ANTIMALARIAL AGENTS

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

The present invention relates to compounds of Formula (I), or pharmaceutically acceptable salts thereof, useful for the treatment of Plasmodium infections. More specifically, the present invention relates to compounds of Formula (I), or pharmaceutically acceptable salts thereof, useful for the treatment of Plasmodium infections, more particularly for the treatment of malaria.


BACKGROUND OF THE INVENTION

Malaria is a major disease in humans with several hundred million infections and over 450,000 deaths each year. The most lethal form of malaria is caused by Plasmodium falciparum. This protozoan parasite is responsible for almost all malarial deaths with most occurring in Africa. P. falciparum has a complex life cycle starting in the Anopheles mosquito vector when sporozoite forms are injected into the human host during a blood feed. These sporozoites migrate to the liver and invade hepatocytes in which they develop to form thousands of liver merozoites that egress into the blood where they invade erythrocytes to commence the asexual cycle of the parasite responsible for the symptoms of malaria. The parasite develops within the protected niche of the red cell to form 16-32 merozoites that, once mature, egress from the host cell to invade new red blood cells. Some of these parasites differentiate to form gametocytes, the sexual form of the parasite. These can be taken up by the mosquito where male and female gametes form, fuse and differentiate into oocysts on the mosquito midgut extracellular matrix. Sporozoites form within the oocyst and upon egress migrate to the salivary gland for delivery to the next host during blood feeding for perpetuation and survival of the parasite.


Other forms of malaria include a relapsing form of malaria caused by P. vivax which is responsible for significant morbidity, can cause virulent forms of this disease with some deaths and is mainly a problem outside Africa. P. knowlesi is found in South East Asia and is a zoonotic parasite that normally infects long-tailed macaques but has been shown to infect humans in Malaysian Borneo.


Artemisinin combined with partner drugs have become a mainstay in the treatment and control of malaria. Currently, the WHO recommend artemisinin-based combinations (ACTs) for treatment of uncomplicated malaria caused by P. falciparum. These are very effective; however, ACT resistance is now leading to treatment failures in the Greater Mekong Subregion (GMS) and the prospect of spread outside this region is extremely concerning. However, due to the increasing threat of artemisinin-based combination therapy (ACT) drug resistance, the development of new antimalarials with novel targets that inhibit multiple steps in the parasite life cycle is an urgent priority for the malaria control field. Such novel antimalarials, as monotherapies or ACT partner drugs, could make strides towards malaria elimination as there is a reduced likelihood of parasites with preexisting resistance mutations being present in the parasite population.


Currently, aspartic acid proteases are prime targets for drug development: the HIV aspartic acid protease has been successfully targeted with a drug in clinical use; inhibitors that target human renin, BACE1 and gamma-secretase have been or are in clinical development. In the antimalarial drug space, P. falciparum aspartic acid proteases plasmepsin X and IX (PMX and PMIX) have been identified as potential targets since inhibitors block parasite egress and invasion of the host cell and prevent maturation of some rhoptry and micronemal proteins required for this process (Pino P, Caldelari R, Mukherjee B, Vahokoski J, Klages N, Maco B, et al. A multistage antimalarial targets the plasmepsins IX and X essential for invasion and egress. Science. 2017; 358(6362):522-8.)


SUMMARY OF THE INVENTION

The present invention is directed to compounds of Formula (I):




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wherein R1, R2, R3, R4, R5, R6 and R9 are described below.


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


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


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


Moreover, the present invention provides methods for the use of pharmaceutical compositions comprising one or more of said compounds in the free form or in pharmaceutically acceptable salt form, together with one or more customary pharmaceutical excipient(s), for the treatment of Plasmodium infections, the treatment of malaria, the inhibition of plasmepsin X, or, possibly in some embodiments, the dual inhibition of plasmepsin X and plasmepsin IX. Methods for the use of combinations of the compounds or salts of the invention together with one or more additional pharmaceutically active agents are also provided.


The present invention may further provide methods for the inhibition of plasmepsin X, or dual inhibition of plasmepsin X and plasmepsin IX activity and for treatment, prevention, amelioration and/or delaying onset of diseases or disorders in which the inhibition of plasmepsin X and/or plasmepsin IX has or may have a therapeutic effect, e.g. malaria.


The present invention further provides methods for the inhibition of P. falciparum aspartic acid proteases. The present invention may further provide methods for blocking P. falciparum growth by inhibiting Plasmepsin X. The present invention may further provide methods for blocking P. falciparum growth by inhibiting both Plasmepsin X and Plasmepsin IX. In certain embodiments, the present invention may provide a method for blocking P. falciparum growth in an animal, preferably a human, comprising administering to the animal an inhibitor of Plasmepsin IX and Plasmepsin X or a pharmaceutically acceptable salt thereof.


The present invention may further provide methods for the treatment of malaria by inhibiting plasmepsin X. The present invention may further provide methods for the treatment of malaria by inhibiting both Plasmepsin X and Plasmepsin IX. In certain embodiments, the present invention may provide a method for treating malaria in an animal, preferably a human, comprising administering to the animal an inhibitor of Plasmepsin IX and Plasmepsin X or a pharmaceutically acceptable salt thereof.


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







DETAILED DESCRIPTION OF THE INVENTION

Described herein are compounds having the structural Formula (I):




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or a pharmaceutically acceptable salt thereof, wherein:


R1 is a heterocycloalkyl, C3-C12cycloalkyl, aryl, C1-C6alkylaryl, wherein the heterocycloalkyl, C3-C12cycloalkyl, aryl or C1-C6alkylaryl is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OH, alkoxy, haloalkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C3-C6cycloalkyl, spiroC3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) and C1-C6alkylN(R7)(R8);


R2 is hydrogen, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl or C1-C6alkylOH;


R3 is hydrogen, halogen, CN, OH, C3-C6cycloalkyl or C1-C6alkyl;


R4 is hydrogen, halogen, CN, OH, C3-C6cycloalkyl or C1-C6alkyl;


R5 is hydrogen, halogen, CN, OH, alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) or C1-C6alkylN(R7)(R8) or when taken with R6 forms a C3-C6cycloalkyl or C3-C6heterocycloalkyl;


R6 is hydrogen, halogen, CN, OH, alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) or C1-C6alkylN(R7)(R8) or when taken with R5 forms a C3-C6cycloalkyl or C3-C6heterocycloalkyl;


R7 is hydrogen, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl or C1-C6alkylOH;


R8 is hydrogen, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl or C1-C6alkylOH; and


R9 is hydrogen, halogen, CN, alkoxy, C1-C6alkyl, heterocycloalkyl, heteroaryl, C3-C12cycloalkyl, aryl, COOH, oxo, COOC1-C6alkyl, haloC1-C6alkyl, OH, CON(R7)(R8) and N(R7)(R8), wherein the C1-C6alkyl can be unsubstituted or substituted with one, two or three substituents selected from the group consisting of halogen, CN, OH, alkoxy, heterocycloalkyl, heteroaryl, C3-C12cycloalkyl, aryl, COOH, oxo, COOC1-C6alkyl, haloC1-C6alkyl, OH, CON(R7)(R8) and N(R7)(R8), and wherein the heterocycloalkyl, heteroaryl, C3-C12cycloalkyl and aryl can be unsubstituted or substituted with one, two or three substituents selected from the group consisting of halogen, CN, OH, alkoxy, C1-C6alkyl, COOH, oxo, COOC1-C6alkyl, haloC1-C6alkyl, OH, CON(R7)(R8) and N(R7)(R8).


In the embodiments described herein, R1 is a heterocycloalkyl, C3-C12cycloalkyl, aryl, C1-C6alkylaryl, wherein the heterocycloalkyl, C3-C12cycloalkyl, aryl or C1-C6alkylaryl is unsubstituted or substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OH, alkoxy, haloalkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C3-C6cycloalkyl, spiroC3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) and C1-C6alkylN(R7)(R8).


In certain embodiments, R1 is a bicyclic ring. In certain embodiments, R1 is a bicyclic heterocycloalkyl, bicyclic C3-C12cycloalkyl or bicyclic aryl ring. In certain embodiments, R1 is a fused bycyclic ring having an A ring fused with a B ring, wherein the A ring is a 5, 6 or 7-membered saturated ring and the B ring is a phenyl or a 5 or 6-membered heteroaryl ring. In certain embodiments, the A ring includes at least one O, N, or S. In certain embodiments, the A ring includes at least one 0.


In certain embodiments, R1 is a heterocycloalkyl. 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 oxides thereof. Non-limiting examples of bicyclic heterocycloalkyl groups include, but are not limited to,




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In certain embodiments, R1 is a C3-C2cycloalkyl. In certain embodiments, the cycloalkyl is a monocyclic cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, the cycloalkyl is a bicyclic cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to:




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In certain embodiments, R1 is an aryl ring. Suitable examples of aryls include, but are not limited to, monocyclic aryl groups such as, phenyl and bicyclic aryl groups such as naphthyl.


In certain embodiments, R1 is a C1-C6alkylaryl ring. Suitable examples of C1-C6alkylaryls include, but are not limited to:




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In certain embodiments, R1 is a chomane or indane.


In certain embodiments, R1 is unsubstituted. In other embodiments, R1 is substituted with 1 to 5 substituents independently selected from the group consisting of halogen, CN, OH, alkoxy, haloalkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C3-C6cycloalkyl, spiroC3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) and C1-C6alkylN(R7)(R8). In certain embodiments, R1 is substituted with 1 substituent. In certain embodiments, R1 is substituted with 2 substituents. In certain embodiments, R1 is substituted with 3 substituents. In certain embodiments, R1 is substituted with 4 substituents. In certain embodiments, R1 is substituted with 5 substituents.


In certain embodiments, R1 is substituted with halogen. Examples of suitable halogens include, but are not limited to, chlorine, bromine, fluorine and iodine. In certain embodiments, R1 is substituted with CN. In certain embodiments, R1 is substituted with OH. In certain embodiments, R1 is substituted with an oxo group.


In certain embodiments, R1 is substituted with alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R1 is substituted with C1-C6alkylOC1-C6alkyl. In certain embodiments, R1 is substituted with haloalkoxy. Suitable haloalkoxys include, but are not limited to, trifluoromethoxy, fluoromethoxy and difluoromethoxy. In certain embodiments, R1 is substituted with C1-C6alkylOC1-C6alkyl. Suitable C1-C6alkylOC1-C6alkyls include, but are not limited to, CH2OCH3. In certain embodiments, R1 is substituted with C1-C6alkylCOOH. In certain embodiments, R1 is substituted with COOH. In certain embodiments, R1 is substituted with C1-C6alkylCOOC1-C6alkyl.


In certain embodiments, R1 is substituted with C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R1 is substituted with cyclopropyl:




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In certain embodiments, R1 is substituted with spiroC3-C6cycloalkyl. Suitable examples of spirocycloalkyls include, but are not limited to, spirocyclopropyl, spirocyclobutyl, spirocyclopentyl and spirocyclohexyl. In certain embodiments, R1 is substituted with spirocyclobutyl:




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In certain embodiments, R1 is substituted with C1-C6alkyl. Examples of C1-C6alkyl groups can 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, R1 is substituted with haloC1-C6alkyl. Suitable examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R1 is substituted with C1-C6alkylOH. Examples of suitable alcohols, include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R1 is substituted with CON(R7)(R8). In certain embodiments, R1 is substituted with N(R7)(R8). In certain embodiments, R1 is substituted with C1-C6alkylN(R7)(R8), wherein R7 and R8 will be described in detail below.


In certain embodiments, R1 is substituted with 1 to 4 substituents selected independently from the group consisting of bromine, fluorine, chlorine, methyl, ethyl, t-butyl, methoxy, OH, CN oxo, CH2OCH3, cyclopropyl, spirocyclobutyl, trifluoromethoxy and trifluoromethyl.


In certain embodiments, R1 is




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and is substituted with 1 to 4 substituents selected independently from the group consisting of bromine, fluorine, chlorine, methyl, ethyl, t-butyl, methoxy, OH, CN oxo, CH2OCH3, cyclopropyl, spirocyclobutyl, trifluoromethoxy and trifluoromethyl.


In certain embodiments, R1 is




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and is substituted with 1 to 4 substituents selected independently from the group consisting of bromine, fluorine, chlorine, methyl, ethyl, t-butyl, methoxy, OH, CN oxo, CH2OCH3, cyclopropyl, spirocyclobutyl, trifluoromethoxy and trifluoromethyl.


In certain embodiments, R1 is




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and is substituted with 1 to 4 substituents selected independently from the group consisting of bromine, fluorine, chlorine, methyl, ethyl, t-butyl, methoxy, OH, CN oxo, CH2OCH3, cyclopropyl, spirocyclobutyl, trifluoromethoxy and trifluoromethyl. In certain embodiments described herein, R2 is hydrogen, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl or C1-C6alkylOH. In certain embodiments, R2 is hydrogen. In certain embodiments, R2 is C1-C6alkylCOOH. In certain embodiments, R2 is COOH. In certain embodiments, R2 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R2 is C1-C6alkyl. Examples of C1-C6alkyl groups can 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, R2 is haloC1-C6alkyl. Suitable examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R2 is C1-C6alkylOH. Examples of suitable alcohols, include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol.


With regard to the compounds described herein, R3 is hydrogen, halogen, CN, OH, C3-C6cycloalkyl or C1-C6alkyl. In certain embodiments, R3 is hydrogen. In certain embodiments, R3 is halogen. Suitable halogens include, but are not limited to, fluorine, chlorine, bromine, or iodine. In certain embodiments, R3 is CN. In certain embodiments, R3 is OH.


In certain embodiments, R3 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R3 is C1-C6alkyl. Examples of C1-C6alkyl groups can 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, R3 is hydrogen, fluorine, methyl, ethyl or




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In certain embodiments, R3 is taken with R4 to form oxetanyl.


With regard to the compounds described herein, R4 is hydrogen, halogen, CN, OH, C3-C6cycloalkyl or C1-C6alkyl. In certain embodiments, R4 is hydrogen. In certain embodiments, R4 is halogen. Suitable halogens include, but are not limited to, fluorine, chlorine, bromine, or iodine. In certain embodiments, R4 is CN. In certain embodiments, R4 is OH.


In certain embodiments, R4 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R4 is C1-C6alkyl. Examples of C1-C6alkyl groups can 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, R4 is hydrogen, methyl, or fluorine. In certain embodiments, R3 and R4 are both hydrogen, methyl or fluorine.


In certain embodiments, R3 is hydrogen and R4 is hydrogen, methyl or fluorine.


With regard to the compounds described herein, R5 is hydrogen, halogen, CN, OH, alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) or C1-C6alkylN(R7)(R8) or when taken with R6 forms a C3-C6cycloalkyl or C3-C6heterocycloalkyl. In certain embodiments, R5 is hydrogen. In certain embodiments, R5 is halogen. Suitable halogens include, but are not limited to, fluorine, chlorine, bromine, or iodine. In certain embodiments, R5 is CN. In certain embodiments, R5 is OH.


In certain embodiments, R5 is alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R5 is C1-C6alkylOC1-C6alkyl. In certain embodiments, R5 is COOH. In certain embodiments, R5 is C1-C6alkylCOOH. In certain embodiments, R5 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R5 is C1-C6alkyl. Examples of C1-C6alkyl groups can 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, R5 is haloC1-C6alkyl. Suitable examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R5 is C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R5 is CON(R7)(R8). In certain embodiments, R5 is N(R7)(R8). In certain embodiments, R5 is C1-C6alkylN(R7)(R8). R7 and R8 will be discussed in detail below.


In certain embodiments, R5 is taken with R6 and forms a C3-C6cycloalkyl or C3-C6heterocycloalkyl. In certain embodiments, R5 is taken with R6 and forms a C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R5 is taken with R6 and forms a C3-C6heterocycloalkyl. Suitable examples of heterocycloalkyls include, but are not limited to, 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 oxides thereof.


In certain embodiments, R5 is methyl, ethyl or t-butyl.


With regard to the compounds described herein, R6 is hydrogen, halogen, CN, OH, alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) or C1-C6alkylN(R7)(R8) or when taken with R5 forms a C3-C6cycloalkyl or C3-C6heterocycloalkyl. In certain embodiments, R6 is hydrogen. In certain embodiments, R6 is halogen. Suitable halogens include, but are not limited to, fluorine, chlorine, bromine, or iodine. In certain embodiments, R6 is CN. In certain embodiments, R6 is OH.


In certain embodiments, R6 is alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R6 is C1-C6alkylOC1-C6alkyl. In certain embodiments, R6 is COOH. In certain embodiments, R6 is C1-C6alkylCOOH. In certain embodiments, R6 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R6 is C1-C6alkyl. Examples of C1-C6alkyl groups can 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, R6 is haloC1-C6alkyl. Suitable examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R6 is C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R6 is CON(R7)(R8). In certain embodiments, R6 is N(R7)(R8). In certain embodiments, R6 is C1-C6alkylN(R7)(R8). R7 and R8 will be discussed in detail below.


In certain embodiments, R6 is taken with R5 and forms a C3-C6cycloalkyl or C3-C6heterocycloalkyl. In certain embodiments, R6 is taken with R5 and forms a C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R6 is taken with R5 and forms a C3-C6heterocycloalkyl. Suitable examples of heterocycloalkyls include, but are not limited to, 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 oxides thereof.


In certain embodiments, R6 is methyl, ethyl or t-butyl.


With regard to the compounds described herein, R7 is hydrogen, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl or C1-C6alkylOH.


In certain embodiments, R7 is hydrogen. In certain embodiments, R7 is C1-C6alkylCOOH. In certain embodiments, R7 is COOH. In certain embodiments, R7 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R7 is C1-C6alkyl. Examples of C1-C6alkyl groups can 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, R7 is haloC1-C6alkyl. Suitable examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R7 is C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol.


With regard to the compounds described herein, R8 is hydrogen, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl or C1-C6alkylOH.


In certain embodiments, R8 is hydrogen. In certain embodiments, R8 is C1-C6alkylCOOH. In certain embodiments, R8 is COOH. In certain embodiments, R8 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R8 is C1-C6alkyl. Examples of C1-C6alkyl groups can 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, R8 is haloC1-C6alkyl. Suitable examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R8 is C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol.


With regard to the compounds described herein, R9 is hydrogen, halogen, CN, OH, alkoxy, C1-C6alkyl, heterocycloalkyl, heteroaryl, C3-C12cycloalkyl, aryl, COOH, oxo, COOC1-C6alkyl, haloC1-C6alkyl, OH, CON(R7)(R8) and N(R7)(R8), wherein the C1-C6alkyl can be unsubstituted or substituted with one, two or three substituents selected from the group consisting of halogen, CN, OH, alkoxy, heterocycloalkyl, heteroaryl, C3-C12cycloalkyl, aryl, COOH, oxo, COOC1-C6alkyl, haloC1-C6alkyl, OH, CON(R7)(R8) and N(R7)(R8), and wherein the heterocycloalkyl, heteroaryl, C3-C12cycloalkyl and aryl can be unsubstituted or substituted with one, two or three substituents selected from the group consisting of halogen, CN, OH, alkoxy, C1-C6alkyl, COOH, oxo, COOC1-C6alkyl, haloC1-C6alkyl, OH, CON(R7)(R8) and N(R7)(R8).


In certain embodiments, R9 is hydrogen. In certain embodiments, R9 is halogen. Suitable halogens include, but are not limited to, fluorine, chlorine, bromine, or iodine. In certain embodiments, R9 is CN.


In certain embodiments, R9 is alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R9 is C1-C6alkyl. Examples of C1-C6alkyl groups can 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, R9 is haloC1-C6alkyl. Suitable examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl.


In certain embodiments, R9 is a heterocycloalkyl. 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 oxides thereof. In certain embodiments, R9 is a heteroaryl group. Suitable heteroaryls include, but are not limited to, pyridyl (pyridinyl), imidazolyl, triazolyl, triazinyl, pyrimidyl, pyridazinyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl, isoquinolyl. In certain embodiments, R9 is a pyridine.


In certain embodiments, R9 is a C3-C12cycloalkyl. In certain embodiments, the cycloalkyl is a monocyclic cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, the cycloalkyl is a bicyclic cycloalkyl.


In certain embodiments, R9 is an aryl ring. Suitable examples of aryls include, but are not limited to, monocyclic aryl groups such as, phenyl and bicyclic aryl groups such as naphthyl.


In certain embodiments, R9 is COOH. In certain embodiments, R9 is oxo. In certain embodiments, R9 is C1-C6alkylCOOC1-C6alkyl. In certain embodiments, R9 is haloC1-C6alkyl.


Suitable examples of haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2-difluoroethyl and 2,2-difluoroethyl. In certain embodiments, R9 is CON(R7)(R8). In certain embodiments, R9 is N(R7)(R8). In certain embodiments, R9 is C1-C6alkylN(R7)(R8).


In certain embodiments, R9 is unsubstituted or substituted. In certain embodiments, when R9 is C1-C6alkyl, C1-C6alkyl can be unsubstituted or substituted with one, two or three substituents selected from the group consisting of halogen, CN, OH, alkoxy, heterocycloalkyl, heteroaryl, C3-C12cycloalkyl, aryl, COOH, oxo, COOC1-C6alkyl, haloC1-C6alkyl, OH, CON(R7)(R8) and N(R7)(R8). In certain embodiments, R9 is




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In certain embodiments, R9 is




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In certain embodiments, when R9 is heterocycloalkyl, heteroaryl, C3-C12cycloalkyl or aryl, the heterocycloalkyl, heteroaryl, C3-C12cycloalkyl or aryl the can be unsubstituted or substituted with one, two or three substituents selected from the group consisting of halogen, CN, OH, alkoxy, C1-C6alkyl, COOH, oxo, COOC1-C6alkyl, haloC1-C6alkyl, OH, CON(R7)(R8) and N(R7)(R8). In certain embodiments, R9 is pyridine substituted with fluorine, chlorine or methoxy. In certain embodiments, R9 is phenyl substituted with CN.


Also described herein are compounds of Formula (IA), (IB), (IC) and (ID):




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wherein R3, R4, R5, R6 and R9 are as described above;


R10 is halogen, OH, alkoxy, haloalkoxy, C1-C6alkylOC1-C6alkyl, C3-C6cycloalkyl, spiroC3-C6cycloalkyl, C1-C6alkyl or haloC1-C6alkyl;


R11 is OH or C1-C6alkyl;


R12 is C1-C6alkyl; and


m, n and q are independently 0, 1, 2, 3 or 4.


In each of the various embodiments of the invention, in the compounds used in the methods herein, each variable (including those in each of Formula (I), (IA), (IB), (IC) and (ID), and the various embodiments thereof) it shall be understood that each variable is to be selected independently of the others unless otherwise indicated.


In each of the various embodiments of the invention, the compounds described herein, including those in each of Formula (I), (IA), (IB), (IC) and (ID) and the various embodiments thereof, may exit in different forms of the compounds such as, for example, any solvates, hydrates, stereoisomers, and tautomers of said compounds and of any pharmaceutically acceptable salts thereof.


In certain embodiments, compounds described herein include:




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The compounds described and exemplified herein, can also be described using IUPAC nomenclature:

  • [1-[1-[(1R,2R)-2-[[(4S)-2,2-dimethylchroman-4-yl]carbamoyl]cyclopropyl]-3-methoxy-propyl]-4,4-diethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[1-[(1R,2R)-2-[[(4R)-2,2-dimethylchroman-4-yl]carbamoyl]cyclopropyl]-3-methoxy-propyl]-4,4-diethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[(1R,2R)-2-[[(4S)-2,2-dimethylchroman-4-yl]carbamoyl]cyclopropyl]-pyridin-1-ium-3-yl-methyl]-4,4-diethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [4,4-diethyl-6-oxo-1-[[(1S,2S)-2-[[(1S)-1-phenylethyl]carbamoyl]cyclopropyl]methyl]hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [4,4-diethyl-6-oxo-1-[[2-[[(1R)-1-phenylethyl]carbamoyl]cyclopropyl]methyl]hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[(1S,2S)-2-[[(4S)-chroman-4-yl]carbamoyl]cyclopropyl]methyl]-4,4-diethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[(1S,2S)-2-[[(4R)-chroman-4-yl]carbamoyl]cyclopropyl]methyl]-4,4-diethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[2-[[(4S)-chroman-4-yl]carbamoyl]cyclopropyl]methyl]-4,4-diethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[(1R,2R)-2-[[(4S)-2,2-dimethylchroman-4-yl]carbamoyl]cyclopropyl]methyl]-4,4-diethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [4,4-diethyl-1-[[(1S,2S)-2-[[(1R,2R)-2-hydroxyindan-1-yl]carbamoyl]cyclopropyl]methyl]-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [4,4-diethyl-1-[[(1R,2R)-2-[(6-fluoro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]methyl]-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [4,4-diethyl-6-oxo-1-[[(1R,2R)-2-[[2-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]methyl]hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • (1R,2R)—N-[(4S)-chroman-4-yl]-2-[(4,4-diethyl-2-imino-6-oxo-hexahydropyrimidin-1-yl)-(3-pyridyl)methyl]cyclopropanecarboxamide;
  • (1R,2R)-2-[(4,4-diethyl-2-imino-6-oxo-hexahydropyrimidin-1-yl)-(3-pyridyl)methyl]-N-[(1R,2R)-2-hydroxyindan-1-yl]cyclopropanecarboxamide;
  • [4,4-diethyl-1-[[(1R,2R)-2-[(3-hydroxy-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-pyridin-1-ium-3-yl-methyl]-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [4,4-diethyl-6-oxo-1-[pyridin-1-ium-3-yl-[(1R,2R)-2-[[(2R,4S)-2-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]methyl]hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [4,4-diethyl-1-[1-[(1R,2R)-2-[[(1R,2R)-2-hydroxyindan-1-yl]carbamoyl]cyclopropyl]-3-methoxy-propyl]-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [4,4-diethyl-1-[3-methoxy-1-[(1R,2R)-2-[[(2R,4S)-2-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]propyl]-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[3-[[(4S)-chroman-4-yl]carbamoyl]-2,2-difluoro-cyclopropyl]methyl]-4,4-diethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[3-[[(4R)-chroman-4-yl]carbamoyl]-2,2-difluoro-cyclopropyl]methyl]-4,4-diethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[3-[[(4S)-2,2-dimethylchroman-4-yl]carbamoyl]-2,2-difluoro-cyclopropyl]methyl]-4,4-diethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[3-[[(4R)-2,2-dimethylchroman-4-yl]carbamoyl]-2,2-difluoro-cyclopropyl]methyl]-4,4-diethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[2,2-difluoro-3-[[(2R,4S)-2-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]methyl]-4,4-diethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[2,2-difluoro-3-[[(2R,4R)-2-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]methyl]-4,4-diethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[2,2-difluoro-3-[[(3S,4R)-3-hydroxy-2,2-dimethyl-chroman-4-yl]carbamoyl]cyclopropyl]methyl]-4,4-diethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[2,2-difluoro-3-[[(3S,4S)-3-hydroxy-2,2-dimethyl-chroman-4-yl]carbamoyl]cyclopropyl]methyl]-4,4-diethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[1-[(1R,2R)-2-[(3,3-dimethylchroman-4-yl)carbamoyl]cyclopropyl]-3-methoxy-propyl]-4,4-diethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [(4S)-1-[1-[(1R,2R)-2-[[(4S)-2,2-dimethylchroman-4-yl]carbamoyl]cyclopropyl]-3-methoxy-propyl]-4-isopropyl-4-methyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [(4R)-4-isopropyl-1-[3-methoxy-1-[(1R,2R)-2-[[(2R,4S)-2-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]propyl]-4-methyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [(4S)-4-isopropyl-1-[3-methoxy-1-[(1R,2R)-2-[[(2R,4S)-2-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]propyl]-4-methyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [(4R)-1-[1-[(1R,2R)-2-[[(4S)-chroman-4-yl]carbamoyl]cyclopropyl]-3-methoxy-propyl]-4-isopropyl-4-methyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1R)-1-[(1R,2R)-2-[[(4R)-2,2-dimethylchroman-4-yl]carbamoyl]cyclopropyl]-3-methoxy-propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1S)-[(1R,2R)-2-[[(4S)-2,2-dimethylchroman-4-yl]carbamoyl]cyclopropyl]-3-methoxy-propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1R)-3-methoxy-1-[(1R,2R)-2-[[(2S,4R)-2-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[3-methoxy-1-[(1R,2R)-2-[[(2R,4S)-2-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[3-methoxy-1-[(1R,2R)-2-[[(2R,4R)-2-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[2-[[(4S)-2,2-dimethylchroman-4-yl]carbamoyl]-3-methyl-cyclopropyl]methyl]-4,4-diethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[2-[[(4R)-2,2-dimethylchroman-4-yl]carbamoyl]-3-methyl-cyclopropyl]methyl]-4,4-diethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[(1R,2R)-2-[[(4S)-2,2-dimethylchroman-4-yl]carbamoyl]cyclopropyl]-pyridin-1-ium-3-yl-methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[(1R,2R)-2-[[(3 S,4R)-3-hydroxy-2,2-dimethyl-chroman-4-yl]carbamoyl]cyclopropyl]-pyridin-1-ium-3-yl-methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [4,4-diethyl-1-[[2-methyl-3-[[(2R,4S)-2-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]methyl]-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [4,4-diethyl-1-[[2-methyl-3-[[(2R,4R)-2-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]methyl]-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • 2-[(4,4-diethyl-2-imino-6-oxo-hexahydropyrimidin-1-yl)methyl]-N-[(1R,2S)-2-hydroxy-2-methyl-indan-1-yl]-3-methyl-cyclopropanecarboxamide;
  • 2-[(4,4-diethyl-2-imino-6-oxo-hexahydropyrimidin-1-yl)methyl]-N-[(1R,2R)-2-hydroxy-2-methyl-indan-1-yl]-3-methyl-cyclopropanecarboxamide;
  • 2-[(4,4-diethyl-2-imino-6-oxo-hexahydropyrimidin-1-yl)methyl]-N-[(1S,2S)-2-hydroxy-2-methyl-indan-1-yl]-3-methyl-cyclopropanecarboxamide;
  • [4,4-diethyl-1-[[2-[[(3S,4R)-3-hydroxy-2,2-dimethyl-chroman-4-yl]carbamoyl]-3-methyl-cyclopropyl]methyl]-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [4,4-diethyl-1-[[2-[[(3R,4R)-3-hydroxy-2,2-dimethyl-chroman-4-yl]carbamoyl]-3-methyl-cyclopropyl]methyl]-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[2,2-dimethyl-3-[[(2R,4S)-2-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]methyl]-4,4-diethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • 3-[(4,4-diethyl-2-imino-6-oxo-hexahydropyrimidin-1-yl)methyl]-2,2-dimethyl-N-[(2R,4S)-2-(trifluoromethyl)chroman-4-yl]cyclopropanecarboxamide;
  • [4,4-dimethyl-6-oxo-1-[pyridin-1-ium-3-yl-[(1R,2R)-2-[[(2R,4S)-2-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]methyl]hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [4,4-diethyl-1-[[2-[[(1R,2R)-2-hydroxyindan-1-yl]carbamoyl]-3-methyl-cyclopropyl]methyl]-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • 3-[(4,4-diethyl-2-imino-6-oxo-hexahydropyrimidin-1-yl)methyl]-N-[(4S)-2,2-dimethylchroman-4-yl]-2,2-dimethyl-cyclopropanecarboxamide;
  • 2-[(4,4-diethyl-2-imino-6-oxo-hexahydropyrimidin-1-yl)methyl]-N-[(3R,4R)-3-hydroxy-3-methyl-chroman-4-yl]-3-methyl-cyclopropanecarboxamide;
  • 2-[(4,4-diethyl-2-imino-6-oxo-hexahydropyrimidin-1-yl)methyl]-N-[(3S,4R)-3-hydroxy-3-methyl-chroman-4-yl]-3-methyl-cyclopropanecarboxamide;
  • [1-[[(2S)-[(2,2-dimethyl-3H-benzofuran-3-yl)carbamoyl]-3-methyl-cyclopropyl]methyl]-4,4-diethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[(2R)-[(2,2-dimethyl-3H-benzofuran-3-yl)carbamoyl]-3-methyl-cyclopropyl]methyl]-4,4-diethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(6-methoxy-3-pyridyl)-[(1R,2R)-2-[[(2R,4S)-2-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[(1R,2R)-2-[[(4S)-2,2-dimethylchroman-4-yl]carbamoyl]cyclopropyl]-(6-methoxy-3-pyridyl)methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[(1R,2R)-2-[[(3 S,4R)-3-hydroxy-2,2-dimethyl-chroman-4-yl]carbamoyl]cyclopropyl]-(6-methoxy-3-pyridyl)methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[(1R,2R)-2-[[(4R)-2,2-dimethylchroman-4-yl]carbamoyl]cyclopropyl]-(5-methoxy-3-pyridyl)methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(5-methoxy-3-pyridyl)-[(1R,2R)-2-[[(2R,4S)-2-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[(1R,2R)-2-[[(3S,4R)-3-hydroxy-2,2-dimethyl-chroman-4-yl]carbamoyl]cyclopropyl]-(5-methoxy-3-pyridyl)methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[2,2-dimethyl-3-[[(2R,4S)-2-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]-pyridin-1-ium-3-yl-methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[2,2-dimethyl-3-[[(2R,4R)-2-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]-pyridin-1-ium-3-yl-methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[2,2-dimethyl-3-[[(2S,4S)-2-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]-pyridin-1-ium-3-yl-methyl]-4,4-diethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[2,2-dimethyl-3-[[(2S,4R)-2-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]-pyridin-1-ium-3-yl-methyl]-4,4-diethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(4-cyanophenyl)-[(1R,2R)-2-[[(4S)-2,2-dimethylchroman-4-yl]carbamoyl]cyclopropyl]methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(4-cyanophenyl)-[(1R,2R)-2-[[(4R)-2,2-dimethylchroman-4-yl]carbamoyl]cyclopropyl]methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(4-cyanophenyl)-[(1R,2R)-2-[[(3S,4R)-3-hydroxy-2,2-dimethyl-chroman-4-yl]carbamoyl]cyclopropyl]methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(4-cyanophenyl)-[(1R,2R)-2-[[(2R,4S)-2-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(4-cyanophenyl)-[(1R,2R)-2-[[(2R,4R)-2-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[3-[[(4S)-2,2-dimethylchroman-4-yl]carbamoyl]-2,2-dimethyl-cyclopropyl]-pyridin-1-ium-3-yl-methyl]-4,4-diethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[3-[[(4R)-2,2-dimethylchroman-4-yl]carbamoyl]-2,2-dimethyl-cyclopropyl]-pyridin-1-ium-3-yl-methyl]-4,4-diethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(3-cyanophenyl)-[(1R,2R)-2-[[(4S)-2,2-dimethylchroman-4-yl]carbamoyl]cyclopropyl]methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(3-cyanophenyl)-[(1R,2R)-2-[[(3 S,4R)-3-hydroxy-2,2-dimethyl-chroman-4-yl]carbamoyl]cyclopropyl]methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(3-cyanophenyl)-[(1R,2R)-2-[[(2R,4S)-2-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(3-cyanophenyl)-[(1R,2R)-2-[(6-fluoro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [4,4-dimethyl-1-[[2-methyl-3-[[(2R,4S)-2-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]-pyridin-1-ium-3-yl-methyl]-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [4,4-diethyl-1-[[2-methyl-3-[[(2R,4S)-2-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]-pyridin-1-ium-3-yl-methyl]-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [4,4-diethyl-1-[[2-methyl-3-[[(2R,4S)-2-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]-pyridin-1-ium-3-yl-methyl]-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[2-[[(4S)-2,2-dimethylchroman-4-yl]carbamoyl]-3-methyl-cyclopropyl]-pyridin-1-ium-3-yl-methyl]-4,4-diethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[2-[[(4R)-2,2-dimethylchroman-4-yl]carbamoyl]-3-methyl-cyclopropyl]-pyridin-1-ium-3-yl-methyl]-4,4-diethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(5-chloro-3-pyridyl)-[(1R,2R)-2-[[(4S)-2,2-dimethylchroman-4-yl]carbamoyl]cyclopropyl]methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(5-chloro-3-pyridyl)-[(1R,2R)-2-[[(4R)-2,2-dimethylchroman-4-yl]carbamoyl]cyclopropyl]methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(5-chloro-3-pyridyl)-[(1R,2R)-2-[[(3 S,4R)-3-hydroxy-2,2-dimethyl-chroman-4-yl]carbamoyl]cyclopropyl]methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(5-chloro-3-pyridyl)-[(1R,2R)-2-[[(2R,4S)-2-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(5-chloro-3-pyridyl)-[(1R,2R)-2-[[(2R,4R)-2-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [(4R)-4-ethyl-1-[1-[(1R,2R)-2-[[(3S,4R)-3-hydroxy-2,2-dimethyl-chroman-4-yl]carbamoyl]cyclopropyl]-3-methoxy-propyl]-4-methyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [(4R)-4-ethyl-1-[3-methoxy-1-[(1R,2R)-2-[[(2R,4S)-2-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]propyl]-4-methyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [(4R)-4-ethyl-1-[3-methoxy-1-[(1R,2R)-2-[[(2R,4S)-2-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]propyl]-4-methyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [(4R)-1-[[(1R,2R)-2-[[(4S)-2,2-dimethylchroman-4-yl]carbamoyl]cyclopropyl]-pyridin-1-ium-3-yl-methyl]-4-ethyl-4-methyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [(4R)-1-[1-[(1R,2R)-2-[[(4R)-2,2-dimethylchroman-4-yl]carbamoyl]cyclopropyl]-3-methoxy-propyl]-4-ethyl-4-methyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [(4S)-1-[1-[(1R,2R)-2-[[(4S)-2,2-dimethylchroman-4-yl]carbamoyl]cyclopropyl]-3-methoxy-propyl]-4-ethyl-4-methyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[(1R,2R)-2-[(7-methoxy-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-pyridin-1-ium-3-yl-methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [(4R)-4-ethyl-1-[(5-fluoro-3-pyridyl)-[(1R,2R)-2-[[(3 S,4R)-3-hydroxy-2,2-dimethyl-chroman-4-yl]carbamoyl]cyclopropyl]methyl]-4-methyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [(4S)-1-[[(1R,2R)-2-[[(4S)-2,2-dimethylchroman-4-yl]carbamoyl]cyclopropyl]-(5-fluoro-3-pyridyl)methyl]-4-ethyl-4-methyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [(4R)-1-[[(1R,2R)-2-[[(4R)-2,2-dimethylchroman-4-yl]carbamoyl]cyclopropyl]-(5-fluoro-3-pyridyl)methyl]-4-ethyl-4-methyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [(4R)-4-ethyl-1-[(5-fluoro-3-pyridyl)-[(1R,2R)-2-[[(2R,4S)-2-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]methyl]-4-methyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [(4S)-4-ethyl-1-[[(1R,2R)-2-[(6-fluoro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-(5-fluoro-3-pyridyl)methyl]-4-methyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [(4R)-4-ethyl-1-[[(1R,2R)-2-[(6-fluoro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-(5-fluoro-3-pyridyl)methyl]-4-methyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[3-methoxy-1-[(1R,2R)-2-[(7-methoxy-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[(1R,2R)-2-[(6-fluoro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[(1R,2R)-2-[(5-methoxy-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1R)-3-methoxy-1-[(1R,2R)-2-[(5-methoxy-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1S)-3-methoxy-1-[(1R,2R)-2-[(5-methoxy-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1R)-1-[(1R,2R)-2-[(2-ethyl-2-methyl-chroman-4-yl)carbamoyl]cyclopropyl]-3-methoxy-propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1S)-1-[(1R,2R)-2-[(2-ethyl-2-methyl-chroman-4-yl)carbamoyl]cyclopropyl]-3-methoxy-propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1R)-1-[(1R,2R)-2-[(7-fluoro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-3-methoxy-propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1R)-1-[(1R,2R)-2-[(7-fluoro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-3-methoxy-propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(S)-[(1R,2R)-2-[(7-fluoro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-pyridin-1-ium-3-yl-methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(R)-[(1R,2R)-2-[(7-fluoro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-pyridin-1-ium-3-yl-methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[(1R,2R)-2-[(2-ethyl-2-methyl-chroman-4-yl)carbamoyl]cyclopropyl]methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[(1R,2R)-2-[(2-isopropyl-2-methyl-chroman-4-yl)carbamoyl]cyclopropyl]methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[(1R,2R)-2-[(2-isopropyl-2-methyl-chroman-4-yl)carbamoyl]cyclopropyl]methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1R)-1-[(1R,2R)-2-[(2-isopropyl-2-methyl-chroman-4-yl)carbamoyl]cyclopropyl]-3-methoxy-propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1S)-1-[(1R,2R)-2-[(2-isopropyl-2-methyl-chroman-4-yl)carbamoyl]cyclopropyl]-3-methoxy-propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(S)-[(1R,2R)-2-[(2-isopropyl-2-methyl-chroman-4-yl)carbamoyl]cyclopropyl]-pyridin-1-ium-3-yl-methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(R)-[(1R,2R)-2-[(2-isopropyl-2-methyl-chroman-4-yl)carbamoyl]cyclopropyl]-pyridin-1-ium-3-yl-methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1R)-3-methoxy-1-[(1R,2R)-2-[[2-(methoxymethyl)-2-methyl-chroman-4-yl]carbamoyl]cyclopropyl]propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1S)-3-methoxy-1-[(1R,2R)-2-[[2-(methoxymethyl)-2-methyl-chroman-4-yl]carbamoyl]cyclopropyl]propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1R)-3-methoxy-1-[(1R,2R)-2-[(2,2,7-trimethylchroman-4-yl)carbamoyl]cyclopropyl]propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [4,4-dimethyl-6-oxo-1-[[(1R,2R)-2-[(2,2,7-trimethylchroman-4-yl)carbamoyl]cyclopropyl]methyl]hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [4,4-dimethyl-6-oxo-1-[(S)-pyridin-1-ium-3-yl-[(1R,2R)-2-[(2,2,7-trimethylchroman-4-yl)carbamoyl]cyclopropyl]methyl]hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [4,4-dimethyl-6-oxo-1-[(R)-pyridin-1-ium-3-yl-[(1R,2R)-2-[(2,2,7-trimethylchroman-4-yl)carbamoyl]cyclopropyl]methyl]hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(S)-[(1R,2R)-2-[(5-fluoro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-pyridin-1-ium-3-yl-methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(R)-[(1R,2R)-2-[(5-fluoro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-pyridin-1-ium-3-yl-methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[(1R,2R)-2-[(5-fluoro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1R)-1-[(1R,2R)-2-[(5-fluoro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-3-methoxy-propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1S)-1-[(1R,2R)-2-[(5-fluoro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-3-methoxy-propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1R)-1-[(1R,2R)-2-[(7-chloro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-3-methoxy-propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[(1R,2R)-2-[(7-chloro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(S)-[(1R,2R)-2-[(7-chloro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-pyridin-1-ium-3-yl-methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(R)-[(1R,2R)-2-[(7-chloro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-pyridin-1-ium-3-yl-methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1R)-1-[(1R,2R)-2-[(2,2-diethylchroman-4-yl)carbamoyl]cyclopropyl]-3-methoxy-propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1S)-1-[(1R,2R)-2-[(2,2-diethylchroman-4-yl)carbamoyl]cyclopropyl]-3-methoxy-propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(S)-[(1R,2R)-2-[(8-fluoro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-pyridin-1-ium-3-yl-methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(R)-[(1R,2R)-2-[(8-fluoro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-pyridin-1-ium-3-yl-methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(S)-[(1R,2R)-2-[(6,8-dichloro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-pyridin-1-ium-3-yl-methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(R)-[(1R,2R)-2-[(6,8-dichloro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-pyridin-1-ium-3-yl-methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[(1R,2R)-2-[[(4S)-6-chloro-2,2-dimethyl-chroman-4-yl]carbamoyl]cyclopropyl]methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[(1R,2R)-2-[(5-methoxy-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-pyridin-1-ium-3-yl-methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[(1R,2R)-2-[(5-methoxy-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-pyridin-1-ium-3-yl-methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[(1R,2R)-2-[(6,8-dichloro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(S)-[(1R,2R)-2-[(6-fluoro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-pyridin-1-ium-3-yl-methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[(1R,2R)-2-[[5-fluoro-2,2-dimethyl-8-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[(1R,2R)-2-[[2,2-dimethyl-6-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1R)-1-[(1R,2R)-2-[[(4S)-6-chloro-2,2-dimethyl-chroman-4-yl]carbamoyl]cyclopropyl]-3-methoxy-propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [(4R)-1-[[(1R,2R)-2-[(3,3-dimethylchroman-4-yl)carbamoyl]cyclopropyl]-(5-fluoro-3-pyridyl)methyl]-4-ethyl-4-methyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [(4S)-1-[[(1R,2R)-2-[(3,3-dimethylchroman-4-yl)carbamoyl]cyclopropyl]-(5-fluoro-3-pyridyl)methyl]-4-ethyl-4-methyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [(4R)-4-ethyl-1-[(5-fluoro-3-pyridyl)-[(1R,2R)-2-[(3-hydroxy-2,2,3-trimethyl-chroman-4-yl)carbamoyl]cyclopropyl]methyl]-4-methyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [(4S)-4-ethyl-1-[(5-fluoro-3-pyridyl)-[(1R,2R)-2-[(3-hydroxy-2,2,3-trimethyl-chroman-4-yl)carbamoyl]cyclopropyl]methyl]-4-methyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [(4R)-4-ethyl-1-[(5-fluoro-3-pyridyl)-[(1R,2R)-2-[[3-hydroxy-2-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]methyl]-4-methyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [(4S)-4-ethyl-1-[(5-fluoro-3-pyridyl)-[(1R,2R)-2-[[3-hydroxy-2-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]methyl]-4-methyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(S)-[(1R,2R)-2-[(2-ethyl-2-methyl-chroman-4-yl)carbamoyl]cyclopropyl]-pyridin-1-ium-3-yl-methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(R)-[(1R,2R)-2-[(2-ethyl-2-methyl-chroman-4-yl)carbamoyl]cyclopropyl]-pyridin-1-ium-3-yl-methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1R)-1-[(1R,2R)-2-[(6,8-dichloro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-3-methoxy-propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1S)-1-[(1R,2R)-2-[(6,8-dichloro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-3-methoxy-propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1R)-1-[(1R,2R)-2-[[2,2-dimethyl-5-(trifluoromethoxy)chroman-4-yl]carbamoyl]cyclopropyl]-3-methoxy-propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1S)-1-[(1R,2R)-2-[[2,2-dimethyl-5-(trifluoromethoxy)chroman-4-yl]carbamoyl]cyclopropyl]-3-methoxy-propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(S)-[(1R,2R)-2-[[2-(methoxymethyl)-2-methyl-chroman-4-yl]carbamoyl]cyclopropyl]-(3-pyridyl)methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(R)-[(1R,2R)-2-[[2-(methoxymethyl)-2-methyl-chroman-4-yl]carbamoyl]cyclopropyl]-pyridin-1-ium-3-yl-methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(S)-[(1R,2R)-2-[[2-(methoxymethyl)-2-methyl-chroman-4-yl]carbamoyl]cyclopropyl]-pyridin-1-ium-3-yl-methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(S)-[(1R,2R)-2-[[2-(methoxymethyl)-2-methyl-chroman-4-yl]carbamoyl]cyclopropyl]-(3-pyridyl)methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(S)-[(1R,2R)-2-[[2,2-dimethyl-6-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]-pyridin-1-ium-3-yl-methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(R)-[(1R,2R)-2-[[2,2-dimethyl-6-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]-pyridin-1-ium-3-yl-methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1R)-1-[(1R,2R)-2-[[2,2-dimethyl-6-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]-3-methoxy-propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1R)-1-[(1R,2R)-2-[[2,2-dimethyl-6-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]-3-methoxy-propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1R)-1-[(1R,2R)-2-[(8-fluoro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-3-methoxy-propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1S)-1-[(1R,2R)-2-[(8-fluoro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-3-methoxy-propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1R)-1-[(1R,2R)-2-[(8-chloro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-3-methoxy-propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1S)-1-[(1R,2R)-2-[(8-chloro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-3-methoxy-propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1R)-1-[(1R,2R)-2-[(6,8-difluoro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-3-methoxy-propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • 30 [1-[(1S)-1-[(1R,2R)-2-[(6,8-difluoro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-3-methoxy-propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1R)-1-[(1R,2R)-2-[[5-fluoro-2,2-dimethyl-8-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]-3-methoxy-propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1S)-1-[(1R,2R)-2-[[5-fluoro-2,2-dimethyl-8-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]-3-methoxy-propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(S)-[(1R,2R)-2-[[5-fluoro-2,2-dimethyl-8-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]-pyridin-1-ium-3-yl-methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(R)-[(1R,2R)-2-[[5-fluoro-2,2-dimethyl-8-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]-pyridin-1-ium-3-yl-methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1R)-1-[(1R,2R)-2-[(5-chloro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-3-methoxy-propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1R)-1-[(1R,2R)-2-[(5-chloro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-3-methoxy-propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(S)-[(1R,2R)-2-[(5-chloro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-(3-pyridyl)methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(R)-[(1R,2R)-2-[(5-chloro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-(3-pyridyl)methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[(1R,2R)-2-[[2,2-dimethyl-5-(trifluoromethoxy)chroman-4-yl]carbamoyl]cyclopropyl]methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • (1R,2R)—N-(5-chloro-2,2-dimethyl-chroman-4-yl)-2-[(2-imino-4,4-dimethyl-6-oxo-hexahydropyrimidin-1-yl)methyl]cyclopropanecarboxamide;
  • [1-[(S)-[(1R,2R)-2-[[(4S)-6-chloro-2,2-dimethyl-chroman-4-yl]carbamoyl]cyclopropyl]-pyridin-1-ium-3-yl-methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(R)-[(1R,2R)-2-[(8-chloro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-pyridin-1-ium-3-yl-methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(S)-[(1R,2R)-2-[(8-chloro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-(3-pyridyl)methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(S)-[(1R,2R)-2-[(6,8-difluoro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-pyridin-1-ium-3-yl-methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(R)-[(1R,2R)-2-[(6,8-difluoro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-pyridin-1-ium-3-yl-methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [(4R)-4-ethyl-1-[(1R)-3-methoxy-1-[(1R,2R)-2-[[(4S)-2,2,6-trimethylchroman-4-yl]carbamoyl]cyclopropyl]propyl]-4-methyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [(4R)-1-[(1R)-1-[(1R,2R)-2-[[(4S)-6-chloro-2,2-dimethyl-chroman-4-yl]carbamoyl]cyclopropyl]-3-methoxy-propyl]-4-ethyl-4-methyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[(1R,2R)-2-[[2,2-dimethyl-6-(trifluoromethoxy)chroman-4-yl]carbamoyl]cyclopropyl]methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1R)-1-[(1R,2R)-2-[[2,2-dimethyl-6-(trifluoromethoxy)chroman-4-yl]carbamoyl]cyclopropyl]-3-methoxy-propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [(4R)-1-[(1R)-1-[(1R,2R)-2-[[2,2-dimethyl-6-(trifluoromethyl)chroman-4-yl]carbamoyl]cyclopropyl]-3-methoxy-propyl]-4-ethyl-4-methyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [4,4-dimethyl-6-oxo-1-[[(1R,2R)-2-[[(4S)-2,2,6-trimethylchroman-4-yl]carbamoyl]cyclopropyl]methyl]hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [(4R)-1-[(1R)-1-[(1R,2R)-2-[[2,2-dimethyl-6-(trifluoromethoxy)chroman-4-yl]carbamoyl]cyclopropyl]-3-methoxy-propyl]-4-ethyl-4-methyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [(4S)-1-[(1R)-1-[(1R,2R)-2-[[2,2-dimethyl-6-(trifluoromethoxy)chroman-4-yl]carbamoyl]cyclopropyl]-3-methoxy-propyl]-4-ethyl-4-methyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [(4R)-4-ethyl-1-[(1R)-1-[(1R,2R)-2-[(6-fluoro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-3-methoxy-propyl]-4-methyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [(4S)-4-ethyl-1-[(1R)-1-[(1R,2R)-2-[(6-fluoro-2,2-dimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-3-methoxy-propyl]-4-methyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1R)-3-methoxy-1-[(1R,2R)-2-(spiro[chromane-2,1′-cyclobutane]-4-ylcarbamoyl)cyclopropyl]propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • 10 [1-[(1S)-3-methoxy-1-[(1R,2R)-2-(spiro[chromane-2,1′-cyclobutane]-4-ylcarbamoyl)cyclopropyl]propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1R)-3-methoxy-1-[(1R,2R)-2-[[(4S)-2,2,6-trimethylchroman-4-yl]carbamoyl]cyclopropyl]propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[(1R,2R)-2-[(2-ethylchroman-4-yl)carbamoyl]cyclopropyl]methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1R)-1-[(1R,2R)-2-[[2,2-dimethyl-7-(trifluoromethoxy)chroman-4-yl]carbamoyl]cyclopropyl]-3-methoxy-propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1S)-1-[(1R,2R)-2-[[2,2-dimethyl-7-(trifluoromethoxy)chroman-4-yl]carbamoyl]cyclopropyl]-3-methoxy-propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [4,4-dimethyl-6-oxo-1-[[(1R,2R)-2-(spiro[chromane-2,1′-cyclobutane]-4-ylcarbamoyl)cyclopropyl]methyl]hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[(1R,2R)-2-[(6-chloro-2,2,7-trimethyl-chroman-4-yl)carbamoyl]cyclopropyl]methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1S)-1-[(1R,2R)-2-[(6-chloro-2,2,7-trimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-3-methoxy-propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1R)-1-[(1R,2R)-2-[(6-chloro-2,2,7-trimethyl-chroman-4-yl)carbamoyl]cyclopropyl]-3-methoxy-propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1R)-3-methoxy-1-[(1R,2R)-2-[(2,2,6,7-tetramethylchroman-4-yl)carbamoyl]cyclopropyl]propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[(1S)-3-methoxy-1-[(1R,2R)-2-[(2,2,6,7-tetramethylchroman-4-yl)carbamoyl]cyclopropyl]propyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[(1R,2R)-2-[(6-fluoro-2-methyl-chroman-4-yl)carbamoyl]cyclopropyl]methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • [1-[[(1R,2R)-2-[(2-cyclopropylchroman-4-yl)carbamoyl]cyclopropyl]methyl]-4,4-dimethyl-6-oxo-hexahydropyrimidin-2-ylidene]ammonium;2,2,2-trifluoroacetate;
  • (1R,2R)-2-[(1R)-1-(4,4-diethyl-2-imino-6-oxo-hexahydropyrimidin-1-yl)-3-methoxy-propyl]-N-[(4R)-2,2-dimethylchroman-4-yl]cyclopropanecarboxamide;
  • (1R,2R)-2-[1-(4,4-diethyl-2-imino-6-oxo-hexahydropyrimidin-1-yl)-3-methoxy-butyl]-N-[(4S)-2,2-dimethylchroman-4-yl]cyclopropanecarboxamide;
  • (1R,2R)-2-[1-(4,4-diethyl-2-imino-6-oxo-hexahydropyrimidin-1-yl)-3-methoxy-butyl]-N-[(4S)-2,2-dimethylchroman-4-yl]cyclopropanecarboxamide;
  • (1R,2R)-2-[1-(4,4-diethyl-2-imino-6-oxo-hexahydropyrimidin-1-yl)-3-methoxy-butyl]-N-[(4S)-2,2-dimethylchroman-4-yl]cyclopropanecarboxamide;
  • (1R,2R)-2-[1-(4,4-diethyl-2-imino-6-oxo-hexahydropyrimidin-1-yl)-3-methoxy-butyl]-N-[(4S)-2,2-dimethylchroman-4-yl]cyclopropanecarboxamide;
  • (1R,2R)-2-[1-(4,4-diethyl-2-imino-6-oxo-hexahydropyrimidin-1-yl)-3-methoxy-butyl]-N-[(4R)-2,2-dimethylchroman-4-yl]cyclopropanecarboxamide;
  • (1R,2R)-2-[1-(4,4-diethyl-2-imino-6-oxo-hexahydropyrimidin-1-yl)-3-methoxy-butyl]-N-[(4R)-2,2-dimethylchroman-4-yl]cyclopropanecarboxamide;
  • (1R,2R)-2-[1-(4,4-diethyl-2-imino-6-oxo-hexahydropyrimidin-1-yl)-3-methoxy-butyl]-N-[(4R)-2,2-dimethylchroman-4-yl]cyclopropanecarboxamide;
  • (1R,2R)-2-[(1R)-1-(4,4-diethyl-2-imino-6-oxo-hexahydropyrimidin-1-yl)-3-methoxy-propyl]-N-[(3R,4S)-3-hydroxy-2,2-dimethyl-chroman-4-yl]cyclopropanecarboxamide;
  • (1R,2R)-2-[(1R)-1-(4,4-diethyl-2-imino-6-oxo-hexahydropyrimidin-1-yl)-3-methoxy-propyl]-N-[(3S,4R)-3-hydroxy-2,2-dimethyl-chroman-4-yl]cyclopropanecarboxamide;
  • (1R,2R)—N-[(4S)-6-chloro-2,2-dimethyl-chroman-4-yl]-2-[(1R)-1-(4,4-diethyl-2-imino-6-oxo-hexahydropyrimidin-1-yl)-3-methoxy-propyl]cyclopropanecarboxamide;
  • (1R,2R)—N-(7-chloro-2,2-dimethyl-chroman-4-yl)-2-[(1R)-1-(4,4-diethyl-2-imino-6-oxo-hexahydropyrimidin-1-yl)-3-methoxy-propyl]cyclopropanecarboxamide;
  • (1R,2R)—N-(7-chloro-2,2-dimethyl-chroman-4-yl)-2-[(1R)-1-(4,4-diethyl-2-imino-6-oxo-hexahydropyrimidin-1-yl)-3-methoxy-propyl]cyclopropanecarboxamide;
  • (1R,2R)—N-(8-chloro-2,2-dimethyl-chroman-4-yl)-2-[(1R)-1-(4,4-diethyl-2-imino-6-oxo-hexahydropyrimidin-1-yl)-3-methoxy-propyl]cyclopropanecarboxamide;
  • (1R,2R)—N-(8-chloro-2,2-dimethyl-chroman-4-yl)-2-[(1R)-1-(4,4-diethyl-2-imino-6-oxo-hexahydropyrimidin-1-yl)-3-methoxy-propyl]cyclopropanecarboxamide;
  • (1R,2R)—N-(5-chloro-2,2-dimethyl-chroman-4-yl)-2-[(1R)-1-(4,4-diethyl-2-imino-6-oxo-hexahydropyrimidin-1-yl)-3-methoxy-propyl]cyclopropanecarboxamide;
  • (1R,2R)—N-(5-chloro-2,2-dimethyl-chroman-4-yl)-2-[(1R)-1-(4,4-diethyl-2-imino-6-oxo-hexahydropyrimidin-1-yl)-3-methoxy-propyl]cyclopropanecarboxamide; and
  • (1R,2R)—N-[(3S,4R)-6-chloro-3-hydroxy-2,2-dimethyl-chroman-4-yl]-2-[(1R)-1-(4,4-diethyl-2-imino-6-oxo-hexahydropyrimidin-1-yl)-3-methoxy-propyl]cyclopropanecarboxamide.


Definitions and Abbreviations

The terms used herein have their ordinary meaning and the meaning of such terms is independent at each occurrence thereof. That notwithstanding and except where stated otherwise, the following definitions apply throughout the specification and claims. Chemical names, common names and chemical structures may be used interchangeably to describe that same structure. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Hence the definition of “alkyl” applies to “alkyl” as well as the “alkyl” portion of “hydroxyalkyl”, “haloalkyl”, arylalkyl-, alkylaryl-, “alkoxy” etc.


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


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


“Drug resistant” means, in connection with a Plasmodium parasite strain, a Plasmodium species which is no longer susceptible to at least one previously effective drug; which has developed the ability to withstand attack by at least one previously effective drug. A drug resistant strain may relay that ability to withstand to its progeny. Said resistance may be due to random genetic mutations in the bacterial cell that alters its sensitivity to a single drug or to different drugs.


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


“Pharmaceutical composition” (or “pharmaceutically acceptable composition”) means a composition suitable for administration to a patient. Such compositions may contain the neat compound (or compounds) of the invention or mixtures thereof, or salts, solvates, prodrugs, isomers, or tautomers thereof, and one or more pharmaceutically acceptable carriers or diluents. The term “pharmaceutical composition” is also intended to encompass both the bulk composition and individual dosage units comprised of one or more (e.g., two) pharmaceutically active agents such as, for example, a compound of the present invention and an additional agent selected from the lists of the additional agents described herein, along with any pharmaceutically inactive excipients. The bulk composition and each individual dosage unit can contain fixed amounts of the afore-said “more than one pharmaceutically active agents”. The bulk composition is material that has not yet been formed into individual dosage units. An illustrative dosage unit is an oral dosage unit such as tablets, pills and the like. Similarly, the herein-described method of treating a patient by administering a pharmaceutical composition of the present invention is also intended to encompass the administration of the afore-said bulk composition and individual dosage units.


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


“Alkyl” means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. “Lower alkyl” means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl.


“Haloalkyl” means an alkyl as defined above wherein one or more hydrogen atoms on the alkyl is replaced by a halo group defined above.


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


“Cycloalkyl” means a non-aromatic mono- or multicyclic ring system comprising 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 optionally substituted with one or more substituents, which may be the same or different, as described herein. Monocyclic cycloalkyl refers to monocyclic versions of the cycloalkyl moieties described herein. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Multicyclic cycloalkyls refers to multicyclic, including bicyclic, rings that include a non-aromatic ring. Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like. In certain embodiments, a non-aromatic ring is fused to an aromatic ring. Further non-limiting examples of cycloalkyl include the following:




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“Heterocycloalkyl” (or “heterocyclyl”) means a non-aromatic, saturated or partially saturated monocyclic or multicyclic ring system comprising 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, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present 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 may exist protected such as, for example, as an —N(Boc), —N(CBz), —N(Tos) group and the like; such protections are also considered part of this invention. The heterocyclyl can be optionally substituted by one or more substituents, which may be the same or different, as described herein. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Thus, the term “oxide,” when it appears in a definition of a variable in a general structure described herein, refers to the corresponding N-oxide, S-oxide, or S,S-dioxide. “Heterocyclyl” also includes rings wherein ═O replaces two available hydrogens on the same carbon atom (i.e., heterocyclyl includes rings having a carbonyl group in the ring). Such ═O groups may be referred to herein as “oxo.” An example of such a moiety is pyrrolidinone (or pyrrolidone):




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As used herein, the term “monocyclic heterocycloalkyl” refers monocyclic versions of the heterocycloalkyl moieties described herein and include a 4- to 7-membered monocyclic heterocycloalkyl groups comprising from 1 to 4 ring heteroatoms, said ring heteroatoms being 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 to 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, beta lactam, gamma lactam, delta lactam, beta lactone, gamma lactone, delta lactone, and pyrrolidinone, and oxides thereof. A non-limiting example of a monocyclic heterocycloalkyl group include the moiety:




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




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The term “heteroaryl” means an aromatic heterocycle that contains at least one ring heteroatom selected from O, S and N. Examples of heteroaryl groups include pyridyl (pyridinyl), oxazolyl, imidazolyl, triazolyl, furyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, benzimidazolyl, quinolyl, isoquinolyl, and the like.


“SpiroC1-C6cycloalkyl” means a cycloalkyl that is linked to another ring system by one common atom, for example




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“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 designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency 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. By “stable compound” or “stable structure” is meant 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 groups, radicals or moieties.


When a variable appears more than once in a group, e.g., R8 in —N(R8)2, or a variable appears more than once in a structure presented herein, the variables can be the same or different.


A solid line custom-character, as a bond generally indicates a mixture of, or either of, the possible isomers, e.g., containing (R)- and (S)-stereochemistry. For example:




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means containing either one of or both N




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The wavy line custom-character, as used herein shown crossing a line representing a chemical bond, indicates a point of attachment to the rest of the compound. Lines drawn into the ring systems, such as, for example




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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 in a cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, or another ring described herein, e.g.,




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In this specification, where there are multiple oxygen and/or sulfur atoms in a ring system, there cannot be any adjacent oxygen and/or sulfur present in said ring system.


As well known in the art, a bond drawn from a particular atom wherein no moiety is depicted at the terminal end of the bond indicates a methyl group bound through that bond to the atom, unless stated otherwise. For example:




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In another embodiment, the compounds useful in the methods of the invention, and/or compositions comprising them useful in said methods, are present in isolated and/or purified form. The term “purified”, “in purified form” or “in isolated and purified form” for a compound refers to the physical state of said compound after being isolated from a synthetic process (e.g. from a reaction mixture), or natural source or combination thereof. Thus, the term “purified”, “in purified form” or “in isolated and purified form” for a compound refers to the physical state of said compound (or a tautomer or stereoisomer thereof, or pharmaceutically acceptable salt or solvate of said compound, said stereoisomer, or said tautomer) after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization and the like), in sufficient purity to be suitable for in vivo or medicinal use and/or characterizable by standard analytical techniques described herein or well known to the skilled artisan.


It shall be understood that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.


When a functional group in a compound is termed “protected”, this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as 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 in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press. The term “prodrug” means a compound (e.g., a drug precursor) that is transformed in vivo to yield a compound of the invention or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through 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 in Bioreversible 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 pharmaceutically acceptable salt thereof, contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (C1-C8)alkyl, (C2-C12)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N—(C1-C2)alkylamino(C2-C3)alkyl (such as β-dimethylaminoethyl), carbamoyl-(C1-C2)alkyl, N,N-di (C1-C2)alkylcarbamoyl-(C1-C2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-C3)alkyl, and the like.


Similarly, if a compound used in the methods of the invention contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (C1-C6)alkanoyloxymethyl, 1-((C1-C6)alkanoyloxy)ethyl, 1-methyl-1-((C1-C6)alkanoyloxy)ethyl, (C1-C6)alkoxycarbonyloxymethyl, N—(C1-C6)alkoxycarbonylaminomethyl, succinoyl, (C1-C6)alkanoyl, α-amino(C1-C4)alkanyl, arylacyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2, —P(O)(O(C1-C6)alkyl)2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate), and the like.


If a compound used in the methods of the invention incorporates an amine functional group, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR′-carbonyl where R and R′ are each independently (C1-C10)alkyl, (C3-C7) cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl or natural α-aminoacyl, —C(OH)C(O)OY1 wherein Y1 is H, (C1-C6)alkyl or benzyl, —C(OY2)Y3 wherein Y2 is (C1-C4) alkyl and Y3 is (C1-C6)alkyl, carboxy (C1-C6)alkyl, amino(C1-C4)alkyl or mono-N— or di-N,N—(C1-C6)alkylaminoalkyl, —C(Y4)Y5 wherein Y4 is H or methyl and Y5 is mono-N— or di-N,N—(C1-C6)alkylamino morpholino, piperidin-1-yl or pyrrolidin-1-yl, and the like.


One or more compounds used in the methods of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. “Solvate” means a physical association of a compound of the invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. “Hydrate” is a solvate wherein the solvent molecule is H2O.


One or more compounds used in the methods of the invention may optionally be converted to a solvate. Preparation of solvates is generally known. Thus, for example M. Caira et al, J. Pharmaceutical Sci., 1993, 3, 601-611, describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, hemisolvate, hydrates and the like 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 inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example 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 meant to describe an amount of compound or a composition used in the methods of the present invention effective in inhibiting the above-noted diseases or enzyme activity and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect.


Another embodiment provides pharmaceutically acceptable salts of the compounds to be used in the methods of the invention. Thus, reference to a compound used in the methods of the invention herein is understood to include reference to salts thereof, unless otherwise indicated. The term “salt(s)”, as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of the invention contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions (“inner salts”) may be formed and are included within the term “salt(s)” as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compounds used in the methods of the invention may be formed, for example, by reacting a compound of the invention with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.


Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977), 66(1), 1-19; P. Gould, International J. of Pharmaceutics (1986), 33, 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto.


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


All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.


Another embodiment provides pharmaceutically 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 the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, C1-4alkyl, or C1-4alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate esters may be further esterified by, for example, a C1-20 alcohol or reactive derivative thereof, or by a 2,3-di (C6-24)acyl glycerol.


As mentioned herein, another embodiment provides tautomers of the compounds of the invention to be used in the methods herein, and salts, solvates, esters and prodrugs of said tautomers. It shall 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, when present, are included in the invention.


The compounds used in the methods of the invention may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds used in the methods of the invention as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention embraces use of all geometric and positional isomers. For example, if a compound used in the methods of the invention incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.


Another embodiment provides for diastereomeric mixtures and individual enantiomers of the compounds used in the methods of the invention. 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, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds used in the methods of the invention may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of chiral HPLC column.


All stereoisomers (for example, geometric isomers, optical isomers and the like) of the compounds used in the methods of the invention (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated as embodiments within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example, if a compound of the invention incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced 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 may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.


Another embodiment provides isotopically-labelled compounds to be used in the methods the invention. Such compounds are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the 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-labelled compounds of the invention (e.g., those labeled with 3H and 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labelled compounds of the invention can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples hereinbelow, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.


In the compounds used in the methods of the invention, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of the invention. For example, different isotopic forms of hydrogen (H) include protium (1H) and deuterium (2H). The presence of deuterium in the compounds of the invention is indicated by “D”. Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds of the invention can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the schemes and examples herein using appropriate isotopically-enriched reagents and/or intermediates.


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


Methods of Treatment

The present invention is directed to methods of blocking P. falciparum growth in an animal, preferably a human, comprising administering to the animal an inhibitor with possible dual-targeting activity of Plasmepsin IX and Plasmepsin X or a pharmaceutically acceptable salt thereof. Plasmepsin IX and Plasmepsin X are responsible for critical processing of multiple other proteins required for the parasite to productively invade and egress from various cell types along the pathway of its lifecycle.


In certain embodiments, the present invention may provide a method for treating malaria in an animal, preferably a human, comprising administering to the animal an inhibitor with dual-targeting activity of Plasmepsin IX and Plasmepsin X or a pharmaceutically acceptable salt thereof. The present invention is directed to methods of treatment of Plasmodium infections comprising administering to a subject in need thereof a compound described herein, or a pharmaceutically acceptable salt thereof. More specifically, the methods of the invention comprise administration of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In certain embodiments, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, are administered in the form of a pharmaceutical composition, further comprising a pharmaceutically acceptable carrier or excipient.


The present invention provides a method for treating a Plasmodium infection, or for treating malaria, or for possibly inhibiting plasmepsin X which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, said compound having the structural Formula (I), (IA), (IB), (IC) or (ID) described in the Summary of the Invention. In some embodiments, the compounds of Formula (I), (IA), (IB), (IC) or (ID), or pharmaceutically acceptable salts thereof, are administered with a pharmaceutically acceptable carrier, as a pharmaceutical composition. Also provided herein are various embodiments of these methods, as described, infra.


The invention also relates to the use of a compound of Formula (I), (IA), (IB), (IC) or (ID) or a pharmaceutically acceptable salt thereof for the possible inhibition of plasmepsin X activity, for treating a Plasmodium infection, or for treating malaria. The invention further relates to the use of a compound of Formula (I), (IA), (IB), (IC) or (ID) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the possible inhibition of plasmepsin X activity, for treating a Plasmodium infection, or for treating malaria. The compounds of Formula (I), (IA), (IB), (IC) or (ID) or pharmaceutically acceptable salts thereof described in any of the embodiments of the invention herein are useful for any of the uses above.


The present invention provides a method for treating a Plasmodium infection, or for treating malaria, or for the possible inhibition of plasmepsin IX which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, said compound having the structural Formula (I) described in the Summary of the Invention. In some embodiments, the compounds of Formula (I), or pharmaceutically acceptable salts thereof, are administered with a pharmaceutically acceptable carrier, as a pharmaceutical composition. Also provided herein are various embodiments of these methods, as described, infra.


The invention also relates to the use of a compound of Formula (I), (IA), (IB), (IC) or (ID) or a pharmaceutically acceptable salt thereof for the possible inhibition of plasmepsin IX activity, for treating a Plasmodium infection, or for treating malaria. The invention further relates to the use of a compound of Formula (I), (IA), (IB), (IC) or (ID) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the possible inhibition of plasmepsin IX activity, for treating a Plasmodium infection, or for treating malaria. The compounds of Formula (I), (IA), (IB), (IC) or (ID) or pharmaceutically acceptable salts thereof described in any of the embodiments of the invention herein are useful for any of the uses above.


The present invention provides a method for treating a Plasmodium infection, or for treating malaria, or for the possible inhibition of plasmepsin X and plasmepsin IX which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, said compound having the structural Formula (I) described in the Summary of the Invention. In some embodiments, the compounds of Formula (I), or pharmaceutically acceptable salts thereof, are administered with a pharmaceutically acceptable carrier, as a pharmaceutical composition. Also provided herein are various embodiments of these methods, as described, infra.


The invention also relates to the use of a compound of Formula (I), (IA), (IB), (IC) or (ID) or a pharmaceutically acceptable salt thereof for the possible inhibition of plasmepsin X and plasmepsin IX activity, for treating a Plasmodium infection, or for treating malaria. The invention further relates to the use of a compound of Formula (I), (IA), (IB), (IC) or (ID) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the possible inhibition of plasmepsin X and plasmepsin IX activity, for treating a Plasmodium infection, or for treating malaria. The compounds of Formula (I), (IA), (IB), (IC) or (ID) or pharmaceutically acceptable salts thereof described in any of the embodiments of the invention herein are useful for any of the uses above.


The methods of the present invention are useful for treating malaria in that they inhibit the onset, growth, or progression of the condition, ameliorate the symptoms of the condition, cause regression of the condition, cure the condition, or otherwise improve the general well-being of a subject afflicted with, or at risk of, contracting the condition. Thus, in accordance with the presently disclosed subject matter, the terms “treat”, “treating”, and grammatical variations thereof, as well as the phrase “method of treating”, are meant to encompass any desired therapeutic intervention, including but not limited to a method for treating an existing infection in a subject of infection, such as in a subject that has been exposed to a parasite as disclosed herein.


Embodiments of the invention also include one or more of the compounds of Formula (I), (IA), (IB), (IC) or (ID) or a pharmaceutically acceptable salt thereof (i) for use in, (ii) for use as a medicament or composition for, or (iii) for use in the preparation of a medicament for: (a) therapy (e.g., of the human body); (b) medicine; (c) inhibition of parasite/Plasmodium growth, (d) treatment or prophylaxis of infection by Plasmodium species; (e) reduction of the progression, onset or severity of pathological symptoms associated with Plasmodium infection and/or reduction of the likelihood of severe Plasmodium infection or, (f) treatment, prophylaxis of, or delay in the onset, severity, or progression of Plasmodium-associated disease(s), including, but not limited to: malaria.


Accordingly, another embodiment provides methods for the treatment of malaria or for the treatment of Plasmodium infection, comprising administration of combinations comprising an amount of at least one compound of Formula (I), (A), (IB), (IC) or (ID), 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 for the treatment of malaria or for the treatment of Plasmodium infection, comprising administration of combinations comprising an amount of at least one compound of Formula (I), (A), (IB), (IC) or (ID), or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and an effective amount of one or more additional anit-malarial agents. In certain embodiments, described herein are methods for the treatment of malaria by inhibition of plasmepsin X, IX and at least one other mechanism, comprising administration of combinations comprising an amount of at least one compound of Formula (I), (A), (IB), (IC) or (ID), or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and an effective amount of one or more additional anit-malarial agents, wherein the additional anti-malarial agents act through a different mechanism than inhibiting plasmepsin IX or plasmepsin X. The pharmacological properties of the compounds of Formula (I), (IA), (IB), (IC) or (ID), or a pharmaceutically acceptable salt thereof may be confirmed by several pharmacological assays. Certain assays are exemplified herein.


Dosage and Administration

Another embodiment provides suitable dosages and dosage forms of the compounds used in the methods of the invention. Suitable doses for administering compounds used in the methods of the invention to patients may readily be determined by those skilled in the art, e.g., by an attending physician, pharmacist, or other skilled worker, and may vary according to patient health, age, weight, frequency of administration, use with other active ingredients, and/or indication for which the compounds are administered. Doses may range from about 0.001 to 500 mg/kg of body weight/day of the compound of the invention. In one embodiment, the dosage is from about 0.01 to about 25 mg/kg of body weight/day of a compound of the invention, or a pharmaceutically acceptable salt or solvate of said compound. In another embodiment, the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 100 mg, in specific embodiments from about 1 mg to about 50 mg, in specific embodiments from about 1 mg to about 25 mg, according to the particular application. In another embodiment, a typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 500 mg/day, in specific embodiments 1 mg/day to 200 mg/day, in two to four divided doses.


As discussed above, the amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated.


Liquid form preparations include solutions, suspensions and emulsions. As an example, may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.


Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically 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.


Another embodiment provides for use of compositions comprising a compound of Formula (I), (IA), (IB), (IC) or (ID), or a pharmaceutically acceptable salt thereof formulated for transdermal delivery. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.


Another embodiment provides for use of compositions comprising a compound of Formula (I), (IA), (IB), (IC) or (ID), or a pharmaceutically acceptable salt thereof formulated for subcutaneous delivery. Another embodiment provides for use of compositions suitable for oral delivery. In some embodiments, it may be advantageous for the pharmaceutical preparation comprising one or more compounds of Formula (I), (IA), (IB), (IC) or (ID), or a pharmaceutically acceptable salt thereof to be prepared in a unit dosage form. In such forms, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose. Each of the foregoing alternatives is considered as included in the various embodiments of the invention.


When used in combination with one or more additional therapeutic agents (“combination therapy”), the compounds used in the methods of this invention, i.e. the compounds of Formula (I), (A), (IB), (IC) or (ID), may be administered together or sequentially. When administered sequentially, compounds of the invention may be administered before or after the one or more additional therapeutic agents, as determined by those skilled in the art or patient preference.


If formulated as a fixed dose, such combination products employ the compounds of Formula (I), (IA), (IB), (IC) or (ID), or a pharmaceutically acceptable salt thereof within the dosage range described herein and the other pharmaceutically active agent or treatment within its dosage range.


Combination Therapy

Another embodiment provides for methods of treatment using pharmaceutically acceptable compositions comprising a compound of the invention, either as the neat chemical or optionally further comprising additional ingredients. Such compositions are contemplated for preparation and use alone or in combination therapy. For preparing pharmaceutical compositions from the compounds of the invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent 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 pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pa.


Non-limiting examples of additional drugs and active agents useful in combination therapies for the treatment of malaria, include the following: Coartem® (Novartis International AG, Basel, Switzerland; artemether+lumefantrine), Eurartesim® (Sigma-Tau Pharmaceuticals, Inc., Rome, Italy; dihydroartemisinin-piperaquine), Pyramax® (Shin Poong Pharmaceutical Co., Ltd., Seoul, Korea; pyronaridine-artesunate), 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)). Additional examples of drugs and active agents useful in combination therapies for the treatment of malaria, include the following: Ganaplacide, MMV048 and M5717. Compounds described herein exhibit asexual stage parasite killing and have reasonable half-lives, and therefore have the potential to form part of a single-exposure radical cure (SERC). Compounds described herein have demonstrated excellent transmission-blocking activity in a Standard Membrane Feeding Assay and therefore likely block transmission to mosquitos. They also display liver schizonticidal activity and therefore would also be a suitable chemo-prophylactic. Compounds described herein having a mechanism of action targeting both PM IX and X that is distinct from other antimalarial agents, will potentially display very little risk of cross-resistance to other antimalarials. Furthermore, the dual targeting action of the compounds described herein are likely to mean a substantial barrier to resistance acquisition in the field. Selection of such additional active ingredients will be according to the diseases or disorders present for which treatment is desired, as determined by the attending physician or other health care provider.


Thus, the invention also provides methods of using the compounds of Formula (I), (IA), (IB), (IC) or (ID), or a pharmaceutically acceptable salt thereof for the possible inhibition of plasmepsin X, plasmepsin IX or plasmepsin X and IX, to treat Plasmodium infection or treat malaria wherein the method further comprises administering to a subject in need thereof, one or more additional anti-malarial agents. In some embodiments, the one or more additional anti-malarial agents are selected from the group consisting of: artemether, lumefantrine, dihydroartemisinin, piperaquine, pyronaridine, artesunate, amodiaquine, mefloquine, sulfadoxine, pyrimethamine, lumefantrine, quinine, chloroquine, atovaquone, and proguanil.


EXAMPLES

ACN=acetonitrile=MeCN


AcOEt=ethylacetate


DCM=dichloromethane


DIAD=Diisopropyl azodicarboxylate


DIEA=N, N-Diisopropylethylamine, or Hunig's base


DMF=N,N-Dimethylformamide

DMP=dimethyl phthalate


EDC=EDCI=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide


EtOAc=ethyl acetate


EtOH=ethanol


h=hours


H2=hydrogen


HPLC=High Performance Liquid Chromatography
HOBt=Hydroxybenzotriazole

LCMS=Liquid chromatography-mass spectrometry


LHMDS=LiHMDS=lithium bis(trimethylsilyl)amide


LiAlH4=lithium aluminum hydride


min=minutes


Me=methyl


MeOH═CH3OH=methanol


N2=nitrogen


NaBH4=sodium borohydride


NaH=sodium hydride


Na2SO4=sodium sulfate


NH4Cl=Ammonium chloride


Pd(dppf)Cl2=[1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride


SFC=Supercritical Fluid Chromatography

SiO2=Silicon dioxide


TBAF=Tetra-n-butylammonium fluoride


TFA=trifluoroacetic acid


THF=tetrahydrofuran


TMS=Trimethylsilyl

CDCl3=heavy chloroform


CD3OD=heavy methanol


1 Standard atmosphere [atm]=101325 pascal [Pa]=14.6959488 psi


The meanings of the abbreviations in the nuclear magnetic resonance spectra are shown below: s=singlet, d=doublet, dd=double doublet, dt=double triplet, ddd=double double doublet, sept=septet, t=triplet, m=multiplet, br=broad, brs=broad singlet, q=quartet, J=coupling constant and Hz=hertz.


Several methods for preparing the compounds of this disclosure are described in the following Schemes and Examples. Starting materials and intermediates were purchased commercially from common catalog sources or were made using known procedures, or as otherwise illustrated. Some frequently applied routes to the compounds of Formula I are described in in the Schemes that follow. In some cases, the order of carrying out the reaction steps in the schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. An asterisk (*) may be used in a chemical structure drawing that indicates the location of a chiral center.




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Intermediate compounds of Formula S-2 are prepared from chiral epoxides S-1, in which P is an alcohol protecting group, after cyclopropanation conditions such as (EtO)2POCH2CO2R/NaH followed by alcohol deprotection. Alcohol oxidation in S-2 can be performed using oxidants such as Dess-Martin peiodinane to yield aldehydes S-3. Treatment of S-3 with an organometallic reagent S-4, in which M is a metal and X is a halogen, such as organozinc (M=Zn) and organomagnesium (M=Mg) species gives secondary alcohol intermediates S-5. Iminopyrimidones or iminohydantoins S-6 are introduced under Mitsunobu conditions to give intermediates S-7. Alternatively, alcohol in intermediates S-5 could be transformed into a leaving group such as a mesylate, tosylate, triflate or halogen which can be displaced with intermeidates S-6 to give intermediates S-7. At this step diastereomeric mixtures can be separated by SFC and the resulting chiral esters subjected to acid or base catalyzed hydrolysis or hydrogenation to give chiral acid intermediates S-8. Finally, S-8 intermediates are coupled with amines S-7 to provide final products of Formula S-10 after iminopyrimidone deprotection using acids as TFA or Zn.


Reactions sensitive to moisture or air were performed inside a glove-box or under nitrogen or argon using anhydrous solvents and reagents. The progress of reactions was determined by either analytical thin layer chromatography (TLC) usually performed with E. Merck pre-coated TLC plates, silica gel 60F-254, layer thickness 0.25 mm or liquid chromatography-mass spectrometry (LC/MS).


Typically, the analytical LC-MS system used consisted of a Waters ZQ™ platform with electrospray ionization in positive ion detection mode with an Agilent 1100 series HPLC with autosampler. The column was commonly 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 210-400 nm. The mobile phase consisted of solvent A (water plus 0.05% TFA) and solvent B (MeCN plus 0.05% TFA) with a gradient of 100% solvent A for 0.7 min changing to 100% solvent B over 3.75 min, maintained for 1.1 min, then reverting to 100% solvent A over 0.2 min.


Preparative HPLC purifications were usually performed using either a mass spectrometry directed system or a non-mass guided system. Usually they were performed on a Waters Chromatography Workstation configured with LC-MS System consisting of: Waters ZQ™ single quad MS system with Electrospray Ionization, Waters 2525 Gradient Pump, Waters 2767 Injecto/Collector, Waters 996 PDA Detector, the MS Conditions of: 150-750 amu, Positive Electrospray, Collection Triggered by MS, and a Waters SUNFIRE© C-18 5-micron, 30 mm (id)×100 mm column. The mobile phases consisted of mixtures of acetonitrile (10-100%) in water containing 0.1% TFA. Flow rates were maintained at 50 mL/min, the injection volume was 1800 μL, and the UV detection range was 210-400 nm. An alternate preparative HPLC system used was a Gilson Workstation consisting of: Gilson GX-281 Injector/Collector, Gilson UV/VIS-155 Detector, Gilson 333 and 334 Pumps, and either a Phenomenex Gemini-NX C-18 5-micron, 50 mm (id)×250 mm column or a Waters XBridge™ C-18 5-micron OBD™, 30 mm (id)×250 mm column. The mobile phases consisted of mixtures of acetonitrile (0-75%) in water containing 5 mmol (NH4)HCO3. Flow rates were maintained at 50 mL/min for the Waters Xbridge™ column and 90 mL/min for the Phenomenex Gemini column. The injection volume ranged from 1000-8000 μL, and the UV detection range was 210-400 nm. Mobile phase gradients were optimized for the individual compounds. Reactions performed using microwave irradiation were normally carried out using an Emrys Optimizer manufactured by Personal Chemistry, or an Initiator manufactured by Biotage. Concentration of solutions was carried out on a rotary evaporator under reduced pressure. Flash chromatography was usually performed using either a Biotage© Flash Chromatography apparatus (Dyax Corp.), an ISCO CombiFlash® Rf apparatus, or an ISCO CombiFlash® Companion XL on silica gel (32-63 μM, 60 Å pore size) in pre-packed cartridges of the size noted. 1H NMR spectra were acquired at 500 MHz spectrometers in CDCl3 solutions unless otherwise noted. Chemical shifts were reported in parts per million (ppm). Tetramethylsilane (TMS) was used as internal reference in CDCl3 solutions, and residual CH3OH peak or TMS was used as internal reference in CD3OD solutions. Coupling constants (J) were reported in hertz (Hz). Chiral analytical chromatography was most commonly performed on one of CHIRALPAK© AS, CHIRALPAK©AD, CHIRALCEL© OD, CHIRALCEL©IA, or CHIRALCEL© OJ columns (250×4.6 mm) (Daicel Chemical Industries, Ltd.) with noted percentage of either ethanol in hexane (% Et/Hex) or isopropanol in heptane (% IPA/Hep) as isocratic solvent systems. Chiral preparative chromatography was conducted on one of CHIRALPAK AS, of CHIRALPAK AD, CHIRALCEL© OD, CHIRALCEL©IA, CHIRALCEL© OJ columns (20×250 mm) (Daicel Chemical Industries, Ltd.) with desired isocratic solvent systems identified on chiral analytical chromatography or by supercritical fluid (SFC) conditions. It is understood that a chiral center in a compound may exist in the “S” or “R”


stereo-configuration, or as a mixture of both. Within a molecule, each bond drawn as a straight line from a chiral center includes both the (R) and (S) stereoisomers as well as mixtures thereof.


Intermediate 1



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(1R,2R)-ethyl 2-(hydroxymethyl)cyclopropanecarboxylate
Step 1



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Ethyl 2-diethoxyphosphorylacetate (546 g, 2.44 mol, 2.0 eq) was added dropwise to a suspension of NaH (97.4 g, 2.44 mol, 60% purity, 2.0 eq) in toluene (2.0 L) at 5° C. The resulting mixture was stirred for 30 min at 5° C. Then (S)-2-((benzyloxy)methyl)oxirane (compound 1) (200 g, 1.22 mol, 1.0 eq) was added to the mixture at 5° C. and the resulting mixture was stirred for 12 h at 95° C. Then, the mixture was poured into sat.NH4Cl (30 L) at 0° C. under N2, and the aqueous phase was extracted with EtOAc (4 L×2). The combined organic layer was washed with brine (3.0 L) and dried with Na2SO4, filtered, and the solvent evaporated in vacuo to give a residue that was purified by silica gel chromatography (SiO2, petroleum ether:EtOAc=10:0 to 0:1) to give compound 2.


H-NMR: (400 MHz, DMSO): δ: 7.26-7.37 (m, 5H), 4.47 (s, 2H), 4.02-4.08 (m, 2H), 3.44-3.48 (m, 1H), 3.28-3.31 (m, 1H), 1.55-1.59 (m, 2H), 1.16-1.20 (m, 3H), 1.03-1.04 (m, 1H), 0.88-0.89 (m, 1H).


Step 2



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A solution of compound 2 (100 g, 362.80 mmol, 1 eq) in EtOH (1000 mL) was added into a hydrogenation bottle previously charged with Pd/C (20 g, 10% purity) at 25° C. The mixture was purged with H2 three times and stirred under H2 (30 Psi) at 25° C. for 24 h. Then the mixture was filtered and the volatiles removed in vacuo to give a residue that was purified by silica gel chromatography (SiO2, Petroleum ether:EtOAc=10:1 to 0:1) to give Intermediate 1.


H-NMR: (400 MHz, CDCl3): δ: 4.10-4.17 (m, 2H), 3.61-3.64 (m, 1H), 3.48-3.51 (m, 1H), 1.57-1.78 (m, 3H), 1.21-1.28 (m, 4H), 0.86-0.88 (m, 1H).


Example 1



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Step 1



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TBAF (155 mL, 155 mmol) was added to a solution of (1R,2R)-ethyl 2-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropanecarboxylate (20 g, 77 mmol) in THF (150 mL) and the mixture was stirred at 26° C. for 2 hours. The mixture was diluted with water (300 mL), extracted with EtOAc (400 mL×3). The organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (Petroleum ether/EtOAc=100:1-10:1) to afford product (1R,2R)-ethyl 2-(hydroxymethyl)cyclopropanecarboxylate.



1H NMR (400 MHz, chloroform-d) δ=4.22-4.05 (m, 2H), 3.64 (td, J=5.9, 11.6 Hz, 1H), 3.55-3.42 (m, 1H), 1.80-1.68 (m, 1H), 1.57 (td, J=4.4, 8.5 Hz, 1H), 1.49 (t, J=5.7 Hz, 1H), 1.32-1.18 (m, 4H), 0.87 (ddd, J=4.4, 6.2, 8.4 Hz, 1H)


Step 2



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DMP (46.3 g, 109 mmol) was added to a solution of (1R,2R)-ethyl 2-(hydroxymethyl)cyclopropanecarboxylate (10.5 g, 72.8 mmol) in DCM (400 mL). The mixture was stirred at 25° C. for 10 h under N2 atmosphere. The mixture was filtered, then concentrated and purified by flash column (Petroleum ether/EtOAc=100:0 to 10:1) to afford product (1R,2R)-ethyl 2-formylcyclopropanecarboxylate.



1H NMR (500 MHz, chloroform-d) δ=9.31 (s, 1H), 4.15-4.22 (m, 2H), 2.39-2.49 (m, 1H), 2.06-2.26 (m, 1H), 1.60-1.62 (m, 1H), 1.50-1.51 (m, 1H), 1.27-1.30 (m, 3H)


Step 3



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Zinc (4.60 g, 70.3 mmol) was added to a solution of (1R,2R)-ethyl 2-formylcyclopropanecarboxylate (5 g, 35.2 mmol) and 3-iodoprop-1-ene (8.86 g, 52.8 mmol) in THE (80 mL) under N2. The mixture was stirred at 25° C. for 12 h. The mixture was filtered, and the filtrate was concentrated. The residue was purified by column chromatography (Petroleum ether/EtOAc=30:1-5:1) to afford product (1R,2R)-ethyl 2-(1-hydroxybut-3-en-1-yl)cyclopropanecarboxylate.



1H NMR (500 MHz, chloroform-d) δ=5.76-5.94 (m, 1H), 5.08-5.23 (m, 2H), 4.07-4.23 (m, 2H), 3.15-3.40 (m, 1H), 2.26-2.49 (m, 2H), 1.58-1.67 (m, 2H), 1.26-1.28 (mz, 3H), 1.25-1.26 (m, 1H), 0.84-1.03 (m, 1H)


Step 4



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Tertbutylchlorodiphenylsilane (5.97 g, 21.71 mmol) and imidazole (2.217 g, 32.6 mmol) were added to a solution of (1R,2R)-ethyl 2-(1-hydroxybut-3-en-1-yl)cyclopropanecarboxylate (2 g, 10.86 mmol) in DCM (70 mL), and the mixture was stirred at 25° C. for 12 hours under N2 atmosphere. The mixture was diluted with water (50 mL), extracted with DCM (50 mL×3). The organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (Petroleum ether/EtOAc=100:1-50:1) to afford product (1R,2R)-ethyl 2-(1-((tert-butyldiphenylsilyl)oxy)but-3-en-1-yl)cyclopropanecarboxylate.



1H NMR (400 MHz, chloroform-d) δ 7.62-7.79 (m, 4H), 7.31-7.50 (m, 6H), 5.69-5.94 (m, 1H), 4.90-5.07 (m, 2H), 3.86-4.15 (m, 2H), 3.16-3.38 (m, 1H), 2.31 (s, 2H), 1.57-1.69 (m, 1H), 1.32-1.42 (m, 1H), 1.14-1.29 (m, 4H), 1.03-1.05 (m, 10H), 0.81-0.99 (m, 1H), 0.47-0.71 (m, 1H)


Step 5



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2,6-dimethylpyridine (2.370 mL, 20.35 mmol), osmium tetroxide (0.160 mL, 0.509 mmol) and sodium periodate (8.70 g, 40.7 mmol) were added to a solution of (1R,2R)-ethyl 2-(1-((tert-butyldiphenylsilyl)oxy)but-3-en-1-yl)cyclopropanecarboxylate (4.3 g, 10.17 mmol) in 1,4-dioxane (90 mL) and water (30 mL). The mixture was stirred at 25° C. for 2 h. The mixture was quenched with water (80 mL), then extracted with EtOAc (100 mL×3). The organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo to give (1R,2R)-ethyl 2-(1-((tert-butyldiphenylsilyl)oxy)-3-oxopropyl)cyclopropanecarboxylate, which was used for the next step directly.



1H NMR (500 MHz, chloroform-d) δ 9.75-9.83 (m, 1H), 7.68-7.74 (m, 3H), 7.65 (dd, J=1.5, 8.0 Hz, 1H), 7.41-7.48 (m, 3H), 7.38-7.41 (m, 3H), 4.06-4.10 (m, 1H), 3.80-4.01 (m, 1H), 3.55-3.77 (m, 1H), 2.56-2.77 (m, 2H), 1.63-1.77 (m, 1H), 1.17-1.42 (m, 4H), 1.02 (d, J=16.0 Hz, 10H), 0.46-0.64 (m, 1H)


Step 6



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NaBH4 (0.766 g, 20.25 mmol) was added to solution of (1R,2R)-ethyl 2-(1-((tert-butyldiphenylsilyl)oxy)-3-oxopropyl)cyclopropanecarboxylate (4.3 g, 0.00 mmol) in MeOH (50 mL). The mixture was stirred at −40° C. for 10 min. The mixture was then diluted with water (60 mL) and extracted with EtOAc (80 mL×3). The organic layers were washed with brine (80 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (Petroleum ether/EtOAc=20:1) to afford product (1R,2R)-ethyl 2-(1-((tert-butyldiphenylsilyl)oxy)-3-hydroxypropyl)cyclopropanecarboxylate.


H NMR (500 MHz, chloroform-d) δ 7.67-7.75 (m, 4H), 7.37-7.48 (m, 6H), 4.07 (q, J=7.0 Hz, 1H), 3.85-3.99 (m, 1H), 3.69-3.85 (m, 2H), 3.25-3.42 (m, 1H), 1.78-1.94 (m, 2H), 1.61-1.74 (m, 2H), 1.29-1.32 (m, 0.5H), 1.14-1.24 (m, 3H), 1.08-1.11 (m, 0.5H), 1.04 (d, J=15.0 Hz, 10H), 0.35-0.58 (m, 1H)


Step 7



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Trimethyloxonium tetrafluoroborate (1.352 g, 9.14 mmol) and 1,8-bis(dimethylamino)naphthalene (2.61 g, 12.19 mmol) was added to a solution of (1R,2R)-ethyl 2-(1-((tert-butyldiphenylsilyl)oxy)-3-hydroxypropyl)cyclopropanecarboxylate (1.3 g, 3.05 mmol) in DCM (50 mL). The mixture was stirred at 25° C. for 13 hrs. The mixture was diluted with water (30 mL) and extracted with DCM (30 mL×3). The organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Prep.TLC (Petroleum ether/EtOAc=20:1) to afford product (1R,2R)-ethyl 2-(1-((tert-butyldiphenylsilyl)oxy)-3-methoxypropyl)cyclopropanecarboxylate.



1H NMR (500 MHz, chloroform-d) δ 7.62-7.82 (m, 4H), 7.31-7.51 (m, 6H), 4.04-4.13 (m, 1H), 3.76-4.00 (m, 1H), 3.42-3.57 (m, 2H), 3.20-3.34 (m, 4H), 1.73-2.01 (m, 2H), 1.60-1.67 (m, 0.5H), 1.31-1.34 (m, 0.5H), 1.12-1.25 (m, 3H), 0.99-1.03 (m, 10H), 0.79-0.91 (m, 1H), 0.58-0.59 (m, 0.5H), 0.36-0.40 (m, 0.5H)


Step 8



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TBAF (6.99 mL, 6.99 mmol) was added to a solution of (1R,2R)-ethyl 2-(1-((tert-butyldiphenylsilyl)oxy)-3-methoxypropyl)cyclopropanecarboxylate (1.54 g, 3.49 mmol) in THE (20 mL). The mixture was stirred at 26° C. for 2 hours. The mixture was then diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (Petroleum ether/EtOAc=20:1-2:1) to afford product (1R,2R)-ethyl 2-(1-hydroxy-3-methoxypropyl)cyclopropanecarboxylate.



1H NMR (500 MHz, chloroform-d) δ 4.08-4.18 (m, 2H), 3.67 (td, J=5.0, 9.5 Hz, 1H), 3.53-3.62 (m, 1H), 3.40-3.53 (m, 1H), 3.36 (d, J=2.0 Hz, 3H), 2.90 (d, J=2.0 Hz, 1H), 1.81-1.91 (m, 2H), 1.58-1.73 (m, 2H), 1.27 (dt, J=2.5, 7.0 Hz, 3H), 1.17 (qd, J=4.5, 16.5 Hz, 1H), 0.86-1.05 (m, 1H)


Step 9



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(E)-diisopropyl diazene-1,2-dicarboxylate (0.916 mL, 4.65 mmol) was added dropwise, at 0° C., under N2 atmosphere to a solution of (E)-tert-butyl (4,4-diethyl-6-oxotetrahydropyrimidin-2(1H)-ylidene)carbamate (626 mg, 2.324 mmol), (1R,2R)-ethyl 2-(1-hydroxy-3-methoxypropyl)cyclopropanecarboxylate (470 mg, 2.324 mmol) and triphenylphosphine (1219 mg, 4.65 mmol) in THF (15 mL). The mixture was stirred at 25° C. for 12 h. The mixture was then concentrated in vacuo. The residue was purified by column chromatography (Petroleum ether:EtOAc=15:1-5:1) to afford product (1R,2R)-ethyl 2-(1-((E)-2-((tert-butoxycarbonyl)imino)-4,4-diethyl-6-oxotetrahydropyrimidin-1(2H)-yl)-3-methoxypropyl)cyclopropanecarboxylate. MS (ESI) m z 454.3 (M+H+)


Step 10



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(1R,2R)-ethyl 2-(1-(2-((tert-butoxycarbonyl)imino)-4,4-diethyl-6-oxotetrahydropyrimidin-1(2H)-yl)-3-methoxypropyl)cyclopropanecarboxylate (800 mg, 1.429 mmol) was separated by SFC (Instrument SFC-16 Method Column Phenomenex-Cellulose-2 (250 mm*30 mm, 5 um) Condition 0.1% NH3H2O EtOH Begin B 15% End B 15% Gradient Time (min) 100% B Hold Time (min) FlowRate (mL/min) 60 Injections 150) to afford product (1R,2R)-ethyl 2-((R)-1-(2-((tert-butoxycarbonyl)imino)-4,4-diethyl-6-oxotetrahydropyrimidin-1(2H)-yl)-3-methoxypropyl)cyclopropanecarboxylate (Peak 1, Rt=2.072) and (1R,2R)-ethyl 2-((R)-1-(2-((tert-butoxycarbonyl)imino)-4,4-diethyl-6-oxotetrahydropyrimidin-1(2H)-yl)-3-methoxypropyl)cyclopropanecarboxylate (Peak 2, Rt=2.356) both as a colorless oil.


MS (ESI) m z 454.3 (M+H+).


Peak 1: 1H NMR (500 MHz, chloroform-d) δ=9.60-10.17 (m, 1H), 4.36-4.52 (m, 1H), 3.97-4.14 (m, 2H), 3.32-3.53 (m, 2H), 3.28 (s, 3H), 2.50-2.63 (m, 3H), 2.30-2.45 (m, 1H), 2.01-2.19 (m, 1H), 1.60-1.66 (m, 5H), 1.39-1.52 (m, 9H), 1.19-1.21 (m, 4H), 0.87-1.03 (m, 7H)


Peak 2: 1H NMR (500 MHz, chloroform-d) δ=9.72-10.07 (m, 1H), 4.45 (s, 1H), 4.12-4.13 (m, 2H), 3.39-3.42 (m, 2H), 3.33 (s, 3H), 2.56 (s, 2H), 2.23-2.42 (m, 2H), 1.62 (s, 5H), 1.46-1.52 (m, 9H), 1.24-1.27 (m, 4H), 0.86-1.04 (m, 7H)


Step 11



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Lithium hydroxide monohydrate (486 mg, 11.57 mmol) was added to a solution of (1R,2R)-ethyl 2-((R)-1-((E)-2-((tert-butoxycarbonyl)imino)-4,4-diethyl-6-oxotetrahydropyrimidin-1(2H)-yl)-3-methoxypropyl)cyclopropanecarboxylate (350 mg, 0.772 mmol) in MeOH (6 mL), THE (6 mL) and water (1.2 mL). The mixture was stirred at 30° C. for 4 hours. EtOAc (4 mL) was added to the mixture and the mixture was neutralized to pH 5-6 with citric acid. The mixture was then quenched with water (10 mL), and extracted with EtOAc (15 mL×3). The organic layers were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford crude product (1R,2R)-2-((R)-1-((E)-2-((tert-butoxycarbonyl)imino)-4,4-diethyl-6-oxotetrahydropyrimidin-1(2H)-yl)-3-methoxypropyl)cyclopropanecarboxylic acid, which was used for next step directly.


MS (ESI) m/z 426.2 (M+H+).


Step 12



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DIEA (0.205 mL, 1.175 mmol) was added to a solution of (1R,2R)-2-((R)-1-(2-((tert-butoxycarbonyl)imino)-4,4-diethyl-6-oxotetrahydropyrimidin-1(2H)-yl)-3-methoxypropyl)cyclopropanecarboxylic acid (100 mg, 0.00 mmol), (S)-2,2-dimethylchroman-4-amine hydrochloride (60.3 mg, 0.282 mmol), HOBt (72.0 mg, 0.470 mmol) and EDCI (180 mg, 0.940 mmol) in THE (6 mL). The mixture was stirred at 25° C. for 2 hours. The mixture was quenched with water (10 mL), and extracted with EtOAc (10 mL×3). The organic layers were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford crude product, then purified by Prep-TLC (Petroleum ether/EtOAc=1:2) to give the product tert-butyl (1-((R)-1-((1R,2R)-2-(((S)-2,2-dimethylchroman-4-yl)carbamoyl)cyclopropyl)-3-methoxypropyl)-4,4-diethyl-6-oxotetrahydropyrimidin-2(1H)-ylidene)carbamate.


MS (ESI) m z 585.4 (M+H+).


Step 13



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TFA (4 mL) at 22° C. was added to a solution of tert-butyl (1-((R)-1-((1R,2R)-2-(((S)-2,2-dimethylchroman-4-yl)carbamoyl)cyclopropyl)-3-methoxypropyl)-4,4-diethyl-6-oxotetrahydropyrimidin-2(1H)-ylidene)carbamate (100 mg, 0.171 mmol) in DCM (12 mL). The reaction was stirred for 1 h. The mixture was concentrated in vacuo, purified by HPLC (Boston Green ODS 150*30 5u, Condition water (0.1% TFA)-ACN, Begin B 33, End B 63, Gradient Time (min) 10, 100% B Hold Time (min) 2, FlowRate (mL/min) 25, Injections 3), then lyphilized to give the product (1R,2R)-2-((R)-1-(4,4-diethyl-2-imino-6-oxotetrahydropyrimidin-1(2H)-yl)-3-methoxypropyl)-N—((S)-2,2-dimethylchroman-4-yl)cyclopropanecarboxamide. MS (ESI) m z 485.4 (M+H+).


Example 1: 1H NMR (500 MHz, METHANOL-d4) δ=8.50-8.23 (m, 1H), 7.15-7.14 (m, 1H), 7.08 (d, J=7.5 Hz, 1H), 6.88 (dt, J=1.0, 7.5 Hz, 1H), 6.74 (dd, J=1.0, 8.0 Hz, 1H), 5.37-5.18 (m, 1H), 3.58-3.44 (m, 2H), 3.39 (s, 1H), 3.35 (s, 3H), 2.89 (d, J=16.0 Hz, 1H), 2.70 (d, J=16.0 Hz, 1H), 2.51 (s, 2H), 2.58-2.40 (m, 1H), 2.22 (m, 1H), 2.14-2.02 (m, 1H), 1.88-1.50 (m, 6H), 1.44 (s, 3H), 1.35 (m, 1H), 1.32-1.25 (m, 3H), 0.99-0.71 (m, 6H).


Example 2



embedded image


Example 2
Step 1



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TBAF (232 mL, 232 mmol) was added to a solution of (1R,2R)-ethyl 2-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropanecarboxylate (30 g, 116 mmol) in THE (150 mL). The mixture was stirred at 26° C. for 2 hours. The mixture was diluted with water (300 mL), and extracted with EtOAc (400 mL×3). The organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography (Petroleum ether/EtOAc=100:1-10:1) to afford product (1R,2R)-ethyl 2-(hydroxymethyl)cyclopropanecarboxylate.



1H NMR (500 MHz, chloroform-d) δ=4.19-4.07 (m, 2H), 3.63 (td, J1=5.0, J2=11.0 Hz, 1H), 3.54-3.43 (m, 1H), 1.72-1.73 (m, 1H), 1.56-1.58 (m, 2H), 1.31-1.25 (m, 3H), 1.22-1.23 (m, 1H), 0.92-0.82 (m, 1H).


Step 2



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DMP (70.6 g, 166 mmol) was added to a solution of (1R,2R)-ethyl 2-(hydroxymethyl)cyclopropanecarboxylate (16 g, 111 mmol) in DCM (600 mL). The mixture was stirred under nitrogen at 20° C. for 10 h. The mixture was filtered, then concentrated and purified by flash column (Petroleum ether/EtOAc=100:0 to 10:1) to afford product (1R,2R)-ethyl 2-formylcyclopropanecarboxylate.



1H NMR (500 MHz, chloroform-d) δ=9.31 (d, J=4.0 Hz, 1H), 4.27-4.15 (m, 2H), 2.41-2.44 (m, 1H), 2.32-2.22 (m, 1H), 1.61-1.62 (m, 1H), 1.57-1.49 (m, 1H), 1.30-1.27 (m, 3H)


Step 3



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Isopropylmagnesium lithium chloride (30.3 mL, 39.4 mmol) was added dropwise to a solution of 3-iodopyridine (8.08 g, 39.4 mmol) and zinc(II) chloride (1.970 mL, 1.970 mmol) in THE (50 mL) at 0° C. under N2 atmosphere. Then the mixture was stirred at 15° C. for 20 min. Then the mixture was cooled to −20° C. (1R,2R)-ethyl 2-formylcyclopropanecarboxylate (4 g, 19.70 mmol) in THE (20 mL) was added to the mixture dropwise. The mixture was stirred at −20° C. for 1 h. The mixture was quenched with sat. a.q. NH4Cl (40 mL), and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, concentrated in vacuo. The residue was purified by flash column (Petroleum ether/EtOAc=10:1 to 1:1) to afford (1R,2R)-ethyl 2-(hydroxy(pyridin-3-yl)methyl)cyclopropanecarboxylate. MS (ESI) m z 222.1 (M+H+).



1H NMR (500 MHz, chloroform-d) δ 8.57 (s, 1H), 8.51 (td, J1=1.5 Hz, J2=5.0 Hz, 1H), 7.84-7.72 (m, 1H), 7.31 (td, J1=4.0 Hz, J2=8.0 Hz, 1H), 4.52 (d, J=6.0 Hz, 1H), 4.29 (d, J=7.0 Hz, 1H), 4.16-4.03 (m, 2H), 1.89-1.76 (m, 2H), 1.29-1.22 (m, 4H), 1.19-1.11 (m, 1H), 1.06-0.96 (m, 1H)


Step 4



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(E)-diisopropyl diazene-1,2-dicarboxylate (1.247 mL, 6.33 mmol) was added dropwise to a solution of (E)-tert-butyl (4,4-diethyl-6-oxotetrahydropyrimidin-2(1H)-ylidene)carbamate (0.852 g, 3.16 mmol), (1R,2R)-ethyl 2-(hydroxy(pyridin-3-yl)methyl)cyclopropanecarboxylate (0.7 g, 3.16 mmol) and triphenylphosphine (1.660 g, 6.33 mmol) in THE (20 mL) at 0° C. under N2 atmosphere. Then the mixture was stirred at 23° C. for 12 h. Water (20 mL) was added to the mixture, and extracted with EtOAc (15 mL×3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered, concentrated in vacuo. The residue was purified by column chromatography (Petroleum ether:EtOAc=10:1-5:1), then purified by Prep-TLC (Petroleum ether:EtOAc=3:2) to afford (1R,2R)-ethyl 2-(((E)-2-((tert-butoxycarbonyl)imino)-4,4-diethyl-6-oxotetrahydropyrimidin-1(2H)-yl)(pyridin-3-yl)methyl)cyclopropanecarboxylate. MS (ESI) m z 473.3 (M+H+).



1H NMR (500 MHz, METHANOL-d4) δ=8.55 (d, J=2.0 Hz, 1H), 8.45-8.37 (m, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.46-7.34 (m, 1H), 5.66-5.51 (m, 1H), 4.23-4.12 (m, 2H), 2.69 (s, 2H), 1.78-1.58 (m, 5H), 1.55-1.41 (m, 10H), 1.32-1.16 (m, 7H), 1.13-1.04 (m, 1H), 1.01-0.85 (m, 7H)


Step 5



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(1R,2R)-ethyl 2-((S)-((E)-2-((tert-butoxycarbonyl)imino)-4,4-diethyl-6-oxotetrahydropyrimidin-1(2H)-yl)(pyridin-3-yl)methyl)cyclopropanecarboxylate (440 mg, 0.931 mmol) was separated by SFC (Instrument SFC 13 Method Column DAICEL CHIRALPAK IC (250 mm*30 mm, 5 um) Condition 0.1% NH3H2O EtOH Begin B 35% End B 35% Gradient Time (min) 100% B Hold Time (min) FlowRate (mL/min) 60 Injections 120) to afford product (1R,2R)-ethyl 2-((S)-((E)-2-((tert-butoxycarbonyl)imino)-4,4-diethyl-6-oxotetrahydropyrimidin-1(2H)-yl)(pyridin-3-yl)methyl)cyclopropanecarboxylate (Peak 1, Rt=3.403) and (1R,2R)-ethyl 2-((S)-((E)-2-((tert-butoxycarbonyl)imino)-4,4-diethyl-6-oxotetrahydropyrimidin-1(2H)-yl)(pyridin-3-yl)methyl)cyclopropanecarboxylate (Peak 2, Rt=4.649).


MS (ESI) m z 473.3 (M+H+)


Step 6



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Lithium hydroxide monohydrate (124 mg, 2.96 mmol) was added to a solution of (1R,2R)-ethyl 2-((S)-((E)-2-((tert-butoxycarbonyl)imino)-4,4-diethyl-6-oxotetrahydropyrimidin-1(2H)-yl)(pyridin-3-yl)methyl)cyclopropanecarboxylate (140 mg, 0.296 mmol) in MeOH (4 mL), THE (4 mL) and water (0.4 mL). The mixture was stirred at 25° C. for 2 hours. EtOAc (4 mL) was added to the mixture and the mixture was neutralized to pH 5-6 with citric acid. The mixture was quenched with water (10 mL), and extracted with EtOAc (15 mL×3). The organic layers were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford crude product (1R,2R)-2-((S)-((E)-2-((tert-butoxycarbonyl)imino)-4,4-diethyl-6-oxotetrahydropyrimidin-1(2H)-yl)(pyridin-3-yl)methyl)cyclopropanecarboxylic acid, which was used for next step directly. MS (ESI) m z 445.2 (M+H+)


Step 7



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DIEA (0.196 mL, 1.125 mmol) was added to a solution of (1R,2R)-2-((S)-((E)-2-((tert-butoxycarbonyl)imino)-4,4-diethyl-6-oxotetrahydropyrimidin-1(2H)-yl)(pyridin-3-yl)methyl)cyclopropanecarboxylic acid (100 mg, crude), (S)-2,2-dimethylchroman-4-amine (61.7 mg, 0.225 mmol), HOBt (68.9 mg, 0.450 mmol), EDCI (86 mg, 0.450 mmol) in THF (8 mL). The mixture was stirred at 22° C. for 12 hours. The mixture was quenched with water (15 mL), and extracted with EtOAc (15 mL×3). The organic layers were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford crude product, then purified by Prep-TLC (Petroleum ether/EtOAc=1:2) to give the product tert-butyl (1-((S)-((1R,2R)-2-(((S)-2,2-dimethylchroman-4-yl)carbamoyl)cyclopropyl)(pyridin-3-yl)methyl)-4,4-diethyl-6-oxotetrahydropyrimidin-2(1H)-ylidene)carbamate. MS (ESI) m z 604.3 (M+H+)


Step 8



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TFA (2 mL) was added to a solution of tert-butyl (1-((S)-((1R,2R)-2-(((S)-2,2-dimethylchroman-4-yl)carbamoyl)cyclopropyl)(pyridin-3-yl)methyl)-4,4-diethyl-6-oxotetrahydropyrimidin-2(1H)-ylidene)carbamate (90 mg, 0.149 mmol) in DCM (6 mL). The reaction was stirred at 23° C. for 1 h. The mixture was concentrated in vacuo, then purified by HPLC (Instrument ee Method Column YMC-Actus Pro C18 150*30 5u Condition water (0.1% TFA)-ACN Begin B 24 End B 54 Gradient Time (min) 11 100% B Hold Time (min) 1.1 FlowRate (mL/min) 40 Injections 3) to give the product (1R,2R)-2-((S)-(4,4-diethyl-2-imino-6-oxotetrahydropyrimidin-1(2H)-yl)(pyridin-3-yl)methyl)-N—((S)-2,2-dimethylchroman-4-yl)cyclopropanecarboxamide. MS (ESI) m z 504.2 (M+H+).



1H NMR (500 MHz, METHANOL-d4) δ 8.85 (s, 1H), 8.66 (s, 1H), 8.58 (d, J=8.5 Hz, 1H), 8.29 (d, J=8.0 Hz, 1H), 7.74 (s, 1H), 7.17-7.08 (m, 2H), 6.89-6.82 (m, 1H), 6.74 (d, J=8.0 Hz, 1H), 5.25-5.18 (m, 1H), 4.95 (d, J=3.0 Hz, 1H), 2.98-2.90 (m, 1H), 2.87-2.66 (m, 2H), 2.09-2.11 (in, 1H), 1.85-1.92 (m, 1H), 1.82 (t, J=12.5 Hz, 1H), 1.75-1.66 (m, 3H), 1.65-1.56 (m, 2H), 1.43 (s, 3H), 1.29 (s, 3H), 1.21 (s, 1H), 0.92 (t, J=7.5 Hz, 3H), 0.83 (t, J=7.5 Hz, 3H)


The compounds in Table 1 and 2 were made in accordance with the general schemes and Example 1 and 2 described above.











TABLE 1







LC/MS


Ex.
Structure
(M + 1)+

















 1A


embedded image


485.3





 1B


embedded image


485.4





 2


embedded image


504.3





 3A


embedded image


371.1





 3B


embedded image


371.3





 4A


embedded image


399.2





 4B


embedded image


399.2





 4C


embedded image


399.3





 4D


embedded image


399.2





 5


embedded image


427.3





 6A


embedded image


399.1





 6B


embedded image


399.2





 7A


embedded image


445.3





 7B


embedded image


445.3





 8A


embedded image


467.3





 8B


embedded image


467.3





 9


embedded image


476.3





 10


embedded image


476.3





 11A


embedded image


520.3





 11B


embedded image


520.3





 12


embedded image


544.3





 13


embedded image


457.4





 14


embedded image


525.3





 15A


embedded image


435.2





 15B


embedded image


435.2





 16A


embedded image


463.3





 16B


embedded image


463.3





 17A


embedded image


503.2





 17B


embedded image


503.2





 18A


embedded image


479.2





 18B


embedded image


479.3





 19A


embedded image


485.3





 19B


embedded image


485.4





 20


embedded image


485.3





 21A


embedded image


525.2





 21B


embedded image


525.2





 22


embedded image


457.2





 23A


embedded image


457.3





 23B


embedded image


457.3





 24A


embedded image


497.2





 24B


embedded image


497.2





 24C


embedded image


497.1





 25A


embedded image


441.3





 25B


embedded image


441.3





 26


embedded image


476.3





 27


embedded image


492.3





 28A


embedded image


481.3





 28B


embedded image


481.3





 29A


embedded image


427.3





 29B


embedded image


427.3





 29C


embedded image


427.3





 30A


embedded image


457.3





 30B


embedded image


457.3





 31A


embedded image


495.3





 31B


embedded image


495.2





 32


embedded image


516.2





 33


embedded image


413.3





 34


embedded image


455.3





 35A


embedded image


443.3





 35B


embedded image


443.1





 36A


embedded image


427.3





 36B


embedded image


427.3





 37


embedded image


546.2





 38


embedded image


506.3





 39


embedded image


522.3





 40


embedded image


506.2





 41


embedded image


546.1





 42


embedded image


522.2





 43A


embedded image


544.2





 43B


embedded image


544.2





 44A


embedded image


572.2





 44B


embedded image


572.3





 45A


embedded image


500.2





 45B


embedded image


500.2





 46


embedded image


516.2





 47A


embedded image


540.2





 47B


embedded image


540.1





 48A


embedded image


532.3





 48B


embedded image


532.3





 49A


embedded image


504.3





 49B


embedded image


504.2





 50


embedded image


500.2





 51


embedded image


516.2





 52


embedded image


540.2





 53A


embedded image


518.2





 53B


embedded image


518.3





 54A


embedded image


530.2





 54B


embedded image


530





 55A


embedded image


558.3





 55B


embedded image


558





 56A


embedded image


518.1





 56B


embedded image


518.1





 57A


embedded image


490.3





 57B


embedded image


490.1





 58A


embedded image


510.2





 58B


embedded image


510.2





 59


embedded image


526.2





 60A


embedded image


550.2





 60B


embedded image


550.2





 61


embedded image


487.3





 62A


embedded image


511.3





 62B


embedded image


511.3





 63


embedded image


490.3





 64A


embedded image


471.3





 64B


embedded image


471.3





 65A


embedded image


506.3





 65B


embedded image


506.3





 66


embedded image


524.3





 67A


embedded image


508.3





 67B


embedded image


508.3





 68


embedded image


548.2





 69A


embedded image


526.2





 69B


embedded image


526.3





 69C


embedded image


526.3





 69D


embedded image


526.2





 69E


embedded image


526.2





 70A


embedded image


487.3





 70B


embedded image


487.3





 71


embedded image


417.2





 72A


embedded image


475.3





 72B


embedded image


475.3





 73


embedded image


429.3





 74A


embedded image


487.3





 74B


embedded image


487.3





 75A


embedded image


471.3





 75B


embedded image


471.3





 75C


embedded image


471.3





 75D


embedded image


471.3





 76A


embedded image


475.3





 76B


embedded image


475.3





 77A


embedded image


494.3





 77B


embedded image


494.3





 78


embedded image


413.3





 79A


embedded image


427.3





 79B


embedded image


427.3





 79C


embedded image


427.3





 80A


embedded image


485.4





 80B


embedded image


485.3





 80C


embedded image


485.3





 80D


embedded image


485.3





 81A


embedded image


504.4





 81B


embedded image


504.3





 81C


embedded image


504.4





 81D


embedded image


504.4





 82A


embedded image


487.3





 82B


embedded image


487.3





 82C


embedded image


487.3





 82D


embedded image


487.3





 83A


embedded image


471.3





 83B


embedded image


471.3





 84


embedded image


413.2





 85A


embedded image


490.3





 85B


embedded image


490.3





 86A


embedded image


494.3





 86B


embedded image


494.3





 87


embedded image


417.3





 88A


embedded image


475.3





 88B


embedded image


475.3





 89A


embedded image


491.3





 89B


embedded image


491.3





 90


embedded image


433.2





 91A


embedded image


510.3





 91B


embedded image


510.3





 92A


embedded image


485.3





 92B


embedded image


485.4





 93A


embedded image


494.3





 93B


embedded image


494.3





 94A


embedded image


544.2, 546.2





 94B


embedded image


544.2, 546.2





 95


embedded image


433.2





 96A


embedded image


506.3





 96B


embedded image


506.3





 97A


embedded image


467.1, 469.2





 97B


embedded image


467.1, 469.2





 98A


embedded image


494.3





 98B


embedded image


494.3





 99


embedded image


485.2





100


embedded image


467.2





101


embedded image


491.3





102A


embedded image


508.2





102B


embedded image


508.2





103A


embedded image


538.2





103B


embedded image


538.3





104A


embedded image


564.2





104B


embedded image


564.2





105A


embedded image


490.3





105B


embedded image


490.3





105C


embedded image


490.3





105D


embedded image


490.3





106A


embedded image


525.2, 527.2





106B


embedded image


525.2, 527.2





107A


embedded image


541.3





107B


embedded image


541.3





108A


embedded image


506.3





108B


embedded image


506.2





108C


embedded image


506.3





108D


embedded image


506.3





109A


embedded image


544.3





109B


embedded image


544.3





110A


embedded image


525.3





110B


embedded image


525.3





111A


embedded image


475.3





111B


embedded image


475.3





112A


embedded image


491.3





112B


embedded image


491.3





113A


embedded image


493.3





113B


embedded image


493.3





114A


embedded image


543.3





114B


embedded image


543.2





115A


embedded image


562.2





115B


embedded image


562.2





116A


embedded image


491.2





116B


embedded image


491.3





117A


embedded image


510.2





117B


embedded image


510.3





118


embedded image


483.2





119


embedded image


433.2





120


embedded image


510.3





121A


embedded image


510.2





121B


embedded image


510.3





122A


embedded image


512.2





122B


embedded image


512.2





123


embedded image


485.3





124


embedded image


505.3





125A


embedded image


483.1





125B


embedded image


483.1





126A


embedded image


541.3





126B


embedded image


541.3





127A


embedded image


539.3





127B


embedded image


539.3





128


embedded image


413.3





129A


embedded image


555.3





129B


embedded image


555.2





130A


embedded image


489.3





130B


embedded image


489.2





131A


embedded image


469.2





131B


embedded image


469.3





132


embedded image


471.3





133A


embedded image


399.3





133B


embedded image


399.2





134A


embedded image


541.1





134B


embedded image


541.1





135


embedded image


411.2





136


embedded image


447.3





137A


embedded image


505.3





137B


embedded image


505.3





138A


embedded image


485.2





138B


embedded image


485.2





139A


embedded image


403.2





139B


embedded image


403.1





140A


embedded image


411.1





140B


embedded image


411.2


















TABLE 2







LC/MS


Ex.
Structure
(M + 1)+







141


embedded image


485.3





142A


embedded image


499.4





142B


embedded image


499.4





142C


embedded image


499.4





142D


embedded image


499.3





143A


embedded image


499.4





143B


embedded image


499.4





143C


embedded image


499.4





144


embedded image


501.3





145


embedded image


501.1





146


embedded image


519.3





147A


embedded image


519.1





147B


embedded image


519.1





148A


embedded image


519.1





148B


embedded image


519.1





149A


embedded image


519.3





149B


embedded image


519.3





150


embedded image


535.2









Assessing Antiparasite Potency in a Parasite LDH Growth Assay (Parasite Assay)

The parasite stock was maintained at 400 haematocrit in RPMI-Hepes media buffered with sodium bicarbonate and supplemented with 500 heat inactivated human serum and 0.500 albumax.


Approximately 42 hours prior to the potency assay being set up, parasites were synchronized with 500 sorbitol to select for ring stage parasites. On the day of assay set up, a blood smear of the parasite culture was Giemsa stained and counted. The parasitemia was adjusted to 0.7% rings and the haematocrit was diluted to 2% in RPMI-Hepes media buffered with sodium bicarbonate and supplemented with 500 heat inactivated human serum and 0.5% albumax. 30 ul of diluted parasites are then added into 10 ul of media+compound in pre-prepared Greiner TC assay plates. Parasite assay plates were placed in gassed humidified boxes in single layer and allowed to incubate at 37° C. for 72 hours. After 72 hours growth, assay plates are sealed with parafilm and frozen flat, in single file at −80° C. overnight. On the following day, assay plates are allowed to thaw at room temperature for 4 hours to which an LDH assay is performed to measure parasite growth.


Assay EC50 results are shown in Table 3 and Table 4.












TABLE 3







Example
EC50 (nM)



















 1A
1



 1B
250



 2
0.9



 3A
234



 3B
151



 4A
94



 4B
26



 4C
85



 4D
91



 5
49



 6A
188



 6B
269



 7A
135



 7B
29



 8A
37



 8B
5.3



 9
6.9



 10
27



 11A
4.1



 11B
24



 12
0.9



 13
24



 14
0.9



 15A
240



 15B
230



 16A
33



 16B
119



 17A
47



 17B
20



 18A
39



 18B
180



 19A
28



 19B
4.2



 20
5.3



 21A
260



 21B
1



 22
44



 23A
16



 23B
15



 24A
3.4



 24B
2



 24C
120



 25A
84



 25B
25



 26
4.7



 27
78



 28A
12



 28B
14



 29A
203



 29B
351



 29C
113



 30A
45



 30B
7.7



 31A
215



 31B
213



 32
1.8



 33
76



 34
286



 35A
85



 35B
220



 36A
247



 36B
301



 37
1.2



 38
6.5



 39
10.1



 40
3.1



 41
1.1



 42
18.4



 43A
4



 43B
37



 44A
8.3



 44B
0.9



 45A
2.8



 45B
220



 46
2.5



 47A
155



 47B
0.9



 48A
2.7



 48B
7.4



 49A
20



 49B
14



 50
3



 51
5.3



 52
1



 53A
3.1



 53B
2.1



 54A
1



 54B
130



 55A
0.8



 55B
180



 56A
65



 56B
0.7



 57A
3.2



 57B
100



 58A
210



 58B
1



 59
3.8



 60A
0.5



 60B
100



 61
6.9



 62A
31



 62B
0.8



 63
1.2



 64A
2.3



 64B
195



 65A
2.8



 65B
8



 66
2.6



 67A
0.9



 67B
0.6



 68
0.3



 69A
1



 69B
1.9



 69C
0.8



 69D
0.3



 69E
300



 70A
77



 70B
19



 71
125



 72A
11



 72B
2.5



 73
192



 74A
33



 74B
3.1



 75A
8.2



 75B
7.5



 75C
7



 75D
7



 76A
17



 76B
15



 77A
1.7



 77B
2.3



 78
300



 79A
255



 79B
275



 79C
289



 80A
9.4



 80B
6.6



 80C
14



 80D
21



 81A
2.7



 81B
1



 81C
0.9



 81D
1.3



 82A
24.4



 82B
57



 82C
53



 82D
27



 83A
6.6



 83B
26



 84
289



 85A
2.4



 85B
0.9



 86A
2.2



 86B
2.8



 87
160



 88A
5.2



 88B
10



 89A
5.6



 89B
22



 90
225



 91A
0.8



 91B
2.7



 92A
7.6



 92B
7.2



 93A
3.3



 93B
2.4



 94A
0.9



 94B
0.9



 95
110



 96A
2.7



 96B
3.3



 97A
180



 97B
220



 98A
0.9



 98B
2.2



 99
130



100
170



101
2.9



102A
0.8



102B
2.5



103A
29



103B
2.1



104A
4



104B
22



105A
0.9



105B
1.8



105C
0.8



105D
0.9



106A
7.4



106B
10



107A
2.1



107B
11



108A
70



108B
3.7



108C
6



108D
8.5



109A
2.3



109B
1



110A
21



110B
7.2



111A
24



111B
15



112A
18



112B
9.4



113A
19



113B
7.5



114A
89



114B
5.1



115A
6.6



115B
1



116A
0.8



116B
18



117A
0.8



117B
2.7



118
63



119
26



120
1



121A
2.5



121B
2



122A
2.3



122B
2.2



123
2



124
0.8



125A
231



125B
160



126A
4.7



126B
8.4



127A
1.1



127B
2.6



128
280



129A
1.3



129B
2.5



130A
0.9



130B
2.4



131A
6.8



131B
6.1



132
6.7



133A
210



133B
100



134A
71



134B
25



135
190



136
160



137A
12



137B
6.4



138A
7.4



138B
18



139A
99



139B
130



140A
220



140B
280




















TABLE 4









141
4.7



142A
1.9



142B
0.7



142C
204.9



142D
114.9



143A
4.6



143B
2.4



143C
57.9



144
164.9



145
8.4



146
1.1



147A
2.8



147B
8.2



148A
2.7



148B
1.9



149A
1.0



149B
1.2



150
3.9









Claims
  • 1. A compound having the structural Formula (I):
  • 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of:
  • 3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is:
  • 4. The compound of claims 1-2, or a pharmaceutically acceptable salt thereof, wherein R1 is:
  • 5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen.
  • 6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is a chromane or indane moiety.
  • 7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein R1 is:
  • 8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from hydrogen, halogen or C1-C6alkyl.
  • 9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 is selected from hydrogen, halogen or C1-C6alkyl.
  • 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R5 and R6 are independently selected from hydrogen or C1-C6alkyl.
  • 11. (canceled)
  • 12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R5 and R6 are independently selected from methyl or ethyl.
  • 13. (canceled)
  • 14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R9 is hydrogen, C1-C6alkyl, heteroaryl, or aryl, wherein the C1-C6alkyl, heteroaryl or aryl can be unsubstituted or substituted with one, two or three substituents selected from the group consisting of halogen, CN, OH, alkoxy.
  • 15. A compound selected from the group consisting of:
  • 16. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • 17. (canceled)
  • 18. A method for treating a Plasmodium infection, or for treating malaria, which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.
  • 19. A method for inhibiting plasmepsin X which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.
  • 20. A method for inhibiting plasmepsin IX which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.
  • 21. A method for dual inhibition of plasmepsin IX and plasmepsin X which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.
  • 22-25. (canceled)
  • 26. A method for treating a Plasmodium infection, or for treating malaria, comprising administration of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and an effective amount of one or more additional anti-malarial agents.
  • 27. A method for the treatment of malaria by inhibition of plasmepsin X, IX and at least one other mechanism, comprising administration of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and an effective amount of one additional anti-malarial agent, wherein the additional anti-malarial agent acts through a different mechanism than inhibiting plasmepsin IX or plasmepsin X.
Priority Claims (1)
Number Date Country Kind
PCT/CN2019/119495 Nov 2019 CN national
PCT Information
Filing Document Filing Date Country Kind
PCT/US2020/060713 11/16/2020 WO