WO2014181101A1 - 2-acyl-4-oxy-1,2-dihydropyrrol-5-one compounds for improving memory and cognitive function - Google Patents

2-acyl-4-oxy-1,2-dihydropyrrol-5-one compounds for improving memory and cognitive function Download PDF

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WO2014181101A1
WO2014181101A1 PCT/GB2014/051391 GB2014051391W WO2014181101A1 WO 2014181101 A1 WO2014181101 A1 WO 2014181101A1 GB 2014051391 W GB2014051391 W GB 2014051391W WO 2014181101 A1 WO2014181101 A1 WO 2014181101A1
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compound according
nhr
independently
alkyl
groups
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PCT/GB2014/051391
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French (fr)
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Stephen Hilton
Arnaud RUIZ
Blanka SZULC
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Ucl Business Plc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/38—2-Pyrrolones
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention pertains generally to the field of therapeutic compounds, and more specifically to certain compounds (for convenience, collectively referred to herein as "2-acyl-4-oxy-1 ,2-dihydropyrrol-5-one compounds” and "DHP compounds"), which, inter alia, are useful in methods of improving memory and/or cognitive function, and in the treatment of memory-related disorders and cognitive decline.
  • the present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions in the treatment of central nervous system (CNS) disorders such as memory deficit, memory-related disorders, disorders associated with cognitive decline, and cognitive impairment, including, for example, mild cognitive impairment (MCI), dementia, and Alzheimer's disease.
  • CNS central nervous system
  • Alzheimer's disease is the most common form, affecting 62% of those living with dementia.
  • Many of these people have a mixed pattern of dementia, with the second most common type, vascular dementia, also contributing to their condition.
  • acetylcholinesterase inhibitors such as donepezil
  • NMDA N- methyl-D-aspartate receptor blockers
  • memantine may be of benefit, but the evidence is less conclusive than for AChEls. Due to their differing mechanisms of action, memantine and AChEls can be used in combination. However, the benefit of using such a combination is slight.
  • Nootropic drugs also known as memory enhancers, smart drugs, and cognitive enhancers, are drugs that improve cognitive function, memory, and concentration. Their action alters the availability and balance of brain neurotransmitters, hormones, and enzymes, but the mechanisms by which they improve learning and memory are not fully understood.
  • One plausible mode of action is that they strengthen inter-synaptic communication between neurons and brain circuits that are important for learning and memory.
  • nootropic drugs facilitate the induction of long-term potentiation (LTP) in the hippocampus, a phenomenon leading to synapse reinforcement which is thought to underlie memory storage and recall in this brain structure.
  • LTP long-term potentiation
  • one candidate mechanism by which a drug could prove beneficial for treating the progressive decline typical of these disorders would be by lowering the threshold for long- term potentiation (LTP) induction in the hippocampus.
  • LTP long- term potentiation
  • the hippocampal formation is a region of the brain that plays a central role in learning and memory. It takes the form of an elongated C-shaped structure with a long axis (also known as the "septotemporal axis"), spanning rostro-dorsally from the septal nuclei near the midline of the brain to caudo-ventrally behind the thalamus of the temporal lobe, and a transverse axis, spanning the width of the formation. See, e.g., Amaral et al., 1989.
  • hippocampal formation refers to six regions which are functionally connected in a uni- or bi-directional fashion: the dentate gyrus, the CA regions (also termed hippocampus) consisting of CA1 , CA2, and CA3, the subiculum, the presubiculum, the parasubiculum, and the entorhinal cortex.
  • the term was used to refer to a uni-directional "trisynaptic" loop between the entorhinal cortex, dentate gyrus, CA3 and CA1 (see, e.g., Andersen et al., 1971).
  • use of the term has changed because the subiculum and its adjacent parts (the pre- and para-subiculum) also play important roles in learning and memory, and because the different regions are interconnected.
  • Granule cells within the dentate gyrus project a thin unmyelinated axon that forms a single parent fibre into the hippocampus proper, where it makes synaptic contacts onto CA3 pyramidal cells and various types of interneurones (see, e.g., Ascady et al., 1998).
  • These unusual axons (referred to as "mossy fibres") provide one of the most powerful glutamatergic inputs in the brain, amid the low basal firing rate observed in granule cells in vivo ( ⁇ 0.5 Hz) and the inability of granule cells to fire action potentials for extended periods of time (see, e.g., Henze et al., 2002).
  • Mossy fibre-CA3 synapses display a unique form of frequency-dependent facilitation of transmitter release consecutive to modest increases in presynaptic firing frequency (e.g., from 0.1 to 1 Hz), hence driving CA3 network activity very efficiently (see, e.g., Salin et al., 1996).
  • mossy fibre-CA3 synapses display a presynaptic form of LTP that is expressed by persistent changes in the probability of glutamate release.
  • ionotropic receptors i.e., receptors permeable to ions
  • ion channels localised in presynaptic membranes, in mossy fibres themselves, or in postsynaptic densities in CA3 pyramidal neurons (see, e.g., Ruiz et al., 2013).
  • Compounds that interact with pre- or post-synaptic receptor function thus represent powerful modulators of excitatory connections at the interface between neocortical and dentate structures and the hippocampus itself, where memory formation and information recall occurs.
  • LTP is impaired in the CA1 and CA3 areas (see, e.g., Francis et al., 2009; Simmons et al., 2009; Chong et al., 2011). This translates into a form of LTP having a magnitude that is much less than that which occurs in healthy individuals. However, little is known about changes occurring in CA3, where LTP is thought to be mainly expressed as a change in presynaptic release probability.
  • Excitatory synapses generally express both AMPA (2-amino-3-(3-hydroxy-5-methyl- isoxazol-4-yl)propanoic acid) and NMDA (N-methyl-D-aspartate) receptors, with AMPA receptors mediating the major component of the synaptic response (see, e.g., Zucker et al., 1998).
  • NMDA receptors are permeable to calcium as well as sodium and potassium, but they are blocked by magnesium at resting membrane potential.
  • repetitive activation of AMPA receptors can cause sufficient depolarisation to relieve the magnesium block, enabling a slower NMDA-receptor-mediated component of the response that is associated with calcium influx into the post-synaptic neuron.
  • This influx triggers various forms of synaptic plasticity, including LTP, which results from the activation of calcium- dependent signal transduction cascades that cause trafficking of AMPA receptors into the synapse, thus strengthening synaptic signalling.
  • NMDA receptors are the switches that trigger LTP, which is expressed and maintained by the presence of an increased number of active AMPA receptors at the potentiated synapse.
  • compounds that modulate AMPA receptor function may prove good candidates to strengthen excitatory synapses in diseases affecting memory binding and information recall as in the demented brain.
  • An alternative route by which compounds may enhance synaptic transmission and lower the threshold for LTP induction is by modulating presynaptic Ca 2+ channel function.
  • Voltage-gated Ca 2+ channels are a group of ion channels that are involved in a variety of processes including neurotransmitter exocytosis, synaptic plasticity, and gene expression. VGCCs are classified according to their a1 subunit. High-voltage activated channels consist of the Cav1 and Cav2 sub-families and include L-type (Cav1.1-1.4), P/Q-type (Cav2.1), N-type (Cav2.2) and R-type (Cav2.3) VGCCs. In contrast, low- voltage activated channels carry the Cav3 sub-family, consisting of the T-type
  • P/Q- and N-type VGCCs ensure efficient and rapid exocytosis and account for more than 90% of all VGCCs.
  • the remaining fraction consists of R-type VGCCs, which have been shown to be important for short-term plasticity and LTP at these synapses.
  • L-type VGCCs expressed at postsynaptic membranes are also important for LTP at the mossy fibre-CA3 synapse.
  • a compound that enhances one of the most powerful synapses in the brain is likely to be useful in methods of reducing memory deficits and improving the cognitive faculties of patients suffering from neurodegenerative disorders, such as dementia (and including, for example, senile dementia, vascular dementia, fronto-temporal dementia, and milder forms of dementia), Parkinson's disease, Huntington's disease, and other basal ganglia- related disorders where progressive memory decline is often symptomatic.
  • dementia and including, for example, senile dementia, vascular dementia, fronto-temporal dementia, and milder forms of dementia
  • Parkinson's disease Huntington's disease
  • basal ganglia- related disorders where progressive memory decline is often symptomatic.
  • the present invention provides novel compounds, as described herein, which provide surprising and unexpected activity, for example, as potentiators of excitatory synaptic transmission, enhancers of glutamatergic synapses, and/or positive modulators of AMPA receptors, and which may be useful in the treatment of such diseases and disorders.
  • Racetams are a class of nootropic drugs that share a pyrrolidone core. Piracetam was the first racetam to be discovered and is currently sold across the world under a variety of brand names (e.g., Nootropyl, Nootropil, Lucetam, Oikamid, Smart, Geratam, Biotropil). It is used for a wide range of applications including, for example, applications which rely on its nootropic properties, and treatment of myoclonus (involuntary twitching of a muscle or a group of muscles).
  • Nootropyl Nootropil
  • Lucetam Oikamid, Smart
  • Geratam Biotropil
  • myoclonus involuntary twitching of a muscle or a group of muscles.
  • Several related nootropic compounds including I eveti racetam, oxiracetam, nefiracetam, aniracetam, and pramiracetam, have also been described.
  • Clausenamide is a pyrrolidone-based compound which has been found to possess 50- 100 times greater nootropic activity than piracetam, and to enhance long-term potentiation (see, e.g., Feng et al., 2009). It is a naturally occurring compound which is isolated from extracts of dry leaves of Clausena Lansium, which is used in Chinese folk medicine. Clausenamide has four chiral centres, giving rise to sixteen stereoisomers (eight pairs of enantiomers). In nature, however, the compound appears as a racemate of (-)-clausenamide and (+)-clausenamide.
  • One aspect of the invention pertains to certain 2-acyl-4-oxy-1 ,2-dihydropyrrol-5-one compounds (also referred to herein as DHP compounds), as described herein.
  • compositions e.g., a pharmaceutical composition
  • a pharmaceutical composition comprising a DHP compound, as described herein, and a pharmaceutically acceptable carrier or diluent.
  • a method of preparing a composition comprising the step of mixing a DHP compound, as described herein, and a pharmaceutically acceptable carrier or diluent.
  • Another aspect of the present invention pertains to a DHP compound, as described herein, for use in a method of improving memory and/or cognitive function in a patient.
  • Another aspect of the present invention pertains to use of a DHP compound, as described herein, in the manufacture of a medicament for improving memory and/or cognitive function in a patient.
  • Another aspect of the present invention pertains to a method of improving memory and/or cognitive function comprising administering to a patient in need of improved memory and/or cognitive function a therapeutically effective amount of a DHP compound, as described herein, preferably in the form of a pharmaceutical composition.
  • Another aspect of the present invention pertains to a DHP compound, as described herein, for use in a method of treatment of the human or animal body by therapy, for example, for use a method of treatment of a disorder (e.g., a disease) as described herein.
  • a disorder e.g., a disease
  • Another aspect of the present invention pertains to use of a DHP compound, as described herein, in the manufacture of a medicament for treatment, for example, treatment of a disorder (e.g., a disease) as described herein.
  • Another aspect of the present invention pertains to a method of treatment, for example, of a disorder (e.g., a disease) as described herein, comprising administering to a patient in need of treatment a therapeutically effective amount of a DHP compound, as described herein, preferably in the form of a pharmaceutical composition.
  • kits comprising (a) a DHP compound, as described herein, preferably provided as a pharmaceutical composition and in a suitable container and/or with suitable packaging; and (b) instructions for use, for example, written instructions on how to administer the compound.
  • Another aspect of the present invention pertains to a DHP compound obtainable by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
  • Another aspect of the present invention pertains to a DHP compound obtained by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
  • Another aspect of the present invention pertains to novel intermediates, as described herein, which are suitable for use in the methods of synthesis described herein.
  • Another aspect of the present invention pertains to the use of such novel intermediates, as described herein, in the methods of synthesis described herein.
  • Figure 1 shows that DHP-001 facilitates excitatory synaptic transmission from the dentate gyrus to CA3.
  • Panel A, top Example traces of excitatory synaptic potentials
  • field-EPSPs recorded with an extracellular electrode (each trace is an average of 20 consecutive field-EPSPs taken at 5 second intervals) before (BASELINE) and following superfusion with DHP-001 (100 ⁇ ) are shown.
  • the right-most trace shows field-EPSPs in the presence of DMSO (100 ⁇ , VEHICLE).
  • Figure 2 shows that superfusion with DHP-001 does not alter the input resistance of dentate granule cells.
  • Panel A Sample traces from a granule cellrecording showing the l-V relationship (membrane potential is -81 mV).
  • Panel B A plot of the l-V relationship (voltage in mV versus current in pA) before and after superfusion with DHP-001 (100 ⁇ ). No difference was found.
  • Panel C A bar graph of R in put ( ⁇ ) for control and DHP-001 , for pooled data from 5 neurons.
  • Figure 3 is a set of graphs illustrating the effect of DHP-001 on evoked AMPA currents in CA3 pyramidal neurons.
  • Bottom left Plot of normalised EPSC amplitude against time showing an increase upon superfusion with DHP-001 (100 ⁇ ) and depression by the group II metabotropic glutamate receptor agonist DCG-IV (1 ⁇ ).
  • Top Representative examples for each condition are shown (data from one CA3 pyramidal neuron).
  • Figure 4 is a concentration-facilitation curve for DHP-001. Each concentration was tested in at least 3 neurons. A logistic function was used to fit the data and each point represents the mean ⁇ S.E.M. The EC 50 inferred from the fit of the concentration- facilitation curve is 12 ⁇ .
  • One aspect of the present invention relates to certain compounds which are related to 2,5-dihydro-1 H-pyrrole, more specifically 1 ,2-dihydropyrrol-5-one:
  • one aspect of the present invention is a compound of the following formula, or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of the foregoing, wherein -J, -Q, -V, and -T are as defined herein (for convenience, collectively referred to herein as "2-acyl-4-oxy-1 ,2-dihydropyrrol-5-one compounds” and "DHP compounds”):
  • -J is independently -OH, -OR JE , -NH 2 , -NHR JN , -NR JN R JN2 , or -NR JN3 R'
  • Ci -6 alkyl is linear or branched saturated Ci -6 alkyl
  • -R JE2 is linear or branched C 2 - 6 alkenyl
  • -R JE3 is linear or branched C 2 - 6 alkynyl
  • each -R JE4 is saturated C 3 . 6 cycloalkyl
  • each -R JE5 is C 3 . 6 cycloalkenyl
  • each -R JE6 is non-aromatic C 3 . 7 heterocyclyl
  • each -R JE7 is independently phenyl or naphthyl
  • each -R JE8 is C 5 .i 0 heteroaryl
  • each -L JE - is linear or branched saturated Ci_ 4 alkylene; wherein: each -R K1C is independently: -F, -CI, -Br, -I,
  • each -R K2C is independently:
  • each -R c is independently: -R KK ,
  • each -R K2N and each -R K3N is independently: -R KK ,
  • Ci -4 alkyl group is optionally substituted with one or more groups independently selected from -OH, -OR KKK , -NH 2 , -NHR KKK , and -NR KKK 2 ;
  • each of said phenyl groups is optionally substituted with one or more groups independently selected from -F, -CI, -Br, -I, -R KKK , -CF 3 , -OH, -OR KKK , -OCF 3 , -NH 2 , -NHR KKK , and -NR KKK 2 ;
  • each -R KKK is linear or branched saturated Ci -4 alkyl
  • each -R JN is independently linear or branched saturated Ci -4 alkyl, phenyl, or -L JN -phenyl;
  • Ci -4 alkyl group is optionally substituted with one or more groups independently selected from -OH, -OR JN A , -NH 2 , -NHR JN A , and -NR JN A 2 ;
  • each of said phenyl groups is optionally substituted with one or more groups independently selected from -F, -CI, -Br, -I, -R JN A , -CF 3 , -OH, -OR JN A , -OCF 3 , -NH 2 , -NHR JN A , and -NR JN A 2 ;
  • each -R JN A is linear or branched saturated C -4 alkyl
  • _ JN - is linear or branched saturated Ci_ 3 alkylene; each -R JN2 is independently linear or branched saturated Ci -4 alkyl, phenyl, or -L JN2 -phenyl;
  • Ci -4 alkyl group is optionally substituted with one or more groups independently selected from -OH, -OR JN2A , -NH 2 , -NHR JN2A , and -NR JN2A 2 ;
  • each of said phenyl groups is optionally substituted with one or more groups independently selected from -F, -CI, -Br, -I, -R JN2A , -CF 3 , -OH, -OR JN2A , -OCF 3 , -NH 2 , -NHR JN2A , and -NR JN2A 2 ;
  • each -R JN2A is linear or branched saturated C -4 alkyl
  • _ JN2 - is linear or branched saturated Ci_ 3 alkylene
  • -Q is independently -H, -Q A , or -Q B ;
  • -Q A is independently:
  • -R QA2 is linear or branched C ⁇ alkenyl
  • -R QA3 is linear or branched C ⁇ alkynyl
  • each -R 0 ⁇ 4 is saturated C 3 . 6 cycloalkyl
  • each -R 0 ⁇ 5 is C 3 . 6 cycloalkenyl
  • each -R 0 ⁇ 6 is non-aromatic C 3 . 7 heterocyclyl
  • each -R ⁇ 7 is independently phenyl or naphthyl
  • each -R 0 ⁇ 8 is C 5 .i 0 heteroaryl
  • each -L QA - is linear or branched saturated Ci_ 4 alkylene; wherein: each -R S C is independently: -F, -CI, -Br, -I,
  • each -R S2C is independently:
  • R is independently:
  • two adjacent groups -R S3C may together form: -0-CH 2 -0- or -0-CH 2 CH 2 -0-;
  • R S2N and each -R S3N is independently:
  • Ci_ 4 alkyl group is optionally substituted with one or more groups independently selected from -OH, -OR sss , -NH 2 , -NHR SSS , and -NR SSS 2 ;
  • each of said phenyl groups is optionally substituted with one or more groups independently selected from -F, -CI, -Br, -I, -R sss , -CF 3 , -OH, -OR sss , -OCF 3 , -NH 2 , -NHR SSS , and -NR sss 2 ;
  • each -R sss is linear or branched saturated Ci -4 alkyl
  • -Q B is independently -Q B , -Q B2 , -Q B3 , -Q B4 , -Q B5 , -Q B6 , or -Q B7 ;
  • -Q B is independently -OH or -OR QB ;
  • -Q B2 is independently -NH 2 , -NHR QB , -NR QB 2 , or -NR QB2 R QB3 ;
  • -Q B6 is -N0 2 ;
  • -Q B7 is independently -F, -CI, -Br, or -I; each -R QB is independently linear or branched saturated C -4 alkyl, phenyl, or -L QB -phenyl;
  • Ci_ 4 alkyl group is optionally substituted with one or more groups independently selected from -OH, -OR QBB , -NH 2 , -NHR QBB , and -NR QBB 2 ;
  • each of said phenyl groups is optionally substituted with one or more groups independently selected from -F, -CI, -Br, -I, -R QBB , -CF 3 , -OH, -OR QBB , -OCF 3 , -NH 2 , -NHR QBB , and -NR QBB 2 ;
  • each -R QBB is linear or branched saturated Ci -4 alkyl; -NR Q R Q is independently azetidino, pyrrolidino, piperidino, piperizino,
  • -T is independently -H or -R T ;
  • -R T is independently:
  • -R TA is independently linear or branched saturated Ci -4 alkyl, phenyl, or
  • Ci -4 alkyl group is optionally substituted with one or more groups independently selected from -OH, -OR TAA , -NH 2 , -NHR TAA , and -NR TAA 2 ;
  • each of said phenyl groups is optionally substituted with one or more groups independently selected from -F, -CI, -Br, -I, -R TAA , -CF 3 , -OH, -OR TAA , -OCF 3 , -NH 2 , -NHR TAA , and -NR TAA 2 ;
  • each -R TAA is linear or branched saturated Ci -4 alkyl
  • each -R TB is independently linear or branched saturated Ci -4 alkyl, phenyl, or -L TB -phenyl
  • Ci -4 alkyl group is optionally substituted with one or more groups independently selected from -OH, -OR TBB , -NH 2 , -NHR TBB , and -NR TBB 2 ;
  • each of said phenyl groups is optionally substituted with one or more groups independently selected from -F, -CI, -Br, -I, -R TBB , -CF 3 , -OH, -OR TBB , -OCF 3 , -NH 2 , -NHR TBB , and -NR TBB 2 ;
  • each -R TBB is linear or branched saturated Ci -4 alkyl
  • each -R TN is independently linear or branched saturated Ci -4 alkyl, phenyl, or -L TN -phenyl
  • Ci -4 alkyl group is optionally substituted with one or more groups independently selected from -OH, -OR TN A , -NH 2 , -NHR TN A , and -NR TN A 2 ; wherein each of said phenyl groups is optionally substituted with one or more groups independently selected from -F, -CI, -Br, -I , -R TN A , -CF 3 , -OH, -OR TN A , -OCF 3 , -NH 2 , -NH R TN A , and -NR TN A 2 ;
  • each -R TN A is linear or branched saturated d_ 4 alkyl
  • -R TN2 is linear or branched saturated Ci -4 alkyl
  • -V is independently -H or -R v ;
  • Ci -4 alkyl is linear or branched saturated Ci -4 alkyl.
  • -Q and -O-V together form a ring fused to the ring to which they are attached.
  • the carbon atom at this position may be in either (R) or (S) configuration.
  • a reference to one enantiomer/diastereomer is intended to be a reference to both enantiomers/all diastereomers.
  • R 4 when R 4 is -H, the compound may form the corresponding tautomer, for example, as shown below. Unless otherwise stated, a reference to one tautomer is intended to be a reference to both tautomers:
  • C3. 7 heterocyclyl refers to the number of ring atoms, which may be carbon atoms or heteroatoms (e.g., N, O, S).
  • pyridyl is an example of a
  • heteroaryl refers to a group that is attached to the rest of the molecule by an atom that is part of an aromatic ring, wherein the aromatic ring is part of an aromatic ring system, and the aromatic ring system has one or more heteroatoms (e.g., N, O, S).
  • heteroatoms e.g., N, O, S.
  • pyridyl is an example of a C 6 heteroaryl group
  • quinolyl is an example of a Cioheteroaryl group.
  • heterocyclyl refers to a group that is attached to the rest of the molecule by a ring atom that is not part of an aromatic ring (i.e., the ring is partially or fully saturated), and the ring contains one or more heteroatoms (e.g., N, O, S).
  • heteroatoms e.g., N, O, S.
  • piperidino is an example of a C 6 heterocyclyl group.
  • substituted on carbon is intended to refer to a substituent which is attached to a carbon ring atom.
  • substituted on secondary nitrogen is intended to refer to a substituent which is attached to a nitrogen ring atom which, in the absence of the substituent, would be a secondary nitrogen ring atom (i.e., -NH-). Consequently, a pyridyl group may only have “substituents on carbon", whereas 1 H-pyrrole may have both "substituents on carbon” and a “substituent on secondary nitrogen", as illustrated below. a substituent on carbon
  • a piperidino group may only have “substituents on carbon”, whereas piperizino may have both “substituents on carbon” and a “substituent on secondary nitrogen”, as illustrated below.
  • a substituent on carbon a substituent on secondary nitrogen a substituent on secondary nitrogen
  • -R JE if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
  • the Group -R JE4 (44) A compound according to any one of (1) to (43), wherein each -R JE4 , if present, is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and is optionally substituted with one or more groups -R K2C .
  • each -R JE4 if present, is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • each -R JE5 is independently cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl, and is optionally substituted with one or more groups -R K2C .
  • each -R JE5 if present, is independently cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl.
  • the Group -R' is independently cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl.
  • each -R is independently oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, or diazepanyl,
  • each -R JE6 is independently tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl,
  • each -R JE6 if present, is independently tetrahydrofuranyl, tetrahydropyranyl, or dioxanyl,
  • each -R JE6 is independently pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl,
  • each -R JE7 if present, is phenyl, and is optionally substituted with one or more groups -R K3C .
  • each -R JE7 if present, is naphthyl, and is optionally substituted with one or more groups -R K3C .
  • each -R JE8 if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzoimidazolyl, indazolyl, benzofuranyl, benzothienyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl,
  • each -R if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl,
  • each -R JE8 if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, or isothiazolyl,
  • each -R JE8 is independently pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl,
  • the Group -L JE - (58) A compound according to any one of (1) to (57), wherein each -L JE -, if present, is independently -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH 2 CH 2 CH 2 -.
  • each -L JE - is independently -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, or -CH 2 CH 2 -.
  • each -L JE -, if present, is independently -CH 2 -, -CH(CH 3 )-, or -C(CH 3 ) 2 -.
  • (61) A compound according to any one of (1) to (57), wherein each -L JE -, if present, is independently -CH 2 - or -CH 2 CH 2 -.
  • each -L - is independently -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, -CH 2 CH 2 CH 2 -.
  • each -L -, if present, is independently -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, or -CH 2 CH 2 -.
  • each -L -, if present, is independently -CH 2 -, -CH(CH 3 )-, or -C(CH 3 ) 2 -.
  • each -R if present, is independently linear or branched saturated Ci -4 alkyl, phenyl, or -L KK -phenyl, wherein said Ci_ 4 alkyl group is unsubstituted, and each of said phenyl groups is unsubstituted.
  • each -R KK if present, linear or branched saturated C -4 alkyl, wherein said C -4 alkyl group is optionally substituted with one or more groups independently selected from -OH, -OR KKK , -NH -NHR KKK , and -NR 2 .
  • each -R if present, is linear or branched saturated Ci -4 alkyl, wherein said Ci -4 alkyl group is unsubstituted.
  • each -R if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
  • each -R KK if present, is independently -Me, -Et, -nPr, or -iPr.
  • each -R is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
  • the Group -L KK - (92) A compound according to any one of (1) to (91), wherein -L KK -, if present, is independently -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH 2 CH 2 CH 2 -.
  • each -R if present, is independently pyrrolidino, piperidino, piperizino, (N-Ci_ 4 alkyl)-piperizino,
  • each -R JN if present, is independently linear or branched saturated Ci -4 alkyl, phenyl, or -L JN -phenyl, wherein said Ci_ 4 alkyl group is unsubstituted, and each of said phenyl groups is unsubstituted.
  • each -R JN if present, is linear or branched saturated C -4 alkyl, wherein said C -4 alkyl group is optionally substituted with one or more groups independently selected from -OH, -OR JN A , -NH 2 , -NHR JN A , and -NR JN A 2 .
  • each -R JN if present, is linear or branched saturated Ci -4 alkyl, wherein said Ci -4 alkyl group is unsubstituted.
  • each -R JN is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
  • each -R if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
  • the Group -L JN - (1 14) A compound according to any one of (1) to (113), wherein -L JN1 -, if present, is independently -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH 2 CH 2 CH 2 -.
  • Ci -4 alkyl group is optionally substituted with one or more groups independently selected from -OH, -OR JN2A , -NH 2 , -NHR JN2A , and -NR JN2A 2 .
  • each -R JN2A is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
  • each -R JN2A if present, is independently -Me, -Et, -nPr, or -iPr.
  • -L JN2 - if present, is independently -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, or -CH 2 CH 2 -.
  • (132) A compound according to any one of (1) to (129), wherein -L -, if present, is independently -CH 2 -, -CH(CH 3 )-, or -C(CH 3 ) 2 -.
  • (133) A compound according to any one of (1) to (129), wherein -L JN2 -, if present, is independently -CH 2 - or -CH 2 CH 2 -.
  • a compound according to any one of (1) to (134), wherein -NR JN3 R JN4 , if present, is independently azetidino, pyrrolidino, piperidino, piperizino, (N-Ci. 4 alkyl)-piperizino, (N-Ci- 4 alkyl-C( 0))-piperizino, or morpholino; and is optionally substituted with one or more groups selected from linear or branched saturated Ci -4 alkyl.
  • (141) A compound according to any one of (1) to (140), wherein -Q A , if present, is independently -R QM , -R ⁇ 5 , -R QA6 , -R QA7 , or -R QA8 .
  • QA7 (145) A compound according to any one of (1) to (140), wherein -Q A , i present, is -R (
  • QA5 150
  • the Group -R (159) A compound according to any one of (1) to (158), wherein -R QA , if present, is linear or branched saturated Ci -6 alkyl. (160) A compound according to any one of (1) to (158), wherein -R , if present, is linear or branched saturated d_ 4 alkyl, and is optionally substituted with one or more groups
  • each -R QM is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and is optionally substituted with one or more groups -R S2C .
  • each -R if present, is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • each -R QA5 if present, is independently cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl, and is optionally substituted with one or more groups -R S2C .
  • each -R QA5 if present, is independently cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl.
  • the Group -R QAS is independently cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl.
  • each -R QA6 is independently oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, or diazepanyl,
  • each -R QA6 is independently tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl,
  • each -R QA6 if present, is independently pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl,
  • each -R QA7 if present, is phenyl, and is optionally substituted with one or more groups -R S3C .
  • each -R QA7 if present, is naphthyl, and is optionally substituted with one or more groups -R S3C .
  • the Group -R QA8
  • each -R QA8 if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzoimidazolyl, indazolyl, benzofuranyl, benzothienyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl,
  • each -R Q is independently furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl,
  • each -R QA8 if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, or isothiazolyl,
  • each -R QA8 is independently pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl,
  • each -L - is independently -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH 2 CH 2 CH 2 -.
  • each -L -, if present, is independently -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, or -CH 2 CH 2 -.
  • each -L -, if present, is independently -CH 2 -, -CH(CH 3 )-, or -C(CH 3 ) 2 -.
  • each -R S2N and each -R S3N is independently -R ss .
  • each -L s - is independently -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH 2 CH 2 CH 2 -.
  • each -L s - is independently -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, or -CH 2 CH 2 -.
  • each -L s - is independently -CH 2 -, -CH(CH 3 )-, or -C(CH 3 ) 2 -.
  • each -R if present, is independently linear or branched saturated d_ 4 alkyl, phenyl, or -L ss -phenyl, wherein said Ci_ 4 alkyl group is unsubstituted, and each of said phenyl groups is unsubstituted.
  • each -R if present, is linear or branched saturated Ci -4 alkyl, wherein said Ci -4 alkyl group is optionally substituted with one or more groups independently selected from -OH, -OR sss , -NH 2 , -NHR SSS , and -NR SSS 2 .
  • each -R ss if present, is linear or branched saturated Ci -4 alkyl, wherein said Ci -4 alkyl group is unsubstituted.
  • each -R sss is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
  • each -R SM if present, is independently azetidino, pyrrolidino, piperidino, piperizino, (N-Ci. 4 alkyl)-piperizino,
  • each -R SM if present, is independently pyrrolidino, piperidino, piperizino, (N-Ci_ 4 alkyl)-piperizino,
  • each -R if present, is independently linear or branched saturated d_ 4 alkyl, phenyl, or -L QB -phenyl, wherein said Ci_ 4 alkyl group is unsubstituted, and each of said phenyl groups is unsubstituted.
  • each -R if present, linear or branched saturated C -4 alkyl, wherein said C -4 alkyl group is optionally substituted with one or more groups independently selected from -OH, -OR QBB , -NH 2 , -NHR QBB , and -NR QBB 2 .
  • each -R if present, is linear or branched saturated Ci -4 alkyl, wherein said Ci -4 alkyl group is unsubstituted.
  • each -R if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
  • each -R if present, is independently -Me, -Et, -nPr, or -iPr.
  • each -R QB if present, is independently -Me or -Et.
  • (260) A compound according to any one of (1) to (259), wherein -L QB -, if present, is independently -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH 2 CH 2 CH 2 -.
  • each -R QBB is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
  • (280) A compound according to any one of (1) to (279), wherein -R , if present, is independently linear or branched saturated Ci -4 alkyl, phenyl, or -L TA -phenyl, wherein said Ci -4 alkyl group is unsubstituted, and each of said phenyl groups is unsubstituted.
  • Ci -4 alkyl group is optionally substituted with one or more groups independently selected from from -OH, -OR TAA , -NH 2 , -NHR TAA , and
  • each -R TAA is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
  • each -R TB if present, is independently linear or branched saturated Ci -4 alkyl, phenyl, or -L TN -phenyl, wherein said Ci_ 4 alkyl group is unsubstituted, and each of said phenyl groups is unsubstituted.
  • each -R TB if present, is linear or branched saturated C -4 alkyl, wherein said C -4 alkyl group is optionally substituted with one or more groups independently selected from -OH, -OR TBB , -NH 2 , -NHR TBB , and -NR TBB 2 .
  • each -R TB if present, is linear or branched saturated Ci -4 alkyl, wherein said Ci -4 alkyl group is unsubstituted.
  • each -R TB is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
  • each -R TB is independently -Me, -Et, -nPr, or -iPr.
  • each -R TBB is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
  • each -R TBB is independently -Me, -Et, -nPr, or -iPr.
  • the Group -L TB - (309) A compound according to any one of (1) to (308), wherein -L TB -, if present, is independently -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH 2 CH 2 CH 2 -.
  • (311) A compound according to any one of (1) to (308), wherein -L TB -, if present, is independently -CH 2 -, -CH(CH 3 )-, or -C(CH 3 ) 2 -.
  • (312) A compound according to any one of (1) to (308), wherein -L TB -, if present, is independently -CH 2 - or -CH 2 CH 2 -.
  • each -R TN if present, is independently linear or branched saturated d_ 4 alkyl, phenyl, or -L TN -phenyl, wherein said Ci_ 4 alkyl group is unsubstituted, and each of said phenyl groups is unsubstituted.
  • each -R TN if present, is linear or branched saturated Ci -4 alkyl, wherein said Ci -4 alkyl is optionally substituted with one or more groups independently selected from -OH, -OR TN A , -NH 2 , -NHR TN A , and -NR TN1A 2 .
  • each -R TN if present, is linear or branched saturated Ci -4 alkyl, wherein said Ci -4 alkyl group is unsubstituted.
  • each -R TN is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
  • each -R TN A is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
  • each -R TN A is independently -Me, -Et, -nPr, or -iPr.
  • the Group -R TN2 The Group -R TN2
  • a compound according to any one of (1) to (334), wherein -NR TN3 R TN4 , if present, is independently azetidino, pyrrolidino, piperidino, piperizino, (N-Ci_ 4 alkyl)-piperizino, (N-Ci- 4 alkyl-C( 0))-piperizino, or morpholino; and is optionally substituted with one or more groups selected from linear or branched saturated C -4 alkyl.
  • each -L T - is independently -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH 2 CH 2 CH 2 -.
  • each -L T - is independently -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, or -CH 2 CH(CH 3 )-.
  • each -L T - is independently -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, or -CH 2 CH(CH 3 )-.
  • each -L T - is independently -CH 2 -, -CH(CH 3 )-, or -C(CH 3 ) 2 -.
  • Substantially Purified Forms One aspect of the present invention pertains to DHP compounds, as described herein, in substantially purified form and/or in a form substantially free from contaminants.
  • the substantially purified form is at least 50% by weight, e.g., at least 60% by weight, e.g., at least 70% by weight, e.g., at least 80% by weight, e.g., at least 90% by weight, e.g., at least 95% by weight, e.g., at least 97% by weight, e.g., at least 98% by weight, e.g., at least 99% by weight.
  • substantially purified form refers to the compound in any
  • the substantially purified form refers to a mixture of stereoisomers, i.e., purified with respect to other compounds. In one embodiment, the substantially purified form refers to one
  • the substantially purified form refers to a mixture of enantiomers. In one embodiment, the substantially purified form refers to a equimolar mixture of enantiomers (i.e., a racemic mixture, a racemate). In one embodiment, the substantially purified form refers to one enantiomer, e.g., optically pure enantiomer.
  • the contaminants represent no more than 50% by weight, e.g., no more than 40% by weight, e.g., no more than 30% by weight, e.g., no more than 20% by weight, e.g., no more than 10% by weight, e.g., no more than 5% by weight, e.g., no more than 3% by weight, e.g., no more than 2% by weight, e.g., no more than 1 % by weight.
  • the contaminants refer to other compounds, that is, other than stereoisomers or enantiomers. In one embodiment, the contaminants refer to other compounds and other stereoisomers. In one embodiment, the contaminants refer to other compounds and the other enantiomer.
  • the substantially purified form is at least 60% optically pure (i.e., 60% of the compound, on a molar basis, is the desired stereoisomer or enantiomer, and 40% is the undesired stereoisomer(s) or enantiomer), e.g., at least 70% optically pure, e.g., at least 80% optically pure, e.g., at least 90% optically pure, e.g., at least 95% optically pure, e.g., at least 97% optically pure, e.g., at least 98% optically pure, e.g., at least 99% optically pure.
  • 60% optically pure i.e., 60% of the compound, on a molar basis, is the desired stereoisomer or enantiomer, and 40% is the undesired stereoisomer(s) or enantiomer
  • at least 70% optically pure e.g., at least 80% optically pure, e.g., at least 90%
  • Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diastereoisomeric, epimeric, atropic, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and l-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; a- and ⁇ -forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as "isomers” (or "isomeric forms").
  • a reference to a class of structures may well include structurally isomeric forms falling within that class (e.g., Ci -7 alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).
  • reference to a specifc group or substitution pattern is not intended to include other structural (or constitutional isomers) which differ with respect to the connections between atoms rather than by positions in space.
  • a reference to a methoxy group, -OCH 3 is not to be construed as a reference to its structural isomer, a
  • ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl.
  • keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime,
  • H may be in any isotopic form, including H, 2 H (D), and 3 H (T); C may be in any isotopic form, including 2 C, 3 C, and 4 C; O may be in any isotopic form, including 6 0 and 8 0; and the like.
  • a reference to a particular compound includes all such isomeric forms, including mixtures (e.g., racemic mixtures) thereof.
  • Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner.
  • Salts It may be convenient or desirable to prepare, purify, and/or handle a corresponding salt of the compound, for example, a pharmaceutically-acceptable salt.
  • suitable inorganic cations include, but are not limited to, alkali metal ions such as Na + and K + , alkaline earth cations such as Ca 2+ and Mg 2+ , and other cations such as Al 3+ .
  • suitable organic cations include, but are not limited to, ammonium ion (i.e., NH 4 + ) and substituted ammonium ions (e.g., NH 3 R + , NH 2 R 2 + , NHR 3 + , NR 4 + ).
  • suitable substituted ammonium ions are those derived from:
  • ethylamine diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine.
  • An example of a common quaternary ammonium ion is N(CH 3 ) 4 + .
  • a salt may be formed with a suitable anion.
  • suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.
  • Suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric.
  • Examples of some preferred salts suitable for amines include: chloride, sulfate, bromide, mesylate, maleate, citrate, tartrate, phosphate, acetate, and iodide.
  • a reference to a particular compound also includes salt forms thereof.
  • solvate is used herein in the conventional sense to refer to a complex of solute (e.g., compound, salt of compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.
  • a reference to a particular compound also includes solvate and hydrate forms thereof.
  • chemically protected form is used herein in the conventional chemical sense and pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions under specified conditions (e.g., pH, temperature, radiation, solvent, and the like).
  • specified conditions e.g., pH, temperature, radiation, solvent, and the like.
  • well known chemical methods are employed to reversibly render unreactive a functional group, which otherwise would be reactive, under specified conditions.
  • one or more reactive functional groups are in the form of a protected or protecting group (also known as a masked or masking group or a blocked or blocking group).
  • a hydroxy group may be protected as an ether (-OR) or an ester
  • the aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.
  • an amine group may be protected, for example, as an amide (-NRCO-R) or a urethane (-NRCO-OR), for example, as: a methyl amide (-NHCO-CH 3 ); a
  • benzyloxycarbonyl amide (-NHCO-OCH 2 C 6 H 5 , -NH-Cbz); as a t-butoxycarbonyl amine (-NHCO-OC(CH 3 ) 3 , -NH-Boc); a 2-biphenyl-2-propoxycarbonyl amine
  • 2-trimethylsilylethyloxycarbonyl amine (-NH-Teoc), as a 2,2,2-trichloroethyloxycarbonyl amine (-NH-Troc), as an allyloxycarbonyl amine (-NH-Alloc), as a
  • a carboxylic acid group may be protected as an ester for example, as: a Ci- 7 alkyl ester (e.g., a methyl ester; a t-butyl ester); a Ci_ 7 haloalkyl ester (e.g., a C -7 trihaloalkyl ester); a triCi. 7 alkylsilyl-Ci. 7 alkyl ester; or a C 5 _ 2 oaryl-Ci_ 7 alkyl ester (e.g., a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as a methyl amide.
  • a Ci- 7 alkyl ester e.g., a methyl ester; a t-butyl ester
  • a Ci_ 7 haloalkyl ester e.g., a C -7 trihaloalkyl ester
  • prodrug refers to a compound which, when metabolised (e.g., in vivo), yields the desired active compound.
  • the prodrug is inactive, or less active than the desired active compound, but may provide advantageous handling, administration, or metabolic properties.
  • DHP compounds having a 2-carboxylate group may be prepared by a method that involves Lewis acid mediated cyclisation of an amide (7) to give the corresponding DHP compound (8).
  • a range of Lewis acids may be used to achieve this, for example, boron trifluoride dietherate and titanium tetrachloride.
  • the amides (7) may be prepared, for example, by reaction of the corresponding dehydro- compounds (6) with diacetoxy acetyl chloride, for example, in a method analogous to that described in Cook et al., 2009, where the amine is reacted with the acid chloride using a biphasic mixture of water and an organic solvent in the presence of a base.
  • the dehydro compounds (6) may be prepared, for example, from the amino derivative (5) by reaction with a halogenating agent, such as N-chlorosuccinimide or tert-butyl hypochlorite and a base, such as DABCO or DBU, or an oxidant, such as DDQ, for example, in a method analogous to that described in Shimohiagashi et al., 1983.
  • a halogenating agent such as N-chlorosuccinimide or tert-butyl hypochlorite
  • a base such as DABCO or DBU
  • an oxidant such as DDQ
  • the amine (5) may be prepared from the protected amine (4), for example, using known deprotection methods, for example, by reaction of the tert-butyl carbamate protected amine with an acid, as described in Dutton et al., 2003.
  • the protected amine (4) may be prepared, for example, by reaction of the protected amine (3) using a base and a suitable alkyi halide or halo substituted alkyi derivative, for example, as described in Ohmura et al., 2008. In this reaction, the tert-butyl carboxamide group is preferred, but alternative protecting groups such as carboxybenzyl may also be used.
  • the protected amine (3) may be obtained from commercial sources, or may be prepared, for example, from the corresponding amine or protonated amine salt (2) using well known conditions for the protection of amines, for example, as described in Ohmura et al., 2008.
  • An example of such a method is illustrated in the following scheme, wherein (P) denotes a protecting group.
  • the amine (2) may be obtained from commercial sources, or may be prepared from the amino acid using well known esterification techniques, for example, as described in Ohmura et al., 2008.
  • the amine (5) may be prepared by reductive amination, for example, in a manner similar to the method described by Fitch et al., 2005, where the amine is reacted with a range of aldehydes, followed by treatment with a suitable reducing agent, such as sodium borohydride.
  • a suitable reducing agent such as sodium borohydride.
  • the ester (8) may be hydrolysed under basic conditions with a suitable base, such as an aqueous solution of sodium hydroxide, followed by acidic workup to obtain the carboxylic acid, for example as described in Krasnov et al., 2008.
  • a suitable base such as an aqueous solution of sodium hydroxide
  • the amide (10) may be obtained by reaction of the ester (8) with ammonia, or by reaction of the acid with a suitable amine using well-known coupling conditions, for example, as described in Feng et al., 2010.
  • the ether (11 ) may be obtained from the alcohol (9) by reaction with an alky halide, such as methyl iodide, using, for example, mild basic conditions, for example, as described in Devert et al., 2010.
  • an alky halide such as methyl iodide
  • the corresponding N-unsubstituted amide (12) may be reacted with a suitable Lewis acid, such as titanium tetrachloride, to give the corresponding amide (13).
  • a suitable Lewis acid such as titanium tetrachloride
  • the amide (12) may be prepared from the corresponding amine (14), for example, by reaction with diacetoxy acetyl chloride under basic conditions, for example, as described in Cook et al., 2009.
  • the amine (14) may be prepared from the ester (15) by the use of dehydrogenation conditions, for example, as described in Shimohiagashi et al., 1983.
  • compositions e.g., a pharmaceutical composition
  • a composition comprising a DHP compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • the composition further comprises one or more (e.g., 1 , 2, 3, 4) additional therapeutic agents, as described herein.
  • Another aspect of the present invention pertains to a method of preparing a composition (e.g., a pharmaceutical composition) comprising admixing a DHP compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • compositions e.g., a pharmaceutical composition
  • a composition comprising admixing a DHP compound, as described herein; one or more (e.g., 1 , 2, 3, 4) additional therapeutic agents, as described herein; and a pharmaceutically acceptable carrier, diluent, or excipient.
  • the DHP compounds described herein are useful, for example, in methods of improving memory and/or cognitive function, and in the treatment of memory-related disorders and cognitive decline.
  • DHP compounds described herein are useful as nootropic agents (e.g., memory enhancers; cognitive enhancers), for example, to improve memory and/or cognitive function in a patient.
  • nootropic agents e.g., memory enhancers; cognitive enhancers
  • one aspect of the present invention pertains to a DHP compound, as described herein, for use in a method of improving memory and/or cognitive function in a patient.
  • Another aspect of the present invention pertains to use of a DHP compound, as described herein, in the manufacture of a medicament for improving memory and/or cognitive function in a patient.
  • Another aspect of the present invention pertains to a method of improving memory and/or cognitive function comprising administering to a patient in need of improved memory and/or cognitive function a therapeutically effective amount of a DHP compound, as described herein, preferably in the form of a pharmaceutical composition.
  • a DHP compound as described herein, preferably in the form of a pharmaceutical composition.
  • the DHP compounds described herein are useful in methods of:
  • Such methods may, for example, comprise the step of contacting a neuron or neurons with an effective amount of a DHP compound, as described herein.
  • the method is performed in vitro.
  • the method is performed in vivo.
  • the DHP compound is provided in the form of a pharmaceutically acceptable composition.
  • Another aspect of the present invention pertains to a DHP compound, as described herein, for use in a method of treatment of the human or animal body by therapy, for example, for use a method of treatment of a disorder (e.g., a disease) as described herein.
  • Another aspect of the present invention pertains to a DHP compound, as described herein, in combination with one or more (e.g., 1 , 2, 3, 4) additional therapeutic agents, as described herein, for use in a method of treatment of the human or animal body by therapy, for example, for use a method of treatment of a disorder (e.g., a disease) as described herein.
  • Another aspect of the present invention pertains to use of a DHP compound, as described herein, in the manufacture of a medicament for treatment, for example, treatment of a disorder (e.g., a disease) as described herein.
  • a disorder e.g., a disease
  • the medicament comprises the DHP compound.
  • Another aspect of the present invention pertains to use of a DHP compound, as described herein, and one or more (e.g., 1 , 2, 3, 4) additional therapeutic agents, as described herein, in the manufacture of a medicament for treatment, for example, treatment of a disorder (e.g., a disease) as described herein.
  • a disorder e.g., a disease
  • the medicament comprises the DHP compound and the one or more (e.g., 1 , 2, 3, 4) additional therapeutic agents.
  • Another aspect of the present invention pertains to a method of treatment, for example, of a disorder (e.g., a disease) as described herein, comprising administering to a patient in need of treatment a therapeutically effective amount of a DHP compound, as described herein, preferably in the form of a pharmaceutical composition.
  • a disorder e.g., a disease
  • a DHP compound as described herein, preferably in the form of a pharmaceutical composition.
  • Another aspect of the present invention pertains to a method of treatment, for example, of a disorder (e.g., a disease) as described herein, comprising administering to a patient in need of treatment a therapeutically effective amount of a DHP compound, as described herein, preferably in the form of a pharmaceutical composition, and one or more (e.g., 1 , 2, 3, 4) additional therapeutic agents, as described herein, preferably in the form of a pharmaceutical composition.
  • a disorder e.g., a disease
  • the treatment is treatment of a central nervous system (CNS) disorder.
  • CNS central nervous system
  • the treatment is treatment of a neurodegenerative disorder of the central nervous system (CNS). See, e.g., O'Neill et al., 2004.
  • CNS central nervous system
  • the treatment is treatment of memory deficit, for example, deficient memory binding and/or deficient information recall. ln one embodiment, the treatment is treatment of a memory-related disorder.
  • the treatment is treatment of a disorder associated with cognitive decline.
  • the treatment is treatment of cognitive impairment, for example, mild cognitive impairment (MCI).
  • MCI mild cognitive impairment
  • the treatment is treatment of dementia. See, e.g., Akhondzadeh, 1999; Addae et al., 2003; Fitzjohn et al., 2008.
  • the treatment is treatment of: senile dementia (see, e.g., Shi-Lei et al., 2002; Palop et al., 2006; Zhang et al., 2008); vascular dementia (see, e.g., Chang et al., 1997; Xu et al., 2012); fronto-temporal lobe dementia (see, e.g., Chang et al., 1997), etc.
  • senile dementia see, e.g., Shi-Lei et al., 2002; Palop et al., 2006; Zhang et al., 2008
  • vascular dementia see, e.g., Chang et al., 1997; Xu et al., 2012
  • fronto-temporal lobe dementia see, e.g., Chang et al., 1997), etc.
  • the treatment is treatment of Alzheimer's disease (see, e.g., Harrison et al., 1990; Ikonomovic et al., 1995; Armstrong et al., 1996; Jacob et al., 2007; Chen et al., 2010; Chong et al., 2011).
  • the treatment is treatment of a movement disorder. See, e.g., Calabresi et al., 1997.
  • the treatment is treatment of Huntington's disease (see, e.g., Gibson et al., 2005; Andre et al., 2006; Maheshwari et al., 2012).
  • the treatment is treatment of Parkinson's disease (see, e.g., Parkinson's disease (see, e.g., Parkinson's disease).
  • the treatment is treatment of a mental disability disorder.
  • the treatment is treatment of an autism spectrum disorder (see, e.g., Moretti et al., 2006; Bozdagi et al., 2010); fragile-X syndrome; or Rett syndrome (see, e.g., Ivanco et al., 2002; Yun et al., 2011 ; Lanore et al., 2012).
  • an autism spectrum disorder see, e.g., Moretti et al., 2006; Bozdagi et al., 2010
  • fragile-X syndrome see, e.g., Ivanco et al., 2002; Yun et al., 2011 ; Lanore et al., 2012.
  • the treatment is treatment of a mood disorder.
  • the treatment is treatment of a depression disorder (see, e.g., O'Neill et al., 2007), for example, major depressive disorder (see, e.g., Holderbach et al., 2007; Gao et al., 201 1).
  • the treatment is treatment of a basal-ganglia-related disorder, for example, a basal-ganglia-related disorder where progressive memory decline is symptomatic.
  • the treatment is treatment of a disease which is ameliorated by inhibiting acetylcholinesterase.
  • the treatment is treatment of a disease which is ameliorated by inhibition of methyl-D-aspartate (NMDA).
  • NMDA methyl-D-aspartate
  • the treatment is treatment of: a disease which is ameliorated by potentiating excitatory synaptic transmission; a disease which is ameliorated by directly regulating excitatory synapses; a disease which is ameliorated by induction of long-term potentiation; a disease which is ameliorated by lowering the threshold for long-term potentiation induction; a disease which is ameliorated by induction of long-term
  • potentiation in the CA1 a disease which is ameliorated by induction of long-term potentiation in the CA3; a disease which is ameliorated by enhancing glutamatergic synapses; a disease which is ameliorated by modulating AMPA receptor function; a disease which is ameliorated by positively modulating AMPA receptor function; a disease which is ameliorated by indirectly modulating signalling cascades initiated by endogenous growth factors; a disease which is ameliorated by indirectly modulating signalling cascades initiated by BDNF; a disease which is ameliorated by indirectly modulating signalling cascades initiated by NGR; a disease which is ameliorated by modulating presynaptic Ca 2+ channel function; a disease which is ameliorated by modulating R-type voltage-gated Ca 2+ channels; or a disease which is ameliorated by modulating L-type voltage-gated Ca 2+ channels.
  • treatment refers generally to treatment and therapy, whether of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, alleviation of symptoms of the condition, amelioration of the condition, and cure of the condition.
  • Treatment as a prophylactic measure i.e. , prophylaxis
  • treatment use with patients who have not yet developed the condition, but who are at risk of developing the condition, is encompassed by the term "treatment”.
  • treatment of dementia includes the prophylaxis of dementia, reducing the incidence of dementia, reducing the severity of dementia, alleviating the symptoms of dementia, etc.
  • therapeutically-effective amount pertains to that amount of a compound, or a material, composition or dosage form comprising a compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.
  • treatment includes combination treatments and therapies, in which two or more treatments or therapies are combined, for example, sequentially or simultaneously.
  • the compounds described herein may also be used in combination therapies, e.g., in conjunction with other agents, for example, anti-cholinesterase agents, NMDA receptor antagonists, L-dopamine, etc.
  • treatments and therapies include, but are not limited to, chemotherapy (the administration of active agents, including, e.g., drugs, antibodies (e.g., as in immunotherapy), prodrugs (e.g., as in photodynamic therapy, GDEPT, ADEPT, etc.); surgery; radiation therapy; photodynamic therapy; gene therapy; and controlled diets.
  • One aspect of the present invention pertains to a compound as described herein, in combination with one or more additional therapeutic agents, as described below.
  • the particular combination would be at the discretion of the physician who would select dosages using his common general knowledge and dosing regimens known to a skilled practitioner.
  • the agents may be administered simultaneously or sequentially, and may be administered in individually varying dose schedules and via different routes.
  • the agents can be administered at closely spaced intervals (e.g., over a period of 5-10 minutes) or at longer intervals (e.g., 1 , 2, 3, 4 or more hours apart, or even longer periods apart where required), the precise dosage regimen being commensurate with the properties of the therapeutic agent(s).
  • agents i.e., the compound described here, plus one or more other agents
  • the agents may be formulated together in a single dosage form, or alternatively, the individual agents may be formulated separately and presented together in the form of a kit, optionally with instructions for their use. Additional Therapeutic Agents For Use In Combination Therapy
  • Drugs which are known to be useful for therapy of the disorders ⁇ e.g., diseases) discussed above may be used in combination therapy with a DHP compound as described herein.
  • cholinesterase inhibitors e.g., donepezil hydrochloride (Aricept), rivastigmine (Exelon), galantamine (Reminyl)), NM DA receptor antagonists (e.g., memantine (Ebixa)
  • non-steroidal anti-inflammatory drugs e.g., salicylates (such as aspirin (acetylsalicylic acid), diflunisal, salsalate), propionic acid derivatives (such as ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen), acetic acid derivatives (such as indomethacin, tolmetin, sulindac, etodolac, keto
  • mefenamic acid meclofenamic acid, flufenamic acid, tolfenamic acid
  • selective COX-2 inhibitors such as celecoxib, parecoxib, lumiracoxib, sulphonanilides, nimesulide), licofelone, lysine clonixinate.
  • Known drugs for the treatment of Huntington's disease may be used in combination therapy with a DPH compound as described herein.
  • examples of such drugs include: tetrabenazine, haloperidol, olanzapine, risperidone, andquetiapine, pimozide, clonidine, sulpiride, propranolol (or another beta-adrenoceptor blocking drug), piracetam, riluzole.
  • dopaminergic drugs for the treatment of Parkinson's disease may be used in combination therapy with a DPH compound as described herein.
  • examples of such drugs include: dopamine-receptor agonists (e.g., apomorphine hydrochloride,
  • bromocriptine cabergoline, pergolide, pramipexole, ropinirole, rotigotine, levodopa
  • monoamine-oxidase-B inhibitors e.g., rasagiline, selegiline hydrochloride
  • catechol- O-methyltransferase inhibitors e.g., entacapone, tolcapone, amantadine
  • Antipsychotic drugs may be used in the treatment of behavioural and psychological symptoms of dementia, and as such may be used in combination with a DHP compound to give an additive therapeutic benefit.
  • antipsychotic drugs include: first generation antipsychotic drugs (e.g., chlorpromazine, levomepromazine, promazine, pericyazine pipotiazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine) and second generation antipsychotic drugs (e.g., amisulpride, clozapine, olanzapine, paliperidone, quetiapine, risperidone, aripiprazole).
  • first generation antipsychotic drugs e.g., chlorpromazine, levomepromazine, promazine, pericyazine pipotiazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine
  • second generation antipsychotic drugs e.g.,
  • Antidepressants and anticonvulsants may be used in the treatment of behavioural and psychological symptoms of dementia, and as such may be used in combination with a DHP compound to give an additive therapeutic benefit.
  • antidepressants and anticonvlusants include: tricyclic antidepressants (e.g., amitriptyline hydrochloride, clomipramine hydrochloride, dosulepine hydrochloride, doxepin, imipramine
  • hydrochloride lofepramine, nortriptyline, trimipramine
  • tricyclic-related antidepressants e.g., mianserin hydrochloride, trazodone hydrochloride
  • MAOIs monoamine-oxydase inhibitors
  • SSRIs selective serotonin re-uptake inhibitors
  • Hypnotics may be used in the treatment of behavioural and psychological symptoms of dementia, and as such may be used in combination with a DHP compound to give an additive therapeutic benefit.
  • hypnotics include: benzodiazepines (diazepam, alprazolam, chlordiazepoxide hydrochloride, lorazepam, oxazepam), Z-drugs (zaleplon, Zolpidem, zopiclone), clomethiazole, antihistamines, ethyl alcohol, sodium oxybate, and melatonin.
  • Anxiolytics may be used in the treatment of behavioural and psychological symptoms of dementia, and as such may be used in combination with a DHP compound to give an additive therapeutic benefit.
  • Examples of anxiolytics include: diazepam, alprazolam, chlordiazepoxide hydrochloride, buspirone, and meprobamate.
  • the DHP compounds described herein may also be used as part of an in vitro assay, for example, in order to determine whether a candidate host is likely to benefit from treatment with the compound in question.
  • the DHP compounds described herein may also be used as a standard, for example, in an assay, in order to identify other compounds, other cognitive enhancers, other anti-dementia agents, etc.
  • kits comprising (a) a DHP compound as described herein, or a composition comprising a DHP compound as described herein, e.g., preferably provided in a suitable container and/or with suitable packaging; and (b) instructions for use, e.g., written instructions on how to administer the compound or composition.
  • the kit further comprises one or more ⁇ e.g., 1 , 2, 3, 4) additional therapeutic agents, as described herein.
  • the written instructions may also include a list of indications for which the active ingredient is a suitable treatment.
  • the DHP compound or pharmaceutical composition comprising the DHP compound may be administered to a subject by any convenient route of administration, whether systemically/peripherally or topically (i.e., at the site of desired action).
  • Routes of administration include, but are not limited to, oral ⁇ e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal ⁇ e.g., by nasal spray, drops or from an atomiser or dry powder delivery device); ocular ⁇ e.g., by eyedrops); pulmonary ⁇ e.g., by inhalation or insufflation therapy using, e.g., an aerosol, e.g., through the mouth or nose); rectal ⁇ e.g., by suppository or enema); vaginal ⁇ e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intra
  • the subject/patient may be a chordate, a vertebrate, a mammal, a placental mammal, a marsupial ⁇ e.g., kangaroo, wombat), a rodent ⁇ e.g., a guinea pig, a hamster, a rat, a mouse), murine ⁇ e.g., a mouse), a lagomorph ⁇ e.g., a rabbit), avian ⁇ e.g., a bird), canine ⁇ e.g., a dog), feline ⁇ e.g., a cat), equine ⁇ e.g., a horse), porcine ⁇ e.g., a pig), ovine ⁇ e.g., a sheep), bovine ⁇ e.g., a cow), a primate, simian ⁇ e.g., a monkey or ape), a monkey
  • the subject/patient may be any of its forms of development, for example, a foetus.
  • the subject/patient is a human.
  • the DHP compound While it is possible for the DHP compound to be administered alone, it is preferable to present it as a pharmaceutical formulation (e.g., composition, preparation, medicament) comprising at least one DHP compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, including, but not limited to, pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, anti-oxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents.
  • the formulation may further comprise other active agents, for example, other therapeutic or prophylactic agents.
  • the present invention further provides pharmaceutical compositions, as defined above, and methods of making a pharmaceutical composition comprising admixing at least one DHP compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, e.g., carriers, diluents, excipients, etc. If formulated as discrete units (e.g., tablets, etc.), each unit contains a predetermined amount (dosage) of the compound.
  • pharmaceutically acceptable pertains to compounds, ingredients, materials, compositions, dosage forms, etc., which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject in question (e.g., human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • Each carrier, diluent, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.

Abstract

The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain compounds of the following formula (for convenience, collectively referred to herein as "2-acyl-4-oxy-1,2-dihydropyrrol-5-one compounds" and "DHP compounds"), which, inter alia, are useful in methods of improving memory and/or cognitive function, and in the treatment of memory-related disorders and cognitive decline. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions in the treatment of central nervous system (CNS) disorders such as memory deficit, memory-related disorders, disorders associated with cognitive decline, cognitive impairment, including, for example, mild cognitive impairment (MCI), dementia, and Alzheimer's disease.

Description

2-ACYL-4-OXY-1 ,2-DIHYDROPYRROL-5-ONE COMPOUNDS FOR
IMPROVING MEMORY AND COGNITIVE FUNCTION
RELATED APPLICATION This application is related to United Kingdom patent application number 1308217.7 filed 08 May 2013, the contents of which are incorporated herein by reference in their entirety.
TECHNICAL FIELD
The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain compounds (for convenience, collectively referred to herein as "2-acyl-4-oxy-1 ,2-dihydropyrrol-5-one compounds" and "DHP compounds"), which, inter alia, are useful in methods of improving memory and/or cognitive function, and in the treatment of memory-related disorders and cognitive decline. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions in the treatment of central nervous system (CNS) disorders such as memory deficit, memory-related disorders, disorders associated with cognitive decline, and cognitive impairment, including, for example, mild cognitive impairment (MCI), dementia, and Alzheimer's disease.
BACKGROUND
A number of patents and publications are cited herein in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Each of these references is incorporated herein by reference in its entirety into the present disclosure, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference. Throughout this specification, including the claims which follow, unless the context requires otherwise, the word "comprise," and variations such as "comprises" and
"comprising," will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a pharmaceutical carrier" includes mixtures of two or more such carriers, and the like. Ranges are often expressed herein as from "about" one particular value, and/or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent "about," it will be understood that the particular value forms another embodiment.
This disclosure includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
Dementia
Dementia is a widespread and growing problem worldwide. In the UK alone, around 800,000 people have been diagnosed with the condition, and the Alzheimer's Society
(UK) predicts this number will increase to 1 million by 2021 and 1.7 million by 2051.
Furthermore, these figures may be much higher, since many cases of dementia go undiagnosed (especially in the early stages of dementia). The rise in the number of dementia sufferers is attributed to increasing longevity, due to advances in public health and medical care. For example, there is a sharp increase in the prevalence of dementia with age; for example, while one in twenty-five people aged 70 to 79 has some form of dementia, this rises to one in six people over the age of 80.
There are approximately one hundred different types of dementia. Of these, Alzheimer's disease is the most common form, affecting 62% of those living with dementia. Many of these people have a mixed pattern of dementia, with the second most common type, vascular dementia, also contributing to their condition.
At present, there are no medications which have been shown to prevent or cure dementia. One of the main obstacles to creating effective treatments for dementia is that the disease is not fully understood. The condition appears to result from a complex interaction of genes, lifestyle factors, and other environmental influences. Wthout knowing the exact mechanisms that cause damage, especially in Alzheimer's disease, it is difficult to target the disease process effectively. A further obstacle is the difficulty of effectively delivering medicaments for treating dementia across the blood-brain barrier. For example, drugs may only partly cross the barrier (due to their size or shape), meaning that dosing levels become toxic, even lethal.
Currently, medications are used to treat the behavioural and cognitive symptoms of dementia, but have no effect on the underlying pathophysiology. For example, acetylcholinesterase inhibitors (AChEls), such as donepezil, may be useful for Alzheimer's disease and other dementias such as Parkinson's or vascular dementia. N- methyl-D-aspartate (NMDA) receptor blockers, such as memantine, may be of benefit, but the evidence is less conclusive than for AChEls. Due to their differing mechanisms of action, memantine and AChEls can be used in combination. However, the benefit of using such a combination is slight.
In addition, current drug regimens do not effectively treat diseases associated with memory impairments. For example, many of the drugs used in clinical practice seek to improve memory deficits by targeting cholinergic neurotransmitter systems and serotoninergic pathway, but less than 10% of patients respond to such treatment.
Nootropic drugs, also known as memory enhancers, smart drugs, and cognitive enhancers, are drugs that improve cognitive function, memory, and concentration. Their action alters the availability and balance of brain neurotransmitters, hormones, and enzymes, but the mechanisms by which they improve learning and memory are not fully understood. One plausible mode of action is that they strengthen inter-synaptic communication between neurons and brain circuits that are important for learning and memory. Consistent with this hypothesis, in vitro studies and studies in animal behavior suggest that nootropic drugs facilitate the induction of long-term potentiation (LTP) in the hippocampus, a phenomenon leading to synapse reinforcement which is thought to underlie memory storage and recall in this brain structure.
Thus, one candidate mechanism by which a drug could prove beneficial for treating the progressive decline typical of these disorders would be by lowering the threshold for long- term potentiation (LTP) induction in the hippocampus.
Anatomy and Role of the Hippocampus
The hippocampal formation is a region of the brain that plays a central role in learning and memory. It takes the form of an elongated C-shaped structure with a long axis (also known as the "septotemporal axis"), spanning rostro-dorsally from the septal nuclei near the midline of the brain to caudo-ventrally behind the thalamus of the temporal lobe, and a transverse axis, spanning the width of the formation. See, e.g., Amaral et al., 1989. The term "hippocampal formation" refers to six regions which are functionally connected in a uni- or bi-directional fashion: the dentate gyrus, the CA regions (also termed hippocampus) consisting of CA1 , CA2, and CA3, the subiculum, the presubiculum, the parasubiculum, and the entorhinal cortex. Initially, the term was used to refer to a uni-directional "trisynaptic" loop between the entorhinal cortex, dentate gyrus, CA3 and CA1 (see, e.g., Andersen et al., 1971). However, use of the term has changed because the subiculum and its adjacent parts (the pre- and para-subiculum) also play important roles in learning and memory, and because the different regions are interconnected.
Cellular Neurophysiology of Mossy Fibre Inputs to CA3 Pyramidal Neurons
Granule cells within the dentate gyrus project a thin unmyelinated axon that forms a single parent fibre into the hippocampus proper, where it makes synaptic contacts onto CA3 pyramidal cells and various types of interneurones (see, e.g., Ascady et al., 1998). These unusual axons (referred to as "mossy fibres") provide one of the most powerful glutamatergic inputs in the brain, amid the low basal firing rate observed in granule cells in vivo (< 0.5 Hz) and the inability of granule cells to fire action potentials for extended periods of time (see, e.g., Henze et al., 2002).
Mossy fibre-CA3 synapses display a unique form of frequency-dependent facilitation of transmitter release consecutive to modest increases in presynaptic firing frequency (e.g., from 0.1 to 1 Hz), hence driving CA3 network activity very efficiently (see, e.g., Salin et al., 1996). In addition, mossy fibre-CA3 synapses display a presynaptic form of LTP that is expressed by persistent changes in the probability of glutamate release. It is now emerging that many of these physiological processes are regulated by ionotropic receptors (i.e., receptors permeable to ions) and ion channels localised in presynaptic membranes, in mossy fibres themselves, or in postsynaptic densities in CA3 pyramidal neurons (see, e.g., Ruiz et al., 2013). Compounds that interact with pre- or post-synaptic receptor function thus represent powerful modulators of excitatory connections at the interface between neocortical and dentate structures and the hippocampus itself, where memory formation and information recall occurs. Several lines of evidence have shown that in disease models of neurodegeneration, such as in Alzheimer's or Huntington's disease models, LTP is impaired in the CA1 and CA3 areas (see, e.g., Francis et al., 2009; Simmons et al., 2009; Chong et al., 2011). This translates into a form of LTP having a magnitude that is much less than that which occurs in healthy individuals. However, little is known about changes occurring in CA3, where LTP is thought to be mainly expressed as a change in presynaptic release probability.
Cellular Targets and Putative Signalling Pathways
Excitatory synapses generally express both AMPA (2-amino-3-(3-hydroxy-5-methyl- isoxazol-4-yl)propanoic acid) and NMDA (N-methyl-D-aspartate) receptors, with AMPA receptors mediating the major component of the synaptic response (see, e.g., Zucker et al., 1998).
NMDA receptors are permeable to calcium as well as sodium and potassium, but they are blocked by magnesium at resting membrane potential. However, repetitive activation of AMPA receptors can cause sufficient depolarisation to relieve the magnesium block, enabling a slower NMDA-receptor-mediated component of the response that is associated with calcium influx into the post-synaptic neuron. This influx triggers various forms of synaptic plasticity, including LTP, which results from the activation of calcium- dependent signal transduction cascades that cause trafficking of AMPA receptors into the synapse, thus strengthening synaptic signalling.
NMDA receptors are the switches that trigger LTP, which is expressed and maintained by the presence of an increased number of active AMPA receptors at the potentiated synapse. Thus, compounds that modulate AMPA receptor function may prove good candidates to strengthen excitatory synapses in diseases affecting memory binding and information recall as in the demented brain.
In this regard, the non-competitive AMPA receptor antagonists talempanel and perampanel have shown good clinical potential for the treatment of Huntington's disease. However, perampanel was not effective as an add-on therapy to levodopa in the treatment of Parkinson's disease, and its development program was terminated by Eisai Pharmaceuticals (see, e.g., Swanson, 2009; Bernard et al., 2010). In addition, compelling evidence has emerged that some AMPA receptor modulators, known as "AMPAkines", increase the brain's production of two endogenous neurotrophins (BDNF and NGF) that are important for developmental processes, learning and memory (see, e.g., Baumbarger et al., 2001 ; Simmons et al., 2009). Thus, compounds that target glutamate receptors offer different therapeutic windows, either by directly regulating excitatory synapses or by indirectly modulating signalling cascades initiated by endogenous growth factors.
An alternative route by which compounds may enhance synaptic transmission and lower the threshold for LTP induction is by modulating presynaptic Ca2+ channel function.
Voltage-gated Ca2+ channels (VGCCs) are a group of ion channels that are involved in a variety of processes including neurotransmitter exocytosis, synaptic plasticity, and gene expression. VGCCs are classified according to their a1 subunit. High-voltage activated channels consist of the Cav1 and Cav2 sub-families and include L-type (Cav1.1-1.4), P/Q-type (Cav2.1), N-type (Cav2.2) and R-type (Cav2.3) VGCCs. In contrast, low- voltage activated channels carry the Cav3 sub-family, consisting of the T-type
(Cav3.1-3.3).
At mossy fibre terminals, P/Q- and N-type VGCCs ensure efficient and rapid exocytosis and account for more than 90% of all VGCCs. The remaining fraction consists of R-type VGCCs, which have been shown to be important for short-term plasticity and LTP at these synapses. L-type VGCCs expressed at postsynaptic membranes are also important for LTP at the mossy fibre-CA3 synapse. A compound that enhances one of the most powerful synapses in the brain is likely to be useful in methods of reducing memory deficits and improving the cognitive faculties of patients suffering from neurodegenerative disorders, such as dementia (and including, for example, senile dementia, vascular dementia, fronto-temporal dementia, and milder forms of dementia), Parkinson's disease, Huntington's disease, and other basal ganglia- related disorders where progressive memory decline is often symptomatic.
The present invention provides novel compounds, as described herein, which provide surprising and unexpected activity, for example, as potentiators of excitatory synaptic transmission, enhancers of glutamatergic synapses, and/or positive modulators of AMPA receptors, and which may be useful in the treatment of such diseases and disorders.
Racetams are a class of nootropic drugs that share a pyrrolidone core. Piracetam was the first racetam to be discovered and is currently sold across the world under a variety of brand names (e.g., Nootropyl, Nootropil, Lucetam, Oikamid, Smart, Geratam, Biotropil). It is used for a wide range of applications including, for example, applications which rely on its nootropic properties, and treatment of myoclonus (involuntary twitching of a muscle or a group of muscles). Several related nootropic compounds, including I eveti racetam, oxiracetam, nefiracetam, aniracetam, and pramiracetam, have also been described.
Figure imgf000007_0001
Piracetam Leveti racetam Oxiracetam
Figure imgf000008_0001
Nefiracetam Aniracetam Pramiracetam
Clausenamide is a pyrrolidone-based compound which has been found to possess 50- 100 times greater nootropic activity than piracetam, and to enhance long-term potentiation (see, e.g., Feng et al., 2009). It is a naturally occurring compound which is isolated from extracts of dry leaves of Clausena Lansium, which is used in Chinese folk medicine. Clausenamide has four chiral centres, giving rise to sixteen stereoisomers (eight pairs of enantiomers). In nature, however, the compound appears as a racemate of (-)-clausenamide and (+)-clausenamide.
Figure imgf000008_0002
(-)-Clausenamide (+)-Clausenamide
Studies have shown that potency varies between the sixteen stereoisomers (see, e.g., Feng et al., 2009). In the synthesis strategy used to prepare the sixteen different stereoisomers of clausenamide, a chemical intermediate was prepared in which three of the four chiral centres were removed (Compound 26 in Scheme 3 in Feng et ai, 2009; shown below). This chemical intermediate was then used as the starting material in reactions to introduce the various chiral centres for the sixteen different stereoisomers.
Figure imgf000008_0003
It appears that the following "carboxylic acid salt" compounds may be known:
Figure imgf000009_0001
Figure imgf000009_0002
Figure imgf000010_0001
SUMMARY OF THE I NVENTION
One aspect of the invention pertains to certain 2-acyl-4-oxy-1 ,2-dihydropyrrol-5-one compounds (also referred to herein as DHP compounds), as described herein.
Another aspect of the invention pertains to a composition (e.g., a pharmaceutical composition) comprising a DHP compound, as described herein, and a pharmaceutically acceptable carrier or diluent. Another aspect of the invention pertains to a method of preparing a composition (e.g., a pharmaceutical composition) comprising the step of mixing a DHP compound, as described herein, and a pharmaceutically acceptable carrier or diluent.
Another aspect of the present invention pertains to a DHP compound, as described herein, for use in a method of improving memory and/or cognitive function in a patient.
Another aspect of the present invention pertains to use of a DHP compound, as described herein, in the manufacture of a medicament for improving memory and/or cognitive function in a patient.
Another aspect of the present invention pertains to a method of improving memory and/or cognitive function comprising administering to a patient in need of improved memory and/or cognitive function a therapeutically effective amount of a DHP compound, as described herein, preferably in the form of a pharmaceutical composition.
Another aspect of the present invention pertains to a DHP compound, as described herein, for use in a method of treatment of the human or animal body by therapy, for example, for use a method of treatment of a disorder (e.g., a disease) as described herein.
Another aspect of the present invention pertains to use of a DHP compound, as described herein, in the manufacture of a medicament for treatment, for example, treatment of a disorder (e.g., a disease) as described herein. Another aspect of the present invention pertains to a method of treatment, for example, of a disorder (e.g., a disease) as described herein, comprising administering to a patient in need of treatment a therapeutically effective amount of a DHP compound, as described herein, preferably in the form of a pharmaceutical composition. Another aspect of the present invention pertains to a kit comprising (a) a DHP compound, as described herein, preferably provided as a pharmaceutical composition and in a suitable container and/or with suitable packaging; and (b) instructions for use, for example, written instructions on how to administer the compound.
Another aspect of the present invention pertains to a DHP compound obtainable by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein. Another aspect of the present invention pertains to a DHP compound obtained by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
Another aspect of the present invention pertains to novel intermediates, as described herein, which are suitable for use in the methods of synthesis described herein.
Another aspect of the present invention pertains to the use of such novel intermediates, as described herein, in the methods of synthesis described herein.
As will be appreciated by one of skill in the art, features and preferred embodiments of one aspect of the invention will also pertain to other aspects of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows that DHP-001 facilitates excitatory synaptic transmission from the dentate gyrus to CA3. Panel A, top: Example traces of excitatory synaptic potentials
(field-EPSPs) recorded with an extracellular electrode (each trace is an average of 20 consecutive field-EPSPs taken at 5 second intervals) before (BASELINE) and following superfusion with DHP-001 (100 μΜ) are shown. The right-most trace shows field-EPSPs in the presence of DMSO (100 μΜ, VEHICLE). Panel A, bottom: A plot of the normalised field-EPSP amplitude (μν) versus time (min) for data from 1 slice.
Panel B: A bar graph showing normalized field-EPSP amplitude for control and DHP-001 for pooled data, which shows an increase of field-EPSP amplitude in the presence of DHP-001 (n = 4, P < 0.01 , paired f-test).
Figure 2 shows that superfusion with DHP-001 does not alter the input resistance of dentate granule cells. Panel A: Sample traces from a granule cellrecording showing the l-V relationship (membrane potential is -81 mV). Panel B: A plot of the l-V relationship (voltage in mV versus current in pA) before and after superfusion with DHP-001 (100 μΜ). No difference was found. Panel C: A bar graph of Rinput (ΜΩ) for control and DHP-001 , for pooled data from 5 neurons.
Figure 3 is a set of graphs illustrating the effect of DHP-001 on evoked AMPA currents in CA3 pyramidal neurons. Bottom left. Plot of normalised EPSC amplitude against time showing an increase upon superfusion with DHP-001 (100 μΜ) and depression by the group II metabotropic glutamate receptor agonist DCG-IV (1 μΜ). Top: Representative examples for each condition are shown (data from one CA3 pyramidal neuron).
Bottom right. Summary plot based on data from 5 neurons (each point represents the mean ± S.E.M).
Figure 4 is a concentration-facilitation curve for DHP-001. Each concentration was tested in at least 3 neurons. A logistic function was used to fit the data and each point represents the mean ± S.E.M. The EC50 inferred from the fit of the concentration- facilitation curve is 12 μΜ.
Figure 5 shows that DHP-001 facilitates mossy fibre LTP induction in CA3 pyramidal neurons. It is a plot of the field-EPSP amplitude (measured in μν, as a percentage of control) against time showing that a sub-threshold high-frequency stimulus train (HFSi: 100 Hz for 1 second, repeated 3 times with an interval of 10 seconds) does not induce LTP in contrast to a second sub-threshold stimulus (HFS2) delivered 20 minutes following DHP-001 (100 μΜ) superfusion, leading to sustained LTP. Data are represented as mean ± S.E.M, n = 4 slices. DETAILED DESCRIPTION OF THE INVENTION
Compounds One aspect of the present invention relates to certain compounds which are related to 2,5-dihydro-1 H-pyrrole, more specifically 1 ,2-dihydropyrrol-5-one:
Figure imgf000014_0001
2,5-dihydro-1 H-pyrrole 1 ,2-dihydropyrrol-5-one
All of the compounds of the present invention have: (a) a "oxy" substituent at the 4-position, denoted herein as -O-V; (b) a "carboxylic acid", "carboxylate", or "amide" substituent at the 2-position, denoted herein as -C(=0)-J; as in, for example:
Figure imgf000014_0002
1 1
4-hydroxy-5-oxo- 4- hydroxy- 5- oxo- 1 ,2-dihydropyrrole- 1 ,2-dihydropyrrole- 2-carboxylic acid 2-carboxamide
Thus, one aspect of the present invention is a compound of the following formula, or a tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of the foregoing, wherein -J, -Q, -V, and -T are as defined herein (for convenience, collectively referred to herein as "2-acyl-4-oxy-1 ,2-dihydropyrrol-5-one compounds" and "DHP compounds"):
Figure imgf000014_0003
Some embodiments of the invention include the following:
(1) A compound of the following formula:
Figure imgf000015_0001
or a tautomer thereof;
or a pharmaceutically acceptable salt, hydrate, or solvate of the foregoing; wherein: -J is independently -OH, -ORJE, -NH2, -NHRJN , -NRJN RJN2, or -NRJN3R'
>JE s independently:
DJE1 DJE2 DJE3 DJE4 DJE5 DJE6 DJE7 DJE8
-fx , - fx , - fx , - fx , -fx , -fx , -fx , -fx ,
-LJE-RJE4, -LJE-RJE5, -LJE-RJE6, -LJE-RJE7, or -LJE-RJE8;
-RJE is linear or branched saturated Ci-6alkyl,
and is optionally substituted with one or more groups -RK C;
-RJE2 is linear or branched C2-6alkenyl,
and is optionally substituted with one or more groups -RK C;
-RJE3 is linear or branched C2-6alkynyl,
and is optionally substituted with one or more groups -RK C;
each -RJE4 is saturated C3.6cycloalkyl,
and is optionally substituted with one or more groups -RK2C;
each -RJE5 is C3.6cycloalkenyl,
and is optionally substituted with one or more groups -RK2C;
each -RJE6 is non-aromatic C3.7heterocyclyl,
and is optionally substituted on carbon with one or more groups -R K2C and is optionally substituted on secondary nitrogen, if present, with a group -RK2N;
each -RJE7 is independently phenyl or naphthyl,
and is optionally substituted with one or more groups -RK3C;
each -RJE8 is C5.i0heteroaryl,
and is optionally substituted on carbon with one or more groups -RK3C, and is optionally substituted on secondary nitrogen, if present, with a group -RK3N;
each -LJE- is linear or branched saturated Ci_4alkylene; wherein: each -RK1C is independently: -F, -CI, -Br, -I,
-OH, -ORKK,
-OCF3,
-NH2, -NHRKK, -NRKK 2, -RKM,
-C(=0)OH, -C(=0)ORKK, -OC(=0)RKK,
-C(=0)NH2, -C(=0)NHRKK, -C(=0)NRKK 2, -C(=0)RKM,
-NHC(=0)RKK, -NRKNC(=0)RKK,
-NHC(=0)NH2, -NHC(=0)NHRKK, -NHC(=0)NRKK 2, -NHC(=0)RKM, -NRKNC(=0)NH2, -NRKNC(=0)NHRKK, -NRKNC(=0)NRKK 2, -NRKNC(=0)RKM, -NHC(=0)ORKK, -NRKNC(=0)ORKK,
-OC(=0)NH2, -OC(=0)NHRKK, -OC(=0)NRKK 2, -OC(=0)RKM,
-C(=0)RKK,
-S(=0)2NH2, -S(=0)2NHRKK, -S(=0)2NRKK 2, -S(=0)2RKM,
-NHS(=0)2RKK, -NRKNS(=0)2RKK,
-S(=0)2RKK,
-CN, -N02, or -SRKK; each -RK2C is independently:
-RKK,
-F, -CI, -Br, -I,
-OH, -ORKK,
-LK-OH, -LK-ORKK,
-CF3, -OCF3,
-NH2, -NHRKK, -NRKK 2, -RKM,
-LK-NH2, -LK-NHRKK, -LK-NRKK 2, -LK-RKM,
-C(=0)OH, -C(=0)ORKK, -OC(=0)RKK,
-C(=0)NH2, -C(=0)NHRKK, -C(=0)NRKK 2, -C(=0)RKM,
-NHC(=0)RKK, -NRKNC(=0)RKK,
-NHC(=0)NH2, -NHC(=0)NHRKK, -NHC(=0)NRKK 2, -NHC(=0)RKM, -NRKNC(=0)NH2, -NRKNC(=0)NHRKK, -NRKNC(=0)NRKK 2, -NRKNC(=0)RKM,
-NHC(=0)ORKK, -NRKNC(=0)ORKK,
-OC(=0)NH2, -OC(=0)NHRKK, -OC(=0)NRKK 2, -OC(=0)RKM,
-C(=0)RKK,
-S(=0)2NH2, -S(=0)2NHRKK, -S(=0)2NRKK 2, -S(=0)2RKM,
-NHS(=0)2RKK, -NRKNS(=0)2RKK,
-S(=0)2RKK, -CN, -NO2, -SR , or =0; each -R c is independently: -RKK,
-F, -CI, -Br, -I,
-OH, -ORKK,
-LK-OH, -LK-ORKK,
Figure imgf000017_0001
-IMH2, -NHRKK, -NRKK 2, -RKM,
-LK-NH2, -LK-NHRKK, -LK-NRKK 2, -LK-RKM,
-C(=0)OH, -C(=0)ORKK, -OC(=0)RKK,
-C(=0)NH2, -C(=0)NHRKK, -C(=0)NRKK 2, -C(=0)RKM,
-NHC(=0)RKK, -NRKNC(=0)RKK,
-NHC(=0)NH2, -NHC(=0)NHRKK, -NHC(=0)NRKK 2, -NHC(=0)RKM,
-NRKNC(=0)NH2, -NRKNC(=0)NHRKK, -NRKNC(=0)NRKK 2, -NRKNC(=0)RKM,
-NHC(=0)ORKK, -NRKNC(=0)ORKK,
-OC(=0)NH2, -OC(=0)NHRKK, -OC(=0)NRKK 2, -OC(=0)RKM,
-C(=0)RKK,
-S(=0)2NH2, -S(=0)2NHRKK, -S(=0)2NRKK 2, -S(=0)2RKM,
-NHS(=0)2RKK, -NRKNS(=0)2RKK,
-S(=0)2RKK,
-CN, -N02, or -SRKK; and additionally, two adjacent groups -RK3C, if present, may together form:
-0-CH2-0- or -0-CH2CH2-0-; each -RK2N and each -RK3N is independently: -RKK,
-LK-OH, -LK-ORKK,
-LK-NH2, -LK-NHRKK, -LK-NRKK 2, -LK-RKM,
-C(=0)RKK,
-C(=0)ORKK,
-C(=0)NH2, -C(=0)NHRKK, -C(=0)NRKK 2, -C(=0)RKM, or
-S(=0)2RKK; wherein: each -L - is linear or branched saturated Ci_4alkylene; each -R is independently linear or branched saturated d_4alkyl, phenyl, or -LKK-phenyl;
wherein said Ci-4alkyl group is optionally substituted with one or more groups independently selected from -OH, -ORKKK, -NH2, -NHRKKK, and -NRKKK 2;
wherein each of said phenyl groups is optionally substituted with one or more groups independently selected from -F, -CI, -Br, -I, -RKKK, -CF3, -OH, -ORKKK, -OCF3, -NH2, -NHRKKK, and -NRKKK 2;
wherein each -RKKK is linear or branched saturated Ci-4alkyl; and
wherein -LKK- is linear or branched saturated Ci.3alkylene; each -R is linear or branched saturated Ci-4alkyl; each -R is independently azetidino, pyrrolidino, piperidino, piperizino, (N-Ci-4alkyl)-piperizino, (N-Ci.4alkyl-C(=0))-piperizino, morpholino, thiomorpholino, azepino, diazepino, (N-Ci_4alkyl)-diazepino, or (N-Ci_4alkyl-C(=0))-diazepino;
and is optionally substituted with one or more groups selected from linear or branched saturated Ci-4alkyl; and wherein: each -RJN is independently linear or branched saturated Ci-4alkyl, phenyl, or -LJN -phenyl;
wherein said Ci-4alkyl group is optionally substituted with one or more groups independently selected from -OH, -ORJN A, -NH2, -NHRJN A, and -NRJN A 2;
wherein each of said phenyl groups is optionally substituted with one or more groups independently selected from -F, -CI, -Br, -I, -RJN A, -CF3, -OH, -ORJN A, -OCF3, -NH2, -NHRJN A, and -NRJN A 2;
wherein each -RJN A is linear or branched saturated C -4alkyl; and
wherein -|_JN - is linear or branched saturated Ci_3alkylene; each -RJN2 is independently linear or branched saturated Ci-4alkyl, phenyl, or -LJN2-phenyl;
wherein said Ci-4alkyl group is optionally substituted with one or more groups independently selected from -OH, -ORJN2A, -NH2, -NHRJN2A, and -NRJN2A 2;
wherein each of said phenyl groups is optionally substituted with one or more groups independently selected from -F, -CI, -Br, -I, -RJN2A, -CF3, -OH, -ORJN2A, -OCF3, -NH2, -NHRJN2A, and -NRJN2A 2;
wherein each -RJN2A is linear or branched saturated C -4alkyl; and
wherein -|_JN2- is linear or branched saturated Ci_3alkylene; -NRJN3RJN4 is independently azetidino, pyrrolidino, piperidino, piperizino, (N-Ci.4alkyl)-piperizino, (N-Ci.4alkyl-C(=0))-piperizino, morpholino, thiomorpholino, azepino, diazepino, (N-Ci_4alkyl)-diazepino, or (N-Ci_4alkyl-C(=0))-diazepino;
and is optionally substituted with one or more groups selected from linear or branched saturated C -4alkyl; and wherein:
-Q is independently -H, -QA, or -QB; -QA is independently:
RQA1 DQA2 DQA3 DQA4 DQA5 DQA6 DQA7 DQA8
-LQA-RQA4 -LQA-RQA5 -LQA-RQA6 -LQA-RQA7 or -LQA-RQA8' -RQA is linear or branched saturated Ci-6alkyl,
and is optionally substituted with one or more groups -RS C;
-RQA2 is linear or branched C^alkenyl,
and is optionally substituted with one or more groups -RS C;
-RQA3 is linear or branched C^alkynyl,
and is optionally substituted with one or more groups -RS C;
each -R0^4 is saturated C3.6cycloalkyl,
and is optionally substituted with one or more groups -RS2C;
each -R0^5 is C3.6cycloalkenyl,
and is optionally substituted with one or more groups -RS2C;
each -R0^6 is non-aromatic C3.7heterocyclyl,
and is optionally substituted on carbon with one or more groups -RS2C, and is optionally substituted on secondary nitrogen, if present, with a group -RS2N;
each -R^7 is independently phenyl or naphthyl,
and is optionally substituted with one or more groups -RS3C;
each -R0^8 is C5.i0heteroaryl,
and is optionally substituted on carbon with one or more groups -RS3C, and is optionally substituted on secondary nitrogen, if present, with a group -RS3N;
each -LQA- is linear or branched saturated Ci_4alkylene; wherein: each -RS C is independently: -F, -CI, -Br, -I,
-OH, -ORss, -OCF3,
-NH2, -NHRSS, -NRSS2, -RSM,
-C(=0)OH, -C(=0)ORss, -OC(=0)Rss,
-C(=0)NH2, -C(=0)NHRss, -C(=0)NRss 2, -C(=0)RSM,
-NHC(=0)Rss, -NRKNC(=0)Rss,
-NHC(=0)NH2, -NHC(=0)NHRss, -NHC(=0)NRss 2, -NHC(=0)RSM, -NRSNC(=0)NH2, -NRSNC(=0)NHRss, -NRSNC(=0)NRss 2, -NRSNC(=0)R; -NHC(=0)ORss, -NRKNC(=0)ORss,
-OC(=0)NH2, -OC(=0)NHRss, -OC(=0)NRss 2, -OC(=0)RSM,
-C(=0)Rss,
-S(=0)2NH2, -S(=0)2NHRss, -S(=0)2NRss 2, -S(=0)2RSM,
-NHS(=0)2Rss, -NRSNS(=0)2Rss,
-S(=0)2Rss,
-CN, -N02, or -SRss; each -RS2C is independently:
-F, -CI, -Br, -I,
-OH, -ORss,
-Ls-OH, -Ls-ORss,
Figure imgf000020_0001
-NH2, -NHRSS, -NRSS2, -RSM,
-LS-NH2, -LS-NHRSS, -LS-NRSS 2, -LS-RSM,
-C(=0)OH, -C(=0)ORss, -OC(=0)Rss,
-C(=0)NH2, -C(=0)NHRss, -C(=0)NRss 2, -C(=0)RSM,
-NHC(=0)Rss, -NRSNC(=0)Rss,
-NHC(=0)NH2, -NHC(=0)NHRss, -NHC(=0)NRss 2, -NHC(=0)RSM, -NRSNC(=0)NH2, -NRSNC(=0)NHRss, -NRSNC(=0)NRss 2, -NRSNC(=0)R; -NHC(=0)ORss, -NRSNC(=0)ORss,
-OC(=0)NH2, -OC(=0)NHRss, -OC(=0)NRss 2, -OC(=0)RSM,
-C(=0)Rss,
-S(=0)2NH2, -S(=0)2NHRss, -S(=0)2NRss 2, -S(=0)2RSM,
-NHS(=0)2Rss, -NRKNS(=0)2Rss,
-S(=0)2Rss,
-CN, -N02, -SRSS, or =0; R is independently:
-Rss,
-F, -CI, -Br, -I,
-OH, -ORss,
-Ls-OH, -Ls-ORss,
Figure imgf000021_0001
-NH2, -NHRSS, -NRSS2, -RSM,
-LS-NH2, -LS-NHRSS, -LS-NRSS 2, -LS-RSM,
-C(=0)OH, -C(=0)ORss, -OC(=0)Rss,
-C(=0)NH2, -C(=0)NHRss, -C(=0)NRss 2, -C(=0)RSM,
-NHC(=0)Rss, -NRSNC(=0)Rss,
-NHC(=0)NH2, -NHC(=0)NHRss, -NHC(=0)NRss 2, -NHC(=0)RSM, -NRSNC(=0)NH2, -NRSNC(=0)NHRss, -NRSNC(=0)NRss 2, -NRSNC(=0)RSM, -NHC(=0)ORss, -NRSNC(=0)ORss,
-OC(=0)NH2, -OC(=0)NHRss, -OC(=0)NRss 2, -OC(=0)RSM,
-C(=0)Rss,
-S(=0)2NH2, -S(=0)2NHRss, -S(=0)2NRss 2, -S(=0)2RSM,
-NHS(=0)2Rss, -NRSNS(=0)2Rss,
-S(=0)2Rss,
-CN, -N02, or -SRss; and additionally, two adjacent groups -RS3C, if present, may together form: -0-CH2-0- or -0-CH2CH2-0-;
RS2N and each -RS3N is independently:
-Rss
-Ls-OH, -Ls-ORss,
-LS-NH2, -LS-NHRSS, -LS-NRSS 2, -LS-RSM,
-C(=0)Rss,
-C(=0)ORss,
-C(=0)NH2, -C(=0)NHRss, -C(=0)NRss 2, -C(=0)RSM, or
-S(=0)2Rss; wherein: each -Ls- is linear or branched saturated d_4alkylene; each -R is independently linear or branched saturated d_4alkyl, phenyl, or -Lss-phenyl;
wherein said Ci_4alkyl group is optionally substituted with one or more groups independently selected from -OH, -ORsss, -NH2, -NHRSSS, and -NRSSS 2;
wherein each of said phenyl groups is optionally substituted with one or more groups independently selected from -F, -CI, -Br, -I, -Rsss, -CF3, -OH, -ORsss, -OCF3, -NH2, -NHRSSS, and -NRsss 2;
wherein each -Rsss is linear or branched saturated Ci-4alkyl; and
wherein -Lss- is linear or branched saturated Ci.3alkylene; each -R is linear or branched saturated Ci-4alkyl; each -R is independently azetidino, pyrrolidino, piperidino, piperizino, (N-Ci-4alkyl)-piperizino, (N-Ci.4alkyl-C(=0))-piperizino, morpholino, thiomorpholino, azepino, diazepino, (N-Ci_4alkyl)-diazepino, or (N-Ci_4alkyl-C(=0))-diazepino;
and is optionally substituted with one or more groups selected from linear or branched saturated Ci-4alkyl; and wherein:
-QB is independently -QB , -QB2, -QB3, -QB4, -QB5, -QB6, or -QB7;
-QB is independently -OH or -ORQB ;
-QB2 is independently -NH2, -NHRQB , -NRQB 2, or -NRQB2RQB3;
-QB3 is independently -NHC(=0)RQB or -NRQB C(=0)RQB ;
-QB4 is -S(=0)2RQB ;
-QB5 is independently -S(=0)2NH2, -S(=0)2NRQB , -S(=0)2NRQB 2, or
-S(=0)2NRQB2RQB3;
-QB6 is -N02;
-QB7 is independently -F, -CI, -Br, or -I; each -RQB is independently linear or branched saturated C -4alkyl, phenyl, or -LQB-phenyl;
wherein said Ci_4alkyl group is optionally substituted with one or more groups independently selected from -OH, -ORQBB, -NH2, -NHRQBB, and -NRQBB 2;
wherein each of said phenyl groups is optionally substituted with one or more groups independently selected from -F, -CI, -Br, -I, -RQBB, -CF3, -OH, -ORQBB, -OCF3, -NH2, -NHRQBB, and -NRQBB 2;
wherein -LQB- is linear or branched saturated Ci_3alkylene;
wherein each -RQBB is linear or branched saturated Ci-4alkyl; -NRQ RQ is independently azetidino, pyrrolidino, piperidino, piperizino,
(N-Ci.4alkyl)-piperizino, (N-Ci.4alkyl-C(=0))-piperizino, morpholino, thiomorpholino, azepino, diazepino, (N-Ci_4alkyl)-diazepino, or (N-Ci_4alkyl-C(=0))-diazepino;
and is optionally substituted with one or more groups selected from linear or branched saturated C -4alkyl; and wherein:
-T is independently -H or -RT;
-RT is independently:
-RTA
-C(=0)-RTB, -LT-C(=0)-RTB,
-LT-C(=0)-NH2, -LT-C(=0)-NHRTN ,
- LT-C (= O) - N RTN RTN2 , or -LTA-C(=0)-NRTN3RTN4;
-RTA is independently linear or branched saturated Ci-4alkyl, phenyl, or
-LTA-phenyl;
wherein said Ci-4alkyl group is optionally substituted with one or more groups independently selected from -OH, -ORTAA, -NH2, -NHRTAA, and -NRTAA 2;
wherein each of said phenyl groups is optionally substituted with one or more groups independently selected from -F, -CI, -Br, -I, -RTAA, -CF3, -OH, -ORTAA, -OCF3, -NH2, -NHRTAA, and -NRTAA 2;
wherein -LTA- is linear or branched saturated d_3alkylene;
wherein each -RTAA is linear or branched saturated Ci-4alkyl; each -RTB is independently linear or branched saturated Ci-4alkyl, phenyl, or -LTB-phenyl;
wherein said Ci-4alkyl group is optionally substituted with one or more groups independently selected from -OH, -ORTBB, -NH2, -NHRTBB, and -NRTBB 2;
wherein each of said phenyl groups is optionally substituted with one or more groups independently selected from -F, -CI, -Br, -I, -RTBB, -CF3, -OH, -ORTBB, -OCF3, -NH2, -NHRTBB, and -NRTBB 2;
wherein -LTB- is linear or branched saturated Ci_3alkylene;
wherein each -RTBB is linear or branched saturated Ci-4alkyl; and each -RTN is independently linear or branched saturated Ci-4alkyl, phenyl, or -LTN -phenyl;
wherein said Ci-4alkyl group is optionally substituted with one or more groups independently selected from -OH, -ORTN A, -NH2, -NHRTN A, and -NRTN A 2; wherein each of said phenyl groups is optionally substituted with one or more groups independently selected from -F, -CI, -Br, -I , -RTN A, -CF3, -OH, -ORTN A, -OCF3, -NH2, -NH RTN A, and -NRTN A 2;
wherein -LTN - is linear or branched saturated Ci.3alkylene;
wherein each -RTN A is linear or branched saturated d_4alkyl; and
-RTN2 is linear or branched saturated Ci-4alkyl;
-NRTN3RTN4 is independently azetidino, pyrrolidino, piperidino, piperizino, (N-Ci-4alkyl)-piperizino, (N-Ci.4alkyl-C(=0))-piperizino, morpholino, thiomorpholino, azepino, diazepino, (N-Ci_4alkyl)-diazepino, or (N-Ci_4alkyl-C(=0))-diazepino;
and is optionally substituted with one or more groups selected from linear or branched saturated Ci-4alkyl; each -LT- is linear or branched saturated Ci.3alkylene; and wherein:
-V is independently -H or -Rv; and
-Rv is linear or branched saturated Ci-4alkyl.
For the avoidance of doubt, it is not intended that any two or more of -C(=0)-J, -Q, -O-V, and -T together form a ring fused to the ring to which they are attached. For example, it is not intended that -Q and -O-V together form a ring fused to the ring to which they are attached. Similarly, it is not intended that -C(=0)-J and -Q together form a ring fused to the ring to which they are attached. Similarly, it is not intended that -C(=0)-J and -T together form a ring fused to the ring to which they are attached.
Note that the compounds have at least one chiral centre, specifically, the carbon ring atom to which the group -C(=0)-J is attached, marked with an asterisk (*) in the following formula. The carbon atom at this position may be in either (R) or (S) configuration. Unless otherwise stated, a reference to one enantiomer/diastereomer is intended to be a reference to both enantiomers/all diastereomers.
Figure imgf000024_0001
Also note that when R4 is -H, the compound may form the corresponding tautomer, for example, as shown below. Unless otherwise stated, a reference to one tautomer is intended to be a reference to both tautomers:
Figure imgf000025_0001
For the avoidance of doubt, the index "Cx.y" in terms such as "C5.i0heteroaryl",
"C3.7heterocyclyl", and the like, refers to the number of ring atoms, which may be carbon atoms or heteroatoms (e.g., N, O, S). For example, pyridyl is an example of a
C6heteroaryl group, and piperidino is an example of a C6heterocyclyl group.
The term "heteroaryl" refers to a group that is attached to the rest of the molecule by an atom that is part of an aromatic ring, wherein the aromatic ring is part of an aromatic ring system, and the aromatic ring system has one or more heteroatoms (e.g., N, O, S). For example, pyridyl is an example of a C6heteroaryl group, and quinolyl is an example of a Cioheteroaryl group.
The term "heterocyclyl" refers to a group that is attached to the rest of the molecule by a ring atom that is not part of an aromatic ring (i.e., the ring is partially or fully saturated), and the ring contains one or more heteroatoms (e.g., N, O, S). For example, piperidino is an example of a C6heterocyclyl group.
For the avoidance of doubt, the phrase "substituent on carbon" is intended to refer to a substituent which is attached to a carbon ring atom. Similarly, the phrase "substituent on secondary nitrogen" is intended to refer to a substituent which is attached to a nitrogen ring atom which, in the absence of the substituent, would be a secondary nitrogen ring atom (i.e., -NH-). Consequently, a pyridyl group may only have "substituents on carbon", whereas 1 H-pyrrole may have both "substituents on carbon" and a "substituent on secondary nitrogen", as illustrated below. a substituent on carbon
substituent on secondary nitrogen
Figure imgf000026_0001
a substituent on carbon
Similarly, a piperidino group may only have "substituents on carbon", whereas piperizino may have both "substituents on carbon" and a "substituent on secondary nitrogen", as illustrated below. - a substituent on carbon a substituent on secondary nitrogen
a substituent on carbon
Figure imgf000026_0002
The Group -J
(2) A compound according to (1), wherein -J is independently -OH or -OR JE
(3) A compound according to (1 , wherein -J is -OH.
(4) A compound according to (1 , wherein -J is -OR JE
(5) A compound according to (1 , wherein -J is independently -NH2, -NHR
or -NRJN3RJN4.
(6) A compound according to (1 , wherein -J is -NH2. compound according to (1 , wherein -J is -NHR JN1 compound according to (1 . wherein -J is -NR JN1 D RJN2 compound according to (1 , wherein -J is -NR JN3D RJN4 The Group -R JE
(10) A compound according to any one of (1) to (9), wherein -RJE, if present, is independently:
Figure imgf000027_0001
-L JJEt-R-)JJE"4, -L JJEt-R-)JJE"5, -L JJEt- DRJJEt6e, -L JJEt- DRJJEt7', or -L JJEt-R-)JE8
(1 1) A compound according to any one of (1) to (9), wherein -RJE, if present, is independently:
_ JE1 _ JE2 _ JE3 _ JE7 _RJE8
Figure imgf000027_0002
(12) A compound according to any one of (1) to (9), wherein -RJE, if present, is independently:
-RJE1 , -RJE2, or -RJE3.
(13) A compound according to any one of (1) to (9), wherein -RJE, if present, is independently:
-RJE1 , -RJE7, -RJE8, -LJE-RJE7, or -LJE-RJE8.
(14) A compound according to any one of (1) to (9), wherein -RJE, if present, independently:
RJE1. -RJE7. or -LJE-RJE7
(15) A compound according to any one of (1) to (9), wherein -RJE if present, is -RJE .
(16) A compound according to any one of (1) to (9), wherein -RJE if present, is -RJE2.
(17) A compound according to any one of (1) to (9), wherein -R JE if present, is -R JE3 (18) A compound according to any one of (1) to (9), wherein -RJE if present, is -R JE4
(19) A compound according to any one of (1) to (9), wherein -RJE if present, is JE5
(20) A compound according to any one of (1) to (9), wherein -RJE if present, is
(21) A compound according to any one of (1) to (9), wherein -RJE if present, is
(22) A compound according to any one of (1) to (9), wherein -RJE if present, is -R JE8
(23) A compound according to any one of (1) to (9), wherein -R JE if present, is -L JE -R-)JE4 (24) A compound according to any one of (1) to (9), wherein -RJE, if present, is -LJE-RJE5.
(25) A compound according to any one of (1) to (9), wherein -RJE, if present, is -LJE-RJE6. (26) A compound according to any one of (1) to (9), wherein -RJE, if present, is -LJE-RJE7.
(27) A compound according to any one of (1) to (9), wherein -RJE, if present, is -LJE-RJE8. The Group -RJE
(28) A compound according to any one of (1) to (27), wherein -RJE , if present, is linear or branched saturated Ci-6alkyl.
(29) A compound according to any one of (1) to (27), wherein -RJE , if present, is linear or branched saturated Ci-4alkyl, and is optionally substituted with one or more groups -RK C.
(30) A compound according to any one of (1) to (27), wherein -RJE , if present, is linear or branched saturated Ci-4alkyl. (31) A compound according to any one of (1) to (27), wherein -RJE , if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
(32) A compound according to any one of (1) to (27), wherein -RJE , if present, is independently -Me, -Et, -nPr, or -iPr.
(33) A compound according to any one of (1) to (27), wherein -RJE , if present, is independently -Me or -Et.
(34) A compound according to any one of (1) to (27), wherein -RJE , if present, is -Me.
(35) A compound according to any one of (1) to (27), wherein -RJE , if present, is -Et.
(36) A compound according to any one of (1) to (27), wherein -RJE , if present, is -nPr. (37) A compound according to any one of (1) to (27), wherein -RJE , if present, is -iPr.
The Group -RJE2
(38) A compound according to any one of (1) to (37), wherein -RJE2, if present, is independently C^alkenyl, and is optionally substituted with one or more groups -RK C. (39) A compound according to any one of (1) to (37), wherein -R , if present, is independently C2.4alkenyl.
(40) A compound according to any one of (1) to (37), wherein -RJE2, if present, is independently -CH=CH, -CH=C-CH3, -CH2-CH=CH, or -CH2-CH=CH-CH3.
The Group -RJE3
(41) A compound according to any one of (1) to (40), wherein -RJE3, if present, is independently C2.4alkynyl, and is optionally substituted with one or more groups -RK C.
(42) A compound according to any one of (1) to (40), wherein -RJE3, if present, is independently C2.4alkynyl. (43) A compound according to any one of (1) to (40), wherein -RJE3, if present, is independently -C≡CH, -C≡C-CH3, -CH2-C≡CH, or -CH2-C≡C-CH3.
The Group -RJE4 (44) A compound according to any one of (1) to (43), wherein each -RJE4, if present, is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and is optionally substituted with one or more groups -RK2C.
(45) A compound according to any one of (1) to (43), wherein each -RJE4, if present, is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
The Group -RJE5
(46) A compound according to any one of (1) to (45), wherein each -RJE5, if present, is independently cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl, and is optionally substituted with one or more groups -RK2C.
(47) A compound according to any one of (1) to (45), wherein each -RJE5, if present, is independently cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl. The Group -R'
(48) A compound according to any one of (1) to (47), wherein each -R , if present, is independently oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, or diazepanyl,
and is optionally substituted on carbon with one or more groups -RK2C,
and is optionally substituted on secondary nitrogen, if present, with a group -R
(49) A compound according to any one of (1) to (47), wherein each -RJE6, if present, is independently tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl,
and is optionally substituted on carbon with one or more groups -R
and is optionally substituted on secondary nitrogen, if present, with a group -R K2N (50) A compound according to any one of (1) to (47), wherein each -RJE6, if present, is independently tetrahydrofuranyl, tetrahydropyranyl, or dioxanyl,
and is optionally substituted on carbon with one or more groups -RK2C.
(51) A compound according to any one of (1) to (47), wherein each -RJE6, if present, is independently pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl,
and is optionally substituted on carbon with one or more groups -RK2C,
and is optionally substituted on secondary nitrogen, if present, with a group -RK2N.
The Group -RJE7
(52) A compound according to any one of (1) to (51), wherein each -RJE7, if present, is phenyl, and is optionally substituted with one or more groups -RK3C.
(53) A compound according to any one of (1) to (51), wherein each -RJE7, if present, is naphthyl, and is optionally substituted with one or more groups -RK3C.
The Group -RJE8
(54) A compound according to any one of (1) to (53), wherein each -RJE8, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzoimidazolyl, indazolyl, benzofuranyl, benzothienyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl,
benzoisothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, quinazolinyl, or phthalazinyl,
and is optionally substituted on carbon with one or more groups -RK3C,
and is optionally substituted on secondary nitrogen, if present, with a group -RK3N. (55) A compound according to any one of (1) to (53), wherein each -R , if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl,
and is optionally substituted on carbon with one or more groups -RK3C,
and is optionally substituted on secondary nitrogen, if present, with a group -RK3N.
(56) A compound according to any one of (1) to (53), wherein each -RJE8, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, or isothiazolyl,
and is optionally substituted on carbon with one or more groups -RK3C,
and is optionally substituted on secondary nitrogen, if present, with a group -RK3N.
(57) A compound according to any one of (1) to (53), wherein each -RJE8, if present, is independently pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl,
and is optionally substituted on carbon with one or more groups -RK3C.
The Group -LJE- (58) A compound according to any one of (1) to (57), wherein each -LJE-, if present, is independently -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, or -CH2CH2CH2-.
(59) A compound according to any one of (1) to (57), wherein each -LJE-, if present, is independently -CH2-, -CH(CH3)-, -C(CH3)2-, or -CH2CH2-.
(60) A compound according to any one of (1) to (57), wherein each -LJE-, if present, is independently -CH2-, -CH(CH3)-, or -C(CH3)2-. (61) A compound according to any one of (1) to (57), wherein each -LJE-, if present, is independently -CH2- or -CH2CH2-.
(62) A compound according to any one of (1) to (57), wherein each -LJE-, if present, is -CH2-. The Group -RK C
(63) A compound according to any one of (1) to (62), wherein each -RK C is independently:
-F, -CI, -Br, -I,
-OH, -ORKK,
-OCFs,
-NH2, -NHRKK, -NRKK2, -RKM,
-C(=0)OH, -C(=0)ORKK, -OC(=0)RKK,
-C(=0)NH2, -C(=0)NHRKK, -C(=0)NRKK 2, -C(=0)RKM,
-NHC(=0)RKK, or -NRKNC(=0)RKK.
(64) A compound according to any one of (1) to (62), wherein each -RK C is independently:
-F, -CI, -Br, -I,
-OH, -ORKK,
-OCFs,
-NH2, -NHRKK, -NRKK2, or -RKM. (65) A compound according to any one of (1) to (62), wherein each -RK C is independently:
-F, -CI, -Br, -I,
-OH, -ORKK,
-NH2, -NHRKK, -NRKK2, or -RKM.
The Group -R K2C
(66) A compound according to any one of (1) to (65), wherein each -RK2C is independently:
-RKK,
-F, -CI, -Br, -I,
-OH, -ORKK,
-LK-OH, -LK-ORKK,
-CF3, -OCFs,
-NH2, -NHRKK, -NRKK 2, -RKM,
-LK-NH2, -LK-NHRKK, -LK-NRKK 2, -LK-RKM,
-C(=0)OH, -C(=0)ORKK, -OC(=0)RKK,
-C(=0)NH2, -C(=0)NHRKK, -C(=0)NRKK 2, -C(=0)RKM,
-NHC(=0)RKK, or -NRKNC(=0)RKK. (67) A compound according to any one of (1 ) to (65), wherein each -R independently:
-RKK,
-F, -CI, -Br, -I,
-OH, -ORKK,
-CF3, -OCF3,
-NH2, -NHRKK, -NRKK2, or -RKM.
(68) A compound according to any one of (1) to (65), wherein each -R is independently:
-RKK,
-F, -CI, -Br, -I,
-OH, -ORKK,
-NH2, -NHRKK, -NRKK2, or -RKM.
The Group -R'
(69) A compound according to any one of (1) to (68), wherein each -R is independently:
-RKK,
-F, -CI, -Br, -I,
-OH, -ORKK,
-LK-OH, -LK-ORKK,
-CF3, -OCF3,
-NH2, -NHRKK, -NRKK 2, -RKM,
-LK-NH2, -LK-NHRKK, -LK-NRKK 2, -LK-RKM,
-C(=0)OH, -C(=0)ORKK, -OC(=0)RKK,
-C(=0)NH2, -C(=0)NHRKK, -C(=0)NRKK 2, -C(=0)RKM,
-NHC(=0)RKK, -NRKNC(=0)RKK,
-C(=0)RKK,
-CN, or -N02.
(70) A compound according to any one of (1) to (68), wherein each -RK3C is independently:
-RKK,
-F, -CI, -Br, -I,
-OH, -ORKK,
-CF3, -OCF3,
-NH2, -NHRKK, -NRKK 2, -RKM,
-C(=0)OH, -C(=0)ORKK, -OC(=0)RKK,
-C(=0)NH2, -C(=0)NHRKK, -C(=0)NRKK 2, -C(=0)RKM, -NHC(=0)RKK, -NRKNC(=0)RKK,
-C(=0)RKK,
-CN, or -N02. (71) A compound according to any one of (1) to (68), wherein each -RK3C is
independently:
-RKK,
-F, -CI, -Br, -I,
-OH, -ORKK,
Figure imgf000034_0001
-NH2, -NHRKK, -NRKK2, -RKM,
-CN, or -N02.
(72) A compound according to any one of (1) to (68), wherein each -RK3C is
independently:
-RKK,
-F, -CI, -Br, -I,
-OH, -ORKK,
Figure imgf000034_0002
-NH2, -NHRKK, -NRKK2, or -RKM.
The Groups -RK2N and -RK3N
(73) A compound according to any one of (1) to (72), wherein each -RK2N and each -RK3N is independently:
-RKK,
-C(=0)RKK,
-C(=0)ORKK,
-C(=0)NH2, -C(=0)NHRKK, -C(=0)NRKK 2, -C(=0)RKM, or
-S(=0)2RKK.
(74) A compound according to any one of (1) to (72), wherein each -RK2N and each -RK3N is independently -RKK or -C(=0)RKK.
(75) A compound according to any one of (1) to (72), wherein each -R ^N and each is independently -R KK The Group -LK-
(76) A compound according to any one of (1) to (75), wherein each -L -, if present, is independently -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -CH2CH2CH2-.
(77) A compound according to any one of (1) to (75), wherein each -L -, if present, is independently -CH2-, -CH(CH3)-, -C(CH3)2-, or -CH2CH2-. (78) A compound according to any one of (1) to (75), wherein each -L -, if present, is independently -CH2-, -CH(CH3)-, or -C(CH3)2-.
(79) A compound according to any one of (1) to (75), wherein each -LK-, if present, is independently -CH2- or -CH2CH2-.
(80) A compound according to any one of (1) to (75), wherein each -LK-, if present, is -CH2-.
The Group -R'
(81) A compound according to any one of (1) to (80), wherein each -R , if present, is independently linear or branched saturated Ci-4alkyl, phenyl, or -LKK-phenyl, wherein said Ci_4alkyl group is unsubstituted, and each of said phenyl groups is unsubstituted.
(82) A compound according to any one of (1) to (80), wherein each -RKK, if present, linear or branched saturated C -4alkyl, wherein said C -4alkyl group is optionally substituted with one or more groups independently selected from -OH, -ORKKK, -NH -NHRKKK, and -NR 2. (83) A compound according to any one of (1) to (80), wherein each -R , if present, is linear or branched saturated Ci-4alkyl, wherein said Ci-4alkyl group is unsubstituted.
(84) A compound according to any one of (1) to (80), wherein each -R , if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
(85) A compound according to any one of (1) to (80), wherein each -RKK, if present, is independently -Me, -Et, -nPr, or -iPr.
(86) A compound according to any one of (1) to (80), wherein each -R , if present, is independently -Me or -Et. (87) A compound according to any one of (1) to (80), wherein each -RKK, if present, is -Me.
The Group -R KKK
(88) A compound according to any one of (1) to (87), wherein each -R , if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
(89) A compound according to any one of (1) to (87), wherein each -R , if present, is independently -Me, -Et, -nPr, or -iPr.
(90) A compound according to any one of (1) to (87), wherein each -RKKK, if present, is independently -Me or -Et. (91) A compound according to any one of (1) to (87), wherein each -RKKK, if present, is -Me.
The Group -LKK- (92) A compound according to any one of (1) to (91), wherein -LKK-, if present, is independently -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, or -CH2CH2CH2-.
(93) A compound according to any one of (1) to (91), wherein -LKK-, if present, is independently -CH2-, -CH(CH3)-, -C(CH3)2-, or -CH2CH2-.
(94) A compound according to any one of (1) to (91), wherein -LKK-, if present, is independently -CH2-, -CH(CH3)-, or -C(CH3)2-. (95) A compound according to any one of (1) to (91), wherein -LKK-, if present, is independently -CH2- or -CH2CH2-.
(96) A compound according to any one of (1) to (91), wherein -LKK-, if present, is -CH2-. The Group -RKN
(97) A compound according to any one of (1) to (96), wherein each -RKN, if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu. (98) A compound according to any one of (1) to (96), wherein each -R , if present, is independently -Me, -Et, -nPr, or -iPr. (99) A compound according to any one of (1) to (96), wherein each -R , if present, is independently -Me or -Et. (100) A compound according to any one of (1) to (96), wherein each -RKN, if present, is -Me.
The Group -RKM (101) A compound according to any one of (1) to (100), wherein each -RKM, if present, is independently azetidino, pyrrolidino, piperidino, piperizino, (N-Ci.4alkyl)-piperizino, (N-Ci-4alkyl-C(=0))-piperizino, or morpholino; and is optionally substituted with one or more groups selected from linear or branched saturated Ci-4alkyl.
(102) A compound according to any one of (1) to (100), wherein each -R , if present, is independently pyrrolidino, piperidino, piperizino, (N-Ci_4alkyl)-piperizino,
(N-Ci-4alkyl-C(=0))-piperizino, or morpholino.
The Group -R JN1
(103) A compound according to any one of (1) to (102), wherein each -RJN , if present, is independently linear or branched saturated Ci-4alkyl, phenyl, or -LJN -phenyl, wherein said Ci_4alkyl group is unsubstituted, and each of said phenyl groups is unsubstituted. (104) A compound according to any one of (1) to (102), wherein each -RJN , if present, is linear or branched saturated C -4alkyl, wherein said C -4alkyl group is optionally substituted with one or more groups independently selected from -OH, -ORJN A, -NH2, -NHRJN A, and -NRJN A 2. (105) A compound according to any one of (1) to (102), wherein each -RJN , if present, is linear or branched saturated Ci-4alkyl, wherein said Ci-4alkyl group is unsubstituted.
(106) A compound according to any one of (1) to (102), wherein each -RJN , if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
(107) A compound according to any one of (1) to (102), wherein each -RJN , if present, is independently -Me, -Et, -nPr, or -iPr.
(108) A compound according to any one of (1) to (102), wherein each -RJN , if present, is independently -Me or -Et. (109) A compound according to any one of (1) to (102), wherein each -R , if present, is -Me.
The Group -R JN1A
(1 10) A compound according to any one of (1) to (109), wherein each -R , if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
(1 11) A compound according to any one of (1) to (109), wherein each -R , if present, is independently -Me, -Et, -nPr, or -iPr.
(1 12) A compound according to any one of (1) to (109), wherein each -R , if present, is independently -Me or -Et. (1 13) A compound according to any one of (1) to (109), wherein each -RJN A, if present, is -Me.
The Group -LJN - (1 14) A compound according to any one of (1) to (113), wherein -LJN1-, if present, is independently -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, or -CH2CH2CH2-.
(1 15) A compound according to any one of (1) to (113), wherein -LJN1-, if present, is independently -CH2-, -CH(CH3)-, -C(CH3)2-, or -CH2CH2-.
(1 16) A compound according to any one of (1) to (113), wherein -LJN1-, if present, is independently -CH2-, -CH(CH3)-, or -C(CH3)2-. (1 17) A compound according to any one of (1) to (113), wherein -LJN1-, if present, is independently -CH2- or -CH2CH2-.
(1 18) A compound according to any one of (1) to (113), wherein -L JN1 -, if present, is -CH2-.
The Group -R JN2
(1 19) A compound according to any one of (1) to (118), wherein -RJN2, if present, is independently linear or branched saturated Ci-4alkyl, phenyl, or -LJN2-phenyl, wherein said Ci_4alkyl group is unsubstituted, and each of said phenyl groups is unsubstituted. (120) A compound according to any one of (1) to (118), wherein -RJN2, if present, is linear or branched saturated Ci-4alkyl, wherein said Ci-4alkyl group is optionally substituted with one or more groups independently selected from -OH, -ORJN2A, -NH2, -NHRJN2A, and -NRJN2A 2.
(121) A compound according to any one of (1) to (118), wherein -RJN2, if present, is linear or branched saturated Ci-4alkyl, wherein said Ci-4alkyl group is unsubstituted.
(122) A compound according to any one of (1) to (118), wherein -RJN2, if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
(123) A compound according to any one of (1) to (118), wherein -RJN2, if present, is independently -Me, -Et, -nPr, or -iPr. (124) A compound according to any one of (1) to (118), wherein -RJN2, if present, is independently -Me or -Et.
(125) A compound according to any one of (1) to (118), wherein -RJN2, if present, is -Me. The Group -RJN2A
(126) A compound according to any one of (1) to (125), wherein each -RJN2A, if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu. (127) A compound according to any one of (1) to (125), wherein each -RJN2A, if present, is independently -Me, -Et, -nPr, or -iPr.
(128) A compound according to any one of (1) to (125), wherein each -R , if present, is independently -Me or -Et.
(129) A compound according to any one of (1) to (125), wherein each -RJN2A, if present, is -Me.
The Group -LJN2-
(130) A compound according to any one of (1) to (129), wherein -LJN2-, if present, is independently -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, or -CH2CH2CH2-. (131) A compound according to any one of (1) to (129), wherein -LJN2-, if present, is independently -CH2-, -CH(CH3)-, -C(CH3)2-, or -CH2CH2-. (132) A compound according to any one of (1) to (129), wherein -L -, if present, is independently -CH2-, -CH(CH3)-, or -C(CH3)2-. (133) A compound according to any one of (1) to (129), wherein -LJN2-, if present, is independently -CH2- or -CH2CH2-.
(134) A compound according to any one of (1) to (129), wherein -LJN2-, if present, is -CH2-.
Figure imgf000040_0001
(135) A compound according to any one of (1) to (134), wherein -NRJN3RJN4, if present, is independently azetidino, pyrrolidino, piperidino, piperizino, (N-Ci.4alkyl)-piperizino, (N-Ci-4alkyl-C(=0))-piperizino, or morpholino; and is optionally substituted with one or more groups selected from linear or branched saturated Ci-4alkyl.
(136) A compound according to any one of (1) to (134), wherein -NRJN3RJN4, if present, is independently pyrrolidino, piperidino, piperizino, (N-Ci_4alkyl)-piperizino,
(N-Ci-4alkyl-C(=0))-piperizino, or morpholino.
The Group -Q
(137) A compound according to any one of (1) to (136), wherein -Q is -QA or -QB.
(138) A compound according to any one of (1) to (136), wherein -Q is -QA.
(139) A compound according to any one of (1) to (136), wherein -Q is -QB. (140) A compound according to any one of (1) to (136), wherein -Q is -H.
The Group -QA
(141) A compound according to any one of (1) to (140), wherein -QA, if present, is independently -RQM, -R^5, -RQA6, -RQA7, or -RQA8.
(142) A compound according to any one of (1) to (140), wherein -QA, if present, is independently -RQM, -R^6, -RQA7, or -RQA8. (143) A compound according to any one of (1) to (140), wherein -QA, if present, is independently -RQA7 or -RQA8. (144) A compound according to any one of (1) to (140), wherein -QA, i present, is independently -RQA , -R^2, or -RQA3.
QA7 (145) A compound according to any one of (1) to (140), wherein -QA, i present, is -R(
QA1
(146) A compound according to any one of (1) to (140) wherein -QA present is -R(
QA2
(147) A compound according to any one of (1) to (140) wherein -QA present is -R(
QA3
(148) A compound according to any one of (1) to (140) wherein -QA present is -R(
QA4
(149) A compound according to any one of (1) to (140) wherein -QA present is -R(
QA5 (150) A compound according to any one of (1) to (140) wherein -QA present is -R(
QA6
(151 ) A compound according to any one of (1) to (140) wherein -QA present
QA7
(152) A compound according to any one of (1) to (140) wherein -QA present
QA8
(153) A compound according to any one of (1) to (140) wherein -QA present
(154) A compound according to any one of (1) to (140), wherein -Q present, is
I QA DQA4
(155) A compound according to any one of (1) to (140), wherein -QA, i present, is
■ QA DQA5
(156) A compound according to any one of (1) to (140), wherein -QA, i present, is
(157) A compound according to any one of (1) to (140), wherein -QA, present, is -LQA-RQA7
(158) A compound according to any one of (1) to (140), wherein -Q , present, is
I QA DQA8
QA1
The Group -R (159) A compound according to any one of (1) to (158), wherein -RQA , if present, is linear or branched saturated Ci-6alkyl. (160) A compound according to any one of (1) to (158), wherein -R , if present, is linear or branched saturated d_4alkyl, and is optionally substituted with one or more groups
-R S1C
(161) A compound according to any one of (1) to (158), wherein -RQA , if present, is linear or branched saturated Ci-4alkyl.
(162) A compound according to any one of (1) to (158), wherein -RQA , if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
(163) A compound according to any one of (1) to (158), wherein -RQA , if present, is independently -Me, -Et, -nPr, or -iPr. (164) A compound according to any one of (1) to (158), wherein -RQA , if present, is independently -Me or -Et.
(165) A compound according to any one of (1) to (158), wherein -RQA , if present, is -Me. (166) A compound according to any one of (1) to (158), wherein -RQA , if present, is -Et.
(167) A compound according to any one of (1) to (158), wherein -RQA , if present, is -nPr.
(168) A compound according to any one of (1) to (158), wherein -RQA , if present, is -iPr. The Group -RQA2
(169) A compound according to any one of (1) to (168), wherein -RQA2, if present, is independently C2.4alkenyl, and is optionally substituted with one or more groups -R S1C
(170) A compound according to any one of (1) to (168), wherein -R , if present, is independently C2.4alkenyl.
(171) A compound according to any one of (1) to (168), wherein -RQA2, if present, is independently -CH=CH, -CH=C-CH3, -CH2-CH=CH, or -CH2-CH=CH-CH3.
The Group -R QA3
(172) A compound according to any one of (1) to (171), wherein -RQA3, if present, is independently C2.4alkynyl, and is optionally substituted with one or more groups -RS C. (173) A compound according to any one of (1) to (171), wherein -RQA3, if present, is independently C^alkynyl.
(174) A compound according to any one of (1) to (171), wherein -RQA3, if present, is independently -C≡CH, -C≡C-CH3, -CH2-C≡CH, or -CH2-C≡C-CH3.
The Group -RQM
(175) A compound according to any one of (1) to (174), wherein each -RQM, if present, is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and is optionally substituted with one or more groups -RS2C.
(176) A compound according to any one of (1) to (174), wherein each -R , if present, is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
The Group -R QA5
(177) A compound according to any one of (1) to (176), wherein each -RQA5, if present, is independently cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl, and is optionally substituted with one or more groups -RS2C.
(178) A compound according to any one of (1) to (176), wherein each -RQA5, if present, is independently cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl. The Group -RQAS
(179) A compound according to any one of (1) to (178), wherein each -RQA6, if present, is independently oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, or diazepanyl,
and is optionally substituted on carbon with one or more groups -RS2C, and is optionally substituted on secondary nitrogen, if present, with a group -RS2N.
(180) A compound according to any one of (1) to (178), wherein each -RQA6, if present, is independently tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl,
and is optionally substituted on carbon with one or more groups -RS2C, and is optionally substituted on secondary nitrogen, if present, with a group -RS2N.
(181) A compound according to any one of (1) to (178), wherein each -RQA6, if present, is independently tetrahydrofuranyl, tetrahydropyranyl, or dioxanyl,
and is optionally substituted on carbon with one or more groups -RS2C. (182) A compound according to any one of (1) to (178), wherein each -RQA6, if present, is independently pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl,
and is optionally substituted on carbon with one or more groups -RS2C,
and is optionally substituted on secondary nitrogen, if present, with a group -RS2N.
The Group -RQA7
(183) A compound according to any one of (1) to (182), wherein each -RQA7, if present, is phenyl, and is optionally substituted with one or more groups -RS3C.
(184) A compound according to any one of (1) to (182), wherein each -RQA7, if present, is naphthyl, and is optionally substituted with one or more groups -RS3C. The Group -RQA8
(185) A compound according to any one of (1) to (184), wherein each -RQA8, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzoimidazolyl, indazolyl, benzofuranyl, benzothienyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl,
benzoisothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, quinazolinyl, or phthalazinyl,
and is optionally substituted on carbon with one or more groups -R'
and is optionally substituted on secondary nitrogen, if present, with a group -R S3N
(186) A compound according to any one of (1) to (184), wherein each -RQ , if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl,
and is optionally substituted on carbon with one or more groups -RS3C,
and is optionally substituted on secondary nitrogen, if present, with a group -RS3N.
(187) A compound according to any one of (1) to (184), wherein each -RQA8, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, or isothiazolyl,
and is optionally substituted on carbon with one or more groups -RS3C,
and is optionally substituted on secondary nitrogen, if present, with a group -RS3N.
(188) A compound according to any one of (1) to (184), wherein each -RQA8, if present, is independently pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl,
and is optionally substituted on carbon with one or more groups -RS3C. The Group -L0*-
(189) A compound according to any one of (1) to (188), wherein each -L -, if present, is independently -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, or -CH2CH2CH2-.
(190) A compound according to any one of (1) to (188), wherein each -L -, if present, is independently -CH2-, -CH(CH3)-, -C(CH3)2-, or -CH2CH2-. (191) A compound according to any one of (1) to (188), wherein each -L -, if present, is independently -CH2-, -CH(CH3)-, or -C(CH3)2-.
(192) A compound according to any one of (1) to (188), wherein each
independently -CH2- or -CH2CH2-.
(193) A compound according to any one of (1) to (188), wherein each
-CH2-.
The Group -R'
(194) A compound according to any one of (1) to (193), wherein each -RS C is independently:
-F, -CI, -Br, -I,
-OH, -ORss,
-OCF3,
-NH2, -NHRSS, -NRSS2, -RSM,
-C(=0)OH, -C(=0)ORss, -OC(=0)Rss,
-C(=0)NH2, -C(=0)NHRss, -C(=0)NRss 2, -C(=0)RSM,
-NHC(=0)Rss, or -NRSNC(=0)Rss.
(195) A compound according to any one of (1) to (193), wherein each -RS C is independently:
-F, -CI, -Br, -I,
-OH, -ORss,
-OCF3,
-NH2, -NHRSS, -NRSS2, or -RSM. (196) A compound according to any one of (1) to (193), wherein each -RS C is independently:
-F, -CI, -Br, -I,
-OH, -ORss,
-NH2, -NHRSS, -NRSS2, or -RSM.
The Group -RS2C
(197) A compound according to any one of (1) to (196), wherein each -RS2C is independently:
-Rss,
-F, -CI, -Br, -I,
-OH, -ORss,
-Ls-OH, -Ls-ORss,
Figure imgf000046_0001
-NH2, -NHRSS, -NRSS2, -RSM,
-LS-NH2, -LS-NHRSS, -LS-NRSS 2, -LS-RSM,
-C(=0)OH, -C(=0)ORss, -OC(=0)Rss,
-C(=0)NH2, -C(=0)NHRss, -C(=0)NRss 2, -C(=0)RSM,
-NHC(=0)Rss, or -NRSNC(=0)Rss.
(198) A compound according to any one of (1) to (196), wherein each -RS2C is independently:
-Rss,
-F, -CI, -Br, -I,
-OH, -ORss,
Figure imgf000046_0002
-NH2, -NHRSS, -NRSS2, or -RSM. (199) A compound according to any one of (1) to (196), wherein each -RS2C is independently:
-Rss,
-F, -CI, -Br, -I,
-OH, -ORss,
-NH2, -NHRSS, -NRSS 2, or -RSM. The Group -RS3C
(200) A compound according to any one of (1) to (199), wherein each -RS3C is independently:
-Rss,
-F, -CI, -Br, -I,
-OH, -ORss,
-Ls-OH, -Ls-ORss,
-CF3, -OCFs,
-NH2, -NHRSS, -NRSS2, -RSM,
-LS-NH2, -LS-NHRSS, -LS-NRSS 2, -LS-RSM,
-C(=0)OH, -C(=0)ORss, -OC(=0)Rss,
-C(=0)NH2, -C(=0)NHRss, -C(=0)NRss 2, -C(=0)RSM,
-NHC(=0)Rss, -NRSNC(=0)Rss,
-C(=0)Rss,
-CN, or -N02.
(201) A compound according to any one of (1) to (199), wherein each -RS3C is independently:
-Rss,
-F, -CI, -Br, -I,
-OH, -ORss,
Figure imgf000047_0001
-NH2, -NHRSS, -NRSS2, -RSM,
-C(=0)OH, -C(=0)ORss, -OC(=0)Rss,
-C(=0)NH2, -C(=0)NHRss, -C(=0)NRss 2, -C(=0)RSM,
-NHC(=0)Rss, -NRSNC(=0)Rss,
-C(=0)Rss,
-CN, or -N02.
(202) A compound according to any one of (1) to (199), wherein each -RS3C is independently:
-Rss,
-F, -CI, -Br, -I,
-OH, -ORss,
-CF3, -OCF3,
-NH2, -NHRSS, -NRSS2, -RSM,
-CN, or -N02. (203) A compound according to any one of (1) to (199), wherein each -RS3C is independently:
-Rss,
-F, -CI, -Br, -I,
-OH, -ORss,
-CF3, -OCFs,
-NH2, -NHRSS, -NRSS2, or -RSM. The Groups -RS2N and -RS3N
(204) A compound according to any one of (1) to (203), wherein each -RS2N and each -RS3N is independently:
-Rss,
-C(=0)Rss,
-C(=0)ORss,
-C(=0)NH2, -C(=0)NHRss, -C(=0)NRss 2, -C(=0)RSM, or
-S(=0)2Rss.
(205) A compound according to any one of (1) to (203), wherein each -RS2N and each -RS3N is independently -Rss or -C(=0)Rss.
(206) A compound according to any one of (1) to (203), wherein each -RS2N and each -RS3N is independently -Rss. The Group -Ls-
(207) A compound according to any one of (1) to (206), wherein each -Ls-, if present, is independently -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, or -CH2CH2CH2-.
(208) A compound according to any one of (1) to (206), wherein each -Ls-, if present, is independently -CH2-, -CH(CH3)-, -C(CH3)2-, or -CH2CH2-.
(209) A compound according to any one of (1) to (206), wherein each -Ls-, if present, is independently -CH2-, -CH(CH3)-, or -C(CH3)2-.
(210) A compound according to any one of (1) to (206), wherein each -Ls-, if present, is independently -CH2- or -CH2CH2-. (211) A compound according to any one of (1) to (206), wherein each -Ls-, if present, is -CH2-. The Group -R'
(212) A compound according to any one of (1) to (21 1), wherein each -R , if present, is independently linear or branched saturated d_4alkyl, phenyl, or -Lss-phenyl, wherein said Ci_4alkyl group is unsubstituted, and each of said phenyl groups is unsubstituted.
(213) A compound according to any one of (1) to (21 1), wherein each -R , if present, is linear or branched saturated Ci-4alkyl, wherein said Ci-4alkyl group is optionally substituted with one or more groups independently selected from -OH, -ORsss, -NH2, -NHRSSS, and -NRSSS 2.
(214) A compound according to any one of (1) to (21 1), wherein each -Rss, if present, is linear or branched saturated Ci-4alkyl, wherein said Ci-4alkyl group is unsubstituted.
(215) A compound according to any one of (1) to (21 1), wherein each -Rss, if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
(216) A compound according to any one of (1) to (21 1), wherein each -Rss, if present, is independently -Me, -Et, -nPr, or -iPr.
(217) A compound according to any one of (1) to (21 1), wherein each -Rss, if present, is independently -Me or -Et. (218) A compound according to any one of (1) to (21 1), wherein each -Rss, if present, is -Me.
The Group -Rsss (219) A compound according to any one of (1) to (218), wherein each -Rsss, if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
(220) A compound according to any one of (1) to (218), wherein each -Rsss, if present, is independently -Me, -Et, -nPr, or -iPr.
(221) A compound according to any one of (1) to (218), wherein each -Rsss, if present, is independently -Me or -Et.
(222) A compound according to any one of (1) to (218), wherein each -Rsss, if present, is -Me. The Group -Lss-
(223) A compound according to any one of (1) to (222), wherein -Lss-, if present, is independently -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, or -CH2CH2CH2-.
(224) A compound according to any one of (1) to (222), wherein -Lss-, if present, is independently -CH2-, -CH(CH3)-, -C(CH3)2-, or -CH2CH2-. (225) A compound according to any one of (1) to (222), wherein -Lss-, if present, is independently -CH2-, -CH(CH3)-, or -C(CH3)2-.
(226) A compound according to any one of (1) to (222), wherein -Lss-, if present, is independently -CH2- or -CH2CH2-.
(227) A compound according to any one of (1) to (222), wherein -Lss-, if present, is -CH2-. The Group -RSN (228) A compound according to any one of (1) to (227), wherein each -RSN, if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
(229) A compound according to any one of (1) to (227), wherein each -RSN, if present, is independently -Me, -Et, -nPr, or -iPr.
(230) A compound according to any one of (1) to (227), wherein each -RSN, if present, is independently -Me or -Et.
(231) A compound according to any one of (1) to (227), wherein each -RSN, if present, is -Me.
The Group -RSM
(232) A compound according to any one of (1) to (231), wherein each -RSM, if present, is independently azetidino, pyrrolidino, piperidino, piperizino, (N-Ci.4alkyl)-piperizino,
(N-Ci_4alkyl-C(=0))-piperizino, or morpholino; and is optionally substituted with one or more groups selected from linear or branched saturated Ci-4alkyl.
(233) A compound according to any one of (1) to (231), wherein each -RSM, if present, is independently pyrrolidino, piperidino, piperizino, (N-Ci_4alkyl)-piperizino,
(N-Ci-4alkyl-C(=0))-piperizino, or morpholino. The Group -QE
(234) A compound according to any one of (1) to (233), wherein -Q if present, is -Q B1
(235) A compound according to any one of (1) to (233), wherein -Q if present, is -Q B2
(236) A compound according to any one of (1) to (233), wherein -Q if present, is -Q B3
(237) A compound according to any one of (1) to (233), wherein -Q if present, is -Q B4
(238) A compound according to any one of (1) to (233), wherein -Q' if present, is -Q B5
(239) A compound according to any one of (1) to (233), wherein -Q if present, is -Q
(240) A compound according to any one of (1) to (233), wherein -Q if present, is -Q
The Group -Q B1
(241) A compound according to any one of (1) to (240), wherein -QB , if present,
(242) A compound according to any one of (1) to (240), wherein -Q , if present, is -ORQB . The Group -Q B2
(243) A compound according to any one of (1) to (242), wherein -Q , if present, is -NH2
(244) A compound according to any one of (1) to (242), wherein -Q , if present, is independently -NHRQB , -NRQB 2, or -NRQB2RQB3.
The Group -Q B3
(245) A compound according to any one of (1) to (244), wherein -Q , if present, is -NHC(=0)RQB .
(246) A compound according to any one of (1) to (244), wherein -Q , if present, is -NRQB C(=0)RQB . The Group -QB5
(247) A compound according to any one of (1) to (246), wherein -Q , if present, is -S(=0)2NH2.
(248) A compound according to any one of (1) to (246), wherein -QB5, if present, is independently -S(=0)2NRQB , -S(=0)2NRQB 2, or -S(=0)2NRQB2RQB3.
The Group -Q B7
(249) A compound according to any one of (1) to (248), wherein -QB7, if present, is independently -F, -CI, or -Br.
(250) A compound according to any one of (1) to (248), wherein -QB7, if present, is independently -F or -CI.
(251) A compound according to any one of (1) to (248), wherein -QB7, if present, is -F.
(252) A compound according to any one of (1) to (248), wherein -QB7, if present, is -CI.
The Group -RQB
(253) A compound according to any one of (1) to (252), wherein each -R , if present, is independently linear or branched saturated d_4alkyl, phenyl, or -LQB-phenyl, wherein said Ci_4alkyl group is unsubstituted, and each of said phenyl groups is unsubstituted.
(254) A compound according to any one of (1) to (252), wherein each -R , if present, linear or branched saturated C -4alkyl, wherein said C -4alkyl group is optionally substituted with one or more groups independently selected from -OH, -ORQBB, -NH2, -NHRQBB, and -NRQBB 2.
(255) A compound according to any one of (1) to (252), wherein each -R , if present, is linear or branched saturated Ci-4alkyl, wherein said Ci-4alkyl group is unsubstituted. (256) A compound according to any one of (1) to (252), wherein each -R , if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
(257) A compound according to any one of (1) to (252), wherein each -R , if present, is independently -Me, -Et, -nPr, or -iPr. (258) A compound according to any one of (1) to (252), wherein each -RQB , if present, is independently -Me or -Et.
(259) A compound according to any one of (1) to (252), wherein each -RQB , if present, is -Me.
The Group -LQB-
(260) A compound according to any one of (1) to (259), wherein -LQB-, if present, is independently -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, or -CH2CH2CH2-.
(261) A compound according to any one of (1) to (259), wherein -LQB-, if present, is independently -CH2-, -CH(CH3)-, -C(CH3)2-, or -CH2CH2-.
(262) A compound according to any one of (1) to (259), wherein -LQB-, if present, is independently -CH2-, -CH(CH3)-, or -C(CH3)2-.
(263) A compound according to any one of (1) to (259), wherein -LQB-, if present, is independently -CH2- or -CH2CH2-.
(264) A compound according to any one of (1) to (259), wherein -LQB-, if present, is -CH2-. The Group -RQBB
(265) A compound according to any one of (1) to (264), wherein each -RQBB, if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
(266) A compound according to any one of (1) to (264), wherein each -RQBB, if present, is independently -Me, -Et, -nPr, or -iPr.
(267) A compound according to any one of (1) to (264), wherein each -RQBB, if present, is independently -Me or -Et. (268) A compound according to any one of (1) to (264), wherein each -RQBB, if present, is -Me. The Group -NR R'
(269) A compound according to any one of (1) to (268), wherein each -NRQB2RQB3, if present, is independently azetidino, pyrrolidino, piperidino, piperizino,
(N-Ci_4alkyl)-piperizino, (N-Ci_4alkyl-C(=0))-piperizino, or morpholino; and is optionally substituted with one or more groups selected from linear or branched saturated Ci-4alkyl.
(270) A compound according to any one of (1) to (268), wherein each -NRQB2RQB3, if present, is independently pyrrolidino, piperidino, piperizino, (N-Ci_4alkyl)-piperizino, (N-Ci-4alkyl-C(=0))-piperizino, or morpholino.
The Group -T
(271) A compound according to any one of (1) to (270), wherein -T is -H.
(272) A compound according to any one of (1) to (270), wherein -T is -RT. The Group -RT (273) A compound according to any one of (1) to (272), wherein -RT, if present, is independently -RTA, -C(=0)-RTB, or -LT-C(=0)-RTB.
(274) A compound according to any one of (1) to (272), wherein -RT, if present, is -R TA (275) A compound according to any one of (1) to (272), wherein -RT, if present, is independently -C(=0)-RTB or -LT-C(=0)-RTB.
(276) A compound according to any one of (1) to (272), wherein -RT, if present, is
-C(=0)-RTB.
(277) A compound according to any one of (1) to (272), wherein -RT, if present, is -LT-C(=0)-RTB.
(278) A compound according to any one of (1) to (272), wherein -RT, if present, is independently -LT-C(=0)-NH2, -LT-C(=0)-NHRTN , -LT-C(=0)-NRTN RTN2, or
-LTA-C(=0)-NRTN3RTN4.
(279) A compound according to any one of (1) to (272), wherein -RT, if present, is independently -LT-C(=0)-NH2, -LT-C(=0)-NHRTN , or -LT-C(=0)-NRTN RTN2. The Group -RTA
(280) A compound according to any one of (1) to (279), wherein -R , if present, is independently linear or branched saturated Ci-4alkyl, phenyl, or -LTA-phenyl, wherein said Ci-4alkyl group is unsubstituted, and each of said phenyl groups is unsubstituted.
(281) A compound according to any one of (1) to (279), wherein -R , if present, is linear or branched saturated Ci-4alkyl, wherein said Ci-4alkyl group is optionally substituted with one or more groups independently selected from from -OH, -ORTAA, -NH2, -NHRTAA, and
(282) A compound according to any one of (1) to (279), wherein -R , if present, is linear or branched saturated Ci-4alkyl, wherein said Ci-4alkyl group is unsubstituted. (283) A compound according to any one of (1) to (279), wherein -R , if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
(284) A compound according to any one of (1) to (279), wherein -R , if present, is independently -Me, -Et, -nPr, or -iPr.
(285) A compound according to any one of (1) to (279), wherein -RTA, if present, is -Me.
(286) A compound according to any one of (1) to (279), wherein -R , if present,
(287) A compound according to any one of (1) to (279), wherein -R , if present, is -nPr.
(288) A compound according to any one of (1) to (279), wherein -R , if present, is -iPr.
The Group -R
(289) A compound according to any one of (1) to (288), wherein each -RTAA, if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
(290) A compound according to any one of (1) to (288), wherein each -R , if present, is independently -Me, -Et, -nPr, or -iPr.
(291) A compound according to any one of (1) to (288), wherein each -R , if present, is independently -Me or -Et. (292) A compound according to any one of (1) to (288), wherein each -R , if present, is -Me. The Group -L -
(293) A compound according to any one of (1) to (292), wherein -LTA-, if present, is independently -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, or -CH2CH2CH2-.
(294) A compound according to any one of (1) to (292), wherein -LTA-, if present, is independently -CH2-, -CH(CH3)-, -C(CH3)2-, or -CH2CH2-.
(295) A compound according to any one of (1) to (292), wherein -LTA-, if present, is independently -CH2-, -CH(CH3)-, or -C(CH3)2-.
(296) A compound according to any one of (1) to (292), wherein -LTA-, if present, is independently -CH2- or -CH2CH2-.
(297) A compound according to any one of (1) to (292), wherein -LTA-, if present, is -CH2-. The Group -RTB
(298) A compound according to any one of (1) to (297), wherein each -RTB, if present, is independently linear or branched saturated Ci-4alkyl, phenyl, or -LTN -phenyl, wherein said Ci_4alkyl group is unsubstituted, and each of said phenyl groups is unsubstituted. (299) A compound according to any one of (1) to (297), wherein each -RTB, if present, is linear or branched saturated C -4alkyl, wherein said C -4alkyl group is optionally substituted with one or more groups independently selected from -OH, -ORTBB, -NH2, -NHRTBB, and -NRTBB 2. (300) A compound according to any one of (1) to (297), wherein each -RTB, if present, is linear or branched saturated Ci-4alkyl, wherein said Ci-4alkyl group is unsubstituted.
(301) A compound according to any one of (1) to (297), wherein each -RTB, if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
(302) A compound according to any one of (1) to (297), wherein each -RTB, if present, is independently -Me, -Et, -nPr, or -iPr.
(303) A compound according to any one of (1) to (297), wherein each -RTB, if present, is independently -Me or -Et. (304) A compound according to any one of (1) to (297), wherein each -R , if present, is -Me.
The Group -RTBB
(305) A compound according to any one of (1) to (304), wherein each -RTBB, if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
(306) A compound according to any one of (1) to (304), wherein each -RTBB, if present, is independently -Me, -Et, -nPr, or -iPr.
(307) A compound according to any one of (1) to (304), wherein each -RTBB, if present, is independently -Me or -Et. (308) A compound according to any one of (1) to (304), wherein each -RTBB, if present, is -Me.
The Group -LTB- (309) A compound according to any one of (1) to (308), wherein -LTB-, if present, is independently -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, or -CH2CH2CH2-.
(310) A compound according to any one of (1) to (308), wherein -LTB-, if present, is independently -CH2-, -CH(CH3)-, -C(CH3)2-, or -CH2CH2-.
(311) A compound according to any one of (1) to (308), wherein -LTB-, if present, is independently -CH2-, -CH(CH3)-, or -C(CH3)2-. (312) A compound according to any one of (1) to (308), wherein -LTB-, if present, is independently -CH2- or -CH2CH2-.
(313) A compound according to any one of (1) to (308), wherein -LTB-, if present, is -CH2-. The Group -RTN
(314) A compound according to any one of (1) to (313), wherein each -RTN , if present, is independently linear or branched saturated d_4alkyl, phenyl, or -LTN -phenyl, wherein said Ci_4alkyl group is unsubstituted, and each of said phenyl groups is unsubstituted. (315) A compound according to any one of (1) to (313), wherein each -RTN , if present, is linear or branched saturated Ci-4alkyl, wherein said Ci-4alkyl is optionally substituted with one or more groups independently selected from -OH, -ORTN A, -NH2, -NHRTN A, and -NRTN1A 2.
(316) A compound according to any one of (1) to (313), wherein each -RTN , if present, is linear or branched saturated Ci-4alkyl, wherein said Ci-4alkyl group is unsubstituted.
(317) A compound according to any one of (1) to (313), wherein each -RTN , if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
(318) A compound according to any one of (1) to (313), wherein each -RTN , if present, is independently -Me, -Et, -nPr, or -iPr. (319) A compound according to any one of (1) to (313), wherein each -RTN , if present, is independently -Me or -Et.
(320) A compound according to any one of (1) to (313), wherein each -R , if present, is -Me.
The Group -R TN1A
(321) A compound according to any one of (1) to (320), wherein each -RTN A, if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
(322) A compound according to any one of (1) to (320), wherein each -RTN A, if present, is independently -Me, -Et, -nPr, or -iPr.
(323) A compound according to any one of (1) to (320), wherein each -RTN A, if present, is independently -Me or -Et.
(324) A compound according to any one of (1) to (320), wherein each -RTN A, if present, is -Me. The Group -LTN -
(325) A compound according to any one of (1) to (324), wherein -LTN1-, if present, is independently -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, or -CH2CH2CH2-. (326) A compound according to any one of (1) to (324), wherein -L -, if present, is independently -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH3)CH2-, or -CH2CH(CH3)-.
(327) A compound according to any one of (1) to (324), wherein -LTN1-, if present, is independently -CH2-, -CH(CH3)-, -C(CH3)2-, or -CH2CH2-.
(328) A compound according to any one of (1) to (324), wherein -LTN1-, if present, is independently -CH2-, -CH(CH3)-, or -C(CH3)2-. (329) A compound according to any one of (1) to (324), wherein -LTN1-, if present, is independently -CH2- or -CH2CH2-.
(330) A compound according to any one of (1) to (324), wherein -LTN1-, if present, is independently -CH2-.
The Group -RTN2
(331) A compound according to any one of (1) to (330), wherein -RTN2, if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
(332) A compound according to any one of (1) to (330), wherein -RTN2, if present, is independently -Me, -Et, -nPr, or -iPr.
(333) A compound according to any one of (1) to (330), wherein -RTN2, if present, is independently -Me or -Et.
(334) A compound according to any one of (1) to (330), wherein -RTN2, if present, is -Me. The Group -NRTN3RTN4
(335) A compound according to any one of (1) to (334), wherein -NRTN3RTN4, if present, is independently azetidino, pyrrolidino, piperidino, piperizino, (N-Ci_4alkyl)-piperizino, (N-Ci-4alkyl-C(=0))-piperizino, or morpholino; and is optionally substituted with one or more groups selected from linear or branched saturated C -4alkyl.
(336) A compound according to any one of (1) to (334), wherein -NRTN3RTN4, if present, is independently pyrrolidino, piperidino, piperizino, (N-Ci_4alkyl)-piperizino,
(N-Ci_4alkyl-C(=0))-piperizino, or morpholino. The Group -LT-
(337) A compound according to any one of (1) to (336), wherein each -LT-, if present, is independently -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, or -CH2CH2CH2-.
(338) A compound according to any one of (1) to (336), wherein each -LT-, if present, is independently -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH3)CH2-, or -CH2CH(CH3)-. (339) A compound according to any one of (1) to (336), wherein each -LT-, if present, is independently -CH2-, -CH(CH3)-, -C(CH3)2-, or -CH2CH2-.
(340) A compound according to any one of (1) to (336), wherein each -LT-, if present, is independently -CH2-, -CH(CH3)-, or -C(CH3)2-.
(341 ) A compound according to any one of (1) to (336), wherein each -LT-, if present, is independently -CH2- or -CH2CH2-.
(342) A compound according to any one of (1) to (336), wherein each -LT-, if present, is independently -CH2-.
The Group -V
(343) A compound according to any one of (1) to (342), wherein -V is -H.
(344) A compound according to any one of (1) to (342), wherein -V is -Rv. The Group -Rv (345) A compound according to any one of (1) to (344), wherein -Rv, if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, or -tBu.
(346) A compound according to any one of (1) to (344), wherein -Rv, if present, is independently -Me, -Et, -nPr, or -iPr.
(347) A compound according to any one of (1) to (344), wherein -Rv, if present, is independently -Me or -Et.
(348) A compound according to any one of (1) to (344), wherein -Rv, if present, is -Me.
(349) A compound according to any one of (1) to (344), wherein -Rv, if present, is -Et. Certain Preferred Compounds
(350) A compound according to (1 which is a compound of the following formula,
Figure imgf000061_0001
or a tautomer thereof;
or a pharmaceutically acceptable salt, hydrate, or solvate of the foregoing.
(351) A compound according to (1 , which is a compound of the following formula,
Figure imgf000061_0002
or a tautomer thereof;
or a pharmaceutically acceptable salt, hydrate, or solvate of the foregoing.
(351) A compound according to (1 which is a compound of the following formula,
Figure imgf000061_0003
or a tautomer thereof;
or a pharmaceutically acceptable salt, hydrate, or solvate of the foregoing. Combinations
It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination. All combinations of the embodiments pertaining to the chemical groups represented by the variables (e.g., -J, -Q, -V, -T, -RJE, -RJE , -RJE2, -RJ1
DJE6 DJE7 DJE8 JE DK1C DK2C DK2N DK3C DK3N ι K nKK ι KK
-RJE4, - RJE5, - fx , - fx , -fx , -L -, -fx , - fx , -fx , - fx , - fx , -L -, -fx , - L - ,
-RKKK _ KM _pJ 1 _ JN1A _|_JN1_ _pJ 2 _ JN2A _|_JN2_ _|^ JN3 JN4 _QA _QB _RQA1
- RKN,
_RQA2 _ QA3 DQA4 DQA5 DQA6 DQA7 DQA8 ι OA DS1C DS2C DS2N DS3C DS3N DSS
, - fx , -fx , -fx , - fx , - fx , -L -, -fx , -fx , - fx , -fx , - fx , -fx
-LS- , - RSSS |_SS-, -RSN, -RSM, -QB , -QB2, -QB3, -QB4, -QB5, -QB6, -QB7, -RQB , -LQB-, -RQBB,
,QB2DQB3 nT DTA ι TA DTAA nTB ι TB DTBB DTN1 ι TN1 DTN1A DTN2
-NRTN3RTN4, -LT-, -Rv, etc.) are specifically embraced by the present invention and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace compounds that are stable compounds (i.e., compounds that can be isolated, characterised, and tested for biological activity). In addition, all sub-combinations of the chemical groups listed in the
embodiments describing such variables are also specifically embraced by the present invention and are disclosed herein just as if each and every such sub-combination of chemical groups was individually and explicitly disclosed herein.
Substantially Purified Forms One aspect of the present invention pertains to DHP compounds, as described herein, in substantially purified form and/or in a form substantially free from contaminants.
In one embodiment, the substantially purified form is at least 50% by weight, e.g., at least 60% by weight, e.g., at least 70% by weight, e.g., at least 80% by weight, e.g., at least 90% by weight, e.g., at least 95% by weight, e.g., at least 97% by weight, e.g., at least 98% by weight, e.g., at least 99% by weight.
Unless specified, the substantially purified form refers to the compound in any
stereoisomeric or enantiomeric form. For example, in one embodiment, the substantially purified form refers to a mixture of stereoisomers, i.e., purified with respect to other compounds. In one embodiment, the substantially purified form refers to one
stereoisomer, e.g., optically pure stereoisomer. In one embodiment, the substantially purified form refers to a mixture of enantiomers. In one embodiment, the substantially purified form refers to a equimolar mixture of enantiomers (i.e., a racemic mixture, a racemate). In one embodiment, the substantially purified form refers to one enantiomer, e.g., optically pure enantiomer. ln one embodiment, the contaminants represent no more than 50% by weight, e.g., no more than 40% by weight, e.g., no more than 30% by weight, e.g., no more than 20% by weight, e.g., no more than 10% by weight, e.g., no more than 5% by weight, e.g., no more than 3% by weight, e.g., no more than 2% by weight, e.g., no more than 1 % by weight.
Unless specified, the contaminants refer to other compounds, that is, other than stereoisomers or enantiomers. In one embodiment, the contaminants refer to other compounds and other stereoisomers. In one embodiment, the contaminants refer to other compounds and the other enantiomer.
In one embodiment, the substantially purified form is at least 60% optically pure (i.e., 60% of the compound, on a molar basis, is the desired stereoisomer or enantiomer, and 40% is the undesired stereoisomer(s) or enantiomer), e.g., at least 70% optically pure, e.g., at least 80% optically pure, e.g., at least 90% optically pure, e.g., at least 95% optically pure, e.g., at least 97% optically pure, e.g., at least 98% optically pure, e.g., at least 99% optically pure.
Isomers
Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diastereoisomeric, epimeric, atropic, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and l-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; a- and β-forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as "isomers" (or "isomeric forms"). A reference to a class of structures may well include structurally isomeric forms falling within that class (e.g., Ci-7alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl). However, reference to a specifc group or substitution pattern is not intended to include other structural (or constitutional isomers) which differ with respect to the connections between atoms rather than by positions in space. For example, a reference to a methoxy group, -OCH3, is not to be construed as a reference to its structural isomer, a
hydroxymethyl group, -CH2OH. Similarly, a reference to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl.
The above exclusion does not pertain to tautomeric forms, for example, keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime,
thioketone/enethiol, N-nitroso/hydroxyazo, and nitro/aci-nitro.
Figure imgf000064_0001
keto enol enolate
Note that specifically included in the term "isomer" are compounds with one or more isotopic substitutions. For example, H may be in any isotopic form, including H, 2H (D), and 3H (T); C may be in any isotopic form, including 2C, 3C, and 4C; O may be in any isotopic form, including 60 and 80; and the like.
Unless otherwise specified, a reference to a particular compound includes all such isomeric forms, including mixtures (e.g., racemic mixtures) thereof. Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner.
Salts It may be convenient or desirable to prepare, purify, and/or handle a corresponding salt of the compound, for example, a pharmaceutically-acceptable salt. Examples of
pharmaceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sci.. Vol. 66, pp. 1-19. For example, if the compound is anionic, or has a functional group which may be anionic (e.g., -COOH may be -COO"), then a salt may be formed with a suitable cation.
Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na+ and K+, alkaline earth cations such as Ca2+ and Mg2+, and other cations such as Al3+. Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH4 +) and substituted ammonium ions (e.g., NH3R+, NH2R2 +, NHR3 +, NR4 +). Examples of some suitable substituted ammonium ions are those derived from:
ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH3)4 +.
If the compound is cationic, or has a functional group which may be cationic (e.g., -NH2 may be -NH3 +), then a salt may be formed with a suitable anion. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous. Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.
Examples of some preferred salts suitable for amines (such as the DHP compounds described herein) include: chloride, sulfate, bromide, mesylate, maleate, citrate, tartrate, phosphate, acetate, and iodide.
Unless otherwise specified, a reference to a particular compound also includes salt forms thereof.
Solvates and Hydrates
It may be convenient or desirable to prepare, purify, and/or handle a corresponding solvate of the compound. The term "solvate" is used herein in the conventional sense to refer to a complex of solute (e.g., compound, salt of compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.
Unless otherwise specified, a reference to a particular compound also includes solvate and hydrate forms thereof.
Chemically Protected Forms
It may be convenient or desirable to prepare, purify, and/or handle the compound in a chemically protected form. The term "chemically protected form" is used herein in the conventional chemical sense and pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions under specified conditions (e.g., pH, temperature, radiation, solvent, and the like). In practice, well known chemical methods are employed to reversibly render unreactive a functional group, which otherwise would be reactive, under specified conditions. In a chemically protected form, one or more reactive functional groups are in the form of a protected or protecting group (also known as a masked or masking group or a blocked or blocking group). By protecting a reactive functional group, reactions involving other unprotected reactive functional groups can be performed, without affecting the protected group; the protecting group may be removed, usually in a subsequent step, without substantially affecting the remainder of the molecule. See, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts; 4th Edition; John Wiley and Sons, 2006).
A wide variety of such "protecting," "blocking," or "masking" methods are widely used and well known in organic synthesis. For example, a compound which has two nonequivalent reactive functional groups, both of which would be reactive under specified conditions, may be derivatized to render one of the functional groups "protected," and therefore unreactive, under the specified conditions; so protected, the compound may be used as a reactant which has effectively only one reactive functional group. After the desired reaction (involving the other functional group) is complete, the protected group may be "deprotected" to return it to its original functionality.
For example, a hydroxy group may be protected as an ether (-OR) or an ester
(-OC(=0)R), for example, as: a t-butyl ether; a benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether; a tnmethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (-OC(=0)CH3, -OAc).
For example, an aldehyde or ketone group may be protected as an acetal (R-CH(OR)2) or ketal (R2C(OR)2), respectively, in which the carbonyl group (>C=0) is converted to a diether (>C(OR)2), by reaction with, for example, a primary alcohol. The aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.
For example, an amine group may be protected, for example, as an amide (-NRCO-R) or a urethane (-NRCO-OR), for example, as: a methyl amide (-NHCO-CH3); a
benzyloxycarbonyl amide (-NHCO-OCH2C6H5, -NH-Cbz); as a t-butoxycarbonyl amine (-NHCO-OC(CH3)3, -NH-Boc); a 2-biphenyl-2-propoxycarbonyl amine
(-NHCO-OC(CH3)2C6H4C6H5, -NH-Bpoc), as a 9-fluorenylmethoxycarbonyl amine
(-NH-Fmoc), as a 6-nitroveratryloxycarbonyl amine (-NH-Nvoc), as a
2-trimethylsilylethyloxycarbonyl amine (-NH-Teoc), as a 2,2,2-trichloroethyloxycarbonyl amine (-NH-Troc), as an allyloxycarbonyl amine (-NH-Alloc), as a
2(-phenylsulfonyl)ethyloxycarbonyl amine (-NH-Psec); or, in suitable cases (e.g., cyclic amines), as a nitroxide radical (>Ν-0·).
For example, a carboxylic acid group may be protected as an ester for example, as: a Ci-7alkyl ester (e.g., a methyl ester; a t-butyl ester); a Ci_7haloalkyl ester (e.g., a C -7trihaloalkyl ester); a triCi.7alkylsilyl-Ci.7alkyl ester; or a C5_2oaryl-Ci_7alkyl ester (e.g., a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as a methyl amide.
For example, a thiol group may be protected as a thioether (-SR), for example, as: a benzyl thioether; an acetamidomethyl ether (-S-CH2NHC(=0)CH3).
Prodrugs
It may be convenient or desirable to prepare, purify, and/or handle the compound in the form of a prodrug. The term "prodrug," as used herein, pertains to a compound which, when metabolised (e.g., in vivo), yields the desired active compound. Typically, the prodrug is inactive, or less active than the desired active compound, but may provide advantageous handling, administration, or metabolic properties. For example, some prodrugs are esters of the active compound (e.g., a physiologically acceptable metabolically labile ester). During metabolism, the ester group (-C(=0)OR) is cleaved to yield the active drug. Such esters may be formed by esterification, for example, of any of the carboxylic acid groups (-C(=0)OH) in the parent compound, with, where appropriate, prior protection of any other reactive groups present in the parent compound, followed by deprotection if required.
General Chemical Synthesis
Methods for the chemical synthesis of compounds of the present invention are described herein. These and/or other well-known methods may be modified and/or adapted in known ways in order to facilitate the synthesis of additional compounds within the scope of the present invention.
In one approach, DHP compounds having a 2-carboxylate group may be prepared by a method that involves Lewis acid mediated cyclisation of an amide (7) to give the corresponding DHP compound (8). A range of Lewis acids may be used to achieve this, for example, boron trifluoride dietherate and titanium tetrachloride.
An example of such a method is illustrated in the following scheme.
Scheme 1
Figure imgf000068_0001
The amides (7) may be prepared, for example, by reaction of the corresponding dehydro- compounds (6) with diacetoxy acetyl chloride, for example, in a method analogous to that described in Cook et al., 2009, where the amine is reacted with the acid chloride using a biphasic mixture of water and an organic solvent in the presence of a base.
An example of such a method is illustrated in the following scheme.
Scheme 2
Figure imgf000068_0002
6
The dehydro compounds (6) may be prepared, for example, from the amino derivative (5) by reaction with a halogenating agent, such as N-chlorosuccinimide or tert-butyl hypochlorite and a base, such as DABCO or DBU, or an oxidant, such as DDQ, for example, in a method analogous to that described in Shimohiagashi et al., 1983. An example of such a method is illustrated in the following scheme.
Scheme 3
Figure imgf000069_0001
The amine (5) may be prepared from the protected amine (4), for example, using known deprotection methods, for example, by reaction of the tert-butyl carbamate protected amine with an acid, as described in Dutton et al., 2003.
An example of such a method is illustrated in the following scheme, wherein (P) denotes a protecting group.
Scheme 4
Figure imgf000069_0002
The protected amine (4) may be prepared, for example, by reaction of the protected amine (3) using a base and a suitable alkyi halide or halo substituted alkyi derivative, for example, as described in Ohmura et al., 2008. In this reaction, the tert-butyl carboxamide group is preferred, but alternative protecting groups such as carboxybenzyl may also be used.
An example of such a method is illustrated in the following scheme, wherein (P) denotes a protecting group.
Figure imgf000069_0003
The protected amine (3) may be obtained from commercial sources, or may be prepared, for example, from the corresponding amine or protonated amine salt (2) using well known conditions for the protection of amines, for example, as described in Ohmura et al., 2008. An example of such a method is illustrated in the following scheme, wherein (P) denotes a protecting group.
Scheme 6
Figure imgf000070_0001
The amine (2) may be obtained from commercial sources, or may be prepared from the amino acid using well known esterification techniques, for example, as described in Ohmura et al., 2008.
An example of such a method is illustrated in the following scheme.
Figure imgf000070_0002
In another approach, the amine (5) may be prepared by reductive amination, for example, in a manner similar to the method described by Fitch et al., 2005, where the amine is reacted with a range of aldehydes, followed by treatment with a suitable reducing agent, such as sodium borohydride. An example of such a method is illustrated in the following scheme.
Scheme 8
Figure imgf000070_0003
For DHP compounds having a 2-carboxylic acid group, the ester (8) may be hydrolysed under basic conditions with a suitable base, such as an aqueous solution of sodium hydroxide, followed by acidic workup to obtain the carboxylic acid, for example as described in Krasnov et al., 2008.
An example of such a method is illustrated in the following scheme.
Scheme 9
Figure imgf000071_0001
For DHP compounds having a 2-carboxamide group, the amide (10) may be obtained by reaction of the ester (8) with ammonia, or by reaction of the acid with a suitable amine using well-known coupling conditions, for example, as described in Feng et al., 2010.
An example of such a method is illustrated in the following scheme.
Scheme 10
Figure imgf000071_0002
In another approach, the ether (11 ) may be obtained from the alcohol (9) by reaction with an alky halide, such as methyl iodide, using, for example, mild basic conditions, for example, as described in Devert et al., 2010.
An example of such an approach is shown in the following scheme.
Scheme 11
Figure imgf000071_0003
8 11 For DHP compounds without an N-substituent, the corresponding N-unsubstituted amide (12) may be reacted with a suitable Lewis acid, such as titanium tetrachloride, to give the corresponding amide (13).
An example of such an approach is shown in the following scheme.
Scheme 12
Figure imgf000072_0001
12 13
The amide (12) may be prepared from the corresponding amine (14), for example, by reaction with diacetoxy acetyl chloride under basic conditions, for example, as described in Cook et al., 2009. The amine (14) may be prepared from the ester (15) by the use of dehydrogenation conditions, for example, as described in Shimohiagashi et al., 1983.
An example of such an approach is shown in the following scheme.
Scheme 13
Figure imgf000072_0002
15 14
Acylation
Figure imgf000072_0003
12 Compositions
One aspect of the present invention pertains to a composition (e.g., a pharmaceutical composition) comprising a DHP compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.
In one embodiment, the composition further comprises one or more (e.g., 1 , 2, 3, 4) additional therapeutic agents, as described herein. Another aspect of the present invention pertains to a method of preparing a composition (e.g., a pharmaceutical composition) comprising admixing a DHP compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.
Another aspect of the present invention pertains to a method of preparing a composition (e.g., a pharmaceutical composition) comprising admixing a DHP compound, as described herein; one or more (e.g., 1 , 2, 3, 4) additional therapeutic agents, as described herein; and a pharmaceutically acceptable carrier, diluent, or excipient.
Uses
The DHP compounds described herein are useful, for example, in methods of improving memory and/or cognitive function, and in the treatment of memory-related disorders and cognitive decline. Use as a Nootropic Agent
The DHP compounds described herein are useful as nootropic agents (e.g., memory enhancers; cognitive enhancers), for example, to improve memory and/or cognitive function in a patient.
Thus, one aspect of the present invention pertains to a DHP compound, as described herein, for use in a method of improving memory and/or cognitive function in a patient.
Another aspect of the present invention pertains to use of a DHP compound, as described herein, in the manufacture of a medicament for improving memory and/or cognitive function in a patient.
Another aspect of the present invention pertains to a method of improving memory and/or cognitive function comprising administering to a patient in need of improved memory and/or cognitive function a therapeutically effective amount of a DHP compound, as described herein, preferably in the form of a pharmaceutical composition. Similarly, the DHP compounds described herein are useful in methods of:
potentiating excitatory synaptic transmission;
directly regulating excitatory synapses;
induction of long-term potentiation;
lowering the threshold for long-term potentiation induction;
induction of long-term potentiation in the CA1 ;
induction of long-term potentiation in the CA3;
enhancing glutamatergic synapses;
modulating AM PA receptor function;
positively modulating AMPA receptor function;
indirectly modulating signalling cascades initiated by endogenous growth factors;
indirectly modulating signalling cascades initiated by BDNF;
indirectly modulating signalling cascades initiated by NGR;
modulating presynaptic Ca2+ channel function;
modulating R-type voltage-gated Ca2+ channels; and
modulating L-type voltage-gated Ca2+ channels.
Such methods may, for example, comprise the step of contacting a neuron or neurons with an effective amount of a DHP compound, as described herein.
In one embodiment, the method is performed in vitro.
In one embodiment, the method is performed in vivo. In one embodiment, the DHP compound is provided in the form of a pharmaceutically acceptable composition.
Use in Methods of Therapy Another aspect of the present invention pertains to a DHP compound, as described herein, for use in a method of treatment of the human or animal body by therapy, for example, for use a method of treatment of a disorder (e.g., a disease) as described herein. Another aspect of the present invention pertains to a DHP compound, as described herein, in combination with one or more (e.g., 1 , 2, 3, 4) additional therapeutic agents, as described herein, for use in a method of treatment of the human or animal body by therapy, for example, for use a method of treatment of a disorder (e.g., a disease) as described herein. Use in the Manufacture of Medicaments
Another aspect of the present invention pertains to use of a DHP compound, as described herein, in the manufacture of a medicament for treatment, for example, treatment of a disorder (e.g., a disease) as described herein.
In one embodiment, the medicament comprises the DHP compound.
Another aspect of the present invention pertains to use of a DHP compound, as described herein, and one or more (e.g., 1 , 2, 3, 4) additional therapeutic agents, as described herein, in the manufacture of a medicament for treatment, for example, treatment of a disorder (e.g., a disease) as described herein.
In one embodiment, the medicament comprises the DHP compound and the one or more (e.g., 1 , 2, 3, 4) additional therapeutic agents.
Methods of Treatment
Another aspect of the present invention pertains to a method of treatment, for example, of a disorder (e.g., a disease) as described herein, comprising administering to a patient in need of treatment a therapeutically effective amount of a DHP compound, as described herein, preferably in the form of a pharmaceutical composition.
Another aspect of the present invention pertains to a method of treatment, for example, of a disorder (e.g., a disease) as described herein, comprising administering to a patient in need of treatment a therapeutically effective amount of a DHP compound, as described herein, preferably in the form of a pharmaceutical composition, and one or more (e.g., 1 , 2, 3, 4) additional therapeutic agents, as described herein, preferably in the form of a pharmaceutical composition.
Conditions Treated
In one embodiment, the treatment is treatment of a central nervous system (CNS) disorder.
In one embodiment, the treatment is treatment of a neurodegenerative disorder of the central nervous system (CNS). See, e.g., O'Neill et al., 2004.
In one embodiment, the treatment is treatment of memory deficit, for example, deficient memory binding and/or deficient information recall. ln one embodiment, the treatment is treatment of a memory-related disorder.
In one embodiment, the treatment is treatment of a disorder associated with cognitive decline.
In one embodiment, the treatment is treatment of cognitive impairment, for example, mild cognitive impairment (MCI).
In one embodiment, the treatment is treatment of dementia. See, e.g., Akhondzadeh, 1999; Addae et al., 2003; Fitzjohn et al., 2008.
In one embodiment, the treatment is treatment of: senile dementia (see, e.g., Shi-Lei et al., 2002; Palop et al., 2006; Zhang et al., 2008); vascular dementia (see, e.g., Chang et al., 1997; Xu et al., 2012); fronto-temporal lobe dementia (see, e.g., Chang et al., 1997), etc.
In one embodiment, the treatment is treatment of Alzheimer's disease (see, e.g., Harrison et al., 1990; Ikonomovic et al., 1995; Armstrong et al., 1996; Jacob et al., 2007; Chen et al., 2010; Chong et al., 2011).
In one embodiment, the treatment is treatment of a movement disorder. See, e.g., Calabresi et al., 1997.
In one embodiment, the treatment is treatment of Huntington's disease (see, e.g., Gibson et al., 2005; Andre et al., 2006; Maheshwari et al., 2012).
In one embodiment, the treatment is treatment of Parkinson's disease (see, e.g.,
Calabresi et al., 1997; O'Neill et al., 2007). In one embodiment, the treatment is treatment of a mental disability disorder.
In one embodiment, the treatment is treatment of an autism spectrum disorder (see, e.g., Moretti et al., 2006; Bozdagi et al., 2010); fragile-X syndrome; or Rett syndrome (see, e.g., Ivanco et al., 2002; Yun et al., 2011 ; Lanore et al., 2012).
In one embodiment, the treatment is treatment of a mood disorder.
In one embodiment, the treatment is treatment of a depression disorder (see, e.g., O'Neill et al., 2007), for example, major depressive disorder (see, e.g., Holderbach et al., 2007; Gao et al., 201 1). ln one embodiment, the treatment is treatment of a basal-ganglia-related disorder, for example, a basal-ganglia-related disorder where progressive memory decline is symptomatic. In one embodiment, the treatment is treatment of a disease which is ameliorated by inhibiting acetylcholinesterase.
In one embodiment, the treatment is treatment of a disease which is ameliorated by inhibition of methyl-D-aspartate (NMDA).
In one embodiment, the treatment is treatment of: a disease which is ameliorated by potentiating excitatory synaptic transmission; a disease which is ameliorated by directly regulating excitatory synapses; a disease which is ameliorated by induction of long-term potentiation; a disease which is ameliorated by lowering the threshold for long-term potentiation induction; a disease which is ameliorated by induction of long-term
potentiation in the CA1 ; a disease which is ameliorated by induction of long-term potentiation in the CA3; a disease which is ameliorated by enhancing glutamatergic synapses; a disease which is ameliorated by modulating AMPA receptor function; a disease which is ameliorated by positively modulating AMPA receptor function; a disease which is ameliorated by indirectly modulating signalling cascades initiated by endogenous growth factors; a disease which is ameliorated by indirectly modulating signalling cascades initiated by BDNF; a disease which is ameliorated by indirectly modulating signalling cascades initiated by NGR; a disease which is ameliorated by modulating presynaptic Ca2+ channel function; a disease which is ameliorated by modulating R-type voltage-gated Ca2+ channels; or a disease which is ameliorated by modulating L-type voltage-gated Ca2+ channels.
Treatment The term "treatment," as used herein in the context of treating a condition, pertains generally to treatment and therapy, whether of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, alleviation of symptoms of the condition, amelioration of the condition, and cure of the condition. Treatment as a prophylactic measure (i.e. , prophylaxis) is also included. For example, use with patients who have not yet developed the condition, but who are at risk of developing the condition, is encompassed by the term "treatment". For example, treatment of dementia includes the prophylaxis of dementia, reducing the incidence of dementia, reducing the severity of dementia, alleviating the symptoms of dementia, etc. The term "therapeutically-effective amount," as used herein, pertains to that amount of a compound, or a material, composition or dosage form comprising a compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen. Combination Therapies
The term "treatment" includes combination treatments and therapies, in which two or more treatments or therapies are combined, for example, sequentially or simultaneously. For example, the compounds described herein may also be used in combination therapies, e.g., in conjunction with other agents, for example, anti-cholinesterase agents, NMDA receptor antagonists, L-dopamine, etc. Examples of treatments and therapies include, but are not limited to, chemotherapy (the administration of active agents, including, e.g., drugs, antibodies (e.g., as in immunotherapy), prodrugs (e.g., as in photodynamic therapy, GDEPT, ADEPT, etc.); surgery; radiation therapy; photodynamic therapy; gene therapy; and controlled diets.
One aspect of the present invention pertains to a compound as described herein, in combination with one or more additional therapeutic agents, as described below. The particular combination would be at the discretion of the physician who would select dosages using his common general knowledge and dosing regimens known to a skilled practitioner.
The agents (i.e., the compound described herein, plus one or more other agents) may be administered simultaneously or sequentially, and may be administered in individually varying dose schedules and via different routes. For example, when administered sequentially, the agents can be administered at closely spaced intervals (e.g., over a period of 5-10 minutes) or at longer intervals (e.g., 1 , 2, 3, 4 or more hours apart, or even longer periods apart where required), the precise dosage regimen being commensurate with the properties of the therapeutic agent(s).
The agents (i.e., the compound described here, plus one or more other agents) may be formulated together in a single dosage form, or alternatively, the individual agents may be formulated separately and presented together in the form of a kit, optionally with instructions for their use. Additional Therapeutic Agents For Use In Combination Therapy
Drugs which are known to be useful for therapy of the disorders {e.g., diseases) discussed above may be used in combination therapy with a DHP compound as described herein.
Known drugs for the treatment of Alzheimer's disease may be used in combination therapy with a DPH compound as described herein. Examples of such drugs include: cholinesterase inhibitors (e.g., donepezil hydrochloride (Aricept), rivastigmine (Exelon), galantamine (Reminyl)), NM DA receptor antagonists (e.g., memantine (Ebixa)), and non-steroidal anti-inflammatory drugs (e.g., salicylates (such as aspirin (acetylsalicylic acid), diflunisal, salsalate), propionic acid derivatives (such as ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen), acetic acid derivatives (such as indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, nabumetone), enolic acid (oxicam) derivatives (such as piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam), fenamic acid derivatives (such as
mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid), selective COX-2 inhibitors (such as celecoxib, parecoxib, lumiracoxib, sulphonanilides, nimesulide), licofelone, lysine clonixinate).
Known drugs for the treatment of Huntington's disease may be used in combination therapy with a DPH compound as described herein. Examples of such drugs include: tetrabenazine, haloperidol, olanzapine, risperidone, andquetiapine, pimozide, clonidine, sulpiride, propranolol (or another beta-adrenoceptor blocking drug), piracetam, riluzole.
Known dopaminergic drugs for the treatment of Parkinson's disease may be used in combination therapy with a DPH compound as described herein. Examples of such drugs include: dopamine-receptor agonists (e.g., apomorphine hydrochloride,
bromocriptine, cabergoline, pergolide, pramipexole, ropinirole, rotigotine, levodopa), monoamine-oxidase-B inhibitors (e.g., rasagiline, selegiline hydrochloride) and catechol- O-methyltransferase inhibitors (e.g., entacapone, tolcapone, amantadine).
Antipsychotic drugs may be used in the treatment of behavioural and psychological symptoms of dementia, and as such may be used in combination with a DHP compound to give an additive therapeutic benefit. Examples of antipsychotic drugs include: first generation antipsychotic drugs (e.g., chlorpromazine, levomepromazine, promazine, pericyazine pipotiazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine) and second generation antipsychotic drugs (e.g., amisulpride, clozapine, olanzapine, paliperidone, quetiapine, risperidone, aripiprazole). Antidepressants and anticonvulsants may be used in the treatment of behavioural and psychological symptoms of dementia, and as such may be used in combination with a DHP compound to give an additive therapeutic benefit. Examples of antidepressants and anticonvlusants include: tricyclic antidepressants (e.g., amitriptyline hydrochloride, clomipramine hydrochloride, dosulepine hydrochloride, doxepin, imipramine
hydrochloride, lofepramine, nortriptyline, trimipramine), tricyclic-related antidepressants (e.g., mianserin hydrochloride, trazodone hydrochloride), monoamine-oxydase inhibitors (MAOIs) (e.g., phenelzine, isocarboxazid, tranylcypromine, moclobemide), and selective serotonin re-uptake inhibitors (SSRIs) (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine maleate, paroxetine, sertraline).
Hypnotics may be used in the treatment of behavioural and psychological symptoms of dementia, and as such may be used in combination with a DHP compound to give an additive therapeutic benefit. Examples of hypnotics include: benzodiazepines (diazepam, alprazolam, chlordiazepoxide hydrochloride, lorazepam, oxazepam), Z-drugs (zaleplon, Zolpidem, zopiclone), clomethiazole, antihistamines, ethyl alcohol, sodium oxybate, and melatonin.
Anxiolytics may be used in the treatment of behavioural and psychological symptoms of dementia, and as such may be used in combination with a DHP compound to give an additive therapeutic benefit. Examples of anxiolytics include: diazepam, alprazolam, chlordiazepoxide hydrochloride, buspirone, and meprobamate.
Other Uses
The DHP compounds described herein may also be used as part of an in vitro assay, for example, in order to determine whether a candidate host is likely to benefit from treatment with the compound in question. The DHP compounds described herein may also be used as a standard, for example, in an assay, in order to identify other compounds, other cognitive enhancers, other anti-dementia agents, etc.
Kits
One aspect of the invention pertains to a kit comprising (a) a DHP compound as described herein, or a composition comprising a DHP compound as described herein, e.g., preferably provided in a suitable container and/or with suitable packaging; and (b) instructions for use, e.g., written instructions on how to administer the compound or composition. ln one embodiment, the kit further comprises one or more {e.g., 1 , 2, 3, 4) additional therapeutic agents, as described herein.
The written instructions may also include a list of indications for which the active ingredient is a suitable treatment.
Routes of Administration
The DHP compound or pharmaceutical composition comprising the DHP compound may be administered to a subject by any convenient route of administration, whether systemically/peripherally or topically (i.e., at the site of desired action).
Routes of administration include, but are not limited to, oral {e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal {e.g., by nasal spray, drops or from an atomiser or dry powder delivery device); ocular {e.g., by eyedrops); pulmonary {e.g., by inhalation or insufflation therapy using, e.g., an aerosol, e.g., through the mouth or nose); rectal {e.g., by suppository or enema); vaginal {e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital,
intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.
The Subject/Patient
The subject/patient may be a chordate, a vertebrate, a mammal, a placental mammal, a marsupial {e.g., kangaroo, wombat), a rodent {e.g., a guinea pig, a hamster, a rat, a mouse), murine {e.g., a mouse), a lagomorph {e.g., a rabbit), avian {e.g., a bird), canine {e.g., a dog), feline {e.g., a cat), equine {e.g., a horse), porcine {e.g., a pig), ovine {e.g., a sheep), bovine {e.g., a cow), a primate, simian {e.g., a monkey or ape), a monkey
{e.g., marmoset, baboon), an ape {e.g., gorilla, chimpanzee, orangutang, gibbon), or a human.
Furthermore, the subject/patient may be any of its forms of development, for example, a foetus.
In one preferred embodiment, the subject/patient is a human. Formulations
While it is possible for the DHP compound to be administered alone, it is preferable to present it as a pharmaceutical formulation (e.g., composition, preparation, medicament) comprising at least one DHP compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, including, but not limited to, pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, anti-oxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents. The formulation may further comprise other active agents, for example, other therapeutic or prophylactic agents.
Thus, the present invention further provides pharmaceutical compositions, as defined above, and methods of making a pharmaceutical composition comprising admixing at least one DHP compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, e.g., carriers, diluents, excipients, etc. If formulated as discrete units (e.g., tablets, etc.), each unit contains a predetermined amount (dosage) of the compound. The term "pharmaceutically acceptable," as used herein, pertains to compounds, ingredients, materials, compositions, dosage forms, etc., which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject in question (e.g., human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Each carrier, diluent, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.
Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical texts, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, Pa., 1990; and Handbook of Pharmaceutical Excipients, 5th edition, 2005.
The formulations may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the compound with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the compound with carriers (e.g., liquid carriers, finely divided solid carrier, etc.), and then shaping the product, if necessary. The formulation may be prepared to provide for rapid or slow release; immediate, delayed, timed, or sustained release; or a combination thereof. Formulations may suitably be in the form of liquids, solutions {e.g., aqueous, nonaqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries, mouthwashes, drops, tablets (including, e.g., coated tablets), granules, powders, losenges, pastilles, capsules (including, e.g., hard and soft gelatin capsules), cachets, pills, ampoules, boluses, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, mists, or aerosols.
Formulations may suitably be provided as a patch, adhesive plaster, bandage, dressing, or the like which is impregnated with one or more compounds and optionally one or more other pharmaceutically acceptable ingredients, including, for example, penetration, permeation, and absorption enhancers. Formulations may also suitably be provided in the form of a depot or reservoir. The compound may be dissolved in, suspended in, or admixed with one or more other pharmaceutically acceptable ingredients. The compound may be presented in a liposome or other micro particulate which is designed to target the compound, for example, to blood components or one or more organs. Formulations suitable for oral administration (e.g., by ingestion) include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries, tablets, granules, powders, capsules, cachets, pills, ampoules, boluses. Formulations suitable for buccal administration include mouthwashes, losenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs. Losenges typically comprise the compound in a flavored basis, usually sucrose and acacia or tragacanth. Pastilles typically comprise the compound in an inert matrix, such as gelatin and glycerin, or sucrose and acacia. Mouthwashes typically comprise the compound in a suitable liquid carrier.
Formulations suitable for sublingual administration include tablets, losenges, pastilles, capsules, and pills. Formulations suitable for oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil- in-water, water-in-oil), mouthwashes, losenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs. Formulations suitable for non-oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions {e.g., oil-in-water, water-in-oil), suppositories, pessaries, gels, pastes, ointments, creams, lotions, oils, as well as patches, adhesive plasters, depots, and reservoirs.
Formulations suitable for transdermal administration include gels, pastes, ointments, creams, lotions, and oils, as well as patches, adhesive plasters, bandages, dressings, depots, and reservoirs.
Tablets may be made by conventional means, e.g., compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the compound in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g., povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropyl methyl cellulose); fillers or diluents (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, silica); disintegrants (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose); surface-active or dispersing or wetting agents (e.g., sodium lauryl sulfate); preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid); flavours, flavour enhancing agents, and sweeteners. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the compound therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with a coating, for example, to affect release, for example an enteric coating, to provide release in parts of the gut other than the stomach.
Ointments are typically prepared from the compound and a paraffinic or a water-miscible ointment base.
Creams are typically prepared from the compound and an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example, at least about 30% w/w of a polyhydric alcohol, i.e. , an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1 ,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the compound through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogues.
Emulsions are typically prepared from the compound and an oily phase, which may optionally comprise merely an emulsifier (otherwise known as an emulgent), or it may comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabiliser. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabiliser(s) make up the so-called emulsifying wax, and the wax together with the oil and/or fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
Suitable emulgents and emulsion stabilisers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate. The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the compound in most oils likely to be used in pharmaceutical emulsion formulations may be very low. Thus the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used. Formulations suitable for intranasal administration, where the carrier is a liquid, include, for example, nasal spray, nasal drops, or by aerosol administration by nebuliser, include aqueous or oily solutions of the compound.
Formulations suitable for intranasal administration, where the carrier is a solid, include, for example, those presented as a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Formulations suitable for pulmonary administration (e.g., by inhalation or insufflation therapy) include those presented as an aerosol spray from a pressurised pack, with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases. Formulations suitable for ocular administration include eye drops wherein the compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the compound.
Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, for example, cocoa butter or a salicylate; or as a solution or suspension for treatment by enema.
Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the compound, such carriers as are known in the art to be appropriate.
Formulations suitable for parenteral administration (e.g., by injection), include aqueous or non-aqueous, isotonic, pyrogen-free, sterile liquids (e.g., solutions, suspensions), in which the compound is dissolved, suspended, or otherwise provided (e.g., in a liposome or other micro particulate). Such liquids may additional contain other pharmaceutically acceptable ingredients, such as anti-oxidants, buffers, preservatives, stabilisers, bacteriostats, suspending agents, thickening agents, and solutes which render the formulation isotonic with the blood (or other relevant bodily fluid) of the intended recipient. Examples of excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like. Examples of suitable isotonic carriers for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection.
Typically, the concentration of the compound in the liquid is from about 1 ng/mL to about 10 μg/mL, for example from about 10 ng/mL to about 1 μg/mL. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.
Dosage
It will be appreciated by one of skill in the art that appropriate dosages of the DH P compounds, and compositions comprising the DHP compounds, can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects. The selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular DHP compound, the route of administration, the time of administration, the rate of excretion of the DHP compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, the severity of the condition, and the species, sex, age, weight, condition, general health, and prior medical history of the patient. The amount of DHP compound and route of administration will ultimately be at the discretion of the physician, veterinarian, or clinician, although generally the dosage will be selected to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects. Administration can be effected in one dose, continuously or intermittently {e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell(s) being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician, veterinarian, or clinician.
In general, a suitable dose of the DHP compound is in the range of about 10 μg to about 250 mg (more typically about 100 μg to about 25 mg) per kilogram body weight of the subject per day. Where the compound is a salt, an ester, an amide, a prodrug, or the like, the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately.
EXAMPLES
Chemical Synthesis
The following examples are provided solely to illustrate the present invention and are not intended to limit the scope of the invention, as described herein.
Synthesis 1
Methyl 2-(ferf-butoxy henylpropanoate (1 )
Figure imgf000088_0001
Di-ferf-butyl dicarbonate (19.4 mL, 83.0 mmol) was added to a solution of /.-phenylalanine methyl ester hydrochloride (15.0 g, 69.5 mmol) and triethylamine (19.6 mL, 139 mmol) in dichloromethane (200 mL) and the resulting solution stirred at room temperature for 48 hours. Solvent was removed under reduced pressure and the residue partitioned between DCM (100 mL) and a saturated aqueous solution of sodium bicarbonate
(50 mL). The combined organic layers were washed with an aqueous solution of sodium bicarbonate (50 mL) and dried (MgS04). The residue was purified via Biotage (1 :2, EtOAc-petroleum ether (40-60 °C), snap 50 g column, Rf: 0.73) to give the title compound (1 ) as a colourless oil (19.4 g, 69.6 mmol, 99%). H NMR (400 MHz, CDCI3) δ 7.27 (5H, m, ArCH), 7.08 (1 H, br s, -NH-), 4.94 (0.6H, s, NHCH), 4.53 (0.4H, s, NHCH), 3.62 (3H, s, COOCH3), 3.04 (2H, m, ArCH2COOCH3), 1.38 (9H, s, HN-COOC(CH3)3); 3C NMR (100 MHz, CDCI3) δ 172.55 (COOCH3), 155.40 (NC(0)OC(CH3)3), 136.44 (quaternary C), 129.44 (ArCH), 128.69 (ArCH), 127.27 (ArCH), 76.85 (C(CH3)3), 54.63 (CH2CHC(0)OCH3), 51.68 (OCH3), 38.46 (CH2), 27.18 (C(CH3)3); m/z: 302.1 (100%, [M+Na]+); Found [M+Na]+ 302.1364, C15H21 NNa04 requires 302.1368.
Synthesis 2
Methyl 2-(fert-butoxycar )-3-phenylpropanoate (2)
Figure imgf000088_0002
A suspension of sodium hydride 60% (0.17 g, 4.32 mmol) was added to a solution of methyl 2-(fert-butoxycarbonylamino)-3-phenylpropanoate (1.05 g, 3.59 mmol) (1) in DMF (15 mL) and the resulting mixture stirred for 4 hours, lodomethane (0.45 mL, 7.20 mmol) was added to the resulting solution and the mixture stirred for 24 hours at room temperature. The final mixture was quenched by addition of a solution of saturated aqueous ammonium chloride (15 mL) and solvent removed under reduced pressure. The residue was partitioned between water (50 mL) and ethyl acetate (50 mL) and the combined organic extracts washed with brine (100 mL), dried (MgS04), filtered and solvent removed under reduced pressure. The residue was purified via Biotage (1 :6, EtOAc-petroleum ether (40-60 °C), snap 50 g column, Rf: 0.50) to give the title compound (2) as a light oil as a 0.6 : 0.4 mixture of amide rotamers (0.82 g, 2.80 mmol, 78%). H NMR (400 MHz, CDCI3) δ 7-12-7.26 (5H, m, Ar-H), 4.90 (0.6H, s, CH), 4.53 (0.4H, s, CH), 3.70 (3H, s, COOCHs), 3.22 (1 H, m, CH2), 2.94 (1 H, m, CH2), 2.67 (3H, s, NCH3), 1.30 (9H, s, C(CH3)3); 3C NMR (100 MHz, CDCI3) δ 172.1 1 (COOCH3), 171.82
(COOCH3), 156.01 (NCOOC(CH3)3), 155.16 (NCOOC(CH3)3), 137.92 (ArCH),
137.61 (ArCH), 129.24 (ArCH), 129.15 (ArCH), 128.74 (ArCH), 128.58 (ArCH),
126.84(ArCH), 126.78 (ArCH), 80.46 (C(CH3)3), 80.18 (C(CH3)3), 61.86
(CH2CHC(0)OCH3), 59.73 (CH2CHC(0)OCH3), 52.35 (OCH3), 35.75 (CH2), 35.26 (CH2), 32.75 (CH3N), 32.12 (CH3N), 28.43 (C(CH3)3), 28.39 (C(CH3)3); m/z: 246 (26%); Found [M+Na]+ 316.1523, C16H23NNa04 requires 316.1525.
Synthesis 3
A/-Methyl phe thyl ester (3)
Figure imgf000089_0001
Trifluoroacetic acid (1.2 mL, 15.58 mmol) was added to a solution of A/-Boc-A/-methyl phenylalanine methyl ester (2) (0.82 g, 2.80 mmol) in DCM (10 mL) at room temperature and the resulting solution stirred for 6 hours. The resulting mixture was quenched by addition of saturated aqueous sodium hydrogen carbonate solution. Solvent as well as excess trifluoroacetic acid was removed under reduced pressure. The residue was partitioned between dichloromethane (50 mL) and saturated aqueous sodium hydrogen carbonate solution (50 mL). The combined organic layers were dried (MgS04), filtered and solvent removed under reduced pressure to give the title compound (3) as a pale yellow oil (0.53 g, 2.76 mmol, 99%). H NMR (400 MHz, CDCI3) δ 7.15-7.29 (5H, m, Ar-H), 3.64 (3H, s, COOCH3), 3.44 (1 H, t, J = 6.7 Hz, CH), 2.94 (2H, d, J = 6.7 Hz, CH2), 2.35 (3H, s, NCH3), 1.60 (1 H, s, NH); 3C NMR (100 MHz, CDCI3) δ 174.64 (COOCH3), 137.07 (quaternary C), 129.0 (ArCH), 128.37 (ArCH), 126.65 (ArCH), 64.69 (CH), 51.66 (OCH3), 39.51 (CH2), 34.62 (CH3N); m/z: 194.1 (100%, [M+H]+); Found [M+H]+ 194.1 183, CnH16N02 requires 194.1181. Svnthesis 4
2-((3-Methoxy-3-oxo-1-phenylprop-1-en-2-yl)(methyl)amino)-2-oxoethane-1 ,1-diyl diacetate (4)
Figure imgf000090_0001
ferf-Butyl hypochlorite (1.78 g, 16.4 mmol) was added in one portion to a stirred solution of A/-methyl phenylalanine methyl ester (3) (3.01 g, 15.6 mmol) in diethyl ether (60 mL) in the dark (foil wrapped) and the solution stirred for two hours. DABCO (2.75 g, 24.5 mmol) was added and stirring was continued in the absence of light for 12 hours. The reaction mixture was filtered and the solids washed with a little dry ether (15 mL). Solvent was removed under reduced pressure to give the crude dehydrogenated product. The crude product thus obtained, was taken up in dichloromethane (100 mL) and a solution of sodium hydrogen carbonate (2.62 g, 31.2 mmol) in water (50 mL) was added, followed by rapid addition of a solution of diacetoxy acetyl chloride (1.59 g, 8.19 mmol) in
dichloromethane (20 mL). The resulting biphasic mixture was stirred rapidly for 24 hours. The layers were separated and the aqueous phase extracted with dichloromethane (2 x 50 mL). The combined extracts were dried (MgS04), filtered, and solvent removed under reduced pressure. Purification by Biotage (1 :2, EtOAc-petroleum ether (40-60 °C), snap 50 g column, Rf: 0.31) gave the title compound (4) as a yellow oil (3.82 g, 10.9 mmol, 70%). H NMR (400 MHz, CDCI3) δ 7.20-7.40 (5H, m, Ar-H), 3.89 (1 H, s, HC=COOCH3), 3.71 (3H, s, COOCHs), 3.19 (3H, s, NCH3), 2.1 1 (6H, s, (CH(OC(0)CH3)2); 3C NMR (100 MHz, CDCI3) δ 170.29 (COOCH3), 164.94 (NCO(C(0)COCH3)2), 142.15 (quaternary C), 132.56 (HC=C), 131.39 (Ar-CH), 130.86 (Ar-CH), 129.70 (Ar-CH), 100.21 (HC=C), 83.48 (C(0)CH(OAc)2), 52.30 (COOCH3), 36.23 (NCH3), 20.41 (CH(OC(0)CH3)2); m/z 349 (31 %, M+), 218 (36), 191 (100), 131 (51); Found, Found [El] [M+] 349.11615, C17H19N07 requires 349.1 1686. Synthesis 5
Methyl 4-hydroxy-1-methyl-5-oxo-3-phenyl-4, 5-dihydro-1 --pyrrole-2-carboxylate (5)
(DHP-001)
Figure imgf000090_0002
Boron trifluoride diethyl etherate (8.00 ml_, 63.1 mmol) was added to a solution of amide (4) (1.64 g, 4.69 mmol) at room temperature and stirred for 36 hours. The resulting mixture was poured into water (40-50 ml_) and extracted with dichloromethane (3 x 30 ml_). The combined organic extracts were washed with water (2 x 50 ml_), dried (MgS04), filtered and solvent removed under reduced pressure. The residue was purified by
Biotage (1 :2, EtOAc-petroleum ether (40-60 °C), snap 25 g column, Rf: 0.21) and further purified by recrystallisation (methanol) to give the title compound (5) as a colourless solid (0.86 g, 3.94 mmol, 72%); mp. 219-221 °C. H NMR (400 MHz, CDCI3) δ 7.72 - 7.66 (2 H, m, Ar-H), 7.27 - 7.36 (2 H, m, Ar-H), 7.17- 7.24 (1 H, m, Ar-H), 6.42 (1 H, s, OH), 4.92 (1 H, s, CHC02CH3), 3.63 (3 H, s, C02CH3), 3.01 (3 H, s, NCH3); 3C NMR (100 MHz, CDCI3) δ 168.93 (C02CH3), 167.75 (NCO), 143.45 (C(OH)=C(Ph)), 130.78 (quaternary C), 128.59 (Ar-CH), 127.90 (Ar-CH), 126.85 (Ar-CH), 1 16.98 (C(OH)=C(Ph)), 63.28 (CH(COOCH3), 53.01 (OCH3), 28.61 (NCH3); m/z 246 (100%, M-H+), 217.9 (43 %); Found [M+H+] 248.0931 , C13H14N04 requires 248.0923.
The racemic mixture of alcohol (5) (200 mg) was subjected to purification by chiral preparative HPLC (Lux Cellulose-4, 21.2 x 250 mm, 5 μηι column) using 20% methanol in water as eluent with a flow rate of 60 mL/minute to separate each enantiomer (>99.8% ee).
Isomer 5-1 : 84.5 mg, EE>99.8%, purity 100%, Rt 2.21 min (Lux Cellulose-4 4.6 x 250 mm 5 μηι column). Isomer 5-2: 85.1 mg, EE>99.8%, purity 100%, Rt 2.69 min (Lux Cellulose-4 4.6 x 250 mm 5 μηι column).
Biological Methods
All experiments were performed on male Sprague Dawley rats (Harlan Laboratories Ltd., Oxon, UK), aged postnatal day 21 - 40, in agreement with UK Home Office regulations. Animals were placed inside a chamber saturated with an isoflurane/02 mixture and anesthetised. The level of anaesthesia was tested by a paw pinch. After decapitation, the brain was removed and kept in ice-cold dissecting solution.
Transverse hippocampal slices (300 μηι) were obtained using a vibratome (Leica, VT-1200S). Slices were stored at 35°C for 30 minutes after slicing and then at 22°C. For the dissection and storage of slices, the solution contained: NaCI (87 mM), NaHC03 (25 mM), glucose (10 mM), sucrose (75 mM), KCI (2.5 mM), NaH2P04 (1.25 mM), CaCI2 (0.5 mM) and MgCI2 (7 mM). For experiments, the slices were superfused with artificial cerebro-spinal fluid solution (ACSF) containing: NaCI (125 mM), NaHC03 (25 mM), glucose (25 mM), KCI (2.5 mM), NaH2P04 (1.25 mM), CaCI2 (4 mM) and MgCI2 (4 mM), equilibrated with 95% 02 / 5% C02. The osmolarity and pH of both solutions were adjusted to -320 mOsmol/L and 7.3, respectively.
Slices were handled as follows. A slice was transferred into the recording chamber and was secured by nylon strings attached to a platinum wire. Perfusion rate was set to 4 mL/min. The slice was visualised with an Olympus BX 51 Wl microscope (Olympus Europa Holding GmbH, Hamburg, Germany) which was connected to a KPM-3 Hitachi infrared (IR) video camera. Stimulation electrodes (bipolar tungsten electrodes purchased from FHC Inc., Bowdoin, Maine, USA) were positioned under a low
magnification (10x) objective (Olympus), while for patch-clamp experiments, neurons were visualised under IR-differential interference contrast (DIC) imaging with a water-emersion high magnification (60x) objective (Olympus) and a four-fold
magnification changer (Luigs & Neumann GmbH, Ratingen, Germany). All recordings were performed at room temperature. Synaptic currents were recorded with a Multiclamp 700-B amplifier (Molecular Devices), filtered at 2 kHz (internal 4-pole low-pass Bessel filter), and sampled at 10 kHz. The access resistance, monitored throughout the experiments, was < 20 ΜΩ and results were discarded if it changed by more than 20%. Junction potentials were not corrected.
The pipette solution used for excitatory post-synaptic potentials (EPSCs) recorded at 'holding = -70 mV contained: CsCI (120 mM), QX314 Br (i.e., Λ/-(2,6- dimethylphenylcarbamoylmethyl)triethylammonium bromide) (5 mM), NaCI (8 mM), MgCI2 (0.2 mM), HEPES (i.e., 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) (10 mM), EGTA (i.e., ethylene glycol tetraacetic acid) (2 mM), MgATP (i.e., adenosine 5'- triphosphate magnesium salt) (2 mM), and Na3GTP (i.e. , guanosine 5'-triphosphate sodium salt hydrate) (0.3 mM), at pH 7.2 and osmolarity 310 mOsm/L.
The pipette solution used for current-clamp recordings contained: KCI (155 mM), HEPES (10 mM), MgATP (2 mM), Na3GTP (0.3 mM), and EGTA (0.2 mM).
EPSCs evoked by dentate gyrus stimulation (20 με; 20-100 μν) were only analyzed if currents were reversibly depressed > 40% by superfusion of DCG-IV (i.e. ,
(2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine) (1 μΜ) at the end of each experiment, consistent with the selective sensitivity of mossy fibre synapses.
GABAA and GABAB receptors were routinely blocked by picrotoxin (50 μΜ) and CGP- 52432 (i.e., 3-[[(3,4-Dichlorophenyl)methyl]amino]propyl] diethoxymethyl)phosphinic acid) (5μΜ), and NMDA receptors by D-APV (i.e. , D-2-amino-5-phosphonopentanoic acid) (50 μΜ).
Evoked excitatory currents were fully abolished by addition of CNQX (i.e., 6-cyano-7- nitroquinoxaline-2,3-dione) (50 μΜ) or NBQX (i.e., 2,3-dihydroxy-6-nitro-7-sulfamoyl- benzo[f]quinoxaline-2,3-dione) (20 μΜ) confirming that they were mediated by AM PA and kainate receptors.
Study 1
Effect of DHP-001 on Glutamatergic Synaptic Transmission
from the Dentate Gyrus to CA3
This study was performed in order to determine the effects of DHP-001 on excitatory synaptic transmission mediated by activation of mossy fibre synapses in CA3 pyramidal neurons. Assay 1 - Basal Excitatory Synaptic Transmission in Neuron Populations
This approach is based on extracellular recordings of field-potentials created by mossy fibre synapse activation in a population of CA3 neurons, in response to electrical stimuli delivered in the dentate gyrus. It is less challenging a method as compared with whole- cell recordings because it does not rely on forming a giga-seal onto individual neurons. However, this recording configuration does not allow the detection of changes in the electrical properties of individual neurons (e.g., input resistance, Rin) or fine alterations of neuronal firing properties in response to application of a drug or a modulator of synaptic transmission. This assay served as an initial screen to determine the acute effect of compound DHP-001 on excitatory synaptic transmission. Field excitatory post-synaptic potentials (field-EPSPs) were evoked every 10 seconds using paired electrical stimuli (inter-stimulus interval: 20 ms; constant current, 0.3-1.5 μΑ, 50 με) delivered via a bipolar tungsten electrode implanted in the dentate granule cell layer.
The results are illustrated in Figure 1.
Figure 1 shows that DHP-001 facilitates excitatory synaptic transmission from the dentate gyrus to CA3. Panel A, top. Example traces of excitatory synaptic potentials
(field-EPSPs) recorded with an extracellular electrode (each trace is an average of 20 consecutive field-EPSPs taken at 5 second intervals) before and during the
superfusion of DHP-001 (100 μΜ). The right-most trace shows field-EPSPs in the presence of DMSO (100 μΜ, Vehicle). Panel A, bottom: A plot of the normalised field- EPSP amplitude (μν) versus time (min) for data from 1 slice. Panel B: A bar graph showing normalized field-EPSP amplitude for control and DHP-001 for pooled data, which shows an increase of field-EPSP amplitude in the presence of DHP-001 (n = 4, P < 0.01 , paired f-test).
The data demonstrate that superfusion with DHP-001 (100 μΜ) increased field-EPSP amplitude by 59 ± 28.2 % of control (Figure 1 ; n = 4, p < 0.05, paired f-test). This effect was reversible upon removal of the compound. Application of the vehicle (DMSO) at a similar concentration as that used to solubilise DHP-001 had no effect.
These results demonstrate that DHP-001 has a reversible enhancing effect on excitatory synaptic transmission mediated by mossy fibre synapses onto CA3 pyramidal neurons. The data also indicate that the method used for solubilisation of DHP-001 does not have any effect per se.
Assay 2 - Electrical Properties of Single Neurons
In the whole-cell configuration, there is direct access to the intracellular compartment of individual neurons which permits a measurement of the trans-membrane potential as well as the input resistance and cell capacitance. Furthermore, the membrane of an individual neuron can be maintained at a defined potential (e.g., clamped at -70 mV), thus enabling the resolution of synaptic currents at the sub-millisecond scale. In addition, the intracellular ionic composition or the trans-membrane potential can be manipulated in order to interfere with the driving force of synaptic currents evoked by neurotransmitter release. This technique was used to establish the initial concentration-response relationship for the effect of DHP-001 in CA3 pyramidal neurons in-situ.
The results are illustrated in Figure 2. Figure 2 shows that superfusion with DHP-001 does not alter the input resistance of dentate granule cells. Panel A. Sample traces from a granule cell recording showing the l-V relationship (membrane potential is -81 mV). Panel B: A plot of the l-V relationship (voltage in mV versus current in pA) before and after superfusion with DHP-001 (100 μΜ). No difference was found. Panel C: A bar graph of Rinput (ΜΩ) for control and DHP-001 , for pooled data from 5 neurons.
The results demonstrate that superfusion with DHP-001 (100 μΜ) did not alter the l-V relationship nor the membrane potential of individual granule cells held in current-clamp (Figure 2). No major effect was observed for action potential threshold and maximum firing rate. These findings support the notion that DHP-001 has little effect on intrinsic neuronal properties and favour the hypothesis that enhancement of synaptic transmission is consecutive to action on glutamate receptors or ion channels located at mossy fibre-CA3 synapses.
Study 2
Effect of DHP-001 on Electrical Properties of Principal Neurons in CA3 and on Excitatory Synaptic Transmission
Assay 3 - AMPA Receptor Mediated EPSCs in CA3 Pyramidal Neurons
In order to examine how a compound alters the electrical properties of individual neurons, it is necessary to characterise the current-voltage (l-V) relationship in response to hyperpolarising and depolarising current steps, and to determine the threshold for action potential (AP) generation and the maximum firing rate. To do this, neurons are held in current-clamp mode, thus enabling trans-membrane potential measurements (mV) from the patch pipette used to inject current (pA). A measure of the input resistance of the cell (ΜΩ) can be obtained by fitting the linear portion of the l-V relationship; the maximum firing frequency (Hz) can be calculated by dividing the maximum number of APs generated by a depolarising pulse of a given duration (ms).
The results are illustrated in Figure 3 and Figure 4. Figure 3 is a set of graphs illustrating the effect of DHP-001 on evoked AMPA receptor mediated EPSCs in CA3 pyramidal neurons. Bottom left. Plot of normalised EPSC amplitude against time showing an increase upon superfusion with DHP-001 (100 μΜ) and depression by the group II metabotropic glutamate receptor agonist DCG-IV (1 μΜ). Top: Representative examples for each condition are shown (data from one CA3 pyramidal neuron). Bottom right. Summary plot based on data from 5 neurons (each point represents the mean ± S.E.M). Superfusion of DHP-001 (100 μΜ) increased the amplitude of evoked EPSCs by
77.8 ± 11.3 % of control (Figure 3; n = 5, p < 0.003, paired f-test). The holding current measured before and after application of DHP-001 was not significantly different (delta \hoiding- 10.9 ± 8.3 pA, p > 0.1 , paired f-test).
Figure 4 is a concentration-facilitation curve for DHP-001. Each concentration was tested in at least 3 neurons. A logistic function was used to fit the data and each point represents the mean ± S.E.M. The EC50 inferred from the fit of the concentration- facilitation curve is 12 μΜ.
The effect of DHP-001 on evoked EPSCs effect was clearly reversible and dose- dependent with a half-maximum effect present at 12 μΜ (Figure 4). Evoked synaptic currents were suppressed by addition to the perfusion medium of DCG-IV (1 μΜ) showing that the responses were mediated by mossy fibre synapses.
These results demonstrate the enhancing effect of DHP-001 on AM PA receptor mediated synaptic currents in CA3 pyramidal neurons. They also indicate that DHP-001 has a relatively high potency and does not change cellular excitability. Finally, they confirm the observations made with extracellular recordings (see Assay 1 , above) showing the large increase in synaptic transmission in the presence of DHP-001.
Study 3
Mossy Fibre Long-Term Potentiation (LTP)
LTP of glutamatergic transmission at mossy fibre-CA3 synapses is dependent on presynaptic membrane depolarization which in turn facilitates the influx of Ca2+ ions through voltage gated Ca2+ channels, hence the persistent increase in glutamate release. Several lines of crucial evidence have shown that in disease models of
neurodegeneration, such as in Alzheimer or Huntington disease models, LTP is impaired in the CA1 area of the hippocampus. This translates into a form of LTP whose magnitude is much less than occurs in the wild-type. However, nothing is known about changes occurring in CA3. Assay 4 - Mossy Fibre Long-Term Potentiation (LTP)
This assay relied on field-EPSPs measurement (Assay 1) in slices superfused with GABAA, GABAB, and NMDA receptor antagonists. After a period of stable baseline, mossy fibre LTP was induced by delivering 3 consecutive high-frequency stimulus bursts (100 Hz for 1 second) every 10 seconds, via a bipolar tungsten electrode positioned in the dentate gyrus. The amplitude of field-EPSPs (mV) was compared before and 15 minutes after the induction paradigm. For each slice, field-EPSPs amplitude was normalised to baseline.
The results are illustrated in Figure 5.
Figure 5 shows that DHP-001 facilitates mossy fibre LTP induction in CA3 pyramidal neurons. It is a plot of the field-EPSP amplitude (measured in μν, as a percentage of control) against time showing that a sub-threshold high-frequency stimulus train (HFSi: 100 Hz for 1 second, repeated 3 times with an interval of 10 seconds) does not induce LTP in contrast to a second sub-threshold stimulus (HFS2) delivered 20 minutes following DHP-001 (100 μΜ) superfusion, leading to sustained LTP. Data are represented as mean ± S.E.M, n = 4 slices.
The facilitation of AMPA receptor mediated EPSCs in CA3 pyramidal neurons could result either from modulation of presynaptic Ca2+ channel activity or direct modulation of AMPA receptors at postsynaptic densities. We looked for an effect of BRS-015 on LTP induction in view of the enhancement on basal synaptic transmission. The data shown in Figure 5 demonstrate that a sub-threshold high-frequency stimulation protocol applied to mossy fibres (HFS) elicits LTP only in the presence of DHP-001 (100 μΜ). The amplitude of field-EPSPs measured 20 minutes after HFS2 was 132.1 ± 17.1 % of baseline (n = 4, p < 0.001 , paired f-test). These results demonstrate that DHP-001 facilitates LTP by lowering the threshold for induction. This may be a consequence of presynaptic modulation or the result of enhanced AMPA receptor function.
The foregoing has described the principles, preferred embodiments, and modes of operation of the present invention. However, the invention should not be construed as limited to the particular embodiments discussed. Instead, the above-described embodiments should be regarded as illustrative rather than restrictive. It should be appreciated that variations may be made in those embodiments by workers skilled in the art without departing from the scope of the present invention. REFERENCES
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Claims

A compound of the followin
Figure imgf000104_0001
or a tautomer thereof;
or a pharmaceutically acceptable salt, hydrate, or solvate of the foregoing; wherein:
-J is independently -OH, -ORJE, -NH2, -NHRJN , -NRJN RJN2, or -NRJN3RJN4;
>JE s independently:
DJE1 DJE2 DJE3 DJE4 DJE5 DJE6 DJE7 DJE8
-fx , - fx , - fx , - fx , -fx , -fx , -fx , -fx ,
-LJE-RJE4, -LJE-RJE5, -LJE-RJE6, -LJE-RJE7, or -LJE-RJE8;
-RJE is linear or branched saturated Ci-6alkyl,
and is optionally substituted with one or more groups -RK C;
-RJE2 is linear or branched C2-6alkenyl,
and is optionally substituted with one or more groups -RK C;
-RJE3 is linear or branched C2-6alkynyl,
and is optionally substituted with one or more groups -RK C;
each -RJE4 is saturated C3.6cycloalkyl,
and is optionally substituted with one or more groups -RK2C;
each -RJE5 is C3.6cycloalkenyl,
and is optionally substituted with one or more groups -RK2C;
each -RJE6 is non-aromatic C3.7heterocyclyl,
and is optionally substituted on carbon with one or more groups -R K2C and is optionally substituted on secondary nitrogen, if present, with a group -RK2N;
each -RJE7 is independently phenyl or naphthyl,
and is optionally substituted with one or more groups -RK3C;
each -RJE8 is C5.i0heteroaryl,
and is optionally substituted on carbon with one or more groups -RK3C, and is optionally substituted on secondary nitrogen, if present, with a group -RK3N;
each -LJE- is linear or branched saturated Ci_4alkylene; wherein: each -RK1C is independently: -F, -CI, -Br, -I,
-OH, -ORKK,
-OCF3,
-NH2, -NHRKK, -NRKK 2, -RKM,
-C(=0)OH, -C(=0)ORKK, -OC(=0)RKK,
-C(=0)NH2, -C(=0)NHRKK, -C(=0)NRKK 2, -C(=0)RKM,
-NHC(=0)RKK, -NRKNC(=0)RKK,
-NHC(=0)NH2, -NHC(=0)NHRKK, -NHC(=0)NRKK 2, -NHC(=0)RKM, -NRKNC(=0)NH2, -NRKNC(=0)NHRKK, -NRKNC(=0)NRKK 2, -NRKNC(=0)RKM, -NHC(=0)ORKK, -NRKNC(=0)ORKK,
-OC(=0)NH2, -OC(=0)NHRKK, -OC(=0)NRKK 2, -OC(=0)RKM,
-C(=0)RKK,
-S(=0)2NH2, -S(=0)2NHRKK, -S(=0)2NRKK 2, -S(=0)2RKM,
-NHS(=0)2RKK, -NRKNS(=0)2RKK,
-S(=0)2RKK,
-CN, -N02, or -SRKK; each -RK2C is independently:
-RKK,
-F, -CI, -Br, -I,
-OH, -ORKK,
-LK-OH, -LK-ORKK,
-CF3, -OCF3,
-NH2, -NHRKK, -NRKK 2, -RKM,
-LK-NH2, -LK-NHRKK, -LK-NRKK 2, -LK-RKM,
-C(=0)OH, -C(=0)ORKK, -OC(=0)RKK,
-C(=0)NH2, -C(=0)NHRKK, -C(=0)NRKK 2, -C(=0)RKM,
-NHC(=0)RKK, -NRKNC(=0)RKK,
-NHC(=0)NH2, -NHC(=0)NHRKK, -NHC(=0)NRKK 2, -NHC(=0)RKM, -NRKNC(=0)NH2, -NRKNC(=0)NHRKK, -NRKNC(=0)NRKK 2, -NRKNC(=0)RKM,
-NHC(=0)ORKK, -NRKNC(=0)ORKK,
-OC(=0)NH2, -OC(=0)NHRKK, -OC(=0)NRKK 2, -OC(=0)RKM,
-C(=0)RKK,
-S(=0)2NH2, -S(=0)2NHRKK, -S(=0)2NRKK 2, -S(=0)2RKM,
-NHS(=0)2RKK, -NRKNS(=0)2RKK,
-S(=0)2RKK, -CN, -N02, -SR , or =0; each -R c is independently: -RKK,
-F, -CI, -Br, -I,
-OH, -ORKK,
-LK-OH, -LK-ORKK,
-CF3, -OCFs,
-NH2, -NHRKK, -NRKK2, -RKM,
-LK-NH2, -LK-NHRKK, -LK-NRKK 2, -LK-RKM,
-C(=0)OH, -C(=0)ORKK, -OC(=0)RKK,
-C(=0)NH2, -C(=0)NHRKK, -C(=0)NRKK 2, -C(=0)RKM,
-NHC(=0)RKK, -NRKNC(=0)RKK,
-NHC(=0)NH2, -NHC(=0)NHRKK, -NHC(=0)NRKK 2, -NHC(=0)RKM,
-NRKNC(=0)NH2, -NRKNC(=0)NHRKK, -NRKNC(=0)NRKK 2, -NRKNC(=0)RKM,
-NHC(=0)ORKK, -NRKNC(=0)ORKK,
-OC(=0)NH2, -OC(=0)NHRKK, -OC(=0)NRKK 2, -OC(=0)RKM,
-C(=0)RKK,
-S(=0)2NH2, -S(=0)2NHRKK, -S(=0)2NRKK 2, -S(=0)2RKM,
-NHS(=0)2RKK, -NRKNS(=0)2RKK,
-S(=0)2RKK,
-CN, -N02, or -SRKK; and additionally, two adjacent groups -RK3C, if present, may together form:
-0-CH2-0- or -0-CH2CH2-0-; each -RK2N and each -RK3N is independently: -RKK,
-LK-OH, -LK-ORKK,
-LK-NH2, -LK-NHRKK, -LK-NRKK 2, -LK-RKM,
-C(=0)RKK,
-C(=0)ORKK,
-C(=0)NH2, -C(=0)NHRKK, -C(=0)NRKK 2, -C(=0)RKM, or
-S(=0)2RKK; wherein:
each -L - is linear or branched saturated Ci_4alkylene; each -R is independently linear or branched saturated d_4alkyl, phenyl, or -LKK-phenyl;
wherein said Ci_4alkyl group is optionally substituted with one or more groups independently selected from -OH, -ORKKK, -NH2, -NHRKKK, and -NRKKK 2; wherein each of said phenyl groups is optionally substituted with one or more groups independently selected from -F, -CI, -Br, -I, -RKKK, -CF3, -OH, -ORh -OCF3, -NH2, -NHRKKK, and -NRKKK 2;
wherein each -RKKK is linear or branched saturated Ci-4alkyl; and wherein -LKK- is linear or branched saturated Ci.3alkylene; each -RKN is linear or branched saturated Ci-4alkyl; each -RKM is independently azetidino, pyrrolidino, piperidino, piperizino,
(N-Ci-4alkyl)-piperizino, (N-Ci.4alkyl-C(=0))-piperizino, morpholino,
thiomorpholino, azepino, diazepino, (N-Ci_4alkyl)-diazepino, or
(N-Ci.4alkyl-C(=0))-diazepino;
and is optionally substituted with one or more groups selected from linear or branched saturated Ci-4alkyl; and wherein: each -RJN is independently linear or branched saturated Ci-4alkyl, phenyl, or -LJN -phenyl;
wherein said Ci_4alkyl group is optionally substituted with one or more groups independently selected from -OH, -ORJN A, -NH2, -NHRJN A, and -NRJN A 2; wherein each of said phenyl groups is optionally substituted with one or more groups independently selected from -F, -CI, -Br, -I, -RJN A, -CF3, -OH, -ORJN A, -OCF3, -NH2, -NHRJN A, and -NRJN A 2;
wherein each -RJN A is linear or branched saturated Ci-4alkyl; and wherein -|_JN - is linear or branched saturated d.3alkylene; each -RJN2 is independently linear or branched saturated C -4alkyl, phenyl, or -LJN2-phenyl;
wherein said Ci_4alkyl group is optionally substituted with one or more groups independently selected from -OH, -ORJN2A, -NH2, -NHRJN2A, and -NRJN2A 2; wherein each of said phenyl groups is optionally substituted with one or more groups independently selected from -F, -CI, -Br, -I, -RJN2A, -CF3, -OH, -ORJN2A, -OCF3, -NH2, -NHRJN2A, and -NRJN2A 2;
wherein each -RJN2A is linear or branched saturated Ci-4alkyl; and wherein -|_JN2- is linear or branched saturated Ci.3alkylene; -NR R is independently azetidino, pyrrolidino, piperidino, piperizino, (N-Ci.4alkyl)-piperizino, (N-Ci.4alkyl-C(=0))-piperizino, morpholino, thiomorpholino, azepino, diazepino, (N-Ci.4alkyl)-diazepino, or
(N-Ci.4alkyl-C(=0))-diazepino;
and is optionally substituted with one or more groups selected from linear or branched saturated Ci-4alkyl; and wherein: -Q is independently -H, -QA, or -QB;
-QA is independently:
-LQA-RQA4 -LQA-RQA5 -LQA-RQA6 -LQA-RQA7 or -L^-R^8'
-RQA is linear or branched saturated Ci-6alkyl,
and is optionally substituted with one or more groups -RS C;
-RQA2 is linear or branched C^ealkenyl,
and is optionally substituted with one or more groups -RS C;
-RQA3 is linear or branched C2-ealkynyl,
and is optionally substituted with one or more groups -RS C;
each -R0^4 is saturated C3-6cycloalkyl,
and is optionally substituted with one or more groups -RS2C;
each -R0^5 is C3.6cycloalkenyl,
and is optionally substituted with one or more groups -RS2C;
each -R0^6 is non-aromatic C3-7heterocyclyl,
and is optionally substituted on carbon with one or more groups -R and is optionally substituted on secondary nitrogen, if present, with a group -RS2N;
each -R^7 is independently phenyl or naphthyl,
and is optionally substituted with one or more groups -RS3C;
each -R0^8 is C5.i0heteroaryl,
and is optionally substituted on carbon with one or more groups -RS3C and is optionally substituted on secondary nitrogen, if present, with a group -RS3N;
each -LQA- is linear or branched saturated Ci_4alkylene; wherein: each -Rbl° is independently: -F, -CI, -Br, -I,
-OH, -ORss,
-OCFs,
-NH2, -NHRSS, -NRSS2, -RSM,
-C(=0)OH, -C(=0)ORss, -OC(=0)Rss,
-C(=0)NH2, -C(=0)NHRss, -C(=0)NRss 2, -C(=0)RSM,
-NHC(=0)Rss, -NRKNC(=0)Rss,
-NHC(=0)NH2, -NHC(=0)NHRss, -NHC(=0)NRss 2, -NHC(=0)RSM, -NRSNC(=0)NH2, -NRSNC(=0)NHRss, -NRSNC(=0)NRss 2, -NRSNC(=0)RSM, -NHC(=0)ORss, -NRKNC(=0)ORss,
-OC(=0)NH2, -OC(=0)NHRss, -OC(=0)NRss 2, -OC(=0)RSM,
-C(=0)Rss,
-S(=0)2NH2, -S(=0)2NHRss, -S(=0)2NRss 2, -S(=0)2RSM,
-NHS(=0)2Rss, -NRSNS(=0)2Rss,
-S(=0)2Rss,
-CN, -N02, or -SRss; each -RS2C is independently:
-Rss,
-F, -CI, -Br, -I,
-OH, -ORss,
-Ls-OH, -Ls-ORss,
-CF3, -OCF3,
-NH2, -NHRSS, -NRSS2, -RSM,
-LS-NH2, -LS-NHRSS, -LS-NRSS 2, -LS-RSM,
-C(=0)OH, -C(=0)ORss, -OC(=0)Rss,
-C(=0)NH2, -C(=0)NHRss, -C(=0)NRss 2, -C(=0)RSM,
-NHC(=0)Rss, -NRSNC(=0)Rss,
-NHC(=0)NH2, -NHC(=0)NHRss, -NHC(=0)NRss 2, -NHC(=0)RSM, -NRSNC(=0)NH2, -NRSNC(=0)NHRss, -NRSNC(=0)NRss 2, -NRSNC(=0)RSM,
-NHC(=0)ORss, -NRSNC(=0)ORss,
-OC(=0)NH2, -OC(=0)NHRss, -OC(=0)NRss 2, -OC(=0)RSM,
-C(=0)Rss,
-S(=0)2NH2, -S(=0)2NHRss, -S(=0)2NRss 2, -S(=0)2RSM,
-NHS(=0)2Rss, -NRKNS(=0)2Rss,
-S(=0)2Rss, -CN, -N02, -SRSS, or =0; each -RS3C is independently: -Rss,
-F, -CI, -Br, -I,
-OH, -ORss,
-Ls-OH, -Ls-ORss,
Figure imgf000110_0001
-NH2, -NHRSS, -NRSS2, -RSM,
-LS-NH2, -LS-NHRSS, -LS-NRSS 2, -LS-RSM,
-C(=0)OH, -C(=0)ORss, -OC(=0)Rss,
-C(=0)NH2, -C(=0)NHRss, -C(=0)NRss 2, -C(=0)RSM,
-NHC(=0)Rss, -NRSNC(=0)Rss,
-NHC(=0)NH2, -NHC(=0)NHRss, -NHC(=0)NRss 2, -NHC(=0)RSM,
-NRSNC(=0)NH2, -NRSNC(=0)NHRss, -NRSNC(=0)NRss 2, -NRSNC(=0)RSM,
-NHC(=0)ORss, -NRSNC(=0)ORss,
-OC(=0)NH2, -OC(=0)NHRss, -OC(=0)NRss 2, -OC(=0)RSM,
-C(=0)Rss,
-S(=0)2NH2, -S(=0)2NHRss, -S(=0)2NRss 2, -S(=0)2RSM,
-NHS(=0)2Rss, -NRSNS(=0)2Rss,
-S(=0)2Rss,
-CN, -N02, or -SRSS; and additionally, two adjacent groups -RS3C, if present, may together form:
-0-CH2-0- or -0-CH2CH2-0-; each -RS2N and each -RS3N is independently: -Rss,
-Ls-OH, -Ls-ORss,
-LS-NH2, -LS-NHRSS, -LS-NRSS 2, -LS-RSM,
-C(=0)Rss,
-C(=0)ORss,
-C(=0)NH2, -C(=0)NHRss, -C(=0)NRss 2, -C(=0)RSM, or
-S(=0)2Rss; wherein: each -Ls- is linear or branched saturated d_4alkylene; each -R is independently linear or branched saturated C -4alkyl, phenyl, or -Lss-phenyl;
wherein said Ci-4alkyl group is optionally substituted with one or more groups independently selected from -OH, -ORsss, -NH2, -NHRSSS, and -NRSSS 2; wherein each of said phenyl groups is optionally substituted with one or more groups independently selected from -F, -CI, -Br, -I, -Rsss, -CF3, -OH, -OR1 -OCF3, -NH2, -NHRSSS, and -NRSSS 2;
wherein each -Rsss is linear or branched saturated Ci-4alkyl; and wherein -Lss- is linear or branched saturated Ci.3alkylene; each -RSN is linear or branched saturated Ci-4alkyl; each -RSM is independently azetidino, pyrrolidino, piperidino, piperizino, (N-Ci-4alkyl)-piperizino, (N-Ci.4alkyl-C(=0))-piperizino, morpholino,
thiomorpholino, azepino, diazepino, (N-Ci_4alkyl)-diazepino, or
(N-Ci.4alkyl-C(=0))-diazepino;
and is optionally substituted with one or more groups selected from linear or branched saturated Ci-4alkyl; and wherein:
-QB is independently -QB , -QB2, -QB3, -QB4, -QB5, -QB6, or -QB7;
-QB is independently -OH or -ORQB ;
-QB2 is independently -NH2, -NHRQB , -NRQB 2, or -NRQB2RQB3;
-QB3 is independently -NHC(=0)RQB or -NRQB C(=0)RQB ;
-QB4 is -S(=0)2RQB ;
-QB5 is independently -S(=0)2NH2, -S(=0)2NRQB , -S(=0)2NRQB 2, or
-S(=0)2NRQB2RQB3;
-QB6 is -N02;
-QB7 is independently -F, -CI, -Br, or -I; each -RQB is independently linear or branched saturated d_4alkyl, phenyl, or -LQB-phenyl;
wherein said Ci_4alkyl group is optionally substituted with one or more groups independently selected from -OH, -ORQBB, -NH2, -NHRQBB, and -NRQBB 2; wherein each of said phenyl groups is optionally substituted with one or more groups independently selected from -F, -CI, -Br, -I, -RQBB, -CF3, -OH, -OR' -OCF3, -NH2, -NHRQBB, and -NRQBB 2;
wherein -LQB- is linear or branched saturated Ci.3alkylene;
wherein each -RQBB is linear or branched saturated Ci-4alkyl;
-NRQB2RQB3 is independently azetidino, pyrrolidino, piperidino, piperizino, (N-Ci-4alkyl)-piperizino, (N-Ci.4alkyl-C(=0))-piperizino, morpholino,
thiomorpholino, azepino, diazepino, (N-Ci_4alkyl)-diazepino, or
(N-Ci.4alkyl-C(=0))-diazepino;
and is optionally substituted with one or more groups selected from linear or branched saturated Ci-4alkyl; and wherein: -T is independently -H or -RT;
-RT is independently:
-RTA,
-C(=0)-RTB, -LT-C(=0)-RTB,
-LT-C(=0)-NH2, -LT-C(=0)-NHRTN ,
- LT-C (= O) - N RTN RTN2 , or -LTA-C(=0)-NRTN3RTN4;
-R is independently linear or branched saturated C -4alkyl, phenyl, or
-LTA-phenyl;
wherein said Ci_4alkyl group is optionally substituted with one or more groups independently selected from -OH, -ORTAA, -NH2, -NHRTAA, and -NRTAA 2; wherein each of said phenyl groups is optionally substituted with one or more groups independently selected from -F, -CI, -Br, -I, -RTAA, -CF3, -OH, -OR1 -OCF3, -NH2, -NHRTAA, and -NRTAA 2;
wherein -LTA- is linear or branched saturated Ci.3alkylene;
wherein each -RTAA is linear or branched saturated C -4alkyl; each -RTB is independently linear or branched saturated d_4alkyl, phenyl, or -LTB-phenyl;
wherein said Ci-4alkyl group is optionally substituted with one or more groups independently selected from -OH, -ORTBB, -NH2, -NHRTBB, and -NRTBB 2; wherein each of said phenyl groups is optionally substituted with one or more groups independently selected from -F, -CI, -Br, -I, -RTBB, -CF3, -OH, -ORTBB, -OCF3, -NH2, -NHRTBB, and -NRTBB 2;
wherein -LTB- is linear or branched saturated Ci.3alkylene;
wherein each -RTBB is linear or branched saturated Ci-4alkyl; and each -RTN is independently linear or branched saturated Ci-4alkyl, phenyl, or -LTN -phenyl;
wherein said Ci-4alkyl group is optionally substituted with one or more groups independently selected from -OH, -ORTN A, -NH2, -NHRTN A, and -NRTN A 2; wherein each of said phenyl groups is optionally substituted with one or more groups independently selected from -F, -CI, -Br, -I, -RTN A, -CF3, -OH, -ORTN A, -OCF3, -NH2, -NHRTN A, and -NRTN A 2;
wherein -|_TN - is linear or branched saturated Ci.3alkylene;
wherein each -RTN A is linear or branched saturated Ci-4alkyl; and
-R is linear or branched saturated Ci-4alkyl;
-NRTN3RTN4 is independently azetidino, pyrrolidino, piperidino, piperizino,
(N-Ci_4alkyl)-piperizino, (N-Ci.4alkyl-C(=0))-piperizino, morpholino,
thiomorpholino, azepino, diazepino, (N-Ci_4alkyl)-diazepino, or
(N-d.4alkyl-C(=0))-diazepino;
and is optionally substituted with one or more groups selected from linear or branched saturated C -4alkyl; each -LT- is linear or branched saturated d.3alkylene; and wherein:
-V is independently -H or -R ; and
-Rv is linear or branched saturated Ci-4alkyl.
2. A compound according to claim 1 , wherein -J is independently -OH or -ORJE.
JE
A compound according to claim 1 , wherein -J is -OR
A compound according to claim 1 , wherein -J is independently -NH2, -N HR , -NRJN1 RJN2, or -N RJN3RJN4.
A compound according to any one of claims 1 to 4, wherein -RJE, if present, is -RJE1.
A compound according to any one of claims 1 to 5, wherein -RJE , if present, is linear or branched saturated Ci-4alkyl.
A compound according to any one of claims 1 to 5, wherein -RJE , if present, is -Me.
A compound according to any one of claims 1 to 7, wherein -Q is -QA or -QB.
A compound according to any one of claims 1 to 7, wherein -Q is -QA.
A compound according to any one of claims 1 to 7, wherein -Q is -QB.
A compound according to any one of claims 1 to 10, wherein -QA, if present, is independently -RQA7 or -RQA8.
A compound according to any one of claims 1 to 10, wherein -QA, if present, is
DQA7
A compound according to any one of claims 1 to 10, wherein -QA, if present, is
DQA8
A compound according to any one of claims 1 to 13, wherein each -R , if present, is phenyl, and is optionally substituted with one or more groups -RS3C.
A compound according to any one of claims 1 to 14, wherein each -RQA8, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl, and is optionally substituted on carbon with one or more groups -RS3C, and is optionally substituted on secondary nitrogen, if present, with a group -RS3
16. A compound according to any one of claims 1 to 15, wherein -T is -H.
17. A compound according to any one of claims 1 to 16, wherein -T is -RT.
18. A compound according to any one of claims 1 to 17, wherein -RT, if present, is -RTA.
19. A compound according to any one of claims 1 to 18, wherein -RTA, if present, is linear or branched saturated Ci-4alkyl, wherein said Ci-4alkyl group is
unsubstituted.
20. A compound according to any one of claims 1 to 18, wherein -RTA, if present, is -Me.
21. A compound according to any one of claims 1 to 20, wherein -V is -H.
22. A compound according to claim 1 , which is a compound of the following formula,
Figure imgf000115_0001
or a tautomer thereof;
or a pharmaceutically acceptable salt, hydrate, or solvate of the foregoing.
A compound according to claim 1 which is a compound of the following formula,
Figure imgf000115_0002
or a tautomer thereof;
or a pharmaceutically acceptable salt, hydrate, or solvate of the foregoing.
24. A compound according to claim 1 , which is a compound of the following formula,
Figure imgf000116_0001
or a tautomer thereof;
or a pharmaceutically acceptable salt, hydrate, or solvate of the foregoing.
A composition comprising a compound according to any one of claims 1 to 24, and a pharmaceutically acceptable carrier or diluent.
A method of preparing a composition comprising the step of mixing a compound according to any one of claims 1 to 24 and a pharmaceutically acceptable carrier or diluent.
A compound according to any one of claims 1 to 24 for use in a method of improving memory and/or cognitive function in a patient.
Use of a compound according to any one of claims 1 to 24 in the manufacture of a medicament for improving memory and/or cognitive function in a patient.
A method of improving memory and/or cognitive function comprising administering to a patient in need of improved memory and/or cognitive function a
therapeutically effective amount of a compound according to any one of claims 1 to 24.
A compound according to any one of claims 1 to 24 for use in a method of treatment of the human or animal body by therapy.
A compound according to any one of claims 1 to 24 for use in a method of treatment of a disorder.
Use of a compound according to any one of claims 1 to 24 in the manufacture of a medicament for treatment of a disorder.
A method of treatment of a disorder comprising administering to a patient in need of treatment a therapeutically effective amount of a compound according to any one of claims 1 to 24.
34. A compound according to claim 31 , use according to claim 32, or a method according to claim 33, wherein the treatment is treatment of a central nervous system (CNS) disorder.
35. A compound according to claim 31 , use according to claim 32, or a method
according to claim 33, wherein the treatment is treatment of a neurodegenerative disorder of the central nervous system (CNS). 36. A compound according to claim 31 , use according to claim 32, or a method
according to claim 33, wherein the treatment is treatment of memory deficit, for example, deficient memory binding and/or deficient information recall.
A compound according to claim 31 , use according to claim 32, or a method according to claim 33, wherein the treatment is treatment of a memory-related disorder.
A compound according to claim 31 , use according to claim 32, or a method according to claim 33, wherein the treatment is treatment of a disorder associated with cognitive decline.
A compound according to claim 31 , use according to claim 32, or a method according to claim 33, wherein the treatment is treatment of cognitive impairment, for example, mild cognitive impairment (MCI).
A compound according to claim 31 , use according to claim 32, or a method according to claim 33, wherein the treatment is treatment of dementia.
A compound according to claim 31 , use according to claim 32, or a method according to claim 33, wherein the treatment is treatment of senile dementia; vascular dementia; or fronto-temporal lobe dementia.
A compound according to claim 31 , use according to claim 32, or a method according to claim 33, wherein the treatment is treatment of Alzheimer's disease.
A compound according to claim 31 , use according to claim 32, or a method according to claim 33, wherein the treatment is treatment of a movement disorder.
44. A compound according to claim 31 , use according to claim 32, or a method
according to claim 33, wherein the treatment is treatment of Huntington's disease. A compound according to claim 31 , use according to claim 32, or a method according to claim 33, wherein the treatment is treatment of Parkinson's disease.
A compound according to claim 31 , use according to claim 32, or a method according to claim 33, wherein the treatment is treatment of a mental disability disorder.
A compound according to claim 31 , use according to claim 32, or a method according to claim 33, wherein the treatment is treatment of an autism spectrum disorder; fragile-X syndrome; or Rett syndrome.
A compound according to claim 31 , use according to claim 32, or a method according to claim 33, wherein the treatment is treatment of a mood disorder.
A compound according to claim 31 , use according to claim 32, or a method according to claim 33, wherein the treatment is treatment of a depression disorder, for example, major depressive disorder.
A compound according to claim 31 , use according to claim 32, or a method according to claim 33, wherein the treatment is treatment of a basal-ganglia- related disorder, for example, a basal-ganglia-related disorder where progressive memory decline is symptomatic.
A compound according to claim 31 , use according to claim 32, or a method according to claim 33, wherein the treatment is treatment of a disease which is ameliorated by inhibiting acetylcholinesterase.
52. A compound according to claim 31 , use according to claim 32, or a method
according to claim 33, wherein the treatment is treatment of a disease which is ameliorated by inhibition of methyl-D-aspartate (NMDA).
A compound according to claim 31 , use according to claim 32, or a method according to claim 33, wherein the treatment is treatment of: a disease which is ameliorated by potentiating excitatory synaptic transmission; a disease which is ameliorated by directly regulating excitatory synapses; a disease which is ameliorated by induction of long-term potentiation; a disease which is ameliorated by lowering the threshold for long-term potentiation induction; a disease which is ameliorated by induction of long-term potentiation in the CA1 ; a disease which is ameliorated by induction of long-term potentiation in the CA3; a disease which is ameliorated by enhancing glutamatergic synapses; a disease which is ameliorated by modulating AM PA receptor function; a disease which is ameliorated by positively modulating AMPA receptor function; a disease which is ameliorated by indirectly modulating signalling cascades initiated by endogenous growth factors; a disease which is ameliorated by indirectly modulating signalling cascades initiated by BDNF; a disease which is ameliorated by indirectly modulating signalling cascades initiated by NGR; a disease which is ameliorated by modulating presynaptic Ca2+ channel function; a disease which is ameliorated by modulating R-type voltage-gated Ca2+ channels; or a disease which is ameliorated by modulating L-type voltage-gated Ca2+ channels.
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