JP2024545498A - Antimalarial drugs - Google Patents

Abstract

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

The present invention relates to a compound represented by formula (I) or a pharma- ceutically acceptable salt thereof, which is useful for the treatment of a malaria parasite infection. More particularly, the present invention relates to a compound represented by formula (I) or a pharma- ceutically acceptable salt thereof, which is useful for the treatment of a malaria parasite infection, in particular for the treatment of malaria.

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

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

Artemisinin in combination with a partner drug has become the mainstay of malaria treatment and control. However, due to the growing threat of drug resistance to artemisinin-based combination therapies (ACTs), the development of novel antimalarials with new targets that inhibit multiple stages in the parasite's life cycle is an urgent priority for the malaria control field. Such novel antimalarials (e.g., monotherapy or ACT partner drugs) could be a step forward towards malaria elimination, as parasites with pre-existing resistance mutations are less likely to exist in the parasite population.

Currently, aspartic proteases are major targets for drug development: HIV aspartic protease has been successfully targeted with drugs in clinical use; inhibitors targeting human renin, BACE1 and γ-secretase are already in or under clinical development. In the field of antimalarial drugs, the Plasmodium falciparum aspartic proteases plasmepsin X and plasmepsin IX (PMX and PMIX) have been identified as potential targets because inhibitors block the parasite's escape from and invasion of host cells, preventing the maturation of some rhoptry and microneme proteins required for this process (Pino P, Caldelari R, Mukherjee B, Vahokoski J, Klages N, Maco B, et al. A multistage antimalarial targets the plasmepsins IX and X essential for invasion and egress. Science. 2017;358(6362):522-8).

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 a compound of formula (I):

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

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

Furthermore, the present specification describes a method for treating malaria, comprising administering to a subject in need of such treatment a compound represented by formula (I) or a pharma- ceutically acceptable salt thereof.

The present invention further provides the use of a composition (which includes a pharmaceutical composition) for treating malaria, wherein the composition comprises one or more compounds of the invention (e.g., a compound of the invention) or a tautomer thereof, or a pharma- ceutically acceptable salt or solvate of said compound and/or said tautomer, optionally together with one or more additional therapeutic agents, optionally in an acceptable (e.g., pharma- ceutically acceptable) carrier or diluent.

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

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

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

The present invention further provides a method for treating malaria by inhibiting plasmepsin X. The present invention further provides a method for treating malaria by inhibiting both PMX and plasmepsin IX.

These and other embodiments of the invention are described in detail below or will become apparent to those skilled in the art, and such embodiments are within the scope of the invention.

Described herein is a compound of structural formula (I):

[Wherein,
A is a straight or branched chain saturated or unsaturated (C ₃ -C ₁₀ )alkylene, phenyl(C _{3 -C 10 )alkylene or cycloalkyl(C 3 -C 10 ) alkylene} containing at least one -CH ₂ - group, where one or more additional -CH ₂ - groups within A may be independently replaced with a moiety selected from the group consisting of O, S, NR, CONR, NRCO, SO ₂ and SO ₂ NR, and where one or more of the hydrogens along A may be replaced with a group independently 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 is ^CR9 or N, where when Y is N, Z is ^CR11 and V is ^CR10 ;
V is CR ¹⁰ or N, where if 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, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, 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 alkylCOOH, COOH, oxo, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkylC ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C _{1 -C 6} alkylOH, CON(R ₇ ) _{(R 8 ), N(R 7 )(R 8 ) or C 1 -C 6} ^alkylN _{( R} ^{7 )} _{( R} ^{8 ) or} , when taken together with R ^b , C and forming a C 3 -C ₆ cycloalkyl or heterocycloalkyl, wherein the C ₃ -C ₆ cycloalkyl or heterocycloalkyl is unsubstituted or is selected from halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOH, COOH, oxo, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOC ₁ -C ₆ alkyl, C ₃ -C _{6 cycloalkyl, C 1 -C 6 alkylC 3 -C 6 cycloalkyl , C 1 -C 6} alkyl, -C ₁ -C ₆ alkylOhaloC ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, _CON (R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) and C substituted with 1 or 2 substituents selected from the group consisting of ₁ - _C6 alkylN(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 alkylCOOH, COOH, oxo, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkylC ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C _{1 -C 6} alkylOH, CON(R ₇ )( _R ⁸ ), _N ( _R ⁷ )(R ⁸ ) or C _{1 -C 6} alkylN(R ⁷ )( ^{R 8 )} or, when taken together with R ^a , is C and forming a C 3 -C ₆ cycloalkyl or heterocycloalkyl, wherein the C ₃ -C ₆ cycloalkyl or heterocycloalkyl is unsubstituted or is selected from halogen, CN, OH, C ₁ -C ₆ alkoxy, _{C 1} -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOH, COOH, oxo, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOC ₁ -C ₆ alkyl, C ₃ -C _{6 cycloalkyl, C 1 -C 6 alkylC 3 -C 6 cycloalkyl, C 1 -C 6 alkyl , -C 1} -C ₆ alkylOhaloC ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) and C substituted with 1 to 3 substituents selected from the group consisting of ₁ - _C6 alkylN(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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ), C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ), C ₁ -C ₆ alkyl(OCH ₂ CH ₂ ) _n N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylOHhaloC ₁ -C ₆ alkyl, or when taken together with R ⁴ 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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ), C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ), C ₁ -C ₆ alkyl(OCH ₂ CH ₂ ) _n N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylOHhaloC 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, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, 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, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, 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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ );
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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ );
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, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ );
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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ );
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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ );
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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ), and C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ );
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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ );
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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ), and C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ );
m is 0 or 1;
n is 1, 2, 3 or 4; and
p is 0 or 1.
It is a compound having the formula:

In embodiments described herein, X is a bond, C(R ¹⁴ ) ₂ , O, S, SO, SO ₂ , or NH. In certain embodiments described herein, X is a bond. In certain embodiments, X is C(R ¹⁴ ) ₂ , where R ¹⁴ is discussed in more detail below. In certain embodiments, X is a bond, CH ₂ , CH(CH ₃ ), C(CH ₃ ) ₂ , O, CH(OCH ₃ ), SO ₂ , or CF _2. In another embodiment, X is CH ₂ , O, S, SO, SO ₂ , or NH. In certain embodiments, X is CH _2. In embodiments described herein, X is O. In certain embodiments described herein, X is S. In certain embodiments described herein, X is SO. In another embodiment described herein, X is SO _2. In certain embodiments described herein, X is NH.

In the embodiments described herein, Y is ^CR9 or N. In certain embodiments, Y is ^CR9 , where ^R9 is discussed in detail below. In certain embodiments, Y is N. In certain embodiments, Y is CH. In certain embodiments, when Y is N, Z is ^CR11 and V is ^CR10 .

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

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

In certain embodiments, X is O, Y and V are each CH, and Z is N. In certain embodiments, X is O, Y and Z are each CH, and V is N. In certain embodiments, X is O, and V, Y, and Z are all simultaneously CH.

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 alkylCOOH, COOH, oxo, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkylC ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C _{1 -C 6} alkylOH, _CON (R ⁷ )( _R ⁸ ) _{, N} (R ⁷ )(R ⁸ ₎ or _{C 1} -C ₆ alkylN(R ⁷ )(R ⁸ ), or R When taken together with ^b , they form a C ₃ -C ₆ cycloalkyl or heterocycloalkyl, where the C ₃ -C ₆ cycloalkyl or heterocycloalkyl is unsubstituted or is selected from the group consisting of halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOH, COOH, oxo, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkylC ₃ -C ₆ cycloalkyl, _{C 1 -C 6} alkyl, -C _{1 -C 6} alkylOH, _CON (R ⁷ )(R ⁸ ), _N (R ⁷ ) _{( R} ⁸ ) and C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ).

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

In certain embodiments, R ^a is halogen. Suitable examples of halogen 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 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 an oxo group.

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 include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

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

And more.

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

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

And more.

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

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

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 alkylN(R ⁷ )(R ⁸ ), where R ⁷ and R ⁸ are described in more detail below.

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

It is represented by

In certain embodiments, R ^a together with R ^b form a C ₃ -C ₆ cycloalkyl or heterocycloalkyl, where the C ₃ -C ₆ cycloalkyl or heterocycloalkyl is unsubstituted or is selected from the group consisting of halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOH, COOH, oxo, COOC ₁ -C ₆ alkyl, C _{1 -C 6} alkylCOOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkylC _{3 -C 6 cycloalkyl, C 1 -C 6 alkyl , -C 1 -C 6 alkylOH ,} CON( _R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ), and C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ).

In certain embodiments, R ^a together with R ^b form a C ₃ -C ₆ cycloalkyl, where the cycloalkyl is unsubstituted or selected from halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOH, COOH, oxo, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOC ₁ -C ₆ alkyl, _{C 3} -C ₆ cycloalkyl, C _{1 -C 6 alkylC 3 -C 6 cycloalkyl, C 1 -C 6 alkyl , -C 1 -C 6} alkylOH, _CON (R ⁷ )(R ⁸ ), _N (R ⁷ )(R ⁸ ), _{and C} Substituted with 1 or 2 substituents selected from the group consisting of ₁ - _C6 alkylN(R ⁷ )(R ⁸ ).

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

In certain embodiments, the cycloalkyl is unsubstituted. In certain embodiments, the heterocycloalkyl is selected from halogen, CN, OH, C ₁ -C ₆ alkoxy, C _{1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH , COOH} , oxo, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, _{C 1 -C 6 alkylC 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, -C 1 -C 6 alkylOH , CON ( R 7 ) (} ^R ₈ ⁾ , _N (R ⁷ )(R ⁸ ), _and C _{1 -C 6} alkylN ₍ R ⁷ )(R ⁸ ) is substituted with one or two substituents selected from the group consisting of

In certain embodiments, the cycloalkyl is substituted with one 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 alkylCOOH, COOH, oxo, COOC ₁ -C ₆ alkyl, C _{1 -C 6} alkylCOOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, _{C 1} -C ₆ alkylC ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkylOH, _CON (R ⁷ )( _R ⁸ ) _{, N} (R ⁷ )(R ⁸ ) and C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ).

In certain embodiments, the 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 alkylCOOH, COOH, oxo, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkylC ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkylOH haloC ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) and C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ).

In certain embodiments, the cycloalkyl is substituted with OH.

In certain embodiments, R ^a together with R ^b form a heterocycloalkyl, where the heterocycloalkyl is unsubstituted or is selected from the group consisting of halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOH, COOH, oxo, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, _{C 1 -C 6 alkylC 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, -C 1 -C 6 alkylOH , CON ( R 7 ) ( R} ^{8 )} , _N (R ⁷ )(R ⁸ ), _{and C 1 -C 6} alkylN(R ⁷ )(R ⁸ ).

Non-limiting examples of monocyclic heterocycloalkyl groups include piperidyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, beta-lactam, gamma-lactam, delta-lactam, beta-lactone, gamma-lactone, delta-lactone, and pyrrolidinone and their oxides. Non-limiting examples of heterocycloalkyl groups include, but are not limited to,

And more.

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

And more.

In certain embodiments, R ^a together with R ^b represents:

form.

In certain embodiments, the heterocycloalkyl is unsubstituted. In certain embodiments, the heterocycloalkyl is selected from halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOH, COOH, oxo, COOC ₁ -C ₆ alkyl, _{C 1} -C ₆ alkylCOOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkylC ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkylOH, CON(R ⁷ )( _R ⁸ ), _N (R ⁷ )(R ⁸ ), _and C _{1 -C 6 alkylN} (R ⁷ )(R ⁸ ) is substituted with one or two substituents selected from the group consisting of

In certain embodiments, the heterocycloalkyl is selected from halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOH, COOH, oxo, COOC ₁ -C ₆ alkyl, _{C 1} -C ₆ alkylCOOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkylC ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkylOH, CON(R ⁷ )( _R ⁸ ), _N (R ⁷ )(R ⁸ ), _and C _{1 -C 6 alkylN} (R ⁷ )(R ⁸ ) is substituted with one substituent selected from the group consisting of

In certain embodiments, the heterocycloalkyl is selected from halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOH, COOH, oxo, COOC ₁ -C ₆ alkyl, _{C 1} -C ₆ alkylCOOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkylC ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkylOH, CON(R ⁷ )( _R ⁸ ), _N (R ⁷ )(R ⁸ ), _and C _{1 -C 6 alkylN} (R ⁷ )(R ⁸ ) is substituted with two substituents selected from the group consisting of

In certain embodiments, the 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 alkylCOOH, COOH, oxo, COOC 1 -C ₆ alkyl, C ₁ -C ₆ alkylCOOC ₁ -C ₆ alkyl, C ₃ -C 6 cycloalkyl, C ₁ -C ₆ alkylC ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkylOH haloC ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C _{6 alkylOH} , CON(R ⁷ )(R ⁸ ) _, N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ), or R When taken together with ^a , they form a C ₃ -C ₆ cycloalkyl or heterocycloalkyl, where the C ₃ -C ₆ cycloalkyl or heterocycloalkyl is unsubstituted or is selected from the group consisting of halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOH, COOH, oxo, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkylC ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkylOhaloC ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) and C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ).

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

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

In certain embodiments, R ^b is CN.

In certain embodiments, R ^b is OH.

In certain embodiments, R ^b is C ₁ -C ₆ alkoxy. Suitable alkoxy 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 alkylCOOH.

In certain embodiments, R ^b is COOH.

In certain embodiments, R ^b is an oxo 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 include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

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

And more.

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

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

And more.

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

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

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 alkylN(R ⁷ )(R ⁸ ), where R ⁷ and R ⁸ are described in more detail below.

In certain embodiments, R ^b together with R ^a form a cycloalkyl or heterocycloalkyl, where the cycloalkyl or heterocycloalkyl is unsubstituted or is selected from the group consisting of halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOH, COOH, oxo, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOC ₁ -C ₆ alkyl, C _{3 -C 6 cycloalkyl} , C ₁ -C ₆ alkylC ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ ^{-C 6 alkylOH, CON(R 7} _{) (} R ⁸ ), _N (R ⁷ )(R ⁸ ) _{, and} C Substituted with 1 or 2 substituents selected from the group consisting of ₁ - _C6 alkylN(R ⁷ )(R ⁸ ).

In certain embodiments, R ^b taken together with R ^a forms a cycloalkyl, where the cycloalkyl is unsubstituted or is selected from the group consisting of halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOH, COOH, oxo, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkylC ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C _{1 -C 6} alkylOH, CON( _R ⁷ )(R ⁸ ), _N (R ⁷ )(R ⁸ ), _{and C 1 -C 6} alkylN(R ⁷ )(R ⁸ ).

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

In certain embodiments, the cycloalkyl is unsubstituted. In certain embodiments, the heterocycloalkyl is selected from halogen, CN, OH, C ₁ -C ₆ alkoxy, C _{1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH , COOH} , oxo, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, _{C 1 -C 6 alkylC 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, -C 1 -C 6 alkylOH , CON ( R 7 ) (} ^R ₈ ⁾ , _N (R ⁷ )(R ⁸ ), _and C _{1 -C 6} alkylN ₍ R ⁷ )(R ⁸ ) is substituted with one or two substituents selected from the group consisting of

In certain embodiments, the cycloalkyl is substituted with one 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 alkylCOOH, COOH, oxo, COOC ₁ -C ₆ alkyl, C _{1 -C 6} alkylCOOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, _{C 1} -C ₆ alkylC ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkylOH, _CON (R ⁷ )( _R ⁸ ) _{, N} (R ⁷ )(R ⁸ ) and C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ).

In certain embodiments, the 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 alkylCOOH, COOH, oxo, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkylC ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkylOH haloC ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) and C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ).

In certain embodiments, the cycloalkyl is substituted with OH.

In certain embodiments, R ^b taken together with R ^a forms a heterocycloalkyl, where the heterocycloalkyl is unsubstituted or is selected from the group consisting of halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOH, COOH, oxo, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkylC ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C _{1 -C 6} alkylOH, CON(R ⁷ )(R ⁸ ) _{, N} (R ⁷ )(R ⁸ ₎ , _{and C 1} -C ₆ alkylN(R ⁷ )(R ⁸ ).

Non-limiting examples of monocyclic heterocycloalkyl groups include piperidyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, beta-lactam, gamma-lactam, delta-lactam, beta-lactone, gamma-lactone, delta-lactone, and pyrrolidinone and their oxides. Non-limiting examples of heterocycloalkyl groups include, but are not limited to,

etc.

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

And more.

In certain embodiments, R ^b , taken together with R ^a , is

form.

In certain embodiments, the cycloalkyl or heterocycloalkyl is unsubstituted. In certain embodiments, the cycloalkyl or heterocycloalkyl is selected from halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOH, COOH, oxo, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkylC ₃ -C ₆ cycloalkyl, C _{1 -C 6} alkyl, -C _{1 -C 6} alkylOH, CON(R ⁷ )( _R ⁸ ), _N (R ⁷ )(R ⁸ ), _{and C 1} -C ₆ alkylN(R ⁷ )(R ⁸ ) is substituted with one or two substituents selected from the group consisting of In certain embodiments, the cycloalkyl or heterocycloalkyl is selected from halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOH, COOH, oxo, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkylC ₃ -C ₆ cycloalkyl, C _{1 -C 6} alkyl, -C _{1 -C 6} alkylOH, CON(R ⁷ )( _R ⁸ ), _N (R ⁷ )(R ⁸ ), _{and C 1} -C ₆ alkylN(R ⁷ )(R ⁸ ) is substituted with one substituent selected from the group consisting of In certain embodiments, the cycloalkyl or heterocycloalkyl is selected from halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOH, COOH, oxo, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkylC ₃ -C ₆ cycloalkyl, C _{1 -C 6} alkyl, -C _{1 -C 6} alkylOH, CON(R ⁷ )( _R ⁸ ), _N (R ⁷ )(R ⁸ ), _{and C 1} -C ₆ alkylN(R ⁷ )(R ⁸ ) is substituted with two substituents selected from the group consisting of

In certain embodiments, the 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 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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C _{6 alkyl, C 1 -C 6 alkylOH ,} CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ), C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ), C ₁ -C ₆ alkyl(OCH ₂ CH ₂ ) _n N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylOHhaloC ₁ -C ₆ alkyl, or when taken together with R ⁴ , 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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ), or C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ), or when taken together with R ⁴ , forms a C ₃ -C ₆ cycloalkyl or a C ₃ -C ₆ heterocycloalkyl. In certain embodiments, R ³ is hydrogen. In certain embodiments, R ³ is halogen. Suitable halogens include fluorine, chlorine, bromine, and iodine. In certain embodiments, R ³ is CN. In certain embodiments, R ³ is OH.

In certain embodiments, R ³ is C ₁ -C ₆ alkoxy. Suitable alkoxy includes, but is 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, R ³ is COOH. In certain embodiments, R ³ is C ₁ -C ₆ alkylCOOH. In certain embodiments, R ³ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl 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 include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In certain embodiments, R ³ is haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R ³ is C ₁ -C ₆ alkylOH. Suitable examples of alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol. In certain embodiments, R ³ is CON(R ⁷ )(R ⁸ ). 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 alkylN(R ⁷ )(R ⁸ ). Suitable examples of C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ) include, but are not limited to,

etc. ^R7 and ^R8 are discussed in more detail below.

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

And more.

In certain embodiments, R ³ is C ₁ -C ₆ alkyl(OCH ₂ CH ₂ ) _n N(R ⁷ )(R ⁸ ). R ⁷ , R ⁸ and n are discussed in more 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 more.

For 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 together with R ⁴ form a C ₃ -C ₆ cycloalkyl or a C ₃ -C ₆ heterocycloalkyl. In certain embodiments, R ³ together with R ⁴ form a C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R ³ together with R ⁴ form a C ₃ -C ₆ heterocycloalkyl. Suitable examples of heterocycloalkyl include, but are not limited to, piperidyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, β-lactam, γ-lactam, δ-lactam, β-lactone, γ-lactone, δ-lactone, and pyrrolidinone, and oxides thereof.

In certain embodiments, R ³ is hydrogen, fluorine, methyl, ethyl, OH, methoxy,

It is.

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

It is.

In certain embodiments, R ³ together with R ⁴ forms an 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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ), C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ), C ₁ -C ₆ alkyl(OCH ₂ CH ₂ ) _n N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylOHhaloC ₁ -C ₆ alkyl, or when taken together with R ³ , C ₃ -C ₆ cycloalkyl or C ₃ -C 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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C _{1 -C 6} alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ), or when taken together with R ³ , forms a C ₃ -C ₆ cycloalkyl or a C ₃ -C ₆ heterocycloalkyl. In certain embodiments, R ⁴ is hydrogen. In certain embodiments, R ⁴ 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 includes, but is 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 alkylCOOH. In certain embodiments, R ⁴ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl 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 include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In certain embodiments, R ⁴ is haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R ⁴ is a C ₁ -C ₆ alkylOH. Suitable examples of alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol. In certain embodiments, R ⁴ is CON(R ⁷ )(R ⁸ ). 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 alkylN(R ⁷ )(R ⁸ ). Suitable examples of C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ) include, but are not limited to,

etc. ^R7 and ^R8 are discussed in more detail below.

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

And more.

In certain embodiments, R ⁴ is C ₁ -C ₆ alkyl(OCH ₂ CH ₂ ) _n N(R ⁷ )(R ⁸ ). R ⁷ , R ⁸ are discussed in detail below, and n 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 more.

In certain embodiments, R ⁴ together with R ³ forms a C ₃ -C ₆ cycloalkyl or a C ₃ -C ₆ heterocycloalkyl. In certain embodiments, R ⁴ together with R ³ forms a C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R ⁴ together with R ³ forms a C ₃ -C ₆ heterocycloalkyl. Suitable examples of heterocycloalkyl include, but are not limited to, piperidyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, β-lactam, γ-lactam, δ-lactam, β-lactone, γ-lactone, δ-lactone, and pyrrolidinone, and oxides thereof.

In certain embodiments, R ⁴ is hydrogen or methyl. In certain embodiments, R ⁴ is hydrogen, methyl, ethyl or

In certain embodiments, R ⁴ taken together with R ³ forms oxetanyl. In certain embodiments, R ³ and R ⁴ are both hydrogen, methyl, or ethyl.

In certain embodiments, R ³ is hydrogen and R ⁴ is hydrogen.

In certain embodiments, R ³ and R ⁴ are both halogen, wherein the halogen is selected from 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 alkylCOOH, COOH, oxo, COOC ₁ -C ₆ alkyl, C ₁ -C 6 alkylCOOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkylC _{3 -C 6} cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkylOH haloC ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ).

In certain embodiments described herein, R ⁵ is hydrogen.

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

In certain embodiments, R ⁵ is CN.

In certain embodiments, R ⁵ is OH.

In certain embodiments, R ⁵ is C ₁ -C ₆ alkoxy. Suitable alkoxy 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 alkylCOOH.

In certain embodiments, R ⁵ is COOH.

In certain embodiments, R ⁵ is an oxo group.

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 include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

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

And more.

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

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

And more.

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

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

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 alkylN(R ⁷ )(R ⁸ ), where R ⁷ and R ⁸ are described in more detail below.

In certain embodiments, R ⁵ is hydrogen, methyl, ethyl, or t-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 alkylCOOH, COOH, oxo, COOC ₁ -C ₆ alkyl, C ₁ -C 6 alkylCOOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkylC _{3 -C 6} cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkylOH haloC ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ).

In certain embodiments described herein, R ⁶ is hydrogen.

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

In certain embodiments, R ⁶ is CN.

In certain embodiments, R ⁶ is OH.

In certain embodiments, R ⁶ is C ₁ -C ₆ alkoxy. Suitable alkoxy 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 alkylCOOH.

In certain embodiments, ^R6 is COOH.

In certain embodiments, R ⁶ is an oxo group.

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 include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

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

And more.

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

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

And more.

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

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

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 alkylN(R ⁷ )(R ⁸ ), where R ⁷ and R ⁸ are described in more detail below.

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

In the embodiments described herein, R ⁷ is hydrogen, C ₁ -C ₆ alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C 6 alkylOH, COC ₁ -C ₆ alkyl, or COOC ₁ -C ₆ alkyl. In certain embodiments, R ⁷ is hydrogen, C ₁ -C ₆ alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl _, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, or C ₁ -C ₆ alkylOH.

In certain embodiments, R ⁷ is hydrogen. In certain embodiments, R ⁷ is C ₁ -C ₆ alkylCOOH. In certain embodiments, R ⁷ is COOH. In certain embodiments, R ⁷ is C 3 -C ₆ cycloalkyl. Suitable examples of cycloalkyl 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 include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In certain embodiments, R ⁷ is a haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R ⁷ is C ₁ -C ₆ alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol.

In certain embodiments, R ⁷ is COC ₁ -C ₆ alkyl. Suitable examples include, but are not limited to, COCH _3. 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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C 6 alkylOH, COC ₁ -C ₆ alkyl, or COOC ₁ -C ₆ alkyl. In certain embodiments, R ⁸ is hydrogen, C ₁ -C ₆ alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl _, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, or C ₁ -C ₆ alkylOH.

In certain embodiments, R ⁸ is hydrogen. In certain embodiments, R ⁸ is C ₁ -C ₆ alkylCOOH. In certain embodiments, R ⁸ is COOH. In certain embodiments, R 8 is C 3 -C ₆ cycloalkyl. Suitable examples of cycloalkyl 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 include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In certain embodiments, R ⁸ is haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R ⁸ is C ₁ -C ₆ alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol.

In certain embodiments, R ⁸ is COC ₁ -C ₆ alkyl. Suitable examples include, but are not limited to, COCH _3. In certain embodiments, R ⁸ is COOC ₁ -C ₆ alkyl. Suitable examples include, but are not limited to, COOCH ₃ .

In 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 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl , haloC 1} -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), and N(R ⁷ )(R ⁸ ). In certain embodiments, R ^{9 is hydrogen. In certain embodiments, R 9 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 includes, but is 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 alkylCOOH. In certain embodiments, R ⁹ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl 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 include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In certain embodiments, R ⁹ is haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R ⁹ is a C ₁ -C ₆ alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol. In certain embodiments, R ⁹ is CON(R ⁷ )(R ⁸ ). In certain embodiments, R ⁹ is N(R ⁷ )(R ⁸ ). In certain embodiments, R ⁹ is a C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ).

With respect to 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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC 1 -C ₆ alkyl, C ₁ -C ₆ alkylOH, _CON (R ⁷ )(R ⁸ ), 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 includes, but is 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 alkylCOOH. In certain embodiments, R ¹⁰ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl 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 include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In certain embodiments, R ¹⁰ is haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R ¹⁰ is C ₁ -C ₆ alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol. In certain embodiments, R ¹⁰ is CON(R ⁷ )(R ⁸ ). In certain embodiments, R ¹⁰ is N(R ⁷ )(R ⁸ ). In certain embodiments, R ¹⁰ is C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ).

In 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 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl , haloC 1} -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), 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 includes, but is 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 alkylCOOH. In certain embodiments, R ¹¹ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl 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 include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In certain embodiments, R ¹¹ is haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R ¹¹ is C ₁ -C ₆ alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol. In certain embodiments, R ¹¹ is CON(R ^{7 )(R 8 ). In certain embodiments, R 11 is N(R 7 )(R 8 ) . In} certain embodiments, R ¹¹ is C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ).

In 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 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl , haloC} ^{1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7} _{) ( R 8} ^{) or C} ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ). In certain embodiments, R ¹² is hydrogen. In certain embodiments, R ¹² 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, R ¹² is COOH. In certain embodiments, R ¹² is C ₁ -C ₆ alkylCOOH. In certain embodiments, R ¹² is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl 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 include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In certain embodiments, R ¹² is haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R ¹² is C ₁ -C ₆ alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol. In certain embodiments, R ¹² is CON(R ⁷ )(R ⁸ ). In certain embodiments, R ¹² is N(R ⁷ )(R ⁸ ). In certain embodiments, R ¹² is C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ).

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

It is.

In certain embodiments, R ¹² is hydrogen or

In 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 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl , haloC 1} -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ). In certain embodiments, R ^{13 is hydrogen. In certain embodiments, R 13 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 alkylCOOH. In certain embodiments, R ¹³ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl 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 include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In certain embodiments, R ¹³ is haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R ¹³ is C ₁ -C ₆ alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol. In certain embodiments, R ¹³ is CON(R ⁷ )(R ⁸ ). In certain embodiments, R ¹³ is N(R ⁷ )(R ⁸ ). In certain embodiments, R ¹³ is C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ).

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

It is.

In certain embodiments, R ¹³ is hydrogen or

It is.

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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ). In certain embodiments, R ¹⁴ is hydrogen. In certain embodiments, R ¹⁴ 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 alkylCOOH. In certain embodiments, R ¹⁴ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl 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 include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In certain embodiments, R ¹⁴ is haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R ¹⁴ is C ₁ -C ₆ alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol. In certain embodiments, R ¹⁴ is CON(R ⁷ )(R ⁸ ). In certain embodiments, R ¹⁴ is N(R ⁷ )(R ⁸ ). In certain embodiments, R ¹⁴ is C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ).

In certain embodiments, when X is C(R ¹⁴ ) ₂ , R ¹⁴ is independently selected from the group consisting of hydrogen, halogen, OH, C ₁ -C ₆ alkylOH, C ₁ -C ₆ alkylalkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, and C ₁ -C ₆ alkyl.

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

It is.

In 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 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl , haloC 1} -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), and N(R ⁷ )(R ⁸ ). In certain embodiments, R ^{15 is hydrogen. In certain embodiments, R 15 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 includes, but is 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 alkylCOOH. In certain embodiments, R ¹⁵ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl 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 include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In certain embodiments, R ¹⁵ is ethyl.

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

In certain embodiments, R ¹⁵ is methyl or ethyl.

In 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 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl , haloC 1} -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), and N(R ⁷ )(R ⁸ ). In certain embodiments, R ^{16 is hydrogen. In certain embodiments, R 16 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 includes, but is 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 alkylCOOH. In certain embodiments, R ¹⁶ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl 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 include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In certain embodiments, R ¹⁶ is haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R ¹⁶ is a C ₁ -C ₆ alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol. In certain embodiments, R ¹⁶ is CON(R ⁷ )(R ⁸ ). In certain embodiments, R ¹⁶ is N(R ⁷ )(R ⁸ ). In certain embodiments, R ¹⁶ is a C ₁ -C ₆ alkylN(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 straight or branched chain saturated or unsaturated (C ₃ -C ₁₀ ) alkylene, phenyl(C ₃ -C ₁₀ ) alkylene or cycloalkyl(C ₃ -C ₁₀ ) alkylene containing at least one -CH ₂ - group, where one or more additional -CH ₂ - groups within A may be independently replaced with a moiety selected from the group consisting of O, S, NR, CONR, NRCO, SO ₂ and SO ₂ NR, and where one or more of the hydrogens along A may be replaced with a group independently selected from hydroxyl, halogen and C _1-3 haloalkyl. In certain embodiments, A is a straight or branched, saturated or unsaturated (C ₃ -C ₁₀ )alkylene or cycloalkyl(C ₃ -C ₁₀ )alkylene, where one or more -CH ₂ - groups within A may be independently replaced with a moiety selected from the group consisting of O, S, and NH. In certain embodiments, A always has at least one -CH ₂ - group.

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

And more.

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

And more.

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

And more.

In certain embodiments, A is an unsaturated (C ₃ -C ₁₀ ) alkylene. Suitable unsaturated (C ₃ -C ₁₀ ) alkylenes include those in which any of the saturated (C ₃ -C ₁₀ ) alkylenes have had a hydrogen removed and there is one or more double or triple covalent bonds between adjacent carbon atoms. Examples of unsaturated (C ₃ -C ₁₀ ) alkylenes include, but are not limited to,

And more.

In another embodiment, A is a straight chain cycloalkyl(C ₃ -C ₁₀ )alkylene. Suitable straight chain cycloalkyl(C ₃ -C ₁₀ )alkylenes include cycloalkyl(C ₃ -C ₁₀ )alkylenes where two carbons in the chain are included in the (C ₃ -C ₁₀ )cycloalkyl. Examples of straight chain cycloalkyl(C ₃ -C ₁₀ )alkylenes include, but are not limited to,

And more.

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

And more.

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

And more.

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

And more.

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

And more.

In another embodiment, one or more -CH ₂ - groups in A may be independently replaced with a moiety selected from the group consisting of O, S, NR, CONR, NRCO, SO ₂ and SO ₂ NR. In another embodiment, one or more -CH ₂ - groups in A may be independently replaced with a moiety selected from the group consisting of O, S and NH. In another embodiment, one or more -CH ₂ - groups in A may be independently replaced with O. In another embodiment, one or more -CH ₂ - groups in A may be independently replaced with S. In another embodiment, one or more -CH ₂ - groups in A may be independently replaced with NR. In another embodiment, one or more -CH ₂ - groups in A may be independently replaced with CONR. In another embodiment, one or more -CH _{2 - groups in A may be independently replaced with NRCO. In another embodiment, one or more -CH 2 -} groups in A may be independently replaced with SO ₂ . In another embodiment, one or more -CH ₂ - groups in A may be independently replaced with SO ₂ NR, where R is described in more detail below.

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

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

In certain embodiments, R is COC ₁ -C ₆ alkyl. Suitable examples include, but are not limited to, COCH _3. 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:

And more.

In certain embodiments, A is

It is.

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

It is.

Further described herein is a compound represented by structural formula (III):

[Wherein,
A is a straight or branched chain saturated or unsaturated (C ₃ -C ₁₀ )alkylene, phenyl(C _{3 -C 10 )alkylene or cycloalkyl(C 3 -C 10 ) alkylene} containing at least one -CH ₂ - group, where one or more additional -CH ₂ - groups within A may be independently replaced with a moiety selected from the group consisting of O, S, NR, CONR, NRCO, SO ₂ and SO ₂ NR, and where one or more of the hydrogens along A may be replaced with a group independently selected from hydroxyl, halogen and C _1-3 haloalkyl;
Q is C(R ¹⁶ ) ₂ , O, S, SO, SO ₂ or NH;
X is a bond, C(R ¹⁴ ) ₂ , O, S, SO, SO ₂ or NH;
Y is ^CR9 or N, where when Y is N, Z is ^CR11 and V is ^CR10 ;
V is CR ¹⁰ or N, where if 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, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, 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 alkylCOOH, COOH, oxo, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkylC ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkylOH haloC ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ );
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 alkylCOOH, COOH, oxo, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkylC ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkylOH haloC ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ );
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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ), C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ), C ₁ -C ₆ alkyl(OCH ₂ CH ₂ ) _n N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylOHhaloC ₁ -C ₆ alkyl, or when taken together with R ⁴ 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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ), C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ), C ₁ -C ₆ alkyl(OCH ₂ CH ₂ ) _n N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylOHhaloC 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 alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ );
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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ );
R ⁷ is hydrogen, C ₁ -C ₆ alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, COC ₁ -C ₆ alkyl or COOC ₁ -C ₆ alkyl;
R ⁸ is hydrogen, C ₁ -C ₆ alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, COC ₁ -C ₆ alkyl or COOC ₁ -C ₆ 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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ );
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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ );
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, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ );
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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ );
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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ );
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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ), and C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ );
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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ );
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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ), and C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ );
l is 0 or 1;
m is 0 or 1;
n is 1, 2, 3 or 4; and
p is 0 or 1.
It is a compound having the formula:

In embodiments described herein, Q is C(R ¹⁶ ) ₂ , O, S, SO, SO ₂ , or NH. In certain embodiments, Q is C(R ¹⁶ ) ₂ , where R ¹⁶ is discussed in more detail below. In certain embodiments, Q is CH ₂ , CH(CH ₃ ), C(CH ₃ ) ₂ , O, CH(OCH ₃ ), SO ₂ , or CF _2. In another embodiment, Q is CH ₂ , O, S, SO, SO ₂ , or NH. In certain embodiments, Q is CH _2. In certain embodiments described herein, Q is O. In certain embodiments described herein, Q is S. In another embodiment described herein, Q is SO. In another embodiment described herein, Q is SO _2. In certain embodiments described herein, Q is NH. In another embodiment described herein, Q is O or SO ₂ . In still other embodiments described herein, Q is O or _CH2 .

In embodiments described herein, X is a bond, C(R ¹⁴ ) ₂ , O, S, SO, SO ₂ , or NH. In certain embodiments described herein, X is a bond. In certain embodiments, X is C(R ¹⁴ ) ₂ , where R ¹⁴ is discussed in more detail below. In certain embodiments, X is a bond, CH ₂ , CH(CH ₃ ), C(CH ₃ ) ₂ , O, CH(OCH ₃ ), SO ₂ , or CF _2. In another embodiment, X is CH ₂ , O, S, SO, SO ₂ , or NH. In certain embodiments, X is CH _2. In embodiments described herein, X is O. In certain embodiments described herein, X is S. In certain embodiments described herein, X is SO. In another embodiment described herein, X is SO _2. In certain embodiments described herein, X is NH.

In the embodiments described herein, Y is ^CR9 or N. In certain embodiments, Y is ^CR9 , where ^R9 is discussed in detail below. In certain embodiments, Y is N. In certain embodiments, Y is CH. In certain embodiments, when Y is N, Z is ^CR11 and V is ^CR10 .

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

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

In certain embodiments, X is O, Y and V are each CH, and Z is N. In certain embodiments, X is O, Y and Z are each CH, and V is N. In certain embodiments, X is O, and V, Y, and Z are all simultaneously CH.

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.

Further described herein is a compound represented by structural formula (IIIA):

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹⁵ , A and Q are as defined herein.
The compound represented by the formula: An embodiment of the present invention is realized when R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹⁵ , A and Q are as described in formula III. Another embodiment of formula IIIA is realized when R ³ and R ⁴ are both hydrogen, methyl, ethyl or halogen. Another embodiment of formula IIIA is realized when R ³ and R ⁴ are both halogen selected from chlorine and fluorine. Another embodiment of formula IIIA is realized when Q is CH ₂ , CH(CH ₃ ), C(CH ₃ ) ₂ , O, CH(OCH ₃ ), SO ₂ or CF _2. In another embodiment described herein, Q in formula IIIA is O or SO _2. In yet another embodiment described herein, Q in formula IIIA is O or CH ₂ . Another embodiment of formula IIIA is realized when A is a straight or branched, saturated or unsaturated (C ₃ -C ₁₀ ) alkylene containing at least one —CH ₂ — group, where one or more additional —CH ₂ — groups in A may be independently replaced with a moiety selected from the group consisting of O, S, NR, CONR, NRCO, SO ₂ and SO ₂ NR, and where one or more of the hydrogens along A can be replaced with a group independently selected from hydroxyl, halogen and C _1-3 haloalkyl.

Further described herein is a compound represented by structural formula (IIIB):

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹⁵ , A and Q are as defined herein.
The compound is represented by the formula: An embodiment of the present invention is realized when R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹⁵ , A and Q are as described in formula III. Another embodiment of formula IIIB is realized when R ³ and R ⁴ are both hydrogen, methyl, ethyl or halogen. Another embodiment of formula IIIB is realized when R ³ and R ⁴ are both halogen selected from chlorine and fluorine. Another embodiment of formula IIIB is realized when Q is CH ₂ , CH(CH ₃ ), C(CH ₃ ) ₂ , O, CH(OCH ₃ ), SO ₂ or CF _2. In another embodiment described herein, Q in formula IIIB is O or SO _2. In yet another embodiment described herein, Q in formula IIIB is O or CH ₂ . Another embodiment of formula IIIB is realized when A is a straight or branched, saturated or unsaturated (C ₃ -C ₁₀ ) alkylene containing at least one —CH ₂ — group, where one or more additional —CH ₂ — groups in A may be independently replaced with a moiety selected from the group consisting of O, S, NR, CONR, NRCO, SO ₂ and SO ₂ NR, and where one or more of the hydrogens along A may be replaced with a group independently selected from hydroxyl, halogen and C _1-3 haloalkyl.

Particular embodiments are of Formula IV-VI:

is expressed as:

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 alkylCOOH, COOH, oxo, COOC ₁ -C ₆ alkyl, C ₁ -C 6 alkylCOOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkylC _{3 -C 6} cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkylOH haloC ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ).

In certain embodiments described herein, R ¹ is hydrogen.

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

In certain embodiments, R ¹ is CN.

In certain embodiments, R ¹ is OH.

In certain embodiments, R ¹ is C ₁ -C ₆ alkoxy. Suitable alkoxy 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, R ¹ is C ₁ -C ₆ alkylCOOH.

In certain embodiments, R ¹ is COOH.

In certain embodiments, R ¹ is an oxo group.

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 include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

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

And more.

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

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

And more.

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

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

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 alkylN(R ⁷ )(R ⁸ ), where R ⁷ and R ⁸ are described in more detail below.

In certain embodiments, R ¹ is hydrogen, bromine, fluorine, chlorine, methyl, OH, halogen, CN oxo, methoxymethyl, COOCH ₂ CH ₃ 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 alkylCOOH, COOH, oxo, COOC ₁ -C ₆ alkyl, C ₁ -C 6 alkylCOOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkylC _{3 -C 6} cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkylOH haloC ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ).

In certain embodiments described herein, R ² is hydrogen.

In certain embodiments, ^R2 is a 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, ^R2 is _C1 - _C6 alkoxy. Suitable alkoxy 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 alkylCOOH.

In certain embodiments, ^R2 is COOH.

In certain embodiments, R ² is an oxo group.

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 include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

In certain embodiments, ^R2 is _C1 - _C6 alkyl or _C3 - _C6 cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to,

And more.

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

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

And more.

In certain embodiments, ^R2 is _haloC1 - _C6 alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl.

In certain embodiments, R ² is C ₁ -C ₆ alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol.

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 alkylN(R ⁷ )(R ⁸ ), where R ⁷ and R ⁸ are described in more detail below.

In certain embodiments, ^R2 is hydrogen, bromine, fluorine, chlorine, methyl, OH, halogen, CN oxo, methoxymethyl, _COOCH2CH3 or _{trifluoromethyl} .

In certain embodiments, R ¹ and R ² are both hydrogen. In certain embodiments, R ¹ is OH and R ² 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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C _{6 alkyl, C 1 -C 6 alkylOH ,} CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ), C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ), C ₁ -C ₆ alkyl(OCH ₂ CH ₂ ) _n N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylOHhaloC ₁ -C ₆ alkyl, or when taken together with R ⁴ , 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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ), or C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ), or when taken together with R ⁴ , forms a C ₃ -C ₆ cycloalkyl or a C ₃ -C ₆ heterocycloalkyl. In certain embodiments, R ³ is hydrogen. In certain embodiments, R ³ is halogen. Suitable halogens include fluorine, chlorine, bromine, and iodine. In certain embodiments, R ³ is CN. In certain embodiments, R ³ is OH.

In certain embodiments, R ^{3 is C 1 -C 6 alkoxy. Suitable alkoxy includes, but is 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, R ³ is COOH. In certain embodiments, R ³ is C ₁ -C ₆ alkylCOOH. In certain embodiments, R ³ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl 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 include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In certain embodiments, R ³ is haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R ³ is C ₁ -C ₆ alkylOH. Suitable examples of alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol. In certain embodiments, R ³ is CON(R ⁷ )(R ⁸ ). 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 alkylN(R ⁷ )(R ⁸ ). Suitable examples of C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ) include, but are not limited to,

etc. ^R7 and ^R8 are discussed in more detail below.

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

And more.

In certain embodiments, R ³ is C ₁ -C ₆ alkyl(OCH ₂ CH ₂ ) _n N(R ⁷ )(R ⁸ ). R ⁷ , R ⁸ and n are discussed in more 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 more.

For 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 together with R ⁴ form a C ₃ -C ₆ cycloalkyl or a C ₃ -C ₆ heterocycloalkyl. In certain embodiments, R ³ together with R ⁴ form a C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R ³ together with R ⁴ form a C ₃ -C ₆ heterocycloalkyl. Suitable examples of heterocycloalkyl include, but are not limited to, piperidyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, β-lactam, γ-lactam, δ-lactam, β-lactone, γ-lactone, δ-lactone, and pyrrolidinone, and oxides thereof.

In certain embodiments, R ³ is hydrogen, fluorine, methyl, ethyl, OH, methoxy,

It is.

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

It is.

In certain embodiments, R ³ together with R ⁴ forms an 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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ), C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ), C ₁ -C ₆ alkyl(OCH ₂ CH ₂ ) _n N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylOHhaloC ₁ -C ₆ alkyl, or when taken together with R ³ , C ₃ -C ₆ cycloalkyl or C ₃ -C 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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C _{1 -C 6} alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ), or when taken together with R ³ , forms a C ₃ -C ₆ cycloalkyl or a C ₃ -C ₆ heterocycloalkyl. In certain embodiments, R ⁴ is hydrogen. In certain embodiments, R ⁴ 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 includes, but is 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 alkylCOOH. In certain embodiments, R ⁴ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl 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 include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In certain embodiments, R ⁴ is haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R ⁴ is a C ₁ -C ₆ alkylOH. Suitable examples of alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol. In certain embodiments, R ⁴ is CON(R ⁷ )(R ⁸ ). 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 alkylN(R ⁷ )(R ⁸ ). Suitable examples of C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ) include, but are not limited to,

etc. ^R7 and ^R8 are discussed in more detail below.

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

And more.

In certain embodiments, R ⁴ is C ₁ -C ₆ alkyl(OCH ₂ CH ₂ ) _n N(R ⁷ )(R ⁸ ). R ⁷ , R ⁸ are discussed in detail below, and n 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 more.

In certain embodiments, R ⁴ together with R ³ forms a C ₃ -C ₆ cycloalkyl or a C ₃ -C ₆ heterocycloalkyl. In certain embodiments, R ⁴ together with R ³ forms a C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In certain embodiments, R ⁴ together with R ³ forms a C ₃ -C ₆ heterocycloalkyl. Suitable examples of heterocycloalkyl include, but are not limited to, piperidyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, β-lactam, γ-lactam, δ-lactam, β-lactone, γ-lactone, δ-lactone, and pyrrolidinone, and oxides thereof.

In certain embodiments, R ⁴ is hydrogen or methyl. In certain embodiments, R ⁴ is hydrogen, methyl, ethyl or

In certain embodiments, R ⁴ taken together with R ³ forms oxetanyl. In certain embodiments, R ³ and R ⁴ are both hydrogen, methyl, or ethyl.

In certain embodiments, R ³ is hydrogen and R ⁴ 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 alkylCOOH, COOH, oxo, COOC ₁ -C ₆ alkyl, C ₁ -C 6 alkylCOOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkylC _{3 -C 6} cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkylOH haloC ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ).

In certain embodiments described herein, R ⁵ is hydrogen.

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

In certain embodiments, R ⁵ is CN.

In certain embodiments, R ⁵ is OH.

In certain embodiments, R ⁵ is C ₁ -C ₆ alkoxy. Suitable alkoxy 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 alkylCOOH.

In certain embodiments, R ⁵ is COOH.

In certain embodiments, R ⁵ is an oxo group.

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 include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

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

And more.

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

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

And more.

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

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

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 alkylN(R ⁷ )(R ⁸ ), where R ⁷ and R ⁸ are described in more detail below.

In certain embodiments, R ⁵ is hydrogen, methyl, ethyl, or t-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 alkylCOOH, COOH, oxo, COOC ₁ -C ₆ alkyl, C ₁ -C 6 alkylCOOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkylC _{3 -C 6} cycloalkyl, C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkylOH haloC ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ).

In certain embodiments described herein, R ⁶ is hydrogen.

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

In certain embodiments, R ⁶ is CN.

In certain embodiments, R ⁶ is OH.

In certain embodiments, R ⁶ is C ₁ -C ₆ alkoxy. Suitable alkoxy 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 alkylCOOH.

In certain embodiments, ^R6 is COOH.

In certain embodiments, R ⁶ is an oxo group.

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 include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

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

And more.

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

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

And more.

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

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

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 alkylN(R ⁷ )(R ⁸ ), where R ⁷ and R ⁸ are described in more detail below.

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

In the embodiments described herein, R ⁷ is hydrogen, C ₁ -C ₆ alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C 6 alkylOH, COC ₁ -C ₆ alkyl, or COOC ₁ -C ₆ alkyl. In certain embodiments, R ⁷ is hydrogen, C ₁ -C ₆ alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl _, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, or C ₁ -C ₆ alkylOH.

In certain embodiments, R ⁷ is hydrogen. In certain embodiments, R ⁷ is C ₁ -C ₆ alkylCOOH. In certain embodiments, R ⁷ is COOH. In certain embodiments, R 7 is C 3 -C ₆ cycloalkyl. Suitable examples of cycloalkyl 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 include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In certain embodiments, R ⁷ is a haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R ⁷ is C ₁ -C ₆ alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol.

In certain embodiments, R ⁷ is COC ₁ -C ₆ alkyl. Suitable examples include, but are not limited to, COCH _3. 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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C 6 alkylOH, COC ₁ -C ₆ alkyl, or COOC ₁ -C ₆ alkyl. In certain embodiments, R ⁸ is hydrogen, C ₁ -C ₆ alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl _, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, or C ₁ -C ₆ alkylOH.

In certain embodiments, R ⁸ is hydrogen. In certain embodiments, R ⁸ is C ₁ -C ₆ alkylCOOH. In certain embodiments, R ⁸ is COOH. In certain embodiments, R 8 is C 3 -C ₆ cycloalkyl. Suitable examples of cycloalkyl 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 include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In certain embodiments, R ⁸ is haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R ⁸ is C ₁ -C ₆ alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol.

In certain embodiments, R ⁸ is COC ₁ -C ₆ alkyl. Suitable examples include, but are not limited to, COCH _3. In certain embodiments, R ⁸ is COOC ₁ -C ₆ alkyl. Suitable examples include, but are not limited to, COOCH ₃ .

In 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 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl , haloC 1} -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ) and N(R ⁷ )(R ⁸ ). In certain embodiments, R ⁹ is hydrogen. In certain embodiments, R ⁹ 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 includes, but is 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 alkylCOOH. In certain embodiments, R ⁹ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl 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 include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In certain embodiments, R ⁹ is haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R ⁹ is a C ₁ -C ₆ alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol. In certain embodiments, R ⁹ is CON(R ⁷ )(R ⁸ ). In certain embodiments, R ⁹ is N(R ⁷ )(R ⁸ ). In certain embodiments, R ⁹ is a C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ).

With respect to 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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC 1 -C ₆ alkyl, C ₁ -C ₆ alkylOH, _CON (R ⁷ )(R ⁸ ), 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 includes, but is 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 alkylCOOH. In certain embodiments, R ¹⁰ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl 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 include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In certain embodiments, R ¹⁰ is haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R ¹⁰ is C ₁ -C ₆ alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol. In certain embodiments, R ¹⁰ is CON(R ^{7 )(R 8 ). In certain embodiments, R 10 is N(R 7 )(R 8 ) . In} certain embodiments, R ¹⁰ is C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ).

In 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 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl , haloC 1} -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), 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 includes, but is 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 alkylCOOH. In certain embodiments, R ¹¹ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl 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 include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In certain embodiments, R ¹¹ is haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R ¹¹ is C ₁ -C ₆ alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol. In certain embodiments, R ¹¹ is CON(R ^{7 )(R 8 ). In certain embodiments, R 11 is N(R 7 )(R 8 ) . In} certain embodiments, R ¹¹ is C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ).

In 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 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl , haloC} ^{1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7} _{) ( R 8} ^{) or C} ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ). In certain embodiments, R ¹² is hydrogen. In certain embodiments, R ¹² 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, R ¹² is COOH. In certain embodiments, R ¹² is C ₁ -C ₆ alkylCOOH. In certain embodiments, R ¹² is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl 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 include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In certain embodiments, R ¹² is haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R ¹² is C ₁ -C ₆ alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol. In certain embodiments, R ¹² is CON(R ⁷ )(R ⁸ ). In certain embodiments, R ¹² is N(R ⁷ )(R ⁸ ). In certain embodiments, R ¹² is C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ).

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

It is.

In certain embodiments, R ¹² is hydrogen or

It is.

In 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 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl , haloC} ^{1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7} _{) ( R 8} ^{) or C} ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ). In certain embodiments, R ¹³ is hydrogen. In certain embodiments, R ¹³ 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 alkylCOOH. In certain embodiments, R ¹³ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl 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 include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In certain embodiments, R ¹³ is haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R ¹³ is C ₁ -C ₆ alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol. In certain embodiments, R ¹³ is CON(R ⁷ )(R ⁸ ). In certain embodiments, R ¹³ is N(R ⁷ )(R ⁸ ). In certain embodiments, R ¹³ is C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ).

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

It is.

In certain embodiments, R ¹³ is hydrogen or

It is.

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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ). In certain embodiments, R ¹⁴ is hydrogen. In certain embodiments, R ¹⁴ 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 alkylCOOH. In certain embodiments, R ¹⁴ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl 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 include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In certain embodiments, R ¹⁴ is haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R ¹⁴ is C ₁ -C ₆ alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol. In certain embodiments, R ¹⁴ is CON(R ⁷ )(R ⁸ ). In certain embodiments, R ¹⁴ is N(R ⁷ )(R ⁸ ). In certain embodiments, R ¹⁴ is C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ).

In certain embodiments, when X is C(R ¹⁴ ) ₂ , R ¹⁴ is independently selected from the group consisting of hydrogen, halogen, OH, C ₁ -C ₆ alkylOH, C ₁ -C ₆ alkylalkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, and C ₁ -C ₆ alkyl.

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

It is.

In 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 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl , haloC 1} -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), and N(R ⁷ )(R ⁸ ). In certain embodiments, R ^{15 is hydrogen. In certain embodiments, R 15 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 includes, but is 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 alkylCOOH. In certain embodiments, R ¹⁵ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl 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 include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In certain embodiments, R ¹⁵ is ethyl.

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

In certain embodiments, R ¹⁵ is methyl or ethyl.

In 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 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl , haloC 1} -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), and N(R ⁷ )(R ⁸ ). In certain embodiments, R ^{16 is hydrogen. In certain embodiments, R 16 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 includes, but is 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 alkylCOOH. In certain embodiments, R ¹⁶ is C ₃ -C ₆ cycloalkyl. Suitable examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

In certain embodiments, R ¹⁶ is a C ₁ -C ₆ alkyl. Examples of C ₁ -C ₆ alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl, and 1-ethyl-1-methylpropyl. In certain embodiments, R ¹⁶ is a haloC ₁ -C ₆ alkyl. Suitable examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl, and 2,2-difluoroethyl. In certain embodiments, R ¹⁶ is a C ₁ -C ₆ alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, and iso-butanol. In certain embodiments, R ¹⁶ is CON(R ⁷ )(R ⁸ ). In certain embodiments, R ¹⁶ is N(R ⁷ )(R ⁸ ). In certain embodiments, R ¹⁶ is a C ₁ -C ₆ alkylN(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 O.

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

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

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

In certain embodiments, m is 0, p is 1, and X is C(R ¹⁴ ) ₂ , where each occurrence of R ¹⁴ is independently selected from the group consisting of hydrogen, halogen, OH, C ₁ -C ₆ alkoxy, and C ₁ -C ₆ alkyl.

In certain embodiments, m is 1 and X is C(R ¹⁴ ) ₂ , where each occurrence of R ¹⁴ is independently selected from the group consisting of hydrogen, halogen, OH, C ₁ -C ₆ alkoxy, and C ₁ -C ₆ alkyl.

For example, in certain embodiments of formula (I), l is 0; m is 1; p is 1; X is O; V, Y and Z are CH; and Q is _CH2 , as shown in formula (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).

In the embodiments described herein, A is a straight or branched chain saturated or unsaturated (C ₃ -C ₁₀ ) alkylene, phenyl(C ₃ -C ₁₀ ) alkylene or cycloalkyl(C ₃ -C ₁₀ ) alkylene containing at least one -CH ₂ - group, where one or more additional -CH ₂ - groups within A may be independently replaced with a moiety selected from the group consisting of O, S, NR, CONR, NRCO, SO ₂ and SO ₂ NR, and where one or more of the hydrogens along A may be replaced with a group independently selected from hydroxyl, halogen and C _1-3 haloalkyl. In certain embodiments, A is a straight or branched, saturated or unsaturated (C ₃ -C ₁₀ )alkylene or cycloalkyl(C ₃ -C ₁₀ )alkylene, where one or more -CH ₂ - groups within A may be independently replaced with a moiety selected from the group consisting of O, S, and NH. In certain embodiments, A always has at least one -CH ₂ - group.

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

And more.

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

And more.

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

And more.

In certain embodiments, A is an unsaturated (C ₃ -C ₁₀ ) alkylene. Suitable unsaturated (C ₃ -C ₁₀ ) alkylenes include those in which any of the saturated (C ₃ -C ₁₀ ) alkylenes have had a hydrogen removed and there is one or more double or triple covalent bonds between adjacent carbon atoms. Examples of unsaturated (C ₃ -C ₁₀ ) alkylenes include, but are not limited to,

And more.

In another embodiment, A is a straight chain cycloalkyl(C ₃ -C ₁₀ )alkylene. Suitable straight chain cycloalkyl(C ₃ -C ₁₀ )alkylenes include cycloalkyl(C ₃ -C ₁₀ )alkylenes where two carbons in the chain are included in the (C ₃ -C ₁₀ )cycloalkyl. Examples of straight chain cycloalkyl(C ₃ -C ₁₀ )alkylenes include, but are not limited to,

And more.

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

And more.

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

And more.

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

And more.

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

And more.

In another embodiment, one or more -CH ₂ - groups in A may be independently replaced with a moiety selected from the group consisting of O, S, NR, CONR, NRCO, SO ₂ and SO ₂ NR. In another embodiment, one or more -CH ₂ - groups in A may be independently replaced with a moiety selected from the group consisting of O, S and NH. In another embodiment, one or more -CH ₂ - groups in A may be independently replaced with O. In another embodiment, one or more -CH ₂ - groups in A may be independently replaced with S. In another embodiment, one or more -CH ₂ - groups in A may be independently replaced with NR. In another embodiment, one or more -CH ₂ - groups in A may be independently replaced with CONR. In another embodiment, one or more -CH _{2 - groups in A may be independently replaced with NRCO. In another embodiment, one or more -CH 2 -} groups in A may be independently replaced with SO ₂ . In another embodiment, one or more -CH ₂ - groups in A may be independently replaced with SO ₂ NR, where R is described in more detail below.

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

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

In certain embodiments, R is COC ₁ -C ₆ alkyl. Suitable examples include, but are not limited to, COCH _3. 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:

And more.

In certain embodiments, A is

It is.

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

It is.

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

In each of the various embodiments of the present invention, the compounds described herein, including each of the compounds of formula (I)-(VIII) and their various embodiments, may exist in various forms of the compound, such as any solvates, hydrates, stereoisomers, and tautomers of the compound, and any pharma- ceutically acceptable salts thereof.

In certain embodiments, the compounds described herein include the following compounds:

In certain embodiments, the compounds described herein include the following compounds or pharma- ceutically acceptable salts thereof:

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

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

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

"Drug resistance" means, in relation to Plasmodium parasite strains, that are no longer sensitive to at least one previously effective drug; that have developed the ability to withstand attack by at least one previously effective drug. Drug-resistant strains can pass on that ability to their progeny. The resistance can result from random genetic mutations in the bacterial cell that alter susceptibility to a single drug or to a variety of drugs.

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

"Pharmaceutical composition" (or "Pharmaceutically acceptable composition") means a composition suitable for administration to a patient. Such a composition may contain a neat compound (or compounds) of the invention or a mixture thereof, or a salt, solvate, prodrug, isomer or tautomer thereof, and one or more pharma- ceutically acceptable carriers or diluents. The term "pharmaceutical composition" is further intended to encompass both bulk compositions and individual dosage units that are composed of one or more (e.g., two) pharma- ceutically active agents (e.g., a compound of the invention and an additional agent selected from the list of additional agents described herein) and any pharma- ceutically inactive excipients. The bulk composition and each individual dosage unit may contain a fixed amount of the "two or more pharma- ceutically active agents". The bulk composition is material that has not yet been formed into individual dosage units. Exemplary dosage units are oral dosage units such as tablets, pills, and the like. Similarly, the methods described herein for treating a patient by administering a pharmaceutical composition of the invention are intended to encompass administration of the bulk composition 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 radical having the stated number of carbon atoms. For example, -( _{C1 - C5} )alkylene _includes , for example, _-CH2- , -CH2CH2- _{, -CH2CH2CH2- , -CH2CH2CH2CH2-} , _-CH2CH ( _{CH3 ) CH2- ,} or _{-CH2CH2CH2CH2CH2CH2-} . _Straight chain alkylene means _a divalent straight chain hydrocarbon chain radical having _the stated number of carbon atoms. Branched chain alkylene means a divalent branched chain hydrocarbon chain radical having _the stated number of carbon atoms. Saturated alkylene _means a divalent saturated hydrocarbon chain radical having the stated number of carbon atoms. Unsaturated alkylene means a divalent hydrocarbon chain radical having the stated number of carbon atoms and having one or more double or triple covalent bonds within the chain. Cycloalkylene means a divalent hydrocarbon chain radical having the specified number of carbon atoms and having a cycloalkyl moiety within the chain.

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

"Haloalkyl" means an alkyl as defined above in which one or more hydrogen atoms on the alkyl is 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 can be substituted with one or more "ring system substituents" which may be the same or different, as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl. "Monocyclic aryl" means phenyl.

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

"Heterocycloalkyl" (or "heterocyclyl") means a non-aromatic saturated or partially saturated monocyclic or polycyclic ring system containing about 3 to about 10 ring atoms (preferably about 5 to about 10 ring atoms) in which one or more of the atoms in the ring system is an element other than carbon, alone or in combination, such as nitrogen, oxygen or sulfur. There are no adjacent oxygen and/or sulfur atoms in the ring system. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom, respectively, is present as a ring atom. Any -NH in a heterocyclyl ring can be present protected, for example, as an -N(Boc), -N(CBz), -N(Tos) group, and the like; such protection is also considered as part of this invention. The heterocyclyl can be substituted with one or more substituents which may be the same or different, as described herein. The nitrogen or sulfur atom of the heterocyclyl can be oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Thus, the term "oxide", when it appears in the definitions of variables in the general structures described herein, means the corresponding N-oxide, S-oxide or S,S-dioxide. "Heterocyclyl" also includes rings in which =0 replaces two available hydrogens on the same carbon atom (i.e., heterocyclyl includes rings having a carbonyl group within the ring). Such =0 groups may be referred to herein as "oxo". An example of such a moiety is pyrrolidinone (or pyrrolidone):

The term "monocyclic heterocycloalkyl," as used herein, refers to a monocyclic version of the heterocycloalkyl moieties described herein and includes 4-7 membered monocyclic heterocycloalkyl groups containing 1-4 ring heteroatoms, where the ring heteroatoms are independently selected from the group consisting of N, N-oxide, O, S, S-oxide, S(O) and S(O) ₂ . The point of attachment to the parent moiety is at any available ring carbon or ring heteroatom. Non-limiting examples of monocyclic heterocycloalkyl groups include piperidyl, oxetanyl, pyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, β-lactam, γ-lactam, δ-lactam, β-lactone, γ-lactone, δ-lactone and pyrrolidinone and their oxides. Non-limiting examples of monocyclic heterocycloalkyl groups include the moiety:

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

And more.

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

The term "substituted" means that one or more hydrogens on the specified atom are replaced with one selected from the indicated group, provided 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 permissible only if such combinations result in stable compounds. A "stable compound" or "stable structure" means a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and formulation into an efficacious therapeutic agent.

The term "optionally substituted" means optional substitution with the specified group, radical, or substructure.

When a variable occurs more than once in a group (e.g., ^R in -N( ^R ) ₂ ) or in the structures described herein, the variable can be the same or different.

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

teeth,

means that it contains either one or both of them.

As used herein, a wavy line ---- shown crossing a line representing a chemical bond indicates the point of attachment to the remainder of the compound.

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

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

It is.

As used herein, when there are multiple oxygen and/or sulfur atoms in a ring system, there cannot be adjacent oxygen and/or sulfur atoms in that ring system.

As is well known in the art, a bond drawn from a particular atom that does not have a moiety drawn at the end of the bond represents a methyl group attached to that atom through that bond, unless otherwise indicated. For example,

teeth,

represents.

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

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

When a functional group in a compound is referred to as "protected," this means that the group is in a modified form to prevent undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those skilled in the art by reference to standard textbooks such as, for example, "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. A discussion of prodrugs is provided by T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and Bioversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press. The term "prodrug" means a compound (e.g., a drug precursor) that is transformed in vivo to yield a compound of the invention, or a pharma- ceutically acceptable salt, hydrate, or solvate of the compound. Such transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), for example, by hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and Bioversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

For example, if a compound useful in the methods of the invention or a pharma- ceutically acceptable salt thereof contains a carboxylic acid functional group, the prodrug may replace a hydrogen atom of the acid group with, for example, a ( _C1 - _C8 ) alkyl, ( _C2 - _C12 ) alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, γ-butyrolactone-4-yl, di-N,N-( _C1 - _C2 ) alkylamino(C ₂ - _C3 )alkyl (e.g., β-dimethylaminoethyl), carbamoyl-( _C1 - _C2 )alkyl, N,N-di( _C1 - _C2 )alkylcarbamoyl-( _C1 - _C2 )alkyl, and esters formed by replacement with groups such as piperidino-, pyrrolidino-, or morpholino( _C2 - _C3 )alkyl.

Similarly, if the compound used in the methods of the invention contains an alcohol functional group, the prodrug may replace the hydrogen atom of the alcohol group with a suitable alkyl group, such as, for example, (C ₁ -C ₆ )alkanoyloxymethyl, 1-((C ₁ -C ₆ )alkanoyloxy)ethyl, 1-methyl-1-((C ₁ -C ₆ )alkanoyloxy)ethyl, (C ₁ -C ₆ )alkoxycarbonyloxymethyl, N-(C ₁ -C ₆ )alkoxycarbonylaminomethyl, succinoyl, (C _{1 -C 6 )alkanoyl, α-amino(C 1 -C 4} )alkanyl, arylacyl and α-aminoacyl or α-aminoacyl-α-aminoacyl, where each α-aminoacyl group is selected from the group consisting of the naturally occurring L-amino acids, P(O)(OH) ₂ , -P(O)(O(C ₁ -C ₆ )alkyl) _{. 2} or glycosyl (a radical obtained by removing the hydroxyl group of the hemiacetal form of a carbohydrate), etc.

When the compound used in the methods of the invention contains an amine functional group, the prodrug may replace a hydrogen atom in the amine group with, 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 a natural α-aminoacyl or natural-aminoacyl, -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 is (C ₁ -C ₄ )alkyl and Y ³ is (C ₁ -C ₆ )alkyl, carboxy(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 )alkylamino, morpholino, piperidin-1-yl or pyrrolidin-1-yl.

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

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

"Effective amount" or "therapeutically effective amount" is intended to refer to an amount of a compound or composition used in the methods of the invention that is effective to inhibit the disease or enzyme activity described above, and thus effective to produce the desired therapeutic, ameliorative, suppressive or preventative effect.

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

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

Additionally, acids that are generally considered suitable for forming pharma- ceutical useful salts from basic pharmaceutical compounds are described, for example, in 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( 1), and P. 201-217, Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York, and The Orange Book (Food & Drug Administration, Washington, D.C. on their website), the disclosures of which are incorporated herein by reference.

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

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

Another embodiment provides pharma- ceutically acceptable esters of the compounds used in the methods of the invention. Such esters include the following groups: (1) carboxylic acid esters obtained by esterification of a hydroxy group, where the non-carbonyl portion of the carboxylic acid moiety of the ester group is selected from straight or branched chain alkyl (e.g., acetyl, n-propyl, t-butyl or n-butyl), alkoxyalkyl (e.g., methoxymethyl), aralkyl (e.g., benzyl), aryloxyalkyl (e.g., phenoxymethyl), aryl (e.g., phenyl, which may be substituted, for example, with halogen, _C1-4 alkyl or _C1-4 alkoxy or amino); (2) sulfonic acid esters, such as alkylsulfonyl or aralkylsulfonyl (e.g., methanesulfonyl); (3) amino acid esters (e.g., L-valyl or L-isoleucine); (4) phosphate esters, and (5) mono-, di- or triphosphate esters. The phosphate esters may be further esterified by, for example, a C _1-20 alcohol or reactive derivative thereof, or by a 2,3-di (C _6-24 )acyl glycerol.

As noted herein, in another embodiment, tautomers of the compounds of the invention used in the methods herein are provided, as well as salts, solvates, esters and prodrugs of the tautomers. It is to be understood that all tautomeric forms of such compounds are within the scope of the compounds used in the methods of the invention. For example, all keto-enol and imine-enamine forms of the compounds, if they exist, are encompassed by the invention.

The compounds used in the methods of the invention may contain asymmetric or chiral centers and therefore may exist in various stereoisomeric forms. All stereoisomeric forms of the compounds used in the methods of the invention, as well as mixtures thereof, including racemic mixtures, are intended to form part of the present invention. Furthermore, the present invention encompasses the use of all geometric and positional isomers. For example, if a compound used in the methods of the invention contains a double bond or a fused ring, both the cis- and trans-forms, (E)- and (Z)-forms, as well as mixtures, are encompassed within the scope of the invention.

In another embodiment, diastereomeric mixtures and individual enantiomers of the compounds used in the methods of the invention are provided. Diastereomeric mixtures can be separated into their individual diastereomers based on their physical chemical differences by methods well known to those skilled in the art, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture to a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary, e.g., a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Furthermore, some of the compounds used in the methods of the invention can be atropisomers (e.g., substituted biaryls) and are considered part of the invention. Enantiomers can also be separated using a chiral HPLC column.

All stereoisomers (e.g., geometric isomers, optical isomers, etc.) of the compounds used in the methods of the invention (including salts, solvates, esters and prodrugs of the compounds, and salts, solvates and esters of the prodrugs), such as isomers that may exist due to asymmetric carbons on various substituents, such as enantiomeric forms (which may exist even when there are no asymmetric carbons), rotamer forms, atropisomers and diastereomeric forms, are contemplated as embodiments within the scope of the invention, as well as positional isomers (e.g., 4-pyridyl and 3-pyridyl). (For example, when the compounds of the invention contain double bonds or fused rings, both the cis and trans forms, as well as mixtures, are included within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the methods of the invention.)

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

In another embodiment, there is provided an isotopically labeled compound that is used in the method of the present invention.Such compounds are identical to those described herein, except for the fact that one or more atoms are replaced by atoms with atomic mass or mass number different from the atomic mass or mass number that is usually found in nature.Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ^2H , ^3H , ^13C , ^14C , ^15N , ^18O , ^17O , ^31P , ^32P , ^35S , ^18F and ^36Cl , respectively.

Certain isotopically labeled compounds of the present invention (e.g., compounds labeled with ³ H and ¹⁴ C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., ³ H) and carbon-14 (i.e., ¹⁴ C) isotopes are particularly preferred due to their ease of preparation and detectability. In addition, substitution with heavier isotopes such as deuterium (i.e., ² H) can provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and therefore may be preferred in some circumstances. Isotopically labeled compounds of the present invention can generally be prepared by following methods analogous to those disclosed in the following schemes and/or examples, substituting the appropriate isotopically labeled reagent for a non-isotopically labeled reagent.

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

Polymorphic forms of the compounds used in the methods of the invention, as well as polymorphic forms of the salts, solvates, esters and prodrugs of the compounds of the invention, are intended to be encompassed by the present invention.

Methods of Treatment The present invention is directed to a method of treating a malaria parasite infection, comprising administering to a subject in need of such treatment a compound described herein or a pharma- ceutically acceptable salt thereof. More specifically, the methods of the present invention comprise administering a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In certain embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in the form of a pharmaceutical composition further comprising a pharma- ceutically acceptable carrier or excipient.

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

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

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

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

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

The invention further relates to the use of compounds of formula (I)-(VIII) or pharma- ceutically acceptable salts thereof for inhibiting the activity of plasmepsin X and plasmepsin IX, for treating a malaria parasite infection, or for treating malaria. The invention further relates to the use of compounds of formula (I)-(VIII) or pharma-ceutically acceptable salts thereof in the manufacture of a medicament for inhibiting the activity of plasmepsin X and plasmepsin IX, for treating a malaria parasite infection, or for treating malaria. Compounds of formula (I)-(VIII) or pharma-ceutically acceptable salts thereof as described in any of the embodiments of the invention herein are useful for any of the above uses.

The methods of the present invention are useful for treating malaria in that they inhibit the onset, development or progression of the condition, ameliorate the symptoms of the condition, cause regression of the condition, treat the condition, or otherwise improve the general health of a subject suffering from or at risk of suffering from the condition. Thus, in accordance with the presently disclosed subject matter, the terms "treat," "treating," and grammatical variations thereof, and the phrase "methods of treating," are intended to encompass any desired therapeutic intervention, including, but not limited to, methods of treating an existing infection in an infected subject, e.g., in a subject exposed to a parasite disclosed herein.

Embodiments of the invention further include one or more of the compounds of formula (I)-(VIII) or pharma- ceutically acceptable salts thereof for use in, (ii) as a medicament or composition for, or (iii) in the preparation of a medicament for: (a) treatment (e.g., treatment of the human body); (b) medical treatment; (c) inhibition of parasite/malaria parasite growth; (d) treatment or prevention of infections caused by Plasmodium species; (e) reducing the progression, onset or severity of pathological symptoms associated with malaria parasite infection and/or reducing the likelihood of severe malaria parasite infection; or (f) treatment, prevention, or delay in onset, severity or progression of malaria parasite-associated diseases, including, but not limited to, malaria.

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

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

As discussed above, the dosage and frequency of administration of the compounds of the invention and/or their pharma- ceutically acceptable salts will be adjusted according to the judgment of the attending clinician, taking into account factors such as the age, condition and size of the patient and the severity of the condition being treated.

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

Aerosol preparations suitable for inhalation include solutions and solids in powder form, which may be combined with a pharma- ceutically acceptable carrier, such as an inert compressed gas (e.g., nitrogen).

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

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

In another embodiment, there is provided a use of a composition comprising a compound of Formula (I)-(VIII) or a pharma- ceutically acceptable salt thereof formulated for subcutaneous delivery. In another embodiment, there is provided a use of a composition suitable for oral delivery. In some embodiments, a pharmaceutical formulation comprising one or more compounds of Formula (I)-(VIII) or a pharma- ceutically acceptable salt thereof may be advantageously prepared in a unit dosage form. In such form, the formulation is subdivided into suitably sized unit doses containing appropriate amounts of the active ingredient (e.g., an effective amount to achieve a desired purpose). Each of the foregoing alternatives is considered to be encompassed by various embodiments of the present invention.

When used in combination with one or more additional therapeutic agents ("combination therapy"), the compounds used in the methods of the invention, i.e., compounds of Formulae (I)-(VIII), can be administered together or sequentially. When administered sequentially, the compounds of the invention can be administered before or after the one or more additional therapeutic agents, as determined by one of skill in the art or by the patient's preference.

When formulated as a fixed dose, such combination products employ a compound of Formulas (I)-(VIII) or a pharma- ceutically acceptable salt thereof within the dosage ranges described herein, and the other pharma- ceutically active agent or treatment within the dosage ranges.

Combination Therapy In another embodiment, a method of treatment is provided using a pharma- ceutically acceptable composition containing the compounds of the present invention as a neat chemical or optionally further containing additional ingredients. Such compositions are contemplated for preparation and use in monotherapy or combination therapy. For preparing pharmaceutical compositions from the compounds of the present invention, inert, pharma- ceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories. Powders and tablets may be comprised of about 5 to about 95% active ingredient. Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar, or lactose. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharma- ceutically acceptable carriers and methods for preparing various compositions can be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pennsylvania.

Non-limiting examples of additional drugs and active agents useful in combination therapy to treat malaria include: Coartem® (Novartis International AG, Basel, Switzerland; artemether + lumefantrine), Eurartesim® (Sigma-Tau Pharmaceuticals, Inc., Rome, Italy; dihydroartemisinin-piperaquine), Pyramax® (Shin Poong Pharmaceutical Co., Ltd., Seoul, Korea; pyronaridine-artesunate), ASAQ Winthrop® (Sanofi SA (Gentilly, (France)/DNDi (Geneva, Switzerland); artesunate + amodiaquine), ASMQ (Cipla Limited (Mumbai, India)/DNDi; artesunate + mefloquine), SPAQ-CO ^™ (Guilin Pharmaceutical Co., Ltd. (Shanghai); amodiaquine + sulfadoxine, pyrimethamine), Artesun® (Guilin Pharmaceutical; artesunate), artemether, artesunate, dihydroartemisinin, lumefantrine, amodiaquine, mefloquine, piperaquine, quinine, chloroquine, atovaquone and proguanil and sulfadoxine-pyrimethamine, tafenoquine (Glaxosmithkline), OZ439/PQP (Sanofi), OZ439/FQ (Sanofi), KAE609 (Novartis), KAF156 (Novartis), DSM265 (NIH/Takeda), and MK-4815 (Merck & Co., Inc., Powles et al., Antimicrobial Agents and Chemotherapy 56(5): 2414-2419 (2012)). The choice of such additional active ingredients will be determined by the attending physician or other healthcare provider according to the existing disease or disorder for which treatment is desired.

The present invention therefore further provides methods of using a compound of formula (I)-(VIII) or a pharma- ceutically acceptable salt thereof to inhibit plasmepsin X, plasmepsin IX, or plasmepsin X and plasmepsin IX, to treat a malaria parasite infection, or to treat malaria, wherein the methods further comprise administering to a subject in need of such inhibition or treatment one or more additional antimalarial drugs. In some embodiments, the one or more additional antimalarial drugs are selected from the group consisting of artemether, lumefantrine, dihydroartemisinin, piperaquine, pyronaridine, artesunate, amodiaquine, mefloquine, sulfadoxine, pyrimethamine, lumefantrine, quinine, chloroquine, atovaquone, and proguanil.

EXAMPLES The meanings of the abbreviations used in the examples are as follows:

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

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

Scheme 1

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

Scheme 2

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

Scheme 3

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

Scheme 4

The product represented by formula S-10 is prepared from S-9, where X is a halogen (e.g., Cl, Br, and I), following a transition metal catalyzed intramolecular cross-coupling reaction (e.g., palladium catalyzed C-O coupling reaction).

Scheme 5

Products of formula S-12 are prepared from S-11 after an intramolecular S N ₂ reaction between an alcohol and X, where X is a leaving group such as Cl, Br, I, OMs, OTs, or OTf. Products of formula S-12 are also prepared from S-11 diols after dehydration conditions using acids or other dehydrating reagents.

Scheme 6

Products of formula S-12 are prepared from intermediates S-13 or S-14 following intramolecular reductive etherification using conditions such as TMSOTf and Et ₃ SiH.

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

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

Preparative HPLC purifications were usually performed using either mass spectrometry directed or non-mass guided systems. Typically, they use the "Waters Chromatography" LC-MS System, which is composed of: Waters ZQ ^™ single quad MS system (electrospray ionization), Waters 2525 Gradient Pump, Waters 2767 Injecto/Collector, Waters 996 PDA Detector; MS conditions are as follows: 150-750 amu, Positive Electrospray, Collection Triggered by MS, and a Waters SUNFIRE® C-18 5 micron, 30 mm (id) x 100 mm column. The analysis was performed on a 350-well PCT Workstation. The mobile phase consisted of a mixture of acetonitrile (10-100%) in water containing 0.1% TFA. The flow rate was maintained at 50 mL/min, the injection volume was 1800 μL, and the UV detection range was 210-400 nm. The alternative preparative HPLC system used was a Gilson Workstation consisting of a Gilson GX-281 Injector/Collector, Gilson UV/VIS-155 Detector, Gilson 333 and 334 Pumps, and a Phenomenex Gemini-NX C-18 5 micron, 50 mm (id) x 250 mm column or a Waters XBridge ^™ C-18 5 micron OBD ^™ , 30 mm (id) x 250 mm column. The mobile phase consisted of a mixture of acetonitrile (0-75%) in water containing 5 mmol ( _NH4 ) _HCO3 . Flow rates were maintained at 50 mL/min for the Waters Xbridge ^TM column and 90 mL/min for the Phenomenex Gemini column. Injection volumes were in the range of 1000-8000 μL and UV detection range was 210-400 nm. Mobile phase gradients were optimized for individual compounds. Reactions performed with microwave irradiation were typically performed using an Emrys Optimizer (Personal Chemistry) or Initiator (Biotage). Solutions were concentrated on a rotary evaporator under reduced pressure. Flash chromatography was typically performed on silica gel (32-63 μM, 60 Å pore size) in prepacked cartridges of the sizes indicated using either a Biotage® Flash Chromatography apparatus (Dyax Corp.), an ISCO CombiFlash® Rf apparatus, or an ISCO CombiFlash® Companion XL. ¹ H NMR spectra were obtained on a 500 MHz spectrometer in CDCl ₃ solutions unless otherwise indicated. Chemical shifts are reported in parts per million (ppm). Tetramethylsilane (TMS) was used as an internal reference in the CDCl ₃ solutions, and the residual CH ₃ OH peak or TMS was used as an internal reference in the CD ₃ OD solutions. Coupling constants (J) are reported in Hertz (Hz). Chiral analytical chromatography was most commonly performed on one of the following columns (Daicel Chemical Industries, Ltd.): CHIRALPAK® AS column (250×4.6 mm), CHIRALPAK® AD column (250×4.6 mm), CHIRALCEL® OD column (250×4.6 mm), CHIRALCEL® IA column (250×4.6 mm), or CHIRALCEL® OJ column (250×4.6 mm) (Daicel Chemical Industries, Ltd.), using the stated percentages of either ethanol in hexane (%Et/Hex) or isopropanol in heptane (%IPA/Hep) as the isocratic solvent system. Chiral preparative chromatography was performed on one of the following columns (Daicel Chemical Industries, Ltd.): CHIRALPAK AS column (20×250 mm), CHIRALPAK AD column (20×250 mm), CHIRALCEL® OD column (20×250 mm), CHIRALCEL® IA column (20×250 mm), CHIRALCEL® OJ column (20×250 mm) with the desired isocratic solvent system certified for chiral analytical chromatography or by supercritical fluid (SFC) conditions.

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

Intermediate 1
Preparation of Intermediate 1-2

DBU (21.72 mL, 144 mmol) and diphenylphosphinyl were added to a mixture of methyl (S)-4-hydroxychroman-6-carboxylate (INT1-1) (10 g, 48.0 mmol) in THF (80 mL). Azide (35.0 g, 144 mmol) was then 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 gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, eluent 15% EtOAc/petroleum ether gradient @ 50 mL/min) to give methyl (R)-4-azidochroman-6-carboxylate (INT1-2).

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

Pd—C (2.510 g, 4.72 mmol) was added to a solution of methyl (R)-4-azidochroman-6-carboxylate (INT1-2) (11 g, 47.2 mmol) in THF (200 mL) under _N2 atmosphere. The mixture was degassed and backfilled with _H2 (3 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 give methyl (R)-4-aminochroman-6-carboxylate (INT1-3).

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

Sodium hydride (3.77 g, 94 mmol) was added in portions 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 h at this temperature, 2,2,2-trifluoroacetic anhydride (8.82 mL, 61.3 mmol) was added dropwise. The mixture was stirred at 0 °C for 1 h. A solution of methyl (R)-4-aminochroman-6-carboxylate (INT1-3) (9.77 g, 47.1 mmol) in THF (50 mL) was added dropwise at 0 °C. The mixture was stirred at 0 °C for 2 h. The mixture was quenched with water (80 mL) and extracted with EtOAc (3 x 50 mL). The organic layer was washed with brine (40 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, eluent 20% EtOAc/petroleum ether gradient @ 50 mL/min) to give methyl (R)-4-(3-(tert-butoxycarbonyl)thioureido)chroman-6-carboxylate (INT-1).

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

To a solution of pent-4-enoic acid (INT2-1) (40 g, 400 mmol), EDCI (92 g, 479 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (64.8 g, 479 mmol), and N-ethyl-N-isopropylpropan-2-amine (279 mL, 1598 mmol) in DCM (400 mL) was added N,O-dimethylhydroxylamine hydrochloride (54.6 g, 559 mmol). The reaction was stirred at 25 °C under _N2 atmosphere for 12 h. LCMS showed the 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 Na ₂ SO ₄ , filtered, concentrated under reduced pressure and the crude was purified by flash silica gel chromatography (ISCO®; 220 g Agela Silica Flash Column, eluent 8% ethyl acetate/petroleum ether gradient @ 50 mL/min) to give N-methoxy-N-methylpent-4-enamide (INT2-2).

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

To a solution of N-methoxy-N-methylpent-4-enamide (INT2-2) (20 g, 140 mmol) in THF (200 mL) was added ethylmagnesium bromide (69.8 mL, 210 mmol) dropwise at 0° C. under _N2 atmosphere. The reaction was stirred at 25° C. for 1 h under _N2 atmosphere. TLC showed a new spot. The mixture was quenched with saturated aqueous _NH4Cl (100 mL) and water (100 mL) and extracted with EtOAc (3×100 mL). The organic layer was washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure and the crude was purified by flash silica gel chromatography (ISCO®; 120 g Agela Silica Flash Column, eluent 5% ethyl acetate/petroleum ether gradient @ 40 mL/min) to give hept-6-en-3-one (INT2-3).

^1H NMR (500 MHz, chloroform-d) δ 5.78-5.83 (m, 1H), 4.92-5.07 (m, 2H), 2.48-2.54 (m, 2H), 2.43 (q, J = 7.0 Hz, 2H), 2.29-2.37 (m, 2H), 1.06 (t, J = 7.0 Hz, 3H).
Preparation of intermediate 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 Ti(EtO) ₄ (37.5 mL, 178 mmol) and the reaction was then stirred at 75° C. for 12 h under N ₂ atmosphere. TLC showed a new spot. The final mixture was cooled to room temperature and then diluted with DCM (200 mL) and stirred for 15 min, then washed with ice-cold saturated aqueous sodium bicarbonate (50 mL) and Na ₂ SO ₄ , then filtered and concentrated under reduced pressure. The crude material was purified by flash silica gel chromatography (ISCO®; 120 g Agela Silica Flash Column, eluent 8% ethyl acetate/petroleum ether gradient @ 40 mL/min) to give (R,E)-N-(hept-6-en-3-ylidene)-2-methylpropane-2-sulfinamide (INT2-4).

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

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 give LDA. Methyl acetate (7.48 mL, 93 mmol) and Ti(OiPr) ₃ Cl (116 mL, 116 mmol) were added in anhydrous 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) was added dropwise and the mixture was stirred at −78° C. for 3 h. There was no change in color, remaining yellow. LCMS showed major DP mass. The mixture was quenched with ice-cold half-saturated aqueous ammonium chloride (60 mL). The slurry was diluted with EtOAc (200 mL) then filtered and rinsed with EtOAc and water. The organic layer was washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 120 g Agela Silica Flash Column, eluent 25% ethyl acetate/petroleum ether gradient @ 40 mL/min) to give methyl 3-(((R)-tert-butylsulfinyl)amino)-3-ethylhept-6-enoate (INT2-5).

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 Intermediate 2-6

Methyl 3-(((R)-tert-butylsulfinyl)amino)-3-ethylhept-6-enoate (INT2-5) (12 g, 41.5 mmol) was purified using a SFC column DAICEL CHIRALPAK AD (250 mm x 50 mm, 10 um) Conditions 0.1% NH ₃ H ₂ O IPA Start B 15 End B 15 Gradient Time (min) 100% B Hold Time (min) Flow (mL/min) 200 Inject 200) and a column DAICEL CHIRALPAK AD (250 mm x 50 mm, 10 um) Conditions 0.1% NH ₃ H ₂ O IPA Start B 12 End B 12 Gradient Time (min) 100% B Hold Time (min) Separation at a flow rate (mL/min) of 200 injects 240 gave methyl (R)-3-(((R)-tert-butylsulfinyl)amino)-3-ethylhept-6-enoate (INT2-6_P1, desired) (tR=1.978 min, UV=220 nm) and methyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-ethylhept-6-enoate (INT2-6_P2) (tR=2.132 min, UV=220 nm).

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

A solution of methyl (R)-3-(((R)-tert-butylsulfinyl)amino)-3-ethylhept-6-enoate (INT2-6_P1) (20 g, 69.1 mmol) in HCl-dioxane (4N) (100 mL) and MeOH (200 mL) was stirred at 25°C for 2 h. LCMS showed the reaction was complete. The solvent was evaporated under reduced pressure to give the product methyl (R)-3-amino-3-ethylhept-6-enoate hydrochloride (INT2-7).

MS (ESI) m/z 186.3 (M+H) ^+
1H NMR (500 MHz, methanol- _d4 ) δ 5.80-5.87 (m, 1H), 5.07-5.15 (m, 1H), 5.02-5.04 (m, 1H), 3.73 (s, 3H), 2.71-2.79 (m, 2H), 2.07-2.18 (m, 2H), 1.75-1.85 (m, 4H), 0.99 (t, J = 7.6 Hz, 3H).
Preparation of intermediate 2-8

To a solution of DMB-BOC-thiourea (5 g, 15.32 mmol), methyl (R)-3-amino- _3- ethylhept-6-enoate hydrochloride (INT2-7) (3.74 g, 16.85 mmol), and EDC (7.34 g, 38.3 mmol) in acetonitrile (100 mL) was added DIEA (12.04 mL, 68.9 mmol). The reaction was stirred at 15 °C under N2 atmosphere for 12 h. LCMS showed the desired mass and some ring-opened by-product ester. It was then warmed to 50 °C and stirred at 50 °C for 2 h. LCMS showed only the mass of the desired product. The mixture was concentrated under reduced pressure. The crude was dissolved in EtOAc (100 mL) and water (100 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude was purified by flash column (ISCO®; 80 g Agela Silica Flash Column, eluent 15% ethyl acetate/petroleum ether gradient @ 30 mL/min) to give tert-butyl (R,E)-(4-(but-3-en-1-yl)-1-(2,4-dimethoxybenzyl)-4-ethyl-6-oxotetrahydropyrimidin-2(1H)-ylidene)carbamate (INT2-8).

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 = 7.6Hz, 3H)
Preparation of Intermediate 2-9

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

MS (ESI) m/z 196.0 (M+H) ⁺
Preparation of intermediate 2

To a solution of (R)-6-(but-3-en-1-yl)-6-ethyl-2-iminotetrahydropyrimidin-4(1H)-one (INT2-9) (438 mg, 2.243 mmol) in water (10 mL) and THF (3 mL) was added NaHCO ₃ (942 mg, 11.22 mmol) and (BOC) ₂ O (1.042 mL, 4.49 mmol) in small portions at 0° C. The reaction was stirred at 25° C. for 16 h. LCMS showed the desired mass. The mixture was extracted with EtOAc (3×10 mL). The organic layer was washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude was purified by flash column (ISCO®; 12 g Agela Silica Flash Column, eluent 20% EE (EtOAC/EtOH=3:1)/petroleum ether gradient @ 30 mL/min) to give tert-butyl (R,E)-(4-(but-3-en-1-yl)-4-ethyl-6-oxotetrahydropyrimidin-2(1H)-ylidene)carbamate (Intermediate 2).

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

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

Trifluoromethanesulfonic acid (503 mg, 3.35 mmol) and N-bromosuccinimide (596 mg, 3.35 mmol) were added to a solution of (1R,2R)-1-amino-2,3-dihydro-1H-inden-2-ol (1-1) (500 mg, 3.35 mmol) in DCM (10 mL) at 0° C. The reaction was stirred at 18° C. under _N2 atmosphere for 1 h. The mixture was quenched with saturated sodium bicarbonate solution (10 mL) at 0° C. and extracted with DCM (1×10 mL) followed by EtOAc (3×10 mL). The organic layer was washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure and the crude was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, eluent 10% MeOH/DCM (with 1% ammonium hydroxide) gradient @ 50 mL/min) to give (1R,2R)-1-amino-6-bromo-2,3-dihydro-1H-inden-2-ol (1-2).

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 Compound 1-3

To a solution of (R)-4-((R,E)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxo-4-(pent-4-en-1-yl)tetrahydropyrimidin-1(2H)-yl)chroman-6-carboxylic acid (1-2) (96 mg, 0.198 mmol), EDC (189 mg, 0.989 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (134 mg, 0.989 mmol), and (1R,2R)-1-amino-6-bromo-2,3-dihydro-1H-inden-2-ol (45.1 mg, 0.198 mmol) in THF (5 mL) was added DIEA (0.276 mL, 1.582 mmol). The reaction was stirred at 18° C. for 2 h. The mixture was quenched with water (5 mL) and extracted with EtOAc (3×5 mL). The organic layer was washed with brine (5 mL), dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the crude was purified by prep-TLC (petroleum ether/EtOAc=1:1) to give tert-butyl ((R,E)-1-((R)-6-(((1R,2R)-6-bromo-2-hydroxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)chroman-4-yl)-4-ethyl-6-oxo-4-(pent-4-en-1-yl)tetrahydropyrimidin-2(1H)-ylidene)carbamate (1-3).

MS (ESI) m/z: 695.1, 697.1 (M+H ⁺ )
Preparation of Compound 1-4A, Compound 1-4B, and Compound 1-4C

To a solution of tert-butyl ((R,E)-1-((R)-6-((1R,2R)-6-bromo-2-hydroxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)chroman-4-yl)-4-ethyl-6-oxo-4-(pent-4-en-1-yl)tetrahydropyrimidin-2(1H)-ylidene)carbamate (1-3) (100 mg, 0.144 mmol) dissolved in dioxane (1.5 mL) was added chloro[tri(o-tolyl)phosphine][2-(2'-amino-1,1'-biphenyl)]palladium(II) (8.83 mg, 0.014 mmol) and N,N-dicyclohexylmethylamine (140 mg, 0.719 mmol) in a glove box at 25°C. The reaction was stirred at 70° C. for 16 hours. The mixture was quenched with water (3 mL) and extracted with EtOAc (3×5 mL). The organic layer was washed with brine (5 mL), dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the crude was purified by reverse prep HPLC (Instrument ED; Method Column Boston Prime C18 150×30 mm, 5 um; Conditions 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 Retention Time (min) 2 Flow (mL/min) 25; Injection 5) to give: tert-butyl ((4aR,8R,12E,18R,18aR,28E)-8-ethyl-18-hydroxy-6,20-dioxo-4,4a,7,8,9,10,11,17,18,18a,19,20-dodecahydro-3H,6H-1,21-(epiethan[1,2]diylidene)-8,5-(epiminomethano)-14,16-ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclononadecin-28-ylidene)carbamate (1-4A); tert-butyl ((4aR,8R,12Z,18R,18aR,28E)-8-ethyl-18-hydroxy-6,20-dioxo-4,4a,7,8,9,10,11,17,18,18a,19,20-dodecahydro-3H,6H-1,21-(epiethan[1,2]diylidene)-8,5-(epiminomethano)-14,16-ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclononadecin-28-ylidene)carbamate (1-4B); and tert-butyl ((4aR,8R,17R,17aR,E)-8-ethyl-17-hydroxy-12-methylene-6,19-dioxo-4,4a,6,7,8,9,10,11,12,16,17,17a,18,19-tetradecahydro-3H-1,20-(epiethan[1,2]diylidene)-8,5-(epiminomethano)-13,15-ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclooctadecin-27-ylidene)carbamate (1-4C).

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 Compound 1-5

To a solution of tert-butyl ((4aR,8R,17R,17aR,E)-8-ethyl-17-hydroxy-12-methylene-6,19-dioxo-4,4a,6,7,8,9,10,11,12,16,17,17a,18,19-tetradecahydro-3H-1,20-(epiethan[1,2]diylidene)-8,5-(epiminomethano)-13,15-ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclooctadecin-27-ylidene)carbamate (1-4C) (10 mg, 0.016 mmol) in MeOH (2 mL) was added Pd—C (1.731 mg, 3.25 μmol) under _N2 atmosphere. The mixture was degassed and backfilled with _H2 (3 times). The resulting mixture was stirred under _H2 (15 psi) at 25 °C for 12 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give tert-butyl ((4aR,8R,17R,17aR,E)-8-ethyl-17-hydroxy-12-methyl-6,19-dioxo-4,4a,6,7,8,9,10,11,12,16,17,17a,18,19-tetradecahydro-3H-1,20-(epiethan[1,2]diylidene)-8,5-(epiminomethano)-13,15-ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclooctadecin-27-ylidene)carbamate (1-5).

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

To a solution of tert-butyl ((4aR,8R,17R,17aR,E)-8-ethyl-17-hydroxy-12-methyl-6,19-dioxo-4,4a,6,7,8,9,10,11,12,16,17,17a,18,19-tetradecahydro-3H-1,20-(epiethan[1,2]diylidene)-8,5-(epiminomethano)-13,15-ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclooctadecin-27-ylidene)carbamate (1-5) (8 mg, 0.013 mmol) in DCM (3 mL) was added zinc(II) bromide (29.2 mg, 0.130 mmol) under _N2 atmosphere at 22 °C. The mixture was stirred at 22° C. for 16 hours. The mixture was cooled and the solvent was evaporated under reduced pressure to give the crude product. The residue was purified by reverse preparative HPLC (Instrument EJ Method Column Boston Green ODS 150×30 mm, 5 um Conditions Water (TFA)-ACN Start B 22 End B 52 Gradient Time (min) 10 100% B Retention Time (min) 2 Flow (mL/min) 25 Inject 1) to give 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]dotriaconta-11,13,20,22,27,29-hexaene-19,32-dione
Preparation of Compound 2-1

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

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

To a solution of tert-butyl ((4aR,8R,18R,18aR,E)-8-ethyl-18-hydroxy-6,20-dioxo-4,4a,7,8,9,10,11,12,13,17,18,18a,19,20-tetradecahydro-3H,6H-1,21-(epiethan[1,2]diylidene)-8,5-(epiminomethano)-14,16-ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclononadecin-28-ylidene)carbamate (2-1) (13 mg, 0.021 mmol) in DCM (3 mL) was added zinc(II) bromide (47.5 mg, 0.211 mmol) under _N2 atmosphere. The mixture was stirred at 22° C. for 16 hours. The mixture was concentrated under reduced pressure to give the crude product. The residue was purified by reverse preparative HPLC (Instrument EJ; Method Column Boston Green ODS 150×30 mm, 5 um, Conditions Water (TFA)-ACN Start B 22; End B 52 Gradient Time (min) 10; 100% B Retention Time (min) 2 Flow (mL/min) 25; Purification by injection 1) gave (4aR,8R,18R,18aR)-8-ethyl-18-hydroxy-28-imino-4,4a,8,9,10,11,12,13,17,18,18a,19-dodecahydro-3H,6H-1,21-(epiethan[1,2]diylidene)-8,5-(epiminomethano)-14,16-ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclononadecyne-6,20(7H)-dione (Example 2).

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]dotriaconta-10,12,20,22,27,29-hexaene-19,32-dione
Preparation of Compound 3-2

To a solution of pent-4-enoic acid (40 g, 400 mmol), EDC (92 g, 479 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (3-1) (64.8 g, 479 mmol), and N-ethyl-N-isopropylpropan-2-amine (279 mL, 1598 mmol) in DCM (400 mL) was added N,O-dimethylhydroxylamine hydrochloride (54.6 g, 559 mmol). The reaction was stirred at 25 °C under _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 Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the crude was purified by flash silica gel chromatography (ISCO®; 220 g Agela Silica Flash Column, eluent 8% ethyl acetate/petroleum ether gradient @ 50 mL/min) to give N-methoxy-N-methylpent-4-enamide (3-2).

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

To a solution of N-methoxy-N-methylpent-4-enamide (3-2) (20 g, 140 mmol) in THF (200 mL) under _N2 atmosphere was added ethylmagnesium bromide (69.8 mL, 210 mmol) dropwise at 0° C. The reaction was stirred at 25° C. under _N2 atmosphere for 1 h. The mixture was quenched with saturated aqueous _NH4Cl (100 mL) and water (100 mL) and extracted with EtOAc (3×100 mL). The organic layer was washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the crude was purified by flash silica gel chromatography (ISCO®; 120 g Agela Silica Flash Column, eluent 5% ethyl acetate/petroleum ether gradient @ 40 mL/min) to give hept-6-en-3-one (3-3).

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

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

MS (ESI) m/z 216.2 (M+H ⁺ )
^1H NMR (500 MHz, chloroform-d) δ 5.73-5.88 (m, 1H), 4.94-5.10 (m, 2H), 2.64-2.87 (m, 2H), 2.31-2.58 (m, 4H), 1.22 (s, 9H), 1.05-1.20 (m, 3H).
Preparation of 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 generate LDA. The resulting LDA (76 mL, 93 mmol) was added dropwise to a −78° C. mixture of ethyl acetate (7.48 mL, 93 mmol) and Ti(OiPr) ₃ Cl (116 mL, 116 mmol) in anhydrous THF (90 mL). After 1 h, a solution of (R,E)-N-(hept-6-en-3-ylidene)-2-methylpropane-2-sulfinamide (3-4) (10 g, 46.4 mmol) in anhydrous THF (20 mL) was added dropwise and the mixture was stirred at −78° C. for 3 h. The mixture was quenched with ice-cold, half-saturated aqueous ammonium chloride solution (60 mL). The slurry was diluted with EtOAc (200 mL), filtered, and rinsed with EtOAc and water. The organic layer was washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 120 g Agela Silica Flash Column, eluent 25% ethyl acetate/petroleum ether gradient @ 40 mL/min) to give methyl 3-(((R)-tert-butylsulfinyl)amino)-3-ethylhept-6-enoate (3-5).

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

A solution of methyl 3-(((R)-tert-butylsulfinyl)amino)-3-ethylhept-6-enoate (3-5) (9 g, 31.1 mmol) in 4N HCl-dioxane (20 mL) and MeOH (20.00 mL) was stirred under _N2 atmosphere at 25 °C for 1 h. The solvent was evaporated under reduced pressure to give the crude product methyl 3-amino-3-ethylhept-6-enoate hydrochloride (3-6), which was used directly in the next step crude.

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

To a solution of EDC (9.08 g, 47.4 mmol), methyl 3-amino-3-ethylhept-6-enoate hydrochloride (3-6) (3.5 g, 15.79 mmol), and methyl (R)-4-(3-(tert-butoxycarbonyl)thioureido)chroman-6-carboxylate (INT-1) (5.78 g, 15.79 mmol) in ACN (30 mL) was added N-ethyl-N-isopropylpropan-2-amine (13.79 mL, 79 mmol). The reaction was stirred at 25 °C under _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 Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give methyl (4R)-4-((Z)-2-(tert-butoxycarbonyl)-3-(3-ethyl-1-methoxy-1-oxohept-6-en-3-yl)guanidino)chroman-6-carboxylate (3-7), which was used directly crude in the next step.

MS (ESI) m/z 518.2 (M+H ⁺ )
Preparation of Compound 3-8

To a solution of methyl (4R)-4-((Z)-2-(tert-butoxycarbonyl)-3-(3-ethyl-1-methoxy-1-oxohept-6-en-3-yl)guanidino)chroman-6-carboxylate (3-7) (8.17 g, 15.78 mmol) in THF (50 mL) was added DBU (11.90 mL, 79 mmol ₎ . The mixture was stirred at 50 °C under _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 under reduced pressure. The crude material was purified by flash silica gel chromatography (ISCO®; 120 g Agela Silica Flash Column, eluent 25% ethyl acetate/petroleum ether gradient @ 40 mL/min) to give methyl (4R)-4-((E)-4-(but-3-en-1-yl)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydropyrimidin-1(2H)-yl)chroman-6-carboxylate (3-8).

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

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

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=7.5Hz, 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 trimethylsilanolate (872 mg, 6.80 mmol) was added to a solution of methyl (R)-4-((R,E)-4-(but-3-en-1-yl)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydropyrimidin-1(2H)-yl)chroman-6-carboxylate (3-9A) (550 mg, 1.133 mmol) in THF (5 mL). The reaction was stirred at 25°C for 0.5 h. The solution of (R)-4-((R,E)-4-(but-3-en-1-yl)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydropyrimidin-1(2H)-yl)chroman-6-carboxylic acid (3-10) was used directly in the next step without further manipulation or purification.

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

To a solution of (R)-4-((R,E)-4-(but-3-en-1-yl)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydropyrimidin-1(2H)-yl)chroman-6-carboxylic acid (3-10) (534 mg, 1.132 mmol), EDC (1085 mg, 5.66 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (765 mg, 5.66 mmol), and (S)-2,2-dimethyl-6-vinylchroman-4-amine (253 mg, 1.246 mmol) in THF (50 mL) was added DIEA (1.582 mL, 9.06 mmol). The reaction was stirred at 25° C. for 12 h. The mixture was quenched with water (20 mL) and extracted with EtOAc (3×20 mL). The organic layer was washed with brine (15 mL), dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and the crude was purified by prep-TLC (petroleum ether/EtOAc=2:1) to give tert-butyl ((R,E)-4-(but-3-en-1-yl)-1-((R)-6-(((S)-2,2-dimethyl-6-vinylchroman-4-yl)carbamoyl)chroman-4-yl)-4-ethyl-6-oxotetrahydropyrimidin-2(1H)-ylidene)carbamate (3-11).

MS (ESI) m/z 657.3 (M+H ⁺ )
Preparation of Compound 3-12

To a solution of tert-butyl ((R,E)-4-(but-3-en-1-yl)-1-((R)-6-(((S)-2,2-dimethyl-6-vinylchroman-4-yl)carbamoyl)chroman-4-yl)-4-ethyl-6-oxotetrahydropyrimidin-2(1H)-ylidene)carbamate (3-11) (500 mg, 0.761 mmol) in DCE (500 mL) was added (1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)ruthenium (95 mg, 0.152 mmol). The reaction was stirred at 50 °C under _N2 atmosphere for 5 h. The mixture was concentrated under reduced pressure and the crude was purified by flash column (petroleum ether/EtOAc/EtOH=8:3:1) to give tert-butyl ((4aR,8R,11E,18aS,28E)-8-ethyl-17,17-dimethyl-6,20-dioxo-4,4a,7,8,9,10,18,18a,19,20-decahydro-3H,6H,17H-8,5-(epiminomethano)-1,21:13,15-diethenodipyrano[4,3-b:4′,3′-h][1,7]diazacyclooctadecin-28-ylidene)carbamate (3-12).

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

To a solution of tert-butyl ((4aR,8R,11E,18aS,28E)-8-ethyl-17,17-dimethyl-6,20-dioxo-4,4a,7,8,9,10,18,18a,19,20-decahydro-3H,6H,17H-8,5-(epiminomethano)-1,21:13,15-diethenodipyrano[4,3-b:4',3'-h][1,7]diazacyclooctadecin-28-ylidene)carbamate (3-12) (300 mg, 0.477 mmol) in MeOH (10 mL) was added Pd—C (50.8 mg, 0.048 mmol) under _N atmosphere. The mixture was degassed and backfilled with _H (3 times). The resulting mixture was stirred under H ₂ (15 psi) at 25° C. for 0.5 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give tert-butyl ((4aR,8R,18aS,E)-8-ethyl-17,17-dimethyl-6,20-dioxo-4,4a,7,8,9,10,11,12,18,18a,19,20-dodecahydro-3H,6H,17H-8,5-(epiminomethano)-1,21:13,15-diethenodipyrano[4,3-b:4′,3′-h][1,7]diazacyclooctadecin-28-ylidene)carbamate (3-13), which was used directly in the next step.

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

A solution of tert-butyl ((4aR,8R,18aS,E)-8-ethyl-17,17-dimethyl-6,20-dioxo-4,4a,7,8,9,10,11,12,18,18a,19,20-dodecahydro-3H,6H,17H-8,5-(epiminomethano)-1,21:13,15-diethenodipyrano[4,3-b:4',3'-h][1,7]diazacyclooctadecin-28-ylidene)carbamate (3-13) (280 mg, 0.444 mmol) in HCl-dioxane (4N) (30 mL) was stirred at 25°C for 16 h. The solvent was evaporated under reduced pressure to give the crude product. The residue was separated by reverse preparative HPLC (Column Boston Green ODS 150×30 mm, 5 um Conditions Water (HCl)-ACN Start B 30 End B 50 Gradient Time (min) 10 100% B Retention Time (min) 2 Flow Rate (mL/min) 25 Purification by injection 6) gave (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-(epiminomethane)-1,21:13,15-diethenodipyrano[4,3-b:4',3'-h][1,7]diazacyclooctadecine-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]tritriaconta-11,13,21,23,28,30-hexaene-20,33-dione
Preparation of Compound 4-2

To a solution of hex-5-enoic acid (4-1) (8 g, 70.1 mmol), EDC (20.15 g, 105 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (14.21 g, 105 mmol), and N,O-dimethylhydroxylamine hydrochloride (7.52 g, 77 mmol) in THF (100 mL) was added DIEA (36.7 mL, 210 mmol). The reaction was stirred at 25° C. for 5 h. The mixture was quenched with water (150 mL) and extracted with EtOAc (3×50 mL). The organic layer was washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, eluent 5% EtOAc/petroleum ether gradient @ 80 mL/min) to give N-methoxy-N-methylhex-5-enamide (4-2).

MS (ESI) m/z 157.7 (M+H ⁺ )
Preparation of Compound 4-3

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

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

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

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

To a solution of LiHMDS (22.67 mL, 22.67 mmol) in anhydrous THF (35 mL) was added methyl acetate (1.545 mL, 19.18 mmol) under _N2 atmosphere at -78 °C. The reaction was stirred at -78 °C for 15 min. Then, (E)-2-methyl-N-(oct-7-en-3-ylidene)propane-2-sulfinamide (4-4) (4 g, 17.44 mmol) in THF (15 mL) was added dropwise and the mixture was stirred at -78 °C for 3 h. The mixture was quenched with ice-cold half-saturated aqueous ammonium chloride solution (30 mL). The slurry was diluted with EtOAc (50 mL), filtered, and rinsed with EtOAc and water. The organic layer was washed with brine (50 mL), dried _{over Na2SO4} , filtered, and concentrated under reduced pressure. The residue was purified by flash column (SiO ₂ , petroleum ether/EtOAc=100:0→10:1) to give methyl 3-((tert-butylsulfinyl)amino)-3-ethyloct-7-enoate (4-5).

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

A solution of methyl 3-((tert-butylsulfinyl)amino)-3-ethyloct-7-enoate (4-5) (2 g, 6.59 mmol) in HCl-dioxane (4N) (5 mL) and MeOH (5 mL) at 15 °C was stirred under _N2 atmosphere at 15 °C for 1 h. The solution was concentrated under reduced pressure to give the crude product methyl 3-amino-3-ethyloct-7-enoate hydrochloride (4-6), which was used without further purification.

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

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

MS (ESI) m/z 532.3 (M+H+).
Preparation of Compound 4-8

To a solution of methyl (4R)-4-((Z)-2-(tert-butoxycarbonyl))-3-(3-ethyl-1-methoxy-1-oxooct-7-en-3-yl)guanidino)chroman-6-carboxylate (4-7) (2.0 g, 3.76 mmol) in THF (20 mL) was added DBU (2.84 mL, 18.81 mmol). The mixture was stirred at 50° C. for 10 h. The mixture was quenched with water (40 mL) and extracted with EtOAc (3×40 mL). The organic layer was washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude material was purified by flash silica gel chromatography (ISCO®; 20 g Agela Silica Flash Column, eluent 15% ethyl acetate/petroleum ether gradient @ 60 mL) to give methyl (4R)-4-((E)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxo-4-(pent-4-en-1-yl)tetrahydropyrimidin-1(2H)-yl)chroman-6-carboxylate (4-8).

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 Compound 4-9A and Compound 4-9B

Methyl (E)-4-(2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxo-4-(pent-4-en-1-yl)tetrahydropyrimidin-1(2H)-yl)chroman-6-carboxylate (4-8) (1.8 g, 3.60 mmol) was separated by SFC (Instrument: SFC-22 Method Column: DAICEL CHIRALPAK AD (250 mm 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 Retention Time (min) Flow Rate (mL/min) 50 Injection 60) to obtain the product (methyl (R)-4-((R,E)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxo-4-(pent-4-en-1-yl)tetrahydropyrimidin-1(2H)-yl)chroman-6-carboxylate (4-9A) (peak 1, R _t =0.816) and (methyl (E)-4-(2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxo-4-(pent-4-en-1-yl)tetrahydropyrimidin-1(2H)-yl)chroman-6-carboxylate (4-9B) (peak 2, R _t =0.879) were obtained.

MS (ESI) m/z: 500.2 (M+H ⁺ )
Preparation of Compound 4-10

To a solution of methyl (R)-4-((R,E)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxo-4-(pent-4-en-1-yl)tetrahydropyrimidin-1(2H)-yl)chroman-6-carboxylate (4-9A) (100 mg, 0.200 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was added 2,6-dimethylpyridine (42.9 mg, 0.400 mmol) and osmium(VIII) oxide (5.09 mg, 0.020 mmol). The resulting solution was stirred at 25° C. for 0.2 hours. Sodium periodate (171 mg, 0.801 mmol) was added and the resulting solution was stirred at 25° C. for 2 hours. The mixture was quenched with saturated Na ₂ SO ₃ (10 mL) and water (5 mL) and extracted with EtOAc (3×10 mL). The organic layer was washed with brine (5 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give methyl (R)-4-((R,E)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxo-4-(4-oxobutyl)tetrahydropyrimidine-1(2H)-yl)chroman-6-carboxylate (4-10), which was used directly crude in the next step.

MS (ESI) m/z: 502.3 (M+H ⁺ )
Preparation of Compound 4-11

To a solution of methyl (R)-4-((R,E)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxo-4-(4-oxobutyl)tetrahydropyrimidine-1(2H)-yl)chroman-6-carboxylate (4-10) (95 mg, 0.189 mmol) in MeOH (2 mL) at 0° C. was added NaBH ₄ (10.75 mg, 0.284 mmol) in portions. The mixture was stirred at 0° C. for 1 h. LCMS showed major mass of desired product. The mixture was quenched with water (5 mL) and extracted with EtOAc (4×5 mL). The combined organic layers were washed with brine (5 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude was purified by prep-TLC (petroleum ether/EtOAc=3:1) to give methyl (R)-4-((R,E)-2-((tert-butoxycarbonyl)imino)-4-ethyl-4-(4-hydroxybutyl)-6-oxotetrahydropyrimidin-1(2H)-yl)chroman-6-carboxylate (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

To a solution of methyl (R)-4-((R,E)-2-((tert-butoxycarbonyl)imino)-4-ethyl-4-(4-hydroxybutyl)-6-oxotetrahydropyrimidine-1(2H)-yl)chroman-6-carboxylate (4-11) (53 mg, 0.105 mmol) in THF (1 mL) was added potassium trimethylsilanolate (81 mg, 0.631 mmol). The reaction was stirred at 25°C for 0.5 h. LCMS showed the major mass of desired product. The solution of (R)-4-((R,E)-2-((tert-butoxycarbonyl)imino)-4-ethyl-4-(4-hydroxybutyl)-6-oxotetrahydropyrimidin-1(2H)-yl)chroman-6-carboxylic acid (4-12) was used in the next step without further manipulation or purification.

MS (ESI) m/z: 490.2 (M+H ⁺ )
Preparation of Compound 4-13

To a solution of (R)-4-((R,E)-2-((tert-butoxycarbonyl)imino)-4-ethyl-4-(4-hydroxybutyl)-6-oxotetrahydropyrimidin-1(2H)-yl)chroman-6-carboxylic acid (4-12) (50 mg, 0.102 mmol), EDC (98 mg, 0.511 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (69.0 mg, 0.511 mmol), and (S)-6-bromo-2,2-dimethylchroman-4-amine (28.8 mg, 0.112 mmol) in THF (5 mL) was added DIEA (0.143 mL, 0.817 mmol). The reaction was stirred at 25° C. for 3 h. The mixture was quenched with water (5 mL) and extracted with EtOAc (3×5 mL). The organic layer was washed with brine (5 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The crude was purified by prep-TLC (petroleum ether/EtOAc=3:1) to give tert-butyl ((R,E)-1-((R)-6-((S)-6-bromo-2,2-dimethylchroman-4-yl)carbamoyl)chroman-4-yl)-4-ethyl-4-(4-hydroxybutyl)-6-oxotetrahydropyrimidin-2(1H)-ylidene)carbamate (4-13).

MS (ESI) m/z: 727.2, 729.2 (M+H ⁺ )
Preparation of Compound 4-14

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

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

To a solution of tert-butyl ((4aR,5R,8R,19aS,E)-8-ethyl-18,18-dimethyl-6,21-dioxo-4,4a,7,8,9,10,11,12,19,19a,20,21-dodecahydro-3H,6H,18H-1,22-(epiethan[1,2]diylidene)-8,5-(epiminomethano)-14,16-ethenodipyrano[3,4-d:3',4'-j][1] in DCM (3 mL) under _N2 atmosphere at 25 °C was added zinc(II) bromide (104 mg, 0.464 mmol) and oxa[6,12]diazacyclononadecin-29-ylidene)carbamate (4-14) (30 mg, 0.046 mmol). The mixture was stirred at 25° C. for 16 hours. The solvent was evaporated under reduced pressure to give the crude product. The residue was purified by reverse preparative HPLC (instrument e.g., Method Column Welch Xtimate C18 150×25 mm, 5 um; Conditions Water (TFA)-ACN Start B 25; End B 55 Gradient Time (min) 11; 100% B Retention Time (min) 2 Flow (mL/min) 25; Purification by injection 1) gave (4aR,5R,8R,19aS)-8-ethyl-29-imino-18,18-dimethyl-4,4a,7,8,9,10,11,12,18,19,19a,20-dodecahydro-3H,6H,21H-1,22-(epiethan[1,2]diylidene)-8,5-(epiminomethano)-14,16-ethenodipyrano[3,4-d:3',4'-j][1]oxa[6,12]diazacyclononadecyne-6,21-dione (Example 4).

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-(epiminomethano)-4,6:17,19-diethenocyclopenta[b]pyrano[4,3-h][1,7]diazacyclooctadecine-13,20(14aH)-dione
Preparation of Compound 5-2

A solution of 5-bromo-2,3-dihydro-1H-inden-1-one (50 g, 237 mmol), ethane-1,2-dithiol (5-1) (26.6 mL, 317 mmol), and 4-methylbenzenesulfonic acid (8.16 g, 47.4 mmol) in toluene (500 mL) was heated to 130° C. for 16 h using a Dean-Stark apparatus. TLC 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 Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, eluent 10% EtOAc/petroleum ether gradient @ 60 mL/min) to give 5-bromo-2,3-dihydrospiro[indene-1,2′-[1,3]dithiolane] (5-2).

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

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. Under N ₂ and at a temperature below −65° C., pyridine hydrofluoride (57.4 mL, 226 mmol) was added dropwise and the mixture was stirred at −70° C. for 30 min. A solution of 5-bromo-2,3-dihydrospiro[indene-1,2′-[1,3]dithiolane] (5-2) (65 g, 226 mmol) in CH ₂ Cl ₂ (200 mL) was added dropwise 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% NaHSO ₃ (600 mL). The aqueous layer was extracted with CH ₂ Cl ₂ (2×600 mL) and the combined organic layers were washed with brine (300 mL), dried over Na ₂ SO ₄ , filtered and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, eluent 100% petroleum ether gradient @ 60 mL/min) to give 2,5-dibromo-1,1-difluoro-2,3-dihydro-1H-indene (5-3).

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-indene (5-3) (60 g, 192 mmol) in DCM (600 mL) was added DBU (43.5 mL, 289 mmol). The mixture was stirred at 25° C. for 16 h. LCMS showed the mass of the desired product. Water (600 mL) was added and the mixture was acidified with concentrated HCl to pH=7. The mixture was filtered through diatomaceous earth, the aqueous layer was extracted with CH ₂ Cl ₂ (2×600 mL), and the combined organic layers were washed with brine (300 mL), dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, eluent 100% petroleum ether gradient @ 50 mL/min) to give 5-bromo-1,1-difluoro-1H-indene (5-4).

No LCMS signal.

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

To a solution of 5-bromo-1,1-difluoro-1H-indene (5-4) (15 g, 64.9 mmol) in iPrOH (250 mL) that had been bubbled with _O for 1 h, phenylsilane (14.05 g, 130 mmol) and Mn(TMHD) ₍ 3.93 g, 6.49 mmol) were added and stirred at 0 °C under _O (15 psi) for 2 h. TLC showed the reaction was complete. The mixture was quenched with water (300 mL) and extracted with EtOAc (3 x 300 mL). The organic layer was washed with brine (300 mL), dried _{over Na} SO , filtered, and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, eluent 17% EtOAc/petroleum ether gradient @ 50 mL/min) to give a mixture of 6-bromo-3,3-difluoro-2,3-dihydro-1H-inden-1-ol (5-5) and 5-bromo-1,1-difluoro-2,3-dihydro-1H-inden-2-ol (5-5a) (5-5:5-5a=7:2).

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

To a solution of 6-bromo-3,3-difluoro-2,3-dihydro-1H-inden-1-ol and 5-bromo-1,1-difluoro-2,3-dihydro-1H-inden-2-ol (11.56 g, 47.3 mmol) (5-5:5-5a=7:2) in MeOH (150 mL) and DMSO (15 mL) was added [1,1′-bis(diphenylphospino)ferrocene]dichloropalladium(II) (2.64 g, 3.61 mmol) and triethylamine (15.67 mL, 108 mmol) under Ar atmosphere at 20° C., and the mixture was stirred at 80° C. for 48 h under CO atmosphere (3.5 mbar). TLC showed the reaction was complete. After cooling, the mixture was filtered through diatomaceous earth, the mixture was diluted with H ₂ O (200 mL), extracted with EtOAc (3×200 mL), dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure to give the crude product, which was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, eluent 17% EtOAc/petroleum ether gradient @ 80 mL/min) to give a mixture of methyl 1,1-difluoro-3-hydroxy-2,3-dihydro-1H-indene-5-carboxylate (5-6) and methyl 1,1-difluoro-2-hydroxy-2,3-dihydro-1H-indene-5-carboxylate (5-6a) (5-6:5-6a=3:1).

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

A mixture of methyl 1,1-difluoro-3-hydroxy-2,3-dihydro-1H-indene-5-carboxylate and methyl 1,1-difluoro-2-hydroxy-2,3-dihydro-1H-indene-5-carboxylate (8.3 g, 36.36 mmol) (5-6:27-6a=3:1) was separated by SFC (column: Chiralpak AD-3 150×4.6 mm I.D., 3 um, mobile phase: A: CO ₂ B: iso-propanol (0.05% DEA), gradient: 5% B→40% in 5 min, 40% B→5% in 0.5 min, then hold at 5% B for 1.5 min, flow rate: 2.5 mL/min, column temperature: 35° C.) to give the product methyl (S)-1,1-difluoro-3-hydroxy-2,3-dihydro-1H-indene-5-carboxylate (5-7_P1, desired) (peak 1, R _t =2.577), methyl (R)-1,1-difluoro-3-hydroxy-2,3-dihydro-1H-indene-5-carboxylate (5-7_P2) (peak 2, R _t =2.944) and a mixture of (5-7_P2 and 5-6a) (2 g, 8.77 mmol) were obtained. The mixture of (5-7_P2 and 5-6a) was separated by SFC (column: Cellulose 2 150×4.6 mm ID, 5 um, mobile phase: A: CO ₂ B: MeOH (0.05% DEA) gradient: 5% B→40% in 5 min, 40% B→5% in 0.5 min, then hold at 5% B for 1.5 min, column temperature: 35° C.) to give methyl 1,1-difluoro-2-hydroxy-2,3-dihydro-1H-indene-5-carboxylate (5-6a).

(5-7_P1): ^1H NMR (500MHz, chloroform-d) δ 8.21 (s, 1H), 8.15 (d, J = 8.0Hz, 1H), 7.65 (d, J = 8.0Hz, 1H), 5.37 (q, J = 6.0Hz, 1H), 3.96 (s, 3H), 3.06-3.17 (m, 1H), 2.54 (dq, J = 5.0, 14.5Hz, 1H)
(5-7_P2): ^1H NMR (500MHz, chloroform-d) δ 8.20 (s, 1H), 8.13 (d, J = 8.0Hz, 1H), 7.64 (d, J = 8.0Hz, 1H), 5.36 (q, J = 5.5Hz, 1H), 3.95 (s, 3H), 3.05-3.17 (m, 1H), 2.54 (dq, J = 5.0, 14.5Hz, 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 Compound 5-8

To a solution of methyl (S)-1,1-difluoro-3-hydroxy-2,3-dihydro-1H-indene-5-carboxylate (5-7_P1) (585 mg, 2.56 mmol), tert-butyl (R,E)-(4-(but _-3 -en-1-yl)-4-ethyl-6-oxotetrahydropyrimidin-2(1H)-ylidene)carbamate (INT-2) (757 mg, 2.56 mmol) and _Ph3P (1009 mg, 3.85 mmol) in THF (10 mL) was added DIAD (0.997 mL, 5.13 mmol) dropwise under N2 atmosphere at 0 °C, and then the mixture was stirred at 18 °C for 2 h. TLC showed no SM. The mixture was concentrated under reduced pressure and the residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, eluent 20% EtOAc/petroleum ether gradient @ 60 mL/min) to give the crude product. The crude product was purified again by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, eluent DCM gradient @ 60 mL/min) to give the product methyl (R)-3-((R,E)-4-(but-3-en-1-yl)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydropyrimidin-1(2H)-yl)-1,1-difluoro-2,3-dihydro-1H-indene-5-carboxylate (5-8).

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 Compound 5-9

To a solution of methyl (R)-3-((R,E)-4-(but-3-en-1-yl)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydropyrimidin-1(2H)-yl)-1,1-difluoro-2,3-dihydro-1H-indene-5-carboxylate (5-8) (900 mg, 1.780 mmol) in THF (9 mL) was added potassium trimethylsilanolate (1370 mg, 10.68 mmol). The reaction was stirred at 18° C. for 0.5 h. LCMS showed the desired mass. H ₃ PO ₄ (0.1 g/mL in H ₂ O) was added to adjust the pH to approximately 6-7 and the mixture was quenched with water (10 mL) and extracted with EtOAc (3×10 mL). The organic layer was washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give the product (R)-3-((R,E)-4-(but-3-en-1-yl)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydropyrimidin-1(2H)-yl)-1,1-difluoro-2,3-dihydro-1H-indene-5-carboxylic acid (5-9).

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

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 a solution of tert-butyl ((R,E)-4-(but-3-en-1-yl)-1-((R)-6-((S)-2,2-dimethyl-6-vinylchroman-4-yl)carbamoyl)-3,3-difluoro-2,3-dihydro-1H-inden-1-yl)-4-ethyl-6-oxotetrahydropyrimidin-2(1H)-ylidene)carbamate (5-10) (1 g, 1.478 mmol) in DCE (500 mL) was added dichloro[1,3-bis(2,6-isopropylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II) (0.105 g, 0.148 mmol). The reaction was stirred at 50 °C _under N for 4 h. LCMS showed the desired mass. The mixture was concentrated under reduced pressure and the crude material was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, eluent 15% EtOAc/petroleum ether gradient @ 60 mL/min) to give tert-butyl 2-(2-methyl-1,2-dihydro-2-propanediol). ((7Z,11R,14R,14aR,21aS,24E)-11-ethyl-16,16-difluoro-2,2-dimethyl-13,20-dioxo-1,2,10,11,12,13,14a,15,16,20,21,21a-dodecahydro-9H-11,14-(epiminomethano)-4,6:17,19-diethenocyclopenta[b]pyrano[4,3-h][1,7]diazacyclooctadecin-24-ylidene)carbamate (5-11a, cis olefin; minor product) and tert-butyl ((7E,11R,14R,14aR,21aS,24E)-11-ethyl-16,16-difluoro-2,2-dimethyl-13,20-dioxo-1,2,10,11,12,13,14a,15,16,20,21,21a-dodecahydro-9H-11,14-(epiminomethano)-4,6:17,19-diethenocyclopenta[b]pyrano[4,3-h][1,7]diazacyclooctadecin-24-ylidene)carbamate (5-11, trans olefin; major product).

(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 a solution of tert-butyl ((7E,11R,14R,14aR,21aS,24E)-11-ethyl-16,16-difluoro-2,2-dimethyl-13,20-dioxo-1,2,10,11,12,13,14a,15,16,20,21,21a-dodecahydro-9H-11,14-(epiminomethane)-4,6:17,19-diethenocyclopenta[b]pyrano[4,3-h][1,7]diazacyclooctadecin-24-ylidene)carbamate (5-11) (780 mg, 1.202 mmol) in MeOH (10 mL) was added 10% Pd—C (128 mg, 0.120 mmol) under N ₂ atmosphere. The mixture was degassed and back-filled with _H2 (3 times). The resulting mixture was stirred under an atmosphere of _H2 (15 psi) at 18°C for 10 min. LCMS showed the reaction was complete. The mixture was filtered and the filtrate was concentrated under reduced pressure to give tert-butyl ((11R,14R,14aR,21aS,E)-11-ethyl-16,16-difluoro-2,2-dimethyl-13,20-dioxo-1,2,8,9,10,11,12,13,14a,15,16,20,21,21a-tetradecahydro-7H-11,14-(epiminomethano)-4,6:17,19-diethenocyclopenta[b]pyrano[4,3-h][1,7]diazacyclooctadecin-24-ylidene)carbamate (5-12), which was used directly in the next step.

MS (ESI) m/z 651.4 (M+H) ⁺
Preparation of Example 5

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

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. Isomers were separated by preparative HPLC or/and preparative chiral SFC.

An asterisk (*) may be used in chemical structure diagrams to indicate the location of a chiral center.

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

Approximately 42 hours prior to setting up the potency assay, parasites were synchronized with 5% sorbitol to select for ring stage parasites. On the day of assay set up, blood smears of parasite cultures were Giemsa stained and counted. Parasitemia was adjusted to 0.7% rings and the hematocrit was diluted to 2% in RPMI-Hepes medium, which was buffered with sodium bicarbonate and supplemented with 5% heat-inactivated human serum and 0.5% albumax. 30 uL of diluted parasites are then added to 10 uL of medium + compound in a pre-prepared Greiner TC assay plate. Parasite assay plates were placed in a single layer in a gas-filled humidified box and incubated at 37°C for 72 hours. After 72 hours of growth, assay plates were sealed with parafilm and frozen flat in single file at -80°C overnight. The next day, the assay plates are thawed at room temperature for 4 hours and an LDH assay is performed on them to measure parasite growth.

The assay EC ₅₀ results are shown in Table 2.

Claims (36)

Structural Formula (I):

[Wherein,
A is a straight or branched chain saturated or unsaturated (C ₃ -C ₁₀ )alkylene, phenyl(C _{3 -C 10 )alkylene or cycloalkyl(C 3 -C 10 ) alkylene} containing at least one -CH ₂ - group, where one or more additional -CH ₂ - groups within A may be independently replaced with a moiety selected from the group consisting of O, S, NR, CONR, NRCO, SO ₂ and SO ₂ NR, and where one or more of the hydrogens along A may be replaced with a group independently 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 is ^CR9 or N, where when Y is N, Z is ^CR11 and V is ^CR10 ;
V is CR ¹⁰ or N, where if 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, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, 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 alkylCOOH, COOH, oxo, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkylC ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C _{1 -C 6} alkylOH, CON(R ₇ ) _{(R 8 ), N(R 7 )(R 8 ) or C 1 -C 6} ^alkylN _{( R} ^{7 )} _{( R} ^{8 ) or} , when taken together with R ^b , C and forming a C 3 -C ₆ cycloalkyl or heterocycloalkyl, wherein the C ₃ -C ₆ cycloalkyl or heterocycloalkyl is unsubstituted or is selected from halogen, CN, OH, C ₁ -C ₆ alkoxy, _{C 1} -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOH, COOH, oxo, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOC ₁ -C ₆ alkyl, C ₃ -C _{6 cycloalkyl, C 1 -C 6 alkylC 3 -C 6 cycloalkyl, C 1 -C 6 alkyl , -C 1} -C ₆ alkylOhaloC ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) and C substituted with 1 or 2 substituents selected from the group consisting of ₁ - _C6 alkylN(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 alkylCOOH, COOH, oxo, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOC ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkylC ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, -C _{1 -C 6} alkylOH, CON(R ₇ )( _R ⁸ ), _N ( _R ⁷ )(R ⁸ ) or C _{1 -C 6} alkylN(R ⁷ )( ^{R 8 )} or, when taken together with R ^a , is C and forming a C 3 -C ₆ cycloalkyl or heterocycloalkyl, wherein the C ₃ -C ₆ cycloalkyl or heterocycloalkyl is unsubstituted or is selected from halogen, CN, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOH, COOH, oxo, COOC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylCOOC ₁ -C ₆ alkyl, C ₃ -C _{6 cycloalkyl, C 1 -C 6 alkylC 3 -C 6 cycloalkyl , C 1 -C 6} alkyl, -C ₁ -C ₆ alkylOhaloC ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, _CON (R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) and C substituted with 1 to 3 substituents selected from the group consisting of ₁ - _C6 alkylN(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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ), C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ), C ₁ -C ₆ alkyl(OCH ₂ CH ₂ ) _n N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylOHhaloC ₁ -C ₆ alkyl, or when taken together with R ⁴ 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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ), C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ ), C ₁ -C ₆ alkyl(OCH ₂ CH ₂ ) _n N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylOHhaloC 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, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, 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, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, 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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ );
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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ );
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, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ );
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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ );
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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ );
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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ), and C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ );
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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ) or C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ );
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 alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, CON(R ⁷ )(R ⁸ ), N(R ⁷ )(R ⁸ ), and C ₁ -C ₆ alkylN(R ⁷ )(R ⁸ );
m is 0 or 1;
n is 1, 2, 3 or 4; and
p is 0 or 1.
or a pharma- ceutically acceptable salt thereof. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein m is 1, p is 1, and X is O. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein m is 1, p is 1, and X is a bond. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein R ^a together with R ^b form a heterocycloalkyl. R ^a together with R ^b form a heterocycloalkyl, where the heterocycloalkyl is:

2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein said heterocycloalkyl is substituted with two _C1 - _C6 alkyl groups. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein R ^a together with R ^b form a C ₃ -C ₆ cycloalkyl. R ^a together with R ^b form a C ₃ -C ₆ cycloalkyl, where the heterocycloalkyl is:

and wherein C ₃ -C ₆ cycloalkyl is unsubstituted or substituted with OH; or a pharma- ceutically acceptable salt thereof. 2. The compound of claim 1 _{, or a pharma- ceutically acceptable salt thereof, wherein R3 is hydrogen, C1-C6 alkylOC1-C6 alkyl or C1-C6} ^alkyl _{, or when taken together} with ^R4 , forms a _C3 - _C6 heterocycloalkyl. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein ^R3 is hydrogen or _C1 - _C6 alkyl, or, when taken together with ^R4 , forms a _C3 - _C6 heterocycloalkyl. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein ^R3 and ^R4 are both halogen. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein ^R15 is hydrogen or _C1 - _C6 alkyl. R ³ and R ⁴ are independently selected from the group consisting of hydrogen, halogen, OH, C _{1 -C6} alkylOH, C _{1 -C6} alkylalkoxy, C 1 _-C6 alkylOC _{1 -C6} alkyl, C _{1 -C6} alkyl, C _{1 -C6} alkylOHhaloC _{1 -C6} alkyl, CON(C _{1 -C6} alkyl) ₂ , C _{1 -C6} alkylN(R ⁷ )(R ⁸ ) and C _{1 -C6} alkyl(OCH ₂ CH ₂ ) _n N( _R ⁷ )(R ⁸ );
R ⁷ is hydrogen, C ₁ -C ₆ alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, COC ₁ -C ₆ alkyl or COOC ₁ -C ₆ alkyl;
R ⁸ is hydrogen, C ₁ -C ₆ alkylCOOH, COOH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, haloC ₁ -C ₆ alkyl, C ₁ -C ₆ alkylOH, COC ₁ -C ₆ alkyl or COOC ₁ -C ₆ alkyl; and
n is 3;
2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof. 2. The compound of claim 1, or a pharma- _ceutically acceptable salt thereof, wherein ^R12 and ^R13 are independently selected from the group consisting of hydrogen, halogen, OH, _C1 - _C6 alkylOH, _C1 - _C6 alkylalkoxy and _{C1 - C6} alkylOC1-C6 alkyl, _C1 - _C6 alkyl. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein X is C( ^R14 ) ₂ and ^R14 is independently selected from the group consisting of hydrogen, halogen, OH, _C1 - _C6 alkylOH, _C1 - _C6 alkylalkoxy, _{C1 - C6} alkylOC1- _C6 alkyl and _C1 - _C6 alkyl.
The compound or pharma- ceutically acceptable salt thereof according to claims 1-14, wherein Y is CH. The compound or pharma- ceutically acceptable salt thereof according to claims 1-14, wherein Z is CH. The compound or pharma- ceutically acceptable salt thereof according to claims 1-14, wherein V is CH. The compound of any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, wherein A is a straight chain saturated or unsaturated ( _C3 - _C10 ) alkylene. The compound of claims 1-14, or a pharma- ceutically acceptable salt thereof, wherein A is a branched, saturated or unsaturated ( _C3 - _C10 ) alkylene. A,

or a pharma- ceutically acceptable salt thereof. below

or a pharma- ceutically acceptable salt thereof. formula

or a pharma- ceutically acceptable salt thereof. formula

or a pharma- ceutically acceptable salt thereof. formula

or a pharma- ceutically acceptable salt thereof. A method for treating a malaria parasite infection or for treating malaria, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 24 or a pharma- ceutically acceptable salt thereof. A method for inhibiting plasmepsin X, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 24 or a pharma- ceutically acceptable salt thereof. A method for inhibiting plasmepsin IX, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 24 or a pharma- ceutically acceptable salt thereof. A method for dually inhibiting plasmepsin X and plasmepsin X, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 24 or a pharma- ceutical acceptable salt thereof. Use of a compound according to any one of claims 1 to 24, or a pharma- ceutically acceptable salt thereof, for treating a malaria parasite infection or malaria in a patient in need of such treatment. Use of a compound according to any one of claims 1 to 24 or a pharma- ceutically acceptable salt thereof for inhibiting plasmepsin X in a patient in need of such inhibition. Use of a compound according to any one of claims 1 to 24 or a pharma- ceutically acceptable salt thereof for inhibiting plasmepsin IX in a patient in need of such inhibition. Use of the compound of claim 1 or a pharma- ceutically acceptable salt thereof for inhibiting plasmepsin IX and plasmepsin X in a patient in need of such inhibition. A pharmaceutical composition comprising the compound of claim 1 or a pharma- ceutical acceptable salt thereof and a pharma- ceutical acceptable carrier. A pharmaceutical composition comprising the compound of claim 1 and a pharma- ceutical acceptable carrier. A method for treating a malaria parasite infection or for treating malaria, comprising administering a compound according to claim 1 or a pharma- ceutically acceptable salt thereof and an effective amount of one or more additional antimalarial drugs. A method for treating malaria by inhibiting plasmepsin X, plasmepsin IX, and at least one other mechanism, comprising administering a compound of claim 1 or a pharma- ceutically acceptable salt thereof and an effective amount of an additional antimalarial drug, wherein the additional antimalarial drug acts by a mechanism different from inhibition of plasmepsin IX or plasmepsin X.