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 a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is useful for treating a malaria parasite infection. More particularly, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is useful for treating a malaria parasite infection, in particular for treating malaria. [Background technology]

[0002] Malaria is a major human disease, infecting hundreds of millions of people and killing more than 450,000 people annually. The most deadly form of malaria is caused by Plasmodium falciparum. This protozoan parasite is responsible for nearly all malaria deaths, most of which occur in Africa. P. falciparum has a complex life cycle that begins in the body of the Anopheles mosquito vector, which injects sporozoite forms into the human host during a blood meal. These sporozoites migrate to the liver and invade hepatocytes, where they mature and form thousands of liver merozoites, which exit the hepatocytes and enter the bloodstream, where they invade red blood cells, initiating the asexual reproduction cycle of the parasite that causes malaria symptoms. The parasite develops within a protected niche in the red blood cell, forming 16–32 merozoites, which mature and exit the host cell to invade new red blood cells. Some of these parasites differentiate to form gametocytes, the sexual form of the parasite. These can be ingested by mosquitoes, where male and female gametes form, fuse, and differentiate into oocysts on the extracellular matrix of the mosquito's midgut. Sporozoites form within the oocysts and migrate to the salivary glands where they are delivered to the next host during a blood meal for the parasite's persistence and survival.

[0003] Another form of malaria is the relapsing form of malaria caused by P. vivax, which can cause significant morbidity and some mortality, resulting in a pathologic form of the disease that is primarily a problem outside of Africa. P. knowlesi is a zoonotic parasite found in Southeast Asia that usually infects cynomolgus monkeys, but has been shown to infect humans in Malaysian Borneo.

[0004] Artemisinin in combination with a partner drug has become a mainstay of malaria treatment and control. However, due to the growing threat of drug resistance to artemisinin-based combination therapies (ACTs), the development of novel antimalarials with new targets that inhibit multiple stages in the parasite's life cycle is an urgent priority for the malaria control field. Such novel antimalarials (e.g., monotherapy or ACT partner drugs) could be a step toward malaria eradication because they reduce the likelihood of parasites with pre-existing resistance mutations existing within the parasite population.

[0005] Currently, aspartic proteases are major targets for drug development: HIV aspartic protease has been successfully targeted with drugs in clinical use; inhibitors targeting human renin, BACE1, and γ-secretase are already in clinical development or are under clinical development. In the field of antimalarial drugs, the aspartic proteases plasmepsin X and plasmepsin IX (PMX and PMIX) of Plasmodium falciparum have been identified as potential targets because inhibitors block the parasite's escape from and invasion of host cells, preventing the maturation of some rhoptry and microneme proteins required 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 Summary of the Invention [Means for solving the problem]

[0007] The present invention relates to a compound of 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 present invention relates to compounds represented by the following formula:

[0009] Also described herein is a method for treating a malaria parasite infection, comprising administering to a subject in need thereof a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. Also described herein is a method for treating a malaria parasite infection, comprising administering to a subject in need thereof a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0010] Also described herein is a method for treating malaria, comprising administering to a subject in need thereof a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0011] The present invention further provides the use of compositions (including pharmaceutical compositions) for treating malaria, wherein the compositions comprise one or more compounds of the invention (e.g., one compound of the invention) or tautomers thereof, or pharmaceutically acceptable salts or solvates of said compounds and / or said tautomers, optionally together with one or more additional therapeutic agents, optionally in an acceptable (e.g., pharmaceutically acceptable) carrier or diluent.

[0012] Furthermore, the present invention provides methods of using pharmaceutical compositions for treating Plasmodium infections, for treating malaria, for inhibiting plasmepsin X, or for dually inhibiting plasmepsin X and plasmepsin IX, wherein the pharmaceutical compositions comprise one or more of the compounds described above, in free form or in the form of a pharmaceutically acceptable salt, together with one or more conventional pharmaceutical excipients. Methods of using a compound or salt combination of the present invention together with one or more additional pharmaceutically active agents are also provided.

[0013] The present invention further provides methods for inhibiting plasmepsin X or dually inhibiting the activity of plasmepsin X and plasmepsin IX, as well as methods for treating, preventing, ameliorating and / or delaying the onset of diseases or disorders in which inhibition of plasmepsin X and / or plasmepsin IX has or may have a therapeutic effect (e.g., malaria).

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

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

[0016] These and other embodiments of the invention are described in detail below or will become apparent to those skilled in the art, and such embodiments are included within the scope of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0017] Described herein are compounds of structural formula (I): [ka]

[0018] [During the ceremony, A is a linear or branched, saturated or unsaturated (C3-C 10 ) alkylene, phenyl (C3-C 10 ) alkylene or cycloalkyl (C3-C 10 ) alkylene, wherein one or more additional —CH— groups within A may be independently replaced with a moiety selected from the group consisting of O, S, NR, CONR, NRCO, SO, and SONR, and wherein one or more of the hydrogens along A are selected from the group consisting of hydroxyl, halogen, and C 1-3 and can be substituted with a group independently selected from 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 and; V is CR 10 or N, where when V is N, Z is CR 11 and Y is CR 9 and; Z is CR 11 or N, where when Z is N, 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 ais 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 alkylOH, -C1-C6 alkylOHhaloC1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) or R b when taken together form a C3-C6 cycloalkyl or heterocycloalkyl, wherein the C3-C6 cycloalkyl or heterocycloalkyl is unsubstituted or selected from the group consisting of 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 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 substituted with one or two substituents selected from the group consisting of: R b is 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 alkylOH, -C1-C6 alkylOHhaloC1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) or R a when taken together form a C3-C6 cycloalkyl or heterocycloalkyl, wherein the C3-C6 cycloalkyl or heterocycloalkyl is unsubstituted or selected from the group consisting of 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 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 ) is substituted with 1 to 3 substituents selected from the group consisting of: R 3 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ), C1-C6 alkylN(R 7 )(R 8 ), C1-C6 alkyl (OCH2CH2) n N(R 7 )(R 8 ) or C1-C6 alkylOhaloC1-C6 alkyl, or R 4 when taken together form a C3-C6 cycloalkyl or a C3-C6 heterocycloalkyl; R 4is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ), C1-C6 alkylN(R 7 )(R 8 ), C1-C6 alkyl (OCH2CH2) n N(R 7 )(R 8 ) or C1-C6 alkylOhaloC1-C6 alkyl, or R 3 when taken together form a C3-C6 cycloalkyl or a C3-C6 heterocycloalkyl; R 7 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 8 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 9 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) and; R 10is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) and; R 11 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) and; R 12 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) and; R 13 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) and; R 14 Each occurrence of is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-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 ) independently selected from the group consisting of: R 15 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) and; R 16 Each occurrence of is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-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 ) independently selected from the group consisting of: m is 0 or 1; n is 1, 2, 3 or 4; and p is 0 or 1. It is a compound having the formula:

[0019] In the embodiments described herein, X is a bond, 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, where R 14 are discussed in more detail below. In certain embodiments, X is a bond, CH, CH(CH), C(CH), O, CH(OCH), SO, or CF. In other embodiments, X is CH, O, S, SO, SO, or NH. In certain embodiments, X is CH. In embodiments described herein, X is O. In certain embodiments described herein, X is S. In certain embodiments described herein, X is SO. In another embodiment described herein, X is SO. In certain embodiments described herein, X is NH.

[0020] In the embodiments described herein, Y is CR 9 or N. In certain embodiments, Y is CR 9 where R 9 are discussed in detail below. In certain embodiments, Y is N. In certain embodiments, Y is CH. In certain embodiments, when Y is N, Z is CR 11 and V is CR 10 is.

[0021] In the embodiments described herein, V is CR 10 or N. In certain embodiments, V is CR 10 where R 10 are discussed in detail below. In certain embodiments, V is N. In certain embodiments, V is CH. In certain embodiments, when V is N, Z is CR 11 and Y is CR 9 is.

[0022] In the embodiments described herein, Z is CR 11 or N. In certain embodiments, Z is CR11 where R 11 are discussed in detail below. In certain embodiments, Z is CH. In certain embodiments, Z is N. In certain embodiments, when Z is N, V ​​is CR 10 and Y is CR 9 is.

[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 simultaneously CH.

[0024] In the compounds described herein, R a is 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 alkylOH, -C1-C6 alkylOHhaloC1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) or R bwhen taken together form a C3-C6 cycloalkyl or heterocycloalkyl, wherein the C3-C6 cycloalkyl or heterocycloalkyl is unsubstituted or selected from the group consisting of 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 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 ) is substituted with one or two substituents selected from the group consisting of

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

[0026] In certain embodiments, R a is a halogen. Suitable examples of halogens include chlorine, bromine, fluorine and iodine.

[0027] In certain embodiments, R a is CN.

[0028] In certain embodiments, R a is OH.

[0029] In certain embodiments, R a is C1-C6 alkoxy. Suitable alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.

[0030] In certain embodiments, R a is C1-C6 alkylOC1-C6 alkyl.

[0031] In certain embodiments, R a is C1-C6 alkyl COOH.

[0032] In certain embodiments, R a is COOH.

[0033] In certain embodiments, R a is an oxo group.

[0034] In certain embodiments, R a is COOC1-C6 alkyl.

[0035] In certain embodiments, R a is C1-C6 alkylCOOC1-C6 alkyl.

[0036] In certain embodiments, R a is C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0037] In certain embodiments, R a is C1-C6 alkyl and C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to: [ka]

[0038] etc.

[0039] In certain embodiments, R ais 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 a is methyl.

[0040] In certain embodiments, R a is C1-C6 alkylOhaloC1-C6 alkyl. Suitable examples of C1-C6 alkylOhaloC1-C6 alkyl include, but are not limited to: [ka]

[0041] etc.

[0042] In certain embodiments, R a is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl.

[0043] In certain embodiments, R a is C1-C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol.

[0044] In certain embodiments, R ais CON(R 7 )(R 8 In certain embodiments, R a is N(R 7 )(R 8 In certain embodiments, R a is C1-C6 alkylN(R 7 )(R 8 ), where R 7 and R 8 is described in detail below.

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

[0046] It is expressed as:

[0047] In certain embodiments, R a is R b and together form a C3-C6 cycloalkyl or heterocycloalkyl, wherein the C3-C6 cycloalkyl or heterocycloalkyl is unsubstituted or selected from the group consisting of 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 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 ) is substituted with one or two substituents selected from the group consisting of

[0048] In certain embodiments, R a is R band together form a C3-C6 cycloalkyl, wherein the cycloalkyl is unsubstituted or selected from the group consisting of 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 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 ) is substituted with one or two substituents selected from the group consisting of

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

[0050] In certain embodiments, the cycloalkyl is unsubstituted. In certain embodiments, the heterocycloalkyl is selected from the group consisting of halogen, CN, OH, C-Calkoxy, C-CalkylOC-Calkyl, C-CalkylCOOH, COOH, oxo, COOC-Calkyl, C-CalkylCOOC-Calkyl, C-Ccycloalkyl, C-CalkylC-Ccycloalkyl, C-Calkyl, —C-CalkylOHhaloC-Calkyl, haloC-Calkyl, C-CalkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 ) is substituted with one or two substituents selected from the group consisting of:

[0051] In certain embodiments, the cycloalkyl is selected from 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 alkylOH, —C1-C6 alkylOHhaloC1-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

[0052] In certain embodiments, the cycloalkyl is selected from 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 alkylOH, —C1-C6 alkylOHhaloC1-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 two substituents selected from the group consisting of

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

[0054] In certain embodiments, R a is R band together form a heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or selected from the group consisting of halogen, CN, OH, C-Calkoxy, C-CalkylOC-Calkyl, C-CalkylCOOH, COOH, oxo, COOC-Calkyl, C-CalkylCOOC-Calkyl, C-Ccycloalkyl, C-CalkylC-Ccycloalkyl, C-Calkyl, —C-CalkylOH, —C-CalkylOH, —C-CalkylOH, —C-CalkylOH, —C-CalkylOH, —C-CalkoxyOH, —C-Calkoxy, —C-CalkylOC-Calkyl, —C-CalkylOH, —C-CalkylOH, —C-CalkoxyOH, —C-Calkoxy, —C-CalkoxyOC-Calkyl, —C-CalkylOH, —C-Calkoxy ... 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 ) 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, beta-lactam, gamma-lactam, delta-lactam, beta-lactone, gamma-lactone, delta-lactone, and pyrrolidinone, and their oxides. Non-limiting examples of heterocycloalkyl groups include, but are not limited to: [ka]

[0056] etc.

[0057] Non-limiting examples of bicyclic heterocycloalkyl groups include, but are not limited to: [ka]

[0058] etc.

[0059] In certain embodiments, R ais R b Together with [ka]

[0060] Form.

[0061] In certain embodiments, the heterocycloalkyl is unsubstituted. In certain embodiments, the heterocycloalkyl is selected from the group consisting of halogen, CN, OH, C-Calkoxy, C-CalkylOC-Calkyl, C-CalkylCOOH, COOH, oxo, COOC-Calkyl, C-CalkylCOOC-Calkyl, C-Ccycloalkyl, C-CalkylC-Ccycloalkyl, C-Calkyl, —C-CalkylOHhaloC-Calkyl, haloC-Calkyl, C-CalkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 ) is substituted with one or two substituents selected from the group consisting of:

[0062] In certain embodiments, the heterocycloalkyl is selected from halogen, CN, OH, C-Calkoxy, C-CalkylOC-Calkyl, C-CalkylCOOH, COOH, oxo, COOC-Calkyl, C-CalkylCOOC-Calkyl, C-Ccycloalkyl, C-CalkylC-Ccycloalkyl, C-Calkyl, —C-CalkylOHhaloC-Calkyl, haloC-Calkyl, C-CalkylOH, 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

[0063] In certain embodiments, the heterocycloalkyl is selected from halogen, CN, OH, C-Calkoxy, C-CalkylOC-Calkyl, C-CalkylCOOH, COOH, oxo, COOC-Calkyl, C-CalkylCOOC-Calkyl, C-Ccycloalkyl, C-CalkylC-Ccycloalkyl, C-Calkyl, —C-CalkylOHhaloC-Calkyl, haloC-Calkyl, C-CalkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 ) is substituted with two substituents selected from the group consisting of

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

[0065] In the compounds described herein, R b is 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 alkylOH, -C1-C6 alkylOHhaloC1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) or R awhen taken together form a C3-C6 cycloalkyl or heterocycloalkyl, wherein the C3-C6 cycloalkyl or heterocycloalkyl is unsubstituted or selected from the group consisting of 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 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 ) is substituted with one or two substituents selected from the group consisting of

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

[0067] In certain embodiments, R b is a halogen. Examples of suitable halogens include chlorine, bromine, fluorine and iodine.

[0068] In certain embodiments, R b is CN.

[0069] In certain embodiments, R b is OH.

[0070] In certain embodiments, R b is C1-C6 alkoxy. Suitable alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.

[0071] In certain embodiments, R b is C1-C6 alkylOC1-C6 alkyl.

[0072] In certain embodiments, R b is C1-C6 alkyl COOH.

[0073] In certain embodiments, R b is COOH.

[0074] In certain embodiments, R b is an oxo group.

[0075] In certain embodiments, R b is COOC1-C6 alkyl.

[0076] In certain embodiments, R b is C1-C6 alkylCOOC1-C6 alkyl.

[0077] In certain embodiments, R b is C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0078] In certain embodiments, R b is C1-C6 alkyl and C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to: [ka]

[0079] etc.

[0080] In certain embodiments, R bis 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 b is methyl.

[0081] In certain embodiments, R b is C1-C6 alkylOhaloC1-C6 alkyl. Suitable examples of C1-C6 alkylOhaloC1-C6 alkyl include, but are not limited to: [ka]

[0082] etc.

[0083] In certain embodiments, R b is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl.

[0084] In certain embodiments, R b is C1-C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol.

[0085] In certain embodiments, R bis CON(R 7 )(R 8 In certain embodiments, R b is N(R 7 )(R 8 In certain embodiments, R b is C1-C6 alkylN(R 7 )(R 8 ), where R 7 and R 8 is described in detail below.

[0086] In certain embodiments, R b is R a and together form a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or selected from the group consisting of halogen, CN, OH, C-Calkoxy, C-CalkylOC-Calkyl, C-CalkylCOOH, COOH, oxo, COOC-Calkyl, C-CalkylCOOC-Calkyl, C-Ccycloalkyl, C-CalkylC-Ccycloalkyl, C-Calkyl, —C-CalkylOH ... 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 ) is substituted with one or two substituents selected from the group consisting of

[0087] In certain embodiments, R b is R aand together form a cycloalkyl, wherein the cycloalkyl is unsubstituted or selected from the group consisting of 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 alkylOH ... 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 ) is substituted with one or two substituents selected from the group consisting of

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

[0089] In certain embodiments, the cycloalkyl is unsubstituted. In certain embodiments, the heterocycloalkyl is selected from the group consisting of halogen, CN, OH, C-Calkoxy, C-CalkylOC-Calkyl, C-CalkylCOOH, COOH, oxo, COOC-Calkyl, C-CalkylCOOC-Calkyl, C-Ccycloalkyl, C-CalkylC-Ccycloalkyl, C-Calkyl, —C-CalkylOHhaloC-Calkyl, haloC-Calkyl, C-CalkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 ) is substituted with one or two substituents selected from the group consisting of:

[0090] In certain embodiments, the cycloalkyl is selected from 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 alkylOH, —C1-C6 alkylOHhaloC1-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

[0091] In certain embodiments, the cycloalkyl is selected from 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 alkylOH, —C1-C6 alkylOHhaloC1-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 two substituents selected from the group consisting of

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

[0093] In certain embodiments, R b is R aand together form a heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or selected from the group consisting of halogen, CN, OH, C-Calkoxy, C-CalkylOC-Calkyl, C-CalkylCOOH, COOH, oxo, COOC-Calkyl, C-CalkylCOOC-Calkyl, C-Ccycloalkyl, C-CalkylC-Ccycloalkyl, C-Calkyl, —C-CalkylOH, —C-CalkylOH, —C-CalkylOH, —C-CalkylOH, —C-CalkylOH, —C-CalkoxyOH, —C-Calkoxy, —C-CalkylOC-Calkyl, —C-CalkylOH, —C-CalkylOH, —C-CalkoxyOH, —C-Calkoxy, —C-CalkoxyOC-Calkyl, —C-CalkylOH, —C-Calkoxy ... 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 ) 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, beta-lactam, gamma-lactam, delta-lactam, beta-lactone, gamma-lactone, delta-lactone, and pyrrolidinone, and their oxides. Non-limiting examples of heterocycloalkyl groups include, but are not limited to: [ka]

[0095] etc.

[0096] Non-limiting examples of bicyclic heterocycloalkyl groups include, but are not limited to: [ka]

[0097] etc.

[0098] In certain embodiments, R bis R a Together with [ka]

[0099] Form.

[0100] In certain embodiments, the cycloalkyl or heterocycloalkyl is unsubstituted. In certain embodiments, the cycloalkyl or heterocycloalkyl is selected from the group consisting of halogen, CN, OH, C-Calkoxy, C-CalkylOC-Calkyl, C-CalkylCOOH, COOH, oxo, COOC-Calkyl, C-CalkylCOOC-Calkyl, C-Ccycloalkyl, C-CalkylC-Ccycloalkyl, C-Calkyl, —C-CalkylOHhaloC-Calkyl, haloC-Calkyl, C-CalkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 In certain embodiments, the cycloalkyl or heterocycloalkyl is substituted with one or two substituents selected from the group consisting of 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 alkylOH, —C1-C6 alkylOHhaloC1-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 8In certain embodiments, the cycloalkyl or heterocycloalkyl is substituted with one substituent selected from the group consisting of halogen, CN, OH, C-Calkoxy, C-CalkylOC-Calkyl, C-CalkylCOOH, COOH, oxo, COOC-Calkyl, C-CalkylCOOC-Calkyl, C-Ccycloalkyl, C-CalkylC-Ccycloalkyl, C-Calkyl, —C-CalkylOH, —C-CalkylOH, —C-CalkylOH, —C-CalkylOH, —C-Calkoxy ... 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6 alkylN(R 7 )(R 8 ) 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 C-C alkyl. In certain embodiments, the cycloalkyl is substituted with two substituents selected from the group consisting of C-C alkyl. In certain embodiments, the cycloalkyl is unsubstituted.

[0102] In the embodiments described herein, R 3 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ), C1-C6 alkylN(R 7 )(R 8 ), C1-C6 alkyl (OCH2CH2) n N(R 7 )(R 8 ) or C1-C6 alkylOhaloC1-C6 alkyl, or R 4When taken together with, they form a C3-C6 cycloalkyl or a C3-C6 heterocycloalkyl.

[0103] In certain embodiments of the compounds described herein, R 3 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) or R 4 When taken together with, form a C3-C6 cycloalkyl or a C3-C6 heterocycloalkyl. In certain embodiments, R 3 is hydrogen. In certain embodiments, R 3 is a halogen. Suitable halogens include fluorine, chlorine, bromine, and iodine. In certain embodiments, R 3 is CN. In certain embodiments, R 3 is OH.

[0104] In certain embodiments, R 3 is C1-C6 alkoxy. Suitable alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. In certain embodiments, R 3 is C1-C6 alkylOC1-C6 alkyl. In certain embodiments, R 3 is COOH. In certain embodiments, R 3 is C1-C6 alkylCOOH. In certain embodiments, R 3 is C-C cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 3is 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 3 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 3 is C1-C6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol. In certain embodiments, R 3 is CON(R 7 )(R 8 ). N(R 7 )(R 8 Suitable examples of R include, but are not limited to, CONH and CON(CH). In certain embodiments, R 3 is N(R 7 )(R 8 ). N(R 7 )(R 8 Suitable examples of N(CH) include, but are not limited to, NH and N(CH). In certain embodiments, R 3 is C1-C6 alkylN(R 7 )(R 8 ) C1-C6 alkylN(R 7 )(R 8 Suitable examples of ) include, but are not limited to: [ka]

[0105] R 7 and R 8 is discussed in more detail below.

[0106] In certain embodiments, R 3 is C1-C6 alkylOhaloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to: [ka]

[0107] etc.

[0108] In certain embodiments, R 3 is C1-C6 alkyl (OCH2CH2) n N(R 7 )(R 8 ) is R 7 , R 8 and n are discussed in more detail below. C1-C6 alkyl(OCH2CH2) n N(R 7 )(R 8 Suitable examples of ) include, but are not limited to: [ka]

[0109] etc.

[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 certain embodiments, R 3 is R 4and together form a C3-C6 cycloalkyl or a C3-C6 heterocycloalkyl. In certain embodiments, R 3 is R 4 and together form a C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 3 is R 4 together form a C3-C6 heterocycloalkyl. Suitable examples of heterocycloalkyl include, but are not limited to, 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 oxides thereof.

[0112] In certain embodiments, R 3 is hydrogen, fluorine, methyl, ethyl, OH, methoxy, [ka]

[0113] is.

[0114] In certain embodiments, R 3 is hydrogen, methyl, ethyl or [ka]

[0115] is.

[0116] In certain embodiments, R 3 is R 4 together to form oxetanyl.

[0117] In certain embodiments described herein, R 4is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ), C1-C6 alkylN(R 7 )(R 8 ), C1-C6 alkyl (OCH2CH2) n N(R 7 )(R 8 ) or C1-C6 alkylOhaloC1-C6 alkyl, or R 3 When taken together with R, they form a C-C cycloalkyl or a C-C heterocycloalkyl. In certain embodiments of the compounds described herein, R 4 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) or R 3 When taken together with, form a C3-C6 cycloalkyl or a C3-C6 heterocycloalkyl. In certain embodiments, R 4 is hydrogen. In certain embodiments, R 4 is a halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R 4 is CN. In certain embodiments, R 4 is OH.

[0118] In certain embodiments, R 4is C1-C6 alkoxy. Suitable alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. In certain embodiments, R 4 is C1-C6 alkylOC1-C6 alkyl. In certain embodiments, R 4 is COOH. In certain embodiments, R 4 is C1-C6 alkylCOOH. In certain embodiments, R 4 is C-C cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 4 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 4 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 4 is C1-C6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol. In certain embodiments, R 4 is CON(R 7 )(R 8 ). N(R 7 )(R8 Suitable examples of R include, but are not limited to, CONH and CON(CH). In certain embodiments, R 4 is N(R 7 )(R 8 ). N(R 7 )(R 8 Suitable examples of N(CH) include, but are not limited to, NH and N(CH). In certain embodiments, R 4 is C1-C6 alkylN(R 7 )(R 8 ) C1-C6 alkylN(R 7 )(R 8 Suitable examples of ) include, but are not limited to: [ka]

[0119] R 7 and R 8 is discussed in more detail below.

[0120] In certain embodiments, R 4 is C1-C6 alkylOhaloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to: [ka]

[0121] etc.

[0122] In certain embodiments, R 4 is C1-C6 alkyl (OCH2CH2) n N(R 7 )(R 8 ) is R 7 , R 8 is discussed in detail below, and n is discussed above. C1-C6 alkyl(OCH2CH2) n N(R 7 )(R 8Suitable examples of ) include, but are not limited to: [ka]

[0123] etc.

[0124] In certain embodiments, R 4 is R 3 and together form a C3-C6 cycloalkyl or a C3-C6 heterocycloalkyl. In certain embodiments, R 4 is R 3 and together form a C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 4 is R 3 together form a C3-C6 heterocycloalkyl. Suitable examples of heterocycloalkyl include, but are not limited to, 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 oxides thereof.

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

[0126] In certain embodiments, R 4 is R 3 and together form oxetanyl. In certain embodiments, R 3 and R 4 are both hydrogen, methyl or ethyl.

[0127] In certain embodiments, R 3 is hydrogen, and R 4 is hydrogen.

[0128] In certain embodiments, R 3 and R 4 and R are both halogens, where the halogens are selected from fluorine, chlorine, bromine, and iodine. 3 and R 4 are both fluorine atoms.

[0129] In the embodiments described herein, R 5 is 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 alkylOH, -C1-C6 alkylOHhaloC1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 )

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

[0131] In certain embodiments, R 5 is a halogen. Examples of suitable halogens include chlorine, bromine, fluorine and iodine.

[0132] In certain embodiments, R 5 is CN.

[0133] In certain embodiments, R 5 is OH.

[0134] In certain embodiments, R 5 is C1-C6 alkoxy. Suitable alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.

[0135] In certain embodiments, R 5 is C1-C6 alkylOC1-C6 alkyl.

[0136] In certain embodiments, R 5 is C1-C6 alkyl COOH.

[0137] In certain embodiments, R 5 is COOH.

[0138] In certain embodiments, R 5 is an oxo group.

[0139] In certain embodiments, R 5 is COOC1-C6 alkyl.

[0140] In certain embodiments, R 5 is C1-C6 alkylCOOC1-C6 alkyl.

[0141] In certain embodiments, R 5 is C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0142] In certain embodiments, R 5 is C1-C6 alkyl and C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to: [ka]

[0143] etc.

[0144] In certain embodiments, R 5 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 5 is methyl.

[0145] In certain embodiments, R 5 is C1-C6 alkylOhaloC1-C6 alkyl. Suitable examples of C1-C6 alkylOhaloC1-C6 alkyl include, but are not limited to: [ka]

[0146] etc.

[0147] In certain embodiments, R 5 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl.

[0148] In certain embodiments, R 5 is C1-C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol.

[0149] In certain embodiments, R 5 is CON(R 7 )(R 8 In certain embodiments, R 1 is N(R 7 )(R 8 In certain embodiments, R 5 is C1-C6 alkylN(R 7 )(R 8 ), where R 7 and R 8 is described in detail below.

[0150] In certain embodiments, R 5 is hydrogen, methyl, ethyl or t-butyl.

[0151] In the embodiments described herein, R 6 is 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 alkylOH, -C1-C6 alkylOHhaloC1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 )

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

[0153] In certain embodiments, R 6 is a halogen. Examples of suitable halogens include chlorine, bromine, fluorine and iodine.

[0154] In certain embodiments, R 6 is CN.

[0155] In certain embodiments, R 6 is OH.

[0156] In certain embodiments, R 6 is C1-C6 alkoxy. Suitable alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.

[0157] In certain embodiments, R 6 is C1-C6 alkylOC1-C6 alkyl.

[0158] In certain embodiments, R 6 is C1-C6 alkyl COOH.

[0159] In certain embodiments, R 6 is COOH.

[0160] In certain embodiments, R 6 is an oxo group.

[0161] In certain embodiments, R 6 is COOC1-C6 alkyl.

[0162] In certain embodiments, R 6 is C1-C6 alkylCOOC1-C6 alkyl.

[0163] In certain embodiments, R 6 is C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0164] In certain embodiments, R 6 is C1-C6 alkyl and C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to: [ka]

[0165] etc.

[0166] In certain embodiments, R 6 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 6 is methyl.

[0167] In certain embodiments, R 6 is C1-C6 alkylOhaloC1-C6 alkyl. Suitable examples of C1-C6 alkylOhaloC1-C6 alkyl include, but are not limited to: [ka]

[0168] etc.

[0169] In certain embodiments, R 6 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl.

[0170] In certain embodiments, R 6 is C1-C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol.

[0171] In certain embodiments, R 6 is CON(R 7 )(R 8 In certain embodiments, R 1 is N(R 7 )(R 8 In certain embodiments, R 6 is C1-C6 alkylN(R 7 )(R 8 ), where R 7 and R 8 is described in detail below.

[0172] In certain embodiments, R 6 is hydrogen, methyl, ethyl or t-butyl.

[0173] In the embodiments described herein, R 7 is hydrogen, C-C alkylCOOH, COOH, C-C cycloalkyl, C-C alkyl, haloC-C alkyl, C-C alkylOH, COC-C alkyl, or COOC-C alkyl. 7 is hydrogen, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl or C1-C6 alkylOH.

[0174] In certain embodiments, R 7 is hydrogen. In certain embodiments, R 7 is C1-C6 alkylCOOH. In certain embodiments, R 7 is COOH. In certain embodiments, R 7is C-C cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 7 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 7 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 7 is C1-C6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol.

[0175] In certain embodiments, R 7 is COC1-C6 alkyl. Suitable examples include, but are not limited to, COCH3. In certain embodiments, R 7 is COOC1-C6 alkyl. Suitable examples include, but are not limited to, COOCH3.

[0176] In the embodiments described herein, R 8is hydrogen, C-C alkylCOOH, COOH, C-C cycloalkyl, C-C alkyl, haloC-C alkyl, C-C alkylOH, COC-C alkyl, or COOC-C alkyl. 8 is hydrogen, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl or C1-C6 alkylOH.

[0177] In certain embodiments, R 8 is hydrogen. In certain embodiments, R 8 is C1-C6 alkylCOOH. In certain embodiments, R 8 is COOH. In certain embodiments, R 8 is C-C cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 8 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 8 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 8is C1-C6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol.

[0178] In certain embodiments, R 8 is COC1-C6 alkyl. Suitable examples include, but are not limited to, COCH3. In certain embodiments, R 8 is COOC1-C6 alkyl. Suitable examples include, but are not limited to, COOCH3.

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

[0180] In certain embodiments, R 9 is C1-C6 alkoxy. Suitable alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. In certain embodiments, R 9 is C1-C6 alkylOC1-C6 alkyl. In certain embodiments, R 9 is COOH. In certain embodiments, R 9 is C1-C6 alkylCOOH. In certain embodiments, R 9is C-C cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 9 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 9 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 9 is C1-C6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol. In certain embodiments, R 9 is CON(R 7 )(R 8 In certain embodiments, R 9 is N(R 7 )(R 8 In certain embodiments, R 9 is C1-C6 alkylN(R 7 )(R 8 )

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

[0182] In certain embodiments, R 10 is C1-C6 alkoxy. Suitable alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. In certain embodiments, R 10 is C1-C6 alkylOC1-C6 alkyl. In certain embodiments, R 10 is COOH. In certain embodiments, R 10 is C1-C6 alkylCOOH. In certain embodiments, R 10 is C-C cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 10is 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 10 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 10 is C1-C6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol. In certain embodiments, R 10 is CON(R 7 )(R 8 In certain embodiments, R 10 is N(R 7 )(R 8 In certain embodiments, R 10 is C1-C6 alkylN(R 7 )(R 8 )

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

[0184] In certain embodiments, R 11 is C1-C6 alkoxy. Suitable alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. In certain embodiments, R 11 is C1-C6 alkylOC1-C6 alkyl. In certain embodiments, R 11 is COOH. In certain embodiments, R 11 is C1-C6 alkylCOOH. In certain embodiments, R 11 is C-C cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 11 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 11is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 11 is C1-C6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol. In certain embodiments, R 11 is CON(R 7 )(R 8 In certain embodiments, R 11 is N(R 7 )(R 8 In certain embodiments, R 11 is C1-C6 alkylN(R 7 )(R 8 )

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

[0186] In certain embodiments, R 12is 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 C1-C6 alkylOC1-C6 alkyl. In certain embodiments, R 12 is COOH. In certain embodiments, R 12 is C1-C6 alkylCOOH. In certain embodiments, R 12 is C-C cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 12 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 12 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 12 is C1-C6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol. In certain embodiments, R 12 is CON(R 7 )(R 8 In certain embodiments, R12 is N(R 7 )(R 8 In certain embodiments, R 12 is C1-C6 alkylN(R 7 )(R 8 )

[0187] In certain embodiments, R 12 is hydrogen, methyl, ethyl, methoxy, OH or [ka]

[0188] is.

[0189] In certain embodiments, R 12 is hydrogen or [ka]

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

[0191] In certain embodiments, R 13is 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 C1-C6 alkylOC1-C6 alkyl. In certain embodiments, R 13 is COOH. In certain embodiments, R 13 is C1-C6 alkylCOOH. In certain embodiments, R 13 is C-C cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 13 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 13 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 13 is C1-C6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol. In certain embodiments, R 13 is CON(R 7 )(R 8 In certain embodiments, R13 is N(R 7 )(R 8 In certain embodiments, R 13 is C1-C6 alkylN(R 7 )(R 8 )

[0192] In certain embodiments, R 13 is hydrogen, methyl, ethyl, methoxy, OH or [ka]

[0193] is.

[0194] In certain embodiments, R 13 is hydrogen or [ka]

[0195] is.

[0196] In certain embodiments, R 12 and R 13 are independently selected from the group consisting of hydrogen and C1-C6 alkyl, O—C1-C6 alkyl, C1-C6 alkyl.

[0197] In certain embodiments described herein, R 14 Each occurrence of is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 In certain embodiments, R 14 is hydrogen. In certain embodiments, R14 is a halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R 14 is CN. In certain embodiments, R 14 is OH.

[0198] In certain embodiments, R 14 is 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 C1-C6 alkylOC1-C6 alkyl. In certain embodiments, R 14 is COOH. In certain embodiments, R 14 is C1-C6 alkylCOOH. In certain embodiments, R 14 is C-C cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 14 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 14 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R14 is C1-C6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol. In certain embodiments, R 14 is CON(R 7 )(R 8 In certain embodiments, R 14 is N(R 7 )(R 8 In certain embodiments, R 14 is C1-C6 alkylN(R 7 )(R 8 )

[0199] In certain embodiments, X is C(R 14 )2, then R 14 are independently selected from the group consisting of hydrogen, halogen, OH, C1-C6 alkylOH, C1-C6 alkylalkoxy, C1-C6 alkylOC1-C6 alkyl, and C1-C6 alkyl.

[0200] In certain embodiments, R 14 is hydrogen, methyl, ethyl, methoxy, OH or [ka]

[0201] is.

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

[0203] In certain embodiments, R 15 is C1-C6 alkoxy. Suitable alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. In certain embodiments, R 15 is C1-C6 alkylOC1-C6 alkyl. In certain embodiments, R 15 is COOH. In certain embodiments, R 15 is C1-C6 alkylCOOH. In certain embodiments, R 15 is C-C cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 15 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 15 is ethyl.

[0204] In certain embodiments, R 15is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 15 is C1-C6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol. In certain embodiments, R 15 is CON(R 7 )(R 8 In certain embodiments, R 15 is N(R 7 )(R 8 In certain embodiments, R 15 is C1-C6 alkylN(R 7 )(R 8 )

[0205] In certain embodiments, R 15 is methyl or ethyl.

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

[0207] In certain embodiments, R 16is C1-C6 alkoxy. Suitable alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. In certain embodiments, R 16 is C1-C6 alkylOC1-C6 alkyl. In certain embodiments, R 16 is COOH. In certain embodiments, R 16 is C1-C6 alkylCOOH. In certain embodiments, R 16 is C-C cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 16 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 16 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 16 is C1-C6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol. In certain embodiments, R 16 is CON(R 7 )(R 8 In certain embodiments, R16 is N(R 7 )(R 8 In certain embodiments, R 16 is C1-C6 alkylN(R 7 )(R 8 )

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

[0209] In 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 10 ) alkylene, phenyl (C3-C 10 ) alkylene or cycloalkyl (C3-C 10 ) alkylene, wherein one or more additional —CH— groups within A may be independently replaced with a moiety selected from the group consisting of O, S, NR, CONR, NRCO, SO, and SONR, and wherein one or more of the hydrogens along A are selected from the group consisting of hydroxyl, halogen, and C 1-3 In certain embodiments, A is a straight or branched chain, saturated or unsaturated (C3-C 10 ) alkylene or cycloalkyl (C3-C 10 ) alkylene, where one or more —CH— groups within A may be independently replaced with a moiety selected from the group consisting of O, S, and NH. In certain embodiments, A always has at least one —CH— group.

[0211] In certain embodiments, A is a straight chain (C3-C 10 ) alkylene. Straight chain (C3-C 10 ) Examples of alkylenes are: [ka]

[0212] etc.

[0213] In certain embodiments, A is a branched chain (C3-C 10 ) alkylene. Suitable branched chain (C3-C 10 ) The alkylene includes, but is not limited to, [ka]

[0214] etc.

[0215] In certain embodiments, A is saturated (C3-C 10 ) alkylene. Examples include: [ka]

[0216] etc.

[0217] In certain embodiments, A is an unsaturated (C3-C 10 ) alkylene. Suitable unsaturated (C3-C 10 ) alkylene, the saturated (C3-C 10 ) alkylenes in which hydrogen has been removed and one or more double or triple covalent bonds exist between adjacent carbon atoms. 10 ) Examples of alkylene include, but are not limited to: [ka]

[0218] etc.

[0219] In another embodiment, A is a straight chain cycloalkyl (C-C10 ) alkylene. Suitable straight chain cycloalkyl (C3-C 10 ) For alkylene, two carbons in the chain are (C3-C 10 ) Cycloalkyl (C3-C 10 ) alkylene. Straight-chain cycloalkyl (C3-C 10 ) Examples of alkylene include, but are not limited to: [ka]

[0220] etc.

[0221] In certain embodiments, A is a branched cycloalkyl (C-C 10 ) alkylene. Suitable branched cycloalkyl (C3-C 10 ) For alkylene, two carbons in the chain are (C3-C 10 ) Cycloalkyl contains branched chain (C3-C 10 ) alkylene, etc. Cycloalkyl (C3-C 10 ) Examples of alkylene include, but are not limited to: [ka]

[0222] etc.

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

[0224] etc.

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

[0226] etc.

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

[0228] etc.

[0229] In another embodiment, one or more -CH2- groups in A may be independently replaced with a moiety 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 a moiety 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 is described in more detail below.

[0230] In the embodiments described herein, R is hydrogen, C-C alkylCOOH, COOH, C-C cycloalkyl, C-C alkyl, haloC-C alkyl, C-C alkylOH, COC-C alkyl, or COOC-C alkyl. In certain embodiments, R is hydrogen, C-C alkylCOOH, COOH, C-C cycloalkyl, C-C alkyl, haloC-C alkyl, or C-C alkylOH.

[0231] In certain embodiments, R is hydrogen. In certain embodiments, R is C1-C6 alkylCOOH. In certain embodiments, R is COOH. In certain embodiments, R is C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R is 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 haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R is C1-C6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol.

[0232] In certain embodiments, R is COC1-C6 alkyl. Suitable examples include, but are not limited to, COCH3. In certain embodiments, R is COOC1-C6 alkyl. Suitable examples include, but are not limited to, COOCH3.

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

[0234] etc.

[0235] In certain embodiments, A is [ka]

[0236] is.

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

[0238] is.

[0239] Further described herein are compounds of structural formula (III): [ka]

[0240] [During the ceremony, A is a linear or branched, saturated or unsaturated (C3-C 10 ) alkylene, phenyl (C3-C 10 ) alkylene or cycloalkyl (C3-C 10 ) alkylene, wherein one or more additional —CH— groups within A may be independently replaced with a moiety selected from the group consisting of O, S, NR, CONR, NRCO, SO, and SONR, and wherein one or more of the hydrogens along A are selected from the group consisting of hydroxyl, halogen, and C 1-3 and can be substituted with a group independently selected from haloalkyl; 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 when Y is N, Z is CR 11 and V is CR 10 and; V is CR 10 or N, where when V is N, Z is CR 11 and Y is CR 9 and; Z is CR 11 or N, where when Z is N, 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 1is 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 alkylOH, -C1-C6 alkylOHhaloC1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) and; R 2 is 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 alkylOH, -C1-C6 alkylOHhaloC1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) and; R 3 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ), C1-C6 alkylN(R 7 )(R 8 ), C1-C6 alkyl (OCH2CH2) n N(R 7 )(R 8) or C1-C6 alkylOhaloC1-C6 alkyl, or R 4 when taken together form a C3-C6 cycloalkyl or a C3-C6 heterocycloalkyl; R 4 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ), C1-C6 alkylN(R 7 )(R 8 ), C1-C6 alkyl (OCH2CH2) n N(R 7 )(R 8 ) or C1-C6 alkylOhaloC1-C6 alkyl, or R 3 when taken together form a C3-C6 cycloalkyl or a C3-C6 heterocycloalkyl; R 5 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) and; R 6 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R8 ) and; R 7 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 8 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 9 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) and; R 10 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) and; R 11 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8) or C1-C6 alkylN(R 7 )(R 8 ) and; R 12 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) and; R 13 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) and; R 14 Each occurrence of is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-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 ) independently selected from the group consisting of: R 15 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) and; R 16 Each occurrence of is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-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 ) independently selected from the group consisting of: l is 0 or 1; m is 0 or 1; n is 1, 2, 3 or 4; and p is 0 or 1. It is a compound having the formula:

[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 16are 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 another embodiment described herein, Q is SO. In another embodiment described herein, Q is SO2. In certain embodiments described herein, Q is NH. In another embodiment 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 a bond, 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, where R 14 are discussed in more detail below. In certain embodiments, X is a bond, CH, CH(CH), C(CH), O, CH(OCH), SO, or CF. In other embodiments, X is CH, O, S, SO, SO, or NH. In certain embodiments, X is CH. In embodiments described herein, X is O. In certain embodiments described herein, X is S. In certain embodiments described herein, X is SO. In another embodiment described herein, X is SO. In certain embodiments described herein, X is NH.

[0243] In the embodiments described herein, Y is CR 9 or N. In certain embodiments, Y is CR 9 where R 9are discussed in detail below. In certain embodiments, Y is N. In certain embodiments, Y is CH. In certain embodiments, when Y is N, Z is CR 11 and V is CR 10 is.

[0244] In the embodiments described herein, V is CR 10 or N. In certain embodiments, V is CR 10 where R 10 are discussed in detail below. In certain embodiments, V is N. In certain embodiments, V is CH. In certain embodiments, when V is N, Z is CR 11 and Y is CR 9 is.

[0245] In the embodiments described herein, Z is CR 11 or N. In certain embodiments, Z is CR 11 where R 11 are discussed in detail below. In certain embodiments, Z is CH. In certain embodiments, Z is N. In certain embodiments, when Z is N, V ​​is CR 10 and Y is CR 9 is.

[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 simultaneously CH.

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

[0248] Further described herein are compounds of 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. An embodiment of the present invention is a compound represented by R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 15 , A and Q are as described in formula III. Another embodiment of formula IIIA is 3 and R 4 and R are both hydrogen, methyl, ethyl, or halogen. Another embodiment of formula IIIA is realized when R 3 and R 4 and Q are both 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 IIIA is O or CH2. Another embodiment of formula IIIA is realized when A is a linear or branched, saturated or unsaturated (C3-C(CH3)) group containing at least one -CH2- group. 10 ) alkylene, wherein one or more additional —CH— groups in A may be independently replaced with a moiety selected from the group consisting of O, S, NR, CONR, NRCO, SO, and SONR, and wherein one or more of the hydrogens along A are selected from the group consisting of hydroxyl, halogen, and C 1-3 This is realized when the aryl group can be replaced with a group independently selected from haloalkyl.

[0250] Further described herein are compounds of 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. An embodiment of the present invention is a compound represented by R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 15 , A and Q are as described in formula III. Another embodiment of formula IIIB is 3 and R 4 and R are both hydrogen, methyl, ethyl, or halogen. Another embodiment of formula IIIB is realized when R 3 and R 4 and Q are both 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 IIIB is O or CH2. Another embodiment of formula IIIB is realized when A is a linear or branched, saturated or unsaturated (C3-C) alkyl group containing at least one -CH2- group. 10 ) alkylene, wherein one or more additional —CH— groups in A may be independently replaced with a moiety selected from the group consisting of O, S, NR, CONR, NRCO, SO, and SONR, and wherein one or more of the hydrogens along A are selected from the group consisting of hydroxyl, halogen, and C 1-3This is realized when the aryl group can be replaced with a group independently selected from haloalkyl.

[0252] Particular embodiments are: Formulas IV-VI: [ka]

[0253] It is expressed as:

[0254] In the embodiments described herein, R 1 is 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 alkylOH, -C1-C6 alkylOHhaloC1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 )

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

[0256] In certain embodiments, R 1 is a halogen. Examples of suitable halogens include chlorine, bromine, fluorine and iodine.

[0257] In certain embodiments, R 1 is CN.

[0258] In certain embodiments, R 1 is OH.

[0259] In certain embodiments, R 1is C1-C6 alkoxy. Suitable alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.

[0260] In certain embodiments, R 1 is C1-C6 alkylOC1-C6 alkyl.

[0261] In certain embodiments, R 1 is C1-C6 alkyl COOH.

[0262] In certain embodiments, R 1 is COOH.

[0263] In certain embodiments, R 1 is an oxo group.

[0264] In certain embodiments, R 1 is COOC1-C6 alkyl.

[0265] In certain embodiments, R 1 is C1-C6 alkylCOOC1-C6 alkyl.

[0266] In certain embodiments, R 1 is C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0267] In certain embodiments, R 1 is C1-C6 alkyl and C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to: [ka]

[0268] etc.

[0269] In certain embodiments, R1 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.

[0270] In certain embodiments, R 1 is C1-C6 alkylOhaloC1-C6 alkyl. Suitable examples of C1-C6 alkylOhaloC1-C6 alkyl include, but are not limited to: [ka]

[0271] etc.

[0272] In certain embodiments, R 1 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl.

[0273] In certain embodiments, R 1 is C1-C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol.

[0274] In certain embodiments, R 1 is CON(R 7 )(R8 In certain embodiments, R 1 is N(R 7 )(R 8 In certain embodiments, R 1 is C1-C6 alkylN(R 7 )(R 8 ), where R 7 and R 8 is described in detail below.

[0275] In certain embodiments, R 1 is hydrogen, bromine, fluorine, chlorine, methyl, OH, halogen, CN oxo, methoxymethyl, COOCH2CH3 or trifluoromethyl.

[0276] In the embodiments described herein, R 2 is 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 alkylOH, -C1-C6 alkylOHhaloC1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 )

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

[0278] In certain embodiments, R 2 is a halogen. Examples of suitable halogens include chlorine, bromine, fluorine and iodine.

[0279] In certain embodiments, R 2 is CN.

[0280] In certain embodiments, R 2 is OH.

[0281] In certain embodiments, R 2 is C1-C6 alkoxy. Suitable alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.

[0282] In certain embodiments, R 2 is C1-C6 alkylOC1-C6 alkyl.

[0283] In certain embodiments, R 2 is C1-C6 alkyl COOH.

[0284] In certain embodiments, R 2 is COOH.

[0285] In certain embodiments, R 2 is an oxo group.

[0286] In certain embodiments, R 2 is COOC1-C6 alkyl.

[0287] In certain embodiments, R 2 is C1-C6 alkylCOOC1-C6 alkyl.

[0288] In certain embodiments, R 2 is C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0289] In certain embodiments, R 2 is C1-C6 alkyl and C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to: [ka]

[0290] etc.

[0291] In certain embodiments, R 2 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.

[0292] In certain embodiments, R 2 is C1-C6 alkylOhaloC1-C6 alkyl. Suitable examples of C1-C6 alkylOhaloC1-C6 alkyl include, but are not limited to: [ka]

[0293] etc.

[0294] In certain embodiments, R 2 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl.

[0295] In certain embodiments, R 2is C1-C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol.

[0296] In certain embodiments, R 2 is CON(R 7 )(R 8 In certain embodiments, R 1 is N(R 7 )(R 8 In certain embodiments, R 2 is C1-C6 alkylN(R 7 )(R 8 ), where R 7 and R 8 is described in detail below.

[0297] In certain embodiments, R 2 is hydrogen, bromine, fluorine, chlorine, methyl, OH, halogen, CN oxo, methoxymethyl, COOCH2CH3 or trifluoromethyl.

[0298] In certain embodiments, R 1 and R 2 and are both hydrogen. In certain embodiments, R 1 is OH, and R 2 is hydrogen.

[0299] In the embodiments described herein, R 3 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ), C1-C6 alkylN(R 7 )(R 8 ), C1-C6 alkyl (OCH2CH2) n N(R 7 )(R8 ) or C1-C6 alkylOhaloC1-C6 alkyl, or R 4 When taken together with, they form a C3-C6 cycloalkyl or a C3-C6 heterocycloalkyl.

[0300] In certain embodiments of the compounds described herein, R 3 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) or R 4 When taken together with, form a C3-C6 cycloalkyl or a C3-C6 heterocycloalkyl. In certain embodiments, R 3 is hydrogen. In certain embodiments, R 3 is a halogen. Suitable halogens include fluorine, chlorine, bromine, and iodine. In certain embodiments, R 3 is CN. In certain embodiments, R 3 is OH.

[0301] In certain embodiments, R 3 is C1-C6 alkoxy. Suitable alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. In certain embodiments, R 3 is C1-C6 alkylOC1-C6 alkyl. In certain embodiments, R 3 is COOH. In certain embodiments, R 3 is C1-C6 alkylCOOH. In certain embodiments, R 3is C-C cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 3 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 3 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 3 is C1-C6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol. In certain embodiments, R 3 is CON(R 7 )(R 8 ). N(R 7 )(R 8 Suitable examples of R include, but are not limited to, CONH and CON(CH). In certain embodiments, R 3 is N(R 7 )(R 8 ). N(R 7 )(R 8 Suitable examples of N(CH) include, but are not limited to, NH and N(CH). In certain embodiments, R 3is C1-C6 alkylN(R 7 )(R 8 ) C1-C6 alkylN(R 7 )(R 8 Suitable examples of ) include, but are not limited to: [ka]

[0302] R 7 and R 8 is discussed in more detail below.

[0303] In certain embodiments, R 3 is C1-C6 alkylOhaloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to: [ka]

[0304] etc.

[0305] In certain embodiments, R 3 is C1-C6 alkyl (OCH2CH2) n N(R 7 )(R 8 ) is R 7 , R 8 and n are discussed in more detail below. C1-C6 alkyl(OCH2CH2) n N(R 7 )(R 8 Suitable examples of ) include, but are not limited to: [ka]

[0306] etc.

[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 certain embodiments, R 3 is R 4 and together form a C3-C6 cycloalkyl or a C3-C6 heterocycloalkyl. In certain embodiments, R 3 is R 4 and together form a C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 3 is R 4 together form a C3-C6 heterocycloalkyl. Suitable examples of heterocycloalkyl include, but are not limited to, 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 oxides thereof.

[0309] In certain embodiments, R 3 is hydrogen, fluorine, methyl, ethyl, OH, methoxy, [ka]

[0310] is.

[0311] In certain embodiments, R 3 is hydrogen, methyl, ethyl or [ka]

[0312] is.

[0313] In certain embodiments, R 3 is R 4 together to form oxetanyl.

[0314] In certain embodiments described herein, R 4 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ), C1-C6 alkylN(R 7 )(R 8 ), C1-C6 alkyl (OCH2CH2) n N(R 7 )(R 8 ) or C1-C6 alkylOhaloC1-C6 alkyl, or R 3 When taken together with R, they form a C-C cycloalkyl or a C-C heterocycloalkyl. In certain embodiments of the compounds described herein, R 4 is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 ) or R 3 When taken together with, form a C3-C6 cycloalkyl or a C3-C6 heterocycloalkyl. In certain embodiments, R 4 is hydrogen. In certain embodiments, R 4is a halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R 4 is CN. In certain embodiments, R 4 is OH.

[0315] In certain embodiments, R 4 is C1-C6 alkoxy. Suitable alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. In certain embodiments, R 4 is C1-C6 alkylOC1-C6 alkyl. In certain embodiments, R 4 is COOH. In certain embodiments, R 4 is C1-C6 alkylCOOH. In certain embodiments, R 4 is C-C cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 4 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 4 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 4is C1-C6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol. In certain embodiments, R 4 is CON(R 7 )(R 8 ). N(R 7 )(R 8 Suitable examples of R include, but are not limited to, CONH and CON(CH). In certain embodiments, R 4 is N(R 7 )(R 8 ). N(R 7 )(R 8 Suitable examples of N(CH) include, but are not limited to, NH and N(CH). In certain embodiments, R 4 is C1-C6 alkylN(R 7 )(R 8 ) C1-C6 alkylN(R 7 )(R 8 Suitable examples of ) include, but are not limited to: [ka]

[0316] R 7 and R 8 is discussed in more detail below.

[0317] In certain embodiments, R 4 is C1-C6 alkylOhaloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to: [ka]

[0318] etc.

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

[0320] etc.

[0321] In certain embodiments, R 4 is R 3 and together form a C3-C6 cycloalkyl or a C3-C6 heterocycloalkyl. In certain embodiments, R 4 is R 3 and together form a C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 4 is R 3 together form a C3-C6 heterocycloalkyl. Suitable examples of heterocycloalkyl include, but are not limited to, 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 oxides thereof.

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

[0323] In certain embodiments, R 4 is R 3 and together form oxetanyl. In certain embodiments, R 3 and R 4 are both hydrogen, methyl or ethyl.

[0324] In certain embodiments, R 3 is hydrogen, and R 4 is hydrogen.

[0325] In the embodiments described herein, R 5 is 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 alkylOH, -C1-C6 alkylOHhaloC1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 )

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

[0327] In certain embodiments, R 5 is a halogen. Examples of suitable halogens include chlorine, bromine, fluorine and iodine.

[0328] In certain embodiments, R 5 is CN.

[0329] In certain embodiments, R 5 is OH.

[0330] In certain embodiments, R 5 is C1-C6 alkoxy. Suitable alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.

[0331] In certain embodiments, R 5 is C1-C6 alkylOC1-C6 alkyl.

[0332] In certain embodiments, R 5 is C1-C6 alkyl COOH.

[0333] In certain embodiments, R 5 is COOH.

[0334] In certain embodiments, R 5 is an oxo group.

[0335] In certain embodiments, R 5 is COOC1-C6 alkyl.

[0336] In certain embodiments, R 5 is C1-C6 alkylCOOC1-C6 alkyl.

[0337] In certain embodiments, R 5 is C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0338] In certain embodiments, R 5 is C1-C6 alkyl and C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to: [ka]

[0339] etc.

[0340] In certain embodiments, R 5 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 5 is methyl.

[0341] In certain embodiments, R 5 is C1-C6 alkylOhaloC1-C6 alkyl. Suitable examples of C1-C6 alkylOhaloC1-C6 alkyl include, but are not limited to: [ka]

[0342] etc.

[0343] In certain embodiments, R 5 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl.

[0344] In certain embodiments, R 5 is C1-C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol.

[0345] In certain embodiments, R 5 is CON(R 7 )(R 8 In certain embodiments, R 1 is N(R 7 )(R 8 In certain embodiments, R 5 is C1-C6 alkylN(R 7 )(R 8 ), where R 7 and R 8 is described in detail below.

[0346] In certain embodiments, R 5 is hydrogen, methyl, ethyl or t-butyl.

[0347] In the embodiments described herein, R 6 is 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 alkylOH, -C1-C6 alkylOHhaloC1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 )

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

[0349] In certain embodiments, R 6 is a halogen. Examples of suitable halogens include chlorine, bromine, fluorine and iodine.

[0350] In certain embodiments, R 6is CN.

[0351] In certain embodiments, R 6 is OH.

[0352] In certain embodiments, R 6 is C1-C6 alkoxy. Suitable alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.

[0353] In certain embodiments, R 6 is C1-C6 alkylOC1-C6 alkyl.

[0354] In certain embodiments, R 6 is C1-C6 alkyl COOH.

[0355] In certain embodiments, R 6 is COOH.

[0356] In certain embodiments, R 6 is an oxo group.

[0357] In certain embodiments, R 6 is COOC1-C6 alkyl.

[0358] In certain embodiments, R 6 is C1-C6 alkylCOOC1-C6 alkyl.

[0359] In certain embodiments, R 6 is C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0360] In certain embodiments, R 6 is C1-C6 alkyl and C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to: [ka]

[0361] etc.

[0362] In certain embodiments, R 6 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 6 is methyl.

[0363] In certain embodiments, R 6 is C1-C6 alkylOhaloC1-C6 alkyl. Suitable examples of C1-C6 alkylOhaloC1-C6 alkyl include, but are not limited to: [ka]

[0364] etc.

[0365] In certain embodiments, R 6 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl.

[0366] In certain embodiments, R 6is C1-C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol.

[0367] In certain embodiments, R 6 is CON(R 7 )(R 8 In certain embodiments, R 1 is N(R 7 )(R 8 In certain embodiments, R 6 is C1-C6 alkylN(R 7 )(R 8 ), where R 7 and R 8 is described in detail below.

[0368] In certain embodiments, R 6 is hydrogen, methyl, ethyl or t-butyl.

[0369] In the embodiments described herein, R 7 is hydrogen, C-C alkylCOOH, COOH, C-C cycloalkyl, C-C alkyl, haloC-C alkyl, C-C alkylOH, COC-C alkyl, or COOC-C alkyl. 7 is hydrogen, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl or C1-C6 alkylOH.

[0370] In certain embodiments, R 7 is hydrogen. In certain embodiments, R 7 is C1-C6 alkylCOOH. In certain embodiments, R 7 is COOH. In certain embodiments, R 7 is C-C cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R7 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 7 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 7 is C1-C6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol.

[0371] In certain embodiments, R 7 is COC1-C6 alkyl. Suitable examples include, but are not limited to, COCH3. In certain embodiments, R 7 is COOC1-C6 alkyl. Suitable examples include, but are not limited to, COOCH3.

[0372] In the embodiments described herein, R 8 is hydrogen, C-C alkylCOOH, COOH, C-C cycloalkyl, C-C alkyl, haloC-C alkyl, C-C alkylOH, COC-C alkyl, or COOC-C alkyl. 8is hydrogen, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl or C1-C6 alkylOH.

[0373] In certain embodiments, R 8 is hydrogen. In certain embodiments, R 8 is C1-C6 alkylCOOH. In certain embodiments, R 8 is COOH. In certain embodiments, R 8 is C-C cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 8 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 8 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 8 is C1-C6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol.

[0374] In certain embodiments, R 8is COC1-C6 alkyl. Suitable examples include, but are not limited to, COCH3. In certain embodiments, R 8 is COOC1-C6 alkyl. Suitable examples include, but are not limited to, COOCH3.

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

[0376] In certain embodiments, R 9 is CN. In certain embodiments, R 9 is OH.

[0377] In certain embodiments, R 9 is C1-C6 alkoxy. Suitable alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. In certain embodiments, R 9 is C1-C6 alkylOC1-C6 alkyl. In certain embodiments, R 9 is COOH. In certain embodiments, R 9 is C1-C6 alkylCOOH. In certain embodiments, R 9 is C-C cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 9is 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 9 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 9 is C1-C6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol. In certain embodiments, R 9 is CON(R 7 )(R 8 In certain embodiments, R 9 is N(R 7 )(R 8 In certain embodiments, R 9 is C1-C6 alkylN(R 7 )(R 8 )

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

[0379] In certain embodiments, R 10 is C1-C6 alkoxy. Suitable alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. In certain embodiments, R 10 is C1-C6 alkylOC1-C6 alkyl. In certain embodiments, R 10 is COOH. In certain embodiments, R 10 is C1-C6 alkylCOOH. In certain embodiments, R 10 is C-C cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 10 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 10is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 10 is C1-C6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol. In certain embodiments, R 10 is CON(R 7 )(R 8 In certain embodiments, R 10 is N(R 7 )(R 8 In certain embodiments, R 10 is C1-C6 alkylN(R 7 )(R 8 )

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

[0381] In certain embodiments, R 11 is C1-C6 alkoxy. Suitable alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. In certain embodiments, R11 is C1-C6 alkylOC1-C6 alkyl. In certain embodiments, R 11 is COOH. In certain embodiments, R 11 is C1-C6 alkylCOOH. In certain embodiments, R 11 is C-C cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 11 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 11 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 11 is C1-C6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol. In certain embodiments, R 11 is CON(R 7 )(R 8 In certain embodiments, R 11 is N(R 7 )(R 8 In certain embodiments, R 11 is C1-C6 alkylN(R 7)(R 8 )

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

[0383] In certain embodiments, R 12 is 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 C1-C6 alkylOC1-C6 alkyl. In certain embodiments, R 12 is COOH. In certain embodiments, R 12 is C1-C6 alkylCOOH. In certain embodiments, R 12 is C-C cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 12is 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 12 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 12 is C1-C6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol. In certain embodiments, R 12 is CON(R 7 )(R 8 In certain embodiments, R 12 is N(R 7 )(R 8 In certain embodiments, R 12 is C1-C6 alkylN(R 7 )(R 8 )

[0384] In certain embodiments, R 12 is hydrogen, methyl, ethyl, methoxy, OH or [ka]

[0385] is.

[0386] In certain embodiments, R 12 is hydrogen or [ka]

[0387] is.

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

[0389] In certain embodiments, R 13 is 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 C1-C6 alkylOC1-C6 alkyl. In certain embodiments, R 13 is COOH. In certain embodiments, R 13 is C1-C6 alkylCOOH. In certain embodiments, R 13is C-C cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 13 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 13 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 13 is C1-C6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol. In certain embodiments, R 13 is CON(R 7 )(R 8 In certain embodiments, R 13 is N(R 7 )(R 8 In certain embodiments, R 13 is C1-C6 alkylN(R 7 )(R 8 )

[0390] In certain embodiments, R 13 is hydrogen, methyl, ethyl, methoxy, OH or [ka]

[0391] is.

[0392] In certain embodiments, R 13 is hydrogen or [ka]

[0393] is.

[0394] In certain embodiments, R 12 and R 13 are independently selected from the group consisting of hydrogen and C1-C6 alkyl, O—C1-C6 alkyl, C1-C6 alkyl.

[0395] In certain embodiments described herein, R 14 Each occurrence of is hydrogen, halogen, CN, OH, C1-C6 alkoxy, C1-C6 alkylOC1-C6 alkyl, C1-C6 alkylCOOH, COOH, C3-C6 cycloalkyl, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6 alkylN(R 7 )(R 8 In certain embodiments, R 14 is hydrogen. In certain embodiments, R 14 is a halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R 14 is CN. In certain embodiments, R 14 is OH.

[0396] In certain embodiments, R 14is 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 C1-C6 alkylOC1-C6 alkyl. In certain embodiments, R 14 is COOH. In certain embodiments, R 14 is C1-C6 alkylCOOH. In certain embodiments, R 14 is C-C cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 14 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 14 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 14 is C1-C6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol. In certain embodiments, R 14 is CON(R 7 )(R 8 In certain embodiments, R14 is N(R 7 )(R 8 In certain embodiments, R 14 is C1-C6 alkylN(R 7 )(R 8 )

[0397] In certain embodiments, X is C(R 14 )2, then R 14 are independently selected from the group consisting of hydrogen, halogen, OH, C1-C6 alkylOH, C1-C6 alkylalkoxy, C1-C6 alkylOC1-C6 alkyl, and C1-C6 alkyl.

[0398] In certain embodiments, R 14 is hydrogen, methyl, ethyl, methoxy, OH or [ka]

[0399] is.

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

[0401] In certain embodiments, R 15is C1-C6 alkoxy. Suitable alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. In certain embodiments, R 15 is C1-C6 alkylOC1-C6 alkyl. In certain embodiments, R 15 is COOH. In certain embodiments, R 15 is C1-C6 alkylCOOH. In certain embodiments, R 15 is C-C cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R 15 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 15 is ethyl.

[0402] In certain embodiments, R 15 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 15 is C1-C6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol. In certain embodiments, R15 is CON(R 7 )(R 8 In certain embodiments, R 15 is N(R 7 )(R 8 In certain embodiments, R 15 is C1-C6 alkylN(R 7 )(R 8 )

[0403] In certain embodiments, R 15 is methyl or ethyl.

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

[0405] In certain embodiments, R 16 is C1-C6 alkoxy. Suitable alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. In certain embodiments, R 16 is C1-C6 alkylOC1-C6 alkyl. In certain embodiments, R 16 is COOH. In certain embodiments, R 16 is C1-C6 alkylCOOH. In certain embodiments, R 16is C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0406] In certain embodiments, R 16 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 16 is haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R 16 is C1-C6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol. In certain embodiments, R 16 is CON(R 7 )(R 8 In certain embodiments, R 16 is N(R 7 )(R 8 In certain embodiments, R 16 is C1-C6 alkylN(R 7 )(R 8 )

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

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

[0409] In 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 certain embodiments, m is 0, p is 1, and X is O.

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

[0414] In certain embodiments, m is 0, p is 1, and X is C(R 14 )2, where R 14 Each occurrence of is independently selected from the group consisting of hydrogen, halogen, OH, C1-C6 alkoxy, and C1-C6 alkyl.

[0415] In certain embodiments, m is 1 and X is C(R 14 )2, where R 14 Each occurrence of is independently selected from the group consisting of hydrogen, halogen, OH, C1-C6 alkoxy, and C1-C6 alkyl.

[0416] For example, in certain embodiments of Formula (I), l is 0; m is 1; p is 1; X is O; V, Y, and Z are CH; and Q is CH, as shown in Formula (VII). [ka]

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

[0418] In the embodiments described herein, A is a linear or branched, saturated or unsaturated (C3-C 10 ) alkylene, phenyl (C3-C 10 ) alkylene or cycloalkyl (C3-C 10 ) alkylene, wherein one or more additional —CH— groups within A may be independently replaced with a moiety selected from the group consisting of O, S, NR, CONR, NRCO, SO, and SONR, and wherein one or more of the hydrogens along A are selected from the group consisting of hydroxyl, halogen, and C 1-3 In certain embodiments, A is a straight or branched chain, saturated or unsaturated (C3-C 10 ) alkylene or cycloalkyl (C3-C 10 ) alkylene, where one or more —CH— groups within A may be independently replaced with a moiety selected from the group consisting of O, S, and NH. In certain embodiments, A always has at least one —CH— group.

[0419] In certain embodiments, A is a straight chain (C3-C 10 ) alkylene. Straight chain (C3-C 10) Examples of alkylenes are: [ka]

[0420] etc.

[0421] In certain embodiments, A is a branched chain (C3-C 10 ) alkylene. Suitable branched chain (C3-C 10 ) The alkylene includes, but is not limited to, [ka]

[0422] etc.

[0423] In certain embodiments, A is saturated (C3-C 10 ) alkylene. Examples include: [ka]

[0424] etc.

[0425] In certain embodiments, A is an unsaturated (C3-C 10 ) alkylene. Suitable unsaturated (C3-C 10 ) alkylene, the saturated (C3-C 10 ) alkylenes in which hydrogen has been removed and one or more double or triple covalent bonds exist between adjacent carbon atoms. 10 ) Examples of alkylene include, but are not limited to: [ka]

[0426] etc.

[0427] In another embodiment, A is a straight chain cycloalkyl (C-C 10 ) alkylene. Suitable straight chain cycloalkyl (C3-C 10 ) For alkylene, two carbons in the chain are (C3-C 10 ) Cycloalkyl (C3-C 10 ) alkylene. Straight-chain cycloalkyl (C3-C 10 ) Examples of alkylene include, but are not limited to: [ka]

[0428] etc.

[0429] In certain embodiments, A is a branched cycloalkyl (C-C 10 ) alkylene. Suitable branched cycloalkyl (C3-C 10 ) For alkylene, two carbons in the chain are (C3-C 10 ) Cycloalkyl contains branched chain (C3-C 10 ) alkylene, etc. Cycloalkyl (C3-C 10 ) Examples of alkylene include, but are not limited to: [ka]

[0430] etc.

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

[0432] etc.

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

[0434] etc.

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

[0436] etc.

[0437] In another embodiment, one or more -CH2- groups in A may be independently replaced with a moiety 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 a moiety 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 is described in more detail below.

[0438] In the embodiments described herein, R is hydrogen, C-C alkylCOOH, COOH, C-C cycloalkyl, C-C alkyl, haloC-C alkyl, C-C alkylOH, COC-C alkyl, or COOC-C alkyl. In certain embodiments, R is hydrogen, C-C alkylCOOH, COOH, C-C cycloalkyl, C-C alkyl, haloC-C alkyl, or C-C alkylOH.

[0439] In certain embodiments, R is hydrogen. In certain embodiments, R is C1-C6 alkylCOOH. In certain embodiments, R is COOH. In certain embodiments, R is C3-C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R is 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 haloC1-C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R is C1-C6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol.

[0440] In certain embodiments, R is COC1-C6 alkyl. Suitable examples include, but are not limited to, COCH3. In certain embodiments, R is COOC1-C6 alkyl. Suitable examples include, but are not limited to, COOCH3.

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

[0442] etc.

[0443] In certain embodiments, A is [ka]

[0444] is.

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

[0446] is.

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

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

[0449] In certain embodiments, the compounds described herein include the following compounds: [ka] TIFF2024545498000086.tif234135TIFF2024545498000087.tif235133TIFF2024545498000088.tif203135 TIFF2024545498000089.tif197133TIFF2024545498000090.tif190134TIFF2024545498000091.tif161134

[0450] In certain embodiments, the compounds described herein include the following compounds or pharmaceutically acceptable salts thereof: [ka] TIFF2024545498000093.tif236135TIFF2024545498000094.tif237134TIFF2024545498000095.tif234134 TIFF2024545498000096.tif214134TIFF2024545498000097.tif236134TIFF2024545498000098.tif208135

[0451] Definitions and Abbreviations: Terms used herein have their ordinary meanings, and the meaning of such terms is independent at each occurrence. Notwithstanding, and unless otherwise indicated, the following definitions apply throughout this specification and claims. Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. These definitions apply regardless of whether the term is used alone or in combination with other terms, unless otherwise indicated. Thus, the definition of "alkyl" applies to "alkyl" as well as the "alkyl" portions of "hydroxyalkyl," "haloalkyl," arylalkyl, alkylaryl, "alkoxy," etc.

[0452] In the various embodiments of the invention described herein, it is to be understood that any variable not expressly defined in connection with that embodiment is as defined in formula (I).

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

[0454] "Drug resistance," in relation to a strain of malaria parasite, means a Plasmodium species that is no longer susceptible to at least one previously effective drug; that has developed the ability to withstand attack by at least one previously effective drug. Drug-resistant strains can pass on this ability to their progeny. The resistance can result from random genetic mutations in the bacterial cell that alter susceptibility to a single drug or to various drugs.

[0455] A "patient" includes both human and non-human animals, including research and companion animals such as mice, rats, primates, monkeys, chimpanzees, apes, dogs, and domestic cats.

[0456] A "pharmaceutical composition" (or "pharmaceutically acceptable composition") refers to a composition suitable for administration to a patient. Such a composition may contain a neat compound (or compounds) of the present invention or a mixture thereof, or a salt, solvate, prodrug, isomer, or tautomer thereof, and one or more pharmaceutically acceptable carriers or diluents. The term "pharmaceutical composition" is further intended to encompass both bulk compositions and individual dosage units comprised of one or more (e.g., two) pharmaceutically active agents (e.g., a compound of the present invention and an additional agent selected from the list of additional agents described herein) and any pharmaceutically inactive excipients. The bulk composition and each individual dosage unit may contain a fixed amount of the "two or more pharmaceutically active agents." The bulk composition is material that has not yet been formed into individual dosage units. Exemplary dosage units are oral dosage units such as tablets, pills, etc. Similarly, the methods described herein for treating a patient by administering a pharmaceutical composition of the present invention are intended to encompass administering the bulk composition and individual dosage units.

[0457] "Halogen" and "halo" mean fluorine, chlorine, bromine or iodine. Preferred are fluorine, chlorine and bromine.

[0458] "Alkylene" by itself or as part of another substituent means a divalent hydrocarbon chain radical having the specified number of carbon atoms. For example, -(C1-C5)alkylene includes, for example, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -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 within the chain. Cycloalkylene means a divalent hydrocarbon chain radical having the specified number of carbon atoms and having a cycloalkyl moiety within the chain.

[0459] "Alkyl" means an aliphatic hydrocarbon group which may be straight or branched and having 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 chain means that one or more lower alkyl groups (e.g., methyl, ethyl or propyl) are attached to a straight alkyl chain. "Lower alkyl" means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl.

[0460] "Haloalkyl" means an alkyl as defined above in which one or more hydrogen atoms on the alkyl is replaced by a halo group defined above.

[0461] "Aryl" means an aromatic monocyclic or multicyclic 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," which may be the same or different, as defined herein. 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). Preferred cycloalkyl rings contain about 5 to about 10 ring atoms. The cycloalkyl can be substituted with one or more substituents, which can be the same or different, as described herein. A monocyclic cycloalkyl refers to a monocyclic version of a cycloalkyl moiety described herein. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, and cycloheptyl. A polycyclic cycloalkyl refers to a polycyclic ring (including bicyclic rings) containing a non-aromatic ring. Non-limiting examples of suitable polycyclic cycloalkyls include 1-decalinyl, norbornyl, and adamantyl. In certain embodiments, a non-aromatic ring is fused to 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), in which one or more atoms in the ring system is an element other than carbon, such as 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 prefix aza, oxa, or thia before the heterocyclyl root name means that at least a nitrogen, oxygen, or sulfur atom, respectively, is present as a ring atom. Any -NH in a heterocyclyl ring can be protected, for example, as an -N(Boc), -N(CBz), -N(Tos), or the like; such protection is also considered part of this 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," when appearing in the definition of a variable in a general structure described herein, refers to the corresponding N-oxide, S-oxide, or S,S-dioxide. "Heterocyclyl" also encompasses rings in which =0 replaces two available hydrogens on the same carbon atom (i.e., heterocyclyl encompasses rings bearing a carbonyl group within the ring). Such =0 groups may be referred to herein as "oxo." An example of such a moiety is pyrrolidinone (or pyrrolidone): [ka]

[0464] As used herein, the term "monocyclic heterocycloalkyl" refers to a monocyclic version of a heterocycloalkyl moiety described herein and includes 4- to 7-membered monocyclic heterocycloalkyl groups containing 1 to 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 point of attachment to the parent moiety is at 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, as well as their oxides. Non-limiting examples of monocyclic heterocycloalkyl groups include the substructure: [ka]

[0465] Non-limiting examples of polycyclic heterocycloalkyl groups include bicyclic heterocycloalkyl groups. Specific examples include, but are not limited to: [ka]

[0466] etc.

[0467] "Alkoxy" means an alkyl-O- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. The bond to the parent moiety is through the ether oxygen.

[0468] The term "substituted" means that one or more hydrogens on the designated atom are replaced with one selected from the indicated group, provided that the normal valence of the designated atom under the existing circumstances is not exceeded and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. A "stable compound" or "stable structure" means a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and formulation into an efficacious therapeutic agent.

[0469] The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties.

[0470] When a variable moiety occurs more than once within a group (e.g., -N(R 8 )2 in R 8 ), or when a variable occurs more than once in the structures described herein, the variable can be the same or different.

[0471] A solid line, as a bond, generally indicates a mixture of possible isomers (e.g., a mixture containing (R)- and (S)-stereochemistry) or any of the possible isomers. For example, [ka]

[0472] teeth, [ka]

[0473] means that it contains either one or both of the following:

[0474] As used herein, a wavy line 〜〜 shown crossing a line representing a chemical bond indicates the point of attachment to the remainder of the compound. [ka]

[0475] indicates that the indicated line (bond) may be attached to any of the substitutable ring atoms.

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

[0477] is.

[0478] As used herein, when more than one oxygen and / or sulfur atom is present in a ring system, there cannot be adjacent oxygen and / or sulfur atoms in said ring system.

[0479] As is well known in the art, a bond drawn from a particular atom without a moiety drawn at the end of the bond represents a methyl group attached to that atom through that bond, unless otherwise indicated. For example, [ka]

[0480] teeth, [ka]

[0481] Represents.

[0482] In another embodiment, the compounds useful in the methods of the invention and / or compositions comprising them useful in the methods are present in isolated and / or purified form. The terms "purified," "in purified form," or "in isolated and purified form" with respect to a compound refer to the physical state of the compound after isolation from a synthetic process (e.g., from a reaction mixture) or from a natural source, or a combination thereof. Thus, the terms "purified," "in purified form," or "in isolated and purified form" with respect to a compound refer to the physical state of the compound (or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt or solvate of the compound, stereoisomer, or tautomer) after obtaining from one or more purification processes described herein or familiar to those of skill in the art (e.g., chromatography, recrystallization, etc.) in a purity sufficient to be suitable for in vivo or pharmaceutical use and / or capable of being characterized by standard analytical techniques described herein or familiar to those of skill in the art.

[0483] It is to be understood that carbon and heteroatoms with unsatisfied valences in the text, schemes, examples, and tables herein are presumed to have sufficient hydrogen atoms to satisfy the valences.

[0484] When a functional group in a compound is referred to as being "protected," this means that the group is in a modified form to prevent undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those skilled in the art by reference 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 invention. For a discussion of prodrugs, see T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 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 yield a compound of the invention or a pharmaceutically acceptable salt, hydrate, or solvate of that compound. Such conversion may occur by various mechanisms (e.g., by metabolic or chemical processes), for example, by hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Prodrugs 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 methods of the invention, or a pharmaceutically acceptable salt thereof, contains a carboxylic acid functional group, a prodrug may be prepared by replacing the hydrogen atom of the acid group with, for example, a (C1-C8) alkyl, (C2-C 12) alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having 3 to 9 carbon atoms, These may include esters formed by replacing the alkyl groups with groups such as 1-(N-(alkoxycarbonyl)amino)ethyl, 3-phthalidyl, 4-crotonolactonyl, γ-butyrolactone-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 a compound used in the methods of the invention contains an alcohol functional group, a prodrug can be formed by replacing the hydrogen atom of the alcohol group with a group such as, for example, (C-C)alkanoyloxymethyl, 1-((C-C)alkanoyloxy)ethyl, 1-methyl-1-((C-C)alkanoyloxy)ethyl, (C-C)alkoxycarbonyloxymethyl, N—(C-C)alkoxycarbonylaminomethyl, succinoyl, (C-C)alkanoyl, α-amino(C-C)alkanyl, arylacyl, and α-aminoacyl or α-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independently selected from natural L-amino acids, P(O)(OH), —P(O)(O(C-C)alkyl), or glycosyl (the radical obtained by removal of the hydroxyl group from the hemiacetal form of a carbohydrate).

[0488] When the compound used in the method of the invention contains an amine functional group, the prodrug may replace a hydrogen atom in the amine group with, for example, an R-carbonyl, RO-carbonyl, NRR′-carbonyl, where R and R′ are each independently (C1-C 10 ) alkyl, (C3-C7) cycloalkyl, benzyl, or R-carbonyl is a naturally occurring α-aminoacyl or naturally occurring aminoacyl, —C(OH)C(O)OY 1 [where Y 1 is H, (C1-C6) alkyl or benzyl], -C(OY 2 )Y 3 [where Y 2 is (C1-C4) alkyl, and Y 3 is (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 [where Y 4 is H or methyl, and Y 5 is mono-N- or di-N,N-(C1-C6) alkylamino, morpholino, piperidin-1-yl or pyrrolidin-1-yl.

[0489] One or more compounds used in the methods of the present invention can exist in unsolvated and solvated forms with pharmaceutically acceptable solvents, such as water, ethanol, and the like, and the present invention is intended to encompass both solvated and unsolvated forms. "Solvate" refers to a physical association of a 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 instances, the solvate is capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. A "hydrate" is a solvate in which the solvent molecule is HO.

[0490] One or more compounds used in the methods of the present invention can be converted into a solvate. The preparation of solvates is generally known. Thus, for example, M. Caira et al., J. Pharmaceutical Sci., 1993, 3, 601-611, describes the preparation of solvates of the antifungal fluconazole in ethyl acetate and from water. Similar preparations of solvates, hemisolvates, 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 a compound of the present invention in a desired amount of a desired solvent (organic or aqueous, 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, such as for example IR spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).

[0491] An "effective amount" or "therapeutically effective amount" is intended to refer to the amount of a compound or composition used in the methods of the present invention that is effective to inhibit the above-described disease or enzymatic activity, and thus effective to bring about the desired therapeutic, ameliorative, suppressive or preventative effect.

[0492] In another embodiment, pharmaceutically acceptable salts of the compounds used in the methods of the present invention are provided. Accordingly, reference herein to a compound used in the methods of the present invention is understood to include reference to its salts, unless otherwise indicated. The term "salt(s)," as used herein, refers to acid salts formed with inorganic and / or organic acids, as well as base salts formed with inorganic and / or organic bases. Furthermore, when a compound of the present invention contains both a basic moiety (e.g., but not limited to, pyridine or imidazole) and an acidic moiety (e.g., but not limited to, a carboxylic acid), zwitterions ("inner salts") may be formed and are encompassed by the term "salt(s)" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of compounds used in the methods of the invention can be formed, for example, by reacting a compound of the invention with a particular amount (e.g., equivalent amount) of acid or base in a medium (e.g., a medium in which the salt precipitates) or an aqueous medium, followed by lyophilization.

[0493] Representative 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, toluenesulfonate (also known as tosylate), and the like.

[0494] Furthermore, acids that are generally considered suitable for forming pharmaceutically useful salts from basic pharmaceutical compounds are listed, for example, in "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) 33 201-217, 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), the disclosures of which are incorporated herein by reference.

[0495] Representative basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (e.g., organic amines) such as dicyclohexylamine and t-butylamine, and salts with amino acids such as arginine and lysine. Basic nitrogen-containing groups can be quaternized with 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), aralkyl halides (e.g., benzyl bromide and phenethyl bromide), and the like.

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

[0497] Another embodiment provides pharmaceutically acceptable esters of the compounds used in the methods of the invention. Such esters include the following: (1) carboxylic acid esters obtained by esterification of a hydroxy group, where the non-carbonyl portion of the carboxylic acid portion of the ester group is selected from linear or branched alkyl (e.g., acetyl, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (e.g., methoxymethyl), aralkyl (e.g., benzyl), aryloxyalkyl (e.g., phenoxymethyl), aryl (e.g., aryloxyalkyl), aryloxyalkyl ... 1-4 Alkyl or C 1-4 (2) sulfonate esters, such as 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 esters are, for example, C 1-20 by alcohol or its reactive derivatives, or by 2,3-di(C 6-24 ) may be further esterified by acylglycerols.

[0498] As described herein, in another embodiment, tautomers of the compounds of the invention used in the methods herein, as well as salts, solvates, esters, and prodrugs of the tautomers, are provided. It should be understood that all tautomeric forms of such compounds are within the scope of the compounds used in the methods of the invention. For example, all keto-enol and imine-enamine forms of the compounds, if they exist, are included in the invention.

[0499] The compounds used in the methods of the present invention may contain asymmetric or chiral centers and, therefore, may exist in various stereoisomeric forms. All stereoisomeric forms of the compounds used in the methods of the present invention, as well as mixtures thereof (including 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 a compound used in the methods of the present invention contains a double bond or a fused ring, both the cis- and trans-forms, (E)- and (Z)-forms, and mixtures thereof, are encompassed within the scope of the present invention.

[0500] In another embodiment, diastereomeric mixtures and individual enantiomers of the compounds used in the methods of the present invention are provided. Diastereomeric mixtures can be separated into their individual diastereomers based on their physical chemical differences by methods well known to those skilled in the art, for example, by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture to a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., a chiral auxiliary, such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Furthermore, some of the compounds used in the methods of the present invention may be atropisomers (e.g., substituted biaryls) and are considered part of the present invention. 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 invention (including salts, solvates, esters, and prodrugs of the compounds, and salts, solvates, and esters of the prodrugs), including isomers that may exist due to asymmetric carbons on various substituents, such as enantiomeric forms (which may exist even when there is no asymmetric carbon), rotamer forms, atropisomeric forms, and diastereomeric forms, are contemplated as embodiments within the scope of the invention, as well as positional isomers (e.g., 4-pyridyl and 3-pyridyl). (For example, if a compound of the invention contains a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are encompassed within the scope of the invention. Furthermore, for example, all keto-enol and imine-enamine forms of the compounds are encompassed in the methods of the invention.)

[0502] Individual stereoisomers of the compounds of the invention can be, for example, substantially free of other isomers, or can be mixed, for example, as a racemate, or mixed with all other stereoisomers or other selected stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of terms such as "salt," "solvate," "ester," "prodrug," and the like is intended to apply equally to salts, solvates, esters, and prodrugs of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates, or prodrugs of the compounds of the invention.

[0503] In another embodiment, isotopically labeled compounds are provided for use 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 with atomic masses or mass numbers different from those usually found in nature.Examples of isotopes that can be incorporated into 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] Certain isotopically labeled compounds of the present invention (e.g., 3 H and 14 C-labeled compounds) are useful in compound and / or substrate tissue distribution assays. 3 H) isotopes and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Additionally, deuterium (i.e., 2 Substitution with heavier isotopes, such as H, can confer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and therefore may be preferred in some circumstances. Isotopically labeled compounds of the invention can generally be prepared by following methods analogous to those disclosed in the Schemes and / or Examples below, substituting the appropriate isotopically labeled reagent for a non-isotopically labeled reagent.

[0505] In the compounds used in the methods of the present invention, the atoms may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number but an atomic mass or mass number different from that predominantly found in nature. The present invention is intended to encompass all suitable isotopic variations of the compounds of the present invention. For example, different isotopic forms of hydrogen (H) include protium ( 1 H) and deuterium ( 2H). The presence of deuterium in the compounds of the invention is indicated by "D." Protium is the predominant hydrogen isotope found in nature. Enrichment with deuterium may provide certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) or may provide compounds useful as standards for characterizing biological samples. Isotopically enriched compounds of the invention can be prepared without undue experimentation by conventional techniques well known to those of skill in the art, or by processes analogous to those described in the schemes and examples herein using appropriate isotopically enriched reagents and / or intermediates.

[0506] Polymorphic forms of the compounds used in the methods of the present invention, and of the 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 is directed to a method for treating a malaria parasite infection, the method comprising administering to a subject in need of such treatment a compound described herein or a pharmaceutically acceptable salt thereof. More specifically, the method of the present invention comprises administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of 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 methods for treating a malaria parasite infection or for treating malaria or for inhibiting plasmepsin X, comprising administering to a subject in need of such treatment a therapeutically effective amount of a particular compound, or a pharmaceutically acceptable salt thereof, wherein the compound has structural formula (I), as described in the Summary of the Invention. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical composition together with a pharmaceutically acceptable carrier. Additionally, various embodiments of these methods, as described below, are also provided herein.

[0509] The present invention further relates to the use of a compound of Formula (I)-(VIII) or a pharmaceutically acceptable salt thereof for inhibiting plasmepsin X activity, for treating a malaria parasite infection, or for treating malaria. The present invention further relates to the use of a compound of Formula (I)-(VIII) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting plasmepsin X activity, for treating a malaria parasite infection, or for treating malaria. The compounds of Formula (I)-(VIII) or a pharmaceutically acceptable salt thereof described in any of the embodiments of the invention herein are useful for any of the above uses.

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

[0511] The present invention further relates to the use of a compound of Formula (I)-(VIII) or a pharmaceutically acceptable salt thereof for inhibiting plasmepsin IX activity, for treating a malarial parasite infection, or for treating malaria. The present invention further relates to the use of a compound of Formula (I)-(VIII) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting plasmepsin IX activity, for treating a malarial parasite infection, or for treating malaria. The compounds of Formula (I)-(VIII) or a pharmaceutically acceptable salt thereof described in any of the embodiments of the invention herein are useful for any of the above uses.

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

[0513] The present invention further relates to the use of compounds of Formula (I)-(VIII) or pharmaceutically acceptable salts thereof for inhibiting the activity of plasmepsin X and plasmepsin IX, for treating a malaria parasite infection, or for treating malaria. The present invention further relates to the use of compounds of Formula (I)-(VIII) or pharmaceutically acceptable salts thereof in the manufacture of a medicament for inhibiting the activity of plasmepsin X and plasmepsin IX, for treating a malaria parasite infection, or for treating malaria. Compounds of Formula (I)-(VIII) or pharmaceutically acceptable salts thereof described in any of the embodiments of the 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 inhibit the onset, development, or progression of the condition, ameliorate the symptoms of the condition, cause regression of the condition, cure the condition, or otherwise improve the general health of a subject suffering from or at risk of suffering from the condition. Thus, in accordance with the presently disclosed subject matter, the terms "treat," "treating," and grammatical variations thereof, and the phrase "method of treating," are intended to encompass any desired therapeutic intervention, including, but not limited to, methods of treating an existing infection in an infected subject, for example, in a subject exposed to a parasite disclosed herein.

[0515] Embodiments of the present invention further include one or more of the compounds of Formulae (I)-(VIII) or pharmaceutically acceptable salts thereof for use in: (i) for use in; (ii) for use as a medicament or composition for; or (iii) for use in the preparation of a medicament for: (a) treatment (e.g., treatment of a human body); (b) medical treatment; (c) inhibiting the growth of parasites / malaria parasites; (d) treating or preventing infections by Plasmodium species; (e) reducing the progression, onset, or severity of pathological symptoms associated with malaria parasite infection and / or reducing the likelihood of severe malaria parasite infection; or (f) treating, preventing, or delaying the onset, severity, or progression of malaria parasite-associated diseases, including, but not limited to, malaria.

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

[0517] Dosage and Administration In another embodiment, appropriate dosages and dosage forms of the compounds used in the methods of the present invention are provided. The appropriate dosage for administering to a patient of the compounds used in the methods of the present invention can be readily determined by one of ordinary skill in the art, e.g., an attending physician, pharmacist, or other skilled practitioner, and may vary depending on the patient's health, age, body weight, frequency of administration, coadministration with other active ingredients, and / or the indication for which the compound is administered. The dosage may range from about 0.001 to 500 mg / kg body weight / day of a compound of the present invention. In one embodiment, the dosage is from about 0.01 to about 25 mg / kg body weight / day of a compound of the present invention or a pharmaceutically acceptable salt or solvate of the compound. In another embodiment, the amount of active compound in a unit dosage of a formulation can be varied or adjusted, depending on the particular application, from about 1 mg to about 100 mg, in certain embodiments, from about 1 mg to about 50 mg, and in certain embodiments, from about 1 mg to about 25 mg. In another embodiment, a typical recommended daily dosage regimen for oral administration can range from about 1 mg / day to about 500 mg / day, and in certain embodiments, from 1 mg / day to 200 mg / day, in two to four divided doses.

[0518] As discussed above, the dosage and frequency of administration of the compounds of the invention and / or pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician, taking into account such factors as the age, condition, and size of the patient and the severity of the condition being treated.

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

[0520] Aerosol preparations suitable for inhalation include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g., nitrogen.

[0521] Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions, and emulsions.

[0522] In another embodiment, there is provided the use of a composition comprising a compound of Formula (I)-(VIII) or a pharmaceutically acceptable salt thereof formulated for transdermal delivery. The transdermal composition can take the form of a cream, lotion, aerosol and / or emulsion and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.

[0523] In another embodiment, there is provided the use of a composition comprising a compound of Formula (I)-(VIII) or a pharmaceutically acceptable salt thereof formulated for subcutaneous delivery. In another embodiment, there is provided the use of a composition suitable for oral delivery. In some embodiments, pharmaceutical formulations comprising one or more compounds of Formula (I)-(VIII) or a pharmaceutically acceptable salt thereof may be advantageously prepared in unit dosage form. In such form, the formulation is subdivided into suitably sized unit doses containing appropriate amounts of the active ingredient (e.g., an effective amount to achieve a desired purpose). Each of the foregoing alternatives is contemplated as encompassed by 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 methods of the present invention, i.e., compounds of Formulae (I)-(VIII), can be administered together or sequentially. When administered sequentially, the compounds of the present invention can be administered before or after the one or more additional therapeutic agents, as determined by the skill of the art or by the patient's preference.

[0525] If formulated as a fixed dose, such combination products utilize a compound of Formulas (I)-(VIII) or a pharmaceutically acceptable salt thereof within the dosage range described herein, and the other pharmaceutically active agent or treatment within the dosage range.

[0526] Combination therapy In another embodiment, methods of treatment are provided using pharmaceutically acceptable compositions containing the compounds of the present invention, either as neat chemicals or optionally further containing additional ingredients. Such compositions are intended for preparation and use in monotherapy or combination therapy. For preparing pharmaceutical compositions from the compounds of the present invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories. Powders and tablets may be comprised 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] Non-limiting examples of additional drugs and active agents useful in combination therapy for treating 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; pyronaridine-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 choice of such additional active ingredients will be determined by the attending physician or other health care provider according to the existing disease or disorder for which treatment is desired.

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

[0529] Example The meanings of the abbreviations used in the examples are as follows: [Table 1] TIFF2024545498000109.tif248170TIFF2024545498000110.tif193160

[0530] Abbreviations in nuclear magnetic resonance spectroscopy have the following meanings: s = singlet, d = doublet, dd = doublet of doublets, dt = triplet of doublets, ddd = doublet of doublets, Sept = septet, t = triplet, m = multiplet, br = broad line, brs = broad singlet, q = quartet, J = coupling constant, and Hz = hertz.

[0531] Several methods for preparing the compounds of the present disclosure are described in the following schemes and examples. Starting materials and intermediates were purchased commercially from common catalog sources or prepared using known methods or as otherwise illustrated. Several frequently applicable routes to compounds of formula (I) are described in the following schemes. In some cases, the order of carrying out reaction steps in the schemes can be varied to facilitate the reaction or to avoid undesired reaction products.

[0532] Scheme 1 [ka]

[0533] Compounds of formula S-2 are prepared from S-1 by macrolactamization using an amide coupling reagent.

[0534] Scheme 2 [ka]

[0535] Intermediate compounds of formula S-4 are prepared from S-3 after a ring-closing metathesis (RCM) reaction using catalysts such as second generation Grubbs catalyst, Zhan catalyst, and Hoveyda / Grubbs catalyst. The double bond in S-4 can be reduced, for example, under hydrogenation conditions, to give products of formula S-5.

[0536] Scheme 3 [ka]

[0537] Intermediate compounds of formula S-7 are prepared from S-6, where X is a halogen (e.g., Cl, Br, and I), following a transition metal-catalyzed intramolecular cross-coupling reaction (e.g., Heck reaction). The resulting double bond in S-7 can be reduced, for example, under hydrogenation conditions, to give products of formula S-8.

[0538] Scheme 4 [ka]

[0539] Products of formula S-10 are prepared from S-9, where X is a halogen (e.g., Cl, Br, and I), following a transition metal-catalyzed intramolecular cross-coupling reaction (e.g., palladium-catalyzed CO coupling reaction).

[0540] Scheme 5 [ka]

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

[0542] Scheme 6 [ka]

[0543] Products of formula S-12 are prepared from intermediates S-13 or S-14 after intramolecular reductive etherification using conditions such as TMSOTf and Et3SiH.

[0544] Moisture- or air-sensitive reactions were carried out in a glove box or under nitrogen or argon using anhydrous solvents and reagents. Reaction progress was monitored by analytical thin-layer chromatography (TLC), usually performed using E. Merck precoated TLC plates (silica gel 60F-254, 0.25 mm layer thickness), or by liquid chromatography-mass spectrometry (LC / MS).

[0545] Typically, the analytical LC-MS system used was a Waters ZQ with electrospray ionization in positive ion detection mode using an Agilent 1100 series HPLC equipped with an autosampler. TM The platform consisted of a Waters Xterra MS C18, 3.0 × 50 mm, 5 μm column or a Waters Acquity UPLC® BEH C18 1.0 × 50 mm, 1.7 μm column. 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 a gradient as follows: 100% solvent A for 0.7 min, change to 100% solvent B over 3.75 min, hold for 1.1 min, then return to 100% solvent A over 0.2 min.

[0546] Preparative HPLC purifications were usually carried out using either a mass spectrometry directed system or a non-mass guided system. Typically, they were carried out using an LC-MS System consisting of: Waters ZQ TMThe analysis was performed on a Waters Chromatography Workstation equipped with a single quad MS system (electrospray ionization), a Waters 2525 Gradient Pump, a Waters 2767 Injector / Collector, and a Waters 996 PDA Detector. MS conditions were as follows: 150-750 amu, positive electrospray, collection triggered by MS, and 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 consisting of a Gilson GX-281 Injector / Collector, a 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 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 controlled by a Waters Xbridge TMThe flow rate was maintained at 50 mL / min for the HPLC column and 90 mL / min for the Phenomenex Gemini column. The injection volume ranged from 1000 to 8000 μL, and the UV detection range was 210 to 400 nm. The mobile phase gradient was optimized for each compound. Reactions performed with microwave irradiation were typically performed using an Emrys Optimizer (Personal Chemistry) or an Initiator (Biotage). Solutions were concentrated under reduced pressure on a rotary evaporator. Flash chromatography was typically performed on silica gel (32-63 μM, 60 Å pore size) in prepacked cartridges of the indicated size using one of the following: a Biotage® Flash Chromatography apparatus (Dyax Corp.), an ISCO CombiFlash® Rf apparatus, or an ISCO CombiFlash® Companion XL. 1H NMR spectra were obtained on a 500 MHz spectrometer in CDCl3 solutions unless otherwise indicated. Chemical shifts are reported in parts per million (ppm). Tetramethylsilane (TMS) was used as an internal reference in CDCl3 solutions, and the residual CH3OH peak or TMS was used as an internal reference in CD3OD solutions. Coupling constants (J) are reported in hertz (Hz). Chiral analytical chromatography was most commonly performed on one of the following columns (Daicel Chemical Industries, Ltd.): a CHIRALPAK® AS column (250 × 4.6 mm), a CHIRALPAK® AD column (250 × 4.6 mm), a CHIRALCEL® OD column (250 × 4.6 mm), a CHIRALCEL® IA column (250 × 4.6 mm), or a CHIRALCEL® OJ column (250 × 4.6 mm) (Daicel Chemical Industries, Ltd.), using the stated percentages of either ethanol in hexane (%Et / Hex) or isopropanol in heptane (%IPA / Hep) as the isocratic solvent system. Chiral preparative chromatography was performed on one of the following columns (Daicel Chemical Industries, Ltd.): a CHIRALPAK AS column (20 × 250 mm), a CHIRALPAK AD column (20 × 250 mm), a CHIRALCEL® OD column (20 × 250 mm), a CHIRALCEL® IA column (20 × 250 mm), or a CHIRALCEL® OJ column (20 × 250 mm) (Daicel Chemical Industries, Ltd.) with the desired isocratic solvent system certified for chiral analytical chromatography or under supercritical fluid (SFC) conditions.

[0547] It is understood that chiral centers in the compounds may exist in the "S" configuration or the "R" configuration, or as a mixture of both. Within a molecule, each bond drawn as a straight line from a chiral center encompasses both the (R) and (S) stereoisomers, as well as mixtures thereof.

[0548] Intermediate 1 Preparation of Intermediate 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 N. The mixture was stirred at 50 °C for 12 h. The mixture was quenched with water (100 mL) and extracted with EtOAc (3 × 100 mL). The organic layer was washed with brine (80 mL), dried over NaSO, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, eluent 15% EtOAc / petroleum ether gradient @ 50 mL / min) to give methyl (R)-4-azidochroman-6-carboxylate (INT1-2).

[0550] MS (ESI) m / z 234.0(M+H + ) 1 H 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 Intermediate 1-3 [ka]

[0551] Pd—C (2.510 g, 4.72 mmol) was added to a solution of methyl (R)-4-azidochroman-6-carboxylate (INT1-2) (11 g, 47.2 mmol) in THF (200 mL) under a N atmosphere. The mixture was degassed and backfilled with H (3 times). The resulting mixture was stirred at 25 °C under a H atmosphere (15 psi) for 12 h. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give 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 portionwise to a solution of N,N-bisBoc-thiourea (16.94 g, 61.3 mmol) in THF (250 mL) at 0 °C under N. After 1 h 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 h. A solution of methyl (R)-4-aminochroman-6-carboxylate (INT1-3) (9.77 g, 47.1 mmol) in THF (50 mL) was added dropwise at 0 °C. The mixture was stirred at 0 °C for 2 h. The mixture was quenched with water (80 mL) and extracted with EtOAc (3 × 50 mL). The organic layer was washed with brine (40 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The crude material was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, eluent 20% EtOAc / petroleum ether gradient @ 50 mL / min) to give methyl (R)-4-(3-(tert-butoxycarbonyl)thioureido)chroman-6-carboxylate (INT-1).

[0554] MS (ESI) m / z 367.1 (M+H + ) 1 H 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] To a solution of pent-4-enoic acid (INT2-1) (40 g, 400 mmol), EDCI (92 g, 479 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (64.8 g, 479 mmol), and N-ethyl-N-isopropylpropan-2-amine (279 mL, 1598 mmol) in DCM (400 mL) was added N,O-dimethylhydroxylamine hydrochloride (54.6 g, 559 mmol). The reaction was stirred at 25 °C under a N atmosphere for 12 h. 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), dried over NaSO, filtered, concentrated under reduced pressure, and the crude 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 afford N-methoxy-N-methylpent-4-enamide (INT2-2).

[0556] MS (ESI) m / z 144.1 (M+H) + 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 Intermediate 2-3 [ka]

[0557] To a solution of N-methoxy-N-methylpent-4-enamide (INT2-2) (20 g, 140 mmol) in THF (200 mL) was added dropwise ethylmagnesium bromide (69.8 mL, 210 mmol) at 0 °C under N2 atmosphere. The reaction was stirred at 25 °C for 1 h under N2 atmosphere. TLC showed a new spot. The mixture was quenched with saturated aqueous NH4Cl (100 mL) and water (100 mL) and extracted with EtOAc (3 × 100 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and 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 give hept-6-en-3-one (INT2-3).

[0558] 1 H 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 Intermediate 2-4 [ka]

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

[0560] MS (ESI) m / z 216.2 (M+H) + 1 H 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 Intermediate 2-5 [ka]

[0561] To a solution of diisopropylamine (19.64 mL, 139 mmol) in anhydrous THF (40 mL) was added butyllithium (55.7 mL, 139 mmol) dropwise at −78 °C under a N atmosphere. The reaction was stirred at 0 °C for 30 min to form LDA. Methyl acetate (7.48 mL, 93 mmol) and Ti(OiPr)3Cl (116 mL, 116 mmol) were added to anhydrous THF (90 mL). LDA (76 mL, 93 mmol) was then added dropwise to the mixture at −78 °C. After 1 h, a solution of (R,E)-N-(hept-6-en-3-ylidene)-2-methylpropane-2-sulfinamide (INT2-4) (10 g, 46.4 mmol) in anhydrous THF (20 mL) was added dropwise, and the mixture was stirred at −78° C. for 3 h. The color remained yellow. LCMS showed a major DP mass. The mixture was quenched with ice-cold, half-saturated aqueous ammonium chloride (60 mL). The slurry was diluted with EtOAc (200 mL), then filtered and rinsed with EtOAc and water. The organic layer was washed with brine (50 mL), dried over NaSO, 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 give methyl 3-(((R)-tert-butylsulfinyl)amino)-3-ethylhept-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 Intermediate 2-6 [ka]

[0563] Methyl 3-(((R)-tert-butylsulfinyl)amino)-3-ethylhept-6-enoate (INT2-5) (12 g, 41.5 mmol) was separated on an SFC column, DAICEL CHIRALPAK AD (250 mm × 50 mm, 10 μm), conditions: 0.1% NH3H2O, IPA, start B 15, end B 15, gradient time (min), 100% B, hold time (min), flow rate (mL / min) 200, injection 200) and a column, DAICEL CHIRALPAK AD (250 mm × 50 mm, 10 μm), conditions: 0.1% NH3H2O, IPA, start B 12, end B 12, gradient time (min), 100% B, hold time (min), flow rate (mL / min) 200, injection 240), to obtain methyl 3-(((R)-tert-butylsulfinyl)amino)-3-ethylhept-6-enoate (INT2-5) (12 g, 41.5 mmol) (R)-3-(((R)-tert-butylsulfinyl)amino)-3-ethylhept-6-enoate (INT2-6_P1, desired) (tR = 1.978 min, UV = 220 nm) and methyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-ethylhept-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 Intermediate 2-7 [ka]

[0565] A solution of methyl (R)-3-(((R)-tert-butylsulfinyl)amino)-3-ethylhept-6-enoate (INT2-6_P1) (20 g, 69.1 mmol) in HCl-dioxane (4 N) (100 mL) and MeOH (200 mL) was stirred at 25 °C for 2 h. LCMS showed the reaction was complete. The solvent was evaporated under reduced pressure to give the product, methyl (R)-3-amino-3-ethylhept-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 Intermediate 2-8

change

[0567] To a solution of DMB-BOC-thiourea (5 g, 15.32 mmol), methyl (R)-3-amino-3-ethylhept-6-enoate hydrochloride (INT2-7) (3.74 g, 16.85 mmol), and EDC (7.34 g, 38.3 mmol) in acetonitrile (100 mL) was added DIEA (12.04 mL, 68.9 mmol). The reaction was stirred at 15 °C under a N atmosphere for 12 h. LCMS showed the desired mass and some ring-opened by-product ester. The mixture was then warmed to 50 °C and stirred at 50 °C for 2 h. LCMS showed only the mass of the desired product. The mixture was concentrated under reduced pressure. The crude material was dissolved in EtOAc (100 mL) and water (100 mL), and the layers were separated. The aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The crude material was purified by flash column (ISCO®; 80 g Agela Silica Flash Column, eluent 15% ethyl acetate / petroleum ether gradient @ 30 mL / min) to give tert-butyl (R,E)-(4-(but-3-en-1-yl)-1-(2,4-dimethoxybenzyl)-4-ethyl-6-oxotetrahydropyrimidin-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 Intermediate 2-9 [ka]

[0569] A solution of tert-butyl (R,E)-(4-(but-3-en-1-yl)-1-(2,4-dimethoxybenzyl)-4-ethyl-6-oxotetrahydropyrimidin-2(1H)-ylidene)carbamate (INT2-8) (1.0 g, 2.244 mmol) in TFA (10 mL) was stirred at 60 °C for 16 h. LCMS showed the desired mass. The mixture was concentrated under reduced pressure. The residue was partitioned between petroleum ether / EtOAc (v / v = 4:1, 10 mL) and water (10 mL). LCMS showed that the product was present only in the aqueous phase and was fairly pure. (R)-6-(but-3-en-1-yl)-6-ethyl-2-iminotetrahydropyrimidin-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] To a solution of (R)-6-(but-3-en-1-yl)-6-ethyl-2-iminotetrahydropyrimidin-4(1H)-one (INT2-9) (438 mg, 2.243 mmol) in water (10 mL) and THF (3 mL) was added NaHCO (942 mg, 11.22 mmol) and (BOC)O (1.042 mL, 4.49 mmol) in small portions at 0 °C. The reaction was stirred at 25 °C for 16 h. LCMS showed the desired mass. The mixture was extracted with EtOAc (3 × 10 mL). The organic layer was washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The crude material 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 give tert-butyl (R,E)-(4-(but-3-en-1-yl)-4-ethyl-6-oxotetrahydropyrimidin-2(1H)-ylidene)carbamate (Intermediate 2).

[0572] MS (ESI) m / z 296.2 (M+H) + 1 H 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]hentriaconta-10,12,19,21,26,28-hexaene-18,31-dione Preparation of Compound 1-2 [ka]

[0574] Trifluoromethanesulfonic acid (503 mg, 3.35 mmol) and N-bromosuccinimide (596 mg, 3.35 mmol) were added to a solution of (1R,2R)-1-amino-2,3-dihydro-1H-inden-2-ol (1-1) (500 mg, 3.35 mmol) in DCM (10 mL) at 0° C. The reaction was stirred at 18° C. under a N atmosphere for 1 h. The mixture was quenched with saturated sodium bicarbonate solution (10 mL) at 0° C. and extracted with DCM (1×10 mL) followed by EtOAc (3×10 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, concentrated under reduced pressure, and the crude was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, eluent 10% MeOH / DCM (with 1% ammonium hydroxide) gradient @ 50 mL / min) to give (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] To a solution of (R)-4-((R,E)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxo-4-(pent-4-en-1-yl)tetrahydropyrimidin-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]triazol-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) in THF (5 mL) was added DIEA (0.276 mL, 1.582 mmol). The reaction was stirred at 18 °C for 2 h. The mixture was quenched with water (5 mL) and extracted with EtOAc (3 × 5 mL). The organic layer was washed with brine (5 mL), dried over NaSO, filtered, concentrated under reduced pressure, and the crude was purified by prep-TLC (petroleum ether / EtOAc = 1:1) to give tert-butyl ((R,E)-1-((R)-6-(((1R,2R)-6-bromo-2-hydroxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)chroman-4-yl)-4-ethyl-6-oxo-4-(pent-4-en-1-yl)tetrahydropyrimidin-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 of tert-butyl ((R,E)-1-((R)-6-((1R,2R)-6-bromo-2-hydroxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)chroman-4-yl)-4-ethyl-6-oxo-4-(pent-4-en-1-yl)tetrahydropyrimidin-2(1H)-ylidene)carbamate (1-3) (100 mg, 0.144 mmol) in dioxane (1.5 mL) was added 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) in a glove box at 25 °C. The reaction was stirred for 16 h at 70° C. The mixture was quenched with water (3 mL) and extracted with EtOAc (3×5 mL).The organic layer was washed with brine (5 mL), dried over Na2SO4, filtered, concentrated under reduced pressure, and the crude was purified by reverse preparative HPLC (Instrument ED; Method Column Boston Prime C18 150 x 30 mm, 5 um; 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 give: 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-(epiethan[1,2]diylidene)-8,5-(epiminomethano)-14,16-ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclononadecin-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-(epiethan[1,2]diylidene)-8,5-(epiminomethano)-14,16-ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclononadecin-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-(epiethan[1,2]diylidene)-8,5-(epiminomethano)-13,15-ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclooctadecin-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 [Chemical formula]

[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-(epiethan[1,2]diylidene)-8,5-(epiminomethano)-13,15-ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclooctadecin-27-ylidene)carbamate (1-4C) (10 mg, 0.016 mmol) in MeOH (2 mL) was added Pd-C (1.731 mg, 3.25 μmol) under a N atmosphere. The mixture was degassed and backfilled with H (3 times). The resulting mixture was stirred under H (15 psi) at 25 °C for 12 h. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give 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-(epiethan[1,2]diylidene)-8,5-(epiminomethano)-13,15-ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclooctadecin-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-(epiethan[1,2]diylidene)-8,5-(epiminomethano)-13,15-ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclooctadecin-27-ylidene)carbamate (1-5) (8 mg, 0.013 mmol) in DCM (3 mL) was added zinc(II) bromide (29.2 mg, 0.130 mmol) at 22 °C under a N atmosphere. The mixture was stirred at 22°C for 16 hours. The mixture was cooled, and the solvent was evaporated under reduced pressure to give the crude product. The residue was purified by reverse preparative HPLC (Instrument EJ Method Column Boston Green ODS 150 x 30 mm, 5 µm 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 give 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-(epiethan[1,2]diylidene)-8,5-(epiminomethano)-14,16-ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclononadecin-28-ylidene)carbamate (2-1) (13 mg, 0.021 mmol) in MeOH (4 mL) was added Pd—C (2.250 mg, 4.23 μmol) under a N atmosphere. The mixture was degassed and backfilled with H (3 times). The resulting mixture was stirred under H (15 psi) at 20 °C for 2 h. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give 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-(epiethan[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-(epiethan[1,2]diylidene)-8,5-(epiminomethano)-14,16-ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclononadecin-28-ylidene)carbamate (2-1) (13 mg, 0.021 mmol) in DCM (3 mL) was added zinc(II) bromide (47.5 mg, 0.211 mmol) under a N atmosphere. The mixture was stirred at 22 °C for 16 h. The mixture was concentrated under reduced pressure to give the crude product, and the residue was purified by reverse preparative HPLC (EJ; Column: Boston Green ODS 150×30 mm, 5 μm; 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) gave (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-(epiethan[1,2]diylidene)-8,5-(epiminomethano)-14,16-ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclononadecyne-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] To a solution of pent-4-enoic acid (40 g, 400 mmol), EDC (92 g, 479 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (3-1) (64.8 g, 479 mmol), and N-ethyl-N-isopropylpropan-2-amine (279 mL, 1598 mmol) in DCM (400 mL) was added N,O-dimethylhydroxylamine hydrochloride (54.6 g, 559 mmol). The reaction was stirred at 25 °C under a N atmosphere for 12 h. The mixture was quenched with water (300 mL) and extracted with DCM (3 × 100 mL). The organic layer was washed with brine (100 mL), dried over NaSO, filtered, concentrated under reduced pressure, and the crude 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 give N-methoxy-N-methylpent-4-enamide (3-2).

[0591] MS (ESI) m / z 144.1 (M+H + ) 1 H 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] To a solution of N-methoxy-N-methylpent-4-enamide (3-2) (20 g, 140 mmol) in THF (200 mL) was added ethylmagnesium bromide (69.8 mL, 210 mmol) dropwise at 0 °C under a N atmosphere. The reaction was stirred at 25 °C for 1 h under a N atmosphere. The mixture was quenched with saturated aqueous NH Cl (100 mL) and water (100 mL) and extracted with EtOAc (3 × 100 mL). The organic layer was washed with brine (50 mL), dried over Na SO , filtered, and concentrated under reduced pressure, and the crude material 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 give hept-6-en-3-one (3-3).

[0593] 1 H 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 Compound 3-4 [ka]

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

[0595] MS (ESI) m / z 216.2(M+H + ) 1 H 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] To a solution of diisopropylamine (19.64 mL, 139 mmol) in anhydrous THF (40 mL) was added butyllithium (55.7 mL, 139 mmol) dropwise under a N atmosphere at −78 °C. The reaction was stirred at 0 °C for 30 min to form LDA. The resulting 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 h, a solution of (R,E)-N-(hept-6-en-3-ylidene)-2-methylpropane-2-sulfinamide (3-4) (10 g, 46.4 mmol) in anhydrous THF (20 mL) was added dropwise, and the mixture was stirred at −78 °C for 3 h. The mixture was quenched with ice-cold, half-saturated aqueous ammonium chloride (60 mL). The slurry was diluted with EtOAc (200 mL), filtered, and rinsed with EtOAc and water. The organic layer was washed with brine (50 mL), dried over NaSO, 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 give methyl 3-(((R)-tert-butylsulfinyl)amino)-3-ethylhept-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-ethylhept-6-enoate (3-5) (9 g, 31.1 mmol) in 4 N HCl-dioxane (20 mL) and MeOH (20.00 mL) was stirred at 25 °C for 1 h under a N atmosphere. The solvent was evaporated under reduced pressure to give the crude product, methyl 3-amino-3-ethylhept-6-enoate hydrochloride (3-6), which was used directly crude in the next step.

[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] To a solution of EDC (9.08 g, 47.4 mmol), methyl 3-amino-3-ethylhept-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) in ACN (30 mL) was added N-ethyl-N-isopropylpropan-2-amine (13.79 mL, 79 mmol). The reaction was stirred at 25 °C under a N atmosphere for 12 h. The mixture was quenched with water (50 mL) and extracted with EtOAc (3 × 50 mL). The organic layer was washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give methyl (4R)-4-((Z)-2-(tert-butoxycarbonyl)-3-(3-ethyl-1-methoxy-1-oxohept-6-en-3-yl)guanidino)chroman-6-carboxylate (3-7), which was used directly crude in the next step.

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

[0602] To a solution of methyl (4R)-4-((Z)-2-(tert-butoxycarbonyl)-3-(3-ethyl-1-methoxy-1-oxohept-6-en-3-yl)guanidino)chroman-6-carboxylate (3-7) (8.17 g, 15.78 mmol) in THF (50 mL) was added DBU (11.90 mL, 79 mmol). The mixture was stirred at 50 °C under a N atmosphere for 16 h. The mixture was quenched with water (50 mL) and extracted with EtOAc (3 × 50 mL). The organic layer was washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The crude material 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 give methyl (4R)-4-((E)-4-(but-3-en-1-yl)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydropyrimidin-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 Compounds 3-9A and 3-9B [ka]

[0604] Methyl (4R)-4-((E)-4-(but-3-en-1-yl)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydropyrimidine-1(2H)-yl)chroman-6-carboxylate (3-8) (4 g, 8.24 mmol) was separated by SFC (Column Boston Green ODS 150 x 30 mm, 5 μm, 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) to obtain (P1) methyl (4R)-4-((E)-4-(but-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 = 220 nm) and (P2) methyl (4R)-4-((E)-4-(but-3-en-1-yl)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydropyrimidin-1(2H)-yl)chroman-6-carboxylate (3-9B) (t R = 2.251 min, UV = 220 nm).

[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-(but-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) in THF (5 mL) was added potassium trimethylsilanolate (872 mg, 6.80 mmol). The reaction was stirred at 25 °C for 0.5 h. The solution of (R)-4-((R,E)-4-(but-3-en-1-yl)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydropyrimidin-1(2H)-yl)chroman-6-carboxylic acid (3-10) was used directly in the next step without further manipulation or purification.

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

[0608] To a solution of (R)-4-((R,E)-4-(but-3-en-1-yl)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydropyrimidin-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]triazol-1-ol (765 mg, 5.66 mmol), and (S)-2,2-dimethyl-6-vinylchroman-4-amine (253 mg, 1.246 mmol) in THF (50 mL) was added DIEA (1.582 mL, 9.06 mmol). The reaction was stirred at 25 °C for 12 h. The mixture was quenched with water (20 mL) and extracted with EtOAc (3 × 20 mL). The organic layer was washed with brine (15 mL), dried over NaSO, filtered, concentrated under reduced pressure, and the crude was purified by prep-TLC (petroleum ether / EtOAc = 2:1) to give tert-butyl ((R,E)-4-(but-3-en-1-yl)-1-((R)-6-(((S)-2,2-dimethyl-6-vinylchroman-4-yl)carbamoyl)chroman-4-yl)-4-ethyl-6-oxotetrahydropyrimidin-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-(but-3-en-1-yl)-1-((R)-6-(((S)-2,2-dimethyl-6-vinylchroman-4-yl)carbamoyl)chroman-4-yl)-4-ethyl-6-oxotetrahydropyrimidin-2(1H)-ylidene)carbamate (3-11) (500 mg, 0.761 mmol) in DCE (500 mL) was added (1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)ruthenium (95 mg, 0.152 mmol). The reaction was stirred at 50 °C under a N atmosphere for 5 h. The mixture was concentrated under reduced pressure, and the crude was purified by flash column (petroleum ether / EtOAc / EtOH=8:3:1) to give 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-diethenodipyrano[4,3-b:4′,3′-h][1,7]diazacyclooctadecin-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 Compounds 3-13

Chem.

[0612] To a solution 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-diethenodipyrano[4,3-b:4',3'-h][1,7]diazacyclooctadecin-28-ylidene)carbamate (3-12) (300 mg, 0.477 mmol) in MeOH (10 mL) was added Pd-C (50.8 mg, 0.048 mmol) under N atmosphere. The mixture was degassed and backfilled with H (3 times). The resulting mixture was stirred under H (15 psi) at 25 °C for 0.5 h. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give 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-diethenodipyrano[4,3-b:4',3'-h][1,7]diazacyclooctadecin-28-ylidene)carbamate (3-13), which 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-diethenodipyrano[4,3-b:4',3'-h][1,7]diazacyclooctadecin-28-ylidene)carbamate (3-13) (280 mg, 0.444 mmol) in HCl-dioxane (4N) (30 mL) was stirred at 25 °C for 16 h. The solvent was evaporated under reduced pressure to give the crude product. The residue was purified by reverse preparative HPLC (Boston Green ODS Column 150 × 30 mm, 5 μm, 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 give (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-diethenodipyrano[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] To a solution of hex-5-enoic acid (4-1) (8 g, 70.1 mmol), EDC (20.15 g, 105 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (14.21 g, 105 mmol), and N,O-dimethylhydroxylamine hydrochloride (7.52 g, 77 mmol) in THF (100 mL) was added DIEA (36.7 mL, 210 mmol). The reaction was stirred at 25 °C for 5 h. The mixture was quenched with water (150 mL) and extracted with EtOAc (3 × 50 mL). The organic layer was washed with brine (50 mL), dried over NaSO, 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% EtOAc / petroleum ether gradient @ 80 mL / min) to give N-methoxy-N-methylhex-5-enamide (4-2).

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

[0619] To a solution of N-methoxy-N-methylhex-5-enamide (4-2) (9 g, 57.2 mmol) in THF (120 mL) was added ethylmagnesium bromide (38.2 mL, 114 mmol) dropwise at 0 °C under a N atmosphere. The mixture was then stirred at 20 °C for 2 h. The mixture was quenched with saturated aqueous NH Cl (25 mL). The mixture was quenched with water (150 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (80 mL), dried over Na SO , and filtered. The solvent was evaporated under reduced pressure to give the crude product. This was purified by column chromatography (SiO, petroleum ether: EtOAc = 100:1 to 10:1) to give oct-7-en-3-one (4-3).

[0620] 1 H 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 oct-7-en-3-one (4-3) (5.5 g, 43.6 mmol) in THF (80 mL) was added 2-methylpropane-2-sulfinamide (6.34 g, 52.3 mmol), followed by Ti(EtO) (18.31 mL, 87 mmol). The reaction was stirred at 75 °C for 16 h under a N atmosphere. The final mixture was cooled to 0 °C, diluted with DCM (100 mL), and stirred for 15 min. Ice-cold saturated aqueous sodium bicarbonate (15 mL) was added, and the solution was filtered and concentrated under reduced pressure. The crude material was purified by flash column (SiO, petroleum ether / EtOAc = 100:1 to 5:1) to give (E)-2-methyl-N-(oct-7-en-3-ylidene)propane-2-sulfinamide (4-4).

[0622] MS (ESI) m / z 230.2 (M+H + ) 1 H 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) in anhydrous THF (35 mL) was added methyl acetate (1.545 mL, 19.18 mmol) under a N atmosphere at −78 °C. The reaction was stirred at −78 °C for 15 min. Then, (E)-2-methyl-N-(oct-7-en-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 h. The mixture was quenched with ice-cold half-saturated aqueous ammonium chloride solution (30 mL). The slurry was diluted with EtOAc (50 mL), filtered, and rinsed with EtOAc and water. The organic layer was washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column (SiO 2 , petroleum ether / EtOAc=100:0→10:1) to give methyl 3-((tert-butylsulfinyl)amino)-3-ethyloct-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] A solution of methyl 3-((tert-butylsulfinyl)amino)-3-ethyloct-7-enoate (4-5) (2 g, 6.59 mmol) in HCl-dioxane (4N) (5 mL) and MeOH (5 mL) at 15 °C was stirred under a N atmosphere at 15 °C for 1 h. The solution was concentrated under reduced pressure to give the crude product, methyl 3-amino-3-ethyloct-7-enoate hydrochloride (4-6), which was used without further purification.

[0626] 1 H 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] To a solution of methyl (R)-4-(3-(tert-butoxycarbonyl)thioureido)chroman-6-carboxylate (INT-1) (1.5 g, 4.09 mmol), methyl 3-amino-3-ethyloct-7-enoate hydrochloride (4-6) (1.448 g, 6.14 mmol), and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (2.354 g, 12.28 mmol) in acetonitrile (30 mL) was added N-ethyl-N-isopropylpropan-2-amine (4.37 mL, 24.56 mmol). The mixture was stirred at 15 °C for 10 h. The mixture was quenched with water (50 mL) and extracted with EtOAc (3 × 40 mL). The organic layer was washed with brine (20 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give methyl (4R)-4-((Z)-2-(tert-butoxycarbonyl)-3-(3-ethyl-1-methoxy-1-oxooct-7-en-3-yl)guanidino)chroman-6-carboxylate (4-7), which was used directly crude in the next step.

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

[0629] To a solution of methyl (4R)-4-((Z)-2-(tert-butoxycarbonyl))-3-(3-ethyl-1-methoxy-1-oxooct-7-en-3-yl)guanidino)chroman-6-carboxylate (4-7) (2.0 g, 3.76 mmol) in THF (20 mL) was added DBU (2.84 mL, 18.81 mmol). The mixture was stirred at 50 °C for 10 h. The mixture was quenched with water (40 mL) and extracted with EtOAc (3 × 40 mL). The organic layer was washed with brine (20 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The crude material was purified by flash silica gel chromatography (ISCO®; 20 g Agela Silica Flash Column, eluent 15% ethyl acetate / petroleum ether gradient @ 60 mL) to give methyl (4R)-4-((E)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxo-4-(pent-4-en-1-yl)tetrahydropyrimidin-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-(pent-4-en-1-yl)tetrahydropyrimidine-1(2H)-yl)chroman-6-carboxylate (4-8) (1.8 g, 3.60 mmol) was separated by SFC (Instrument: SFC-22 Method; Column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); Conditions: 0.1% NH3H2O, IPA; Start: 10% B; End: 10% B; Gradient Time (min); 100% B; Retention Time (min); Flow Rate (mL / min): 50; Injection: 60). (R)-4-((R,E)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxo-4-(pent-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-(pent-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] To a solution of methyl (R)-4-((R,E)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxo-4-(pent-4-en-1-yl)tetrahydropyrimidin-1(2H)-yl)chroman-6-carboxylate (4-9A) (100 mg, 0.200 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was added 2,6-dimethylpyridine (42.9 mg, 0.400 mmol) and osmium(VIII) oxide (5.09 mg, 0.020 mmol). The resulting solution was stirred at 25 °C for 0.2 h. Sodium periodate (171 mg, 0.801 mmol) was added, and the resulting solution was stirred at 25 °C for 2 h. The mixture was quenched with saturated NaSO (10 mL) and water (5 mL) and extracted with EtOAc (3 × 10 mL). The organic layer was washed with brine (5 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give 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), which was used crude directly in the next step.

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

[0635] To a solution of 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) in MeOH (2 mL) at 0 °C, NaBH (10.75 mg, 0.284 mmol) was added portionwise. The mixture was stirred at 0 °C for 1 h. LCMS showed the major mass of desired product. The mixture was quenched with water (5 mL) and extracted with EtOAc (4 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The crude was purified by prep-TLC (petroleum ether / EtOAc=3:1) to give 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] To a solution of methyl (R)-4-((R,E)-2-((tert-butoxycarbonyl)imino)-4-ethyl-4-(4-hydroxybutyl)-6-oxotetrahydropyrimidin-1(2H)-yl)chroman-6-carboxylate (4-11) (53 mg, 0.105 mmol) in THF (1 mL) was added potassium trimethylsilanolate (81 mg, 0.631 mmol). The reaction was stirred at 25 °C for 0.5 h. LCMS showed the major mass of desired product. The solution of (R)-4-((R,E)-2-((tert-butoxycarbonyl)imino)-4-ethyl-4-(4-hydroxybutyl)-6-oxotetrahydropyrimidin-1(2H)-yl)chroman-6-carboxylic acid (4-12) was used in the next step without further manipulation or purification.

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

[0639] To a solution of (R)-4-((R,E)-2-((tert-butoxycarbonyl)imino)-4-ethyl-4-(4-hydroxybutyl)-6-oxotetrahydropyrimidin-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]triazol-1-ol (69.0 mg, 0.511 mmol), and (S)-6-bromo-2,2-dimethylchroman-4-amine (28.8 mg, 0.112 mmol) in THF (5 mL) was added DIEA (0.143 mL, 0.817 mmol). The reaction was stirred at 25 °C for 3 h. The mixture was quenched with water (5 mL) and extracted with EtOAc (3 × 5 mL). The organic layer was washed with brine (5 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The crude was purified by prep-TLC (petroleum ether / EtOAc = 3:1) to give 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-oxotetrahydropyrimidin-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, to 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-oxotetrahydropyrimidin-2(1H)-ylidene)carbamate (4-13) (70 mg, 0.096 mmol) in dioxane (3 mL) was added [(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 CsCO (37.1 mg, 0.192 mmol). The mixture was stirred at 70 °C for 3 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (3×10 mL), and the organic layer was washed with brine (5 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude was purified by prep-TLC (petroleum ether / EtOAc = 2:1) to give 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-(epiethan[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

Chem.

[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-(epiethan[1,2]diylidene)-8,5-(epiminomethano)-14,16-ethenodipyrano[3,4-d:3',4'-j][1] in DCM (3 mL) under a N atmosphere at 25 °C was added zinc(II) bromide (104 mg, 0.464 mmol) and oxa[6,12]diazacyclononadecin-29-ylidene)carbamate (4-14) (30 mg, 0.046 mmol). The mixture was stirred at 25° C. for 16 hours. The solvent was evaporated under reduced pressure to give the crude product. The residue was purified by reverse preparative HPLC (instrument, e.g., Method Column Welch Xtimate C18 150×25 mm, 5 μm; 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) gave (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-(epiethan[1,2]diylidene)-8,5-(epiminomethano)-14,16-ethenodipyrano[3,4-d:3',4'-j][1]oxa[6,12]diazacyclononadecyne-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 [[ID=1,6]]

Chem.

[0646] A solution of 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 to 130 °C for 16 h using a Dean-Stark apparatus. TLC indicated 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 combined organic layers were washed with brine (300 mL), dried over NaSO, filtered, and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, eluent 10% EtOAc / petroleum ether gradient @ 60 mL / min) to give 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 H 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) in anhydrous CHCl (700 mL) was cooled to −70 °C in a dry ice-acetone bath. Under N, pyridine hydrofluoride (57.4 mL, 226 mmol) was added dropwise at a temperature below −65 °C, and the mixture was stirred at −70 °C for 30 min. A solution of 5-bromo-2,3-dihydrospiro[indene-1,2′-[1,3]dithiolane] (5-2) (65 g, 226 mmol) in CHCl (200 mL) was added dropwise, and the mixture was stirred at −70 °C for 4 h and then at 25 °C overnight. TLC indicated the reaction was complete. The mixture was poured into 39% NaHSO (600 mL) in 2 M NaOH (300 mL). The aqueous layer was extracted with CHCl (2 × 600 mL), and the combined organic layers were washed with brine (300 mL), dried over NaSO, filtered, and the solvent was evaporated under reduced pressure to give the crude product, which was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, eluent 100% petroleum ether gradient @ 60 mL / min) to give 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] To a solution of 2,5-dibromo-1,1-difluoro-2,3-dihydro-1H-indene (5-3) (60 g, 192 mmol) in DCM (600 mL) was added DBU (43.5 mL, 289 mmol). The mixture was stirred at 25 °C for 16 h. LCMS 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 CHCl (2 × 600 mL), and the combined organic layers were washed with brine (300 mL), dried over NaSO, filtered, and the solvent was evaporated under reduced pressure to give 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 give 5-bromo-1,1-difluoro-1H-indene (5-4).

[0652] No LCMS signal.

[0653] 1 H 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] To a solution of 5-bromo-1,1-difluoro-1H-indene (5-4) (15 g, 64.9 mmol) in iPrOH (250 mL) that had been bubbled with O for 1 h, phenylsilane (14.05 g, 130 mmol) and Mn(TMHD) (3.93 g, 6.49 mmol) were added and stirred at 0 °C under O (15 psi) for 2 h. TLC showed the reaction was complete. The mixture was quenched with water (300 mL) and extracted with EtOAc (3 × 300 mL). The organic layer was washed with brine (300 mL), dried over NaSO, filtered, and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, eluent 17% EtOAc / petroleum ether gradient @ 50 mL / min) to give 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 H 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] To a solution 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) (5:5:5a = 7:2) in MeOH (150 mL) and DMSO (15 mL) was added [1,1'-bis(diphenylphospino)ferrocene]dichloropalladium(II) (2.64 g, 3.61 mmol) and triethylamine (15.67 mL, 108 mmol) under Ar at 20 °C, and the mixture was stirred at 80 °C under CO atmosphere (3.5 mbar) for 48 h. TLC showed the reaction was complete. After cooling, the mixture was filtered through diatomaceous earth, diluted with HO (200 mL), extracted with EtOAc (3 × 200 mL), dried over NaSO, filtered, and the solvent was evaporated under reduced pressure to give the crude product, which was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, eluent 17% EtOAc / petroleum ether gradient @ 80 mL / min) to give 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 H 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 (8.3 g, 36.36 mmol) (5:6:27:6a = 3:1) was separated by SFC (column: Chiralpak AD-3 150 × 4.6 mm ID, 3 μm, mobile phase: A:CO₂, B: isopropanol (0.05% DEA), gradient: 5% B → 40% B in 5 min, 40% B → 5% B in 0.5 min, then hold at 5% B for 1.5 min, flow rate: 2.5 mL / min, column temperature: 35 °C) to give the product methyl (S)-1,1-Difluoro-3-hydroxy-2,3-dihydro-1H-indene-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 =2.944) and a mixture of (5-7_P2 and 5-6a) (2 g, 8.77 mmol) was obtained. The mixture of (5-7_P2 and 5-6a) was separated by SFC (column: Cellulose 2 150 × 4.6 mm ID, 5 μm, mobile phase: A:CO₂B:MeOH (0.05% DEA) gradient: 5% B → 40% B over 5 min, 40% B → 5% B over 0.5 min, then hold at 5% B for 1.5 min, column temperature: 35 °C) to give methyl 1,1-difluoro-2-hydroxy-2,3-dihydro-1H-indene-5-carboxylate (5-6a).

[0659] (5-7_P1): 1 H 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] To a solution of 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-(but-3-en-1-yl)-4-ethyl-6-oxotetrahydropyrimidin-2(1H)-ylidene)carbamate (INT-2) (757 mg, 2.56 mmol), and Ph3P (1009 mg, 3.85 mmol) in THF (10 mL) was added dropwise DIAD (0.997 mL, 5.13 mmol) under a N2 atmosphere at 0 °C, and the mixture was then stirred at 18 °C for 2 h. TLC showed no 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% EtOAc / petroleum ether gradient @ 60 mL / min) to give the crude product. The crude product was purified again by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, eluent DCM gradient @ 60 mL / min) to give the product methyl (R)-3-((R,E)-4-(but-3-en-1-yl)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydropyrimidin-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] To a solution of methyl (R)-3-((R,E)-4-(but-3-en-1-yl)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydropyrimidin-1(2H)-yl)-1,1-difluoro-2,3-dihydro-1H-indene-5-carboxylate (5-8) (900 mg, 1.780 mmol) in THF (9 mL) was added potassium trimethylsilanolate (1370 mg, 10.68 mmol). The reaction was stirred at 18 °C for 0.5 h. LCMS showed the desired mass. The pH was adjusted to approximately 6-7 by the addition of H3PO4 (0.1 g / mL in HO), and the mixture was quenched with water (10 mL) and extracted with EtOAc (3 × 10 mL). The organic layer was washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the product (R)-3-((R,E)-4-(but-3-en-1-yl)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydropyrimidin-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] To a solution of (R)-3-((R,E)-4-(but-3-en-1-yl)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydropyrimidin-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]triazol-1-ol (0.718 g, 5.31 mmol) in THF (15 mL) was added DIEA (2.473 mL, 14.16 mmol) and (S)-2,2-dimethyl-6-vinylchroman-4-amine (0.396 g, 1.947 mmol). The reaction was stirred at 18° C. for 12 hours. LCMS showed the desired mass. The mixture was quenched with water (15 mL) and extracted with EtOAc (3×15 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, eluent 17% EtOAc / petroleum ether gradient @ 60 mL / min) to give the product tert-butyl ((R,E)-4-(but-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-oxotetrahydropyrimidin-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] To a solution of tert-butyl ((R,E)-4-(but-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-oxotetrahydropyrimidin-2(1H)-ylidene)carbamate (5-10) (1 g, 1.478 mmol) in DCE (500 mL) was added dichloro[1,3-bis(2,6-isopropylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II) (0.105 g, 0.148 mmol). The reaction was stirred at 50 °C under N for 4 h. LCMS showed the desired mass. The mixture was concentrated under reduced pressure, and the crude material was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, eluent 15% EtOAc / petroleum ether gradient @ 60 mL / min) to give 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]diazacyclooctadecin-24-ylidene)carbamate (5-11a, cis olefin; The trans olefin (5-11, trans olefin; minor 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]diazacyclooctadecin-24-ylidene)carbamate (5-11, trans olefin; major product) were obtained.

[0667] (5-11a, cis olefin): 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, trans olefin): 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-diethenocyclopenta[b]pyrano[4,3-h][1,7]diazacyclooctadecin-24-ylidene)carbamate (5-11) (780 mg, 1.202 mmol) in MeOH (10 mL) was added 10% Pd-C (128 mg, 0.120 mmol) under a N atmosphere. The mixture was degassed and backfilled with H (3 times). The resulting mixture was stirred under an atmosphere of H (15 psi) at 18 °C for 10 min. LCMS indicated the reaction was complete. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give 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]diazacyclooctadecin-24-ylidene)carbamate (5-12). This was used directly in the next step.

[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]diazacyclooctadecin-24-ylidene)carbamate (5-12) (700 mg, 1.076 mmol) in HCl-dioxane (4N) (10 mL) was stirred at 18 °C for 12 h. LCMS showed the reaction was complete. The solvent was evaporated under reduced pressure to give 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) gave (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 in a manner similar to that described for Example 1 and / or Example 5. Isomers were separated by preparative HPLC or / and preparative chiral SFC.

[0672] An asterisk (*) may be used in chemical structure diagrams to indicate the location of a chiral center. [Table 2] TIFF2024545498000181.tif191166TIFF2024545498000182.tif210166TIFF2024545498000183.tif197166TIFF2024545498000184.tif210166TIFF2024545498000185.tif204166TIFF2024545498000186.tif198167TIFF2024545498000187.tif197166TIFF2024545498000188.tif216167TIFF2024545498000189.tif198169TIFF2024545498000190.tif248168TIFF2024545498000191.tif248169TIFF2024545498000192.tif191170TIFF2024545498000193.tif191168TIFF2024545498000194.tif199168TIFF2024545498000195.tif198168TIFF2024545498000196.tif246169TIFF2024545498000197.tif247169TIFF2024545498000198.tif190169TIFF2024545498000199.tif191168TIFF2024545498000200.tif192168TIFF2024545498000201.tif186168TIFF2024545498000202.tif198169TIFF2024545498000203.tif198168TIFF2024545498000204.tif210169TIFF2024545498000205.tif203170TIFF2024545498000206.tif211169TIFF2024545498000207.tif204169TIFF2024545498000208.tif204169TIFF2024545498000209.tif185170TIFF2024545498000210.tif211169TIFF2024545498000211.tif217168TIFF2024545498000212.tif210169TIFF2024545498000213.tif209169TIFF2024545498000214.tif210170TIFF2024545498000215.tif190168TIFF2024545498000216.tif191169TIFF2024545498000217.tif198168TIFF2024545498000218.tif190168TIFF2024545498000219.tif197169TIFF2024545498000220.tif197168TIFF2024545498000221.tif210168TIFF2024545498000222.tif204168TIFF2024545498000223.tif210168TIFF2024545498000224.tif211168TIFF2024545498000225.tif198169TIFF2024545498000226.tif199168TIFF2024545498000227.tif209169TIFF2024545498000228.tif217169TIFF2024545498000229.tif210168TIFF2024545498000230.tif217168TIFF2024545498000231.tif211169TIFF2024545498000232.tif211169TIFF2024545498000233.tif209167TIFF2024545498000234.tif193168TIFF2024545498000235.tif198169TIFF2024545498000236.tif203168TIFF2024545498000237.tif197168TIFF2024545498000238.tif210168TIFF2024545498000239.tif199168TIFF2024545498000240.tif211169TIFF2024545498000241.tif209168TIFF2024545498000242.tif210169TIFF2024545498000243.tif210168TIFF2024545498000244.tif210168TIFF2024545498000245.tif217168TIFF2024545498000246.tif237168TIFF2024545498000247.tif222170TIFF2024545498000248.tif223169TIFF2024545498000249.tif20916 8TIFF2024545498000250.tif211168TIFF2024545498000251.tif217168TIFF2024545498000252.tif210170TIFF2024 545498000253.tif197169TIFF2024545498000254.tif223169TIFF2024545498000255.tif198169TIFF202454549800 0256.tif229168TIFF2024545498000257.tif210169TIFF2024545498000258.tif223168TIFF2024545498000259.tif2 22169TIFF2024545498000260.tif235169TIFF2024545498000261.tif216169TIFF2024545498000262.tif209169TIF F2024545498000263.tif211168TIFF2024545498000264.tif230169TIFF2024545498000265.tif223169TIFF20245454 98000266.tif224169TIFF2024545498000267.tif223169TIFF2024545498000268.tif224170TIFF2024545498000269. tif216169TIFF2024545498000270.tif224168TIFF2024545498000271.tif223169TIFF2024545498000272.tif79168.

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

[0674] Approximately 42 hours before setting up the potency assay, parasites were synchronized with 5% sorbitol to select for ring-stage parasites. On the day of assay setup, blood smears of parasite cultures were Giemsa stained and counted. Parasitemia was adjusted to 0.7% rings, and the hematocrit was diluted to 2% in RPMI-Hepes medium (buffered with sodium bicarbonate and supplemented with 5% heat-inactivated human serum and 0.5% albumin). 30 μL of diluted parasites were then added to 10 μL of medium + compound in a pre-prepared Greiner TC assay plate. The parasite assay plate was placed in a single layer 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 at -80°C overnight. The next day, the assay plates are thawed at room temperature for 4 hours and an LDH assay is performed on them to measure parasite growth.

[0675] Assay EC 50 The results are shown in Table 2. [Table 3] TIFF2024545498000274.tif248133TIFF2024545498000275.tif249134TIFF2024545498000276.tif248133TIFF2024545498 000277.tif249134TIFF2024545498000278.tif248132TIFF2024545498000279.tif248132TIFF2024545498000280.tif99131

Claims

1. Structural formula (I): [Formula 1] [During the ceremony, A is at least one -CH ２ -group-containing linear or branched, saturated or unsaturated (C ３ -C １０ ) alkylene, phenyl (C ３ -C １０ ) alkylene or cycloalkyl (C ３ -C １０ ) alkylene, where A is one or more additional —CH ２ The - groups are independently O, S, NR, CONR, NRCO, SO ２ and S.O. ２ and wherein one or more of the hydrogens along A are replaced with a moiety selected from the group consisting of hydroxyl, halogen, and C. １－３ may be substituted with a group independently selected from haloalkyl; X is a bond, C(R １４ ) ２ ,O,S,SO,SO ２ or NH; Y is CR ９ or N, where when Y is N, Z is CR １１ and V is CR １０ and V is CR １０ or N, where when V is N, Z is CR １１ and Y is CR ９ and Z is CR １１ or N, where when Z is N, 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, haloC １ -C ６ Alkyl, C １ -C ６ AlkylOH, COC １ -C ６ Alkyl or COOC １ -C ６ is alkyl; R ａ 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, 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 AlkylOHaloC １ -C ６ Alkyl, haloC １ -C ６ Alkyl, C １ -C ６ AlkylOH, CON(R ７ ) (R ８ ), N(R ７ ) (R ８ ) or C １ -C ６ AlkylN(R ７ ) (R ８ ) or R ｂ When combined with C ３ -C ６ cycloalkyl or heterocycloalkyl, wherein the C ３ -C ６Cycloalkyl or heterocycloalkyl may be unsubstituted or substituted with 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, 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 AlkylOHaloC １ -C ６ Alkyl, haloC １ -C ６ Alkyl, C １ -C ６ AlkylOH, CON(R ７ ) (R ８ ), N(R ７ ) (R ８ ) and C １ -C ６ AlkylN(R ７ ) (R ８ ) is substituted with 1 or 2 substituents selected from the group consisting of: R ｂ 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, 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 AlkylOHaloC １ -C ６ Alkyl, haloC １ -C ６ Alkyl, C １ -C ６ AlkylOH, CON(R ７ ) (R ８ ), N(R ７ ) (R ８ ) or C １ -C ６ AlkylN(R ７ ) (R ８ ) or R ａ When combined with C ３ -C ６ cycloalkyl or heterocycloalkyl, wherein the C ３ -C ６ Cycloalkyl or heterocycloalkyl may be unsubstituted or substituted with 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, 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 ６Cycloalkyl, C １ -C ６ Alkyl, -C １ -C ６ AlkylOHaloC １ -C ６ Alkyl, haloC １ -C ６ Alkyl, C １ -C ６ AlkylOH, CON(R ７ ) (R ８ ), N(R ７ ) (R ８ ) and C １ -C ６ AlkylN(R ７ ) (R ８ ) is substituted with 1 to 3 substituents selected from the group consisting of; 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, haloC １ -C ６ Alkyl, C １ -C ６ AlkylOH, CON(R ７ ) (R ８ ), N(R ７ ) (R ８ ), C １ -C ６ AlkylN(R ７ ) (R ８ ), C １ -C ６ Alkyl (OCH ２ CH ２ ) ｎ N (R ７ ) (R ８ ) or C １ -C ６ AlkylOHaloC １ -C ６alkyl or R ４ When combined with C ３ -C ６ Cycloalkyl or C ３ -C ６ forming a heterocycloalkyl; 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, haloC １ -C ６ Alkyl, C １ -C ６ AlkylOH, CON(R ７ ) (R ８ ), N(R ７ ) (R ８ ), C １ -C ６ AlkylN(R ７ ) (R ８ ), C １ -C ６ Alkyl (OCH ２ CH ２ ) ｎ N (R ７ ) (R ８ ) or C １ -C ６ AlkylOHaloC １ -C ６ alkyl or R ３ When combined with C ３ -C ６ Cycloalkyl or C ３ -C ６ forming a heterocycloalkyl; R ７ is hydrogen, C １ -C ６ Alkyl COOH, COOH, C ３ -C ６Cycloalkyl, C １ -C ６ Alkyl, haloC １ -C ６ Alkyl, C １ -C ６ AlkylOH, COC １ -C ６ Alkyl or COOC １ -C ６ is alkyl; R ８ is hydrogen, C １ -C ６ Alkyl COOH, COOH, C ３ -C ６ Cycloalkyl, C １ -C ６ Alkyl, haloC １ -C ６ Alkyl, C １ -C ６ AlkylOH, COC １ -C ６ Alkyl or COOC １ -C ６ 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, haloC １ -C ６ Alkyl, C １ -C ６ AlkylOH, CON(R ７ ) (R ８ ), N(R ７ ) (R ８ ) or C １ -C ６ AlkylN(R ７ ) (R ８ ) and R １０is 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, haloC １ -C ６ Alkyl, C １ -C ６ AlkylOH, CON(R ７ ) (R ８ ), N(R ７ ) (R ８ ) or C １ -C ６ AlkylN(R ７ ) (R ８ ) and 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, haloC １ -C ６ Alkyl, C １ -C ６ AlkylOH, CON(R ７ ) (R ８ ), N(R ７ ) (R ８ ) or C １ -C ６ AlkylN(R ７ ) (R ８ ) and 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, haloC １ -C ６ Alkyl, C １ -C ６ AlkylOH, CON(R ７ ) (R ８ ), N(R ７ ) (R ８ ) or C １ -C ６ AlkylN(R ７ ) (R ８ ) and 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, haloC １ -C ６ Alkyl, C １ -C ６ AlkylOH, CON(R ７ ) (R ８ ), N(R ７ ) (R ８ ) or C １ -C ６ AlkylN(R ７ ) (R ８ ) and R １４ Each occurrence of 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, haloC １ -C ６ Alkyl, C １ -C ６ AlkylOH, CON(R ７ ) (R ８ ), N(R ７ ) (R ８ ) and C １ -C ６ AlkylN(R ７ ) (R ８ ) independently selected from the group consisting of: 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, haloC １ -C ６ Alkyl, C １ -C ６ AlkylOH, CON(R ７ ) (R ８ ), N(R ７ ) (R ８ ) or C １ -C ６ AlkylN(R ７ ) (R ８ ) and R １６ Each occurrence of 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, haloC １ -C ６ Alkyl, C １ -C ６ AlkylOH, CON(R ７ ) (R ８ ), N(R ７ ) (R ８ ) and C １ -C ６ AlkylN(R ７ ) (R ８ ) independently selected from the group consisting of: m is 0 or 1; n is 1, 2, 3 or 4; and p is 0 or 1. or a pharma- ceutically acceptable salt thereof.

2. 2. The compound of claim 1, wherein m is 1, p is 1, and X is O, or a pharma- ceutically acceptable salt thereof.

3. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein m is 1, p is 1, and X is a bond.

4. R ａ R ｂ or a pharma- ceutically acceptable salt thereof, which is taken together with a heterocycloalkyl.

5. R ａ R ｂ together with [Case 2] and wherein the heterocycloalkyl is one of two C １ -C ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, which is substituted with an alkyl group.

6. R ａ R ｂ Together with C ３ -C ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, which forms a cycloalkyl.

7. R ａ R ｂ Together with C ３ -C ６ cycloalkyl, where the heterocycloalkyl is [C3] and where C ３ -C ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein cycloalkyl is unsubstituted or substituted with OH.

8. R ３ is hydrogen, C １ -C ６ Alkyl OC １ -C ６ Alkyl or C １ -C ６ alkyl or R ４ When combined with C ３ -C ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, which forms a heterocycloalkyl.

9. R ３ is hydrogen or C １ -C ６ alkyl or R ４ When combined with C ３ -C ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, which forms a heterocycloalkyl.

10. R ３ and R ４ or a pharma- ceutically acceptable salt thereof, according to claim 1, wherein:

11. R １５ is hydrogen or C １ -C ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein R is an alkyl group.

12. R ３ and R ４ But hydrogen, halogens, OH, C １ -C ６ AlkylOH, C １ -C ６ Alkylalkoxy, C １ -C ６ Alkyl OC １ -C ６ Alkyl, C １ -C ６ Alkyl, C １ -C ６ AlkylOHaloC １ -C ６ Alkyl, CON(C １ -C ６ Alkyl) ２ , C １ -C ６ AlkylN(R ７ ) (R ８ ) and C １ -C ６ Alkyl (OCH ２ CH ２ ) ｎ N (R ７ ) (R ８ ) independently selected from the group consisting of: R ７ is hydrogen, C １ -C ６ Alkyl COOH, COOH, C ３ -C ６ Cycloalkyl, C １ -C ６ Alkyl, haloC １ -C ６ Alkyl, C １ -C ６ AlkylOH, COC １ -C ６ Alkyl or COOC １ -C ６ is alkyl; R ８ is hydrogen, C １ -C ６ Alkyl COOH, COOH, C ３ -C ６ Cycloalkyl, C １ -C ６ Alkyl, haloC １ -C ６ Alkyl, C １ -C ６ AlkylOH, COC １ -C ６ Alkyl or COOC １ -C ６ is alkyl; and n is 3; 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

13. R １２ and R １３ But hydrogen, halogens, OH, C １ -C ６ AlkylOH, C １ -C ６ Alkylalkoxy and C １ -C ６ Alkyl OC １ -C ６ Alkyl, C １ -C ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein each of the groups is independently selected from the group consisting of alkyl.

14. X is C(R １４ ) ２ and R １４ But hydrogen, halogens, OH, C １ -C ６ AlkylOH, C １ -C ６ Alkylalkoxy, C １ -C ６ Alkyl OC １ -C ６ Alkyl and C １ -C ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein each of the groups is independently selected from the group consisting of alkyl.

15. 15. The compound of claim 1-14, or a pharma- ceutically acceptable salt thereof, wherein Y is CH.

16. 15. The compound of claim 1-14, or a pharma- ceutically acceptable salt thereof, wherein Z is CH.

17. 15. The compound of claim 1-14, or a pharma- ceutically acceptable salt thereof, wherein V is CH.

18. A is a linear saturated or unsaturated (C ３ -C １０ 15. The compound of claim 1, wherein R is 1 or 2; or a pharma- ceutically acceptable salt thereof.

19. A is a branched, saturated or unsaturated (C ３ -C １０ 15. The compound of claim 1, wherein R is 1 or 2; or a pharma- ceutically acceptable salt thereof.

20. A, [C4] or a pharma- ceutically acceptable salt thereof.

21. below [C5] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof.

22. formula [C6] or a pharma- ceutically acceptable salt thereof.

23. formula [C7] or a pharma- ceutically acceptable salt thereof.

24. formula [C8] or a pharma- ceutically acceptable salt thereof.

25. 25. A method of treating a malarial parasite infection or treating malaria, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 24 or a pharma- ceutically acceptable salt thereof.

26. 25. A method of inhibiting plasmepsin X, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 24, or a pharma- ceutically acceptable salt thereof.

27. 25. A method of inhibiting plasmepsin IX, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 24, or a pharma- ceutically acceptable salt thereof.

28. A method for dually inhibiting plasmepsin X and plasmepsin X, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 24, or a pharma- ceutical acceptable salt thereof.

29. 25. Use of a compound according to any one of claims 1 to 24, or a pharma- ceutically acceptable salt thereof, for treating a plasmodium infection or malaria in a patient in need thereof.

30. 25. Use of a compound according to any one of claims 1 to 24, or a pharma- ceutically acceptable salt thereof, to inhibit plasmepsin X in a patient in need thereof.

31. 25. Use of a compound according to any one of claims 1 to 24, or a pharma- ceutically acceptable salt thereof, for inhibiting plasmepsin IX in a patient in need thereof.

32. 13. Use of a compound of claim 1, or a pharma- ceutically acceptable salt thereof, for inhibiting plasmepsin IX and plasmepsin X in a patient in need of such inhibition.

33. 10. A pharmaceutical composition comprising a compound of claim 1 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier.

34. 10. A pharmaceutical composition comprising a compound of claim 1 and a pharma- ceutically acceptable carrier.

35. 13. A method for treating a malarial infection or treating malaria, comprising administering a compound of claim 1 or a pharma- ceutically acceptable salt thereof and an effective amount of one or more additional antimalarial agents.

36. A method for treating malaria by inhibiting plasmepsin X, plasmepsin IX and by at least one other mechanism, comprising administering a compound of claim 1 or a pharma- ceutically acceptable salt thereof and an effective amount of an additional antimalarial drug, wherein the additional antimalarial drug acts by a mechanism different from the inhibition of plasmepsin IX or plasmepsin X.

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