WO2023102747A1 - Agents antipaludiques - Google Patents

Agents antipaludiques Download PDF

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Publication number
WO2023102747A1
WO2023102747A1 PCT/CN2021/136177 CN2021136177W WO2023102747A1 WO 2023102747 A1 WO2023102747 A1 WO 2023102747A1 CN 2021136177 W CN2021136177 W CN 2021136177W WO 2023102747 A1 WO2023102747 A1 WO 2023102747A1
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Prior art keywords
alkyl
certain embodiments
cycloalkyl
pharmaceutically acceptable
alkyloh
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PCT/CN2021/136177
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English (en)
Inventor
John A. Mccauley
Manuel De Lera Ruiz
Lianyun Zhao
Zhuyan Guo
Zhiyu Lei
Bin Hu
Dongmei ZHAN
Philippe Nantermet
Michael J. Kelly, Iii
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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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 PCT/CN2021/136177 priority Critical patent/WO2023102747A1/fr
Priority to AU2022404966A priority patent/AU2022404966A1/en
Priority to PCT/US2022/051770 priority patent/WO2023107356A1/fr
Priority to CA3240145A priority patent/CA3240145A1/fr
Priority to TW111146559A priority patent/TWI842251B/zh
Priority to ARP220103334A priority patent/AR127872A1/es
Publication of WO2023102747A1 publication Critical patent/WO2023102747A1/fr

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms 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 malaria.
  • 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 acomplex 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 tocommence 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.
  • 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.
  • 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, et al.
  • a multistage antimalarial targets the plasmepsins IX and X essential for invasion and egress. Science. 2017; 358 (6362) : 522-8. )
  • the present invention is directed to compounds of Formula (I) :
  • compositions including pharmaceuticalcompositions, comprising one or more compounds of the invention (e.g., onecompound of the invention) , or a tautomer thereof, or a pharmaceutically acceptable salt or solvate of saidcompound (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.
  • pharmaceuticalcompositions comprising one or more compounds of the invention (e.g., onecompound of the invention) , or a tautomer thereof, or a pharmaceutically acceptable salt or solvate of saidcompound (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 pharmaceuticalcompositionscomprising 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 ofcombinations of the compoundsor 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 ofP. falciparum aspartic acid proteases.
  • the present invention further provides methods for blockingP. falciparum growth by inhibitingplasmepsin X.
  • the present invention further provides methods for blocking P. falciparum growth by inhibiting both plasmepsin X 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 plasmepsin X 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 ) alkylenecomprising 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 halogen;
  • 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 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 9 ;
  • Z is CR 11 or N, wherein when Z is N, V is CR 10 and Y is CR 9 ;
  • each occurrence of R is independently hydrogen, C 1 -C 6 alkylCOOH, -COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, -COC 1 -C 6 alkyl or -COOC 1 -C 6 alkyl;
  • R a is hydrogen, halogen, -CN, -OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, -COOH, oxo, -COOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkylC 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 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
  • 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 ) or C 1 -C 6 alkylN (R 7 ) (R 8 ) or when taken with R a forms a C 3
  • 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 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;
  • each occurrence of R 7 is independently 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;
  • each occurrence of R 8 is independently hydrogen, C 1 -C 6 alkylCOOH, -COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, -COC 1 -C 6 alkyl or -COOC 1 -C 6 alkyl;
  • R 9 is hydrogen, halogen, -CN, -OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, -COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, -CON (R 7 ) (R 8 ) , -N (R 7 ) (R 8 ) or C 1 -C 6 alkylN (R 7 ) (R 8 ) ;
  • R 10 is hydrogen, halogen, -CN, -OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, -COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, -CON (R 7 ) (R 8 ) , -N (R 7 ) (R 8 ) or C 1 -C 6 alkylN (R 7 ) (R 8 ) ;
  • R 11 is hydrogen, halogen, -CN, -OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, -COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, -CON (R 7 ) (R 8 ) , -N (R 7 ) (R 8 ) or C 1 -C 6 alkylN (R 7 ) (R 8 ) ;
  • R 12 is hydrogen, halogen, -CN, -OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, -COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, -CON (R 7 ) (R 8 ) , -N (R 7 ) (R 8 ) or C 1 -C 6 alkylN (R 7 ) (R 8 ) ;
  • R 13 is hydrogen, halogen, -CN, -OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, -COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, -CON (R 7 ) (R 8 ) , -N (R 7 ) (R 8 ) or C 1 -C 6 alkylN (R 7 ) (R 8 ) ;
  • each occurrence of R 14 is independently selected from the group consisting of hydrogen, halogen, -CN, -OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, -COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, -CON (R 7 ) (R 8 ) , -N (R 7 ) (R 8 ) and C 1 -C 6 alkylN (R 7 ) (R 8 ) ;
  • R 15 is hydrogen, halogen, -CN, -OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, -COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, -CON (R 7 ) (R 8 ) , -N (R 7 ) (R 8 ) or C 1 -C 6 alkylN (R 7 ) (R 8 ) ;
  • n 0 or 1
  • n 1, 2, 3 or 4;
  • p 0 or 1.
  • 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 lymphmbodiments 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 SO 2 . In certain embodiments described herein, X is NH.
  • 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 .
  • 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 .
  • 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.
  • 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 a is hydrogen
  • R a is halogen.
  • suitable halogens include chlorine, bromine, fluorine and iodine.
  • R a is -CN.
  • R a is -OH.
  • R a is C 1 -C 6 alkoxy.
  • Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
  • R a is C 1 -C 6 alkylOC 1 -C 6 alkyl.
  • R a is C 1 -C 6 alkylCOOH.
  • R a is -COOH
  • R a is an oxo group.
  • R a is -COOC 1 -C 6 alkyl.
  • R a is C 1 -C 6 alkylCOOC 1 -C 6 alkyl.
  • R a is C 3 -C 6 cycloalkyl.
  • Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R a is C 1 -C 6 alkylC 3 -C 6 cycloalkyl.
  • Suitable examples of cycloalkyls include, but are not limited to
  • R a is C 1 -C 6 alkyl.
  • C 1 -C 6 alkyl groups include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1, 2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2, 2-dimethylbutyl, 1-ethylbutyl, 1, 1, 2-trimethylpropyl, 1, 2, 2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl
  • R a is C 1 -C 6 alkylOhaloC 1 -C 6 alkyl.
  • Suitable examples of C 1 -C 6 alkylOhaloC 1 -C 6 alkyls include, but are not limited to,
  • R a 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.
  • R a is C 1 -C 6 alkylOH.
  • Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol.
  • R a is -CON (R 7 ) (R 8 ) . In certain embodiments, R a is -N (R 7 ) (R 8 ) . In certain embodiments, R a is C 1 -C 6 alkylN (R 7 ) (R 8 ) , wherein R 7 and R 8 will be described in detail below.
  • the compounds described herein have the Formula (II) :
  • 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 to foursubstituents independently 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, hal
  • R a is taken with R b and forms a C 3 -C 6 cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one to foursubstituents independently 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 alkyl, C 1
  • Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • the cycloalkyl is unsubstituted.
  • the heterocycloalkyl is substituted with one to four substituents independently 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 ) ,
  • 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 (
  • the cycloalkyl is substituted with two substituents independently 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 alkyl
  • the cycloalkyl is substituted with three substituents independently 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 alkyl
  • the cycloalkyl is substituted with -OH.
  • the cycloalkyl is substituted with four substituents independently 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 alkyl
  • R a is taken with R b and forms a heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one to foursubstituents independently 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 (
  • 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,
  • bicyclic heterocycloalkyl groups include, but are not limited to,
  • R a is taken with R b and forms:
  • the heterocycloalkyl is unsubstituted. In certain embodiments, the heterocycloalkyl is substituted with one to foursubstituents independently 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 )
  • the 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 (
  • the heterocycloalkyl is substituted with two substituents independently 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 alkyl
  • the heterocycloalkyl is substituted with two C 1 -C 6 alkylsubstituents.
  • the heterocycloalkyl is substituted with three substituents independently 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 alkyl
  • the heterocycloalkyl is substituted with threesubstituents independently selected from the group consisting of C 1 -C 6 alkyl and -OH.
  • the heterocycloalkyl is substituted with four substituents independently 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 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 ) or C 1 -C 6 alkylN (R 7 ) (R 8 ) or when taken with
  • R b is hydrogen
  • R b is halogen.
  • suitable halogens include chlorine, bromine, fluorine and iodine.
  • R b is -CN.
  • R b is -OH.
  • R b is C 1 -C 6 alkoxy.
  • Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
  • R b is C 1 -C 6 alkylOC 1 -C 6 alkyl.
  • R b is C 1 -C 6 alkylCOOH.
  • R b is -COOH
  • R b is an oxo group.
  • R b is -COOC 1 -C 6 alkyl.
  • R b is C 1 -C 6 alkylCOOC 1 -C 6 alkyl.
  • R b is C 3 -C 6 cycloalkyl.
  • Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R b is C 1 -C 6 alkylC 3 -C 6 cycloalkyl.
  • Suitable examples of C 1 -C 6 alkylC 3 -C 6 cycloalkyls include, but are not limited to
  • R b is C 1 -C 6 alkyl.
  • C 1 -C 6 alkyl groups include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1, 2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2, 2-dimethylbutyl, 1-ethylbutyl, 1, 1, 2-trimethylpropyl, 1, 2, 2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl
  • R b is C 1 -C 6 alkylOhaloC 1 -C 6 alkyl.
  • Suitable examples of C 1 -C 6 alkylOhaloC 1 -C 6 alkyls include, but are not limited to,
  • 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.
  • 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 ) . In certain embodiments, R b is N (R 7 ) (R 8 ) . In certain embodiments, R b is C 1 -C 6 alkylN (R 7 ) (R 8 ) , 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 to foursubstituents independently 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
  • R b is taken with R a and forms a cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with one to foursubstituents independently 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 (
  • Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • the cycloalkyl is unsubstituted. In certain embodiments, the cycloalkyl is substituted with one to four substituents independently 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, heterooxo, -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 ) ,
  • 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 (
  • the cycloalkyl is substituted with two substituents independently 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 alkyl
  • the cycloalkyl is substituted with three substituents independently 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 alkyl
  • the cycloalkyl is substituted with -OH.
  • the cycloalkyl is substituted with four substituents independently 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 alkyl
  • R b is taken with R a and forms a heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with one to foursubstituents independently 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 (
  • 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,
  • bicyclic heterocycloalkyl groups include, but are not limited to,
  • R b is taken with R a and forms:
  • the heterocycloalkyl is unsubstituted. In certain embodiments, the heterocycloalkyl is substituted with one to four substituents independently 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 ) ,
  • the 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 (
  • the heterocycloalkyl is substituted with two substituents independently 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 alkyl
  • the heterocycloalkyl is substituted with two C 1 -C 6 alkylsubstituents.
  • the heterocycloalkyl is substituted with three substituents independently 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 alkyl
  • the heterocycloalkyl is substituted with three substituents independently selected from the group consisting of C 1 -C 6 alkyl and -OH.
  • the heterocycloalkyl is substituted with four substituents independently 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 alkyl
  • 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 or when taken with R 4
  • 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.
  • R 3 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 3 is C 1 -C 6 alkylOC 1 -C 6 alkyl. In certain embodiments, R 3 is -COOH. In certain embodiments, R 3 is C 1 -C 6 alkylCOOH. In certain embodiments, R 3 is C 3 -C 6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 3 is C 1 -C 6 alkyl.
  • C 1 -C 6 alkyl groups include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1, 2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2, 2-dimethylbutyl, 1-ethylbutyl, 1, 1, 2-trimethylpropyl, 1, 2, 2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1
  • 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.
  • R 3 is C 1 -C 6 alkylOH.
  • suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol.
  • R 3 is -CON (R 7 ) (R 8 ) .
  • Suitable examples of -CON (R 7 ) (R 8 ) include, but are not limited to, -CONH 2 and -CON (CH 3 ) 2 .
  • R 3 is N (R 7 ) (R 8 ) .
  • Suitable examples of N (R 7 ) (R 8 ) include, but are not limited to, NH 2 and N (CH 3 ) 2 .
  • R 3 is C 1 -C 6 alkylN (R 7 ) (R 8 ) .
  • Suitable examples of C 1 -C 6 alkylN (R 7 ) (R 8 ) include, but are not limited to, R 7 and R 8 are discussed in further detail below.
  • R 3 is C 1 -C 6 alkylOhaloC 1 -C 6 alkyl.
  • Suitable examples of C 1 - C 6 alkylOhaloalkyls include, but are not limited to,
  • R 3 is C 1 -C 6 alkyl (OCH 2 CH 2 ) n N (R 7 ) (R 8 ) .
  • R 7 , R 8 and n are discussed in detail below.
  • Suitable examples of C 1 -C 6 alkyl (OCH 2 CH 2 ) n N (R 7 ) (R 8 ) include, but are not limited to,
  • 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.
  • R 3 is taken with R 4 and forms a C 3 -C 6 cycloalkyl or C 3 -C 6 heterocycloalkyl. In certain embodiments, R 3 is taken with R 4 and forms a C 3 -C 6 cycloalkyl. 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 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 3 is hydrogen, fluorine, methyl, ethyl, -OH, methoxy, -CON (CH 3 ) 2 ,
  • R 3 is hydrogen, methyl, ethyl or
  • 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 or when taken with R 3
  • 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.
  • R 4 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 4 is C 1 -C 6 alkylOC 1 -C 6 alkyl. In certain embodiments, R 4 is -COOH. In certain embodiments, R 4 is C 1 -C 6 alkylCOOH. In certain embodiments, R 4 is C 3 -C 6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • 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
  • 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 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 4 is -CON (R 7 ) (R 8 ) .
  • Suitable examples of -CON (R 7 ) (R 8 ) include, but are not limited to, -CONH 2 and -CON (CH 3 ) 2 .
  • R 4 is N (R 7 ) (R 8 ) .
  • Suitable examples of N (R 7 ) (R 8 ) include, but are not limited to, NH 2 and N (CH 3 ) 2 .
  • R 4 is C 1 -C 6 alkylN (R 7 ) (R 8 ) .
  • Suitable examples of C 1 -C 6 alkylN (R 7 ) (R 8 ) include, but are not limited to, R 7 and R 8 are discussed in further detail below.
  • R 4 is C 1 -C 6 alkylOhaloC 1 -C 6 alkyl.
  • Suitable examples of 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. In certain embodiments, 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. In certain embodiments, 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. In certain embodiments, R 4 is hydrogen, methyl, ethyl or In certain embodiments, R 4 is taken with R 3 to form oxetanyl. In certain embodiments, 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, 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 5 is hydrogen
  • R 5 is halogen.
  • suitable halogens include chlorine, bromine, fluorine and iodine.
  • R 5 is -CN.
  • R 5 is -OH.
  • R 5 is C 1 -C 6 alkoxy.
  • Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
  • R 5 is C 1 -C 6 alkylOC 1 -C 6 alkyl.
  • R 5 is C 1 -C 6 alkylCOOH.
  • R 5 is -COOH.
  • R 5 is an oxo group.
  • R 5 is -COOC 1 -C 6 alkyl.
  • R 5 is C 1 -C 6 alkylCOOC 1 -C 6 alkyl.
  • R 5 is C 3 -C 6 cycloalkyl.
  • Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 5 is C 1 -C 6 alkylC 3 -C 6 cycloalkyl.
  • Suitable examples of cycloalkyls include, but are not limited to
  • 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
  • R 5 is C 1 -C 6 alkylOhaloC 1 -C 6 alkyl.
  • Suitable examples of C 1 - C 6 alkylOhaloC 1 -C 6 alkyls include, but are not limited to,
  • 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.
  • 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 ) . In certain embodiments, R 5 is N (R 7 ) (R 8 ) . In certain embodiments, 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, 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 6 is hydrogen
  • R 6 is halogen.
  • suitable halogens include chlorine, bromine, fluorine and iodine.
  • R 6 is -CN.
  • R 6 is -OH.
  • R 6 is C 1 -C 6 alkoxy.
  • Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
  • R 6 is C 1 -C 6 alkylOC 1 -C 6 alkyl.
  • R 6 is C 1 -C 6 alkylCOOH.
  • R 6 is -COOH.
  • R 6 is an oxo group.
  • R 6 is -COOC 1 -C 6 alkyl.
  • R 6 is C 1 -C 6 alkylCOOC 1 -C 6 alkyl.
  • R 6 is C 3 -C 6 cycloalkyl.
  • Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 6 is C 1 -C 6 alkylC 3 -C 6 cycloalkyl.
  • Suitable examples of C 1 -C 6 alkylC 3 -C 6 cycloalkyls include, but are not limited to
  • R 6 is C 1 -C 6 alkyl.
  • C 1 -C 6 alkyl groups include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1, 2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2, 2-dimethylbutyl, 1-ethylbutyl, 1, 1, 2-trimethylpropyl, 1, 2, 2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1
  • R 6 is C 1 -C 6 alkylOhaloC 1 -C 6 alkyl.
  • Suitable examples of C 1 -C 6 alkylOhaloC 1 -C 6 alkyls include, but are not limited to,
  • R 6 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.
  • R 6 is C 1 -C 6 alkylOH.
  • Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol.
  • R 6 is -CON (R 7 ) (R 8 ) . In certain embodiments, R 6 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.
  • 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. In certain embodiments, R 7 is C 1 -C 6 alkylCOOH. In certain embodiments, R 7 is -COOH. In certain embodiments, R 7 is C 3 -C 6 cycloalkyl. Suitable examples of 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 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.
  • R 7 is C 1 -C 6 alkylOH.
  • suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol.
  • R 7 is -COC 1 -C 6 alkyl. Suitable examples include, but are not limited to, -COCH 3 . In certain embodiments, R 7 is -COOC 1 -C 6 alkyl. Suitable examples include, but are not limited to, -COOCH 3.
  • 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. 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. In certain embodiments, R 8 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 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.
  • R 8 is C 1 -C 6 alkylOH.
  • suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol.
  • R 8 is -COC 1 -C 6 alkyl. Suitable examples include, but are not limited to, -COCH 3 . In certain embodiments, R 8 is -COOC 1 -C 6 alkyl. Suitable examples include, but are not limited to, -COOCH 3.
  • 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.
  • R 9 is -CN.
  • R 9 is -OH.
  • R 9 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 9 is C 1 -C 6 alkylOC 1 -C 6 alkyl. In certain embodiments, R 9 is -COOH. In certain embodiments, R 9 is C 1 -C 6 alkylCOOH. In certain embodiments, R 9 is C 3 -C 6 cycloalkyl. Suitable examples of 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
  • 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 ) . In certain embodiments, R 9 is C 1 -C 6 alkylN (R 7 ) (R 8 ) .
  • R 10 is hydrogen, halogen, -CN, -OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, -COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, -CON (R 7 ) (R 8 ) orN (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. In certain embodiments, R 10 is C 1 -C 6 alkylOC 1 -C 6 alkyl. In certain embodiments, R 10 is -COOH. In certain embodiments, R 10 is C 1 -C 6 alkylCOOH. In certain embodiments, R 10 is C 3 -C 6 cycloalkyl. Suitable examples of 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
  • R 10 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 10 is C 1 -C 6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R 10 is -CON (R 7 ) (R 8 ) . In certain embodiments, R 10 is N (R 7 ) (R 8 ) . In certain embodiments, R 10 is C 1 -C 6 alkylN (R 7 ) (R 8 ) .
  • 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 ) orN (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. 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 C 1 -C 6 alkyl.
  • C 1 -C 6 alkyl groups include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1, 2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2, 2-dimethylbutyl, 1-ethylbutyl, 1, 1, 2-trimethylpropyl, 1, 2, 2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1
  • 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 ) . In certain embodiments, 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.
  • R 12 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine.
  • R 12 is -CN.
  • R 12 is -OH.
  • R 12 is C 1 -C 6 alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R 12 is C 1 -C 6 alkylOC 1 -C 6 alkyl. In certain embodiments, R 12 is -COOH. In certain embodiments, R 12 is C 1 -C 6 alkylCOOH. In certain embodiments, R 12 is C 3 -C 6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 12 is C 1 -C 6 alkyl.
  • C 1 -C 6 alkyl groups include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1, 2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2, 2-dimethylbutyl, 1-ethylbutyl, 1, 1, 2-trimethylpropyl, 1, 2, 2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1
  • 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 ) . In certain embodiments, R 12 is C 1 -C 6 alkylN (R 7 ) (R 8 ) .
  • R 12 is hydrogen, methyl, ethyl, methoxy, -OH or
  • R 12 is hydrogen or
  • R 13 is hydrogen, halogen, -CN, -OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, -COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, -CON (R 7 ) (R 8 ) , -N (R 7 ) (R 8 ) or C 1 -C 6 alkylN (R 7 ) (R 8 ) .
  • R 13 is hydrogen.
  • R 13 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine.
  • R 13 is -CN.
  • R 13 is -OH.
  • 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 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 13 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 13 is C 1 -C 6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R 13 is -CON (R 7 ) (R 8 ) . In certain embodiments, R 13 is N (R 7 ) (R 8 ) . In certain embodiments, R 13 is C 1 -C 6 alkylN (R 7 ) (R 8 ) .
  • R 13 is hydrogen, methyl, ethyl, methoxy, -OH or
  • R 13 is hydrogen or
  • R 12 and R 13 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkylOC 1 -C 6 alkyl, and 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 ) andC 1 -C 6 alkylN (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 C 1 -C 6 alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R 14 is C 1 -C 6 alkylOC 1 -C 6 alkyl. In certain embodiments, R 14 is -COOH. In certain embodiments, R 14 is C 1 -C 6 alkylCOOH. In certain embodiments, R 14 is C 3 -C 6 cycloalkyl. Suitable examples of 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 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 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 C 1 -C 6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R 14 is -CON (R 7 ) (R 8 ) . In certain embodiments, R 14 is N (R 7 ) (R 8 ) . In certain embodiments, R 14 is C 1 -C 6 alkylN (R 7 ) (R 8 ) .
  • 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 ) orN (R 7 ) (R 8 ) .
  • R 15 is hydrogen.
  • R 15 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine.
  • R 15 is -CN.
  • R 15 is -OH.
  • 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 C 1 -C 6 alkylOC 1 -C 6 alkyl. In certain embodiments, R 15 is -COOH. In certain embodiments, R 15 is C 1 -C 6 alkylCOOH. In certain embodiments, R 15 is C 3 -C 6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 15 is C 1 -C 6 alkyl.
  • C 1 -C 6 alkyl groups include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1, 2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2, 2-dimethylbutyl, 1-ethylbutyl, 1, 1, 2-trimethylpropyl, 1, 2, 2-trimethylpropyl, 1-ethyl-2- methylpropyl and 1-ethyl
  • 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 ) . In certain embodiments, R 15 is N (R 7 ) (R 8 ) . In certain embodiments, R 15 is C 1 -C 6 alkylN (R 7 ) (R 8 ) .
  • R 15 is methyl or ethyl.
  • R 16 is hydrogen, halogen, -CN, -OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, -COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, -CON (R 7 ) (R 8 ) orN (R 7 ) (R 8 ) .
  • R 16 is hydrogen.
  • R 16 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine.
  • R 16 is -CN.
  • R 16 is -OH.
  • R 16 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 16 is C 1 -C 6 alkylOC 1 -C 6 alkyl. In certain embodiments, R 16 is -COOH. In certain embodiments, R 16 is C 1 -C 6 alkylCOOH. In certain embodiments, R 16 is C 3 -C 6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 16 is C 1 -C 6 alkyl.
  • C 1 -C 6 alkyl groups include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1, 2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2, 2-dimethylbutyl, 1-ethylbutyl, 1, 1, 2-trimethylpropyl, 1, 2, 2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1
  • R 16 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 16 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 16 is -CON (R 7 ) (R 8 ) . In certain embodiments, R 16 is N (R 7 ) (R 8 ) . In certain embodiments, R 16 is C 1 -C 6 alkylN (R 7 ) (R 8 ) .
  • n is 0 or 1. In certain embodiments, m is 0. In certain embodiments, m is 1.
  • p is 0 or 1. In certain embodiments, p is 0. In certain embodiments, 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 ) alkylenecomprising 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 halogen.
  • A is a straight or branched, saturated or unsaturated (C 3 -C 10 ) alkylene or cycloalkyl (C 3 -C 10 ) alkylene, wherein one or more –CH 2 -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 –CH 2 -group.
  • A is a straight (C 3 -C 10 ) alkylene.
  • straight (C 3 -C 10 ) alkylenes include,
  • A is a branched (C 3 -C 10 ) alkylene.
  • Suitable branched (C 3 -C 10 ) alkylenes include but are not limited to:
  • A is a saturated (C 3 -C 10 ) alkylene. Examples include,
  • A is an unsaturated (C 3 -C 10 ) alkylene.
  • Suitable unsaturated (C 3 -C 10 ) alkylenes include any of the saturated (C 3 -C 10 ) alkylene, wherein hydrogens have been removed and one or more double or triplecovalent bonds exist between adjacent carbon atoms.
  • Examples of unsaturated (C 3 -C 10 ) alkylenes include, but are not limited to,
  • A is a straight cycloalkyl (C 3 -C 10 ) alkylene.
  • Suitable straight cycloalkyl (C 3 -C 10 ) alkylenes include a cycloalkyl (C 3 -C 10 ) 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 (C 3 -C 10 ) alkylene.
  • Suitable branched cycloalkyl (C 3 -C 10 ) alkylenes include a branched (C 3 -C 10 ) alkylene wherein two carbons in a chain are included in a (C 3 -C 10 ) cycloalkyl.
  • Examples of cycloalkyl (C 3 -C 10 ) alkylenes include, but are not limited to,
  • A is a saturated cycloalkyl (C 3 -C 10 ) alkylene.
  • saturated cycloalkyl (C 3 -C 10 ) alkylenes include, but are not limited to,
  • A is an unsaturatedcycloalkyl (C 3 -C 10 ) alkylene.
  • unsaturatedcyclo (C 3 -C 10 ) alkylenes include, but are not limited to,
  • A is an unsaturatedor saturated phenyl (C 3 -C 10 ) alkylene.
  • unsaturatedand saturated phenyl (C 3 -C 10 ) alkylenes include, but are not limited to,
  • one or more –CH 2 -groups in A are optionally and independently replaced with a moiety selected from the group consisting of O, S, NR, -CONR, NRCO, SO 2 , and SO 2 NR.
  • one or more –CH 2 -groups in A are optionally and independently replaced with a moiety selected from the group consisting of O, S and NH.
  • one or more –CH 2 -groups in A are optionally and independently replaced with O.
  • one or more –CH 2 -groups in A are optionally and independently replaced with S.
  • one or more –CH 2 -groups in A are optionally and independently replaced with NR.
  • 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. In other embodiments, one or more –CH 2 -groups in A are optionally and independently replaced withSO 2 . In other embodiments, one or more –CH 2 -groups in A are optionally and independently replaced withand SO 2 NR. R will be described in further detail below.
  • R is hydrogen, C 1 -C 6 alkylCOOH, -COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, -COC 1 -C 6 alkyl or -COOC 1 -C 6 alkyl.
  • R 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 is hydrogen. In certain embodiments, R is C 1 -C 6 alkylCOOH. In certain embodiments, R is -COOH. In certain embodiments, R is C 3 -C 6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R is C 1 -C 6 alkyl.
  • C 1 -C 6 alkyl groups include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1, 2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2, 2-dimethylbutyl, 1-ethylbutyl, 1, 1, 2-trimethylpropyl, 1, 2, 2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1-methylpropyl.
  • R 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.
  • R is C 1 -C 6 alkylOH.
  • suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol.
  • R is -COC 1 -C 6 alkyl. Suitable examples include, but are not limited to, -COCH 3 . In certain embodiments, Ris -COOC 1 -C 6 alkyl. Suitable examples include, but are not limited to, -COOCH 3.
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • one or more of the hydrogens along A is replaced with a halogen.
  • suitable halogens include chlorine, bromine, fluorine and iodine.
  • A is
  • 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 ) alkylenecomprising 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 halogen;
  • 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 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 9 ;
  • Z is CR 11 or N, wherein when Z is N, V is CR 10 and Y is CR 9 ;
  • each occurrence of R is independently hydrogen, C 1 -C 6 alkylCOOH, -COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, -COC 1 -C 6 alkyl or -COOC 1 -C 6 alkyl;
  • R 1 is hydrogen, halogen, -CN, -OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, -COOH, oxo, -COOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkylC 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, -C 1 -C 6 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, 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 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 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 5 is hydrogen, halogen, -CN, -OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, -COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, -CON (R 7 ) (R 8 ) , -N (R 7 ) (R 8 ) or C 1 -C 6 alkylN (R 7 ) (R 8 ) ;
  • R 6 is hydrogen, halogen, -CN, -OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, -COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, -CON (R 7 ) (R 8 ) , -N (R 7 ) (R 8 ) or C 1 -C 6 alkylN (R 7 ) (R 8 ) ;
  • each occurrence of R 7 is independently 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;
  • each occurrence of R 8 is independently hydrogen, C 1 -C 6 alkylCOOH, -COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, -COC 1 -C 6 alkyl or -COOC 1 -C 6 alkyl;
  • R 9 is hydrogen, halogen, -CN, -OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, -COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, -CON (R 7 ) (R 8 ) , -N (R 7 ) (R 8 ) or C 1 -C 6 alkylN (R 7 ) (R 8 ) ;
  • R 10 is hydrogen, halogen, -CN, -OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, -COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, -CON (R 7 ) (R 8 ) , -N (R 7 ) (R 8 ) or C 1 -C 6 alkylN (R 7 ) (R 8 ) ;
  • R 11 is hydrogen, halogen, -CN, -OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, -COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, -CON (R 7 ) (R 8 ) , -N (R 7 ) (R 8 ) or C 1 -C 6 alkylN (R 7 ) (R 8 ) ;
  • R 12 is hydrogen, halogen, -CN, -OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, -COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, -CON (R 7 ) (R 8 ) , -N (R 7 ) (R 8 ) or C 1 -C 6 alkylN (R 7 ) (R 8 ) ;
  • R 13 is hydrogen, halogen, -CN, -OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, -COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, -CON (R 7 ) (R 8 ) , -N (R 7 ) (R 8 ) or C 1 -C 6 alkylN (R 7 ) (R 8 ) ;
  • each occurrence of R 14 is independently selected from the group consisting of hydrogen, halogen, -CN, -OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, -COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, -CON (R 7 ) (R 8 ) , -N (R 7 ) (R 8 ) and C 1 -C 6 alkylN (R 7 ) (R 8 ) ;
  • R 15 is hydrogen, halogen, -CN, -OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, -COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, -CON (R 7 ) (R 8 ) , -N (R 7 ) (R 8 ) or C 1 -C 6 alkylN (R 7 ) (R 8 ) ;
  • each occurrence of R 16 is independently selected from the group consisting of hydrogen, halogen, -CN, -OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, -COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, -CON (R 7 ) (R 8 ) , -N (R 7 ) (R 8 ) and C 1 -C 6 alkylN (R 7 ) (R 8 ) ;
  • l is 0 or 1;
  • n 0 or 1
  • n 1, 2, 3 or 4;
  • p 0 or 1.
  • Q is C (R 16 ) 2 , O, S, SO, SO 2 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 . In certain embodiments described herein, 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 . In other embodiments X is CH 2 , O, S, SO, SO 2 or NH. In certain embodiments, X is CH 2 . In lymphmbodiments 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 SO 2 . In certain embodiments described herein, X is NH.
  • 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 .
  • 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 .
  • 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.
  • 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
  • R 1 is halogen.
  • suitable halogens include chlorine, bromine, fluorine and iodine.
  • R 1 is -CN.
  • R 1 is -OH.
  • R 1 is C 1 -C 6 alkoxy.
  • Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
  • R 1 is C 1 -C 6 alkylOC 1 -C 6 alkyl.
  • R 1 is C 1 -C 6 alkylCOOH.
  • R 1 is -COOH.
  • R 1 is an oxo group.
  • R 1 is -COOC 1 -C 6 alkyl.
  • R 1 is C 1 -C 6 alkylCOOC 1 -C 6 alkyl.
  • R 1 is C 3 -C 6 cycloalkyl.
  • Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 1 is C 1 -C 6 alkylC 3 -C 6 cycloalkyl.
  • Suitable examples of cycloalkyls include, but are not limited to
  • R 1 is C 1 -C 6 alkyl.
  • C 1 -C 6 alkyl groups include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1, 2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2, 2-dimethylbutyl, 1-ethylbutyl, 1, 1, 2-trimethylpropyl, 1, 2, 2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1
  • R 1 is C 1 -C 6 alkylOhaloC 1 -C 6 alkyl.
  • Suitable examples of C 1 -C 6 alkylOhaloC 1 -C 6 alkyls include, but are not limited to,
  • 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.
  • 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 ) . In certain embodiments, R 1 is N (R 7 ) (R 8 ) . In certain embodiments, R 1 is C 1 -C 6 alkylN (R 7 ) (R 8 ) , wherein R 7 and R 8 will be described in detail below.
  • R 1 is hydrogen, bromine, fluorine, chlorine, methyl, -OH, halogen, -CNoxo, 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
  • R 2 is halogen.
  • suitable halogens include chlorine, bromine, fluorine and iodine.
  • R 2 is -CN.
  • R 2 is -OH.
  • R 2 is C 1 -C 6 alkoxy.
  • Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
  • R 2 is C 1 -C 6 alkylOC 1 -C 6 alkyl.
  • R 2 is C 1 -C 6 alkylCOOH.
  • R 2 is -COOH
  • R 2 is an oxo group.
  • R 2 is -COOC 1 -C 6 alkyl.
  • R 2 is C 1 -C 6 alkylCOOC 1 -C 6 alkyl.
  • R 2 is C 3 -C 6 cycloalkyl.
  • Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 2 is C 1 -C 6 alkylC 3 -C 6 cycloalkyl.
  • Suitable examples of cycloalkyls include, but are not limited to
  • R 2 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
  • R 2 is C 1 -C 6 alkylOhaloC 1 -C 6 alkyl.
  • Suitable examples of C 1 -C 6 alkylOhaloC 1 -C 6 alkyls include, but are not limited to,
  • 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.
  • 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 ) . In certain embodiments, R 2 is N (R 7 ) (R 8 ) . In certain embodiments, R 2 is C 1 -C 6 alkylN (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, -COOCH 2 CH 3 or trifluoromethyl.
  • R 1 and R 2 are bothhydrogen. In certain embodiments, R 1 is -OH and R 2 is hydrogen.
  • 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 or when taken with R 4
  • 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 includefluorine, chlorine, bromine, and iodine. In certain embodiments, R 3 is -CN. In certain embodiments, R 3 is -OH.
  • R 3 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 3 is C 1 -C 6 alkylOC 1 -C 6 alkyl. In certain embodiments, R 3 is -COOH. In certain embodiments, R 3 is C 1 -C 6 alkylCOOH. In certain embodiments, R 3 is C 3 -C 6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • 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
  • 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.
  • R 3 is C 1 -C 6 alkylOH.
  • suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol.
  • R 3 is -CON (R 7 ) (R 8 ) .
  • N (R 7 ) (R 8 ) include, but are not limited to, -CONH 2 and -CON (CH 3 ) 2 .
  • R 3 is N (R 7 ) (R 8 ) .
  • Suitable examples of N (R 7 ) (R 8 ) include, but are not limited to, NH 2 and N (CH 3 ) 2 .
  • R 3 is C 1 -C 6 alkylN (R 7 ) (R 8 ) .
  • Suitable examples of C 1 -C 6 alkylN (R 7 ) (R 8 ) include, but are not limited to, R 7 and R 8 are discussed in further detail below.
  • R 3 is C 1 -C 6 alkylOhaloC 1 -C 6 alkyl.
  • Suitable examples of haloalkyls include, but are not limited to,
  • R 3 is C 1 -C 6 alkyl (OCH 2 CH 2 ) n N (R 7 ) (R 8 ) .
  • R 7 , R 8 and n are discussed in detail below.
  • Suitable examples of C 1 -C 6 alkyl (OCH 2 CH 2 ) n N (R 7 ) (R 8 ) include, but are not limited to,
  • 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.
  • R 3 is taken with R 4 and forms a C 3 -C 6 cycloalkyl or C 3 -C 6 heterocycloalkyl. In certain embodiments, R 3 is taken with R 4 and forms a C 3 -C 6 cycloalkyl. 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 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 3 is hydrogen, fluorine, methyl, ethyl, -OH, methoxy, -CON (CH 3 ) 2 ,
  • R 3 is hydrogen, methyl, ethyl or
  • 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 or when taken with R 3
  • 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 includefluorine, chlorine, bromine, or iodine. In certain embodiments, R 4 is -CN. In certain embodiments, R 4 is -OH.
  • R 4 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 4 is C 1 -C 6 alkylOC 1 -C 6 alkyl. In certain embodiments, R 4 is -COOH. In certain embodiments, R 4 is C 1 -C 6 alkylCOOH. In certain embodiments, R 4 is C 3 -C 6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • 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
  • 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 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 4 is -CON (R 7 ) (R 8 ) .
  • Suitable examples of CON (R 7 ) (R 8 ) include, but are not limited to, -CONH 2 and -CON (CH 3 ) 2 .
  • R 4 is N (R 7 ) (R 8 ) .
  • Suitable examples of N (R 7 ) (R 8 ) include, but are not limited to, NH 2 and N (CH 3 ) 2 .
  • R 4 is C 1 -C 6 alkylN (R 7 ) (R 8 ) .
  • Suitable examples of C 1 -C 6 alkylN (R 7 ) (R 8 ) include, but are not limited to, R 7 and R 8 are discussed in further detail below.
  • R 4 is C 1 -C 6 alkylOhaloC 1 -C 6 alkyl.
  • Suitable examples of 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. In certain embodiments, 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. In certain embodiments, 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. In certain embodiments, R 4 is hydrogen, methyl, ethyl or In certain embodiments, R 4 is taken with R 3 to form oxetanyl. In certain embodiments, 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, 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 5 is hydrogen
  • R 5 is halogen.
  • suitable halogens include chlorine, bromine, fluorine and iodine.
  • R 5 is -CN.
  • R 5 is -OH.
  • R 5 is C 1 -C 6 alkoxy.
  • Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
  • R 5 is C 1 -C 6 alkylOC 1 -C 6 alkyl.
  • R 5 is C 1 -C 6 alkylCOOH.
  • R 5 is -COOH.
  • R 5 is an oxo group.
  • R 5 is -COOC 1 -C 6 alkyl.
  • R 5 is C 1 -C 6 alkylCOOC 1 -C 6 alkyl.
  • R 5 is C 3 -C 6 cycloalkyl.
  • Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 5 is C 1 -C 6 alkylC 3 -C 6 cycloalkyl.
  • Suitable examples of cycloalkyls include, but are not limited to
  • 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
  • R 5 is C 1 -C 6 alkylOhaloC 1 -C 6 alkyl.
  • Suitable examples of C 1 -C 6 alkylOhaloC 1 -C 6 alkyls include, but are not limited to,
  • 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.
  • 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 ) . In certain embodiments, R 5 is N (R 7 ) (R 8 ) . In certain embodiments, 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, 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 6 is hydrogen
  • R 6 is halogen.
  • suitable halogens include chlorine, bromine, fluorine and iodine.
  • R 6 is -CN.
  • R 6 is -OH.
  • R 6 is C 1 -C 6 alkoxy.
  • Suitable alkoxys include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
  • R 6 is C 1 -C 6 alkylOC 1 -C 6 alkyl.
  • R 6 is C 1 -C 6 alkylCOOH.
  • R 6 is -COOH.
  • R 6 is an oxo group.
  • R 6 is -COOC 1 -C 6 alkyl.
  • R 6 is C 1 -C 6 alkylCOOC 1 -C 6 alkyl.
  • R 6 is C 3 -C 6 cycloalkyl.
  • Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • 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 C 1 -C 6 alkyl.
  • C 1 -C 6 alkyl groups include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1, 2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2, 2-dimethylbutyl, 1-ethylbutyl, 1, 1, 2-trimethylpropyl, 1, 2, 2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1
  • R 6 is C 1 -C 6 alkylOhaloC 1 -C 6 alkyl.
  • Suitable examples of C 1 -C 6 alkylOhaloC 1 -C 6 alkyls include, but are not limited to,
  • R 6 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.
  • R 6 is C 1 -C 6 alkylOH.
  • Suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol.
  • R 6 is -CON (R 7 ) (R 8 ) . In certain embodiments, R 6 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.
  • 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. In certain embodiments, R 7 is C 1 -C 6 alkylCOOH. In certain embodiments, R 7 is -COOH. In certain embodiments, R 7 is C 3 -C 6 cycloalkyl. Suitable examples of 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 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.
  • R 7 is C 1 -C 6 alkylOH.
  • suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol.
  • R 7 is -COC 1 -C 6 alkyl. Suitable examples include, but are not limited to, -COCH 3 . In certain embodiments, R 7 is -COOC 1 -C 6 alkyl. Suitable examples include, but are not limited to, -COOCH 3.
  • 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. 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. In certain embodiments, R 8 is C 1 -C 6 alkyl.
  • C 1 -C 6 alkyl groups include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1, 2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1, 2-dimethylbutyl, 2, 2-dimethylbutyl, 1-ethylbutyl, 1, 1, 2-trimethylpropyl, 1, 2, 2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1-methylpropyl.
  • 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.
  • R 8 is C 1 -C 6 alkylOH.
  • suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol.
  • R 8 is -COC 1 -C 6 alkyl. Suitable examples include, but are not limited to, -COCH 3 . In certain embodiments, R 8 is -COOC 1 -C 6 alkyl. Suitable examples include, but are not limited to, -COOCH 3.
  • 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 ) orN (R 7 ) (R 8 ) .
  • R 9 is hydrogen.
  • R 9 is halogen. Suitable halogens includefluorine, chlorine, bromine, or iodine.
  • R 9 is -CN.
  • R 9 is -OH.
  • R 9 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 9 is C 1 -C 6 alkylOC 1 -C 6 alkyl. In certain embodiments, R 9 is -COOH. In certain embodiments, R 9 is C 1 -C 6 alkylCOOH. In certain embodiments, R 9 is C 3 -C 6 cycloalkyl. Suitable examples of 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 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 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 ) . In certain embodiments, R 9 is C 1 -C 6 alkylN (R 7 ) (R 8 ) .
  • R 10 is hydrogen, halogen, -CN, -OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, -COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, -CON (R 7 ) (R 8 ) orN (R 7 ) (R 8 ) .
  • R 10 is hydrogen.
  • R 10 is halogen. Suitable halogens includefluorine, 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. In certain embodiments, R 10 is C 1 -C 6 alkylOC 1 -C 6 alkyl. In certain embodiments, R 10 is -COOH. In certain embodiments, R 10 is C 1 -C 6 alkylCOOH. In certain embodiments, R 10 is C 3 -C 6 cycloalkyl. Suitable examples of 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 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 10 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 10 is C 1 -C 6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R 10 is -CON (R 7 ) (R 8 ) . In certain embodiments, R 10 is N (R 7 ) (R 8 ) . In certain embodiments, R 10 is C 1 -C 6 alkylN (R 7 ) (R 8 ) .
  • 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 ) orN (R 7 ) (R 8 ) .
  • R 11 is hydrogen.
  • R 11 is halogen. Suitable halogens includefluorine, 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. 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 C 1 -C 6 alkyl.
  • C 1 -C 6 alkyl groups include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1, 2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2, 2-dimethylbutyl, 1-ethylbutyl, 1, 1, 2-trimethylpropyl, 1, 2, 2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1
  • 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 ) . In certain embodiments, 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.
  • R 12 is halogen. Suitable halogens includefluorine, chlorine, bromine, andiodine.
  • R 12 is -CN.
  • R 12 is -OH.
  • R 12 is C 1 -C 6 alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R 12 is C 1 -C 6 alkylOC 1 -C 6 alkyl. In certain embodiments, R 12 is -COOH. In certain embodiments, R 12 is C 1 -C 6 alkylCOOH. In certain embodiments, R 12 is C 3 -C 6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 12 is C 1 -C 6 alkyl.
  • C 1 -C 6 alkyl groups include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1, 2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2, 2-dimethylbutyl, 1-ethylbutyl, 1, 1, 2-trimethylpropyl, 1, 2, 2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1
  • 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 ) . In certain embodiments, R 12 is C 1 -C 6 alkylN (R 7 ) (R 8 ) .
  • R 12 is hydrogen, methyl, ethyl, methoxy, -OH or
  • R 12 is hydrogen or
  • R 13 is hydrogen, halogen, -CN, -OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, -COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, -CON (R 7 ) (R 8 ) , -N (R 7 ) (R 8 ) or C 1 -C 6 alkylN (R 7 ) (R 8 ) .
  • R 13 is hydrogen.
  • R 13 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine.
  • R 13 is -CN.
  • R 13 is -OH.
  • 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 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 13 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 13 is C 1 -C 6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R 13 is -CON (R 7 ) (R 8 ) . In certain embodiments, R 13 is N (R 7 ) (R 8 ) . In certain embodiments, R 13 is C 1 -C 6 alkylN (R 7 ) (R 8 ) .
  • R 13 is hydrogen, methyl, ethyl, methoxy, -OH or
  • R 13 is hydrogen or
  • R 12 and R 13 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkylOC 1 -C 6 alkyl, and 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 ) andC 1 -C 6 alkylN (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 C 1 -C 6 alkoxy. Suitable alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. In certain embodiments, R 14 is C 1 -C 6 alkylOC 1 -C 6 alkyl. In certain embodiments, R 14 is -COOH. In certain embodiments, R 14 is C 1 -C 6 alkylCOOH. In certain embodiments, R 14 is C 3 -C 6 cycloalkyl. Suitable examples of 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 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 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 C 1 -C 6 alkylOH. Examples of suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol. In certain embodiments, R 14 is -CON (R 7 ) (R 8 ) . In certain embodiments, R 14 is N (R 7 ) (R 8 ) . In certain embodiments, R 14 is C 1 -C 6 alkylN (R 7 ) (R 8 ) .
  • 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 ) orN (R 7 ) (R 8 ) .
  • R 15 is hydrogen.
  • R 15 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine.
  • R 15 is -CN.
  • R 15 is -OH.
  • 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 C 1 -C 6 alkylOC 1 -C 6 alkyl. In certain embodiments, R 15 is -COOH. In certain embodiments, R 15 is C 1 -C 6 alkylCOOH. In certain embodiments, R 15 is C 3 -C 6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 15 is C 1 -C 6 alkyl.
  • C 1 -C 6 alkyl groups include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1, 2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2, 2-dimethylbutyl, 1-ethylbutyl, 1, 1, 2-trimethylpropyl, 1, 2, 2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1
  • 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 ) . In certain embodiments, R 15 is N (R 7 ) (R 8 ) . In certain embodiments, R 15 is C 1 -C 6 alkylN (R 7 ) (R 8 ) .
  • R 15 is methyl or ethyl.
  • R 16 is hydrogen, halogen, -CN, -OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, -COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, -CON (R 7 ) (R 8 ) orN (R 7 ) (R 8 ) .
  • R 16 is hydrogen.
  • R 16 is halogen. Suitable halogens include fluorine, chlorine, bromine, or iodine.
  • R 16 is -CN.
  • R 16 is -OH.
  • R 16 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 16 is C 1 -C 6 alkylOC 1 -C 6 alkyl. In certain embodiments, R 16 is -COOH. In certain embodiments, R 16 is C 1 -C 6 alkylCOOH. In certain embodiments, R 16 is C 3 -C 6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 16 is C 1 -C 6 alkyl.
  • C 1 -C 6 alkyl groups include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1, 2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2, 2-dimethylbutyl, 1-ethylbutyl, 1, 1, 2-trimethylpropyl, 1, 2, 2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1
  • R 16 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 16 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 16 is -CON (R 7 ) (R 8 ) . In certain embodiments, R 16 is N (R 7 ) (R 8 ) . In certain embodiments, R 16 is C 1 -C 6 alkylN (R 7 ) (R 8 ) .
  • l is 0 or 1. In certain embodiments, l is 0. In certain embodiments, l is 1.
  • n is 0 or 1. In certain embodiments, m is 0. In certain embodiments, m is 1.
  • p is 0 or 1. In certain embodiments, p is 0. In certain embodiments, 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.
  • n 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, C 1 -C 6 alkoxy and C 1 -C 6 alkyl.
  • 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, C 1 -C 6 alkoxy and C 1 -C 6 alkyl.
  • 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 ) alkylenecomprising 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 halogen.
  • A is a straight or branched, saturated or unsaturated (C 3 - C 10 ) alkylene or cycloalkyl (C 3 -C 10 ) alkylene, wherein one or more –CH 2 -groups in A are optionally and independently replaced with a moiety selected from the group consisting of O, S and NH. In certain embodiments, A will always have at least one –CH 2 -group.
  • A is a straight (C 3 -C 10 ) alkylene.
  • straight (C 3 -C 10 ) alkylenes include,
  • A is a branched (C 3 -C 10 ) alkylene.
  • Suitable branched (C 3 -C 10 ) alkylenes include but are not limited to:
  • A is a saturated (C 3 -C 10 ) alkylene. Examples include,
  • A is an unsaturated (C 3 -C 10 ) alkylene.
  • Suitable unsaturated (C 3 -C 10 ) alkylenes include any of the saturated (C 3 -C 10 ) alkylene, wherein hydrogens have been removed and one or more double or triplecovalent bonds exist between adjacent carbon atoms.
  • Examples of unsaturated (C 3 -C 10 ) alkylenes include, but are not limited to,
  • A is a straight cycloalkyl (C 3 -C 10 ) alkylene.
  • Suitable straight cycloalkyl (C 3 -C 10 ) alkylenes include a cycloalkyl (C 3 -C 10 ) 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 (C 3 -C 10 ) alkylene.
  • Suitable branched cycloalkyl (C 3 -C 10 ) alkylenes include a branched (C 3 -C 10 ) alkylene wherein two carbons in a chain are included in a (C 3 -C 10 ) cycloalkyl.
  • Examples of cycloalkyl (C 3 -C 10 ) alkylenes include, but are not limited to,
  • A is a saturated cycloalkyl (C 3 -C 10 ) alkylene.
  • saturated cycloalkyl (C 3 -C 10 ) alkylenes include, but are not limited to,
  • A is an unsaturatedcycloalkyl (C 3 -C 10 ) alkylene.
  • unsaturatedcycloalkyl (C 3 -C 10 ) alkylenes include, but are not limited to,
  • A is an unsaturatedor saturated phenyl (C 3 -C 10 ) alkylene.
  • unsaturatedand saturated phenyl (C 3 -C 10 ) alkylenes include, but are not limited to,
  • one or more –CH 2 -groups in A are optionally and independently replaced with a moiety selected from the group consisting of O, S, NR, -CONR, NRCO, SO 2 , and SO 2 NR.
  • one or more –CH 2 -groups in A are optionally and independently replaced with a moiety selected from the group consisting of O, S and NH.
  • one or more –CH 2 -groups in A are optionally and independently replaced with O.
  • one or more –CH 2 -groups in A are optionally and independently replaced withS.
  • one or more –CH 2 -groups in A are optionally and independently replaced with NR.
  • 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. In other embodiments, one or more –CH 2 -groups in A are optionally and independently replaced withSO 2 . In other embodiments, one or more –CH 2 -groups in A are optionally and independently replaced withand SO 2 NR. R will be described in further detail below.
  • R is hydrogen, C 1 -C 6 alkylCOOH, -COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, -COC 1 -C 6 alkyl or -COOC 1 -C 6 alkyl.
  • R 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 is hydrogen. In certain embodiments, R is C 1 -C 6 alkylCOOH. In certain embodiments, R is -COOH. In certain embodiments, R is C 3 -C 6 cycloalkyl. Suitable examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certain embodiments, R is C 1 -C 6 alkyl.
  • C 1 -C 6 alkyl groups include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1, 2-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2, 2-dimethylbutyl, 1-ethylbutyl, 1, 1, 2-trimethylpropyl, 1, 2, 2-trimethylpropyl, 1-ethyl-2-methylpropyl and 1-ethyl-1-methylpropyl.
  • R 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.
  • R is C 1 -C 6 alkylOH.
  • suitable alcohols include, but are not limited to, methanol, ethanol, propanol, butanol and iso-butanol.
  • R is -COC 1 -C 6 alkyl. Suitable examples include, but are not limited to, -COCH 3 . In certain embodiments, Ris -COOC 1 -C 6 alkyl. Suitable examples include, but are not limited to, -COOCH 3.
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • one or more of the hydrogens along A can be replaced with a halogen.
  • 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 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.
  • compounds described herein include:
  • alkyl refers to “alkyl” as well as the “alkyl” portion of “hydroxyalkyl” , “haloalkyl” , “arylalkyl-” , “alkylaryl-” , “alkoxy” etc.
  • each variable is selected independently of the others unless otherwise indicated.
  • “Drug resistant” means, inconnection 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.
  • Non-human animals include those research animals andcompanion animals such as mice, rats, primates, monkeys, chimpanzees, great apes, dogs, and house cats.
  • “Pharmaceuticalcomposition” means acomposition suitable for administration to a patient. Suchcompositions maycontain the 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.
  • pharmaceutically acceptable carriers or diluents include but not limited to, ethanol, sulfate, a pharmaceutically acceptable carriers or diluents.
  • pharmaceutically acceptable carriers or diluents is also intended to encompass both the bulkcomposition and individual dosage unitscomprised of one or more (e.g., two) pharmaceutically active agents such as, for example, acompound 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 bulkcomposition and each individual dosage unit cancontain fixed amounts of the afore-said "more than one pharmaceutically active agents" .
  • the bulkcomposition is materialthat 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.
  • the herein-described method of treating a patient by administering a pharmaceuticalcomposition of the present invention is also intended to encompass the administration of the afore-said bulkcomposition 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.
  • - (C 1 -C 5 ) alkylene would include, e.g., -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH (CH 3 ) CH 2 -or -CH 2 CH 2 CH 2 CH 2 CH 2 -.
  • 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 triplecovalent bonds within the chain.
  • a cycloalkylalkylene means a divalent hydrocarbon chain radical having the stated number of carbon atoms and a cycloalkyl moiety within the chain.
  • Aphenylalkylene means a divalent hydrocarbon chain radical having the stated number of carbon atoms and a phenyl group within the chain.
  • Alkyl means an aliphatic hydrocarbon group which may be straight or branched andcomprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groupscontain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groupscontain about 1 toabout 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 systemcomprising 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 systemcomprising about 3 to about 12 carbon atoms, preferably about 3 to about 10 carbon atoms. Preferred cycloalkyl ringscontain 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 systemcomprising 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 incombination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclylscontain 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 alsoconsidered 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 thecorresponding N-oxide, S-oxide or S, S-dioxide.
  • oxygen when it appears in a definition of a variable in a general structure described herein, refers to thecorresponding N-oxide, S-oxide, or S, S-dioxide.
  • pyrrolidinone or pyrrolidone
  • the term “monocyclic heterocycloalkyl” refers monocyclic versions of the heterocycloalkyl moietiesdescribed herein and include a 4-to 7-membered monocyclic heterocycloalkyl groupscomprising 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 stablecompound. combinations of substituents and/or variables are permissible only if suchcombinations result in stable compounds.
  • stablecompound or “stable structure” is meant acompound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • 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.
  • 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 thecompound. 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, e.g.,
  • the compoundsuseful in the methods of the invention, and/orcompositionscomprising them useful in said methods are present in isolated and/or purified form.
  • purified refers to the physical state of saidcompound after being isolated from a synthetic process (e.g. from a reaction mixture) , or natural source orcombination thereof.
  • purified in purified form or “in isolated and purified form” for acompound refers to the physical state of saidcompound (or a tautomer or stereoisomer thereof, or pharmaceutically acceptable salt or solvate of saidcompound, 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.
  • protecting groups When a functional group in acompound is termed “protected” , this means that the group is in modified form to preclude undesired side reactions at the protected site when thecompound 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.
  • 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 acompound (e.g., a drug precursor) that is transformed in vivo to yield acompound of the invention or a pharmaceutically acceptable salt, hydrate or solvate of thecompound. The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes) , such as, for example, through hydrolysis in blood.
  • prodrugs are used 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.
  • a prodrug cancomprise 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- (alkoxycarbonyloxy) ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl) aminomethyl having from 3 to 9 carbon atoms, 1- (N-(alkoxycarbony
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (C 1 -C 6 ) alkanoyloxymethyl, 1- ( (C 1 -C 6 ) alkanoyloxy) ethyl, 1-methyl-1- ( (C 1 -C 6 ) alkanoyloxy) ethyl, (C 1 -C 6 ) alkoxycarbonyloxymethyl, N- (C 1 -C 6 ) alkoxycarbonylaminomethyl, succinoyl, (C 1 -C 6 ) alkanoyl, ⁇ -amino (C 1 -C 4 ) alkanyl, arylacyl and ⁇ -aminoacyl, or ⁇ -aminoacyl- ⁇ -aminoacyl, where each ⁇ -aminoacyl group is independently selected from the naturally occurring L-a 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 (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 )
  • One or more compoundsused 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 acompound of the invention with one or more solvent molecules. This physical association involves varying degrees of ionic andcovalentbonding, 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 compoundsused in the methods of the invention may optionally beconverted to a solvate.
  • Preparation of solvates is generally known.
  • 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 inventivecompound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, andcooling 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 ofcompound or acompositionused in the methods of the present invention effective in inhibiting the above-noted diseases or enzyme activity and thus producing the desiredtherapeutic, 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.
  • zwitterions when acompound of the inventioncontains 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 compoundsused in the methods of the invention may be formed, for example, by reacting acompound 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 nitrogencontaining 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
  • 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, C 1-4 alkyl, or C 1-4 alkoxy or amino) ; (2) sulfonate esters, such as alkyl-or aralkylsulfonyl (for example, methanesulfonyl) ; (3) amino acid
  • another embodiment provides tautomers of the compounds of the invention to be used in the methods herein, and salts, solvates, esters and prodrugs of saidtautomers. It shall be understood that all tautomeric forms of such compounds are within the scope of the compoundsused 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 compoundsused in the methods of the invention maycontain asymmetric orchiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compoundsused in the methods of the invention as well as mixtures thereof, including racemic mixtures, form part of the present invention.
  • the present invention embraces use of all geometric and positional isomers. For example, if acompoundused 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.
  • 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, bychromatography and/or fractional crystallization.
  • Enantiomers can be separated byconverting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically activecompound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride) , separating the diastereomers andconverting (e.g., hydrolyzing) the individual diastereomers to thecorresponding pure enantiomers.
  • an appropriate optically activecompound e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride
  • some of the compoundsused in the methods of the invention may be atropisomers (e.g., substituted biaryls) and areconsidered as part of this invention. Enantiomers can also be separated by use of chiral HPLCcolumn.
  • All stereoisomers for example, geometric isomers, optical isomers and the like
  • the compoundsused 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
  • 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, arecontemplated as embodiments within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl) .
  • 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 Rconfiguration 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.
  • isotopically-labelled compoundsto 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 that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • Certain isotopically-labelled compounds of the invention are useful incompound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) 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.
  • 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 acompound useful as a standard for characterization of biological samples.
  • Isotopically-enriched compounds of the invention can be prepared without undue experimentation byconventional 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.
  • the present invention is directed to methods of treatment of Plasmodium infectionscomprising administering to a subject in need thereof acompound described herein, or a pharmaceutically acceptable salt thereof. More specifically, the methods of the inventioncomprise administration of acompound of any of Formulas (I) – (VIII) , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compounds of any of Formulas (I) – (VIII) , or a pharmaceutically acceptable salt thereof, are administered in the form of a pharmaceuticalcomposition, furthercomprising 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 whichcomprises administering to a subject in need of such treatment a therapeutically effective amount of acompound, or a pharmaceutically acceptable salt thereof, saidcompound having any ofstructural Formulas (I) – (VIII) described in the Summary of the Invention.
  • the compounds of any of Formulas (I) , - (VIII) or pharmaceutically acceptable salts thereof are administered with a pharmaceutically acceptable carrier, as a pharmaceuticalcomposition. Also provided herein are various embodiments of these methods, as described, infra.
  • the invention also relates to the use of acompound 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 acompound of Formulae (I) - (VIII) or a pharmaceutically acceptable salt thereof inthe 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 whichcomprises administering to a subject in need of such treatment a therapeutically effective amount of acompound, or a pharmaceutically acceptable salt thereof, saidcompound 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 pharmaceuticalcomposition.
  • a pharmaceutically acceptable carrier as a pharmaceuticalcomposition.
  • the invention also relates to the use of acompound 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 acompound 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 whichcomprises administering to a subject in need of such treatment a therapeutically effective amount of acompound, or a pharmaceutically acceptable salt thereof, saidcompound 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 pharmaceuticalcomposition.
  • a pharmaceutically acceptable carrier as a pharmaceuticalcomposition.
  • the invention also relates to the use of acompound 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 acompound 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 thecondition, ameliorate the symptoms of thecondition, cause regression of thecondition, cure thecondition, or otherwise improve the general well-being of a subject afflicted with, or at risk of, contracting thecondition.
  • 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 orcomposition 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
  • another embodiment provides methods for the treatment of malaria or for the treatment of Plasmodium infection, comprising administration ofcombinationscomprising an amount of at least onecompound 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.
  • described herein are methods for the treatment of malaria or for the treatment of Plasmodium infection, comprising administration ofcombinationscomprising an amount of at least onecompound 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 ofcombinationscomprising an amount of at least onecompound 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 beconfirmed by several pharmacological assays.
  • Suitable dosages and dosage forms of the compoundsused in the methods of the invention 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 thecompound of the invention. In one embodiment, the dosage is from about 0.01 to about 25 mg/kg of body weight/day of acompound of theinvention, or a pharmaceutically acceptable salt or solvate of saidcompound.
  • the quantity of activecompound 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 clinicianconsidering 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 incombination with a pharmaceutically acceptable carrier, such as an inertcompressed gas, e.g. nitrogen.
  • a pharmaceutically acceptable carrier such as an inertcompressed gas, e.g. nitrogen.
  • solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for either oral or parenteral administration.
  • liquid forms include solutions, suspensions and emulsions.
  • compositionscomprising acompound of Formulae (I) - (VIII) , or a pharmaceutically acceptable salt thereofformulated for transdermal delivery 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 areconventional in the art for this purpose.
  • compositionscomprising acompound of Formulae (I) - (VIII) , or a pharmaceutically acceptable salt thereofformulated for subcutaneous delivery Another embodiment provides for use ofcompositions suitable for oral delivery.
  • pharmaceutical preparationcomprising one or more compounds of Formulae (I) - (VIII) , or a pharmaceutically acceptable salt thereofto be prepared in a unit dosage form. In such forms, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the activecomponent, e.g., an effective amount to achieve the desired purpose.
  • the compoundsused in the methods of this invention i.e. the compounds of Formulae (I) - (VIII)
  • compounds of the invention may be administered together or 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.
  • suchcombination products employ the compoundsof Formulae (I) - (VIII) , or a pharmaceutically acceptable salt thereofwithin the dosage range described herein and the other pharmaceutically active agent or treatment within its dosage range.
  • compositions comprising acompound of the invention, either as the neat chemical or optionally furthercomprising additional ingredients.
  • Suchcompositions arecontemplated for preparation and use alone or incombination therapy.
  • 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 becomprised 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 variouscompositions may be found in A. Gennaro (ed. ) , Remington’s Pharmaceutical Sciences, 18 th Edition, (1990) , Mack PublishingCo., Easton, Pennsylvania.
  • Non-limiting examples of additional drugs and active agents useful incombination therapies for the treatment of malaria include the following: (Novartis International AG, Basel, Switzerland; artemether + lumefantrine) , (Sigma-Tau Pharmaceuticals, Inc., Rome, Italy; dihydroartemisinin-piperaquine) , (Shin Poong PharmaceuticalCo., Ltd., Seoul, Korea; pyronaridine-artesunate) , ASAQ (Sanofi SA (Gentilly, France) /DNDi (Geneva, Switzerland) ; artesunate + amodiaquine) , ASMQ (Cipla Limited (Mumbai, India) /DNDi, artesunate + mefloquine) , SPAQ-CO TM (Guilin PharmaceuticalCo., Ltd.
  • the invention also provides methods of using the compounds of Formulae (I) -(VIII) , or a pharmaceutically acceptable salt thereofto inhibit plasmepsin X, plasmepsin IX or plasmepsin X and IX, to treat Plasmodium infection or treat malaria wherein the method furthercomprises 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.
  • AIBN Azobisisobutyronitrile
  • DDQ 2, 3-Dichloro-5, 6-dicyano-1, 4-benzoquinone
  • DIBALH diisobutylaluminum hydride
  • HATU 1- [Bis (dimethylamino) methylene] -1H-1, 2, 3-triazolo [4, 5-b] pyridinium 3-oxid
  • K 3 PO 4 Tripotassium phosphate
  • KHMDS Potassium bis (trimethylsilyl) amide
  • LiAlH 4 lithium aluminum hydride
  • MgSO 4 Magnesium sulfate
  • NaBH 4 sodium borohydrate
  • Na 2 SO 3 sodium sulfite
  • Na 2 SO 4 sodium sulfate
  • NaHMDS sodium bis (trimethylsilyl) amide
  • PdCl 2 (dppf) -CH 2 Cl 2 [1, 1′-Bis (diphenylphosphino) ferrocene] dichloropalladium (II)
  • TBAF Tetra-n-butylammonium fluoride
  • Ti (EtO) 4 titanium ethoxide
  • TMSOTf Trimethylsilyl trifluoromethanesulfonate
  • Compounds of Formula S-2 are prepared from S-1 by macrolactamization using amidecoupling reagents.
  • 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 hydrogenationconditions to yield the products of Formula S-5.
  • RCM ring closing metathesis
  • 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 crosscoupling reactions such as Heck reactions. Resulting double bonds in S-7 can be reduced under for example hydrogenationconditions to yield the products of Formula S-8.
  • 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 crosscoupling reactions such as palladium catalyzed C-Ocoupling reactions.
  • X is a halogen such as Cl, Br and I
  • transition metal catalyzed intramolecular crosscoupling reactions such as palladium catalyzed C-Ocoupling reactions.
  • 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 diolsafter dehydrationconditions using an acid or other dehydration reagents.
  • Products of Formula S-12 are prepared from intermediates S-13 or S-14 after intramolecular reductive etherification usingconditions such as TMSOTf and Et 3 SiH.
  • 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 (Merck KGaA, Darmstadt, Germany) , silica gel 60F-254, layer thickness 0.25 mm or liquid chromatography-mass spectrometry (LC/MS) .
  • TLC analytical thin layer chromatography
  • Thecolumn wascommonly a Waters Xterra MS C18, 3.0 ⁇ 50 mm, 5 ⁇ m or a Waters Acquity BEH C18 1.0 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.
  • 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 Workstationconfigured with 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 MSconditions of: 150-750 amu, Positive Electrospray, Collection Triggered by MS, and a Waters C-18 5-micron, 30 mm (id) x 100 mmcolumn. The mobile phasesconsisted of mixtures of acetonitrile (10-100%) in watercontaining 0.1%TFA.
  • Flow rates were maintained at 50 mL/min, the injectionvolume was 1800 ⁇ L, and the UV detection range was 210–400nm.
  • 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 mmcolumn or a Waters XBridge TM C-18 5-micron OBD TM , 30 mm (id) x 250 mmcolumn.
  • Flash chromatography was usually performed using either a Flash Chromatography apparatus (DyaxCorp. ) , an Rf apparatus, or an companion XL on silica gel (32-63 ⁇ M, 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.
  • Couplingconstants (J) were reported in hertz (Hz) .
  • Chiral analytical chromatography was mostcommonly performed on one of AS, AD, OD, IA, or OJcolumns (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 wasconducted on one of CHIRALPAK AS, of CHIRALPAK AD, OD, IA, OJcolumns (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
  • a chiral center in acompound may exist in the "S" or "R” stereo-configuration, or as a mixture of both.
  • each bond drawn as a straight line from a chiral center includes both the (R) and (S) stereoisomers as well as mixtures thereof.
  • 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 N 2 atmosphere.
  • the mixture was quenched with saturated sodium bicarbonate solution (10 mL) at 0 °C, and extracted with DCM (10 mL*1) then extracted with EtOAc (10 mL*3) .
  • Pd-C (1.731 mg, 3.25 ⁇ mol) 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 N 2 atmosphere.
  • 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 N 2 atmosphere.
  • Example 1 The mixture was stirred at 22 °C for 16 h. The mixture wascooled, 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*30mm*5umcondition 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 yield Example 1.
  • Pd-C (2.250 mg, 4.23 ⁇ mol) 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 N 2 atmosphere.
  • tert-butyl (4aR, 8R, 12E, 18R, 18aR, 28E) -8-ethyl-18-hydroxy-6, 20-dioxo-4,
  • 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 N 2 atmosphere.
  • tert-butyl (4aR, 8R, 18R, 18aR, E) -8-ethyl-18-hydroxy-6, 20-dioxo-4,
  • 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 N 2 atmosphere.
  • 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 N 2 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) 3 Cl (116 mL, 116 mmol) in anhydrous THF (90 mL) .
  • N-ethyl-N-isopropylpropan-2-amine 13.79 mL, 79 mmol
  • EDC 9.08 g, 47.4 mmol
  • methyl 3-amino-3-ethylhept-6-enoate hydrochloride 3-6
  • 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 N 2 atmosphere.
  • 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 N 2 atmosphere.
  • tert-butyl (4aR, 8R, 11E, 18aS, 28E) -8-ethyl-17, 17-dimethyl-6, 20-dioxo-4, 4a, 7, 8, 9, 10, 18, 18a
  • 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) .
  • 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) .
  • 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 N 2 atmosphere.
  • An asterisk (*) may be used in a chemical structure drawing that indicates the location of a chiral center.
  • 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 andcounted. 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.
  • 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 ) alkylenecomprising 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 halogen;
  • 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 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 9 ;
  • Z is CR 11 or N, wherein when Z is N, V is CR 10 and Y is CR 9 ;
  • each occurrence of R is indenpendently hydrogen, C 1 -C 6 alkylCOOH, -COOH, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkylOH, -COC 1 -C 6 alkyl or -COOC 1 -C 6 alkyl;
  • R a is hydrogen, halogen, -CN, -OH, C 1 -C 6 alkoxy, C 1 -C 6 alkylOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOH, -COOH, oxo, -COOC 1 -C 6 alkyl, C 1 -C 6 alkylCOOC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkylC 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, -C 1 -C 6 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

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Abstract

L'invention concerne des procédés de traitement du paludisme comprenant l'administration de composés de formule (I) ou d'un sel pharmaceutiquement acceptable de ceux-ci, à un sujet en ayant besoin, les variables étant telles que définies dans la description. La présente invention concerne également l'utilisation des composés de formule (I), tels que définis dans la description, pour inhiber l'activité de la plasmepsine X, de la plasmepsine IX ou des plasmepsines X et IX, pour traiter une infection à Plasmodium et pour traiter le paludisme. L'invention concerne également des procédés de traitement comprenant en outre l'administration d'un ou de plusieurs composés antipaludiques supplémentaires.
PCT/CN2021/136177 2020-08-12 2021-12-07 Agents antipaludiques WO2023102747A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
PCT/CN2021/136177 WO2023102747A1 (fr) 2021-12-07 2021-12-07 Agents antipaludiques
AU2022404966A AU2022404966A1 (en) 2021-12-07 2022-12-05 Antimalarial agents
PCT/US2022/051770 WO2023107356A1 (fr) 2021-12-07 2022-12-05 Agents antipaludiques
CA3240145A CA3240145A1 (fr) 2021-12-07 2022-12-05 Agents antipaludiques
TW111146559A TWI842251B (zh) 2021-12-07 2022-12-05 抗瘧疾藥劑
ARP220103334A AR127872A1 (es) 2020-08-12 2022-12-05 Agentes contra el paludismo

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008103351A2 (fr) * 2007-02-23 2008-08-28 Schering Corporation Inhibiteurs de la protéase d'aspartyle hétérocycliques
WO2011044181A1 (fr) * 2009-10-08 2011-04-14 Schering Corporation Composés de dioxyde d'iminothiadiazine comme inhibiteurs de bace, compositions et leur utilisation
WO2017089453A1 (fr) * 2015-11-25 2017-06-01 Ucb Biopharma Sprl Dérivés d'iminotétrahydropyrimidinone utilisés comme inhibiteurs de plasmepsine v
WO2017142825A2 (fr) * 2016-02-18 2017-08-24 Merck Sharp & Dohme Corp. Iminopyrimidinones substituées par n3 à titre d'agents antipaludéens
WO2017144517A1 (fr) * 2016-02-23 2017-08-31 Ucb Biopharma Sprl Dérivés de dioxyde d'iminothiadiazinane utilisés comme inhibiteurs de la plasmepsine v
WO2021026884A1 (fr) * 2019-08-15 2021-02-18 Merck Sharp & Dohme Corp. Agents antipaludiques

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008103351A2 (fr) * 2007-02-23 2008-08-28 Schering Corporation Inhibiteurs de la protéase d'aspartyle hétérocycliques
WO2011044181A1 (fr) * 2009-10-08 2011-04-14 Schering Corporation Composés de dioxyde d'iminothiadiazine comme inhibiteurs de bace, compositions et leur utilisation
WO2017089453A1 (fr) * 2015-11-25 2017-06-01 Ucb Biopharma Sprl Dérivés d'iminotétrahydropyrimidinone utilisés comme inhibiteurs de plasmepsine v
WO2017142825A2 (fr) * 2016-02-18 2017-08-24 Merck Sharp & Dohme Corp. Iminopyrimidinones substituées par n3 à titre d'agents antipaludéens
WO2017144517A1 (fr) * 2016-02-23 2017-08-31 Ucb Biopharma Sprl Dérivés de dioxyde d'iminothiadiazinane utilisés comme inhibiteurs de la plasmepsine v
WO2021026884A1 (fr) * 2019-08-15 2021-02-18 Merck Sharp & Dohme Corp. Agents antipaludiques

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