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WO2016004297A1 - Nouveaux inhibiteurs de méthionyl t-arn synthétase (tb metrs) de trypanosoma brucei pour le traitement de la trypanosomiase africaine - Google Patents

Nouveaux inhibiteurs de méthionyl t-arn synthétase (tb metrs) de trypanosoma brucei pour le traitement de la trypanosomiase africaine Download PDF

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WO2016004297A1
WO2016004297A1 PCT/US2015/038974 US2015038974W WO2016004297A1 WO 2016004297 A1 WO2016004297 A1 WO 2016004297A1 US 2015038974 W US2015038974 W US 2015038974W WO 2016004297 A1 WO2016004297 A1 WO 2016004297A1
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substituted
alkyl
groups
heteroaryl
compound
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Stephen F. Martin
James J. SAHN
Alan R. MEIS
Lance T. LEPOVITZ
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University of Texas System
University of Texas at Austin
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
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    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
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    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates generally to the fields of medicine, pharmaceutical agents, and antimicrobial agents. More particularly, it relates to compounds which can be used to treat human African trypanosomiasis.
  • the present invention rovides compounds of the formula:
  • R5 is hydrogen, alkyl(c ⁇ i2), acyl(c ⁇ i2), substituted alkyl(c ⁇ i2), or substituted acyl(c ⁇ i2), or is taken together with R 2 as described below;
  • R6 is alkyl( C ⁇ i2), cycloalkyl( C ⁇ i2), alkanediyl(c ⁇ 8) ⁇ cycloalkyl(c ⁇ i2), aryl(c ⁇ i2), heteroaryl ( c ⁇ i2), aralkyl ( c ⁇ i2), heterocycloalkyl(c ⁇ i2), acyl(c ⁇ i2), -alkanediyl(c ⁇ 8) _ heterocycloalkyl( C ⁇ i2), or a substituted version of any of these groups, or is taken together with R 5 as described below; R5 and R6 are taken together and are alkanediyl(c ⁇ 8), alkoxydiyl(c ⁇ 8), alkyla
  • X 4 is hydrogen, alkyl(c ⁇ 8), or substituted alkyl(c ⁇ 8); and Ri 4 is hydroxy or alkoxy(c ⁇ i2), aryloxy(c ⁇ i2), aralkoxy(c ⁇ i2), or a substituted version of any of these groups; provided that when Rs is pyridylmethyl, then R5 and R6 are not taken together as alkylaminodiyl(c ⁇ i2) or R ⁇ is not methyl; or a compound of the formula:
  • Ri is hydrogen, hydroxy, amino, halo, nitro, carboxy, cyano, sulfate, or alkyl( C ⁇ i8), aryl(c ⁇ i8), aralkyl (c ⁇ i8), heteroaryl (c ⁇ i8), heteroaralkyl (c ⁇ i8), alkylamino (c ⁇ i2), dialkylamino (c ⁇ i2), arylaminO(c ⁇ i2), heteroarylaminO(c ⁇ i2), aralkylaminO(c ⁇ i2), or a substituted version of any of these groups or alkyl( C ⁇ i8), aryl( C ⁇ i8), aralkyl( C ⁇ i8), and heteroaryl( C ⁇ i8) are also substituted with amino, alkylamino, or dialkylamino provided that the total number of carbons is not greater than the carbon limit; y is 1, 2, 3, or 4; R 2 is hydrogen, or alkylamino, or dial
  • R 9 is aryl( C ⁇ i2), substituted aryl( C ⁇ i2), heteroaryl( C ⁇ i2), or substituted heteroaryl( C ⁇ i2); Rio is heterocycloalkyl( C ⁇ i8), heteroaryl( C ⁇ i8), or a substituted version of either of these groups, or either of these groups wherein the group is substituted with alkyl( C ⁇ i2), aryl( C ⁇ i2), aralkyl( C ⁇ i2), heteroaryl( C ⁇ i2) wherein any one of these groups have been substituted with amino, alkylaminO(c ⁇ 6), or dialkylaminO(c ⁇ 6), alkylaminO(c ⁇ i2), dialkylaminO(c ⁇ i2), arylaminO(c ⁇ i2), heteroarylaminO(c ⁇ i2); and y2 is 0, 1, 2, 3, or 4; or
  • Ri 2 is aryl( C ⁇ i2), substituted aryl( C ⁇ i2), heteroaryl( C ⁇ i2), or substituted heteroaryl( C ⁇ i2); Ri3 is heterocycloalkyl( C ⁇ i8), heteroaryl( C ⁇ i8), or a substituted version of either of these groups, or either of these groups wherein the group is substituted with alkyl( C ⁇ i2), aryl( C ⁇ i2), aralkyl( C ⁇ i2), heteroaryl( C ⁇ i2) wherein any one of these groups have been substituted with amino; alkylaminO(c ⁇ 6); or dialkylaminO(c ⁇ 6), alkylaminO(c ⁇ i2), dialkylaminO(c ⁇ i2), arylaminO(c ⁇ i2), heteroarylaminO(c ⁇ i2); and y3 is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt, optical isomer, or tautomer thereof.
  • the compounds are further defined as:
  • R5 is hydrogen, alkyl(c ⁇ i2), acyl(c ⁇ i2), substituted alkyl(c ⁇ i2), or substituted acyl(c ⁇ i2), or is taken together with R 2 as described below;
  • R6 is alkyl( C ⁇ i2), cycloalkyl( C ⁇ i2), -alkanediyl(c ⁇ 8)-cycloalkyl ( c ⁇ i2), aryl (c ⁇ i 2 ), heteroaryl (c ⁇ i 2 ), aralkyl (c ⁇ i 2 ), heterocycloalkyl(c ⁇ i2), acyl(c ⁇ i2), -alkanediyl(c ⁇ 8) _ heterocycloalkyl( C ⁇ i2), or a substituted version of any of these groups, or is taken together with R 5 as described below; R5 and R6 are taken together and are alkanediyl(c ⁇ 8), alkoxydiyl(c ⁇ 8), alky
  • Ri is hydrogen, hydroxy, amino, halo, nitro, carboxy, cyano, sulfate, or alkyl( C ⁇ i8), aryl(c ⁇ i8), aralkyl (c ⁇ i8), heteroaryl (c ⁇ i8), heteroaralkyl (c ⁇ i8), alkylamino (c ⁇ i2), dialkylamino (c ⁇ i2), arylaminO(c ⁇ i2), heteroarylaminO(c ⁇ i2), aralkylaminO(c ⁇ i2), or a substituted version of any of these groups or alkyl( C ⁇ i8), aryl( C ⁇ i8), aralkyl( C ⁇ i8), and heteroaryl( C ⁇ i8) are also substituted with amino, alkylamino, or dialkylamino provided that the total number of carbons is not greater than the carbon limit; y is 1, 2, 3, or 4; R 2 is hydrogen, or alkyl( C ⁇ i
  • R 9 is aryl( C ⁇ i2), substituted aryl( C ⁇ i2), heteroaryl( C ⁇ i2), or substituted heteroaryl( C ⁇ i2); Rio is heterocycloalkyl(c ⁇ i8), heteroaryl(c ⁇ i8), or a substituted version of either of these groups, or either of these groups wherein the group is substituted with alkyl( C ⁇ i2), aryl( C ⁇ i2), aralkyl(c ⁇ i2), heteroaryl( C ⁇ i2) wherein any one of these groups have been substituted with amino, alkylaminO(c ⁇ 6), or dialkylaminO(c ⁇ 6), alkylaminO(c ⁇ i2), dialkylaminO(c ⁇ i2), arylaminO(c ⁇ i2), heteroarylaminO(c ⁇ i2); and y2 is 0, 1, 2, 3, or 4; or a compound of the formula:
  • Ri 2 is aryl( C ⁇ i2), substituted aryl( C ⁇ i2), heteroaryl( C ⁇ i2), or substituted heteroaryl( C ⁇ i2); Ri3 is heterocycloalkyl( C ⁇ i8), heteroaryl( C ⁇ i8), or a substituted version of either of these groups, or either of these groups wherein the group is substituted with alkyl( C ⁇ i2), aryl( C ⁇ i2), aralkyl( C ⁇ i2), heteroaryl( C ⁇ i2) wherein any one of these groups have been substituted with amino; alkylaminO(c ⁇ 6); or dialkylaminO(c ⁇ 6), alkylaminO(c ⁇ i2), dialkylaminO(c ⁇ i2), arylamino(c ⁇ i2), heteroarylamino(c ⁇ i2); and y3 is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt, optical isomer, or tautomer thereof.
  • the compounds are further defined as:
  • Ri is hydrogen, hydroxy, amino, halo, nitro, carboxy, cyano, sulfate, or alkyl( C ⁇ i8), aryl(c ⁇ i8), aralkyl( C ⁇ i8), heteroaryl( C ⁇ i8), heteroaralkyl( C ⁇ i8), alkylaminO( C ⁇ i2), dialkylaminO( C ⁇ i2), arylaminO(c ⁇ i2), heteroarylaminO(c ⁇ i2), aralkylaminO(c ⁇ i2), or a substituted version of any of these groups or alkyl( C ⁇ i8), aryl( C ⁇ i8), aralkyl( C ⁇ i8), and heteroaryl( C ⁇ i8) are also substituted with amino, alkylamino, or dialkylamino provided that the total number of carbons is not greater than the carbon limit; y is 1, 2, 3, or 4; R 2 is aryl( C ⁇ i2)
  • the compounds are further defined as:
  • Ri is hydrogen, hydroxy, amino, halo, nitro, carboxy, cyano, sulfate, or alkyl( C ⁇ i8), aryl(c ⁇ i8), aralkyl (c ⁇ i8), heteroaryl (c ⁇ i8), heteroaralkyl (c ⁇ i8), alkylamino (c ⁇ i2), dialkylamino (c ⁇ i2), arylaminO(c ⁇ i2), heteroarylaminO(c ⁇ i2), aralkylaminO(c ⁇ i2), or a substituted version of any of these groups or alkyl( C ⁇ i8), aryl( C ⁇ i8), aralkyl( C ⁇ i8), and heteroaryl( C ⁇ i8) are also substituted with amino, alkylamino, or dialkylamino provided that the total number of carbons is not greater than the carbon limit; y is 1, 2, 3, or 4; R 2 is aryl( C ⁇ i2)
  • R 2 is not , when R4 is hydroxy.
  • the compounds are further defined
  • Ri is hydrogen, hydroxy, amino, halo, nitro, carboxy, cyano, sulfate, or alkyl( C ⁇ i8), aryl(c ⁇ i8), aralkyl (c ⁇ i8), heteroaryl (c ⁇ i8), heteroaralkyl (c ⁇ i8), alkylamino (c ⁇ i2), dialkylamino (c ⁇ i2), arylaminO(c ⁇ i2), heteroarylaminO(c ⁇ i2), aralkylaminO(c ⁇ i2), or a substituted version of any of these groups or alkyl( C ⁇ i8), aryl( C ⁇ i8), aralkyl( C ⁇ i8), and heteroaryl( C ⁇ i8) are also substituted with amino, alkylamino, or dialkylamino provided that the total number of carbons is not greater than the carbon limit; y is 1, 2, 3, or 4; R 2 is aryl( C ⁇ i2)
  • R 5 is hydrogen, alkyl( C ⁇ i2), acyl(c ⁇ i2), substituted alkyl( C ⁇ i2), or substituted acyl(c ⁇ i2);
  • Re is alkyl ( c ⁇ i2), cycloalkyl (c ⁇ i2), -alkanediyl ( c ⁇ 8)-cycloalkyl (c ⁇ i2), aryl (c ⁇ i 2 ), heteroaryl (c ⁇ i 2 ), aralkyl( C ⁇ i2), heterocycloalkyl( C ⁇ i2), acyl(c ⁇ i2), -alkanediyl(c ⁇ 8) ⁇ heterocycloalkyl( C ⁇ i2), or a substituted version of any of these groups;
  • R7 is hydrogen, alkyl( C ⁇ i2), or substituted alkyl(c ⁇ i2);
  • X2 is -C(O)-, alkanediyl(c ⁇ 8),
  • R 8 is a group of the formula:
  • X 4 is hydrogen, alkyl( C ⁇ 8), or substituted alkyl( C ⁇ 8); and Ri 4 is hydroxy or alkoxy(c ⁇ i2), aryloxy(c ⁇ i2), aralkoxy(c ⁇ i2), or a substituted version of any of these groups; or a pharmaceutically acceptable salt, optical isomer, or tautomer thereof.
  • the compounds are further defined as:
  • R5 is hydrogen, alkyl(c ⁇ i2), or substituted alkyl(c ⁇ i2);
  • Re is alkyl(c ⁇ i2), cycloalkyl(c ⁇ i2), -alkanediyl(c ⁇ 8)-cycloalkyl ( c ⁇ i2), aryl (c ⁇ i 2 ), heteroaryl (c ⁇ i 2 ), aralkyl (c ⁇ i 2 ), heterocycloalkyl(c ⁇ i2), acyl(c ⁇ i2), -alkanediyl(c ⁇ 8) _ heterocycloalkyl( C ⁇ i2), or a substituted version of any of these groups;
  • R7 is hydrogen, alkyl( C ⁇ i2), or substituted alkyl( C ⁇ i2);
  • 2 is alkanediyl(c ⁇ 8), cycloalkanediyl(c ⁇ 8), alkoxydiyl(c ⁇ 8), alkylaminodiy
  • X 4 is hydrogen, alkyl( C ⁇ 8), or substituted alkyl( C ⁇ 8); and Ri 4 is hydroxy or alkoxy(c ⁇ i2), aryloxy(c ⁇ i2), aralkoxy(c ⁇ i2), or a substituted version of any of these groups; or a pharmaceutically acceptable salt, optical isomer, or tautomer thereof.
  • the compounds are further defined as:
  • R 5 is hydrogen, alkyl( C ⁇ i2), or substituted alkyl( C ⁇ i2);
  • R6 is -alkanediyl(c ⁇ 8)-cycloalkyl ( c ⁇ i2), aryl (c ⁇ i 2 ), heteroaryl (c ⁇ i 2 ), aralkyl (c ⁇ i 2 ), heterocycloalkyl(c ⁇ i2), -alkanediyl(c ⁇ 8) _ heterocycloalkyl( C ⁇ i2), or a substituted version of any of these groups;
  • R7 is hydrogen, alkyl( C ⁇ i2), or substituted alkyl( C ⁇ i2);
  • X2 is alkanediyl(c ⁇ 8), cycloalkanediyl(c ⁇ 8), alkoxydiyl(c ⁇ 8), alkylaminodiyl(c ⁇ 8), or a substituted version of any of these groups;
  • R 8 is alky
  • X 4 is hydrogen, alkyl( C ⁇ 8), or substituted alkyl( C ⁇ 8); and Ri 4 is hydroxy or alkoxy(c ⁇ i2), aryloxy(c ⁇ i2), aralkoxy(c ⁇ i2), or a substituted version of any of these groups; or a pharmaceutically acceptable salt, optical isomer, or tautomer thereof.
  • the compound is further defined as:
  • R 5 is hydrogen, alkyl( C ⁇ i2), or substituted alkyl( C ⁇ i2)
  • R6 is -alkanediyl(c ⁇ 8)-cycloalkyl ( c ⁇ i2), aryl (c ⁇ i 2 ), heteroaryl (c ⁇ i 2 ), aralkyl (c ⁇ i 2 ), heterocycloalkyl(c ⁇ i2), -alkanediyl(c ⁇ 8) _ heterocycloalkyl( C ⁇ i2), or a substituted version of any of these groups
  • R7 is hydrogen, alkyl( C ⁇ i2), or substituted alkyl( C ⁇ i2)
  • X2 is alkanediyl(c ⁇ 8), cycloalkanediyl(c ⁇ 8), alkoxydiyl(c ⁇ 8), alkylaminodiyl(c ⁇ 8), or a substituted version of any of these groups
  • Rs is aryl(
  • X 4 is hydrogen, alkyl( C ⁇ 8), or substituted alkyl( C ⁇ 8); and Ri 4 is hydroxy or alkoxy(c ⁇ i2), aryloxy(c ⁇ i2), aralkoxy(c ⁇ i2), or a substituted version of any of these groups; or a pharmaceutically acceptable salt, optical isomer, or tautomer thereof.
  • the compounds are further defined as: wherein: R 9 is substituted aryl( C ⁇ i2) or substituted heteroaryl( C ⁇ i2); Rio is heterocycloalkyl( C ⁇ i8), heteroaryl( C ⁇ i8), or a substituted version of either of these groups, or either of these groups wherein the group is substituted with alkyl(c ⁇ i2), aryl(c ⁇ i2), aralkyl(c ⁇ i2), heteroaryl(c ⁇ i2) wherein any one of these groups have been substituted with amino; alkylaminO(c ⁇ 6); or dialkylamino(c ⁇ 6), alkylamino(c ⁇ i2), dialkylamino(c ⁇ i2), arylamino(c ⁇ i2), heteroarylamino(c ⁇ i2); and y2 is 0, 1 , 2, 3, or 4.
  • the compounds are further defined as:
  • R 9 is substituted aryl( C ⁇ i2) or substituted heteroaryl( C ⁇ i2); Rio is heterocycloalkyl( C ⁇ i8), heteroaryl( C ⁇ i8), or substituted heteroaryl( C ⁇ i 8); and y2 is 0, 1 , 2, 3, or 4.
  • the compounds are further defined as:
  • Ri 2 is substituted aryl( C ⁇ i2) or substituted heteroaryl( C ⁇ i2); Ri3 is heterocycloalkyl(c ⁇ i8), heteroaryl( C ⁇ i8), or a substituted version of either of these groups, or either of these groups wherein the group is substituted with alkyl( C ⁇ i2), aryl( C ⁇ i2), aralkyl( C ⁇ i2), heteroaryl( C ⁇ i2) wherein any one of these groups have been substituted with amino; alkylamino(c ⁇ 6); or dialkylamino(c ⁇ 6), alkylamino(c ⁇ i2), dialkylamino(c ⁇ i2), arylamino(c ⁇ i2), heteroarylaminO(c ⁇ i2); and y3 is 0, 1, 2, 3, or 4.
  • the compounds are further defined as :
  • Ri 2 is substituted aryl( C ⁇ i2) or substituted heteroaryl( C ⁇ i2);
  • R-13 is heterocycloalkyl( C ⁇ i8), heteroaryl( C ⁇ i8), or substituted heteroaryl( C ⁇ i8); and
  • y3 is 0, 1, 2, 3, or 4.
  • the compound is of formula I. In other embodiments, the compound is of formula II. In other embodiments, the compound is of formula III. In other embodiments, the compound is of formula IV.
  • Ri is fluoro, chloro, bromo, or iodo.
  • Ri is aryl(c ⁇ i2), heteroaryl(c ⁇ i2), alkylamino(c ⁇ i2), arylamino(c ⁇ i2), heteroarylamino(c ⁇ i2), aralkylaminO(c ⁇ i2), or a substituted version of any of these groups.
  • Ri is alkyl(c ⁇ i8), aryl( C ⁇ i8), aralkyl( C ⁇ i8), and heteroaryl( C ⁇ i8) are substituted with amino, alkylamino, or dialkylamino provided that the total number of carbons is not greater than the carbon limit.
  • R2 is aralkyl(c ⁇ i8). In some embodiments, R2 is benzyl or phenethyl. In other embodiments, R2 is heteroaryl(c ⁇ i2) or heteroaralkyl(c ⁇ i8). In some embodiments, R3 is alkyl( C ⁇ i2). In some embodiments, R3 is methyl. In some embodiments, R4 is hydroxy. In some embodiments, Xi is hydrogen.
  • R5 is hydrogen, alkyl( C ⁇ i2), or substituted alkyl( C ⁇ i2). In some embodiments, R5 is hydrogen. In other embodiments, R5 is alkyl( C ⁇ i2). In some embodiments, R5 is methyl. In some embodiments, R6 is alkyl( C ⁇ i2) or substituted alkyl( C ⁇ i2). In some embodiments, Rs is -CH(C02H)CH 2 CH 2 SCH3 or -CH(CH 2 OH)CH2CH 2 SCH3.
  • R6 is -alkanediyl(c ⁇ 8) ⁇ cycloalkyl( C ⁇ i2) or substituted -alkanediyl(c ⁇ 8) ⁇ cycloalkyl(c ⁇ i2).
  • Re is -CH2C6H11.
  • R6 is aralkyl( C ⁇ i2) or substituted aralkyl( C ⁇ i2).
  • R6 is aralkyl(c ⁇ i2).
  • R6 is benzyl or phenethyl.
  • R6 is substituted aralkyl( C ⁇ i2).
  • R6 is 3-chlorobenzyl, 3-methoxybenzyl, 3- thiomethylbenzyl, 5-methoxybenzyl, 3-chloro-5-methoxybenzyl, 3,5-dichlorobenzyl, 3,5- dimethoxybenzyl, 3,4,5-trimethoxybenzyl, or a group of the formula:
  • R7 is hydrogen. In other embodiments, R7 is alkyl( C ⁇ i2) or substituted alkyl( C ⁇ i2 ) . In some embodiments, R7 is hydroxymethyl, 1 -hydroxy ethyl, or 1- methoxyethyl. In some embodiments, the bond between the carbon atoms 1 and 2 of formula II is a single bond. In some embodiments, the bond between the carbon atoms 1 and 2 of formula II is a double bond. In some embodiments, X2 is alkanediyl(c ⁇ 8). In some embodiments, X2 is -CH 2 - -CH 2 CH 2 -, or -CH2CH2CH2-. In other embodiments, X2 is alkoxydiyl(c ⁇ 8). In some embodiments, X2 is -CH 2 CH 2 0-.
  • Rs is aryl( C ⁇ is) or substituted aryl( C ⁇ is). In some embodiments, Rs is phenyl. In other embodiments, Rs is substituted aryl( C ⁇ is). In some embodiments, Rs is 2-hydroxyphenyl. In other embodiments, Rs is heteroaryl( C ⁇ is) or substituted heteroaryl( C ⁇ is). In some embodiments, Rs is heteroaryl( C ⁇ is). In some embodiments, Rs is 3-indolyl. In other embodiments, Rs is substituted heteroaryl( C ⁇ is). In some embodiments, Rs is 4-hydroxy-3- indolyl, 5-hydroxy-3-indolyl, and 5-methoxy-3-indolyl. In some embodiments, Rs is heterocycloalkyl(c ⁇ i2). In other embodiments, Rs is further defined as:
  • X 4 is hydrogen, alkyl( C ⁇ s), or substituted alkyl( C ⁇ 8); and Ri 4 is hydroxy or alkoxy(c ⁇ i2), aryloxy(c ⁇ i2), aralkoxy(c ⁇ i2), or a substituted version of any of these groups.
  • X 4 is hydrogen.
  • X 4 is methyl.
  • Ri 4 is aralkoxy(c ⁇ i2) or substituted aralkoxy(c ⁇ i2).
  • Ri 4 is benzyloxy.
  • X2 and Rs when taken together are selected from:
  • R 5 is hydrogen, alkyl( C ⁇ i2), acyl(c ⁇ i 2 ), substituted alkyl( C ⁇ i2), or substituted acyl(c ⁇ i 2 ), or is taken with R 2 as described below;
  • R6 is alkyl( C ⁇ i2), aryl( C ⁇ i2), heteroaryl( C ⁇ i2), aralkyl( C ⁇ i2), acyl(c ⁇ i2), or a substituted version of any of these groups;
  • R5 and R6 are taken together and are alkanediyl(c ⁇ 8), alkoxyldiyl(c ⁇ 8), alkylaminodiyl(c ⁇ 8), or a substituted version of any of these groups; provided that when the compound contains a pyridylmethyl, then R 5 and R6 are not taken together as alkylaminodiyl(c ⁇ i2) or R ⁇ is not methyl; or a pharmaceutically acceptable salt, optical isomer, or
  • y2 is 1, 2, 3, or 4.
  • R9 is 3,5-dichlorophenyl, 3,5-difluorophenyl, 3,4-methylenedixoyphenyl, 4- chlorophenyl, 4-fluorophenyl, or 3,5-dichloro-3-pyridine.
  • 50 The compound according to any one of claims 1, 9-10, 15, and 48, wherein R 10 is
  • y 4 is equal to 0 to the number of hydrogen atoms on the ring system
  • Rn is hydrogen, halo, or alkyl( C ⁇ i2), aryl( C ⁇ i2), aralkyl( C ⁇ i2), heteroaryl( C ⁇ i2) wherein any one of these groups have been substituted with amino; alkylaminO(c ⁇ 6); or dialkylaminO(c ⁇ 6), alkylaminO(c ⁇ i2), dialkylaminO(c ⁇ i2), arylaminO(c ⁇ i2), heteroarylaminO(c ⁇ i2), or a substituted version of any of these groups; and Ri 4 and R15 are each individually hydrogen, amino, or alkyl(c ⁇ i2), alkoxy(c ⁇ i2), or a substituted version of either of these groups.
  • Rio is
  • y 4 is equal to 0 to the number of hydrogen atoms on the ring system;
  • Rn is hydrogen, halo, or alkyl( C ⁇ i2), alkylaminO(c ⁇ i2), dialkylaminO(c ⁇ i2), arylaminO(c ⁇ i2), heteroarylaminO(c ⁇ i2), or a substituted version of any of these groups; and
  • R14 and R15 are each individually hydrogen, amino, or alkyl( C ⁇ i2), alkoxy(c ⁇ i2), or a substituted version of either of these groups.
  • y 4 is 0, 1, 2, 3, or 5.
  • y 4 is 0, 1, or 2.
  • y 4 is 0 or 1.
  • y 4 is 0. In other embodiments, y 4 is 1. In some embodiments, wherein y 3 is 1, 2, 3, or 4.
  • R12 is 3,5-dichlorophenyl, 3,5-difluorophenyl, 3,4-methylenedixoyphenyl, 4- chlorophenyl, 4-fluorophenyl, or 3,5-dichloro-3-pyridine. In some embodiments, R13 is
  • y 4 is equal to 0 to the number of hydrogen atoms on the ring system
  • Rn is hydrogen, halo, or alkyl( C ⁇ i2), aryl( C ⁇ i2), aralkyl( C ⁇ i2), heteroaryl( C ⁇ i2) wherein any one of these groups have been substituted with amino; alkylaminO(c ⁇ 6); or dialkylaminO(c ⁇ 6), alkylaminO(c ⁇ i2), dialkylaminO(c ⁇ i2), arylaminO(c ⁇ i2), heteroarylaminO(c ⁇ i2), or a substituted version of any of these groups; and Ri 4 and R15 are each individually hydrogen, amino, or alkyl( C ⁇ i2), alkoxy(c ⁇ i2), or a substituted version of either of these groups.
  • R13 is
  • y 4 is equal to 0 to the number of hydrogen atoms on the ring system;
  • Rn is hydrogen, halo, or alkyl(c ⁇ i2), alkylamino(c ⁇ i2), dialkylamino(c ⁇ i2), arylamino(c ⁇ i2), heteroarylaminO(c ⁇ i2), or a substituted version of any of these groups; and
  • R14 and R15 are each individually hydrogen, amino, or alkyl( C ⁇ i2), alkoxy(c ⁇ i2), or a substituted version of either of these groups.
  • y 4 is 0, 1, 2, 3, or 5.
  • y 4 is 0, 1, or 2.
  • y 4 is 0 or 1.
  • y 4 is 0.
  • y 4 is 1.
  • the compounds are further defined as:
  • the present disclosure relates to pharmaceutical compositions comprising a compound of the instant disclosure and an excipient.
  • the present disclosure provides methods of treating or preventing a disease or disorder comprising administering a pharmaceutically effective amount of a compound or composition of the instant disclosure.
  • the disease or disorder is human African trypanosomiasis.
  • the compound is administered with a second therapeutic agent.
  • the second therapeutic agent is pentamidine, suramin, eflornithine, nifurtimox, or melarsoprol.
  • the present disclosure provides methods of inhibiting Trypanosoma brucei methionyl t-RNA synthetase comprising administering an effective amount of a compound or composition of the instant disclosure.
  • the effective amount of the compound leads to greater than 50% inhibition of Trypanosoma brucei methionyl t-RNA synthetase.
  • the effective amount of the compound leads to greater than 80% inhibition of Trypanosoma brucei methionyl t-RNA synthetase.
  • the effective amount of the compound leads to greater than 95% inhibition of Trypanosoma brucei methionyl t-RNA synthetase. It is contemplated that any method or composition described herein can be implemented with respect to any other method or composition described herein.
  • a method, composition, kit, or system that "comprises,” “has,” “contains,” or “includes” one or more recited steps or elements possesses those recited steps or elements, but is not limited to possessing only those steps or elements; it may possess (i.e., cover) elements or steps that are not recited.
  • an element of a method, composition, kit, or system that "comprises,” “has,” “contains,” or “includes” one or more recited features possesses those features, but is not limited to possessing only those features; it may possess features that are not recited.
  • any embodiment of any of the present methods, composition, kit, and systems may consist of or consist essentially of— rather than comprise/include/contain/have— the described steps and/or features.
  • the term “consisting of or “consisting essentially of may be substituted for any of the open-ended linking verbs recited above, in order to change the scope of a given claim from what it would otherwise be using the open-ended linking verb.
  • FIGs. 1A-C Cell density of T. brucei treated with 1 ⁇ (A) or 10 ⁇ (B) of drug compounds for 48 hours in vitro. Percentage of growth inhibition as determined by comparing the final cell density of drug treated samples to the DMSO control (C).
  • FIGs. 2A-B Cell density of T. brucei treated with 1 ⁇ (A) or 10 ⁇ (B) of drug compounds 1313-1317 and 213 for 48 hours in vitro.
  • the present disclosure describes new compounds which can be used to treat human African trypanosomiasis (i.e. sleeping sickness).
  • the compounds of the present invention comprise two major classes of compounds including a 4-amino-2-piperidone and a tetracyclic tetrahydro-beta-carboline.
  • the compounds are useful in that the compound selectively inhibits the methionyl t-RNA synthetase of Trypanosoma brucei. Screening has shown that one of the tetracyclic compounds exhibits no off-target activity when screened against a panel of 45 CNS proteins.
  • the symbol “-” means a single bond
  • “ ⁇ ” means triple bond.
  • the symbol " " represents an optional bond, which if present is either single or double.
  • the formula includes and And it is understood that no one such ring atom forms part of more than one double bond.
  • the covalent bond symbol when connecting one or two stereogenic atoms does not indicate any preferred stereochemistry. Instead, it covers all stereoisomers as well as mixtures thereof.
  • the symbol “ » ⁇ " when drawn perpendicularly across a bond (e.g. , j— CH 3 for methyl) indicates a point of attachment of the group.
  • the point of attachment is typically only identified in this manner for larger groups in order to assist the reader in unambiguously identifying a point of attachment.
  • the symbol "- ⁇ ⁇ " means a single bond where the group attached to the thick end of the wedge is “out of the page.”
  • the symbol “"HI " means a single bond where the group attached to the thick end of the wedge is “into the page”.
  • the symbol " ⁇ ⁇ . " means a single bond where the geometry around a double bond (e.g., either E or Z) is undefined. Both options, as well as combinations thereof are therefore intended. Any undefined valency on an atom of a structure shown in this application implicitly represents a hydrogen atom bonded to that atom. A bold dot on a carbon atom indicates that the hydrogen attached to that carbon is oriented out of the plane of the paper.
  • R may replace any hydrogen atom attached to any of the ring atoms, including a depicted, implied, or expressly defined hydrogen, so long as a stable structure is formed.
  • R may replace any hydrogen atom attached to any of the ring atoms, including a depicted, implied, or expressly defined hydrogen, so long as a stable structure is formed.
  • R may replace any hydrogen atom attached to any of the ring atoms of either of the fused rings unless specified otherwise.
  • Replaceable hydrogen atoms include depicted hydrogens (e.g., the hydrogen atom attached to the nitrogen atom in the formula above), implied hydrogens (e.g., a hydrogen atom of the formula above that is not shown but understood to be present), expressly defined hydrogen atoms, and optional hydrogen atoms whose presence depends on the identity of a ring atom (e.g., a hydrogen atom attached to group X, when X equals -CH-), so long as a stable structure is formed.
  • R may reside on either the 5-membered or the 6-membered ring of the fused ring system.
  • (Cn) defines the exact number (n) of carbon atoms in the group/class.
  • (C ⁇ n) defines the maximum number (n) of carbon atoms that can be in the group/class, with the minimum number as small as possible for the group in question, e.g., it is understood that the minimum number of carbon atoms in the group “alkenyl(c ⁇ 8) " or the class “alkene(c ⁇ 8)” is two.
  • alkoxy(c ⁇ io) designates those alkoxy groups having from 1 to 10 carbon atoms.
  • (Cn-n') defines both the minimum (n) and maximum number ( ⁇ ') of carbon atoms in the group.
  • alkyl (C2-1 o ) designates those alkyl groups having from 2 to 10 carbon atoms.
  • saturated means the compound or group so modified has no carbon-carbon double and no carbon-carbon triple bonds, except as noted below.
  • one or more carbon oxygen double bond or a carbon nitrogen double bond may be present. And when such a bond is present, then carbon- carbon double bonds that may occur as part of keto-enol tautomerism or imine/enamine tautomerism are not precluded.
  • aliphatic when used without the "substituted” modifier signifies that the compound/group so modified is an acyclic or cyclic, but non-aromatic hydrocarbon compound or group.
  • the carbon atoms can be joined together in straight chains, branched chains, or non-aromatic rings (alicyclic).
  • Aliphatic compounds/groups can be saturated, that is joined by single bonds (alkanes/alkyl), or unsaturated, with one or more double bonds (alkenes/alkenyl) or with one or more triple bonds (alkynes/alkynyl).
  • alkyl when used without the “substituted” modifier refers to a monovalent saturated aliphatic group with a carbon atom as the point of attachment, a linear or branched acyclic structure, and no atoms other than carbon and hydrogen.
  • alkanediyl when used without the "substituted” modifier refers to a divalent saturated aliphatic group, with one or two saturated carbon atom(s) as the point(s) of attachment, a linear or branched acyclic structure, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen.
  • the groups, -CH 2 - (methylene), -CH 2 CH 2 - -CH 2 C(CH 3 ) 2 CH 2 - and -CH 2 CH 2 CH 2 - are non-limiting examples of alkanediyl groups.
  • An “alkane” refers to the compound H-R, wherein R is alkyl as this term is defined above.
  • haloalkyl is a subset of substituted alkyl, in which one or more hydrogen atoms has been substituted with a halo group and no other atoms aside from carbon, hydrogen and halogen are present.
  • the group, -CH 2 C1 is a non-limiting example of a haloalkyl.
  • fluoroalkyl is a subset of substituted alkyl, in which one or more hydrogen has been substituted with a fluoro group and no other atoms aside from carbon, hydrogen and fluorine are present.
  • the groups, -CH 2 F, -CF 3 , and -CH 2 CF 3 are non-limiting examples of fluoroalkyl groups.
  • aryl when used without the "substituted” modifier refers to a monovalent unsaturated aromatic group with an aromatic carbon atom as the point of attachment, said carbon atom forming part of a one or more six-membered aromatic ring structure, wherein the ring atoms are all carbon, and wherein the group consists of no atoms other than carbon and hydrogen. If more than one ring is present, the rings may be fused or unfused. As used herein, the term does not preclude the presence of one or more alkyl or aralkyl groups (carbon number limitation permitting) attached to the first aromatic ring or any additional aromatic ring present.
  • Non-limiting examples of aryl groups include phenyl (Ph), methylphenyl, (dimethyl)phenyl, -C 6 H 4 CH 2 CH 3 (ethylphenyl), naphthyl, and a monovalent group derived from biphenyl.
  • the term "arenediyl” when used without the “substituted” modifier refers to a divalent aromatic group with two aromatic carbon atoms as points of attachment, said carbon atoms forming part of one or more six-membered aromatic ring structure(s) wherein the ring atoms are all carbon, and wherein the monovalent group consists of no atoms other than carbon and hydrogen.
  • the term does not preclude the presence of one or more alkyl, aryl or aralkyl groups (carbon number limitation permitting) attached to the first aromatic ring or any additional aromatic ring present. If more than one ring is present, the rings may be fused or unfused. Unfused rings may be connected via one or more of the following: a covalent bond, alkanediyl, or alkenediyl groups (carbon number limitation permitting).
  • arenediyl groups include:
  • an “arene” refers to the compound H-R, wherein R is aryl as that term is defined above. Benzene and toluene are non-limiting examples of arenes. When any of these terms are used with the "substituted" modifier one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, -NH 2 , -N0 2 , "C0 2 H, -C0 2 CH 3 , -CN, -SH, -OCH 3 , -SCH 3 , -OCH 2 CH 3 , -C(0)CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -C(0) H 2 , -OC(0)CH 3 , -S(0) 2 NH 2 , or is substituted twice with a group of the formula -OCH 2 0- or -OCH 2 CH 2 0-.
  • aralkyl when used without the “substituted” modifier refers to the monovalent group -alkanediyl-aryl, in which the terms alkanediyl and aryl are each used in a manner consistent with the definitions provided above.
  • Non-limiting examples of aralkyls are: phenylmethyl (benzyl, Bn) and 2-phenyl-ethyl.
  • aralkyl When the term aralkyl is used with the "substituted" modifier one or more hydrogen atom from the alkanediyl and/or the aryl group has been independently replaced by -OH, -F, -CI, -Br, -I, - H 2 , -N0 2 , -C0 2 H, -C0 2 CH 3 , -CN, -SH, -OCH 3 , -SCH 3 , -OCH 2 CH 3 , -C(0)CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -C(0)NH 2 , -OC(0)CH 3 , -S(0) 2 NH 2 , or is substituted twice with a group of the formula -OCH 2 0- or -OCH 2 CH 2 0-
  • substituted aralkyls are: (3-chlorophenyl)-methyl, and 2-chloro-2-
  • heteroaryl when used without the "substituted” modifier refers to a monovalent aromatic group with an aromatic carbon atom or nitrogen atom as the point of attachment, said carbon atom or nitrogen atom forming part of one or more aromatic ring structures wherein at least one of the ring atoms is nitrogen, oxygen or sulfur, and wherein the heteroaryl group consists of no atoms other than carbon, hydrogen, oxygen, aromatic nitrogen, aromatic oxygen, and aromatic sulfur. If more than one ring is present, the rings may be fused or unfused. As used herein, the term does not preclude the presence of one or more alkyl, aryl, and/or aralkyl groups (carbon number limitation permitting) attached to the aromatic ring or aromatic ring system.
  • heteroaryl groups include furanyl, imidazolyl, indolyl, indazolyl (Im), isoxazolyl, methylpyridinyl, oxazolyl, phenylpyridinyl, pyridinyl, pyrrolyl, pyrimidinyl, pyrazinyl, quinolyl, quinazolyl, quinoxalinyl, triazinyl, tetrazolyl, thiazolyl, thienyl, and triazolyl.
  • N-heteroaryl refers to a heteroaryl group with a nitrogen atom as the point of attachment.
  • heteroaryl when used without the "substituted” modifier refers to an divalent aromatic group, with two aromatic carbon atoms, two aromatic nitrogen atoms, or one aromatic carbon atom and one aromatic nitrogen atom as the two points of attachment, said atoms forming part of one or more aromatic ring structure(s) wherein at least one of the ring atoms is nitrogen, oxygen or sulfur, and wherein the divalent group consists of no atoms other than carbon, hydrogen, oxygen, aromatic nitrogen, aromatic oxygen and aromatic sulfur. If more than one ring is present, the rings may be fused or unfused.
  • Unfused rings may be connected via one or more of the following: a covalent bond, alkanediyl, or alkenediyl groups (carbon number limitation permitting). Additionally, the ring may contain one or more carbonyl groups (-C(O)-) on a carbon of the ring system so long as the overall ring system is still aromatic. As used herein, the term does not preclude the presence of one or more alkyl, aryl, and/or aralkyl groups (carbon number limitation permitting) attached to the aromatic ring or aromatic ring system.
  • heteroarenediyl groups include:
  • a “heteroarene” refers to the compound H-R, wherein R is heteroaryl. Pyridine and quinoline are non-limiting examples of heteroarenes. When these terms are used with the "substituted" modifier one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, -NH 2 , -N0 2 , "C0 2 H, -C0 2 CH 3 , -CN, -SH, -OCH 3 , -SCH 3 , -OCH 2 CH 3 , -C(0)CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -C(0)NH 2 , -OC(0)CH 3 , -S(0) 2 NH 2 , or is substituted twice with a group of the formula -OCH 2 0- or -OCH 2 CH 2 0-.
  • heteroaralkyl when used without the “substituted” modifier refers to the monovalent group -alkanediyl-heteroaryl, in which the terms alkanediyl and heteroaryl are each used in a manner consistent with the definitions provided above.
  • Non-limiting examples of heteroaralkyls are: pyridinylmethyl and 2-furanyl-propyl.
  • heteroaralkyl When the term heteroaralkyl is used with the "substituted" modifier one or more hydrogen atom from the alkanediyl and/or the heteroaryl group has been independently replaced by -OH, -F, -CI, -Br, -I, -NH 2 , -N0 2 , -C0 2 H, -C0 2 CH 3 , -CN, -SH, -OCH 3 , -SCH 3 , -OCH 2 CH 3 , -C(0)CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -C(0)NH 2 , -OC(0)CH 3 , -S(0) 2 NH 2 , or is substituted twice with a group of the formula -OCH 2 0 ⁇ or -OCH 2 CH 2 0-
  • substituted heteroaralkyls are: (3-chloropyridinyl)-methyl, and 2-ch
  • heterocycloalkyl when used without the "substituted” modifier refers to a monovalent non-aromatic group with a carbon atom or nitrogen atom as the point of attachment, said carbon atom or nitrogen atom forming part of one or more non-aromatic ring structures wherein at least one of the ring atoms is nitrogen, oxygen or sulfur, and wherein the heterocycloalkyl group consists of no atoms other than carbon, hydrogen, nitrogen, oxygen and sulfur. If more than one ring is present, the rings may be fused or unfused. As used herein, the term does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to the ring or ring system.
  • heterocycloalkyl groups include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, pyranyl, oxiranyl, and oxetanyl.
  • N-heterocycloalkyl refers to a heterocycloalkyl group with a nitrogen atom as the point of attachment.
  • heterocycloalkanediyl when used without the “substituted” modifier refers to an divalent cyclic group, with two carbon atoms, two nitrogen atoms, or one carbon atom and one nitrogen atom as the two points of attachment, said atoms forming part of one or more ring structure(s) wherein at least one of the ring atoms is nitrogen, oxygen or sulfur, and wherein the divalent group consists of no atoms other than carbon, hydrogen, nitrogen, oxygen and sulfur. If more than one ring is present, the rings may be fused or unfused.
  • Unfused rings may be connected via one or more of the following: a covalent bond, alkanediyl, or alkenediyl groups (carbon number limitation permitting).
  • alkanediyl or alkenediyl groups (carbon number limitation permitting).
  • the term does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to the ring or ring system.
  • the term does not preclude the presence of one or more double bonds in the ring or ring system, provided that the resulting group remains non-aromatic.
  • heterocycloalkanediyl groups include:
  • one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, -NH 2 , -N0 2 , "C0 2 H, -C0 2 CH 3 , -CN, -SH, -OCH3, -SCH3, -OCH 2 CH 3 , -C(0)CH 3 , -NHCH3, -NHCH 2 CH 3 , -N(CH 3 ) 2 , -C(0)NH 2 , -OC(0)CH 3 , -S(0) 2 NH 2 , or -C(0)OC(CH 3 ) 3 (tert-butyloxycarbonyl, BOC).
  • acyl when used without the “substituted” modifier refers to the group -C(0)R, in which R is a hydrogen, alkyl, aryl, aralkyl or heteroaryl, as those terms are defined above.
  • the groups, -CHO, -C(0)CH 3 (acetyl, Ac), -C(0)CH 2 CH 3 , -C(0)CH 2 CH 2 CH 3 , -C(0)CH(CH 3 ) 2 , -C(0)CH(CH 2 ) 2 , -C(0)C 6 H 5 , -C(0)C 6 H 4 CH 3 , -C(0)CH 2 C 6 H 5 , -C(0)(imidazolyl) are non-limiting examples of acyl groups.
  • a “thioacyl” is defined in an analogous manner, except that the oxygen atom of the group -C(0)R has been replaced with a sulfur atom, -C(S)R.
  • aldehyde corresponds to an alkane, as defined above, wherein at least one of the hydrogen atoms has been replaced with a -CHO group.
  • one or more hydrogen atom (including a hydrogen atom directly attached the carbonyl or thiocarbonyl group, if any) has been independently replaced by -OH, -F, -CI, -Br, -I, -NH 2 , -N0 2 , -C0 2 H, -C0 2 CH 3 , -CN, -SH, -OCH 3 , -SCH 3 , -OCH 2 CH 3 , -C(0)CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -C(0)NH 2 , -OC(0)CH 3 , or -S(0) 2 NH 2 .
  • the groups, -C(0)CH 2 CF 3 , -C0 2 H (carboxyl), -C0 2 CH 3 (methylcarboxyl), -C0 2 CH 2 CH 3 , -C(0)NH 2 (carbamoyl), and -CON(CH 3 ) 2 are non-limiting examples of substituted acyl groups.
  • alkoxy when used without the "substituted” modifier refers to the group -OR, in which R is an alkyl, as that term is defined above.
  • alkoxy groups include: -OCH 3 (methoxy), -OCH 2 CH 3 (ethoxy), -OCH 2 CH 2 CH 3 , -OCH(CH 3 ) 2 (isopropoxy), -OC(CH 3 ) 3 (tert-butoxy), -OCH(CH 2 ) 2 , -O-cyclopentyl, and -O-cyclohexyl.
  • alkenyloxy when used without the “substituted” modifier, refers to groups, defined as -OR, in which R is alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and acyl, respectively.
  • alkoxydiyl refers to the divalent group -O-alkanediyl-, -O-alkanediyl-0-, or -alkanediyl-O-alkanediyl-.
  • alkylthio and acylthio when used without the “substituted” modifier refers to the group -SR, in which R is an alkyl and acyl, respectively.
  • alcohol corresponds to an alkane, as defined above, wherein at least one of the hydrogen atoms has been replaced with a hydroxy group.
  • ether corresponds to an alkane, as defined above, wherein at least one of the hydrogen atoms has been replaced with an alkoxy group.
  • one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, -NH 2 , -N0 2 , -C0 2 H, -C0 2 CH 3 , -CN, -SH, -OCH 3 , -SCH 3 , -OCH 2 CH 3 , -C(0)CH 3 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -C(0)NH 2 , -OC(0)CH 3 , or -S(0) 2 NH 2 .
  • alkylamino when used without the "substituted” modifier refers to the group -NHR, in which R is an alkyl, as that term is defined above.
  • alkylamino groups include: -NHCH 3 and -NHCH 2 CH 3 .
  • dialkylamino when used without the “substituted” modifier refers to the group -NRR', in which R and R' can be the same or different alkyl groups, or R and R' can be taken together to represent an alkanediyl.
  • dialkylamino groups include: -N(CH 3 ) , -N(CH 3 )(CH 2 CH 3 ), and N-pyrrolidinyl.
  • alkoxyamino refers to groups, defined as -NHR, in which R is alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and alkylsulfonyl, respectively.
  • R is alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and alkylsulfonyl, respectively.
  • a non-limiting example of an arylamino group is -NHC63 ⁇ 4.
  • amido (acylamino), when used without the “substituted” modifier, refers to the group -NHR, in which R is acyl, as that term is defined above.
  • a non- limiting example of an amido group is -NHC(0)CH 3 .
  • alkylaminodiyl refers to the divalent group -NH-alkanediyl-, -NH-alkanediyl-NH-, or -alkanediyl-NH-alkanediyl- When any of these terms is used with the "substituted" modifier one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, -NH 2 , -N0 2 , "C0 2 H, -C0 2 CH 3 , -CN, -SH, -OCH3, -SCH3, -OCH 2 CH 3 , -C(0)CH 3 , -NHCH3, -NHCH 2 CH 3 , -N(CH 3 ) 2 , -C(0)NH 2 , -OC(0)CH 3 , or -S(0) 2 NH 2 .
  • the groups -NHC(0)OCH 3 and -NHC(0)NHCH 3 are non-limiting
  • IC5 0 refers to an inhibitory dose which is 50% of the maximum response obtained. This quantitative measure indicates how much of a particular drug or other substance (inhibitor) is needed to inhibit a given biological, biochemical or chemical process (or component of a process, i.e. an enzyme, cell, cell receptor or microorganism) by half.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues, organs, and/or bodily fluids of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable salts” means salts of compounds of the present invention which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as 1,2-ethanedisulfonic acid, 2 -hydroxy ethanesulfonic acid, 2-naphthalenesulfonic acid, 3-phenylpropionic acid, 4,4'-methylenebis(3-hydroxy-2-ene-l-carboxylic acid), 4-methylbicyclo[2.2.2]oct-2-ene- 1 -carboxylic acid, acetic acid, aliphatic mono- and dicarboxylic acids, aliphatic sulfuric acids, aromatic sulfuric acids, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, cinnamic
  • Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases.
  • Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide.
  • Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like. It should be recognized that the particular anion or cation forming a part of any salt of this invention is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (P. H. Stahl & C. G. Wermuth eds., Verlag Helvetica Chimica Acta, 2002).
  • Prevention includes: (1) inhibiting the onset of a disease in a subject or patient which may be at risk and/or predisposed to the disease but does not yet experience or display any or all of the pathology or symptomatology of the disease, and/or (2) slowing the onset of the pathology or symptomatology of a disease in a subject or patient which may be at risk and/or predisposed to the disease but does not yet experience or display any or all of the pathology or symptomatology of the disease.
  • Prodrug means a compound that is convertible in vivo metabolically into an inhibitor according to the present invention.
  • the prodrug itself may or may not also have activity with respect to a given target protein.
  • a compound comprising a hydroxy group may be administered as an ester that is converted by hydrolysis in vivo to the hydroxy compound.
  • esters that may be converted in vivo into hydroxy compounds include acetates, citrates, lactates, phosphates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-P-hydroxynaphthoate, gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, -toluenesulfonates, cyclohexylsulfamates, quinates, esters of amino acids, and the like.
  • a compound comprising an amine group may be administered as an amide that is converted by hydrolysis in vivo to the amine compound.
  • a “stereoisomer” or “optical isomer” is an isomer of a given compound in which the same atoms are bonded to the same other atoms, but where the configuration of those atoms in three dimensions differs.
  • “Enantiomers” are stereoisomers of a given compound that are mirror images of each other, like left and right hands.
  • “Diastereomers” are stereoisomers of a given compound that are not enantiomers.
  • Chiral molecules contain a chiral center, also referred to as a stereocenter or stereogenic center, which is any point, though not necessarily an atom, in a molecule bearing groups such that an interchanging of any two groups leads to a stereoisomer.
  • the chiral center is typically a carbon, phosphorus or sulfur atom, though it is also possible for other atoms to be stereocenters in organic and inorganic compounds.
  • a molecule can have multiple stereocenters, giving it many stereoisomers.
  • the total number of hypothetically possible stereoisomers will not exceed 2 n , where n is the number of tetrahedral stereocenters.
  • Molecules with symmetry frequently have fewer than the maximum possible number of stereoisomers.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture.
  • a mixture of enantiomers can be enantiomerically enriched so that one enantiomer is present in an amount greater than 50%.
  • enantiomers and/or diastereomers can be resolved or separated using techniques known in the art. It is contemplated that that for any stereocenter or axis of chirality for which stereochemistry has not been defined, that for tetrahedral stereogenic centers the stereocenter or axis of chirality can be present in its R form, 5 * form, or as a mixture of the R and S forms, including racemic and non-racemic mixtures.
  • the phrase "substantially free from other stereoisomers" means that the composition contains ⁇ 15%, more preferably ⁇ 10%, even more preferably ⁇ 5%, or most preferably ⁇ 1% of another stereoisomer(s).
  • Treatment includes (1) inhibiting a disease in a subject or patient experiencing or displaying the pathology or symptomatology of the disease (e.g., arresting further development of the pathology and/or symptomatology), (2) ameliorating a disease in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease (e.g., reversing the pathology and/or symptomatology), and/or (3) effecting any measurable decrease in a disease in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease.
  • the present invention relates to compounds of the formula:
  • R5 is hydrogen, alkyl( C ⁇ i2), acyl(c ⁇ i2), substituted alkyl( C ⁇ i2), or substituted acyl(c ⁇ i2), or is taken together with R 2 as described below;
  • R 6 is alkyl ( c ⁇ i2), cycloalkyl (c ⁇ i2), -alkanediyl ( c ⁇ 8)-cycloalkyl (c ⁇ i2), aryl (c ⁇ i 2 ), heteroaryl(c ⁇ i2), aralkyl (c ⁇ i2), heterocycloalkyl (c ⁇ i2), acyl (c ⁇ i2),
  • R5 and R6 are taken together and are alkanediyl(c ⁇ 8), alkoxydiyl(c ⁇ 8), alkylaminodiyl(c ⁇ 8), or a substituted version of any of these groups;
  • R7 is hydrogen, alkyl( C ⁇ i2), or substituted alkyl( C ⁇ i2);
  • X 2 is -C(O)-
  • R 8 is alkyl ( c ⁇ i2), aryl (c ⁇ i8), heteroaryl (c ⁇ i8), aralkyl (c ⁇ i8), heteroaralkyl (c ⁇ i8), heterocycloalkyl(c ⁇ i2), acyl(c ⁇ i2), -alkanediyl(c ⁇ 8) ⁇ heterocycloalkyl( C ⁇ i2), or a substituted version of any of these groups; or
  • Re is a group of the formula
  • X 4 is hydrogen, alkyl(c ⁇ 8), or substituted alkyl(c ⁇ 8);
  • Ri4 is hydroxy or alkoxy(c ⁇ i2), aryloxy(c ⁇ i2), aralkoxy(c ⁇ i2), or a substituted version of any of these groups;
  • R5 and R6 are not taken together as alkylaminodiyl(c ⁇ i2) or R6 is not methyl;
  • Ri is hydrogen, hydroxy, amino, halo, nitro, carboxy, cyano, sulfate, or
  • R-2 is hydrogen, or
  • R3 is hydrogen, alkyl( C ⁇ i2), or substituted alkyl( C ⁇ i2);
  • R4 is hydrogen or hydroxy
  • Xi is hydrogen, or
  • R 2 is not 5 ; or ; when R4 is hydroxy; or
  • R9 is aryl( C ⁇ i2), substituted aryl( C ⁇ i2), heteroaryl( C ⁇ i2), or substituted heteroaryl( C ⁇ i2);
  • Rio is heterocycloalkyl(c ⁇ i8), heteroaryl(c ⁇ i8), or a substituted version of either of these groups, or either of these groups wherein the group is substituted with alkyl( C ⁇ i2), aryl( C ⁇ i2), aralkyl( C ⁇ i2), heteroaryl( C ⁇ i2) wherein any one of these groups have been substituted with amino, alkylaminO(c ⁇ 6), or dialkylaminO(c ⁇ 6), alkylaminO(c ⁇ i2), dialkylaminO(c ⁇ i2), arylaminO(c ⁇ i2), heteroarylaminO(c ⁇ i2); and y 2 is 0, 1, 2, 3, or 4; or a compound of the formula:
  • Ri2 is aryl( C ⁇ i2), substituted aryl( C ⁇ i2), heteroaryl( C ⁇ i2), or substituted heteroaryl( C ⁇ i2);
  • Ri3 is heterocycloalkyl( C ⁇ i8), heteroaryl( C ⁇ i8), or a substituted version of either of these groups, or either of these groups wherein the group is substituted with alkyl( C ⁇ i2), aryl( C ⁇ i2), aralkyl( C ⁇ i2), heteroaryl( C ⁇ i2) wherein any one of these groups have been substituted with amino; alkylaminO(c ⁇ 6); or dialkylaminO(c ⁇ 6), alkylaminO(c ⁇ i2), dialkylaminO(c ⁇ i2), arylaminO(c ⁇ i2), heteroarylaminO(c ⁇ i2); and y 3 is 0, 1, 2, 3, or 4;
  • Compounds of the invention may contain one or more asymmetrically-substituted carbon or nitrogen atoms, and may be isolated in optically active or racemic form. Thus, all chiral, diastereomeric, racemic form, epimeric form, and all geometric isomeric forms of a chemical formula are intended, unless the specific stereochemistry or isomeric form is specifically indicated. Compounds may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. In some embodiments, a single diastereomer is obtained.
  • the stereogenic centers in the compounds involving a tetrahedral atom of the present invention can have the S or the R configuration.
  • Chemical formulas used to represent compounds of the invention will typically only show one of possibly several different tautomers. For example, many types of ketone groups are known to exist in equilibrium with corresponding enol groups. Similarly, many types of imine groups exist in equilibrium with enamine groups. Regardless of which tautomer is depicted for a given compound, and regardless of which one is most prevalent, all tautomers of a given chemical formula are intended.
  • Compounds of the invention may also have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile (e.g., higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the indications stated herein or otherwise.
  • a better pharmacokinetic profile e.g., higher oral bioavailability and/or lower clearance
  • atoms making up the compounds of the present invention are intended to include all isotopic forms of such atoms.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium
  • isotopes of carbon include 13 C and 14 C.
  • Compounds of the present invention may also exist in prodrug form. Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.), the compounds employed in some methods of the invention may, if desired, be delivered in prodrug form. Thus, the invention contemplates prodrugs of compounds of the present invention as well as methods of delivering prodrugs. Prodrugs of the compounds employed in the invention may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.
  • prodrugs include, for example, compounds described herein in which a hydroxy, amino, or carboxy group is bonded to any group that, when the prodrug is administered to a subject, cleaves to form a hydroxy, amino, or carboxylic acid, respectively.
  • African trypanosomiasis is a disease caused by the Trypanosoma brucei parasite and generally spread by the tsetse fly. Also known as sleeping sickness, the disease is endemic to rural parts of Africa and other locations in which the tsetse fly thrives. The disease is transmitted when a person is bitten by the fly and is infected by one of two different subspecies of Trypanosoma brucei: a Trypanosoma brucei rhodesiense infection or a Trypanosoma brucei gambiense infection.
  • the rhodesiense infection is typically an acute infection which last for a few weeks to several months while the gambiense infection is typically chronic and can last several years including long periods of time when the patient is asymptomatic.
  • Typical symptoms of the disease include headaches, fever, weakness, itchiness, pain in the joints, and stiffness. After time, the disease can spread to the brain and cause damage to the central nervous system leading to such complications as psychiatric disorders, trouble sleeping, tremor, paralysis, seizures, and coma before finally leading causing death. If untreated, the disease is fatal.
  • the compounds of the present invention are ordinarily combined with one or more excipients appropriate to the indicated route of administration.
  • the compounds of the present invention may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and tableted or encapsulated for convenient administration.
  • the conjugates may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers.
  • Other excipients and modes of administration are well and widely known in the pharmaceutical art.
  • the pharmaceutical compositions useful in the present invention may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional pharmaceutical carriers and excipients such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc.
  • the compounds of the present invention may be administered by a variety of methods, e.g., orally or by injection (e.g. subcutaneous, intravenous, intraperitoneal, etc.).
  • the novel conjugates may be coated in a material to protect the compound from the action of acids and other natural conditions which may inactivate the compound. They may also be administered by continuous perfusion/infusion of a disease or wound site.
  • the therapeutic compound may be administered to a patient in an appropriate carrier, for example, liposomes, or a diluent.
  • suitable diluents include saline and aqueous buffer solutions.
  • Liposomes include water- in-oil-in-water CGF emulsions as well as conventional liposomes. Additionally, Trapasol®, Travasol®, cyclodextrin, and other drug carrier molecules may be used in combination with the present invention.
  • the compounds of the present invention may also be administered parenterally, intraperitoneally, intraspinally, or intracerebrally.
  • Dispersions can be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion are also envisioned.
  • the composition must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (such as, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.
  • Sterile injectable solutions can be prepared by incorporating the compounds of the present invention in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the therapeutic compound into a sterile carrier which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient (i.e., the therapeutic compound) plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the compounds of the present invention can be orally administered, for example, with an inert diluent or an assimilable edible carrier.
  • the therapeutic compound and other ingredients may also be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or incorporated directly into the subject's diet.
  • the conjugates may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • the percentage of the therapeutic compound in the compositions and preparations may, of course, be varied.
  • the amount of the compounds of the present invention in such therapeutically useful compositions is such that a suitable dosage will be obtained.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit containing a predetermined quantity of the compounds of the present invention calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the compounds of the present invention and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such a therapeutic compound for the treatment of a selected condition in a patient.
  • the therapeutic compound may also be administered topically to the skin, eye, or mucosa. Alternatively, if local delivery to the lungs is desired the therapeutic compound may be administered by inhalation in a dry-powder or aerosol formulation.
  • the compound of the present invention describe in this disclosure are administered at a therapeutically effective dosage sufficient to treat a condition associated with a condition in a patient.
  • the efficacy of the compound of the present invention can be evaluated in an animal model system that may be predictive of efficacy in treating the disease in humans, such as the model systems shown in the examples and drawings.
  • the actual dosage amount of the compound of the present disclosure or composition comprising the conjugates of the present disclosure administered to a subject may be determined by physical and physiological factors such as age, sex, body weight, severity of condition, the type of disease being treated, previous or concurrent therapeutic interventions, idiopathy of the subject and on the route of administration. These factors may be determined by a skilled artisan. The practitioner responsible for administration will typically determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual subject. The dosage may be adjusted by the individual physician in the event of any complication.
  • An effective amount typically will vary from about 1 mg/kg to about 50 mg/kg, in one or more dose administrations daily, for one or several days (depending of course of the mode of administration and the factors discussed above). In some particular embodiments, the amount is less than 5,000 mg per day with a range of 10 mg to 4500 mg per day.
  • the effective amount may be less than 10 mg/kg/day, less than 50 mg kg/day, less than 100 mg/kg/day, less than 250 mg/kg/day. It may alternatively be in the range of 1 mg/kg/day to 250 mg/kg/day.
  • a dose may also comprise from about 0.1 mg/kg/body weight, about 1 mg/kg/body weight, about 10 g/kg/body weight, about 50 g/kg/body weight, or more per administration, and any range derivable therein.
  • a derivable range from the numbers listed herein, a range of about 1 mg/kg/body weight to about 50 mg/kg/body weight, about 5 g/kg/body weight to about 10 g/kg/body weight, etc., can be administered, based on the numbers described above.
  • a pharmaceutical composition of the present disclosure may comprise, for example, at least about 0.1% of a conjugate described in the present disclosure.
  • the compound of the present disclosure may comprise between about 0.25% to about 75% of the weight of the unit, or between about 25% to about 60%, or between about 1% to about 10%, for example, and any range derivable therein.
  • Desired time intervals for delivery of multiple doses can be determined by one of ordinary skill in the art employing no more than routine experimentation. As an example, subjects may be administered two doses daily at approximately 12 hour intervals. In some embodiments, the agent is administered once a day.
  • the compounds may be administered on a routine schedule.
  • a routine schedule refers to a predetermined designated period of time.
  • the routine schedule may encompass periods of time which are identical or which differ in length, as long as the schedule is predetermined.
  • the routine schedule may involve administration twice a day, every day, every two days, every three days, every four days, every five days, every six days, a weekly basis, a monthly basis or any set number of days or weeks there- between.
  • the predetermined routine schedule may involve administration on a twice daily basis for the first week, followed by a daily basis for several months, etc.
  • the invention provides that the agent(s) may taken orally and that the timing of which is or is not dependent upon food intake. Thus, for example, the agent can be taken every morning and/or every evening, regardless of when the subject has eaten or will eat.
  • the compound of the present invention may also find use in combination therapies.
  • Effective combination therapy may be achieved with a single composition or pharmacological formulation that includes both agents, or with two distinct compositions or formulations, administered at the same time, wherein one composition includes a compound, and the other includes the second agent(s).
  • the other therapeutic modality may be administered before, concurrently with, or following administration of the compound of the present invention.
  • the therapy using the compound of the present invention may precede or follow administration of the other agent(s) by intervals ranging from minutes to weeks.
  • the other agent and the compounds of the present disclosure are administered separately, one would generally ensure that a significant period of time did not expire between the time of each delivery, such that each agent would still be able to exert an advantageously combined effect.
  • Non-limiting examples of pharmacological agents that may be used in the present invention include any pharmacological agent known to be of benefit in the treatment of a sleeping sickness or other microbial or parasitic infections.
  • the second therapeutic agent could include pentamidine, suramin, eflornithine, nifurtimox, or melarsoprol.
  • Crotonoyl chloride (317 mg, 3.03 mmol) was added dropwise over 5 min to a stirred solution of N-(2-(lH-Indol-3-yl)ethyl)-3,3-dimethoxypropan-l-amine (664 mg, 2.53 mmol) and Hunig's base (785 mg, 6.07 mmol) in (3 ⁇ 4(3 ⁇ 4 (25 mL) at -78 °C. The solution was stirred at -78 °C for 2 h, then partitioned between a saturated aqueous aHC0 3 solution (20 mL) and CH2CI2 (30 mL).
  • the reaction was partitioned between a saturated aqueous aHC0 3 solution (6.5 niL), ethyl acetate (6.5 mL), and methanol (0.5 mL). The two phases were separated and the aqueous phase extracted with ethyl acetate (2 x 6.5 mL). The combined organic fractions were washed with brine (6.5 mL) and dried ( a 2 S04). The solution was filtered and concentrated in vacuo to give crude the title compound as an opaque viscous oil.
  • Enzyme activity was quantified by the attachment of [ 3 H]methionine to tRNA in the presence of the T. brucei MetRS enzyme. Reactions were performed in 96-well filter plates with Durapore membranes (MSHV 4B 10; Millipore) in volumes of 75 mL. The reaction was performed with 25 mM HEPES (pH 7.9), 10 mM MgCl 2 , 50 mM KC1, 0.2 mM spermine, 0.1 mg/mL bovine serum albumin, 2.5 mM dithiothreitol, 1% DMSO, and 1 U/mL pyrophosphatase (11643; Sigma).
  • Recombinant enzyme (10 nM) and compound inhibitors starting concentration varied depending on potency and included 12 serial 2-fold dilutions
  • a concentration of compound inhibitors 100 ⁇ g/mL
  • 0.1 mM ATP 0.1 mM
  • 250 nM [ 3 H]methionine 80 Ci/mmol
  • the plate was incubated without shaking at room temperature for 120 min.
  • the reactions were stopped by the addition of 100 ⁇ ⁇ cold 10% trichloroacetic acid.
  • the reaction components were separated from tRNA by filtration through a vacuum manifold and washed three times with cold 10% trichloroacetic acid.
  • T. brucei brucei (bloodstream form strain 427) were cultured in HMI-9 medium containing 10% fetal bovine serum, penicillin, and streptomycin at 37 °C with 5% CO 2 and T. brucei rhodesiense (bloodstream form STIB900) were grown in HMI-18 containing 20% fetal bovine serum, penicillin, and streptomycin (Hirumi and Hirumi, 1989). Drug sensitivity of the T. brucei strain was determined in 24-well or 96-well microtiter plates in triplicate with an initial inoculum of 5 x 10 4 trypomastigotes per well.
  • Table I Percent growth inhibition for compounds with designated 3 ⁇ 4 and R3 ⁇ 4 at 10 ⁇ treatment for 48 hours
  • Table 3 EC 50 and IC ⁇ e values for T. brucei cell growth inhibition following treatment by specific compounds.
  • JJS-4- 150-1 > 20000.0 > 10000.0
  • JJS-4- 150-2 > 20000.0 > 10000.0
  • compositions and methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of certain embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and methods and in the steps or in the sequence of steps of the methods described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

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Abstract

La présente invention concerne des composés qui peuvent être utilisés pour traiter la maladie du sommeil et des infections de Trypanosoma brucei. La présente invention concerne également des compositions pharmaceutiques et des méthodes d'utilisation desdits composés.
PCT/US2015/038974 2014-07-02 2015-07-02 Nouveaux inhibiteurs de méthionyl t-arn synthétase (tb metrs) de trypanosoma brucei pour le traitement de la trypanosomiase africaine Ceased WO2016004297A1 (fr)

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WO2018115275A1 (fr) 2016-12-23 2018-06-28 Irbm Science Park S.P.A. Composés utilisés pour traiter une infection cinétoplastide
WO2019106368A1 (fr) * 2017-12-01 2019-06-06 The University Court Of The University Of Edinburgh Dérivés de pyrrolo[3,2-c]pyridin-4-one utilisés en tant qu'inhibiteurs de pfk utiles pour le traitement d'infections protozoaires

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Cited By (3)

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Publication number Priority date Publication date Assignee Title
WO2018115275A1 (fr) 2016-12-23 2018-06-28 Irbm Science Park S.P.A. Composés utilisés pour traiter une infection cinétoplastide
US10815222B2 (en) 2016-12-23 2020-10-27 C.N.C.C.S. S.C.A.R.L. Collezione Nazionale Dei Composti Chimici E Centro Screening Compounds for use in the treatment of kinetoplastid infection
WO2019106368A1 (fr) * 2017-12-01 2019-06-06 The University Court Of The University Of Edinburgh Dérivés de pyrrolo[3,2-c]pyridin-4-one utilisés en tant qu'inhibiteurs de pfk utiles pour le traitement d'infections protozoaires

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