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WO2012154880A1 - Régulateurs de protéostasie pour le traitement de la mucoviscidose et autres maladies de mauvais repliement des protéines - Google Patents

Régulateurs de protéostasie pour le traitement de la mucoviscidose et autres maladies de mauvais repliement des protéines Download PDF

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Publication number
WO2012154880A1
WO2012154880A1 PCT/US2012/037159 US2012037159W WO2012154880A1 WO 2012154880 A1 WO2012154880 A1 WO 2012154880A1 US 2012037159 W US2012037159 W US 2012037159W WO 2012154880 A1 WO2012154880 A1 WO 2012154880A1
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optionally substituted
cycloalkyl
heteroaryl
cycloalkenyl
group
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Bradley Tait
Noel A. POWELL
Matthew Cullen
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Kineta Inc
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Proteostasis Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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

Definitions

  • Protein homeostasis a balance between protein synthesis, folding, trafficking, aggregation, and degradation, referred to as protein homeostasis, utilizing sensors and networks of pathways [Sitia et al., Nature 426: 891-894, 2003; Ron et al, Nat Rev Mol Cell Biol 8: 519-529, 2007].
  • the cellular maintenance of protein homeostasis, or proteostasis refers to controlling the conformation, binding interactions, location and concentration of individual proteins making up the proteome. Protein folding in vivo is accomplished through interactions between the folding polypeptide chain and
  • Cystic Fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene 1 which encodes a multi-membrane spanning epithelial chloride channel.
  • CFTR cystic fibrosis transmembrane conductance regulator
  • AF508 also impacts the normal function of additional organs (pancreas, intestine, gall bladder), suggesting that the loss-of- function impacts multiple downstream pathways that will require correction.
  • CF and other maladies of protein misfolding arise as a result of an imbalance in the capacity of the protein homeostasis (proteostasis) environment to handle the reduced energetic stability of misfolded, mutated proteins that are critical for normal physiology 4"6 .
  • proteostasis protein homeostasis
  • the cellular proteomic and metabolic environment is highly adaptable, and responds to stress and disease through numerous signaling pathways that include, among others, the unfolded protein response (UPR) and heat shock response (HSR).
  • URR unfolded protein response
  • HSR heat shock response
  • the present invention is directed to compounds having the Formulae (Ia-Ib), (Ila- lid), (Illa-IIIb), (IV), (V), (VI), (Vlla-VIIc), (VIII), (IXa-IXb), (Xa-Xb), (XIa-XIb) and (Xlla-XIIb), compositions thereof and methods for the treatment of a condition associated with a dysfunction in proteostasis comprising an effective amount of these compounds.
  • the invention is a compound having the Formula (la):
  • G is a 3- to 7-membered optionally substituted heterocyclic or an optionally substituted heteroaryl
  • Ai is N(R a ) 2 ;
  • Each Ri is independently selected from the group consisting of hydi
  • Ci-Cio alkyl optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo OR b , SR b , NR b R b , C(0)OR b , N0 2 , CN, C(0)R b , C(0)C(0)R b , C(0)NR b R b , NR b C(0)R b , NR b S(0) n R b , N(R b )(COOR b ), NR b C(0)C(0)R b , NR b C(0)R b , NR b C(0)N(R b ) 2 , NR b S(0) n NR b
  • Each R a is independently selected from the group consisting of hydrogen, optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, C(0)OR b , C(0)R b , C(0)C(0)R b and S(0) n R b; or the two R a groups are taken together with the nitrogen atom which they are attached to form an optionally substituted 3- to 8-membered heterocyclic or optionally substituted heteroaryl;
  • Each R b is independently selected from the group consisting of H, optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2- C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl; or two R b groups are taken together with the atom which they are attached to form a C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 3- to 8-membered heterocyclic, aryl or heteroaryl, each optionally substituted; and
  • n 0, 1 or 2.
  • the invention is directed to a compound having the Formula (lb):
  • Gi is optionally substituted pyridyl or optionally substituted pyrimidyl
  • Ai is N(R a ) 2 ;
  • Each Ri is independently selected from the group consisting of hydrogen, optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo OR b , SR b , NR b R b , C(0)OR b , N0 2 , CN, C(0)R b , C(0)C(0)R b , C(0)NR b R b , NR b C(0)N(R b ) 2 , NR b C(0)R b , NR b S(0) n R b , N(R b )(COOR b ), NR b C(0)C(0)R b , NR b C(0)R
  • Each R a is independently selected from the group consisting of hydrogen, optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, C(0)OR b , C(0)R b , C(0)C(0)R b , and S(0) n R b ; or the two R a groups are taken together with the nitrogen atom which they are attached to form an optionally substituted 3- to 8-membered heterocyclic or optionally substituted heteroaryl;
  • Each R b is independently selected from the group consisting of H, optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2- Cio alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl; or two R b groups are taken together with the atom which they are attached to form a C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 3- to 8-membered heterocyclic, aryl or heteroaryl, each optionally substituted; and
  • n 0, 1 or 2.
  • the invention additionally encompasses a method of treating cancer or a tumor comprising administering to a patient in need thereof an effective amount of a compound having the Formula (Ia-Ib), (Ila-IId), (III), (IV), (V), (VI), (Vlla-VIIc), (VIII), (IXa-IXb), (Xa-Xb), (XIa-XIb) or (Xlla-XIIb), or a pharmaceutically acceptable salt, solvate, clathrate or prodrug of any of thereof.
  • the Figure is an immunoblot analysis showing enhanced levels of bands B and C when CFBE41o- lung cells were cultured in the presence and absence of DMSO (lane 1) and compound 1 (lane 2) in the assay described below in the Exemplification section.
  • a cell encompasses both a single cell and a combination of two or more cells.
  • G3 is an optionally substituted 3- to 8-membered heterocyclic, aryl, or heteroaryl, each optionally substituted;
  • Ri is selected from the group consisting of hydrogen, optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR b , SR b , NR b R b , C(0)OR b , N0 2 , CN, C(0)R b , C(0)C(0)R b ,
  • Di is phenyl substituted with one or more substituents selected from the group consisting of optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR b , SR b , NR b R b , C(0)OR b , N0 2 , CN, C(0)R b , C(0)C(0)R b , C(0)NR b R b , NR b C(0)R b , NR b C(0)N(R b ) 2 , NR b S(0) n R b ,
  • N(R b )(COOR b ), NR b C(0)C(0)R b , NR b C(0)R b , NR b S(0) n NR b R b , NR b S(0) n R b , S(0) n R b , S(0) n NR b R b , OC(0)OR b , and (C NR b )R b ;
  • R a is selected from the group consisting of hydrogen, optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, C(0)OR b , C(0)R b , C(0)C(0)R b and S(0) n R b ;
  • Each 3 ⁇ 4 is independently selected from the group consisting of H, optionally substituted Ci-Cio alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C 2 - C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substitute
  • n 0, 1 or 2.
  • the invention is a compound having the Formula (lib).
  • G3 is an optionally substituted 3- to 7-membered heterocyclic, aryl, or heteroaryl, each optionally substituted;
  • R a is selected from the group consisting of hydrogen, optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, C(0)OR b , C(0)R b , C(0)C(0)R b and S(0) n R b ;
  • Each R b is independently selected from the group consisting of H, optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2- C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl; or two R b groups are taken together with the atom which they are attached to form a C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 3- to 8-membered heterocyclic, aryl or heteroaryl, each optionally substituted;
  • D 2 is selected from the group consisting of optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted benzyl, optionally substituted heteroaryl, and C(Rs)3;
  • Ri is selected from the group consisting of hydrogen, optionally substituted Ci-Cio alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR b , SR b , NR b R b , C(0)OR b , N0 2 , CN, C(0)R b , C(0)C(0)R b ,
  • Each R 5 is independently selected from the group consisting of optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2- C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR b , SR b , NR b R b , C(0)OR b , N0 2 , CN, C(0)R b , C(0)C(0)R b , C(0)NR b R b , NR b C(0)R b , NR b C(0)N(R b ) 2 , NR b S(0) n R b , N(R b )(COOR b ),
  • NR b C(0)C(0)R b , NR b C(0)R b , NR b S(0) n NR b R b , NR b S(0) n R b , S(0) n R b , S(0) n NR b R b , OC(0)OR b; and (C NR b )R b ; alternatively, two R5 groups can be taken together with the carbon to which they are attached to form a spiro C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 3- to 8-membered heterocyclic, aryl or heteroaryl; and n is 0, 1 or 2.
  • G 4 is a 6-membered heteroaryl containing one or more ring nitrogen atoms
  • D 3 is optionally substituted aryl or optionally substituted heteroaryl;
  • Each Ri is independently selected from the group consisting of hydrogen, optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR b , SR b , NR b R b , C(0)OR b , N0 2 , CN, C(0)R b , C(0)C(0)R b , C(0)NR b R b , NR b C(0)R b , NR b C(0)N(R b ) 2 , NR b S(0) n R b , N(R b )(COOR b
  • Each R a is selected from the group consisting of hydrogen, optionally substituted Ci-Cio alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, C(0)OR b , C(0)R b , C(0)C(0)R b and S(0) n R b ;
  • Each R b is independently selected from the group consisting of H, optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2- Cio alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;or two R b groups are taken together with the atom which they are attached to form a C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 3- to 8-membered heterocyclic, aryl or heteroaryl, each optionally substituted; and
  • n 0, 1 or 2.
  • the invention is a compound having Formula (lid):
  • D 4 is selected from the group consisting of optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl;
  • Ri is selected from the group consisting of hydrogen, optionally substituted C1-C1 0 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR b , SR b , NR b R b , C(0)OR b , N0 2 , CN, C(0)R b , C(0)C(0)R b ,
  • Each R a is selected from the group consisting of hydrogen, optionally substituted
  • Ci-Cio alkyl optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, C(0)OR b , C(0)R b , C(0)C(0)R b and S(0) n R b ;
  • Each R c is independently selected from the group consisting of hydrogen, optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR b , SR b , NR b R b , C(0)OR b , N0 2 , CN, C(0)R b , C(0)C(0)R b , C(0)NR b R b , NR b C(0)R b , NR b C(0)N(R b ) 2 , NR b S(0) n R b , N(R b )(COOR b ), NR b C(0)C(0)R b , NR b C(0)
  • Each R b is independently selected from the group consisting of H, optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2- Cio alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl; or two R b groups are taken together with the atom which they are attached to form a C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 3- to 8-membered heterocyclic, aryl or heteroaryl, each optionally substituted; and
  • n 0, 1 or 2.
  • the invention is a compound having the Formula (Ilia):
  • G3 is an optionally substituted 3- to 7-membered heterocyclic, aryl, or heteroaryl, each optionally substituted;
  • Ri is selected from the group consisting of hydrogen, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, optionally substituted C3-C 12 cycloalkyl, optionally substituted C3-C 12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR b , SR b , NR b R b , C(0)OR b , N0 2 , CN, C(0)R b , C(0)C(0)R b ,
  • Each R 3 is independently selected from the group consisting of hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C 2 -C 10 alkynyl, optionally substituted C3-C 12 cycloalkyl, optionally substituted C3-C 12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR b , SR b , NR b R b , C(0)OR b , N0 2 , CN, C(0)R b , C(0)C(0)R b , C(0)NR b R b , NR b C(0)R b , NR b C(0)N(R b ) 2 , NR b S(0) n R b , N(R b )(COOR b ), NR b C(0)C(0)R b , NR b S(0) n
  • Re is phenyl substituted with one or more substituents selected from the group consisting of optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, optionally substituted C3-C 12 cycloalkyl, optionally substituted C3-C 12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR b , SR b , NR b R b , C(0)OR b , N0 2 , CN, C(0)R b , C(0)C(0)R b , C(0)NR b R b , NR b C(0)R b , NR b C(0)N(R b ) 2 , NR b S(0) n R b ,
  • N(R b )(COOR b ), NR b C(0)C(0)R b , NR b C(0)R b , NR b C(0)NR b , NR b S(0) n NR b R b , NR b S(0) n R b , S(0) n R b , S(0) n NR b R b , OC(0)OR b, and (C NR b )R b ;
  • Each R b is independently selected from the group consisting of H, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 - C 10 alkynyl, optionally substituted C3-C 12 cycloalkyl, optionally substituted C3-C 12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;or two R b groups are taken together with the atom which they are attached to form a C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 3- to 8-membered heterocyclic, aryl or heteroaryl, each optionally substituted; and
  • n 0, 1 or 2.
  • the invention is a compound having the Formula (Illb):
  • G3 is an optionally substituted 3- to 7-membered heterocyclic, aryl, or heteroaryl, each optionally substituted;
  • R2 is selected from the group consisting of optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, and optionally substituted C3-C12 cycloalkenyl;
  • Each R 3 is independently selected from the group consisting of hydrogen, optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR b , SR b , NR b R b , C(0)OR b , N0 2 , CN, C(0)R b , C(0)C(0)R b , C(0)NR b R b , NR b C(0)R b , NR b C(0)N(R b ) 2 , NR b S(0) n R b , N(R b )(COOR b ), NR b C(0)C(0)R b , NR b C(0)R
  • R6 is phenyl substituted with one or more substituents selected from the group consisting of optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR b , SR b , NR b R b , C(0)OR b , N0 2 , CN, C(0)R b , C(0)C(0)R b , C(0)NR b R b , NR b C(0)R b , NR b C(0)N(R b ) 2 , NR b S(0) n R b ,
  • Each 3 ⁇ 4 is independently selected from the group consisting of H, optionally substituted Ci-Cio alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C 2 - C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl, or two Rb groups are taken together with the atom which they are attached to form a C3-C8
  • n 0, 1 or 2.
  • the invention is a compound having the Formula (IV):
  • G3 is an optionally substituted 3- to 7-membered heterocyclic, an aryl, or a heteroaryl, each optionally substituted;
  • Rs is selected from the group consisting of hydrogen, optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR b , SR b , NR b R b , C(0)OR b , N0 2 , CN, C(0)R b , C(0)C(0)R b ,
  • R6 is phenyl substituted with one or more substituents selected from the group consisting of optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, ORb, SRb, RbRb, C(0)ORb, N0 2 , CN, C(0)R b , C(0)C(0)R b , C(0)NR b Rb, NR b C(0)R b , NR b C(0)N(R b ) 2 , NR b S(0) n R b ,
  • Each 3 ⁇ 4 is independently selected from the group consisting of H, optionally substituted Ci-Cio alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 - C 10 alkynyl, optionally substituted C3-C 12 cycloalkyl, optionally substituted C3-C 12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl, wherein the two R b groups can be taken together with the atom which they are attached to form a C3-C8 cycloalkyl
  • n 0, 1 or 2.
  • Gi is an optionally pyridyl or an optionally substituted pyrimidyl
  • R9 is selected from the group consisting of substituted methyl, optionally substituted C 2 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 - Cio alkynyl, optionally substituted C3-C 12 cycloalkyl, optionally substituted C3-C 12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR b , SR b , NR b R b , C(0)OR b , N0 2 , CN, C(0)R b , C(0)C(0)R b , C(0)NR b R b , NR b C(0)Rb, NR b C(0)N(R b ) 2 , NR b S(0) n R b , N(R b )(COOR b ),
  • Each R 3 is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C 12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR b , SR b , NR b R b , C(0)OR b , N0 2 , CN, C(0)R b , C(0)C(0)R b , C(0)NR b R b , NR b C(0)R b , NR b C(0)N(R b ) 2 , NR b S(0) n R b , N(R b )(COOR b ), NR b C(0)C(0)Rb, NR b C(0)Rb,
  • Each R a is independently selected from the group consisting of hydrogen, optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, C(0)OR b , C(0)R b , C(0)C(0)R b and S(0) n R b ;
  • Each R 7 is independently selected from the group consisting of hydrogen, optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, C(0)OR b , C(0)R b , C(0)C(0)R b and S(0) n R b ;
  • the two R7 are taken together with the nitrogen atom to which they are attached to form a 3- to 7- membered heterocyclic or heteroaryl;
  • Each R b is independently selected from the group consisting of H, optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2- C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl; or two R b groups are taken together with the atom which they are attached to form a C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 3- to 8-membered heterocyclic, aryl or heteroaryl, each optionally substituted; and
  • n 0, 1 or 2.
  • e invention is a compound having the Formula (VI):
  • B is selected from the group consisting of hydrogen, optionally substituted Ci-Cio alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl;
  • Rio is selected from the group consisting of hydrogen, optionally substituted Ci- C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR b , SR b , NR b R b , C(0)OR b , N0 2 , CN, C(0)R b , C(0)C(0)R b ,
  • Each R a is selected from the group consisting of hydrogen, optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, C(0)OR b , C(0)R b , C(0)C(0)R b and S(0) n R b ;
  • Each R c is independently selected from the group consisting of hydrogen, optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR b , SR b , NR b R b , C(0)OR b , N0 2 , CN, C(0)R b , C(0)C(0)R b , C(0)NR b R b , NR b C(0)R b , NR b C(0)N(R b ) 2 , NR b S(0) n R b , N(R b )(COOR b ), NR b C(0)C(0)R b , NR b C(0)
  • Each R b is independently selected from the group consisting of H, optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2- C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl, or two R b groups are taken together with the atom which they are attached to form a C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 3- to 8-membered heterocyclic, aryl or heteroaryl, each optionally substituted; and
  • n 0, 1 or 2.
  • the invention is a compound having the Formula (Vila), (Vllb) or (VIIc):
  • G5 is optionally substituted pyrimidyl
  • a 2 is N(R a ) 2 ;
  • R 11 is selected from the group consisting of hydrogen, optionally substituted Ci- C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C 12 cycloalkyl, optionally substituted C3-C 12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR b , SR b , NR b R b , C(0)OR b , N0 2 , CN, C(0)R b , C(0)C(0)R b ,
  • Each Ra is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, optionally substituted C3-C 12 cycloalkyl, optionally substituted C3-C 12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, C(0)OR b , C(0)R b , C(0)C(0)R b and S(0) n R b ; or the two R a groups are taken together with the nitrogen atom which they are attached to form an optionally substituted 3- to 8-membered heterocyclic or optionally substituted heteroaryl;
  • Each R b is independently selected from the group consisting of H, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 - C 10 alkynyl, optionally substituted C3-C 12 cycloalkyl, optionally substituted C3-C 12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl; or two R b groups are taken together with the atom which they are attached to form a C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 3- to 8-membered heterocyclic, aryl or heteroaryl, each optionally substituted; and
  • n 0, 1 or 2.
  • the invention is a compound having the Formula
  • Xi is selected from the group consisting of O and S;
  • G5 is optionally substituted pyrimidyl
  • a 2 is N(R a ) 2 ;
  • R12 is selected from the group consisting of hydrogen, optionally substituted Ci- C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR b , SR b , NR b R b , C(0)OR b , N0 2 , CN, C(0)R b , C(0)C(0)R b ,
  • Each R a is independently selected from the group consisting of hydrogen, optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, C(0)OR b , C(0)R b , C(0)C(0)R b and S(0) n R b ; or the two R a groups are taken together with the nitrogen atom which they are attached to form an optionally substituted 3- to 8-membered heterocyclic or optionally substituted heteroaryl;
  • Each R b is independently selected from the group consisting of H, optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2- Cio alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl; or two R b groups are taken together with the atom which they are attached to form a C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 3- to 8-membered heterocyclic, aryl or heteroaryl, each optionally substituted; and
  • n 0, 1 or 2;
  • the invention is a compound having the Formula (IXa) or
  • G5 is optionally substituted pyrimidyl
  • a 2 is N(R a ) 2 ;
  • Each R 3 is independently selected from the group consisting of hydrogen, optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR b , SR b , NR b R b , C(0)OR b , N0 2 , CN, C(0)R b , C(0)C(0)R b , C(0)NR b R b , NR b C(0)R b , NR b C(0)N(R b ) 2 , NR b S(0) n R b , N(R b )(COOR b ), NR b C(0)C(0)R b , NR b C(0)R
  • Each R a is independently selected from the group consisting of hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, C(0)OR b , C(0)R b , C(0)C(0)R b and S(0) n R b , or the two R a groups are taken together with the nitrogen atom which they are attached to form an optionally substituted 3- to 8-membered heterocyclic or optionally substituted heteroaryl;
  • Each R b is independently selected from the group consisting of H, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2- C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl; or two R b groups are taken together with the atom which they are attached to form a C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 3- to 8-membered heterocyclic, aryl or heteroaryl, each optionally substituted; and
  • n 0, 1 or 2.
  • the invention is additionally directed to a compound having the Formula (Xa) or
  • G6 is nitrogen or C-H
  • D5 is selected from the group consisting of optionally substituted C1-C10 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, C(0)OR b , C(0)R b , C(0)NR b R b , and S(0) n R b ;
  • Each Ri is independently selected from the group consisting of hydrogen, optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR b , SR b , NR b R b , C(0)OR b , N0 2 , CN, C(0)R b , C(0)C(0)R b , C(0)NR b R b , NR b C(0)R b , NR b C(0)N(R b ) 2 , NR b S(0) n R b , N(R b )(COOR b ), NR b C(0)C(0)R b , NR b C(0)R
  • Both Ri can join with the carbon atoms to which they are attached to form an optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl;
  • Each R 3 is independently selected from the group consisting of hydrogen, optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR b , SR b , NR b R b , C(0)OR b , N0 2 , CN, C(0)R b , C(0)C(0)R b , C(0)NR b R b , NR b C(0)R b , NR b C(0)N(R b ) 2 , NR b S(0) n R b , N(R b )(COOR b ), NR b C(0)C(0)R b , NR b C
  • Any two R3 can join to form an optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl;
  • Each R b is independently selected from the group consisting of H, optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2- C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl;or two R b groups are taken together with the atom which they are attached to form a C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 3- to 8-membered heterocyclic, aryl or heteroaryl, each optionally substituted; and
  • n 0, 1 or 2.
  • Preferred compounds of Formula (Xa) and (Xb) are represented by Formulas (XIa) and (Xlb), respectively, which include all tautomeric forms, including those represented by Formulas (Xlla) and (Xllb), respectively.
  • R g and R h independently have the meanings given for R3 in Formulas (Xa) and (Xb); R; and R j independently have the meanings given for Ri in Formulas (Xa) and (Xb) and D5 has the meaning given for this variable in Formulas (Xa) and (Xb).
  • R g and R h are each independently hydrogen or Ci-C6-alkyl, or R g and R h are taken with the carbon atoms to which they are attached to form an optionally substituted benzo ring.
  • R g and R h are each independently hydrogen or methyl.
  • R g and R h are both hydrogen, R g and R h are both methyl, or R h is methyl and R g is hydrogen.
  • Ri and R j are each independently selected from hydrogen and Ci-C6-alkyl.
  • R j is hydrogen and R; is Ci-C6-alkyl, such as methyl.
  • D 5 is preferably Ci- C6-alkyl, Cs-Cs-cycloalkyl, aryl-Ci-C6-alkyl, such as benzyl, or optionally substituted phenyl, such as phenyl substituted with up to three substituents independently selected from halogen, Ci-C6-alkyl and Ci-C6-alkoxy, such as methoxy.
  • phenyl is unsubstituted or non-substituted, for example with chloro, CN, Ci-C4-alkyl or methoxy.
  • the pharmaceutical composition comprises a compound of Formula (Ia-Ib), (Ila-IId), (Illa-IIIb), (IV), (V), (VI), (Vlla-VIIc), (VIII), (IXa-IXb), (Xa-Xb), (Xla- Xlb) or (Xlla-XIIb), or a pharmaceutically acceptable salt, prodrug or solvate thereof.
  • the invention also includes a method of treating a patient suffering from a condition associated with a dysfunction in proteostasis comprising administering an effective amount of a compound of Formula (Ia-Ib), (Ila-IId), (Illa-IIIb), (IV), (V), (VI), (Vlla-VIIc), (VIII), (IXa-IXb), (Xa-Xb), (XIa-XIb) or (Xlla-XIIb), or a pharmaceutically acceptable salt, prodrug or solvate thereof.
  • a compound of Formula Ia-Ib), (Ila-IId), (Illa-IIIb), (IV), (V), (VI), (Vlla-VIIc), (VIII), (IXa-IXb), (Xa-Xb), (XIa-XIb) or (Xlla-XIIb), or a pharmaceutically acceptable salt, prodrug or solvate thereof.
  • the invention further includes a method of treating a patient suffering from a condition associated with a dysfunction in proteostasis comprising administering to said patient an effective amount of a compound of Formula (Ia-Ib), (Ila-IId), (Illa-IIIb), (IV), (V), (VI), (Vlla-VIIc), (VIII), (IXa-IXb), (Xa-Xb), (XIa-XIb) or (Xlla-XIIb), or a pharmaceutically acceptable salt, prodrug or solvate thereof.
  • a compound of Formula Ia-Ib), (Ila-IId), (Illa-IIIb), (IV), (V), (VI), (Vlla-VIIc), (VIII), (IXa-IXb), (Xa-Xb), (XIa-XIb) or (Xlla-XIIb), or a pharmaceutically acceptable salt, prodrug or solvate thereof.
  • the invention is a method of treating a patient suffering from a condition associated with a dysfunction in proteostasis comprising administering to said patient an effective amount of a compound having the Formula (Ia-Ib), (Ila-IId), (Illa- Illb), (IV), (V), (VI), (Vlla-VIIc), (VIII), (IXa-IXb), (Xa-Xb), (XIa-XIb) or (Xlla-XIIb), or a pharmaceutically acceptable salt, prodrug or solvate thereof.
  • the invention is directed to a pharmaceutical composition comprising:
  • the present invention is directed to compounds of Formulae (Ia-Ib), (Ila-IId), (III), (IV), (V), (VI), (Vlla-VIIc), (VIII), (IXa-IXb), (Xa-Xb), (XIa-XIb) and (Xlla-XIIb), and pharmaceutically acceptable salts, prodrugs or solvates thereof, pharmaceutical compositions thereof and methods of use thereof in the treatment of conditions associated with a dysfunction in proteostasis.
  • the invention is directed to a compound of Formula (la), pharmaceutical compositions thereof or methods of use thereof.
  • the invention is a compound of Formula (lb), or a pharmaceutically acceptable salt, prodrug or solvate thereof.
  • the compound has the Formula (lb), wherein Gi is an optionally substituted pyrimidyl.
  • the invention is directed to a compound of Formula (Ila), or a pharmaceutically acceptable salt, prodrug or solvate thereof.
  • the compound has the Formula (Ila), wherein G3 is a 3- to 8-membered heterocyclic or a heteroaryl, each optionally substituted.
  • the compound has the Formula (Ila), wherein Di is phenyl substituted in its para position with a substituent selected from the group consisting of optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR b , SR b , NR b R b , C(0)OR b , N0 2 , CN, C(0)R b , C(0)C(0)R b , C(0)NR b R b , NR b C(0)R b , NR b S(0) n R b , N(R b )(COOR b ), NR b C(0)C(0)R
  • the compound has the Formula (Ila), wherein Di is phenyl substituted with a group selected from optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, and optionally substituted C2-C10 alkynyl.
  • Di is phenyl substituted at its para position with a group selected from optionally substituted Ci- Cio alkyl, optionally substituted C2-C1 0 alkenyl, and optionally substituted C2-C1 0 alkynyl.
  • the compound has the Formula (Ila), wherein Ri is optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR b , SR b , NR b R b , C(0)OR b , N0 2 , CN, C(0)R b , C(0)C(0)R b , C(0)NR b R b , NR b C(0)R b , NR b C(0)N(R b ) 2 , NR b S(0) n R b , N(R b )(COOR b ), NR b C(0)C(0)R b , NR
  • the compound has the Formula (Ila), wherein R a is selected from the group consisting hydrogen, and optionally substituted C1-C1 0 alkyl.
  • the compound has the Formula (Ila), wherein G 3 is selected from the group consisting of, azetidinyl, azolidinyl, oxolanyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, piperidinyl, pyridyl, pyrimidyl, diazinyl, triazinyl, and
  • the compound has the Formula (Ila), wherein G 3 is selected from the group consisting of optionally substituted pyridyl and optionally substituted pyrimidyl.
  • the invention additionally encompasses compounds having the Formula (lib), pharmaceutically acceptable salts, prodrugs or solvates thereof.
  • the compound has the Formula (lib), wherein Ri is selected from the group consisting of optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR b , SR b , NR b R b , C(0)OR b , N0 2 , CN, C(0)R b , C(0)C(0)R b , C(0)NR b R b , NR b C(0)R b , NR b C(0)N(R b ) 2 , NR b S(0) n
  • Ri is selected from the group consisting of optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl.
  • the compound has the Formula (lib), wherein D 2 is selected from the group consisting of optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted benzyl, and optionally substituted heteroaryl.
  • the compound has the Formula (lib), wherein D 2 is C(Rs)3 and each R 5 is independently selected from the group consisting of optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl.
  • the compound has the Formula (lib), wherein G 3 is selected from the group consisting of optionally substituted heterocyclic and optionally substituted heteroaryl, such as optionally substituted pyridyl and optionally substituted pyrimidyl. In one embodiment, the compound has the Formula (lib), wherein G3 is optionally substituted pyrimidyl.
  • the invention also encompasses compounds having the Formula (lie), and pharmaceutically acceptable salts, prodrugs and solvates thereof.
  • the compound has the Formula (lie), wherein each Ri is independently selected from the group consisting of optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR,, SR b , NR b R b , C(0)ORb, NO2, CN, C(0)R b , C(0)C(0)R b , C(0)NR b R b , NR b C(0)R b , NR b S(0) n R b , N(R b )(COOR b ), NR b
  • optionally substituted C1-C1 0 alkyl optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl.
  • the compound has the Formula (lie), wherein G 4 is selected from the group consisting of optionally substituted pyridyl, optionally substituted pyrimidyl, optionally substituted diazinyl, and optionally substituted traizinyl. In an additional embodiment, G 4 is optionally substituted pyrimidyl. In another aspect, the compound has the Formula (lie), wherein D3 is optionally substituted phenyl.
  • D 3 is phenyl substituted with one or more optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR b , SR b , NR b R b , C(0)OR b , N0 2 , CN, C(0)R b , C(0)C(0)R b , C(0)NR b R b , NR b C(0)R b , NR b C(0)N(R b ) 2 , NR b S(0) n R b , N(R b )(COOR b ), NR b C(0)C(0)R b , NR
  • the compound of the invention has the Formula (lid), or is a pharmaceutically acceptable salt, prodrug or solvate thereof.
  • the compound has the Formula (lid), wherein Ri is selected from the group consisting of optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR b , SR b , NR b R b , C(0)OR b , N0 2 , CN, C(0)R b , C(0)C(0)R b , C(0)NR b R b , NR b C(0)R b , NR b C(0)N(R b ) 2 , NR b S(0) n R b ,
  • N(R b )(COOR b ), NR b C(0)C(0)R b , NR b C(0)R b , NR b S(0) n NR b R b , NR b S(0) n R b , S(0) n R b , S(0) n NR b R b , OC(0)OR b; and (C NR b )R b .
  • Ri is selected from the group consisting of optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl.
  • the invention is a compound having the Formula (lid), wherein each R c is independently selected from the group consisting of hydrogen, optionally substituted C1-C4 alkyl and OR b .
  • R c is OH or O-C1-C4 alkyl, wherein the C1-C4 alkyl is optionally substituted.
  • the invention is directed to a compound having the Formula
  • the compound has the Formula (Ilia), wherein R 6 is phenyl substituted in its para position with a substituent selected from the group consisting of optionally substituted Ci-Cio alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C 2 -Ci 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR b , SR b , NR b R b , C(0)OR b , N0 2 , CN, C(0)R b , C(0)C(0)R b , C(0)NR b R b , NR b C(0)R b , NR b C(0)N(R b ) 2 , NR b S(0) n R b
  • the compound has the Formula (Ilia), wherein Ri is selected from the group consisting of optionally substituted Ci-Cio alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR b , SR b , NR b R b , C(0)OR b , N0 2 , CN, C(0)R b , C(0)C(0)R b , C(0)NR b R b , NR b C(0)R b ,
  • the invention has the Formula (Ilia), wherein Ri is selected from the group consisting of optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl.
  • Ri is selected from the group consisting of optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl.
  • the compound has the Formula (Ilia), wherein G 3 is selected from the group consisting of optionally substituted heterocyclic and optionally substituted heteroaryl. In another embodiment, G 3 is selected from the group consisting of optionally substituted pyridyl and optionally substituted pyrimidyl. In a further aspect, the compound has the Formula (Ilia), wherein G 3 is optionally substituted pyrimidyl.
  • the compound of the invention has the Formula (Illb).
  • the compound has the Formula (Illb), wherein G 3 is selected from the group consisting of optionally substituted heterocyclic and optionally substituted heteroaryl.
  • G 3 is selected from the group consisting of optionally substituted pyridyl and optionally substituted pyrimidyl.
  • the compound has the Formula (Illb) wherein G 3 is optionally substituted pyrimidyl.
  • the invention is directed to a compound of Formula (IV), or a pharmaceutically acceptable salt, prodrug or solvate thereof.
  • the compound has the Formula (IV), wherein R 6 is phenyl substituted in its para position with a substituent selected from the group consisting of optionally substituted C1-C1 0 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR b , SR b , NR b R b , C(0)OR b , N0 2 , CN, C(0)R b , C(0)C(0)R b , C(0)NR b R b , NR b C(0)R b , NR b
  • the compound has the Formula (IV), wherein R 8 is selected from the group consisting of optionally substituted C1-C1 0 alkyl, optionally substituted C2- C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl.
  • the compound has the Formula (IV), wherein G 3 is selected from the group consisting of optionally substituted heterocyclic and optionally substituted heteroaryl.
  • G 3 can be optionally substituted pyridyl or optionally substituted pyrimidyl.
  • the invention is directed to a compound of Formula
  • the compound has the Formula (V), wherein R 9 is selected from the group consisting of optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, ORb, SR b , NRbRb, C(0)OR b , N0 2 , CN, C(0)R b , C(0)C(0)R b , C(0)NR b R b , NR b C(0)R b , NR b S(0) n Rb, N(Rb)(COORb), NR b C(0)C(0)R b , NR b C(0)R b , NR b C(0)N
  • R 9 is selected from the group consisting of optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl.
  • the invention also encompasses a compound having the Formula (V), or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein at least one R3 is selected from the group consisting of optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, ORb, SRb, NRbRb, C(0)OR b , N0 2 , CN, C(0)R b , C(0)C(0)R b , C(0)NR b R b , NR b C(0)R b , NR b S(0) n R b , N(R b )(COOR b ), NR b C(0)C(0)
  • the invention is directed to a compound havin the Formula (V), wherein Gi is optionally substituted pyrimidyl.
  • a non-limiting example of a compound having the Formula (V) is:
  • the invention is directed to a compound having the Formula (VI).
  • the compounds has the Formula (VI), Rio is selected from the group consisting of optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C4-C12 cycloalkyl, optionally substituted C3-C12 cyloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally sustituted heteroaryl, halo, OR b , SR b , NR b R b , C(0)OR b , N0 2 , CN, C(0)R b , C(0)C(0)R b , CO)NR b R b , NR b C(0)R b , NR b C(0)N(R b ) 2 , NR b S(0) n R b , N(R b )(COOR b ),
  • Rio is selected from the group consisting of optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C4-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, halo, OR b , SR b , NR b R b , C(0)OR b , N0 2 , CN, C(0)R b , C(0)C(0)R b , C(0)NR b R b , NR b C(0)R b , NR b C(0)N(R b ) 2 , NR b S(0) n R b , N(R b )(COOR b ), NR b C(0)C(0)R b , NR b C(0)R b , NR b S(0) n NR b NR b b ), NR
  • the compound has the Formula (VI), wherein B is
  • each R 3 is as previously defined and each R f is independently selected from the group consisting of hydrogen, optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR b , SR b , NRbRb, C(0)OR b , N0 2 , CN, C(0)R b , C(0)C(0)R b , C(0)NR b R b , NR b C(0)R b , NR b C(0)N(R b ) 2 , NR b S(0) n R b , N(R b )(COOR
  • the compound has the Formula (VI), wherein each R c is independently selected from the group consisting of hydrogen, optionally substituted Ci- C 4 alkyl and OR b .
  • the compound has the Formula (VI), wherein R c is selected from the group consisting of hydroxyl and optionally substituted O- Ci-C 4 alkyl.
  • Non-limiting examples of compounds having the Formula (VI) are selected from the group consistin
  • the invention is a compound having the Formula (Vila), (Vllb), or (VIIc), or a pharmaceutically acceptable salt, prodrug or solvate thereof.
  • the invention is a compound having the Formula (Vila), (Vllb) or (VIIc), wherein R n is selected from the group consisting of optionally substituted Ci-Cio alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR b , SR b , NR b R b , C(0)OR b , N0 2 , CN, C(0)R b , C(0)C(0)R b ,
  • Rn is selected from the group consisting of optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl.
  • the compound has the Formula (Vila), (Vllb) or (VIIc), wherein A 2 is NR a Rg, wherein R g is optionally substituted C1-C1 0 alkyl, optionally substituted C2- C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, C(0)OR b , C(0)R b , and C(0)C(0)Rb.
  • R g is optionally substituted aryl or optionally substituted heteroaryl.
  • the invention also encompasses compounds having the Formula (VIII), and pharmaceutically acceptable salts, prodrugs and solvates thereof.
  • the compound has the Formula (VIII), wherein Ri 2 is selected from the group consisting of optionally substituted Ci-Cio alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR b , SR b , NR b R b , C(0)OR b , N0 2 , CN, C(0)R b , C(0)C(0)R b , C(0)NR b R b , NR b C(0)R b , NR b S(0) n R b , N(R b )(CO
  • R12 is selected from the group consisting of optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl.
  • the compound has the Formula (VIII), wherein Xi is O. In a further aspect, the compound has the Formula (VIII), wherein Xi is S.
  • the invention is also directed to compounds having the Formula (IXa) or (IXb), or a pharmaceutically acceptable salt, prodrug or solvate thereof.
  • the compound has the Formula (IXa) or (IXb), wherein at least one R13 is selected from the group consisting of optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR b , SR b , NR b R b , C(0)OR b , NO2, CN, C(0)R b , C(0)C(0)R b , C(0)NR b R b , NR b C(0)R b , NR b S(0)
  • At least one R1 3 is selected from the group consisting of optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C 3 -C12 cycloalkyl, optionally substituted C 3 -C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl.
  • the compound has the Formula (IXa) or (IXb), wherein A2 is RaRg, wherein R g is optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, C(0)ORb, C(0)Rb, and C(0)C(0)Rb.
  • A2 is RaRg
  • R g is optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optional
  • the invention is directed to a compound of Formula (Ila), (lib), (Ilia), (Illb) or (IV), wherein G3 is selected from the group consisting of:
  • each R c is independently selected from the group consisting of hydrogen, optionally substituted Ci-Cio alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR b , SR b , NR b R b , C(0)OR b , N0 2 , CN, C(0)R b , C(0)C(0)R b , C(0)NR b R b , NR b C(0)R b , NR b C(0)N(R b ) 2 , NR b S(0) n R b , N(R b )(COOR b ), NR b C(0)C(0)R b , NR b C(0)
  • Rd is hydrogen, optionally substituted C1-C1 0 alkyl, optionally substituted C2-C1 0 alkenyl, optionally substituted C2-C1 0 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl; and
  • R e is (R a ), O, or S.
  • the compound has the Formula (Ila), (lib), (III), or (IV) wherein G3 is selected from the group consisting of:
  • the invention is directed to a compound of Formula (V), wherein Gi is selected from the rou consistin
  • each R a , R c and Ra are as defined above.
  • the invention is a compound having the Formula (V), wherein Gi is selected from the group consisting of:
  • the invention is a compound of Formula (la), (lb), (Vlla- VIIc), (VIII), or (IXa-Ixb), wherein each of Ai or A 2 is independently:
  • p 0, 1, 2 or 3;
  • Each R 3 is independently selected from the group consisting of hydrogen, optionally substituted Ci-Cio alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, optionally substituted C3-C 12 cycloalkyl, optionally substituted C3-C 12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, halo, OR b , SR b , NR b Rb, C(0)OR b , N0 2 , CN, C(0)R b , C(0)C(0)R b , C(0)NR b R b , NR b C(0)R b , NR b C(0)N(R b ) 2 , NR b S(0) n R b , N(R b )(COOR b ), NR b C(0)C(0)R b , NR b C(0)R b
  • Each R4 is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, optionally substituted C3-C 12 cycloalkyl, optionally substituted C3-C 12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, C(0)OR b , C(0)R b , C(0)C(0)R b and S(0) n R b ; or alternatively, the two R4 groups are taken together with the nitrogen atom which they are attached to form an optionally substituted 3- to 8-membered heterocyclic or optionally substituted heteroaryl.
  • the compound is selected from those shown below in
  • compositions comprising a pharmaceutically acceptable carrier and an effective amount of a compound of Formula (Ia-Ib), (Ila-IId), (Illa-IIIb), (IV), (V), (VI), (Vlla-VIIc), (VIII), (IXa-IXb), (Xa-Xa), (XIa-XIb) or (Xlla- Xllb) are encompassed by the invention.
  • a pharmaceutical compositions comprising a pharmaceutically acceptable carrier and an effective amount of a compound of Formula (Ia-Ib), (Ila-IId), (Illa-IIIb), (IV), (V), (VI), (Vlla-VIIc), (VIII), (IXa-IXb), (Xa-Xa), (XIa-XIb) or (Xlla- Xllb) are encompassed by the invention.
  • the pharmaceutical composition comprises an effective amount of a compound shown above in Table 1.
  • Ri was defined as optionally substituted Ci-Cio alkyl, optionally substituted C2-C1 0 alkenyl and optionally substituted C2-C1 0 alkynyl and G3 was defined as optionally substituted pyrimidyl in an additional embodiment above.
  • the invention thus, for example, encompasses compounds of Formula (Ila), wherein Ri is optionally substituted Ci-Cio alkyl, optionally substituted C2-C1 0 alkenyl and optionally substituted C2-C1 0 alkynyl and G3 is optionally substituted pyrimidyl.
  • alkyl refers to both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; for example, "C1-C1 0 alkyl” denotes alkyl having 1 to 10 carbon atoms.
  • alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec -butyl, t-butyl, n-pentyl, n-hexyl, 2-methylbutyl, 2-methylpentyl, 2- ethylbutyl, 3-methylpentyl, and 4-methylpentyl.
  • alkenyl refers to both straight and branched-chain moieties having the specified number of carbon atoms and having at least one carbon- carbon double bond.
  • alkynyl refers to both straight and branched-chain moieties having the specified number or carbon atoms and having at least one carbon- carbon triple bond.
  • cycloalkyl refers to cyclic alkyl moieties having 3 or more carbon atoms.
  • examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and adamantyl.
  • cycloalkenyl refers to cyclic alkenyl moieties having 3 or more carbon atoms.
  • cycloalkynyl refers to cyclic alkynyl moieties having 5 or more carbon atoms.
  • heterocyclic encompasses heterocycloalkyl, heterocycloalkenyl, heterobicycloalkyl, heterobicycloalkenyl, heteropolycycloalkyl, heteropolycycloalkenyl and the like.
  • Heterocycloalkyl refers to cycloalkyl groups containing one or more heteroatoms (O, S, or N) within the ring.
  • Heterocycloalkenyl as used herein refers to cycloalkenyl groups containing one or more heteroatoms (O, S or N) within the ring.
  • Heterobicycloalkyl refers to bicycloalkyl groups containing one or more heteroatoms (O,
  • Heterobicycloalkenyl refers to bicycloalkenyl groups containing one or more heteroatoms (O, S or N) within a ring.
  • Cycloalkyl, cycloalkenyl, heterocyclic, groups also include groups similar to those described above for each of these respective categories, but which are substituted with one or more oxo moieties.
  • aryl refers to mono- or polycyclic aromatic carbocyclic ring systems.
  • a polycyclic aryl is a polycyclic ring system that comprises at least one aromatic ring.
  • Polycyclic aryls can comprise fused rings, covalently attached rings or a combination thereof.
  • aryl embraces aromatic radicals, such as, phenyl, naphthyl, indenyl, tetrahydronaphthyl, and indanyl.
  • An aryl group may be substituted or unsubstituted.
  • the aryl is a C4-C10 aryl.
  • heteroaryl refers to aromatic carbocyclic groups containing one or more heteroatoms (O, S, or N) within a ring.
  • a heteroaryl group can be monocyclic or polycyclic.
  • a heteroaryl group may additionally be substituted or unsubstituted.
  • the heteroaryl groups of this invention can also include ring systems substituted with one or more oxo moieties.
  • a polycyclic heteroaryl can comprise fused rings, covalently attached rings or a combination thereof.
  • heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzotriazolyl, benzothiazolyl, benzo
  • heteroaryl groups may be C-attached or heteroatom-attached (where such is possible).
  • a group derived from pyrrole may be pyrrol- 1-yl (N-attached) or pyrrol-3-yl (C- attached).
  • the heteroaryl is 4- to 10-membered heteroaryl.
  • substituted refers to substitution by independent replacement of one, two, or three or more of the hydrogen atoms with substituents including, but not limited to, -Ci-Ci 2 alkyl, -C 2 -C 12 alkenyl, -C 2 -C 12 alkynyl, -C 3 -C 12 cycloalkyl, -C 3 -C 12 cycloalkenyl, C 3 -Ci 2 cycloalkynyl, -heterocyclic, -F, -CI, -Br, -I, -OH, -N0 2 , -N 3 , -CN, -NH 2 , oxo, thioxo, -NHR X , -NR X R X , dialkylamino, -diarylamino, -diheteroarylamino, -OR x , -C(0)R y , - C
  • haloalkyl refers to an alkyl group having 1 to (2n+l) subsistent(s) independently selected from F, CI, Br or I, where n is the maximum number of carbon atoms in the alkyl group.
  • H is the symbol for hydrogen
  • N is the symbol for nitrogen
  • S is the symbol for sulfur
  • O is the symbol for oxygen
  • Me is an abbreviation for methyl.
  • Non-limiting examples of optionally substituted aryl are phenyl, substituted phenyl, napthyl and substituted naphthyl.
  • Enantiomers are a pair of stereoisomers that are non-superimposable mirror images of each other.
  • a 1 : 1 mixture of a pair of enantiomers is a “racemic” mixture.
  • the term “( ⁇ )” is used to designate a racemic mixture where appropriate.
  • “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror- images of each other. The absolute stereochemistry is specified according to the Cahn- Ingold-Prelog R— S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S.
  • Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line.
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Where a particular stereochemistry is described or depicted it is intended to mean that a particular enantiomer is present in excess relative to the other enantiomer.
  • a compound has an R-configuration at a specific position when it is present in excess compared to the compound having an S-configuration at that position.
  • a compound has an S-configuration at a specific position when it is present in excess compared to the compound having an R-configuration at that position.
  • atoms making up the compounds of the present invention are intended to include isotopic forms of such atoms.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • Isotopes of hydrogen include, for example, tritium and deuterium
  • isotopes of carbon include, for example, 13 C and 14 C.
  • the invention therefore encompasses embodiments in which one or more of the hydrogen atoms in Formulae (Ia-Ib), (Ila-IId), (Illa-IIIb), (IV), (V), (VI), (Vlla-VIIc), (VIII), (LXa-LXb), (Xa-Xb), (XIa-XIb) and (Xlla-XIIb) are replaced with deuterium.
  • the invention also encompasses embodiments wherein one or more of the carbon atoms in Formulae (Ia-Ib), (Ila-IId), (Illa-IIIb), (IV), (V), (VI), (Vlla-VIIc), (VIII), (IXa-IXb), (Xa-Xb), (XIa-XIb) and (Xlla-XIIb) is replaced with silicon atoms.
  • the invention additionally encompasses embodiment wherein one or more of the nitrogen atoms in Formulae (Ia-Ib), (Ila-IId), (Illa-IIIb), (IV), (V), (VI), (Vlla-VIIc), (VIII), (IXa-IXb), (Xa-Xb), (XIa-XIb) and (Xlla-XIIb) are oxidized to N-oxide.
  • 6-methyl-2-thioxo-2,3- dihydropyrimidin-4(lH)-one is treated with methyl iodide and potassium carbonate, in dimethyl sulfoxide, to afford 6-methyl-2-(methylthio)prymidin-4(lH)-one (CAS: 6328-58- l).
  • the resulting 6-methyl-2-(methylthio)prymidin-4(lH)-one was treated with hydrazine and potassium carbonate in 2-propanol, at reflux, to afford 2-hydrazinyl-6- methylpryimidin-4(lH)-one (CAS: 37893-08-6).
  • Scheme 2 depicts another potential method for the synthesis of compounds described in the invention from a substituted 2-chloropyrimidine.
  • the preparation of Compound 6 from 2-chloro-4,6-dimethylpyrimidine is shown as an example.
  • a solution of 2-chloro-4,6-dimethylpyrimidine in ethanol was treated with hydrazine hydrate and then heated at reflux to afford 2-hydrazinyl-4,6-dimethylpyrimidine.
  • Scheme 3 illustrates an alternative route to the synthesis of 5-alkylamino
  • the pyrrazole core is prepared as presented in Scheme 1 and 2. Then
  • Scheme 4 is another alternative route to pyrazole heterocycles.
  • the appropriate ⁇ -ketoamide is treated with hydrazine.
  • 26 The resulting pyrazole is alkylated with the appropriate aromatic chloride to afford the desired product.
  • the invention encompasses pharmaceutically acceptable salts of the compounds described herein.
  • the invention is directed to pharmaceutically acceptable salts of compounds of Formulae (Ia-Ib), (Ila-IId), (Illa-IIIb), (IV), (V), (VI), (Vlla-VIIc), (VIII), (IXa-IXb), (Xa-Xb), (XIa-XIb) and (Xlla-XIIb).
  • a "pharmaceutically acceptable salt” includes an ionic bond-containing product of the reaction between the disclosed compound with either an acid or a base, suitable for administering to a subject.
  • compositions are well known in the art and are described, for example, in Berge et al. (1977), Pharmaceutical Salts, Journal of Pharmaceutical Sciences, 69(1): 1-19, the contents of which are herein incorporated by reference.
  • a non-limiting example of a pharmaceutically acceptable salt is an acid salt of a compound containing an amine or other basic group which can be obtained by reacting the compound with a suitable organic or inorganic acid.
  • Examples of pharmaceutically acceptable salts also can be metallic salts including, but not limited to, sodium, magnesium, calcium, lithium and aluminum salts.
  • salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g. (+)-tartrates, (-)-tartrates or mixtures thereof including racemic mixtures), succinates, benzoates and salts with amino acids such as glutamic acid.
  • Salts can also be formed with suitable organic bases when the compound comprises an acid functional group such as -COOH or -SO 3 H.
  • bases suitable for the formation of a pharmaceutically acceptable base addition salts with compounds of the present invention include organic bases that are nontoxic and strong enough to react with the acid functional group.
  • Such organic bases include amino acids such as arginine and lysine, mono-, di-, and triethanolamine, choline, mono-, di-, and trialkylamine, such as methylamine, dimethylamine, and trimethylamine, guanidine, N-benzylphenethylamine, N-methylglucosamine, N- methylpiperazine, morpholine, ethylendiamine, tris(hydroxymethyl)aminomethane and the like.
  • amino acids such as arginine and lysine, mono-, di-, and triethanolamine, choline, mono-, di-, and trialkylamine, such as methylamine, dimethylamine, and trimethylamine, guanidine, N-benzylphenethylamine, N-methylglucosamine, N- methylpiperazine, morpholine, ethylendiamine, tris(hydroxymethyl)aminomethane and the like.
  • the invention also includes hydrates of the compounds described herein, including for example solvates of the compounds described herein.
  • the invention is to solvates of compounds of Formulae (Ia-Ib), (Ila-IId), (Illa-IIIb), (IV), (V), (VI), (Vlla-VIIc), (VIII), (IXa-IXb), (Xa-Xb), (XIa-XIb) and (Xlla-XIIb).
  • prodrugs of the compounds described herein for example, prodrugs of compounds of Formulae ((Ia-Ib), (Ila-IId), (Illa-IIIb), (TV), (V), (VI), (Vlla-VIIc), (VIII), (IXa-IXb), (Xa-Xb), (XIa-XIb) and (Xlla-XIIb).
  • the invention additionally includes clathrates of the compounds described herein.
  • the invention is directed to clathrates of compounds of Formulae (Ia-Ib), (Ila-IId), (Illa-IIIb), (IV), (V), (VI), (Vlla-VIIc), (VIII), (IXa-IXb), (Xa-Xb), (Xla- Xlb) and (Xlla-XIIb).
  • the invention includes pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and a compound described herein.
  • the excipient can be chosen based on the expected route of administration of the composition in therapeutic applications. The route of administration of the
  • composition depends on the condition to be treated. For example, intravenous injection may be preferred for treatment of a systemic disorder and oral administration may be preferred to treat a gastrointestinal disorder.
  • the route of administration and the dosage of the composition to be administered can be determined by the skilled artisan without undue experimentation in conjunction with standard dose-response studies. Relevant circumstances to be considered in making those determinations include the condition or conditions to be treated, the choice of composition to be administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms.
  • compositions comprising compounds of Formulae (Ia-Ib), (Ila-IId), (Illa-IIIb), (IV), (V), (VI), (Vlla-VIIc), (VIII), (IXa-IXb), (Xa-Xb), (XIa-XIb) and (Xlla- Xllb), and pharmaceutically acceptable salts, solvates, clathrates or prodrugs of any of thereof, can be administered by a variety of routes including, but not limited to, parenteral, oral, pulmonary, ophthalmic, nasal, rectal, vaginal, aural, topical, buccal, transdermal, intravenous, intramuscular, subcutaneous, intradermal, intraocular, intracerebral, intralymphatic, intraarticular, intrathecal and intraperitoneal.
  • compositions can also include, depending on the formulation desired, pharmaceutically-acceptable, non-toxic carriers or diluents, which are defined as vehicles commonly used to formulate pharmaceutical compositions for animal or human administration.
  • diluent is selected so as not to affect the biological activity of the pharmacologic agent or composition. Examples of such diluents are distilled water, physiological phosphate-buffered saline, Ringer's solutions, dextrose solution, and Hank's solution.
  • the pharmaceutical composition or formulation may also include other carriers, adjuvants, or nontoxic, nontherapeutic, nonimmunogenic stabilizers and the like.
  • compositions can also include large, slowly metabolized macromolecules such as proteins, polysaccharides such as chitosan, polylactic acids, polyglycolic acids and copolymers (such as latex functionalized SEPHAROSETM, agarose, cellulose, and the like), polymeric amino acids, amino acid copolymers, and lipid aggregates (such as oil droplets or liposomes).
  • macromolecules such as proteins, polysaccharides such as chitosan, polylactic acids, polyglycolic acids and copolymers (such as latex functionalized SEPHAROSETM, agarose, cellulose, and the like), polymeric amino acids, amino acid copolymers, and lipid aggregates (such as oil droplets or liposomes).
  • compositions can be administered parenterally such as, for example, by intravenous, intramuscular, intrathecal or subcutaneous injection.
  • parenteral such as, for example, by intravenous, intramuscular, intrathecal or subcutaneous injection.
  • compositions can be accomplished by incorporating a composition into a solution or suspension.
  • solutions or suspensions may also include sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents.
  • Parenteral formulations may also include antibacterial agents such as, for example, benzyl alcohol or methyl parabens, antioxidants such as, for example, ascorbic acid or sodium bisulfite and chelating agents such as EDTA.
  • Buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose may also be added.
  • the parenteral preparation can be enclosed in ampules, disposable syringes or multiple dose vials made of glass or plastic.
  • auxiliary substances such as wetting or emulsifying agents, surfactants, pH buffering substances and the like can be present in compositions.
  • Other components of pharmaceutical compositions are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, and mineral oil.
  • glycols such as propylene glycol or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions.
  • Injectable formulations can be prepared either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection can also be prepared.
  • the preparation also can also be emulsified or encapsulated in liposomes or micro particles such as polylactide, polyglycolide, or copolymer for enhanced adjuvant effect, as discussed above. Langer, Science 249: 1527, 1990 and Hanes, Advanced Drug Delivery Reviews 28: 97-1 19, 1997.
  • the compositions and pharmacologic agents described herein can be administered in the form of a depot injection or implant preparation which can be formulated in such a manner as to permit a sustained or pulsatile release of the active ingredient.
  • binders and carriers include, for example, polyalkylene glycols or triglycerides; such suppositories can be formed from mixtures containing the active ingredient in the range of about 0.5% to about 10%, preferably about 1%- to about 2%.
  • Oral formulations include excipients, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, and magnesium carbonate.
  • Topical application can result in transdermal or intradermal delivery. Transdermal delivery can be achieved using a skin patch or using transferosomes.
  • the pharmaceutical composition for the purpose of oral therapeutic administration, the pharmaceutical
  • compositions can be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like.
  • Tablets, pills, capsules, troches and the like may also contain binders, excipients, disintegrating agent, lubricants, glidants, sweetening agents, and flavoring agents.
  • binders include microcrystalline cellulose, gum tragacanth or gelatin.
  • excipients include starch or lactose.
  • disintegrating agents include alginic acid, corn starch and the like.
  • lubricants include magnesium stearate or potassium stearate.
  • An example of a glidant is colloidal silicon dioxide.
  • sweetening agents include sucrose, saccharin and the like.
  • flavoring agents include peppermint, methyl salicylate, orange flavoring and the like.
  • Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used.
  • the composition is administered as a tablet or a capsule.
  • tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor, and the like.
  • a pharmaceutical composition may be presented as pessaries, tampons, creams, gels, pastes, foams or spray.
  • nasally administering or nasal administration includes administering the composition to the mucus membranes of the nasal passage or nasal cavity of the patient.
  • pharmaceutical compositions for nasal administration of a composition include therapeutically effective amounts of the compounds prepared by well-known methods to be administered, for example, as a nasal spray, nasal drop, suspension, gel, ointment, cream or powder. Administration of the composition may also take place using a nasal tampon or nasal sponge.
  • suitable formulations may include biocompatible oil, wax, gel, powder, polymer, or other liquid or solid carriers. Such formulations may be administered by applying directly to affected tissues, for example, a liquid formulation to treat infection of conjunctival tissue can be administered dropwise to the subject's eye, or a cream formulation can be administered to the skin.
  • Rectal administration includes administering the pharmaceutical compositions into the rectum or large intestine. This can be accomplished using suppositories or enemas.
  • Suppository formulations can easily be made by methods known in the art. For example, suppository formulations can be prepared by heating glycerin to about 120°C, dissolving the pharmaceutical composition in the glycerin, mixing the heated glycerin after which purified water may be added, and pouring the hot mixture into a suppository mold.
  • Transdermal administration includes percutaneous absorption of the composition through the skin.
  • Transdermal formulations include patches, ointments, creams, gels, salves and the like.
  • pulmonary will also mean to include a tissue or cavity that is contingent to the respiratory tract, in particular, the sinuses.
  • an aerosol formulation containing the active agent a manual pump spray, nebulizer or pressurized metered-dose inhaler as well as dry powder formulations are contemplated.
  • Suitable formulations of this type can also include other agents, such as antistatic agents, to maintain the disclosed compounds as effective aerosols.
  • a drug delivery device for delivering aerosols comprises a suitable aerosol canister with a metering valve containing a pharmaceutical aerosol formulation as described and an actuator housing adapted to hold the canister and allow for drug delivery.
  • the canister in the drug delivery device has a head space representing greater than about 15% of the total volume of the canister.
  • the compound intended for pulmonary administration is dissolved, suspended or emulsified in a mixture of a solvent, surfactant and propellant. The mixture is maintained under pressure in a canister that has been sealed with a metering valve.
  • Treating” or “treatment” includes preventing or delaying the onset of the symptoms, complications, or biochemical indicia of a disease, alleviating or ameliorating the symptoms or arresting or inhibiting further development of the disease, condition, or disorder.
  • a “patient” is a human subject in need of treatment.
  • an “effective amount” refers to that amount of the therapeutic agent that is sufficient to ameliorate of one or more symptoms of a disorder and/or prevent
  • the term “inhibiting” or “decreasing” encompasses causing a net decrease by either direct or indirect means.
  • the term “increasing” means to cause a net gain by either direct or indirect means.
  • the invention encompasses the treatment of a condition associated with a dysfunction in proteostasis.
  • Proteostasis refers to protein homeostasis.
  • Dysfunction in protein homeostasis is a result of protein misfolding, protein aggregation, defective protein trafficking or protein degradation.
  • Exemplary proteins of which there can be a dysfunction in proteostasis, for example that can exist in a misfolded state include, but are not limited to, glucocerebrosidase, hexosamine A, cystic fibrosis transmembrane conductance regulator, aspartylglucsaminidase, a-galactosidase A, cysteine transporter, acid ceremidase, acid a-L-fucosidase, protective protein, cathepsin A, acid ⁇ -glucosidase, acid ⁇ -galactosidase, iduronate 2-sulfatase, a-L-iduronidase, galactocerebrosidase, acid a -mannosidase, acid ⁇ -mannosidase, arylsulfatase B, arylsulfatase A, N- acetylgalactosamine-6-sulfate
  • the protein is selected from the group consisting of huntingtin, tau, alpha-synuclein, a 1 anti-trypsin, cystic fibrosis transmembrane conductance regulator and superoxide dismutase.
  • Protein conformational diseases encompass gain of function disorders and loss of function disorders.
  • the protein conformational disease is a gain of function disorder.
  • gain of function disorder is a disease characterized by increased aggregation- associated proteotoxicity. In these diseases, aggregation exceeds clearance inside and/or outside of the cell. Gain of function diseases include, but are not limited to
  • Neurodegenerative diseases associated with aggregation of polyglutamine include, but are not limited to, Huntington's disease, dentatorubral and pallidoluysian atrophy, several forms of spino-cerebellar ataxia, and spinal and bulbar muscular atrophy.
  • Alzheimer's disease is characterized by the formation of two types of aggregates: extracellular aggregates of ⁇ peptide and intracellular aggregates of the microtubule associated protein tau.
  • Transthyretin-associated aggregation diseases include, for example, senile systemic amyloidoses and familial amyloidotic neuropathy.
  • Lewy body diseases are characterized by an aggregation of a-synuclein protein and include, for example, Parkinson's disease.
  • Prion diseases also known as transmissible spongiform encephalopathies or TSEs
  • Exemplary human prion diseases are Creutzfeldt- Jakob Disease (CJD), Variant Creutzfeldt-Jakob Disease, Gerstmann-Straussler-Scheinker Syndrome, Fatal Familial Insomnia and Kuru.
  • the protein conformation disease is a loss of function disorder.
  • the terms "loss of function disease” and “loss of function disorder” are used interchangeably herein.
  • Loss of function diseases are a group of diseases characterized by inefficient folding of a protein resulting in excessive degradation of the protein. Loss of function diseases include, for example, cystic fibrosis and lysosomal storage diseases. In cystic fibrosis, the mutated or defective enzyme is the cystic fibrosis transmembrane conductance regulator (CFTR).
  • CFTR cystic fibrosis transmembrane conductance regulator
  • Lysosomal storage diseases are a group of diseases characterized by a specific lysosomal enzyme deficiency which may occur in a variety of tissues, resulting in the build-up of molecules normally degraded by the deficient enzyme.
  • the lysosomal enzyme deficiency can be in a lysosomal hydrolase or a protein involved in the lysosomal trafficking.
  • Lysosomal storage diseases include, but are not limited to, aspartylglucosaminuria, Fabry's disease, Batten disease, Cystinosis, Farber, Fucosidosis, Galactasidosialidosis, Gaucher' s disease (including Types 1, 2 and 3), Gml gangliosidosis, Hunter's disease, Hurler-Scheie's disease, Krabbe's disease, a-Mannosidosis, B-Mannosidosis, Maroteaux-Lamy's disease, Metachromatic Leukodystrophy, Morquio A syndrome, Morquio B syndrome, Mucolipidosis II,
  • Mucolipidosis III Neimann-Pick Disease (including Types A, B and C), Pompe's disease, Sandhoff disease, Sanfilippo syndrome (including Types A, B, C and D), Schindler disease, Schindler-Kanzaki disease, Sialidosis, Sly syndrome, Tay-Sach's disease and Wolman disease.
  • the disease associated with a dysfunction in proteostasis and/or in the heat shock response is a cardiovascular disease.
  • Cardiovascular diseases include, but are not limited to coronary artery disease, myocardial infarction, stroke, restenosis and arteriosclerosis.
  • Conditions associated with a dysfunction of proteostasis also include ischemic conditions, such as, ischemia/reperfusion injury, myocardial ischemia, stable angina, unstable angina, stroke, ischemic heart disease and cerebral ischemia.
  • the disease associated with a dysfunction in proteostasis is diabetes or diabetic retinopathy.
  • the condition is selected from the group consisting of cystic fibrosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, diabetic retinopathy, diabetes, and other retinal disorders. In one embodiment, the condition is cystic fibrosis.
  • the invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of any one of Formulae (Ia-Ib), (Ila-IId), (Illa-IIIb), (TV), (V), (VI), (Vlla-VIIc), (VIII), (LXa-LXb), (Xa-Xb), (XIa-XIb) and (Xlla-XIIb), and a second agent, wherein the second agent is selected from the group consisting of a pharmacologic chaperone and a proteostasis regulator.
  • the invention also encompasses a method of treating a patient suffering from a condition associated with a dysfunction in proteostasis comprising administering a therapeutically effective amount of a compound of the invention and a second agent, wherein the second agent is a pharmacologic chaperone.
  • Pharmacologic chaperones or kinetic stabilizers refer to compounds that bind an existing steady state level of the folded mutant protein and chemically enhance the folding equilibrium by stabilizing the fold [Bouvier, Chem Biol 14: 241-242, 2007; Fan et al, Nat Med 5: 112-115, 1999; Sawkar et al, Proc Natl Acad Sci U S A 99: 15428- 15433 , 2002; Johnson and Kelly, Accounts of Chemical Research 38: 911-921, 2005].
  • the pharmacologic chaperone is administered in amount that in combination with a compound described herein in an amount that is sufficient to treat a patient suffering from a condition associated with a dysfunction in proteostasis.
  • exemplary pharmacologic chaperones are described in U.S. Patent Publication No's. 20080056994, 20080009516, 20070281975, 20050130972, 20050137223, 20050203019, 20060264467 and 20060287358, the contents of which are incorporated by reference herein.
  • the invention is a method of treating a patient suffering from a condition associated with a dysfunction in proteostasis comprising administering therapeutically effective amount of a compound of the invention and a second agent, wherein the second agent is a proteostasis regulator.
  • proteostasis regulator refers to small molecules, siRNA and biologicals (including, for example, proteins) that enhance cellular protein homeostasis.
  • proteostasis regulators can be agents that influence protein synthesis, folding, trafficking and degradation pathways.
  • Proteostasis regulators encompass pharmacologic agents that stimulate the HSR signaling activity.
  • Proteostasis regulators function by manipulating signaling pathways, including, but not limited to, the heat shock response or the unfolded protein response, or both, resulting in transcription and translation of proteostasis network components.
  • Proteostasis regulators can enhance the folding, trafficking and function of proteins (for example, mutated proteins).
  • Proteostasis regulators can also regulate protein chaperones by upregulating transcription or translation of the protein chaperone, or inhibiting degradation of the protein chaperone.
  • Proteostasis regulators can influence the biology of folding, often by the coordinated increase in chaperone and folding enzyme levels and
  • the proteostasis regulator is distinct from a chaperone in that the proteostasis regulator can enhance the homeostasis of a mutated protein but does not bind the mutated protein.
  • proteostasis regulators can upregulate an aggregation pathway or a disaggregase activity.
  • Exemplary proteostasis regulators are the celastrols, MG-132 and L-type Ca 2+ channel blockers (e.g., dilitiazem and verapamil).
  • celastrol refers to celastrol and derivatives or analogs thereof, including, but not limited to, those celastrol derivatives described in Westerheide et al, J Biol Chem, 2004. 279(53): p. 56053-60, the contents of which are expressly incorporated by reference herein.
  • Celastrol derivatives include, for example, celastrol methyl ester, dihydrocelastrol diacetate, celastrol butyl ether, dihydrocelastrol, celastrol benzyl ester, primesterol, primesterol diacetate and triacetate of celastrol.
  • the proteostasis regulator is a heat shock response activator.
  • a heat shock response activator is an agent that indirectly or directly activates the heat shock response, for example, by directly or indirectly activating heat shock transcription factor 1 (HSF1), inhibiting Hsp90, and/or activating chaperone expression (Westerheide et al, J Biol Chem, 2004. 279(53): p. 56053-60, the contents of which are expressly incorporated by reference herein).
  • HSF1 heat shock transcription factor 1
  • chaperone expression Westerheide et al, J Biol Chem, 2004. 279(53): p. 56053-60, the contents of which are expressly incorporated by reference herein.
  • the terms “heat shock response activator,” “heat shock activator,” “heat shock response inducer,” and “heat shock inducer” are used interchangeably herein.
  • Non- limiting examples of heat shock response activators are celastrols, non-steroidal antiinflammatory drugs, ansamycin, geldenamycin, radiciol, glucuronic acid, and tributylin. Heat shock response activators have also been described, for example, in U.S. Patent Application Publication No's. 20070259820, 20070207992, 20070179087, 20060148767, the contents of each of which are expressly incorporated by reference herein. In some embodiments, the heat shock response activator is a small molecule heat shock response activator.
  • the invention also encompasses a method of treating cancer or a tumor in a patient in need thereof comprising administering to said patient an effective amount of a compound described herein.
  • Cancers that can be treated according to methods of the present invention include, but are not limited to, breast cancer, colon cancer, pancreatic cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, multiple myeloma, basal cell carcinoma, neuroblastoma, hematologic cancer, rhabdomyosarcoma, liver cancer, skin cancer, leukemia, basal cell carcinoma, bladder cancer, endometrial cancer, glioma, lymphoma, and gastrointestinal cancer.
  • the invention is a method of treating cancer or a tumor comprising administering an effective amount of a compound described herein in combination with the administration of a chemotherapeutic agent.
  • Chemotherapeutic agents that can be utilized include, but are not limited to, alkylating agents such as cyclosphosphamide (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamine; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride,
  • mycophenolic acid nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane
  • aldophosphamide glycoside aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate;
  • etoglucid gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2- ethylhydrazide; procarbazine; PSK®; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; urethan; vindesine; dacarbazine;
  • ifosfamide mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT-11 ; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoic acid; esperamicins;
  • the invention is a method of treating cancer or a tumor comprising administering to a patient in need thereof an effective amount of a compound described herein in combination with radiation therapy.
  • the HC1 salt can also be prepared.
  • reaction mixture was concentrated in vacuo and the remaining residue was purified by column chromatography on silica using a mixture of dichloromethane/methanol as the eluant.
  • the product obtained this way was further purified by preparative HPLC and then crystallization from a mixture of methanol and hexanes to afford 61 mg of l-(4,6-dimethylpyrimidin-2-yl)-3-methyl-N-(p-tolyl)-lH- pyrazol-5 -amine as a pale yellow solid.
  • the crude product was purified by column chromatography on silica using a mixture of dichloromethane/methanol as the eluant.
  • the product obtained from this purification was further purified in another round of column chromatography on silica using a mixture of ethyl acetate/hexanes as the eluant to afford 130 mg of 2-(5-(isopropylamino)-3-methyl-lH-pyrazol-l-yl)-6-methylpyrimidin- 4(lH)-one as a white solid.
  • the crude product was purified by column chromatography on silica using a mixture of hexanes/ethyl acetate as the eluant to afford 20 mg of 3 -methyl- l-(pyridin-2 - yl)-N-(/ tolyl)-lH-pyrazol-5 -amine as a yellow solid.
  • CFTR transport assays AF508 expressing CFBE41° " lung cells were cultured in the presence of compound 1 in 12 well Sarstedt dishes, harvested, lysed and the processing of CFTR from the band B to the band C glycoform detected by SDS-PAGE and
  • FluroChemSP Alpha Inotech densitometer/software package. Where band B and C were quantified from different exposures, an internal reference was used to normalize the signal intensity. This method has been described in detail in Hutt et al. (2010), 28 Reduced histone deacetylase 7 activity restores function to misfolded CFTR in cystic fibrosis, Nature Chemical Biology, 6(1), 25-33, the contents of which are expressly incorporated by reference herein.
  • CFTR and halide-sensitive YFP were incubated at 27°C for 20 to 24 h. After incubation, cells were washed with PBS (containing 137 mM NaCl, 2.7 mM KC1, 8.1 mM Na 2 HP04, 1.5 mMKH 2 P0 4 , lmMCaCl 2 , 0.5mMMgCl 2 ) and stimulated for 20 min with forskolin and test compounds. Microplates were read using a plate reader equipped with excitation (HQ500/20X: 500 nm) and emission (HQ535/30M: 535 nm) filters for yellow fluorescent protein.
  • Each assay consisted of a continuous 30-s fluorescence reading (5 points per second) with 3 s before and 27 s after injection of 165 ul of an iodide-containing solution (PBS with CI " replaced by T). Final iodide concentration in the wells was 100 mM. These data were normalized to the initial background subtracted fluorescence.
  • Table 6 shows percent quenching of yellow fluorescent protein (YFP) by select compounds described in the invention. Quenching values for the selected compounds were obtained at 10 ⁇ . Quenching of YFP signal is an indirect measure of CFTR function. Table 6: Activities for select compounds of the invention for the CFBE-YFP Quenching Assay
  • Multigene Assay Monitoring of HSF-1 Activity via HSPA5 Transcript Levels in IMR 32 Human Neuroblastoma Cells
  • This assay uses the QuantiGene Plex 2.0 Reagent System from Affymetrix. This assay combines the use of bDNA (branch DNA) and xMAP magnetic capture beads from Luminex Technologies to quantitatively and simultaneously detect multiple mRNA transcripts per well.
  • Proteinase K should be used cold. Use lOul of Proteinase K per 1ml of Lysis mixture to make the lysis buffer. Add 50% v/v of the lysis mixture per well. Mix well to ensure proper lysing. Seal the plates with adhesive aluminum plate seals and incubate at 50°C for 30 minutes. Mix well again 10 times. Store plates at -80°C until assay is performed.
  • a master mix pool without beads Prepare a master mix pool without beads. Distribute the master mix equally in 8 tubes and then add the respective bead mix to each tube. Vortex and add 20ul/well of the master mix to the 96-well plate. After transfer, add 80ul/well of the lysates to respective plates.
  • the amount of cell lysate to be used in the assay should be determined either by performing an assay linearity test or by determining the sample input empirically for each cell line. In order to avoid signal saturation, sample input should be less than 400 cells/ul. Dilute cell lysates with DLM. Keep three wells in each plate as assay background (no cell lysates in these wells, only diluted lysis mixture as described previously and on the next page).
  • DLM Dilute Lysis Mixture
  • RNA Sample Prep 80 ul of DLM (33% lysis mixture) + 1 ul of RNA (250 ng/ul).
  • Preamplifier Solution Add 7.5 ul of preamplifier to every 1ml of Amplifier Diluent.
  • Amplifier Solution Add 7.5 ul of Amplifier to every 1ml of Amplifier Diluent.
  • Label Probe Solution Add 7.5 ul of Label Probe to every 1ml of Label Probe Diluent.
  • SAPE Solution Add 3.0 ul of SAPE to every 1ml of SAPE Diluent.
  • PreAmplifier Hyb Step Soak compression plate for 2 min on Magnetic Separation device. Compression plate should make contact with the magnetic device at all time. Wash plate 4 times with 100 ul QGP 2.0 wash buffer, 60 second soak in between each wash required. Remove wash buffer from the final wash. Add 60 ul of Preamp solution per well. Incubate at 50°C for 1 hr with 300 RPM shaking (ThermoMaxQ plate shaker).
  • Amplifier Hyb Step Soak compression plate for 2 min on Magnetic Separation Device. Compression plate should make contact with the magnetic device at all time. Wash plate 4 times with 100 ul QGP 2.0 wash buffer, 60 second soak in between each wash required. Remove wash buffer from the final wash. Add 60 ul of Amp solution per well. Incubate at 50°C for 1 hr with 300 RPM shaking (ThermoMaxQ plate shaker).
  • Label Probe Hyb Step Soak compression plate for 2 min on Magnetic Separation Device. Compression plate should make contact with the magnetic device at all time. Wash plate 4 times with 100 ul QGP 2.0 wash buffer, 60 second soak in between each wash required. Remove wash buffer from the final wash. Add 60 ul of Label Probe solution per well. Incubate at 50°C for 1 hr with 300 RPM shaking (ThermoMaxQ plate shaker).
  • SAPE Hyb Step Soak compression plate for 2 min on Magnetic Separation Device. Compression plate should make contact with the magnetic device at all time. Wash plate 4 times with 100 ul QGP 2.0 wash buffer, 60 second soak in between each wash required. Remove wash buffer from the final wash. Add 60 ul of SAPE solution per well. Incubate at room temperature for 30 min with 600 RPM shaking. The plate needs to be protected from light by wrapping in foil or by dimming the light.
  • Control genes used to monitor general transcriptional effects include Tubl (alpha- tubulin) and TBP (TATA binding protein).
  • Table 7 Activities for select compounds described in the invention for their ability to induce induction of the HSPA5 gene in IMR32 cells
  • Acute ENaC stimulation by cAMP in a kidney cell line is mediated by exocytic insertion from a recycling channel pool. J Gen Physiol 125, 81-101 (2005).

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Abstract

La présente invention porte sur des composés des Formules (Ia-Ib), (IIa-IId), (IIIa- IIIb), (IV), (V), (VI), (VIIa-VIIc), (VIII), (IXa-IXb), (Xa-Xb), (XIa-XIb) et (XIIa-XIIb), sur des compositions pharmaceutiques à base de ces composés, et sur leurs procédés d'utilisation dans le traitement d'états associés à un dysfonctionnement de la protéostasie.
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