WO2023107356A1 - Antimalarial agents - Google Patents

Antimalarial agents Download PDF

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Publication number
WO2023107356A1
WO2023107356A1 PCT/US2022/051770 US2022051770W WO2023107356A1 WO 2023107356 A1 WO2023107356 A1 WO 2023107356A1 US 2022051770 W US2022051770 W US 2022051770W WO 2023107356 A1 WO2023107356 A1 WO 2023107356A1
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WIPO (PCT)
Prior art keywords
alkyl
certain embodiments
c6alkyl
compound
pharmaceutically acceptable
Prior art date
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PCT/US2022/051770
Other languages
French (fr)
Inventor
John A. Mccauley
Manuel De Lera Ruiz
Zhuyan Guo
Philippe Nantermet
Michael J. KELLY III
Alvaro GUTIERREZ BONET
Lianyun Zhao
Zhiyu Lei
Bin Hu
Dongmei ZHAN
Anthony HODDER
Original Assignee
Merck Sharp & Dohme Llc
The Walter And Eliza Hall Institute Of Medical Research
Msd R&D (China) Co., Ltd.
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Priority claimed from PCT/CN2021/136177 external-priority patent/WO2023102747A1/en
Application filed by Merck Sharp & Dohme Llc, The Walter And Eliza Hall Institute Of Medical Research, Msd R&D (China) Co., Ltd. filed Critical Merck Sharp & Dohme Llc
Priority to AU2022404966A priority Critical patent/AU2022404966A1/en
Priority to CA3240145A priority patent/CA3240145A1/en
Publication of WO2023107356A1 publication Critical patent/WO2023107356A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings

Definitions

  • 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.
  • 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.
  • P. falciparum aspartic acid proteases plasmepsin X and IX 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): wherein A, X, V, Y, Z, R a , R b , R 3 , R 4 , R 12 , R 13 , R 15 , m and p 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 treatment of malaria comprising administering to a subject in need thereof a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • 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.
  • 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.
  • 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 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 further provides methods for the inhibition of plasmepsin X, or the dual inhibition of plasmepsin X and plasmepsin IX activity and of 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 further provides methods for blocking P. falciparum growth by inhibiting plasmepsin X.
  • the present invention further provides methods for blocking P. falciparum growth by inhibiting both PMX and Plasmepsin IX.
  • the present invention further provides methods for the treatment of malaria by inhibiting plasmepsin X.
  • the present invention further provides methods for the treatment of malaria by inhibiting both PMX and Plasmepsin IX.
  • A is a straight or branched, saturated or unsaturated (C 3 -C 10 )alkylene, phenyl(C 3 - C 10 )alkylene or cycloalkyl(C 3 -C 10 )alkylene comprising at least one –CH 2 - group, wherein one or more additional –CH2- groups in A are optionally and independently replaced with a moiety selected from the group consisting of O, S, NR, CONR, NRCO, SO2, and SO2NR and wherein one or more of the hydrogens along A can be replaced with a group independently selected from hydroxyl, halogen and C1-3 haloalkyl;
  • X is a bond, C(R 14 )2, O, S, SO, SO2 or NH;
  • Y is CR 9 or N, wherein when Y is N, Z is CR 11 and V is CR 10 ;
  • V is CR 10 or N, wherein when V is N, Z is CR 11 and Y is CR
  • X is a bond, C(R 14 ) 2 , O, S, SO, SO 2 or NH. In certain embodiments described herein X is a bond. In certain embodiments, X is C(R 14 ) 2 , wherein R 14 is discussed in further detail below. In certain embodiments, X is a bond, CH 2 , CH(CH 3 ), C(CH 3 ) 2 , O, CH(OCH 3 ), SO 2 or CF 2 . In other embodiments X is CH 2 , O, S, SO, SO 2 or NH. In certain embodiments, X is CH 2 . In the embodiments described herein, X is O. In certain embodiments described herein, X is S.
  • X is SO. In other embodiments described herein, X is SO2. In certain embodiments described herein, X is NH. In the embodiments described herein, Y is CR 9 or N. In certain embodiments, Y is CR 9 , wherein R 9 is discussed in detail below. In certain embodiments, Y is N. In certain embodiments, Y is CH. In certain embodiments, wherein when Y is N, Z is CR 11 and V is CR 10 . In the embodiments described herein, V is CR 10 or N. In certain embodiments, V is CR 10 , wherein R 10 is discussed in detail below. In certain embodiments, V is N. In certain embodiments, V is CH.
  • Z is CR 11 and Y is CR 9 .
  • Z is CR 11 or N.
  • Z is CR 11 , wherein R 11 is discussed in detail below.
  • Z is CH.
  • Z is N.
  • V is CR 10 and Y is CR 9 .
  • X is O, Y and V are each CH and Z is N.
  • X is O, Y and Z are each CH and V is N.
  • X is O and V, Y and Z are all simultaneously CH.
  • R a is hydrogen, halogen, CN, OH, C 1 - C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, oxo, COOC 1 -C 6 alkyl, C 1 - C 6 alkylCOOC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkylC 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, -C 1 - C 6 alkylOhaloC 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C 1 - C 6 alkylN(R 7 )(R 8 ) or when taken with R b forms a C 3 -C 6
  • R a is hydrogen. In certain embodiments, R a is halogen. Examples of suitable halogens include chlorine, bromine, fluorine and iodine. In certain embodiments, R a is CN. In certain embodiments, R a is OH. In certain embodiments, R a is C 1 -C 6 alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R a is C 1 -C 6 alkylOC 1 -C 6 alkyl. In certain embodiments, R a is C 1 -C 6 alkylCOOH.
  • R a is COOH. In certain embodiments, R a is an oxo group. In certain embodiments, R a is COOC1-C6alkyl. In certain embodiments, R a is C1-C6alkylCOOC1-C6alkyl. In certain embodiments, R a is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R a is C1-C6alkylC3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to .
  • R a is C 1 -C 6 alkyl.
  • C 1 -C 6 alkyl 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-eth
  • R a is methyl. In certain embodiments, R a is C 1 -C 6 alkylOhaloC 1 -C 6 alkyl. Suitable examples of C1-C6alkylOhaloC1-C6alkyls include, but are not limited to, . In certain embodiments, R a 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, R a is C1-C6alkylOH.
  • Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol.
  • R a is CON(R 7 )(R 8 ).
  • R a is N(R 7 )(R 8 ).
  • R a is C 1 -C 6 alkylN(R 7 )(R 8 ), wherein R 7 and R 8 will be described in detail below.
  • R a is taken with R b and forms a C 3 -C 6 cycloalkyl or heterocycloalkyl, wherein the C 3 -C 6 cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of halogen, CN, OH, C 1 - C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, oxo, COOC 1 -C 6 alkyl, C 1 - C 6 alkylCOOC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkylC 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, -C 1 - C6alkylOhaloC1-C
  • R a is taken with R b and forms a C3-C6cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkylC 3 - C 6 cycloalkyl, C 1 -C 6 alkyl, -C 1 -C 6 alkylOhaloC 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ), N(R
  • Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, the cycloalkyl is unsubstituted.
  • the heterocycloalkyl is substituted with one or two substituents selected from the group consisting of halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1-C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3- C6cycloalkyl, C1-C6alkyl, -C1-C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6alkylN(R 7 )(R 8 ).
  • the cycloalkyl is substituted with one substituent selected from the group consisting of halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1- C 6 alkylCOOH, COOH, oxo, COOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 - C 6 alkylC 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, -C 1 -C 6 alkylOhaloC 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 - C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C 1 -C 6 alkylN(R 7 )(R 8 ).
  • the cycloalkyl is substituted with two substituents selected from the group consisting of halogen, CN, OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, oxo, COOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkylC 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, -C 1 -C 6 alkylOhaloC 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 - C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C 1 -C 6 alkylN(R 7 )(R 8 ).
  • the cycloalkyl is substituted with OH.
  • R a is taken with R b and forms a heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1- C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1-C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1- C6alkylC3-C6cycloalkyl, C1-C6alkyl, -C1-C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1- C6alkylOH, CON(R 7 )(R 8 ), N
  • 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 heterocycloalkyl groups include, but are not limited to,
  • Non-limiting examples of bicyclic heterocycloalkyl groups include, but are not limited to,
  • R a is taken with R b and forms: O .
  • the heterocycloalkyl is unsubstituted.
  • the heterocycloalkyl is substituted with one or two substituents selected from the group consisting of halogen, CN, OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, oxo, COOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkylC 3 - C 6 cycloalkyl, C 1 -C 6 alkyl, -C 1 -C 6 alkylOhaloC 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C 1 -C 6 alkylN(R 7 )(R 8 ).
  • the heterocycloalkyl is substituted with one substituent selected from the group consisting of halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1-C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3-C6cycloalkyl, C1-C6alkyl, -C1-C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1- C6alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6alkylN(R 7 )(R 8 ).
  • the heterocycloalkyl is substituted with two substituents selected from the group consisting of halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1-C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C 1 -C 6 alkylC 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, -C 1 -C 6 alkylOhaloC 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 - C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C 1 -C 6 alkylN(R 7 )(R 8 ).
  • the heterocycloalkyl is substituted with two substituents selected from the group consisting of C 1 -C 6 alkyl.
  • R b is hydrogen, halogen, CN, OH, C 1 - C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, oxo, COOC 1 -C 6 alkyl, C 1 - C 6 alkylCOOC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkylC 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, -C 1 - C 6 alkylOhaloC 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 )
  • R b is hydrogen. In certain embodiments, R b is halogen. Examples of suitable halogens include chlorine, bromine, fluorine and iodine. In certain embodiments, R b is CN. In certain embodiments, R b is OH. In certain embodiments, R b is C1-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R b is C1-C6alkylOC1-C6alkyl. In certain embodiments, R b is C 1 -C 6 alkylCOOH. In certain embodiments, R b is COOH.
  • R b is an oxo group. In certain embodiments, R b is COOC 1 -C 6 alkyl. In certain embodiments, R b is C 1 -C 6 alkylCOOC 1 -C 6 alkyl. In certain embodiments, R b is C 3 -C 6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R b is C 1 -C 6 alkylC 3 -C 6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to .
  • R b is C1-C6alkyl.
  • 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
  • R b is methyl. In certain embodiments, R b is C 1 -C 6 alkylOhaloC 1 -C 6 alkyl. Suitable examples of C1-C6alkylOhaloC1-C6alkyls include, but are not limited to, . In certain embodiments, R b is haloC 1 -C 6 alkyl. 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, R b is C 1 -C 6 alkylOH.
  • Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol.
  • R b is CON(R 7 )(R 8 ).
  • R b is N(R 7 )(R 8 ).
  • R b is C1-C6alkylN(R 7 )(R 8 ), wherein R 7 and R 8 will be described in detail below.
  • R b is taken with R a and forms a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1-C6alkylCOOC1- C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3-C6cycloalkyl, C1-C6alkyl, -C1-C6alkylOhaloC1-C6alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7
  • R b is taken with R a and forms a cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of halogen, CN, OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, oxo, COOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkylC 3 - C 6 cycloalkyl, C 1 -C 6 alkyl, -C 1 -C 6 alkylOhaloC 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ), N(R
  • Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, the cycloalkyl is unsubstituted.
  • the heterocycloalkyl is substituted with one or two substituents selected from the group consisting of halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1-C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3- C6cycloalkyl, C1-C6alkyl, -C1-C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6alkylN(R 7 )(R 8 ).
  • the cycloalkyl is substituted with one substituent selected from the group consisting of halogen, CN, OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 - C 6 alkylCOOH, COOH, oxo, COOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 - C 6 alkylC 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, -C 1 -C 6 alkylOhaloC 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 - C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C 1 -C 6 alkylN(R 7 )(R 8 ).
  • the cycloalkyl is substituted with two substituents selected from the group consisting of halogen, CN, OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, oxo, COOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkylC 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, -C 1 -C 6 alkylOhaloC 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 - C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C 1 -C 6 alkylN(R 7 )(R 8 ).
  • the cycloalkyl is substituted with OH.
  • R b is taken with R a and forms a heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1- C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1-C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1- C6alkylC3-C6cycloalkyl, C1-C6alkyl, -C1-C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1- C6alkylOH, CON(R 7 )(R 8 ), N
  • 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 heterocycloalkyl groups include, but are not limited to
  • Non-limiting examples of bicyclic heterocycloalkyl groups include, but are not limited to, .
  • R b is taken with R a and forms: .
  • the cycloalkyl or heterocycloalkyl is unsubstituted.
  • the cycloalkyl or heterocycloalkyl is substituted with one or two substituents selected from the group consisting of halogen, CN, OH, C 1 -C 6 alkoxy, C 1 - C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, oxo, COOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOC 1 - C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkylC 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, -C 1 -C 6 alkylOhaloC 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C
  • the cycloalkyl or heterocycloalkyl is substituted with one substituent selected from the group consisting of halogen, CN, OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 - C 6 alkylCOOH, COOH, oxo, COOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 - C 6 alkylC 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, -C 1 -C 6 alkylOhaloC 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 - C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C 1 -C 6 alkylN(R 7 )(
  • the cycloalkyl or heterocycloalkyl is substituted with two substituents selected from the group consisting of halogen, CN, OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1-C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3- C6cycloalkyl, C1-C6alkyl, -C1-C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) and C1-C6alkylN(R 7 )(R 8 ).
  • the heterocycloalkyl is substituted with two substituents selected from the group consisting of C1-C6alkyl. In certain embodiments, the cycloalkyl is substituted with two substituents selected from the group consisting of C1-C6alkyl. In certain embodiments, the cycloalkyl is unsubstituted.
  • R 3 is hydrogen, halogen, CN, OH, C 1 - C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ), C 1 -C 6 alkylN(R 7 )(R 8 ), C 1 - C 6 alkyl(OCH 2 CH 2 ) n N(R 7 )(R 8 ) or C 1 -C 6 alkylOhaloC 1 -C 6 alkyl or when taken with R 4 forms a C 3 - C 6 cycloalkyl or C 3 -C 6 heterocycloalkyl.
  • R 3 is hydrogen, halogen, CN, OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, C 3 - C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C 1 - C6alkylN(R 7 )(R 8 ) or when taken with R 4 forms a C3-C6cycloalkyl or C3-C6heterocycloalkyl.
  • R 3 is hydrogen. In certain embodiments, R 3 is halogen. Suitable halogens include fluorine, chlorine, bromine, and iodine. In certain embodiments, R 3 is CN. In certain embodiments, R 3 is OH. In certain embodiments, R 3 is C1-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R 3 is C1-C6alkylOC1-C6alkyl. In certain embodiments, R 3 is COOH. In certain embodiments, R 3 is C1- C6alkylCOOH.
  • R 3 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R 3 is C 1 -C 6 alkyl.
  • C 1 -C 6 alkyl 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.
  • R 3 is haloC 1 -C 6 alkyl. 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, R 3 is C 1 -C 6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R 3 is CON(R 7 )(R 8 ).
  • N(R 7 )(R 8 ) include, but are not limited to, CONH2 and CON(CH3)2.
  • R 3 is N(R 7 )(R 8 ).
  • Suitable examples of N(R 7 )(R 8 ) include, but are not limited to, NH2 and N(CH3)2.
  • R 3 is C1-C6alkylN(R 7 )(R 8 ).
  • Suitable examples of C1-C6alkylN(R 7 )(R 8 ) include, but are not limited to, , below.
  • R 3 is C 1 -C 6 alkylOhaloC 1 -C 6 alkyl.
  • haloalkyls include, but are not limited to, .
  • R 3 is C1-C6alkyl(OCH2CH2)nN(R 7 )(R 8 ).
  • R 7 , R 8 and n are discussed in detail below.
  • Suitable examples of C1-C6alkyl(OCH2CH2)nN(R 7 )(R 8 ) include, but .
  • n is 1, 2, 3 or 4.
  • n is 1.
  • n is 2.
  • n is 3.
  • n is 4.
  • R 3 is taken with R 4 and forms a C3-C6cycloalkyl or C3- C6heterocycloalkyl. In certain embodiments, R 3 is taken with R 4 and forms a C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R 3 is taken with R 4 and forms a C3- C 6 heterocycloalkyl.
  • 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.
  • R 3 is hydrogen, fluorine, methyl, ethyl, OH, methoxy, In certain embodiments, R 3 is hydrogen, methyl, ethyl or . In certain embodiments, R 3 is taken with R 4 to form oxetanyl.
  • R 4 is hydrogen, halogen, CN, OH, C 1 - C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ), C 1 -C 6 alkylN(R 7 )(R 8 ), C 1 - C 6 alkyl(OCH 2 CH 2 ) n N(R 7 )(R 8 ) or C 1 -C 6 alkylOhaloC 1 -C 6 alkyl or when taken with R 3 forms a C 3 - C 6 cycloalkyl or C 3 -C 6 heterocycloalkyl.
  • R 4 is hydrogen, halogen, CN, OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 - C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C 1 -C 6 alkylN(R 7 )(R 8 ) or when taken with R 3 forms a C 3 -C 6 cycloalkyl or C3-C6heterocycloalkyl.
  • R 4 is hydrogen. In certain embodiments, R 4 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R 4 is CN. In certain embodiments, R 4 is OH. In certain embodiments, R 4 is C1-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R 4 is C1-C6alkylOC1-C6alkyl. In certain embodiments, R 4 is COOH. In certain embodiments, R 4 is C1- C6alkylCOOH.
  • R 4 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R 4 is C 1 -C 6 alkyl.
  • C 1 -C 6 alkyl 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.
  • R 4 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, R 4 is C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R 4 is CON(R 7 )(R 8 ).
  • N(R 7 )(R 8 ) include, but are not limited to, CONH2 and CON(CH3)2.
  • R 4 is N(R 7 )(R 8 ).
  • Suitable examples of N(R 7 )(R 8 ) include, but are not limited to, NH2 and N(CH3)2.
  • R 4 is C1-C6alkylN(R 7 )(R 8 ).
  • Suitable examples of C 1 -C 6 alkylN(R 7 )(R 8 ) include, but are not limited to, , are discussed in further detail below.
  • R 4 is C1-C6alkylOhaloC1-C6alkyl.
  • haloalkyls include, but are not limited to, .
  • R 4 is C 1 -C 6 alkyl(OCH 2 CH 2 ) n N(R 7 )(R 8 ).
  • R 7 , R 8 are discussed in detail below and n is discussed above.
  • Suitable examples of C 1 - C 6 alkyl(OCH 2 CH 2 ) n N(R 7 )(R 8 ) include, but are not limited to, ,
  • R 4 is taken with R 3 and forms a C 3 -C 6 cycloalkyl or C 3 - C 6 heterocycloalkyl.
  • R 4 is taken with R 3 and forms a C 3 -C 6 cycloalkyl.
  • Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 4 is taken with R 3 and forms a C 3 - C 6 heterocycloalkyl.
  • 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.
  • R 4 is hydrogen or methyl.
  • R 4 is hydrogen, methyl, ethyl or .
  • R 4 is taken with R 3 to form oxetanyl.
  • R 3 and R 4 are both hydrogen, methyl or ethyl.
  • R 3 is hydrogen and R 4 is hydrogen.
  • R 3 and R 4 are both halogen, where the halogen is selected from fluorine, chlorine, bromine and iodine. In certain embodiments, R 3 and R 4 are both fluorine.
  • R 5 is hydrogen, halogen, CN, OH, C1- C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1- C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3-C6cycloalkyl, C1-C6alkyl, -C1- C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1- C 6 alkylN(R 7 )(R 8 ).
  • R 5 is hydrogen. In certain embodiments, R 5 is halogen. Examples of suitable halogens include chlorine, bromine, fluorine and iodine. In certain embodiments, R 5 is CN. In certain embodiments, R 5 is OH. In certain embodiments, R 5 is C 1 -C 6 alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R 5 is C1-C6alkylOC1-C6alkyl. In certain embodiments, R 5 is C1-C6alkylCOOH. In certain embodiments, R 5 is COOH.
  • R 5 is an oxo group. In certain embodiments, R 5 is COOC1-C6alkyl. In certain embodiments, R 5 is C1-C6alkylCOOC1-C6alkyl. In certain embodiments, R 5 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, C 6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited In certain embodiments, R 5 is C 1 -C 6 alkyl.
  • C 1 -C 6 alkyl 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.
  • R 5 is methyl. In certain embodiments, R 5 is C1-C6alkylOhaloC1-C6alkyl. Suitable examples of C 1 -C 6 alkylOhaloC 1 -C 6 alkyls include, but are not limited to, . In certain embodiments, R 5 is haloC 1 -C 6 alkyl. 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, R 5 is C 1 -C 6 alkylOH.
  • Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol.
  • R 5 is CON(R 7 )(R 8 ).
  • R 1 is N(R 7 )(R 8 ).
  • R 5 is C1-C6alkylN(R 7 )(R 8 ), wherein R 7 and R 8 will be described in detail below.
  • R 5 is hydrogen, methyl, ethyl or t-butyl.
  • R 6 is hydrogen, halogen, CN, OH, C1- C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1- C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3-C6cycloalkyl, C1-C6alkyl, -C1- C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1- C6alkylN(R 7 )(R 8 ).
  • R 6 is hydrogen. In certain embodiments, R 6 is halogen. Examples of suitable halogens include chlorine, bromine, fluorine and iodine. In certain embodiments, R 6 is CN. In certain embodiments, R 6 is OH. In certain embodiments, R 6 is C 1 -C 6 alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R 6 is C1-C6alkylOC1-C6alkyl. In certain embodiments, R 6 is C1-C6alkylCOOH. In certain embodiments, R 6 is COOH.
  • R 6 is an oxo group. In certain embodiments, R 6 is COOC 1 -C 6 alkyl. In certain embodiments, R 6 is C 1 -C 6 alkylCOOC 1 -C 6 alkyl. In certain embodiments, R 6 is C 3 -C 6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R 6 is C1-C6alkylC3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to .
  • R 6 is C1-C6alkyl.
  • 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
  • R 6 is methyl. In certain embodiments, R 6 is C 1 -C 6 alkylOhaloC 1 -C 6 alkyl. Suitable examples of F F 1 6 1 6 mited to, O F C -C alkylOhaloC -C alkyls include, but are not li . In certain embodiments, R 6 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.
  • R 6 is C 1 -C 6 alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R 6 is CON(R 7 )(R 8 ). In certain embodiments, R 1 is N(R 7 )(R 8 ). In certain embodiments, R 6 is C 1 -C 6 alkylN(R 7 )(R 8 ), wherein R 7 and R 8 will be described in detail below. In certain embodiments, R 6 is hydrogen, methyl, ethyl or t-butyl.
  • R 7 is hydrogen, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, COC 1 -C 6 alkyl or COOC 1 -C 6 alkyl.
  • R 7 is hydrogen, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl or C1-C6alkylOH.
  • R 7 is hydrogen.
  • R 7 is C 1 - C 6 alkylCOOH. In certain embodiments, R 7 is COOH. In certain embodiments, R 7 is C 3 - C 6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R 7 is C 1 -C 6 alkyl.
  • C 1 -C 6 alkyl 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.
  • R 7 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, R 7 is C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso- butanol. In certain embodiments, R 7 is COC 1 -C 6 alkyl. Suitable examples include, but are not limited to, COCH 3 .
  • R 7 is COOC 1 -C 6 alkyl. Suitable examples include, but are not limited to, COOCH 3.
  • R 8 is hydrogen, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, COC 1 -C 6 alkyl or COOC 1 -C 6 alkyl.
  • R 8 is hydrogen, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl or C 1 -C 6 alkylOH.
  • R 8 is hydrogen.
  • R 8 is C1- C6alkylCOOH.
  • R 8 is COOH.
  • R 8 is C3- C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 8 is C1-C6alkyl.
  • 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-eth
  • R 8 is haloC 1 -C 6 alkyl. 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, R 8 is C 1 -C 6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso- butanol. In certain embodiments, R 8 is COC 1 -C 6 alkyl. Suitable examples include, but are not limited to, COCH 3 .
  • R 8 is COOC 1 -C 6 alkyl. Suitable examples include, but are not limited to, COOCH 3.
  • R 9 is hydrogen, halogen, CN, OH, C 1 - C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ) and N(R 7 )(R 8 ).
  • R 9 is hydrogen.
  • R 9 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R 9 is CN. In certain embodiments, R 9 is OH. In certain embodiments, R 9 is C1-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R 9 is C1-C6alkylOC1-C6alkyl. In certain embodiments, R 9 is COOH. In certain embodiments, R 9 is C1- C6alkylCOOH. In certain embodiments, R 9 is C3-C6cycloalkyl.
  • Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 9 is C 1 -C 6 alkyl.
  • C 1 -C 6 alkyl 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.
  • R 9 is haloC 1 -C 6 alkyl. 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, R 9 is C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R 9 is CON(R 7 )(R 8 ). In certain embodiments, R 9 is N(R 7 )(R 8 ).
  • R 9 is C1-C6alkylN(R 7 )(R 8 ).
  • R 10 is hydrogen, halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1- C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R 7 )(R 8 ) and N(R 7 )(R 8 ).
  • R 10 is hydrogen.
  • R 10 is halogen.
  • Suitable halogens include fluorine, chlorine, bromine, or iodine.
  • R 10 is CN.
  • R 10 is OH.
  • R 10 is C 1 -C 6 alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
  • R 10 is C 1 -C 6 alkylOC 1 -C 6 alkyl.
  • R 10 is COOH.
  • R 10 is C 1 -C 6 alkylCOOH.
  • R 10 is C 3 -C 6 cycloalkyl.
  • Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 10 is C 1 -C 6 alkyl.
  • C 1 -C 6 alkyl 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.
  • R 10 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, R 10 is C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R 10 is CON(R 7 )(R 8 ). In certain embodiments, R 10 is N(R 7 )(R 8 ).
  • R 10 is C1-C6alkylN(R 7 )(R 8 ).
  • R 11 is hydrogen, halogen, CN, OH, C 1 - C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ) and N(R 7 )(R 8 ).
  • R 11 is hydrogen.
  • R 11 is halogen.
  • Suitable halogens include fluorine, chlorine, bromine, or iodine.
  • R 11 is CN.
  • R 11 is OH.
  • R 11 is C 1 -C 6 alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
  • R 11 is C 1 -C 6 alkylOC 1 -C 6 alkyl.
  • R 11 is COOH.
  • R 11 is C1-C6alkylCOOH.
  • R 11 is C3-C6cycloalkyl.
  • Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 11 is C1-C6alkyl.
  • 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.
  • R 11 is haloC 1 -C 6 alkyl. 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, R 11 is C 1 -C 6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R 11 is CON(R 7 )(R 8 ). In certain embodiments, R 11 is N(R 7 )(R 8 ).
  • R 11 is C 1 -C 6 alkylN(R 7 )(R 8 ).
  • R 12 is hydrogen, halogen, CN, OH, C 1 - C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C 1 -C 6 alkylN(R 7 )(R 8 ).
  • R 12 is hydrogen. In certain embodiments, R 12 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R 12 is CN. In certain embodiments, R 12 is OH. In certain embodiments, R 12 is C1-C6alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R 12 is C1-C6alkylOC1-C6alkyl. In certain embodiments, R 12 is COOH. In certain embodiments, R 12 is C1-C6alkylCOOH.
  • R 12 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R 12 is C1-C6alkyl.
  • 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.
  • R 12 is haloC 1 -C 6 alkyl. 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, R 12 is C 1 -C 6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R 12 is CON(R 7 )(R 8 ). In certain embodiments, R 12 is N(R 7 )(R 8 ).
  • R 12 is C1-C6alkylN(R 7 )(R 8 ). In certain embodiments, R 12 is hydrogen, methyl, ethyl, methoxy, OH or . In certain embodiments, R 12 is hydrogen or .
  • R 13 is hydrogen, halogen, CN, OH, C1- C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6alkylN(R 7 )(R 8 ).
  • R 13 is hydrogen.
  • R 13 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine.
  • R 13 is CN. In certain embodiments, R 13 is OH. In certain embodiments, R 13 is C 1 -C 6 alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R 13 is C 1 -C 6 alkylOC 1 -C 6 alkyl. In certain embodiments, R 13 is COOH. In certain embodiments, R 13 is C 1 -C 6 alkylCOOH. In certain embodiments, R 13 is C 3 -C 6 cycloalkyl.
  • Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 13 is C 1 -C 6 alkyl.
  • C 1 -C 6 alkyl 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.
  • R 13 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, R 13 is C 1 -C 6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R 13 is CON(R 7 )(R 8 ). In certain embodiments, R 13 is N(R 7 )(R 8 ).
  • R 13 is C 1 -C 6 alkylN(R 7 )(R 8 ). In certain embodiments, R 13 is hydrogen, methyl, ethyl, methoxy, OH or . In certain embodiments, R 13 is hydrogen or . In certain embodiments, R 12 and R 13 are independently selected from the group consisting of hydrogen and C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkyl.
  • each occurrence of R 14 is independently selected from the group consisting of hydrogen, halogen, CN, OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 - C6alkyl, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6alkylN(R 7 )(R 8 ).
  • R 14 is hydrogen.
  • R 14 is halogen.
  • Suitable halogens include fluorine, chlorine, bromine, or iodine.
  • R 14 is CN.
  • R 14 is OH.
  • R 14 is C1-C6alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
  • R 14 is C1-C6alkylOC1-C6alkyl.
  • R 14 is COOH.
  • R 14 is C1-C6alkylCOOH.
  • R 14 is C3-C6cycloalkyl.
  • Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 14 is C 1 -C 6 alkyl.
  • C 1 -C 6 alkyl 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.
  • R 14 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, R 14 is C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R 14 is CON(R 7 )(R 8 ). In certain embodiments, R 14 is N(R 7 )(R 8 ).
  • R 14 is C1-C6alkylN(R 7 )(R 8 ).
  • R 14 is independently selected from the group consisting of hydrogen, halogen, OH, C 1 -C 6 alkylOH, C 1 -C 6 alkylalkoxy, C 1 - C 6 alkylOC 1 -C 6 alkyl and C 1 -C 6 alkyl.
  • R 14 is hydrogen, methyl, ethyl, methoxy, OH or .
  • R 15 is hydrogen, halogen, CN, OH, C 1 - C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ) and N(R 7 )(R 8 ).
  • R 15 is hydrogen.
  • R 15 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine.
  • R 15 is CN. In certain embodiments, R 15 is OH. In certain embodiments, R 15 is C1-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R 15 is C1-C6alkylOC1-C6alkyl. In certain embodiments, R 15 is COOH. In certain embodiments, R 15 is C1-C6alkylCOOH. In certain embodiments, R 15 is C3-C6cycloalkyl.
  • Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 15 is C1-C6alkyl.
  • 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.
  • R 15 is ethyl. In certain embodiments, R 15 is haloC 1 -C 6 alkyl. 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, R 15 is C 1 -C 6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso- butanol. In certain embodiments, R 15 is CON(R 7 )(R 8 ).
  • R 15 is N(R 7 )(R 8 ). In certain embodiments, R 15 is C 1 -C 6 alkylN(R 7 )(R 8 ). In certain embodiments, R 15 is methyl or ethyl.
  • R 16 is hydrogen, halogen, CN, OH, C1- C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R 7 )(R 8 ) and N(R 7 )(R 8 ).
  • R 16 is hydrogen. In certain embodiments, R 16 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R 16 is CN. In certain embodiments, R 16 is OH. In certain embodiments, R 16 is C1-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R 16 is C 1 -C 6 alkylOC 1 -C 6 alkyl. In certain embodiments, R 16 is COOH. In certain embodiments, R 16 is C 1 -C 6 alkylCOOH.
  • R 16 is C 3 -C 6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R 16 is C 1 -C 6 alkyl.
  • C 1 -C 6 alkyl 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.
  • R 16 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, R 16 is C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R 16 is CON(R 7 )(R 8 ). In certain embodiments, R 16 is N(R 7 )(R 8 ).
  • R 16 is C1-C6alkylN(R 7 )(R 8 ).
  • m is 0 or 1.
  • m is 0.
  • m is 1.
  • p is 0 or 1.
  • p is 0.
  • p is 1.
  • A is a straight or branched, saturated or unsaturated (C 3 -C 10 )alkylene, phenyl(C 3 -C 10 )alkylene or cycloalkyl(C 3 -C 10 )alkylene comprising at least one –CH 2 - group, wherein one or more additional –CH 2 - groups in A are optionally and independently replaced with a moiety selected from the group consisting of O, S, NR, CONR, NRCO, SO 2 , and SO 2 NR and wherein one or more of the hydrogens along A can be replaced with a group independently selected from hydroxyl, halogen and C 1-3 haloalkyl.
  • A is a straight or branched, saturated or unsaturated (C 3 -C 10 )alkylene or cycloalkyl(C3-C10)alkylene, wherein one or more –CH2- groups in A are optionally and independently replaced with a moiety selected from the group consisting of O, S and NH. In certain embodiment, A will always have at least one –CH2- group.
  • A is a straight (C3-C10)alkylene. Examples of straight (C3-C10)alkylenes include, .
  • A is a branched (C 3 -C 10 )alkylene. Suitable branched (C 3 - C 10 )alkylenes include but are not limited to: In certain embodiments, A is a saturated (C3-C10)alkylene. Examples include,
  • A is an unsaturated (C3-C10)alkylene.
  • Suitable unsaturated (C3-C10)alkylenes include any of the saturated (C3-C10)alkylene, wherein hydrogens have been removed and one or more double or triple covalent bonds exist between adjacent carbon atoms. Examples of unsaturated (C3-C10)alkylenes include, but are not limited to, .
  • A is a straight cycloalkyl(C3-C10)alkylene.
  • Suitable straight cycloalkyl(C3-C10)alkylenes include a cycloalkyl(C3-C10)alkylene wherein two carbons in a chain are included in a (C 3 -C 10 )cycloalkyl.
  • Examples of straight cycloalkyl(C 3 -C 10 )alkylenes include, but are not limited to,
  • A is a branched cycloalkyl(C3-C10)alkylene.
  • Suitable branched cycloalkyl(C3-C10)alkylenes include a branched (C3-C10)alkylene wherein two carbons in a chain are included in a (C3-C10)cycloalkyl.
  • Examples of cycloalkyl(C3-C10)alkylenes include, but are not limited to, .
  • A is a saturated cycloalkyl(C 3 -C 10 )alkylene. Examples of saturated cycloalkyl(C 3 -C 10 )alkylenes include, but are not limited to,
  • A is an unsaturated cycloalkyl(C 3 -C 10 )alkylene.
  • unsaturated cyclo(C 3 -C 10 )alkylenes include, but are not limited to, .
  • A is an unsaturated or saturated phenyl(C3-C10)alkylene.
  • unsaturated and saturated phenyl(C 3 -C 10 )alkylenes include, but are not limited to, .
  • one or more –CH2- groups in A are optionally and independently replaced with a moiety selected from the group consisting of O, S, NR, CONR, NRCO, SO2, and SO2NR.
  • one or more –CH2- groups in A are optionally and independently replaced with a moiety selected from the group consisting of O, S and NH. In other embodiments, one or more –CH2- groups in A are optionally and independently replaced with O. In other embodiments, one or more –CH2- groups in A are optionally and independently replaced with S. In other embodiments, one or more –CH 2 - groups in A are optionally and independently replaced with NR. In other embodiments, one or more –CH 2 - groups in A are optionally and independently replaced with CONR. In other embodiments, one or more –CH 2 - groups in A are optionally and independently replaced with NRCO.
  • one or more –CH 2 - groups in A are optionally and independently replaced with SO 2 . In other embodiments, one or more –CH 2 - groups in A are optionally and independently replaced with and SO 2 NR.
  • R will be described in further detail below.
  • R is hydrogen, C 1 -C 6 alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, COC1-C6alkyl or COOC1-C6alkyl.
  • R is hydrogen, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl or C1-C6alkylOH.
  • R is hydrogen.
  • R is C1- C6alkylCOOH.
  • R is COOH.
  • R is C3- C6cycloalkyl.
  • Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R is C1-C6alkyl.
  • C 1 -C 6 alkyl 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.
  • R is haloC 1 -C 6 alkyl.
  • haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2- difluoroethyl and 2,2-difluoroethyl.
  • R is C 1 -C 6 alkylOH.
  • suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso- butanol.
  • R is COC1-C6alkyl. Suitable examples include, but are not limited to, COCH3. In certain embodiments, R is COOC1-C6alkyl.
  • Suitable examples include, but are not limited to, COOCH3. Examples of such embodiments include, but are not limited to, .
  • A is .
  • one or more of the hydrogens along A can be replaced with a group independently selected from hydroxyl, halogen and C1-3 haloalkyl. Examples of suitable halogens include chlorine, bromine, fluorine and iodine. In certain embodiments, A is .
  • A is a straight or branched, saturated or unsaturated (C3-C10)alkylene, phenyl(C3- C 10 )alkylene or cycloalkyl(C 3 -C 10 )alkylene comprising at least one –CH 2 - group, wherein one or more additional –CH 2 - groups in A are optionally and independently replaced with a moiety selected from the group consisting of O, S, NR, CONR, NRCO, SO 2 , and SO 2 NR and wherein one or more of the hydrogens along A can be replaced with a group independently selected from hydroxyl, halogen and C 1-3 haloalkyl;
  • Q is C(R 16 ) 2 , O, S, SO, SO 2 or NH;
  • X is a bond, C(R 14 ) 2 , O, S, SO, SO 2 or NH;
  • Y is CR 9 or N, wherein when Y is N, Z is
  • Q is C(R 16 )2, O, S, SO, SO2 or NH. In certain embodiments, Q is C(R 16 ) 2 , wherein R 16 is discussed in further detail below. In certain embodiments, Q is CH 2 , CH(CH 3 ), C(CH 3 ) 2 , O, CH(OCH 3 ), SO 2 or CF 2 . In other embodiments Q is CH 2 , O, S, SO, SO 2 or NH. In certain embodiments, Q is CH 2 . In certain embodiments described herein, Q is O. In certain embodiments described herein, Q is S. In other embodiments described herein, Q is SO. In other embodiments described herein, Q is SO 2 .
  • Q is NH. In other embodiments described herein, Q is O or SO 2 . In still other embodiments described herein, Q is O or CH 2 .
  • X is a bond, C(R 14 ) 2 , O, S, SO, SO 2 or NH. In certain embodiments described herein X is a bond. In certain embodiments, X is C(R 14 ) 2 , wherein R 14 is discussed in further detail below. In certain embodiments, X is a bond, CH 2 , CH(CH 3 ), C(CH 3 ) 2 , O, CH(OCH 3 ), SO 2 or CF 2 .
  • X is CH 2 , O, S, SO, SO 2 or NH. In certain embodiments, X is CH2. In the embodiments described herein, X is O. In certain embodiments described herein, X is S. In certain embodiments described herein, X is SO. In other embodiments described herein, X is SO2. In certain embodiments described herein, X is NH. In the embodiments described herein, Y is CR 9 or N. In certain embodiments, Y is CR 9 , wherein R 9 is discussed in detail below. In certain embodiments, Y is N. In certain embodiments, Y is CH. In certain embodiments, wherein when Y is N, Z is CR 11 and V is CR 10 .
  • V is CR 10 or N. In certain embodiments, V is CR 10 , wherein R 10 is discussed in detail below. In certain embodiments, V is N. In certain embodiments, V is CH. In certain embodiments, wherein when V is N, Z is CR 11 and Y is CR 9 . In the embodiments described herein, Z is CR 11 or N. In certain embodiments, Z is CR 11 , wherein R 11 is discussed in detail below. In certain embodiments, Z is CH. In certain embodiments, Z is N. In certain embodiments, wherein when Z is N, V is CR 10 and Y is CR 9 . In certain embodiments, X is O, Y and V are each CH and Z is N.
  • X is O, Y and Z are each CH and V is N. In certain embodiments, X is O and V, Y and Z are all simultaneously CH. In certain embodiments, X is a bond, Y and V are each CH and Z is N. In certain embodiments, X is a bond, Y and Z are each CH and V is N. In certain embodiments, X is a bond and V, Y and Z are all simultaneously CH. Also described herein are compounds of Formula III represented by structural Formula (IIIA):
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 15 , A, and Q are as described herein.
  • An embodiment of this invention is realized when R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 15 , A, and Q, are as described in Formula III.
  • Another embodiment of Formula IIIA is realized when R 3 and R 4 are both hydrogen, methyl, ethyl, or halogen.
  • Another embodiment of Formula IIIA is realized when R 3 and R 4 are both halogen selected from chlorine and fluorine.
  • Another embodiment of Formula IIIA is realized when Q is CH2, CH(CH3), C(CH3)2, O, CH(OCH3), SO2 or CF2.
  • Q in Formula IIIA is O or SO2.
  • Q in Formula IIIIA is O or CH2.
  • A is a straight or branched, saturated or unsaturated (C3-C10)alkylene comprising at least one –CH 2 - group, wherein one or more additional –CH 2 - groups in A are optionally and independently replaced with a moiety selected from the group consisting of O, S, NR, CONR, NRCO, SO 2 , and SO 2 NR and wherein one or more of the hydrogens along A can be replaced with a group independently selected from hydroxyl, halogen and C 1-3 haloalkyl.
  • An embodiment of this invention is realized when R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 15 , A, and Q, are as described in Formula III.
  • Another embodiment of Formula IIIB is realized when R 3 and R 4 are both hydrogen, methyl, ethyl, or halogen.
  • Another embodiment of Formula IIIB is realized when R 3 and R 4 are both halogen selected from chlorine and fluorine.
  • Formula IIIB Another embodiment of Formula IIIB is realized when Q is CH 2 , CH(CH 3 ), C(CH 3 ) 2 , O, CH(OCH 3 ), SO 2 or CF 2 .
  • Q in Formula IIIB is O or SO2.
  • Q in Formula IIIIB is O or CH2.
  • A is a straight or branched, saturated or unsaturated (C3-C10)alkylene comprising at least one –CH2- group, wherein one or more additional –CH2- groups in A are optionally and independently replaced with a moiety selected from the group consisting of O, S, NR, CONR, NRCO, SO2, and SO2NR and wherein one or more of the hydrogens along A can be replaced with a group independently selected from hydroxyl, halogen and C1-3 haloalkyl.
  • R 1 is hydrogen, halogen, CN, OH, C 1 - C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, oxo, COOC 1 -C 6 alkyl, C 1 - C 6 alkylCOOC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkylC 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, -C 1 - C 6 alkylOhaloC 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C 1 - C 6 alkylN(R 7 )(R 8 ).
  • R 1 is hydrogen. In certain embodiments, R 1 is halogen. Examples of suitable halogens include chlorine, bromine, fluorine and iodine. In certain embodiments, R 1 is CN. In certain embodiments, R 1 is OH. In certain embodiments, R 1 is C 1 -C 6 alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R 1 is C 1 -C 6 alkylOC 1 -C 6 alkyl. In certain embodiments, R 1 is C 1 -C 6 alkylCOOH. In certain embodiments, R 1 is COOH.
  • R 1 is an oxo group. In certain embodiments, R 1 is COOC1-C6alkyl. In certain embodiments, R 1 is C1-C6alkylCOOC1-C6alkyl. In certain embodiments, R 1 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R 1 is C1-C6alkylC3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to . In certain embodiments, R 1 is C 1 -C 6 alkyl.
  • C 1 -C 6 alkyl 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.
  • R 1 is C1-C6alkylOhaloC1-C6alkyl. Suitable examples of C 1 -C 6 alkylOhaloC 1 -C 6 alkyls include, but are not limited to, . In certain embodiments, R 1 is haloC 1 -C 6 alkyl. 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, R 1 is C 1 -C 6 alkylOH.
  • Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol.
  • R 1 is CON(R 7 )(R 8 ).
  • R 1 is N(R 7 )(R 8 ).
  • R 1 is C1-C6alkylN(R 7 )(R 8 ), wherein R 7 and R 8 will be described in detail below.
  • R 1 is hydrogen, bromine, fluorine, chlorine, methyl, OH, halogen, CN oxo, methoxymethyl, COOCH 2 CH 3 or trifluoromethyl.
  • R 2 is hydrogen, halogen, CN, OH, C 1 - C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, oxo, COOC 1 -C 6 alkyl, C 1 - C 6 alkylCOOC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkylC 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, -C 1 - C 6 alkylOhaloC 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C 1 - C 6 alkylN(R 7 )(R 8 ).
  • R 2 is hydrogen. In certain embodiments, R 2 is halogen. Examples of suitable halogens include chlorine, bromine, fluorine and iodine. In certain embodiments, R 2 is CN. In certain embodiments, R 2 is OH. In certain embodiments, R 2 is C1-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R 2 is C 1 -C 6 alkylOC 1 -C 6 alkyl. In certain embodiments, R 2 is C 1 -C 6 alkylCOOH. In certain embodiments, R 2 is COOH.
  • R 2 is an oxo group. In certain embodiments, R 2 is COOC 1 -C 6 alkyl. In certain embodiments, R 2 is C 1 -C 6 alkylCOOC 1 -C 6 alkyl. In certain embodiments, R 2 is C 3 -C 6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R 2 is C1-C6alkylC3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to .
  • R 2 is C1-C6alkyl.
  • 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
  • R 2 is C 1 -C 6 alkylOhaloC 1 -C 6 alkyl. Suitable examples of C1-C6alkylOhaloC1-C6alkyls include, but are not limited to, . In certain embodiments, R 2 is haloC 1 -C 6 alkyl. 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, R 2 is C 1 -C 6 alkylOH.
  • Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol.
  • R 2 is CON(R 7 )(R 8 ).
  • R 1 is N(R 7 )(R 8 ).
  • R 2 is C1-C6alkylN(R 7 )(R 8 ), wherein R 7 and R 8 will be described in detail below.
  • R 2 is hydrogen, bromine, fluorine, chlorine, methyl, OH, halogen, CN oxo, methoxymethyl, COOCH2CH3 or trifluoromethyl.
  • R 1 and R 2 are both hydrogen.
  • R 1 is OH and R 2 is hydrogen.
  • R 3 is hydrogen, halogen, CN, OH, C1- C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ), C 1 -C 6 alkylN(R 7 )(R 8 ), C 1 - C 6 alkyl(OCH 2 CH 2 ) n N(R 7 )(R 8 ) or C 1 -C 6 alkylOhaloC 1 -C 6 alkyl or when taken with R 4 forms a C 3 - C 6 cycloalkyl or C 3 -C 6 heterocycloal
  • R 3 is hydrogen, halogen, CN, OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, C 3 - C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C 1 - C 6 alkylN(R 7 )(R 8 ) or when taken with R 4 forms a C 3 -C 6 cycloalkyl or C 3 -C 6 heterocycloalkyl.
  • R 3 is hydrogen. In certain embodiments, R 3 is halogen. Suitable halogens include fluorine, chlorine, bromine, and iodine. In certain embodiments, R 3 is CN. In certain embodiments, R 3 is OH. In certain embodiments, R 3 is C1-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R 3 is C1-C6alkylOC1-C6alkyl. In certain embodiments, R 3 is COOH. In certain embodiments, R 3 is C1- C6alkylCOOH.
  • R 3 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R 3 is C 1 -C 6 alkyl.
  • C 1 -C 6 alkyl 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.
  • R 3 is haloC 1 -C 6 alkyl. 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, R 3 is C 1 -C 6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R 3 is CON(R 7 )(R 8 ).
  • N(R 7 )(R 8 ) include, but are not limited to, CONH 2 and CON(CH3)2.
  • R 3 is N(R 7 )(R 8 ).
  • Suitable examples of N(R 7 )(R 8 ) include, but are not limited to, NH2 and N(CH3)2.
  • R 3 is C1-C6alkylN(R 7 )(R 8 ).
  • Suitable examples of C1-C6alkylN(R 7 )(R 8 ) include, but are not limited to, , are discussed in further detail below.
  • R 3 is C 1 -C 6 alkylOhaloC 1 -C 6 alkyl.
  • haloalkyls include, but are not limited to, .
  • R 3 is C1-C6alkyl(OCH2CH2)nN(R 7 )(R 8 ).
  • R 7 , R 8 and n are discussed in detail below.
  • Suitable examples of C1-C6alkyl(OCH2CH2)nN(R 7 )(R 8 ) include, but .
  • n is 1, 2, 3 or 4.
  • n is 1.
  • n is 2.
  • n is 3.
  • n is 4.
  • R 3 is taken with R 4 and forms a C3-C6cycloalkyl or C3- C6heterocycloalkyl. In certain embodiments, R 3 is taken with R 4 and forms a C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R 3 is taken with R 4 and forms a C3- C6heterocycloalkyl.
  • 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.
  • R 3 is hydrogen, fluorine, methyl, ethyl, OH, methoxy, In certain embodiments, R 3 is hydrogen, methyl, ethyl or . In certain embodiments, R 3 is taken with R 4 to form oxetanyl.
  • R 4 is hydrogen, halogen, CN, OH, C1- C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ), C 1 -C 6 alkylN(R 7 )(R 8 ), C 1 - C 6 alkyl(OCH 2 CH 2 ) n N(R 7 )(R 8 ) or C 1 -C 6 alkylOhaloC 1 -C 6 alkyl or when taken with R 3 forms a C 3 - C 6 cycloalkyl or C 3 -C 6 heterocycloalkyl.
  • R 4 is hydrogen, halogen, CN, OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 - C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C 1 -C 6 alkylN(R 7 )(R 8 ) or when taken with R 3 forms a C 3 -C 6 cycloalkyl or C 3 -C 6 heterocycloalkyl.
  • R 4 is hydrogen. In certain embodiments, R 4 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R 4 is CN. In certain embodiments, R 4 is OH. In certain embodiments, R 4 is C1-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R 4 is C1-C6alkylOC1-C6alkyl. In certain embodiments, R 4 is COOH. In certain embodiments, R 4 is C1- C6alkylCOOH.
  • R 4 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R 4 is C 1 -C 6 alkyl.
  • C 1 -C 6 alkyl 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.
  • R 4 is haloC 1 -C 6 alkyl. 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, R 4 is C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R 4 is CON(R 7 )(R 8 ).
  • N(R 7 )(R 8 ) include, but are not limited to, CONH2 and CON(CH3)2.
  • R 4 is N(R 7 )(R 8 ).
  • Suitable examples of N(R 7 )(R 8 ) include, but are not limited to, NH2 and N(CH3)2.
  • R 4 is C1-C6alkylN(R 7 )(R 8 ).
  • Suitable examples of C1- C 6 alkylN(R 7 )(R 8 ) include, but are not limited to, are discussed in further detail below.
  • R 4 is C1-C6alkylOhaloC1-C6alkyl.
  • haloalkyls include, but are not limited to, .
  • R 4 is C 1 -C 6 alkyl(OCH 2 CH 2 ) n N(R 7 )(R 8 ).
  • R 7 , R 8 are discussed in detail below and n is discussed above.
  • Suitable examples of C 1 - C alkyl(OCH CH ) N(R 7 8 6 2 2 n )(R ) include, but are not limited to, ,
  • R 4 is taken with R 3 and forms a C 3 -C 6 cycloalkyl or C 3 - C 6 heterocycloalkyl.
  • R 4 is taken with R 3 and forms a C 3 -C 6 cycloalkyl.
  • Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 4 is taken with R 3 and forms a C3- C6heterocycloalkyl.
  • 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.
  • R 4 is hydrogen or methyl.
  • R 4 is hydrogen, methyl, ethyl or .
  • R 4 is taken with R 3 to form oxetanyl.
  • R 3 and R 4 are both hydrogen, methyl or ethyl.
  • R 3 is hydrogen and R 4 is hydrogen.
  • R 5 is hydrogen, halogen, CN, OH, C1- C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1- C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3-C6cycloalkyl, C1-C6alkyl, -C1- C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ), N(R 7 )(R 8
  • R 5 is hydrogen. In certain embodiments, R 5 is halogen. Examples of suitable halogens include chlorine, bromine, fluorine and iodine. In certain embodiments, R 5 is CN. In certain embodiments, R 5 is OH. In certain embodiments, R 5 is C 1 -C 6 alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R 5 is C 1 -C 6 alkylOC 1 -C 6 alkyl. In certain embodiments, R 5 is C 1 -C 6 alkylCOOH. In certain embodiments, R 5 is COOH.
  • R 5 is an oxo group. In certain embodiments, R 5 is COOC1-C6alkyl. In certain embodiments, R 5 is C1-C6alkylCOOC1-C6alkyl. In certain embodiments, R 5 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R 5 is C1-C6alkylC3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to . In certain embodiments, R 5 is C 1 -C 6 alkyl.
  • C 1 -C 6 alkyl 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.
  • R 5 is methyl. In certain embodiments, R 5 is C 1 -C 6 alkylOhaloC 1 -C 6 alkyl. Suitable examples of C1-C6alkylOhaloC1-C6alkyls include, but are not limited to, . In certain embodiments, R 5 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, R 5 is C 1 -C 6 alkylOH.
  • Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol.
  • R 5 is CON(R 7 )(R 8 ).
  • R 1 is N(R 7 )(R 8 ).
  • R 5 is C 1 -C 6 alkylN(R 7 )(R 8 ), wherein R 7 and R 8 will be described in detail below.
  • R 5 is hydrogen, methyl, ethyl or t-butyl.
  • R 6 is hydrogen, halogen, CN, OH, C1- C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1- C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3-C6cycloalkyl, C1-C6alkyl, -C1- C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1- C6alkylN(R 7 )(R 8 ).
  • R 6 is hydrogen. In certain embodiments, R 6 is halogen. Examples of suitable halogens include chlorine, bromine, fluorine and iodine. In certain embodiments, R 6 is CN. In certain embodiments, R 6 is OH. In certain embodiments, R 6 is C 1 -C 6 alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R 6 is C 1 -C 6 alkylOC 1 -C 6 alkyl. In certain embodiments, R 6 is C 1 -C 6 alkylCOOH. In certain embodiments, R 6 is COOH.
  • R 6 is an oxo group. In certain embodiments, R 6 is COOC1-C6alkyl. In certain embodiments, R 6 is C 1 -C 6 alkylCOOC 1 -C 6 alkyl. In certain embodiments, R 6 is C 3 -C 6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R 6 is C 1 -C 6 alkylC 3 -C 6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to .
  • R 6 is C1-C6alkyl.
  • 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
  • R 6 is methyl. In certain embodiments, R 6 is C 1 -C 6 alkylOhaloC 1 -C 6 alkyl. Suitable examples of C1-C6alkylOhaloC1-C6alkyls include, but are not limited to, . In certain embodiments, R 6 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, R 6 is C1-C6alkylOH.
  • Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol.
  • R 6 is CON(R 7 )(R 8 ).
  • R 1 is N(R 7 )(R 8 ).
  • R 6 is C 1 -C 6 alkylN(R 7 )(R 8 ), wherein R 7 and R 8 will be described in detail below.
  • R 6 is hydrogen, methyl, ethyl or t-butyl.
  • R 7 is hydrogen, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, COC 1 -C 6 alkyl or COOC 1 -C 6 alkyl.
  • R 7 is hydrogen, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl or C 1 -C 6 alkylOH.
  • R 7 is hydrogen.
  • R 7 is C 1 - C6alkylCOOH. In certain embodiments, R 7 is COOH. In certain embodiments, R 7 is C3- C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R 7 is C1-C6alkyl.
  • C 1 -C 6 alkyl 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.
  • R 7 is haloC 1 -C 6 alkyl. 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, R 7 is C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso- butanol. In certain embodiments, R 7 is COC1-C6alkyl. Suitable examples include, but are not limited to, COCH3.
  • R 7 is COOC1-C6alkyl. Suitable examples include, but are not limited to, COOCH3.
  • R 8 is hydrogen, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, COC 1 -C 6 alkyl or COOC 1 -C 6 alkyl.
  • R 8 is hydrogen, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl or C 1 -C 6 alkylOH. In certain embodiments, R 8 is hydrogen. In certain embodiments, R 8 is C 1 - C 6 alkylCOOH. In certain embodiments, R 8 is COOH. In certain embodiments, R 8 is C 3 - C 6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 8 is C 1 -C 6 alkyl.
  • 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-e
  • R 8 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, R 8 is C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso- butanol. In certain embodiments, R 8 is COC 1 -C 6 alkyl. Suitable examples include, but are not limited to, COCH 3 .
  • R 8 is COOC 1 -C 6 alkyl. Suitable examples include, but are not limited to, COOCH 3.
  • R 9 is hydrogen, halogen, CN, OH, C 1 - C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ) and N(R 7 )(R 8 ).
  • R 9 is hydrogen.
  • R 9 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R 9 is CN. In certain embodiments, R 9 is OH. In certain embodiments, R 9 is C1-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R 9 is C1-C6alkylOC1-C6alkyl. In certain embodiments, R 9 is COOH. In certain embodiments, R 9 is C1- C6alkylCOOH. In certain embodiments, R 9 is C3-C6cycloalkyl.
  • Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 9 is C1-C6alkyl.
  • 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.
  • R 9 is haloC 1 -C 6 alkyl. 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, R 9 is C 1 -C 6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R 9 is CON(R 7 )(R 8 ). In certain embodiments, R 9 is N(R 7 )(R 8 ).
  • R 9 is C1- C6alkylN(R 7 )(R 8 ).
  • R 10 is hydrogen, halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1- C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R 7 )(R 8 ) and N(R 7 )(R 8 ).
  • R 10 is hydrogen.
  • R 10 is halogen.
  • Suitable halogens include fluorine, chlorine, bromine, or iodine.
  • R 10 is CN.
  • R 10 is OH.
  • R 10 is C 1 -C 6 alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
  • R 10 is C 1 -C 6 alkylOC 1 -C 6 alkyl.
  • R 10 is COOH.
  • R 10 is C 1 -C 6 alkylCOOH.
  • R 10 is C 3 -C 6 cycloalkyl.
  • Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 10 is C 1 -C 6 alkyl.
  • C 1 -C 6 alkyl 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.
  • R 10 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, R 10 is C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R 10 is CON(R 7 )(R 8 ). In certain embodiments, R 10 is N(R 7 )(R 8 ).
  • R 10 is C1-C6alkylN(R 7 )(R 8 ).
  • R 11 is hydrogen, halogen, CN, OH, C1- C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ) and N(R 7 )(R 8 ).
  • R 11 is hydrogen.
  • R 11 is halogen.
  • Suitable halogens include fluorine, chlorine, bromine, or iodine.
  • R 11 is CN. In certain embodiments, R 11 is OH. In certain embodiments, R 11 is C 1 -C 6 alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R 11 is C 1 -C 6 alkylOC 1 -C 6 alkyl. In certain embodiments, R 11 is COOH. In certain embodiments, R 11 is C 1 -C 6 alkylCOOH. In certain embodiments, R 11 is C 3 -C 6 cycloalkyl.
  • Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 11 is C1-C6alkyl.
  • 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.
  • R 11 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, R 11 is C 1 -C 6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R 11 is CON(R 7 )(R 8 ). In certain embodiments, R 11 is N(R 7 )(R 8 ).
  • R 11 is C 1 -C 6 alkylN(R 7 )(R 8 ).
  • R 12 is hydrogen, halogen, CN, OH, C 1 - C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C 1 -C 6 alkylN(R 7 )(R 8 ).
  • R 12 is hydrogen. In certain embodiments, R 12 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R 12 is CN. In certain embodiments, R 12 is OH. In certain embodiments, R 12 is C1-C6alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R 12 is C1-C6alkylOC1-C6alkyl. In certain embodiments, R 12 is COOH. In certain embodiments, R 12 is C1-C6alkylCOOH.
  • R 12 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R 12 is C1-C6alkyl.
  • 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.
  • R 12 is haloC 1 -C 6 alkyl. 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, R 12 is C 1 -C 6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R 12 is CON(R 7 )(R 8 ). In certain embodiments, R 12 is N(R 7 )(R 8 ).
  • R 12 is C1-C6alkylN(R 7 )(R 8 ). In certain embodiments, R 12 is hydrogen, methyl, ethyl, methoxy, OH or . In certain embodiments, R 12 is hydrogen or .
  • R 13 is hydrogen, halogen, CN, OH, C1- C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6alkylN(R 7 )(R 8 ).
  • R 13 is hydrogen.
  • R 13 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine.
  • R 13 is CN. In certain embodiments, R 13 is OH. In certain embodiments, R 13 is C 1 -C 6 alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R 13 is C 1 -C 6 alkylOC 1 -C 6 alkyl. In certain embodiments, R 13 is COOH. In certain embodiments, R 13 is C 1 -C 6 alkylCOOH. In certain embodiments, R 13 is C 3 -C 6 cycloalkyl.
  • Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 13 is C 1 -C 6 alkyl.
  • C 1 -C 6 alkyl 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.
  • R 13 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, R 13 is C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R 13 is CON(R 7 )(R 8 ). In certain embodiments, R 13 is N(R 7 )(R 8 ).
  • R 13 is C 1 -C 6 alkylN(R 7 )(R 8 ). In certain embodiments, R 13 is hydrogen, methyl, ethyl, methoxy, OH or . In certain embodiments, R 13 is hydrogen or . In certain embodiments, R 12 and R 13 are independently selected from the group consisting of hydrogen and C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkyl.
  • each occurrence of R 14 is independently selected from the group consisting of hydrogen, halogen, CN, OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 - C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ), N(R 7 )(R 8 ) or C1-C6alkylN(R 7 )(R 8 ).
  • R 14 is hydrogen.
  • R 14 is halogen.
  • Suitable halogens include fluorine, chlorine, bromine, or iodine.
  • R 14 is CN.
  • R 14 is OH.
  • R 14 is C1-C6alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
  • R 14 is C1-C6alkylOC1-C6alkyl.
  • R 14 is COOH.
  • R 14 is C1-C6alkylCOOH.
  • R 14 is C3-C6cycloalkyl.
  • Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 14 is C 1 -C 6 alkyl.
  • C 1 -C 6 alkyl 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.
  • R 14 is haloC 1 -C 6 alkyl. 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, R 14 is C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R 14 is CON(R 7 )(R 8 ). In certain embodiments, R 14 is N(R 7 )(R 8 ).
  • R 14 is C1-C6alkylN(R 7 )(R 8 ).
  • R 14 is independently selected from the group consisting of hydrogen, halogen, OH, C1-C6alkylOH, C1-C6alkylalkoxy, C1- C 6 alkylOC 1 -C 6 alkyl and C 1 -C 6 alkyl.
  • R 14 is hydrogen, methyl, ethyl, methoxy, OH or .
  • R 15 is hydrogen, halogen, CN, OH, C 1 - C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, CON(R 7 )(R 8 ) and N(R 7 )(R 8 ).
  • R 15 is hydrogen.
  • R 15 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine.
  • R 15 is CN. In certain embodiments, R 15 is OH. In certain embodiments, R 15 is C 1 -C 6 alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R 15 is C1-C6alkylOC1-C6alkyl. In certain embodiments, R 15 is COOH. In certain embodiments, R 15 is C1-C6alkylCOOH. In certain embodiments, R 15 is C3-C6cycloalkyl.
  • Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 15 is C1-C6alkyl.
  • 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.
  • R 15 is ethyl. In certain embodiments, R 15 is haloC 1 -C 6 alkyl. 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, R 15 is C 1 -C 6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso- butanol. In certain embodiments, R 15 is CON(R 7 )(R 8 ).
  • R 15 is N(R 7 )(R 8 ). In certain embodiments, R 15 is C 1 -C 6 alkylN(R 7 )(R 8 ). In certain embodiments, R 15 is methyl or ethyl.
  • R 16 is hydrogen, halogen, CN, OH, C1- C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R 7 )(R 8 ) and N(R 7 )(R 8 ).
  • R 16 is hydrogen. In certain embodiments, R 16 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R 16 is CN. In certain embodiments, R 16 is OH. In certain embodiments, R 16 is C1-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R 16 is C 1 -C 6 alkylOC 1 -C 6 alkyl. In certain embodiments, R 16 is COOH. In certain embodiments, R 16 is C 1 -C 6 alkylCOOH.
  • R 16 is C 3 -C 6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R 16 is C 1 -C 6 alkyl.
  • C 1 -C 6 alkyl 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.
  • R 16 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, R 16 is C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R 16 is CON(R 7 )(R 8 ). In certain embodiments, R 16 is N(R 7 )(R 8 ).
  • R 16 is C1-C6alkylN(R 7 )(R 8 ).
  • l is 0 or 1.
  • l is 0.
  • l is 1.
  • m is 0 or 1.
  • m is 0.
  • m is 1.
  • p is 0 or 1.
  • p is 0.
  • p is 1.
  • m and p are 1 and X is O.
  • m and p are 1 and X is CH 2 .
  • m is 0, p is 1 and X is O.
  • m and p are 1 and X is SO 2 .
  • m is 0, p is 1 and X is C(R 14 ) 2 , wherein each occurrence of R 14 is independently selected from the group consisting of hydrogen, halogen, OH, C1- C6alkoxy and C1-C6alkyl.
  • m is 1 and X is C(R 14 )2, wherein each occurrence of R 14 is independently selected from the group consisting of hydrogen, halogen, OH, C1-C6alkoxy and C1-C6alkyl.
  • l is 0; m is 1; p is 1; X is O; V, Y and Z are CH; and Q is CH2 as shown in formula (VII).
  • l, m and p are 1; X is O; V, Y and Z are CH; and Q is O as shown in Formula (VIII).
  • A is a straight or branched, saturated or unsaturated (C 3 -C 10 )alkylene, phenyl(C 3 -C 10 )alkylene or cycloalkyl(C 3 -C 10 )alkylene comprising at least one –CH 2 - group, wherein one or more additional –CH 2 - groups in A are optionally and independently replaced with a moiety selected from the group consisting of O, S, NR, CONR, NRCO, SO 2 , and SO 2 NR and wherein one or more of the hydrogens along A can be replaced with a group independently selected from hydroxyl, halogen and C 1-3 haloalkyl.
  • A is a straight or branched, saturated or unsaturated (C3-C10)alkylene or cycloalkyl(C3-C10)alkylene, wherein one or more –CH2- groups in A are optionally and independently replaced with a moiety selected from the group consisting of O, S and NH. In certain embodiment, A will always have at least one –CH2- group.
  • A is a straight (C3-C10)alkylene. Examples of straight (C3-C10)alkylenes include, .
  • A is a branched (C 3 -C 10 )alkylene. Suitable branched (C 3 - C 10 )alkylenes include but are not limited to: In certain embodiments, A is a saturated (C3-C10)alkylene. Examples include,
  • A is an unsaturated (C3-C10)alkylene.
  • Suitable unsaturated (C3-C10)alkylenes include any of the saturated (C3-C10)alkylene, wherein hydrogens have been removed and one or more double or triple covalent bonds exist between adjacent carbon atoms. Examples of unsaturated (C3-C10)alkylenes include, but are not limited to, .
  • A is a straight cycloalkyl(C3-C10)alkylene.
  • Suitable straight cycloalkyl(C3-C10)alkylenes include a cycloalkyl(C3-C10)alkylene wherein two carbons in a chain are included in a (C 3 -C 10 )cycloalkyl.
  • Examples of straight cycloalkyl(C 3 -C 10 )alkylenes include, but are not limited to,
  • A is a branched cycloalkyl(C3-C10)alkylene.
  • Suitable branched cycloalkyl(C3-C10)alkylenes include a branched (C3-C10)alkylene wherein two carbons in a chain are included in a (C3-C10)cycloalkyl.
  • Examples of cycloalkyl(C3-C10)alkylenes include, but are not limited to, .
  • A is a saturated cycloalkyl(C 3 -C 10 )alkylene. Examples of saturated cycloalkyl(C 3 -C 10 )alkylenes include, but are not limited to,
  • A is an unsaturated cycloalkyl(C 3 -C 10 )alkylene.
  • unsaturated cyclo(C 3 -C 10 )alkylenes include, but are not limited to, .
  • A is an unsaturated or saturated phenyl(C3-C10)alkylene.
  • unsaturated and saturated phenyl(C 3 -C 10 )alkylenes include, but are not limited to, .
  • one or more –CH2- groups in A are optionally and independently replaced with a moiety selected from the group consisting of O, S, NR, CONR, NRCO, SO2, and SO2NR.
  • one or more –CH2- groups in A are optionally and independently replaced with a moiety selected from the group consisting of O, S and NH. In other embodiments, one or more –CH2- groups in A are optionally and independently replaced with O. In other embodiments, one or more –CH2- groups in A are optionally and independently replaced with S. In other embodiments, one or more –CH 2 - groups in A are optionally and independently replaced with NR. In other embodiments, one or more –CH 2 - groups in A are optionally and independently replaced with CONR. In other embodiments, one or more –CH 2 - groups in A are optionally and independently replaced with NRCO.
  • one or more –CH 2 - groups in A are optionally and independently replaced with SO 2 . In other embodiments, one or more –CH 2 - groups in A are optionally and independently replaced with and SO 2 NR.
  • R will be described in further detail below.
  • R is hydrogen, C 1 -C 6 alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, COC1-C6alkyl or COOC1-C6alkyl.
  • R is hydrogen, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl or C1-C6alkylOH.
  • R is hydrogen.
  • R is C1- C6alkylCOOH.
  • R is COOH.
  • R is C3- C6cycloalkyl.
  • Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R is C1-C6alkyl.
  • C 1 -C 6 alkyl 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.
  • R is haloC 1 -C 6 alkyl.
  • haloalkyls include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,2- difluoroethyl and 2,2-difluoroethyl.
  • R is C 1 -C 6 alkylOH.
  • suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso- butanol.
  • R is COC1-C6alkyl. Suitable examples include, but are not limited to, COCH3. In certain embodiments, R is COOC1-C6alkyl.
  • Suitable examples include, but are not limited to, COOCH3. Examples of such embodiments include, but are not limited to, .
  • A is .
  • one or more of the hydrogens along A can be replaced with a group independently selected from hydroxyl, halogen and C1-3 haloalkyl. Examples of suitable halogens include chlorine, bromine, fluorine and iodine.
  • A is .
  • each variable including those in each of Formulae (I) - (VIII), and the various embodiments thereof) it shall be understood that each variable is to be selected independently of the others unless otherwise indicated.
  • the compounds described herein 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.
  • compounds described herein include:
  • compounds described herein include:
  • any variable not explicitly defined in the context of the embodiment is as defined in Formula (I).
  • 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” 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.
  • 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.
  • Halogen and halo mean fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine.
  • Alkylene by itself or as part of another substituent means a divalent hydrocarbon chain radical having the stated number of carbon atoms.
  • -(C1- C5)alkylene would include, e.g., -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, - CH2CH(CH3)CH2- or -CH2CH2CH2CH2CH2-.
  • a straight alkylene means a divalent straight hydrocarbon chain radical having the stated number of carbon atoms.
  • a branched alkylene means a divalent branched hydrocarbon chain radical having the stated number of carbon atoms.
  • a saturated alkylene means a divalent saturated hydrocarbon chain radical having the stated number of carbon atoms.
  • An unsaturated alkylene means a divalent hydrocarbon chain radical having the stated number of carbon atoms and one or more double or triple covalent bonds within the chain.
  • a cycloalkylene means a divalent hydrocarbon chain radical having the stated number of carbon atoms and a cycloalkyl moiety within the chain.
  • 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.
  • 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.
  • 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.
  • 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.
  • suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like.
  • a non-aromatic ring is fused to an aromatic ring.
  • “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.
  • An example of such a moiety is pyrrolidinone (or pyrrolidone): .
  • 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: .
  • Non-limiting examples of multicyclic heterocycloalkyl groups include, bicyclic heterocycloalkyl groups. Specific examples include, but are not limited to, .
  • Alkoxy means an alkyl-O- group in which the alkyl group is as previously described.
  • suitable alkoxy groups include methoxy, ethoxy, n- propoxy, isopropoxy and n-butoxy.
  • the bond to the parent moiety is through the ether oxygen.
  • 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.
  • a solid line as a bond generally indicates a mixture of, or either of, the possible isomers, e.g., containing (R)- and (S)-stereochemistry.
  • the wavy line 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 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, 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.
  • 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: .
  • 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.
  • purified 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.
  • 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.
  • 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.
  • 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.
  • prodrugs 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.
  • prodrugs are provided by T. Higuchi and W.
  • 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, (C 1 –C 8 )alkyl, (C 2 -C 12 )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-(alk
  • 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, ⁇ -amino(C1-C4)alkanyl, arylacyl and ⁇ -aminoacyl, or ⁇ -aminoacyl- ⁇ -aminoacyl, where each ⁇ -aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH) 2 , -P(O)(O(C 1 ).
  • 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 (C 1 -C 10 )alkyl, (C 3 -C 7 ) cycloalkyl, benzyl, or R-carbonyl is a natural ⁇ - aminoacyl or natural ⁇ -aminoacyl, -C(OH)C(O)OY 1 wherein Y 1 is H, (C 1 -C 6 )alkyl or benzyl, -C(OY 2 )Y 3 wherein Y 2 is (C 1 -C 4 ) alkyl and Y 3 is (C 1 -C 6 )alkyl, carboxy (C 1 -C 6 )alkyl, amino(C 1 - C 4 )alkyl or mono
  • 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.
  • suitable solvates include ethanolates, methanolates, and the like.
  • “Hydrate” is a solvate wherein the solvent molecule is H 2 O.
  • 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.
  • 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.
  • salts denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases.
  • 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.
  • 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.
  • 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 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
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride
  • 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).
  • positional isomers such as, for example, 4-pyridyl and 3-
  • 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.
  • 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.
  • salt 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.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • Certain isotopically-labelled compounds of the invention e.g., those labeled with 3 H and 14 C
  • Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability.
  • 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.
  • 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.
  • different isotopic forms of hydrogen (H) include protium ( 1 H) and deuterium ( 2 H).
  • the presence of deuterium in the compounds of the invention is indicated by "D".
  • Protium is the 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.
  • 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 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) described in the Summary of the Invention.
  • 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 Formulae (I) - (VIII) or a pharmaceutically acceptable salt thereof for inhibiting plasmepsin X activity, for treating a Plasmodium infection, or for treating malaria.
  • the invention further relates to the use of a compound of Formulae (I) - (VIII) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting plasmepsin X activity, for treating a Plasmodium infection, or for treating malaria.
  • the compounds of Formulae (I) - (VIII) 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 inhibiting 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.
  • 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 Formulae (I) - (VIII) or a pharmaceutically acceptable salt thereof for inhibiting plasmepsin IX activity, for treating a Plasmodium infection, or for treating malaria.
  • the invention further relates to the use of a compound of Formulae (I) - (VIII) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting plasmepsin IX activity, for treating a Plasmodium infection, or for treating malaria.
  • the compounds of Formulae (I) - (VIII) 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 inhibiting 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.
  • 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 Formulae (I) - (VIII) or a pharmaceutically acceptable salt thereof for inhibiting 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 Formulae (I) - (VIII) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting plasmepsin X and plasmepsin IX activity, for treating a Plasmodium infection, or for treating malaria.
  • the compounds of Formulae (I) - (VIII) 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.
  • 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 Formulae (I) - (VIII) 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.
  • therapy e.g., of the human body
  • medicine e.g., of the human body
  • inhibition of parasite/Plasmodium growth e.g.
  • 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 Formulae (I) - (VIII), or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and an effective amount of one or more additional agents described below.
  • 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 Formulae (I) - (VIII), or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and an effective amount of one or more additional anti-malarial agents.
  • 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 Formulae (I) - (VIII), or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and an effective amount of one or more additional anti-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 Formulae (I) - (VIII), or a pharmaceutically acceptable salt thereof may be confirmed by several pharmacological assays.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • compositions comprising a compound of Formulae (I) - (VIII), 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 Formulae (I) - (VIII), or a pharmaceutically acceptable salt thereof formulated for subcutaneous delivery.
  • compositions suitable for oral delivery is another embodiment.
  • the pharmaceutical preparation comprising one or more compounds of Formulae (I) - (VIII), or a pharmaceutically acceptable salt thereof to be prepared in a unit dosage form.
  • 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.
  • appropriate quantities of the active component e.g., an effective amount to achieve the desired purpose.
  • compounds of the invention 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 Formulae (I) - (VIII), 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.
  • 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, 18 th Edition, (1990), Mack Publishing Co., Easton, Pennsylvania.
  • 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-COTM (Guilin Pharmaceutical Co., Ltd.
  • the invention also provides methods of using the compounds of Formulae (I) - (VIII), or a pharmaceutically acceptable salt thereof to inhibit 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.
  • 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.
  • SCHEME 2 ''' '''''''' Intermediate compounds of Formula S-4 are prepared from S-3 after ring closing metathesis (RCM) reactions using catalysts such as the 2 nd generation Grubbs’, Zhan’s and Hoveyda/Grubbs’ catalysts. Double bonds in S-4 can be reduced under for example hydrogenation conditions to yield the products of Formula S-5.
  • SCHEME 3 Intermediate compounds of Formula S-7 are prepared from S-6, in which X is a halogen such as Cl, Br and I, after transition metal catalyzed intramolecular cross-coupling reactions such as Heck reactions. Resulting double bonds in S-7 can be reduced under for example hydrogenation conditions to yield the products of Formula S-8.
  • SCHEME 4 S-9 Products of Formula S-10 are prepared from S-9, in which X is a halogen such as Cl, Br and I, after transition metal catalyzed intramolecular cross-coupling reactions such as palladium catalyzed C-O coupling reactions.
  • SCHEME 5 Products of Formula S-12 are prepared from S-11 after intramolecular S N 2 reactions between an alcohol and X, in which X is a leaving group such as Cl, Br, I, OMs, OTs or OTf.
  • Products of Formula S-12 are also prepared from S-11 diols after dehydration conditions using an acid or other dehydration reagents.
  • the analytical LC-MS system used consisted of a Waters ZQ TM 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 ⁇ m or a Waters Acquity UPLC ® BEH C181.0 x 50 mm, 1.7 ⁇ m.
  • the flow rate was 1 mL/min, and the injection volume was 10 ⁇ L.
  • 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.
  • LC-MS System consisting of: Waters ZQ TM 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-185-micron, 30 mm (id) x 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 ⁇ L, 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) x 250 mm column or a Waters XBridgeTM C-185-micron OBDTM, 30 mm (id) x 250 mm column.
  • the mobile phases consisted of mixtures of acetonitrile (0-75%) in water containing 5mmol (NH4)HCO3.
  • Flow rates were maintained at 50 mL/min for the Waters XbridgeTM column and 90 mL/min for the Phenomenex Gemini column.
  • the injection volume ranged from 1000-8000 ⁇ L, 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 ⁇ M, 60 ⁇ pore size) in pre-packed cartridges of the size noted.
  • 1 H NMR spectra were acquired at 500 MHz spectrometers in CDCl 3 solutions unless otherwise noted. Chemical shifts were reported in parts per million (ppm). Tetramethylsilane (TMS) was used as internal reference in CDCl 3 solutions, and residual CH 3 OH peak or TMS was used as internal reference in CD 3 OD 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 (250x4.6 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.
  • CHIRALPAK AS Chiral preparative chromatography was conducted on one of CHIRALPAK AS, of CHIRALPAK AD, CHIRALCEL ® OD, CHIRALCEL ® IA, CHIRALCEL ® OJ columns (20x250 mm) (Daicel Chemical Industries, Ltd.) with desired isocratic solvent systems identified on chiral analytical chromatography or by supercritical fluid (SFC) conditions.
  • SFC supercritical fluid
  • the reaction was stirred at 18 °C for 1h under N 2 atmosphere.
  • the mixture was quenched with saturated sodium bicarbonate solution (10 mL) at 0 °C, and extracted with DCM (1 x 10 mL) then extracted with EtOAc (3 x 10 mL).
  • Example 1 The mixture was stirred at 22 °C for 16 h. The mixture was cooled, the solvent was evaporated under reduced pressure to give the crude product. The residue was purified by reverse preparative HPLC (Instrument EJ Method Column Boston Green ODS 150 x30mm, 5um Condition water(TFA)-ACN Begin B 22 End B 52 Gradient Time(min) 10100%B Hold Time(min) 2 FlowRate(ml/min) 25 Injections 1) to yield Example 1.
  • the aqueous layer was extracted with CH2Cl2 (2 ⁇ 600 mL) and the combined organic layer washed with brine (300 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give the crude product.
  • the crude product was purified by flash silica gel chromatography (ISCO ® ; 220 g SepaFlash ® Silica Flash Column, Eluent of 100% Pet.ether gradient @ 60 mL/min) to give 2,5-dibromo-1,1-difluoro-2,3-dihydro-1H-indene (5-3). No LCMS signal.
  • the parasite stock was maintained at 4% haematocrit in RPMI-Hepes media 30 buffered with sodium bicarbonate and supplemented with 5% heat inactivated human serum and 0.5% albumax. Approximately 42 hours prior to the potency assay being set up, parasites were synchronized with 5% 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 35 adjusted to 0.7% rings and the haematocrit was diluted to 2% in RPMI-Hepes media buffered with sodium bicarbonate and supplemented with 5% heat inactivated human serum and 0.5% albumax.30ul of diluted parasites are then added into 10ul 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 2. Table 2

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Abstract

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

Description

TITLE OF THE INVENTION ANTIMALARIAL AGENTS 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. 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):
Figure imgf000003_0001
wherein A, X, V, Y, Z, Ra, Rb, R3, R4, R12, R13, R15, m and p 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 treatment 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 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 further provides methods for the inhibition of plasmepsin X, or the dual inhibition of plasmepsin X and plasmepsin IX activity and of 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 further provides methods for blocking P. falciparum growth by inhibiting plasmepsin X. The present invention further provides methods for blocking P. falciparum growth by inhibiting both PMX and Plasmepsin IX. The present invention further provides methods for the treatment of malaria by inhibiting plasmepsin X. The present invention further provides methods for the treatment of malaria by inhibiting both PMX and Plasmepsin IX. 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):
,
Figure imgf000005_0001
wherein A is a straight or branched, saturated or unsaturated (C3-C10)alkylene, phenyl(C3- C10)alkylene or cycloalkyl(C3-C10)alkylene comprising at least one –CH2- group, wherein one or more additional –CH2- groups in A are optionally and independently replaced with a moiety selected from the group consisting of O, S, NR, CONR, NRCO, SO2, and SO2NR and wherein one or more of the hydrogens along A can be replaced with a group independently selected from hydroxyl, halogen and C1-3 haloalkyl; X is a bond, C(R14)2, O, S, SO, SO2 or NH; Y is CR9 or N, wherein when Y is N, Z is CR11 and V is CR10; V is CR10 or N, wherein when V is N, Z is CR11 and Y is CR9; Z is CR11 or N, wherein when Z is N, V is CR10 and Y is CR9; R is hydrogen, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1- C6alkylOH, COC1-C6alkyl or COOC1-C6alkyl; Ra is hydrogen, halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1-C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3- C6cycloalkyl, C1-C6alkyl, -C1-C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) or C1-C6alkylN(R7)(R8) or when taken with Rb forms a C3-C6cycloalkyl or heterocycloalkyl, wherein the C3-C6cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1- C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3-C6cycloalkyl, C1-C6alkyl, -C1- C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) and C1- C6alkylN(R7)(R8); Rb is hydrogen, halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1-C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3- C6cycloalkyl, C1-C6alkyl, -C1-C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) or C1-C6alkylN(R7)(R8) or when taken with Ra forms a C3-C6cycloalkyl or heterocycloalkyl, wherein the C3-C6cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or three substituents selected from the group consisting of halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1- C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3-C6cycloalkyl, C1-C6alkyl, -C1- C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) and C1- C6alkylN(R7)(R8); R3 is hydrogen, halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8), C1-C6alkylN(R7)(R8), C1-C6alkyl(OCH2CH2)nN(R7)(R8) or C1-C6alkylOhaloC1-C6alkyl or when taken with R4 forms a C3-C6cycloalkyl or C3-C6heterocycloalkyl; R4 is hydrogen, halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8), C1-C6alkylN(R7)(R8), C1-C6alkyl(OCH2CH2)nN(R7)(R8) or C1-C6alkylOhaloC1-C6alkyl or when taken with R3 forms a C3-C6cycloalkyl or C3-C6heterocycloalkyl; R7 is hydrogen, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1- C6alkylOH, COC1-C6alkyl or COOC1-C6alkyl; R8 is hydrogen, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1- C6alkylOH, COC1-C6alkyl or COOC1-C6alkyl; R9 is hydrogen, halogen, CN, OH, C1-C6alkoxy, 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); R10 is hydrogen, halogen, CN, OH, C1-C6alkoxy, 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); R11 is hydrogen, halogen, CN, OH, C1-C6alkoxy, 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); R12 is hydrogen, halogen, CN, OH, C1-C6alkoxy, 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); R13 is hydrogen, halogen, CN, OH, C1-C6alkoxy, 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); each occurrence of R14 is independently selected from the group consisting of hydrogen, halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, C3- C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) and C1- C6alkylN(R7)(R8); R15 is hydrogen, halogen, CN, OH, C1-C6alkoxy, 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); each occurrence of R16 is independently selected from the group consisting of hydrogen, halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, C3- C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) and C1- C6alkylN(R7)(R8); m is 0 or 1; n is 1, 2, 3 or 4; and p is 0 or 1. In the embodiments described herein, X is a bond, C(R14)2, O, S, SO, SO2 or NH. In certain embodiments described herein X is a bond. In certain embodiments, X is C(R14)2, wherein R14 is discussed in further detail below. In certain embodiments, X is a bond, CH2, CH(CH3), C(CH3)2, O, CH(OCH3), SO2 or CF2. In other embodiments X is CH2, O, S, SO, SO2 or NH. In certain embodiments, X is CH2. In the embodiments described herein, X is O. In certain embodiments described herein, X is S. In certain embodiments described herein, X is SO. In other embodiments described herein, X is SO2. In certain embodiments described herein, X is NH. In the embodiments described herein, Y is CR9 or N. In certain embodiments, Y is CR9, wherein R9 is discussed in detail below. In certain embodiments, Y is N. In certain embodiments, Y is CH. In certain embodiments, wherein when Y is N, Z is CR11 and V is CR10. In the embodiments described herein, V is CR10 or N. In certain embodiments, V is CR10, wherein R10 is discussed in detail below. In certain embodiments, V is N. In certain embodiments, V is CH. In certain embodiments, wherein when V is N, Z is CR11 and Y is CR9. In the embodiments described herein, Z is CR11 or N. In certain embodiments, Z is CR11, wherein R11 is discussed in detail below. In certain embodiments, Z is CH. In certain embodiments, Z is N. In certain embodiments, wherein when Z is N, V is CR10 and Y is CR9. In certain embodiments, X is O, Y and V are each CH and Z is N. In certain embodiments, X is O, Y and Z are each CH and V is N. In certain embodiments, X is O and V, Y and Z are all simultaneously CH. In the compounds described herein, Ra is hydrogen, halogen, CN, OH, C1- C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1- C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3-C6cycloalkyl, C1-C6alkyl, -C1- C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) or C1- C6alkylN(R7)(R8) or when taken with Rb forms a C3-C6cycloalkyl or heterocycloalkyl, wherein the C3-C6cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of halogen, CN, OH, C1-C6alkoxy, C1- C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1-C6alkylCOOC1- C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3-C6cycloalkyl, C1-C6alkyl, -C1-C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) and C1-C6alkylN(R7)(R8). In certain embodiments described herein, Ra is hydrogen. In certain embodiments, Ra is halogen. Examples of suitable halogens include chlorine, bromine, fluorine and iodine. In certain embodiments, Ra is CN. In certain embodiments, Ra is OH. In certain embodiments, Ra is C1-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, Ra is C1-C6alkylOC1-C6alkyl. In certain embodiments, Ra is C1-C6alkylCOOH. In certain embodiments, Ra is COOH. In certain embodiments, Ra is an oxo group. In certain embodiments, Ra is COOC1-C6alkyl. In certain embodiments, Ra is C1-C6alkylCOOC1-C6alkyl. In certain embodiments, Ra is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, Ra is C1-C6alkylC3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to
Figure imgf000008_0001
. In certain embodiments, Ra 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, Ra is methyl. In certain embodiments, Ra is C1-C6alkylOhaloC1-C6alkyl. Suitable examples of C1-C6alkylOhaloC1-C6alkyls include, but are not limited to,
Figure imgf000009_0001
. In certain embodiments, Ra 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, Ra is C1-C6alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, Ra is CON(R7)(R8). In certain embodiments, Ra is N(R7)(R8). In certain embodiments, Ra is C1-C6alkylN(R7)(R8), wherein R7 and R8 will be described in detail below. In certain embodiments, the compounds described herein have the Formula (II):
Figure imgf000009_0002
In certain embodiments, Ra is taken with Rb and forms a C3-C6cycloalkyl or heterocycloalkyl, wherein the C3-C6cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of halogen, CN, OH, C1- C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1- C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3-C6cycloalkyl, C1-C6alkyl, -C1- C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) and C1- C6alkylN(R7)(R8). In certain embodiments, Ra is taken with Rb and forms a C3-C6cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1-C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3- C6cycloalkyl, C1-C6alkyl, -C1-C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) and C1-C6alkylN(R7)(R8). Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, the cycloalkyl is unsubstituted. In certain embodiments, the heterocycloalkyl is substituted with one or two substituents selected from the group consisting of halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1-C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3- C6cycloalkyl, C1-C6alkyl, -C1-C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) and C1-C6alkylN(R7)(R8). In certain embodiments, the cycloalkyl is substituted with one substituent selected from the group consisting of halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1- C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1-C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1- C6alkylC3-C6cycloalkyl, C1-C6alkyl, -C1-C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1- C6alkylOH, CON(R7)(R8), N(R7)(R8) and C1-C6alkylN(R7)(R8). In certain embodiments, the cycloalkyl is substituted with two substituents selected from the group consisting of halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1-C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3-C6cycloalkyl, C1-C6alkyl, -C1-C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1- C6alkylOH, CON(R7)(R8), N(R7)(R8) and C1-C6alkylN(R7)(R8). In certain embodiments, the cycloalkyl is substituted with OH. In certain embodiments, Ra is taken with Rb and forms a heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1- C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1-C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1- C6alkylC3-C6cycloalkyl, C1-C6alkyl, -C1-C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1- C6alkylOH, CON(R7)(R8), N(R7)(R8) and C1-C6alkylN(R7)(R8). 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 heterocycloalkyl groups include, but are not limited to,
Figure imgf000011_0001
Non-limiting examples of bicyclic heterocycloalkyl groups include, but are not limited to,
Figure imgf000011_0002
In certain embodiments, Ra is taken with Rb and forms: O . In certain embodiments, the heterocycloalkyl is unsubstituted. In certain embodiments, the heterocycloalkyl is substituted with one or two substituents selected from the group consisting of halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1-C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3- C6cycloalkyl, C1-C6alkyl, -C1-C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) and C1-C6alkylN(R7)(R8). In certain embodiments, the heterocycloalkyl is substituted with one substituent selected from the group consisting of halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1-C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3-C6cycloalkyl, C1-C6alkyl, -C1-C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1- C6alkylOH, CON(R7)(R8), N(R7)(R8) and C1-C6alkylN(R7)(R8). In certain embodiments, the heterocycloalkyl is substituted with two substituents selected from the group consisting of halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1-C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3-C6cycloalkyl, C1-C6alkyl, -C1-C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1- C6alkylOH, CON(R7)(R8), N(R7)(R8) and C1-C6alkylN(R7)(R8). In certain embodiments, the heterocycloalkyl is substituted with two substituents selected from the group consisting of C1-C6alkyl. In the compounds described herein, Rb is hydrogen, halogen, CN, OH, C1- C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1- C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3-C6cycloalkyl, C1-C6alkyl, -C1- C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) or C1- C6alkylN(R7)(R8) or when taken with Ra forms a C3-C6cycloalkyl or heterocycloalkyl, wherein the C3-C6cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of halogen, CN, OH, C1-C6alkoxy, C1- C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1-C6alkylCOOC1- C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3-C6cycloalkyl, C1-C6alkyl, -C1-C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) and C1-C6alkylN(R7)(R8). In certain embodiments described herein, Rb is hydrogen. In certain embodiments, Rb is halogen. Examples of suitable halogens include chlorine, bromine, fluorine and iodine. In certain embodiments, Rb is CN. In certain embodiments, Rb is OH. In certain embodiments, Rb is C1-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, Rb is C1-C6alkylOC1-C6alkyl. In certain embodiments, Rb is C1-C6alkylCOOH. In certain embodiments, Rb is COOH. In certain embodiments, Rb is an oxo group. In certain embodiments, Rb is COOC1-C6alkyl. In certain embodiments, Rb is C1-C6alkylCOOC1-C6alkyl. In certain embodiments, Rb is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, Rb is C1-C6alkylC3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to
Figure imgf000012_0001
. In certain embodiments, Rb 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, Rb is methyl. In certain embodiments, Rb is C1-C6alkylOhaloC1-C6alkyl. Suitable examples of C1-C6alkylOhaloC1-C6alkyls include, but are not limited to,
Figure imgf000012_0002
. In certain embodiments, Rb 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, Rb is C1-C6alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, Rb is CON(R7)(R8). In certain embodiments, Rb is N(R7)(R8). In certain embodiments, Rb is C1-C6alkylN(R7)(R8), wherein R7 and R8 will be described in detail below. In certain embodiments, Rb is taken with Ra and forms a cycloalkyl or heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1-C6alkylCOOC1- C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3-C6cycloalkyl, C1-C6alkyl, -C1-C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) and C1-C6alkylN(R7)(R8). In certain embodiments, Rb is taken with Ra and forms a cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1-C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3- C6cycloalkyl, C1-C6alkyl, -C1-C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) and C1-C6alkylN(R7)(R8). Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, the cycloalkyl is unsubstituted. In certain embodiments, the heterocycloalkyl is substituted with one or two substituents selected from the group consisting of halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1-C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3- C6cycloalkyl, C1-C6alkyl, -C1-C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) and C1-C6alkylN(R7)(R8). In certain embodiments, the cycloalkyl is substituted with one substituent selected from the group consisting of halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1- C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1-C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1- C6alkylC3-C6cycloalkyl, C1-C6alkyl, -C1-C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1- C6alkylOH, CON(R7)(R8), N(R7)(R8) and C1-C6alkylN(R7)(R8). In certain embodiments, the cycloalkyl is substituted with two substituents selected from the group consisting of halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1-C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3-C6cycloalkyl, C1-C6alkyl, -C1-C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1- C6alkylOH, CON(R7)(R8), N(R7)(R8) and C1-C6alkylN(R7)(R8). In certain embodiments, the cycloalkyl is substituted with OH. In certain embodiments, Rb is taken with Ra and forms a heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1- C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1-C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1- C6alkylC3-C6cycloalkyl, C1-C6alkyl, -C1-C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1- C6alkylOH, CON(R7)(R8), N(R7)(R8) and C1-C6alkylN(R7)(R8). 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 heterocycloalkyl groups include, but are not limited to,
Figure imgf000014_0001
Non-limiting examples of bicyclic heterocycloalkyl groups include, but are not limited to,
Figure imgf000014_0002
. In certain embodiments, Rb is taken with Ra and forms:
Figure imgf000014_0003
. In certain embodiments, the cycloalkyl or heterocycloalkyl is unsubstituted. In certain embodiments, the cycloalkyl or heterocycloalkyl is substituted with one or two substituents selected from the group consisting of halogen, CN, OH, C1-C6alkoxy, C1- C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1-C6alkylCOOC1- C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3-C6cycloalkyl, C1-C6alkyl, -C1-C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) and C1-C6alkylN(R7)(R8). In certain embodiments, the cycloalkyl or heterocycloalkyl is substituted with one substituent selected from the group consisting of halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1- C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1-C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1- C6alkylC3-C6cycloalkyl, C1-C6alkyl, -C1-C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1- C6alkylOH, CON(R7)(R8), N(R7)(R8) and C1-C6alkylN(R7)(R8). In certain embodiments, the cycloalkyl or heterocycloalkyl is substituted with two substituents selected from the group consisting of halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1-C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3- C6cycloalkyl, C1-C6alkyl, -C1-C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) and C1-C6alkylN(R7)(R8). In certain embodiments, the heterocycloalkyl is substituted with two substituents selected from the group consisting of C1-C6alkyl. In certain embodiments, the cycloalkyl is substituted with two substituents selected from the group consisting of C1-C6alkyl. In certain embodiments, the cycloalkyl is unsubstituted. In the embodiments described herein, R3 is hydrogen, halogen, CN, OH, C1- C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8), C1-C6alkylN(R7)(R8), C1- C6alkyl(OCH2CH2)nN(R7)(R8) or C1-C6alkylOhaloC1-C6alkyl or when taken with R4 forms a C3- C6cycloalkyl or C3-C6heterocycloalkyl. In certain embodiments of the compounds described herein, R3 is hydrogen, halogen, CN, OH, C1-C6alkoxy, 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 R4 forms a C3-C6cycloalkyl or C3-C6heterocycloalkyl. In certain embodiments, R3 is hydrogen. In certain embodiments, R3 is halogen. Suitable halogens include fluorine, chlorine, bromine, and iodine. In certain embodiments, R3 is CN. In certain embodiments, R3 is OH. In certain embodiments, R3 is C1-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R3 is C1-C6alkylOC1-C6alkyl. In certain embodiments, R3 is COOH. In certain embodiments, R3 is C1- C6alkylCOOH. 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 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, R3 is C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R3 is CON(R7)(R8). Suitable examples of N(R7)(R8) include, but are not limited to, CONH2 and CON(CH3)2. In certain embodiments, R3 is N(R7)(R8). Suitable examples of N(R7)(R8) include, but are not limited to, NH2 and N(CH3)2. In certain embodiments, R3 is C1-C6alkylN(R7)(R8). Suitable examples of C1-C6alkylN(R7)(R8) include, but are not limited to,
Figure imgf000016_0001
,
Figure imgf000016_0002
below. In certain embodiments, R3 is C1-C6alkylOhaloC1-C6alkyl. Suitable examples of haloalkyls include, but are not limited to,
Figure imgf000016_0003
. In certain embodiments, R3 is C1-C6alkyl(OCH2CH2)nN(R7)(R8). R7, R8 and n are discussed in detail below. Suitable examples of C1-C6alkyl(OCH2CH2)nN(R7)(R8) include, but
Figure imgf000016_0004
. With regard to the compounds described herein, n is 1, 2, 3 or 4. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, R3 is taken with R4 and forms a C3-C6cycloalkyl or C3- C6heterocycloalkyl. In certain embodiments, R3 is taken with R4 and forms a C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R3 is taken with R4 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, R3 is hydrogen, fluorine, methyl, ethyl, OH, methoxy,
Figure imgf000017_0001
In certain embodiments, R3 is hydrogen, methyl, ethyl or
Figure imgf000017_0002
. In certain embodiments, R3 is taken with R4 to form oxetanyl. In certain embodiments described herein, R4 is hydrogen, halogen, CN, OH, C1- C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8), C1-C6alkylN(R7)(R8), C1- C6alkyl(OCH2CH2)nN(R7)(R8) or C1-C6alkylOhaloC1-C6alkyl or when taken with R3 forms a C3- C6cycloalkyl or C3-C6heterocycloalkyl. In certain embodiments of the compounds described herein, R4 is hydrogen, halogen, CN, OH, C1-C6alkoxy, 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 R3 forms a C3-C6cycloalkyl or C3-C6heterocycloalkyl. In certain embodiments, R4 is hydrogen. In certain embodiments, R4 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R4 is CN. In certain embodiments, R4 is OH. In certain embodiments, R4 is C1-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R4 is C1-C6alkylOC1-C6alkyl. In certain embodiments, R4 is COOH. In certain embodiments, R4 is C1- C6alkylCOOH. 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 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, R4 is C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R4 is CON(R7)(R8). Suitable examples of N(R7)(R8) include, but are not limited to, CONH2 and CON(CH3)2. In certain embodiments, R4 is N(R7)(R8). Suitable examples of N(R7)(R8) include, but are not limited to, NH2 and N(CH3)2. In certain embodiments, R4 is C1-C6alkylN(R7)(R8). Suitable examples of C1-C6alkylN(R7)(R8) include, but are not limited to,
Figure imgf000018_0001
,
Figure imgf000018_0002
are discussed in further detail below. In certain embodiments, R4 is C1-C6alkylOhaloC1-C6alkyl. Suitable examples of haloalkyls include, but are not limited to,
Figure imgf000018_0003
. In certain embodiments, R4 is C1-C6alkyl(OCH2CH2)nN(R7)(R8). R7, R8 are discussed in detail below and n is discussed above. Suitable examples of C1- C6alkyl(OCH2CH2)nN(R7)(R8) include, but are not limited to,
Figure imgf000018_0004
,
Figure imgf000018_0005
In certain embodiments, R4 is taken with R3 and forms a C3-C6cycloalkyl or C3- C6heterocycloalkyl. In certain embodiments, R4 is taken with R3 and forms a C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R4 is taken with R3 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, R4 is hydrogen or methyl. In certain embodiments, R4 is hydrogen, methyl, ethyl or
Figure imgf000019_0001
. In certain embodiments, R4 is taken with R3 to form oxetanyl. In certain embodiments, R3 and R4 are both hydrogen, methyl or ethyl. In certain embodiments, R3 is hydrogen and R4 is hydrogen. In certain embodiments, R3 and R4 are both halogen, where the halogen is selected from fluorine, chlorine, bromine and iodine. In certain embodiments, R3 and R4 are both fluorine. In the embodiments described herein, R5 is hydrogen, halogen, CN, OH, C1- C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1- C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3-C6cycloalkyl, C1-C6alkyl, -C1- C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) or C1- C6alkylN(R7)(R8). In certain embodiments described herein, R5 is hydrogen. In certain embodiments, R5 is halogen. Examples of suitable halogens include chlorine, bromine, fluorine and iodine. In certain embodiments, R5 is CN. In certain embodiments, R5 is OH. In certain embodiments, R5 is C1-C6alkoxy. 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 C1-C6alkylCOOH. In certain embodiments, R5 is COOH. In certain embodiments, R5 is an oxo group. In certain embodiments, R5 is COOC1-C6alkyl. In certain embodiments, R5 is C1-C6alkylCOOC1-C6alkyl. 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, C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited
Figure imgf000019_0002
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 methyl. In certain embodiments, R5 is C1-C6alkylOhaloC1-C6alkyl. Suitable examples of C1-C6alkylOhaloC1-C6alkyls include, but are not limited to,
Figure imgf000020_0001
. 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. 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, R1 is N(R7)(R8). In certain embodiments, R5 is C1-C6alkylN(R7)(R8), wherein R7 and R8 will be described in detail below. In certain embodiments, R5 is hydrogen, methyl, ethyl or t-butyl. In the embodiments described herein, R6 is hydrogen, halogen, CN, OH, C1- C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1- C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3-C6cycloalkyl, C1-C6alkyl, -C1- C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) or C1- C6alkylN(R7)(R8). In certain embodiments described herein, R6 is hydrogen. In certain embodiments, R6 is halogen. Examples of suitable halogens include chlorine, bromine, fluorine and iodine. In certain embodiments, R6 is CN. In certain embodiments, R6 is OH. In certain embodiments, R6 is C1-C6alkoxy. 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 C1-C6alkylCOOH. In certain embodiments, R6 is COOH. In certain embodiments, R6 is an oxo group. In certain embodiments, R6 is COOC1-C6alkyl. In certain embodiments, R6 is C1-C6alkylCOOC1-C6alkyl. 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-C6alkylC3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to
Figure imgf000021_0001
. 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 methyl. In certain embodiments, R6 is C1-C6alkylOhaloC1-C6alkyl. Suitable examples of F F 1 6 1 6 mited to, O F C -C alkylOhaloC -C alkyls include, but are not li . 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. 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, R1 is N(R7)(R8). In certain embodiments, R6 is C1-C6alkylN(R7)(R8), wherein R7 and R8 will be described in detail below. In certain embodiments, R6 is hydrogen, methyl, ethyl or t-butyl. In the embodiments described herein, R7 is hydrogen, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, COC1-C6alkyl or COOC1-C6alkyl. In certain embodiments, 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. In certain embodiments, R7 is COC1-C6alkyl. Suitable examples include, but are not limited to, COCH3. In certain embodiments, R7 is COOC1-C6alkyl. Suitable examples include, but are not limited to, COOCH3. In the embodiments described herein, R8 is hydrogen, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, COC1-C6alkyl or COOC1-C6alkyl. In certain embodiments, 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. In certain embodiments, R8 is COC1-C6alkyl. Suitable examples include, but are not limited to, COCH3. In certain embodiments, R8 is COOC1-C6alkyl. Suitable examples include, but are not limited to, COOCH3. In the embodiments described herein, R9 is hydrogen, halogen, CN, OH, C1- C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8) and N(R7)(R8). In certain embodiments, R9 is hydrogen. In certain embodiments, R9 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R9 is CN. In certain embodiments, R9 is OH. In certain embodiments, R9 is C1-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R9 is C1-C6alkylOC1-C6alkyl. In certain embodiments, R9 is COOH. In certain embodiments, R9 is C1- C6alkylCOOH. In certain embodiments, R9 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. 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 C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. 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). With regard to the compounds described herein, R10 is hydrogen, halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1- C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8) and N(R7)(R8). In certain embodiments, R10 is hydrogen. In certain embodiments, R10 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R10 is CN. In certain embodiments, R10 is OH. In certain embodiments, R10 is C1-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R10 is C1-C6alkylOC1-C6alkyl. In certain embodiments, R10 is COOH. In certain embodiments, R10 is C1-C6alkylCOOH. In certain embodiments, R10 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R10 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, R10 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, R10 is C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R10 is CON(R7)(R8). In certain embodiments, R10 is N(R7)(R8). In certain embodiments, R10 is C1-C6alkylN(R7)(R8). In the embodiments, described herein, R11 is hydrogen, halogen, CN, OH, C1- C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8) and N(R7)(R8). In certain embodiments, R11 is hydrogen. In certain embodiments, R11 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R11 is CN. In certain embodiments, R11 is OH. In certain embodiments, R11 is C1-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R11 is C1-C6alkylOC1-C6alkyl. In certain embodiments, R11 is COOH. In certain embodiments, R11 is C1-C6alkylCOOH. In certain embodiments, R11 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R11 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, R11 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, R11 is C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R11 is CON(R7)(R8). In certain embodiments, R11 is N(R7)(R8). In certain embodiments, R11 is C1-C6alkylN(R7)(R8). In the embodiments described herein, R12 is hydrogen, halogen, CN, OH, C1- C6alkoxy, 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). In certain embodiments, R12 is hydrogen. In certain embodiments, R12 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R12 is CN. In certain embodiments, R12 is OH. In certain embodiments, R12 is C1-C6alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R12 is C1-C6alkylOC1-C6alkyl. In certain embodiments, R12 is COOH. In certain embodiments, R12 is C1-C6alkylCOOH. In certain embodiments, R12 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R12 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, R12 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, R12 is C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R12 is CON(R7)(R8). In certain embodiments, R12 is N(R7)(R8). In certain embodiments, R12 is C1-C6alkylN(R7)(R8). In certain embodiments, R12 is hydrogen, methyl, ethyl, methoxy, OH or
Figure imgf000025_0001
. In certain embodiments, R12 is hydrogen or
Figure imgf000025_0002
. In the embodiments described herein, R13 is hydrogen, halogen, CN, OH, C1- C6alkoxy, 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). In certain embodiments, R13 is hydrogen. In certain embodiments, R13 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R13 is CN. In certain embodiments, R13 is OH. In certain embodiments, R13 is C1-C6alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R13 is C1-C6alkylOC1-C6alkyl. In certain embodiments, R13 is COOH. In certain embodiments, R13 is C1-C6alkylCOOH. In certain embodiments, R13 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R13 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, R13 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, R13 is C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R13 is CON(R7)(R8). In certain embodiments, R13 is N(R7)(R8). In certain embodiments, R13 is C1-C6alkylN(R7)(R8). In certain embodiments, R13 is hydrogen, methyl, ethyl, methoxy, OH or
Figure imgf000026_0001
. In certain embodiments, R13 is hydrogen or
Figure imgf000026_0002
. In certain embodiments, R12 and R13 are independently selected from the group consisting of hydrogen and C1-C6alkylOC1-C6alkyl, C1-C6alkyl. In certain embodiments described herein, each occurrence of R14 is independently selected from the group consisting of hydrogen, halogen, CN, OH, C1-C6alkoxy, 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). In certain embodiments, R14 is hydrogen. In certain embodiments, R14 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R14 is CN. In certain embodiments, R14 is OH. In certain embodiments, R14 is C1-C6alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R14 is C1-C6alkylOC1-C6alkyl. In certain embodiments, R14 is COOH. In certain embodiments, R14 is C1-C6alkylCOOH. In certain embodiments, R14 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R14 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, R14 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, R14 is C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R14 is CON(R7)(R8). In certain embodiments, R14 is N(R7)(R8). In certain embodiments, R14 is C1-C6alkylN(R7)(R8). In certain embodiments, wherein X is C(R14)2, R14 is independently selected from the group consisting of hydrogen, halogen, OH, C1-C6alkylOH, C1-C6alkylalkoxy, C1- C6alkylOC1-C6alkyl and C1-C6alkyl. In certain embodiments, R14 is hydrogen, methyl, ethyl, methoxy, OH or
Figure imgf000027_0001
. In the embodiments described herein, R15 is hydrogen, halogen, CN, OH, C1- C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8) and N(R7)(R8). In certain embodiments, R15 is hydrogen. In certain embodiments, R15 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R15 is CN. In certain embodiments, R15 is OH. In certain embodiments, R15 is C1-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R15 is C1-C6alkylOC1-C6alkyl. In certain embodiments, R15 is COOH. In certain embodiments, R15 is C1-C6alkylCOOH. In certain embodiments, R15 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R15 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, R15 is ethyl. In certain embodiments, R15 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, R15 is C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso- butanol. In certain embodiments, R15 is CON(R7)(R8). In certain embodiments, R15 is N(R7)(R8). In certain embodiments, R15 is C1-C6alkylN(R7)(R8). In certain embodiments, R15 is methyl or ethyl. In the embodiments described herein, R16 is hydrogen, halogen, CN, OH, C1- C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8) and N(R7)(R8). In certain embodiments, R16 is hydrogen. In certain embodiments, R16 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R16 is CN. In certain embodiments, R16 is OH. In certain embodiments, R16 is C1-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R16 is C1-C6alkylOC1-C6alkyl. In certain embodiments, R16 is COOH. In certain embodiments, R16 is C1-C6alkylCOOH. In certain embodiments, R16 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R16 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, R16 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, R16 is C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R16 is CON(R7)(R8). In certain embodiments, R16 is N(R7)(R8). In certain embodiments, R16 is C1-C6alkylN(R7)(R8). In the embodiments of the compounds described herein, m is 0 or 1. In certain embodiments, m is 0. In certain embodiments, m is 1. In the embodiments of the compounds described herein, p is 0 or 1. In certain embodiments, p is 0. In certain embodiments, p is 1. In the embodiments described herein, A is a straight or branched, saturated or unsaturated (C3-C10)alkylene, phenyl(C3-C10)alkylene or cycloalkyl(C3-C10)alkylene comprising at least one –CH2- group, wherein one or more additional –CH2- groups in A are optionally and independently replaced with a moiety selected from the group consisting of O, S, NR, CONR, NRCO, SO2, and SO2NR and wherein one or more of the hydrogens along A can be replaced with a group independently selected from hydroxyl, halogen and C1-3 haloalkyl. In certain embodiments, A is a straight or branched, saturated or unsaturated (C3-C10)alkylene or cycloalkyl(C3-C10)alkylene, wherein one or more –CH2- groups in A are optionally and independently replaced with a moiety selected from the group consisting of O, S and NH. In certain embodiment, A will always have at least one –CH2- group. In certain embodiments, A is a straight (C3-C10)alkylene. Examples of straight (C3-C10)alkylenes include,
Figure imgf000029_0001
. In certain embodiments, A is a branched (C3-C10)alkylene. Suitable branched (C3- C10)alkylenes include but are not limited to:
Figure imgf000029_0002
In certain embodiments, A is a saturated (C3-C10)alkylene. Examples include,
Figure imgf000030_0001
. In certain embodiments, A is an unsaturated (C3-C10)alkylene. Suitable unsaturated (C3-C10)alkylenes include any of the saturated (C3-C10)alkylene, wherein hydrogens have been removed and one or more double or triple covalent bonds exist between adjacent carbon atoms. Examples of unsaturated (C3-C10)alkylenes include, but are not limited to,
Figure imgf000030_0002
. In other embodiments, A is a straight cycloalkyl(C3-C10)alkylene. Suitable straight cycloalkyl(C3-C10)alkylenes include a cycloalkyl(C3-C10)alkylene wherein two carbons in a chain are included in a (C3-C10)cycloalkyl. Examples of straight cycloalkyl(C3-C10)alkylenes include, but are not limited to,
Figure imgf000031_0001
In certain embodiments, A is a branched cycloalkyl(C3-C10)alkylene. Suitable branched cycloalkyl(C3-C10)alkylenes include a branched (C3-C10)alkylene wherein two carbons in a chain are included in a (C3-C10)cycloalkyl. Examples of cycloalkyl(C3-C10)alkylenes include, but are not limited to,
Figure imgf000031_0002
. In certain embodiments, A is a saturated cycloalkyl(C3-C10)alkylene. Examples of saturated cycloalkyl(C3-C10)alkylenes include, but are not limited to,
Figure imgf000032_0001
. In certain embodiments, A is an unsaturated cycloalkyl(C3-C10)alkylene. Examples of unsaturated cyclo(C3-C10)alkylenes include, but are not limited to,
Figure imgf000032_0002
. In certain embodiments, A is an unsaturated or saturated phenyl(C3-C10)alkylene. Examples of unsaturated and saturated phenyl(C3-C10)alkylenes include, but are not limited to,
Figure imgf000032_0003
. In other embodiments, one or more –CH2- groups in A are optionally and independently replaced with a moiety selected from the group consisting of O, S, NR, CONR, NRCO, SO2, and SO2NR. In other embodiments, one or more –CH2- groups in A are optionally and independently replaced with a moiety selected from the group consisting of O, S and NH. In other embodiments, one or more –CH2- groups in A are optionally and independently replaced with O. In other embodiments, one or more –CH2- groups in A are optionally and independently replaced with S. In other embodiments, one or more –CH2- groups in A are optionally and independently replaced with NR. In other embodiments, one or more –CH2- groups in A are optionally and independently replaced with CONR. In other embodiments, one or more –CH2- groups in A are optionally and independently replaced with NRCO. In other embodiments, one or more –CH2- groups in A are optionally and independently replaced with SO2. In other embodiments, one or more –CH2- groups in A are optionally and independently replaced with and SO2NR. R will be described in further detail below. In the embodiments described herein, R is hydrogen, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, COC1-C6alkyl or COOC1-C6alkyl. In certain embodiments, R is hydrogen, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl or C1-C6alkylOH. In certain embodiments, R is hydrogen. In certain embodiments, R is C1- C6alkylCOOH. In certain embodiments, R is COOH. In certain embodiments, R is C3- C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R 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, R 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, R is C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso- butanol. In certain embodiments, R is COC1-C6alkyl. Suitable examples include, but are not limited to, COCH3. In certain embodiments, R is COOC1-C6alkyl. Suitable examples include, but are not limited to, COOCH3. Examples of such embodiments include, but are not limited to,
Figure imgf000033_0001
. In certain embodiments, A is
Figure imgf000034_0001
. In certain embodiments, one or more of the hydrogens along A can be replaced with a group independently selected from hydroxyl, halogen and C1-3 haloalkyl. Examples of suitable halogens include chlorine, bromine, fluorine and iodine. In certain embodiments, A is
Figure imgf000034_0002
. Also described herein are compounds having the structural Formula (III):
Figure imgf000034_0003
wherein, A is a straight or branched, saturated or unsaturated (C3-C10)alkylene, phenyl(C3- C10)alkylene or cycloalkyl(C3-C10)alkylene comprising at least one –CH2- group, wherein one or more additional –CH2- groups in A are optionally and independently replaced with a moiety selected from the group consisting of O, S, NR, CONR, NRCO, SO2, and SO2NR and wherein one or more of the hydrogens along A can be replaced with a group independently selected from hydroxyl, halogen and C1-3 haloalkyl; Q is C(R16)2, O, S, SO, SO2 or NH; X is a bond, C(R14)2, O, S, SO, SO2 or NH; Y is CR9 or N, wherein when Y is N, Z is CR11 and V is CR10; V is CR10 or N, wherein when V is N, Z is CR11 and Y is CR9; Z is CR11 or N, wherein when Z is N, V is CR10 and Y is CR9; R is hydrogen, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1- C6alkylOH, COC1-C6alkyl or COOC1-C6alkyl; R1 is hydrogen, halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1-C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3- C6cycloalkyl, C1-C6alkyl, -C1-C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) or C1-C6alkylN(R7)(R8); R2 is hydrogen, halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1-C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3- C6cycloalkyl, C1-C6alkyl, -C1-C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) or C1-C6alkylN(R7)(R8); R3 is hydrogen, halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8), C1-C6alkylN(R7)(R8), C1-C6alkyl(OCH2CH2)nN(R7)(R8) or C1-C6alkylOhaloC1-C6alkyl or when taken with R4 forms a C3-C6cycloalkyl or C3-C6heterocycloalkyl; R4 is hydrogen, halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8), C1-C6alkylN(R7)(R8), C1-C6alkyl(OCH2CH2)nN(R7)(R8) or C1-C6alkylOhaloC1-C6alkyl or when taken with R3 forms a C3-C6cycloalkyl or C3-C6heterocycloalkyl; R5 is hydrogen, halogen, CN, OH, C1-C6alkoxy, 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); R6 is hydrogen, halogen, CN, OH, C1-C6alkoxy, 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); R7 is hydrogen, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1- C6alkylOH, COC1-C6alkyl or COOC1-C6alkyl; R8 is hydrogen, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1- C6alkylOH, COC1-C6alkyl or COOC1-C6alkyl; R9 is hydrogen, halogen, CN, OH, C1-C6alkoxy, 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); R10 is hydrogen, halogen, CN, OH, C1-C6alkoxy, 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); R11 is hydrogen, halogen, CN, OH, C1-C6alkoxy, 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); R12 is hydrogen, halogen, CN, OH, C1-C6alkoxy, 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); R13 is hydrogen, halogen, CN, OH, C1-C6alkoxy, 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); each occurrence of R14 is independently selected from the group consisting of hydrogen, halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, C3- C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) and C1- C6alkylN(R7)(R8); R15 is hydrogen, halogen, CN, OH, C1-C6alkoxy, 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); each occurrence of R16 is independently selected from the group consisting of hydrogen, halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, C3- C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) and C1- C6alkylN(R7)(R8); l is 0 or 1; m is 0 or 1; n is 1, 2, 3 or 4; and p is 0 or 1. In the embodiments described herein, Q is C(R16)2, O, S, SO, SO2 or NH. In certain embodiments, Q is C(R16)2, wherein R16 is discussed in further detail below. In certain embodiments, Q is CH2, CH(CH3), C(CH3)2, O, CH(OCH3), SO2 or CF2. In other embodiments Q is CH2, O, S, SO, SO2 or NH. In certain embodiments, Q is CH2. In certain embodiments described herein, Q is O. In certain embodiments described herein, Q is S. In other embodiments described herein, Q is SO. In other embodiments described herein, Q is SO2. In certain embodiments described herein, Q is NH. In other embodiments described herein, Q is O or SO2. In still other embodiments described herein, Q is O or CH2. In the embodiments described herein, X is a bond, C(R14)2, O, S, SO, SO2 or NH. In certain embodiments described herein X is a bond. In certain embodiments, X is C(R14)2, wherein R14 is discussed in further detail below. In certain embodiments, X is a bond, CH2, CH(CH3), C(CH3)2, O, CH(OCH3), SO2 or CF2. In other embodiments X is CH2, O, S, SO, SO2 or NH. In certain embodiments, X is CH2. In the embodiments described herein, X is O. In certain embodiments described herein, X is S. In certain embodiments described herein, X is SO. In other embodiments described herein, X is SO2. In certain embodiments described herein, X is NH. In the embodiments described herein, Y is CR9 or N. In certain embodiments, Y is CR9, wherein R9 is discussed in detail below. In certain embodiments, Y is N. In certain embodiments, Y is CH. In certain embodiments, wherein when Y is N, Z is CR11 and V is CR10. In the embodiments described herein, V is CR10 or N. In certain embodiments, V is CR10, wherein R10 is discussed in detail below. In certain embodiments, V is N. In certain embodiments, V is CH. In certain embodiments, wherein when V is N, Z is CR11 and Y is CR9. In the embodiments described herein, Z is CR11 or N. In certain embodiments, Z is CR11, wherein R11 is discussed in detail below. In certain embodiments, Z is CH. In certain embodiments, Z is N. In certain embodiments, wherein when Z is N, V is CR10 and Y is CR9. In certain embodiments, X is O, Y and V are each CH and Z is N. In certain embodiments, X is O, Y and Z are each CH and V is N. In certain embodiments, X is O and V, Y and Z are all simultaneously CH. In certain embodiments, X is a bond, Y and V are each CH and Z is N. In certain embodiments, X is a bond, Y and Z are each CH and V is N. In certain embodiments, X is a bond and V, Y and Z are all simultaneously CH. Also described herein are compounds of Formula III represented by structural Formula (IIIA):
Figure imgf000038_0001
wherein R1, R2, R3, R4, R5, R6, R15, A, and Q, are as described herein. An embodiment of this invention is realized when R1, R2, R3, R4, R5, R6, R15, A, and Q, are as described in Formula III. Another embodiment of Formula IIIA is realized when R3 and R4 are both hydrogen, methyl, ethyl, or halogen. Another embodiment of Formula IIIA is realized when R3 and R4 are both halogen selected from chlorine and fluorine. Another embodiment of Formula IIIA is realized when Q is CH2, CH(CH3), C(CH3)2, O, CH(OCH3), SO2 or CF2. In other embodiments described herein, Q in Formula IIIA is O or SO2. In still other embodiments described herein, Q in Formula IIIIA is O or CH2. Another embodiment of Formula IIIA is realized when A is a straight or branched, saturated or unsaturated (C3-C10)alkylene comprising at least one –CH2- group, wherein one or more additional –CH2- groups in A are optionally and independently replaced with a moiety selected from the group consisting of O, S, NR, CONR, NRCO, SO2, and SO2NR and wherein one or more of the hydrogens along A can be replaced with a group independently selected from hydroxyl, halogen and C1-3 haloalkyl. Also described herein are compounds of Formula III represented by structural Formula (IIIB):
Figure imgf000038_0002
(IIIB) wherein R1, R2, R3, R4, R5, R6, R15, A, and Q, are as described herein. An embodiment of this invention is realized when R1, R2, R3, R4, R5, R6, R15, A, and Q, are as described in Formula III. Another embodiment of Formula IIIB is realized when R3 and R4 are both hydrogen, methyl, ethyl, or halogen. Another embodiment of Formula IIIB is realized when R3 and R4 are both halogen selected from chlorine and fluorine. Another embodiment of Formula IIIB is realized when Q is CH2, CH(CH3), C(CH3)2, O, CH(OCH3), SO2 or CF2. In other embodiments described herein, Q in Formula IIIB is O or SO2. In still other embodiments described herein, Q in Formula IIIIB is O or CH2. Another embodiment of Formula IIIB is realized when A is a straight or branched, saturated or unsaturated (C3-C10)alkylene comprising at least one –CH2- group, wherein one or more additional –CH2- groups in A are optionally and independently replaced with a moiety selected from the group consisting of O, S, NR, CONR, NRCO, SO2, and SO2NR and wherein one or more of the hydrogens along A can be replaced with a group independently selected from hydroxyl, halogen and C1-3 haloalkyl. Certain embodiments are represented as Formulas IV - VI:
Figure imgf000039_0001
In the embodiments described herein, R1 is hydrogen, halogen, CN, OH, C1- C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1- C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3-C6cycloalkyl, C1-C6alkyl, -C1- C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) or C1- C6alkylN(R7)(R8). In certain embodiments described herein, R1 is hydrogen. In certain embodiments, R1 is halogen. Examples of suitable halogens include chlorine, bromine, fluorine and iodine. In certain embodiments, R1 is CN. In certain embodiments, R1 is OH. In certain embodiments, R1 is C1-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R1 is C1-C6alkylOC1-C6alkyl. In certain embodiments, R1 is C1-C6alkylCOOH. In certain embodiments, R1 is COOH. In certain embodiments, R1 is an oxo group. In certain embodiments, R1 is COOC1-C6alkyl. In certain embodiments, R1 is C1-C6alkylCOOC1-C6alkyl. In certain embodiments, R1 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R1 is C1-C6alkylC3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to
Figure imgf000040_0001
. In certain embodiments, R1 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, R1 is C1-C6alkylOhaloC1-C6alkyl. Suitable examples of C1-C6alkylOhaloC1-C6alkyls include, but are not limited to,
Figure imgf000040_0002
. In certain embodiments, R1 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, R1 is C1-C6alkylOH. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R1 is CON(R7)(R8). In certain embodiments, R1 is N(R7)(R8). In certain embodiments, R1 is C1-C6alkylN(R7)(R8), wherein R7 and R8 will be described in detail below. In certain embodiments, R1 is hydrogen, bromine, fluorine, chlorine, methyl, OH, halogen, CN oxo, methoxymethyl, COOCH2CH3 or trifluoromethyl. In the embodiments described herein, R2 is hydrogen, halogen, CN, OH, C1- C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1- C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3-C6cycloalkyl, C1-C6alkyl, -C1- C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) or C1- C6alkylN(R7)(R8). In certain embodiments described herein, R2 is hydrogen. In certain embodiments, R2 is halogen. Examples of suitable halogens include chlorine, bromine, fluorine and iodine. In certain embodiments, R2 is CN. In certain embodiments, R2 is OH. In certain embodiments, R2 is C1-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R2 is C1-C6alkylOC1-C6alkyl. In certain embodiments, R2 is C1-C6alkylCOOH. In certain embodiments, R2 is COOH. In certain embodiments, R2 is an oxo group. In certain embodiments, R2 is COOC1-C6alkyl. In certain embodiments, R2 is C1-C6alkylCOOC1-C6alkyl. 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-C6alkylC3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to
Figure imgf000041_0001
. 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 C1-C6alkylOhaloC1-C6alkyl. Suitable examples of C1-C6alkylOhaloC1-C6alkyls include, but are not limited to,
Figure imgf000041_0002
. 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. Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R2 is CON(R7)(R8). In certain embodiments, R1 is N(R7)(R8). In certain embodiments, R2 is C1-C6alkylN(R7)(R8), wherein R7 and R8 will be described in detail below. In certain embodiments, R2 is hydrogen, bromine, fluorine, chlorine, methyl, OH, halogen, CN oxo, methoxymethyl, COOCH2CH3 or trifluoromethyl. In certain embodiments, R1 and R2 are both hydrogen. In certain embodiments, R1 is OH and R2 is hydrogen. In the embodiments described herein, R3 is hydrogen, halogen, CN, OH, C1- C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8), C1-C6alkylN(R7)(R8), C1- C6alkyl(OCH2CH2)nN(R7)(R8) or C1-C6alkylOhaloC1-C6alkyl or when taken with R4 forms a C3- C6cycloalkyl or C3-C6heterocycloalkyl. In certain embodiments of the compounds described herein, R3 is hydrogen, halogen, CN, OH, C1-C6alkoxy, 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 R4 forms a C3-C6cycloalkyl or C3-C6heterocycloalkyl. In certain embodiments, R3 is hydrogen. In certain embodiments, R3 is halogen. Suitable halogens include fluorine, chlorine, bromine, and iodine. In certain embodiments, R3 is CN. In certain embodiments, R3 is OH. In certain embodiments, R3 is C1-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R3 is C1-C6alkylOC1-C6alkyl. In certain embodiments, R3 is COOH. In certain embodiments, R3 is C1- C6alkylCOOH. 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 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, R3 is C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R3 is CON(R7)(R8). Suitable examples of N(R7)(R8) include, but are not limited to, CONH2 and CON(CH3)2. In certain embodiments, R3 is N(R7)(R8). Suitable examples of N(R7)(R8) include, but are not limited to, NH2 and N(CH3)2. In certain embodiments, R3 is C1-C6alkylN(R7)(R8). Suitable examples of C1-C6alkylN(R7)(R8) include, but are not limited to,
Figure imgf000043_0001
,
Figure imgf000043_0002
are discussed in further detail below. In certain embodiments, R3 is C1-C6alkylOhaloC1-C6alkyl. Suitable examples of haloalkyls include, but are not limited to,
Figure imgf000043_0003
. In certain embodiments, R3 is C1-C6alkyl(OCH2CH2)nN(R7)(R8). R7, R8 and n are discussed in detail below. Suitable examples of C1-C6alkyl(OCH2CH2)nN(R7)(R8) include, but
Figure imgf000043_0004
. With regard to the compounds described herein, n is 1, 2, 3 or 4. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, R3 is taken with R4 and forms a C3-C6cycloalkyl or C3- C6heterocycloalkyl. In certain embodiments, R3 is taken with R4 and forms a C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R3 is taken with R4 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, R3 is hydrogen, fluorine, methyl, ethyl, OH, methoxy,
Figure imgf000044_0001
In certain embodiments, R3 is hydrogen, methyl, ethyl or
Figure imgf000044_0002
. In certain embodiments, R3 is taken with R4 to form oxetanyl. In certain embodiments described herein, R4 is hydrogen, halogen, CN, OH, C1- C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8), C1-C6alkylN(R7)(R8), C1- C6alkyl(OCH2CH2)nN(R7)(R8) or C1-C6alkylOhaloC1-C6alkyl or when taken with R3 forms a C3- C6cycloalkyl or C3-C6heterocycloalkyl. In certain embodiments of the compounds described herein, R4 is hydrogen, halogen, CN, OH, C1-C6alkoxy, 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 R3 forms a C3-C6cycloalkyl or C3-C6heterocycloalkyl. In certain embodiments, R4 is hydrogen. In certain embodiments, R4 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R4 is CN. In certain embodiments, R4 is OH. In certain embodiments, R4 is C1-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R4 is C1-C6alkylOC1-C6alkyl. In certain embodiments, R4 is COOH. In certain embodiments, R4 is C1- C6alkylCOOH. 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 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, R4 is C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R4 is CON(R7)(R8). Suitable examples of N(R7)(R8) include, but are not limited to, CONH2 and CON(CH3)2. In certain embodiments, R4 is N(R7)(R8). Suitable examples of N(R7)(R8) include, but are not limited to, NH2 and N(CH3)2. In certain embodiments, R4 is C1-C6alkylN(R7)(R8). Suitable examples of C1- C6alkylN(R7)(R8) include, but are not limited to,
Figure imgf000045_0001
Figure imgf000045_0002
are discussed in further detail below. In certain embodiments, R4 is C1-C6alkylOhaloC1-C6alkyl. Suitable examples of haloalkyls include, but are not limited to,
Figure imgf000045_0003
. In certain embodiments, R4 is C1-C6alkyl(OCH2CH2)nN(R7)(R8). R7, R8 are discussed in detail below and n is discussed above. Suitable examples of C1- C alkyl(OCH CH ) N(R7 8
Figure imgf000045_0004
6 2 2 n )(R ) include, but are not limited to, ,
Figure imgf000045_0005
In certain embodiments, R4 is taken with R3 and forms a C3-C6cycloalkyl or C3- C6heterocycloalkyl. In certain embodiments, R4 is taken with R3 and forms a C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R4 is taken with R3 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, R4 is hydrogen or methyl. In certain embodiments, R4 is hydrogen, methyl, ethyl or
Figure imgf000046_0001
. In certain embodiments, R4 is taken with R3 to form oxetanyl. In certain embodiments, R3 and R4 are both hydrogen, methyl or ethyl. In certain embodiments, R3 is hydrogen and R4 is hydrogen. In the embodiments described herein, R5 is hydrogen, halogen, CN, OH, C1- C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1- C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3-C6cycloalkyl, C1-C6alkyl, -C1- C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) or C1- C6alkylN(R7)(R8). In certain embodiments described herein, R5 is hydrogen. In certain embodiments, R5 is halogen. Examples of suitable halogens include chlorine, bromine, fluorine and iodine. In certain embodiments, R5 is CN. In certain embodiments, R5 is OH. In certain embodiments, R5 is C1-C6alkoxy. 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 C1-C6alkylCOOH. In certain embodiments, R5 is COOH. In certain embodiments, R5 is an oxo group. In certain embodiments, R5 is COOC1-C6alkyl. In certain embodiments, R5 is C1-C6alkylCOOC1-C6alkyl. 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-C6alkylC3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to
Figure imgf000046_0002
. 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 methyl. In certain embodiments, R5 is C1-C6alkylOhaloC1-C6alkyl. Suitable examples of C1-C6alkylOhaloC1-C6alkyls include, but are not limited to,
Figure imgf000047_0001
. 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. 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, R1 is N(R7)(R8). In certain embodiments, R5 is C1-C6alkylN(R7)(R8), wherein R7 and R8 will be described in detail below. In certain embodiments, R5 is hydrogen, methyl, ethyl or t-butyl. In the embodiments described herein, R6 is hydrogen, halogen, CN, OH, C1- C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1- C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3-C6cycloalkyl, C1-C6alkyl, -C1- C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) or C1- C6alkylN(R7)(R8). In certain embodiments described herein, R6 is hydrogen. In certain embodiments, R6 is halogen. Examples of suitable halogens include chlorine, bromine, fluorine and iodine. In certain embodiments, R6 is CN. In certain embodiments, R6 is OH. In certain embodiments, R6 is C1-C6alkoxy. 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 C1-C6alkylCOOH. In certain embodiments, R6 is COOH. In certain embodiments, R6 is an oxo group. In certain embodiments, R6 is COOC1-C6alkyl. In certain embodiments, R6 is C1-C6alkylCOOC1-C6alkyl. 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-C6alkylC3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to
Figure imgf000048_0001
. 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 methyl. In certain embodiments, R6 is C1-C6alkylOhaloC1-C6alkyl. Suitable examples of C1-C6alkylOhaloC1-C6alkyls include, but are not limited to,
Figure imgf000048_0002
. 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. 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, R1 is N(R7)(R8). In certain embodiments, R6 is C1-C6alkylN(R7)(R8), wherein R7 and R8 will be described in detail below. In certain embodiments, R6 is hydrogen, methyl, ethyl or t-butyl. In the embodiments described herein, R7 is hydrogen, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, COC1-C6alkyl or COOC1-C6alkyl. In certain embodiments, 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. In certain embodiments, R7 is COC1-C6alkyl. Suitable examples include, but are not limited to, COCH3. In certain embodiments, R7 is COOC1-C6alkyl. Suitable examples include, but are not limited to, COOCH3. In the embodiments described herein, R8 is hydrogen, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, COC1-C6alkyl or COOC1-C6alkyl. In certain embodiments, 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. In certain embodiments, R8 is COC1-C6alkyl. Suitable examples include, but are not limited to, COCH3. In certain embodiments, R8 is COOC1-C6alkyl. Suitable examples include, but are not limited to, COOCH3. In the embodiments described herein, R9 is hydrogen, halogen, CN, OH, C1- C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8) and N(R7)(R8). In certain embodiments, R9 is hydrogen. In certain embodiments, R9 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R9 is CN. In certain embodiments, R9 is OH. In certain embodiments, R9 is C1-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R9 is C1-C6alkylOC1-C6alkyl. In certain embodiments, R9 is COOH. In certain embodiments, R9 is C1- C6alkylCOOH. In certain embodiments, R9 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. 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 C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. 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). With regard to the compounds described herein, R10 is hydrogen, halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1- C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8) and N(R7)(R8). In certain embodiments, R10 is hydrogen. In certain embodiments, R10 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R10 is CN. In certain embodiments, R10 is OH. In certain embodiments, R10 is C1-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R10 is C1-C6alkylOC1-C6alkyl. In certain embodiments, R10 is COOH. In certain embodiments, R10 is C1-C6alkylCOOH. In certain embodiments, R10 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R10 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, R10 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, R10 is C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R10 is CON(R7)(R8). In certain embodiments, R10 is N(R7)(R8). In certain embodiments, R10 is C1-C6alkylN(R7)(R8). In the embodiments, described herein, R11 is hydrogen, halogen, CN, OH, C1- C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8) and N(R7)(R8). In certain embodiments, R11 is hydrogen. In certain embodiments, R11 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R11 is CN. In certain embodiments, R11 is OH. In certain embodiments, R11 is C1-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R11 is C1-C6alkylOC1-C6alkyl. In certain embodiments, R11 is COOH. In certain embodiments, R11 is C1-C6alkylCOOH. In certain embodiments, R11 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R11 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, R11 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, R11 is C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R11 is CON(R7)(R8). In certain embodiments, R11 is N(R7)(R8). In certain embodiments, R11 is C1-C6alkylN(R7)(R8). In the embodiments described herein, R12 is hydrogen, halogen, CN, OH, C1- C6alkoxy, 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). In certain embodiments, R12 is hydrogen. In certain embodiments, R12 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R12 is CN. In certain embodiments, R12 is OH. In certain embodiments, R12 is C1-C6alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R12 is C1-C6alkylOC1-C6alkyl. In certain embodiments, R12 is COOH. In certain embodiments, R12 is C1-C6alkylCOOH. In certain embodiments, R12 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R12 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, R12 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, R12 is C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R12 is CON(R7)(R8). In certain embodiments, R12 is N(R7)(R8). In certain embodiments, R12 is C1-C6alkylN(R7)(R8). In certain embodiments, R12 is hydrogen, methyl, ethyl, methoxy, OH or
Figure imgf000052_0001
. In certain embodiments, R12 is hydrogen or
Figure imgf000052_0002
. In the embodiments described herein, R13 is hydrogen, halogen, CN, OH, C1- C6alkoxy, 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). In certain embodiments, R13 is hydrogen. In certain embodiments, R13 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R13 is CN. In certain embodiments, R13 is OH. In certain embodiments, R13 is C1-C6alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R13 is C1-C6alkylOC1-C6alkyl. In certain embodiments, R13 is COOH. In certain embodiments, R13 is C1-C6alkylCOOH. In certain embodiments, R13 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R13 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, R13 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, R13 is C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R13 is CON(R7)(R8). In certain embodiments, R13 is N(R7)(R8). In certain embodiments, R13 is C1-C6alkylN(R7)(R8). In certain embodiments, R13 is hydrogen, methyl, ethyl, methoxy, OH or
Figure imgf000053_0001
. In certain embodiments, R13 is hydrogen or
Figure imgf000053_0002
. In certain embodiments, R12 and R13 are independently selected from the group consisting of hydrogen and C1-C6alkylOC1-C6alkyl, C1-C6alkyl. In certain embodiments described herein, each occurrence of R14 is independently selected from the group consisting of hydrogen, halogen, CN, OH, C1-C6alkoxy, 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). In certain embodiments, R14 is hydrogen. In certain embodiments, R14 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R14 is CN. In certain embodiments, R14 is OH. In certain embodiments, R14 is C1-C6alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R14 is C1-C6alkylOC1-C6alkyl. In certain embodiments, R14 is COOH. In certain embodiments, R14 is C1-C6alkylCOOH. In certain embodiments, R14 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R14 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, R14 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, R14 is C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R14 is CON(R7)(R8). In certain embodiments, R14 is N(R7)(R8). In certain embodiments, R14 is C1-C6alkylN(R7)(R8). In certain embodiments, wherein X is C(R14)2, R14 is independently selected from the group consisting of hydrogen, halogen, OH, C1-C6alkylOH, C1-C6alkylalkoxy, C1- C6alkylOC1-C6alkyl and C1-C6alkyl. In certain embodiments, R14 is hydrogen, methyl, ethyl, methoxy, OH or
Figure imgf000054_0001
. In the embodiments described herein, R15 is hydrogen, halogen, CN, OH, C1- C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8) and N(R7)(R8). In certain embodiments, R15 is hydrogen. In certain embodiments, R15 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R15 is CN. In certain embodiments, R15 is OH. In certain embodiments, R15 is C1-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R15 is C1-C6alkylOC1-C6alkyl. In certain embodiments, R15 is COOH. In certain embodiments, R15 is C1-C6alkylCOOH. In certain embodiments, R15 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R15 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, R15 is ethyl. In certain embodiments, R15 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, R15 is C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso- butanol. In certain embodiments, R15 is CON(R7)(R8). In certain embodiments, R15 is N(R7)(R8). In certain embodiments, R15 is C1-C6alkylN(R7)(R8). In certain embodiments, R15 is methyl or ethyl. In the embodiments described herein, R16 is hydrogen, halogen, CN, OH, C1- C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8) and N(R7)(R8). In certain embodiments, R16 is hydrogen. In certain embodiments, R16 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine. In certain embodiments, R16 is CN. In certain embodiments, R16 is OH. In certain embodiments, R16 is C1-C6alkoxy. Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R16 is C1-C6alkylOC1-C6alkyl. In certain embodiments, R16 is COOH. In certain embodiments, R16 is C1-C6alkylCOOH. In certain embodiments, R16 is C3-C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R16 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, R16 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, R16 is C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R16 is CON(R7)(R8). In certain embodiments, R16 is N(R7)(R8). In certain embodiments, R16 is C1-C6alkylN(R7)(R8). In the embodiments of the compounds described herein, l is 0 or 1. In certain embodiments, l is 0. In certain embodiments, l is 1. In the embodiments of the compounds described herein, m is 0 or 1. In certain embodiments, m is 0. In certain embodiments, m is 1. In the embodiments of the compounds described herein, p is 0 or 1. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, m and p are 1 and X is O. In certain embodiments, m and p are 1 and X is CH2. In certain embodiments, m is 0, p is 1 and X is O. In certain embodiments, m and p are 1 and X is SO2. In certain embodiments, m is 0, p is 1 and X is C(R14)2, wherein each occurrence of R14 is independently selected from the group consisting of hydrogen, halogen, OH, C1- C6alkoxy and C1-C6alkyl. In certain embodiments, m is 1 and X is C(R14)2, wherein each occurrence of R14 is independently selected from the group consisting of hydrogen, halogen, OH, C1-C6alkoxy and C1-C6alkyl. For example, in certain embodiments of Formula (I), l is 0; m is 1; p is 1; X is O; V, Y and Z are CH; and Q is CH2 as shown in formula (VII).
Figure imgf000056_0001
For example, in certain embodiments of Formula (I), l, m and p are 1; X is O; V, Y and Z are CH; and Q is O as shown in Formula (VIII).
Figure imgf000056_0002
In the embodiments described herein, A is a straight or branched, saturated or unsaturated (C3-C10)alkylene, phenyl(C3-C10)alkylene or cycloalkyl(C3-C10)alkylene comprising at least one –CH2- group, wherein one or more additional –CH2- groups in A are optionally and independently replaced with a moiety selected from the group consisting of O, S, NR, CONR, NRCO, SO2, and SO2NR and wherein one or more of the hydrogens along A can be replaced with a group independently selected from hydroxyl, halogen and C1-3 haloalkyl. In certain embodiments, A is a straight or branched, saturated or unsaturated (C3-C10)alkylene or cycloalkyl(C3-C10)alkylene, wherein one or more –CH2- groups in A are optionally and independently replaced with a moiety selected from the group consisting of O, S and NH. In certain embodiment, A will always have at least one –CH2- group. In certain embodiments, A is a straight (C3-C10)alkylene. Examples of straight (C3-C10)alkylenes include,
Figure imgf000057_0001
. In certain embodiments, A is a branched (C3-C10)alkylene. Suitable branched (C3- C10)alkylenes include but are not limited to:
Figure imgf000057_0002
In certain embodiments, A is a saturated (C3-C10)alkylene. Examples include,
Figure imgf000058_0001
. In certain embodiments, A is an unsaturated (C3-C10)alkylene. Suitable unsaturated (C3-C10)alkylenes include any of the saturated (C3-C10)alkylene, wherein hydrogens have been removed and one or more double or triple covalent bonds exist between adjacent carbon atoms. Examples of unsaturated (C3-C10)alkylenes include, but are not limited to,
Figure imgf000058_0002
. In other embodiments, A is a straight cycloalkyl(C3-C10)alkylene. Suitable straight cycloalkyl(C3-C10)alkylenes include a cycloalkyl(C3-C10)alkylene wherein two carbons in a chain are included in a (C3-C10)cycloalkyl. Examples of straight cycloalkyl(C3-C10)alkylenes include, but are not limited to,
Figure imgf000059_0001
In certain embodiments, A is a branched cycloalkyl(C3-C10)alkylene. Suitable branched cycloalkyl(C3-C10)alkylenes include a branched (C3-C10)alkylene wherein two carbons in a chain are included in a (C3-C10)cycloalkyl. Examples of cycloalkyl(C3-C10)alkylenes include, but are not limited to,
Figure imgf000059_0002
. In certain embodiments, A is a saturated cycloalkyl(C3-C10)alkylene. Examples of saturated cycloalkyl(C3-C10)alkylenes include, but are not limited to,
Figure imgf000060_0001
. In certain embodiments, A is an unsaturated cycloalkyl(C3-C10)alkylene. Examples of unsaturated cyclo(C3-C10)alkylenes include, but are not limited to,
Figure imgf000060_0002
. In certain embodiments, A is an unsaturated or saturated phenyl(C3-C10)alkylene. Examples of unsaturated and saturated phenyl(C3-C10)alkylenes include, but are not limited to,
Figure imgf000060_0003
. In other embodiments, one or more –CH2- groups in A are optionally and independently replaced with a moiety selected from the group consisting of O, S, NR, CONR, NRCO, SO2, and SO2NR. In other embodiments, one or more –CH2- groups in A are optionally and independently replaced with a moiety selected from the group consisting of O, S and NH. In other embodiments, one or more –CH2- groups in A are optionally and independently replaced with O. In other embodiments, one or more –CH2- groups in A are optionally and independently replaced with S. In other embodiments, one or more –CH2- groups in A are optionally and independently replaced with NR. In other embodiments, one or more –CH2- groups in A are optionally and independently replaced with CONR. In other embodiments, one or more –CH2- groups in A are optionally and independently replaced with NRCO. In other embodiments, one or more –CH2- groups in A are optionally and independently replaced with SO2. In other embodiments, one or more –CH2- groups in A are optionally and independently replaced with and SO2NR. R will be described in further detail below. In the embodiments described herein, R is hydrogen, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, COC1-C6alkyl or COOC1-C6alkyl. In certain embodiments, R is hydrogen, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl or C1-C6alkylOH. In certain embodiments, R is hydrogen. In certain embodiments, R is C1- C6alkylCOOH. In certain embodiments, R is COOH. In certain embodiments, R is C3- C6cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R 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, R 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, R is C1-C6alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso- butanol. In certain embodiments, R is COC1-C6alkyl. Suitable examples include, but are not limited to, COCH3. In certain embodiments, R is COOC1-C6alkyl. Suitable examples include, but are not limited to, COOCH3. Examples of such embodiments include, but are not limited to,
Figure imgf000061_0001
. In certain embodiments, A is
Figure imgf000062_0001
. In certain embodiments, one or more of the hydrogens along A can be replaced with a group independently selected from hydroxyl, halogen and C1-3 haloalkyl. Examples of suitable halogens include chlorine, bromine, fluorine and iodine. In certain embodiments, A is
Figure imgf000062_0002
. In each of the various embodiments of the invention, in the compounds used in the methods herein, each variable (including those in each of Formulae (I) - (VIII), 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 Formulae (I) - (VIII)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:
Figure imgf000062_0003
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
In certain embodiments, compounds described herein include:
Figure imgf000068_0002
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
or a pharmaceutically acceptable salt thereof. 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. “Alkylene," by itself or as part of another substituent means a divalent hydrocarbon chain radical having the stated number of carbon atoms. For example, -(C1- C5)alkylene, would include, e.g., -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, - CH2CH(CH3)CH2- or -CH2CH2CH2CH2CH2-. A straight alkylene means a divalent straight hydrocarbon chain radical having the stated number of carbon atoms. A branched alkylene means a divalent branched hydrocarbon chain radical having the stated number of carbon atoms. A saturated alkylene means a divalent saturated hydrocarbon chain radical having the stated number of carbon atoms. An unsaturated alkylene means a divalent hydrocarbon chain radical having the stated number of carbon atoms and one or more double or triple covalent bonds within the chain. A cycloalkylene means a divalent hydrocarbon chain radical having the stated number of carbon atoms and a cycloalkyl moiety within the chain. "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. “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 HN
Figure imgf000077_0001
“oxo.” An example of such a moiety is pyrrolidinone (or pyrrolidone):
Figure imgf000077_0002
. 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:
Figure imgf000078_0001
. Non-limiting examples of multicyclic heterocycloalkyl groups include, bicyclic heterocycloalkyl groups. Specific examples include, but are not limited to,
Figure imgf000078_0002
. "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 , as a bond generally indicates a mixture of, or either of, the possible isomers, e.g., containing (R)- and (S)-stereochemistry. For example:
Figure imgf000078_0005
Figure imgf000078_0003
. The wavy line , 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
Figure imgf000078_0004
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,
Figure imgf000079_0001
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: .
Figure imgf000079_0002
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) 33201-217; 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, (E) and (Z) 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 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 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) 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 Formulae (I) - (VIII) or a pharmaceutically acceptable salt thereof for inhibiting plasmepsin X activity, for treating a Plasmodium infection, or for treating malaria. The invention further relates to the use of a compound of Formulae (I) - (VIII) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting plasmepsin X activity, for treating a Plasmodium infection, or for treating malaria. The compounds of Formulae (I) - (VIII) 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 inhibiting 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 Formulae (I) - (VIII) or a pharmaceutically acceptable salt thereof for inhibiting plasmepsin IX activity, for treating a Plasmodium infection, or for treating malaria. The invention further relates to the use of a compound of Formulae (I) - (VIII) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting plasmepsin IX activity, for treating a Plasmodium infection, or for treating malaria. The compounds of Formulae (I) - (VIII) 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 inhibiting 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 Formulae (I) - (VIII) or a pharmaceutically acceptable salt thereof for inhibiting 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 Formulae (I) - (VIII) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting plasmepsin X and plasmepsin IX activity, for treating a Plasmodium infection, or for treating malaria. The compounds of Formulae (I) - (VIII) 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 Formulae (I) - (VIII) 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 Formulae (I) - (VIII), or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and an effective amount of one or more additional agents described below. In certain embodiments, described herein are methods 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 Formulae (I) - (VIII), or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and an effective amount of one or more additional anti-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 Formulae (I) - (VIII), or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and an effective amount of one or more additional anti-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 Formulae (I) - (VIII), or a pharmaceutically acceptable salt thereof may be confirmed by several pharmacological assays. 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 Formulae (I) - (VIII), 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 Formulae (I) - (VIII), 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 Formulae (I) - (VIII), 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 Formulae (I) - (VIII), 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 Formulae (I) - (VIII), 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, Pennsylvania. 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)). 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 Formulae (I) - (VIII), or a pharmaceutically acceptable salt thereof to inhibit 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 The meanings of the abbreviations in Examples are shown below. ACN = MeCN = CH3CN = acetonitrile AcOH = acetic acid AIBN = Azobisisobutyronitrile Ar = argon BBr3 = Boron tribromide BF3 Et2O = Boron trifluoride etherate Boc2O = di-tert-butyl dicarbonate Cbz = carboxybenzyl CbzOSu = N-(Benzyloxycarbonyloxy)succinimide CBr4 = Tetrabromomethane CCl4 = carbontetrachloride CELITE = diatomaceous earthConc. = concentrated Cs2CO3 = Cesium carbonate DBU = 1,8-Diazabicyclo[5.4.0]undec-7-ene DCE = dichloroethane DCM = dichloromethane DDQ = 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone DIBALH = diisobutylaluminum hydride DIPEA = DIEA= N, N-Diisopropylethylamine, or Hünig's base DMA = dimethylacetamide DMAP = 4-dimethylaminopyridine DMF = N,N-Dimethylformamide DMP = Dess–Martin periodinane DMSO = dimethyl sulfoxide DPPE = 1,2-Bis(diphenylphosphino)ethane DPPF = 1,1'-Bis(diphenylphosphino)ferrocene EDCI = EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Et2O = diethyl ether EtOAc = ethyl acetate EtOH = ethanol Et3SiH = Triethylsilane h = hours H2 = hydrogen HATU = 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate HCl = hydrochloric acid HFBA= Heptafluorobutyric acid HOAc = acetic acid I2 = iodine IPA= isopropyl alcohol [Ir(cod)Cl]2 = cyclooctadiene iridium chloride dimer K2CO3 = potassium carbonate K3PO4 = Tripotassium phosphate KF = Potassium fluoride KHMDS = Potassium bis(trimethylsilyl)amide KOTMS = Potassium trimethylsilanolate LCMS = Liquid chromatography–mass spectrometry LDA = Lithium diisopropylamide LHMDS = LiHMDS= lithium bis(trimethylsilyl)amide LiAlH4 = lithium aluminum hydride LiOH = lithium hydroxide min = minutes Me = methyl MeCN = Acetonitrile MeOH = CH3OH = methanol MgSO4 = Magnesium sulfate MsCl = methanesulfonyl chloride N2 = nitrogen NaBH4 = sodium borohydrate NaH = sodium hydride NaHCO3 = Sodium hydrogencarbonate NaIO4 = sodium periodate NaOH = sodium hydroxide Na2CO3 = sodium carbonate Na2SO3 = sodium sulfite Na2SO4 = sodium sulfate NH4Cl = Ammonium chloride NH4OH = Ammonium hydroxide NH4OAc = Ammonium acetate NaHMDS = sodium bis(trimethylsilyl)amide OMs = mesylate OTs = tosylate OTf = trifluoromethanesulfonyl Pd(OH)2/C = Pearlman's Catalyst - Palladium hydroxide on carbon-C Pd-C = Palladium on carbon-C [Pd(C3H5)Cl2] = Allylpalladium(II) chloride dimer PdCl2(dppf)-CH2Cl2 = [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) PPh3 = Triphenylphosphine RuO2.H2O = ruthenium(IV)oxide hydrate RP-HPLC = reverse phase high performance liquid chromatography SFC = Supercritical Fluid Chromatography TBDPS-Cl = TBSCl = tert-Butyl(chloro)diphenylsilane TEA = Et3N = triethylamine TBAF = Tetra-n-butylammonium fluoride TFA = trifluoroacetic acid THF = tetrahydrofuran Ti(EtO)4 = titanium ethoxide TMS = Trimethylsilylb TMSOTf = Trimethylsilyl trifluoromethanesulfonate TsOH = p-Toluenesulfonic acid 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 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. SCHEME 1
Figure imgf000094_0001
Compounds of Formula S-2 are prepared from S-1 by macrolactamization using amide coupling reagents. SCHEME 2 ''' '''
Figure imgf000094_0002
Intermediate compounds of Formula S-4 are prepared from S-3 after ring closing metathesis (RCM) reactions using catalysts such as the 2nd generation Grubbs’, Zhan’s and Hoveyda/Grubbs’ catalysts. Double bonds in S-4 can be reduced under for example hydrogenation conditions to yield the products of Formula S-5. SCHEME 3
Figure imgf000095_0001
Intermediate compounds of Formula S-7 are prepared from S-6, in which X is a halogen such as Cl, Br and I, after transition metal catalyzed intramolecular cross-coupling reactions such as Heck reactions. Resulting double bonds in S-7 can be reduced under for example hydrogenation conditions to yield the products of Formula S-8. SCHEME 4
Figure imgf000095_0004
Figure imgf000095_0002
S-9
Figure imgf000095_0003
Products of Formula S-10 are prepared from S-9, in which X is a halogen such as Cl, Br and I, after transition metal catalyzed intramolecular cross-coupling reactions such as palladium catalyzed C-O coupling reactions. SCHEME 5
Figure imgf000096_0001
Products of Formula S-12 are prepared from S-11 after intramolecular SN2 reactions between an alcohol and X, in which X is a leaving group such as Cl, Br, I, OMs, OTs or OTf. Products of Formula S-12 are also prepared from S-11 diols after dehydration conditions using an acid or other dehydration reagents. SCHEME 6
Figure imgf000096_0002
Products of Formula S-12 are prepared from intermediates S-13 or S-14 after intramolecular reductive etherification using conditions such as TMSOTf and Et3SiH. 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 C181.0 x 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-185-micron, 30 mm (id) x 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) x 250 mm column or a Waters XBridge™ C-185-micron OBD™, 30 mm (id) x 250 mm column. The mobile phases consisted of mixtures of acetonitrile (0-75%) in water containing 5mmol (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 (250x4.6 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 (20x250 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 Preparation of Intermediate 1-2
Figure imgf000098_0001
INT1-1 INT1-2 DBU (21.72 mL, 144 mmol) and diphenylphosphinyl was added to a mixture of methyl (S)-4-hydroxychromane-6-carboxylate (INT1-1) (10 g, 48.0 mmol) in THF (80 mL). Azide (35.0 g, 144 mmol) was then added under N2. The mixture was stirred at 50 °C for 12 h. The mixture was quenched with water (100 mL), and extracted with EtOAc (3 x 100 mL). The organic layers were washed with brine (80 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 15% EtOAc/Pet.ether gradient @ 50 mL/min) to give methyl (R)- 4-azidochromane-6-carboxylate (INT1-2). MS (ESI) m/z 234.0(M+H+) 1H NMR (500 MHz, CHLOROFORM-d) δ 7.93-7.96 (m, 2H), 6.91 (d, J=8.5 Hz, 1H), 4.65 (t, J=3.5 Hz, 1H), 4.29-4.35 (m, 2H), 3.90 (s, 3H), 2.14-2.26 (m, 1H), 2.06-2.12 (m, 1H) Preparation of Intermediate 1-3
Figure imgf000099_0001
INT1-2 INT1-3 Pd-C (2.510 g, 4.72 mmol) was added to a solution of methyl (R)-4- azidochromane-6-carboxylate (INT1-2) (11 g, 47.2 mmol) in THF (200 mL) under N2 atmosphere. The mixture was degassed and backfilled with H2 (three times). The resulting mixture was stirred at 25 °C for 12 h under H2 (15 psi) atmosphere. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give methyl (R)-4-aminochromane-6- carboxylate (INT1-3). MS (ESI) m/z: 191.1 (M-17+H+) Preparation of Intermediate 1
Figure imgf000099_0002
INT1-3 INT-1 Sodium hydride (3.77 g, 94 mmol) was added to a solution of N,N-bisboc- thiourea (16.94 g, 61.3 mmol) in THF (250 mL) at 0°C in portions under N2. After 1hr at this temperature, 2,2,2-trifluoroacetic anhydride (8.82 mL, 61.3 mmol) was added dropwise. The mixture was stirred at 0 °C for 1h. A solution of methyl (R)-4-aminochromane-6-carboxylate (INT1-3) (9.77 g, 47.1 mmol) in THF (50 mL) was added dropwise at 0 °C. The mixture was stirred at 0 °C for 2 h. The mixture was quenched with water (80 mL), and extracted with EtOAc (3 x 50 mL). The organic layers were washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, Eluent of 20% EtOAc/Pet.ether gradient @ 50 mL/min) to afford methyl (R)-4-(3-(tert-butoxycarbonyl)thioureido)chromane-6-carboxylate (INT-1). MS (ESI) m/z 367.1 (M+H+) 1H NMR (500 MHz, CHLOROFORM-d) δ 8.01 (d, J=1.5 Hz, 1H), 7.96 (s, 1H), 7.89 (dd, J=2.0, 9.0 Hz, 1H), 6.89 (d, J=9.0 Hz, 1H), 4.34-4.41 (m, 1H), 4.19-4.26 (m, 1H), 3.88 (s, 3H), 2.25- 2.40 (m, 2H), 1.47 (s, 9H) INTERMEDIATE 2 Preparation of Intermediate 2-2
Figure imgf000100_0001
INT2-1 INT2-2 To a solution of pent-4-enoic acid (INT2-1) (40 g, 400 mmol), EDCI (92 g, 479 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (64.8 g, 479 mmol) and N-ethyl-N-isopropylpropan-2- amine (279 mL, 1598 mmol) in DCM (400 mL) was added N,O-dimethylhydroxylamine hydrochloride (54.6 g, 559 mmol). The reaction was stirred at 25 °C for 12 h under N2 atmosphere. LCMS showed desired mass. The mixture was quenched with water (300 mL), and extracted with DCM (3 x 100 mL). The organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo, and the crude was purified by flash silica gel chromatography (ISCO®; 220g Agela Silica Flash Column, eluent of 8% ethyl acetate/pet. ether gradient @ 50 mL/min) to afford N-methoxy-N-methylpent-4-enamide (INT2-2). MS (ESI) m/z 144.1 (M+H)+ 1H NMR (500 MHz, CHLOROFORM-d) δ 5.83-5.92 (m, 1H), 4.94-5.10 (m, 2H), 3.68 (s, 3H), 3.18 (s, 3H), 2.50-2.56 (m, 2H), 2.35-2.42 (m, 2H) Preparation of Intermediate 2-3
Figure imgf000100_0002
A solution of N-methoxy-N-methylpent-4-enamide (INT2-2) (20 g, 140 mmol) in THF (200 mL) under N2 atmosphere at 0 °C, was then added ethylmagnesium bromide (69.8 mL, 210 mmol) dropwise at 0 °C. The reaction was stirred at 25 °C for 1 h under N2 atmosphere. TLC showed a new spot. The mixture was quenched with Sat. NH4Cl a.q.(100 mL) and water (100 mL), extracted with EtOAc (3 x 100 mL). The organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo, and the crude was purified by flash silica gel chromatography (ISCO®; 120g Agela Silica Flash Column, eluent of 5% ethyl acetate/pet. ether gradient @ 40 mL/min) to afford hept-6-en-3-one (INT2-3). 1H NMR (500 MHz, CHLOROFORM-d) δ 5.78-5.83 (m, 1H), 4.92-5.07 (m, 2H), 2.48-2.54 (m, 2H), 2.43 (q, J = 7.0 Hz, 2H), 2.29-2.37 (m, 2H), 1.06 (t, J = 7.0 Hz, 3H) Preparation of Intermediate 2-4
Figure imgf000101_0001
To a solution hept-6-en-3-one (INT2-3) (10 g, 89 mmol) in THF (100 mL) was added (R)-2-methylpropane-2-sulfinamide (12.97 g, 107 mmol) followed by Ti(EtO)4 (37.5 mL, 178 mmol), then the reaction was stirred at 75 °C for 12 h under N2 atmosphere. TLC showed new spots. The final mixture was cooled to room temperature, then diluted with DCM (200 mL), stirred 15 min, then ice cold-saturated aqueous sodium bicarbonate solution (50 mL) and Na2SO4 then filtered and concentrated in vacuo. The crude was purified by flash silica gel chromatography (ISCO®; 120g Agela Silica Flash Column, eluent of 8% ethyl acetate/pet. ether gradient @ 40 mL/min) to afford (R,E)-N-(hept-6-en-3-ylidene)-2-methylpropane-2-sulfinamide (INT2-4). MS (ESI) m/z 216.2 (M+H)+ 1H NMR (500 MHz, CHLOROFORM-d) δ 5.73-5.88 (m, 1H), 4.94-5.10 (m, 2H), 2.64-2.87 (m, 2H), 2.31-2.58 (m, 4H), 1.22 (s, 9H), 1.05-1.20 (m, 3H) Preparation of Intermediate 2-5
Figure imgf000101_0002
To a solution of diisopropylamine (19.64 mL, 139 mmol) in anhydrous THF (40 mL) at -78 °C was added butyllithium (55.7 mL, 139 mmol) dropwise under N2 atmosphere. The reaction was stirred at 0 °C for 30 min to make LDA. Methyl acetate (7.48 mL, 93 mmol) and Ti(OiPr)3Cl (116 mL, 116 mmol) were added to anhydrous THF (90 mL). LDA (76 mL, 93 mmol) was then added dropwise to the mixture at -78 °C. After 1 h, a solution of (R,E)-N-(hept- 6-en-3-ylidene)-2-methylpropane-2-sulfinamide (INT2-4) (10 g, 46.4 mmol) in anhydrous THF (20 mL) was then added dropwise and the mixture was stirred at -78 °C for 3 h. The color was no change and yellow. LCMS showed major DP mass. The mixture was quenched with ice-cold half-saturated aqueous ammonium chloride solution (60 mL). The slurry was diluted with EtOAc (200 mL) then filtered, rinsing with EtOAc and water. The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 120g Agela Silica Flash Column, eluent of 25% ethyl acetate/pet. ether gradient @ 40 mL/min) to afford methyl 3-(((R)-tert-butylsulfinyl)amino)-3- ethylhept-6-enoate (INT2-5). MS (ESI) m/z 290.1 (M+H)+ 1H NMR (500 MHz, CHLOROFORM-d) δ 5.76-5.82 (m, 1H), 5.01-5.05 (m, 1H), 4.97 (dd, J = 1.0, 10.0 Hz, 1H), 4.63 (br d, J = 17.0 Hz, 1H), 3.68 (s, 3H), 2.72 (dd, J = 5.0, 16.0 Hz, 1H), 2.52 (dd, J = 2.5, 16.0 Hz, 1H), 2.07-2.13 (m, 1H), 1.82-1.91 (m, 1H), 1.76-1.81 (m, 1H), 1.71-1.75 (m, 1H), 1.26 (t, J = 7.0 Hz, 2H), 1.24 (s, 9H), 0.87-0.95 (m, 3H) Preparation of Intermediate 2-6
Figure imgf000102_0001
INT2-5 INT2-6_P1 INT2-6_P2 Methyl 3-(((R)-tert-butylsulfinyl)amino)-3-ethylhept-6-enoate (INT2-5) (12 g, 41.5 mmol) was separated by SFC Column DAICEL CHIRALPAK AD(250mm x50mm, 10um) Condition 0.1%NH3H2O IPA Begin B 15 End B 15 Gradient Time(min) 100%B Hold Time(min) FlowRate(mL/min) 200 Injections 200) and Column DAICEL CHIRALPAK AD(250mm x 50mm, 10um) Condition 0.1%NH3H2O IPA Begin B 12 End B 12 Gradient Time(min) 100%B Hold Time(min) FlowRate(mL/min) 200 Injections 240) to give methyl (R)- 3-(((R)-tert-butylsulfinyl)amino)-3-ethylhept-6-enoate (INT2-6_P1, desired) (tR=1.978 min, UV = 220 nm) and methyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-ethylhept-6-enoate (INT2-6_P2) (tR=2.132min, UV = 220 nm). MS (ESI) m/z 290.1 (M+H)+ INT2-6_P1:1H NMR (500 MHz, CHLOROFORM-d) δ 5.79 (tdd, J = 6.56, 10.32, 16.99 Hz, 1H), 4.93-5.09 (m, 2H), 3.62-3.73 (m, 3H), 2.72 (d, J = 15.87 Hz, 1H), 2.52 (d, J = 15.87 Hz, 1H), 2.48 (s, 1H), 2.00-2.09 (m, 2H), 1.76-1.88 (m, 2H), 1.68-1.74 (m, 2H), 1.23 (s, 9H), 0.86- 0.95 (m, 3H). INT2-6_P2: 1H NMR (500 MHz, CHLOROFORM-d) δ 5.71-5.87 (m, 1H), 4.94- 5.07 (m, 2H), 3.65-3.73 (m, 3H), 2.72 (d, J = 16.02 Hz, 1H), 2.52 (d, J = 16.02 Hz, 1H), 2.00- 2.14 (m, 2H), 1.83-1.91 (m, 1H), 1.74-1.80 (m, 1H), 1.67-1.74 (m, 2H), 1.20-1.25 (m, 8H), 0.83- 0.89 (m, 3H). Preparation of Intermediate 2-7
Figure imgf000103_0001
A solution of methyl (R)-3-(((R)-tert-butylsulfinyl)amino)-3-ethylhept-6-enoate (INT2-6_P1) (20 g, 69.1 mmol) in HCl-dioxane(4N) (100 mL) and MeOH (200 mL) was stirred at 25 °C for 2 h. LCMS showed the reaction was complete. Solvent was evaporated under reduced pressure to give the product methyl (R)-3-amino-3-ethylhept-6-enoate hydrochloride (INT2-7). MS (ESI) m/z 186.3 (M+H)+ 1H NMR (500 MHz, METHANOL-d4) δ 5.80-5.87 (m, 1H), 5.07-5.15 (m, 1H), 5.02-5.04 (m, 1H), 3.73 (s, 3H), 2.71-2.79 (m, 2H), 2.07-2.18 (m, 2H), 1.75-1.85 (m, 4H), 0.99 (t, J = 7.6 Hz, 3H) Preparation of Intermediate 2-8
Figure imgf000103_0002
To a solution of DMB-BOC-THIOUREA (5 g, 15.32 mmol), methyl (R)-3- amino-3-ethylhept-6-enoate hydrochloride (INT2-7) (3.74 g, 16.85 mmol) and EDC (7.34 g, 38.3 mmol) in Acetonitrile (100 mL) was added DIEA (12.04 mL, 68.9 mmol). The reaction was stirred at 15 °C for 12 h under N2 atmosphere. LCMS showed desired mass, and some ring- opened byproduct ester. Then warmed to 50 °C and stirred at 50 °C for 2 h. LCMS showed only desired product mass. The mixture was concentrated in vauo. The crude was dissolved EtOAc (100 mL) and water (100 mL), and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude was purified by flash column (ISCO®; 80 g Agela Silica Flash Column, eluent of 15% ethyl acetate/pet. ether gradient @ 30 mL/min) to afford tert-butyl (R,E)-(4-(but-3-en-1-yl)-1-(2,4-dimethoxybenzyl)-4-ethyl-6- oxotetrahydropyrimidin-2(1H)-ylidene)carbamate (INT2-8). MS (ESI) m/z 390.1 (M+H-56)+ 1H NMR (400 MHz, CHLOROFORM-d) δ 9.92 (br s, 1H), 7.10 (br d, J = 8.8 Hz, 1H), 6.33-6.50 (m, 2H), 5.63-5.83 (m, 1H), 5.09 (s, 2H), 4.96-5.06 (m, 2H), 3.78 (dd, J = 1.6, 4.4 Hz, 6H), 2.61 (s, 2H), 1.98-2.12 (m, 2H), 1.59-1.70 (m, 4H), 1.49 (s, 9H), 0.92 (t, J = 7.6 Hz, 3H) Preparation of Intermediate 2-9
Figure imgf000104_0001
INT2-9 A solution of tert-butyl (R,E)-(4-(but-3-en-1-yl)-1-(2,4-dimethoxybenzyl)-4- ethyl-6-oxotetrahydropyrimidin-2(1H)-ylidene)carbamate (INT2-8) (1.0 g, 2.244 mmol) in TFA (10 mL) was stirred at 60 °C for 16 h. LCMS showed desired mass. The mixture was concentrated in vacuo. The residue was partitioned between Pet.ether/EtOAc (v/v=4:1, 10 mL) and water (10 mL). And LCMS showed the product was only in aqueous phase, and pretty clean. (R)-6-(but-3-en-1-yl)-6-ethyl-2-iminotetrahydropyrimidin-4(1H)-one (INT2-9) in water (10 mL) was used for the next step directly. MS (ESI) m/z 196.0 (M+H)+ Preparation of Intermediate 2
Figure imgf000105_0001
INT2-9 To a solution of (R)-6-(but-3-en-1-yl)-6-ethyl-2-iminotetrahydropyrimidin-4(1H)- one (INT2-9) (438 mg, 2.243 mmol) in Water (10 mL) and THF (3 mL) was added NaHCO3 (942 mg, 11.22 mmol) and (BOC)2O (1.042 mL, 4.49 mmol) at 0°C in portions. The reaction was stirred at 25 °C for 16 h. LCMS showed desired mass. The mixture was extracted with EtOAc (3 x 10 mL). The organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude was purified by flash column (ISCO®; 12 g Agela Silica Flash Column, eluent of 20% EE(EtOAC/EtOH = 3:1)/Pet.ether gradient @ 30 mL/min) to afford tert-butyl (R,E)-(4-(but-3-en-1-yl)-4-ethyl-6-oxotetrahydropyrimidin-2(1H)- ylidene)carbamate Intermediate 2 MS (ESI) m/z 296.2 (M+H)+ 1H NMR (400 MHz, CHLOROFORM-d) δ 9.37 (br s, 1H), 5.74-5.81 (m, 1H), 4.90-5.17 (m, 2H), 2.59 (s, 2H), 2.07-2.10 (m, 2H), 1.62-1.78 (m, 4H), 1.51 (s, 9H), 0.97 (t, J = 7.2 Hz, 3H) EXAMPLE 1
Figure imgf000105_0002
(1R,5R,15R,16R)-5-ethyl-15-hydroxy-3-imino-9-methyl-23-oxa-2,4,17- triazahexacyclo[17.6.2.22,5.210,13.012,16.022,26]hentriaconta-10,12,19,21,26,28-hexaene- 18,31-dione Preparation of Compound 1-2
Figure imgf000106_0001
Trifluoromethanesulfonic acid (503 mg, 3.35 mmol) and N-bromosuccinimide (596 mg, 3.35 mmol) was added to a solution of (1R, 2R)-1-amino-2,3-dihydro-1H-inden-2-ol (1-1) (500 mg, 3.35 mmol) in DCM (10 mL) at 0 °C. The reaction was stirred at 18 °C for 1h under N2 atmosphere. The mixture was quenched with saturated sodium bicarbonate solution (10 mL) at 0 °C, and extracted with DCM (1 x 10 mL) then extracted with EtOAc (3 x 10 mL). The organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuum, the crude was purified by purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 10% MeOH/DCM (added 1% ammonium hydroxide) gradient @ 50 mL/min) with to afford (1R,2R)-1-amino-6-bromo-2,3-dihydro-1H-inden-2-ol (1- 2). MS (ESI) m/z: 228.1, 230.1(M+H+) 1H NMR (400 MHz, METHANOL-d4) δ 7.50 (s, 1H), 7.33 (dd, J=1.6, 8.0 Hz, 1H), 7.10 (d, J=8.0 Hz, 1H), 4.10 (q, J=6.8 Hz, 1H), 4.01-4.05 (m, 1H), 3.15 (dd, J=6.8, 15.6 Hz, 1H), 2.68 (dd, J=7.2, 15.6 Hz, 1H) Preparation of Compound 1-3
Figure imgf000106_0002
DIEA (0.276 mL, 1.582 mmol) was added to a solution of (R)-4-((R,E)-2-((tert- butoxycarbonyl)imino)-4-ethyl-6-oxo-4-(pent-4-en-1-yl)tetrahydropyrimidin-1(2H)- yl)chromane-6-carboxylic acid (1-2) (96 mg, 0.198 mmol), EDC (189 mg, 0.989 mmol), 1H- benzo[d][1,2,3]triazol-1-ol (134 mg, 0.989 mmol) and (1R,2R)-1-amino-6-bromo-2,3-dihydro- 1H-inden-2-ol (45.1 mg, 0.198 mmol) in THF (5 mL). The reaction was stirred at 18 °C for 2 h. The mixture was quenched with water (5 mL), and extracted with EtOAc (3 x 5 mL). The organic layers were washed with brine (5 mL), dried over Na2SO4, filtered and concentrated in vacuum, and the crude was purified by prep-TLC (Pet. ether/EtOAc=1:1) to afford tert-butyl ((R,E)-1-((R)-6-(((1R,2R)-6-bromo-2-hydroxy-2,3-dihydro-1H-inden-1-yl)carbamoyl)chroman- 4-yl)-4-ethyl-6-oxo-4-(pent-4-en-1-yl)tetrahydropyrimidin-2(1H)-ylidene)carbamate (1-3). MS (ESI) m/z: 695.1, 697.1 (M+H+) Preparation of Compound 1-4A, 1-4B, and 1-4C
Figure imgf000107_0001
Chloro[tri(o-tolyl)phosphine][2-(2'-amino-1,1'-biphenyl)]palladium(II) (8.83 mg, 0.014 mmol) and N,N-dicyclohexylmethylamine (140 mg, 0.719 mmol) was added to a solution of tert-butyl ((R,E)-1-((R)-6-(((1R,2R)-6-bromo-2-hydroxy-2,3-dihydro-1H-inden-1- yl)carbamoyl)chroman-4-yl)-4-ethyl-6-oxo-4-(pent-4-en-1-yl)tetrahydropyrimidin-2(1H)- ylidene)carbamate (1-3) (100 mg, 0.144 mmol) in dioxane (1.5 mL) at 25 °C in a glove box. The reaction was stirred at 70 °C for 16h. The mixture was quenched with water (3 mL), and extracted with EtOAc (3 x 5 mL). The organic layers were washed with brine (5 mL), dried over Na2SO4, filtered and concentrated in vacuum, and the crude was purified by reverse preparative HPLC (Instrument ED; Method Column Boston Prime C18150 x 30mm, 5um; Condition water(0.04%NH3H2O+10mM NH4HCO3)-ACN Begin B 65; End B 95 Gradient Time(min) 10; 100%B Hold Time(min) 2 FlowRate(mL/min) 25; Injections 5) to afford: tert-butyl ((4aR,8R,12E,18R,18aR,28E)-8-ethyl-18-hydroxy-6,20-dioxo-4,4a,7,8,9,10,11,17,18,18a,19,20- dodecahydro-3H,6H-1,21-(epiethane[1,2]diylidene)-8,5-(epiminomethano)-14,16- ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclononadecin-28-ylidene)carbamate (1-4A); tert- butyl ((4aR,8R,12Z,18R,18aR,28E)-8-ethyl-18-hydroxy-6,20-dioxo- 4,4a,7,8,9,10,11,17,18,18a,19,20-dodecahydro-3H,6H-1,21-(epiethane[1,2]diylidene)-8,5- (epiminomethano)-14,16-ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclononadecin-28- ylidene)carbamate (1-4B); and tert-butyl ((4aR,8R,17R,17aR,E)-8-ethyl-17-hydroxy-12- methylene-6,19-dioxo-4,4a,6,7,8,9,10,11,12,16,17,17a,18,19-tetradecahydro-3H-1,20- (epiethane[1,2]diylidene)-8,5-(epiminomethano)-13,15-ethenocyclopenta[h]pyrano[4,3- b][1,7]diazacyclooctadecin-27-ylidene)carbamate (1-4C). MS (ESI) m/z: 486.2 (M+H+) 1-4A: 1H NMR (500 MHz, CHLOROFORM-d) δ 10.09 (s, 1H), 7.93 (dd, J=1.5, 8.50 Hz, 1H), 7.21-7.26 (m, 2H), 7.14 (d, J=8.0 Hz, 1H), 6.91-6.98 (m, 2H), 6.42-6.54 (m, 3H), 5.82-5.92 (m, 1H), 5.25 (t, J=5.5 Hz, 1H), 4.94 (s, 1H), 4.40-4.50 (m, 2H), 4.25-4.35 (m, 1H), 3.34 (dd, J=8.0, 15.5 Hz, 1H), 2.99-3.05 (m, 1H), 2.67-2.86 (m, 2H), 2.57 (d, J=13.5 Hz, 1H), 2.40 (d, J=15.5 Hz, 1H), 2.07 (s, 2H), 1.82 (d, J=11.0 Hz, 2H), 1.62-1.67 (m, 4H), 1.49 (s, 9H), 0.96 (t, J=7.5 Hz, 3H) 1-4B: 1H NMR (500 MHz, CHLOROFORM-d) δ 10.13 (s, 1H), 7.90 (dd, J=2.0, 8.50 Hz, 1H), 7.37 (s, 1H), 7.25 (d, J=7.5 Hz, 1H), 7.17 (s, 1H), 7.12 (d, J=7.5 Hz, 1H), 6.96 (d, J=8.50 Hz, 1H), 6.41-6.48 (m, 2H), 6.26 (dd, J=7.0, 9.0 Hz, 1H), 5.60-5.70 (m, 1H), 5.34 (t, J=6.5 Hz, 1H), 4.60 (s, 1H), 4.46-4.54 (m, 1H), 4.42 (td, J=4.0, 11.0 Hz, 1H), 4.21 (dt, J=2.5, 11.0 Hz, 1H), 3.34 (dd, J=7.5, 16.0 Hz, 1H), 2.97 (dd, J=7.5, 16.0 Hz, 1H), 2.60-2.72 (m, 2H), 2.49-2.53 (m, 2H), 2.22-2.30 (m, 1H), 2.13-2.18 (m, 1H), 2.03-2.12 (m, 2H), 1.72-1.82 (m, 4H), 1.49 (s, 9H), 1.00 (t, J=7.5 Hz, 3H) 1-4C: 1H NMR (500 MHz, CHLOROFORM-d) δ 10.04 (s, 1H), 7.81 (dd, J=2.0, 8.5 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 6.99-7.16 (m, 2H), 6.91 (d, J=8.50 Hz, 1H), 6.38-6.50 (m, 2H), 5.44 (s, 1H), 5.31 (t, J=6.5 Hz, 1H), 5.13 (s, 1H), 4.41-4.57 (m, 2H), 4.36 (s, 1H), 4.23 (dt, J=2.0, 11.50 Hz, 1H), 3.34 (dd, J=8.0, 16.0 Hz, 1H), 2.98 (dd, J=8.0, 16.0 Hz, 1H), 2.69-2.79 (m, 1H), 2.59-2.63 (m, 1H), 2.45-2.52 (m, 2H), 1.93-2.09 (m, 2H), 1.86 (d, J=12.0 Hz, 2H), 1.53-1.65 (m, 4H), 1.45 (s, 9H), 0.98 (t, J=7.5 Hz, 3H) Preparation of Compound 1-5
Figure imgf000108_0001
Pd-C (1.731 mg, 3.25 µmol) was added to a solution of tert-butyl ((4aR,8R,17R,17aR,E)-8-ethyl-17-hydroxy-12-methylene-6,19-dioxo- 4,4a,6,7,8,9,10,11,12,16,17,17a,18,19-tetradecahydro-3H-1,20-(epiethane[1,2]diylidene)-8,5- (epiminomethano)-13,15-ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclooctadecin-27- ylidene)carbamate (1-4C) (10 mg, 0.016 mmol) in MeOH (2 ml) under N2 atmosphere. The mixture was degassed and backfilled with H2 (three times). The resulting mixture was stirred under H2 (15 psi) at 25 °C for 12 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give tert-butyl ((4aR,8R,17R,17aR,E)-8-ethyl-17-hydroxy-12-methyl- 6,19-dioxo-4,4a,6,7,8,9,10,11,12,16,17,17a,18,19-tetradecahydro-3H-1,20- (epiethane[1,2]diylidene)-8,5-(epiminomethano)-13,15-ethenocyclopenta[h]pyrano[4,3- b][1,7]diazacyclooctadecin-27-ylidene)carbamate (1-5). MS (ESI) m/z: 617.3 (M+H+) Preparation of Example 1
Figure imgf000109_0001
Zinc(II) bromide (29.2 mg, 0.130 mmol) was added to a solution of tert-butyl ((4aR,8R,17R,17aR,E)-8-ethyl-17-hydroxy-12-methyl-6,19-dioxo- 4,4a,6,7,8,9,10,11,12,16,17,17a,18,19-tetradecahydro-3H-1,20-(epiethane[1,2]diylidene)-8,5- (epiminomethano)-13,15-ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclooctadecin-27- ylidene)carbamate (1-5) (8 mg, 0.013 mmol) in DCM (3 ml), at 22 °C under N2 atmosphere. The mixture was stirred at 22 °C for 16 h. The mixture was cooled, the solvent was evaporated under reduced pressure to give the crude product. The residue was purified by reverse preparative HPLC (Instrument EJ Method Column Boston Green ODS 150 x30mm, 5um Condition water(TFA)-ACN Begin B 22 End B 52 Gradient Time(min) 10100%B Hold Time(min) 2 FlowRate(ml/min) 25 Injections 1) to yield Example 1. MS (ESI) m/z: 517.2 (M+H+) 1H NMR (500 MHz, METHANOL-d4) δ 8.49 (d, J=9.0 Hz, 1H), 7.72 (dd, J=2.0, 8.5 Hz, 1H), 7.39 (d, J=1.0 Hz, 1H), 7.19-7.24 (m, 1H), 7.14-7.19 (m, 1H), 6.91-6.96 (m, 2H), 5.30-5.39 (m, 2H), 4.38-4.53 (m, 2H), 4.13-4.15 (m, 1H), 3.18-3.29 (m, 1H), 2.75-2.94 (m, 3H), 2.61-2.72 (m, 2H), 2.20-2.30 (m, 1H), 1.74-1.85 (m, 3H), 1.58-1.68 (m, 2H), 1.50-1.57 (m, 1H), 1.31 (d, J=7.0 Hz, 3H), 1.24-1.29 (m, 1H), 1.11-1.20 (m, 1H), 0.97 (t, J=7.5 Hz, 3H) EXAMPLE 2
Figure imgf000110_0001
(1R,5R,16R,17R)-5-ethyl-16-hydroxy-3-imino-24-oxa-2,4,18- triazahexacyclo[18.6.2.22,5.211,14.013,17.023,27]dotriaconta-11,13,20,22,27,29-hexaene- 19,32-dione Preparation of Compound 2-1
Figure imgf000110_0002
Pd-C (2.250 mg, 4.23 µmol) was added to a solution of tert-butyl ((4aR,8R,12E,18R,18aR,28E)-8-ethyl-18-hydroxy-6,20-dioxo-4,4a,7,8,9,10,11,17,18,18a,19,20- dodecahydro-3H,6H-1,21-(epiethane[1,2]diylidene)-8,5-(epiminomethano)-14,16- ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclononadecin-28-ylidene)carbamate (2-1) (13 mg, 0.021 mmol) in MeOH (4 mL) under N2 atmosphere. The mixture was degassed and backfilled with H2 (three times). The resulting mixture was stirred under H2 (15 psi) at 20 °C for 2 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give tert- butyl ((4aR,8R,18R,18aR,E)-8-ethyl-18-hydroxy-6,20-dioxo- 4,4a,7,8,9,10,11,12,13,17,18,18a,19,20-tetradecahydro-3H,6H-1,21-(epiethane[1,2]diylidene)- 8,5-(epiminomethano)-14,16-ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclononadecin-28- ylidene)carbamate (2-1). MS (ESI) m/z: 617.2 (M+H+) Preparation of Example 2
Figure imgf000111_0001
Zinc(II) bromide (47.5 mg, 0.211 mmol) was added to a solution of tert-butyl ((4aR,8R,18R,18aR,E)-8-ethyl-18-hydroxy-6,20-dioxo-4,4a,7,8,9,10,11,12,13,17,18,18a,19,20- tetradecahydro-3H,6H-1,21-(epiethane[1,2]diylidene)-8,5-(epiminomethano)-14,16- ethenocyclopenta[h]pyrano[4,3-b][1,7]diazacyclononadecin-28-ylidene)carbamate (2-1) (13 mg, 0.021 mmol) in DCM (3 mL), under N2 atmosphere. The mixture was stirred at 22 °C for 16 h. The mixture was concentrated under reduced pressure to give the crude product. The residue was purified by reverse preparative HPLC (Instrument EJ; Method Column Boston Green ODS 150 x 30mm, 5um, Condition water(TFA)-ACN Begin B 22; End B 52 Gradient Time(min) 10; 100%B Hold Time(min) 2 FlowRate(mL/min) 25; Injections 1) to give (4aR,8R,18R,18aR)-8- ethyl-18-hydroxy-28-imino-4,4a,8,9,10,11,12,13,17,18,18a,19-dodecahydro-3H,6H-1,21- (epiethane[1,2]diylidene)-8,5-(epiminomethano)-14,16-ethenocyclopenta[h]pyrano[4,3- b][1,7]diazacyclononadecine-6,20(7H)-dione Example 2. MS (ESI) m/z: 517.2 (M+H+) 1H NMR (500 MHz, METHANOL-d4) δ 7.76 (dd, J=2.0, 8.5 Hz, 1H), 7.46 (d, J=1.5 Hz, 1H), 7.13 (d, J=8.0 Hz, 1H), 6.99-7.06 (m, 2H), 6.93 (d, J=8.5 Hz, 1H), 5.21 (t, J=7.5 Hz, 1H), 5.07 (d, J=5.5 Hz, 1H), 4.54-4.62 (m, 1H), 4.38-4.49 (m, 1H), 4.09-4.19 (m, 1H), 3.23-3.28 (m, 1H), 2.90 (d, J=16.5 Hz, 1H), 2.79 (dd, J=6.0, 16.0 Hz, 1H), 2.62-2.74 (m, 2H), 2.50-2.61 (m, 2H), 2.20-2.34 (m, 1H), 1.81 (s, 1H), 1.62-1.76 (m, 3H), 1.49 (t, J=11.5 Hz, 1H), 1.12-1.44 (m, 6H), 0.95 (t, J=7.5 Hz, 3H) EXAMPLE 3A
Figure imgf000112_0001
(1R,5R,17S)-5-ethyl-3-imino-15,15-dimethyl-14,24-dioxa-2,4,18- triazahexacyclo[18.6.2.22,5.210,13.012,17.023,27]dotriaconta-10,12,20,22,27,29-hexaene- 19,32-dione Preparation of Compound 3-2
Figure imgf000112_0002
N,O-dimethylhydroxylamine hydrochloride (54.6 g, 559 mmol) was added to a solution of pent-4-enoic acid (40 g, 400 mmol), EDC (92 g, 479 mmol), 1H- benzo[d][1,2,3]triazol-1-ol (3-1) (64.8 g, 479 mmol) and N-ethyl-N-isopropylpropan-2-amine (279 mL, 1598 mmol) in DCM (400 mL). The reaction was stirred at 25 °C for 12 h under N2 atmosphere. The mixture was quenched with water (300 mL), and extracted with DCM (3 x 100 mL). The organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo, and the crude was purified by flash silica gel chromatography (ISCO®; 220g Agela Silica Flash Column, eluent of 8% ethyl acetate/pet. ether gradient @ 50 mL/min) to afford N-methoxy-N-methylpent-4-enamide (3-2). MS (ESI) m/z 144.1 (M+H+) 1H NMR (500 MHz, CHLOROFORM-d) δ 5.83-5.92 (m, 1H), 4.94-5.10 (m, 2H), 3.68 (s, 3H), 3.18 (s, 3H), 2.50-2.56 (m, 2H), 2.35-2.42 (m, 2H) Preparation of Compound 3-3
Figure imgf000112_0003
Ethylmagnesium bromide (69.8 mL, 210 mmol) was added dropwise to a solution of N-methoxy-N-methylpent-4-enamide (3-2) (20 g, 140 mmol) in THF (200 mL) under N2 atmosphere at 0 °C. The reaction was stirred at 25 °C for 1 h under N2 atmosphere. The mixture was quenched with saturated NH4Cl aqueous (100 mL) and water (100 mL), extracted with EtOAc (3 x 100 mL). The organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo, and the crude was purified by flash silica gel chromatography (ISCO®; 120g Agela Silica Flash Column, eluent of 5% ethyl acetate/pet. ether gradient @ 40 mL/min) to afford hept-6-en-3-one (3-3). 1H NMR (500 MHz, CHLOROFORM-d) δ 5.78-5.83 (m, 1H), 4.92-5.07 (m, 2H), 2.48-2.54 (m, 2H), 2.43 (q, J=7.0 Hz, 2H), 2.29-2.37 (m, 2H), 1.06 (t, J=7.0 Hz, 3H) Preparation of Compound 3-4
Figure imgf000113_0001
(R)-2-methylpropane-2-sulfinamide (12.97 g, 107 mmol) was added to a solution hept-6-en-3-one (3-3) (10 g, 89 mmol) in THF (100 mL). Ti(EtO)4 (37.5 mL, 178 mmol) was also added and the reaction was stirred at 75 °C for 12 h under N2 atmosphere. The mixture was cooled to room temperature, diluted with DCM (200 mL) and stirred for 15 min. Ice cold- saturated aqueous sodium bicarbonate solution (50 mL) and Na2SO4 was added and the mixture was filtered and concentrated in vacuo. The crude was purified by flash silica gel chromatography (ISCO®; 120g Agela Silica Flash Column, eluent of 8% ethyl acetate/pet. ether gradient @ 40 mL/min) to afford (R,E)-N-(hept-6-en-3-ylidene)-2-methylpropane-2-sulfinamide (3-4). MS (ESI) m/z 216.2(M+H+) 1H NMR (500 MHz, CHLOROFORM-d) δ 5.73-5.88 (m, 1H), 4.94-5.10 (m, 2H), 2.64-2.87 (m, 2H), 2.31-2.58 (m, 4H), 1.22 (s, 9H), 1.05-1.20 (m, 3H) Preparation of compound 3-5
Figure imgf000114_0001
Butyllithium (55.7 mL, 139 mmol), at -78 °C, was added dropwise to a solution of diisopropylamine (19.64 mL, 139 mmol) in anhydrous THF (40 mL) under N2 atmosphere. The reaction was stirred at 0 °C for 30 min to make LDA. The resulting LDA (76 mL, 93 mmol) was dropped to a mixture at -78 °C of ethyl acetate (7.48 mL, 93 mmol) and Ti(OiPr)3Cl (116 mL, 116 mmol) in anhydrous THF(90 mL). After 1 h, a solution of (R,E)-N-(hept-6-en-3- ylidene)-2-methylpropane-2-sulfinamide (3-4) (10 g, 46.4 mmol) in anhydrous THF (20 mL) was then added dropwise and the mixture was stirred at -78 °C for 3h. The mixture was quenched with ice-cold half-saturated aqueous ammonium chloride solution (60 mL). The slurry was diluted with EtOAc (200 mL) then filtered, rinsing with EtOAc and water. The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 120g Agela Silica Flash Column, eluent of 25% ethyl acetate/pet. ether gradient @ 40 mL/min) to afford methyl 3-(((R)- tert-butylsulfinyl)amino)-3-ethylhept-6-enoate (3-5). MS (ESI) m/z 290.1 (M+H+) 1H NMR (500 MHz, CHLOROFORM-d) δ 5.76-5.82 (m, 1H), 5.01-5.05 (m, 1H), 4.97 (dd, J=1.0, 10.0 Hz, 1H), 4.63 (br d, J=17.0 Hz, 1H), 3.68 (s, 3H), 2.72 (dd, J=5.0, 16.0 Hz, 1H), 2.52 (dd, J=2.5, 16.0 Hz, 1H), 2.07-2.13 (m, 1H), 1.82-1.91 (m, 1H), 1.76-1.81 (m, 1H), 1.71-1.75 (m, 1H), 1.26 (t, J=7.0 Hz, 2H), 1.24 (s, 9H), 0.87-0.95 (m, 3H) Preparation of Compound 3-6
Figure imgf000114_0002
A solution of methyl 3-(((R)-tert-butylsulfinyl)amino)-3-ethylhept-6-enoate (3-5) (9 g, 31.1 mmol) in 4N HCl-dioxane (20 mL) and MeOH (20.00 mL) at 25 °C under N2 atmosphere was stirred for 1 h. Solvent was evaporated under reduced pressure to give the crude product methyl 3-amino-3-ethylhept-6-enoate hydrochloride (3-6) used crude for the next step directly. MS (ESI) m/z 186.2 (M+H+) 1H NMR (500 MHz, CHLOROFORM-d) δ 5.75-5.80 (m, 1H), 5.08 (dd, J=1.0, 18.0 Hz, 1H), 4.98 (d, J=10.22 Hz, 1H), 3.72-3.75 (m, 3H), 2.78-2.85 (m, 2H), 2.21-2.29 (m, 2H), 1.84-2.00 (m, 4H), 1.06 (t, J=7.5 Hz, 3H) Preparation of Compound 3-7
Figure imgf000115_0001
N-ethyl-N-isopropylpropan-2-amine (13.79 mL, 79 mmol) was added to a solution of EDC (9.08 g, 47.4 mmol), methyl 3-amino-3-ethylhept-6-enoate hydrochloride (3-6) (3.5 g, 15.79 mmol) and methyl (R)-4-(3-(tert-butoxycarbonyl)thioureido)chromane-6- carboxylate (INT-1) (5.78 g, 15.79 mmol) in ACN (30 mL). The reaction was stirred at 25 °C for 12 h under N2 atmosphere. The mixture was quenched with water (50 mL), and extracted with EtOAc (3 x 50 mL). The organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford methyl (4R)-4-((Z)-2-(tert-butoxycarbonyl)-3-(3- ethyl-1-methoxy-1-oxohept-6-en-3-yl)guanidino)chromane-6-carboxylate (3-7) used crude for the next step directly. MS (ESI) m/z 518.2 (M+H+) Preparation of Compound 3-8
Figure imgf000115_0002
DBU (11.90 mL, 79 mmol) was added to a solution of methyl (4R)-4-((Z)-2-(tert- butoxycarbonyl)-3-(3-ethyl-1-methoxy-1-oxohept-6-en-3-yl)guanidino)chromane-6-carboxylate (3-7) (8.17 g, 15.78 mmol) in THF (50 mL). The mixture was stirred at 50 °C for 16 h under N2 atmosphere. The mixture was quenched with water (50 mL), and extracted with EtOAc (3 x 50 mL). The organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by flash silica gel chromatography (ISCO®; 120g Agela Silica Flash Column, eluent of 25% ethyl acetate/pet. ether gradient @ 40 mL/min) to afford methyl (4R)-4-((E)-4-(but-3-en-1-yl)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6- oxotetrahydropyrimidin-1(2H)-yl)chromane-6-carboxylate (3-8). MS (ESI) m/z 486.2(M+H+) 1H NMR (500 MHz, CHLOROFORM-d) δ 7.77 (td, J=2.0, 8.5 Hz, 1H), 7.62 (s, 1H), 6.84 (dd, J=2.0, 8.5 Hz, 1H), 6.33-6.42 (m, 1H), 5.76-5.90 (m, 1H), 5.00-5.14 (m, 2H), 4.42-4.49 (m, 1H), 4.22-4.23 (m, 1H), 3.81-3.86 (m, 3H), 2.70-2.81 (m, 1H), 2.51-2.60 (m, 2H), 2.03-2.16 (m, 4H), 1.75-1.84 (m, 2H), 1.65-1.73 (m, 4H), 1.52 (s, 9H), 0.98-1.04 (m, 3H) Preparation of Compounds 3-9A & 3-9B
Figure imgf000116_0001
3-8 3-9A & 3-9B Methyl (4R)-4-((E)-4-(but-3-en-1-yl)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6- oxotetrahydropyrimidin-1(2H)-yl)chromane-6-carboxylate (3-8) (4 g, 8.24 mmol) was separated by SFC (Column Boston Green ODS 150 x30mm, 5um Condition water(TFA)-ACN Begin B 48 End B 78 Gradient Time(min) 10100%B Hold Time (min) 2 FlowRate (mL/min) 25 Injections 1) to give P1 methyl (4R)-4-((E)-4-(but-3-en-1-yl)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6- oxotetrahydropyrimidin-1(2H)-yl)chromane-6-carboxylate (3-9A) (tR=2.105 min, UV = 220 nm). P2 methyl (4R)-4-((E)-4-(but-3-en-1-yl)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6- oxotetrahydropyrimidin-1(2H)-yl)chromane-6-carboxylate (3-9B) (tR=2.251 min, UV = 220 nm). MS (ESI) m/z 486.2 (M+H+) 3-9A: 1H NMR (500 MHz, CHLOROFORM-d) δ 7.77 (dd, J=1.5, 8.5 Hz, 1H), 7.62 (s, 1H), 6.84 (d, J=9.0 Hz, 1H), 6.37 (br dd, J=7.0, 10.0 Hz, 1H), 5.81-5.86 (m, 1H), 5.00-5.12 (m, 2H), 4.42-4.45 (m, 2H), 4.21-4.24 (m, 1H), 3.83 (s, 3H), 2.68-2.78 (m, 1H), 2.07-2.16 (m, 3H), 1.66- 1.83 (m, 5H), 1.51 (s, 9H), 0.96 (t, J=7.5 Hz, 3H) 3-9B: 1H NMR (500 MHz, CHLOROFORM-d) δ 7.77 (br d, J=8.70 Hz, 1H), 7.62 (s, 1H), 6.84 (d, J=8.5 Hz, 1H), 6.39 (br dd, J=7.0, 10.0 Hz, 1H), 5.74-5.86 (m, 1H), 5.00-5.10 (m, 2H), 4.41- 4.50 (m, 1H), 4.21-4.25 (m, 1H), 3.83 (s, 3H), 2.73-2.81 (m, 1H), 2.06-2.12 (m, 3H), 1.68-1.83 (m, 5H), 1.52 (s, 9H), 0.98-1.04 (m, 3H) Preparation of Compound 3-10
Figure imgf000117_0001
Potassium trimethylsilanolate (872 mg, 6.80 mmol) was added to a solution of methyl (R)-4-((R,E)-4-(but-3-en-1-yl)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6- oxotetrahydropyrimidin-1(2H)-yl)chromane-6-carboxylate (3-9A) (550 mg, 1.133 mmol) in THF (5 mL). The reaction was stirred at 25 °C for 0.5 h. The solution of (R)-4-((R,E)-4-(but-3-en-1- yl)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydropyrimidin-1(2H)-yl)chromane-6- carboxylic acid (3-10) was used for next step directly without any further manipulation or purification. MS (ESI) m/z 472.2 (M+H+). Preparation of Compound 3-11
Figure imgf000117_0002
3-10 3-11 DIEA (1.582 mL, 9.06 mmol) was added to a solution of (R)-4-((R,E)-4-(but-3- en-1-yl)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydropyrimidin-1(2H)-yl)chromane- 6-carboxylic acid (3-10) (534 mg, 1.132 mmol), EDC (1085 mg, 5.66 mmol), 1H- benzo[d][1,2,3]triazol-1-ol (765 mg, 5.66 mmol) and (S)-2,2-dimethyl-6-vinylchroman-4-amine (253 mg, 1.246 mmol) in THF (50 mL). The reaction was stirred at 25 °C for 12 h. The mixture was quenched with water (20 mL), and extracted with EtOAc (3 x 20 mL). The organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated in vacuo, and the crude was purified by prep-TLC (Pet. ether/EtOAc=2:1) to afford tert-butyl ((R,E)-4-(but-3-en- 1-yl)-1-((R)-6-(((S)-2,2-dimethyl-6-vinylchroman-4-yl)carbamoyl)chroman-4-yl)-4-ethyl-6- oxotetrahydropyrimidin-2(1H)-ylidene)carbamate (3-11). MS (ESI) m/z 657.3 (M+H+) Preparation of Compound 3-12
Figure imgf000118_0001
(1,3-Bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o- isopropoxyphenylmethylene)ruthenium (95 mg, 0.152 mmol) was added to a solution of tert- butyl ((R,E)-4-(but-3-en-1-yl)-1-((R)-6-(((S)-2,2-dimethyl-6-vinylchroman-4- yl)carbamoyl)chroman-4-yl)-4-ethyl-6-oxotetrahydropyrimidin-2(1H)-ylidene)carbamate (3-11) (500 mg, 0.761 mmol) in DCE (500 mL). The reaction was stirred at 50 °C for 5 h under N2 atmosphere. The mixture was concentrated in vacuo, and the crude was purified by flash column (Pet. ether/EtOAc/EtOH=8:3:1) to afford tert-butyl ((4aR,8R,11E,18aS,28E)-8-ethyl-17,17- dimethyl-6,20-dioxo-4,4a,7,8,9,10,18,18a,19,20-decahydro-3H,6H,17H-8,5-(epiminomethano)- 1,21:13,15-diethenodipyrano[4,3-b:4',3'-h][1,7]diazacyclooctadecin-28-ylidene)carbamate (3- 12). MS (ESI) m/z 629.3 (M+H+) 1H NMR (500 MHz, CHLOROFORM-d) δ 7.67 (dd, J=1.5, 8.5 Hz, 1H), 7.36 (s, 1H), 7.19 (s, 1H), 7.05-7.10 (m, 1H), 6.91 (d, J=8.5 Hz, 1H), 6.69 (d, J=8.5 Hz, 1H), 6.37 (d, J=15.5 Hz, 1H), 6.09-6.22 (m, 2H), 5.92-5.93 (m, 1H), 5.40-5.42 (m, 1H), 4.49 (td, J=4.0, 11.5 Hz, 1H), 2.93- 3.04 (m, 2H), 2.46-2.53 (m, 2H), 2.35-2.41 (m, 1H), 2.29 (dd, J=6.5, 13.0 Hz, 1H), 1.91-1.99 (m, 1H), 1.71-1.78 (m, 2H), 1.66-1.71 (m, 4H), 1.61-1.66 (m, 1H), 1.50-1.53 (m, 1H), 1.46-1.50 (m, 1H), 1.43 (s, 3H), 1.37 (s, 3H), 1.26 (s, 9H), 0.95 (t, J=7.48 Hz, 3H) Preparation of Compound 3-13
Figure imgf000119_0001
Pd-C (50.8 mg, 0.048 mmol) was added to a solution of tert-butyl ((4aR,8R,11E,18aS,28E)-8-ethyl-17,17-dimethyl-6,20-dioxo-4,4a,7,8,9,10,18,18a,19,20- decahydro-3H,6H,17H-8,5-(epiminomethano)-1,21:13,15-diethenodipyrano[4,3-b:4',3'- h][1,7]diazacyclooctadecin-28-ylidene)carbamate (3-12) (300 mg, 0.477 mmol) in MeOH (10 mL), under N2 atmosphere. The mixture was degassed and backfilled with H2 (three times). The resulting mixture was stirred at 25 °C for 0.5 h under H2 (15 psi). The catalyst was filtered off and filtrate was concentrated under reduced pressure to give tert-butyl ((4aR,8R,18aS,E)-8-ethyl- 17,17-dimethyl-6,20-dioxo-4,4a,7,8,9,10,11,12,18,18a,19,20-dodecahydro-3H,6H,17H-8,5- (epiminomethano)-1,21:13,15-diethenodipyrano[4,3-b:4',3'-h][1,7]diazacyclooctadecin-28- ylidene)carbamate (3-13) which was used for the next step directly. MS (ESI) m/z 631.3(M+H+) Preparation of Example 3A
Figure imgf000119_0002
A solution of tert-butyl ((4aR,8R,18aS,E)-8-ethyl-17,17-dimethyl-6,20-dioxo- 4,4a,7,8,9,10,11,12,18,18a,19,20-dodecahydro-3H,6H,17H-8,5-(epiminomethano)-1,21:13,15- diethenodipyrano[4,3-b:4',3'-h][1,7]diazacyclooctadecin-28-ylidene)carbamate (3-13) (280 mg, 0.444 mmol) in HCl-dioxane(4N) (30 mL) was stirred at 25 °C for 16 h. The solvent was evaporated under reduced pressure to give the crude product. The residue was purified by reverse preparative HPLC (Column Boston Green ODS 150 x 30mm, 5um Condition water (HCl)-ACN Begin B 30 End B 50 Gradient Time (min) 10100%B Hold Time (min) 2 FlowRate (mL/min) 25 Injections 6) to give (4aR,8R,18aS)-8-ethyl-28-imino-17,17-dimethyl- 4,4a,7,8,9,10,11,12,17,18,18a,19-dodecahydro-3H,6H,20H-8,5-(epiminomethano)-1,21:13,15- diethenodipyrano[4,3-b:4',3'-h][1,7]diazacyclooctadecine-6,20-dione Example 3A. MS (ESI) m/z 531.2 (M+H+) 1H NMR (500 MHz, METHANOL-d4) δ 7.73 (dd, J=2.0, 8.5 Hz, 1H), 7.45 (s, 1H), 7.02 (s, 1H), 6.92-6.99 (m, 2H), 6.70 (d, J=8.5 Hz, 1H), 5.37-5.44 (m, 2H), 4.44-4.47 (m, 1H), 4.12-4.17 (m, 1H), 2.93 (d, J=16.5 Hz, 1H), 2.55-2.70 (m, 4H), 2.23-2.31 (m, 1H), 2.12 (dd, J=6.5, 13.0 Hz, 1H), 1.81-1.87 (m, 1H), 1.66-1.80 (m, 5H), 1.49-1.59 (m, 1H), 1.42 (s, 3H), 1.34-1.40 (m, 2H), 1.32 (s, 3H), 0.98 (t, J=7.5 Hz, 3H) EXAMPLE 4
Figure imgf000120_0001
(1R,5R,18S)-5-ethyl-3-imino-16,16-dimethyl-10,15,25-trioxa-2,4,19- triazahexacyclo[19.6.2.22,5.211,14.013,18.024,28]tritriaconta-11,13,21,23,28,30-hexaene-20,33- dione Preparation of Compound 4-2
Figure imgf000120_0002
4-1 4-2 DIEA (36.7 mL, 210 mmol) was added to a solution of hex-5-enoic acid (4-1) (8 g, 70.1 mmol), EDC (20.15 g, 105 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (14.21 g, 105 mmol) and N,O-dimethylhydroxylamine hydrochloride (7.52 g, 77 mmol) in THF (100 mL). The reaction was stirred at 25 °C for 5 h. The mixture was quenched with water (150 mL), and extracted with EtOAc (3 x 50 mL). The organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 5% EtOAc/Pet.ether gradient @ 80 mL/min) to give N-methoxy-N-methylhex-5-enamide (4-2). MS (ESI) m/z 157.7 (M+H+) Preparation of compound 4-3
Figure imgf000121_0001
Ethylmagnesium bromide (38.2 mL, 114 mmol), at 0 °C, was added dropwise to a solution of N-methoxy-N-methylhex-5-enamide (4-2) (9 g, 57.2 mmol) in THF (120 mL) under N2 atmosphere. Then the mixture was stirred 20 °C for 2 h. The mixture was quenched with saturated aqueous NH4Cl (25 mL). The mixture was quenched with water (150 ml) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered. Solvent was removed under reduced pressure to give crude product which was purified by column chromatography (SiO2, Pet.ether: EtOAc=100:1~10:1) to afford oct-7- en-3-one (4-3). 1H NMR (500 MHz, CHLOROFORM-d) δ 5.76 (m, 1H), 4.93-5.04 (m, 2H), 2.38-2.44 (m, 4H), 2.05 (q, J=7.0 Hz, 2H), 1.68 (m, 2H), 1.04 (t, J=7.5 Hz, 3H). Preparation of Compound 4-4
Figure imgf000121_0002
2-methylpropane-2-sulfinamide (6.34 g, 52.3 mmol) was added to a solution oct- 7-en-3-one (4-3) (5.5 g, 43.6 mmol) in THF (80 mL), followed by Ti(EtO)4 (18.31 ml, 87 mmol). The reaction was stirred at 75 °C for 16 h under N2 atmosphere. The final mixture was cooled to 0 °C, diluted with DCM (100 mL) and stirred for 15min. Ice cold-saturated aqueous sodium bicarbonate solution (15 mL) was added and the solution was filtered and concentrated in vacuo. The crude was purified by flash column (SiO2, Pet. ether/EtOAc = 100:1 to 5:1) to afford ((E)-2- methyl-N-(oct-7-en-3-ylidene)propane-2-sulfinamide (4-4). MS (ESI) m/z 230.2 (M+H+) 1H NMR (500 MHz, CHLOROFORM-d) δ 5.78-5.80 (m, 1H), 4.96-5.07 (m, 2H), 2.62-2.76 (m, 2H), 2.39-2.50 (m, 2H), 2.04-2.17 (m, 2H), 1.67-1.76 (m, 2H), 1.23 (s, 9H), 1.06-1.21 (m, 3H) Preparation of Compound 4-5
Figure imgf000122_0001
Methyl acetate (1.545 ml, 19.18 mmol) at -78 °C was added to a solution of LiHMDS (22.67 ml, 22.67 mmol) in anhydrous THF (35 mL) under N2 atmosphere. The reaction was stirred at -78 °C for 15min. (E)-2-methyl-N-(oct-7-en-3-ylidene)propane-2-sulfinamide (4- 4) (4 g, 17.44 mmol) in THF (15 mL) was then added dropwise and the mixture was stirred at - 78 °C for 3h. The mixture was quenched with ice-cold half-saturated aqueous ammonium chloride solution (30 mL). The slurry was diluted with EtOAc (50 mL) then filtered, rinsing with EtOAc and water. The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column (SiO2, Pet. ether/EtOAc=100:0 to 10:1) to afford methyl 3-((tert-butylsulfinyl)amino)-3-ethyloct-7-enoate (4-5). MS (ESI) m/z 304.3 (M+H+). 1H NMR (500 MHz, CHLOROFORM-d) δ 5.72-5.86 (m, 1H), 4.91-5.06 (m, 2H), 4.59-4.61 (m, 1H), 3.63-3.76 (m, 3H), 2.68-2.71 (m, 1H), 2.42-2.55 (m, 1H), 1.99-2.13 (m, 2H), 1.58-1.91 (m, 5H), 1.31-1.48 (m, 2H), 1.16-1.24 (m, 9H), 0.80-0.93 (m, 3H) Preparation of Compound 4-6
Figure imgf000122_0002
A solution of methyl 3-((tert-butylsulfinyl)amino)-3-ethyloct-7-enoate (4-5) (2 g, 6.59 mmol) in HCl-dioxane (4N) (5 mL) and MeOH (5mL) at 15 °C under N2 atmosphere was stirred at 15 °C for 1 h. The solution was concentrated in vacuo to give the crude product methyl 3-amino-3-ethyloct-7-enoate hydrochloride (4-6) which was used without any further purification. 1H NMR (500 MHz, CHLOROFORM-d) δ 5.77 (m, 1H), 4.93-5.06 (m, 2H), 3.73 (s, 3H), 2.72- 2.88 (m, 2H), 2.02-2.14 (m, 2H), 1.70-2.00 (m, 5H), 1.56 (m, 2H), 1.04 (t, J = 7.50 Hz, 3H) Preparation of compound 4-7
Figure imgf000123_0001
N-ethyl-N-isopropylpropan-2-amine (4.37 ml, 24.56 mmol) was added to a solution of methyl (R)-4-(3-(tert-butoxycarbonyl)thioureido)chromane-6-carboxylate (INT-1) (1.5 g, 4.09 mmol), methyl 3-amino-3-ethyloct-7-enoate hydrochloride (4-6) (1.448 g, 6.14 mmol) and N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (2.354 g, 12.28 mmol) in acetonitrile (30 mL). The mixture was stirred at 15 °C for 10 h. The mixture was quenched with water (50 mL), and extracted with EtOAc (3 x 40 mL). The organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford methyl (4R)-4-((Z)-2-(tert-butoxycarbonyl)-3-(3-ethyl-1-methoxy-1-oxooct-7-en-3- yl)guanidino)chromane-6-carboxylate (4-7) which was used crude for the next step directly. MS (ESI) m/z 532.3 (M+H + ). Preparation of Compound 4-8
Figure imgf000123_0002
DBU (2.84 mL, 18.81 mmol) was added to a solution of methyl (4R)-4-((Z)-2- (tert-butoxycarbonyl)-3-(3-ethyl-1-methoxy-1-oxooct-7-en-3-yl)guanidino)chromane-6- carboxylate (4-7) (2.0 g, 3.76 mmol) in THF (20 mL). The mixture was stirred at 50 °C for 10 h. The mixture was quenched with water (40 mL), and extracted with EtOAc (3 x 40 mL). The organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude was purified by flash silica gel chromatography (ISCO®; 20 g Agela Silica Flash Column, eluent of 15% ethyl acetate/pet. ether gradient @ 60 mL/min) to afford methyl (4R)-4-((E)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxo-4-(pent-4-en-1- yl)tetrahydropyrimidin-1(2H)-yl)chromane-6-carboxylate (4-8).MS (ESI) m/z: 500.6 (M+H+). 1H NMR (400 MHz, CHLOROFORM-d) δ 10.10 (s, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.61 (s, 1H), 6.83 (dd, J = 0.8, 8.8 Hz, 1H), 6.31-6.46 (m, 1H), 5.77 (m, 1H), 4.97-5.10 (m, 2H), 4.43 (d, J = 11.2 Hz, 1H), 4.17-4.29 (m, 1H), 3.82 (s, 3H), 2.68-2.86 (m, 1H), 2.47-2.59 (m, 2H), 2.06-2.18 (m, 2H), 1.56-1.81 (m, 5H), 1.51 (s, 9H), 1.45 (s, 3H), 1.40 (s, 1H) Preparation of Compounds 4-9A & 4-9B
Figure imgf000124_0001
Methyl (E)-4-(2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxo-4-(pent-4-en-1- yl)tetrahydropyrimidin-1(2H)-yl)chromane-6-carboxylate (4-8) (1.8 g, 3.60 mmol) was separated by SFC (Instrument SFC-22 Method Column DAICEL CHIRALPAK AD (250mm x30mm, 10um) Condition 0.1%NH3H2O IPA Begin B 10% End B 10% Gradient Time (min) 100%B Hold Time (min) FlowRate(mL/min) 50 Injections 60) to afford product (methyl (R)-4-((R,E)-2- ((tert-butoxycarbonyl)imino)-4-ethyl-6-oxo-4-(pent-4-en-1-yl)tetrahydropyrimidin-1(2H)- yl)chromane-6-carboxylate (4-9A) (peak1, Rt=0.816) and (methyl (E)-4-(2-((tert- butoxycarbonyl)imino)-4-ethyl-6-oxo-4-(pent-4-en-1-yl)tetrahydropyrimidin-1(2H)- yl)chromane-6-carboxylate (4-9B) (peak2, Rt=0.879). MS (ESI) m/z: 500.2 (M+H+) Preparation of Compound 4-10
Figure imgf000125_0001
2,6-dimethylpyridine (42.9 mg, 0.400 mmol) and osmium (VIII) oxide (5.09 mg, 0.020 mmol) were added to a solution of methyl (R)-4-((R,E)-2-((tert-butoxycarbonyl)imino)-4- ethyl-6-oxo-4-(pent-4-en-1-yl)tetrahydropyrimidin-1(2H)-yl)chromane-6-carboxylate (4-9A) (100 mg, 0.200 mmol) in 1,4-dioxane (4 mL) and water (1 mL). The resulting solution was stirred for 0.2 h at 25 °C. Sodium periodate (171 mg, 0.801 mmol) was added and the resulting solution was stirred for 2 h at 25 °C. The mixture was quenched with Sat. Na2SO3 (10 mL) and water (5 mL), and extracted with EtOAc (3 x 10 mL). The organic layers were washed with brine (5 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford methyl (R)-4-((R,E)-2- ((tert-butoxycarbonyl)imino)-4-ethyl-6-oxo-4-(4-oxobutyl)tetrahydropyrimidin-1(2H)- yl)chromane-6-carboxylate (4-10) which was used crude for the next step directly. MS (ESI) m/z: 502.3 (M+H+) Preparation of compound 4-11
Figure imgf000125_0002
NaBH4 (10.75 mg, 0.284 mmol) was added in portions to a solution of methyl (R)-4-((R, E)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6-oxo-4-(4-oxobutyl)tetrahydropyrimidin- 1(2H)-yl)chromane-6-carboxylate (4-10) (95 mg, 0.189 mmol) in MeOH (2mL) at 0 °C. The mixture was stirred at 0 °C for 1 h. LCMS showed major desired product mass. The mixture was quenched with water (5 mL), and extracted with EtOAc (4 x 5 mL). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated in vacuum, the crude was purified by prep-TLC (Pet. ether/EtOAc=3:1) to afford methyl (R)-4-((R,E)-2- ((tert-butoxycarbonyl)imino)-4-ethyl-4-(4-hydroxybutyl)-6-oxotetrahydropyrimidin-1(2H)- yl)chromane-6-carboxylate (4-11). MS (ESI) m/z: 504.4 (M+H+) 1H NMR (400 MHz, CHLOROFORM-d) δ 10.14 (s, 1H), 7.76 (dd, J = 2.0, 8.4 Hz, 1H), 7.65 (s, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.36 (dd, J = 7.2, 10.0 Hz, 1H), 4.43-4.46 (m, 1H), 4.22-4.26 (m, 1H), 3.84 (s, 3H), 3.68 (t, J = 6.4 Hz, 2H), 2.69-2.78 (m, 1H), 2.51-2.62 (m, 2H), 1.95-2.24 (m, 2H), 1.64-1.69 (m, 6H), 1.52 (s, 9H), 1.43-1.49 (m, 2H), 0.97 (t, J = 7.6 Hz, 3H) Preparation of Compound 4-12
Figure imgf000126_0001
Potassium trimethylsilanolate (81 mg, 0.631 mmol) was added to a solution of methyl (R)-4-((R,E)-2-((tert-butoxycarbonyl)imino)-4-ethyl-4-(4-hydroxybutyl)-6- oxotetrahydropyrimidin-1(2H)-yl)chromane-6-carboxylate (4-11) (53 mg, 0.105 mmol) in THF (1 mL). The reaction was stirred at 25 °C for 0.5 h. LCMS showed major desired product mass. The solution of (R)-4-((R, E)-2-((tert-butoxycarbonyl)imino)-4-ethyl-4-(4-hydroxybutyl)-6- oxotetrahydropyrimidin-1(2H)-yl)chromane-6-carboxylic acid (4-12) was used in the next step without any further manipulation or purification. MS (ESI) m/z: 490.2 (M+H+) Preparation of Compound 4-13
Figure imgf000126_0002
DIEA (0.143 mL, 0.817 mmol) was added to a solution of (R)-4-((R,E)-2-((tert- butoxycarbonyl)imino)-4-ethyl-4-(4-hydroxybutyl)-6-oxotetrahydropyrimidin-1(2H)- yl)chromane-6-carboxylic acid (4-12) (50 mg, 0.102 mmol), EDC (98 mg, 0.511 mmol), 1H- benzo[d][1,2,3]triazol-1-ol (69.0 mg, 0.511 mmol) and (S)-6-bromo-2,2-dimethylchroman-4- amine (28.8 mg, 0.112 mmol) in THF (5 mL). The reaction was stirred at 25 °C for 3 h. The mixture was quenched with water (5 mL), and extracted with EtOAc (3 x 5 mL). The organic layers were washed with brine (5 mL), dried over Na2SO4, filtered and concentrated in vacuum, the crude was purified by prep-TLC (Pet. ether/EtOAc=3:1) to afford tert-butyl ((R,E)-1-((R)-6- (((S)-6-bromo-2,2-dimethylchroman-4-yl)carbamoyl)chroman-4-yl)-4-ethyl-4-(4-hydroxybutyl)- 6-oxotetrahydropyrimidin-2(1H)-ylidene)carbamate (4-13). MS (ESI) m/z: 727.2, 729.2 (M+H+) Preparation of Compound 4-14
Figure imgf000127_0001
In a glove box, [(2-Di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2- (2'-amino-1,1'-biphenyl)] palladium(II) methanesulfonate (7.64 mg, 9.62 µmol) and CsCO3 (37.1 mg, 0.192 mmol) was added to a mixture of tert-butyl ((R,E)-1-((R)-6-(((S)-6-bromo-2,2- dimethylchroman-4-yl)carbamoyl)chroman-4-yl)-4-ethyl-4-(4-hydroxybutyl)-6- oxotetrahydropyrimidin-2(1H)-ylidene)carbamate (4-13) (70 mg, 0.096 mmol) in dioxane (3 mL). The mixture was stirred at 70 °C for 3 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The organic layers were washed with brine (5 mL), dried over Na2SO4, filtered and concentrated in vacuum. The crude was purified by prep-TLC (Pet. ether/EtOAc=2:1) to afford tert-butyl ((4aR,5R,8R,19aS,E)-8-ethyl-18,18-dimethyl-6,21-dioxo- 4,4a,7,8,9,10,11,12,19,19a,20,21-dodecahydro-3H,6H,18H-1,22-(epiethane[1,2]diylidene)-8,5- (epiminomethano)-14,16-ethenodipyrano[3,4-d:3',4'-j][1]oxa[6,12]diazacyclononadecin-29- ylidene)carbamate (4-14). MS (ESI) m/z: 647.3 (M+H+) 1H NMR (500 MHz, CHLOROFORM-d) δ 7.81 (dd, J = 2.0, 8.5 Hz, 1H), 7.01 (s, 1H), 6.93 (d, J = 8.5 Hz, 1H), 6.88 (d, J = 1.0 Hz, 1H), 6.78 (s, 2H), 6.40 (dd, J = 7.0, 10.0Hz, 1H), 6.13 (d, J = 8.50 Hz, 1H), 5.37-5.44 (m, 1H), 4.44 (td, J = 3.5, 11.5 Hz, 1H), 4.17-4.23 (m, 2H), 3.82 (dt, J = 5.0, 9.5 Hz, 1H), 2.71-2.79 (m, 2H), 2.53 (d, J = 16.0 Hz, 1H), 2.35 (dd, J = 6.5, 13.0 Hz, 1H), 2.07-2.14 (m, 2H), 1.78 (dd, J = 7.50, 10.50 Hz, 4H), 1.52 (s, 2H), 1.49 (s, 9H), 1.42 (s, 3H), 1.37 (s, 3H), 0.95 (t, J = 7.5 Hz, 3H) Preparation of Example 4
Figure imgf000128_0001
Zinc(II) bromide (104 mg, 0.464 mmol) and oxa[6,12]diazacyclononadecin-29- ylidene)carbamate (4-14) (30 mg, 0.046 mmol) in DCM (3 mL) at 25 °C were added to a solution of tert-butyl ((4aR,5R,8R,19aS,E)-8-ethyl-18,18-dimethyl-6,21-dioxo- 4,4a,7,8,9,10,11,12,19,19a,20,21-dodecahydro-3H,6H,18H-1,22-(epiethane[1,2]diylidene)-8,5- (epiminomethano)-14,16-ethenodipyrano[3,4-d:3',4'-j][1], under N2 atmosphere. The mixture was stirred at 25 °C for 16 h. The solvent was evaporated under reduced pressure to give the crude product and the residue was purified by reverse preparative HPLC (Instrument e.g., Method Column Welch Xtimate C18150 x 25mm, 5um; Condition water(TFA)-ACN Begin B 25; End B 55 Gradient Time(min) 11; 100%B Hold Time(min) 2 FlowRate(mL/min) 25; Injections 1) to give (4aR,5R,8R,19aS)-8-ethyl-29-imino-18,18-dimethyl- 4,4a,7,8,9,10,11,12,18,19,19a,20-dodecahydro-3H,6H,21H-1,22-(epiethane[1,2]diylidene)-8,5- (epiminomethano)-14,16-ethenodipyrano[3,4-d:3',4'-j][1]oxa[6,12]diazacyclononadecine-6,21- dione Example 4. MS (ESI) m/z: 547.2 (M+H+) 1H NMR (500 MHz, METHANOL-d4) δ 8.55 (d, J = 8.5 Hz, 1H), 7.73 (dd, J = 2.0, 8.5 Hz, 1H), 7.45 (d, J = 1.5 Hz, 1H), 6.94 (d, J = 8.50 Hz, 1H), 6.86 (d, J = 2.5 Hz, 1H), 6.76-6.82 (m, 1H), 6.70 (d, J = 9.0 Hz, 1H), 5.35-5.40 (m, 1H), 5.24-5.32 (m, 1H), 4.47 (td, J = 4.5, 11.50 Hz, 1H), 4.13-4.21 (m, 2H), 3.90-3.92 (m, 1H), 2.75-2.88 (m, 2H), 2.60-2.72 (m, 1H), 2.22-2.31 (m, 1H), 2.15 (dd, J = 6.5, 13.0 Hz, 1H), 1.66-1.85 (m, 7H), 1.47-1.60 (m, 2H), 1.40 (s, 3H), 1.33 (s, 3H), 0.97 (t, J = 7.5 Hz, 3H) EXAMPLE 5
Figure imgf000129_0001
(11R,14R,14aR,21aS)-11-ethyl-16,16-difluoro-24-imino-2,2-dimethyl- 1,2,7,8,9,10,11,12,15,16,21,21a-dodecahydro-13H-11,14-(epiminomethano)-4,6:17,19- diethenocyclopenta[b]pyrano[4,3-h][1,7]diazacyclooctadecine-13,20(14aH)-dione Preparation of Compound 5-2
Figure imgf000129_0002
A solution of 5-bromo-2,3-dihydro-1H-inden-1-one (50 g, 237 mmol), ethane- 1,2-dithiol (5-1) (26.6 mL, 317 mmol) and 4-methylbenzenesulfonic acid (8.16 g, 47.4 mmol) in toluene (500 mL) was heated to 130˚C for 16 h using a Dean-Stark apparatus. TLC showed the reaction was complete. The cooled solution was washed with 10% NaOH (600 mL), and the aqueous layer extracted with DCM (3×600 mL). The combined organic layer was washed with brine (300 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 10% EtOAc/Pet.ether gradient @ 60 mL/min) to give 5-bromo-2,3-dihydrospiro[indene-1,2'- [1,3]dithiolane] (5-2). MS (ESI) m/z 286.9, 288.9 (M+H)+ 1H NMR (500 MHz, CHLOROFORM-d) δ 7.40-7.44 (m, 1H), 7.31-7.38 (m, 2H), 3.50-3.56 (m, 2H), 3.40-3.47 (m, 2H), 2.96 (t, J = 6.5 Hz, 2H), 2.69 (t, J = 6.5 Hz, 2H) Preparation of Compound 5-3
Figure imgf000130_0001
- - 3 h 5-2 5-3 A solution of 1,3-dibromo-5,5-dimethylhydantoin (194 g, 679 mmol) in anhydrous CH2Cl2 (700 mL) was cooled to -70 °C in a dry ice-acetone bath. Pyridine hydrofluoride (57.4 mL, 226 mmol) was added dropwise at a temperature below -65 °C under N2, and the mixture stirred at -70 °C for 30 min. A solution of 5-bromo-2,3-dihydrospiro[indene- 1,2'-[1,3]dithiolane] (5-2) (65 g, 226 mmol) in CH2Cl2 (200 mL) was added dropwise and the mixture was stirred at -70 °C for 4 h, and then at 25 °C overnight. TLC showed the reaction was complete. The mixture was poured into NaOH (2 M, 300 mL) containing 39% NaHSO3 (600 mL) solution. The aqueous layer was extracted with CH2Cl2 (2×600 mL) and the combined organic layer washed with brine (300 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, Eluent of 100% Pet.ether gradient @ 60 mL/min) to give 2,5-dibromo-1,1-difluoro-2,3-dihydro-1H-indene (5-3). No LCMS signal. 1H NMR (500 MHz, CHLOROFORM-d) δ 7.52-7.58 (m, 1H), 7.47 (d, J = 6.5 Hz, 2H), 4.57 (tt, J = 7.0, 10.5 Hz, 1H), 3.57 (ddd, J = 2.0, 7.5, 16.5 Hz, 1H), 3.27 (dd, J = 7.0, 16.5 Hz, 1H) Preparation of Compound 5-4
Figure imgf000130_0002
5-3 5-4 To a solution of 2,5-dibromo-1,1-difluoro-2,3-dihydro-1H-indene (5-3) (60 g, 192 mmol) in DCM (600 mL) was added DBU (43.5 mL, 289 mmol). The mixture was stirred at 25 °C for 16 h. LCMS showed desired product mass. Water (600 mL) was added, the mixture was acidified with con.HCl to pH=7. Filtered the mixture with diatomite, and the aqueous layer was extracted with CH2Cl2 (2×600 mL) and the combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 100% Pet.ether gradient @ 50 mL/min) to give 5-bromo-1,1-difluoro-1H-indene (5-4). No LCMS signal. 1H NMR (500 MHz, CHLOROFORM-d) δ 7.41 (dd, J = 1.5, 8.0 Hz, 1H), 7.29-7.35 (m, 2H), 6.75 (d, J = 6.0 Hz, 1H), 6.22 (d, J = 6.0 Hz, 1H) Preparation of Compound 5-5
Figure imgf000131_0001
To a solution of 5-bromo-1,1-difluoro-1H-indene (5-4) (15 g, 64.9 mmol) in iPrOH (250 mL) which was bubble with O2 for 1 h, was added PHENYLSILANE (14.05 g, 130 mmol) and Mn(TMHD)3 (3.93 g, 6.49 mmol) and stirred at 0 °C for 2 h under O2 (15 psi). TLC showed the reaction was complete. The mixture was quenched with water (300 mL), and extracted with EtOAc (3 x 300 mL). The organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 17% EtOAc/Pet.ether gradient @ 50 mL/min) to give a mixture of 6-bromo-3,3-difluoro-2,3-dihydro-1H-inden-1-ol (5-5) and 5-bromo-1,1-difluoro- 2,3-dihydro-1H-inden-2-ol (5-5a); (5-5: 5-5a =7:2). 1H NMR (500 MHz, CHLOROFORM-d) δ 7.68 (s, 1H), 7.59-7.62 (m, 1H), 7.43-7.46 (m, 1H), 5.31 (q, J = 6.0 Hz, 1H), 3.01-3.12 (m, 1H), 2.49 (dq, J = 5.0, 14.5 Hz, 1H)
Figure imgf000131_0002
To a solution of mix of 6-bromo-3,3-difluoro-2,3-dihydro-1H-inden-1-ol and 5- bromo-1,1-difluoro-2,3-dihydro-1H-inden-2-ol (11.56 g, 47.3 mmol) (5-5: 5-5a =7:2) in MeOH (150 mL) and DMSO (15 mL) was added [1,1'- Bis(diphenylphospino)ferrocene]dichloropalladium(II) (2.64 g, 3.61 mmol) and triethylamine (15.67 mL, 108 mmol) under Ar atmosphere at 20°C and the mixture was stirred at 80 °C for 48 h under CO atmosphere (3.5 mbar). TLC showed the reaction was complete. After cooled, filtered the mixture with diatomite, and the mixture was diluted with H2O (200 mL), extracted with EtOAc (3x200 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 17% EtOAc / Pet.ether gradient @ 80 mL/min) to give a mixture of methyl 1,1-difluoro-3-hydroxy-2,3- dihydro-1H-indene-5-carboxylate (5-6) and methyl 1,1-difluoro-2-hydroxy-2,3-dihydro-1H- indene-5-carboxylate (5-6a); (5-6: 5-6a =3:1). 1H NMR (500 MHz, chloroform-d) δ 8.21 (s, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 5.37 (quin, J = 6.0 Hz, 1H), 3.96 (s, 3H), 3.05-3.17 (m, 1H), 2.54 (dq, J = 5.0, 14.5 Hz, 1H) Preparation of Compound 5-7 P1
Figure imgf000132_0001
The mixture of methyl 1,1-difluoro-3-hydroxy-2,3-dihydro-1H-indene-5- carboxylate and methyl 1,1-difluoro-2-hydroxy-2,3-dihydro-1H-indene-5-carboxylate (8.3 g, 36.36 mmol) (5-6: 27-6a = 3:1) was separated by SFC (Column: Chiralpak AD-3150 x 4.6mm I.D., 3um, Mobile phase: A:CO2 B:iso-propanol (0.05% DEA), Gradient: from 5% to 40% of B in 5 min and from 40% to 5% of B in 0.5 min, then hold at 5% of B for 1.5 min, Flow rate: 2.5mL/min, Column temp.: 35°C) to afford product methyl (S)-1,1-difluoro-3-hydroxy-2,3- dihydro-1H-indene-5-carboxylate (5-7_P1, desired) (peak1, Rt=2.577), methyl (R)-1,1-difluoro- 3-hydroxy-2,3-dihydro-1H-indene-5-carboxylate (5-7_P2) (peak2, Rt=2.944) and a mixture of (5-7_P2 and 5-6a) (2 g, 8.77 mmol). The mixture of (5-7_P2 and 5-6a) was separated by SFC (Column: Cellulose 2150 x 4.6mm I.D., 5um, Mobile phase: A: CO2 B:MeOH (0.05% DEA) Gradient: from 5% to 40% of B in 5 min and from 40% to 5% of B in 0.5 min, then hold 5% of B for 1.5 min, Column temp.: 35°C) to give methyl 1,1-difluoro-2-hydroxy-2,3-dihydro-1H- indene-5-carboxylate (5-6a). (5-7_P1): 1H NMR (500 MHz, chloroform-d) δ 8.21 (s, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 5.37 (q, J = 6.0 Hz, 1H), 3.96 (s, 3H), 3.06-3.17 (m, 1H), 2.54 (dq, J = 5.0, 14.5 Hz, 1H) (5-7_P2): 1H NMR (500 MHz, chloroform-d) δ 8.20 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 5.36 (q, J = 5.5 Hz, 1H), 3.95 (s, 3H), 3.05-3.17 (m, 1H), 2.54 (dq, J = 5.0, 14.5 Hz, 1H) (5-6a): 1H NMR (500 MHz, chloroform-d) δ 8.05 (d, J = 8.0 Hz, 1H), 7.98 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H), 4.53-4.68 (m, 1H), 3.95 (s, 3H), 3.40 (dd, J = 7.0, 16.0 Hz, 1H), 2.95 (dd, J = 5.0, 16.5 Hz, 1H) Preparation of Compound 5-8
Figure imgf000133_0001
_ To a solution of methyl (S)-1,1-difluoro-3-hydroxy-2,3-dihydro-1H-indene-5- carboxylate (5-7_P1) (585 mg, 2.56 mmol), tert-butyl (R,E)-(4-(but-3-en-1-yl)-4-ethyl-6- oxotetrahydropyrimidin-2(1H)-ylidene)carbamate (INT-2) (757 mg, 2.56 mmol) and Ph3P (1009 mg, 3.85 mmol) in THF (10 mL) was added DIAD (0.997 mL, 5.13 mmol) dropwise at 0 °C under N2 atmosphere, then the mixture was stirred at 18 °C for 2 h. TLC showed no SM. The mixture was concentrated in vacuo, and the residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 20% EtOAc/Pet.ether gradient @ 60 mL/min) to afford crude product. The crude product was re-purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of DCM gradient @ 60 mL/min) to afford product methyl (R)-3-((R,E)-4-(but-3-en-1-yl)-2-((tert- butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydropyrimidin-1(2H)-yl)-1,1-difluoro-2,3-dihydro- 1H-indene-5-carboxylate (5-8). MS (ESI) m/z 506.2 (M+H)+ 1H NMR (400 MHz, chloroform-d) δ 10.08 (br s, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.78 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 6.74 (q, J = 7.2 Hz, 1H), 5.80-5.87 (m, 1H), 4.95-5.21 (m, 2H), 4.05- 4.19 (m, 1H), 3.91 (s, 3H), 2.92-3.14 (m, 2H), 2.58 (s, 2H), 2.07-2.19 (m, 2H), 1.63-1.78 (m, 4H), 1.52 (s, 9H), 0.97 (t, J = 7.6 Hz, 3H) Preparation of Compound 5-9
Figure imgf000134_0001
To a solution of methyl (R)-3-((R,E)-4-(but-3-en-1-yl)-2-((tert- butoxycarbonyl)imino)-4-ethyl-6-oxotetrahydropyrimidin-1(2H)-yl)-1,1-difluoro-2,3-dihydro- 1H-indene-5-carboxylate (5-8) (900 mg, 1.780 mmol) in THF (9 mL) was added potassium trimethylsilanolate (1370 mg, 10.68 mmol). The reaction was stirred at 18 °C for 0.5 h. LCMS showed desired mass. Added H3PO4 (0.1 g/mL in H2O) to adjust pH to about 6~7, and the mixture was quenched with water (10 mL), and extracted with EtOAc (3 x 10 mL). The organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford the product (R)-3-((R,E)-4-(but-3-en-1-yl)-2-((tert-butoxycarbonyl)imino)-4-ethyl-6- oxotetrahydropyrimidin-1(2H)-yl)-1,1-difluoro-2,3-dihydro-1H-indene-5-carboxylic acid (5-9). MS (ESI) m/z 492.1 (M+H)+ 1H NMR (400 MHz, chloroform-d) δ 10.08 (br s, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.82 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 6.72-6.77 (m, 1H), 5.80-5.89 (m, 1H), 4.99-5.16 (m, 2H), 2.98-3.14 (m, 2H), 2.59 (s, 2H), 2.11-2.13 (m, 2H), 1.64-1.83 (m, 4H), 1.53 (s, 9H), 0.98 (t, J = 7.6 Hz, 3H) Preparation of Compound 5-10
Figure imgf000134_0002
To a solution of (R)-3-((R,E)-4-(but-3-en-1-yl)-2-((tert-butoxycarbonyl)imino)-4- ethyl-6-oxotetrahydropyrimidin-1(2H)-yl)-1,1-difluoro-2,3-dihydro-1H-indene-5-carboxylic acid (5-9) (0.87 g, 1.770 mmol), EDC (1.697 g, 8.85 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (0.718 g, 5.31 mmol) in THF (15 mL) was added DIEA (2.473 mL, 14.16 mmol) and (S)-2,2-dimethyl-6- vinylchroman-4-amine (0.396 g, 1.947 mmol). The reaction was stirred at 18 °C for 12 h. LCMS showed desired mass. The mixture was quenched with water (15 mL), and extracted with EtOAc (3 x 15 mL). The organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo, and the crude was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 17% EtOAc/Pet.ether gradient @ 60 mL/min) to afford product tert-butyl ((R,E)-4-(but-3-en-1-yl)-1-((R)-6-(((S)-2,2-dimethyl-6- vinylchroman-4-yl)carbamoyl)-3,3-difluoro-2,3-dihydro-1H-inden-1-yl)-4-ethyl-6- oxotetrahydropyrimidin-2(1H)-ylidene)carbamate (5-10). MS (ESI) m/z 677.4 (M+H)+ 1H NMR (400 MHz, CHLOROFORM-d) δ 10.08 (br s, 1H), 7.72-7.78 (m, 1H), 7.61-7.69 (m, 2H), 7.28-7.34 (m, 2H), 6.81 (d, J = 8.4 Hz, 1H), 6.76-6.77 (m, 1H), 6.58-6.62 (m, 1H), 6.22 (br d, J = 8.8 Hz, 1H), 5.72-5.77 (m, 1H), 5.46-5.61 (m, 2H), 5.11 (d, J = 11.2 Hz, 1H), 5.06-5.08 (m, 1H), 4.97-5.00 (m, 1H), 2.96-3.14 (m, 2H), 2.58 (s, 2H), 2.29-2.34 (m, 1H), 2.10 (br d, J = 6.0 Hz, 2H), 1.71-1.81 (m, 1H), 1.63-1.74 (m, 4H), 1.52 (s, 9H), 1.46 (s, 3H), 1.38 (s, 3H), 0.96 (t, J = 7.6 Hz, 3H). Preparation of Compound 5-11
Figure imgf000135_0001
To a solution of tert-butyl ((R,E)-4-(but-3-en-1-yl)-1-((R)-6-(((S)-2,2-dimethyl-6- vinylchroman-4-yl)carbamoyl)-3,3-difluoro-2,3-dihydro-1H-inden-1-yl)-4-ethyl-6- oxotetrahydropyrimidin-2(1H)-ylidene)carbamate (5-10) (1 g, 1.478 mmol) in DCE (500 mL) was added Dichloro[1,3-bis(2,6-isopropylphenyl)-2-imidazolidinylidene](2- isopropoxyphenylmethylene)ruthenium(II) (0.105 g, 0.148 mmol). The reaction was stirred at 50 °C for 4 h with N2. LCMS showed desired mass. The mixture was concentrated in vacuo, and the crude was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 15% EtOAc/Pet.ether gradient @ 60 mL/min) to afford tert-butyl ((7Z,11R,14R,14aR,21aS,24E)-11-ethyl-16,16-difluoro-2,2-dimethyl-13,20-dioxo- 1,2,10,11,12,13,14a,15,16,20,21,21a-dodecahydro-9H-11,14-(epiminomethano)-4,6:17,19- diethenocyclopenta[b]pyrano[4,3-h][1,7]diazacyclooctadecin-24-ylidene)carbamate (5-11a, cis olefin; minor product) and tert-butyl ((7E,11R,14R,14aR,21aS,24E)-11-ethyl-16,16-difluoro- 2,2-dimethyl-13,20-dioxo-1,2,10,11,12,13,14a,15,16,20,21,21a-dodecahydro-9H-11,14- (epiminomethano)-4,6:17,19-diethenocyclopenta[b]pyrano[4,3-h][1,7]diazacyclooctadecin-24- ylidene)carbamate (5-11, trans olefin; major product). (5-11a, cis olefin): MS (ESI) m/z 649.3 (M+H)+ 1H NMR (400 MHz, CHLOROFORM-d) δ 10.12 (s, 1H), 8.06 (d, J = 7.6 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.17 (s, 1H), 6.99-7.01 (m, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.64-6.76 (m, 1H), 6.39 (d, J = 11.2 Hz, 1H), 6.28 (br d, J = 8.8 Hz, 1H), 5.58-5.61 (m, 1H), 5.41-5.45 (m, 1H), 3.01- 3.13 (m, 2H), 2.66 (d, J = 16.4 Hz, 1H), 2.42-2.45 (m, 2H), 2.20-2.30 (m, 1H), 1.96-2.04 (m, 1H), 1.63-1.86 (m, 5H), 1.51 (s, 9H), 1.46 (s, 3H), 1.39 (s, 3H), 1.02 (t, J = 7.2 Hz, 3H) (5-11, trans olefin): MS (ESI) m/z 649.3 (M+H)+ 1H NMR (400 MHz, CHLOROFORM-d) δ 10.15 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.35 (s, 1H), 7.23 (s, 1H), 7.06 (dd, J = 2.0, 8.4 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H), 6.61-6.70 (m, 1H), 6.39 (d, J = 15.6 Hz, 1H), 6.06 (d, J = 9.2 Hz, 1H), 5.68-5.89 (m, 1H), 5.47- 5.50 (m, 1H), 2.95-3.14 (m, 2H), 2.68 (d, J = 16.4 Hz, 1H), 2.55 (d, J = 16.4 Hz, 1H), 2.32-2.35 (m, 3H), 1.85-1.97 (m, 1H), 1.64-1.76 (m, 4H), 1.47 (s, 3H), 1.41 (s, 9H), 1.40 (br s, 3H), 0.97 (t, J = 7.6 Hz, 3H) Preparation of Compound 5-12
Figure imgf000136_0001
To a solution of tert-butyl ((7E,11R,14R,14aR,21aS,24E)-11-ethyl-16,16- difluoro-2,2-dimethyl-13,20-dioxo-1,2,10,11,12,13,14a,15,16,20,21,21a-dodecahydro-9H-11,14- (epiminomethano)-4,6:17,19-diethenocyclopenta[b]pyrano[4,3-h][1,7]diazacyclooctadecin-24- ylidene)carbamate (5-11) (780 mg, 1.202 mmol) in MeOH (10 mL) was added 10%Pd-C (128 mg, 0.120 mmol) under N2 atmosphere. The mixture was degassed and backfilled with H2 (three times). The resulting mixture was stirred at 18 °C for 10 min under H2 (15 psi) atmosphere. LCMS showed the reaction was complete. The mixture was filtered and the filtrate was concentrated under reduced pressure to give tert-butyl ((11R,14R,14aR,21aS,E)-11-ethyl-16,16- difluoro-2,2-dimethyl-13,20-dioxo-1,2,8,9,10,11,12,13,14a,15,16,20,21,21a-tetradecahydro-7H- 11,14-(epiminomethano)-4,6:17,19-diethenocyclopenta[b]pyrano[4,3- h][1,7]diazacyclooctadecin-24-ylidene)carbamate (5-12), which was used as is directly in next step. MS (ESI) m/z 651.4 (M+H)+ Preparation of Example 5
Figure imgf000137_0001
A solution of tert-butyl ((11R,14R,14aR,21aS,E)-11-ethyl-16,16-difluoro-2,2- dimethyl-13,20-dioxo-1,2,8,9,10,11,12,13,14a,15,16,20,21,21a-tetradecahydro-7H-11,14- (epiminomethano)-4,6:17,19-diethenocyclopenta[b]pyrano[4,3-h][1,7]diazacyclooctadecin-24- ylidene)carbamate (5-12) (700 mg, 1.076 mmol) in HCl-dioxane (4N) (10 mL) was stirred at 18 °C for 12 h. LCMS showed the reaction was complete. Solvent was evaporated under reduced pressure to give the crude product. The residue was purified by reverse preparative HPLC (Instrument 3-101(EK) Method Phase separation Column Boston Uni C18150 x 40mm, 5um Condition water (0.04%HCl)-ACN Begin B 33 End B 63 Gradient Time(min) 10100%B Hold Time 2 Flow Rate(mL/min) 60 Injections 2) to afford (11R,14R,14aR,21aS)-11-ethyl-16,16- difluoro-24-imino-2,2-dimethyl-1,2,7,8,9,10,11,12,15,16,21,21a-dodecahydro-13H-11,14- (epiminomethano)-4,6:17,19-diethenocyclopenta[b]pyrano[4,3-h][1,7]diazacyclooctadecine- 13,20(14aH)-dione Example 5. MS (ESI) m/z 551.3 (M+H)+ 1H NMR (400 MHz, METHANOL-d4) δ 7.98 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.62 (s, 1H), 7.03 (s, 1H), 6.97-7.00 (m, 1H), 6.70 (d, J = 8.0 Hz, 1H), 5.72 (br d, J = 6.4 Hz, 1H), 5.42 (dd, J = 6.4, 11.6 Hz, 1H), 3.22-3.31 (m, 1H), 2.95-3.15 (m, 2H), 2.46-2.63 (m, 3H), 2.14- 2.17 (m, 1H), 1.73-1.91 (m, 5H), 1.55-1.72 (m, 2H), 1.39-1.51 (m, 5H), 1.33 (s, 3H), 0.98 (t, J = 7.2 Hz, 3H) The compounds in Table 1 were prepared in an analogous fashion to that described for Example 1 and/or Example 5. The isomers were separated by preparative HPLC or/and preparative chiral SFC. An asterisk (*) may be used in a chemical structure drawing that indicates the location of a chiral center. TABLE 1
Figure imgf000138_0001
Figure imgf000139_0001
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Figure imgf000210_0001
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Figure imgf000224_0001
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Figure imgf000226_0001
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Figure imgf000230_0001
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Figure imgf000256_0001
Figure imgf000257_0001
Figure imgf000258_0001
Assessing antiparasite potency in a parasite LDH growth assay (Parasite Assay) The parasite stock was maintained at 4% haematocrit in RPMI-Hepes media 30 buffered with sodium bicarbonate and supplemented with 5% heat inactivated human serum and 0.5% albumax. Approximately 42 hours prior to the potency assay being set up, parasites were synchronized with 5% 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 35 adjusted to 0.7% rings and the haematocrit was diluted to 2% in RPMI-Hepes media buffered with sodium bicarbonate and supplemented with 5% heat inactivated human serum and 0.5% albumax.30ul of diluted parasites are then added into 10ul 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 2. Table 2
Figure imgf000259_0001
Figure imgf000260_0001
Figure imgf000261_0001
Figure imgf000262_0001
Figure imgf000263_0001
Figure imgf000264_0001
Figure imgf000265_0001
Figure imgf000266_0001

Claims

WHAT IS CLAIMED: 1. A compound having the structural Formula (I):
Figure imgf000267_0001
or a pharmaceutically acceptable salt thereof, wherein: A is a straight or branched, saturated or unsaturated (C3-C10)alkylene, phenyl(C3-C10)alkylene or cycloalkyl(C3-C10)alkylene comprising at least one –CH2- group, wherein one or more additional –CH2- groups in A are optionally and independently replaced with a moiety selected from the group consisting of O, S, NR, CONR, NRCO, SO2, and SO2NR and wherein one or more of the hydrogens along A can be replaced with a group independently selected from hydroxyl, halogen and C1-3 haloalkyl; X is a bond, C(R14)2, O, S, SO, SO2 or NH; Y is CR9 or N, wherein when Y is N, Z is CR11 and V is CR10; V is CR10 or N, wherein when V is N, Z is CR11 and Y is CR9; Z is CR11 or N, wherein when Z is N, V is CR10 and Y is CR9; R is hydrogen, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1- C6alkylOH, COC1-C6alkyl or COOC1-C6alkyl; Ra is hydrogen, halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1-C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3- C6cycloalkyl, C1-C6alkyl, -C1-C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) or C1-C6alkylN(R7)(R8) or when taken with Rb forms a C3-C6cycloalkyl or heterocycloalkyl, wherein the C3-C6cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1- C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3-C6cycloalkyl, C1-C6alkyl, -C1- C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) and C1- C6alkylN(R7)(R8); Rb is hydrogen, halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1-C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3- C6cycloalkyl, C1-C6alkyl, -C1-C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) or C1-C6alkylN(R7)(R8) or when taken with Ra forms a C3-C6cycloalkyl or heterocycloalkyl, wherein the C3-C6cycloalkyl or heterocycloalkyl is unsubstituted or substituted with one or three substituents selected from the group consisting of halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, oxo, COOC1-C6alkyl, C1- C6alkylCOOC1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylC3-C6cycloalkyl, C1-C6alkyl, -C1- C6alkylOhaloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) and C1- C6alkylN(R7)(R8); R3 is hydrogen, halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8), C1-C6alkylN(R7)(R8), C1-C6alkyl(OCH2CH2)nN(R7)(R8) or C1-C6alkylOhaloC1-C6alkyl or when taken with R4 forms a C3-C6cycloalkyl or C3-C6heterocycloalkyl; R4 is hydrogen, halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8), C1-C6alkylN(R7)(R8), C1-C6alkyl(OCH2CH2)nN(R7)(R8) or C1-C6alkylOhaloC1-C6alkyl or when taken with R3 forms a C3-C6cycloalkyl or C3-C6heterocycloalkyl; R7 is hydrogen, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1- C6alkylOH, COC1-C6alkyl or COOC1-C6alkyl; R8 is hydrogen, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1- C6alkylOH, COC1-C6alkyl or COOC1-C6alkyl; R9 is hydrogen, halogen, CN, OH, C1-C6alkoxy, 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); R10 is hydrogen, halogen, CN, OH, C1-C6alkoxy, 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); R11 is hydrogen, halogen, CN, OH, C1-C6alkoxy, 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); R12 is hydrogen, halogen, CN, OH, C1-C6alkoxy, 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); R13 is hydrogen, halogen, CN, OH, C1-C6alkoxy, 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); each occurrence of R14 is independently selected from the group consisting of hydrogen, halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, C3- C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) and C1- C6alkylN(R7)(R8); R15 is hydrogen, halogen, CN, OH, C1-C6alkoxy, 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); each occurrence of R16 is independently selected from the group consisting of hydrogen, halogen, CN, OH, C1-C6alkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkylCOOH, COOH, C3- C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkylOH, CON(R7)(R8), N(R7)(R8) and C1- C6alkylN(R7)(R8); m is 0 or 1; n is 1, 2, 3 or 4; and p is 0 or 1. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 1, p is 1 and X is O. 3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 1, p is 1 and X is a bond. 4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ra is taken with Rb and forms a heterocycloalkyl. 5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ra is taken with Rb and forms a heterocycloalkyl, wherein the heterocycloalkyl is
Figure imgf000269_0001
, and wherein the heterocycloalkyl is substituted with two C1-C6alkyl groups.
6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ra is taken with Rb and forms a C3-C6cycloalkyl. 7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ra is taken with Rb and forms a C3-C6cycloalkyl, wherein the heterocycloalkyl is , and wherein the C3-C6cycloalkyl is unsubstituted or substituted with OH. 8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen, C1-C6alkylOC1-C6alkyl or C1-C6alkyl or when taken with R4 forms a C3- C6heterocycloalkyl. 9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen or C1-C6alkyl or when taken with R4 forms a C3-C6heterocycloalkyl. 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 and R4 are both halogen. 11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R15 is hydrogen or C1-C6alkyl. 12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 and R4 are independently selected from the group consisting of hydrogen, halogen, OH, C1- C6alkylOH, C1-C6alkylalkoxy, C1-C6alkylOC1-C6alkyl, C1-C6alkyl, C1-C6alkylOhaloC1-C6alkyl, CON(C1-C6alkyl)2, C1-C6alkylN(R7)(R8) and C1-C6alkyl(OCH2CH2)nN(R7)(R8); R7 is hydrogen, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1- C6alkylOH, COC1-C6alkyl or COOC1-C6alkyl; R8 is hydrogen, C1-C6alkylCOOH, COOH, C3-C6cycloalkyl, C1-C6alkyl, haloC1-C6alkyl, C1- C6alkylOH, COC1-C6alkyl or COOC1-C6alkyl; and n is 3.
13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R12 and R13 are independently selected from the group consisting of hydrogen, halogen, OH, C1- C6alkylOH, C1-C6alkylalkoxy and C1-C6alkylOC1-C6alkyl, C1-C6alkyl. 14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is C(R14)2, R14 is independently selected from the group consisting of hydrogen, halogen, OH, C1-C6alkylOH, C1-C6alkylalkoxy, C1-C6alkylOC1-C6alkyl and C1-C6alkyl. 15. The compound of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein Y is CH. 16. The compound of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein Z is CH. 17. The compound of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein V is CH. 18. The compound of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein A is a straight, saturated or unsaturated (C3-C10)alkylene. 19. The compound of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein A is a branched, saturated or unsaturated (C3-C10)alkylene. 20. The compound of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein A is
Figure imgf000271_0001
. 21. A compound selected from the group consisting of
Figure imgf000272_0001
Figure imgf000273_0001
Figure imgf000274_0001
Figure imgf000275_0001
Figure imgf000276_0001
Figure imgf000277_0001
Figure imgf000278_0001
Figure imgf000279_0001
Figure imgf000280_0001
Figure imgf000281_0001
Figure imgf000282_0001
Figure imgf000283_0001
Figure imgf000284_0001
Figure imgf000285_0001
Figure imgf000286_0001
Figure imgf000287_0001
Figure imgf000288_0001
Figure imgf000289_0001
Figure imgf000290_0001
Figure imgf000291_0001
Figure imgf000292_0001
Figure imgf000293_0001
Figure imgf000294_0001
Figure imgf000295_0001
Figure imgf000296_0001
Figure imgf000297_0001
Figure imgf000298_0001
Figure imgf000299_0001
Figure imgf000300_0001
Figure imgf000301_0001
Figure imgf000302_0001
Figure imgf000303_0001
Figure imgf000304_0001
Figure imgf000305_0001
Figure imgf000306_0001
Figure imgf000307_0001
Figure imgf000308_0001
Figure imgf000309_0001
Figure imgf000310_0001
Figure imgf000311_0001
Figure imgf000312_0001
Figure imgf000313_0001
Figure imgf000314_0001
Figure imgf000315_0001
Figure imgf000316_0001
Figure imgf000317_0001
Figure imgf000318_0001
Figure imgf000319_0001
Figure imgf000320_0001
Figure imgf000321_0001
Figure imgf000322_0001
Figure imgf000323_0001
Figure imgf000324_0001
Figure imgf000325_0001
Figure imgf000326_0001
Figure imgf000327_0001
Figure imgf000328_0001
Figure imgf000329_0001
Figure imgf000330_0001
Figure imgf000331_0001
Figure imgf000332_0001
Figure imgf000333_0001
Figure imgf000334_0001
Figure imgf000335_0001
Figure imgf000336_0001
Figure imgf000337_0001
Figure imgf000338_0001
Figure imgf000339_0002
, or a pharmaceutically acceptable salt thereof. 22. A compound having the formula
Figure imgf000339_0001
, p y p . 24. A compound having the formula:
Figure imgf000340_0001
pharmaceutically acceptable salt thereof. 25. 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 any one of claims 1-24, or a pharmaceutically acceptable salt thereof. 26. 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 any one of claims 1-24, or a pharmaceutically acceptable salt thereof. 27. 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 any one of claims 1-24, or a pharmaceutically acceptable salt thereof. 28. A method for dual inhibition of plasmepsin X and plasmepsin X which comprises administering to a subject in need of such treatment a therapeutically effective amount of a compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof. 29. The use of a compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-24 to treat a Plasmodium infection, or malaria in a patient in need thereof. 30. The use of a compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-24 to inhibit plasmepsin X in a patient in need thereof. 31. The use of a compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-24 to inhibit plasmepsin IX in a patient in need thereof. 32. The use of a compound, or pharmaceutically acceptable salt thereof, of claim 1 to inhibit plasmepsin IX and plasmepsin X, in a patient in need thereof.
33. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 34. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier. 35. 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. 36. 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.
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Citations (1)

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WO2021155791A1 (en) * 2020-02-09 2021-08-12 Merck Sharp & Dohme Corp. Antimalarial agents

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WO2021155791A1 (en) * 2020-02-09 2021-08-12 Merck Sharp & Dohme Corp. Antimalarial agents

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