TW202334161A - Antimalarial agents - Google Patents

Abstract

The present invention provides methods of treating malaria comprising administration of compounds of Formula (I): or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein the variables are as defined herein. The invention also provides uses of the compounds of Formula (I), as defined herein, for inhibiting plasmepsin X, plasmepsin IX or plasmepsin X and IX activity, for treating a Plasmodium infection, and for treating malaria. Also provided are methods of treatment further comprising administration of one or more additional anti-malarial compounds.

Description

antimalarial agents

The present invention relates to compounds of formula (I), or pharmaceutically acceptable salts thereof, which are suitable for treating Plasmodium infection. More specifically, the present invention relates to compounds of formula (I), or pharmaceutically acceptable salts thereof, which are suitable for the treatment of Plasmodium infections, more particularly for the treatment of malaria.

Malaria is a major disease in humans, infecting hundreds of millions of people and killing more than 450,000 people each year. The most lethal form of malaria is caused by Plasmodium falciparum . This protozoan parasite is responsible for nearly all malaria deaths, most of which occur in Africa. Plasmodium falciparum ( P. falciparum ) has a complex life cycle that begins with anopheles vectors that inject sporophytic forms into the human host during blood feeding. These sporophytes migrate to the liver and invade liver cells. These sporophytes develop in the liver cells to form thousands of liver merozoites. These liver merozoites enter the blood, which is equivalent to invading red blood cells in the blood to begin parasitism. The insect's asexual reproductive cycle, which causes malaria symptoms. The parasite develops within a protected niche in red blood cells to form 16 to 32 merozoites, which, once mature, are excreted from 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 midgut. Sporophytes form within the oocysts and upon expulsion migrate to the salivary glands for delivery to the next host during blood feeding for the persistence and survival of the parasite.

Other forms of malaria include recurrent forms of malaria caused by Plasmodium vivax ( P. vivax ) that cause substantial morbidity, a causative form of the disease that causes death in some people and is primarily a problem outside Africa. Plasmodium knowlesi is a zoonotic parasite found in Southeast Asia. It usually infects long-tailed macaques but has been shown to infect humans in Malaysian Borneo.

The combination of artemisinin and partner drugs has become the mainstay in the treatment and control of malaria. However, due to the growing threat of resistance to artemisinin-based combination therapies (ACTs), the development of novel antimalarial drugs with novel targets that inhibit multiple steps in the parasite life cycle is an urgent priority in the field of malaria control. These novel antimalarial drugs (either as monotherapies or ACT partner drugs) can make progress toward malaria elimination by reducing the likelihood of parasites possessing pre-existing resistance mutations present in the parasite population.

Of course, aspartic acid protease is the main target for drug development: HIV aspartic acid protease has been successfully targeted by drugs in clinical use; inhibitors targeting human renin, BACE1 and γ-secretase are already in or It is in clinical development. In the field of antimalarial drugs, the Plasmodium falciparum aspartate protease malarial hemes X and IX (PMX and PMIX) have been identified as potential targets because inhibitors block parasite egress and entry into host cells and prevent The maturation of some rhoptry and micronemal 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).

The present invention relates to compounds of formula (I): (I) wherein A, X, V, Y, Z, Ra, ^Rb , ^{R3 , R4} , ^R12 , ^R13 , ^R15 , m and p are as described below.

Also described herein are methods of treating Plasmodium infection comprising administering to a subject in need thereof a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Also described herein are methods of treating Plasmodium infection comprising administering to a subject in need thereof a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Also described herein are methods of treating malaria comprising administering to a subject in need thereof a compound of formula (I), or a pharmaceutically acceptable salt thereof.

The invention further provides the use of compositions (including pharmaceutical compositions) for treating malaria, such compositions comprising one or more compounds of the invention (eg, a compound of the invention), or tautomers thereof, or the ( etc.) compounds and/or pharmaceutically acceptable salts or solvates of such tautomer(s), optionally together with one or more additional therapeutic agents, optionally in an acceptable (e.g., pharmaceutically acceptable ) in the carrier or diluent.

In addition, the present invention provides methods of using pharmaceutical compositions to treat Plasmodium infection, treat malaria, inhibit malaria hemin X or dually inhibit malaria hemin form or in the form of a pharmaceutically acceptable salt, together with one or more commonly used pharmaceutical excipients. The invention also provides methods of using a compound or salt of the invention in combination with one or more additional pharmaceutically active agents.

The present invention further provides methods for inhibiting malaria heme X or dual inhibition of malaria heme A method of inhibiting the onset of a disease or disorder (for example, malaria) that has or may have a therapeutic effect.

The present invention further provides methods for inhibiting Plasmodium falciparum aspartic acid protease. The present invention further provides methods for blocking the growth of Plasmodium falciparum by inhibiting Plasmodium falciparum X. The present invention further provides methods for blocking the growth of Plasmodium falciparum by inhibiting both PMX and malarial heme IX.

The present invention further provides methods for treating malaria by inhibiting malaria heme X. The present invention further provides methods of treating malaria by inhibiting both PMX and malarial heme IX.

These and other embodiments of the invention which are described in detail below, or which will become apparent to one of ordinary skill in the art, are included within the scope of the invention.

Described herein are compounds of formula (I): , _{(I) wherein A is a linear or branched chain, saturated or unsaturated (C 3 -C 10} ) alkylene group, phenyl (C ₃ -C ₁₀ ) alkylene group containing at least one -CH 2 - group or cycloalkyl (C ₃ -C ₁₀ ) alkylene, wherein one or more additional -CH ₂ - groups in A are optionally and independently replaced with a moiety selected from the group consisting of: O, S , NR, CONR, NRCO, SO ₂ and SO ₂ NR and one or more of the hydrogens along A can be independently replaced by a group selected from hydroxyl, halogen and C _1-3 haloalkyl; X is 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 ; V is CR ¹⁰ or N , where when V is N, Z is CR ¹¹ and Y is CR ⁹ ; Z is CR ¹¹ or N, where when Z is N, V is CR ¹⁰ and Y is CR ⁹ ; R is hydrogen, C ₁ -C ₆ alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, COC ₁ -C ₆ alkyl Or COOC ₁ -C ₆ alkyl; R ^a is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, side oxygen group, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl O halo C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl radical OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ) or when taken together with R ^b forms C ₃ - C ₆ cycloalkyl or heterocycloalkyl, wherein the C ₃ -C ₆ cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of: halogen, CN , OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, side oxy group, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOC 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 alkylO halo C ₁ -C ₆ alkyl, halo C ₁ -C 6 alkyl _, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) and C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ); 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, side oxy group, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl O halo C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl N(R ⁷ )( R ⁸ ) or when taken together with R ^a forms a C ₃ -C ₆ cycloalkyl or heterocycloalkyl group, wherein the C ₃ -C ₆ cycloalkyl or heterocycloalkyl group is unsubstituted or substituted by one or three Substituted with a substituent selected from the following group: halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, side oxygen group, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl _O halo C ₁ -C ₆ alkyl, halo C ₁ -C 6 alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) and C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ); R ³ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C _{6 alkylOC 1} -C 6 alkyl, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, Halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ), C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ), C ₁ -C ₆ alkyl (OCH ₂ CH ₂ ) _n N (R ⁷ ) (R ⁸ ) or C ₁ -C ₆ alkyl O halo C ₁ -C ₆ alkyl or when combined with R ⁴ together form C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ heterocycloalkyl; R ⁴ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl Base OC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo group C ₁ -C ₆ alkyl, C ₁ - C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ), C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ), C ₁ -C ₆ alkyl (OCH ₂ CH ₂ ) _n N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl O halo C ₁ -C ₆ alkyl or when taken together with R ³ forms C ₃ -C ₆ cycloalkyl Or C ₃ -C ₆ heterocycloalkyl; R ⁷ is hydrogen, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, COC ₁ -C ₆ alkyl or COOC ₁ -C ₆ alkyl; R ⁸ is hydrogen, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, COC ₁ -C ₆ alkyl or COOC ₁ -C ₆ alkyl; R ⁹ series Hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C _{1 -C 6} alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl group, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl N (R ⁷ ) (R ⁸ ); R ¹⁰ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl , C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON ( R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ); R ¹¹ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C _{6 alkylOC 1} -C 6 alkyl, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl N(R ⁷ )( R ⁸ ); R ¹² is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C 6 alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N( ^R ₇ )(R ⁸ ) or C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ); R ¹³ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl OC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ); each occurrence of R ¹⁴ is independently Selected from the group consisting of hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C 6 alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N( ^R ₇ )(R ⁸ ) and C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ); R ¹⁵ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl OC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ); each occurrence of R ¹⁶ is independently Selected from the group consisting of hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C 6 alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N( ^R ₇ )(R ⁸ ) and C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ); m is 0 or 1; n is 1, 2, 3 or 4; and p is 0 or 1.

In the embodiments described herein, X is a bond, C( ^R14 ) 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 , wherein R ¹⁴ is discussed in further detail below. In certain embodiments, X is a bond, _CH2 , CH( _CH3 ), C( _CH3 ) ₂ , O, CH( _OCH3 ), _SO2 , or _CF2 . In other embodiments, X is _CH2 , O, S, SO, _SO2, or NH. In certain embodiments, X is _CH2 . In the embodiments described herein, X is O. In certain embodiments described herein, X is S. In certain embodiments described herein, X is SO. In other embodiments described herein, X is _SO2 . In certain embodiments described herein, X is NH.

In the embodiments described herein, Y is CR ⁹ or N. In certain embodiments, Y is ^CR9 , wherein ^R9 is discussed in detail below. In certain embodiments, Y is N. In certain embodiments, Y is CH. In certain embodiments, where Y is N, Z is CR ¹¹ and V is CR ¹⁰ .

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

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

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

In the compounds described herein, R ^a is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH , COOH, side oxygen group, 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 alkyl O halo _{C 1} -C 6 alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH , CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ) or when taken together with R ^b forms C ₃ -C ₆ Cycloalkyl or heterocycloalkyl, wherein the C ₃ -C ₆ cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of: halogen, CN, OH , C ₁ -C ₆ alkoxy, C ₁ -C 6 alkylOC ₁ -C ₆ alkyl, C _{1 -C 6 alkyl} COOH, COOH, side oxy group, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ - C ₆ alkyl O halo C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )( R ⁸ ) and C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ).

In certain embodiments described herein, ^Ra is hydrogen.

In certain embodiments, ^Ra is halogen. Examples of suitable halogens include chlorine, bromine, fluorine and iodine.

In certain embodiments, R ^a is CN.

In certain embodiments, R ^a is OH.

In certain embodiments, R ^a is C ₁ -C ₆ alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.

In certain embodiments, R ^a is C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl.

In certain embodiments, R ^a is C ₁ -C ₆ alkylCOOH.

In certain embodiments, R ^a is COOH.

In certain embodiments, R ^a is pendant oxy.

In certain embodiments, R ^a is COOC ₁ -C ₆ alkyl.

In certain embodiments, R ^a is C ₁ -C ₆ alkylCOOC ₁ -C ₆ alkyl.

In certain embodiments, R ^a is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In certain embodiments, R ^a is C ₁ -C ₆ alkyl C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to .

In certain embodiments, R ^a is C ₁ -C ₆ alkyl. Examples of C ₁ -C ₆ alkyl groups may include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl Base, isopentyl, neopentyl, third pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl base, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 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.

In certain embodiments, R ^a is C ₁ -C ₆ alkylO haloC ₁ -C ₆ alkyl. Suitable examples of C ₁ -C ₆ alkyl O halo C ₁ -C ₆ alkyl include (but are not limited to) .

In certain embodiments, R ^a is haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl.

In certain embodiments, R ^a is C ₁ -C ₆ alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and isobutanol.

In certain embodiments, R ^a is CON(R ⁷ )(R ⁸ ). In certain embodiments, R ^a is N(R ⁷ )(R ⁸ ). In certain embodiments, R ^a is C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ), wherein R ⁷ and R ⁸ are described in detail below.

In certain embodiments, compounds described herein have formula (II): (II)

In certain embodiments, R ^a is taken together with R ^b and forms a C ₃ -C ₆ cycloalkyl or heterocycloalkyl group, wherein the C ₃ -C ₆ cycloalkyl or heterocycloalkyl group is unsubstituted or Substituted with one or two substituents selected from the group consisting of: halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, side oxygen group, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl O halo C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) and C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ).

In certain embodiments, R ^a is taken together with R ^b and forms a C ₃ -C ₆ cycloalkyl group, wherein the cycloalkyl group is unsubstituted or substituted with one or two substituents selected from the group consisting of : Halogen, CN, OH, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkyl OC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, side oxy group, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkylC ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl base, -C ₁ -C ₆ alkyl O halo C ₁ -C 6 alkyl, halo C ₁ -C ₆ alkyl, C _{1 -C 6} alkyl OH, CON (R ⁷ ) (R ⁸ ), N(R ⁷ )(R ⁸ ) and C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ).

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

In certain embodiments, cycloalkyl is unsubstituted. In certain embodiments, heterocycloalkyl is substituted with one or two substituents selected from the group consisting of: 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, side oxy group, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl O halo C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) and C ₁ -C ₆ alkyl N(R ⁷ )( ^R8 ).

In certain embodiments, cycloalkyl is substituted with a substituent selected from the group consisting of: halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, side oxygen group, COOC ₁ -C ₆ alkyl, C ₁ -C 6 alkyl COOC _{1 -C 6 alkyl} , C ₃ -C ₆ cycloalkyl , C ₁ -C ₆ alkyl C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl O halo C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) and C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ).

In certain embodiments, cycloalkyl is substituted with two substituents selected from the group consisting of: halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ - C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, side oxy group, COOC ₁ -C ₆ alkyl, C ₁ -C 6 alkyl COOC _{1 -C 6 alkyl} , C ₃ -C ₆ cycloalkyl base, C ₁ -C ₆ alkyl C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl O halo C ₁ -C ₆ alkyl, halo C ₁ - C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) and C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ) .

In certain embodiments, cycloalkyl is substituted with OH.

In certain embodiments, R ^a is taken together with R ^b and forms a heterocycloalkyl group, wherein the heterocycloalkyl group is unsubstituted or substituted with one or two substituents selected from the group consisting of: halogen, CN, OH, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl group, C ₁ -C ₆ alkyl COOH, COOH, side oxy group, COOC ₁ -C ₆ alkyl group , C ₁ -C ₆ alkylCOOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, - C ₁ -C ₆ alkyl O halo C ₁ -C ₆ alkyl, halo C 1 -C 6 alkyl _{, C 1 -C 6 alkyl OH ,} CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) and C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ).

Non-limiting examples of monocyclic heterocycloalkyl groups include piperidinyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxane base, tetrahydrofuranyl, tetrahydrothienyl, β-lactam, γ-lactam, δ-lactam, β-lactone, γ-lactone, δ-lactone and pyrrolidone, and their oxides. Non-limiting examples of heterocycloalkyl include, but are not limited to , and

Non-limiting examples of bicyclic heterocycloalkyl include, but are not limited to and .

In certain embodiments, R ^a is taken together with R ^b and forms: .

In certain embodiments, heterocycloalkyl is unsubstituted. In certain embodiments, the heterocycloalkyl is substituted with one or two substituents selected from the group consisting of: halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl Base OC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, side oxygen group, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOC ₁ -C ₆ alkyl, C ₃ - C ₆ cycloalkyl, C ₁ -C ₆ alkyl C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl O halo C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) and C ₁ -C ₆ alkyl N(R ⁷ ) (R ⁸ ).

In certain embodiments, heterocycloalkyl is substituted with a substituent selected from the group consisting of: halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ - C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, side oxy group, COOC ₁ -C ₆ alkyl, C ₁ -C 6 alkyl COOC _{1 -C 6 alkyl} , C ₃ -C ₆ cycloalkyl base, C ₁ -C ₆ alkyl C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl O halo C ₁ -C ₆ alkyl, halo C ₁ - C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) and C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ) .

In certain embodiments, heterocycloalkyl is substituted with two substituents selected from the group consisting of: 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, side oxy group, COOC ₁ -C ₆ alkyl, C ₁ -C 6 alkyl COOC _{1 -C 6 alkyl} , C ₃ -C ₆ ring Alkyl, C ₁ -C ₆ alkyl C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl O halo C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) and C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ).

In certain embodiments, heterocycloalkyl is substituted with two substituents selected from the group consisting of: C ₁ -C ₆ alkyl.

In the compounds described herein, R ^b is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH , COOH, side oxygen group, 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 alkyl O halo _{C 1} -C 6 alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH , CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ) or when taken together with R ^a forms C ₃ -C ₆ Cycloalkyl or heterocycloalkyl, wherein the C ₃ -C ₆ cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of: halogen, CN, OH , C ₁ -C ₆ alkoxy, C ₁ -C 6 alkylOC ₁ -C ₆ alkyl, C _{1 -C 6 alkyl} COOH, COOH, side oxy group, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ - C ₆ alkyl O halo C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )( R ⁸ ) and C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ).

In certain embodiments described herein, R ^b is hydrogen.

In certain embodiments, ^Rb is halogen. Examples of suitable halogens include chlorine, bromine, fluorine and iodine.

In certain embodiments, ^Rb is CN.

In certain embodiments, ^Rb is OH.

In certain embodiments, R ^b is C ₁ -C ₆ alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.

In certain embodiments, R ^b is C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl.

In certain embodiments, R ^b is C ₁ -C ₆ alkyl COOH.

In certain embodiments, R ^b is COOH.

In certain embodiments, R ^b is a pendant oxy group.

In certain embodiments, R ^b is COOC ₁ -C ₆ alkyl.

In certain embodiments, R ^b is C ₁ -C ₆ alkylCOOC ₁ -C ₆ alkyl.

In certain embodiments, R ^b is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In certain embodiments, R ^b is C ₁ -C ₆ alkyl C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to .

In certain embodiments, R ^b is C ₁ -C ₆ alkyl. Examples of C ₁ -C ₆ alkyl groups may include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl Base, isopentyl, neopentyl, third pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl base, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 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.

In certain embodiments, R ^b is C ₁ -C ₆ alkylO haloC ₁ -C ₆ alkyl. Suitable examples of C ₁ -C ₆ alkyl O halo C ₁ -C ₆ alkyl include (but are not limited to) .

In certain embodiments, R ^b is haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl.

In certain embodiments, R ^b is C ₁ -C ₆ alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and isobutanol.

In certain embodiments, R ^b is CON(R ⁷ )(R ⁸ ). In certain embodiments, R ^b is N(R ⁷ )(R ⁸ ). In certain embodiments, R ^b is C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ), wherein R ⁷ and R ⁸ are described in detail below.

In certain embodiments, R ^b is taken together with R ^a and forms a cycloalkyl or heterocycloalkyl group, wherein the cycloalkyl or heterocycloalkyl group is unsubstituted or substituted with one or two selected from the group consisting of: Group substituent substitution: halogen, CN, OH, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkyl OC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, side oxy group , COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl O halo _{C 1} -C 6 alkyl, halo C _{1 -C 6} alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ ) (R ⁸ ), N(R ⁷ )(R ⁸ ) and C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ).

In certain embodiments, R ^b is taken together with R ^a and forms a cycloalkyl group, wherein the cycloalkyl group is unsubstituted or substituted with one or two substituents selected from the group consisting of: halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C 6 _{alkylOC 1} -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, side oxy group, 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 alkylO halo C ₁ -C ₆ alkyl, _halo C ₁ -C 6 alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ ) (R ⁸ ) and C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ).

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

In certain embodiments, cycloalkyl is unsubstituted. In certain embodiments, the heterocycloalkyl is substituted with one or two substituents selected from the group consisting of: halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl Base OC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, side oxygen group, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOC ₁ -C ₆ alkyl, C ₃ - C ₆ cycloalkyl, C ₁ -C ₆ alkyl C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl O halo C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) and C ₁ -C ₆ alkyl N(R ⁷ ) (R ⁸ ).

In certain embodiments, cycloalkyl is substituted with a substituent selected from the group consisting of: halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, side oxygen group, COOC ₁ -C ₆ alkyl, C ₁ -C 6 alkyl COOC _{1 -C 6 alkyl} , C ₃ -C ₆ cycloalkyl , C ₁ -C ₆ alkyl C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl O halo C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) and C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ).

In certain embodiments, cycloalkyl is substituted with two substituents selected from the group consisting of: halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ - C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, side oxy group, COOC ₁ -C ₆ alkyl, C ₁ -C 6 alkyl COOC _{1 -C 6 alkyl} , C ₃ -C ₆ cycloalkyl base, C ₁ -C ₆ alkyl C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl O halo C ₁ -C ₆ alkyl, halo C ₁ - C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) and C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ) .

In certain embodiments, cycloalkyl is substituted with OH.

In certain embodiments, R ^b is taken together with R ^a and forms a heterocycloalkyl group, wherein the heterocycloalkyl group is unsubstituted or substituted with one or two substituents selected from the group consisting of: halogen, CN, OH, C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl group, C ₁ -C ₆ alkyl COOH, COOH, side oxy group, COOC ₁ -C ₆ alkyl group , C ₁ -C ₆ alkylCOOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, - C ₁ -C ₆ alkyl O halo C ₁ -C ₆ alkyl, halo C ₁ -C 6 alkyl _, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) and C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ).

Non-limiting examples of monocyclic heterocycloalkyl groups include piperidinyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxane base, tetrahydrofuranyl, tetrahydrothiophenyl, β-lactam, γ-lactam, δ-lactam, β-lactone, γ-lactone, δ-lactone, and pyrrolidone, and their oxides. Non-limiting examples of heterocycloalkyl include, but are not limited to , and

Non-limiting examples of bicyclic heterocycloalkyl include, but are not limited to and .

In certain embodiments, R ^b is taken together with R ^a and forms: .

In certain embodiments, cycloalkyl or heterocycloalkyl is unsubstituted. In certain embodiments, the cycloalkyl or heterocycloalkyl is substituted with one or two substituents selected from the group consisting of: halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, side oxy group, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOC ₁ -C ₆ alkyl , C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl O halo C ₁ -C ₆ Alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) and C ₁ -C ₆ alkyl N (R ⁷ )(R ⁸ ). In certain embodiments, the cycloalkyl or heterocycloalkyl is substituted with a substituent selected from the group consisting of: halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ AlkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, side oxy group, COOC ₁ -C ₆ alkyl, C ₁ -C 6 alkyl COOC _{1 -C 6 alkyl} , C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl O halo C ₁ -C ₆ alkyl, Halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) and C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ). In certain embodiments, the cycloalkyl or heterocycloalkyl is substituted with two substituents selected from the group consisting of: halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, side oxy group, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl O halo C _{1 -} C ₆ alkyl , halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) and C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ).

In certain embodiments, heterocycloalkyl is substituted with two substituents selected from the group consisting of: C ₁ -C ₆ alkyl. In certain embodiments, the cycloalkyl is substituted with two substituents selected from the group consisting of: C ₁ -C ₆ alkyl. In certain embodiments, the cycloalkyl group is unsubstituted.

In the embodiments described herein, R ³ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ), C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ), C ₁ -C ₆ alkyl (OCH ₂ CH ₂ ) _n N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl O halo C ₁ -C ₆ alkyl or when taken together with R ⁴ forms C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ heterocycloalkyl.

In certain embodiments of the compounds described herein, R ³ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ - C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )( R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ) or when taken together with R ⁴ forms a C ₃ -C ₆ cycloalkyl or C ₃ - C ₆ heterocycloalkyl. In certain embodiments, ^R3 is hydrogen. In certain embodiments, ^R3 is halogen. Suitable halogens include fluorine, chlorine, bromine and iodine. In certain embodiments, ^R3 is CN. In certain embodiments, ^R3 is OH.

In certain embodiments, R ³ is C ₁ -C ₆ alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R ³ is C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl. In certain embodiments, ^R3 is COOH. In certain embodiments, R ³ is C ₁ -C ₆ alkyl COOH. In certain embodiments, R ³ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R ³ is C ₁ -C ₆ alkyl. Examples of C ₁ -C ₆ alkyl groups may include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl Base, isopentyl, neopentyl, third pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl base, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 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 haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R ³ is C ₁ -C ₆ alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol. In certain embodiments, R ³ is CON(R ⁷ )(R ⁸ ). Suitable examples of N(R ⁷ )(R ⁸ ) include, but are not limited to, CONH ₂ and CON(CH ₃ ) ₂ . In certain embodiments, R ³ is N(R ⁷ )(R ⁸ ). Suitable examples of N(R ⁷ )(R ⁸ ) include, but are not limited to, NH ₂ and N(CH ₃ ) ₂ . In certain embodiments, R ³ is C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ). Suitable examples of C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ) include (but are not limited to) , and . ^R7 and ^R8 are discussed in further detail below.

In certain embodiments, R ³ is C ₁ -C ₆ alkylO haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl include, but are not limited to .

In certain embodiments, R ³ is C ₁ -C ₆ alkyl(OCH ₂ CH ₂ ) _n N(R ⁷ )(R ⁸ ). The R ⁷ , R ⁸ and n systems are discussed in detail below. Suitable examples of C ₁ -C ₆ alkyl (OCH ₂ CH ₂ ) _n N(R ⁷ )(R ⁸ ) include (but are not limited to) , and .

With regard 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.

In certain embodiments, R ³ takes together with R ⁴ and forms C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ heterocycloalkyl. In certain embodiments, R ³ is taken together with R ⁴ to form a C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R ³ is taken together with R ⁴ to form C ₃ -C ₆ heterocycloalkyl. Suitable examples of heterocycloalkyl include, but are not limited to, piperidinyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl Alkyl, tetrahydrofuryl, tetrahydrothienyl, beta lactam, gamma lactone, delta lactone, beta lactone, gamma lactone, delta lactone, and pyrrolidone, and their oxides.

In certain embodiments, ^R3 is hydrogen, fluorine, methyl, ethyl, OH, methoxy, , CON(CH ₃ ) ₂ , , , , , , , or .

In certain embodiments, ^R3 is hydrogen, methyl, ethyl or .

In certain embodiments, R ³ and R ⁴ together form oxetanyl.

In certain embodiments described herein, R ⁴ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ Alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ), C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ), C ₁ -C ₆ alkyl (OCH ₂ CH ₂ ) _n N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl O halo C ₁ -C ₆ alkyl or when taken together with R ³ forms C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ heterocycloalkyl. In certain embodiments of the compounds described herein, R ⁴ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ - C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )( R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ) or when taken together with R ³ forms a C ₃ -C ₆ cycloalkyl or C ₃ - C ₆ heterocycloalkyl. In certain embodiments, ^R4 is hydrogen. In certain embodiments, ^R4 is halogen. Suitable halogens include fluorine, chlorine, bromine or iodine. In certain embodiments, R ⁴ is CN. In certain embodiments, R ⁴ is OH.

In certain embodiments, R ⁴ is C ₁ -C ₆ alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R ⁴ is C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl. In certain embodiments, R ⁴ is COOH. In certain embodiments, R ⁴ is C ₁ -C ₆ alkyl COOH. In certain embodiments, R ⁴ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R ⁴ is C ₁ -C ₆ alkyl. Examples of C ₁ -C ₆ alkyl groups may include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl Base, isopentyl, neopentyl, third pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl base, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 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 haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R ⁴ is C ₁ -C ₆ alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol. In certain embodiments, R ⁴ is CON(R ⁷ )(R ⁸ ). Suitable examples of N(R ⁷ )(R ⁸ ) include, but are not limited to, CONH ₂ and CON(CH ₃ ) ₂ . In certain embodiments, R ⁴ is N(R ⁷ )(R ⁸ ). Suitable examples of N(R ⁷ )(R ⁸ ) include, but are not limited to, NH ₂ and N(CH ₃ ) ₂ . In certain embodiments, R ⁴ is C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ). Suitable examples of C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ) include (but are not limited to) , and . ^R7 and ^R8 are discussed in further detail below.

In certain embodiments, R ⁴ is C ₁ -C ₆ alkylO haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl include, but are not limited to .

In certain embodiments, R ⁴ is C ₁ -C ₆ alkyl(OCH ₂ CH ₂ ) _n N(R ⁷ )(R ⁸ ). The R ⁷ and R ⁸ systems are discussed in detail below and the n system is discussed above. Suitable examples of C ₁ -C ₆ alkyl (OCH ₂ CH ₂ ) _n N(R ⁷ )(R ⁸ ) include (but are not limited to) , and .

In certain embodiments, R ⁴ is taken together with R ³ to form C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ heterocycloalkyl. In certain embodiments, R ⁴ is taken together with R ³ to form a C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R ⁴ together with R ³ form C ₃ -C ₆ heterocycloalkyl. Suitable examples of heterocycloalkyl include, but are not limited to, piperidinyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl Alkyl, tetrahydrofuryl, tetrahydrothienyl, beta lactam, gamma lactone, delta lactone, beta lactone, gamma lactone, delta lactone, and pyrrolidone, and their oxides.

In certain embodiments, R ⁴ is hydrogen or methyl. In certain embodiments, R ⁴ is hydrogen, methyl, ethyl or . In certain embodiments, R ⁴ and R ³ together form oxetanyl. In certain embodiments, R ³ and R ⁴ are each hydrogen, methyl, or ethyl.

In certain embodiments, ^R3 is hydrogen and ^R4 is hydrogen.

In certain embodiments, R ³ and R ⁴ are each halogen, wherein the halogen is selected from the group consisting of fluorine, chlorine, bromine, and iodine. In certain embodiments, R ³ and R ⁴ are both fluorine.

In the embodiments described herein, R ⁵ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, side oxygen group, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl C ₃ - C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl O halo C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ).

In certain embodiments described herein, ^R5 is hydrogen.

In certain embodiments, ^R5 is halogen. Examples of suitable halogens include chlorine, bromine, fluorine and iodine.

In certain embodiments, ^R5 is CN.

In certain embodiments, ^R5 is OH.

In certain embodiments, R ⁵ is C ₁ -C ₆ alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.

In certain embodiments, R ⁵ is C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl.

In certain embodiments, R ⁵ is C ₁ -C ₆ alkyl COOH.

In certain embodiments, ^R5 is COOH.

In certain embodiments, R ⁵ is pendant oxy.

In certain embodiments, R ⁵ is COOC ₁ -C ₆ alkyl.

In certain embodiments, R ⁵ is C ₁ -C ₆ alkylCOOC ₁ -C ₆ alkyl.

In certain embodiments, R ⁵ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In certain embodiments, R ⁵ is C ₁ -C ₆ alkyl C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to .

In certain embodiments, R ⁵ is C ₁ -C ₆ alkyl. Examples of C ₁ -C ₆ alkyl groups may include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl Base, isopentyl, neopentyl, third pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl base, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl -1-Methylpropyl. In certain embodiments, ^R5 is methyl.

In certain embodiments, R ⁵ is C ₁ -C ₆ alkylO haloC ₁ -C ₆ alkyl. Suitable examples of C ₁ -C ₆ alkyl O halo C ₁ -C ₆ alkyl include (but are not limited to) .

In certain embodiments, R ⁵ is haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl.

In certain embodiments, R ⁵ is C ₁ -C ₆ alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and isobutanol.

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 C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ), wherein R ⁷ and R ⁸ are described in detail below.

In certain embodiments, ^R5 is hydrogen, methyl, ethyl, or tert-butyl.

In the embodiments described herein, R ⁶ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, side oxygen group, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl C ₃ - C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl O halo C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ).

In certain embodiments described herein, ^R6 is hydrogen.

In certain embodiments, ^R6 is halogen. Examples of suitable halogens include chlorine, bromine, fluorine and iodine.

In certain embodiments, ^R6 is CN.

In certain embodiments, R ⁶ is OH.

In certain embodiments, R ⁶ is C ₁ -C ₆ alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.

In certain embodiments, R ⁶ is C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl.

In certain embodiments, R ⁶ is C ₁ -C ₆ alkyl COOH.

In certain embodiments, ^R6 is COOH.

In certain embodiments, ^R6 is pendant oxy.

In certain embodiments, R ⁶ is COOC ₁ -C ₆ alkyl.

In certain embodiments, R ⁶ is C ₁ -C ₆ alkylCOOC ₁ -C ₆ alkyl.

In certain embodiments, R ⁶ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In certain embodiments, R ⁶ is C ₁ -C ₆ alkyl C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to .

In certain embodiments, R ⁶ is C ₁ -C ₆ alkyl. Examples of C ₁ -C ₆ alkyl groups may include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl Base, isopentyl, neopentyl, third pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl base, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl -1-Methylpropyl. In certain embodiments, ^R6 is methyl.

In certain embodiments, R ⁶ is C ₁ -C ₆ alkylO haloC ₁ -C ₆ alkyl. Suitable examples of C ₁ -C ₆ alkyl O halo C ₁ -C ₆ alkyl include (but are not limited to) .

In certain embodiments, R ⁶ is haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl.

In certain embodiments, R ⁶ is C ₁ -C ₆ alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and isobutanol.

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 C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ), wherein R ⁷ and R ⁸ are described in detail below.

In certain embodiments, ^R6 is hydrogen, methyl, ethyl, or tert-butyl.

In the embodiments described herein, R ⁷ is hydrogen, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl , C ₁ -C ₆ alkyl OH, COC ₁ -C ₆ alkyl or COOC ₁ -C ₆ alkyl. In certain embodiments, R ⁷ is hydrogen, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkyl OH.

In certain embodiments, R ⁷ is hydrogen. In certain embodiments, R ⁷ is C ₁ -C ₆ alkyl COOH. In certain embodiments, ^R7 is COOH. In certain embodiments, R ⁷ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R ⁷ is C ₁ -C ₆ alkyl. Examples of C ₁ -C ₆ alkyl groups may include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl Base, isopentyl, neopentyl, third pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl base, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 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 haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R ⁷ is C ₁ -C ₆ alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol.

In certain embodiments, R ⁷ is COC ₁ -C ₆ alkyl. Suitable examples include, but are not limited to, _COCH3 . In certain embodiments, R ⁷ is COOC ₁ -C ₆ alkyl. Suitable examples include, but are not limited to, COOCH ₃ .

In the embodiments described herein, R ⁸ is hydrogen, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl , C ₁ -C ₆ alkyl OH, COC ₁ -C ₆ alkyl or COOC ₁ -C ₆ alkyl. In certain embodiments, R ⁸ is hydrogen, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkyl OH.

In certain embodiments, ^R8 is hydrogen. In certain embodiments, R ⁸ is C ₁ -C ₆ alkyl COOH. In certain embodiments, ^R8 is COOH. In certain embodiments, R ⁸ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R ⁸ is C ₁ -C ₆ alkyl. Examples of C ₁ -C ₆ alkyl groups may include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl Base, isopentyl, neopentyl, third pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl base, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 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 haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R ⁸ is C ₁ -C ₆ alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol.

In certain embodiments, R ⁸ is COC ₁ -C ₆ alkyl. Suitable examples include, but are not limited to, _COCH3 . In certain embodiments, R ⁸ is COOC ₁ -C ₆ alkyl. Suitable examples include, but are not limited to, COOCH ₃ .

In the embodiments described herein, R ⁹ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ) and N(R ⁷ )(R ⁸ ). In certain embodiments, R ⁹ is hydrogen. In certain embodiments, ^R9 is halogen. Suitable halogens include fluorine, chlorine, bromine or iodine. In certain embodiments, R ⁹ is CN. In certain embodiments, R ⁹ is OH.

In certain embodiments, R ⁹ is C ₁ -C ₆ alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R ⁹ is C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl. In certain embodiments, R ⁹ is COOH. In certain embodiments, R ⁹ is C ₁ -C ₆ alkyl COOH. In certain embodiments, R ⁹ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R ⁹ is C ₁ -C ₆ alkyl. Examples of C ₁ -C ₆ alkyl groups may include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl Base, isopentyl, neopentyl, third pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl base, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 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 haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R ⁹ is C ₁ -C ₆ alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol. 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 C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ).

Regarding the compounds described herein, R ¹⁰ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C 6 alkylOC ₁ -C ₆ alkyl, C _{1 -C 6 alkyl} COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ ) (R ⁸ ) and N( R ⁷ )(R ⁸ ). In certain embodiments, R ¹⁰ is hydrogen. In certain embodiments, R ¹⁰ is halogen. Suitable halogens include fluorine, chlorine, bromine or iodine. In certain embodiments, R ¹⁰ is CN. In certain embodiments, R ¹⁰ is OH.

In certain embodiments, R ¹⁰ is C ₁ -C ₆ alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R ¹⁰ is C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl. In certain embodiments, R ¹⁰ is COOH. In certain embodiments, R ¹⁰ is C ₁ -C ₆ alkyl COOH. In certain embodiments, R ¹⁰ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R ¹⁰ is C ₁ -C ₆ alkyl. Examples of C ₁ -C ₆ alkyl groups may include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl Base, isopentyl, neopentyl, third pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl base, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 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 haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R ¹⁰ is C ₁ -C ₆ alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol. 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 C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ).

In the embodiments described herein, R ¹¹ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ) and N(R ⁷ )(R ⁸ ). In certain embodiments, R ¹¹ is hydrogen. In certain embodiments, R ¹¹ is halogen. Suitable halogens include fluorine, chlorine, bromine or iodine. In certain embodiments, R ¹¹ is CN. In certain embodiments, R ¹¹ is OH.

In certain embodiments, R ¹¹ is C ₁ -C ₆ alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R ¹¹ is C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl. In certain embodiments, R ¹¹ is COOH. In certain embodiments, R ¹¹ is C ₁ -C ₆ alkyl COOH. In certain embodiments, R ¹¹ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R ¹¹ is C ₁ -C ₆ alkyl. Examples of C ₁ -C ₆ alkyl groups may include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl Base, isopentyl, neopentyl, third pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl base, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 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 haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R ¹¹ is C ₁ -C ₆ alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol. 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 C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ).

In the embodiments described herein, R ¹² is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ). In certain embodiments, R ¹² is hydrogen. In certain embodiments, ^R12 is halogen. Suitable halogens include fluorine, chlorine, bromine or iodine. In certain embodiments, R ¹² is CN. In certain embodiments, R ¹² is OH.

In certain embodiments, R ¹² is C ₁ -C ₆ alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R ¹² is C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl. In certain embodiments, ^R12 is COOH. In certain embodiments, R ¹² is C ₁ -C ₆ alkyl COOH. In certain embodiments, R ¹² is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R ¹² is C ₁ -C ₆ alkyl. Examples of C ₁ -C ₆ alkyl groups may include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl Base, isopentyl, neopentyl, third pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl base, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 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 haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R ¹² is C ₁ -C ₆ alkyl OH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol. 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 C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ).

In certain embodiments, R ¹² is hydrogen, methyl, ethyl, methoxy, OH or .

In certain embodiments, R ¹² is hydrogen or .

In the embodiments described herein, R ¹³ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ). In certain embodiments, R ¹³ is hydrogen. In certain embodiments, ^R13 is halogen. Suitable halogens include fluorine, chlorine, bromine or iodine. In certain embodiments, R ¹³ is CN. In certain embodiments, R ¹³ is OH.

In certain embodiments, R ¹³ is C ₁ -C ₆ alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R ¹³ is C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl. In certain embodiments, R ¹³ is COOH. In certain embodiments, R ¹³ is C ₁ -C ₆ alkyl COOH. In certain embodiments, R ¹³ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R ¹³ is C ₁ -C ₆ alkyl. Examples of C ₁ -C ₆ alkyl groups may include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl Base, isopentyl, neopentyl, third pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl base, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 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 haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R ¹³ is C ₁ -C ₆ alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol. 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 C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ).

In certain embodiments, R ¹³ is hydrogen, methyl, ethyl, methoxy, OH or .

In certain embodiments, R ¹³ is hydrogen or .

In certain embodiments, R ¹² and R ¹³ are independently selected from the group consisting of hydrogen and C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl.

In certain embodiments described herein, each occurrence of R ¹⁴ is independently selected from the group consisting of: hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ Alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ). In certain embodiments, R ¹⁴ is hydrogen. In certain embodiments, ^R14 is halogen. Suitable halogens include fluorine, chlorine, bromine or iodine. In certain embodiments, R ¹⁴ is CN. In certain embodiments, R ¹⁴ is OH.

In certain embodiments, R ¹⁴ is C ₁ -C ₆ alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R ¹⁴ is C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl. In certain embodiments, R ¹⁴ is COOH. In certain embodiments, R ¹⁴ is C ₁ -C ₆ alkyl COOH. In certain embodiments, R ¹⁴ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R ¹⁴ is C ₁ -C ₆ alkyl. Examples of C ₁ -C ₆ alkyl groups may include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl Base, isopentyl, neopentyl, third pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl base, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 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 haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R ¹⁴ is C ₁ -C ₆ alkyl OH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol. 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 C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ).

_In ^certain _embodiments ^, _{wherein _ _} Alkoxy group, C ₁ -C ₆ alkyl OC ₁ -C ₆ alkyl group and C ₁ -C ₆ alkyl group.

In certain embodiments, R ¹⁴ is hydrogen, methyl, ethyl, methoxy, OH or .

In the embodiments described herein, R ¹⁵ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ) and N(R ⁷ )(R ⁸ ). In certain embodiments, R ¹⁵ is hydrogen. In certain embodiments, ^R15 is halogen. Suitable halogens include fluorine, chlorine, bromine or iodine. In certain embodiments, R ¹⁵ is CN. In certain embodiments, R ¹⁵ is OH.

In certain embodiments, R ¹⁵ is C ₁ -C ₆ alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R ¹⁵ is C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl. In certain embodiments, R ¹⁵ is COOH. In certain embodiments, R ¹⁵ is C ₁ -C ₆ alkyl COOH. In certain embodiments, R ¹⁵ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R ¹⁵ is C ₁ -C ₆ alkyl. Examples of C ₁ -C ₆ alkyl groups may include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl Base, isopentyl, neopentyl, third pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl base, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 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.

In certain embodiments, R ¹⁵ is haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R ¹⁵ is C ₁ -C ₆ alkyl OH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol. 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 C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ).

In certain embodiments, R ¹⁵ is methyl or ethyl.

In the embodiments described herein, R ¹⁶ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ) and N(R ⁷ )(R ⁸ ). In certain embodiments, R ¹⁶ is hydrogen. In certain embodiments, ^R16 is halogen. Suitable halogens include fluorine, chlorine, bromine or iodine. In certain embodiments, R ¹⁶ is CN. In certain embodiments, R ¹⁶ is OH.

In certain embodiments, R ¹⁶ is C ₁ -C ₆ alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R ¹⁶ is C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl. In certain embodiments, R ¹⁶ is COOH. In certain embodiments, R ¹⁶ is C ₁ -C ₆ alkyl COOH. In certain embodiments, R ¹⁶ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R ¹⁶ is C ₁ -C ₆ alkyl. Examples of C ₁ -C ₆ alkyl groups may include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl Base, isopentyl, neopentyl, third pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl base, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 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 haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R ¹⁶ is C ₁ -C ₆ alkyl OH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol. 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 C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ).

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

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

In the embodiments described herein, A is a linear or branched chain, saturated or unsaturated (C ₃ -C ₁₀ ) alkylene group, phenyl (C ₃ -C ₁₀ ) group containing at least one -CH ₂ - group. Alkylene or cycloalkyl (C ₃ -C ₁₀ ) alkylene, wherein one or more additional -CH ₂ - groups in A are optionally and independently substituted with a moiety selected from the group consisting of: O, S, NR, CONR, NRCO, SO ₂ and SO ₂ NR where one or more of the hydrogens along A may be independently replaced by a group selected from: hydroxyl, halogen and C _1-3 halogen alkyl. In certain embodiments, A is a straight or branched chain, saturated or unsaturated (C ₃ -C ₁₀ )alkylene or cycloalkyl (C ₃ -C ₁₀ )alkylene, wherein one of A or Multiple _-CH2- groups are optionally and independently substituted with a moiety selected from the group consisting of: O, S, and NH. In certain embodiments, A will always have at least one _-CH2- group.

In certain embodiments, A is a straight chain (C ₃ -C ₁₀ )alkylene group. Examples of straight chain (C ₃ -C ₁₀ ) alkylene groups include .

In certain embodiments, A is branched chain (C ₃ -C ₁₀ )alkylene. Suitable branched chain (C ₃ -C ₁₀ ) alkylene groups include (but are not limited to):

In certain embodiments, A is saturated (C ₃ -C ₁₀ )alkylene. Examples include .

In certain embodiments, A is unsaturated (C ₃ -C ₁₀ )alkylene. Suitable unsaturated (C ₃ -C ₁₀ ) alkylene groups include any of the saturated (C ₃ -C ₁₀ ) alkylene groups in which the hydrogens have been removed and there are one or more di or triethyl groups between adjacent carbon atoms. price key. Examples of unsaturated (C ₃ -C ₁₀ ) alkylene groups include (but are not limited to) .

In other embodiments, A is linear cycloalkyl (C ₃ -C ₁₀ )alkylene. Suitable straight chain cycloalkyl (C ₃ -C ₁₀ )alkylene groups include cycloalkyl (C ₃ -C ₁₀ )alkylene groups in which two carbons in the chain are included in the (C ₃ -C ₁₀ )cycloalkylene group. Base in. Examples of linear cycloalkyl (C ₃ -C ₁₀ ) alkylene groups include (but are not limited to) .

In certain embodiments, A is branched chain cycloalkyl (C ₃ -C ₁₀ )alkylene. Suitable branched chain cycloalkylene (C ₃ -C ₁₀ )alkylene groups include branched chain (C ₃ -C ₁₀ )alkylene groups, in which two carbons in the chain are included in the (C ₃ -C ₁₀ )cycloalkylene group. middle. Examples of cycloalkyl (C ₃ -C ₁₀ )alkylene groups include (but are not limited to) .

In certain embodiments, A is saturated cycloalkyl (C ₃ -C ₁₀ )alkylene. Examples of saturated cycloalkyl (C ₃ -C ₁₀ ) alkylene groups include (but are not limited to) .

In certain embodiments, A is unsaturated cycloalkyl (C ₃ -C ₁₀ )alkylene. Examples of unsaturated ring (C ₃ -C ₁₀ ) alkylene groups include (but are not limited to) .

In certain embodiments, A is unsaturated or saturated phenyl (C ₃ -C ₁₀ )alkylene. Examples of unsaturated and saturated phenyl (C ₃ -C ₁₀ ) alkylene groups include (but are not limited to) .

In other embodiments, one or more -CH ₂ - groups in A are optionally and independently replaced with a moiety selected from the group consisting of: O, S, NR, CONR, NRCO, SO ₂ and SO _2nr . In other embodiments, one or more _-CH2- groups in A are optionally and independently replaced with a moiety selected from the group consisting of: O, S, and NH. In other embodiments, one or more _-CH2- groups in A are optionally and independently substituted with O. In other embodiments, one or more _-CH2- groups in A are optionally and independently substituted with S. In other embodiments, one or more _-CH2- groups in A are optionally and independently substituted with NR. In other embodiments, one or more _-CH2- groups in A are optionally and independently substituted with CONR. In other embodiments, one or more _-CH2- groups in A are optionally and independently substituted with NRCO. In other embodiments, one or more _-CH2- groups in A are optionally and independently substituted with _SO2 . In other embodiments, one or more _-CH2- groups in A are optionally and independently replaced with _SO2NR . R is described in further detail below.

In the embodiments described herein, R is hydrogen, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, COC ₁ -C ₆ alkyl or COOC ₁ -C ₆ alkyl. In certain embodiments, R is hydrogen, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkyl OH.

In certain embodiments, R is hydrogen. In certain embodiments, R is C ₁ -C ₆ alkyl COOH. In certain embodiments, R is COOH. In certain embodiments, R is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R is C ₁ -C ₆ alkyl. Examples of C ₁ -C ₆ alkyl groups may include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl Base, isopentyl, neopentyl, third pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl base, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl -1-Methylpropyl. In certain embodiments, R is haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R is C ₁ -C ₆ alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol.

In certain embodiments, R is COC ₁ -C ₆ alkyl. Suitable examples include, but are not limited to, _COCH3 . In certain embodiments, R is COOC ₁ -C ₆ alkyl. Suitable examples include, but are not limited to, COOCH ₃ .

Examples of such embodiments include (but are not limited to) .

In certain embodiments, Series A .

In certain embodiments, one or more of the hydrogens along A can be independently replaced with a group selected from: hydroxyl, halogen, and C _1-3 haloalkyl. Examples of suitable halogens include chlorine, bromine, fluorine and iodine. In certain embodiments, Series A .

Also described herein are compounds of formula (III): (III) Wherein, A is a linear or branched chain, saturated or unsaturated (C ₃ -C ₁₀ ) alkylene group, phenyl (C ₃ -C ₁₀ ) alkylene group containing at least one -CH ₂ - group or cycloalkyl (C ₃ -C ₁₀ ) alkylene, wherein one or more additional -CH ₂ - groups in A are optionally and independently replaced with a moiety selected from the group consisting of: O, S , NR, CONR, NRCO, SO ₂ and SO ₂ NR and one or more of the hydrogens along A may be independently replaced by a group selected from the following: hydroxyl, halogen and C _1-3 haloalkyl; Q is C(R ¹⁶ ) ₂ , O, S, SO, SO ₂ or NH; X is 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 ; V is CR ¹⁰ or N, where V is N, Z is CR ¹¹ and Y is CR ⁹ ; Z is CR ¹¹ or N, where Z When it is N, V is CR ¹⁰ and Y is CR ⁹ ; R is hydrogen, C ₁ -C ₆ alkyl group COOH, COOH, C ₃ -C ₆ cycloalkyl group, C ₁ -C ₆ alkyl group, halo group C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, COC ₁ -C ₆ alkyl or COOC ₁ -C ₆ alkyl; R ¹ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy , C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, side oxy group, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl O halo C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ Alkyl N(R ⁷ )(R ⁸ ); R ² is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ - C ₆ alkyl COOH, COOH, side oxy group, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl O halo C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ - C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ); R ³ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C 6 alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, C _{3 -C 6 cycloalkyl} , C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ), C ₁ -C ₆ Alkyl N(R ⁷ )(R ⁸ ), C ₁ -C ₆ alkyl (OCH ₂ CH ₂ ) _n N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl O halo C ₁ -C ₆ alkyl or when taken together with R ⁴ , it forms C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ heterocycloalkyl; R ⁴ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ), C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ), C ₁ -C ₆ alkyl (OCH ₂ CH ₂ ) _n N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl O haloC ₁ -C ₆ alkyl or when taken together with R ³ forms C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ heterocycloalkyl; R ⁵ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl OC ₁ -C ₆ alkyl Base, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON (R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ); R ⁶ is hydrogen, halogen, CN, OH, C ₁ - C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C 6 alkyl, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C _{6 alkyl} , halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl N(R ⁷ ) (R ⁸ ); R ⁷ is hydrogen, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, COC ₁ -C ₆ alkyl or COOC ₁ -C ₆ alkyl; R ⁸ is hydrogen, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, COC ₁ -C ₆ alkyl or COOC ₁ -C ₆ alkyl; R ⁹ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C 6 alkylOC ₁ -C ₆ alkyl, _{C 1} -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ); R ¹⁰ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ Alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ); R ¹¹ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl _{R 12} ^{_ _ _ _} _{_ _} ^{_ _ _} Hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C 6 alkylOC ₁ -C ₆ alkyl, C _{1 -C 6 alkyl} COOH, COOH, C ₃ -C ₆ ring Alkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl N(R ⁷ ) (R ⁸ ); R ¹³ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl OC ₁ -C ₆ alkyl Base, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON (R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ); each occurrence of R ¹⁴ is independently selected from the group consisting of : Hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ ring Alkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) and C ₁ -C ₆ alkyl N (R ⁷ ) (R ⁸ ); R ¹⁵ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl OC ₁ -C ₆ alkyl Base, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON (R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ); each occurrence of R ¹⁶ is independently selected from the group consisting of : Hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ ring Alkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) and C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ); l is 0 or 1; m is 0 or 1; n is 1, 2, 3 or 4; and p is 0 or 1.

In the embodiments described herein, Q is C( ^R16 ) ₂ , O, S, SO, _SO2, or NH. In certain embodiments, Q is C(R ¹⁶ ) ₂ , wherein R ¹⁶ is discussed in further detail below. In certain embodiments, Q is _CH2 , CH( _CH3 ), C( _CH3 ) ₂ , O, CH( _OCH3 ), _SO2 , or _CF2 . In other embodiments, Q is _CH2 , O, S, SO, _SO2, or NH. In certain embodiments, Q is _CH2 . In certain embodiments described herein, Q is O. In certain embodiments described herein, Q is S. In other embodiments described herein, Q is SO. In other embodiments described herein, Q is _SO2 . In certain embodiments described herein, Q is NH. In other embodiments described herein, Q is O or _SO2 . In yet other embodiments described herein, Q is O or _CH2 .

In the embodiments described herein, X is a bond, C( ^R14 ) 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 , wherein R ¹⁴ is discussed in further detail below. In certain embodiments, X is a bond, _CH2 , CH( _CH3 ), C( _CH3 ) ₂ , O, CH( _OCH3 ), _SO2 , or _CF2 . In other embodiments, X is _CH2 , O, S, SO, _SO2, or NH. In certain embodiments, X is _CH2 . In the embodiments described herein, X is O. In certain embodiments described herein, X is S. In certain embodiments described herein, X is SO. In other embodiments described herein, X is _SO2 . In certain embodiments described herein, X is NH.

In the embodiments described herein, Y is CR ⁹ or N. In certain embodiments, Y is ^CR9 , wherein ^R9 is discussed in detail below. In certain embodiments, Y is N. In certain embodiments, Y is CH. In certain embodiments, where Y is N, Z is CR ¹¹ and V is CR ¹⁰ .

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

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

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

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. In certain embodiments, the X bond and V, Y, and Z are all CH simultaneously.

Also described herein are compounds of formula III represented by structural formula (IIIA): (IIIA) wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹⁵ , A and Q are as defined herein. When R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹⁵ , A and Q are as described in formula III, one embodiment of the present invention is achieved. Another embodiment of formula IIIA is achieved when R ³ and R ⁴ are both hydrogen, methyl, ethyl or halogen. Another embodiment of formula IIIA is achieved when R ³ and R ⁴ are both halogens selected from chlorine and fluorine. Another embodiment of formula IIIA is achieved when Q is _CH2 , CH( _CH3 ), C( _CH3 ) ₂ , O, CH( _OCH3 ), _SO2 or _CF2 . In other embodiments described herein, Q in Formula IIIA is O or _SO2 . In yet other embodiments described herein, Q in Formula IIIA is O or _CH2 . Another embodiment of formula IIIA is achieved when A is a linear or branched, saturated or unsaturated (C ₃ -C ₁₀ )alkylene group containing at least one -CH ₂ - group, in which one of A or A plurality of additional -CH ₂ - groups are optionally and independently substituted with a moiety selected from the group consisting of: O, S, NR, CONR, NRCO, SO ₂ and SO ₂ NR and wherein along the hydrogen of A One or more may be independently replaced with a group selected from: hydroxyl, halogen, and C _1-3 haloalkyl.

Also described herein are compounds of formula III represented by structural formula (IIIB): (IIIB) wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹⁵ , A and Q are as defined herein. When R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹⁵ , A and Q are as described in formula III, one embodiment of the present invention is achieved. Another embodiment of formula IIIB is achieved when R ³ and R ⁴ are both hydrogen, methyl, ethyl or halogen. Another embodiment of formula IIIB is achieved when R ³ and R ⁴ are both halogens selected from chlorine and fluorine. Another embodiment of formula IIIB is achieved when Q is _CH2 , CH( _CH3 ), C( _CH3 ) ₂ , O, CH( _OCH3 ), _SO2 or _CF2 . In other embodiments described herein, Q in Formula IIIB is O or _SO2 . In yet other embodiments described herein, Q in Formula IIIB is O or _CH2 . Another embodiment of the formula IIIB is achieved when A is a linear or branched chain, saturated or unsaturated (C ₃ -C ₁₀ )alkylene group containing at least one -CH ₂ - group, in which one of A or A plurality of additional -CH ₂ - groups are optionally and independently substituted with a moiety selected from the group consisting of: O, S, NR, CONR, NRCO, SO ₂ and SO ₂ NR and wherein along the hydrogen of A One or more may be independently replaced with a group selected from: hydroxyl, halogen, and C _1-3 haloalkyl.

Certain embodiments are represented by formulas IV to VI: (IV) (V) (VI)

In the embodiments described herein, R ¹ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, side oxygen group, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl C ₃ - C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl O halo C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ).

In certain embodiments described herein, ^R1 is hydrogen.

In certain embodiments, ^R1 is halogen. Examples of suitable halogens include chlorine, bromine, fluorine and iodine.

In certain embodiments, ^R1 is CN.

In certain embodiments, ^R1 is OH.

In certain embodiments, R ¹ is C ₁ -C ₆ alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.

In certain embodiments, R ¹ is C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl.

In certain embodiments, ^R1 is _C1 - _C6 alkylCOOH.

In certain embodiments, ^R1 is COOH.

In certain embodiments, ^R1 is pendant oxy.

In certain embodiments, R ¹ is COOC ₁ -C ₆ alkyl.

In certain embodiments, R ¹ is C ₁ -C ₆ alkylCOOC ₁ -C ₆ alkyl.

In certain embodiments, R ¹ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In certain embodiments, R ¹ is C ₁ -C ₆ alkyl C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to .

In certain embodiments, R ¹ is C ₁ -C ₆ alkyl. Examples of C ₁ -C ₆ alkyl groups may include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl Base, isopentyl, neopentyl, third pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl base, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl -1-Methylpropyl.

In certain embodiments, R ¹ is C ₁ -C ₆ alkylO haloC ₁ -C ₆ alkyl. Suitable examples of C ₁ -C ₆ alkyl O halo C ₁ -C ₆ alkyl include (but are not limited to) .

In certain embodiments, R ¹ is haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl.

In certain embodiments, R ¹ is C ₁ -C ₆ alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and isobutanol.

In certain embodiments, R ¹ is CON(R ⁷ )(R ⁸ ). In certain embodiments, R ¹ is N(R ⁷ )(R ⁸ ). In certain embodiments, R ¹ is C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ), wherein R ⁷ and R ⁸ are described in detail below.

In certain embodiments, ^R1 is hydrogen, bromine, fluorine, chlorine, methyl, OH, halogen, CN pendant oxy, methoxymethyl, _{COOCH2CH3 ,} or trifluoromethyl.

In the embodiments described herein, R ² is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, side oxygen group, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl C ₃ - C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl O halo C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ).

In certain embodiments described herein, ^R2 is hydrogen.

In certain embodiments, ^R2 is halogen. Examples of suitable halogens include chlorine, bromine, fluorine and iodine.

In certain embodiments, ^R2 is CN.

In certain embodiments, ^R2 is OH.

In certain embodiments, R ² is C ₁ -C ₆ alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.

In certain embodiments, R ² is C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl.

In certain embodiments, R ² is C ₁ -C ₆ alkyl COOH.

In certain embodiments, ^R2 is COOH.

In certain embodiments, ^R2 is pendant oxy.

In certain embodiments, R ² is COOC ₁ -C ₆ alkyl.

In certain embodiments, R ² is C ₁ -C ₆ alkylCOOC ₁ -C ₆ alkyl.

In certain embodiments, R ² is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In certain embodiments, R ² is C ₁ -C ₆ alkyl C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to .

In certain embodiments, R ² is C ₁ -C ₆ alkyl. Examples of C ₁ -C ₆ alkyl groups may include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl Base, isopentyl, neopentyl, third pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl base, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl -1-Methylpropyl.

In certain embodiments, R ² is C ₁ -C ₆ alkylO haloC ₁ -C ₆ alkyl. Suitable examples of C ₁ -C ₆ alkyl O halo C ₁ -C ₆ alkyl include (but are not limited to) .

In certain embodiments, R ² is haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl.

In certain embodiments, ^R2 is _C1 - _C6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and isobutanol.

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 C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ), wherein R ⁷ and R ⁸ are described in detail below.

In certain embodiments, ^R2 is hydrogen, bromine, fluorine, chlorine, methyl, OH, halogen, CN pendant oxy, methoxymethyl, _{COOCH2CH3 ,} or trifluoromethyl.

In certain embodiments, R ¹ and R ² are both hydrogen. In certain embodiments, ^R1 is OH and ^R2 is hydrogen.

In the embodiments described herein, R ³ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ), C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ), C ₁ -C ₆ alkyl (OCH ₂ CH ₂ ) _n N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl O halo C ₁ -C ₆ alkyl or when taken together with R ⁴ forms C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ heterocycloalkyl.

In certain embodiments of the compounds described herein, R ³ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ - C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )( R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ) or when taken together with R ⁴ forms a C ₃ -C ₆ cycloalkyl or C ₃ - C ₆ heterocycloalkyl. In certain embodiments, ^R3 is hydrogen. In certain embodiments, ^R3 is halogen. Suitable halogens include fluorine, chlorine, bromine and iodine. In certain embodiments, ^R3 is CN. In certain embodiments, ^R3 is OH.

In certain embodiments, R ³ is C ₁ -C ₆ alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R ³ is C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl. In certain embodiments, ^R3 is COOH. In certain embodiments, R ³ is C ₁ -C ₆ alkyl COOH. In certain embodiments, R ³ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R ³ is C ₁ -C ₆ alkyl. Examples of C ₁ -C ₆ alkyl groups may include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl Base, isopentyl, neopentyl, third pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl base, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 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 haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R ³ is C ₁ -C ₆ alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol. In certain embodiments, R ³ is CON(R ⁷ )(R ⁸ ). Suitable examples of N(R ⁷ )(R ⁸ ) include, but are not limited to, CONH ₂ and CON(CH ₃ ) ₂ . In certain embodiments, R ³ is N(R ⁷ )(R ⁸ ). Suitable examples of N(R ⁷ )(R ⁸ ) include, but are not limited to, NH ₂ and N(CH ₃ ) ₂ . In certain embodiments, R ³ is C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ). Suitable examples of C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ) include (but are not limited to) , and . ^R7 and ^R8 are discussed in further detail below.

In certain embodiments, R ³ is C ₁ -C ₆ alkylO haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl include, but are not limited to .

In certain embodiments, R ³ is C ₁ -C ₆ alkyl(OCH ₂ CH ₂ ) _n N(R ⁷ )(R ⁸ ). The R ⁷ , R ⁸ and n systems are discussed in detail below. Suitable examples of C ₁ -C ₆ alkyl (OCH ₂ CH ₂ ) _n N(R ⁷ )(R ⁸ ) include (but are not limited to) , and .

With regard 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.

In certain embodiments, R ³ takes together with R ⁴ and forms C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ heterocycloalkyl. In certain embodiments, R ³ is taken together with R ⁴ to form a C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R ³ is taken together with R ⁴ to form C ₃ -C ₆ heterocycloalkyl. Suitable examples of heterocycloalkyl include, but are not limited to, piperidinyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl Alkyl, tetrahydrofuryl, tetrahydrothienyl, beta lactam, gamma lactone, delta lactone, beta lactone, gamma lactone, delta lactone, and pyrrolidone, and their oxides.

In certain embodiments, ^R3 is hydrogen, fluorine, methyl, ethyl, OH, methoxy, , CON(CH ₃ ) ₂ , , , , , , , or .

In certain embodiments, ^R3 is hydrogen, methyl, ethyl or .

In certain embodiments, R ³ and R ⁴ together form oxetanyl.

In certain embodiments described herein, R ⁴ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ Alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ), C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ), C ₁ -C ₆ alkyl (OCH ₂ CH ₂ ) _n N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl O halo C ₁ -C ₆ alkyl or when taken together with R ³ forms C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ heterocycloalkyl. In certain embodiments of the compounds described herein, R ⁴ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ - C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )( R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ) or when taken together with R ³ forms a C ₃ -C ₆ cycloalkyl or C ₃ - C ₆ heterocycloalkyl. In certain embodiments, ^R4 is hydrogen. In certain embodiments, ^R4 is halogen. Suitable halogens include fluorine, chlorine, bromine or iodine. In certain embodiments, R ⁴ is CN. In certain embodiments, R ⁴ is OH.

In certain embodiments, R ⁴ is C ₁ -C ₆ alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R ⁴ is C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl. In certain embodiments, R ⁴ is COOH. In certain embodiments, R ⁴ is C ₁ -C ₆ alkyl COOH. In certain embodiments, R ⁴ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R ⁴ is C ₁ -C ₆ alkyl. Examples of C ₁ -C ₆ alkyl groups may include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl Base, isopentyl, neopentyl, third pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl base, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 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 haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R ⁴ is C ₁ -C ₆ alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol. In certain embodiments, R ⁴ is CON(R ⁷ )(R ⁸ ). Suitable examples of N(R ⁷ )(R ⁸ ) include, but are not limited to, CONH ₂ and CON(CH ₃ ) ₂ . In certain embodiments, R ⁴ is N(R ⁷ )(R ⁸ ). Suitable examples of N(R ⁷ )(R ⁸ ) include, but are not limited to, NH ₂ and N(CH ₃ ) ₂ . In certain embodiments, R ⁴ is C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ). Suitable examples of C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ) include (but are not limited to) , and . ^R7 and ^R8 are discussed in further detail below.

In certain embodiments, R ⁴ is C ₁ -C ₆ alkylO haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl include, but are not limited to .

In certain embodiments, R ⁴ is C ₁ -C ₆ alkyl(OCH ₂ CH ₂ ) _n N(R ⁷ )(R ⁸ ). The R ⁷ and R ⁸ systems are discussed in detail below and the n system is discussed above. Suitable examples of C ₁ -C ₆ alkyl (OCH ₂ CH ₂ ) _n N(R ⁷ )(R ⁸ ) include (but are not limited to) , and .

In certain embodiments, R ⁴ is taken together with R ³ to form C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ heterocycloalkyl. In certain embodiments, R ⁴ is taken together with R ³ to form a C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R ⁴ together with R ³ form C ₃ -C ₆ heterocycloalkyl. Suitable examples of heterocycloalkyl include, but are not limited to, piperidinyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl Alkyl, tetrahydrofuryl, tetrahydrothienyl, beta lactam, gamma lactone, delta lactone, beta lactone, gamma lactone, delta lactone, and pyrrolidone, and their oxides.

In certain embodiments, R ⁴ is hydrogen or methyl. In certain embodiments, R ⁴ is hydrogen, methyl, ethyl or . In certain embodiments, R ⁴ and R ³ together form oxetanyl. In certain embodiments, R ³ and R ⁴ are each hydrogen, methyl, or ethyl.

In certain embodiments, ^R3 is hydrogen and ^R4 is hydrogen.

In the embodiments described herein, R ⁵ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, side oxygen group, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl C ₃ - C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl O halo C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ).

In certain embodiments described herein, ^R5 is hydrogen.

In certain embodiments, ^R5 is halogen. Examples of suitable halogens include chlorine, bromine, fluorine and iodine.

In certain embodiments, ^R5 is CN.

In certain embodiments, ^R5 is OH.

In certain embodiments, R ⁵ is C ₁ -C ₆ alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.

In certain embodiments, R ⁵ is C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl.

In certain embodiments, R ⁵ is C ₁ -C ₆ alkyl COOH.

In certain embodiments, ^R5 is COOH.

In certain embodiments, R ⁵ is pendant oxy.

In certain embodiments, R ⁵ is COOC ₁ -C ₆ alkyl.

In certain embodiments, R ⁵ is C ₁ -C ₆ alkylCOOC ₁ -C ₆ alkyl.

In certain embodiments, R ⁵ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In certain embodiments, R ⁵ is C ₁ -C ₆ alkyl C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to .

In certain embodiments, R ⁵ is C ₁ -C ₆ alkyl. Examples of C ₁ -C ₆ alkyl groups may include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl Base, isopentyl, neopentyl, third pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl base, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl -1-Methylpropyl. In certain embodiments, ^R5 is methyl.

In certain embodiments, R ⁵ is C ₁ -C ₆ alkylO haloC ₁ -C ₆ alkyl. Suitable examples of C ₁ -C ₆ alkyl O halo C ₁ -C ₆ alkyl include (but are not limited to) .

In certain embodiments, R ⁵ is haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl.

In certain embodiments, R ⁵ is C ₁ -C ₆ alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and isobutanol.

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 C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ), wherein R ⁷ and R ⁸ are described in detail below.

In certain embodiments, ^R5 is hydrogen, methyl, ethyl, or tert-butyl.

In the embodiments described herein, R ⁶ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, side oxygen group, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl C ₃ - C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl O halo C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ).

In certain embodiments described herein, ^R6 is hydrogen.

In certain embodiments, ^R6 is halogen. Examples of suitable halogens include chlorine, bromine, fluorine and iodine.

In certain embodiments, ^R6 is CN.

In certain embodiments, R ⁶ is OH.

In certain embodiments, R ⁶ is C ₁ -C ₆ alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.

In certain embodiments, R ⁶ is C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl.

In certain embodiments, R ⁶ is C ₁ -C ₆ alkyl COOH.

In certain embodiments, ^R6 is COOH.

In certain embodiments, ^R6 is pendant oxy.

In certain embodiments, R ⁶ is COOC ₁ -C ₆ alkyl.

In certain embodiments, R ⁶ is C ₁ -C ₆ alkylCOOC ₁ -C ₆ alkyl.

In certain embodiments, R ⁶ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In certain embodiments, R ⁶ is C ₁ -C ₆ alkyl C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to .

In certain embodiments, R ⁶ is C ₁ -C ₆ alkyl. Examples of C ₁ -C ₆ alkyl groups may include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl Base, isopentyl, neopentyl, third pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl base, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl -1-Methylpropyl. In certain embodiments, ^R6 is methyl.

In certain embodiments, R ⁶ is C ₁ -C ₆ alkylO haloC ₁ -C ₆ alkyl. Suitable examples of C ₁ -C ₆ alkyl O halo C ₁ -C ₆ alkyl include (but are not limited to) .

In certain embodiments, R ⁶ is haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl.

In certain embodiments, R ⁶ is C ₁ -C ₆ alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and isobutanol.

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 C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ), wherein R ⁷ and R ⁸ are described in detail below.

In certain embodiments, ^R6 is hydrogen, methyl, ethyl, or tert-butyl.

In the embodiments described herein, R ⁷ is hydrogen, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl , C ₁ -C ₆ alkyl OH, COC ₁ -C ₆ alkyl or COOC ₁ -C ₆ alkyl. In certain embodiments, R ⁷ is hydrogen, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkyl OH.

In certain embodiments, R ⁷ is hydrogen. In certain embodiments, R ⁷ is C ₁ -C ₆ alkyl COOH. In certain embodiments, ^R7 is COOH. In certain embodiments, R ⁷ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R ⁷ is C ₁ -C ₆ alkyl. Examples of C ₁ -C ₆ alkyl groups may include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl Base, isopentyl, neopentyl, third pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl base, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 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 haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R ⁷ is C ₁ -C ₆ alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol.

In certain embodiments, R ⁷ is COC ₁ -C ₆ alkyl. Suitable examples include, but are not limited to, _COCH3 . In certain embodiments, R ⁷ is COOC ₁ -C ₆ alkyl. Suitable examples include, but are not limited to, COOCH ₃ .

In the embodiments described herein, R ⁸ is hydrogen, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl , C ₁ -C ₆ alkyl OH, COC ₁ -C ₆ alkyl or COOC ₁ -C ₆ alkyl. In certain embodiments, R ⁸ is hydrogen, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkyl OH.

In certain embodiments, ^R8 is hydrogen. In certain embodiments, R ⁸ is C ₁ -C ₆ alkyl COOH. In certain embodiments, ^R8 is COOH. In certain embodiments, R ⁸ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R ⁸ is C ₁ -C ₆ alkyl. Examples of C ₁ -C ₆ alkyl groups may include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl Base, isopentyl, neopentyl, third pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl base, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 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 haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R ⁸ is C ₁ -C ₆ alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol.

In certain embodiments, R ⁸ is COC ₁ -C ₆ alkyl. Suitable examples include, but are not limited to, _COCH3 . In certain embodiments, R ⁸ is COOC ₁ -C ₆ alkyl. Suitable examples include, but are not limited to, COOCH ₃ .

In the embodiments described herein, R ⁹ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ) and N(R ⁷ )(R ⁸ ). In certain embodiments, R ⁹ is hydrogen. In certain embodiments, ^R9 is halogen. Suitable halogens include fluorine, chlorine, bromine or iodine.

In certain embodiments, R ⁹ is CN. In certain embodiments, R ⁹ is OH.

In certain embodiments, R ⁹ is C ₁ -C ₆ alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R ⁹ is C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl. In certain embodiments, R ⁹ is COOH. In certain embodiments, R ⁹ is C ₁ -C ₆ alkyl COOH. In certain embodiments, R ⁹ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R ⁹ is C ₁ -C ₆ alkyl. Examples of C ₁ -C ₆ alkyl groups may include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl Base, isopentyl, neopentyl, third pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl base, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 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 haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R ⁹ is C ₁ -C ₆ alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol. 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 C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ).

Regarding the compounds described herein, R ¹⁰ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C 6 alkylOC ₁ -C ₆ alkyl, C _{1 -C 6 alkyl} COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ ) (R ⁸ ) and N( R ⁷ )(R ⁸ ). In certain embodiments, R ¹⁰ is hydrogen. In certain embodiments, R ¹⁰ is halogen. Suitable halogens include fluorine, chlorine, bromine or iodine. In certain embodiments, R ¹⁰ is CN. In certain embodiments, R ¹⁰ is OH.

In certain embodiments, R ¹⁰ is C ₁ -C ₆ alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R ¹⁰ is C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl. In certain embodiments, R ¹⁰ is COOH. In certain embodiments, R ¹⁰ is C ₁ -C ₆ alkyl COOH. In certain embodiments, R ¹⁰ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In certain embodiments, R ¹⁰ is C ₁ -C ₆ alkyl. Examples of C ₁ -C ₆ alkyl groups may include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl Base, isopentyl, neopentyl, third pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl base, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 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 haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R ¹⁰ is C ₁ -C ₆ alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol. 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 C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ).

In the embodiments described herein, R ¹¹ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ) and N(R ⁷ )(R ⁸ ). In certain embodiments, R ¹¹ is hydrogen. In certain embodiments, R ¹¹ is halogen. Suitable halogens include fluorine, chlorine, bromine or iodine. In certain embodiments, R ¹¹ is CN. In certain embodiments, R ¹¹ is OH.

In certain embodiments, R ¹¹ is C ₁ -C ₆ alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R ¹¹ is C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl. In certain embodiments, R ¹¹ is COOH. In certain embodiments, R ¹¹ is C ₁ -C ₆ alkyl COOH. In certain embodiments, R ¹¹ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R ¹¹ is C ₁ -C ₆ alkyl. Examples of C ₁ -C ₆ alkyl groups may include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl Base, isopentyl, neopentyl, third pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl base, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 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 haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R ¹¹ is C ₁ -C ₆ alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol. 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 C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ).

In the embodiments described herein, R ¹² is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ). In certain embodiments, R ¹² is hydrogen. In certain embodiments, ^R12 is halogen. Suitable halogens include fluorine, chlorine, bromine or iodine. In certain embodiments, R ¹² is CN. In certain embodiments, R ¹² is OH.

In certain embodiments, R ¹² is C ₁ -C ₆ alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R ¹² is C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl. In certain embodiments, ^R12 is COOH. In certain embodiments, R ¹² is C ₁ -C ₆ alkyl COOH. In certain embodiments, R ¹² is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R ¹² is C ₁ -C ₆ alkyl. Examples of C ₁ -C ₆ alkyl groups may include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl Base, isopentyl, neopentyl, third pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl base, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 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 haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R ¹² is C ₁ -C ₆ alkyl OH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol. 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 C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ).

In certain embodiments, R ¹² is hydrogen, methyl, ethyl, methoxy, OH or .

In certain embodiments, R ¹² is hydrogen or .

In the embodiments described herein, R ¹³ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ). In certain embodiments, R ¹³ is hydrogen. In certain embodiments, ^R13 is halogen. Suitable halogens include fluorine, chlorine, bromine or iodine. In certain embodiments, R ¹³ is CN. In certain embodiments, R ¹³ is OH.

In certain embodiments, R ¹³ is C ₁ -C ₆ alkoxy. Suitable alkoxy groups are, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R ¹³ is C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl. In certain embodiments, R ¹³ is COOH. In certain embodiments, R ¹³ is C ₁ -C ₆ alkyl COOH. In certain embodiments, R ¹³ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R ¹³ is C ₁ -C ₆ alkyl. Examples of C ₁ -C ₆ alkyl groups may include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl Base, isopentyl, neopentyl, third pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl base, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 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 haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R ¹³ is C ₁ -C ₆ alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol. 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 C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ).

In certain embodiments, R ¹³ is hydrogen, methyl, ethyl, methoxy, OH or .

In certain embodiments, R ¹³ is hydrogen or .

In certain embodiments, R ¹² and R ¹³ are independently selected from the group consisting of hydrogen and C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl.

In certain embodiments described herein, each occurrence of R ¹⁴ is independently selected from the group consisting of: hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ Alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ). In certain embodiments, R ¹⁴ is hydrogen. In certain embodiments, ^R14 is halogen. Suitable halogens include fluorine, chlorine, bromine or iodine. In certain embodiments, R ¹⁴ is CN. In certain embodiments, R ¹⁴ is OH.

In certain embodiments, R ¹⁴ is C ₁ -C ₆ alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R ¹⁴ is C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl. In certain embodiments, R ¹⁴ is COOH. In certain embodiments, R ¹⁴ is C ₁ -C ₆ alkyl COOH. In certain embodiments, R ¹⁴ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R ¹⁴ is C ₁ -C ₆ alkyl. Examples of C ₁ -C ₆ alkyl groups may include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl Base, isopentyl, neopentyl, third pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl base, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 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 haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R ¹⁴ is C ₁ -C ₆ alkyl OH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol. 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 C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ).

_In ^certain _embodiments ^, _{wherein _ _} Alkoxy group, C ₁ -C ₆ alkyl OC ₁ -C ₆ alkyl group and C ₁ -C ₆ alkyl group.

In certain embodiments, R ¹⁴ is hydrogen, methyl, ethyl, methoxy, OH or .

In the embodiments described herein, R ¹⁵ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ) and N(R ⁷ )(R ⁸ ). In certain embodiments, R ¹⁵ is hydrogen. In certain embodiments, ^R15 is halogen. Suitable halogens include fluorine, chlorine, bromine or iodine. In certain embodiments, R ¹⁵ is CN. In certain embodiments, R ¹⁵ is OH.

In certain embodiments, R ¹⁵ is C ₁ -C ₆ alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R ¹⁵ is C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl. In certain embodiments, R ¹⁵ is COOH. In certain embodiments, R ¹⁵ is C ₁ -C ₆ alkyl COOH. In certain embodiments, R ¹⁵ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R ¹⁵ is C ₁ -C ₆ alkyl. Examples of C ₁ -C ₆ alkyl groups may include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl Base, isopentyl, neopentyl, third pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl base, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 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.

In certain embodiments, R ¹⁵ is haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R ¹⁵ is C ₁ -C ₆ alkyl OH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol. 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 C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ).

In certain embodiments, R ¹⁵ is methyl or ethyl.

In the embodiments described herein, R ¹⁶ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ) and N(R ⁷ )(R ⁸ ). In certain embodiments, R ¹⁶ is hydrogen. In certain embodiments, ^R16 is halogen. Suitable halogens include fluorine, chlorine, bromine or iodine. In certain embodiments, R ¹⁶ is CN. In certain embodiments, R ¹⁶ is OH.

In certain embodiments, R ¹⁶ is C ₁ -C ₆ alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R ¹⁶ is C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl. In certain embodiments, R ¹⁶ is COOH. In certain embodiments, R ¹⁶ is C ₁ -C ₆ alkyl COOH. In certain embodiments, R ¹⁶ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In certain embodiments, R ¹⁶ is C ₁ -C ₆ alkyl. Examples of C ₁ -C ₆ alkyl groups may include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl Base, isopentyl, neopentyl, third pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl base, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 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 haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R ¹⁶ is C ₁ -C ₆ alkyl OH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol. 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 C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ).

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

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

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

In certain embodiments, m and p are 1 and X is 0.

In certain embodiments, m and p are 1 and X is _CH2 .

In certain embodiments, m is 0, p is 1 and X is 0.

In certain embodiments, m and p are 1 and X is _SO2 .

In certain _embodiments ^, m is 0, _p is ¹ and ₆ alkoxy and C ₁ -C ₆ alkyl.

In certain embodiments, m is 1 and X is C( ^R14 ) ₂ , wherein each occurrence of ^R14 is independently selected from the group consisting of: hydrogen, halogen, OH, _C1 - _C6 alkoxy and C ₁ -C ₆ alkyl.

For example, in certain embodiments of formula (I), l is 0; m is 1; p is ₁ ; display. (VII).

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). (VIII).

In the embodiments described herein, A is a linear or branched chain, saturated or unsaturated (C ₃ -C ₁₀ ) alkylene group, phenyl (C ₃ -C ₁₀ ) group containing at least one -CH ₂ - group. Alkylene or cycloalkyl (C ₃ -C ₁₀ ) alkylene, wherein one or more additional -CH ₂ - groups in A are optionally and independently substituted with a moiety selected from the group consisting of: O, S, NR, CONR, NRCO, SO ₂ and SO ₂ NR where one or more of the hydrogens along A may be independently replaced by a group selected from: hydroxyl, halogen and C _1-3 halogen alkyl. In certain embodiments, A is a straight or branched chain, saturated or unsaturated (C ₃ -C ₁₀ )alkylene or cycloalkyl (C ₃ -C ₁₀ )alkylene, wherein one of A or Multiple _-CH2- groups are optionally and independently substituted with a moiety selected from the group consisting of: O, S, and NH. In certain embodiments, A will always have at least one _-CH2- group.

In certain embodiments, A is a straight chain (C ₃ -C ₁₀ )alkylene group. Examples of straight chain (C ₃ -C ₁₀ ) alkylene groups include .

In certain embodiments, A is branched chain (C ₃ -C ₁₀ )alkylene. Suitable branched chain (C ₃ -C ₁₀ ) alkylene groups include (but are not limited to):

In certain embodiments, A is saturated (C ₃ -C ₁₀ )alkylene. Examples include .

In certain embodiments, A is unsaturated (C ₃ -C ₁₀ )alkylene. Suitable unsaturated (C ₃ -C ₁₀ ) alkylene groups include any of the saturated (C ₃ -C ₁₀ ) alkylene groups in which the hydrogens have been removed and there are one or more di or triethyl groups between adjacent carbon atoms. price key. Examples of unsaturated (C ₃ -C ₁₀ ) alkylene groups include (but are not limited to) .

In other embodiments, A is linear cycloalkyl (C ₃ -C ₁₀ )alkylene. Suitable straight chain cycloalkyl (C ₃ -C ₁₀ )alkylene groups include cycloalkyl (C ₃ -C ₁₀ )alkylene groups in which two carbons in the chain are included in the (C ₃ -C ₁₀ )cycloalkylene group. Base in. Examples of linear cycloalkyl (C ₃ -C ₁₀ ) alkylene groups include (but are not limited to) .

In certain embodiments, A is branched chain cycloalkyl (C ₃ -C ₁₀ )alkylene. Suitable branched chain cycloalkylene (C ₃ -C ₁₀ )alkylene groups include branched chain (C ₃ -C ₁₀ )alkylene groups, in which two carbons in the chain are included in the (C ₃ -C ₁₀ )cycloalkylene group. middle. Examples of cycloalkyl (C ₃ -C ₁₀ )alkylene groups include (but are not limited to) .

In certain embodiments, A is saturated cycloalkyl (C ₃ -C ₁₀ )alkylene. Examples of saturated cycloalkyl (C ₃ -C ₁₀ ) alkylene groups include (but are not limited to) .

In certain embodiments, A is unsaturated cycloalkyl (C ₃ -C ₁₀ )alkylene. Examples of unsaturated ring (C ₃ -C ₁₀ ) alkylene groups include (but are not limited to) .

In certain embodiments, A is unsaturated or saturated phenyl (C ₃ -C ₁₀ )alkylene. Examples of unsaturated and saturated phenyl (C ₃ -C ₁₀ ) alkylene groups include (but are not limited to) .

In other embodiments, one or more -CH ₂ - groups in A are optionally and independently replaced with a moiety selected from the group consisting of: O, S, NR, CONR, NRCO, SO ₂ and SO _2nr . In other embodiments, one or more _-CH2- groups in A are optionally and independently replaced with a moiety selected from the group consisting of: O, S, and NH. In other embodiments, one or more _-CH2- groups in A are optionally and independently substituted with O. In other embodiments, one or more _-CH2- groups in A are optionally and independently substituted with S. In other embodiments, one or more _-CH2- groups in A are optionally and independently substituted with NR. In other embodiments, one or more _-CH2- groups in A are optionally and independently substituted with CONR. In other embodiments, one or more _-CH2- groups in A are optionally and independently substituted with NRCO. In other embodiments, one or more _-CH2- groups in A are optionally and independently substituted with _SO2 . In other embodiments, one or more _-CH2- groups in A are optionally and independently replaced with _SO2NR . R is described in further detail below.

In the embodiments described herein, R is hydrogen, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, COC ₁ -C ₆ alkyl or COOC ₁ -C ₆ alkyl. In certain embodiments, R is hydrogen, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkyl OH.

In certain embodiments, R is hydrogen. In certain embodiments, R is C ₁ -C ₆ alkyl COOH. In certain embodiments, R is COOH. In certain embodiments, R is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R is C ₁ -C ₆ alkyl. Examples of C ₁ -C ₆ alkyl groups may include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl Base, isopentyl, neopentyl, third pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl base, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl -1-Methylpropyl. In certain embodiments, R is haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R is C ₁ -C ₆ alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and isobutanol.

In certain embodiments, R is COC ₁ -C ₆ alkyl. Suitable examples include, but are not limited to, _COCH3 . In certain embodiments, R is COOC ₁ -C ₆ alkyl. Suitable examples include, but are not limited to, COOCH ₃ .

Examples of such embodiments include (but are not limited to) .

In certain embodiments, Series A .

In certain embodiments, one or more of the hydrogens along A can be independently replaced with a group selected from: hydroxyl, halogen, and C _1-3 haloalkyl. Examples of suitable halogens include chlorine, bromine, fluorine and iodine. In certain embodiments, Series A .

In each of the various embodiments of the invention, in the compounds used in the methods herein, the variables (including those in each of Formulas (I) to (VIII), and the various embodiments thereof), it is to be understood that unless Otherwise indicated, variables are selected independently of each other.

In each of the various embodiments of the invention, the compounds described herein (including those in each of Formulas (I) to (VIII) and various embodiments thereof) may exist in different forms of such compounds, such as, For example, any solvates, hydrates, stereoisomers and tautomers of these compounds and any pharmaceutically acceptable salts thereof.

In certain embodiments, compounds described herein include:

In certain embodiments, compounds described herein include: or its pharmaceutically acceptable salt.

Definitions and Abbreviations: Terms used herein have a general meaning and the meaning of such terms is independent of each occurrence. Notwithstanding this and unless otherwise specified, the following definitions apply throughout this specification and accompanying claims. Chemical names, common names, and chemical structures are used interchangeably to describe the same structure. Unless otherwise indicated, these definitions apply whether the term is used alone or in combination with other terms. Therefore, the definition of "alkyl" applies to "alkyl" and "alkyl" such as "hydroxyalkyl", "haloalkyl", arylalkyl‑, alkylaryl‑, "alkoxy", etc. part.

It will be appreciated that in the various embodiments of the invention described herein, any variable not explicitly defined herein within the embodiment is as defined in Formula (I).

In the various embodiments described herein, variables are selected independently of each other unless otherwise indicated.

"Resistance" associated with Plasmodium parasite strains means Plasmodium species that are no longer susceptible to at least one previously effective drug; Plasmodium species that have developed the ability to withstand challenge with at least one previously effective drug. Resistant strains can pass this tolerance on to their offspring. This resistance can be based on random genetic mutations in bacterial cells that change their sensitivity to a single drug or to different drugs.

"Patient" includes both humans and non-human animals. Non-human animals include those research animals and companion animals such as mice, rats, primates, monkeys, chimpanzees, great apes, dogs and domestic cats.

"Pharmaceutical composition" (or "pharmaceutically acceptable composition") means a composition suitable for administration to a patient. Such compositions may contain a pure compound (or compounds) of the invention or a mixture thereof, or a salt, solvate, prodrug, isomer or tautomer thereof, and one or more pharmaceutically acceptable carriers or Thinner. The term "pharmaceutical composition" is also intended to encompass a composition comprising one or more (eg, two) pharmaceutically active agents, such as, for example, a compound of the invention and an additional agent selected from the list of additional agents described herein, together with any Both the whole composition and the individual dosage units together with pharmaceutically inactive excipients. The overall composition and each individual dosage unit may contain a fixed amount of the aforementioned "more than one pharmaceutically active agent". The overall composition is not yet formed into individual dosage units. Exemplary dosage units are oral dosage units, such as tablets, pills, and the like. Similarly, the methods of treating a patient by administering a pharmaceutical composition of the present invention described herein are also intended to encompass the administration of the aforementioned composition as a whole and individual dosage units.

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

"Alkylene" (by itself or as part of another substituent) means a divalent hydrocarbon chain group having a specified number of carbon atoms. For example, -(C ₁ -C ₅ )alkylene will include, for example, -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ CH ₂ -, -CH ₂ CH(CH ₃ )CH ₂ - or -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -. Straight-chain alkylene group means a divalent straight-chain hydrocarbon chain group having a specified number of carbon atoms. Branched chain alkylene group means a bivalent branched hydrocarbon chain group having a specified number of carbon atoms. Saturated alkylene group means a divalent saturated hydrocarbon chain group having a specified number of carbon atoms. Unsaturated alkylene group means a divalent hydrocarbon chain group having a specified number of carbon atoms and one or more double or triple covalent bonds in the chain. Cycloalkyl group means a divalent hydrocarbon chain group having a specified number of carbon atoms and having a cycloalkyl moiety within the chain.

"Alkyl" means an aliphatic hydrocarbon group that may be straight or branched and contain about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain from about 1 to about 12 carbon atoms in the chain. More preferably, the alkyl group contains from about 1 to about 6 carbon atoms in the chain. Branched chain means that one or more lower alkyl groups, such as 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 tert-butyl.

"Haloalkyl" means an alkyl group as defined above, wherein one or more hydrogen atoms on the alkyl group are replaced by a halo group as defined above.

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

"Cycloalkyl" means 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 from about 5 to about 10 ring atoms. The cycloalkyl group may optionally be substituted with one or more substituents as described herein, which may be the same or different. Monocyclic cycloalkyl refers to the monocyclic form of the cycloalkyl moiety described herein. Non-limiting examples of suitable monocyclic cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Polycyclic cycloalkyl refers to polycyclic (including bicyclic) rings including non-aromatic rings. Non-limiting examples of suitable polycyclic cycloalkyl groups include 1-decalinyl, norbornyl, adamantyl, and the like. In certain embodiments, non-aromatic ring systems are fused to aromatic rings.

"Heterocycloalkyl" (or "heterocyclyl") means a non-aromatic, saturated or partially saturated monocyclic or polycyclic ring containing about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms. A ring system wherein one or more of the atoms in the ring system is an element other than carbon, such as nitrogen, oxygen, or sulfur alone or in combination. There are no adjacent oxygen and/or sulfur atoms in this ring system. Preferred heterocyclyl groups contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the name of a heterocyclyl radical means that at least one nitrogen, oxygen or sulfur atom, respectively, is present as a ring atom. Any -NH in the heterocyclyl ring may be protected, such as, for example, present as -N(Boc), -N(CBz), -N(Tos) groups, and the like; such protection is also considered are part of the present invention. The heterocyclyl group may optionally be substituted with one or more substituents as described herein, which may be the same or different. The nitrogen or sulfur atom of the heterocyclyl group can be oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide if necessary. Thus, the term "oxide" when it appears in the definition of a variable in the general structures described herein refers to the corresponding N-oxide, S-oxide or S,S-dioxide. "Heterocyclyl" also includes rings in which =O replaces two available hydrogens on the same carbon atom (i.e., heterocyclyl includes rings having a carbonyl group in the ring). These =O groups may be referred to herein as "pendant oxy groups." Examples of this section are pyrrolidinone/pyrrolidone: . As used herein, the term "monocyclic heterocycloalkyl" refers to the monocyclic form of the heterocycloalkyl moiety described herein and includes 4 to 7 membered monocyclic heterocycloalkyl groups containing 1 to 4 ring heteroatoms, 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 any available ring carbon or ring heteroatom. Non-limiting examples of monocyclic heterocycloalkyl groups include piperidinyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxane base, tetrahydrofuranyl, tetrahydrothiophenyl, β-lactam, γ-lactam, δ-lactam, β-lactone, γ-lactone, δ-lactone, and pyrrolidone, and their oxides. Non-limiting examples of monocyclic heterocycloalkyl groups include the following: .

Non-limiting examples of polycyclic heterocycloalkyl groups include bicyclic heterocycloalkyl groups. Specific examples include (but are not limited to) and .

"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 ether oxygen.

The term "substituted" means that one or more hydrogens on a specified atom are selectively replaced by the indicated group, subject to the proviso that the normal valence of the specified atom under the existing circumstances is not exceeded and that the substitution results in a stable compound. Combinations of substituents and/or variables are allowed only if such combinations result in stable compounds. "Stable compound" or "stable structure" means a compound that is stable enough to be isolated from the reaction mixture to a usable purity and formulated into an effective therapeutic agent.

The term "optionally substituted" means optional substitution with a specified group, radical or moiety.

When a variable occurs more than once in a group, for example, ^R8 in -N( ^R8 ) ₂ , or when a variable occurs more than once in a structure presented herein, the variables may be the same or different.

solid line , as a bond generally indicates a mixture of possible isomers (eg, containing (R)- and (S)-stereochemistry), or any one thereof. For example: means containing and Either or both.

As used herein, a wavy line intersecting a line representing a chemical bond is used. Indicates the attachment point to the remainder of the compound. Lines drawn within a ring system, such as, for example The indicator line (bond) may be attached to any of the substitutable ring atoms.

"Pendant oxy" is defined as a double bond to a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, or another ring described herein (e.g., ) of the oxygen atom of the ring carbon.

In this specification, where there are multiple oxygen and/or sulfur atoms in a ring system, there must not be any adjacent oxygen and/or sulfur atoms in the ring system.

As is well known in the art, unless otherwise stated, a bond drawn from a particular atom (with the portion not shown at the end of the bond) indicates the methyl group bound to that atom through the bond. For example: express .

In another embodiment, compounds suitable for use in the methods of the invention and/or compositions comprising the same suitable for use in such methods are in an isolated and/or purified form. The terms "purified", "in purified form" or "in isolated and purified form" when applied to a compound mean that the compound has been isolated from a synthetic process (e.g. from a reaction mixture), or from a natural source or a combination thereof. physical state. Thus, the terms "purified", "in purified form" or "in isolated and purified form" used for a compound mean that the compound (or a tautomer or stereoisomer thereof, or that the compound, The stereoisomer or a pharmaceutically acceptable salt or solvate of the tautomer) is obtained from a purification process or processes (e.g., chromatography, recrystallization, and the like) described herein or known to the skilled artisan. The latter physical state is sufficiently pure for in vivo or medical use and/or can be characterized by standard analytical techniques described herein or known to the skilled artisan.

It should be understood that any carbon and heteroatoms with unsatisfied valences in the text, schemes, examples and tables herein are assumed to have a sufficient number of hydrogen atoms to satisfy such equivalence.

When a functional group in a compound is said to be "protected," this means that the group is in a modified form to exclude undesirable side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be identified by the person of ordinary skill and by reference to standard textbooks such as, for example, T. W. Greene et al., Protective Groups in Organic Synthesis (1991), Wiley, New York.

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

For example, if a compound suitable for use in the methods of the invention, or a pharmaceutically acceptable salt thereof, contains carboxylic acid functionality, the prodrug may comprise an ester formed by replacing the hydrogen atom of the acid group with a group such as, for example (C ₁ -C ₈ )alkyl, (C ₂ -C ₁₂ )alkyloxymethyl, 1-(alkyloxy)ethyl having 4 to 9 carbon atoms, having 5 to 10 carbons Atom 1-methyl-1-(alkyloxy)-ethyl, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1-(alkoxy) having 4 to 7 carbon atoms Carbonyloxy)ethyl, 1-methyl-1-(alkoxycarbonyloxy)ethyl having 5 to 8 carbon atoms, N-(alkoxycarbonyl)amine having 3 to 9 carbon atoms Methyl, 1-(N-(alkoxycarbonyl)amino)ethyl with 4 to 10 carbon atoms, 3-phthalyl, 4-crotonolactonyl, γ-butyrolactone -4-yl, di-N,N-(C ₁ -C ₂ )alkylamino (C ₂ -C ₃ )alkyl (such as β-dimethylaminoethyl), aminoformyl- (C ₁ -C ₂ )alkyl, N,N-di(C ₁ -C ₂ )alkylaminoformyl-(C1-C2)alkyl and piperidinyl-, pyrrolidinyl- or morpholine (C ₂ -C ₃ )alkyl, and the like.

Similarly, if a compound suitable for use in the methods of the invention contains an alcohol functionality, the prodrug can be formed by replacing the hydrogen atom of the alcohol group with a group such as, for example: (C ₁ -C ₆ )alkyloxy Methyl, 1-((C ₁ -C ₆ )alkyloxy)ethyl, 1-methyl-1-((C ₁ -C ₆ )alkyloxy)ethyl, (C ₁ -C ₆ )Alkoxycarbonyloxymethyl, N-(C ₁ -C ₆ )alkoxycarbonylaminomethyl, succinyl, (C ₁ -C ₆ )alkyl, α-amino ( C ₁ -C ₄ ) alkyl group, aryl acyl group and α-amino acyl group or α-amino acyl group-α-amino acyl group, wherein each α-amino acyl group is independently selected from natural The resulting L-amino acid, P(O)(OH) ₂ , -P(O)(O(C ₁ -C ₆ ) alkyl) ₂ or sugar group (by removing the hydroxyl group in the hemiacetal form of carbohydrates generated groups), and the like.

If the compounds used in the methods of the present invention incorporate amine functionality, the prodrug can be formed by replacing a hydrogen atom in the amine group with a group such as, for example: R-carbonyl, RO-carbonyl, NRR'-carbonyl , where R and R' are each independently (C ₁ -C ₁₀ ) alkyl, (C ₃ -C ₇ ) cycloalkyl, benzyl, or R-carbonyl is natural α-amino acyl group or natural α -Amino acyl group, ‑C(OH)C(O)OY ¹ , where Y ¹ is H, (C ₁ -C ₆ ) alkyl or benzyl, ‑C(OY ² )Y ³ , where Y ² (C ₁ -C ₄ ) alkyl and Y ³ (C ₁ -C ₆ ) alkyl, carboxyl (C ₁ -C ₆ ) alkyl, amino (C ₁ -C ₄ ) alkyl or mono-N - or di-N,N-(C ₁ -C ₆ )alkylaminoalkyl, -C(Y ⁴ )Y ⁵ , where Y ⁴ is H or methyl and Y ⁵ is mono-N- or di- N,N-(C ₁ -C ₆ )alkylaminomorpholinyl, piperidin-1-yl or pyrrolidin-1-yl, and the like.

One or more compounds used in the methods of the invention may exist in unsolvated and solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and the invention is intended to encompass solvated forms. and both unsolvated forms. "Solvate" means a physical association of a compound of the invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. Under certain circumstances, the solvate will be isolable, such as when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" encompasses both solution phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate in which the solvent molecule is _H2O .

One or more compounds used in the methods of the invention may optionally be converted to solvates. The preparation of solvates is generally known. Thus, for example, M. Caira et al., J. Pharmaceutical Sci., 1993, 3, 601-611 describe the preparation of solvates of the antifungal fluconazole in ethyl acetate and from water. Similar preparations of solvates, hemisolvates, hydrates, and the like were performed by EC van Tonder et al., AAPS PharmSciTech., 5(1) , Paper 12 (2004); and AL Bingham et al., Chem. Commun., 603 -604 (2001) Description. A typical, non-limiting method involves dissolving a compound of the invention in a desired amount of the desired solvent (organic or water or a mixture thereof) at a temperature above ambient and cooling the solution at a rate sufficient to form crystals, followed by The crystals were isolated by standard methods. Analytical techniques such as, for example, infrared spectroscopy reveal the presence of the solvent (or water) in the crystals as a solvate (or hydrate).

"Effective amount" or "therapeutically effective amount" is intended to describe an amount of a compound or composition used in the methods of the invention that is effective in inhibiting the disease or enzyme activity mentioned above and thereby producing the desired therapeutic, ameliorative, inhibitory or preventive effect. .

Another embodiment provides pharmaceutically acceptable salts of compounds to be used in the methods of the invention. Accordingly, it will be understood that reference herein to a compound in the methods of the invention includes reference to its salts unless otherwise indicated. The term "salt" as used herein means acidic salts with inorganic and/or organic acids, and alkaline salts with inorganic and/or organic bases. Additionally, when compounds of the present invention contain both a basic moiety (such as, but not limited to, pyridine or imidazole), and an acidic moiety (such as, but not limited to, carboxylic acid), zwitterions ("inner salts") can be formed and include Within the term "salt" as used herein. Although other salts are useful, pharmaceutically acceptable (ie, nontoxic, physiologically acceptable) salts are preferred. Salts of compounds used in the methods of the invention may be prepared, for example, by reacting a compound of the invention with an amount (such as equivalents) of an acid or base in a medium (such as one in which the salt is precipitated) or in an aqueous medium. , followed by freeze-drying to form.

Exemplary acid addition salts include acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate Salt, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate acid salts, succinates, sulfates, tartrates, thiocyanates, tosylates (also known as tosylates), and the like.

In addition, acid systems generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds (eg, P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; 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). These disclosures are incorporated herein by reference.

Exemplary 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), and organic bases (e.g., organic amines such as dicyclohexylamine , tert-butylamine) salts, and salts with amino acids (such as arginine, lysine and the like). 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., di- Methyl, diethyl and dibutyl sulfates), long chain halides (such as decyl, dodecyl and stearyl chlorides, bromides and iodides), aralkyl halides (such as benzene Methyl and phenethyl bromide), etc.

It is intended that all such acid acid and base salts are pharmaceutically acceptable salts within the scope of this invention and that for purposes of this invention all acid and base salts are considered equivalent to the free form of the corresponding compound.

Another embodiment provides pharmaceutically acceptable esters of compounds for use in the methods of the invention. Such esters include the following group: (1) Carboxylic acid esters obtained by esterification of hydroxyl groups, in which the non-carbonyl portion of the carboxylic acid portion of the ester group is selected from linear or branched alkyl groups (e.g., acetyl groups , n-propyl, tert-butyl or n-butyl), alkoxyalkyl (e.g., methoxymethyl), aralkyl (e.g., benzyl), aryloxyalkyl (e.g., benzene Oxymethyl), aryl (e.g., phenyl substituted by, for example, halogen, C _1-4 alkyl or C _1-4 alkoxy or amine as appropriate); (2) sulfonate esters, such as Alkyl- or aralkyl sulfonyl group (for example, methane sulfonyl group); (3) Amino acid ester (for example, L-valinyl or L-isoleucinyl group); (4) Phosphonic acid esters and (5) mono-, di- or triphosphates. The phosphate ester may be further esterified, for example, by a C _1-20 alcohol or a reactive derivative thereof, or by 2,3-bis(C _6-24 ) acylglycerol.

As mentioned herein, another embodiment provides tautomers of the compounds of the invention for use in the methods herein, and salts, solvates, esters and prodrugs of such tautomers. It is understood that all tautomeric forms of such compounds are within the scope of compounds useful in the methods of the invention. For example, when present, all keto-enol and imine-enamine forms of these compounds are included in the present invention.

Compounds used in the methods of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds used in the methods of the invention and mixtures thereof (including racemic mixtures) form part of the invention. Additionally, the present invention encompasses the use of all geometric and positional isomers. For example, if the compounds used in the methods of the invention incorporate double bonds or fused rings, then cis and trans forms, both (E) and (Z) forms, and mixtures are included within the scope of the invention.

Another embodiment provides diastereomeric mixtures and individual enantiomers of compounds for use in the methods of the invention. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physicochemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride) The diastereomers are separated by converting (eg, hydrolyzing) the individual diastereomers into the corresponding pure enantiomers. Likewise, some of the compounds used in the methods of the invention may be atropisomers (eg, substituted biaryls) and are considered part of the invention. Enantiomers can also be separated by using chiral HPLC columns.

All stereoisomers (e.g., geometric isomers, optical isomers and the like), such as those that may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons) , rotamer, atropisomer and diastereomeric forms are considered to be examples within the scope of the invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridine base). (For example, if the compounds of the present invention incorporate double bonds or fused rings, both cis and trans forms and mixtures thereof are included within the scope of the present invention. Likewise, for example, all keto-enols and sub-forms of these compounds Amine-enamines are included in the method of the invention).

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

Another embodiment provides isotopically labeled compounds to be used in the methods of the invention. These compounds are identical to those listed herein, but in fact one or more atoms have been replaced by atoms having atomic masses or mass numbers different from those typically found in nature. Examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ^{17 respectively} O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl.

Certain isotopically labeled compounds of the present invention (eg, those labeled with ³ H and ¹⁴ C) are suitable for use in compound and/or substrate tissue distribution analysis. Deuterated (ie, ³ H) and carbon-14 (ie, ¹⁴ C) isotopes are particularly preferred because of their ease of preparation and detectability. Furthermore, substitution with heavier isotopes such as deuterium (i.e., ² H) may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and thus in some cases It can be better. Isotopically labeled compounds of the present invention can generally be prepared by the following procedures similar to those disclosed in the schemes and/or examples below, by substituting appropriate isotopically labeled reagents for non-isotopically labeled reagents.

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 to have the same number of atoms but a different atomic mass than those primarily found in nature. Or a specific isotope with a mass number. This invention is intended to include all suitable isotopic modifications of the compounds of the invention. For example, different isotopic forms of hydrogen (H) include protium ( ¹ H) and deuterium ( ² H). The presence of deuterium in the compounds of the invention is indicated by "D". Protium is the main hydrogen isotope found in nature. Enriching deuterium may provide certain therapeutic advantages, such as increased half-life in vivo or reduced dosage requirements, or may provide compounds suitable as standards for characterization of biological samples. The isotope-enriched compounds of the present invention can be prepared by conventional techniques well known to those skilled in the art or by methods similar to those described in the schemes and examples herein using appropriate isotope-enriched reagents and/or intermediates. No need to over-experiment.

The compounds used in the methods of the invention, and polymorphic forms of salts, solvates, esters and prodrugs of the compounds of the invention are intended to be included in the invention.

Methods of Treatment The present invention is directed to methods of treating Plasmodium infections, which comprise administering to an individual in need thereof a compound described herein, or a pharmaceutically acceptable salt thereof. More specifically, the methods of the present invention include 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.

The present invention provides a method for treating Plasmodium infection, or for treating malaria, or for inhibiting malaria heme X, which includes administering to an individual in need of such treatment a therapeutically effective amount of a compound or its pharmaceutical Acceptable salts of compounds having structural formula (I) 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. Various examples of such methods are also provided herein, as described below.

The present invention also relates to the use of compounds of formulas (I) to (VIII) or pharmaceutically acceptable salts thereof in inhibiting malarial heme X activity, in treating Plasmodium infection, or in treating malaria. The present invention further relates to the use of compounds of formulas (I) to (VIII) or pharmaceutically acceptable salts thereof in the manufacture of medicaments for inhibiting malarial heme X activity, for treating Plasmodium infection, or for treating malaria. . The compounds of formulas (I) to (VIII) or pharmaceutically acceptable salts thereof described in any of the embodiments of the invention herein are suitable for use in any of the above uses.

The present invention provides a method for treating Plasmodium infection or for treating malaria or for inhibiting malaria heme IX, which method includes administering to an individual in need of such treatment a therapeutically effective amount of a compound or a pharmaceutically acceptable amount thereof. The salt of the compound has the structural formula (I) described in the content of the present 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. Various examples of such methods are also provided herein, as described below.

The present invention also relates to the use of compounds of formulas (I) to (VIII) or pharmaceutically acceptable salts thereof in inhibiting malarial heme IX activity, in treating Plasmodium infection, or in treating malaria. The present invention further relates to the use of compounds of formulas (I) to (VIII) or pharmaceutically acceptable salts thereof in the manufacture of medicaments for inhibiting malarial heme IX activity, for treating Plasmodium infection, or for treating malaria. . The compounds of formulas (I) to (VIII) or pharmaceutically acceptable salts thereof described in any of the embodiments of the invention herein are suitable for use in any of the above uses.

The present invention provides a method for treating Plasmodium infection or for treating malaria or for inhibiting malarial heme X and malarial heme IX, which method includes administering a therapeutically effective amount of a compound to an individual in need of such treatment. Or a pharmaceutically acceptable salt thereof, the compound has the structural formula (I) described in the summary of the present 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. Various examples of such methods are also provided herein, as described below.

The present invention also relates to the use of the compounds of formulas (I) to (VIII) or their pharmaceutically acceptable salts in inhibiting the activity of malarial hem X and malarial heme IX, in the treatment of Plasmodium infection, or in the treatment of malaria. The present invention further relates to compounds of formulas (I) to (VIII) or pharmaceutically acceptable salts thereof for use in the manufacture of inhibiting the activity of malarial heme X and malarial heme IX, for treating malarial parasite infections or for Uses of drugs to treat malaria. The compounds of formulas (I) to (VIII) or pharmaceutically acceptable salts thereof described in any of the embodiments of the invention herein are suitable for use in any of the above uses.

The methods of the invention are suitable for treating malaria because they inhibit the onset, growth or progression of the condition, ameliorate the symptoms of the condition, cause regression of the condition, cure the condition or otherwise ameliorate suffering from or being at risk of the condition. , the general sense of well-being of individuals infected with the disease. Accordingly, in accordance with the subject matter disclosed herein, the terms "treat" and "treating" and their grammatical variations, and the phrase "treatment method" are intended to cover any desired therapeutic intervention, including (but not limited to) a method for treating Methods of existing infection in infected individuals, such as those that have been exposed to parasites as disclosed herein.

Embodiments of the present invention also include one or more of the compounds of formulas (I) to (VIII) or pharmaceutically acceptable salts thereof (i) for use in a medicament or composition, (ii) for use in a medicament or composition , or (iii) for the preparation of medicaments for: (a) therapy (e.g., therapy in humans); (b) pharmaceuticals; (c) inhibition of parasite/Plasmodium growth, (d) treatment or prevention of malaria Infections with protozoal species; (e) reduce the progression, onset or severity of pathological symptoms associated with Plasmodium infection and/or reduce the likelihood of severe Plasmodium infection, or (f) treat, prevent, or delay malaria Protozoal-related diseases, including (but not limited to): onset, severity or progression of malaria.

Accordingly, another embodiment provides a method for treating malaria or for treating a Plasmodium infection, comprising administering an amount comprising at least one compound of formulas (I) to (VIII), or a pharmaceutically acceptable salt thereof , a solvate, ester or prodrug, and an effective amount of one or more additional agents described below. In certain embodiments, described herein are methods for treating malaria or for treating Plasmodium infections comprising administering an amount comprising at least one compound of Formulas (I) to (VIII), or a pharmaceutically acceptable compound thereof A combination of a salt, solvate, ester or prodrug and an effective amount of one or more additional antimalarial agents. In certain embodiments, described herein are methods of treating malaria by inhibiting malaria hem X, IX, and at least one other mechanism, comprising administering an amount comprising at least one compound of Formulas (I) to (VIII), or A combination of a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and an effective amount of one or more additional antimalarial agents, wherein the additional antimalarial agents inhibit malaria-lowering heme IX or malaria-lowering hemoglobin through a different The mechanism of prime X comes into play. The pharmacological properties of the compounds of formulas (I) to (VIII), or pharmaceutically acceptable salts thereof, can be confirmed by several pharmacological analyses.

Dosage and Administration Another example provides suitable dosage and dosage forms of compounds for use in the methods of the invention. The dosage of a compound suitable for administration to a patient for use in the methods of the invention can be readily determined by one skilled in the art, for example, by an attending physician, pharmacist, or other skilled worker, and can be based on the health, age, and health of the patient. , weight, frequency of administration, use of other active ingredients and/or indications for which the compounds are administered. Dosages may range from about 0.001 to 500 mg/kg body weight/day of a compound of the invention. In one embodiment, the dosage is from about 0.01 to about 25 mg/kg body weight/day of a compound of the invention, or a pharmaceutically acceptable salt or solvate of the compound. In another example, the amount of active compound in a single dose formulation may vary or be adjusted from about 1 mg to about 100 mg, in certain embodiments from about 1 mg to about 50 mg, in certain embodiments, depending on the particular application. In the examples, the dosage was adjusted from about 1 mg to about 25 mg. In another example, a typical recommended daily dosage regimen for oral administration may range from about 1 mg/day to about 500 mg/day, in specific embodiments 1 mg/day to 200 mg/day. Within, take two to four divided doses.

As discussed above, the amount and frequency of administration of the compounds of the present invention and/or pharmaceutically acceptable salts thereof will be based on the judgment of the attending clinician, taking into account factors such as age, disease and size of the patient and the severity of the symptoms being treated. Factor adjustment.

Liquid form preparations include solutions, suspensions and emulsions. As an example, mention may be made of water or water-propylene glycol solutions for parenteral injection or the addition of sweetening and opacifying agents for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be combined with a pharmaceutically acceptable carrier such as an inert compressed gas, eg, nitrogen.

Also included are solid form preparations which are intended to be converted immediately before use to liquid form preparations for oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

Another embodiment provides the use of a composition comprising a compound of Formulas (I) to (VIII), or a pharmaceutically acceptable salt thereof, formulated for transdermal delivery. Such transdermal compositions may take the form of creams, lotions, aerosols and/or emulsions and may be included in transdermal patches of the matrix or reservoir type, as is customary in the art for this purpose. Know.

Another embodiment provides the use of a composition comprising a compound of Formulas (I) to (VIII), or a pharmaceutically acceptable salt thereof, formulated for subcutaneous delivery. Another embodiment provides the use of a composition suitable for oral delivery. In some embodiments, it may be advantageous to prepare pharmaceutical formulations containing one or more compounds of formulas (I) to (VIII), or pharmaceutically acceptable salts thereof, in unit dosage form. In such forms, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active ingredient, e.g., an effective amount to accomplish the required purpose. Each of the foregoing alternatives is considered to be included in various embodiments of the invention.

When used in combination with one or more additional therapeutic agents ("combination therapy"), the compounds used in the methods of the invention, ie, compounds of formulas (I) to (VIII), can be administered together or sequentially. When administered sequentially, the compounds of the invention may be administered before or after one or more additional therapeutic agents, as determined by one skilled in the art or patient preference.

If formulated as a fixed dose, the combination product employs compounds of Formulas (I) to (VIII) or pharmaceutically acceptable salts thereof within the dosage ranges described herein and other pharmaceutically active agents or treatments within the dosage ranges described herein.

Combination Therapy Another embodiment provides a method of treatment using a pharmaceutically acceptable composition comprising a compound of the invention, either as a pure chemical or, optionally, further comprising additional ingredients. These compositions are carefully considered for preparation and use alone or in combination therapy. For preparing pharmaceutical compositions from the compounds of the present invention, inert pharmaceutically acceptable carriers may be solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. Powders and tablets may contain from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, for example magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules are available as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of making various compositions can be found in A. Gennaro (Ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pennsylvania.

Non-limiting examples of additional drugs and active agents suitable for use in combination therapy for the treatment of malaria include the following: 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) (artesunate)), ASAQ Winthrop® (Sanofi SA (Gentilly, France)/DNDI (Geneva, Switzerland); artesunate + amodiaquine), ASMQ (Cipla Limited (Mumbai, India)/DNDi, Artesunate + mefloquine), SPAQ-CO™ (Guilin Pharmaceutical Co., Ltd. (Shanghai), amodiaquine + sulfadoxine, pyrimethamine), Artesun® (Guilin Pharmaceutical, artesunate), artemether, artesunate, dihydroartemisinin, lumefantrine, amodiaquine, mefloquine, piperaquine, quinine, chloroquine , atovaquone, proguanil, sulfadoxine-pylimamide, Tafenoquine (Glaxosmithkline), OZ439/PQP (Sanofi), OZ439/FQ (Sanofi), KAE609 (Novartis), KAF156 (Novartis), DSM265 (NIH/Takeda), and MK-4815 (Merck & Co., Inc., Powles et al., Antimicrobial Agents and Chemotherapy 56(5): 2414–2419(2012)). The selection of such additional active ingredients will be based on the current disease or condition to be treated, as determined by the attending physician or other health care provider.

Therefore, the present invention also provides the use of compounds of formulas (I) to (VIII) or pharmaceutically acceptable salts thereof to inhibit malaria heme X, malaria heme IX or malaria heme X and IX to treat malaria. A method of parasitic infection or treatment of malaria, wherein the method further comprises administering to an individual in need thereof one or more additional anti-malarial agents. In some embodiments, the one or more additional anti-malarial agents are selected from the group consisting of: artemether, lumefantrine, dihydroartemisinin, piperaquine, pyronidine, artesunate, amor Diquine, mefloquine, sulfadoxine, pirimetamide, lumefantrine, quinine, chloroquine, atovaquone and proguanil.

Examples The meanings of the abbreviations in the examples are shown below. ACN = MeCN = CH ₃ CN = Acetonitrile AcOH = Acetic acid AIBN = Azobisisobutyronitrile Ar = Argon BBr ₃ = Boron tribromide BF ₃ Et ₂ O = Boron trifluoride ethyl ether Boc ₂ O = Dicarbonate dicarbonate Tributyl ester Cbz = Carboxybenzyl CbzOSu = N-(Benzyloxycarbonyloxy)succinimide CBr ₄ = Tetrabromomethane CCl ₄ = Carbon tetrachloride CELITE = Diatomaceous earth Concentration = Concentrated Cs ₂ CO ₃ =Cesium Carbonate DBU = 1,8-Diazabicyclo[5.4.0]Undec-7-ene DCE =Dichloroethane DCM =Dichloromethane DDQ = 2,3-Dichloro-5,6-di Cyano-1,4-benzoquinone DIBALH = diisobutylaluminum hydride DIPEA = DIEA = N,N-diisopropylethylamine or Hünig base DMA = dimethylacetamide DMAP = 4 -Dimethylaminopyridine DMF = N,N-dimethylformamide DMP = Dess-Martin periodate DMSO = Dimethylsine DPPE = 1,2-bis(diphenylphosphino) Ethane DPPF = 1,1'-bis(diphenylphosphino)ferrocene EDCI = EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Et ₂ O = Ether EtOAc = Ethyl acetate EtOH = Ethanol Et ₃ SiH = Triethylsilane h = H ₂ = Hydrogen HATU = 1-[Bis(dimethylamino)methylene]-1H-1,2,3- Triazolo[4,5-b]pyridinium 3-oxyhexafluorophosphate HCl = hydrochloric acid HFBA = heptafluorobutyric acid HOAc = acetic acid I ₂ = iodine IPA = isopropyl alcohol [Ir(cod)Cl] ₂ = Cycloctadiene Iridium Chloride Dimer K ₂ CO ₃ = Potassium Carbonate K ₃ PO ₄ = Tripotassium Phosphate KF = Potassium Fluoride KHMDS = Potassium Bis(trimethylsilyl)amide KOTMS = Trimethylsilyl alcohol Potassium LCMS = liquid chromatography-mass spectrometry LDA = lithium diisopropylamide LHMDS = LiHMDS = lithium bis(trimethylsilyl)amide LiAlH ₄ = lithium aluminum hydride LiOH = lithium hydroxide min = minutes Me = Methyl MeCN = Acetonitrile MeOH = CH ₃ OH = Methanol MgSO ₄ = Magnesium sulfate MsCl = Methanesulfonyl chloride N ₂ = Nitrogen NaBH ₄ = Sodium boron hydrate NaH = Sodium hydride NaHCO ₃ = Sodium bicarbonate NaIO ₄ = Periodic acid Sodium NaOH = Sodium hydroxide Na ₂ CO ₃ = Sodium carbonate Na ₂ SO ₃ = Sodium sulfite Na ₂ SO ₄ = Sodium sulfate NH ₄ Cl = Ammonium chloride NH ₄ OH = Ammonium hydroxide NH ₄ OAc = Ammonium acetate NaHMDS = Bis( Sodium trimethylsilyl)amide OMs = methanesulfonate OTs = toluenesulfonate OTf = trifluoromethanesulfonate Pd(OH) ₂ /C = Pearlman's catalyst-carbon-loaded hydrogen oxidation Palladium-C Pd-C = Palladium on carbon -C [Pd(C ₃ H ₅ )Cl ₂ ] = Allylpalladium(II) chloride dimer PdCl ₂ (dppf)-CH ₂ Cl ₂ = [1, 1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) PPh ₃ = triphenylphosphine RuO ₂ .H ₂ O = ruthenium(IV) oxide hydrate RP-HPLC = reversed phase high performance liquid Phase Chromatography SFC = Supercritical Fluid Chromatography TBDPS-Cl = TBSCl = Tertiary Butyl(chloro)diphenylsilane TEA = Et ₃ N = Triethylamine TBAF = Tetra-n-butylammonium fluoride TFA = THF trifluoroacetate = Tetrahydrofuran Ti(EtO) ₄ = Titanium ethoxide TMS = Trimethylsilyl TMSOTf = Trimethylsilyl trifluoromethanesulfonate TsOH = p-Toluenesulfonic acid CDCl ₃ = Heavy chloroform CD ₃ OD = Heavy Methanol 1 standard atmosphere [atm] = 101325 Pascal [Pa] = 14.6959488 psi The meaning of the abbreviations in the NMR spectrum is shown below: s = singlet, d = doublet, dd = double doublet, dt = double triplet, ddd = doublet, Sept = sept, t = triplet, m = multiplet, br = broadt, brs = broad singlet, q = quartet, J = coupling constant and Hz = Hertz.

Several methods for preparing compounds of the invention are described in the following schemes and examples. Starting materials and intermediates were purchased from common catalog sources or prepared using known processes, or as otherwise stated. Some common pathways for compounds of formula I are described in the following schemes. In some cases, the order in which the reaction steps in these schemes are performed may be varied to facilitate the reaction or to avoid undesired reaction products.

Option 1

Compounds of formula S-2 are prepared from S-1 by macrolactamization using amide coupling reagents.

Option 2

The intermediate compound of formula S-4 is derived from S-3 by using a catalyst (such as the second generation Grubbs', Zhan's and Hoveyda/Grubbs' catalyst) for ring closure. Prepared after metathesis (RCM) reaction. The double bond in S-4 can be reduced, for example, under hydrogenation conditions to yield the product of formula S-5.

Option 3

Intermediate compounds of formula S-7 are prepared from S-6 (wherein The resulting double bond in S-7 can be reduced, for example, under hydrogenation conditions to yield the product of formula S-8.

Option 4

The product of formula S-10 is prepared from S-9 (where

Option 5

The product of formula S-12 is prepared from S-11 following an intramolecular S _N reaction between an alcohol and X, where X is a leaving group such as Cl, Br, I, OMs, OTs or OTf. The product of formula S-12 is also prepared from S-11 diol using acid or other dehydrating reagent after dehydration conditions.

Option 6

The product of formula S-12 is prepared from intermediate S-13 or S-14 after intramolecular reductive etherification using conditions such as TMSOTf and _Et3SiH .

Reactions that are sensitive to moisture or air are performed inside a glove box or under nitrogen or argon using anhydrous solvents and reagents. Reaction progress is determined by analytical thin layer chromatography (TLC) or liquid chromatography-mass spectrometry (LC/MS) typically performed using E. Merck precoated TLC plates, Silica 60F-254, layer thickness 0.25 mm .

Typically, the analytical LC-MS system used consists of a Waters ZQ ^™ platform with electrospray ionization in positive ion detection mode and an Agilent 1100 Series HPLC with an autosampler. Columns are typically Waters Xterra MS C18, 3.0 × 50 mm, 5 μm or Waters Acquity UPLC ^® BEH C18 1.0 × 50 mm, 1.7 μm. The flow rate was 1 mL/min, and the injection volume was 10 μL. UV detection is in the range 210 to 400 nm. The mobile phase consists of solvent A (water plus 0.05% TFA) and solvent B (MeCN plus 0.05% TFA). The gradient is 100% solvent A for 0.7 min, lasting 3.75 min, changing to 100% solvent B, maintaining for 1.1 min, and then lasting 0.2 min. min to return to 100% solvent A.

Preparative HPLC purification is typically performed using mass spectrometry-guided systems or non-mass spectrometry-guided systems. Typically they are performed on a Waters chromatography workstation equipped with an LC-MS system consisting of: Waters ZQ ^™ single quaternary MS system with electrospray ionization, Waters 2525 gradient pump, Waters 2767 syringe/collector, Waters 996 PDA detector, MS conditions: 150 to 750 amu, positive electrospray, MS-triggered collection, and Waters SUNFIRE ^® C-18 5 micron, 30 mm (id) x 100 mm column. The mobile phase consisted of a mixture of acetonitrile (10 to 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 to 400 nm. The alternative preparative HPLC system used was a Gilson workstation consisting of: Gilson GX-281 syringe/collector, Gilson UV/VIS-155 detector, Gilson 333 and 334 pumps, and Phenomenex Gemini-NX C-18 5 micron , 50 mm (id) x 250 mm column or Waters XBridge™ C-18 5 Micron OBD™, 30 mm (id) x 250 mm column. The mobile phase consisted of a mixture of acetonitrile (0 to 75%) in water containing 5 mmol ( _NH4 ) _HCO3 . The flow rate was maintained at 50 mL/min for the Waters Xbridge™ column and 90 mL/min for the Phenomenex Gemini column. The injection volume ranges from 1000 to 8000 μL, and the UV detection range is from 210 to 400 nm. Mobile phase gradients are optimized for individual compounds. Reactions using microwave radiation are typically performed using an Emrys optimizer manufactured by Personal Chemistry, or an initiator manufactured by Biotage. The solution was concentrated on a rotary evaporator under reduced pressure. Flash chromatography is typically performed on silica (32 to 63 µM, 60 Å pore size) using a ^Biotage® flash chromatography device (Dyax Corp.), an ISCO CombiFlash® Rf device, or an ISCO CombiFlash® Companion carried out in the filter cartridge. Unless otherwise stated, ^H NMR spectra were acquired in _CDCl solution at 500 MHz spectrometer. Chemical shifts are reported in parts per million (ppm). Tetramethylsilane (TMS) was used as the internal reference in the CDCl ₃ solution, and the residual CH ₃ OH peak or TMS was used as the internal reference in the CD ₃ OD solution. Coupling constants (J) are reported in Hertz (Hz). Chiral analytical chromatography is most commonly performed on CHIRALPAK ^® AS, which specifies the percentage of ethanol in hexane (%Et/Hex) or isopropyl alcohol in heptane (%IPA/Hep) as the isocratic solvent system. It was performed on one of CHIRALPAK ^® AD, CHIRALCEL ^® OD, CHIRALCEL ^® IA or CHIRALCEL ^® OJ column (250x4.6 mm) (Daicel Chemical Industries, Ltd.). Chiral preparative chromatography is based on CHIRALPAK AS, CHIRALPAK AD, CHIRALCEL ^® OD, CHIRALCEL ^® IA, CHIRALCEL ^® OJ columns (20x250) with isocratic solvent systems required for identification of chiral analytical chromatography. mm) (Daicel Chemical Industries, Ltd.) or by supercritical fluid (SFC) conditions.

It should be understood that the chiral center in a compound can exist in the "S" or "R" configuration, or in a mixture of the two. Within a molecule, bonds drawn as straight lines from the chiral center include both (R) and (S) stereoisomers and mixtures thereof.

Preparation of Intermediate 1 Intermediate 1-2

DBU (21.72 mL, 144 mmol) and diphenylphosphine group were added to (S)-4-hydroxychroman-6-carboxylic acid methyl ester (INT1-1) (10 g, 48.0 mmol) in THF (80 mL). Then azide (35.0 g, 144 mmol) was added under _N2 . The mixture was stirred at 50 °C for 12 h. The mixture was quenched with water (100 mL) and extracted with EtOAc (3 x 100 mL). The organic layer was washed with brine (80 mL), dried _{over Na2SO4} , filtered and concentrated. The crude product was purified by flash silica column chromatography ( ^ISCO® ; 330 g ^SepaFlash® silica flash column, 15% EtOAc/petroleum ether gradient at 50 mL/min) to yield (R )-4-azidochromanane-6-carboxylic acid methyl ester (INT1-2).

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 intermediates 1-3

Pd-C (2.510 g, 4.72 mmol) was added to (R)-4-azidochroman-6-carboxylic acid methyl ester (INT1-2) (11 g, 47.2 mmol) in THF under _N atmosphere (200 mL). The mixture was degassed and backfilled with H ( _three times). The resulting mixture was stirred at 25°C under _H2 (15 psi) atmosphere for 12 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to yield (R)-4-aminochroman-6-carboxylic acid methyl ester (INT1-3).

MS (ESI) m/z: 191.1 (M-17+H ⁺ )

Preparation of intermediate 1

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 _N2 . After 1 hr 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 (R)-4-aminochroman-6-carboxylic acid methyl ester (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 x 50 mL). The organic layer was washed with brine ₍ 40 mL), dried over _Na2SO4 , filtered, and concentrated in vacuo. The crude product was purified by flash silica column chromatography (ISCO ^® ; 220 g SepaFlash ^® silica flash column, 20% EtOAc/petroleum ether gradient at 50 mL/min) to provide (R )-4-(3-(tert-butoxycarbonyl)thiourido)chromane-6-carboxylic acid methyl ester (INT-1).

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)

Preparation of Intermediate 2 Intermediate 2-2

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 Salt (54.6 g, 559 mmol). The reaction was stirred at 25 °C under _N2 atmosphere for 12 h. LCMS shows desired mass. The mixture was quenched with water (300 mL) and extracted with DCM (3 x 100 mL). The organic layer was washed with brine (100 mL), dried over _Na2SO4 , filtered and concentrated in vacuo, and the crude _product was purified by flash silica column chromatography (ISCO®; 220 g Agela silica flash tube column, the eluent was 8% ethyl acetate/petroleum ether gradient at 50 mL/min) and purified to provide N-methoxy-N-methylpent-4-enamide (INT2-2).

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 intermediate 2-3

A solution of N-methoxy-N-methylpent-4-enamide (INT2-2) (20 g, 140 mmol) in THF (200 mL) at 0 °C under _N2 atmosphere followed by Ethyl magnesium bromide (69.8 mL, 210 mmol) was added dropwise at 0°C. The reaction was stirred at 25 °C under _N2 atmosphere for 1 h. TLC shows new points. The mixture was quenched with saturated aqueous _NH4Cl (100 mL) and water (100 mL), and extracted with EtOAc (3 x 100 mL). The organic layer was washed with brine (50 mL), dried over _Na2SO4 , filtered and concentrated in _vacuo , and the crude product was purified by flash silica column chromatography (ISCO®; 120 g Agela silica flash tube column, the eluent was 5% ethyl acetate/petroleum ether gradient at 40 mL/min) and purified to provide hept-6-en-3-one (INT2-3).

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 intermediates 2-4

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 the addition of Ti(EtO) ₄ (37.5 mL, 178 mmol), and the reaction was stirred at 75 °C under a _N atmosphere for 12 h. TLC shows new points. The final mixture was cooled to room temperature, then diluted with DCM (200 mL), stirred for 15 min, then ice-cold with saturated aqueous sodium bicarbonate (50 mL) and _Na2SO4 , then filtered and concentrated in vacuo _. The crude product was purified by flash silica column chromatography (ISCO®; 120 g Agela silica flash column, 8% ethyl acetate/petroleum ether gradient at 40 mL/min) to provide ( R,E)-N-(hept-6-en-3-ylidene)-2-methylpropane-2-sulfinamide (INT2-4).

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 intermediates 2-5

To a solution of diisopropylamine (19.64 mL, 139 mmol) in anhydrous THF (40 mL) was added dropwise butyllithium (55.7 mL, 139 mmol) at -78°C under _N2 atmosphere. The reaction was stirred at 0 °C for 30 min to prepare LDA. Methyl acetate (7.48 mL, 93 mmol) and Ti(OiPr) ₃ Cl (116 mL, 116 mmol) were added to dry THF (90 mL). LDA (76 mL, 93 mmol) was then added dropwise to the mixture at -78°C. After 1 h, (R,E)-N-(hept-6-en-3-ylidene)-2-methylpropane-2-sulfinamide (INT2-4) (10 g, 46.4 mmol) in anhydrous THF (20 mL) and the mixture was stirred at -78 °C for 3 h. There is no change in color and it is yellow. LCMS shows primary DP mass. The mixture was quenched with ice-cold semisaturated aqueous ammonium chloride solution (60 mL). The slurry was diluted with EtOAc (200 mL), filtered, and washed with EtOAc and water. The organic layer _was washed with brine (50 mL), dried over _Na2SO4 , filtered and concentrated in vacuo. The residue was purified by flash silica column chromatography (ISCO®; 120 g Agela silica flash column, 25% ethyl acetate/petroleum ether gradient at 40 mL/min) to provide 3 -(((R)-tert-Butylsulfinyl)amino)-3-ethylhept-6-enoic acid methyl ester (INT2-5).

MS (ESI) m/z 290.1 (M+H) ⁺

¹ H NMR (500 MHz, chloroform-d) δ 5.76-5.82 (m, 1H), 5.01-5.05 (m, 1H), 4.97 (dd, J = 1.0, 10.0 Hz, 1H), 4.63 (br d, J = 17.0 Hz, 1H), 3.68 (s, 3H), 2.72 (dd, J = 5.0, 16.0 Hz, 1H), 2.52 (dd, J = 2.5, 16.0 Hz, 1H), 2.07-2.13 (m, 1H) , 1.82-1.91 (m, 1H), 1.76-1.81 (m, 1H), 1.71-1.75 (m, 1H), 1.26 (t, J = 7.0 Hz, 2H), 1.24 (s, 9H), 0.87-0.95 (m, 3H)

Preparation of intermediates 2-6

3-(((R)-tert-Butylsulfinyl)amino)-3-ethylhept-6-enoic acid methyl ester (INT2-5) (12 g, 41.5 mmol) was purified via SFC tube Column DAICEL CHIRALPAK AD (250 mm x 50 mm, 10 um) 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 column DAICEL CHIRALPAK AD (250 mm x 50 mm, 10 um) 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) Isolation to yield (R)-3-(((R)-tert-Butylsulfinyl)amino)-3-ethylhept-6-enoic acid methyl ester (INT2-6_P1, required) (t _R =1.978 min, UV = 220 nm) and (S)-3-(((R)-tert-butylsulfenyl)amino)-3-ethylhept-6-enoic acid methyl ester (INT2-6_P2) (t _R =2.132 min, UV = 220 nm).

MS (ESI) m/z 290.1 (M+H) ⁺

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

Preparation of intermediates 2-7

(R)-3-(((R)-tert-Butylsulfenyl)amino)-3-ethylhept-6-enoic acid methyl ester (INT2-6_P1) (20 g , 69.1 mmol) in HCl-dioxane (4N) (100 mL) and MeOH (200 mL) was stirred for 2 h. LCMS showed the reaction was complete. The solvent was evaporated under reduced pressure to give the product (R)-3-amino-3-ethylhept-6-enoic acid methyl ester hydrochloride (INT2-7).

MS (ESI) m/z 186.3 (M+H) ⁺

¹ H NMR (500 MHz, methanol-d ₄ ) δ 5.80-5.87 (m, 1H), 5.07-5.15 (m, 1H), 5.02-5.04 (m, 1H), 3.73 (s, 3H), 2.71-2.79 (m, 2H), 2.07-2.18 (m, 2H), 1.75-1.85 (m, 4H), 0.99 (t, J = 7.6 Hz, 3H)

Preparation of intermediates 2-8

To DMB-BOC-thiourea (5 g, 15.32 mmol), (R)-3-amino-3-ethylhept-6-enoic acid methyl ester 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 _N2 atmosphere for 12 h. LCMS showed the desired mass, and some ring-opening by-product ester. Then the temperature was raised to 50°C and stirred at 50°C for 2 h. LCMS only shows the desired product mass. The mixture was concentrated in vacuo. The crude product was dissolved in EtOAc (100 mL) and water (100 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over _Na2SO4 , filtered, and _concentrated in vacuo. The crude product was purified by flash column (ISCO®; 80 g Agela silica flash column, 15% ethyl acetate/petroleum ether gradient at 30 mL/min) to provide (R,E) -(4-(but-3-en-1-yl)-1-(2,4-dimethoxybenzyl)-4-ethyl-6-pentanoxytetrahydropyrimidine-2(1H) -Tert-butyl carbamate (INT2-8).

MS (ESI) m/z 390.1 (M+H-56) ⁺

¹ H NMR (400 MHz, chloroform-d) δ 9.92 (br s, 1H), 7.10 (br d, J = 8.8 Hz, 1H), 6.33-6.50 (m, 2H), 5.63-5.83 (m, 1H) , 5.09 (s, 2H), 4.96-5.06 (m, 2H), 3.78 (dd, J = 1.6, 4.4 Hz, 6H), 2.61 (s, 2H), 1.98-2.12 (m, 2H), 1.59-1.70 (m, 4H), 1.49 (s, 9H), 0.92 (t, J = 7.6 Hz, 3H)

Preparation of intermediates 2-9

(R,E)-(4-(but-3-en-1-yl)-1-(2,4-dimethoxybenzyl)-4-ethyl-6-side at 60°C A solution of tert-butyloxyectoine-2(1H)-ylidene)carbamate (INT2-8) (1.0 g, 2.244 mmol) in TFA (10 mL) was stirred for 16 h. LCMS shows desired mass. The mixture was concentrated in vacuo. The residue was partitioned between petroleum ether/EtOAc (v/v=4:1, 10 mL) and water (10 mL), and LCMS showed that the product was only in the aqueous phase and was quite clean. (R)-6-(but-3-en-1-yl)-6-ethyl-2-iminotetrahydropyrimidin-4(1H)-one (INT2-9) in water (10 mL) ) is used directly in the next step.

MS (ESI) m/z 196.0 (M+H) ⁺

Preparation of intermediate 2

To (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) were added NaHCO ₃ (942 mg, 11.22 mmol) and (BOC) ₂ O (1.042 mL, 4.49 mmol) in portions. The reaction was stirred at 25 °C for 16 h. LCMS shows desired mass. The mixture was extracted with EtOAc (3 x 10 mL). The organic layer _was washed with brine (10 mL), dried over _Na2SO4 , filtered, and concentrated in vacuo. The crude product was purified by flash column (ISCO®; 12 g Agela silica flash column, 20% EE (EtOAC/EtOH = 3:1)/petroleum ether gradient at 30 mL/min) To provide (R,E)-(4-(but-3-en-1-yl)-4-ethyl-6-side oxytetrahydropyrimidine-2(1H)-ylidene)carbamic acid third Butyl ester intermediate 2.

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

(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]Trione-10,12,19,21,26,28-hexene-18,31-dione

Preparation of compound 1-2

Triflate (503 mg, 3.35 mmol) and N-bromosuccinimide (596 mg, 3.35 mmol) were added to (1R,2R)-1-amino-2,3-di at 0°C. Hydrogen-1H-inden-2-ol (1-1) (500 mg, 3.35 mmol) in DCM (10 mL). The reaction was stirred at 18 °C under _N2 atmosphere for 1 h. The mixture was quenched with saturated sodium bicarbonate solution (10 mL) at 0°C and extracted with DCM (1 x 10 mL), then EtOAc (3 x 10 mL). The _organic layer was washed with brine (10 mL), dried over _Na2SO4 , filtered and concentrated in vacuo, and the crude product was purified by flash silica column chromatography ( ^ISCO® ; 12 g ^SepaFlash® silica flash tube column, the eluent was 10% MeOH/DCM (added 1% ammonium hydroxide) gradient at 50 mL/min) purification to provide (1R,2R)-1-amino-6-bromo-2,3-di Hydro-1H-inden-2-ol (1-2).

MS (ESI) m/z: 228.1, 230.1(M+H ⁺ )

¹ H NMR (400 MHz, methanol-d ₄ ) 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

DIEA (0.276 mL, 1.582 mmol) was added to (R)-4-((R,E)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-sideoxy -4-(pent-4-en-1-yl)ectohydropyrimidin-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, A solution of 3-dihydro-1H-inden-2-ol (45.1 mg, 0.198 mmol) in THF (5 mL). The reaction was stirred at 18 °C for 2 h. The mixture was quenched with water (5 mL) and extracted with EtOAc (3 x 5 mL). The organic layer was washed with brine (5 mL), dried over _Na2SO4 , filtered and concentrated in _vacuo , and the crude product was purified by preparative TLC (petroleum ether/EtOAc=1:1) to provide ((R ,E)-1-((R)-6-(((1R,2R)-6-bromo-2-hydroxy-2,3-dihydro-1H-inden-1-yl)aminoformyl) Chroman-4-yl)-4-ethyl-6-side oxy-4-(pent-4-en-1-yl)tetrahydropyrimidine-2(1H)-ylidene)carbamic acid tertiary Butyl ester (1-3).

MS (ESI) m/z: 695.1, 697.1 (M+H ⁺ )

Preparation of compounds 1-4A, 1-4B and 1-4C

Chloro[tris(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) was added to ((R,E)-1-((R)-6-((1R,2R)-6-bromo-2-hydroxy -2,3-Dihydro-1H-inden-1-yl)aminoformyl)chroman-4-yl)-4-ethyl-6-pentanoxy-4-(pent-4-ene - A solution of tert-butyl 1-yl)tetrahydropyrimidine-2(1H)-ylidene)carbamate (1-3) (100 mg, 0.144 mmol) in dioxane (1.5 mL). The reaction was stirred at 70 °C for 16 h. The mixture was quenched with water (3 mL) and extracted with EtOAc (3 x 5 mL). The organic layer was washed with brine (5 mL), dried over _Na2SO4 , filtered and concentrated in _vacuo , and the crude product was analyzed by reverse phase preparative HPLC (Instrument ED; method column Boston Prime C18 150 x 30 mm , 5 um; conditioned water (0.04% NH ₃ H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN start B 65; end B 95 gradient time (min) 10; 100% B holding time (min) 2 flow rate ( mL/min) 25; Injection 5) Purified to provide: ((4aR,8R,12E,18R,18aR,28E)-8-ethyl-18-hydroxy-6,20-bisoxy-4,4a ,7,8,9,10,11,17,18,18a,19,20-dodecahydro-3H,6H-1,21-(epiethane [1,2]diylidene)- 8,5-(epiminomethano)-14,16-vinylidenecyclopenta[h]pyrano[4,3-b][1,7]diaza Heterocyclylnonadiene-28-ylidene)tert-butylcarbamate (1-4A); ((4aR,8R,12Z,18R,18aR,28E)-8-ethyl-18-hydroxy-6, 20-Dilateral oxy-4,4a,7,8,9,10,11,17,18,18a,19,20-dodecahydro-3H,6H-1,21-(table ethane [1, 2]diylidene)-8,5-(imino-bridgemethylene)-14,16-vinylidenecyclopenta[h]pirano[4,3-b][1, 7] Diazacyclononadiene-28-ylidene) tert-butylcarbamate (1-4B); and ((4aR, 8R, 17R, 17aR, E)-8-ethyl-17-hydroxy -12-methylene-6,19-dilateral oxygen-4,4a,6,7,8,9,10,11,12,16,17,17a,18,19-tetradecahydro-3H- 1,20-(Epiethane[1,2]diylidene)-8,5-(Bio-imino-bridgemethylene)-13,15-vinylidenecyclopenta[h]pyran And [4,3-b][1,7]diazacyclooctadien-27-ylidene)carbamic acid tert-butyl ester (1-4C).

MS (ESI) m/z: 486.2 (M+H ⁺ )

1-4A: ¹ H NMR (500 MHz, chloroform-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: ¹ H NMR (500 MHz, chloroform-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: ¹ H 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

Pd-C ( _1.731 mg, 3.25 µmol) was added to ((4aR,8R,17R,17aR,E)-8-ethyl-17-hydroxy-12-methylene-6,19- Two sided oxygen groups-4,4a,6,7,8,9,10,11,12,16,17,17a,18,19-tetradecahydro-3H-1,20-(table ethane [1, 2]diylidene)-8,5-(imino-bridgemethylene)-13,15-vinylidenecyclopenta[h]pirano[4,3-b][1, 7] A solution of tert-butyldiazacyclooctadiene-27-ylidene)carbamate (1-4C) (10 mg, 0.016 mmol) in MeOH (2 ml). The mixture was degassed and backfilled with H ( _three times). The resulting mixture was stirred at 25 °C under _H2 (15 psi) for 12 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to yield ((4aR,8R,17R,17aR,E)-8-ethyl-17-hydroxy-12-methyl-6,19-bisoxy-4 ,4a,6,7,8,9,10,11,12,16,17,17a,18,19-Tetradecahydro-3H-1,20-(table ethane [1,2] diylidene) -8,5-(Bioiminobimethylene)-13,15-vinylidenecyclopenta[h]pyrano[4,3-b][1,7]diazacycle Octadien-27-ylidene)tert-butylcarbamate (1-5).

MS (ESI) m/z: 617.3 (M+H ⁺ )

Preparation of Example 1

Zinc(II) bromide (29.2 mg, 0.130 mmol) was added to ((4aR,8R,17R,17aR,E)-8-ethyl-17-hydroxy-12-methyl at 22 °C under _N atmosphere Base-6,19-dilateral oxygen-4,4a,6,7,8,9,10,11,12,16,17,17a,18,19-tetradecahydro-3H-1,20-( Table ethane[1,2]diylidene)-8,5-(iminobridgemethylene)-13,15-vinylidenecyclopenta[h]pirano[4,3 -b] A solution of [1,7]tert-butyl[1,7]diazacyclooctadiene-27-ylidene)carbamate (1-5) (8 mg, 0.013 mmol) in DCM (3 ml). The mixture was stirred at 22 °C for 16 h. The mixture was cooled and the solvent was evaporated under reduced pressure to give crude product. The residue was analyzed by reverse phase preparative HPLC (Instrument EJ method column Boston Green ODS 150 x 30 mm, 5 um conditioned water (TFA)-ACN Start B 22 End B 52 Gradient time (min) 10 100% B Hold time (min) 2 Flow rate (ml/min) 25 Injection 1) Purification to yield Example 1.

MS (ESI) m/z: 517.2 (M+H ⁺ )

¹ H NMR (500 MHz, methanol-d ₄ ) 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

(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] Triac-11,13,20,22,27,29-hexene-19,32-dione

Preparation of compound 2-1

Pd-C (2.250 mg, 4.23 µmol) was added to ((4aR,8R,12E,18R,18aR,28E)-8-ethyl-18-hydroxy-6,20-bilateral oxy group under _N2 atmosphere -4,4a,7,8,9,10,11,17,18,18a,19,20-dodecahydro-3H,6H-1,21-(table ethane [1,2] diylidene) -8,5-(Bromimino bridgemethylene)-14,16-vinylidenecyclopenta[h]pyrano[4,3-b][1,7]diazacycle Nonadiene-28-ylidene)carbamic acid tert-butyl ester (2-1) (13 mg, 0.021 mmol) in MeOH (4 mL). The mixture was degassed and backfilled with H ( _three times). The resulting mixture was stirred at 20 °C under _H2 (15 psi) for 2 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to yield ((4aR,8R,18R,18aR,E)-8-ethyl-18-hydroxy-6,20-bisoxy-4,4a,7, 8,9,10,11,12,13,17,18,18a,19,20-Tetradecahydro-3H,6H-1,21-(Epiethane[1,2]diylidene)-8, 5-(Bromylidene bridgemethylene)-14,16-vinylidenecyclopenta[h]pirano[4,3-b][1,7]diazacyclononadiene -28-Ylidene)tert-butylcarbamate (2-1).

MS (ESI) m/z: 617.2 (M+H ⁺ )

Preparation of Example 2

Zinc(II) bromide (47.5 mg, 0.211 mmol) was added to ((4aR,8R,18R,18aR,E)-8-ethyl-18-hydroxy-6,20-bis-oxygen under _N2 atmosphere Base-4,4a,7,8,9,10,11,12,13,17,18,18a,19,20-Tetradecahydro-3H,6H-1,21-(table ethane [1,2 ]diylidene)-8,5-(iminobridgemethylene)-14,16-vinylidenecyclopenta[h]pirano[4,3-b][1,7 ] A solution of tert-butyldiazacyclononadien-28-ylidene)carbamate (2-1) (13 mg, 0.021 mmol) in DCM (3 mL). The mixture was stirred at 22 °C for 16 h. The mixture was concentrated under reduced pressure to give crude product. The residue was analyzed by reverse phase preparative HPLC (instrument EJ; method column Boston Green ODS 150 x 30 mm, 5 um, conditioned water (TFA)-ACN start B 22; end B 52 Gradient time (min) 10; 100 % B Hold Time (min) 2 Flow Rate (mL/min) 25; Injection 1) Purification to yield (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-(ethanethane[1,2]diylidene)-8 ,5-(Bromylidene bridgemethylene)-14,16-vinylidenecyclopenta[h]pyrano[4,3-b][1,7]diazacyclononadiene En-6,20(7H)-dione Example 2.

MS (ESI) m/z: 517.2 (M+H ⁺ )

¹ H NMR (500 MHz, methanol-d ₄ ) 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

(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] Triac-10,12,20,22,27,29-hexene-19,32-dione

Preparation of compound 3-2

N,O-dimethylhydroxylamine hydrochloride (54.6 g, 559 mmol) was added to 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) Solution in DCM (400 mL). The reaction was stirred at 25 °C under _N2 atmosphere for 12 h. The mixture was quenched with water (300 mL) and extracted with DCM (3 x 100 mL). The organic layer was washed with brine (100 mL), dried over _Na2SO4 , filtered and concentrated in vacuo, and the crude _product was purified by flash silica column chromatography (ISCO®; 220 g Agela silica flash tube column, the eluent was 8% ethyl acetate/petroleum ether gradient at 50 mL/min) and purified to provide N-methoxy-N-methylpent-4-enamide (3-2).

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

Ethylmagnesium bromide (69.8 mL, 210 mmol) was added dropwise to N-methoxy-N-methylpent-4-enamide (3-2) (20 g) at 0 °C under _N2 atmosphere. , 140 mmol) in THF (200 mL). The reaction was stirred at 25 °C under _N2 atmosphere for 1 h. The mixture was quenched with saturated aqueous NH ₄ Cl (100 mL) and water (100 mL), and extracted with EtOAc (3 x 100 mL). The organic layer was washed with brine (50 mL), dried over _Na2SO4 , filtered and concentrated in _vacuo , and the crude product was purified by flash silica column chromatography (ISCO®; 120 g Agela silica flash tube column, the eluent was 5% ethyl acetate/petroleum ether gradient at 40 mL/min) and purified to provide hept-6-en-3-one (3-3).

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

(R)-2-Methylpropane-2-sulfinamide (12.97 g, 107 mmol) was added to hept-6-en-3-one (3-3) (10 g, 89 mmol) in THF ( 100 mL) solution. Ti(EtO) ₄ (37.5 mL, 178 mmol) was also added and the reaction was stirred at 75 °C under _N2 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 solution (50 mL) and _Na2SO4 were added and the mixture was filtered and concentrated in vacuo. The crude product was purified by flash silica column chromatography (ISCO®; 120 g Agela silica flash column, 8% ethyl acetate/petroleum ether gradient at 40 mL/min) to provide ( R,E)-N-(hept-6-en-3-ylidene)-2-methylpropane-2-sulfinamide (3-4).

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 compound 3-5

Butyllithium (55.7 mL, 139 mmol) was added dropwise to a solution of diisopropylamine (19.64 mL, 139 mmol) in anhydrous THF (40 mL) at -78 °C under _N2 atmosphere. The reaction was stirred at 0 °C for 30 min to prepare LDA. The obtained LDA (76 mL, 93 mmol) was added dropwise to ethyl acetate (7.48 mL, 93 mmol) and Ti(OiPr) ₃ Cl (116 mL, 116 mmol) in anhydrous THF (90 mL) at -78°C. mixture. After 1 h, (R,E)-N-(hept-6-en-3-ylidene)-2-methylpropane-2-sulfinamide (3-4) (10 g, 46.4) was then added dropwise. mmol) in anhydrous THF (20 mL) and the mixture was stirred at -78 °C for 3 h. The mixture was quenched with ice-cold semisaturated aqueous ammonium chloride solution (60 mL). The slurry was diluted with EtOAc (200 mL), filtered, and washed with EtOAc and water. The organic layer _was washed with brine (50 mL), dried over _Na2SO4 , filtered and concentrated in vacuo. The residue was purified by flash silica column chromatography (ISCO®; 120 g Agela silica flash column, 25% ethyl acetate/petroleum ether gradient at 40 mL/min) to provide 3 -(((R)-tert-Butylsulfenyl)amino)-3-ethylhept-6-enoic acid methyl ester (3-5).

MS (ESI) m/z 290.1 (M+H ⁺ )

¹ H 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 compound 3-6

3-(((R) _-tert -butylsulfinyl)amino)-3-ethylhept-6-enoic acid methyl ester (3-5) (9 g, 31.1 mmol) in 4N HCl-dioxane (20 mL) and MeOH (20.00 mL) was stirred for 1 h. The solvent was evaporated under reduced pressure to give crude product 3-amino-3-ethylhept-6-enoic acid methyl ester hydrochloride (3-6), which was used directly in the next step.

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 compound 3-7

N-Ethyl-N-isopropylpropan-2-amine (13.79 mL, 79 mmol) was added to EDC (9.08 g, 47.4 mmol), 3-amino-3-ethylhept-6-enoic acid methyl Ester hydrochloride (3-6) (3.5 g, 15.79 mmol) and (R)-4-(3-(tert-butoxycarbonyl)thiourido)chromane-6-carboxylic acid methyl ester (INT -1) (5.78 g, 15.79 mmol) in ACN (30 mL). The reaction was stirred at 25 °C under _N2 atmosphere for 12 h. The mixture was quenched with water (50 mL) and extracted with EtOAc (3 x 50 mL). The organic layer was washed with brine (30 mL), dried over _Na2SO4 , filtered and concentrated in vacuo to provide ( _4R )-4-((Z)-2-(tert-butoxycarbonyl)-3- (3-ethyl-1-methoxy-1-side oxyhept-6-en-3-yl)guanidino)chromane-6-carboxylic acid methyl ester (3-7) was used as it was in the next step.

MS (ESI) m/z 518.2 (M+H ⁺ )

Preparation of compound 3-8

DBU (11.90 mL, 79 mmol) was added to the (4R)-4-((Z)-2-(tert-butoxycarbonyl)-3-(3-ethyl-1-methoxy-1-side) A solution of oxyhept-6-en-3-yl)guanidino)chroman-6-carboxylic acid methyl ester (3-7) (8.17 g, 15.78 mmol) in THF (50 mL). The mixture was stirred at 50 °C under _N2 atmosphere for 16 h. The mixture was quenched with water (50 mL) and extracted with EtOAc (3 x 50 mL). The organic layer _was washed with brine (30 mL), dried over _Na2SO4 , filtered and concentrated in vacuo. The crude product was purified by flash silica column chromatography (ISCO®; 120 g Agela silica flash column, 25% ethyl acetate/petroleum ether gradient at 40 mL/min) to provide ( 4R)-4-((E)-4-(but-3-en-1-yl)-2-((tertiary butoxycarbonyl)imino)-4-ethyl-6-side oxy Ectoine-1(2H)-yl)chroman-6-carboxylic acid methyl ester (3-8).

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

(4R)-4-((E)-4-(but-3-en-1-yl)-2-((tertiary butoxycarbonyl)imino)-4-ethyl-6-side oxy Methyl ectoine-1(2H)-yl)chroman-6-carboxylate (3-8) (4 g, 8.24 mmol) was purified by SFC (Column Boston Green ODS 150 x 30 mm, 5 um Conditioned Water (TFA)-ACN Start B 48 End B 78 Gradient Time (min) 10 100% B Hold Time (min) 2 Flow Rate (mL/min) 25 Injection 1) Separation to generate P1 (4R)-4 -((E)-4-(but-3-en-1-yl)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-pendantoxytetrahydropyrimidine- 1(2H)-yl)Chromane-6-carboxylic acid methyl ester (3-9A) (t _R =2.105 min, UV = 220 nm). P2 (4R)-4-((E)-4-(but-3-en-1-yl)-2-((tertiary butoxycarbonyl)imino)-4-ethyl-6-side Oxyectoine-1(2H)-yl)chroman-6-carboxylic acid methyl ester (3-9B) (t _R =2.251 min, UV = 220 nm).

MS (ESI) m/z 486.2 (M+H ⁺ )

3-9A: ¹ H NMR (500 MHz, chloroform-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, chloroform-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 compound 3-10

Potassium trimethylsilylate (872 mg, 6.80 mmol) was added to (R)-4-((R,E)-4-(but-3-en-1-yl)-2-((tert-butyl) Oxycarbonyl)imino)-4-ethyl-6-pendant oxytetrahydropyrimidin-1(2H)-yl)chroman-6-carboxylic acid methyl ester (3-9A) (550 mg, 1.133 mmol) in THF (5 mL). The reaction was stirred at 25 °C for 0.5 h. (R)-4-((R,E)-4-(but-3-en-1-yl)-2-((tertiary butoxycarbonyl)imino)-4-ethyl-6- The solution of the pendant oxytetrahydropyrimidin-1(2H)-yl)chroman-6-carboxylic acid (3-10) was used directly in the next step without any further manipulation or purification.

MS (ESI) m/z 472.2 (M+H ⁺ ).

Preparation of compound 3-11

DIEA (1.582 mL, 9.06 mmol) was added to (R)-4-((R,E)-4-(but-3-en-1-yl)-2-((tert-butoxycarbonyl)ylidene) Amino)-4-ethyl-6-pentanoxytetrahydropyrimidin-1(2H)-yl)chromane-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-vinyl chromogen Solution of alkane-4-amine (253 mg, 1.246 mmol) in THF (50 mL). The reaction was stirred at 25 °C for 12 h. The mixture was quenched with water (20 mL) and extracted with EtOAc (3 x 20 mL). The organic _layer was washed with brine (15 mL), dried over _Na2SO4 , filtered and concentrated in vacuo, and the crude product was purified by preparative TLC (petroleum ether/EtOAc=2:1) to provide ((R ,E)-4-(but-3-en-1-yl)-1-((R)-6-(((S)-2,2-dimethyl-6-vinylchromane-4- tert-butyl)aminoformyl)chroman-4-yl)-4-ethyl-6-side oxytetrahydropyrimidine-2(1H)-ylidene)carbamate (3-11 ).

MS (ESI) m/z 657.3 (M+H ⁺ )

Preparation of compound 3-12

(1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)ruthenium(o-isopropoxyphenylmethylene)dichloride (95 mg, 0.152 mmol ) is added to ((R,E)-4-(but-3-en-1-yl)-1-((R)-6-(((S)-2,2-dimethyl-6-ethylene) Basic chroman-4-yl)aminoformyl)chroman-4-yl)-4-ethyl-6-side oxytetrahydropyrimidine-2(1H)-ylidene)carbamic acid tertiary Butyl ester (3-11) (500 mg, 0.761 mmol) in DCE (500 mL). The reaction was stirred at 50 °C under _N2 atmosphere for 5 h. The mixture was concentrated in vacuo, and the crude product was purified by flash column (petroleum ether/EtOAc/EtOH=8:3:1) to provide ((4aR,8R,11E,18aS,28E)-8-ethyl -17,17-dimethyl-6,20-dilateral oxy-4,4a,7,8,9,10,18,18a,19,20-decahydro-3H,6H,17H-8,5 -(Bioiminobimethylene)-1,21:13,15-divinylidenedipirano[4,3-b:4',3'-h][1,7]diaza Heterocyclooctadiene-28-ylidene)carbamic acid tert-butyl ester (3-12).

MS (ESI) m/z 629.3 (M+H ⁺ )

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

Preparation of compound 3-13

Pd-C (50.8 mg, 0.048 mmol) was added to ((4aR,8R,11E,18aS,28E)-8 _- ethyl-17,17-dimethyl-6,20-bis- Oxy-4,4a,7,8,9,10,18,18a,19,20-decahydro-3H,6H,17H-8,5-(imino-bridgemethylene)-1,21 :13,15-Divinylidene dipirano[4,3-b:4',3'-h][1,7]diazacyclooctadien-28-ylidene)carbamic acid A solution of tributyl ester (3-12) (300 mg, 0.477 mmol) in MeOH (10 mL). The mixture was degassed and backfilled with H ( _three times). The resulting mixture was stirred under _H2 (15 psi) at 25 °C for 0.5 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to yield ((4aR,8R,18aS,E)-8-ethyl-17,17-dimethyl-6,20-bisoxy-4,4a, 7,8,9,10,11,12,18,18a,19,20-dodecahydro-3H,6H,17H-8,5-(iminobridgemethylene)-1,21:13 ,15-Divinylidene dipirano[4,3-b:4',3'-h][1,7]diazacyclooctadiene-28-ylidene)tert-butylcarbamate Esters (3-13) were used directly in the next step.

MS (ESI) m/z 631.3(M+H ⁺ )

Preparation of Example 3A ((4aR,8R,18aS,E)-8-ethyl-17,17-dimethyl-6,20-dilateral oxy-4,4a,7,8,9,10, 11,12,18,18a,19,20-dodecahydro-3H,6H,17H-8,5-(imino-bridged methylene)-1,21:13,15-divinylidenebis Pirano[4,3-b:4',3'-h][1,7]diazacyclooctadien-28-ylidene)carbamic acid tert-butyl ester (3-13) (280 mg, 0.444 mmol) in HCl-dioxane (4N) (30 mL) was stirred for 16 h. The solvent was evaporated under reduced pressure to give crude product. The residue was analyzed by reverse phase preparative HPLC (column Boston Green ODS 150 x 30 mm, 5 um conditioned 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) Purification to yield (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-(imino-bridged methylene)-1,21:13,15- Divinylidene dipirano[4,3-b:4',3'-h][1,7]diazacyclooctadiene-6,20-dione Example 3A.

MS (ESI) m/z 531.2 (M+H ⁺ )

¹ H NMR (500 MHz, methanol-d ₄ ) 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

(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]Tritric-11,13,21,23,28,30-hexene-20,33-dione

Preparation of compound 4-2

DIEA (36.7 mL, 210 mmol) was added to hex-5-enoic acid (4-1) (8 g, 70.1 mmol), EDC (20.15 g, 105 mmol), 1H-benzo[d][1,2 ,3] A solution of triazol-1-ol (14.21 g, 105 mmol) and N,O-dimethylhydroxylamine hydrochloride (7.52 g, 77 mmol) in THF (100 mL). The reaction was stirred at 25 °C for 5 h. The mixture was quenched with water (150 mL) and extracted with EtOAc (3 x 50 mL). The organic layer _was washed with brine (50 mL), dried over _Na2SO4 , filtered and concentrated in vacuo. The crude product was purified by flash silica column chromatography (ISCO®; 80 g SepaFlash® silica flash column, 5% EtOAc/petroleum ether gradient at 80 mL/min) to yield N- Methoxy-N-methylhexan-5-enamide (4-2).

MS (ESI) m/z 157.7 (M+H ⁺ )

Preparation of compound 4-3

Ethylmagnesium bromide (38.2 mL, 114 mmol) was added dropwise to N-methoxy-N-methylhex-5-enamide (4-2) (9 g) at 0°C under _N2 atmosphere. , 57.2 mmol) in THF (120 mL). The mixture was then stirred at 20 °C for 2 h. The mixture was quenched with saturated aqueous _NH4Cl (25 mL). The mixture was quenched with water (150 ml) and extracted with EtOAc (3 x 100 mL). _The combined organic layers were washed with brine (80 mL), dried over _Na2SO4 , and filtered. The solvent was removed under reduced pressure to give the crude product, which was purified by column chromatography ( _SiO2 , petroleum ether: EtOAc=100:1~10:1) to afford oct-7-en-3-one ( 4-3).

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

2-Methylpropane-2-sulfinamide (6.34 g, 52.3 mmol) was added to oct-7-en-3-one (4-3) (5.5 g, 43.6 mmol) in THF (80 mL) solution, followed by the addition of Ti(EtO) ₄ (18.31 mL, 87 mmol). The reaction was stirred at 75 °C under _N2 atmosphere for 16 h. The final mixture was cooled to 0 °C, diluted with DCM (100 mL) and stirred for 15 min. Ice-cold saturated aqueous sodium bicarbonate solution (15 mL) was added and the solution was filtered and concentrated in vacuo. The crude product was purified by flash column (SiO ₂ , petroleum ether/EtOAc = 100:1 to 5:1) to provide ((E)-2-methyl-N-(oct-7-en-3-ylidene) base) propane-2-sulfinamide (4-4).

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 compound 4-5

Methyl acetate (1.545 mL, 19.18 mmol) was added to a solution of LiHMDS (22.67 mL, 22.67 mmol) in anhydrous THF (35 mL) at -78 °C under _N2 atmosphere. 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) in THF (15 mL) was added dropwise. , 17.44 mmol) and the mixture was stirred at -78 °C for 3 h. The mixture was quenched with ice-cold semisaturated aqueous ammonium chloride solution (30 mL). The slurry was diluted with EtOAc (50 mL), filtered, and washed with EtOAc and water. The organic layer _was washed with brine (50 mL), dried over _Na2SO4 , filtered and concentrated in vacuo. The residue was purified by flash column (SiO ₂ , petroleum ether/EtOAc = 100:0 to 10:1) to provide 3-((tert-butylsulfinyl)amino)-3-ethyloctyl -7-enoic acid methyl ester (4-5).

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 compound 4-6

3-((tert-Butylsulfenyl)amino)-3-ethyloct-7-enoic acid methyl ester (4-5) (2 g, 6.59 mmol) was prepared at 15°C under _N2 atmosphere. ) in HCl-dioxane (4N) (5 mL) and MeOH (5 mL) was stirred for 1 h. The solution was concentrated in vacuo to give the crude product 3-amino-3-ethyloct-7-enoic acid methyl ester hydrochloride (4-6), which was used without any further purification.

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 compound 4-7

N-Ethyl-N-isopropylpropan-2-amine (4.37 mL, 24.56 mmol) was added to (R)-4-(3-(tert-butoxycarbonyl)thiourido)chroman- 6-Carboxylic acid methyl ester (INT-1) (1.5 g, 4.09 mmol), 3-amino-3-ethyloct-7-enoic acid methyl ester hydrochloride (4-6) (1.448 g, 6.14 mmol) ) and a solution of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (2.354 g, 12.28 mmol) in acetonitrile (30 mL). The mixture was stirred at 15 °C for 10 h. The mixture was quenched with water (50 mL) and extracted with EtOAc (3 x 40 mL). The organic layer was washed with brine (20 mL), dried over _Na2SO4 , filtered, and concentrated in vacuo to provide ( _4R )-4-((Z)-2-(tert-butoxycarbonyl)-3- (3-ethyl-1-methoxy-1-side oxyoct-7-en-3-yl)guanidino)chromane-6-carboxylic acid methyl ester (4-7), which is directly for the next step.

MS (ESI) m/z 532.3 (M+H+).

Preparation of compounds 4-8

DBU (2.84 mL, 18.81 mmol) was added to the (4R)-4-((Z)-2-(tert-butoxycarbonyl)-3-(3-ethyl-1-methoxy-1-side A solution of oxyoct-7-en-3-yl)guanidino)chromane-6-carboxylic acid methyl ester (4-7) (2.0 g, 3.76 mmol) in THF (20 mL). The mixture was stirred at 50 °C for 10 h. The mixture was quenched with water (40 mL) and extracted with EtOAc (3 x 40 mL). The organic layer was washed with brine ₍ 20 mL), dried over _Na2SO4 , filtered, and concentrated in vacuo. The crude product was purified by flash silica column chromatography (ISCO®; 20 g Agela silica flash column, 15% ethyl acetate/petroleum ether gradient at 60 mL/min) to provide ( 4R)-4-((E)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-sideoxy-4-(pent-4-en-1-yl) Ectoine-1(2H)-yl)chroman-6-carboxylic acid methyl ester (4-8). 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

(E)-4-(2-((tert-butoxycarbonyl)imino)-4-ethyl-6-pentoxy-4-(pent-4-en-1-yl)ectohydropyrimidine Methyl -1(2H)-yl)chromane-6-carboxylate (4-8) (1.8 g, 3.60 mmol) was analyzed by SFC (Instrument SFC-22 method column DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 um) Conditions 0.1% NH ₃ H ₂ O IPA Start B 10% End B 10% Gradient Time (min) 100% B Hold Time (min) Flow Rate (mL/min) 50 Injections 60) Separation to provide Product ((R)-4-((R,E)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-pentoxy-4-(pent-4-ene -1-yl)ectohydropyrimidine-1(2H)-yl)chroman-6-carboxylic acid methyl ester (4-9A) (peak 1, Rt=0.816) and ((E)-4-(2- ((tert-butoxycarbonyl)imino)-4-ethyl-6-pendantoxy-4-(pent-4-en-1-yl)ectohydropyrimidine-1(2H)-yl) color Orthoalkane-6-carboxylic acid methyl ester (4-9B) (peak 2, Rt=0.879).

MS (ESI) m/z: 500.2 (M+H ⁺ )

Preparation of compound 4-10

2,6-lutidine (42.9 mg, 0.400 mmol) and osmium(VIII) oxide (5.09 mg, 0.020 mmol) were added to (R)-4-((R,E)-2-((Third Butoxycarbonyl)imino)-4-ethyl-6-pendantoxy-4-(pent-4-en-1-yl)tetrahydropyrimidin-1(2H)-yl)chromane-6 - A solution of methyl carboxylate (4-9A) (100 mg, 0.200 mmol) in 1,4-dioxane (4 mL) and water (1 mL). 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 aqueous _Na2SO3 (10 mL) and water (5 mL), and extracted with EtOAc (3 _x 10 mL). The organic _layer was washed with brine (5 mL), dried over _Na2SO4 , filtered and concentrated in vacuo to provide (R)-4-((R,E)-2-((tert-butoxycarbonyl) Imino)-4-ethyl-6-side oxy-4-(4-side oxybutyl)tetrahydropyrimidine-1(2H)-yl)chromane-6-carboxylic acid methyl ester (4 -10), which was used directly in the next step.

MS (ESI) m/z: 502.3 (M+H ⁺ )

Preparation of compound 4-11

NaBH ₄ (10.75 mg, 0.284 mmol) was added portionwise to (R)-4-((R,E)-2-((tert-butoxycarbonyl)imino)-4-ethyl) at 0 °C. Methyl-6-pentoxy-4-(4-pentyloxybutyl)tetrahydropyrimidin-1(2H)-yl)chroman-6-carboxylate (4-10) (95 mg, 0.189 mmol) in MeOH (2 mL). The mixture was stirred at 0 °C for 1 h. LCMS showed the main desired product mass. The mixture was quenched with water (5 mL) and extracted with EtOAc (4 x 5 mL). The combined organic layers were washed with brine (5 mL), dried over _Na2SO4 , filtered, and concentrated in _vacuo , and the crude product was purified by preparative TLC (petroleum ether/EtOAc=3:1) to provide (R)-4-((R,E)-2-((tert-butoxycarbonyl)imino)-4-ethyl-4-(4-hydroxybutyl)-6-side oxytetrakis Hydropyrimidin-1(2H)-yl)chromane-6-carboxylic acid methyl ester (4-11).

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 compound 4-12

Potassium trimethylsilylate (81 mg, 0.631 mmol) was added to (R)-4-((R,E)-2-((tert-butoxycarbonyl)imino)-4-ethyl- Methyl 4-(4-hydroxybutyl)-6-pentanoxytetrahydropyrimidin-1(2H)-yl)chroman-6-carboxylate (4-11) (53 mg, 0.105 mmol) in THF (1 mL) solution. The reaction was stirred at 25 °C for 0.5 h. LCMS showed the main desired product mass. (R)-4-((R,E)-2-((tert-butoxycarbonyl)imino)-4-ethyl-4-(4-hydroxybutyl)-6-side oxytetrakis The solution of hydropyrimidin-1(2H)-yl)chroman-6-carboxylic acid (4-12) was used in the next step without any further manipulation or purification.

MS (ESI) m/z: 490.2 (M+H ⁺ )

Preparation of compound 4-13

DIEA (0.143 mL, 0.817 mmol) was added to (R)-4-((R,E)-2-((tert-butoxycarbonyl)imino)-4-ethyl-4-(4- Hydroxybutyl)-6-pentanoxytetrahydropyrimidin-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- A solution of amine (28.8 mg, 0.112 mmol) in THF (5 mL). The reaction was stirred at 25 °C for 3 h. The mixture was quenched with water (5 mL) and extracted with EtOAc (3 x 5 mL). The organic layer was washed with brine (5 mL), dried over _Na2SO4 , filtered and _concentrated in vacuo, and the crude product was purified by preparative TLC (petroleum ether/EtOAc=3:1) to provide ((R, E)-1-((R)-6-(((S)-6-bromo-2,2-dimethylchroman-4-yl)aminoformyl)chroman-4-yl )-4-ethyl-4-(4-hydroxybutyl)-6-side oxytetrahydropyrimidine-2(1H)-ylidene)carbamic acid tert-butyl ester (4-13).

MS (ESI) m/z: 727.2, 729.2 (M+H ⁺ )

Preparation of compound 4-14

In the glove box, [(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 ₃ (37.1 mg, 0.192 mmol) were added to ((R,E)-1-((R)-6 -(((S)-6-bromo-2,2-dimethylchroman-4-yl)aminoformyl)chroman-4-yl)-4-ethyl-4-(4 -Hydroxybutyl)-6-pentanoxytetrahydropyrimidine-2(1H)-ylidene)carbamic acid tert-butyl ester (4-13) (70 mg, 0.096 mmol) in dioxane (3 mL) of the mixture. The mixture was stirred at 70 °C for 3 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The organic layer _was washed with brine (5 mL), dried over _Na2SO4 , filtered and concentrated in vacuo. The crude product was purified by preparative TLC (petroleum ether/EtOAc=2:1) to provide ((4aR,5R,8R,19aS,E)-8-ethyl-18,18-dimethyl-6,21 -Dilateral oxy-4,4a,7,8,9,10,11,12,19,19a,20,21-dodecahydro-3H,6H,18H-1,22-(table ethane [1 ,2]diylidene)-8,5-(iminobridgemethylene)-14,16-vinylidene dipyrano[3,4-d:3',4'-j][ 1] Oxa[6,12]diazacyclononadien-29-ylidene)carbamic acid tert-butyl ester (4-14).

MS (ESI) m/z: 647.3 (M+H ⁺ )

¹ H 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

Zinc(II) bromide (104 mg, 0.464 mmol) and oxa[6,12]diazacyclononadiene-29-ylidene were dissolved in DCM (3 mL) at 25 °C under _N2 atmosphere. ethyl)carbamate (4-14) (30 mg, 0.046 mmol) was added to ((4aR,5R,8R,19aS,E)-8-ethyl-18,18-dimethyl-6,21 -Dilateral oxy-4,4a,7,8,9,10,11,12,19,19a,20,21-dodecahydro-3H,6H,18H-1,22-(table ethane [1 ,2]diylidene)-8,5-(iminobridgemethylene)-14,16-vinylidene dipyrano[3,4-d:3',4'-j][ 1] Solution of tert-butyl ester. The mixture was stirred at 25 °C for 16 h. The solvent was evaporated under reduced pressure to give the crude product and the residue was analyzed by reverse phase preparative HPLC (instrument, e.g. method column Welch Xtimate C18 150 x 25 mm, 5 um; Conditioned Water (TFA)-ACN Start B 25; End B 55 Gradient Time (min) 11; 100% B Hold Time (min) 2 Flow Rate (mL/min) 25; Inject Product 1) was purified to produce (4aR,5R,8R,19aS)-8-ethyl-29-imino-18,18-dimethyl-4,4a,7,8,9,10,11,12 ,18,19,19a,20-dodecahydro-3H,6H,21H-1,22-(Epiethane[1,2]diylidene)-8,5-(Bromylidene-bridged methylene )-14,16-vinylidene dipirano[3,4-d:3',4'-j][1]oxa[6,12]diazacyclononadiene-6,21- Diketone Example 4.

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

(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-(imino-bridged methylene)-4,6:17,19-divinylidenecyclopenta[b ]pirano[4,3-h][1,7]diazacyclooctadiene-13,20(14aH)-dione

Preparation of compound 5-2

Using a Dean-Stark apparatus, 5-bromo-2,3-dihydro-1H-inden-1-one (50 g, 237 mmol), ethane-1,2-dithiol A solution of (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. TLC showed 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 _Na2SO4 , filtered and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica column chromatography (ISCO ^® ; 330 g SepaFlash ^® silica flash column, 10% EtOAc/petroleum ether gradient at 60 mL/min) to yield 5 -Bromo-2,3-dihydrospiro[indene-1,2'-[1,3]dithiolane] (5-2).

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

A solution of 1,3-dibromo-5,5-dimethylhydantoin (194 g, 679 mmol) in anhydrous CH ₂ Cl ₂ (700 mL) was cooled to -70°C in a dry ice-acetone bath. . Pyridine hydrofluoride (57.4 mL, 226 mmol) was added dropwise under _N2 at a temperature below -65 °C, and the mixture was stirred at -70 °C for 30 min. Add 5-bromo-2,3-dihydrospiro[indene-1,2'-[1,3]dithiolane] (5-2) (65 g, 226 mmol) dropwise in CH ₂ Cl ₂ (200 mL) and the mixture was stirred at -70 °C for 4 h and then at 25 °C overnight. TLC showed the reaction was complete. The mixture was poured into NaOH (2 M, 300 mL) containing 39% _NaHSO3 (600 mL). The aqueous layer was extracted with _CH2Cl2 (2 x 600 mL) and the combined organic layers were washed _with brine (300 mL), dried over _Na2SO4 , filtered and the solvent evaporated under reduced pressure to give the _crude product. The crude product was purified by flash silica column chromatography (ISCO ^® ; 220 g SepaFlash ^® silica flash column, 100% petroleum ether gradient at 60 mL/min) to yield 2,5 -Dibromo-1,1-difluoro-2,3-dihydro-1H-indene (5-3).

No LCMS signal.

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

To a solution of 2,5-dibromo-1,1-difluoro-2,3-dihydro-1H-indane (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 desired product mass. Water (600 mL) was added and the mixture was acidified with concentrated HCl to pH=7. The mixture was filtered through celite, and the aqueous layer was extracted with CH ₂ Cl ₂ (2 × 600 mL) and the combined organic layer was washed with brine (300 mL), dried over Na ₂ SO ₄ , filtered and dried under reduced pressure. The solvent was evaporated under pressure to give crude product. The crude product was purified by flash silica column chromatography (ISCO ^® ; 330 g SepaFlash ^® silica flash column, 100% petroleum ether gradient at 50 mL/min) to yield 5-bromo -1,1-difluoro-1H-indene (5-4).

No LCMS signal.

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

To a solution of 5-bromo-1,1-difluoro-1H-indene (5-4) (15 g, 64.9 mmol) in iPrOH (250 mL) which was bubbled with O for ₁ h was added the phenyl Silane (14.05 g, 130 mmol) and Mn(TMHD) ₃ (3.93 g, 6.49 mmol) and stirred at 0 °C under O ₂ (15 psi) for 2 h. TLC showed the reaction was complete. The mixture was quenched with water (300 mL) and extracted with EtOAc (3 x 300 mL). _The organic layer was washed with brine (300 mL), dried over _Na2SO4 , filtered and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica column chromatography (ISCO ^® ; 40 g SepaFlash ^® silica flash column, 17% EtOAc/petroleum ether gradient at 50 mL/min) to yield 6 -Bromo-3,3-difluoro-2,3-dihydro-1H-inden-1-ol (5-5) and 5-bromo-1,1-difluoro-2,3-dihydro-1H- Mixture of inden-2-ol (5-5a); (5-5: 5-5a =7:2).

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

To 6-bromo-3,3-difluoro-2,3-dihydro-1H-inden-1-ol and 5-bromo-1,1-difluoro-2,3- A solution of dihydro-1H-inden-2-ol (11.56 g, 47.3 mmol) (5-5: 5-5a =7:2) in MeOH (150 mL) and DMSO (15 mL) was added [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.64 g, 3.61 mmol) and triethylamine (15.67 mL, 108 mmol) at 80 °C in a CO atmosphere (3.5 mbar ) and stirred the mixture for 48 h. TLC showed the reaction was complete. After cooling, the mixture was filtered through celite, and the mixture was diluted with _H2O (200 mL), _extracted with EtOAc (3x200 mL), dried over _Na2SO4 , filtered and the solvent was evaporated under reduced pressure to give crude product. The crude product was purified by flash silica column chromatography ( ^ISCO® ; 120 g ^SepaFlash® silica flash column, 17% EtOAc/petroleum ether gradient at 80 mL/min) to yield 1 ,1-Difluoro-3-hydroxy-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester (5-6) and 1,1-difluoro-2-hydroxy-2,3-dihydro -Mixture of 1H-indene-5-carboxylic acid methyl ester (5-6a); (5-6: 5-6a =3:1).

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

1,1-Difluoro-3-hydroxy-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester and 1,1-difluoro-2-hydroxy-2,3-dihydro-1H-indene A mixture of -5-carboxylic acid methyl ester (8.3 g, 36.36 mmol) (5-6: 27-6a = 3:1) was analyzed by SFC (column: Chiralpak AD-3 150 x 4.6 mm ID, 3 um, Mobile phase: A: CO ₂ B: Isopropanol (0.05% DEA), gradient: 5% to 40% B in 5 min and 40% to 5% B in 0.5 min, then 5% B for 1.5 min, flow rate: 2.5 mL/min, column temperature: 35°C) separation to provide the product (S)-1,1-difluoro-3-hydroxy-2,3-dihydro-1H- Indene-5-carboxylic acid methyl ester (5-7_P1, required) (peak 1, Rt=2.577), (R)-1,1-difluoro-3-hydroxy-2,3-dihydro-1H-indene -A mixture of 5-carboxylic acid methyl ester (5-7_P2) (peak 2, Rt=2.944) and (5-7_P2 and 5-6a) (2 g, 8.77 mmol). The mixture of (5-7_P2 and 5-6a) was analyzed by SFC (column: Cellulose 2 150 x 4.6 mm ID, 5 um, mobile phase: A: CO ₂ B: MeOH (0.05% DEA), gradient: at 5 From 5% to 40% B in 0.5 min and from 40% to 5% B in 0.5 min, then held at 5% B for 1.5 min, column temperature: 35°C) to generate 1,1-difluoro -2-Hydroxy-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester (5-6a).

(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, chloroform-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, chloroform-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

To (S)-1,1-difluoro- ₃ -hydroxy-2,3-dihydro-1H-indane-5-carboxylic acid methyl ester (5-7_P1) (585 mg , 2.56 mmol), (R,E)-(4-(but-3-en-1-yl)-4-ethyl-6-side oxytetrahydropyrimidine-2(1H)-ylidene)amine group To a solution of tert-butyl formate (INT-2) (757 mg, 2.56 mmol) and Ph ₃ P (1009 mg, 3.85 mmol) in THF (10 mL), DIAD (0.997 mL, 5.13 mmol) was added dropwise, and then The mixture was stirred at 18 °C for 2 h. TLC showed no SM. The mixture was concentrated in vacuo, and the residue was passed through flash silica column chromatography ( ^ISCO® ; 20 g ^SepaFlash® silica flash column with a 20% EtOAc/petroleum ether gradient at 60 mL/ min) was purified to provide crude product. The crude product was repurified by flash silica column chromatography (ISCO ^® ; 20 g SepaFlash ^® silica flash column, DCM gradient at 60 mL/min) to provide the product (R)- 3-((R,E)-4-(but-3-en-1-yl)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-pentoxytetrakis Hydropyrimidin-1(2H)-yl)-1,1-difluoro-2,3-dihydro-1H-indane-5-carboxylic acid methyl ester (5-8).

MS (ESI) m/z 506.2 (M+H) ⁺

¹ H 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

To (R)-3-((R,E)-4-(but-3-en-1-yl)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6 -Pendant oxytetrahydropyrimidin-1(2H)-yl)-1,1-difluoro-2,3-dihydro-1H-indane-5-carboxylic acid methyl ester (5-8) (900 mg, 1.780 mmol) in THF (9 mL) was added potassium trimethylsilylate (1370 mg, 10.68 mmol). The reaction was stirred at 18 °C for 0.5 h. LCMS shows desired mass. _H3PO4 (0.1 g/mL in _H2O ) was added to adjust the pH to approximately 6~7, and the _mixture was quenched with water (10 mL) and extracted with EtOAc (3 x 10 mL). The organic layer was washed with brine (10 mL), dried over _Na2SO4 , filtered and concentrated in vacuo to provide the product ₍ R)-3-((R,E)-4-(but-3-ene-1 -yl)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-side-oxytetrahydropyrimidin-1(2H)-yl)-1,1-difluoro-2 ,3-dihydro-1H-indene-5-carboxylic acid (5-9).

MS (ESI) m/z 492.1 (M+H) ⁺

¹ H NMR (400 MHz, chloroform-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

To (R)-3-((R,E)-4-(but-3-en-1-yl)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6 -Pendant oxytetrahydropyrimidine-1(2H)-yl)-1,1-difluoro-2,3-dihydro-1H-indane-5-carboxylic acid (5-9) (0.87 g, 1.770 mmol) , EDC (1.697 g, 8.85 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (0.718 g, 5.31 mmol) in THF (15 mL) was added with 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 h. LCMS shows desired mass. The mixture was quenched with water (15 mL) and extracted with EtOAc (3 x 15 mL). The organic layer was washed with brine (10 mL), dried over _Na2SO4 , filtered and concentrated in _vacuo , and the crude product was purified by flash silica column chromatography ( ^ISCO® ; 12 g ^SepaFlash® silica flash column, the eluent was 17% EtOAc/petroleum ether gradient at 60 mL/min) and purified to provide the product ((R,E)-4-(but-3-en-1-yl)-1-(( R)-6-(((S)-2,2-dimethyl-6-vinylchroman-4-yl)aminoformyl)-3,3-difluoro-2,3-dihydro -1H-Inden-1-yl)-4-ethyl-6-side oxytetrahydropyrimidine-2(1H-ylidene)carbamic acid tert-butyl ester (5-10).

MS (ESI) m/z 677.4 (M+H) ⁺

¹ H NMR (400 MHz, chloroform-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 compound 5-11

To ((R,E)-4-(but-3-en-1-yl)-1-((R)-6-(((S)-2,2-dimethyl-6-vinyl chromogen) Alk-4-yl)aminoformyl)-3,3-difluoro-2,3-dihydro-1H-inden-1-yl)-4-ethyl-6-side oxytetrahydropyrimidine- To a solution of tert-butyl 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 with _N2 at 50 °C for 4 h. LCMS shows desired mass. The mixture was concentrated in vacuo, and the crude product was purified by flash silica column chromatography ( ^ISCO® ; 12 g ^SepaFlash® silica flash column with a 15% EtOAc/petroleum ether gradient at 60 mL/ min) purification to provide ((7Z,11R,14R,14aR,21aS,24E)-11-ethyl-16,16-difluoro-2,2-dimethyl-13,20-disideoxy- 1,2,10,11,12,13,14a,15,16,20,21,21a-dodecahydro-9H-11,14-(iminobridgemethylene)-4,6:17 ,19-Divinylidenecyclopenta[b]pirano[4,3-h][1,7]diazacyclooctadiene-24-ylidene)tert-butylcarbamate (5-11a, cis olefin; minor product) and ((7E,11R,14R,14aR,21aS,24E)-11-ethyl-16,16-difluoro-2,2-dimethyl-13 ,20-dilateral oxygen-1,2,10,11,12,13,14a,15,16,20,21,21a-dodecahydro-9H-11,14-(bridge imino bridge methylene base)-4,6:17,19-divinylidenecyclopenta[b]pirano[4,3-h][1,7]diazacyclooctadien-24-ylidene ) tert-butyl carbamate (5-11, trans olefin; main product).

(5-11a, cis olefin): MS (ESI) m/z 649.3 (M+H) ⁺

¹ H NMR (400 MHz, chloroform-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) ⁺

¹ H 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 compound 5-12

_To ((7E,11R,14R,14aR,21aS,24E)-11-ethyl-16,16-difluoro-2,2-dimethyl-13,20-dilateral oxy- 1,2,10,11,12,13,14a,15,16,20,21,21a-dodecahydro-9H-11,14-(iminobridgemethylene)-4,6:17 ,19-Divinylidenecyclopenta[b]pirano[4,3-h][1,7]diazacyclooctadiene-24-ylidene)tert-butylcarbamate To a solution of (5-11) (780 mg, 1.202 mmol) in MeOH (10 mL) was added 10% Pd-C (128 mg, 0.120 mmol). The mixture was degassed and backfilled with H ( _three times). The resulting mixture was stirred at 18°C under _H2 (15 psi) atmosphere for 10 min. LCMS showed the reaction was complete. The mixture was filtered and the filtrate was concentrated under reduced pressure to yield ((11R,14R,14aR,21aS,E)-11-ethyl-16,16-difluoro-2,2-dimethyl-13,20-di Side oxygen group-1,2,8,9,10,11,12,13,14a,15,16,20,21,21a-tetradecahydro-7H-11,14-(bridge imino bridge methylene base)-4,6:17,19-divinylidenecyclopenta[b]pirano[4,3-h][1,7]diazacyclooctadien-24-ylidene ) tert-butyl carbamate (5-12), which was used directly in the next step.

MS (ESI) m/z 651.4 (M+H) ⁺

Preparation of Example 5

((11R,14R,14aR,21aS,E)-11-ethyl-16,16-difluoro-2,2-dimethyl-13,20-dilateral oxy-1,2 at 18°C ,8,9,10,11,12,13,14a,15,16,20,21,21a-tetradecahydro-7H-11,14-(iminobridgemethylene)-4,6: 17,19-Divinylidene cyclopenta[b]pirano[4,3-h][1,7]diazacyclooctadien-24-ylidene)tert-butylcarbamate A solution of ester (5-12) (700 mg, 1.076 mmol) in HCl-dioxane (4N) (10 mL) was stirred for 12 h. LCMS showed the reaction was complete. The solvent was evaporated under reduced pressure to give crude product. The residue was separated by reverse phase preparative HPLC (Apparatus 3-101 (EK) method phase separation column Boston Uni C18 150 x 40 mm, 5 um conditioned water (0.04% HCl)-ACN start B 33 end B 63 gradient time (min) 10 100% B Hold Time 2 Flow Rate (mL/min) 60 Injection 2) Purification to provide (11R,14R,14aR,21aS)-11-ethyl-16,16-difluoro-24-sub Amino-2,2-dimethyl-1,2,7,8,9,10,11,12,15,16,21,21a-dodecahydro-13H-11,14-(imino Cyclomethylene)-4,6:17,19-Divinylidenecyclopenta[b]pirano[4,3-h][1,7]diazacyclooctadiene-13 ,20(14aH)-diketone Example 5.

MS (ESI) m/z 551.3 (M+H) ⁺

¹ H NMR (400 MHz, methanol-d ₄ ) 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. Isomeric systems are separated by preparative HPLC and/or preparative chiral SFC.

An asterisk (*) may be used in chemical structure diagrams to indicate the location of the chiral center. surface 1 Example structure MS observed values chemical name 3B 531.2 (1R,5S,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] Triac-10,12,20,22,27,29-hexene-19,32-dione 5a 515.3 (1R,5R,9E,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] Heptacene-19,32-dione 6 515.2 (1R,5R,9Z,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] Heptacene-19,32-dione 7 543.3 (1R,5R,9E,18S)-5-ethyl-3-imino-16,16-dimethyl-15,25-dioxa-2,4,19-triazahexacyclo[19.6 .2.22,5.211,14.013,18.024,28]Tritric-9,11,13,21,23,28,30-heptacene-20,33-dione 8 545.3 (1R,5R,18S)-5-ethyl-3-imino-16,16-dimethyl-15,25-dioxa-2,4,19-triazahexacyclo[19.6.2.22 ,5.211,14.013,18.024,28] Triacontan-11,13,21,23,28,30-hexene-20,33-dione 9 545.3 (1R,5S,18S)-5-ethyl-3-imino-16,16-dimethyl-15,25-dioxa-2,4,19-triazahexacyclo[19.6.2.22 ,5.211,14.013,18.024,28] Triacontan-11,13,21,23,28,30-hexene-20,33-dione 10 557.3 (1R,5R,9Z,19S)-5-ethyl-3-imino-17,17-dimethyl-16,26-dioxa-2,4,20-triazahexacyclo[20.6 .2.22,5.212,15.014,19.025,29] Tritetracarbon-9,12,14,22(30),23,25(29),31-heptacene-21,34-dione 11 557.3 (1R,5R,9E,20S)-5-ethyl-3-imino-18,18-dimethyl-17,27-dioxa-2,4,21-triazahexacyclo[21.6 .2.22,5.112,16.015,20.026,30] Tritetracarbon-9,12(32),13,15,23,25,30-heptacene-22,34-dione 12 559.3 (1R,5R,19S)-5-ethyl-3-imino-17,17-dimethyl-16,26-dioxa-2,4,20-triazahexacyclo[20.6.2.22 ,5.212,15.014,19.025,29]34-carbon-12,14,22(30),23,25(29),31-hexene-21,34-dione 13 559.3 (1R,5S,20S)-5-ethyl-3-imino-18,18-dimethyl-17,27-dioxa-2,4,21-triazahexacyclo[21.6.2.22 ,5.112,16.015,20.026,30]34-12(32),13,15,23,25,30-hexene-22,34-dione 14 559.3 (1R,5R,20S)-5-ethyl-3-imino-18,18-dimethyl-17,27-dioxa-2,4,21-triazahexacyclo[21.6.2.22 ,5.112,16.015,20.026,30]34-12(32),13,15,23,25,30-hexene-22,34-dione 15A 561.2 (1R,16R,17R,26R)-5-ethyl-16-hydroxy-3-imino-26-(methoxymethyl)-24-oxa-2,4,18-triazahexa Cyclic [18.6.2.22,5.211,14.013,17.023,27] triac-11,13,20,22,27,29-hexene-19,32-dione 15B 561.2 (1R,16R,17R,26R)-5-ethyl-16-hydroxy-3-imino-26-(methoxymethyl)-24-oxa-2,4,18-triazahexa Cyclic [18.6.2.22,5.211,14.013,17.023,27] triac-11,13,20,22,27,29-hexene-19,32-dione 16A 589.3 (1R,18S,27R)-5-ethyl-3-imino-27-(methoxymethyl)-16,16-dimethyl-15,25-dioxa-2,4,19 -Triazahexacyclo[19.6.2.22,5.211,14.013,18.024,28]Triaza-11,13,21,23,28,30-hexene-20,33-dione 16B 589.3 Racemic-(1R,18S,27R)-5-ethyl-3-imino-27-(methoxymethyl)-16,16-dimethyl-15,25-dioxa-2, 4,19-Triazahexacyclo[19.6.2.22,5.211,14.013,18.024,28]Triaza-11,13,21,23,28,30-hexene-20,33-dione 17 601.3 Racemic-(12R,13R,22S)-8-ethyl-10-imino-13-(methoxymethyl)-24,24-dimethyl-15,25-dioxa-9, 11,21-Triazaheptacyclo[20.6.2.28,11.216,19.02,4.012,17.026,30]Triaza-1(29),16(32),17,19(31),26(30) ,27-hexene-20,33-dione 18 515.2 Racemic-(1R,5R,9E,18S)-5-ethyl-3-imino-15,25-dioxa-2,4,19-triazahexacyclo[19.6.2.22,5.211, 14.013,18.024,28]Tritriatocarbon-9,11,13,21,23,28,30-heptacene-20,33-dione 19 517.2 Racemic-(1R,5R,18S)-5-ethyl-3-imino-15,25-dioxa-2,4,19-triazahexacyclo[19.6.2.22,5.211,14.013, 18.024,28]Tritricone-11,13,21,23,28,30-hexene-20,33-dione 20 529.2 Racemic-(1R,8E,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] Triac-8,10,12,20,22,27,29-heptacene-19,32-dione twenty one 529.2 Racemic-(8R,12R,22S)-8-ethyl-10-imino-15,25-dioxa-9,11,21-triazaheptacyclo[20.6.2.28,11.216,19.02, 4.012,17.026,30]Tritetracarbon-1(29),16(32),17,19(31),26(30),27-hexene-20,33-dione twenty two 545.2 Racemic-(1R,5R,19S)-5-ethyl-3-imino-17,17-dimethyl-16,26-dioxa-2,4,20-triazahexacyclo[ 20.6.2.22,5.111,15.014,19.025,29] Triacontan-11(31),12,14,22,24,29-hexene-21,33-dione twenty three 571.3 Racemic-(1R,11Z,21S)-5-ethyl-3-imino-19,19-dimethyl-18,28-dioxa-2,4,22-triazahexacyclo[ 22.6.2.22,5.113,17.016,21.027,31]Tripentacarbon-11,13(33),14,16,24,26,31-heptacene-23,35-dione 24A 573.3 Racemic-(1R,21S)-5-ethyl-3-imino-19,19-dimethyl-18,28-dioxa-2,4,22-triazahexacyclo[22.6. 2.22,5.113,17.016,21.027,31]Tripentacarbon-13(33),14,16,24,26,31-hexene-23,35-dione 24B 573.3 Racemic-(1R,21S)-5-ethyl-3-imino-19,19-dimethyl-18,28-dioxa-2,4,22-triazahexacyclo[22.6. 2.22,5.113,17.016,21.027,31]Tripentacarbon-13(33),14,16,24,26,31-hexene-23,35-dione 25A 575.4 Racemic-(1R,18S,27R)-3-imino-27-(methoxymethyl)-5,16,16-trimethyl-15,25-dioxa-2,4,19 -Triazahexacyclo[19.6.2.22,5.211,14.013,18.024,28]Triaza-11,13,21,23,28,30-hexene-20,33-dione 25B 575.3 Racemic-(1R,18S,27R)-3-imino-27-(methoxymethyl)-5,16,16-trimethyl-15,25-dioxa-2,4,19 -Triazahexacyclo[19.6.2.22,5.211,14.013,18.024,28]Triaza-11,13,21,23,28,30-hexene-20,33-dione 26A 587.5 Racemic-(1R,9E,18S,27R)-5-ethyl-3-imino-27-(methoxymethyl)-16,16-dimethyl-15,25-dioxa- 2,4,19-triazahexacyclo[19.6.2.22,5.211,14.013,18.024,28] triazocarbon-9,11,13,21,23,28,30-heptacene-20,33- diketone 26B 587.3 Racemic-(1R,9E,18S,27R)-5-ethyl-3-imino-27-(methoxymethyl)-16,16-dimethyl-15,25-dioxa- 2,4,19-triazahexacyclo[19.6.2.22,5.211,14.013,18.024,28] triazocarbon-9,11,13,21,23,28,30-heptacene-20,33- diketone 28 473.2 (1R,5R,8E,15S)-5-ethyl-3-imino-15-methyl-22-oxa-2,4,16-triazapentacyclo[16.6.2.22,5.110,14.021 ,25] 29-8,10,12,14(27),18,20,25-heptacene-17,29-dione 29 487.2 (1R,5R,16S)-5-ethyl-3-imino-16-methyl-23-oxa-2,4,17-triazacyclo[17.6.2.22,5.111,15.08,10.022 ,26] Triacontan-11,13,15(28),19,21,26-hexene-18,30-dione 30 487.2 (1R,5R,15R,16R)-5-ethyl-15-hydroxy-3-imino-2,4,17-triazacyclo[17.5.2.22,5.210,13.012,16.022,25]tri Decacarbon-10,12,19,21,25,27-hexene-18,30-dione 31 489.2 (1R,15R,16R)-15-hydroxy-3-imino-5-methyl-23-oxa-2,4,17-triazahexacyclo[17.6.2.22,5.210,13.012,16.022, 26] Thirty-one carbon-10,12,19,21,26,28-hexene-18,31-dione 32 499.2 (1R,5R,8Z,14S,16S)-5-ethyl-3-imino-14-methyl-23-oxa-2,4,17-triazahexacyclo[17.6.2.22,5.210 ,13.012,16.022,26]Trione-8,10,12,19,21,26,28-heptacene-18,31-dione 33 501.2 (1R,5R,14S,16S)-5-ethyl-3-imino-14-methyl-23-oxa-2,4,17-triazahexacyclo[17.6.2.22,5.210,13.012 ,16.022,26]Trione-10,12,19,21,26,28-hexene-18,31-dione 34 501.3 (1R,5R,14R,16S)-5-ethyl-3-imino-14-methyl-23-oxa-2,4,17-triazahexacyclo[17.6.2.22,5.210,13.012 ,16.022,26]Trione-10,12,19,21,26,28-hexene-18,31-dione 35 501.2 (1R,5R,15R,16R)-5-ethyl-15-hydroxy-3-imino-2,4,17-triazacyclo[17.6.2.22,5.210,13.012,16.022,26]tri Undecane-10,12,19,21,26,28-hexene-18,31-dione 36 502.3 (1R,5R,8Z,17S)-5-ethyl-3-imino-14,24-dioxa-2,4,11,18-tetraazahexacyclo[18.6.2.22,5.210,13.012 ,17.023,27] Triac-8,10,12,20,22,27,29-heptacene-19,32-dione 37 503.2 (1R,5R,15R,16R)-5-ethyl-15-hydroxy-3-imino-23-oxa-2,4,17-triazahexacyclo[17.6.2.22,5.210,13.012, 16.022,26]Trione-10,12,19,21,26,28-hexene-18,31-dione 38 513.2 (1R,5R,8Z,14R,16S)-5,14-diethyl-3-imino-23-oxa-2,4,17-triazacyclo[17.6.2.22,5.210,13.012 ,16.022,26]Trione-8,10,12,19,21,26,28-heptacene-18,31-dione 39 513.3 (1R,5R,8Z,14S,16S)-5,14-diethyl-3-imino-23-oxa-2,4,17-triazacyclo[17.6.2.22,5.210,13.012 ,16.022,26]Trione-8,10,12,19,21,26,28-heptacene-18,31-dione 40 513.2 (1R,5R,8E,14S,16S)-5,14-diethyl-3-imino-23-oxa-2,4,17-triazacyclo[17.6.2.22,5.210,13.012 ,16.022,26]Trione-8,10,12,19,21,26,28-heptacene-18,31-dione 41 513.2 (1R,5R,8E,14R,16S)-5,14-diethyl-3-imino-23-oxa-2,4,17-triazahexacyclo[17.6.2.22,5.210,13.012 ,16.022,26]Trione-8,10,12,19,21,26,28-heptacene-18,31-dione 42 515.3 (1R,5R,8Z,15R,17S)-5-ethyl-3-imino-15-methyl-14,24-dioxa-2,4,18-triazahexacyclo[18.6. 2.22,5.210,13.012,17.023,27] Triac-8,10,12,20,22,27,29-heptacene-19,32-dione 43 515.2 (1R,5R,8Z,16S,17S)-5-ethyl-3-imino-16-methyl-14,24-dioxa-2,4,18-triazahexacyclo[18.6. 2.22,5.210,13.012,17.023,27] Triac-8,10,12,20,22,27,29-heptacene-19,32-dione 44 515.2 (1R,5R,8Z,15R,16R)-5-ethyl-15-hydroxy-3-imino-15-methyl-23-oxa-2,4,17-triazahexacyclo[17.6 .2.22,5.210,13.012,16.022,26]Trione-8,10,12,19,21,26,28-heptacene-18,31-dione 45 515.2 (1R,5R,7E,16S)-5-ethyl-3-imino-14,14-dimethyl-13,23-dioxa-2,4,17-triazahexacyclo[17.6 .2.22,5.29,12.011,16.022,26]Trione-7,9,11,19,21,26,28-heptacene-18,31-dione 46 515.3 (1R,5R,8E,15R,17S)-5-ethyl-3-imino-15-methyl-14,24-dioxa-2,4,18-triazahexacyclo[18.6. 2.22,5.210,13.012,17.023,27] Triac-8,10,12,20,22,27,29-heptacene-19,32-dione 47 515.2 (1R,5R,16R,17R)-5-ethyl-16-hydroxy-3-imino-24-oxa-2,4,18-triazaheptacyclo[18.6.2.22,5.211,14.08, 10.013,17.023,27]Triac-11,13,20,22,27,29-hexene-19,32-dione 48 515.2 1R,5R,9E,18S)-5-ethyl-3-imino-15,25-dioxa-2,4,19-triazahexacyclo[19.6.2.22,5.211,14.013,18.024, 28]Tritric-9,11,13,21,23,28,30-heptacene-20,33-dione 49 515.2 (1R,5R,8E,15R,16R)-5-ethyl-15-hydroxy-3-imino-15-methyl-23-oxa-2,4,17-triazahexacyclo[17.6 .2.22,5.210,13.012,16.022,26]Trione-8,10,12,19,21,26,28-heptacene-18,31-dione 50 515.2 (1R,5R,8E,16R,17S)-5-ethyl-3-imino-16-methyl-14,24-dioxa-2,4,18-triazahexacyclo[18.6. 2.22,5.210,13.012,17.023,27] Triac-8,10,12,20,22,27,29-heptacene-19,32-dione 51 515.2 (1R,5R,8E,16S,17S)-5-ethyl-3-imino-16-methyl-14,24-dioxa-2,4,18-triazahexacyclo[18.6. 2.22,5.210,13.012,17.023,27] Triac-8,10,12,20,22,27,29-heptacene-19,32-dione 52 515.3 (1R,5R,8E,16R)-5-ethyl-3-imino-15,15-dimethyl-14,23-dioxa-2,4,17-triazahexacyclo[17.6 .2.22,5.210,13.012,16.022,26]Trione-8,10,12,19,21,26,28-heptacene-18,31-dione 53 515.3 (1R,5R,14R,16S)-5,14-diethyl-3-imino-23-oxa-2,4,17-triazahexacyclo[17.6.2.22,5.210,13.012,16.022 ,26] Thirty-one carbon-10,12,19,21,26,28-hexene-18,31-dione 54 515.3 (1R,5R,14S,16S)-5,14-diethyl-3-imino-23-oxa-2,4,17-triazahexacyclo[17.6.2.22,5.210,13.012,16.022 ,26] Thirty-one carbon-10,12,19,21,26,28-hexene-18,31-dione 55 515.3 (1R,5R,15R,16R)-5-ethyl-15-hydroxy-3-imino-15-methyl-2,4,17-triazahexacyclo[17.6.2.22,5.210,13.012, 16.022,26]Trione-10,12,19,21,26,28-hexene-18,31-dione 56 517.3 (1R,5R,15R,17S)-5-ethyl-3-imino-15-methyl-14,24-dioxa-2,4,18-triazahexacyclo[18.6.2.22, 5.210,13.012,17.023,27] Triac-10,12,20,22,27,29-hexene-19,32-dione 57 517.2 (1R,5R,16S)-5-ethyl-3-imino-14,14-dimethyl-13,23-dioxa-2,4,17-triazahexacyclo[17.6.2.22 ,5.29,12.011,16.022,26]Trione-9,11,19,21,26,28-hexene-18,31-dione 58 517.3 (1R,5R,15S,17S)-5-ethyl-3-imino-15-methyl-14,24-dioxa-2,4,18-triazahexacyclo[18.6.2.22, 5.210,13.012,17.023,27] Triac-10,12,20,22,27,29-hexene-19,32-dione 59 517.2 (1R,5R,15R,16R)-5-ethyl-15-hydroxy-3-imino-15-methyl-23-oxa-2,4,17-triazahexacyclo[17.6.2.22 ,5.210,13.012,16.022,26]Trione-10,12,19,21,26,28-hexene-18,31-dione 60 517.3 (1R,5R)-5-ethyl-15-hydroxy-3-imino-14-methyl-23-oxa-2,4,17-triazahexacyclo[17.6.2.22,5.210,13.012 ,16.022,26] Thirty-one-10,12,19,21,26,28-hexene-18,31-dione 61 517.3 (1R,5R,15R,16R)-15-hydroxy-3-imino-5-isopropyl-23-oxa-2,4,17-triazacyclo[17.6.2.22,5.210,13.012 ,16.022,26] Thirty-one-10,12,19,21,26,28-hexene-18,31-dione 62 517.2 (1R,5R)-5-ethyl-15-hydroxy-3-imino-14-methyl-23-oxa-2,4,17-triazahexacyclo[17.6.2.22,5.210,13.012 ,16.022,26]Trione-10,12,19,21,26,28-hexene-18,31-dione 63 517.2 (1R,5R,16S)-5-ethyl-3-imino-15,15-dimethyl-13,23-dioxa-2,4,17-triazahexacyclo[17.6.2.22 ,5.29,12.011,16.022,26]Trione-9,11,19,21,26,28-hexene-18,31-dione 64 517.3 (1R,5R,16R)-5-ethyl-3-imino-15,15-dimethyl-14,23-dioxa-2,4,17-triazahexacyclo[17.6.2.22 ,5.210,13.012,16.022,26]Trione-10,12,19,21,26,28-hexene-18,31-dione 65 517.2 (1R,5R,16R,17S)-5-ethyl-3-imino-16-methyl-14,24-dioxa-2,4,18-triazahexacyclo[18.6.2.22, 5.210,13.012,17.023,27] Triac-10,12,20,22,27,29-hexene-19,32-dione 66 517.2 (1R,5R)-5-ethyl-15-hydroxy-3-imino-14-methyl-23-oxa-2,4,17-triazahexacyclo[17.6.2.22,5.210,13.012 ,16.022,26]Trione-10,12,19,21,26,28-hexene-18,31-dione 67 517.3 (1R,5R,16S,17S)-5-ethyl-3-imino-16-methyl-14,24-dioxa-2,4,18-triazahexacyclo[18.6.2.22, 5.210,13.012,17.023,27] Triac-10,12,20,22,27,29-hexene-19,32-dione 68 517.2 (1R,5R,18S)-5-ethyl-3-imino-15,25-dioxa-2,4,19-triazacyclo[19.6.2.22,5.211,14.013,18.024,28 ]Tritric-11,13,21,23,28,30-hexene-20,33-dione 69 517.3 (1R,5R,15R,16R,23S)-5-ethyl-15-hydroxy-3-imino-23-methoxy-2,4,17-triazahexacyclo[17.5.2.22,5.210 ,13.012,16.022,25] Triacontacarbon-10,12,19,21,25,27-hexene-18,30-dione 70 517.2 (1S,8E,15S,23R)-5-ethyl-3-imino-23-(methoxymethyl)-15,23-dimethyl-22-oxa-2,4,16- Triazapentacyclo[16.5.2.22,5.110,14.021,24]octacarbon-8,10,12,14(26),18,20,24-heptacene-17,28-dione 71 517.2 (1R,5R,14S,16S)-5-ethyl-3-imino-14-methoxy-23-oxa-2,4,17-triazahexacyclo[17.6.2.22,5.210, 13.012,16.022,26]Trione-10,12,19,21,26,28-hexene-18,31-dione 72 519.2 (1R,5R,16S)-5-ethyl-3-imino-14,14-dimethyl-8,13,23-trioxa-2,4,17-triazahexacyclo[17.6 .2.22,5.29,12.011,16.022,26]Trione-9,11,19,21,26,28-hexene-18,31-dione 73 519.2 (1R,5R,16S,17R)-5-ethyl-16-hydroxy-3-imino-14,24-dioxa-2,4,18-triazahexacyclo[18.6.2.22,5.210 ,13.012,17.023,27] Triac-10,12,20,22,27,29-hexene-19,32-dione 74 519.2 (1S,15S,23R)-5-ethyl-3-imino-23-(methoxymethyl)-15,23-dimethyl-22-oxa-2,4,16-triazo Heteropentacyclic [16.5.2.22,5.110,14.021,24] 28-carbon-10,12,14(26),18,20,24-hexene-17,28-dione 75A 523.2 (1R,15R,16R)-5-ethyl-23,23-difluoro-15-hydroxy-3-imino-2,4,17-triazahexacyclo[17.5.2.22,5.210,13.012, 16.022,25] Triacontacarbon-10,12,19(26),20,22(25),27-hexene-18,30-dione 75B 523.2 (1R,15R,16R)-5-ethyl-23,23-difluoro-15-hydroxy-3-imino-2,4,17-triazahexacyclo[17.5.2.22,5.210,13.012, 16.022,25] Triacontacarbon-10,12,19(26),20,22(25),27-hexene-18,30-dione 76 527.2 (1R,5R,8Z)-5-ethyl-15-hydroxy-3-imino-spiro[23-oxa-2,4,17-triazahexacyclo[17.6.2.22,5.210,13.012, 16.022,26]trione-8,10,12,19,21,26,28-heptene-14,1'-cyclopropane]-18,31-dione 77 527.3 (1R,5R,8E)-5-ethyl-15-hydroxy-3-imino-spiro[23-oxa-2,4,17-triazahexacyclo[17.6.2.22,5.210,13.012, 16.022,26]trione-8,10,12,19,21,26,28-heptene-14,1'-cyclopropane]-18,31-dione 78 529.2 (1R,5R)-5-ethyl-15-hydroxy-3-imino-spiro[23-oxa-2,4,17-triazahexacyclo[17.6.2.22,5.210,13.012,16.022, 26] Thirty-one carbon-10,12,19,21,26,28-hexene-14,1'-cyclopropane]-18,31-dione 79 529.2 (1R,5R,8Z,15S,17S)-5,15-diethyl-3-imino-14,24-dioxa-2,4,18-triazahexacyclo[18.6.2.22, 5.210,13.012,17.023,27] Triac-8,10,12,20,22,27,29-heptacene-19,32-dione 80 529.3 (7R,11R,21S,23R)-7-ethyl-9-imino-23-methyl-14,24-dioxa-8,10,20-triazaheptacyclo[19.6.2.27, 10.215,18.02,4.011,16.025,29]Tritricone-1(28),15(31),16,18(30),25(29),26-hexene-19,32-dione 81 529.3 (1R,5R,17S)-5-ethyl-3-imino-spiro[14,24-dioxa-2,4,18-triazahexacyclo[18.6.2.22,5.210,13.012,17.023 ,27] Trioc-10(30),11,13(29),20,22,27-hexene-15,1'-cyclopropane]-19,32-dione 82 529.2 (6R,10R,20S)-6-ethyl-8-imino-22,22-dimethyl-13,23-dioxa-7,9,19-triazaheptacyclo[18.6.2.26 ,9.214,17.02,4.010,15.024,28] Triac-1(27),14(30),15,17(29),24(28),25-hexene-18,31-dione 83 529.2 (1R,5R,8Z,17R)-5-ethyl-3-imino-14,14-dimethyl-15,24-dioxa-2,4,18-triazahexacyclo[18.6 .2.22,5.210,13.012,17.023,27] Triac-8,10(30),11,13(29),20,22,27-heptacene-19,32-dione 84 529.3 (7R,11R,21S,23S)-7-ethyl-9-imino-23-methyl-14,24-dioxa-8,10,20-triazaheptacyclo[19.6.2.27, 10.215,18.02,4.011,16.025,29]Tritricone-1(28),15(31),16,18(30),25(29),26-hexene-19,32-dione 85 529.3 (1R,5R,8E,17R)-5-ethyl-3-imino-14,14-dimethyl-15,24-dioxa-2,4,18-triazahexacyclo[18.6 .2.22,5.210,13.012,17.023,27] Triac-8,10(30),11,13(29),20,22,27-heptacene-19,32-dione 86 529.2 (1R,5R,8E,15R,17S)-5,15-diethyl-3-imino-14,24-dioxa-2,4,18-triazahexacyclo[18.6.2.22, 5.210,13.012,17.023,27] Triac-8,10,12,20,22,27,29-heptacene-19,32-dione 87 529.2 (7R,11R,21S,22S)-7-ethyl-9-imino-22-methyl-14,24-dioxa-8,10,20-triazaheptacyclo[19.6.2.27, 10.215,18.02,4.011,16.025,29]Tritricone-1(28),15(31),16,18(30),25(29),26-hexene-19,32-dione 88 529.2 (1R,8E,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] Triac-8,10,12,20,22,27,29-heptacene-19,32-dione 89 529.2 (8R,12R,22S)-8-ethyl-10-imino-15,25-dioxa-9,11,21-triazaheptacyclo[20.6.2.28,11.216,19.02,4.012,17.026 ,30] Tritetracarbon-1(29),16(32),17,19(31),26(30),27-hexene-20,33-dione 90 529.2 (1R,5R,8E,15S,17S)-5,15-diethyl-3-imino-14,24-dioxa-2,4,18-triazahexacyclo[18.6.2.22, 5.210,13.012,17.023,27] Triac-8,10,12,20,22,27,29-heptacene-19,32-dione 91 529.2 (1R,5R,8Z)-5,14-diethyl-15-hydroxy-3-imino-23-oxa-2,4,17-triazahexacyclo[17.6.2.22,5.210,13.012 ,16.022,26]Trione-8,10,12,19,21,26,28-heptacene-18,31-dione 92 529.2 (1R,5R,8E)-5,14-diethyl-15-hydroxy-3-imino-23-oxa-2,4,17-triazahexacyclo[17.6.2.22,5.210,13.012 ,16.022,26]Trione-8,10,12,19,21,26,28-heptacene-18,31-dione 93 530.3 (1R,5R,8Z,17S)-5-ethyl-3-imino-15,15-dimethyl-14,24-dioxa-2,4,18,29-tetraazahexacyclo [18.6.2.22,5.210,13.012,17.023,27]Triac-8,10,12,20,22,27,29-heptacene-19,32-dione 94 530.3 (1R,5R,8E,17S)-5-ethyl-3-imino-15,15-dimethyl-14,24-dioxa-2,4,18,29-tetraazahexacyclo [18.6.2.22,5.210,13.012,17.023,27]Triac-8,10,12,20,22,27,29-heptacene-19,32-dione 95 531.3 (1R,8Z,15R,16R,25R)-15-hydroxy-3-imino-25-(methoxymethyl)-5-methyl-23-oxa-2,4,17-triazo Heterohexacyclo[17.6.2.22,5.210,13.012,16.022,26]Trione-8,10,12,19,21,26,28-heptacene-18,31-dione 96 531.2 (1R,8Z,16S,17R)-16-hydroxy-3-imino-5,15,15-trimethyl-14,24-dioxa-2,4,18-triazahexacyclo[ 18.6.2.22,5.210,13.012,17.023,27] Triac-8,10,12,20,22,27,29-heptacene-19,32-dione 97 531.2 (7R,11R,21R,22S)-7-ethyl-22-hydroxy-9-imino-14,24-dioxa-8,10,20-triazaheptacyclo[19.6.2.27,10.215 ,18.02,4.011,16.025,29]Tritricone-1(28),15(31),16,18(30),25(29),26-hexene-19,32-dione 98 531.2 (1S,8E,15R,16R,24R)-5-ethyl-15-hydroxy-3-imino-24-(methoxymethyl)-24-methyl-23-oxa-2,4 ,17-triazahexacyclo[17.5.2.210,13.12,5.012,16.022,25] 29-8,10,12,19,21,25,27-heptacene-18,29-dione 99 531.2 (1R,5R,8E,16S,17R)-5-ethyl-16-hydroxy-3-imino-16-methyl-14,24-dioxa-2,4,18-triazahexa Cyclic[18.6.2.22,5.210,13.012,17.023,27]tricoc-8,10,12,20,22,27,29-heptacene-19,32-dione 100 531.2 (1R,8E,16S,17R)-16-Hydroxy-3-imino-5,15,15-trimethyl-14,24-dioxa-2,4,18-triazahexacyclo[ 18.6.2.22,5.210,13.012,17.023,27] Triac-8,10,12,20,22,27,29-heptacene-19,32-dione 101 531.3 (1R,5R,7E,14R,15R,24R)-5-ethyl-14-hydroxy-3-imino-24-(methoxymethyl)-22-oxa-2,4,16- Triazahexacyclo[16.6.2.22,5.29,12.011,15.021,25] triazocarbon-7,9,11,18,20,25,27-heptacene-17,30-dione 102 531.2 (1R,5R,8Z)-5-ethyl-16-hydroxy-3-imino-15-methyl-14,24-dioxa-2,4,18-triazahexacyclo[18.6. 2.22,5.210,13.012,17.023,27] Triac-8,10,12,20,22,27,29-heptacene-19,32-dione 103 531.2 (1R,5R,8E)-5-ethyl-16-hydroxy-3-imino-15-methyl-14,24-dioxa-2,4,18-triazahexacyclo[18.6. 2.22,5.210,13.012,17.023,27] Triac-8,10,12,20,22,27,29-heptacene-19,32-dione 104 531.2 (1S,10R,14R,17Z)-14-ethyl-30-fluoro-12-imino-24,24-dimethyl-23-oxa-2,11,13-triazahexacyclo[ 17.6.2.24,7.211,14.06,10.022,26]Tritrione-4,6,17,19(27),20,22(26),30-heptacene-3,29-dione 105 531.2 (1R,5R)-5,14-diethyl-15-hydroxy-3-imino-23-oxa-2,4,17-triazahexacyclo[17.6.2.22,5.210,13.012,16.022 ,26] Thirty-one carbon-10,12,19,21,26,28-hexene-18,31-dione 106 531.3 (1R,5R,17R)-5-ethyl-3-imino-14,14-dimethyl-15,24-dioxa-2,4,18-triazahexacyclo[18.6.2.22 ,5.210,13.012,17.023,27] Triac-10(30),11,13(29),20,22,27-hexene-19,32-dione 107 531.2 (1R,10R,14R,25S)-14-ethyl-25-hydroxy-12-imino-24,24-dimethyl-23-oxa-2,11,13-triazahexacyclo[ 17.6.2.24,7.211,14.06,10.022,26]Trione-4(31),5,7(30),19(27),20,22(26)-hexene-3,29-dione 108 531.3 (1R,5R,15S,17S)-5,15-diethyl-3-imino-14,24-dioxa-2,4,18-triazahexacyclo[18.6.2.22,5.210, 13.012,17.023,27] Triac-10,12,20,22,27,29-hexene-19,32-dione 109 531.2 (1R,5R,15R,17S)-5,15-diethyl-3-imino-14,24-dioxa-2,4,18-triazahexacyclo[18.6.2.22,5.210, 13.012,17.023,27] Triac-10,12,20,22,27,29-hexene-19,32-dione 110 531.3 (1R,5R,17S)-5-ethyl-3-imino-16,16-dimethyl-14,24-dioxa-2,4,18-triazahexacyclo[18.6.2.22 ,5.210,13.012,17.023,27] Triac-10,12,20,22,27,29-hexene-19,32-dione 111 531.3 (1R,5R)-5,14-diethyl-15-hydroxy-3-imino-23-oxa-2,4,17-triazahexacyclo[17.6.2.22,5.210,13.012,16.022 ,26] Thirty-one carbon-10,12,19,21,26,28-hexene-18,31-dione 112 532.2 (1R,5R,17S)-5-ethyl-3-imino-15,15-dimethyl-14,24-dioxa-2,4,18,28-tetraazahexacyclo[18.6 .2.22,5.210,13.012,17.023,27] Triac-10,12,20,22,27,29-hexene-19,32-dione 113 532.3 (1R,5R,17S)-5-ethyl-3-imino-15,15-dimethyl-14,24-dioxa-2,4,18,21-tetraazahexacyclo[18.6 .2.22,5.210,13.012,17.023,27] Triac-10,12,20,22,27,29-hexene-19,32-dione 114 532.3 (1R,5R,17S)-5-ethyl-3-imino-15,15-dimethyl-14,24-dioxa-2,4,18,29-tetraazahexacyclo[18.6 .2.22,5.210,13.012,17.023,27] Triac-10,12,20,22,27,29-hexene-19,32-dione 115 532.2 (1R,5R,17S)-5-ethyl-3-imino-15,15-dimethyl-14,24-dioxa-2,4,18,30-tetraazahexacyclo[18.6 .2.22,5.210,13.012,17.023,27] Triac-10,12,20,22,27,29-hexene-19,32-dione 116 533.2 (1R,5R,16S,17R)-5-ethyl-16-hydroxy-3-imino-16-methyl-14,24-dioxa-2,4,18-triazahexacyclo[ 18.6.2.22,5.210,13.012,17.023,27] Triac-10,12,20,22,27,29-hexene-19,32-dione 117 533.2 (1R,5R,17S)-5-ethyl-3-imino-15,15-dimethyl-8,14,24-trioxa-2,4,18-triazahexacyclo[18.6 .2.22,5.210,13.012,17.023,27] Triac-10,12,20,22,27,29-hexene-19,32-dione 118 533.2 (1R,5R,17S)-5-ethyl-3-imino-15,15-dimethyl-9,14,24-trioxa-2,4,18-triazahexacyclo[18.6 .2.22,5.210,13.012,17.023,27] Triac-10,12,20,22,27,29-hexene-19,32-dione 119 533.3 (1R,16S,17R)-16-Hydroxy-3-imino-5,15,15-trimethyl-14,24-dioxa-2,4,18-triazahexacyclo[18.6. 2.22,5.210,13.012,17.023,27] Triac-10,12,20,22,27,29-hexene-19,32-dione 120 533.2 (1R,5R,15S,16R)-5-ethyl-15-(hydroxymethyl)-3-imino-15-methyl-14,23-dioxa-2,4,17-triazo Heterohexacyclo[17.6.2.22,5.210,13.012,16.022,26]Thirty-one carbon-10,12,19,21,26,28-hexene-18,31-dione 121A 533.3 (1R,5R)-5-ethyl-16-hydroxy-3-imino-15-methyl-14,24-dioxa-2,4,18-triazahexacyclo[18.6.2.22, 5.210,13.012,17.023,27] Triac-10,12,20,22,27,29-hexene-19,32-dione 121B 533.3 (1R,5R)-5-ethyl-16-hydroxy-3-imino-15-methyl-14,24-dioxa-2,4,18-triazahexacyclo[18.6.2.22, 5.210,13.012,17.023,27] Triac-10,12,20,22,27,29-hexene-19,32-dione 121C 533.3 (1R,5R)-5-ethyl-16-hydroxy-3-imino-15-methyl-14,24-dioxa-2,4,18-triazahexacyclo[18.6.2.22, 5.210,13.012,17.023,27] Triac-10,12,20,22,27,29-hexene-19,32-dione 121D 533.3 (1R,5R)-5-ethyl-16-hydroxy-3-imino-15-methyl-14,24-dioxa-2,4,18-triazahexacyclo[18.6.2.22, 5.210,13.012,17.023,27] Triac-10,12,20,22,27,29-hexene-19,32-dione 122 533.2 (1R,5R,15S,16R)-5-ethyl-15-hydroxy-3-imino-14,14-dimethyl-13,23-dioxa-2,4,17-triaza Hexacyclic [17.6.2.22,5.29,12.011,16.022,26]trione-9,11,19,21,26,28-hexene-18,31-dione 123 533.2 (1S,14R,15R,23R)-5-ethyl-14-hydroxy-3-imino-23-(methoxymethyl)-23-methyl-22-oxa-2,4,16 -Triazahexacyclo[16.5.2.22,5.29,12.011,15.021,24]eco-9,11,18,20,24,26-hexene-17,29-dione 124 533.2 (1S,15R,16R,24R)-5-ethyl-15-hydroxy-3-imino-24-(methoxymethyl)-24-methyl-23-oxa-2,4,17 -Triazahexacyclo[17.5.2.210,13.12,5.012,16.022,25] 10,12,19,21,25,27-hexene-18,29-dione 125 533.2 (1R,15R,16R,25R)-15-hydroxy-3-imino-25-(methoxymethyl)-5-methyl-23-oxa-2,4,17-triazahexa Cyclo[17.6.2.22,5.210,13.012,16.022,26]Trione-10,12,19,21,26,28-hexene-18,31-dione 126 533.3 (1R,5R,17S)-5-ethyl-3-imino-15,15-dimethyl-14,24-dioxa-2,4,18,21,28-pentaazahexacyclo [18.6.2.22,5.210,13.012,17.023,27] Triac-10,12,20,22,27,29-hexene-19,32-dione 127 533.2 (1S,10R,14R)-14-ethyl-30-fluoro-12-imino-24,24-dimethyl-23-oxa-2,11,13-triazahexacyclo[17.6. 2.24,7.211,14.06,10.022,26]Trione-4,6,19(27),20,22(26),30-hexene-3,29-dione 128 535.2 (1S,10R,14R,17Z,24R)-14-ethyl-8,8-difluoro-12-imino-24-methyl-23-oxa-2,11,13-triazahexa Cyclo[17.6.2.24,7.211,14.06,10.022,26]trione-4,6,17,19(27),20,22(26),30-heptacene-3,29-dione 129 535.2 (1R,5R,8Z,15R,16R)-5-ethyl-23,23-difluoro-15-hydroxy-3-imino-2,4,17-triazahexacyclo[17.6.2.22, 5.210,13.012,16.022,26]Trione-8,10,12,19,21,26,28-heptacene-18,31-dione 130 535.3 (1R,9Z,16R,17R)-5-ethyl-24,24-difluoro-16-hydroxy-3-imino-2,4,18-triazahexacyclo[18.5.2.22,5.211, 14.013,17.023,26]Trione-9,11,13,20,22,26,28-heptacene-19,31-dione 131 535.3 (1R,9E,16R,17R)-5-ethyl-24,24-difluoro-16-hydroxy-3-imino-2,4,18-triazacyclo[18.5.2.22,5.211, 14.013,17.023,26]Trione-9,11,13,20,22,26,28-heptacene-19,31-dione 132 535.4 (1S,14R,15R,23R)-5-ethyl-14-hydroxy-3-imino-23-(methoxymethyl)-23-methyl-8,22-dioxa-2, 4,16-triazahexacyclo[16.5.2.22,5.29,12.011,15.021,24] 9,11,18,20,24,26-hexene-17,29-dione 133 537.4 (1S,10R)-14-ethyl-8,8-difluoro-12-imino-23,23-dimethyl-22-oxa-2,11,13-triazahexacyclo[16.6 .2.24,7.211,14.06,10.021,25] Triacont-4,6,18(26),19,21(25),29-hexene-3,28-dione 134 537.2 (1S,10R,14R,24R)-14-ethyl-8,8-difluoro-12-imino-24-methyl-23-oxa-2,11,13-triazahexacyclo[ 17.6.2.24,7.211,14.06,10.022,26]Trione-4,6,19(27),20,22(26),30-hexene-3,29-dione 135 537.2 (1S,10R,14R,24S)-14-ethyl-8,8-difluoro-12-imino-24-methyl-23-oxa-2,11,13-triazahexacyclo[ 17.6.2.24,7.211,14.06,10.022,26]Trione-4,6,19(27),20,22(26),30-hexene-3,29-dione 136 537.3 (1R,16R,17R)-5-ethyl-24,24-difluoro-16-hydroxy-3-imino-2,4,18-triazacyclo[18.5.2.22,5.211,14.013, 17.023,26]Trione-11,13,20,22,26,28-hexene-19,31-dione 137 537.2 (1R,5R,15R,16R)-5-ethyl-23,23-difluoro-15-hydroxy-3-imino-2,4,17-triazahexacyclo[17.6.2.22,5.210, 13.012,16.022,26]Trione-10,12,19,21,26,28-hexene-18,31-dione 138 543.2 (1R,5R)-5-ethyl-14,14,23,23-tetrafluoro-3-imino-2,4,17-triazacyclo[17.5.2.22,5.210,13.012,16.022, 25] Triacontan-10,12,19,21,25,27-hexene-18,30-dione 139A 543.2 (7R,11R,21S)-7-ethyl-9-imino-23,23-dimethyl-14,24-dioxa-8,10,20-triazaheptacyclo[19.6.2.27 ,10.215,18.02,4.011,16.025,29]Tritricone-1(28),15(31),16,18(30),25(29),26-hexene-19,32-dione 139B 543.3 (7R,11R,21S)-7-ethyl-9-imino-23,23-dimethyl-14,24-dioxa-8,10,20-triazaheptacyclo[19.6.2.27 ,10.215,18.02,4.011,16.025,29]Tritricone-1(28),15(31),16,18(30),25(29),26-hexene-19,32-dione 140A 543.2 (1R,5S,8Z,17S)-5-ethyl-3-imino-6,15,15-trimethyl-14,24-dioxa-2,4,18-triazahexacyclo [18.6.2.22,5.210,13.012,17.023,27]Triac-8,10,12,20,22,27,29-heptacene-19,32-dione 140B 543.2 (1R,5S,8Z,17S)-5-ethyl-3-imino-6,15,15-trimethyl-14,24-dioxa-2,4,18-triazahexacyclo [18.6.2.22,5.210,13.012,17.023,27]Triac-8,10,12,20,22,27,29-heptacene-19,32-dione 141 543.2 (1R,5S,8E,17S)-5-ethyl-3-imino-6,15,15-trimethyl-14,24-dioxa-2,4,18-triazahexacyclo [18.6.2.22,5.210,13.012,17.023,27]Triac-8,10,12,20,22,27,29-heptacene-19,32-dione 142 543.3 (1R,5R,8Z,15R,17S)-5-ethyl-3-imino-15-isopropyl-14,24-dioxa-2,4,18-triazahexacyclo[18.6 .2.22,5.210,13.012,17.023,27] Triac-8,10,12,20,22,27,29-heptacene-19,32-dione 143 543.2 (1R,5R,8E,15R,17S)-5-ethyl-3-imino-15-isopropyl-14,24-dioxa-2,4,18-triazahexacyclo[18.6 .2.22,5.210,13.012,17.023,27] Triac-8,10,12,20,22,27,29-heptacene-19,32-dione 144 544.2 (7R,11R,21S)-7-ethyl-9-imino-23,23-dimethyl-14,24-dioxa-8,10,17,20-tetraazaheptacyclo[19.6 .2.27,10.215,18.02,4.011,16.025,29]Tritricarbon-1(28),15(31),16,18(30),25(29),26-hexene-19,32-di ketone 145 545.2 (1S,8E,15R,16R,24R)-5-ethyl-15-hydroxy-3-imino-24-(methoxymethyl)-24-methyl-23-oxa-2,4 ,17-triazahexacyclo[17.5.2.22,5.210,13.012,16.022,25]triacontane-8,10,12,19,21,25,27-heptacene-18,30-dione 146 545.2 (1R,5R,8Z,16R,17S)-5-ethyl-3-imino-16-(methoxymethyl)-14,24-dioxa-2,4,18-triaza Hexacyclic [18.6.2.22,5.210,13.012,17.023,27] triac-8,10,12,20,22,27,29-heptacene-19,32-dione 147 545.2 (1R,5R,8Z,16S,17S)-5-ethyl-3-imino-16-(methoxymethyl)-14,24-dioxa-2,4,18-triaza Hexacyclic [18.6.2.22,5.210,13.012,17.023,27] triac-8,10,12,20,22,27,29-heptacene-19,32-dione 148 545.2 (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]Triacon-10(30),11,13(29),20,22,27-hexene-9,19,32-trione 149 545.3 (7R,11R,21R,22S)-7-ethyl-22-hydroxy-9-imino-22-methyl-14,24-dioxa-8,10,20-triazaheptacyclo[ 19.6.2.27,10.215,18.02,4.011,16.025,29] Triacontan-1(28),15(31),16,18(30),25(29),26-hexene-19,32- diketone 150 545.3 (1R,16R,17R,26R)-16-hydroxy-3-imino-26-(methoxymethyl)-5-methyl-24-oxa-2,4,18-triazahepta Cyclo[18.6.2.22,5.211,14.08,10.013,17.023,27]Triac-11,13,20,22,27,29-hexene-19,32-dione 151 545.4 (1R,5R,8Z,15R,16R,25S)-5-ethyl-15-hydroxy-3-imino-25-(methoxymethyl)-23-oxa-2,4,17- Triazahexacyclo[17.6.2.22,5.210,13.012,16.022,26]Triaza-8,10,12,19,21,26,28-heptacene-18,31-dione 152 545.3 (1R,5R,8Z,15R,16R,25R)-5-ethyl-15-hydroxy-3-imino-25-(methoxymethyl)-23-oxa-2,4,17- Triazahexacyclo[17.6.2.22,5.210,13.012,16.022,26]Triaza-8,10,12,19,21,26,28-heptacene-18,31-dione 153 545.2 (1R,5R,8E,16S,17R)-5-ethyl-16-hydroxy-3-imino-15,15-dimethyl-14,24-dioxa-2,4,18-tri Azahexane[18.6.2.22,5.210,13.012,17.023,27]triadeca-8,10,12,20,22,27,29-heptacene-19,32-dione 154 545.2 (1R,5R,8E,16S,17S)-5-ethyl-3-imino-16-(methoxymethyl)-14,24-dioxa-2,4,18-triaza Hexacyclic [18.6.2.22,5.210,13.012,17.023,27] triac-8,10,12,20,22,27,29-heptacene-19,32-dione 155 545.2 (1R,5R,8E,16R,17S)-5-ethyl-3-imino-16-(methoxymethyl)-14,24-dioxa-2,4,18-triaza Hexacyclic [18.6.2.22,5.210,13.012,17.023,27] triac-8,10,12,20,22,27,29-heptacene-19,32-dione 156 545.2 (1R,5R,8E,15R,16R,25R)-5-ethyl-15-hydroxy-3-imino-25-(methoxymethyl)-23-oxa-2,4,17- Triazahexacyclo[17.6.2.22,5.210,13.012,16.022,26]Triaza-8,10,12,19,21,26,28-heptacene-18,31-dione 157 545.2 (7R,11R,20S)-7-ethyl-30-fluoro-9-imino-22,22-dimethyl-23-oxa-8,10,19-triazaheptacyclo[18.6. 2.27,10.214,17.02,4.011,15.024,28] Triac-1(27),14,16,24(28),25,29-hexene-18,31-dione 158 545.2 (1S,9S,10S,14R)-14-ethyl-12-imino-9-methoxy-24,24-dimethyl-23-oxa-2,11,13-triazahexa Ring[17.6.2.24,7.211,14.06,10.022,26]Trione-4(31),5,7(30),19(27),20,22(26)-hexene-3,29- diketone 159 545.3 (1R,5R,16S,17R)-5-ethyl-16-hydroxy-3-imino-15,15-dimethyl-14-oxa-2,4,18-triazahexacyclo[ 18.6.2.22,5.210,13.012,17.023,27] Triac-10,12,20,22,27,29-hexene-19,32-dione 160 545.3 (1R,5R,17S,26S)-5-ethyl-3-imino-15,15,26-trimethyl-14,24-dioxa-2,4,18-triazahexacyclo [18.6.2.22,5.210,13.012,17.023,27] Triac-10,12,20,22,27,29-hexene-19,32-dione 161 545.3 (1R,5R,15R,17S)-5-ethyl-3-imino-15-isopropyl-14,24-dioxa-2,4,18-triazahexacyclo[18.6.2.22 ,5.210,13.012,17.023,27] Triac-10,12,20,22,27,29-hexene-19,32-dione 162A 545.2 (1R,5S,17S)-5-ethyl-3-imino-6,15,15-trimethyl-14,24-dioxa-2,4,18-triazahexacyclo[18.6 .2.22,5.210,13.012,17.023,27] Triac-10,12,20,22,27,29-hexene-19,32-dione 162B 545.2 (1R,5S,17S)-5-ethyl-3-imino-6,15,15-trimethyl-14,24-dioxa-2,4,18-triazahexacyclo[18.6 .2.22,5.210,13.012,17.023,27] Triac-10,12,20,22,27,29-hexene-19,32-dione 163 545.3 (1R,5R,15S,17S)-5-ethyl-3-imino-15-isopropyl-14,24-dioxa-2,4,18-triazahexacyclo[18.6.2.22 ,5.210,13.012,17.023,27] Triac-10,12,20,22,27,29-hexene-19,32-dione 164 545.3 (1S,9R,10S,14R)-14-ethyl-12-imino-9-methoxy-24,24-dimethyl-23-oxa-2,11,13-triazahexa Ring[17.6.2.24,7.211,14.06,10.022,26]Trione-4(31),5,7(30),19(27),20,22(26)-hexene-3,29- diketone 165 546.3 (5R,17S)-5-ethyl-3-imino-15,15,26-trimethyl-14,24-dioxa-2,4,18,28-tetraazahexacyclo[18.6 .2.22,5.210,13.012,17.023,27] Triac-10,12,20,22,27,29-hexene-19,32-dione 166 547.2 (1S,15R,16R,24R)-5-ethyl-15-hydroxy-3-imino-24-(methoxymethyl)-24-methyl-23-oxa-2,4,17 -Triazahexacyclo[17.5.2.22,5.210,13.012,16.022,25] triazocarbon-10,12,19,21,25,27-hexene-18,30-dione 167 547.2 (1R,5R,16S,17R)-5-ethyl-16-hydroxy-3-imino-15,15-dimethyl-14,24-dioxa-2,4,18-triaza Hexacyclic [18.6.2.22,5.210,13.012,17.023,27] triac-10,12,20,22,27,29-hexene-19,32-dione 168 547.3 (1R,5R,16S,17S)-5-ethyl-3-imino-16-(methoxymethyl)-14,24-dioxa-2,4,18-triazahexacyclo [18.6.2.22,5.210,13.012,17.023,27] Triac-10,12,20,22,27,29-hexene-19,32-dione 169 547.2 (1R,5R,16R,17S)-5-ethyl-3-imino-16-(methoxymethyl)-14,24-dioxa-2,4,18-triazahexacyclo [18.6.2.22,5.210,13.012,17.023,27] Triac-10,12,20,22,27,29-hexene-19,32-dione 170 547.3 (1R,5R,17S)-5-ethyl-8-hydroxy-3-imino-15,15-dimethyl-14,24-dioxa-2,4,18-triazahexacyclo [18.6.2.22,5.210,13.012,17.023,27]Triac-10(30),11,13(29),20,22,27-hexene-19,32-dione 171 547.2 (1R,5R,15S,16R)-5-ethyl-3-imino-15-(methoxymethyl)-15-methyl-14,23-dioxa-2,4,17- Triazahexacyclo[17.6.2.22,5.210,13.012,16.022,26]Triaza-10,12,19,21,26,28-hexene-18,31-dione 172 547.3 (1R,5R,15R,16R,25R)-5-ethyl-15-hydroxy-3-imino-25-(methoxymethyl)-23-oxa-2,4,17-triazine Heterohexacyclo[17.6.2.22,5.210,13.012,16.022,26]Thirty-one carbon-10,12,19,21,26,28-hexene-18,31-dione 173 547.3 (1R,5R,15R,16R,25S)-5-ethyl-15-hydroxy-3-imino-25-(methoxymethyl)-23-oxa-2,4,17-triazine Heterohexacyclo[17.6.2.22,5.210,13.012,16.022,26]Thirty-one carbon-10,12,19,21,26,28-hexene-18,31-dione 174 547.2 (1R,5R,18S)-5-ethyl-3-imino-16,16-dimethyl-9,15,25-trioxa-2,4,19-triazahexacyclo[19.6 .2.22,5.211,14.013,18.024,28]Tritric-11,13,21,23,28,30-hexene-20,33-dione 175 547.2 (1R,5R,17S)-5-ethyl-9-hydroxy-3-imino-15,15-dimethyl-14,24-dioxa-2,4,18-triazahexacyclo [18.6.2.22,5.210,13.012,17.023,27]Triac-10(30),11,13(29),20,22,27-hexene-19,32-dione 176 547.2 (1R,18S)-5-ethyl-3-imino-16,16-dimethyl-8,15,25-trioxa-2,4,19-triazahexacyclo[19.6.2.22 ,5.211,14.013,18.024,28] Triacontan-11,13,21,23,28,30-hexene-20,33-dione 177 547.2 (1R,5R)-5-ethyl-16-hydroxy-3-imino-15,16-dimethyl-14,24-dioxa-2,4,18-triazahexacyclo[18.6 .2.22,5.210,13.012,17.023,27] Triac-10,12,20,22,27,29-hexene-19,32-dione 178 549.2 (1S,10R,14R)-14-ethyl-8,8-difluoro-12-imino-spiro[23-oxa-2,11,13-triazahexacyclo[17.6.2.24,7.211 ,14.06,10.022,26]Trione-4,6,19(27),20,22(26),30-hexene-24,1'-cyclopropane]-3,29-dione 179 549.4 (1S,10R,14R,17Z)-14-ethyl-8,8-difluoro-12-imino-24,24-dimethyl-23-oxa-2,11,13-triaza Hexacyclic [17.6.2.24,7.211,14.06,10.022,26]Trione-4,6,17,19(27),20,22(26),30-heptacene-3,29-dione 180 549.3 (1S,10R,14R,17E)-14-ethyl-8,8-difluoro-12-imino-24,24-dimethyl-23-oxa-2,11,13-triaza Hexacyclic [17.6.2.24,7.211,14.06,10.022,26]Trione-4,6,17,19(27),20,22(26),30-heptacene-3,29-dione 181 549.2 (1R,5R)-5-ethyl-23,23-difluoro-15-hydroxy-3-imino-spiro[2,4,17-triazahexacyclo[17.5.2.22,5.210,13.012, 16.022,25]Triacont-10,12,19(26),20,22(25),27-hexene-14,1'-cyclopropane]-18,30-dione 182 549.2 (1S,15R,16R,24R)-5-ethyl-15-hydroxy-3-imino-24-(methoxymethyl)-24-methyl-9,23-dioxa-2, 4,17-triazahexane[17.5.2.22,5.210,13.012,16.022,25]triacontacarbon-10,12,19,21,25,27-hexene-18,30-dione 183 549.3 (1S,15R,16R,24R)-5-ethyl-15-hydroxy-3-imino-24-(methoxymethyl)-24-methyl-8,23-dioxa-2, 4,17-triazahexane[17.5.2.22,5.210,13.012,16.022,25]triacontacarbon-10,12,19,21,25,27-hexene-18,30-dione 184 550.2 (1S,14R,17Z)-14-ethyl-8,8-difluoro-12-imino-24,24-dimethyl-23-oxa-2,5,11,13-tetraaza Hexacyclic [17.6.2.24,7.211,14.06,10.022,26]Trione-4,6,17,19(27),20,22(26),30-heptacene-3,29-dione 185 550.2 (1S,14R,17E)-14-ethyl-8,8-difluoro-12-imino-24,24-dimethyl-23-oxa-2,5,11,13-tetraaza Hexacyclic [17.6.2.24,7.211,14.06,10.022,26]Trione-4,6,17,19(27),20,22(26),30-heptacene-3,29-dione 186 552.2 (1S,14R)-14-ethyl-8,8-difluoro-12-imino-24,24-dimethyl-23-oxa-2,5,11,13-tetraazahexacyclo [17.6.2.24,7.211,14.06,10.022,26]Trione-4,6,19(27),20,22(26),30-hexene-3,29-dione 187 553.3 (1R,10R,14R,25S)-14-ethyl-8,8-difluoro-25-hydroxy-12-imino-25-methyl-23-oxa-2,11,13-triazole Heterohexacyclo[17.6.2.24,7.211,14.06,10.022,26]Trione-4,6,19(27),20,22(26),30-hexene-3,29-dione 188 553.2 (1R,10R,24S)-14-ethyl-8,8-difluoro-24-hydroxy-12-imino-23,23-dimethyl-22-oxa-2,11,13-tri Azahexane[16.6.2.24,7.211,14.06,10.021,25]triacontacarbon-4,6,18(26),19,21(25),29-hexene-3,28-dione 189 555.2 (1S,14R)-14-ethyl-8,8,29-trifluoro-12-imino-23,23-dimethyl-22-oxa-2,11,13-triazahexacyclo [16.6.2.24,7.211,14.06,10.021,25] Triacontane-4,6,18(26),19,21(25),29-hexene-3,28-dione 190 557.3 (1R,5R,14R,16S)-5-ethyl-3-imino-14-(trifluoromethyl)-13,23-dioxa-2,4,17-triazahexacyclo[ 17.6.2.22,5.29,12.011,16.022,26]Trione-9,11,19,21,26,28-hexene-18,31-dione 191 557.3 (1S,9S,10R,14R,17Z)-14-ethyl-12-imino-9-(methoxymethyl)-24,24-dimethyl-23-oxa-2,11, 13-Triazahexacyclo[17.6.2.24,7.211,14.06,10.022,26]Triaza-4(31),5,7(30),17,19(27),20,22(26) -Heptene-3,29-dione 192 557.3 (1S,9R,10R,14R,17Z)-14-ethyl-12-imino-9-(methoxymethyl)-24,24-dimethyl-23-oxa-2,11, 13-Triazahexacyclo[17.6.2.24,7.211,14.06,10.022,26]Triaza-4(31),5,7(30),17,19(27),20,22(26) -Heptene-3,29-dione 193 559.2 (1R,5R)-5-ethyl-14,14,23,23-tetrafluoro-15-hydroxy-3-imino-2,4,17-triazacyclo[17.5.2.22,5.210, 13.012,16.022,25] Triacontacarbon-10,12,19,21,25,27-hexene-18,30-dione 194 559.2 (1S,9Z,16R,17R,25R)-5-ethyl-16-hydroxy-3-imino-25-(methoxymethyl)-25-methyl-24-oxa-2,4 ,18-triazahexacyclo[18.5.2.22,5.211,14.013,17.023,26]trionecarbon-9,11,13,20,22,26,28-heptacene-19,31-dione 195 559.3 (1R,5R,7E,16S,25R)-5-ethyl-3-imino-25-(methoxymethyl)-14,14-dimethyl-13,23-dioxa-2 ,4,17-triazahexacyclo[17.6.2.22,5.29,12.011,16.022,26]trionecarbon-7,9,11,19,21,26,28-heptacene-18,31-di ketone 196 559.4 (1R,8R,10R,14R,17Z,25S)-14-ethyl-25-hydroxy-12-imino-8-methoxy-24,24-dimethyl-23-oxa-2, 11,13-triazahexacyclo[17.6.2.24,7.211,14.06,10.022,26]Triaza-4(31),5,7(30),17,19(27),20,22( 26)-Heptene-3,29-dione 197 559.4 (1R,8R,10R,14R,17E,25S)-14-ethyl-25-hydroxy-12-imino-8-methoxy-24,24-dimethyl-23-oxa-2, 11,13-triazahexacyclo[17.6.2.24,7.211,14.06,10.022,26]Triaza-4(31),5,7(30),17,19(27),20,22( 26)-Heptene-3,29-dione 198 559.3 (1S,9S,10R,14R)-14-ethyl-12-imino-9-(methoxymethyl)-24,24-dimethyl-23-oxa-2,11,13- Triazahexacyclo[17.6.2.24,7.211,14.06,10.022,26]Triaza-4(31),5,7(30),19(27),20,22(26)-hexaene- 3,29-dione 199 559.3 (1S,9R,10R,14R)-14-ethyl-12-imino-9-(methoxymethyl)-24,24-dimethyl-23-oxa-2,11,13- Triazahexacyclo[17.6.2.24,7.211,14.06,10.022,26]Triaza-4(31),5,7(30),19(27),20,22(26)-hexaene- 3,29-dione 200 561.3 (1R,5R,16S,17R)-16-hydroxy-3-imino-5-isopropyl-15,15-dimethyl-14,24-dioxa-2,4,18-triazole Heterohexacyclo[18.6.2.22,5.210,13.012,17.023,27]32-carbon-10,12,20,22,27,29-hexene-19,32-dione 201 561.2 (1S,5R,16R,17R,25R)-5-ethyl-16-hydroxy-3-imino-25-(methoxymethyl)-25-methyl-24-oxa-2,4 ,18-triazahexacyclo[18.5.2.22,5.211,14.013,17.023,26]trionecarbon-11,13,20,22,26,28-hexene-19,31-dione 202 561.4 (1S,9R,10S)-14-ethyl-12-imino-9-(methoxymethyl)-9,23,23-trimethyl-8,22-dioxa-2,11 ,13-triazahexacyclo[16.6.2.24,7.211,14.06,10.021,25]triacontacarbon-4(30),5,7(29),18(26),19,21(25)-six En-3,28-dione 203 561.3 (1R,8S,10R,14R,25S)-14-ethyl-25-hydroxy-12-imino-8-methoxy-24,24-dimethyl-23-oxa-2,11, 13-Triazahexacyclo[17.6.2.24,7.211,14.06,10.022,26]Triaza-4(31),5,7(30),19(27),20,22(26)-six En-3,29-dione 204 561.3 (1R,5R,16S,25R)-5-ethyl-3-imino-25-(methoxymethyl)-14,14-dimethyl-13,23-dioxa-2,4 ,17-triazahexacyclo[17.6.2.22,5.29,12.011,16.022,26]trionecarbon-9,11,19,21,26,28-hexene-18,31-dione 205 563.3 (7R,11R,20S)-7-ethyl-13,13-difluoro-9-imino-22,22-dimethyl-23-oxa-8,10,19-triazaheptacyclo [18.6.2.27,10.214,17.02,4.011,15.024,28] Triac-1(27),14,16,24(28),25,29-hexene-18,31-dione 206 563.3 (1R,5R,8Z,17S)-5-ethyl-24,24-difluoro-3-imino-15,15-dimethyl-14-oxa-2,4,18-triaza Hexacyclic [18.6.2.22,5.210,13.012,17.023,27] triac-8,10,12,20,22,27,29-heptacene-19,32-dione 207 565.3 (1R,10R,14R,17E,25S)-14-ethyl-8,8-difluoro-25-hydroxy-12-imino-24,24-dimethyl-23-oxa-2,11 ,13-triazahexacyclo[17.6.2.24,7.211,14.06,10.022,26]trionecarbon-4,6,17,19(27),20,22(26),30-heptene-3 ,29-diketone 208 565.3 (1R,5R,17S)-5-ethyl-24,24-difluoro-3-imino-15,15-dimethyl-14-oxa-2,4,18-triazahexacyclo [18.6.2.22,5.210,13.012,17.023,27] Triac-10,12,20,22,27,29-hexene-19,32-dione 209 567.2 (1R,5R,17S)-5-ethyl-9,9-difluoro-3-imino-15,15-dimethyl-14,24-dioxa-2,4,18-triaza Heterohexacyclo[18.6.2.22,5.210,13.012,17.023,27]Thirty-two carbon-10(30),11,13(29),20,22,27-hexene-19,32-dione 210 567.3 (1R,10R,14R,25S)-14-ethyl-8,8-difluoro-25-hydroxy-12-imino-24,24-dimethyl-23-oxa-2,11,13 -Triazahexacyclo[17.6.2.24,7.211,14.06,10.022,26]Triaza-4,6,19(27),20,22(26),30-hexene-3,29-di ketone 211 567.3 (1R,5R,17S)-5-ethyl-8,8-difluoro-3-imino-15,15-dimethyl-14,24-dioxa-2,4,18-triazo Heterohexacyclo[18.6.2.22,5.210,13.012,17.023,27]Thirty-two carbon-10(30),11,13(29),20,22,27-hexene-19,32-dione 212 567.5 (1R,5R,16S)-8-(difluoromethyl)-5-ethyl-3-imino-14,14-dimethyl-13,23-dioxa-2,4,17- Triazahexacyclo[17.6.2.22,5.29,12.011,16.022,26]Triaza-9,11,19,21,26,28-hexene-18,31-dione 213 569.3 (1R,5R,8Z,15S,17S)-5-ethyl-3-imino-15-(trifluoromethyl)-14,24-dioxa-2,4,18-triazahexa Cyclo[18.6.2.22,5.210,13.012,17.023,27]tricoc-8,10,12,20,22,27,29-heptacene-19,32-dione 214 569.2 (1R,5R,8Z,15R,17S)-5-ethyl-3-imino-15-(trifluoromethyl)-14,24-dioxa-2,4,18-triazahexa Cyclo[18.6.2.22,5.210,13.012,17.023,27]tricoc-8,10,12,20,22,27,29-heptacene-19,32-dione 215 569.2 (1S,14R)-14-ethyl-8,8,30-trifluoro-12-imino-24,24-dimethyl-23-oxa-2,11,13-triazahexacyclo [17.6.2.24,7.211,14.06,10.022,26]Trione-4,6,19(27),20,22(26),30-hexene-3,29-dione 216 571.2 (1R,5R,15R,17S)-5-ethyl-3-imino-15-(trifluoromethyl)-14,24-dioxa-2,4,18-triazahexacyclo[ 18.6.2.22,5.210,13.012,17.023,27] Triac-10,12,20,22,27,29-hexene-19,32-dione 217 571.2 (1R,5R,15S,17S)-5-ethyl-3-imino-15-(trifluoromethyl)-14,24-dioxa-2,4,18-triazahexacyclo[ 18.6.2.22,5.210,13.012,17.023,27] Triac-10,12,20,22,27,29-hexene-19,32-dione 218 571.3 (1R,11Z,21S)-5-ethyl-3-imino-19,19-dimethyl-18,28-dioxa-2,4,22-triazahexacyclo[22.6.2.22 ,5.113,17.016,21.027,31]Tripentacarbon-11,13(33),14,16,24,26,31-heptacene-23,35-dione 219A 571.3 (7R,11R,12R,20S)-7-ethyl-9-imino-12-(methoxymethyl)-22,22-dimethyl-23-oxa-8,10,19- Triazaheptacyclo[18.6.2.27,10.214,17.02,4.011,15.024,28]Triazine-1(27),14(30),15,17(29),24(28),25-6 En-18,31-dione 219B 571.3 (7R,11R,12R,20S)-7-ethyl-9-imino-12-(methoxymethyl)-22,22-dimethyl-23-oxa-8,10,19- Triazaheptacyclo[18.6.2.27,10.214,17.02,4.011,15.024,28]Triazine-1(27),14(30),15,17(29),24(28),25-6 En-18,31-dione 220 572.3 (1R,5R,15R,17S)-5-ethyl-3-imino-15-(trifluoromethyl)-14,24-dioxa-2,4,18,28-tetraazahexa Cyclo[18.6.2.22,5.210,13.012,17.023,27]Triac-10,12,20,22,27,29-hexene-19,32-dione 221A 573.3 (1R,21S)-5-ethyl-3-imino-19,19-dimethyl-18,28-dioxa-2,4,22-triazacyclo[22.6.2.22,5.113 ,17.016,21.027,31]Tripentacarbon-13(33),14,16,24,26,31-hexene-23,35-dione 221B 573.3 (1R,21S)-5-ethyl-3-imino-19,19-dimethyl-18,28-dioxa-2,4,22-triazacyclo[22.6.2.22,5.113 ,17.016,21.027,31]Tripentacarbon-13(33),14,16,24,26,31-hexene-23,35-dione 222 574.2 (5R,8Z,17S)-5-ethyl-3-imino-26-(methoxymethyl)-15,15-dimethyl-14,24-dioxa-2,4,18 ,28-tetraazahexacyclo[18.6.2.22,5.210,13.012,17.023,27]tricoc-8,10,12,20,22,27,29-heptacene-19,32-dione 223 575.4 (1R,8Z,16S,17R,26R)-16-hydroxy-3-imino-26-(methoxymethyl)-5,15,15-trimethyl-14,24-dioxa- 2,4,18-triazahexacyclo[18.6.2.22,5.210,13.012,17.023,27]tricoc-8,10,12,20,22,27,29-heptacene-19,32- diketone 224 575.3 (1R,8E,16S,17R,26R)-16-hydroxy-3-imino-26-(methoxymethyl)-5,15,15-trimethyl-14,24-dioxa- 2,4,18-triazahexacyclo[18.6.2.22,5.210,13.012,17.023,27]tricoc-8,10,12,20,22,27,29-heptacene-19,32- diketone 225 575.4 (1S,9R,10S,14R)-14-ethyl-12-imino-9-(methoxymethyl)-9,24,24-trimethyl-8,23-dioxa-2 ,11,13-triazahexacyclo[17.6.2.24,7.211,14.06,10.022,26]Triaza-4(31),5,7(30),19(27),20,22(26 )-hexene-3,29-dione 226 575.3 (1R,18S,27R)-3-imino-27-(methoxymethyl)-5,16,16-trimethyl-15,25-dioxa-2,4,19-triaza Heterohexacyclo[19.6.2.22,5.211,14.013,18.024,28]Thirty-three carbon-11,13,21,23,28,30-hexene-20,33-dione 227 575.4 (1R,5R,17S,26R)-5-ethyl-3-imino-26-(methoxymethyl)-15,15-dimethyl-14,24-dioxa-2,4 ,18-triazahexacyclo[18.6.2.22,5.210,13.012,17.023,27]tricona-10,12,20,22,27,29-hexene-19,32-dione 228 576.3 (5R,17S)-5-ethyl-3-imino-26-(methoxymethyl)-15,15-dimethyl-14,24-dioxa-2,4,18,28 -Tetraazahexacyclo[18.6.2.22,5.210,13.012,17.023,27]tri2-10,12,20,22,27,29-hexene-19,32-dione 229 576.3 (5R,16S)-5-ethyl-3-imino-25-(methoxymethyl)-8,14,14-trimethyl-13,23-dioxa-2,4,17 ,27-tetraazahexacyclo[17.6.2.22,5.29,12.011,16.022,26]trionecarbon-9,11,19,21,26,28-hexaene-18,31-dione 230A 577.3 (7R,11R,21S)-7-ethyl-14,14-difluoro-9-imino-23,23-dimethyl-24-oxa-8,10,20-triazaheptacyclo [19.6.2.27,10.215,18.02,4.011,16.025,29]Tritricarbon-1(28),15(31),16,18(30),25(29),26-hexene-19,32 -diketone 230B 577.3 (7R,11R,21S)-7-ethyl-14,14-difluoro-9-imino-23,23-dimethyl-24-oxa-8,10,20-triazaheptacyclo [19.6.2.27,10.215,18.02,4.011,16.025,29]Tritricarbon-1(28),15(31),16,18(30),25(29),26-hexene-19,32 -diketone 231 577.3 (7R,11R,21S)-7-ethyl-14,14-difluoro-9-imino-23,23-dimethyl-24-oxa-8,10,20-triazaheptacyclo [19.6.2.27,10.215,18.02,4.011,16.025,29]Tritricarbon-1(28),15(31),16,18(30),25(29),26-hexene-19,32 -diketone 232 577.3 (1R,5R,16S,17R,26R)-5-ethyl-16-hydroxy-3-imino-26-(methoxymethyl)-16-methyl-14,24-dioxa- 2,4,18-triazahexacyclo[18.6.2.22,5.210,13.012,17.023,27]tricoc-10,12,20,22,27,29-hexene-19,32-dione 233 577.3 (1R,16S,17R,26R)-16-hydroxy-3-imino-26-(methoxymethyl)-5,15,15-trimethyl-14,24-dioxa-2, 4,18-triazahexacyclo[18.6.2.22,5.210,13.012,17.023,27]tricona-10,12,20,22,27,29-hexene-19,32-dione 234 579.2 (1R,5R,8Z,16S,17R)-5-ethyl-24,24-difluoro-16-hydroxy-3-imino-15,15-dimethyl-14-oxa-2,4 ,18-triazahexacyclo[18.6.2.22,5.210,13.012,17.023,27]tricoc-8,10,12,20,22,27,29-heptacene-19,32-dione 235 579.2 (1R,9R,10S,25S)-14-ethyl-25-hydroxy-12-imino-9-(methoxymethyl)-9,25-dimethyl-8,18,23-tri Oxa-2,11,13-triazahexane[17.6.2.24,7.211,14.06,10.022,26]Thirty-one carbon-4(31),5,7(30),19(27),20 ,22(26)-hexene-3,29-dione 236 581.2 (1S,8R,10R,14R,17Z)-14-ethyl-12-imino-24,24-dimethyl-8-(trifluoromethyl)-23-oxa-2,11,13 -Triazahexacyclo[17.6.2.24,7.211,14.06,10.022,26]Triaza-4,6,17,19(27),20,22(26),30-heptene-3,29 -diketone 237 581.3 (1R,5R,16S,17R)-5-ethyl-24,24-difluoro-16-hydroxy-3-imino-15,15-dimethyl-14-oxa-2,4,18 -Triazahexacyclo[18.6.2.22,5.210,13.012,17.023,27]Triazane-10,12,20,22,27,29-hexene-19,32-dione 238 583.3 (7R,11R,21S,23S)-7-ethyl-9-imino-23-(trifluoromethyl)-14,24-dioxa-8,10,20-triazaheptacyclo[ 19.6.2.27,10.215,18.02,4.011,16.025,29] Triacontan-1(28),15(31),16,18(30),25(29),26-hexene-19,32- diketone 239 583.3 (1S,8S,10R,14R)-14-ethyl-12-imino-24,24-dimethyl-8-(trifluoromethyl)-23-oxa-2,11,13-tri Azahexane[17.6.2.24,7.211,14.06,10.022,26]Trione-4,6,19(27),20,22(26),30-hexene-3,29-dione 240 583.2 (1S,8R,10R,14R)-14-ethyl-12-imino-24,24-dimethyl-8-(trifluoromethyl)-23-oxa-2,11,13-tri Azahexane[17.6.2.24,7.211,14.06,10.022,26]Trione-4,6,19(27),20,22(26),30-hexene-3,29-dione 241 583.2 (1S,9R,10R,14R)-14-ethyl-12-imino-24,24-dimethyl-9-(trifluoromethyl)-23-oxa-2,11,13-tri Azahexane[17.6.2.24,7.211,14.06,10.022,26]Trione-4,6,19(27),20,22(26),30-hexene-3,29-dione 242 583.3 (1S,9S,10R,14R)-14-ethyl-12-imino-24,24-dimethyl-9-(trifluoromethyl)-23-oxa-2,11,13-tri Azahexane[17.6.2.24,7.211,14.06,10.022,26]Trione-4,6,19(27),20,22(26),30-hexene-3,29-dione 243 585.3 (1R,5R,8Z)-5-ethyl-16-hydroxy-3-imino-15-(trifluoromethyl)-14,24-dioxa-2,4,18-triazahexa Cyclo[18.6.2.22,5.210,13.012,17.023,27]tricoc-8,10,12,20,22,27,29-heptacene-19,32-dione 244 586.3 (5R,15R,17S)-5-ethyl-3-imino-26-methyl-15-(trifluoromethyl)-14,24-dioxa-2,4,18,28-tetra Azahexane [18.6.2.22,5.210,13.012,17.023,27] tri2-carbon-10,12,20,22,27,29-hexene-19,32-dione 245 587.2 (1R,5R)-5-ethyl-16-hydroxy-3-imino-15-(trifluoromethyl)-14,24-dioxa-2,4,18-triazahexacyclo[ 18.6.2.22,5.210,13.012,17.023,27] Triac-10,12,20,22,27,29-hexene-19,32-dione 246 587.3 (1R,9E,18S,27R)-5-ethyl-3-imino-27-(methoxymethyl)-16,16-dimethyl-15,25-dioxa-2,4 ,19-triazahexacyclo[19.6.2.22,5.211,14.013,18.024,28]Triaza-9,11,13,21,23,28,30-heptacene-20,33-dione 247 589.6 (1R,5R,8Z,16S,17R,26S)-5-ethyl-16-hydroxy-3-imino-26-(methoxymethyl)-15,15-dimethyl-14,24 -dioxa-2,4,18-triazahexacyclo[18.6.2.22,5.210,13.012,17.023,27]triadeca-8,10,12,20,22,27,29-heptene -19,32-dione 248 589.3 (7R,11R,12R,21R,22S)-7-ethyl-22-hydroxy-9-imino-12-(methoxymethyl)-22-methyl-14,24-dioxa- 8,10,20-Triazaheptacyclo[19.6.2.27,10.215,18.02,4.011,16.025,29]Triazocarbon-1(28),15(31),16,18(30),25( 29),26-hexene-19,32-dione 249 589.3 (1R,5R,8E,16S,17R,26R)-5-ethyl-16-hydroxy-3-imino-26-(methoxymethyl)-15,15-dimethyl-14,24 -dioxa-2,4,18-triazahexacyclo[18.6.2.22,5.210,13.012,17.023,27]triadeca-8,10,12,20,22,27,29-heptene -19,32-dione 250 589.2 [(1R,5R,16S,17R)-5-Ethyl-3-imino-15,15-dimethyl-19,32-dilateral oxy-14,24-dioxa-2,4 ,18-triazahexacyclo[18.6.2.22,5.210,13.012,17.023,27]tricoc-10,12,20,22,27,29-hexen-16-yl]acetate 251 589.4 (1S,9R,10S,14R)-14-ethyl-12-imino-9-(methoxymethyl)-9,25,25-trimethyl-8,24-dioxa-2 ,11,13-triazahexacyclo[18.6.2.24,7.211,14.06,10.023,27]Triazine-4(32),5,7(31),20(28),21,23(27 )-hexene-3,30-dione 252 590.2 (1S,14R,17Z,24R)-14-ethyl-8,8-difluoro-12-imino-24-(trifluoromethyl)-23-oxa-2,5,11,13- Tetraazahexacyclo[17.6.2.24,7.211,14.06,10.022,26]Thirty-one carbon-4,6,17,19(27),20,22(26),30-heptene-3,29- diketone 253 591.3 (1S,10R,14R,24R)-14-ethyl-8,8-difluoro-12-imino-24-(trifluoromethyl)-23-oxa-2,11,13-triazo Heterohexacyclo[17.6.2.24,7.211,14.06,10.022,26]Trione-4,6,19(27),20,22(26),30-hexene-3,29-dione 254 591.3 (1R,5R,16S,17R,26R)-5-ethyl-16-hydroxy-3-imino-26-(methoxymethyl)-15,15-dimethyl-14,24-di Oxa-2,4,18-triazahexane[18.6.2.22,5.210,13.012,17.023,27]Triazine-10,12,20,22,27,29-hexene-19,32 -diketone 255 591.3 (1R,5R,16S,17R,26S)-5-ethyl-16-hydroxy-3-imino-26-(methoxymethyl)-15,15-dimethyl-14,24-di Oxa-2,4,18-triazahexane[18.6.2.22,5.210,13.012,17.023,27]Triazine-10,12,20,22,27,29-hexene-19,32 -diketone 256 592.2 (1S,14R,24R)-14-ethyl-8,8-difluoro-12-imino-24-(trifluoromethyl)-23-oxa-2,5,11,13-tetraaza Heterohexacyclo[17.6.2.24,7.211,14.06,10.022,26]Trione-4,6,19(27),20,22(26),30-hexene-3,29-dione 257 595.3 (7R,11R,13R,20S)-7-ethyl-9-imino-22,22-dimethyl-13-(trifluoromethyl)-23-oxa-8,10,19-tri Azaheptacyclo[18.6.2.27,10.214,17.02,4.011,15.024,28]32C-1(27),14,16,24(28),25,29-hexene-18,31-di ketone 258 595.2 (1S,15R,16R,24R)-15-hydroxy-3-imino-24-(methoxymethyl)-24-methyl-5-phenyl-23-oxa-2,4,17 -Triazahexacyclo[17.5.2.22,5.210,13.012,16.022,25] triazocarbon-10,12,19,21,25,27-hexene-18,30-dione 259A 597.3 (1R,5R,17S)-8-(difluoromethyl)-5-ethyl-8-hydroxy-3-imino-15,15-dimethyl-14,24-dioxa-2, 4,18-Triazahexacyclo[18.6.2.22,5.210,13.012,17.023,27]Triazahexane-10(30),11,13(29),20,22,27-hexane-19, 32-diketone 259B 597.3 (1R,5R,17S)-8-(difluoromethyl)-5-ethyl-8-hydroxy-3-imino-15,15-dimethyl-14,24-dioxa-2, 4,18-Triazahexacyclo[18.6.2.22,5.210,13.012,17.023,27]Triazahexane-10(30),11,13(29),20,22,27-hexane-19, 32-diketone 260 599.3 (7R,11R)-7-ethyl-22-hydroxy-9-imino-23-(trifluoromethyl)-14,24-dioxa-8,10,20-triazaheptacyclo[ 19.6.2.27,10.215,18.02,4.011,16.025,29] Triacontan-1(28),15(31),16,18(30),25(29),26-hexene-19,32- diketone 261 599.3 (1R,5R,17S,26S)-5-ethyl-3-imino-15,15-dimethyl-26-(trifluoromethyl)-14,24-dioxa-2,4, 18-Triazahexacyclo[18.6.2.22,5.210,13.012,17.023,27]Triazine-10,12,20,22,27,29-hexene-19,32-dione 262 599.3 (1R,5R,17S,26R)-5-ethyl-3-imino-15,15-dimethyl-26-(trifluoromethyl)-14,24-dioxa-2,4, 18-Triazahexacyclo[18.6.2.22,5.210,13.012,17.023,27]Triazine-10,12,20,22,27,29-hexene-19,32-dione 263 603.3 [(1R,5R,16S,17R)-5-Ethyl-3-imino-15,15-dimethyl-19,32-dilateral oxy-14,24-dioxa-2,4 ,18-triazahexacyclo[18.6.2.22,5.210,13.012,17.023,27]tricoc-10,12,20,22,27,29-hexen-16-yl]propionate 264 613.2 (1R,5R,8Z,15R,17S,26R)-5-ethyl-3-imino-26-(methoxymethyl)-15-(trifluoromethyl)-14,24-dioxy Hetero-2,4,18-triazahexacyclo[18.6.2.22,5.210,13.012,17.023,27]Triac-8,10,12,20,22,27,29-heptacene-19, 32-diketone 265 614.2 (5R,8Z,15R,17S)-5-ethyl-3-imino-26-(methoxymethyl)-15-(trifluoromethyl)-14,24-dioxa-2, 4,18,28-tetraazahexacyclo[18.6.2.22,5.210,13.012,17.023,27]tricoc-8,10,12,20,22,27,29-heptacene-19,32- diketone 266 615.2 (1R,5R,17S)-5-ethyl-9-hydroxy-3-imino-15,15-dimethyl-9-(trifluoromethyl)-14,24-dioxa-2, 4,18-Triazahexacyclo[18.6.2.22,5.210,13.012,17.023,27]Triazahexane-10(30),11,13(29),20,22,27-hexane-19, 32-diketone 267 615.2 (1R,5R,15R,17S,26R)-5-ethyl-3-imino-26-(methoxymethyl)-15-(trifluoromethyl)-14,24-dioxa- 2,4,18-triazahexacyclo[18.6.2.22,5.210,13.012,17.023,27]tricoc-10,12,20,22,27,29-hexene-19,32-dione 268 616.2 (5R,15R,17S)-5-ethyl-3-imino-26-(methoxymethyl)-15-(trifluoromethyl)-14,24-dioxa-2,4, 18,28-tetraazahexacyclo[18.6.2.22,5.210,13.012,17.023,27]tricoc-10,12,20,22,27,29-hexene-19,32-dione 269 617.4 [(1R,5R,16S,17R)-5-Ethyl-3-imino-15,15-dimethyl-19,32-dilateral oxy-14,24-dioxa-2,4 ,18-triazahexacyclo[18.6.2.22,5.210,13.012,17.023,27]tricoc-10,12,20,22,27,29-hexen-16-yl]2-methylpropane acid ester

Antiparasitic potency was assessed in the Parasite LDH Growth Assay ( Parasite Assay ) Parasite base was maintained in RPMI-Hepes Medium 30 buffered with sodium bicarbonate and supplemented with 5% heat-inactivated human serum and 0.5% albumax. 4% hematocrit.

Approximately 42 hours before setting up the titer assay, parasite lines were synchronized with 5% sorbitol to select for ring-stage parasites. On the day the assay was set up, blood smears from parasite cultures were stained with Giemsa and counted. The parasitemia system was adjusted to 0.7% via 35 and the hematocrit system was diluted to 2% in RPMI-Hepes medium buffered with sodium bicarbonate and supplemented with 5% heat-inactivated human serum and 0.5% albumax. . Then add 30 ul of diluted parasites to 10 ul of medium + compound in the previously prepared Greiner TC assay plate. Place the parasite analysis plate in a single layer gas humidified chamber and allow to incubate at 37°C for 72 hours. After 72 hours of growth, the assay plates were sealed with paraffin and frozen in columns at -80°C overnight. The next day, the assay plates were thawed at room temperature for 4 hours for LDH analysis to measure parasite growth.

Analytical EC50 results are shown in Table 2. Table 2 Example EC ₅₀ (nM) 1 2.7 2 11.0 3A 0.2 3B 269.8 4 2.0 5 0.2 5a 0.9 6 2.8 7 0.9 8 1.1 9 76.5 10 2.5 11 4.6 12 1.0 13 22.0 14 34.0 15A 9.2 15B 81.0 16A 61.5 16B 3.4 17 18.9 18 6.0 19 4.8 20 3.6 twenty one 5.1 twenty two 57.4 twenty three 7.5 24A 5.4 24B 2.0 25A 23.0 25B 0.7 26A 189.7 26B 7.4 28 19.4 29 6.3 30 11.3 31 7.8 32 0.7 33 1.0 34 1.6 35 2.5 36 7.0 37 6.2 38 0.7 39 1.7 40 7.0 41 8.8 42 0.7 43 0.7 44 0.8 45 1.5 46 2.6 47 4.2 48 6.0 49 7.3 50 7.7 51 9.1 52 19.5 53 0.7 54 0.7 55 3.1 56 0.2 57 0.3 58 0.4 59 0.6 60 0.9 61 1.0 62 1.0 63 1.8 64 1.9 65 2.0 66 2.2 67 2.6 68 4.8 69 12.0 70 18.0 71 0.7 72 0.7 73 2.1 74 5.2 75A 0.8 75B 1.3 76 0.3 77 7.0 78 0.5 79 0.6 80 0.6 81 0.6 82 0.6 83 0.7 84 1.4 85 2.1 86 2.4 87 3.4 88 3.6 89 5.1 90 6.8 91 0.5 92 6.5 93 3.0 94 8.8 95 1.0 96 1.2 97 1.5 98 2.6 99 3.3 100 7.7 101 8.3 102 0.8 103 6.7 104 0.3 105 0.7 106 0.7 107 0.7 108 0.8 109 1.0 110 1.8 111 0.6 112 0.3 113 0.7 114 1.5 115 3.4 116 0.3 117 0.4 118 0.6 119 1.4 120 1.5 121A 1.6 121B 0.5 121C 0.6 121D 5.7 122 1.9 123 2.3 124 3.8 125 6.0 126 0.8 127 0.6 128 0.3 129 1.1 130 1.9 131 2.1 132 10.6 133 0.3 134 0.3 135 0.5 136 0.9 137 2.0 138 1.6 139A 0.3 139B 0.8 140A 1.0 140B 1.4 141 7.3 142 1.4 143 7.3 144 0.3 145 0.2 146 0.6 147 0.7 148 0.7 149 0.8 150 0.9 151 1.0 152 1.2 153 5.9 154 6.2 155 6.2 156 9.6 157 1.0 158 0.3 159 0.6 160 0.6 161 0.7 162A 1.4 162B 1.1 163 1.1 164 2.1 165 2.4 166 0.4 167 0.4 168 1.2 169 1.4 170 2.5 171 2.9 172 3.1 173 3.2 174 3.4 175 5.0 176 5.3 177 0.7 178 0.4 179 0.8 180 6.7 181 0.6 182 0.8 183 2.4 184 0.9 185 19.5 186 0.8 187 0.6 188 0.6 189 19.4 190 0.5 191 1.0 192 0.9 193 1.7 194 0.9 195 1.1 196 3.6 197 6.6 198 0.7 199 1.9 200 0.4 201 0.6 202 1.1 203 1.8 204 3.2 205 0.3 206 0.9 207 1.9 208 0.7 209 0.4 210 0.7 211 0.7 212 0.9 213 1.2 214 1.9 215 0.6 216 0.2 217 5.6 218 7.5 219A 2.5 219B 6.4 220 1.0 221A 5.4 221B 2.0 222 2.7 223 0.7 224 2.7 225 0.4 226 0.7 227 0.8 228 0.4 229 19.0 230A 0.9 230B 0.8 231 1.1 232 0.2 233 0.8 234 3.1 235 0.4 236 0.8 237 0.7 238 0.8 239 0.2 240 0.6 241 0.7 242 1.2 243 0.4 244 2.4 245 1.4 246 7.4 247 0.3 248 0.7 249 1.2 250 1.3 251 1.0 252 2.1 253 1.0 254 0.3 255 1.2 256 0.7 257 0.6 258 2.4 259A 9.9 259B 2.3 260 0.8 261 2.3 262 6.7 263 0.9 264 0.8 265 1.0 266 16.0 267 1.0 268 1.9 269 1.1

Claims (32)

A compound having structural formula (I): (I) Or a pharmaceutically acceptable salt thereof, or an ester, hydrate, stereoisomer or tautomer of the compound or salt, wherein: A is a linear or tautomer containing at least one -CH ₂ - group Branched chain, saturated or unsaturated (C ₃ -C ₁₀ )alkylene, phenyl (C ₃ -C ₁₀ )alkylene or cycloalkyl (C ₃ -C ₁₀ )alkylene, one of A or more additional -CH ₂ - groups are optionally and independently substituted with a moiety selected from the group consisting of: O, S, NR, CONR, NRCO, SO ₂ and SO ₂ NR and wherein the hydrogen along A One or more of them may be independently replaced by a group selected from hydroxyl, halogen and C _1-3 haloalkyl; X is a bond, C(R ¹⁴ ) ₂ , O, S, SO, SO ₂ or NH; Y series is CR ⁹ or N, where when Y series is N, Z series is CR ¹¹ and V series is CR ¹⁰ ; V series is CR ¹⁰ or N, where when V series is N, Z series is CR ¹¹ and Y series is CR ⁹ ; Z series CR ¹¹ or N, where when Z is N, V is CR ¹⁰ and Y is CR ⁹ ; R is hydrogen, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, COC ₁ -C ₆ alkyl or COOC ₁ -C ₆ alkyl; R ^a is hydrogen, halogen, CN, OH, C _{1 -C 6} alkoxy, C ₁ -C 6 alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, side oxy, COOC ₁ -C ₆ alkyl, C ₁ - C ₆ alkylCOOC 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 _6alkyl O halo C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl N(R ⁷ ) (R ⁸ ) or when taken together with R ^b forms a C ₃ -C ₆ cycloalkyl or heterocycloalkyl, wherein the C ₃ -C ₆ cycloalkyl The base or heterocycloalkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of: 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, side oxy group, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOC ₁ -C ₆ alkyl, C ₃ -C ₆ Cycloalkyl, C ₁ -C ₆ alkyl C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl O halo C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) and C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ); R ^b is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, side Oxygen, COOC ₁ -C ₆ alkyl, C ₁ -C 6 alkyl COOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl C _{3 -C 6 cycloalkyl} , C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl O halo C ₁ -C 6 alkyl, halo C ₁ -C ₆ alkyl, C _{1 -C 6 alkyl} OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ) or when taken together with R ^a forms a C ₃ -C ₆ cycloalkyl or Heterocycloalkyl, wherein the C ₃ -C ₆ cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or three substituents selected from the group consisting of: halogen, CN, OH, C ₁ - C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, side oxy, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl Base COOC ₁ -C ₆ alkyl, C _{3 -C} 6 cycloalkyl, C ₁ -C ₆ alkyl C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl OHalo C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) and C ₁ -C ₆ alkyl N(R ⁷ ) (R ⁸ ); R ³ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl OC ₁ -C ₆ alkyl Base, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON (R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ), C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ), C ₁ -C ₆ alkyl (OCH ₂ CH ₂ ) _n N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl O halo C ₁ -C ₆ alkyl or when taken together with R ⁴ forms a C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ hetero Cycloalkyl; R ⁴ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C 6 alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N( ^R ₇ )(R ⁸ ), C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ), C ₁ -C ₆ alkyl (OCH ₂ CH ₂ ) _n N(R ⁷ )(R ⁸ ) or C ₁ - C ₆ alkylO halo C ₁ -C ₆ alkyl or when taken together with R ³ forms C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ heterocycloalkyl; R ⁷ is hydrogen, C ₁ -C ₆ alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, COC ₁ -C ₆ alkyl Or COOC ₁ -C ₆ alkyl; R ⁸ is hydrogen, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl base, C ₁ -C ₆ alkyl OH, COC ₁ -C ₆ alkyl or COOC ₁ -C ₆ alkyl; R ⁹ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy group, C ₁ - C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ); R ¹⁰ is hydrogen , Halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl , C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ ) (R ⁸ ), N (R ⁷ ) (R ⁸ ) or C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ); R ¹¹ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ); R ¹² is hydrogen, halogen, CN, OH, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ alkyl OC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ); R ¹³ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C 6 alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ ₎ (R ⁸ ) or C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ); Each occurrence of R ¹⁴ is independently selected from the group consisting 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, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) and C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ); R ¹⁵ is hydrogen, halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C 6 alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ ₎ (R ⁸ ) or C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ); Each occurrence of R ¹⁶ is independently selected from the group consisting 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, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) and C ₁ -C ₆ alkyl N(R ⁷ )(R ⁸ ); m is 0 or 1; n is 1, 2, 3 or 4; and p is 0 or 1. For example, the compound of claim 1, or a pharmaceutically acceptable salt thereof, or an ester, hydrate, stereoisomer or tautomer of the compound or salt, wherein m is 1, p is 1 and X is O. For example, the compound of claim 1, or a pharmaceutically acceptable salt thereof, or an ester, hydrate, stereoisomer or tautomer of the compound or salt, wherein m is 1, p is 1 and X is a bond. Such as the compound of claim 1, or a pharmaceutically acceptable salt thereof, or an ester, hydrate, stereoisomer or tautomer of the compound or salt, wherein R ^a and R ^b together form a heterocycloalkane base. Such as the compound of claim 1, or a pharmaceutically acceptable salt thereof, or an ester, hydrate, stereoisomer or tautomer of the compound or salt, wherein R ^a and R ^b together form a heterocycloalkane base, wherein the heterocycloalkyl system , and wherein the heterocycloalkyl group is substituted by two C ₁ -C ₆ alkyl groups. Such as the compound of claim 1, or a pharmaceutically acceptable salt thereof, or an ester, hydrate, stereoisomer or tautomer of the compound or salt, wherein R ^a is together with R ^b and forms C ₃ - C ₆ cycloalkyl. Such as the compound of claim 1, or a pharmaceutically acceptable salt thereof, or an ester, hydrate, stereoisomer or tautomer of the compound or salt, wherein R ^a is together with R ^b and forms C ₃ - C ₆ cycloalkyl, wherein the heterocycloalkyl is , and wherein the C ₃ -C ₆ cycloalkyl group is unsubstituted or substituted by OH. Such as the compound of claim 1, or a pharmaceutically acceptable salt thereof, or an ester, hydrate, stereoisomer or tautomer of the compound or salt, wherein R ³ is hydrogen, C ₁ -C ₆ alkyl OC ₁ -C ₆ alkyl or C ₁ -C ₆ alkyl or when taken together with R ⁴ forms a C ₃ -C ₆ heterocycloalkyl. Such as the compound of claim 1, or a pharmaceutically acceptable salt thereof, or an ester, hydrate, stereoisomer or tautomer of the compound or salt, wherein R ³ is hydrogen or C ₁ -C ₆ alkyl Or when taken together with R ⁴ forms a C ₃ -C ₆ heterocycloalkyl group. For example, the compound of claim 1, or a pharmaceutically acceptable salt thereof, or an ester, hydrate, stereoisomer or tautomer of the compound or salt, wherein R ³ and R ⁴ are both halogen. Such as the compound of claim 1, or a pharmaceutically acceptable salt thereof, or an ester, hydrate, stereoisomer or tautomer of the compound or salt, wherein R ¹⁵ is hydrogen or C ₁ -C ₆ alkyl . For example, the compound of claim 1, or a pharmaceutically acceptable salt thereof, or an ester, hydrate, stereoisomer or tautomer of the compound or salt, wherein R ³ and R ⁴ are independently selected from the following: Group: hydrogen, halogen, OH, C ₁ -C ₆ alkyl OH, C ₁ -C ₆ alkyl alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl base, C ₁ -C ₆ alkyl O halo C ₁ -C ₆ alkyl, CON (C ₁ -C ₆ alkyl) ₂ , C ₁ -C ₆ alkyl N (R ⁷ ) (R ⁸ ) and C ₁ -C ₆ alkyl (OCH ₂ CH ₂ ) _n N (R ⁷ ) (R ⁸ ); R ⁷ is hydrogen, C ₁ -C ₆ alkyl COOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, COC ₁ -C ₆ alkyl or COOC ₁ -C ₆ alkyl; R ⁸ is hydrogen, C ₁ -C ₆ alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl OH, COC ₁ -C ₆ alkyl Or COOC ₁ -C ₆ alkyl; and n series 3. For example, the compound of claim 1, or a pharmaceutically acceptable salt thereof, or an ester, hydrate, stereoisomer or tautomer of the compound or salt, wherein R ¹² and R ¹³ are independently selected from the following: Group: hydrogen, halogen, OH, C ₁ -C ₆ alkyl OH, C ₁ -C ₆ alkyl alkoxy and C ₁ -C ₆ alkyl OC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl base. For example, the compound of claim 1, or a pharmaceutically acceptable salt thereof, or an ester, hydrate, stereoisomer or tautomer of the compound or salt, wherein X is C(R ¹⁴ ) ₂ and R ¹⁴ is Independently selected from the group consisting of hydrogen, halogen, OH, C ₁ -C ₆ alkyl OH, C ₁ -C ₆ alkyl alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, and C ₁ -C ₆ alkyl. Such as the compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, or an ester, hydrate, stereoisomer or tautomer of the compound or salt, wherein Y is CH. Such as the compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, or an ester, hydrate, stereoisomer or tautomer of the compound or salt, wherein Z is CH. Such as the compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, or an ester, hydrate, stereoisomer or tautomer of the compound or salt, wherein V is CH. For example, the compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, or an ester, hydrate, stereoisomer or tautomer of the compound or salt, wherein A is a linear, saturated Or unsaturated (C ₃ -C ₁₀ )alkylene. For example, the compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, or an ester, hydrate, stereoisomer or tautomer of the compound or salt, wherein A is a branched chain, saturated Or unsaturated (C ₃ -C ₁₀ )alkylene. For example, the compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, or an ester, hydrate, stereoisomer or tautomer of the compound or salt, wherein A is . A compound or a pharmaceutically acceptable salt thereof, or an ester, hydrate, stereoisomer or tautomer of the compound or salt, wherein the compound is selected from the group consisting of: and . A compound, or a pharmaceutically acceptable salt thereof, or an ester, hydrate, stereoisomer or tautomer of the compound or salt, wherein the compound has the following formula: . A compound, or a pharmaceutically acceptable salt thereof, or an ester, hydrate, stereoisomer or tautomer of the compound or salt, wherein the compound has the following formula: . A compound, or a pharmaceutically acceptable salt thereof, or an ester, hydrate, stereoisomer or tautomer of the compound or salt, wherein the compound has the following formula: . Use of a compound as claimed in any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof, or an ester, hydrate, stereoisomer or tautomer of the compound or salt, for the manufacture of A drug used to treat Plasmodium infection or malaria. The use of a compound as claimed in any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof, or an ester, hydrate, stereoisomer or tautomer of the compound or salt, for the manufacture of an inhibitor Plasmepsin X drug. The use of a compound as claimed in any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof, or an ester, hydrate, stereoisomer or tautomer of the compound or salt, for the manufacture of an inhibitor Malaria heme IX-lowering drugs. The use of a compound as claimed in any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof, or an ester, hydrate, stereoisomer or tautomer of the compound or salt, for the manufacture of dual Drugs that inhibit malarial heme IX and malarial heme X. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, or an ester, hydrate, stereoisomer or tautomer of the compound or salt, and pharmaceutically acceptable carriers. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 24 and a pharmaceutically acceptable carrier. Use of a compound as claimed in any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof, or an ester, hydrate, stereoisomer or tautomer of the compound or salt, for the manufacture of a therapeutic A drug for Plasmodium infection or treatment of malaria, wherein the drug further contains one or more additional anti-malarial agents or is used in combination with one or more additional anti-malarial agents. Use of a compound as claimed in any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof, or an ester, hydrate, stereoisomer or tautomer of the compound or salt, for the manufacture of A drug for treating malaria by inhibiting malarial heme X, IX and at least one other mechanism, wherein the drug further comprises or is combined with another antimalarial agent, wherein the additional antimalarial agent passes and Malarial heme IX or malarial heme X act by different mechanisms.