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  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/10—Spiro-condensed systems
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  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
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  • A61P25/00—Drugs for disorders of the nervous system
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  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
  • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
  • C07D213/22—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing two or more pyridine rings directly linked together, e.g. bipyridyl
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/55—Acids; Esters
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/79—Acids; Esters
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
  • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
  • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
  • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
  • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
  • C07D295/205—Radicals derived from carbonic acid

Definitions

• proteostasis The regulation of protein synthesis, degradation, folding, trafficking and aggregation within a cell are collectively known as proteostasis.
• proteostasis is maintained by a wide array of cellular machinery that work to ensure that proteins are present in the proper location, amounts and form to perform their respective functions.
• PD Parkinson's disease
• AD Alzheimer's disease
• HD Huntington's disease
• ALS amyotrophic lateral sclerosis
• IDPs intrinsically disordered proteins
• aggregation and oligomerization are used interchangeably.
• IDPs IDP ⁇ -Synudein
• oligomers are associated with the pathogenesis of PD.
• IDPs are named for their lack of tertiary structure allowing them to adopt numerous conformations and interact with multiple binding partners. IDPs are generally short-lived signaling proteins or transcription factors that are highly bound to other cellular components keeping free cytosolic levels low.
• IDPs are readily degraded by the 20S proteasome, the default protease responsible for IDP digestion.
• the accumulation of IDPs seen in neurodegenerative diseases can begin as a result of one of several disruptions (e.g. mutations, changes in expression, oxidative stress, aging, proteasome impairment, etc.) to their normal regulation.
• disruptions e.g. mutations, changes in expression, oxidative stress, aging, proteasome impairment, etc.
• ⁇ -Syn may not be the sole cause of PD, there is strong evidence supporting its key role in the disease, induding familial forms of PD resulting from mutations in the SNCA gene. Elevated monomeric ⁇ -Syn levels are also known to cause apoptosis-inducing aggregation in neurons.
• oligomeric forms of ⁇ -Syn and other IDPs have recently been shown to directly inhibit the proteasome, further disrupting its ability to regulate IDPs concentrations. These data collectively suggest that the accumulation of ⁇ -Syn and formation of oligomeric species of the IDP play a critical role in the progression of PD. Due to a lack of defined binding pockets, IDPs such as ⁇ -Syn, and their aggregation are difficult to target through traditional small molecule drug design. There are currently no effective treatments to hinder the progression of neurodegenerative diseases that are associated with IDP accumulation.
• FIG. 1A is a plot showing the rate of proteolysis of fluorogenic peptide substrates by purified 20S and 26S proteasome in the presence of a concentration response (0-80 ⁇ M) of fluspirilene. These data were collected in triplicate. Error bars denote standard deviation.
• FIG. 2A is a cartoon of the preferred docking site of acyl- fluspirilene (16), utilizing AutoDock Vina, in the a2-3 intersubunit binding pocket of the 20S proteasome's a-ring.
• FIG. 2B a zoomed in image of compound 16 docked in the a2-3 intersubunit binding pocket.
• FIG. 3 is a plot showing the rate of proteolysis of fluorogenic peptide substrates by purified 20S proteasome in the presence of a concentration response (0-80 ⁇ M) of fluspirilene analogues. These data were collected in triplicate. Error bars denote standard deviation.
• FIGS. 4A-4D is a cartoon of binding models of fluspirilene and three analogues, viewed utilizing BIOVIA Discovery Studio 2020: fluspirilene (FIG. 4A), compound 16 (FIG. 4B), compound 11 (FIG. 4C), compound 20 (FIG. 4D).
• FIG. 5A is a plot showing extended fluorogenic peptide analysis of N-acylated fluspirilene.
• FIGS. 6A is a representative silver stain illustrating fluspirilene’s enhancement of ⁇ -Synuclein digestion by the 20S at 1 , 3, and 10 ⁇ M.
• FIG. 7A is a bar graph showing 20S Proteasome activity impaired by ⁇ -Syn mixed aggregates in the presence of a concentration-gradient of fluspirilene.
• FIGS. 7A-7H show proteasome activity assay: Prevention of a- synuclein and amyloid beta (Abeta) oligomer-induced impairment of 20S proteasome activity towards fluorogenic peptide substrates by fluspirilene and N- acyl fluspirilene.
• White bar 20S + vehicle.
• Black bars 20S + IDP oligomer (a- syn or Abeta) + compounds.
• FIG. 7B is a bar graph showing 20S Proteasome activity impaired by ⁇ -Syn mixed aggregates in the presence of a concentration-gradient of N- acylated fluspirilene.
• FIG. 7C is a bar graph showing 20S Proteasome activity impaired by amyloid beta mixed aggregates in the presence of a concentration-gradient of fluspirilene.
• FIG. 7E is a representative western biot analysis of ⁇ -Synuclein oligomer digestion with fluspirilene.
• FIG. 7G is a representative western biot analysis of ⁇ -Synuclein oligomer digestion with N-acylated fluspirilene.
• FIG. 8 shows fluspirilene and N-acylated fluspirilene (16) enhanced proteasomal degradation of cellular A53T ⁇ -Synuclein in transiently transfected HEK-293T cells.
• the disclosure relates to small molecules that enhance proteasome function and restore the activity of impaired proteasomes.
• Small molecule proteasome enhancers prevent the toxic accumulation of aggregation- prone proteins and prevent neuronal cell death caused by aggregation-prone proteins.
• the disclosure therefore relates to the use of small molecules as therapeutic agents to treat neurodegenerative diseases.
• Neurodegenerative diseases include, but are not limited to, Alzheimer’s disease (AD) and other dementias, Parkinson’s disease (PD) and PD-related disorders, Prion disease, Motor neuron diseases (MND), Huntington's disease (HD), Spinocerebellar ataxia (SCA), Spinal muscular atrophy (SMA).
• the disclosure relates to a chemotype that has been shown herein to be a biologically active enhancer of mammalian proteasomes.
• the chemotype described herein is based on fllspirilene and derivatives thereof.
• the disclosure relates to fluspirilene and derivates thereof, and their use to, among other things, prevent or slow down the progression of neurodegenerative diseases.
• the disclosure therefore relates to compounds of the formula (I) or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein: R 1 is alkyl, alkenyl, cycloalkyl, aryl or heteroaryl; and R 2 : is hydrogen, alkyl, cycloalkyl, aryl or heteroaryl.
• An example of a compound of formula (I) is a compound of the formula (la): or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein:
• R 3 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, acyl, amido or ester;
• R 4 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, acyl, amido or ester;
• X 1 is alkyl or alkenyl
• X 2 is N or CR 5 , wherein R 5 is absent (e.g., when X 1 is alkenyl), hydrogen, alkyl or aryl.
• Another example of a compound of formula (I) is a compound of the formula (lb): or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof.
• a compound of formula (I) are compounds of the formulae (Ic) and (Id): or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein: n is 0, 1 or 2.
• Still another example of a compound of formula (I) are compounds of the formulae (le) and (If): or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein: q is 0, 1 or 2.
• X 1 is alkyl (e.g., -(CH 2 ) n -), wherein n is 0, 1 , or 2, or alkenyl; and
• X 2 is N or CR 5 , wherein R 5 is absent (e.g., when X 1 is alkenyl), hydrogen, alkyl or aryl.
• R 5 is absent (e.g., when X 1 is alkenyl), hydrogen, alkyl or aryl.
• the alkyl, alkenyl, cycloalkyl, aryl, and heteroaryl groups of R 1 can be unsubstituted or substituted as described herein.
• the alkyl, cycloalkyl, aryl, and heteroaryl groups of R 1 when substituted, they can be substituted with halo (e.g., Cl, Br, and F), amino, OR 6 , wherein R 6 is hydrogen, alkyl, aryl or arylalkyl, S(O) x , wherein x is 0, 1 or 2, acyl, amido or heterocyclyl.
• the alkyl, cycloalkyl, aryl, and heteroaryl groups of R 2 can be unsubstituted or substituted as described herein.
• the alkyl, cycloalkyl, aryl, and heteroaryl groups of R 2 when substituted, they can be substituted with halo (e.g., Cl, Br, and F), amino, OR 6 , wherein R 6 is hydrogen, alkyl, aryl or arylalkyl, S(O) x , wherein x is 0, 1 or 2, acyl, amido or heterocyclyl.
• the alkyl, cycloalkyl, aryl, heteroaryl, acyl, amido or ester groups of R 3 can be unsubstituted or substituted as described herein.
• alkyl, cycloalkyl, aryl, heteroaryl, acyl, amido or ester groups of R 3 when substituted, they can be substituted with halo (e.g., Cl, Br, and F), amino, OR 6 , wherein R 6 is hydrogen, alkyl, cycloalkyl, aryl or arylalkyl, S(O) x , wherein x is Q, 1 or 2, acyl, amido or heterocyclyl.
• halo e.g., Cl, Br, and F
• R 6 is hydrogen, alkyl, cycloalkyl, aryl or arylalkyl, S(O) x , wherein x is Q, 1 or 2, acyl, amido or heterocyclyl.
• the alkyl, cycloalkyl, aryl, heteroaryl, acyl, amido or ester groups of R 4 can be unsubstituted or substituted as described herein.
• alkyl, cycloalkyl, aryl, heteroaryl, acyl, amido or ester groups of R 4 when substituted, they can be substituted with halo (e.g., Cl, Br, and F), amino, OR 6 , wherein R 6 is hydrogen, alkyl, cycloalkyl, aryl or arylalkyl, S(O) x , wherein x is 0, 1 or 2, acyl, amido or heterocyclyl.
• halo e.g., Cl, Br, and F
• R 6 is hydrogen, alkyl, cycloalkyl, aryl or arylalkyl, S(O) x , wherein x is 0, 1 or 2, acyl, amido or heterocyclyl.
• Examples of compounds of the formulae (I) and (la)-(li) include, but are not limited to, compounds of the formulae: pharmaceutically acceptable salts, polymorphs, prodrugs, soivates or clathrates thereof.
• X 1 is alkyl (e.g., -(CH 2 ) n -) or alkenyl;
• X 2 is N or CR 5 , wherein R 5 is absent (e.g., when X 1 is alkenyl), hydrogen, alkyl or aryl; and
• R 8 is H, alkyl (e.g., arylalkyl), acyl (e.g., arylalkyl carbonyl and heterocyclyl carbonyl), aryl, benzyl or heterocyclyl.
• R 6 can independently be F or CF 3 .
• the disclosure also relates to a compound of the formula (III): wherein: Y 1 is alkyl (e.g., CH 2 ), NR 8 or O, wherein R 8 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl;
• Y 2 is alkyl (e.g., CH 2 ), NR 8 or O;
• R 9- is hydrogen, amino, alkyl, cycloalkyl, aryl, heteroaryl (e.g., heterocyclyl), CH( R 9 ) 2 , CH 2 R 9 , OR 9, NHR 9 or S(O) x R 9 , wherein each alkyl, cycloalkyl, aryl, heteroaryl is optionally substituted with, e.g., groups including halogen (e.g., Cl, Br, and F), aryl, amino, alkoxy, S(O) x , wherein x is 0, 1 or 2, acyl, amido or heterocyclyl; and
• halogen e.g., Cl, Br, and F
• R 10 ‘hydrogen, amino, alkyl, cycloalkyl, aryl, heteroaryl (e.g., heterocyclyl) or CH(R 9 ) 2 , CH 2 R 9 , OR 9 , NHR 9 , S(O) x R 9 , wherein each alkyl, cycloalkyl, aryl, heteroaryl is optionally substituted with, e.g., groups including halogen (e.g., Cl, Br, and F), aryl, amino, alkoxy, S(O) x , wherein x is 0, 1 or 2, acyl, amido or heterocyclyl.
• halogen e.g., Cl, Br, and F
• R 9 -Y 1 can form the same groups or different groups as R 10 -Y 2 .
• Y 1 can be O or NR 8 , wherein R 8 can be alkyl or cycloalkyl.
• Compounds of the formula (III) include compounds of the formulae:
• Y 1 is alkyl (e.g., CH 2 ), NR 8 or O, wherein R 8 Is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl;
• R 9- is hydrogen, amino, alkyl, cycloalkyl, aryl, heteroaryl (e.g., heterocyclyl), CH(R 9 ) 2 , CH 2 R 9 , OR 9 , NHR 9 or S(O) x R 9 , wherein each alkyl, cycloalkyl, aryl, heteroaryl is optionally substituted with, e.g., groups including halogen (e.g., Cl, Br, and F), aryl, amino, alkoxy, S(O) x > wherein x is 0, 1 or 2, acyl, amido or heterocyclyl
• W is N or C-R 9A ;
• X is N or C-R 9A ;
• Y is N or C-R 9A ; and
• Z is N or C-R 9A ; wherein each R 9A is independently H, halo, alkyl, haloalkyl (e.g., CF 3 ), alkoxy (e.g., -OR 9B , wherein R 9B is alkyl, cycloalkyl or aryl, heteroaryl, acyl, amide or carbamate) or heterocyclyl (e.g., heteroaryl); and
• Het 1 and Het 2 are each, independently, a heterocyclyl group, such as furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, and the like.
• the disclosure also relates to a compound of the formula (IV): wherein: X* is CR 8 or N, wherein R 8 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl;
• X 5 is CR 8 or N, wherein R 8 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; each R 13 is independently H, acyl, carboxyl or C(O)R 8 , wherein R 8 is H, alkyl, acyl, aryl, benzyl or heterocyclyl;
• R 14- is hydrogen, amino (e.g., NR 8 R 9 ), alkyl, cycloalkyl, aryl, heteroaryl, acyl (e.g., C(O)R 9 ), thioacyl (e.g., R 14 C(S)), R 14 C(NR 14 ), amido or carbamate, each of which alkyl, cycloalkyl, aryl, heteroaryl, acyl, amido, and carbamate is optionally substituted with cycloalkyl, aryl, heteroaryl, each of which cycloalkyl, aryl, and heteroaryl is optionally substituted with halogen (e.g., Ci, Br, and F), amino, alkoxy, S(O) x , wherein x is 0, 1 or 2, acyl, amido or heterocyclyl; and
• halogen e.g., Ci, Br, and F
• R 15- is hydrogen, amino, alkyl, cycloalkyl, aryl, heteroaryl, acyl (e.g., C(O)R 9 ), thioacyl (e.g., R 14 C(S)), R 14 C(NR 14 ), amido or carbamate, each of which alkyl, cycloalkyl, aryl, heteroaryl, acyl, amido, and carbamate is optionally substituted with cycloalkyl, aryl, heteroaryl, each of which cycloalkyl, aryl, and heteroaryl is optionally substituted with halogen (e.g., Cl, Br, and F), amino, alkoxy, S(O) x , wherein x is 0, 1 or 2, acyl, amido or heterocyclyl; or R 13 and R 14 , together with the atoms to which they are each attached, form a heterocyclyl group.
• R 14 can form the same groups or different groups as
• R 14 and R 15 can be acyl, each of which can be substituted with a group R 9 -Y 1 -, as the group is defined in compounds of the formula (HI).
• the compound can be a compound of the formula: pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof.
• the compound can be a compound of the formula:
• Compounds of the formula (IV) include compounds of the formulae:
• Y 1 is alkyl (e.g., GH 2 ), NR 8 or O, wherein R 8 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl;
• R 9- is hydrogen, amino, alkyl, cycloalkyl, aryl, heteroaryl (e.g., heterocyclyl), CH(R 9 ) 2 , CH 2 R 9 , OR 9 , NHR 9 or S(O) x R 9 , wherein each alkyl, cycloalkyl, aryl, heteroaryl is optionally substituted with, e.g., groups including halogen (e.g., Cl, Br, and F), aryl, amino, alkoxy, S(O) x , wherein x is 0, 1 or 2, acyl, amido or heterocyclyl;
• halogen e.g., Cl, Br, and F
• W is N or C-R 9A ;
• X is N or C-R 9A ;
• Y is N or C-R 9A ; and
• Z is N or C-R 9A ; wherein each R 9A is independently H, halo, alkyl, haloalkyl (e.g., CF 3 ), alkoxy (e.g., -OR 9B , wherein R 9B is alkyl, cycloalkyl or aryl, heteroaryl, acyl, amide or carbamate) or heterocyclyl (e.g., heteroaryl); and
• Het 1 and Het 2 are each, independently, a heterocyclyl group, such as furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, and the like.
• An example of such compounds includes a compound of the formula:
• Y 1 is alkyl (e.g., CH 2 ), NR 8 or O, wherein R 8 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl;
• R 9- is hydrogen, amino, alkyl, cycloalkyl, aryl, heteroaryl (e.g., heterocyclyl), CH(R 9 ) 2 , CH 2 R 9 , OR 9 , NHR 9 or S(O) x R 9 , wherein each alkyl, cycloalkyl, aryl, heteroaryl is optionally substituted with, e.g., groups including halogen (e.g., Cl, Br, and F), aryl, amino, alkoxy, S(O) x , wherein x is 0, 1 or 2, acyl, amido or heterocyclyl;
• halogen e.g., Cl, Br, and F
• W is N or C-R 9A ;
• X is N or C-R 9A ;
• Y is N or C-R 9A ; and
• Z is N or C-R 9A ; wherein each R 9A is independently H, halo, alkyl, haloalkyl (e.g., CF 3 ), alkoxy (e.g., -OR 9B , wherein R 9B is alkyl, cycloalkyl or aryl, heteroaryl, acyl, amide or carbamate) or heterocyclyl (e.g., heteroaryl); and
• Het 1 and Het 2 are each, independently, a heterocyclyl group, such as furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, and the like. Examples of such compounds include compounds of the formulae:
• Y 1 is alkyl (e.g., CH 2 ), NR 8 or O, wherein R 8 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl;
• R -9 is hydrogen, amino, alkyl, cycloalkyl, aryl, heteroaryl (e.g., heterocyclyl), CH(R 9 ) 2 , CH 2 R 9 , OR 9 , NHR 9 or S(O) x R 9 , wherein each alkyl, cycloalkyl, aryl, heteroaryl is optionally substituted with, e.g., groups including halogen (e.g., Cl, Br, and F), aryl, amino, alkoxy, S(O) x , wherein x is 0, 1 or 2, acyl, amido or heterocyclyl;
• halogen e.g., Cl, Br, and F
• W is N or C-R 9A ;
• X is N or C-R 9A ;
• Y is N or C-R 9A ; and
• Z is N or C-R 9A ; wherein each R 9A is independently H, halo, alkyl, haloalkyl (e.g., CF 3 ), alkoxy (e.g., -OR 9B , wherein R 9B is alkyl, cycloalkyl or aryl, heteroaryl, acyl, amide or carbamate) or heterocyclyl (e.g., heteroaryl); and
• Het 1 and Het 2 are each, independently, a heterocyclyl group, such as furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, and the like.
• the disclosure also relates to a compound of the formula (V): or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein:
• X 1 is alkyl (e.g., -(CH 2 )n-) or alkenyl;
• R 2 is hydrogen, alkyl, cycloalkyl, aryl or heteroaryl;
• R 14 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, acyl, amido or carbamate, each of which alkyl, cycloalkyl, aryl, heteroaryl, acyl, amido, carbamate is optionally substituted with cycloalkyl, aryl, heteroaryl, each of which cycloalkyl, aryl, and heteroaryl is optionally substituted with halogen (e.g., Cl, Br, and F), amino, alkoxy, S(O) x , wherein x is 0, 1 or 2, acyl, amido or heterocyclyl;
• halogen e.g., Cl, Br, and F
• R 15- is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, acyl, amido or carbamate, each of which alkyl, cycloalkyl, aryl, heteroaryl, acyl, amido, carbamate is optionally substituted with cycloalkyl, aryl, heteroaryl, each of which cycloalkyl, aryl, and heteroaryl is optionally substituted with halogen (e.g., Cl, Br, and F), amino, alkoxy, S(O) x , wherein x is 0, 1 or 2, acyl, amido or heterocyclyl; and
• halogen e.g., Cl, Br, and F
• R 16 is H, acyl, carboxyl or C(O)R 8 , wherein R 8 is H, alkyl, acyl, aryl, benzyl or heterocyclyl; or
• R 14 and R 15 or R 15 and R 16 together with the atoms to which they are each attached, form a cyclic group (e.g., a cycloalkyl and a heterocyclyl group).
• R 14 and R 15 are halogenated aryl (e.g., para-halogenated, as in para-fluoro), such as, e.g., a compound of the formula:
• R 16 can be C(O)R 8 , such that the compound of the formula (V) is a compound of the formula: or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof.
• the disclosure also relates to a compound of the formula (VI): or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein:
• X 1 is alkyl (e.g., -(CH 2 ) n -) or alkenyl;
• R 2 is hydrogen, alkyl, cycloalkyl, aryl or heteroaryl;
• each R 13 is H, acyl, carboxyl or C(O)R 8 , wherein R 8 is H, alkyl, acyl, aryl, benzyl or heterocyclyl;
• R 17- is hydrogen, alkyl, cycloalky I, aryl, heteroaryl, acyl, amido or carbamate, each of which alkyl, cycloalkyl, aryl, heteroaryl, acyl, amido, carbamate is optionally substituted with cycloalkyl, aryl, heteroaryl, each of which cycloalkyl, aryl, and heteroaryl is optionally substituted with nalogen (e.g., Gl, Br, and Fj, amino, alkoxy, S(O)x, wherein x is 0, 1 or 2, acyl, amido or heterocyclyl;
• R 18- is hydrogen, alkyl, OR 19 (wherein R 19 is hydrogen, alkyl, cycloalkyl, aryl or heteroaryl) cycloalkyl, aryl, heteroaryl, acyl, amido or carbamate, each of which alkyl, cycloalkyl, aryl, heteroaryl,
• R 18 can be C(O)R 8 , such that the compound of the formula (VI) is a compound of the formula: or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof.
• the disclosure also relates to compounds of the formula: or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein: X 4 is CR 8 or N, wherein R 8 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl;
• X 5 is CR 8 or N, wherein R 8 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; each R 13 is independently H, acyl, carboxyl or C(O)R 8 , wherein R 8 is H, alkyl, acyl, aryl, benzyl or heterocyclyl;
• R 14- is hydrogen, amino (e.g., NR 8 R 9 ), alkyl, cycloalkyl, aryl, heteroaryl, acyl (e.g., C(O)R 9 ), thioacyl (e.g., R 14 C(S)), R 14 C(NR 14 ), amido or carbamate, each of which alkyl, cycloalkyl, aryl, heteroaryl, acyl, amido, and carbamate is optionally substituted with cycloalkyl, aryl, heteroaryl, each of which cycloalkyl, aryl, and heteroaryl is optionally substituted with halogen (e.g., Ci, Br, and F), amino, alkoxy, S(O) x , wherein x is 0, 1 or 2, acyl, amido or heterocyclyl; and R 15- and R 16 are each, independently, hydrogen, amino, alkyl, cycloalkyl, aryl, heteroaryl,
• compositions comprising one or more compounds and one or more pharmaceutically acceptable excipients.
• a “pharmaceutical composition” refers to a chemical or biological composition suitable for administration to a subject (e.g., mammal).
• compositions can be specirically rormulated for administration via one or more of a number of routes, including but not limited to buccal, cutaneous, epicutaneous, epidural, infusion, inhalation, intraarterial, intracardial, intracerebroventricular, intradermal, intramuscular, intranasal, intraocular, intraperitoneal, intraspinai, intrathecal, intravenous, oral, parenteral, pulmonary, rectaiiy via an enema or suppository, subcutaneous, subdermal, sublingual, transdermal, and transmucosal.
• administration can by means of capsule, drops, foams, gel, gum, injection, liquid, patch, pill, porous pouch, powder, tablet, or other suitable means of administration.
• a “pharmaceutical excipient” or a “pharmaceutically acceptable excipient” is a carrier, sometimes a liquid, in which an active therapeutic agent is formulated.
• the excipient generally does not provide any pharmacological activity to the formulation, though it can provide chemical and/or biological stability, and release characteristics. Examples of suitable formulations can be found, for example, in Remington, The Science And Practice of Pharmacy, 20th Edition, (Gennaro, A. R., Chief Editor), Philadelphia College of Pharmacy and Science, 2000, which is incorporated by reference in its entirety.
• pharmaceutically acceptable carrier includes, but is not limited to, any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents that are physiologically compatible.
• the carrier is suitable for parenteral administration.
• the carrier can be suitable for intravenous, intraperitoneal, intramuscular, sublingual, or oral administration.
• Pharmaceutically acceptable carriers include steriie aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the pharmaceutical compositions of the invention is contemplated. Supplementary active compounds can also be incorporated into the compositions.
• compositions can be sterile and stable under the conditions of manufacture and storage.
• the composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration.
• the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof.
• the proper fluidity can be maintained, for example, by the use ot a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
• isotonic agents for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition.
• Prolonged absorption of injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, monostearate salts and gelatin.
• the compounds described herein can be formulated in a time release formulation, for exampie in a composition that includes a slow release polymer.
• the active compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants and microencapsulated delivery systems.
• Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid and poiylactic, polyglycolic copolymers (PLG). Many methods for the preparation of such formulations are known to those skilled in the art.
• compositions of the present invention can be orally administered as a capsule (hard or soft), tablet (film coated, enteric coated or uncoated), powder or granules (coated or uncoated) or liquid (solution or suspension).
• the formulations can be conveniently prepared by any of the methods well-known in the art.
• the pharmaceutical compositions of the present invention can include one or more suitable production aids or excipients including fillers, binders, disintegrants, lubricants, diluents, flow agents, buffering agents, moistening agents, preservatives, colorants, sweeteners, flavors, and pharmaceutically compatible carriers.
• the compounds can be administered by a variety of dosage forms as known in the art. Any biologicaliy- acceptable dosage form known to persons of ordinary skill in the art, and combinations thereof, are contemplated. Examples of such dosage forms include, without limitation, chewable tablets, quick dissolve tablets, effervescent tablets, reconstitutabie powders, elixirs, liquids, solutions, suspensions, emulsions, tablets, multi-layer tablets, bi-layer tablets, capsules, soft gelatin capsules, hard gelatin capsules, caplets, lozenges, chewable lozenges, beads, powders, gum, granules, particles, microparticles, dispersible granules, cachets, douches, suppositories, creams, topicals, inhalants, aerosol inhalants, patches, particle inhalants, implants, depot implants, ingestibles, injectables (including subcutaneous, intramuscular, intravenous, and intradermal), infusion
• Other compounds which can be included by admixture are, for example, medically inert ingredients (e.g., solid and liquid diluent), such as lactose, dextrosesaccharose, cellulose, starch or calcium phosphate for tablets or capsules, olive oil or ethyl oleate for soft capsules and water or vegetable oil for suspensions or emulsions; lubricating agents such as silica, talc, stearic acid, magnesium or calcium stearate and/or polyethylene glycols; gelling agents such as colloidal clays; thickening agents such as gum tragacanth or sodium alginate, binding agents such as starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; disintegrating agents such as starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuff; sweeteners; wetting agents such as lecithin,
• Liquid dispersions for oral administration can be syrups, emulsions, solutions, or suspensions.
• the syrups can contain as a carrier, for example, saccharose or saccharose with glycerol and/or mannitol and/or sorbitol.
• the suspensions and the emulsions can contain a carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
• the amount of active compound in a therapeutic composition can vary according to factors such as the disease state, age, gender, weight, patient history, risk factors, predisposition to disease, administration route, pre-existing treatment regime (e.g., possible interactions with other medications), and weight of the subject. Dosage regimens can be adjusted to provide the optimum therapeutic response. For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the exigencies of therapeutic situation.
• a “dosage unit form,” as used herein, refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
• the specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in subjects.
• the compounds of the present invention can be administered in an effective amount.
• the dosages as suitable for this invention can be a composition, a pharmaceutical composition or any other compositions described herein.
• the dosage is typically administered once, twice, or thrice a day, although more frequent dosing intervals are possible.
• the dosage can be administered every day, every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, and/or every 7 days (once a week).
• the dosage can be administered daily for up to and including 30 days, preferably between 7-10 days.
• the dosage can be administered twice a day for 10 days. If the patient requires treatment for a chronic disease or condition, the dosage can be administered for as long as signs and/or symptoms persist.
• the patient can require "maintenance treatment" where the patient is receiving dosages every day for months, years, or the remainder of their lives.
• the composition of this invention can be to effect prophylaxis of recurring symptoms.
• the dosage can be administered once or twice a day to prevent the onset of symptoms in patients at risk, especially for asymptomatic patients.
• the absolute weight of a given compound included in a unit dose for administration to a subject can vary widely. For example, about 0.0001 to about 1 g, or about 0.001 to about 0.5 g, of at least one compound of this disclosure, or a plurality of compounds can be administered.
• the unit dosage can vary from about 0.001 g to about 2g, from about 0.005 g to about 0.5 g, from about 0.01 g to about 0.25 g, from about 0.02 g to about 0.2 g, from about 0.03 g to about 0.15 g, from about 0.04 g to about 0.12 g, or from about 0.05 g to about 0.1 g.
• Daily doses of the compounds can vary as well. Such daily doses can range, for example, from about 0.01 g/day to about 10 g/day, from about 0.02 g/day to about 5 g/day, from about 0.03 g/day to about 4 g/day, from about 0.04 g/day to about 3 g/day, from about 0.05 g/day to about 2 g/day, and from about 0.05 g/day to about 1 g/day.
• the amount of compound(s) for use in treatment will vary not only with the particular carrier selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient. Ultimately the attendant health care provider may determine proper dosage.
• compositions described herein can be administered in any of the following routes: buccal, epicutaneous, epidural, infusion, inhalation, intraarterial, intracardial, intracerebroventricular, intradermal, intramuscular, intranasal, intraocular, intraperitoneal, intraspinal, intrathecal, intravenous, oral, parenteral, pulmonary, rectally via an enema or suppository, subcutaneous, subdermaL sublingual, transdermal, and transmucosal.
• routes of administration are buccal and oral.
• the administration can be local, where the composition is administered directly, close to, in the locality, near, at, about, or in the vicinity of, the site(s) of disease, e.g., inflammation, or systemic, wherein the composition is given to the patient and passes through the body widely, thereby reaching the site(s) of disease.
• Local administration can be administration to, for example, tissue, organ, and/or organ system, which encompasses and/or is affected by the disease, and/or where the disease signs and/or symptoms are active or are likely to occur.
• Administration can be topical with a local effect, composition is applied directly where its action is desired.
• Administration can be enteral wherein the desired effect is systemic (non-local), composition is given via the digestive tract.
• Administration can be parenteral, where the desired effect is systemic, composition is given by other routes than the digestive tract.
• compositions can include the compounds described herein in a “therapeutically effective amount.”
• a therapeutically effective amount is an amount sufficient to obtain the desired physiological effect, such as a reduction of at least one symptom of cancer or an inflammatory disease or condition.
• compositions contemplated herein can contain other ingredients such as chemotherapeutic agents, anti-inflammatory agents, anti- viral agents, antibacterial agents, antimicrobial agents, immunomodulatory drugs, such as lenalidomide, pomalidomide or thalidomide, histone deacetylase inhibitors, such as panobinostat, preservatives or combinations thereof.
• chemotherapeutic agents anti-inflammatory agents
• anti- viral agents antibacterial agents
• antimicrobial agents antimicrobial agents
• immunomodulatory drugs such as lenalidomide, pomalidomide or thalidomide
• histone deacetylase inhibitors such as panobinostat, preservatives or combinations thereof.
• This disclosure also includes methods for treating neurodegenerative diseases, such as Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and ALS, comprising administering a therapeutically effective amount of at least one of the compounds described herein (e.g., fluspirilene or compounds of the formulae (I), (la)-(li), and (II)-(VI)) to a subject in need thereof.
• a therapeutically effective amount of at least one of the compounds described herein e.g., fluspirilene or compounds of the formulae (I), (la)-(li), and (ll)-(VI)
• This disclosure also includes methods for reducing, substantially eliminating or eliminating the accumulation of intrinsically disordered proteins (e.g., ⁇ -Syn) comprising administering a therapeutically effective amount of at least one of the compounds described herein (e.g., fluspirilene or compounds of the formulae (I), (ia)-(li), and (ll)-(VI)) to a subject in need thereof.
• the terms “treat” and “treating” are not limited to the case where the subject (e.g. patient) is cured and the disease is eradicated. Rather, treatment that merely reduces symptoms, and/or delays disease progression is also contemplated.
• compositions disclosed herein can have the ability to effectively treat new patient segments where proteasome inhibition and reduced toxicity is desired or warranted.
• the compounds and methods described herein can be used prophylactically or therapeutically.
• the term “prophylactic” or “therapeutic” treatment refers to administration of a drug to a host before or after onset of a disease or condition. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, i.e., it protects the host against developing the unwanted condition, whereas if administered after manifestation of the unwanted condition, the treatment is therapeutic (i.e., it is intended to diminish, ameliorate or maintain the existing unwanted condition or side effects therefrom).
• Administering the compounds described herein (including enantiomers and salts thereof) is contemplated in both a prophylactic treatment (e.g. to patients at risk for disease, such as elderly patients who, because of their advancing age, are at risk for arthritis, cancer, and the like) and therapeutic treatment (e.g. to patients with symptoms of disease or to patients diagnosed with disease).
• therapeutically effective amount refers to that amount of one or more compounds of the various examples of the present invention that elicits a biological or medicinal response in a tissue system, animal or human, that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
• the therapeutically effective amount is that which can treat or alleviate the disease or symptoms of the disease at a reasonable benefit/risk ratio applicable to any medical treatment.
• the total daily usage of the compounds and compositions described herein can be decided by the attending physician within the scope of sound medical judgment.
• the specific therapeutically-effective dose level for any particular patient will depend upon a variety of factors, including the condition being treated and the severity of the condition; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, gender and diet of the patient: the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidentally with the specific compound employed; and like factors well known to the researcher, veterinarian, medical doctor or other clinician. It is also appreciated that the therapeutically effective amount can be selected with reference to any toxicity, or other undesirable side effect, that might occur during administration of one or more of the compounds described herein.
• alkyl refers to substituted or unsubstituted straight chain, branched and cyclic, saturated mono- or bi-valent groups having from 1 to 20 carbon atoms, 10 to 20 carbon atoms, 12 to 18 carbon atoms, 6 to about 10 carbon atoms, 1 to 10 carbons atoms, 1 to 8 carbon atoms, 2 to 8 carbon atoms, 3 to 8 carbon atoms, 4 to 8 carbon atoms, 5 to 8 carbon atoms, 1 to 6 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, or 1 to 3 carbon atoms.
• Examples of straight chain mono-valent (C 1 -C 20 )-alkyl groups include those with from 1 to 8 carbon atoms such as methyl (i.e., CH 3 ), ethyl, n- propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl groups.
• Examples of branched mono-valent (C 1 -C 20 )-alkyl groups include isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, and isopentyl.
• Examples of straight chain bi-valent (C 1 -C 20 )alkyl groups include those with from 1 to 6 carbon atoms such as -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, and -CH 2 CH 2 CH 2 CH 2 CH 2 -.
• Examples of branched bi-valent alkyl groups include -CH(CH 3 )CH 2 - and -CH 2 CH(CH 3 )CH 2 -.
• cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopently, cyclohexyl, cyclooctyl, bicyclo[1 .1 .1 Jpentyl, bicyclo[2.1 .1 ]hexyl, and bicyclo[2.2.1]heptyl.
• Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like.
• alkyl includes a combination of substituted and unsubstituted alkyl.
• alkyl, and also (C 1 )alkyl includes methyl and substituted methyl.
• (C 1 )alkyl includes benzyl.
• alkyl can include methyl and substituted (C 2 -C 8 )alkyl.
• Alkyl can also include substituted methyl and unsubstituted (C 2 -C 8 )alkyl.
• alkyl can be methyl and C 2 -C 8 linear alkyl.
• alkyl can be methyl and C 2 -C 8 branched alkyl.
• methyl is understood to be -CH 3 , which is not substituted.
• methylene is understood to be -CH 2 -, which is not substituted.
• (C 1 )alkyl is understood to be a substituted or an unsubstituted -CH 3 or a substituted or an unsubstituted -CH 2 -.
• Representative substituted alkyl groups can be substituted one or more times with any of the groups listed herein, for example, cycloalkyl, heterocyclyl, aryl, amino, haloalkyl, hydroxy, cyano, carboxy, nitro, thio, aikoxy, and halogen groups.
• representative substituted alkyl groups can be substituted one or more fluoro, chloro, bromo, iodo, amino, amido, alkyl, alkoxy, alkylamido, alkenyl, alkynyl, aikoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino and dialkylamido.
• representative substituted alkyl groups can be substituted from a set of groups including amino, hydroxy, cyano, carboxy, nitro, thio and alkoxy, but not including halogen groups.
• alkyl can be substituted with a non-halogen group.
• representative substituted alkyl groups can be substituted with a fluoro group, substituted with a bromo group, substituted with a halogen other than bromo, or substituted with a halogen other than fluoro.
• representative substituted alkyl groups can be substituted with one, two, three or more fluoro groups or they can be substituted with one, two, three or more non-fiuoro groups.
• alkyl can be trifluoromethyl, difluoromethyl, or fluoromethyl, or alkyl can be substituted alkyl other than trifluoromethyl, difluoromethyl or fluoromethyl.
• Alkyl can be haloalkyl or alkyl can be substituted alkyl other than haloalkyl.
• alkyl also generally refers to alkyl groups that can comprise one or more heteroatoms in the carbon chain. Thus, for example, “alkyl” also encompasses groups such as -[(CH 2 ) p O] q H and the like.
• alkenyl refers to substituted or unsubstituted straight chain, branched and cyclic, saturated mono- or bi-valent groups having at least one carbon-carbon double bond and from 2 to 20 carbon atoms, 10 to 20 carbon atoms, 12 to 18 carbon atoms, 6 to about 10 carbon atoms, 2 to 10 carbons atoms, 2 to 8 carbon atoms, 3 to 8 carbon atoms, 4 to 8 carbon atoms, 5 to 8 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, 4 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 to 3 carbon atoms.
• the double bonds can be be trans or cis orientation.
• the doubie bonds can be terminal or internal.
• the alkenyl group can be attached via the portion of the alkenyl group containing the double bond, e.g., vinyl, propen-1 -yl and buten-1-yl, or the alkenyl group can be attached via a portion of the alkenyl group that does not contain the double bond, e.g., penten-4-yl.
• Examples of mono-valent (C 2 -C 20 )-alkenyl groups include those with from 1 to 8 carbon atoms such as vinyl, propenyl, propen-1 -yl, propen-2-yl, butenyl, buten-1 -yl, buten-2-yl, sec-buten-1 -yl, sec-buten-3-yl, pentenyl, hexenyl, heptenyl and octenyl groups.
• Examples of branched mono- valent (C 2 -C 20 )-alkenyl groups include isopropenyl, iso-butenyl, sec-butenyl, t- butenyl, neopentenyl, and isopentenyl.
• Examples of straight chain bi-valent (C 2 -C 20 )alkenyl groups include those with from 2 to 6 carbon atoms such as -CHCH- , -CHCHCH 2 -, -CHCHCH 2 CH 2 -, and -CHCHCH 2 CH 2 CH 2 -.
• Examples of branched bi-valent alkyl groups include -C(CH 3 )CH- and -CHC(CH 3 )CH 2 -.
• Examples of cyclic alkenyl groups include cyclopentenyl, cyclohexenyl and cyclooctenyl. It is envisaged that alkenyl can also include masked alkenyl groups, precursors of alkenyl groups or other related groups.
• substituted alkenyl also includes alkenyl groups which are substantially tautomeric with a non-alkenyl group.
• substituted alkenyl can be 2-aminoalkenyl, 2-alkylaminoalkenyl, 2-hydroxyalkenyl, 2- hydroxyvinyl, 2-hydroxypropenyl, but substituted alkenyl is also understood to include the group of substituted alkenyl groups other than alkenyl which are tautomeric with non-alkenyl containing groups.
• alkenyl can be understood to include a combination of substituted and unsubstituted alkenyl.
• alkenyl can be vinyl and substituted vinyl.
• alkenyl can be vinyl and substituted (C3-Ce)alkenyl.
• Alkenyl can also include substituted vinyl and unsubstituted (C 3 -C 8 )alkenyl.
• Representative substituted alkenyl groups can be substituted one or more times with any of the groups listed herein, for example, monoalkylamino, dialkylamino, cyano, acetyl, amido, carboxy, nitro, alkylthio, alkoxy, and halogen groups.
• representative substituted alkenyl groups can be substituted one or more fluoro, chloro, bromo, iodo, amino, amido, alkyl, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylammosulfonyl, sulfonic acid, carboxylic acid, dialkylamino and dialkylamido.
• representative substituted alkenyl groups can be substituted from a set of groups including monoalkylamino, dialkylamino, cyano, acetyl, amido, carboxy, nitro, alkylthio and alkoxy, but not including halogen groups.
• alkenyl can be substituted with a non-halogen group.
• representative substituted alkenyl groups can be substituted with a fluoro group, substituted with a bromo group, substituted with a halogen other than bromo, or substituted with a halogen other than fluoro.
• alkenyl can be 1 -fluorovinyl, 2-fluorovinyl, 1 ,2-difluorovinyl, 1 ,2,2-trifluorovinyl, 2,2- difluorovinyl, trifluoropropen-2-yl, 3,3,3-trifluoropropenyl, 1-fluoropropenyl, 1 - chlorovinyl, 2-chlorovinyl, 1 ,2-dichlorovinyl, 1 ,2,2-trichlorovinyl or 2,2- dichlorovinyl.
• representative substituted alkenyl groups can be substituted with one, two, three or more fluoro groups or they can be substituted with one, two, three or more non-fluoro groups.
• alkynyl refers to substituted or unsubstituted straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms.
• alkynyl groups have from 2 to 50 carbon atoms, 2 to 20 carbon atoms, 10 to 20 carbon atoms, 12 to 18 carbon atoms, 6 to about 10 carbon atoms, 2 to 10 carbons atoms, 2 to 8 carbon atoms, 3 to 8 carbon atoms, 4 to 8 carbon atoms, 5 to 8 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, 4 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 to 3 carbon atoms.
• Examples include, but are not limited to ethynyl, propynyl, propyn- 1 -yl, propyn-2-yl, butynyl, butyn-1 -yl, butyn-2-yl, butyn-3-yl, butyn-4-yl, pentynyl, pentyn-1 -yl, hexynyl, Examples include, but are not limited to -C ⁇ CH, -C ⁇ C(CH 3 ), -C ⁇ C(CH 2 CH 3 ), -CH 2 C ⁇ CH, -CH 2 OC(CH 3 ), and -GH 2 C ⁇ G(CH 2 GH 3 ) among others.
• aryl refers to substituted or unsubstituted univalent groups that are derived by removing a hydrogen atom from an arene, which is a cyclic aromatic hydrocarbon, having from 6 to 20 carbon atoms, 10 to 20 carbon atoms, 12 to 20 carbon atoms, 6 to about 10 carbon atoms or 6 to 8 carbon atoms.
• Examples of (C 6 -C 20 )aryl groups include phenyl, napthaienyl, azuienyl, biphenylyl, Indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, anthracenyl groups.
• Examples include substituted phenyl, substituted napthaienyl, substituted azuienyl, substituted biphenylyl, substituted indacenyl, substituted fluorenyl, substituted phenanthrenyl, substituted tnphenylenyl, substituted pyrenyl, substituted naphthacenyl, substituted chrysenyl, and substituted anthracenyl groups.
• Examples also include unsubstituted phenyl, unsubstituted napthalenyl, unsubstituted azulenyl, unsubstituted biphenylyl, unsubstituted indacenyl, unsubstituted fluorenyl, unsubstituted phenanthrenyl, unsubstituted triphenylenyl, unsubstituted pyrenyl, unsubstituted naphthacenyl, unsubstituted chrysenyl, and unsubstituted anthracenyl groups.
• Aryl includes phenyl groups and also non- phenyl aryl groups.
• (C 8 -C 20 )aryl encompasses mono- and polycyclic (C 8 -C 20 )aryl groups, including fused and non- fused polycyclic (C 6 -C 20 )aryl groups.
• heterocyclyl refers to substituted aromatic, unsubstituted aromatic, substituted non-aromatic, and unsubstituted non-aromatic rings containing 3 or more atoms in the ring, of which, one or more is a heteroatom such as, but not limited to, N, O, and S.
• a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or if polycyclic, any combination thereof.
• heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members.
• heterocyclyl groups include heterocyclyl groups that include 3 to 8 carbon atoms (C3-C 8 ), 3 to 6 carbon atoms (C 3 -C 6 ) or 6 to 8 carbon atoms (C 6 - C 8 ).
• a heterocyclyl group designated as a C 2 -heterocyclyl can be a 5-membered ring with two carbon atoms and three heteroatoms, a 6-membered ring with two carbon atoms and four heteroatoms and so forth.
• a Ca-heterocyclyl can be a 5-membered ring with one heteroatom, a 6-membered ring with two heteroatoms, and so forth.
• heterocyclyl group includes fused ring species including those that include fused aromatic and non -aromatic groups.
• heterocyclyl groups include, but are not limited to piperidynyl, piperazinyl, morpholinyl, furanyl, pyrrolidinyl, pyridinyl, pyrazinyl, pyrimidinyl, triazinyl, thiophenyl, tetrahydrofuranyl, pyrrolyl, oxazolyl, imidazolyl, triazyolyl, tetrazolyl, benzoxazolinyl, and benzimidazolinyl groups.
• heterocyclyl groups include, without limitation:
• a nitrogen-containing heterocyclyl group is a heterocyclyl group containing a nitrogen atom as an atom in the ring.
• the heterocyclyl is other than thiophene or substituted thiophene, in some embodiments, the heterocyclyl is other than furan or substituted furan.
• alkoxy refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined herein.
• linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like.
• branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like.
• cyclic alkoxy examples include but are not limited to cyclopropyloxy, cyciobutyloxy, cyciopentyloxy, cyclohexyloxy, and the like.
• An alkoxy group can include one to about 12-20 or about 12-40 carbon atoms bonded to the oxygen atom, and can further include double or triple bonds, and can also include heteroatoms.
• alkyoxy also includes an oxygen atom connected to an alkyenyl group and oxygen atom connected to an alkynyl group.
• an ailyloxy group is an aikoxy group within the meaning herein.
• a methoxyethoxy group is also an alkoxy group within the meaning herein, as is a methylenedioxy group in a context where two adjacent atoms of a structure are substituted therewith.
• aryloxy refers to an oxygen atom connected to an aryl group as are defined herein.
• aralkyl and arylalkyl refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein.
• Representative aralkyl groups include benzyl, biphenylmethyl and phenylethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl.
• Aralkenyl groups are alkenyl groups as defined herein in which a hydrogen or carbon bond ot an alkyl group is replaced with a bond to an aryl group as defined herein.
• halo means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
• amine and “amino” as used herein refers to a substituent of the form -NH 2 , -NHR, -NR 2 , -NR 3 +, wherein each R is independently selected, and protonated forms of each, except for -NR 3 +, which cannot be protonated. Accordingly, any compound substituted with an amino group can be viewed as an amine.
• An “amino group” within the meaning herein can be a primary, secondary, tertiary, or quaternary amino group.
• An “alkylamino” group includes a monoalkylamino, dialkylamino, and trialkylamino group.
• acyl refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom.
• the carbonyl carbon atom is also bonded to another carbon atom, which can be part of a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, group or the like.
• formyl refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom.
• the carbonyl carbon atom is also bonded to a hydrogen atom.
• alkoxycarbonyl refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom.
• the carbonyl carbon atom is also bonded to an oxygen atom which is further bonded to an alkyl group.
• Alkoxycarbonyl also includes the group where a carbonyl carbon atom is also bonded to an oxygen atom which is further bonded to an alkyenyl group.
• Aikoxycarbonyl also includes the group where a carbonyl carbon atom is also bonded to an oxygen atom which is further bonded to an alkynyl group.
• aikoxycarbonyl as the term is defined herein, and is also included in the term “aryloxycarbonyl,” the carbonyl carbon atom is bonded to an oxygen atom which is bonded to an aryl group instead of an alkyl group.
• arylcarbonyl refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom.
• the carbonyl carbon atom is also bonded to an aryl group.
• alkylamido refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom.
• the carbonyl carbon atom is also bonded to a nitrogen group which is bonded to one or more aikyl groups,
• wnich is also an alkylamido as the term is defined herein, the carbonyl carbon atom is bonded to a nitrogen atom which is bonded to one or more aryl group instead of, or in addition to, the one or more alkyl group.
• the carbonyl carbon atom is bonded to an nitrogen atom which is bonded to one or more alkenyl group instead of, or in addition to, the one or more alkyl and or/aryl group
• the carbonyl carbon atom is bonded to a nitrogen atom which is bonded to one or more alkynyl group instead of, or in addition to, the one or more alkyl, alkenyl and/or aryl group.
• carboxy refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom.
• the carbonyl carbon atom is also bonded to a hydroxy group or oxygen anion so as to result in a carboxylic acid or carboxylate.
• Carboxy also includes both the protonated form of the carboxylic acid and the salt form.
• carboxy can be understood as COOH or CO 2 H.
• amide refers to a group having the formula C(O)NRR, wherein R is defined herein and can each independently be, e.g., hydrogen, alkyl, aryl or each R, together with the nitrogen atom to which they are attached, form a heterocyclyl group.
• alkylthio refers to a sulfur atom connected to an alkyl, alkenyl, or alkynyl group as defined herein.
• arylthio refers to a sulfur atom connected to an aryl group as defined herein.
• alkylsulfonyl refers to a sulfonyl group connected to an alkyl, alkenyl, or alkynyl group as defined herein.
• alkylsulfinyl refers to a sulfinyl group connected to an alkyl, alkenyl, or alkynyl group as defined herein.
• dialkylaminosulfony I refers to a sulfonyl group connected to a nitrogen further connected to two alkyl groups, as defined herein, and which can optionally be linked together to form a ring with the nitrogen. This term also includes the group where the nitrogen is further connected to one or two alkenyl groups in place of the alkyl groups.
• dialkylamino refers to an amino group connected to two alkyl groups, as defined herein, and which can optionally be linked together to form a ring with the nitrogen. This term also includes the group where tne nitrogen is further connected to one or two alkenyl groups in place or the alkyl groups.
• dialkylamido refers to an amido group connected to two alkyl groups, as defined herein, and which can optionally be linked together to form a ring with the nitrogen. This term also includes the group where the nitrogen is further connected to one or two alkenyl groups in place of the alkyl groups.
• substituted refers to a group that is substituted with one or more groups including, but not limited to, the following groups: halogen (e.g., F, Cl, Br, and I), R, OR, ROH (e.g., CH 2 OH), OC(O)N(R) 2 (also known as carbamate), CN, NO, NO 2 , ONO 2 , azido, CF 3 , OCF 3 , methylenedioxy, ethylenedioxy, (C 3 -C 20 )heteroaryl, N(R) 2 , Si(R) 3 , SR, SOR, SO 2 R, SO 2 N(R) 2 , SO 3 R, P(O)(OR) 2 , OP(O)(OR) 2 , C(O)R, C(O)C(O)R, C(O)CH 2 C(O)R, C(S)R, C(O)OR, OC(O)
• halogen e.g., F, Cl,
• Substituted also includes a group that is substituted with one or more groups including, but not limited to, the following groups: fluoro, chloro, bromo, iodo, amino, amido, alkyl, hydroxy, alkoxy, alkylamido, alkenyl, alkynyl, alkoxycarbonyl, acyl, formyl, arylcarbonyl, aryloxycarbonyl, aryloxy, carboxy, haloalkyl, hydroxy, cyano, nitroso, nitro, azido, trifluoromethyl, trifluoromethoxy, thio, alkylthio, arylthiol, alkylsulfonyl, alkylsulfinyl, dialkylaminosulfonyl, sulfonic acid, carboxylic acid, dialkylamino and dialkylamido.
• groups including, but not limited to, the following groups: fluoro, chloro, bromo,
• the substituents can be linked to form a carbocyclic or heterocyclic ring.
• Such adjacent groups can have a vicinal or germinal relationship, or they can be adjacent on a ring in, e.g., an ortho-arrangement.
• Each instance of substituted is understood to be independent.
• a substituted aryl can be substituted with bromo and a substituted heterocycle on the same compound can be substituted with alkyl.
• a substituted group can be substituted with one or more non-fluoro groups.
• a substituted group can be substituted with one or more non-cyano groups.
• a substituted group can be substituted with one or more groups other than haioalkyl.
• a substituted group can be substituted with one or more groups other than tert-butyl.
• a substituted group can be substituted with one or more groups other than trifluoromethyl.
• a substituted group can be substituted with one or more groups other than nitro, other than methyl, other than methoxymethyl, other than dialkylaminosulfonyl, other than bromo, other than chloro, other than amido, other than halo, other than benzodioxepinyl, other than polycyclic heterocyclyl, other than polycyclic substituted aryl, other than methoxycarbonyl, other than alkoxycarbonyl, other than th iophenyl , or other than nitrophenyl, or groups meeting a combination of such descriptions.
• substituted is also understood to include fluoro, cyano, haloalkyl, tert-butyl, trifluoromethyl, nitro, methyl, methoxymethyl, dialkylaminosulfonyl, bromo, chloro, amido, halo, benzodioxepinyl, polycyclic heterocyclyl, polycyclic substituted aryl, methoxycarbonyl, alkoxycarbonyl, thiophenyl, and nitrophenyl groups.
• the compounds described herein can contain chiral centers. All diastereomers of the compounds described herein are contemplated herein, as well as racemates.
• salts and “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
• pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkaii or organic salts of acidic groups such as carboxylic acids.
• Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
• such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfaniiic, 2- acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic, and the like.
• inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric
• organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic
• salts can be synthesized trom the parent compound which contains a basic or acidic moiety by conventional chemical methods.
• such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric (or larger) amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
• Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, the disclosure of 'which is hereby incorporated by reference.
• solvate means a compound, or a salt thereof, that further includes a stoichiometric or non-stoich iometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate.
• prodrug means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide an active compound, particularly a compound of the invention.
• prodrugs include, but are not limited to, derivatives and metabolites of a compound of the invention that include biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues.
• Specific prodrugs of compounds with carboxyl functional groups are the lower alkyl esters of the carboxylic acid.
• the carboxylate esters are conveniently formed by esterifying any of the carboxylic acid moieties present on the molecule.
• Prodrugs can typically be prepared using well-known methods, such as those described by Burger’s Medicinal Chemistry and Drug Discovery 6th ed. (Donald J. Abraham ed., 2001 , Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers GmbH).
• the term “subject” or “patient” refers to any organism to which a composition described herein can be administered, e.g., for experimental, diagnostic, prophylactic and/or therapeutic purposes.
• Subject refers to a mammal receiving the compositions disclosed herein or subject to disclosed methods. It is understood and herein contemplated that “mammal” includes but is not limited to humans, non-human primates, cows, horses, dogs, cats, mice, rats, rabbits, and guinea pigs.
• substantially refers to a majority of, or mostly, as in at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more.
• the human proteasome is part of the cellular machinery that regulates protein degradation. Most proteins are degraded by the 26S proteasome via a ubiquitin-dependent mechanism, however intrinsically disordered proteins (unstructured) proteins can also be degraded the 20S isoform of the proteasome via a ubiquitin-independent mechanism. Intrinsically disordered proteins (IDPs) are named for their lack of tertiary structure allowing them to adopt numerous conformations and interact with multiple binding partners. When the synthesis of IDPs outpaces their rate of degradation, they accumulate and induce toxic signaling events that drive many human diseases.
• IDPs Intrinsically disordered proteins
• c-MYC pro-oncogenic transcription factor
• the disclosure relates to small molecule 20S proteasome activators of the formulae (I), (la)-(li), and (II-(VI) as therapeutic agents to treat amyloidogenic diseases including neurodegenerative diseases and type II diabetes.
• Neurodegenerative diseases include: Alzheimer's disease (AD) and other dementias, Parkinson’s disease (PD) and PD-related disorders, Prion disease, Motor neuron diseases (MND), Huntington’s disease (HD), Spinocerebellar ataxia (SCA) and Spinal muscular atrophy (SMA).
• IDPs intrinsically disordered proteins
• DPR dipeptide repeat
• reagent, blocking grade milk, and precast sodium dodecyl sulfate gels were from Bio-Rad (Hercules, CA).
• the recombinant wild type ⁇ -Synuclein was obtained from Abeam (Cambridge, MA).
• Rabbit polyclonal anti- ⁇ -Synuclein, mouse monoclonal anti-a- synuclein and goat anti-rabbit HRP-linked antibody were purchased from Santa Cruz Biotechnoiogies (Dallas, TX).
• the anti-mouse HRP-linked antibody was purchased from Cell Signaling Technology (Danvers, MA).
• the ⁇ -Synuclein aggregates were obtained from Novus Biologicals (Littleton, CO). Unless otherwise noted, chemicals were purchased from commercial suppliers and used without further purification.
• Fluorogenic peptide degradation 20S proteasome activity assay Activity assays were carried out in a 100 ⁇ L reaction volume. Different concentrations (1-80 ⁇ M) of test compounds were added to a black flat/clear bottom 96-well plate containing 1 nM of human constitutive 20S proteasome, in 50 mM Tris-HCI at pH 7.8, 100 mM NaCI and allowed to incubate for 15 min at 37°C. Fluorogenic substrates were then added and the enzymatic activity measured at 37°C on a SpectraMax M5e spectrometer by measuring the change in fluorescence unit per minute for 1 hour at 380-460 nm.
• the fluorescence units for the vehicle control were set at a 100%, and the ratio of drug-treated sample set to that of vehicle control was used to calculate the fold change in enzymatic activity.
• the fluorogenic substrates used were one of the following: Suc-LLVY- AMC (CT-L activity, 20 ⁇ M), Z-LLE-AMC (Casp-L activity, 20 ⁇ M), Boc-LRR-AMC (T-L activity, 40 ⁇ M) or a combination of the three substrates each at 6.67 ⁇ M.
• Amyloid beta aggregate preparation Synthetic amyloid beta was purchased from Eurogentec. To remove preexisting aggregates, synthetic amyloid beta peptide was dissolved in 100% hexafluoroisopropanol (HFIP) and incubated at 37 °C for 2 h. The HFIP was removed and the remaining peptide films were stored at -80 °C until use. Aggregates were prepared by resuspending amyloid beta films with DMSO (50 ⁇ L per 1 mg of peptide), followed by addition of ultrapure H 2 O (800 ⁇ L) and rapid addition of 2 M Tris-base (10 ⁇ L) at pH 7.6. The solution was then vortexed for 5 seconds and allowed to incubate at room temperature for 5 minutes. The Amyloid beta mixture was then diluted to the desired concentration and used immediately.
• HFIP hexafluoroisopropanol
• IDP oligomer inhibition In fluorogenlc peptide degradation assay. Assays were carried out in a 100 ⁇ L. reaction volume. Different concentrations (1—10 ⁇ M) of test compounds were added to a black flat/clear bottom 96-well plate containing 1 nM of human constitutive 20S proteasome, in 50 mM Tris-HCI at pH 7.8 and allowed to incubate for 15 min at 37°C. Then, 1 ⁇ L of ⁇ -Synuclein or amyloid beta oligomer mixture of was added to each sample to a final concentration of 500 nM for ⁇ -Synuclein and 2,5 ⁇ M for amyloid beta.
• the substrate (5 ⁇ L of 3.3 ⁇ M synuciein oligomer mixture) was then added to the reaction mixture and incubated at 37°C for 24 hours. The reactions were then quenched with concentrated SDS loading buffer. Samples were resolved on a 4-20% Tris-glycine SDS-PAGE and immunoblotted with mouse monoclonal anti ⁇ -Synuclein IgG (1 :2000) and anti-mouse HRP-linked IgG (1 :2000). Blots were developed with ECL western reagent and imaged with an Azure Biosystems 300Q imager.
• HEK293T Human embryonic kidney cells
• DMEM Dulbecco's modified Eagle's medium
• HEK-293T ceils were transfected as described above and incubated for 24 hours. The cells were then treated with 100pg/mL of cycioheximide, in combination with either vehicle (DMSO), fluspirilene (10 or 30 ⁇ M), N-acylated fluspirilene (10 or 30 ⁇ M), bortezomib (100 nM), or a combination thereof for 8 hours. The cells were then lysed using RIPA buffer and the manufacturers protocol. A BCA assay was performed to quantify protein levels and the lysates were normalized to desired concentrations prior to electrophoresis and western blot analysis, performed as described previously.
• vehicle DMSO
• fluspirilene 10 or 30 ⁇ M
• N-acylated fluspirilene 10 or 30 ⁇ M
• bortezomib 100 nM
• the small molecule antipsychotic drug fluspirilene was identified as a promising new scaffold for the development of 20S activators due to its strong enhancement of 20S proteolysis.
• a series of assays were performed using each of three fluorogenic peptide substrates. These substrates were a chymotryptic-like (CT-L), a trypsin- like (T-L) and a caspase-like (Casp-L) substrate, one for each of the catalytic sites of the proteasome. It has been shown that the proteasome’s active sites aiiosterically regulate each other in the presence of their individual substrates.
• C-L chymotryptic-like
• T-L trypsin- like
• Casp-L caspase-like substrate
• Fluspiriiene activates ail three catalytic sites of the 20S proteasome (FIG. 1 ) and achieved a doubling of activity (hereafter referred to as AC 200 ) using the combination ot probes at 2.2 ⁇ M (i.e. AC 200 2.2 ⁇ M), with a maximum raid enhancement of nearly 10-fold (i.e. 1000%).
• fluspirilene did not enhance the proteolytic activity of the 26S proteasome (FIG. 1 A).
• Fluspirilene is a potent dopamine D2 receptor antagonist that has been used for the treatment of schizophrenia. As such, it has good drug-like properties and penetrates the blood brain barrier (BBB) effectively, which makes it a promising scaffold for the development of novel 20S activators. On the other hand, due to its potent D2 receptor activity it cannot be repurposed therapeutically without modification. Therefore, structural modifications known to reduce the dopamine D2 receptor activity were prepared. N-acylated fluspirilene (16), was designed to eliminate fluspirilene's D2 receptor activity. In this scaffold, the basicity of the piperidine’s amine has been reduced through its conversion to an amide. Molecular docking studies were performed using AutoDock Vina.
• Fluspirilene and acyl-fluspirilene were found to preferentially bind to the u2-3 intersubunit pocket (FIG. 2A and FIG. 2B). This mode of binding is different from our previously reported 20S proteasome activators which, when docked, preferentially bind to the ⁇ 1 -2 intersubunit pocket of the 2QS proteasome. To test the importance of the o:2-3 intersubunit pocket, two other analogues of fluspirilene were devised as negative controls.
• Fluspirilene was synthesized according to literature, and several derivatives were prepared. As shown in Scheme 1 , the diphenyl tails were produced using a Grignard reaction between dihydrofuran-2(3H)-one and two equivalents of aryl magnesium bromide. Subsequent dehydration of the tertiary alcohol was performed via reflux in ethanol with addition of hydrochloric acid. The formed alkenes (compounds 6 and 7) were reduced using hydrogen gas with palladium on carbon in ethanol overnight to afford compounds 12 and 13. Bromination via the Appel reaction produced compounds 8, 9, 17, and 18.
• BIOVA Discovery Studio 2020 was used to observe the binding pocket interactions of our analogues within the ⁇ 2-3 intersubunit pocket (FIG. 4). In multiple binding modes, strong hydrogen bond interactions are observed between fluspirilene and compound 16’s amide N-H and a variety of amino acid residues such as LYS77, ILE65, ASN84, TYR75, and GLN111 (FIG. 4A and FIG. 4B).
• the A/-acylated analog achieved higher max fold increases for each substrate/combination (>1500% increase over vehicle) but required slightly higher concentrations to reach doubling of activity at the CT-L (AC 200 4.7 ⁇ M) and Casp-L (AC 200 4.1 ⁇ M) sites (FIG. 5).
• Proteasome impairment is a major contributor to the accumulation of neurotoxic IDP oligomers.
• IDP oligomers associated with neurodegenerative diseases such as ⁇ -Syn, amyloid beta and Huntingtin protein
• This IDP oligomer- induced 20S proteasome impairment has the potential to contribute to further accumulation of the IDPs and thus disease progression.
• 20S proteasome enhancers can protect against IDP-mediated impairment of the 20S proteasome, 20S enhancers may reestablish the clearing of IDPs.
• the A53T mutation of ⁇ -Synuclein has been linked to early on-set familial Parkinson’s disease and appears to oligomerize faster than the wild-type protein.
• fluspirilene and W-acylated fluspirilene (16) on the degradation of the pathogenic A53T a-synuclein mutant in cells, we transiently transfected the A53T ⁇ -Synuclein plasmid into HEK-293T cells and probed for A53T a-synuclein protein in the absence and presence of compound.
• cycloheximide was added to block protein synthesis. As shown in FIG.
• both fluspirilene and N-acylated fluspirilene effectively reduced the accumulation of A53T a-synuclein protein within 8 hours of treatment in a concentration dependent manner.
• the effects of the 20S proteasome enhancer W- acylated fluspirilene (16) was abrogated by blocking proteasome activity, using the proteasome inhibitor, bortezomib (BTZ), thereby implicating the proteasome as the protease responsible for this degradation.
• FIG. 5 shows the results of extended fluorogenic peptide analysis of N-acylated fluspirilene.
• Embodiment 1 relates to a compound of the formula (I): or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein:
• FT is alkyl, alkenyl, cycloalkyl, aryl or heteroaryl
• R 2 is hydrogen, alkyl, cycloalkyl, aryl or heteroaryl.
• Embodiment 2 relates to the compound of Embodiment 1 , wherein the compound of formula (I) is a compound of the formula (la): or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein:
• R 3 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, acyl, amido or ester;
• R 4 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, acyl, amido or ester;
• X 1 is alkyl or alkenyl
• X 2 is N or CR 5 , wherein R 5 is absent, hydrogen, alkyl or aryl.
• Embodiment 3 relates to the compound of Embodiment 1 , wherein the compound of formula (I) is a compound of the formula (lb): or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof.
• Embodiment 4 relates to the compound of Embodiment 1 , wherein the compound of formula (I) is a compound of the formulae (Ic) and (Id): or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein: n is 0, 1 or 2.
• Embodiment 5 relates to the compound of Embodiment 1 , wherein the compound of formula (I) is a compound of the formulae (le) and (If): or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein: q is 0, 1 or 2.
• Embodiment 6 relates to the compound of Embodiment 1 , wherein the compound of formula (I) is a compound of the formula (Ig): or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein: R 2 is hydrogen, alkyl, cycloalkyl, aryl or heteroaryl; each R 6 is independently H, alkyl, halo, SR 7 (wherein each R 7 is H, alkyl, aryl, acyl or heterocyclyl), amino, OR 7 , or acyl;
• X 1 is alkyl or alkenyl
• X 2 is N or CR 5 , wherein R 5 is absent, hydrogen, alkyl or aryl.
• Embodiment 8 relates to the compound of Embodiments 6-7, wherein X 1 is -(CH 2 ) n -, wherein n is 0, 1 or 2.
• Embodiment 9 relates to the compound of Embodiment 1 , wherein the compound of formula (I) is a compound of the formulae (Ih) and (li): or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein: n is 0, 1 or 2; R 2 is hydrogen, alkyl, cycloalkyl, aryl or heteroaryl; and each R 6 is independently H, alkyl, halo, SR 7 (wherein each R 7 is H, alkyl, aryl, acyl or heterocyclyl), amino, OR 7 , or acyl.
• the compound of formula (I) is a compound of the formulae (Ih) and (li): or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein: n is 0, 1 or 2; R 2 is hydrogen, alkyl, cycloalkyl, aryl or heteroaryl; and each R 6 is independently
• Embodiment 11 relates to the compound of Embodiments 1 -10, wherein the compound of formula (I) is a compound of the formula:
• Embodiment 12 relates to the compound of the formula (II): or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein: each R 6 is independently H, alkyl, halo, SR 7 (wherein each R 7 is H, alkyl, aryl, acyl or heterocyclyl), amino, OR 7 , or acyl;
• X 1 is alkyl or alkenyl
• X 2 is N or CR 5 , wherein R 5 is absent, hydrogen, alkyl or aryl; and X3 NR 8 or C(R 8 ) 2 , wherein R 8 is H, alkyl, acyl, aryl, benzyl or heterocyclyl.
• Embodiment 13 relates to the compound of Embodiment 12, wherein X 1 is -(CH 2 ) n- , wherein n is 0, 1 or 2.
• Embodiment 15 relates to the compound or Embodiments 12-14, wherein the compound of formula (II) is a compound of the formula: or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein each R 6 is independently H, alkyl, halo, SR 7 (wherein each R 7 is H, alkyl, aryl, acyl or heterocyclyl), amino, OR 7 , or acyl.
• Embodiment 17 relates to the compound of Embodiments 15-16, wherein at least one of R 6 is F or CF 3 .
• Embodiment 18 relates to the compound of the formula (III): wherein: Y 1 is alkyl, NR 8 or O, wherein R 8 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; Y 2 is alkyl, NR 8 or O;
• R 9- is hydrogen, amino, alkyl, cycloalkyl, aryl, heteroaryl, CH(R 9 ) 2 , CH 2 R 9 , OR 9 , NHRS or S(O) x R 9 , wherein each alkyl, cycloalkyl, aryl, heteroaryl is optionally substituted; and R 10- hydrogen, amino, alkyl, cycloalkyl, aryl, heteroaryl or CH(R 9 ) 2 , CH 2 R 9 , OR 9 , NHR 9 , S(O) x R 9 , wherein each alkyl, cycloalkyl, aryl, heteroaryl is optionally substituted.
• Embodiment 19 relates to the compound of Embodiment 18, wherein R 9 -Y 1 forms the same group or a different group as R 10 -Y 2 .
• Embodiment 20 relates to the compound of Embodiments 18-19 wherein Y 1 is O or NR 8 , wherein R 8 can be alkyl or cycloalkyl.
• Embodiment 21 relates to the compound of Embodiment 18, wherein Y 1 or Y 2 is CH 2 .
• Embodiment 22 relates to the compound of Embodiments 18-21 , wherein R 9 -Y 1 forms different groups than R 10 -Y 2 .
• Embodiment 23 relates to the compound of Embodiments 18-22, wherein the compound is a compound of the formula:
• W is N or C-R 9A ;
• X is N or C-R 9A ;
• Y is N or C-R 9A ; and
• Z is N or C-R 9A ; wherein each R 9A is independentiy H, halo, alkyl, haloalkyl, alkoxy or heterocyclyl; and
• Het 1 and Het 2 are each, independently, a heterocyclyl group.
• Embodiment 24 relates to the compound of Embodiment 23, wherein Het 1 and Het 2 are each, independently, furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, pyridinyl or pyrimidinyl.
• Embodiment 25 relates to the compound of the formula (IV): wherein:
• X 4 is CR 8 or N, wherein R 8 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl;
• X 5 is CR 8 or N, wherein R 8 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; each R 13 is independently H, acyl, carboxyl or C(O)R 8 , wherein R 8 is H, alkyl, acyl, aryl, benzyl or heterocyclyl;
• R 14- is hydrogen, amino, alkyl, cycloalkyl, aryl, heteroaryl, acyl, thioacyl,
• R 15- is hydrogen, amino, alkyl, cycloalkyl, aryl, heteroaryl, acyl, thioacyl,
• R 13 and R 14 together with the atoms to which they are each attached, form a heterocyclyl group.
• Embodiment 26 relates to the compound of Embodiment 25, wherein R 14 or R 15 is R 14 C(S).
• Embodiment 27 relates to the compound of Embodiments 25-26, wherein R 14 forms a different group than R 15 .
• Embodiment 28 relates to the compound of Embodiment 25-27, wherein at least one of R 14 and R 15 can be acyl, each of which can be substituted with a group R 9 - Y 1 -, wherein: Y 1 is alkyl, NR 8 or O, wherein R 8 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; and
• R 9- is hydrogen, amino, alkyl, cycloalkyl, aryl, heteroaryl, CH(R 9 ) 2 , CH 2 R 9 , OR 9 , NHR 9 or S(O) x R 9 , wherein each alkyl, cycloalkyl, aryl, heteroaryl is optionally substituted with, e.g., groups including halogen, aryl, amino, alkoxy, S(O) x , wherein x is 0, 1 or 2, acyl, amido or heterocyclyl.
• Embodiment 29 relates to the compound of Embodiments 25-28, wherein the compound is a compound of the formula: or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof.
• Embodiment 30 relates to the compound of Embodiments 25-29, wherein the compound is a compound of the formula:
• Embodiment 31 relates to the compound of Embodiments 25-29, wherein the compound is a compound of the formula:
• Y 1 is alkyl, NR 8 or O, wherein R 8 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl;
• R 9- is hydrogen, amino, alkyl, cycloalkyl, aryl, heteroaryl, CH(R 9 ) 2 , CH 2 R 9 , OR 9 , NHR 9 or S(O) x R 9 , wherein each alkyl, cycloalkyl, aryl, heteroaryl is optionally substituted with, e.g., groups including halogen, aryl, amino, alkoxy, S(O) x , wherein x is 0, 1 or 2, acyl, amido or heterocyclyl;
• W is N or C-R 9A ;
• X is N or C-R 9A ;
• Y is N or C-R 9A ; and
• Z is N or C-R 9A ; wherein each R 9A is independently H, halo, alkyl, haloalkyl, alkoxy or heterocyclyl; and Het 1 and Het 2 are each, independently, a heterocyclyl group.
• Embodiment 32 relates to the compound of Embodiment 31 , wherein the compound is a compound of the formula:
• Embodiment 33 relates to the compound of Embodiment 25, wherein the compound is a compound of the formula:
• Y 1 is alkyl, NR 8 or O, wherein R 8 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; R 9- is hydrogen, amino, alkyl, cycloalkyl, aryl, heteroaryl, CH(R 9 ) 2 , CH 2 R 9 , OR 9 ,
• NHR 9 or S(O) x R 9 wherein each alkyl, cycloalkyl, aryl, heteroaryl is optionally substituted with, e.g., groups including halogen, aryl, amino, alkoxy, S(O) x , wherein x is 0, 1 or 2, acyl, amido or heterocyclyl;
• W is N or C-R 9A ;
• X is N or C-R 9A ;
• Y is N or C-R 9A ; and
• Z is N or C-R 9A ; wherein each R 9A is independently H, halo, alkyl, haloalkyl, alkoxy or heterocyclyl; and
• Het 1 and Het 2 are each, independently, a heterocyclyl group.
• Embodiment 34 relates to the compound of Embodiment 33, wherein the compound is a compound of the formula
• Embodiment 35 relates to the compound of Embodiment 25, wherein the compound is a compound of the formula:
• Y 1 is alkyl, NR 8 or O, wherein R 8 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl;
• R 9- is hydrogen, amino, alkyl, cycloalkyl, aryl, heteroaryl, CH(R 9 ) 2 , CH 2 R 9 , OR 9 , NHR 9 or S(O) x R 9 , wherein each alkyl, cycloalkyl, aryl, heteroaryl is optionally substituted with, e.g., groups including halogen, aryl, amino, alkoxy, S(O) x , wherein x is 0, 1 or 2, acyl, amido or heterocyclyl;
• W is N or C-R 9A ;
• X is N or C-R 9A ;
• Y is N or C-R 9A ; and
• Z is N or C-R 9A ; wherein each R 9A is independently H, halo, alkyl, haloalkyl, alkoxy or heterocyclyl; and Het 1 and Het 2 are each, independently, a heterocyclyl group.
• Embodiment 36 relates to the compound of the formula (V): or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein:
• X 1 is alkyl or alkenyl
• R 2 is hydrogen, alkyl, cycloalkyl, aryl or heteroaryl
• R 14 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, acyl, amido or carbamate, each of which alkyl, cycloalkyl, aryl, heteroaryl, acyl, amido, carbamate is optionally substituted with cycloalkyl, aryl, heteroaryl, each of which cycloalkyl, aryl, and heteroaryl is optionally substituted with halogen, amino, alkoxy, S(O) x , wherein x is 0, 1 or 2, acyl, amido or heterocyclyl;
• R 15 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, acyl, amido or carbamate, each of which alkyl, cycloalkyl, aryl, heteroaryl, acyl, amido, carbamate is optionally substituted with cycloalkyl, aryl, heteroaryl, each of which cycloalkyl, aryl
• R 16 is H, acyl, carboxyl or C(O)R 8 , wherein R 8 is H, alkyl, acyl, aryl, benzyl or heterocyclyl; or
• R 14 and R 15 or R 15 and R 16 together with the atoms to which they are each attached, form a cyclic group.
• Embodiment 37 relates to the compound of Embodiment 36, wherein R 14 and R 15 or R 15 and R 16 , together with the atoms to which they are each attached, form a cycloalkyl or a heterocyclyl group.
• Embodiment 38 relates to the compound of Embodiments 36-37 wherein X 1 is -(CH 2 ) n ,-, wherein n is 0, 1 or 2.
• Embodiment 39 relates to the compound of Embodiments 36-38, wherein at least one of R 14 and R 15 is halogenated aryl.
• Embodiment 40 relates to the compound of Embodiments 36-39, wherein the halogenated aryl is a para-halogenated aryl.
• Embodiment 41 relates to the compound of Embodiments 36-40, wherein the para-halogenated aryl is a para-fluoro aryl group.
• Embodiment 42 relates to the compound of Embodiment 36, wherein the compound is a compound of the formula: or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof.
• Embodiment 43 relates to the compound of Embodiments 36-42, wherein R 16 is C(O)R 8 .
• Embodiment 44 relates to the compound of Embodiment 36, wherein the compound is a compound of the formula: or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof.
• Embodiment 45 relates to the compound of the formula (VI): or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein:
• X 1 is alkyl or alkenyl
• R 2 is hydrogen, alkyl, cycloalkyl, aryl or heteroaryl
• each R 13 is H, acyl, carboxyl or C(O)R 8 , wherein R 8 is H, alkyl, acyl, aryl, benzyl or heterocyclyl
• R 17- is hydrogen, alkyl, cycloalkyI, aryl, heteroaryl, acyl, amido or carbamate, each of which alkyl, cycloalkyl, aryl, heteroaryl, acyl, amido, carbamate is optionally substituted with cycloalkyl, aryl, heteroaryl, each of which cycloalkyl, aryl, and heteroaryl is optionally substituted with halogen, amino, alkoxy, S(O) x , wherein x is 0, 1 or 2, acyl, amido or heterocyclyl;
• R 18- is hydrogen, alkyl, OR 19 (wherein R 19 is hydrogen, alkyl, cycloalkyl, aryl or heteroaryl) cycloalkyl, aryl, heteroaryl, acyl, amido or carbamate, each of which alkyl, cycloalkyl, aryl, heteroaryl, acyl, amido, carbamate is optionally substituted with cycloalkyl, aryl, heteroaryl, each of which cycloalkyl, aryl, and heteroaryl is optionally substituted with halogen, amino, alkoxy, S(O) x , wherein x is 0, 1 or 2, acyl, amido or heterocyclyl; or
• R 17 and R 18 together with the atoms to which they are attached, form a cycloalkyl, aryl or heterocyclyl group.
• OR 19 forms a heteroaryl group of the formula: or R 13 and R 18 , together with the atoms to which they are each attached, form a heterocyclyl group.
• Embodiment 46 relates to the compound of Embodiment 45, wherein X 1 is -(CH 2 ) n -, wherein n is 0, 1 or 2.
• Embodiment 47 relates to the compound of Embodiments 45-46, wherein R 18 is C(O)R 8 .
• Embodiment 48 relates to the compound of Embodiment 45, wherein the compound is a compound of the formula: or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof.
• Embodiment 49 relates to the compound of the formula: or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein:
• X 4 is CR 8 or N, wherein R 8 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl;
• X 5 is CR 8 or N, wherein R 8 is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl; each R 13 is independently H, acyl, carboxyl or C(O)R 8 , wherein R 8 is H, alkyl, acyl, aryl, benzyl or heterocyclyl;
• R 14- is hydrogen, amino, alkyl, cycloalkyl, aryl, heteroaryl, acyl, thioacyl,
• R 15- and R 16 are each, independently, hydrogen, amino, alkyl, cycloalkyl, aryl, heteroaryl, acyl, thioacyl, R 14 C(NR 14 ), amido or carbamate, each of which alkyl, cycloalkyl, aryl, heteroaryl, acyl, amido, and carbamate is optionally substituted with cycloalkyl, aryl, heteroaryl, each of which cycloalkyl, aryl, and heteroaryl is optionally substituted with halogen, amino, alkoxy, S(O) x , wherein x is 0, 1 or 2, acyl, amido or heterocyclyl; or
• R 13 and R 14 together with the atoms to which they are each attached, form a heterocyclyl group
• R 13 and R 16 together with the atoms to which they are each attached, form a cycloalkyl, heterocyclyl or aryl group.
• Embodiment 50 relates to the compound of Embodiment 49, wherein the compound is a compound of the formula:
• Embodiment 51 relates to a pharmaceutical composition comprising one or more compounds of Embodiments 1 -50 and one or more pharmaceutically acceptable excipients.
• Embodiment 52 relates to a method for treating a neurodegenerative disease comprising administering a therapeutically effective amount of fluspriline, at least one compound of Embodiments 1-50 or a pharmaceutical composition of Emdoiment 51 to a subject in need thereof.
• Embodiment 53 relates to the method of Embodiment 52, wherein the neurodegenerative disease is at least one of Parkinson’s disease, Alzheimer’s disease, Huntington's disease, and ALS.
• Embodiment 54 relates to a method for reducing, substantially eliminating or eliminating dysregulation of proteostasis comprising administering a therapeutically effective amount of fluspriline, at least one compound of Embodiments 1 -50 or a pharmaceutical composition of Embodiment 51 to a subject in need thereof.
• Embodiment 55 relates to a method for reducing, substantially eliminating or eliminating the accumulation of intrinsically disordered proteins comprising administering a therapeutically effective amount of fluspriline, at least one compound of Embodiments 1 -50 or a pharmaceutical composition of Embodiment 51 to a subject in need thereof..

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