=17.0 Hz, 1H), 3.68 (s, 3H), 2.72 (dd, J=5.0, 16.0 Hz, 1H), 2.52 (dd, J=2.5, 16.0 Hz, 1H), 2.07-2.13 (m, 1H), 1.82-1.91 (m, 1H), 1.76-1.81 (m, 1H), 1.71-1.75 (m, 1H), 1.26 (t, J=7.0 Hz, 2H), 1.24 (s, 9H), 0.87-0.95 (m, 3H) Preparation of compounds 3-6 [ka]

[0598] A solution of methyl 3-(((R)-tert-butylsulfinyl)amino)-3-ethylhepta-6-enoate (3-5) (9 g, 31.1 mmol) dissolved in 4N HCl-dioxane (20 mL) and MeOH (20.00 mL) was stirred at 25°C for 1 hour under an N2 atmosphere. The solvent was evaporated under reduced pressure to obtain the crude product methyl 3-amino-3-ethylhepta-6-enoate hydrochloride (3-6). This was used directly in the next step as is.

[0599] MS (ESI) m / z 186.2 (M+H + ) 1 H NMR (500 MHz, chloroform-d) δ 5.75-5.80 (m, 1H), 5.08 (dd, J=1.0, 18.0 Hz, 1H), 4.98 (d, J=10.22 Hz, 1H), 3.72-3.75 (m, 3H), 2.78-2.85 (m, 2H), 2.21-2.29 (m, 2H), 1.84-2.00 (m, 4H), 1.06 (t, J=7.5 Hz, 3H) Preparation of Compounds 3-7 [ka]

[0600] EDC (9.08 g, 47.4 mmol), methyl 3-amino-3-ethylhepta-6-enoate hydrochloride (3-6) (3.5 g, 15.79 mmol), and methyl (R)-4-(3-(tert-butoxycarbonyl)thioureido)chroman-6-carboxylate (INT-1) (5.78 g, 15.79 mmol) were dissolved in ACN (30 mL), to which N-ethyl-N-isopropylpropan-2-amine (13.79 mL, 79 mmol) was added. The reaction product was stirred under an N2 atmosphere at 25°C for 12 hours. The mixture was quenched with water (50 mL) and extracted with ELISA (3 × 50 mL). The organic layer was washed with brine (30 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain methyl (4R)-4-((Z)-2-(tert-butoxycarbonyl)-3-(3-ethyl-1-methoxy-1-oxohepta-6-en-3-yl)guanidino)chroman-6-carboxylate (3-7). This was used directly in its crude form in the next step.

[0601] MS (ESI) m / z 518.2 (M+H + ) Preparation of Compounds 3-8 [ka]

[0602] Methyl (4R)-4-((Z)-2-(tert-butoxycarbonyl)-3-(3-ethyl-1-methoxy-1-oxohepta-6-en-3-yl)guanidino)chroman-6-carboxylate (3-7) (8.17 g, 15.78 mmol) was dissolved in THF (50 mL), and DBU (11.90 mL, 79 mmol) was added to the solution. The mixture was stirred at 50°C for 16 hours under an N2 atmosphere. The mixture was quenched with water (50 mL) and extracted with ELISA (3 × 50 mL). The organic layer was washed with brine (30 mL), dehydrated with Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (ISCO®; 120g Agela Silica Flash Column, eluent 25% ethyl acetate / petroleum ether gradient @ 40mL / min) to obtain methyl (4R)-4-((E)-4-(buta-3-en-1-yl)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydropyrimidine-1(2H)-yl)chroman-6-carboxylate (3-8).

[0603] MS (ESI) m / z 486.2(M+H + ) 1 H NMR (500 MHz, chloroform-d) δ 7.77 (td, J=2.0, 8.5 Hz, 1H), 7.62 (s, 1H), 6.84 (dd, J=2.0, 8.5 Hz, 1H), 6.33-6.42 (m, 1H), 5.76-5.90 (m, 1H), 5.00-5.14 (m, 2H), 4.42-4.49 (m, 1H), 4.22-4.23 (m, 1H), 3.81-3.86 (m, 3H), 2.70-2.81 (m, 1H), 2.51-2.60 (m, 2H), 2.03-2.16 (m, 4H), 1.75-1.84 (m, 2H), 1.65-1.73 (m, 4H), 1.52 (s, 9H), 0.98-1.04 (m, 3H) Preparation of Compound 3-9A and Compound 3-9B [ka]

[0604] Methyl (4R)-4-((E)-4-(buta-3-en-1-yl)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydropyrimidine-1(2H)-yl)chroman-6-carboxylate (3-8) (4g, 8.24 mmol) was separated by SFC (Column Boston Green ODS 150×30mm, 5um Conditions Water (TFA)-ACN Start B 48 End B 78 Gradient Time (min) 10 100% B retention time (min) 2 Flow rate (mL / min) 25 Injection 1), and (P1) methyl (4R)-4-((E)-4-(buta-3-en-1-yl)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydropyrimidine-1(2H)-yl)chroman-6-carboxylate(3-9A)(t R =2.105 min, UV=220nm) and (P2)methyl (4R)-4-((E)-4-(buta-3-en-1-yl)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydropyrimidine-1(2H)-yl)chroman-6-carboxylate(3-9B)(t R A reading of 2.251 minutes (UV=220nm) was obtained.

[0605] MS (ESI) m / z 486.2 (M+H + ) 3-9A: 1H NMR (500 MHz, クロロホルム-d) δ 7.77 (dd, J=1.5, 8.5 Hz, 1H), 7.62 (s, 1H), 6.84 (d, J=9.0 Hz, 1H), 6.37 (br dd, J=7.0, 10.0 Hz, 1H), 5.81-5.86 (m, 1H), 5.00-5.12 (m, 2H), 4.42-4.45 (m, 2H), 4.21-4.24 (m, 1H), 3.83 (s, 3H), 2.68-2.78 (m, 1H), 2.07-2.16 (m, 3H), 1.66-1.83 (m, 5H), 1.51 (s, 9H), 0.96 (t, J=7.5 Hz, 3H) 3-9B: 1 H NMR (500 MHz, クロロホルム-d) δ 7.77 (br d, J=8.70 Hz, 1H), 7.62 (s, 1H), 6.84 (d, J=8.5 Hz, 1H), 6.39 (br dd, J=7.0, 10.0 Hz, 1H), 5.74-5.86 (m, 1H), 5.00-5.10 (m, 2H), 4.41-4.50 (m, 1H), 4.21-4.25 (m, 1H), 3.83 (s, 3H), 2.73-2.81 (m, 1H), 2.06-2.12 (m, 3H), 1.68-1.83 (m, 5H), 1.52 (s, 9H), 0.98–1.04 (m, 3H) Preparation of compounds 3-10

change

[0606] To a solution of methyl (R)-4-((R,E)-4-(buta-3-en-1-yl)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydropyrimidine-1(2H)-yl)chroman-6-carboxylate (3-9A) (550 mg, 1.133 mmol) dissolved in THF (5 mL), potassium trimethylsilanolate (872 mg, 6.80 mmol) was added. The reaction mixture was stirred at 25°C for 0.5 hours. The solution of (R)-4-((R,E)-4-(buta-3-en-1-yl)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydropyrimidine-1(2H)-yl)chroman-6-carboxylic acid (3-10) was used directly in the next step without further processing or purification.

[0607] MS (ESI) m / z 472.2 (M+H + ). Preparation of Compound 3-11 [ka]

[0608] (R)-4-((R,E)-4-(buta-3-en-1-yl)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydropyrimidine-1(2H)-yl)chroman-6-carboxylic acid (3-10) (534 mg, 1.132 mmol), EDC (1085 mg, 5.66 mmol), 1H-benzo[d][1,2,3]triazole-1-ol (765 mg, 5.66 mmol), and (S)-2,2-dimethyl-6-vinylchroman-4-amine (253 mg, 1.246 mmol) were dissolved in THF (50 mL), to which DIEA (1.582 mL, 9.06 mmol) was added. The mixture was stirred at 25 °C for 12 hours. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The organic layer was washed with brine (15 mL), dehydrated with Na₂SO₄, filtered, concentrated under reduced pressure, and the crude product was purified by prep-TLC (petroleum ether / ethyl acetate = 2:1) to obtain tert-butyl ((R,E)-4-(buta-3-en-1-yl)-1-((R)-6-(((S)-2,2-dimethyl-6-vinylchroman-4-yl)carbamoyl)chroman-4-yl)-4-ethyl-6-oxotetrahydropyrimidine-2(1H)-ylidene)carbamate (3-11).

[0609] MS (ESI) m / z 657.3 (M+H + ) Preparation of Compounds 3-12 [ka]

[0610] To a solution of tert-butyl ((R,E)-4-(buta-3-en-1-yl)-1-((R)-6-(((S)-2,2-dimethyl-6-vinylchroman-4-yl)carbamoyl)chroman-4-yl)-4-ethyl-6-oxotetrahydropyrimidine-2(1H)-ylidene)carbamate (3-11) (500 mg, 0.761 mmol) dissolved in DCE (500 mL), (1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)ruthenium (95 mg, 0.152 mmol) was added. The reaction product was stirred at 50°C for 5 hours under an N2 atmosphere. The mixture was concentrated under reduced pressure, and the crude product was purified by flash column (petroleum ether / toluene / EtOH = 8:3:1) to obtain tert-butyl ((4aR,8R,11E,18aS,28E)-8-ethyl-17,17-dimethyl-6,20-dioxo-4,4a,7,8,9,10,18,18a,19,20-decahydro-3H,6H,17H-8,5-(epiminomethano)-1,21:13,15-dietenodipyrano[4,3-b:4',3'-h][1,7]diazacyclooctadecine-28-ylidene)carbamate (3-12).

[0611] MS (ESI) m / z 629.3 (M+H + ) 11H NMR (500 MHz, chloroform-d) δ 7.67 (dd, J = 1.5, 8.5 Hz, 1H), 7.36 (s, 1H), 7.19 (s, 1H), 7.05 - 7.10 (m, 1H), 6.91 (d, J = 8.5 Hz, 1H), 6.69 (d, J = 8.5 Hz, 1H), 6.37 (d, J = 15.5 Hz, 1H), 6.09 - 6.22 (m, 2H), 5.92 - 5.93 (m, 1H), 5.40 - 5.42 (m, 1H), 4.49 (td, J = 4.0, 11.5 Hz, 1H), 2.93 - 3.04 (m, 2H), 2.46 - 2.53 (m, 2H), 2.35 - 2.41 (m, 1H), 2.29 (dd, J = 6.5, 13.0 Hz, 1H), 1.91 - 1.99 (m, 1H), 1.71 - 1.78 (m, 2H), 1.66 - 1.71 (m, 4H), 1.61 - 1.66 (m, 1H), 1.50 - 1.53 (m, 1H), 1.46 - 1.50 (m, 1H), 1.43 (s, 3H), 1.37 (s, 3H), 1.26 (s, 9H), 0.95 (t, J = 7.48 Hz, 3H) Preparation of Compound 3-13

Chem.

[0612] 300 mg, 0.477 mmol of tert-butyl ((4aR,8R,11E,18aS,28E)-8-ethyl-17,17-dimethyl-6,20-dioxo-4,4a,7,8,9,10,18,18a,19,20-decahydro-3H,6H,17H-8,5-(epiminomethano)-1,21:13,15-dietenodipyrano[4,3-b:4',3'-h][1,7]diazacyclooctadecine-28-ylidene)carbamate (3-12) (300 mg, 0.477 mmol) was dissolved in 10 mL of MeOH, and Pd-C (50.8 mg, 0.048 mmol) was added to the solution under an N2 atmosphere. The mixture was degassed and returned to the container with H2 (3 times). The resulting mixture was stirred at 25°C for 0.5 hours under H2 (15 psi). The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to obtain tert-butyl ((4aR,8R,18aS,E)-8-ethyl-17,17-dimethyl-6,20-dioxo-4,4a,7,8,9,10,11,12,18,18a,19,20-dodecahydro-3H,6H,17H-8,5-(epiminomethano)-1,21:13,15-dietenodipyrano[4,3-b:4',3'-h][1,7]diazacyclooctadecine-28-ylidene)carbamate (3-13). This was used directly in the next step.

[0613] MS (ESI) m / z 631.3(M+H + ) Preparation of Example 3A [ka]

[0614] A solution of tert-butyl ((4aR,8R,18aS,E)-8-ethyl-17,17-dimethyl-6,20-dioxo-4,4a,7,8,9,10,11,12,18,18a,19,20-dodecahydro-3H,6H,17H-8,5-(epiminomethano)-1,21:13,15-dietenodipyrano[4,3-b:4',3'-h][1,7]diazacyclooctadecine-28-ylidene)carbamate (3-13) (280 mg, 0.444 mmol) dissolved in HCl-dioxane (4N) (30 mL) was stirred at 25°C for 16 hours. The solvent was evaporated under reduced pressure to obtain the crude product. The residue was purified by reverse preparative HPLC (Column Boston Green ODS 150×30mm, 5um conditions Water (HCl)-ACN Start B 30 End B 50 Gradient Time (min) 10 100% B retention time (min) 2 Flow rate (mL / min) 25 Injection 6) to obtain (4aR,8R,18aS)-8-ethyl-28-imino-17,17-dimethyl-4,4a,7,8,9,10,11,12,17,18,18a,19-dodecahydro-3H,6H,20H-8,5-(epiminomethano)-1,21:13,15-dietenodipyrano[4,3-b:4',3'-h][1,7]diazacyclooctadecine-6,20-dione (Example 3A).

[0615] MS (ESI) m / z 531.2 (M+H + ) 1H NMR (500 MHz, メタノール-d4) δ 7.73 (dd, J=2.0, 8.5 Hz, 1H), 7.45 (s, 1H), 7.02 (s, 1H), 6.92-6.99 (m, 2H), 6.70 (d, J=8.5 Hz, 1H), 5.37-5.44 (m, 2H), 4.44-4.47 (m, 1H), 4.12-4.17 (m, 1H), 2.93 (d, J=16.5 Hz, 1H), 2.55-2.70 (m, 4H), 2.23-2.31 (m, 1H), 2.12 (dd, J=6.5, 13.0 Hz, 1H), 1.81-1.87 (m, 1H), 1.66-1.80 (m, 5H), 1.49-1.59 (m, 1H), 1.42 (s, 3H), 1.34-1.40 (m, 2H), 1.32 (s, 3H), 0.98 (t, J=7.5 Hz, 3H) Example 4

change

[0616] (1R,5R,18S)-5-ethyl-3-imino-16,16-dimethyl-10,15,25-trioxa-2,4,19-triazahexacyclo[19.6.2.22,5.211,14.013,18.024,28]tritriaconta-11,13,21,23,28,30-hexaene-20,33-dione Preparation of compound 4-2

change

[0617] Hexa-5-enoic acid (4-1) (8g, 70.1 mmol), EDC (20.15g, 105 mmol), 1H-benzo[d][1,2,3]triazole-1-ol (14.21g, 105 mmol), and N,O-dimethylhydroxylamine hydrochloride (7.52g, 77 mmol) were dissolved in THF (100 mL) and DIEA (36.7 mL, 210 mmol) was added. The reaction mixture was stirred at 25°C for 5 hours. The mixture was quenched with water (150 mL) and extracted with RINKAN (3 × 50 mL). The organic layer was washed with brine (50 mL), dehydrated with Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, eluent 5% siRNA / petroleum ether gradient @ 80 mL / min) to obtain N-methoxy-N-methylhexa-5-enamide (4-2).

[0618] MS (ESI) m / z 157.7 (M+H + ) Preparation of compound 4-3 [ka]

[0619] N-methoxy-N-methylhexa-5-enamide (4-2) (9 g, 57.2 mmol) was dissolved in THF (120 mL) and ethylmagnesium bromide (38.2 mL, 114 mmol) was added dropwise at 0°C under an N2 atmosphere. The mixture was then stirred at 20°C for 2 hours. The mixture was quenched with saturated aqueous solution NH4Cl (25 mL). The mixture was quenched with water (150 mL) and extracted with siRNA (3 × 100 mL). The organic layers were combined and washed with brine (80 mL), dehydrated with Na2SO4, and filtered. The solvent was removed under reduced pressure to obtain the crude product. This was purified by column chromatography (SiO2, petroleum ether:siRNA = 100:1 to 10:1) to obtain octa-7-en-3-one (4-3).

[0620] 1 ¹H NMR (500 MHz, chloroform-d): δ 5.76 (m, 1H), 4.93-5.04 (m, 2H), 2.38-2.44 (m, 4H), 2.05 (q, J=7.0 Hz, 2H), 1.68 (m, 2H), 1.04 (t, J=7.5 Hz, 3H). Preparation of compound 4-4 [ka]

[0621] To a solution of octa-7-en-3-one (4-3) (5.5 g, 43.6 mmol) dissolved in THF (80 mL), 2-methylpropan-2-sulfinamide (6.34 g, 52.3 mmol) was added, followed by the addition of Ti(EtO)4 (18.31 mL, 87 mmol). The reaction mixture was stirred at 75°C for 16 hours under an N2 atmosphere. The final mixture was cooled to 0°C, diluted with DCM (100 mL), and stirred for 15 minutes. Ice-cold saturated sodium bicarbonate aqueous solution (15 mL) was added, the solution was filtered, and concentrated under reduced pressure. The crude product was purified by flash column (SiO2, petroleum ether / siRNA = 100:1 → 5:1) to obtain (E)-2-methyl-N-(octa-7-en-3-ylidene)propan-2-sulfinamide (4-4).

[0622] MS (ESI) m / z 230.2 (M+H + ) 1 ¹H NMR (500 MHz, chloroform-d) δ 5.78-5.80 (m, 1H), 4.96-5.07 (m, 2H), 2.62-2.76 (m, 2H), 2.39-2.50 (m, 2H), 2.04-2.17 (m, 2H), 1.67-1.76 (m, 2H), 1.23 (s, 9H), 1.06-1.21 (m, 3H) Preparation of Compounds 4-5 [ka]

[0623] To a solution of LiHMDS (22.67 mL, 22.67 mmol) dissolved in anhydrous THF (35 mL), methyl acetate (1.545 mL, 19.18 mmol) was added under an N2 atmosphere at -78°C. The reaction mixture was stirred at -78°C for 15 minutes. Then, (E)-2-methyl-N-(octa-7-ene-3-ylidene)propane-2-sulfinamide (4-4) (4 g, 17.44 mmol) in THF (15 mL) was added dropwise, and the mixture was stirred at -78°C for 3 hours. The mixture was quenched with ice-cold semi-saturated aqueous ammonium chloride solution (30 mL). The slurry was diluted with HCl (50 mL), filtered, and washed with HCl and water. The organic layer was washed with brine (50 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified using a flash column (SiO2, petroleum ether / ethyl = 100:0 → 10:1) to obtain methyl 3-((tert-butylsulfinyl)amino)-3-ethylocta-7-enoate (4-5).

[0624] MS (ESI) m / z 304.3 (M+H + ). 1 H NMR (500 MHz, chloroform-d) δ 5.72-5.86 (m, 1H), 4.91-5.06 (m, 2H), 4.59-4.61 (m, 1H), 3.63-3.76 (m, 3H), 2.68-2.71 (m, 1H), 2.42-2.55 (m, 1H), 1.99-2.13 (m, 2H), 1.58-1.91 (m, 5H), 1.31-1.48 (m, 2H), 1.16-1.24 (m, 9H), 0.80-0.93 (m, 3H) Preparation of compounds 4-6 [ka]

[0625] Methyl 3-((tert-butylsulfinyl)amino)-3-ethylocta-7-enoate (4-5) (2 g, 6.59 mmol) was dissolved in HCl-dioxane (4N) (5 mL) and MeOH (5 mL) at 15°C. The solution was stirred at 15°C for 1 hour under a N2 atmosphere. The solution was concentrated under reduced pressure to obtain the crude product methyl 3-amino-3-ethylocta-7-enoate hydrochloride (4-6). This was used without further purification.

[0626] 1 ¹H NMR (500 MHz, chloroform-d) δ 5.77 (m, 1H), 4.93-5.06 (m, 2H), 3.73 (s, 3H), 2.72-2.88 (m, 2H), 2.02-2.14 (m, 2H), 1.70-2.00 (m, 5H), 1.56 (m, 2H), 1.04 (t, J = 7.50 Hz, 3H) Preparation of Compounds 4-7 [ka]

[0627] Methyl (R)-4-(3-(tert-butoxycarbonyl)thioureido)chroman-6-carboxylate (INT-1) (1.5 g, 4.09 mmol), methyl 3-amino-3-ethylocta-7-enoate hydrochloride (4-6) (1.448 g, 6.14 mmol), and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (2.354 g, 12.28 mmol) were dissolved in acetonitrile (30 mL), to which N-ethyl-N-isopropylpropan-2-amine (4.37 mL, 24.56 mmol) was added. The mixture was stirred at 15 °C for 10 hours. The mixture was quenched with water (50 mL) and extracted with ELISA (3 × 40 mL). The organic layer was washed with brine (20 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain methyl (4R)-4-((Z)-2-(tert-butoxycarbonyl)-3-(3-ethyl-1-methoxy-1-oxoocta-7-en-3-yl)guanidino)chroman-6-carboxylate (4-7). This was used directly in its crude form in the next step.

[0628] MS (ESI) m / z 532.3 (M+H+). Preparation of Compounds 4-8 [ka]

[0629] Methyl (4R)-4-((Z)-2-(tert-butoxycarbonyl))-3-(3-ethyl-1-methoxy-1-oxoocta-7-en-3-yl)guanidino)chroman-6-carboxylate (4-7) (2.0 g, 3.76 mmol) was dissolved in THF (20 mL), and DBU (2.84 mL, 18.81 mmol) was added to the solution. The mixture was stirred at 50 °C for 10 hours. The mixture was quenched with water (40 mL) and extracted with ELISA (3 × 40 mL). The organic layer was washed with brine (20 mL), dehydrated with Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (ISCO®; 20 g Agela Silica Flash Column, eluent 15% ethyl acetate / petroleum ether gradient @ 60 mL) to obtain methyl (4R)-4-((E)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxo-4-(penta-4-en-1-yl)tetrahydropyrimidine-1(2H)-yl)chroman-6-carboxylate (4-8).

[0630] MS (ESI) m / z: 500.6 (M+H + ). 1 H NMR (400 MHz, chloroform-d) δ 10.10 (s, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.61 (s, 1H), 6.83 (dd, J = 0.8, 8.8 Hz, 1H), 6.31-6.46 (m, 1H), 5.77 (m, 1H), 4.97-5.10 (m, 2H), 4.43 (d, J = 11.2 Hz, 1H), 4.17-4.29 (m, 1H), 3.82 (s, 3H), 2.68-2.86 (m, 1H), 2.47-2.59 (m, 2H), 2.06-2.18 (m, 2H), 1.56-1.81 (m, 5H), 1.51 (s, 9H), 1.45 (s, 3H), 1.40 (s, 1H) Preparation of Compounds 4-9A and 4-9B [ka]

[0631] Methyl (E)-4-(2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxo-4-(penta-4-en-1-yl)tetrahydropyrimidine-1(2H)-yl)chroman-6-carboxylate (4-8) (1.8g, 3.60 mmol) was separated by SFC (instrument SFC-22 Method Column DAICEL CHIRALPAK AD (250mm x 30mm, 10um) Conditions 0.1% NH3H2O ​​IPA Start B 10% End B 10% Gradient Time (min) 100% B retention time (min) Flow rate (mL / min) 50 Injection 60) to separate the product (methyl (R)-4-((R,E)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxo-4-(penta-4-en-1-yl)tetrahydropyrimidine-1(2H)-yl)chroman-6-carboxylate(4-9A)(Peak 1, R t =0.816) and (methyl (E)-4-(2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxo-4-(penta-4-en-1-yl)tetrahydropyrimidine-1(2H)-yl)chroman-6-carboxylate (4-9B) (peak 2, R t =0.879) was obtained.

[0632] MS (ESI) m / z: 500.2 (M+H + ) Preparation of compounds 4-10 [ka]

[0633] Methyl (R)-4-((R,E)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxo-4-(penta-4-en-1-yl)tetrahydropyrimidine-1(2H)-yl)chroman-6-carboxylate (4-9A) (100 mg, 0.200 mmol) was dissolved in 1,4-dioxane (4 mL) and water (1 mL). To this solution, 2,6-dimethylpyridine (42.9 mg, 0.400 mmol) and osmium(VIII) oxide (5.09 mg, 0.020 mmol) were added. The resulting solution was stirred at 25°C for 0.2 hours. Sodium periodate (171 mg, 0.801 mmol) was added, and the resulting solution was stirred at 25°C for 2 hours. The mixture was quenched with saturated Na2SO3 (10 mL) and water (5 mL) and extracted with SiO2 (3 × 10 mL). The organic layer was washed with brine (5 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain methyl (R)-4-((R,E)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxo-4-(4-oxobutyl)tetrahydropyrimidine-1(2H)-yl)chroman-6-carboxylate (4-10). This was used directly in the next step as crude.

[0634] MS (ESI) m / z: 502.3 (M+H + ) Preparation of Compounds 4-11 [ka]

[0635] Methyl (R)-4-((R,E)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxo-4-(4-oxobutyl)tetrahydropyrimidine-1(2H)-yl)chroman-6-carboxylate (4-10) (95 mg, 0.189 mmol) was dissolved in MeOH (2 mL), and NaBH4 (10.75 mg, 0.284 mmol) was gradually added at 0°C. The mixture was stirred at 0°C for 1 hour. LC-MS showed the mass of the major desired product. The mixture was quenched with water (5 mL) and extracted with ELISA (4 × 5 mL). The organic layers were combined and washed with brine (5 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by prep-TLC (petroleum ether / ethyl = 3:1) to obtain methyl (R)-4-((R,E)-2-((tert-butoxycarbonyl)imino)-4-ethyl-4-(4-hydroxybutyl)-6-oxotetrahydropyrimidine-1(2H)-yl)chroman-6-carboxylate (4-11).

[0636] MS (ESI) m / z: 504.4 (M+H + ) 1 H NMR (400 MHz, chloroform-d) δ 10.14 (s, 1H), 7.76 (dd, J = 2.0, 8.4 Hz, 1H), 7.65 (s, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.36 (dd, J = 7.2, 10.0 Hz, 1H), 4.43-4.46 (m, 1H), 4.22-4.26 (m, 1H), 3.84 (s, 3H), 3.68 (t, J = 6.4 Hz, 2H), 2.69-2.78 (m, 1H), 2.51-2.62 (m, 2H), 1.95-2.24 (m, 2H), 1.64-1.69 (m, 6H), 1.52 (s, 9H), 1.43-1.49 (m, 2H), 0.97 (t, J = 7.6 Hz, 3H) Preparation of compounds 4-12 [ka]

[0637] Methyl (R)-4-((R,E)-2-((tert-butoxycarbonyl)imino)-4-ethyl-4-(4-hydroxybutyl)-6-oxotetrahydropyrimidine-1(2H)-yl)chroman-6-carboxylate (4-11) (53 mg, 0.105 mmol) was dissolved in THF (1 mL), and potassium trimethylsilanolate (81 mg, 0.631 mmol) was added to the solution. The reaction mixture was stirred at 25 °C for 0.5 hours. LC-MS showed the mass of the main desired product. The solution of (R)-4-((R,E)-2-((tert-butoxycarbonyl)imino)-4-ethyl-4-(4-hydroxybutyl)-6-oxotetrahydropyrimidine-1(2H)-yl)chroman-6-carboxylic acid (4-12) was used in the next step without further processing or purification.

[0638] MS (ESI) m / z: 490.2 (M+H + ) Preparation of Compounds 4-13 [ka]

[0639] (R)-4-((R,E)-2-((tert-butoxycarbonyl)imino)-4-ethyl-4-(4-hydroxybutyl)-6-oxotetrahydropyrimidine-1(2H)-yl)chroman-6-carboxylic acid (4-12) (50 mg, 0.102 mmol), EDC (98 mg, 0.511 mmol), 1H-benzo[d][1,2,3]triazole-1-ol (69.0 mg, 0.511 mmol), and (S)-6-bromo-2,2-dimethylchroman-4-amine (28.8 mg, 0.112 mmol) were dissolved in THF (5 mL), and DIEA (0.143 mL, 0.817 mmol) was added to the solution. The reaction mixture was stirred at 25°C for 3 hours. The mixture was quenched with water (5 mL) and extracted with ELISA (3 × 5 mL). The organic layer was washed with brine (5 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by prep-TLC (petroleum ether / ethyl = 3:1) to obtain tert-butyl ((R,E)-1-((R)-6-((S)-6-bromo-2,2-dimethylchroman-4-yl)carbamoyl)chroman-4-yl)-4-ethyl-4-(4-hydroxybutyl)-6-oxotetrahydropyrimidine-2(1H)-ylidene)carbamate (4-13).

[0640] MS (ESI) m / z: 727.2, 729.2 (M+H + ) Preparation of Compounds 4-14 [ka]

[0641] In a glove box, a mixture of tert-butyl ((R,E)-1-((R)-6-(((S)-6-bromo-2,2-dimethylchroman-4-yl)carbamoyl)chroman-4-yl)-4-ethyl-4-(4-hydroxybutyl)-6-oxotetrahydropyrimidine-2(1H)-ylidene)carbamate (4-13) (70 mg, 0.096 mmol) in dioxane (3 mL) was mixed with [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (7.64 mg, 9.62 μmol) and CsCO3 (37.1 mg, 0.192 mmol). The mixture was stirred at 70°C for 3 hours. The mixture was diluted with water (10 mL) and extracted with dimethyl (3 × 10 mL). The organic layer was washed with brine (5 mL), dehydrated with Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by prep-TLC (petroleum ether / toluene = 2:1) to obtain tert-butyl ((4aR,5R,8R,19aS,E)-8-ethyl-18,18-dimethyl-6,21-dioxo-4,4a,7,8,9,10,11,12,19,19a,20,21-dodecahydro-3H,6H,18H-1,22-(epiethane[1,2]diylidene)-8,5-(epiminomethano)-14,16-ethenodipyrano[3,4-d:3',4'-j][1]oxa[6,12]diazacyclononadecin-29-ylidene)carbamate (4-14).

[0642] MS (ESI) m / z: 647.3 (M+H + ) 11H NMR (500 MHz, chloroform-d) δ 7.81 (dd, J = 2.0, 8.5 Hz, 1H), 7.01 (s, 1H), 6.93 (d, J = 8.5 Hz, 1H), 6.88 (d, J = 1.0 Hz, 1H), 6.78 (s, 2H), 6.40 (dd, J = 7.0, 10.0Hz, 1H), 6.13 (d, J = 8.50 Hz, 1H), 5.37 - 5.44 (m, 1H), 4.44 (td, J = 3.5, 11.5 Hz, 1H), 4.17 - 4.23 (m, 2H), 3.82 (dt, J = 5.0, 9.5 Hz, 1H), 2.71 - 2.79 (m, 2H), 2.53 (d, J = 16.0 Hz, 1H), 2.35 (dd, J = 6.5, 13.0 Hz, 1H), 2.07 - 2.14 (m, 2H), 1.78 (dd, J = 7.50, 10.50 Hz, 4H), 1.52 (s, 2H), 1.49 (s, 9H), 1.42 (s, 3H), 1.37 (s, 3H), 0.95 (t, J = 7.5 Hz, 3H) Preparation of Example 4

Chemical formula

[0643] To a solution of tert-butyl ((4aR,5R,8R,19aS,E)-8-ethyl-18,18-dimethyl-6,21-dioxo-4,4a,7,8,9,10,11,12,19,19a,20,21-dodecahydro-3H,6H,18H-1,22-(epiethane[1,2]diylidene)-8,5-(epiminomethano)-14,16-ethenodipyrano[3,4-d:3',4'-j][1], zinc(II) bromide (104 mg, 0.464 mmol) and oxa[6,12]diazacyclononadecin-29-ylidene)carbamate (4-14) (30 mg, 0.046 mmol) in DCM (3 mL) were added at 25°C under an N2 atmosphere. The mixture was stirred at 25°C for 16 hours. The solvent was evaporated under reduced pressure to obtain the crude product. The residue was back-prepared by HPLC (instrument: Method Column Welch Xtimate C18 150×25mm, 5um; Conditions: Water (TFA)-ACN; Start B 25; End B 55; Gradient Time (min) 11; 100% B retention time (min) 2; Flow rate (mL / min) 25; Purification by injection 1) yielded (4aR,5R,8R,19aS)-8-ethyl-29-imino-18,18-dimethyl-4,4a,7,8,9,10,11,12,18,19,19a,20-dodecahydro-3H,6H,21H-1,22-(epiethane[1,2]diylidene)-8,5-(epiminomethano)-14,16-ethenodipyrano[3,4-d:3',4'-j][1]oxa[6,12]diazacyclononadesine-6,21-dione (Example 4).

[0644] MS (ESI) m / z: 547.2 (M+H + ) 1H NMR (500 MHz, methanol-d4) δ 8.55 (d, J = 8.5 Hz, 1H), 7.73 (dd, J = 2.0, 8.5 Hz, 1H), 7.45 (d, J = 1.5 Hz, 1H), 6.94 (d, J = 8.50 Hz, 1H), 6.86 (d, J = 2.5 Hz, 1H), 6.76 - 6.82 (m, 1H), 6.70 (d, J = 9.0 Hz, 1H), 5.35 - 5.40 (m, 1H), 5.24 - 5.32 (m, 1H), 4.47 (td, J = 4.5, 11.50 Hz, 1H), 4.13 - 4.21 (m, 2H), 3.90 - 3.92 (m, 1H), 2.75 - 2.88 (m, 2H), 2.60 - 2.72 (m, 1H), 2.22 - 2.31 (m, 1H), 2.15 (dd, J = 6.5, 13.0 Hz, 1H), 1.66 - 1.85 (m, 7H), 1.47 - 1.60 (m, 2H), 1.40 (s, 3H), 1.33 (s, 3H), 0.97 (t, J = 7.5 Hz, 3H) Example 5

Chem.

[0645] (11R,14R,14aR,21aS)-11-ethyl-16,16-difluoro-24-imino-2,2-dimethyl-1,2,7,8,9,10,11,12,15,16,21,21a-dodecahydro-13H-11,14-(epiminomethano)-4,6:17,19-diethenocyclopenta[b]pyrano[4,3-h][1,7]diazacyclooctadecine-13,20(14aH)-dione Preparation of compound 5-2

Chem.

[0646] A solution prepared by dissolving 5-bromo-2,3-dihydro-1H-inden-1-one (50 g, 237 mmol), ethane-1,2-dithiol (5-1) (26.6 mL, 317 mmol), and 4-methylbenzenesulfonic acid (8.16 g, 47.4 mmol) in toluene (500 mL) was heated at 130 °C for 16 hours using a Dean-Stark apparatus. TLC indicated that the reaction was complete. The cooled solution was washed with 10% NaOH (600 mL), and the aqueous layer was extracted with DCM (3 × 600 mL). The organic layers were combined and washed with brine (300 mL), dehydrated with Na₂SO₄, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, eluent 10% siRNA / petroleum ether gradient @ 60 mL / min) to obtain 5-bromo-2,3-dihydrospiro[indene-1,2'-[1,3]dithiolane](5-2).

[0647] MS (ESI) m / z 286.9, 288.9 (M+H) + 1 ¹H NMR (500 MHz, chloroform-d) δ 7.40-7.44 (m, 1H), 7.31-7.38 (m, 2H), 3.50-3.56 (m, 2H), 3.40-3.47 (m, 2H), 2.96 (t, J = 6.5 Hz, 2H), 2.69 (t, J = 6.5 Hz, 2H) Preparation of compound 5-3 [ka]

[0648] A solution of 1,3-dibromo-5,5-dimethylhydantoin (194 g, 679 mmol) dissolved in anhydrous CH2Cl2 (700 mL) was cooled to -70°C in a dry ice-acetone bath. Under N2 conditions at a temperature below -65°C, pyridine hydrofluoride (57.4 mL, 226 mmol) was added dropwise, and the mixture was stirred at -70°C for 30 minutes. A solution of 5-bromo-2,3-dihydrospiro[idden-1,2'-[1,3]dithiolane](5-2) (65 g, 226 mmol) dissolved in CH2Cl2 (200 mL) was added dropwise, and the mixture was stirred at -70°C for 4 hours, then stirred overnight at 25°C. TLC showed that the reaction was complete. The mixture was poured into NaOH (2 M, 300 mL) containing a 39% NaHSO3 (600 mL) solution. The aqueous layer was extracted with CH2Cl2 (2 × 600 mL), the organic layer was combined and washed with brine (300 mL), dehydrated with Na2SO4, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, eluent 100% petroleum ether, gradient @ 60 mL / min) to obtain 2,5-dibromo-1,1-difluoro-2,3-dihydro-1H-indene (5-3).

[0649] No LCMS signal.

[0650] 1 H NMR (500 MHz, chloroform-d) δ 7.52-7.58 (m, 1H), 7.47 (d, J = 6.5 Hz, 2H), 4.57 (tt, J = 7.0, 10.5 Hz, 1H), 3.57 (ddd, J = 2.0, 7.5, 16.5 Hz, 1H), 3.27 (dd, J = 7.0, 16.5 Hz, 1H) Preparation of Compound 5-4 [ka]

[0651] 2,5-Dibromo-1,1-Difluoro-2,3-Dihydro-1H-indene(5-3) (60 g, 192 mmol) was dissolved in DCM (600 mL), and DBU (43.5 mL, 289 mmol) was added to the solution. The mixture was stirred at 25°C for 16 hours. LC-MS showed the mass of the desired product. Water (600 mL) was added, and the mixture was acidified with concentrated HCl to pH=7. The mixture was filtered through diatomaceous earth, the aqueous layer was extracted with CH2Cl2 (2 × 600 mL), the organic layer was combined and washed with brine (300 mL), dehydrated with Na2SO4, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, eluent 100% petroleum ether, gradient @ 50 mL / min) to obtain 5-bromo-1,1-difluoro-1H-indene(5-4).

[0652] No LCMS signal.

[0653] 1 ¹H NMR (500 MHz, chloroform-d) δ 7.41 (dd, J = 1.5, 8.0 Hz, 1H), 7.29-7.35 (m, 2H), 6.75 (d, J = 6.0 Hz, 1H), 6.22 (d, J = 6.0 Hz, 1H) Preparation of Compound 5-5 [ka]

[0654] 5-Bromo-1,1-difluoro-1H-indene(5-4) (15 g, 64.9 mmol) was dissolved in iPrOH (250 mL) that had been aerated with O2 for 1 hour. Phenylsilane (14.05 g, 130 mmol) and Mn(TMHD)3 (3.93 g, 6.49 mmol) were added to this solution, and the mixture was stirred at 0°C for 2 hours under O2 (15 psi). TLC showed that the reaction was complete. The mixture was quenched with water (300 mL) and extracted with siRNA (3 × 300 mL). The organic layer was washed with brine (300 mL), dehydrated with Na2SO4, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 40g SepaFlash® Silica Flash Column, eluent 17% Â1 / petroleum ether gradient @ 50 mL / min) to obtain a mixture of 6-bromo-3,3-difluoro-2,3-dihydro-1H-inden-1-ol (5-5) and 5-bromo-1,1-difluoro-2,3-dihydro-1H-inden-2-ol (5-5a) (5-5:5-5a=7:2).

[0655] 1 ¹H NMR (500 MHz, chloroform-d) δ 7.68 (s, 1H), 7.59-7.62 (m, 1H), 7.43-7.46 (m, 1H), 5.31 (q, J = 6.0 Hz, 1H), 3.01-3.12 (m, 1H), 2.49 (dq, J = 5.0, 14.5 Hz, 1H) Preparation of Compounds 5-6 [ka]

[0656] A mixture of 6-bromo-3,3-difluoro-2,3-dihydro-1H-inden-1-ol and 5-bromo-1,1-difluoro-2,3-dihydro-1H-inden-2-ol (11.56 g, 47.3 mmol) (5-5:5-5a=7:2) was dissolved in MeOH (150 mL) and DMSO (15 mL). Under an Ar atmosphere, [1,1'-bis(diphenylfospino)ferrocene]dichloropalladium(II) (2.64 g, 3.61 mmol) and triethylamine (15.67 mL, 108 mmol) were added at 20°C. The mixture was stirred at 80°C for 48 hours under a CO atmosphere (3.5 mbar). TLC showed that the reaction was complete. After cooling, the mixture was filtered through diatomaceous earth, diluted with H2O (200 mL), extracted with siRNA (3 × 200 mL), dehydrated with Na2SO4, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, eluent 17% siRNA / petroleum ether gradient @ 80 mL / min) to obtain a mixture of methyl 1,1-difluoro-3-hydroxy-2,3-dihydro-1H-indene-5-carboxylate (5-6) and methyl 1,1-difluoro-2-hydroxy-2,3-dihydro-1H-indene-5-carboxylate (5-6a) (5-6:5-6a=3:1).

[0657] 1 ¹H NMR (500 MHz, chloroform-d) δ 8.21 (s, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 5.37 (quin, J = 6.0 Hz, 1H), 3.96 (s, 3H), 3.05-3.17 (m, 1H), 2.54 (dq, J = 5.0, 14.5 Hz, 1H) Preparation of compound 5-7_P1 [ka]

[0658] A mixture of methyl 1,1-difluoro-3-hydroxy-2,3-dihydro-1H-indene-5-carboxylate and methyl 1,1-difluoro-2-hydroxy-2,3-dihydro-1H-indene-5-carboxylate (8.3g, 36.36 mmol) (5-6:27-6a=3:1) was separated by SFC (column: Chiralpak AD-3 150×4.6mm ID, 3um, mobile phase: A:CO2 B:iso-propanol (0.05% DEA), gradient: B 5%→40% over 5 minutes, B 40%→5% over 0.5 minutes, then held at B 5% for 1.5 minutes, flow rate: 2.5 mL / min, column temperature: 35°C) to obtain the product methyl (S)-1,1-difluoro-3-hydroxy-2,3-dihydro-1H-inden-5-carboxylate (5-7_P1, desired) (Peak 1, R t =2.577), Methyl (R)-1,1-difluoro-3-hydroxy-2,3-dihydro-1H-indene-5-carboxylate (5-7_P2) (Peak 2, R t A mixture of (5-7_P2 and 5-6a) (2g, 8.77 mmol) was obtained. The mixture of (5-7_P2 and 5-6a) was separated by SFC (column: Cellulose 2 150×4.6mm ID, 5um, mobile phase: A:CO2 B:MeOH (0.05%DEA) gradient: B 5%→40% over 5 minutes, B 40%→5% over 0.5 minutes, then held at B 5% for 1.5 minutes, column temperature: 35℃) to obtain methyl 1,1-difluoro-2-hydroxy-2,3-dihydro-1H-indene-5-carboxylate (5-6a).

[0659] (5-7_P1): 1 ¹H NMR (500 MHz, chloroform-d) δ 8.21 (s, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 5.37 (q, J = 6.0 Hz, 1H), 3.96 (s, 3H), 3.06-3.17 (m, 1H), 2.54 (dq, J = 5.0, 14.5 Hz, 1H) (5-7_P2):1 H NMR (500 MHz, クロロホルム-d) δ 8.20 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 5.36 (q, J = 5.5 Hz, 1H), 3.95 (s, 3H), 3.05-3.17 (m, 1H), 2.54 (dq, J = 5.0, 14.5 Hz, 1H) (5-6a): 1 H NMR (500 MHz, クロロホルム-d) δ 8.05 (d, J = 8.0 Hz, 1H), 7.98 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H), 4.53-4.68 (m, 1H), 3.95 (s, 3H), 3.40 (dd, J = 7.0, 16.0 Hz, 1H), 2.95 (dd, J = 5.0, 16.5 Hz, 1H) Preparation of Compounds 5-8

change

[0660] Methyl (S)-1,1-difluoro-3-hydroxy-2,3-dihydro-1H-indene-5-carboxylate (5-7_P1) (585 mg, 2.56 mmol), tert-butyl (R,E)-(4-(buta-3-en-1-yl)-4-ethyl-6-oxotetrahydropyrimidine-2(1H)-ylidene)carbamate (INT-2) (757 mg, 2.56 mmol), and Ph3P (1009 mg, 3.85 mmol) were dissolved in THF (10 mL). Under an N2 atmosphere, at 0°C, DIAD (0.997 mL, 5.13 mmol) was added dropwise to the solution, and the mixture was then stirred at 18°C ​​for 2 hours. TLC did not show SM. The mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, eluent 20% siRNA / petroleum ether gradient @ 60 mL / min) to obtain the crude product. The crude product was further purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, eluent DCM gradient @ 60 mL / min) to obtain the product methyl (R)-3-((R,E)-4-(buta-3-en-1-yl)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydropyrimidine-1(2H)-yl)-1,1-difluoro-2,3-dihydro-1H-indene-5-carboxylate (5-8).

[0661] MS (ESI) m / z 506.2 (M+H) + 1H NMR (400 MHz, chloroform-d) δ 10.08 (br s, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.78 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 6.74 (q, J = 7.2 Hz, 1H), 5.80-5.87 (m, 1H), 4.95-5.21 (m, 2H), 4.05-4.19 (m, 1H), 3.91 (s, 3H), 2.92-3.14 (m, 2H), 2.58 (s, 2H), 2.07-2.19 (m, 2H), 1.63-1.78 (m, 4H), 1.52 (s, 9H), 0.97 (t, J = 7.6 Hz, 3H) Preparation of compounds 5-9 [ka]

[0662] Methyl (R)-3-((R,E)-4-(buta-3-en-1-yl)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydropyrimidine-1(2H)-yl)-1,1-difluoro-2,3-dihydro-1H-indene-5-carboxylate (5-8) (900 mg, 1.780 mmol) was dissolved in THF (9 mL), and potassium trimethylsilanolate (1370 mg, 10.68 mmol) was added to the solution. The reaction mixture was stirred at 18 °C for 0.5 hours. LC-MS showed the desired mass. H3PO4 (0.1 g / mL in H2O) was added to adjust the pH to approximately 6-7, the mixture was quenched with water (10 mL), and extracted with ELISA (3 × 10 mL). The organic layer was washed with brine (10 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure to obtain the product (R)-3-((R,E)-4-(buta-3-en-1-yl)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydropyrimidine-1(2H)-yl)-1,1-difluoro-2,3-dihydro-1H-indene-5-carboxylic acid (5-9).

[0663] MS (ESI) m / z 492.1 (M+H) + 1 H NMR (400 MHz, クロロホルム-d) δ 10.08 (br s, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.82 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 6.72-6.77 (m, 1H), 5.80-5.89 (m, 1H), 4.99-5.16 (m, 2H), 2.98-3.14 (m, 2H), 2.59 (s, 2H), 2.11-2.13 (m, 2H), 1.64-1.83 (m, 4H), 1.53 (s, 9H), 0.98 (t, J = 7.6 Hz, 3H) Preparation of compounds 5-10

change

[0664] (R)-3-((R,E)-4-(buta-3-en-1-yl)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydropyrimidine-1(2H)-yl)-1,1-difluoro-2,3-dihydro-1H-indene-5-carboxylic acid (5-9) (0.87 g, 1.770 mmol), EDC (1.697 g, 8.85 mmol), and 1H-benzo[d][1,2,3]triazole-1-ol (0.718 g, 5.31 mmol) were dissolved in THF (15 mL), to which DIEA (2.473 mL, 14.16 mmol) and (S)-2,2-dimethyl-6-vinylchroman-4-amine (0.396 g, 1.947 mmol) were added. The reaction mixture was stirred at 18°C ​​for 12 hours. LC-MS showed the desired mass. The mixture was quenched with water (15 mL) and extracted with dimethyl phosphate (3 × 15 mL). The organic layer was washed with brine (10 mL), dehydrated with Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, eluent 17% HCl / petroleum ether gradient @ 60 mL / min) to obtain the product tert-butyl ((R,E)-4-(buta-3-en-1-yl)-1-((R)-6-(((S)-2,2-dimethyl-6-vinylchroman-4-yl)carbamoyl)-3,3-difluoro-2,3-dihydro-1H-inden-1-yl)-4-ethyl-6-oxotetrahydropyrimidine-2(1H)-ylidene)carbamate (5-10).

[0665] MS (ESI) m / z 677.4 (M+H) + 1H NMR (400 MHz, クロロホルム-d) δ 10.08 (br s, 1H), 7.72-7.78 (m, 1H), 7.61-7.69 (m, 2H), 7.28-7.34 (m, 2H), 6.81 (d, J = 8.4 Hz, 1H), 6.76-6.77 (m, 1H), 6.58-6.62 (m, 1H), 6.22 (br d, J = 8.8 Hz, 1H), 5.72-5.77 (m, 1H), 5.46-5.61 (m, 2H), 5.11 (d, J = 11.2 Hz, 1H), 5.06-5.08 (m, 1H), 4.97-5.00 (m, 1H), 2.96-3.14 (m, 2H), 2.58 (s, 2H), 2.29-2.34 (m, 1H), 2.10 (br d, J = 6.0 Hz, 2H), 1.71-1.81 (m, 1H), 1.63-1.74 (m, 4H), 1.52 (s, 9H), 1.46 (s, 3H), 1.38 (s, 3H), 0.96 (t, J = 7.6 Hz, 3H). Preparation of Compounds 5-11

change

[0666] tert-butyl ((R,E)-4-(buta-3-en-1-yl)-1-((R)-6-((S)-2,2-dimethyl-6-vinylchroman-4-yl)carbamoyl)-3,3-difluoro-2,3-dihydro-1H-inden-1-yl)-4-ethyl-6-oxotetrahydropyrimidine-2(1H)-ylidene)carbamate (5-10) (1 g, 1.478 mmol) was dissolved in DCE (500 mL), and dichloro[1,3-bis(2,6-isopropylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II) (0.105 g, 0.148 mmol) was added to the solution. The reaction mixture was stirred under N2 at 50°C for 4 hours. LC-MS showed the desired mass. The mixture was concentrated under reduced pressure, and the crude product was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, eluent 15% SiO2 / petroleum ether gradient @ 60 mL / min) to obtain tert-butyl ((7Z,11R,14R,14aR,21aS,24E)-11-ethyl-16,16-difluoro-2,2-dimethyl-13,20-dioxo-1,2,10,11,12,13,14a,15,16,20,21,21a-dodecahydro-9H-11,14-(epiminomethano)-4,6:17,19-diethenocyclopenta[b]pyrano[4,3-h][1,7]diazacyclooctadecine-24-ylidene)carbamate (5-11a, cisolefin; A small amount of the product and tert-butyl ((7E,11R,14R,14aR,21aS,24E)-11-ethyl-16,16-difluoro-2,2-dimethyl-13,20-dioxo-1,2,10,11,12,13,14a,15,16,20,21,21a-dodecahydro-9H-11,14-(epiminomethano)-4,6:17,19-diethenocyclopenta[b]pyrano[4,3-h][1,7]diazacyclooctadecine-24-ylidene)carbamate (5-11, transolefin; major product) were obtained.

[0667] (5-11a, cisolefin): MS (ESI) m / z 649.3 (M+H) + 1 H NMR (400 MHz, クロロホルム-d) δ 10.12 (s, 1H), 8.06 (d, J = 7.6 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.17 (s, 1H), 6.99-7.01 (m, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.64-6.76 (m, 1H), 6.39 (d, J = 11.2 Hz, 1H), 6.28 (br d, J = 8.8 Hz, 1H), 5.58-5.61 (m, 1H), 5.41-5.45 (m, 1H), 3.01-3.13 (m, 2H), 2.66 (d, J = 16.4 Hz, 1H), 2.42-2.45 (m, 2H), 2.20-2.30 (m, 1H), 1.96-2.04 (m, 1H), 1.63-1.86 (m, 5H), 1.51 (s, 9H), 1.46 (s, 3H), 1.39 (s, 3H), 1.02 (t, J = 7.2 Hz, 3H) (5-11, transolefin): MS (ESI) m / z 649.3 (M+H) + 11H NMR (400 MHz, chloroform-d) δ 10.15 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.35 (s, 1H), 7.23 (s, 1H), 7.06 (dd, J = 2.0, 8.4 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H), 6.61 - 6.70 (m, 1H), 6.39 (d, J = 15.6 Hz, 1H), 6.06 (d, J = 9.2 Hz, 1H), 5.68 - 5.89 (m, 1H), 5.47 - 5.50 (m, 1H), 2.95 - 3.14 (m, 2H), 2.68 (d, J = 16.4 Hz, 1H), 2.55 (d, J = 16.4 Hz, 1H), 2.32 - 2.35 (m, 3H), 1.85 - 1.97 (m, 1H), 1.64 - 1.76 (m, 4H), 1.47 (s, 3H), 1.41 (s, 9H), 1.40 (br s, 3H), 0.97 (t, J = 7.6 Hz, 3H) Preparation of compounds 5-12

Chem.

[0668] To a solution of tert-butyl ((7E,11R,14R,14aR,21aS,24E)-11-ethyl-16,16-difluoro-2,2-dimethyl-13,20-dioxo-1,2,10,11,12,13,14a,15,16,20,21,21a-dodecahydro-9H-11,14-(epiminomethano)-4,6:17,19-dietenocyclopenta[b]pyrano[4,3-h][1,7]diazacyclooctadecine-24-ylidene)carbamate (5-11) (780 mg, 1.202 mmol) dissolved in MeOH (10 mL), 10% Pd-C (128 mg, 0.120 mmol) was added under an N2 atmosphere. The mixture was degassed and repacked with H2 (3 times). The resulting mixture was stirred at 18°C ​​for 10 minutes under an H2 (15 psi) atmosphere. LC-MS indicated that the reaction was complete. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain tert-butyl ((11R,14R,14aR,21aS,E)-11-ethyl-16,16-difluoro-2,2-dimethyl-13,20-dioxo-1,2,8,9,10,11,12,13,14a,15,16,20,21,21a-tetradecahydro-7H-11,14-(epiminomethano)-4,6:17,19-diethenocyclopenta[b]pyrano[4,3-h][1,7]diazacyclooctadecine-24-ylidene)carbamate (5-12). This was used directly in the next stage.

[0669] MS (ESI) m / z 651.4 (M+H) + Preparation of Example 5 [ka]

[0670] A solution of tert-butyl ((11R,14R,14aR,21aS,E)-11-ethyl-16,16-difluoro-2,2-dimethyl-13,20-dioxo-1,2,8,9,10,11,12,13,14a,15,16,20,21,21a-tetradecahydro-7H-11,14-(epiminomethano)-4,6:17,19-diethenocyclopenta[b]pyrano[4,3-h][1,7]diazacyclooctadecine-24-ylidene)carbamate (5-12) (700 mg, 1.076 mmol) dissolved in HCl-dioxane (4N) (10 mL) was stirred at 18°C ​​for 12 hours. LC-MS indicated that the reaction was complete. The solvent was evaporated under reduced pressure to obtain the crude product. The residue was purified by reverse preparative HPLC (equipment 3-101(EK) Method Phase separation Column Boston Uni C18 150×40mm, 5um Conditions Water (0.04%HCl)-ACN Start B 33 End point B 63 Gradient Time (min) 10 100% B retention time 2 Flow rate (mL / min) 60 Purification by injection 2) yielded (11R,14R,14aR,21aS)-11-ethyl-16,16-difluoro-24-imino-2,2-dimethyl-1,2,7,8,9,10,11,12,15,16,21,21a-dodecahydro-13H-11,14-(epiminomethano)-4,6:17,19-diethenocyclopenta[b]pyrano[4,3-h][1,7]diazacyclooctadecine-13,20(14aH)-dione (Example 5).

[0671] MS (ESI) m / z 551.3 (M+H) + 1H NMR (400 MHz, methanol-d4) δ 7.98 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.62 (s, 1H), 7.03 (s, 1H), 6.97-7.00 (m, 1H), 6.70 (d, J = 8.0 Hz, 1H), 5.72 (br d, J = 6.4 Hz, 1H), 5.42 (dd, J = 6.4, 11.6 Hz, 1H), 3.22-3.31 (m, 1H), 2.95-3.15 (m, 2H), 2.46-2.63 (m, 3H), 2.14-2.17 (m, 1H), 1.73-1.91 (m, 5H), 1.55-1.72 (m, 2H), 1.39-1.51 (m, 5H), 1.33 (s, 3H), 0.98 (t, J = 7.2 Hz, 3H) The compounds in Table 1 were prepared by methods similar to those described for Example 1 and / or Example 5. The isomers were separated by preparative HPLC and / or preparative chiral SFC.

[0672] The asterisk (*) can be used in chemical structure diagrams to indicate the location of the chiral center. [Table 2] TIFF0007868149000180.tif191166TIFF0007868149000181.tif210166TIFF0007868149000182.tif197166TIFF0007868149000183.tif210166TIFF0007868149000184.tif204166TIFF0007868149000185.tif198167TIFF0007868149000186.tif197166TIFF0007868149000187.tif216167TIFF0007868149000188.tif198169TIFF0007868149000189.tif248168TIFF0007868149000190.tif248169TIFF0007868149000191.tif191170TIFF0007868149000192.tif191168TIFF0007868149000193.tif199168TIFF0007868149000194.tif198168TIFF0007868149000195.tif246169TIFF0007868149000196.tif247169TIFF0007868149000197.tif190169TIFF0007868149000198.tif191168TIFF0007868149000199.tif192168TIFF0007868149000200.tif186168TIFF0007868149000201.tif198169TIFF0007868149000202.tif198168TIFF0007868149000203.tif210169TIFF0007868149000204.tif203170TIFF0007868149000205.tif211169TIFF0007868149000206.tif204169TIFF0007868149000207.tif204169TIFF0007868149000208.tif185170TIFF0007868149000209.tif211169TIFF0007868149000210.tif217168TIFF0007868149000211.tif210169TIFF0007868149000212.tif209169TIFF0007868149000213.tif210170TIFF0007868149000214.tif190168TIFF0007868149000215.tif191169TIFF0007868149000216.tif198168TIFF0007868149000217.tif190168TIFF0007868149000218.tif197169TIFF0007868149000219.tif197168TIFF0007868149000220.tif210168TIFF0007868149000221.tif204168TIFF0007868149000222.tif210168TIFF0007868149000223.tif211168TIFF0007868149000224.tif198169TIFF0007868149000225.tif199168TIFF0007868149000226.tif209169TIFF0007868149000227.tif217169TIFF0007868149000228.tif210168TIFF0007868149000229.tif217168TIFF0007868149000230.tif211169TIFF0007868149000231.tif211169TIFF0007868149000232.tif209167TIFF0007868149000233.tif193168TIFF0007868149000234.tif198169TIFF0007868149000235.tif203168TIFF0007868149000236.tif197168TIFF0007868149000237.tif210168TIFF0007868149000238.tif199168TIFF0007868149000239.tif211169TIFF0007868149000240.tif209168TIFF0007868149000241.tif210169TIFF0007868149000242.tif210168TIFF0007868149000243.tif210168TIFF0007868149000244.tif217168TIFF0007868149000245.tif237168TIFF0007868149000246.tif222170TIFF0007868149000247.tif223169TIFF0007868149000248.tif20916 8TIFF0007868149000249.tif211168TIFF0007868149000250.tif217168TIFF0007868149000251.tif210170TIFF0007 868149000252.tif197169TIFF0007868149000253.tif223169TIFF0007868149000254.tif198169TIFF000786814900 0255.tif229168TIFF0007868149000256.tif210169TIFF0007868149000257.tif223168TIFF0007868149000258.tif2 22169TIFF0007868149000259.tif235169TIFF0007868149000260.tif216169TIFF0007868149000261.tif209169TIF F0007868149000262.tif211168TIFF0007868149000263.tif230169TIFF0007868149000264.tif223169TIFF00078681 49000265.tif224169TIFF0007868149000266.tif223169TIFF0007868149000267.tif224170TIFF0007868149000268. tif216169TIFF0007868149000269.tif224168TIFF0007868149000270.tif223169TIFF0007868149000271.tif79168.

[0673] Evaluation of antiparasitic efficacy in parasitic LDH proliferation assay (parasitic assay) Parasite stocks were maintained at a hematocrit level of 4% in RPMI-Hepes medium (buffered with sodium bicarbonate and supplemented with 5% heat-inactivated human serum and 0.5% albumx).

[0674] Approximately 42 hours prior to setting up the efficacy assay, the parasites were synchronized with 5% sorbitol to select ring-stage parasites. On the day of the assay setup, blood smears of the parasite cultures were Giemsa stained and counted. Parasitemia was adjusted to a 0.7% ring, and the hematocrit value was diluted to 2% in RPMI-Hepes medium (buffered with sodium bicarbonate and supplemented with 5% heat-inactivated human serum and 0.5% albumx). Then, 30 μL of the diluted parasite was added to 10 μL of medium + compound in a pre-prepared Greiner TC assay plate. The parasite assay plate was placed in a monolayer in a gas-filled, humidified box and incubated at 37°C for 72 hours. After 72 hours of growth, the assay plate was sealed with Parafilm and frozen flat in a single file overnight at -80°C. The following day, the assay plate was thawed at room temperature for 4 hours, and the LDH assay was performed on it to measure the proliferation of parasites.

[0675] Assay EC 50 The results are shown in Table 2. [Table 3] TIFF0007868149000273.tif248133TIFF0007868149000274.tif249134TIFF0007868149000275.tif248133TIFF0007868149 000276.tif249134TIFF0007868149000277.tif248132TIFF0007868149000278.tif248132TIFF0007868149000279.tif99131

Claims

1. Structural formula (I): 【Chemistry 1】 [During the ceremony, A is at least 1 -CH ２ - Saturated or unsaturated (C) linear or branched polymers containing the - group ３ -C １０ ) Alkylene or cycloalkyl (C ３ -C １０ ) is an alkylene, where one or more further -CH in A ２ - The group may be independently replaced by a substructure of O, and here, one or more of the hydrogens along A are hydroxyl, halogen and C １－３ It can be replaced with a group independently selected from the haloalkyl group; X is a bond or C(R １４ ), ２ and is; Y is CR ９ or N, where if Y is N, then Z is CR １１ And V is CR １０ And; V is CR １０ Or N, where if V is N, then Z is CR １１ And Y is CR ９ And; Z is CR １１ Or N, where if Z is N, then V is CR １０ And Y is CR ９ And; R is hydrogen, C １ -C ６ Alkyl COOH, COOH, C ３ -C ６ Cycloalkyl, C １ -C ６ Alkyl, Halo C １ -C ６ Alkyl, C １ -C ６ Alkyl OH, COC １ -C ６ Alkyl or COOC １ -C ６ It is alkyl; R ａ is hydrogen, halogen, OH, C １ -C ６ Alkoxy, C １ -C ６ Alkyl COOH, COOH, C １ -C ６ Alkyl, C １ -C ６ It is either an alkylOH or R ｂ If it is together with C ３ -C ６ Forms a cycloalkyl or heterocycloalkyl, where the C ３ -C ６ Cycloalkyl or heterocycloalkyl groups are either unsubstituted or contain halogens, CN, OH, or C. １ -C ６ Alkoxy, C １ -C ６ Alkyl OC １ -C ６ Alkyl, C １ -C ６ Alkyl COOH, COOH, Oxo, COOC １ -C ６ Alkyl, C １ -C ６ Alkyl COOC １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, C １ -C ６ Alkyl C ３ -C ６ Cycloalkyl, C １ -C ６ Alkyl, -C １ -C ６ Alkyl O Halo C １ -C ６ Alkyl, Halo C １ -C ６ Alkyl, C １ -C ６ It is substituted with one or two substituents selected from the group consisting of alkylOH; R ｂ is hydrogen, halogen, OH, C １ -C ６ alkoxy, C １ -C ６ alkylCOOH, COOH, C １ -C ６ alkyl, C １ -C ６ alkylOH, or when combined with R ａ forms C ３ -C ６ cycloalkyl or heterocycloalkyl, where the C ３ -C ６ cycloalkyl or heterocycloalkyl is unsubstituted or is substituted with 1 to 3 substituents selected from the group consisting of halogen, CN, OH, C １ -C ６ alkoxy, C １ -C ６ alkylOC １ -C ６ alkyl, C １ -C ６ alkylCOOH, COOH, oxo, COOC １ -C ６ alkyl, C １ -C ６ alkylCOOC １ -C ６ alkyl, C ３ -C ６ cycloalkyl, C １ -C ６ alkylC ３ -C ６ cycloalkyl, C １ -C[[ID=​​​​​​​​​​​​​​​​​ R ３ is hydrogen, halogen, CN, OH, C １ -C ６ Alkoxy, C １ -C ６ Alkyl OC １ -C ６ Alkyl, C １ -C ６ Alkyl COOH, COOH, C ３ -C ６ Cycloalkyl, C １ -C ６ Alkyl, Halo C １ -C ６ Alkyl, C １ -C ６ AlkylOH, CON(R) ７ ) (Caution ８ ) or C １ -C ６ Alkyl O Halo C １ -C ６ It is alkyl; R ４ is hydrogen, halogen, CN, OH, C １ -C ６ Alkoxy, C １ -C ６ Alkyl OC １ -C ６ Alkyl, C １ -C ６ Alkyl COOH, COOH, C ３ -C ６ Cycloalkyl, C １ -C ６ Alkyl, Halo C １ -C ６ Alkyl, C １ -C ６ AlkylOH, CON(R) ７ ) (Caution ８ ) or C １ -C ６ Alkyl O Halo C １ -C ６ It is alkyl; R ７ is hydrogen, C １ -C ６ Alkyl COOH, COOH, C ３ -C ６ Cycloalkyl, C １ -C ６ Alkyl, Halo C １ -C ６ Alkyl, C １ -C ６ Alkyl OH, COC １ -C ６ Alkyl or COOC １ -C ６ It is alkyl; R ８ is hydrogen, C １ -C ６ Alkyl COOH, COOH, C ３ -C ６ Cycloalkyl, C １ -C ６ Alkyl, Halo C １ -C ６ Alkyl, C １ -C ６ Alkyl OH, COC １ -C ６ Alkyl or COOC １ -C ６ It is alkyl; R ９ is hydrogen, halogen, CN, OH, C １ -C ６ Alkoxy, C １ -C ６ Alkyl OC １ -C ６ Alkyl, C １ -C ６ Alkyl COOH, COOH, C ３ -C ６ Cycloalkyl, C １ -C ６ Alkyl, Halo C １ -C ６ Alkyl, C １ -C ６ It is an alkylOH; R １０ is hydrogen, halogen, CN, OH, C １ -C ６ Alkoxy, C １ -C ６ Alkyl OC １ -C ６ Alkyl, C １ -C ６ Alkyl COOH, COOH, C ３ -C ６ Cycloalkyl, C １ -C ６ Alkyl, Halo C １ -C ６ Alkyl, C １ -C ６ It is an alkylOH; R １１ is hydrogen, halogen, CN, OH, C １ -C ６ Alkoxy, C １ -C ６ Alkyl OC １ -C ６ Alkyl, C １ -C ６ Alkyl COOH, COOH, C ３ -C ６ Cycloalkyl, C １ -C ６ Alkyl, Halo C １ -C ６ Alkyl, C １ -C ６ It is an alkylOH; R １２ is hydrogen, halogen, CN, OH, C １ -C ６ Alkoxy, C １ -C ６ Alkyl OC １ -C ６ Alkyl, C １ -C ６ Alkyl COOH, COOH, C ３ -C ６ Cycloalkyl, C １ -C ６ Alkyl, Halo C １ -C ６ Alkyl, C １ -C ６ It is an alkylOH; R １３ is hydrogen, halogen, CN, OH, C １ -C ６ Alkoxy, C １ -C ６ Alkyl OC １ -C ６ Alkyl, C １ -C ６ Alkyl COOH, COOH, C ３ -C ６ Cycloalkyl, C １ -C ６ Alkyl, Halo C １ -C ６ Alkyl, C １ -C ６ It is an alkylOH; R １４ Each of these is present in hydrogen, halogen, CN, OH, C １ -C ６ Alkoxy, C １ -C ６ Alkyl OC １ -C ６ Alkyl, C １ -C ６ Alkyl COOH, COOH, C ３ -C ６ Cycloalkyl, C １ -C ６ Alkyl, Halo C １ -C ６ Alkyl, C １ -C ６ Independently selected from the group consisting of alkylOH; R １５ is hydrogen, halogen, CN, OH, C １ -C ６ Alkoxy, C １ -C ６ Alkyl OC １ -C ６ Alkyl, C １ -C ６ Alkyl COOH, COOH, C ３ -C ６ Cycloalkyl, C １ -C ６ Alkyl, Halo C １ -C ６ Alkyl, C １ -C ６ It is an alkylOH; m is 0 or 1; and, p is either 0 or 1. A compound having or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 1, p is 1, and X is a bond.

3. R ａ R ｂ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which together with the other to form a heterocycloalkyl group.

4. R ａ R ｂ Together with, they form a heterocycloalkyl, and here, the heterocycloalkyl is 【Chemistry 2】 And here, the heterocycloalkyl is two C １ -C ６ A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is substituted with an alkyl group.

5. R ａ R ｂ Together with C ３ -C ６ A compound according to claim 1 or a pharmaceutically acceptable salt thereof that forms a cycloalkyl group.

6. R ａ R ｂ Together with C ３ -C ６ A cycloalkyl group is formed, and here, the cycloalkyl group is 【Transformation 3】 And here, C ３ -C ６ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the cycloalkyl group is either unsubstituted or substituted with an OH group.

7. R ３ However, hydrogen, C １ -C ６ Alkyl OC １ -C ６ Alkyl or C １ -C ６ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is alkyl.

8. R ３ However, hydrogen or C １ -C ６ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is alkyl.

9. R ３ and R ４ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein both are halogens.

10. R １５ However, hydrogen or C １ -C ６ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is alkyl.

11. R ３ and R ４ However, hydrogen, halogen, OH, C １ -C ６ Alkyl OH, C １ -C ６ Alkyl OC １ -C ６ Alkyl, C １ -C ６ Alkyl, C １ -C ６ Alkyl O Halo C １ -C ６ Alkyl, CON(C) １ -C ６ Alkyl) ２ Independently selected from the group consisting of; R ７ However, hydrogen, C １ -C ６ Alkyl COOH, COOH, C ３ -C ６ Cycloalkyl, C １ -C ６ Alkyl, Halo C １ -C ６ Alkyl, C １ -C ６ Alkyl OH, COC １ -C ６ Alkyl or COOC １ -C ６ It is alkyl; and R ８ However, hydrogen, C １ -C ６ Alkyl COOH, COOH, C ３ -C ６ Cycloalkyl, C １ -C ６ Alkyl, Halo C １ -C ６ Alkyl, C １ -C ６ Alkyl OH, COC １ -C ６ Alkyl or COOC １ -C ６ It is alkyl; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

12. R １２ and R １３ However, hydrogen, halogen, OH, C １ -C ６ Alkyl OH, C １ -C ６ Alkyl OC １ -C ６ Alkyl and C １ -C ６ A compound according to claim 1, or a pharmaceutically acceptable salt thereof, independently selected from the group consisting of alkyls.

13. X is C(R １４ ) ２ And R １４ However, hydrogen, halogen, OH, C １ -C ６ Alkyl OH, C １ -C ６ Alkyl OC １ -C ６ Alkyl and C １ -C ６ A compound according to claim 1, or a pharmaceutically acceptable salt thereof, independently selected from the group consisting of alkyls.

14. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Y is CH.

15. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Z is CH.

16. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein V is CH.

17. A is a straight-chain saturated or unsaturated (C ３ -C １０ ) The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is alkylene.

18. A is saturated or unsaturated in the branched chain (C ３ -C １０ ) The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is alkylene.

19. A, 【Chemistry 4】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

20. below 【Transformation 5】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 A compound selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

21. formula 【Transformation 6】 A compound represented by or a pharmaceutically acceptable salt thereof.

22. A pharmaceutical composition for treating malaria parasitic infection or malaria, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof.

23. A pharmaceutical composition for inhibiting plasmmepsin X, comprising a therapeutically effective amount of the compound described in any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof.

24. A pharmaceutical composition for inhibiting plasmmepsin IX, comprising a therapeutically effective amount of the compound described in any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof.

25. A pharmaceutical composition for dually inhibiting plasmmepsin X and plasmmepsin IX, comprising a therapeutically effective amount of the compound described in any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof.

26. Use of a compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating malaria parasitic infection or malaria.

27. Use of a compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof in the preparation of a pharmacopoeia for inhibiting plasmmepsin X.

28. Use of a compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof in the preparation of a pharmacopoeia for inhibiting plasmmepsin IX.

29. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a pharmacopoeia for inhibiting plasmmepsin IX and plasmmepsin X.

30. A pharmaceutical composition comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

31. A pharmaceutical composition comprising the compound described in claim 1 and a pharmaceutically acceptable carrier.

32. A pharmaceutical composition for the treatment of malaria infection or malaria, comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof, for use in combination with one or more additional antimalarial drugs in an effective amount.

33. A pharmaceutical composition for the treatment of malaria by inhibition of plasmmepsin X, plasmmepsin IX, and at least one other mechanism, comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof, for use in combination with an effective amount of one additional antimalarial agent, wherein The pharmaceutical composition wherein the additional antimalarial agent acts by a mechanism different from the inhibition of plasmepsin IX or plasmepsin X.

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