WO2024050312A2 - Potentialisateurs de canaux calciques voltage-dépendants de type t - Google Patents

Potentialisateurs de canaux calciques voltage-dépendants de type t Download PDF

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WO2024050312A2
WO2024050312A2 PCT/US2023/073007 US2023073007W WO2024050312A2 WO 2024050312 A2 WO2024050312 A2 WO 2024050312A2 US 2023073007 W US2023073007 W US 2023073007W WO 2024050312 A2 WO2024050312 A2 WO 2024050312A2
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compound
alkyl
subject
methyl
mmol
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WO2024050312A3 (fr
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Michel WEÏWER
Florence Wagner
Joshua SACHER
Ayan GHOSHAL
Qian Pan
Ludovic DECULTOT
Yan-Ling Zhang
Sean Moran
Arthur J. CAMPBELL
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The Broad Institute, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Voltage-gated calcium channels provide the primary pathway for calcium (Ca 2+ ) ions to enter excitable cells by allowing rapid and selective Ca 2+ entry upon membrane depolarization.
  • voltage-gated Ca 2+ channels By transducing natural voltage transients, such as action potentials, into intracellular Ca 2+ transients, voltage-gated Ca 2+ channels not only contribute to active membrane properties such as Ca 2+ spikes and dendritic information integration, but also underlie many cellular functions including neurotransmitter release, neurite outgrowth, cell survival, hormone release, and gene expression.
  • the functional core of the VGCC is comprised of the Cavai subunit, which contains the ion pore, gating mechanism, toxin-binding domains, and consists of four homologous transmembrane domains (I-IV), cytoplasmic amino- and carboxyl- termini, and intracellular loops connecting each transmembrane domain.
  • I-IV homologous transmembrane domains
  • Cav3 channels are also called T-type calcium channels (T for transient) because they inactivate rapidly.
  • Cav3 T-type channels do not interact with the auxiliary P subunit, and their biophysical properties can be fully reconstituted with the ai subunit alone in heterologous expression system, whereas Cavl or Cav2 Ca 2+ channel ai subunits (Cavl/2) require coexpression of auxiliary P subunits facilitate channel trafficking to the membrane surface for expression.
  • Cav3 T-type currents inactivate and activate at much negative potentials compared to Cavl/2 channels and have a smaller single channel conductance of 8-12 pS in 100 mM Ba 2+ .
  • Cav3 T-type Ca 2+ channels have overlapping voltage dependent activation and inactivation curves, displaying “window currents” where a large fraction of the channels is inactivated but a small fraction of the channels remain constitutively open at physiological resting membrane potentials.
  • Cav3 T-type channels also close slower from the open states compared to Cavl/2 families, allowing large amounts of Ca 2+ influx upon repolarization to trigger membrane depolarization.
  • CACNA1G Three genes (CACNA1G, CACNA 1 H and CACNA1I) encode the three (subtypes) ai subunits of Cav3 T-type calcium channels (Cav3.1, Cav3.2, and Cav3.3 respectively). Human genetics have implicated these genes in neurological and neuropsychiatric disorders. Rare mutations of CACNA1G, the gene encoding the Cav3.1 ai subunit, are associated with severe developmental deficits linked to, for example, spinocerebellar ataxia, idiopathic generalized epilepsy, and cerebellar atrophy. Patients with CACNA1H loss of function mutations are found to be resistant to pain perception, thus serving as the biological basis for blocking Cav3.2 for treating pain.
  • the present disclosure provides compounds that potentiate T-type voltage gated calcium channel, and in particular, the Cav3.3 T-type voltage gated calcium channel.
  • the present disclosure provides evidence demonstrating that administration of Cav3.3 potentiators (e.g., the Cav3.3 potentiators of the present disclosure) have effect on disease states and can be used to provide therapeutic treatment to subject in need thereof.
  • the compounds of the present disclosure selectively potentiate the Cav3.3 T-type voltage gated calcium channel, for example, the a.l.I subunit and/or auxiliary subunit.
  • the compounds of the present disclosure potentiate the T-type voltage gated calcium channels Cav3.1 and Cav3.3.
  • the compounds of the present disclosure do not affect Cav3.2 channels (e.g, ECso for Cav3.2 is greater than 20 pM, do not increase current amplitude for Cav3.2) while providing alteration to Cav3.1 and Cav3.3.
  • the Cav3.3 potentiators of the present disclosure comprise a compound having the structure of formula (I): wherein the dotted circle represents an optionally unsaturated e.g., aromatic) ring; p is 0 or 1; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4;
  • XAI is N, O, or C
  • XA2 is N or C
  • XA3 is N or CRAS
  • RAI is independently at each occurence absent, hydrogen, alkyl (e.g., optionally unsaturated Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3), -C(O)OR, -C(O)R, haloalkyl (e.g., Ci-Cs haloalkyl, lower haloalkyl such as C1-C4 haloalkyl, halomethyl, Ci-Cs fluoroalkyl, lower fluoroalkyl such as C1-C4 fluoroalkyl, fluorom ethyl, difluoromethyl, perfluoroalkyl, Ci-Cs perfluoroalkyl, lower perfluoroalkyl such as C1-C4 perfluoroalkyl, perfluoromethyl), hydroxy, or amino (e.g., - NRR); and two RAI
  • RA3 is independently at each occurrence hydrogen, alkyl (e.g., optionally unsaturated Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3,), alkoxy (e.g., Ci-Cs alkoxy, lower alkoxy such as C1-C4 alkoxy, methoxy, alkoxy substituted with, for example, aryl such as benzyloxy), cyano, -C(0)0R, -C(0)R, or halogen (e.g., F, Cl, Br); wherein RA3 may independently at each occurence have one or more (e.g., two, three, four) points of optional substititution;
  • alkyl e.g., optionally unsaturated Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl
  • XBI is N, S, or CRBI, and one XBI may be absent (e.g., the two neighboring groups are joined by the bond such as a single or double bond to optionally preserve aromaticity);
  • XB2 is independently at each occurrence N, or CRB2;
  • RBI is independently selected at each occurrence from hydrogen, alkyl (e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as - CD3,), haloalkyl (e.g., Ci-Cs haloalkyl, lower haloalkyl such as C1-C4 haloalkyl, halomethyl, Ci-Cs fluoroalkyl, lower fluoroalkyl such as C1-C4 fluoroalkyl, fluoromethyl, difluoromethyl, perfluoroalkyl, Ci-Cs perfluoroalkyl, lower perfluoroalkyl such as C1-C4 perfluoroalkyl, perfluoromethyl), halogen (e.g., F, Cl, Br), and -Rc; wherein RBI may independently at each occurence have one or more (e.g., two, three, four)
  • RB2 is independently selected at each occurrence from hydrogen, alkyl (e.g., optionally unsaturated optionally substituted Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3), haloalkyl (e.g., Ci-Cs haloalkyl, lower haloalkyl such as C1-C4 haloalkyl, halomethyl, Ci-Cs fluoroalkyl, lower fluoroalkyl such as C1-C4 fluoroalkyl, fluoromethyl, difluoromethyl, perfluoroalkyl, Ci-Cs perfluoroalkyl, lower perfluoroalkyl such as C1-C4 perfluoroalkyl, perfluoromethyl), halogen (e.g., F, Cl, Br), and -Rc; wherein RB2 may independently at each occurence have one or
  • XC6 is C, CH, CR, or N
  • Xci, Xc2, Xc3, Xc4, and Xcs are independently CH, CR, N, NH, NR, O, or S; and when the group is a five membered ring, Xcs is absent; and
  • Rci, RC2, RC3, RC4, and Res are independently hydrogen, alkyl (e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3,), -C(O)R, -C(O)NRR, halogen (e.g., F, Cl, Br), haloalkyl haloalkyl (e.g., Ci-Cs haloalkyl, lower haloalkyl such as C1-C4 haloalkyl, halomethyl, Ci-Cs fluoroalkyl, lower fluoroalkyl such as C1-C4 fluoroalkyl, fluoromethyl, difluoromethyl, perfluoroalkyl, Ci-Cs perfluoroalkyl, lower perfluoroalkyl such as C1-C4 perfluoroalkyl, perfluoromethyl),
  • R is independently at each occurrence hydrogen or alkyl (e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3,); or a pharmaceutically acceptable salt thereof.
  • the present disclosure also includes compounds where the bicyclic ring system of formula (I) has been opened to form a sulfonamide where the N geminal amino groups do not together form a ring. These sulfonamides have also been shown to be Cav3.3 potentiators herein.
  • compounds of the present disclosure include those having the structure of formula (V): wherein RDI is hydrogen, alkyl (e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3), haloalkyl (e.g., Ci-Cs haloalkyl, lower haloalkyl such as C1-C4 haloalkyl, halomethyl, Ci-Cs fluoroalkyl, lower fluoroalkyl such as C1-C4 fluoroalkyl, fluoromethyl, difluoromethyl, perfluoroalkyl, Ci-Cs perfluoroalkyl, lower perfluoroalkyl such as C1-C4 perfluoroalkyl, perfluoromethyl), mono or bicyclic heterocyclyl, mono or bicyclic heteroaryl, or aryl and RDI may have one or bicycl
  • R D2 is hydrogen or alkyl (e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3) and RD2 may have one or more (e.g., two, three, four) optional points of substitution;
  • XBI is independently at each occurrence N or CRBI;
  • RBI is independently selected at each occurrence from hydrogen, alkyl (e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as - CD3), and -Rc and RBI may have one or more (e.g., two, three, four) optional points of substitution;
  • alkyl e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as - CD3
  • -Rc and RBI may have one or more (e.g., two, three, four) optional points of substitution;
  • RB2 is independently selected at each occurrence from hydrogen, optionally unsaturated alkyl (e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3), and -Rc and RB2 may have one or more (e.g., two, three, four) optional points of substitution; and at least one of RBI or RB2, is a group -Rc having the structure:
  • optionally unsaturated alkyl e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3
  • -Rc and RB2 may have one or more (e.g., two, three, four) optional points of substitution
  • at least one of RBI or RB2 is a group -Rc having the structure:
  • XC 6 is C, CH, CR, or N;
  • Xci, Xc2, Xc3, Xc4, and Xcs are independently CH, CR, N, NH, NR, O, or S; and when the group is a five membered ring, Xcs is absent; and
  • Rci, RC2, RC3, RC4, and Res are independently hydrogen, alkyl (e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3), -C(O)R, -C(O)NRR, halogen (e.g., F, Cl, O), haloalkyl (e.g., Ci-Cs haloalkyl, lower haloalkyl such as C1-C4 haloalkyl, halomethyl, Ci-Cs fluoroalkyl, lower fluoroalkyl such as C1-C4 fluoroalkyl, fluoromethyl, difluoromethyl, perfluoroalkyl, Ci-Cs perfluoroalkyl, lower perfluoroalkyl such as C1-C4 perfluoroalkyl, perfluoromethyl), or cycloalky
  • R is independently at each occurrence hydrogen, or alkyl (e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3,); or a pharmaceutically acceptable salt thereof.
  • alkyl e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3,
  • compositions containing a pharmaceutically acceptable excipient and a compound as disclosed herein e.g., Cav3.3 potentiators, compounds having the structure of Formula (I), (II), (Ila), (lib), (lie), (lid), (lie), (Ilf), (Ilg), (Ilh), (Hi), (III), (Illa), (IHb), (IIIc), (Hid), (Ille), (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), (Vj), one or more of Compounds 1-69, 71-172, 174-176, 179-265, 269-285, 287-288, 290-291, 293-295, 297-298, 300-301, 305, 307, 312, 314-321, 324-325, 327-340, 342-343, 345, 348-357, 360
  • a Cav3.3 potentiator e.g., Cav3.3 potentiators, compounds having the structure of Formula (I), (II), (Ila), (lib), (lie), (lid), (lie), (Ilf), (Ilg), (Ilh), (Ili), (III), (Illa), (Illb), (IIIc), (Hid), (Ille), (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), (Vj), one or more of Compounds 1-69, 71-172, 174-176, 179-265, 269-285, 287-288, 290-291, 293-295, 297-298, 300-301, 305, 30
  • a Cav3.3 potentiator e.g., Cav3.3 potentiators, compounds having the structure of Formula (I), (II), (Ila), (lib), (lie), (
  • Methods of decreasing thalamocortical hyperactivity and/or increasing thalmocoritical hypoactivity in a subject in need thereof comprise administering to the subject a Cav3.3 potentiator e.g., Cav3.3 potentiators, compounds having the structure of Formula (I), (II), (Ila), (lib), (lie), (Hd), (lie), (Ilf), (Ilg), (Ilh), (Ili), (III), (Illa), (Illb), (IIIc), (Illd), (Ille), (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), (Vj), one or more of Compounds 1-69, 71-172, 174-176, 179-265, 269-285, 287-288, 290-291, 293-295, 297- 298, 300-301, 305, 307, 312, 314
  • the subject is a human.
  • the subject has schizophrenia.
  • thalamacortical hyperactivity and/or hypoactivity in different regions of a subject’s brain may be associated with altered rebound bursting in the reticular thalamus (TRN). Normalizing TRN function may independently augment this hyperactivity and/or hypoactivity (dependent on location) in a subject and decrease the progression of a disease, disorder, or condition.
  • a method of increasing rebound bursting in the reticular thalamus (TRN) of a subject in need thereof comprises administering to said subject a Cav3.3 potentiator. In embodiments, such administration results in a decrease in thalamocorgical hyperactivity in brain regions having this hyperactivity.
  • the subject is a human. In certain embodiments, the subject has schizophrenia. In some embodiments, the subject has a neurodevelopmental disorder or condition associated therewith. In some embodiments, the subject has reticular thalamus (TRN) hypofunction related with aging or neurodegeneration or condition associated therewith in a subject in need thereof comprising administering to said subject a Cav3.3 potentiator. In some embodiments, administering the compound may rescue cognitive and/or motor deficiencies (e.g., as associated with a neurodevelopmental disorder).
  • TRN reticular thalamus
  • Methods of improving cognitive function in a subject in need thereof may comprise adminstrati on of a Cav3.3 potentiator (e.g., Cav3.3 potentiators, compounds having the structure of Formula (I), (II), (Ila), (lib), (lie), (lid), (lie), (Ilf), (Ilg), (Ilh), (Hi), (III), (Illa), (nib), (inc), (Illd), (Ille), (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), (Vj), one or more of Compounds 1-69, 71-172, 174-176, 179-265, 269-285, 287- 288, 290-291, 293-295, 297-298, 300-301, 305, 307, 312, 314-321, 324-325, 327-340, 342- 343, 345, 3
  • the subject has a brain dysfunction such as a brain dysfunction is caused by cerebrovascular disease, brain damage, brain tumor, viral encephalitis, hypoxic encephalopathy, or alcoholism.
  • a brain dysfunction such as a brain dysfunction is caused by cerebrovascular disease, brain damage, brain tumor, viral encephalitis, hypoxic encephalopathy, or alcoholism.
  • the subject has a cognitive dysfunction.
  • the cognitive dysfunction is selected from dysmnesia, attentional deficit, executive function deficit, social behavior disorder, neurogedegenerative disease, mental disease, or pervasive developmental disorder.
  • the subject has a Cav3.3 mutation.
  • the subject may be human and the Cav3.3 mutation is an R1346H mutation.
  • the subject is murine and said the CaV3.3 mutation is and R1305H mutation.
  • the Cav3.3 mutation is homozygous or heterozygous in the subject.
  • the present disclosure also provides methods for the treatment or prophylaxis of schizophrenia, neurodevel opmental disorders, reticular thalamus (TRN) hypofunction (e.g., as related with aging or neurodegeneration) or a condition associated therewith (e.g., cognitive deficit) in a subject in need thereof comprising administering to said subject a Cav3.3 potentiator (e.g., Cav3.3 potentiators, compounds having the structure of Formula (I), (II), (Ila), (lib), (lie), (Hd), (lie), (Ilf), (Ilg), (Ilh), (Hi), (III), (Illa), (Illb), (IIIc), (Hid), (Ille), (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), (Vj), one or more of Compounds 1-69, 71-172, 174-176
  • diseases include schizophrenia or conditions, or disorders associated therewith such as cognitive deficit, decreased sleep spindles, decreased TRN function, or thalamocortical hyperactivity, and combinations thereof.
  • the disorder may be a neuro- developmental disorder such as autism spectrum disorder (ASD), schizophrenia, attention deficit hyperactivity disorder (ADHD), schizoaffective disorder, and bipolar affective disorder.
  • disease may be a neurodegenerative disease such as Alzheimer’s Disease. Alzheimer’s Disease, for example, has been shown to have reduced sleep spindles and the compounds of the present disclosure may provide particular benefit to patients having Alzheimer’s (or disorders or conditions associated therewith).
  • Methods of monitoring target engagement and/or treatment efficacy are also provided in a subject comprising: a) measuring spindle density and/or amplitude in the subject to establish a baseline; b) administering a compound to the subject; c) measuring spindle densityand/or amplitude after said administering step; wherein the comparison of spindle density and/or amplitude after said administering step to baseline is used to monitor target engagement and/or treatment efficacy.
  • the compound is a Cav3.3 potentiator (e.g., compounds having the structure of Formula (I), (II), (Ila), (lib), (lie), (lid), (lie), (Ilf), (Ilg), (Ilh), (Hi), (III), (Illa), (Illb), (IIIc), (Illd), (Ille), (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), (Vj), one or more of Compounds 1-69, 71-172, 174-176, 179-265, 269-285, 287-288, 290-291, 293-295, 297-298, 300-301, 305, 307, 312, 314-321, 324-325, 327-340, 342-343, 345, 348-357, 360-362, 364-375, 377-378, 380-3
  • the sleep spindle density is the density of slow sleep spindles (e.g., 9-12 Hz). In various implementation, the sleep spindle density is the density of fast sleep spindles (e.g., 13-15 Hz).
  • the subject has a brain dysfunction such as a brain dysfunction is caused by cerebrovascular disease, brain damage, brain tumor, viral encephalitis, hypoxic encephalopathy, or alcoholism.
  • the subject has a cognitive dysfunction.
  • the cognitive dysfunction is selected from dysmnesia, attentional deficit, executive function deficit, social behavior disorder, neurogedegenerative disease, mental disease, or pervasive developmental disorder.
  • the subject has autism spectrum disorder (ASD), schizophrenia, attention deficit hyperactivity disorder (ADHD), schizoaffective disorder, bipolar affective disorder, or Alzheimer’s Disease.
  • numeric values include the endpoints and all possible values disclosed between the disclosed values.
  • the exact values of all half-integral numeric values are also contemplated as specifically disclosed and as limits for all subsets of the disclosed range.
  • a range of from 0.1% to 3% specifically discloses a percentage of 0.1%, 1%, 1.5%, 2.0%, 2.5%, and 3%.
  • a range of 0.1 to 3% includes subsets of the original range including from 0.5% to 2.5%, from 1% to 3%, or from 0.1% to 2.5%. It will be understood that the sum of all weight % of individual components will not exceed 100%.
  • agent is meant a small compound, polypeptide or polynucleotide.
  • ameliorate is meant decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease.
  • ingredients include only the listed components along with the normal impurities present in commercial materials and with any other additives present at levels which do not affect the operation of the disclosure, for instance at levels less than 5% by weight or less than 1% or even 0.5% by weight.
  • disease is meant any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ.
  • diseases include schizophrenia or conditions, or disorders associated therewith such as cognitive deficit, decreased sleep spindles, decreased TRN function, or thalamocortical hyperactivity, and combinations thereof.
  • the disorder may be a neuro-devel opmental disorder such as autism spectrum disorder (ASD), schizophrenia, attention deficit hyperactivity disorder (ADHD), schizoaffective disorder, and bipolar affective disorder.
  • disease may be a neurodegenerative disease such as Alzheimer’s Disease. Alzheimer’s Disease, for example, has been shown to have reduced sleep spindles and the compounds of the present disclosure may provide particular benefit to patients having Alzheimer’s (or disorders or conditions associated therewith).
  • an agent e.g., a compound described herein
  • the effective amount of active compound(s) used to practice the present invention for therapeutic treatment of a disease varies depending upon the manner of administration, the age, body weight, and general health of the subject. Ultimately, the attending physician or veterinarian will decide the appropriate amount and dosage regimen. Such amount is referred to as an “effective” amount.
  • Agents described herein include compounds having the structure of Formula (I), (II), (Ila), (lib), (lie), (lid), (lie), (Ilf), (Ilg), (Ilh), (Hi), (III), (Illa), (Illb), (IIIc), (Hid), (Ille), (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), (Vj), one or more of Compounds 1-69, 71-172, 174-176, 179-265, 269-285, 287-288, 290-291, 293-295, 297-298, 300-301, 305, 307, 312, 314-321, 324-325, 327-340, 342-343, 345, 348-357, 360-362, 364- 375, 377-378, 380-392, 395-396, 398-423, 425
  • composition represents a composition containing a compound described herein formulated with a pharmaceutically acceptable excipient.
  • the pharmaceutical composition is manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal.
  • Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gel cap); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other formulation described herein (see below).
  • the phrase “pharmaceutically acceptable” indicates a component generally safe for ingestion or contact with biologic tissues at the levels employed. Pharmaceutically acceptable is used interchangeably with physiologically compatible. It will be understood that the pharmaceutical compositions of the disclosure include nutraceutical compositions (e.g., dietary supplements) unless otherwise specified.
  • reference is meant a standard or control condition.
  • the reference is an untreated control cell or animal.
  • the effect of an agent on a cell or animal is compared to the same animal at an earlier point in time or prior to treatment. This earlier time point or the time prior to treatment is considered a reference. Ranges provided herein are understood to be shorthand for all of the values within the range including the endpoints of the range.
  • a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50.
  • the terms “treat,” treating,” “treatment,” and the like refer to reducing or ameliorating a disorder and/or symptoms associated therewith. It will be appreciated that, although not precluded, treating a disorder or condition does not require that the disorder, condition or symptoms associated therewith be completely eliminated.
  • subject is meant a mammal, including, but not limited to, a human or nonhuman mammal, such as a bovine, equine, canine, ovine, or feline. Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans).
  • a subject in need thereof is typically a subject for whom it is desirable to treat a disease, disorder, or condition as described herein.
  • a subject in need thereof may seek or be in need of treatment, require treatment, be receiving treatment, may be receiving treatment in the future, or a human or animal that is under care by a trained professional for a particular disease, disorder, or condition.
  • substituted refers to a group “substituted” on a hydrocarbon, e.g., an alkyl, at any atom of that group, replacing one or more atoms therein (e.g., the point of substitution) including hydrogen atoms.
  • the substituent(s) on a group are independently any one single, or any combination of two or more of the permissible atoms or groups of atoms delineated for that substituent.
  • a substituent may itself be substituted with any one of the substituents described herein. Substituents may be located pendant to the hydrocarbon chain.
  • substituted with a[n] means the specified group may be substituted with one or more of any combination substituents as described in the present application.
  • a group such as an alkyl or heteroaryl group
  • the group may contain one or more unsubstituted C1-C20 alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls.
  • R substituent
  • the group may be referred to as “R-substituted.”
  • R- substituted the moiety is substituted with at least one R substituent and each R substituent is optionally different (e.g., R may be independently selected at each occurrence from C1-C10 alkyl or C1-C10 heteroalkyl each of which may optionally comprise one or more points of substitution).
  • the term “about” is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. About can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from context, all numerical values provided herein are modified by the term about.
  • Cav3.3 polypeptide is meant a protein or fragment thereof having at least about 85% amino acid sequence identity to NCBI Reference Sequence NP 066919.2 and having voltage-dependent T-type calcium channel subunit alpha-1 activity.
  • the Cav3.3 polypeptide is a member of a subfamily of calcium channels referred to as low voltage-activated, T-type, calcium channel.
  • the Cav3.3 protein is typically characterized by a slower activation and inactivation as compared to the other T-type calcium channels.
  • An exemplary Cav3.3 amino acid sequence follows:
  • the Cav3.3 polypeptide may be a protein having at least about 85% amino acid sequence identity to NCBI Reference Sequence NP_001037773.2 or a fragment thereof which is the voltage-dependent T-type calcium channel subunit alpha- 1 for Mus musculus.
  • Another exemplary Cav3.3 protein sequence is:
  • CACNA1I polynucleotide is meant a polynucleotide encoding a Cav3.3 polypeptide.
  • An exemplary CACNA1I polynucleotide sequence is provided at NCBI Accession No. NM_021096, the mRNA sequence of the calcium voltage-gated channel subunit alpha 1 I for Homo sapiens, which is reproduced below:
  • FIG. 1 A provides a schematic of the Fluorescence Imaging Plate Reader (FLIPR) high throughput assay for performing potentiation measurements on the T-type calcium channel subunits similar to the assay disclosed in Zhang, Y-L., et al., ACS Pharmacol Transl Sci 5.3 (2022): 156-168, which is hereby incorporated by reference in its entirety and particularly in relation to the FLIPR assay and protocol therefor.
  • FIG. IB provides exemplary EC 10 and EC90 responses to KC1.
  • FIG. 2 is a schematic of the automated patch-clamp electrophysiology assay which may be used for specific Mechanism of Action measurements and identify differential response in each subunit.
  • FIGS. 3A-3D provide electrophysiology measurements relating administration of Compound 131.
  • FIGS. 4A-4D provide electrophysiology measurements relating administration of Compound 7.
  • FIG. 5 A shows ex vivo measurements of rebound bursting of thalamic reticular nucleus (TRN) neurons following administration of Compound 7.
  • FIG. 5B shows ex vivo measurements illustrating the decrease in voltage threshold of rebound bursts following administration of Compound 7.
  • FIG. 6A shows ex vivo measurements of rebound bursting of thalamic reticular nucleus (TRN) neurons following administration of Compound 131.
  • FIG. 6B shows ex vivo measurements illustrating the decrease in voltage threshold of rebound bursts following administration of Compound 131.
  • FIG. 7 provides in vivo pharmacokinetic measurements of relevant concentrations of plasma (Cp), blood (Cb), unbound plasma (Cb,u), unbound blood (Cb,u), and spinal fluid (CSF) following IP administration of Compound 57 to mice at either 10 mg/kg or 30 mg/kg.
  • Cp plasma
  • Cb blood
  • Cb unbound plasma
  • Cb,u unbound blood
  • CSF spinal fluid
  • FIG. 8A is a schematic of the social interaction assay in mice.
  • FIG 8B demonstrates that Cav3.3 deletion heterozygous and homozygous mice demonstrate a decrease in social interaction as measured by the social index compared to littermate control mice.
  • FIG 8C shows a similar effect in which Cav3.3 R1305H/WT and R1305H/R1305H homozygous mice have decreased social interaction compared to littermate controls.
  • FIG 8D is a schematic of the Novel Object Recognition assay in mice.
  • FIG 8E shows that Cav3.3 homozygous knockout mice have decreased object recognition measured by the object discrimination ratio compared to littermate controls.
  • FIG. 8A is a schematic of the social interaction assay in mice.
  • FIG 8B demonstrates that Cav3.3 deletion heterozygous and homozygous mice demonstrate a decrease in social interaction as measured by the social index compared to littermate control mice.
  • FIG 8C shows a similar effect in which Cav3.3 R1305H/WT and R1305H/R1305H homozy
  • FIG. 9A is a schematic of the social interaction assay in mice.
  • FIG. 9B demonstrates that Compound 57 administered IP 60 minutes before the social interaction assay can rescue the decreased social interaction in the Cav3.3 deletion heterozygous mice with the most effective dose at lOmgs/kg.
  • FIG. 9C demonstrates that Compound 57 administered IP 60 minutes before the social interaction assay can rescue the decreased social interaction in the Cav3.3 R1305H/R1305H homozygous mice with the most effective dose at lOmgs/kg.
  • FIG. 10A is a schematic of the Novel Object Recognition assay in mice.
  • FIG. 10B demonstrates that Compound 57 administered IP 60minutes before the novel object recognition assay can rescue the decreased object recognition in the Cav3.3 R1305H/WT heterozygous mice with the most effective dose at 30mgs/kg.
  • FIG. 10C demonstrates that Compound 57 administered IP 60minutes before the object recognition assay has no effect in Cav3.3 homozygous knockout mice. For each data set, a one-way ANOVA was performed with a multiple comparison posthoc test. *p ⁇ 0.05; **p ⁇ 0.01.
  • FIG. 11 A is a schematic of the Novel Object Recognition assay in mice.
  • FIG. 1 IB demonstrates that Compound 57 administered IP 60minutes before the novel object recognition assay can rescue the decreased object recognition in the 5xFAD heterozygous mice with the most effective dose at 30mgs/kg.
  • FIG. 12A is a schematic of the mouse electroencephalogram (EEG) electrode placement with one electrode in the frontal cortex, one in the parietal cortex, one reference electrode, one ground electrode and an electromyography (EMG) electrode.
  • FIG. 12B is a schematic of the soundproof EEG recording apparatus.
  • FIG. 12C is the dosing paradigm in which mice are recorded for 12 hours during their light cycle (their sleep cycle). First, there is one day in which the mice habituate to the chamber and the recording apparatus.
  • EEG electroencephalogram
  • FIG. 12D demonstrates that Compound 57 increases 11Hz sleep spindle density at 30mg/kg in WT male mice.
  • FIG. 12E demonstrates a similar finding in which Compound 57 increases 11Hz sleep spindle density at both lOmg/kg and 30mg/kg doses in male Cav3.3 R1305H/R1305H homozygous mice.
  • Compounds of the present disclosure potentiate Cav3.3 subtype of T-type channels and administration thereof to ameliorate diseases, disorders, or conditions as described herein (e.g., schizophrenia, cognitive deficits, decreased sleep spindles, decreased reticular thalamus function, thalamocortical hyperactivity, neurodevelopmental disorders, such as autism spectrum disorder (ASD), schizophrenia, attention deficit hyperactivity disorder (ADHD), schizoaffective disorder, and bipolar affective disorder, a neurodegenerative disease such as Alzheimer’s Disease).
  • diseases, disorders, or conditions as described herein e.g., schizophrenia, cognitive deficits, decreased sleep spindles, decreased reticular thalamus function, thalamocortical hyperactivity, neurodevelopmental disorders, such as autism spectrum disorder (ASD), schizophrenia, attention deficit hyperactivity disorder (ADHD), schizoaffective disorder, and bipolar affective disorder, a neurodegenerative disease such as Alzheimer’s Disease).
  • diseases, disorders, or conditions as described herein e.g., schizophrenia, cognitive deficits,
  • CACNA1I was found to be associated with the risk of schizophrenia by genome wide association studies (Pantelis, Christos, et al. Nature 511.7510 (2014): 421-427, which is hereby incorporated by reference in its entirety).
  • rare loss of function mutations was identified in schizophrenia patients by exome sequencing (Gulsuner, Suleyman, et al. Cell 154.3 (2013): 518-529 which is hereby incorporated by reference in its entirety).
  • de novo variants of CACNA II derived from schizophrenia patients have been found to impair channel trafficking as described in Ghoshal, A. et al. Transl. Psychiatry 10 (2020): 29 and Andrade, A.
  • the Cav3.3 potentiators of the present disclosure may be a compound having the structure of formula (I): wherein the dotted circle represents an optionally unsaturated (e.g. aromatic) ring; p is 0 or 1; m is 0 (and each carbon is bonded to one or two hydrogens), 1, 2, 3, or 4; n is 0, 1, 2,3, or 4;
  • XAI is N, O, or C
  • XA2 is N or C
  • XA3 is N or CRAS; RAI is independently at each occurence hydrogen alkyl (e.g., optionally unsaturated Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3,), -C(O)OR, -C(O)R, haloalkyl e.g., Ci-Cs haloalkyl, lower haloalkyl such as C1-C4 haloalkyl, halomethyl, Ci-Cs fluoroalkyl, lower fluoroalkyl such as C1-C4 fluoroalkyl, fluoromethyl, difluoromethyl, perfluoroalkyl, Ci-Cs perfluoroalkyl, lower perfluoroalkyl such as C1-C4 perfluoroalkyl, perfluoromethyl), hydroxy, or amino (e.g., -NRR);
  • RA3 is independently at each occurrence hydrogen, alkyl (e.g., optionally unsaturated Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3,), alkoxy (e.g., Ci-Cs alkoxy, lower alkoxy such as C1-C4 alkoxy, methoxy, alkoxy substituted with, for example, aryl such as benzyloxy), cyano, -C(0)0R, -C(0)R, or halogen (e.g., F, Cl, Br); wherein RA3 may independently at each occurence have one or more (e.g., two, three, four) points of optional substititution;
  • alkyl e.g., optionally unsaturated Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl
  • XBI is independently at each occurrence N, S, or CRBI, and one XBI may be absent;
  • XB2 is independently at each occurrence N, or CRB2;
  • RBI is independently selected at each occurrence from hydrogen, alkyl (e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as - CD3,), haloalkyl (e.g., Ci-Cs haloalkyl, lower haloalkyl such as C1-C4 haloalkyl, halomethyl, Ci-Cs fluoroalkyl, lower fluoroalkyl such as C1-C4 fluoroalkyl, fluoromethyl, difluoromethyl, perfluoroalkyl, Ci-Cs perfluoroalkyl, lower perfluoroalkyl such as C1-C4 perfluoroalkyl, perfluoromethyl), halogen (e.g., F, Cl, Br), and -Rc; wherein RBI may independently at each occurence have one or more (e.g., two, three, four)
  • RB2 is independently selected at each occurrence from hydrogen, alkyl (e.g., optionally unsaturated optionally substituted Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3), haloalkyl (e.g., Ci-Cs haloalkyl, lower haloalkyl such as C1-C4 haloalkyl, halomethyl, Ci-Cs fluoroalkyl, lower fluoroalkyl such as C1-C4 fluoroalkyl, fluoromethyl, difluoromethyl, perfluoroalkyl, Ci-Cs perfluoroalkyl, lower perfluoroalkyl such as C1-C4 perfluoroalkyl, perfluoromethyl), halogen (e.g., F, Cl, Br), and -Rc; wherein RB2 may independently at each occurence have one or
  • XC6 is C, CH, CR, or N
  • Xci, Xc2, Xc3, Xc4, and Xcs are independently CH, CR, N, NH, NR, O, or S; and when the group is a five membered ring, Xcs is absent; and
  • Rci, RC2, RC3, RC4, and Res are independently hydrogen, alkyl (e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3,), -C(O)R, -C(O)NRR, halogen (e.g., F, Cl, Br), haloalkyl haloalkyl (e.g., Ci-Cs haloalkyl, lower haloalkyl such as C1-C4 haloalkyl, halomethyl, Ci-Cs fluoroalkyl, lower fluoroalkyl such as C1-C4 fluoroalkyl, fluoromethyl, difluoromethyl, perfluoroalkyl, Ci-Cs perfluoroalkyl, lower perfluoroalkyl such as C1-C4 perfluoroalkyl, perfluoromethyl),
  • R is independently at each occurrence hydrogen or alkyl (e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3,); or a pharmaceutically acceptable salt thereof.
  • -Rc has the structure
  • alkyl or alkylene groups described herein refer to a branched or straightchain monovalent saturated aliphatic hydrocarbon radical of 1-30 carbon atoms (e.g., 1-16 carbon atoms, 6-20 carbon atoms, 8-16 carbon atoms, or 4-18 carbon atoms, 4-12 carbon atoms).
  • the alkyl or alkylene group may be unsaturated such as to form alkenyl or alkynyl groups.
  • the alkyl group may be substituted with 1, 2, 3, or 4 substituent groups as defined herein.
  • Alkyl or alkylene groups may have from 1-26 carbon atoms.
  • alkyl groups will have from 6-18 or from 1- 8 or from 1-6 or from 1-4 or from 1-3 carbon atoms, including for example, embodiments having one, two, three, four, five, six, seven, eight, nine, or ten carbon atoms. Any alkyl group may be substituted or unsubstituted. Examples of alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl groups.
  • Heteroalkyl or heteroalkylene groups may refer to branched or straight-chain monovalent saturated aliphatic hydrocarbon radicals with one or more heteroatoms (e.g., N, O, S) in the carbon chain. Heteroalkyl groups may have 1-30 carbon atoms (e.g., 1-16 carbon atoms, 6- 20 carbon atoms, 8-16 carbon atoms, or 4-18 carbon atoms, 4-12 carbon atoms). In some embodiments, the heteroalkyl or heteroalkylene group may be substituted with 1, 2, 3, or 4 substituent groups as defined herein. Heteroalkyl or heteroalkylene groups may have from 1- 26 carbon atoms (e.g., and one or more heteroatoms).
  • heteroalkyl or heteroalkylene groups will have from 6-18 or from 1-8 or from 1-6 or from 1-4 or from 1-3 carbon atoms, including for example, embodiments having one, two, three, four, five, six, seven, eight, nine, or ten carbon atoms.
  • the heteroalkyl group or heteroalkylene group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkyl groups.
  • substituent groups are an alkoxy. Alkoxy substituent groups or alkoxy-containing substituent groups may be substituted by, for example, one or more alkyl groups.
  • Cycloalkyl or cycloalkylene groups described may refer to cyclic aliphatic hydrocarbon radical of 3-15 carbon atoms (e.g., 3-12 carbon atoms, 3-8 carbon atoms, 3-6 carbon atoms, or 3-5 carbon atoms, 3-4 carbon atoms).
  • the cycloalkyl group may be substituted with 1, 2, 3, or 4 substituent groups as defined herein.
  • Cycloalkyl groups may have from 3-12 carbon atoms in the carbon ring. Cycloalkyl groups include monocyclic and multicyclic ring systems such as bicyclic and tricyclic groups.
  • cyclalkyl groups will have from 3-8 or from from 3-6 or from 3-4 or 3 carbon atoms, including for example, embodiments having three, four, five, six, seven, eight, nine, or ten carbon atoms.
  • Any cycloalkyl or cycloalkylene group may be substituted or unsubstituted.
  • Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups.
  • Heterocycloalkyl groups or heterocycloalkylene may to cyclo saturated aliphatic hydrocarbon radicals with one or more heteroatoms (e.g., N, O, S) in the ring.
  • Heterocycloalkyl groups or heterocycloalkylene groups may have 3-15 atoms in the ring 3 (e.g., 3-12 atoms, 3-8 atoms, 3-6 atoms, or 3-5 atoms, 3-4 atoms).
  • the hetercyclooalkyl group or heterocycloalkylene group may be substituted with 1, 2, 3, or 4 substituent groups as defined herein.
  • Aryl or aryelene groups may be aromatic mono-or polycyclic radicals of 6 to 12 carbon atoms having at least one aromatic ring.
  • groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalyl, 1,2-dihydronaphthalyl, indanyl, and IH-indenyl.
  • heteroaryls or heteroaryelenes include mono-or polycyclic radical of 5 to 12 atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N, O, and S, with the remaining ring atoms being C.
  • One or two ring carbon atoms of the heteroaryl group may be replaced with a carbonyl group.
  • heteroaryl groups are pyridyl, benzooxazolyl, benzoimidazolyl, and benzothiazolyl.
  • heterocycloalkyl or heteroaryl groups include:
  • Rc may include one or more substituents as described herein e.g., alkyl substituted).
  • a substituted hydrocarbon group may have as a substituent one or more hydrocarbon radicals, substituted hydrocarbon radicals, or may comprise one or more heteroatoms.
  • substituted hydrocarbon radicals include, without limitation, heterocycles, such as heteroaryls.
  • a hydrocarbon substituted with one or more heteroatoms will comprise from 1-20 heteroatoms.
  • a hydrocarbon substituted with one or more heteroatoms will comprise from 1-12 or from 1-8 or from 1-6 or from 1-4 or from 1-3 or from 1-2 heteroatoms.
  • heteroatoms include, but are not limited to, oxygen, nitrogen, sulfur, phosphorous, halogen (e.g., F, Cl, Br, I), boron, or silicon.
  • heteroatoms will be selected from the group consisting of oxygen, nitrogen, sulfur, phosphorous, and halogen (e.g., F, Cl, Br, I).
  • a heteroatom or group may substitute a carbon (e.g., substituted alkyl may include heteroalkyl).
  • a heteroatom or group may substitute a hydrogen.
  • a substituted hydrocarbon may comprise one or more heteroatoms in the backbone or chain of the molecule (e.g., interposed between two carbon atoms, as in “oxa”).
  • a substituted hydrocarbon may comprise one or more heteroatoms pendant from the backbone or chain of the molecule (e.g., covalently bound to a carbon atom in the chain or backbone, as in “oxo”).
  • all groups described herein may optionally contain one or more substituents, to the extent permitted by valency.
  • Substituents include halogen (e.g., F, Cl), C1-12 straight chain or branched chain alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C6-12 aryl, C3-12 heteroaryl, C3-12 heterocyclyl, C1-12 alkylsulfonyl, nitro, cyano, -COOR, -C(O)NRR’, -OR, -SR, -NRR’, and oxo, such as mono-or di-or tri-substitutions with moieties such as halogen, fluoroalkyl, perfluoroalkyl, perfluroalkoxy, trifluoromethoxy, chlorine, bromine, fluorine, methyl, methoxy, pyridyl, furyl, triazyl, piperazinyl, pyrazoyl, imidazoyl, and the like, each optionally containing one or more heteroatom
  • R and R’ are independently hydrogen, C1-12 alkyl, C1-12 haloalkyl, C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyl, C4-24 cycloalkylalkyl, C6-12 aryl, C7-24 aralkyl, C3-12 heterocyclyl, C3-24 heterocyclylalkyl, C3-12 heteroaryl, or C4-24 heteroarylalkyl.
  • the phrase optionally substituted indicates the designated hydrocarbon group may be unsubstituted (e.g., substituted with H) or substituted.
  • substituted hydrocarbons are hydrocarbons with a hydrogen atom removed and replaced by a substituent (e.g., a common substituent).
  • a substituent e.g., a common substituent.
  • Any hydrocarbon in the present disclosure may be considered substituted or “optionally substituted” with, for example, alkyl (e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3,), heteroalkyl (e.g., Ci-Cs heteroalkyl, lower heteroalkyl such as C1-C4 heteroalkyl), alkoxy substituted alkyl (e.g., Ci-Ce alkyl substituted with Ci-Ce alkoxy such as methoxy), cycloalkyl (e.g., C3-C9 cycloalkyl, C3-C5 cycloalkyl, cyclopropyl), alkoxy
  • substitution at a given atom is limited by valency.
  • a substituent (radical) prefix names such as alkyl or alkylene without the modifier optionally substituted or substituted is understood to mean that the particular substituent is unsubstituted unless otherwise indicated.
  • haloalkyl without the modifier optionally substituted or substituted is still understood to mean an alkyl group, in which at least one hydrogen atom is replaced by halo. Where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding with regard to valencies, and to give compounds which are not inherently unstable.
  • any carbon atom will be bonded to two, three, or four other atoms, consistent with the four valence electrons of carbon. Additionally, when a structure has less than the required number of functional groups indicated, those carbon atoms without an indicated functional group are bonded to the requisite number of hydrogen atoms to satisfy the valency of that carbon unless otherwise indicated.
  • Compounds provided herein can have one or more asymmetric carbon atoms and can exist in the form of optically pure enantiomers, mixtures of enantiomers such as racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.
  • the optically active forms can be obtained for example by resolution of the racemates, by asymmetric synthesis or asymmetric chromatography (chromatography with a chiral adsorbent or eluant).
  • certain of the disclosed compounds may exist in various stereoisomeric forms including stereoisomers, enantiomers, diastereomers, or racemates (z.e., the compound exists as a mixture containing two enantiomers and does not rotate polarized light).
  • Enantiomers of a compound can be prepared, for example, by separating an enantiomer from a racemate using one or more well- known techniques and methods, such as chiral chromatography and separation methods based thereon.
  • the appropriate technique and/or method for separating an enantiomer of a compound described herein from a racemic mixture can be readily determined by those of skill in the art.
  • the compound provided herein may also be present as geometric isomer which differ in the orientation of substituent atoms (e.g., to a carbon-carbon double bond, to a cycloalkyl ring, to a bridged bicyclic system).
  • Atoms (other than H) on each side of a carbon-carbon double bond may be in an E (substituents are on opposite sides of the carbon- carbon double bond) or Z (substituents are oriented on the same side) configuration.
  • “R,” “S,” “S*,” “R*,” “E,” “Z,” “cis,” and “trans,” indicate configurations relative to the core molecule and may be used to indicate the geometric configuration of the presently disclosed compounds.
  • Certain of the disclosed compounds may exist in atropisomeric forms.
  • Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers.
  • the compounds disclosed herein may be prepared as individual isomers by either isomer-specific synthesis or resolved from an isomeric mixture.
  • Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods.
  • the named or depicted stereoisomer may be typically more than 50% (e.g., at least 55%, 60%, 70%, 80%, 90%, 99%, or 99.9%) by weight (or mole fraction) relative to the other stereoisomers.
  • the depicted or named enantiomer is more than 50% (e.g., at least 55%, 60%, 70%, 80%, 90%, 99%, or 99.9%) by weight (or mole fraction) optically pure.
  • the depicted or named diastereomer is more than 50% (e.g., at least 55%, 60%, 70%, 80%, 90%, 99%, or 99.9%) by weight (or mole fraction) pure.
  • Percent optical purity is the ratio of the weight of the enantiomer or over the weight of the enantiomer plus the weight of its optical isomer.
  • Diastereomeric purity by weight is the ratio of the weight of one diastereomer or over the weight of all the diastereomers.
  • Percent purity by mole fraction is the ratio of the moles of the enantiomer or over the moles of the enantiomer plus the moles of its optical isomer.
  • percent purity by moles fraction is the ratio of the moles of the diastereomer or over the moles of the diastereomer plus the moles of its isomer.
  • Solvates of the compounds described herein may form the aggregate of the compound or an ion of the compound with one or more solvents. Such solvents may not interfere with the biological activity of the solute.
  • suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH.
  • Solvates wherein water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water.
  • the compounds described herein may be present as a pharmaceutically acceptable salt.
  • salts are composed of a related number of cations and anions (at least one of which is formed from the compounds described herein) coupled together (e.g., the pairs may be bonded ionically) such that the salt is electrically neutral.
  • Pharmaceutically acceptable salts may retain or have similar activity to the parent compound (e.g., an EDso within 10%) and have a toxicity profile within a range that affords utility in pharmaceutical compositions.
  • pharmaceutically acceptable salts may be suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and are commensurate with a reasonable benefit/risk ratio.
  • Salts are described in: Berge et al., J. Pharmaceutical Sciences 66: 1-19, 1977 and in Pharmaceutically acceptable salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. Salts may be prepared from pharmaceutically acceptable nontoxic acids and bases including inorganic and organic acids and bases.
  • Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, dichloroacetate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glutamate, glycerophosphate, hemisulfate, heptonate, hexanoate, hippurate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, isethionate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, mucate, 2-naphthalenesulfonate,
  • Representative basic salts include alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, aluminum salts, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, caffeine, and ethylamine.
  • Pharmaceutically acceptable acid addition salts of the disclosure can be formed by the reaction of a compound of the disclosure with an equimolar or excess amount of acid.
  • hemi-salts can be formed by the reaction of a compound of the disclosure with the desired acid in a 2:1 ratio, compound to acid.
  • the reactants are generally combined in a mutual solvent such as diethyl ether, tetrahydrofuran, methanol, ethanol, /.w-propanol, benzene, or the like.
  • the salts normally precipitate out of solution within, e.g., one hour to ten days and can be isolated by filtration or other conventional methods.
  • the compounds of the present invention include the compounds themselves, as well as their salts and their prodrugs, if applicable.
  • a salt for example, can be formed between an anion (e.g., halide such as chloride, fluoride, bromide, optionally substituted phosphate, optionally substituted sulfonate, optionally substituted acetate) and a positively charged substituent (e.g, optionally substituted ammonium) on a compound described herein.
  • Suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, and acetate.
  • a salt can also be formed between a cation and a negatively charged substituent (e.g., carboxylate) on a compound described herein.
  • Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion.
  • a prodrug generally converts into an active compound following administration to a subject, for example through in vivo hydrolysis.
  • Examples of prodrugs include Ci-6 alkyl esters of carboxylic acid groups, which, upon administration to a subject, are capable of providing active compounds.
  • the compounds of the present disclosure generally comprise a group Rc which may be, for example, an optionally substituted, five or six membered, nitrogen containing heteroaryl.
  • Rc has the structure: wherein indicates the point of attachment to RL (or RB when RL is absent); and the dotted circle indicates optional unsaturation (e.g., aromaticity);
  • XC 6 is C, CR, or N
  • Xci, Xc2, Xc3, Xc4, and Xcs are independently at each occurrence CH, CR, N, NH, NR, O, or S; and when the group is a five membered ring, Xcs is absent (z.e., it is a bond); and
  • Rci, RC2, RC3, RC4, and Res are independently occurrence hydrogen, alkyl (e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as - CD3,), halogen (e.g., F, Cl, Br), haloalkyl (e.g., Ci-Cs haloalkyl, lower haloalkyl such as Ci- C4 haloalkyl, halomethyl, Ci-Cs fluoroalkyl, lower fluoroalkyl such as C1-C4 fluoroalkyl, fluoromethyl, difluoromethyl, perfluoroalkyl, Ci-Cs perfluoroalkyl, lower perfluoroalkyl such as C1-C4 perfluoroalkyl, perfluoromethyl), cycloalkyl (e.g., C3-C9 cycloalky
  • Rc has the structure: wherein Rci is hydrogen, alkyl, halogen, haloalkyl, cycloalkyl, or -C(O)NRR’, where R and R’ are indpendently hydrogen or loweralkyl.
  • Rc has the structure:
  • Rc may have the structure:
  • Rci may be, for example, hydrogen or lower alkyl (e.g., C1-C4 alkyl, methyl), cycloalkyl (e.g., C3-C5 cycloalkyl), haloalkyl (e.g., C1-C4 haloalkyl, C1-C4 fluoroalkyl, fluromethyl, difluoromethyl).
  • alkyl e.g., C1-C4 alkyl, methyl
  • cycloalkyl e.g., C3-C5 cycloalkyl
  • haloalkyl e.g., C1-C4 haloalkyl, C1-C4 fluoroalkyl, fluromethyl, difluoromethyl
  • the Rc group is conjugated to a central six membered ring in the para configuration with respect to the R L group.
  • the compounds of the present disclosure may have the structure of formula (II): or a pharmaceutically acceptable salt thereof.
  • the compound may have the structure of formula (Ila), (lib), (lie), (lid), (lie), (Ilf), (Ilg), (Ilg), (Ili), or (Ilj ):
  • the comopund may be:
  • the compound may be:
  • Compound 7 The compound may be:
  • the compound may be selected from the group consisting of:
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-N-phenyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • the comopund is
  • the comopund is
  • the Rc group may also be conjugated in the meta configuration of the central six membered ring with respect to the R L group.
  • the compound may have the structure of formula (III):
  • the compound may have the structure of formula (Illa), (Illb), (IIIc), (Hid), or (Ille):
  • the compound may be:
  • the compound may be:
  • the compound may have the structure of formula (IV): wherein each dotted circle independently indicates optionally unsaturation;
  • X is N, C, or CR3
  • p is 1, 2, or 3;
  • Ai, A2, and A3 are independently N, C, or CH; G is C, CH or N;
  • J is N, C, or CH
  • E is O or CH
  • Ri is absent, hydrogen or alkyl (e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3);
  • alkyl e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3;
  • R2-R6 are independently hydrogen or alkyl alkyl (e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3); wherein R2-R6 may independently have one or more points of optional substititution;
  • R7-R9 are independently at each occurrence hydrogen or alkyl alkyl (e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3); wherein R7-R9 may independently have one or more points of optional substititution; or pharmaceutically acceptable salts thereof or prodrugs of any of the foregoing.
  • the compound has the structure of formula (IVa) or (IVb): wherein n is 1 or 2; Y is N, CH, or CRio; and
  • Rio is hydrogen or alkyl (e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3), and Rio may have one or more optional points of substitution.
  • alkyl e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3
  • the compound may be:
  • the compound is:
  • the compounds may have alterations on the bicyclic ring system of Formula (I), (II), (Ila), (lib), (lie), (Hd), (lie), (Ilf), (Ilg), (Ilh), (Hi), (III), (Illa), (Illb), (IIIc), (Hid), or (Ille) to result, in for example, sulfonamides.
  • these systems may retain the features of the central ring (R B ) and R c .
  • the Cav3.3 potentiators of the present disclosure include those having the structure of formula (V): wherein RDI is hydrogen, alkyl (e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3), haloalkyl e.g., Ci-Cs haloalkyl, lower haloalkyl such as C1-C4 haloalkyl, halomethyl, Ci-Cs fluoroalkyl, lower fluoroalkyl such as C1-C4 fluoroalkyl, fluoromethyl, difluoromethyl, perfluoroalkyl, Ci-Cs perfluoroalkyl, lower perfluoroalkyl such as C1-C4 perfluoroalkyl, perfluoromethyl), mono or bicyclic heterocyclyl, mono or bicyclic heteroaryl, or aryl and
  • R D2 is hydrogen or alkyl (e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3) and RD2 may have one or more (e.g., two, three, four) optional points of substitution;
  • XBI is independently at each occurrence N or CRBI;
  • RBI is independently selected at each occurrence from hydrogen, alkyl (e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as - CD3), and -Rc and RBI may have one or more (e.g., two, three, four) optional points of substitution;
  • alkyl e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as - CD3
  • -Rc and RBI may have one or more (e.g., two, three, four) optional points of substitution;
  • RB2 is independently selected at each occurrence from hydrogen, optionally unsaturated alkyl (e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3), and -Rc and RB2 may have one or more (e.g., two, three, four) optional points of substitution; and at least one of RBI or RB2, is a group -Rc having the structure: wherein indicates the point of attachment to the compound and the dotted circle indicates optional aromaticity;
  • optionally unsaturated alkyl e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3
  • -Rc and RB2 may have one or more (e.g., two, three, four) optional points of substitution
  • at least one of RBI or RB2 is a
  • XC 6 is C, CH, CR, or N;
  • Xci, Xc2, Xc3, Xc4, and Xcs are independently CH, CR, N, NH, NR, O, or S; and when the group is a five membered ring, Xcs is absent; and Rci, RC2, RC3, RC4, and Res are independently hydrogen, alkyl (e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3), -C(O)R, -C(O)NRR, halogen (e.g., F, Cl, O), haloalkyl (e.g., Ci-Cs haloalkyl, lower haloalkyl such as C1-C4 haloalkyl, halomethyl, Ci-Cs fluoroalkyl, lower fluoroalkyl such as C1-C4 fluoroalkyl, fluor
  • the compound may be:
  • the identified hydrocarbon groups in the compounds of the present disclosure may be optionally substituted one or more times with a substituent as described herein.
  • RDI is alkyl or aryl optionally substituted one or more times with a substituent selected from alkyl, alkoxy, halogen, -NRR, -C(O)R, -NRC(O)R, and -C(O)NRR; and any two vicinal substituents may together form a five or six membered ring (e.g.
  • RDI is phenyl optionally substituted one or more times with alkyl, alkoxy, halogen, -NRR, - C(O)R, -NRC(O)R, and -C(O)NRR, or dihydrobenzo[b][l,4]dioxin-5-yl optionally substituted one or more times with alkyl.
  • RD2 is hydrogen or lower alkyl (e.g., C1-C4 alkyl such as methyl) optionally substituted with alkoxy or -NRR.
  • the alkyl group may be optionally unsaturated (e.g., alkenyl).
  • RB2 is selected from hydrogen or optionally unsaturated alkyl (e.g., C2-C8 alkenyl, C2-C8 alkynyl, C2-C4 alkenyl, C2-C4 alkynyl, ethenyl).
  • the Cav3.3 potentiator (or activator) may have activity as described in an assay presented herein (e.g., in Example 1).
  • the compound potentiator may have an EC50 for Cav3.3 activation (e.g., as measured by 1 hr incubation) of less than (or from 0.1 nM to) 100 pM (e.g., less than 10 pM, less than 1 pM, less than 100 nM).
  • the compound may be selective for Cav3.3 activation (e.g., EC50 for Cav3.3 activation of less than (or from 0.1 nM to) 20 pM) and may be characterized by, for example, an inactivity for Cav3.2 activation such as having an EC50 for Cav3.2 activation of 20 pM or more.
  • the EC50 may be measured, for example, by the assays described in the Examples including the Fluorescence Imaging Plate Reader (FLIPR) assay.
  • the compounds may be characterized by the assays described in Pan, J, et al, Methods Mol Biol 1787 (2016): 235-252, and Baez-Nieto, D, et al., Brain (2017):awab443, Hansen, K.B. and Brauner-Osborne, H. Methods Mol. Biol. 552 (2009): 269-278, Zhu, T. et al. Acta Pharmacol Sin 29 (2008): 507-516, or Yu, H. et al. Acta Pharmacol Sin 37 (2016): 34-43, each of which is incorporated herein by reference in its entirety, and particularly in relation to high- throughput assay protocols.
  • the compound may be any one of Compounds 1-69, 71-172, 174-176, 179-265, 269- 285, 287-288, 290-291, 293-295, 297-298, 300-301, 305, 307, 312, 314-321, 324-325, 327- 340, 342-343, 345, 348-357, 360-362, 364-375, 377-378, 380-392, 395-396, 398-423, 425-
  • the comound is any one of compounds 1-69, 71-172, 174-176, and 179-255.
  • the compound may have the structure of formula (I) or (V) and is not one or more of Compounds 1-69, 71-172, 174-176, 179-265, 269-285, 287-288, 290-291, 293-295, 297-298, 300-301, 305, 307, 312, 314-321, 324-325, 327-340, 342-343, 345, 348-357, 360-362, 364-375, 377-378, 380-392, 395-396, 398-423, 425-435, 438-439, 441-446, 448, 450, 452-456, 458, 460, 462-463, 465-466, 468-469, 473-
  • the compound is any Compound in Table 1 including a compound selected from Compounds 1-69, 71-172, 174-176, 179-265, 269-285, 287-288, 290-291, 293- 295, 297-298, 300-301, 305, 307, 312, 314-321, 324-325, 327-340, 342-343, 345, 348-357, 360-362, 364-375, 377-378, 380-392, 395-396, 398-423, 425-435, 438-439, 441-446, 448, 450, 452-456, 458, 460, 462-463, 465-466, 468-469, 473-481, 483-492, 494, 496-497, 499- 505, 508-509, 512-515, 518-520, 522-523, 525-529, 532-541, 543-551, 553-558, 560-570, 573-575, 577-583, 585
  • each stereochemical designation provided for compounds of the present disclsoure in Table 1 and the synthetic examples should be considered to have the “orl” label.
  • contemplated within the disclosure are compounds where the indicated stereochemistry is the absolute (“abs”) stereochemistry of the compound (and all enantiomers and mixtures thereof may be embraced by an indicated structure).
  • a compound may be characterized by its order of elution in a chiral separation process, such as those described in the synthetic examples.
  • the compound may be the chirally separated from a mixture of enantiomers, and characterized by its order of elution and property (e.g., increased activity, pharmacokinetic paramters).
  • the compound (e.g., Compound 2, 10, 15, 36, 39, 46, 67, 90, 114, 126, 154, 156, 176, 182, 184, 193, 198, 207, 272, 522, 523, 561, 562) may have the structure: be a mixture, including racemic mixture, thereof.
  • the compound e.g., Compound 21, 24, 27, 55, 59, 68, 83, 88, 91, 116, 120, 138, 153, 186, 262, 263, 264, 307, 389, 433, 555, 557) may have the structure: be a mixture, including racemic mixture, thereof.
  • the compound (e.g., Compound 29, 81, 88, 100, 118, 165, 201, 261, 262, 265, 269, 307, 390, 391, 392, 434, 483, 518) may have the structure: be a mixture, including racemic mixture, thereof.
  • the compound e.g., Compound 29, 81, 88, 100, 118, 165, 201, 261, 262, 265, 269, 307, 390, 391, 392, 434, 483, 518) may have the structure: be a mixture, including racemic mixture, thereof.
  • the compound e.g.,
  • Compound 135, 435) may have the structure: be a mixture, including racemic mixture, thereof.
  • the compound e.g., Compound 63, 357
  • the compound may have the structure be a mixture, including racemic mixture, thereof.
  • the compound may have the structure: be a mixture, including racemic mixture, thereof.
  • the compound e.g., the compound (e.g., a)
  • Compound 210, 230 may have the structure: be a mixture, including a racemic mixture, thereof.
  • the compound e.g., Compound 404
  • the structure be a mixture, including a racemic mixture, thereof.
  • the compound is Compound 22, 34, 40, 48, 57, 71, 74, 77, 79,
  • the compound is:
  • the compound is Compound 1, 3-9, 11-17, 19, 23-24, 26-33, 38, 41- 46, 49, 50-56, 58-66, 68, 72, 75, 78, 80-81, 85-86, 88-89, 91, 93-95, 100, 102-103, 105-106, 109, 116-121, 126-127, 129, 134-136, 138-141, 153-154, 168, 170-171, 176, 182, 184, 187, 191, 193, 198, or 201.
  • the compound is Compound 32, 35, 56, 68, 70,
  • the compound is:
  • the compound is:
  • the compound is:
  • the compounds described herein e.g., Cav3.3 potentiators, Compounds having the structure of Formula (I), (la), (lb), (Ic), (II), (Ila), (lib, (lie), (lid), (lie), (Ilf), (Ilg), (Ilh), (lii), (Ilj), (III), (Illa), (Illb), (IIIc), (Illd), (Ille), (IV), (IVa), or (IVb), one or more of Compounds 1-69, 71-172, 174-176, 179-265, 269-285, 287-288, 290-291, 293-295, 297-298, 300-301, 305, 307, 312, 314-321, 324-325, 327-340, 342-343, 345, 348-357, 360-362, 364-375, 377- 378, 380-392, 395-396, 398-423, 425-435, 438-439, 44
  • Pharmaceutical dosage forms are provided as well, which may comprise a compound of the present disclosure (e.g., Cav3.3 potentiators, Compounds having the structure of Formula (I), (la), (lb), (Ic), (II), (Ila), (lib, (lie), (lid), (lie), (Ilf), (Ilg), (Ilh), (lii), (Ilj), (III), (Illa), (Illb), (IIIc), (Illd), (Ille), (IV), (IVa), or (IVb), one or more of Compounds 1-69, 71- 172, 174-176, 179-265, 269-285, 287-288, 290-291, 293-295, 297-298, 300-301, 305, 307, 312, 314-321, 324-325, 327-340, 342-343, 345, 348-357, 360-362, 364-375, 377-378, 380- 392, 395-396, 398-4
  • Unit dosage forms also referred to as unitary dosage forms, often denote those forms of medication supplied in a manner that does not require further weighing or measuring to provide the dosage (e.g., tablet, capsule, caplet).
  • the compositions of the present disclosure may be present as unit dosage forms.
  • a unit dosage form may refer to a physically discrete unit suitable as a unitary dosage for human subjects and other species, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with any suitable pharmaceutical excipient or excipients.
  • Exemplary, non-limiting unit dosage forms include a tablet (e.g., a chewable tablet), caplet, capsule (e.g., a hard capsule or a soft capsule), lozenge, film, strip, and gel cap.
  • the compounds described herein, including crystallized forms, polymorphs, and solvates thereof may be present in a unit dosage form.
  • Useful pharmaceutical carriers, excipients, and diluents for the preparation of the compositions hereof can be solids, liquids, or gases. These include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • the pharmaceutically acceptable carrier or excipient does not destroy the pharmacological activity of the disclosed compound and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.
  • compositions can take the form of tablets, pills, capsules, suppositories, powders, enterically coated or other protected formulations (e.g., binding on ion-exchange resins or packaging in lipid-protein vesicles), sustained release formulations, solutions, suspensions, elixirs, and aerosols.
  • the carrier can be selected from the various oils including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, and sesame oil. Water, saline, aqueous dextrose, and glycols are examples of liquid carriers, particularly (when isotonic with the blood) for injectable solutions.
  • formulations for intravenous administration comprise sterile aqueous solutions of the active ingredient(s) which are prepared by dissolving solid active ingredient(s) in water to produce an aqueous solution and rendering the solution sterile.
  • suitable pharmaceutical excipients include starch, cellulose, chitosan, talc, glucose, lactose, gelatin, malt, rice, flour, chalk, silica, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, glycerol, propylene glycol, water, and ethanol.
  • compositions may be subjected to conventional pharmaceutical additives such as preservatives, stabilizing agents, wetting or emulsifying agents, salts for adjusting osmotic pressure, and buffers.
  • suitable pharmaceutical carriers and their formulation are described in Remington’s Pharmaceutical Sciences by E. W. Martin. Such compositions will, in any event, contain an effective amount of the active compound together with a suitable carrier so as to prepare the proper dosage form for administration to the recipient.
  • Non-limiting examples of pharmaceutically acceptable carriers and excipients include sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as polyethylene glycol and propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate; coloring agents
  • Cyclodextrins such as a-, P-, and y-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2-and 3-hydroxypropyl-cyclodextrins, or other solubilized derivatives can also be used to enhance delivery of the compounds described herein.
  • the compositions of the invention are formulated in pellets or tablets for an oral administration. According to this type of formulation, they comprise lactose monohydrate, cellulose microcrystalline, crospovidone/povidone, aroma, compressible sugar and magnesium stearate as excipients.
  • the compositions are in the form of pellets or tablets, they are for instance 1 mg, 2 mg, or 4 mg pellets or tablets. Such pellets or tablets are divisible so that they can be cut to suit the posology according to the invention in one or two daily takes.
  • the compositions of the disclosure are formulated in injectable solutions or suspensions for a parenteral administration.
  • the injectable compositions are produced by mixing therapeutically efficient quantity of torasemide with a pH regulator, a buffer agent, a suspension agent, a solubilization agent, a stabilizer, a tonicity agent and/or a preservative, and by transformation of the mixture into an intravenous, sub-cutaneous, intramuscular injection or perfusion according to a conventional method. Possibly, the injectable compositions may be lyophilized according to a conventional method.
  • suspension agents include methylcellulose, polysorbate 80, hydroxyethylcellulose, xanthan gum, sodic carboxymethylcellulose and polyethoxylated sorbitan monolaurate.
  • solubilization agent examples include polyoxy ethylene- solidified castor oil, polysorbate 80, nicotinamide, polyethoxylated sorbitan monolaurate, macrogol and ethyl ester of caste oil fatty acid.
  • the stabilizer includes sodium sulfite, sodium metalsulfite and ether, while the preservative includes methyl p-hydroxybenzoate, ethyl p- hydroxybenzoate, sorbic acid, phenol, cresol and chlorocresol.
  • An example of tonicity agent is mannitol.
  • the pharmaceutical composition further comprises a viscosity enhancing agent.
  • the viscosity enhancing agent includes methylcellulose, hydroxy ethylcellulose, hydroxypropylmethylcellulose and smart hydrogel.
  • the viscosity enhancing agent is hydroxyethylcellulose.
  • the pharmaceutical composition comprises 0.01-1.0% (w/v) viscosity enhancing agent.
  • the intranasal pharmaceutical composition comprises 0.05% (w/v) hydroxyethylcellulose.
  • the pH of the pharmaceutical composition is from 4.0 to 7.5. In other embodiments, the pH of the pharmaceutical composition is from 4.0 to 6.5. In another embodiment the pharmaceutical composition has a pH of from 5.5 to 6.5. In further embodiments, the pharmaceutical composition has a pH of from 6.0 to 6.5. In various implementations, the pH of said aqueous solution or liquid formulation is from pH 3 to pH 7, from pH 3 to pH 6, from pH 4 to pH 6, or from pH 5 to pH 6. These pH ranges may be achieved through the incorporation of one or more pH modifying agents, buffers, and the like.
  • compositions of this invention may include solutions, emulsions (including microemulsions), suspensions, creams, lotions, gels, powders, or other typical solid or liquid compositions used for application to skin and other tissues where the compositions may be used.
  • compositions may contain: additional antimicrobials, moisturizers and hydration agents, penetration agents, preservatives, emulsifiers, natural or synthetic oils, solvents, surfactants, detergents, gelling agents, emollients, antioxidants, fragrances, fillers, thickeners, waxes, odor absorbers, dyestuffs, coloring agents, powders, viscosity-controlling agents and water, and optionally including anesthetics, anti-itch actives, botanical extracts, conditioning agents, darkening or lightening agents, glitter, humectants, mica, minerals, polyphenols, silicones or derivatives thereof, sunblocks, vitamins, and phytomedicinals.
  • the composition of the invention is formulated with the above ingredients so as to be stable for a long period of time, as may be beneficial where continual or long-term treatment is intended.
  • Cav3.3 potentiators are able to induce significant therapeutic to patients in need thereof, including increasing sleep spindles, rescuing sleep spindle deficits, increasing rebound bursting in the reticular thalamus (TRN), and/or decreasing thalamocortical hyperactivity. Additionally, Cav3.3 potentiators are shown herein to rescue social interaction and novel object recognition when administered to subjects.
  • agonization of the Cav channel e.g., by administration of a Cav3.3 potentiator to a subject
  • a disease, disorder, or condition e.g., schizophrenia, cognitive deficits, decreased sleep spindles, decreased reticular thalamus function, thalamocortical hyperactivity, neurodevelopmental disorders, such as autism spectrum disorder (ASD), schizophrenia, attention deficit hyperactivity disorder (ADHD), schizoaffective disorder, and bipolar affective disorder, a neurodegenerative disease such as Alzheimer’s Disease
  • ASD autism spectrum disorder
  • ADHD attention deficit hyperactivity disorder
  • bipolar affective disorder a neurodegenerative disease such as Alzheimer’s Disease
  • the compounds e.g., Cav3.3 potentiators, Compounds having the structure of Formula (I), (la), (lb), (Ic), (II), (Ila), (lib, (lie), (lid), (lie), (Ilf), (Ilg), (Ilh), (lii), (Ilj), (III), (Illa), (Illb), (IIIc), (Illd), (Ille), (IV), (IVa), or (IVb), one or more of Compounds 1-69, 71-172, 174-176, 179-265, 269-285, 287-288, 290-291, 293-295, 297-298, 300-301, 305, 307, 312, 314-321, 324-325, 327-340, 342-343, 345, 348-357, 360-362, 364-375, 377-378, 380-392, 395-396, 398-423, 425-435, 438-439, 441-446, 4
  • the compounds may be used for the preparation of a medicament for the treatment of any disease, disorder, condition, or method described herein.
  • Beneficial or desired results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions; diminishment of extent of disease, disorder, or condition; stabilized (i.e., not worsening) state of disease, disorder, or condition; preventing spread of disease, disorder, or condition; delay or slowing the progress of the disease, disorder, or condition; amelioration or palliation of the disease, disorder, or condition; and remission (whether partial or total), whether detectable or undetectable.
  • a disease, disorder, or condition may be palliated which includes that the extent and/or undesirable clinical manifestations of the disease, disorder, or condition are lessened and/or time course of the progression is slowed or lengthened, as compared to the extent or time course in the absence of treatment.
  • a neurodegenerative disease e.g., Cav3.3 potentiators, Compounds having the structure of Formula (I), (la), (lb), (Ic), (II), (Ila), (lib, (lie), (lid), (lie), (Ilf), (Ilg), (Ilh), (lii), (Ilj), (III), (Illa), (Illb), (IIIc), (Illd), (Ille), (IV), (IVa), or (IVb), one or more of Compounds 1-69, 71-172, 174-176, 179-265, 269-285, 287-288, 290-291, 293-295, 297-298, 300-301, 305, 307, 312, 314-321, 324-325, 327-340, 342-343, 345, 348- 357, 360-362
  • the cognitive dysfunction is a disease selected from Alzheimer's disease, Parkinson disease, Pick's disease, and Huntington's disease, schizophrenia, bipolar disorder, depression, phobia, sleep disorder, drug dependence, autism, Asperger's syndrome, mental deficiency, polyergic disorder, and tic disorder.
  • a compound e.g., Cav3.3 potentiators, Compounds having the structure of Formula (I), (la), (Ib), (Ic), (II), (Ila), (lib, (lie), (lid), (lie), (Ilf), (Ilg), (Ilh), (lii), (Ilj), (III), (Illa), (Illb), (IIIc), (Illd), (Ille), (IV), (IVa), or (IVb), one or more of Compounds 1-69, 71-172, 174-176, 179-265, 269-285, 287-288, 290-291, 293-295, 297-298, 300-301, 305, 307, 312, 314-321, 324-325, 327-340, 342-343, 345, 348-357, 360-362, 364-375, 377-378, 380-392, 395-396, 398
  • a compound e.g., Cav3.3 potentiators
  • the improving of the brain function in the present invention includes improving brain dysfunctions, for example, brain dysfunctions caused by cerebrovascular disease, brain damage, brain tumor, viral encephalitis, hypoxic encephalopathy, and alcoholism.
  • the present disclosure may be applied particularly to cognitive dysfunctions, such as dysmnesia, attentional deficit, executive function deficit, social behavior disorder.
  • Cognitive dysfunctions include, for example, neurodegenerative disease (e.g., Alzheimer's disease, Parkinson disease, Pick's disease, and Huntington's disease), mental disease (e.g., schizophrenia, bipolar disorder, depression, phobia, sleep disorder, drug dependence, etc.), and pervasive developmental disorder (e.g., autism, Asperger's syndrome, mental deficiency, polyergic disorder, tic disorder).
  • the method of treatment of a subject in need thereof comprises administration to the subject a compound (e.g., Cav3.3 potentiators, Compounds having the structure of Formula (I), (la), (Ib), (Ic), (II), (Ila), (lib, (lie), (lid), (lie), (Ilf), (Ilg), (Ilh), (lii), (Ilj), (III), (Illa), (Illb), (IIIc), (Illd), (Ille), (IV), (IVa), or (IVb), one or more of Compounds 1-69, 71-172,
  • the compounds of the present disclosure selectively modulate T-type calcium channels associated with schizophrenia and other conditions disclosed herein (e.g., cognitive deficits, decreased sleep spindles, decreased reticular thalamus function, thalamocortical hyperactivity, neurodevelopmental disorders, such as autism spectrum disorder (ASD), schizophrenia, attention deficit hyperactivity disorder (ADHD), schizoaffective disorder, and bipolar affective disorder, a neurodegenerative disease such as Alzheimer’s Disease).
  • ASD autism spectrum disorder
  • ADHD attention deficit hyperactivity disorder
  • schizoaffective disorder schizoaffective disorder
  • bipolar affective disorder a neurodegenerative disease such as Alzheimer’s Disease.
  • These small molecules rescue sleep spindles deficits observed in schizophrenia patients.
  • Sleep spindles are brain oscillations that are particularly important for memory consolidation during sleep, and Cav3.3 function is critical for sleep spindles formation. Methods for reducing sleep spindle formation are also provided.
  • the sleep spindle may be classified into slow sleep spindles and fast sleep spindles.
  • the difference in the distribution of the powers between a mood disorder state and a normal state can be notably seen in the specific types of sleep spindles such as slow sleep spindles. Therefore, it is possible to diagnose whether the test subject is in the mood disorder state by setting the frequency band of the slow sleep spindles as the specific frequency band.
  • a compound of the present disclosure e.g., Cav3.3 potentiators, Compounds having the structure of Formula (I), (la), (lb), (Ic), (II), (Ila), (lib, (lie), (lid), (lie), (Ilf), (Ilg), (Ilh), (lii), (Ilj), (III), (Illa), (Illb), (IIIc), (Illd), (Ille), (IV), (IVa), or (IVb), one or more of Compounds 1-69, 71-172, 174-176, 179-265, 269-285, 287-288, 290-291, 293-295, 297-298, 300-301, 305, 307, 312, 314-321, 324-325, 327-340, 342-343, 345, 348-357, 360-362, 364-375, 377-378, 380-392, 395-396, 398-423, 425-435, 438-439
  • T-type calcium channel modulators serve as schizophrenia therapeutics, particularly to rescue sleep spindle deficits, and alleviate cognitive symptoms (e.g., working memory impairments, attention and learning impairments).
  • Methods of decreasing thalamocortical hyperactivity in a subject in need thereof may comprise administering to the subject a Cav3.3 potentiator (e.g., a compound having the structure of Formula (I), (la), (lb), (Ic), (II), (Ila), (Hb, (lie), (lid), (lie), (Ilf), (Ilg), (Ilh), (lii), (Ilj), (III), (Illa), (Illb), (IIIc), (Illd), (Ille), (IV), (IVa), or (IVb), one or more of Compounds 1-69, 71-172, 174-176, 179-265, 269-285, 287-288, 290-291, 293-295, 297-298, 300-301, 305, 307, 312, 314-321, 324-325, 327-340, 342-343, 345, 348-357, 360-362, 364-375, 377- 378, 380
  • the subject is a human.
  • the subject has schizophrenia.
  • a method of increasing rebound bursting in the reticular thalamus (TRN) of a subject in need thereof may comprise administering to said subject a Cav3.3 potentiator.
  • the subject is a human.
  • the subject has schizophrenia.
  • the present disclosure also provides methods for the treatment or prophylaxis of schizophrenia or a disease disorder or condition associated therewith (e.g., cognitive deficit) in a subject in need thereof comprising administering to said subject a Cav3.3 potentiator.
  • a disease disorder or condition associated therewith e.g., cognitive deficit
  • the compounds or compositions of the present disclosure may be administered at least once a day for at least one week.
  • the composition is administered at least twice a day for at least two days.
  • the composition is administered approximately daily, at least daily, twice a week, weekly, or for once a month.
  • the composition of the invention is administered for several months, such as at least two months, six months, or one year or longer.
  • the invention is further suited for longterm use, which may be particularly beneficial for preventing recurring infection, or for preventing infection or conditions in at-risk or susceptible patients, including immune compromised patients.
  • Such long-term use may involve treatment for at least two years, three years, four years, or even five or more years.
  • Examples of other drugs to combine with the compounds described herein include pharmaceuticals for the treatment of schizophrenia or conditions or disorders associated therewith. Combination methods can involve the use of the two (or more) agents formulated together or separately, as determined to be appropriate. In one example, two or more drugs are formulated together for the simultaneous or near simultaneous administration of the agents. Kits
  • composition of the invention is a kit, which contains the compositions of the present disclosure packaged to facilitate dispensing and/or administration of the compositions disclosed herein (e.g., compositions comprising one or more Cav3.3 potentiators, compositions comprising one or more compounds having the structure of Formula (I), (la), (lb), (Ic), (II), (Ila), (lib, (lie), (lid), (lie), (Ilf), (Ilg), (Ilh), (lii), (Ilj), (III), (Illa), (IHb), (IIIc), (Illd), (Ille), (IV), (IVa), or (IVb), compositions comprising one or more of Compounds 1-69, 71-172, 174-176, 179-265, 269-285, 287-288, 290-291, 293-295, 297- 298, 300-301, 305, 307, 312, 314-321, 324-325, 327-340, 342-343
  • the packaging or dispenser may include a bottle, tube, spray bottle, or other dispenser.
  • the composition is packaged in a concentrated form, and diluted to a desired concentration upon use by the end user.
  • the composition may be formulated and packaged in a manner suitable for long-term storage to maintain efficacy of the composition.
  • the present disclosure also provides synthetic methods for preparing the active compounds of the present disclosure (e.g., compounds having the structure of Formula (I), (la), (lb), (Ic), (II), (Ila), (lib, (lie), (lid), (lie), (Ilf), (Ilg), (Ilh), (lii), (Ilj), (III), (Illa), (Illb), (IIIc), (Illd), (Ille), (IV), (IVa), or (IVb)) as well as compounds useful as intermediates in those synthetic methods.
  • synthetic methods for preparing the active compounds of the present disclosure e.g., compounds having the structure of Formula (I), (la), (lb), (Ic), (II), (Ila), (lib, (lie), (lid), (lie), (Ilf), (Ilg), (Ilh), (lii), (Ilj), (III), (Illa), (Illb), (IIIc), (Illd), (Ille), (
  • the method for producing a compound of Formula (I) may comprise reacting (or contacting) a compound having the structure of Fomula (V) wherein ZBI is independently selected at each occurrence from hydrogen, optionally unsaturated alkyl, halogen, and -Zi, and at least one ZBI is a coupling group Zl; with a compound having the structure of Formula (VI): wherein Z2 is a coupling group for coupling with Zi.
  • one of Zi or Z2 is a boron containing coupling moiety (eg., dioxaborolanes, dioxaborinanes, or boronic acid or boronic ester such as a group selected from: and the other of Zi or Z2 is a pound having the structure of Formula (I).
  • the synthetic method may involve coupling an intermediate having the structure of Formula (Va) or (Vb): with an intermediate having the structure of Formula (Via) wherein Z is a halogen e.g., Cl, Br, I) to form a compound having the structure of formula (I):
  • the synthetic method may involve coupling a compound having the structure of Formula (Vc) or (Vd): wherein Z is a halogen (e.g., Cl, Br, I); with an intermediate having the structure of formula (VIb): to form a compound having the structure of formula (I):
  • Z is a halogen (e.g., Cl, Br, I)
  • the coupling may occur under transmateal catalyzed coupling conditions such as Buchwald- Hartwig couplings (e.g., with tBuXPhos, Pd2(dba)3, CuO, and combinations thereof), Negishi couplings, Suzuki couplings, Kumada coupldings, or Stille couplings.
  • the intermediates may be reacted under alkaline conditions (e.g., basic conditions as produced from an organic base or inorganic base in solvent) in the presence of a metal catalyst.
  • the metal catalyst may be Pd(dppf)C12CH2C12, Pd(OAc)2, Pd(PPh3)4, Ni(cod2), or Ni(dppf)C12.
  • the coupling may occur in a solvent seletcted from toluene, tetrahydrofuran, N,N-dimethylformamide, dioxane, water, and mixtures thereof.
  • the alkaline conditions may be established through the use of a base dissolved in the solvent, where the base may be, for example, sodium carbonate, potassium carbonate, cesium carbonate, potassium carbonate, sodium hydroxide, barium hydroxide, potassium fluoride, cesium fluoride, and sodium tert-butoxide.
  • High-throughput assays able to identify both inhibitors and potentiators (activators) were to screen compounds.
  • the assays involved T-type Ca 2+ channel cell lines expressing Kir2.3, an inward rectifying potassium channel that can hyperpolarize the cells to -70 mV. This inward rectifying potassium channel creates a physiological membrane potential where most T-type Ca 2+ channels are available to open. Additionally, the assay involved a membrane bound version of the stable ultrasensitive Ca 2+ sensor GCaMP6s (GCaMP6s- CAAX).
  • FIG. 1 A A schematic of this assay is provided in FIG. 1 A with a representative stimulation response of ECio KC1 measurements and EC90 Kci, used for the activity analysis, are provided in FIG. IB. Measurements were performed in triplicate and compounds were incubated with the cells for 1 hour before the cells are challenged with the ECio KCI trigger.
  • Table 2 lists the ECso for various compounds of the present disclosure as measured by a Fluorescence Imaging Plate Reader (FLIPR) assay leveraging the Kir2.3 cell line and GCamP6s-CAAX sensor.
  • FLIPR Fluorescence Imaging Plate Reader
  • EMax maximum response
  • the ECso and maximum response (EMax %) were determined by normalization of response to the maximal response identified for KCI and fit to a 4-parameter logistic equation determining the the minimum response, maximum response (EMax%), the concentration giving the half-maximal response (ECso), and the slope factor of the response curve.
  • SMILES strings are provided without stereochemical information. Every chiral center provided by the SMILES string should be considered to have orl stereochemistry. Compounds with multiple chiral centers (e.g., the enantiomeric pair Compound 135 and Compound 435; the enantiomeric pair Compound 63 and Compound 357) should be considered to have orl, orl stereochemistry with relative stereochemistry as illustrated in Table 1.
  • FIG. 3 A illustrates the measured current voltage relationship associated administration of Compound 131 as compared to DMSO and FIGS. 3B-D provide the voltage-dependent activation, current amplitude, deactivation kinetics for Compound 131 split amongst each Calcium channel, respectively.
  • Compound 131 induces a left-shoft voltage dependent activation and increases the current amplitude in the Cav3.3 channel (but not the Cav3.1 or Cav3.2 channels).
  • FIG. 4A illustrates the measured current voltage relationship associated administration of Compound 7 as compared to DMSO and FIGS. 4B-D provide the voltagedependent activation, current amplitude, deactivation kinetics for Compound 7 split amongst each Calcium channel, respectively.
  • Compound 7 increases the current amplitude in the Cav3.1 and Cav3.3 channels (but not Cav3.2 channels).
  • Example 3 Ex vivo measurements: Brain slice electrophysiology
  • FIG. 5 A provides the number of measured bursts, identified as the mass increase in signal observed across all holding potentials of the assay.
  • FIG. 5B illustrates the threshold of rebound bursts as identified by the drop in threshold voltage for ion flow following administration of Compound 7 to the TRN neurons.
  • FIG. 6A illustrates the number of measured bursts and FIG. 6B provides the threshold of rebound bursts in measured neurons in TRN neurons exposed to 5 pM of Compound 131. Concentrations for each compound measured in the assay were altered in relation to the ECso values. As can be seen Cav3.3 activitors, even having a different mechanism of action on the T-type voltage gated calcium channel, modulate TRN rebound bursting.
  • the relationship of dosing to pharmacokinetics was measured for intraperitoneal administration of Compound 57.
  • Compound 57 was administered at either 10 mg/kg or 30 mg/kg and the blood, plasma, unbound blood, unbound plasma, and spinal fluid concentrations were measured over eight hours.
  • FIG. 7 provides the concentrations of each measured parameter.
  • Table 3 provides the brain maximum concentration (Cmax), area under curve (AUC) following administration, brain half-life (T1/2), plasma partition coefficient, and unbound plasma partition coefficient (K pU u) for each dose. By tripling the dose, the maximum concentration was able to increase 5-fold and the brain AUC increased 7-fold.
  • Cav3.3 knock-out (Cacnali' 1 ' (KO) and Cacnalt 1 ' (Het)) and R1305H mutation knock-in mice (Cacnal i mim (RH/RH) and Cacnali + R (RH Het)) were generated.
  • the R1305H mutation in murine Cav3.3 corresponds to R1346H in the human channel:
  • mice were generated as described in Ghosal et al. Translational Psychiatry 10 (2020): 29, which is hereby incorporated by reference in its entirety and particularly in relation to generation of Cav3.3 knock out and Cav3.3 RH knock-in mice.
  • FIG. 8A provides a schematic of the social interaction assay used on the mice. Briefly, mice were habituated in a three-chambered apparatus. Following habituation, cups were placed in the outermost chambers, where an age-, sex-, and strain matched unfamiliar WT mouse was placed under one cup. The social index for each test mouse was monitored as the ratio of time each test mouse spent proximal to the mouse under the cup was monitored (Mouse-Object/Total Time).
  • FIG. 8B provides the social index ratios for the Cav3.3 knock out mice (Het and KO) as compared to a littermate control mouse (WT).
  • FIG. 8C provides the social index scores for the Cav3.3 RH knock in mice (Het and KO) as compared to a littermate control mouse (WT).
  • RH knock-in mice both heterozygous (RH Het) and homozygous (RH/RH), had significantly decreased social index scores as compared to WT control.
  • homozygous RH knock-in mice had significantly decreased social index scores as compared to heterozygous RH knock-in mice.
  • Test wild type (WT), knock out, and knock-in mice were subjected to a novel object recognition assay as well. A schematic is provided in FIG. 8D.
  • mice were habituated with two identical objects in a chamber (identified as boxes in FIG. 8D). Following 10 minutes of habituation, a novel object (identified as a star in FIG. 8D) replaced one of the familiar objects. The discrimination ratio was assessed as the difference in time the mice spent between the novel object (star) and familiar object (box).
  • FIG. 8E provides the discrimination ratios for the knock-out mice where a statistical difference is seen between the homozygous knock out (KO) mice and the WT.
  • FIG. 8F provides the discrimination ratios for the RH knock in mice, where a statistical difference is seen for both the homozygous (RH/RH) and the heterozygous (RH Het) mice as compared to WT.
  • FIG. 9A compares the measured social index ratios for heterozygous knock out mice illustrating statistically significant rescue of the social index ratio at 10 mg/kg IP administration of compound 57.
  • FIG. 9 compares the measured social index ratios for homozygous RH knock in mice (RH homo) illustrating statistically significant rescue of the social index ratio for mice administered 10 mg/kg compound 57.
  • FIG. 9D illustrates the comparative social index ratios for each of the homozygous knock-out mice (KO/KO).
  • FIG. 10A provides a schematic of the assay protocol.
  • FIG. 10B compares the discrimination ratios for RH heterozygous knock in mice (RH het) illustrating a statistically significant rescue in the discrimination ratio at 30 mg/kg.
  • FIG. 10C compares the discrimination ratios for homozygous knock out mice (KO horn). Basal locomotion for wild type mice dosed at each test concentration was also measured. Administration of Compound 57 at each concentration had no effect on basal locomotion after more than 80 minutes following administration (FIG. 10D).
  • the novel object recognition assay was also performed on 5xFAD heterozygous mice as well.
  • 5xFAD heterozygous mice exhibit amyloid deposition, gliosis, and progressive neuronal loss accompanied by cognitive and motor deficiencies, recapitulating many of the features of human Alzheimer’s Disease (AD).
  • a schematic for the novel optical recognition assay is provided in FIG. 11 A.
  • 5xFAD mice were administered 3 mg/kg, 10 mg/kg, or 30 mg/kg of Compound 57 via IP injection 60 minutes prior to habituation.
  • FIG. 1 IB compares the discrimination ratio for these mice illustrating rescue of the decreased object recognition in the 5xFAD mice at higher doses (the most effective dose being 30 mg/kg).
  • FIG. 12A is a schematic of the electrode place for these measurements, showing one electrode placed in the frontal cortex (EEG2), one electrode placed in the parietal cortex (EEG1), reference electrode placement, ground electrode placement, and electromyography (EMG) electrode placement. Mice were placed in a soundproof EEG chamber and recording apparatus as shown in FIG. 12B.
  • FIG. 12C demonstrates the dosing paradigm. Mice were recorded for 12 hours during their light cycle (sleep cycle). Initially, mice habituate to the chamber and recording apparatus.
  • mice were recorded for a day after being dosed IP with vehicle, then a day being dosed IP with 3 mg/kg Compound 57, then a day being dosed IP with 10 mg/kg Compound 57, then a day being dosed IP with 30 mg/kg Compound 57.
  • the spindle density as measured for each mouse is shown in FIG. 12D (Wild Type), FIG. 12E (R1305H homozygous knock in), and FIG. 12F (Cav3.3 knock out) mice.
  • Compound 57 increases 11 Hz sleep spindle density at 30 mg/kg in WT male mice.
  • 1,2,3,4-tetrahydroquinoxaline (0.95 g, 2.29 mmol) were added l-methyl-4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (570 mg, 2.74 mmol), potassium carbonate (948 mg, 6.86 mmol) in 1,4-Dioxane (6 mL) at room temperature and reaction mixture was degassed with argon for 20 min followed by palladium(2+) bis(cyclopenta-l,3-dien-l- yldiphenylphosphane) methylene chloride iron dichloride (187 mg, 0.229 mmol) was added at room temperature and reaction mixture was heated at 100°C for 6 h.
  • reaction mixture was then heated at 120 °C for 16 h. After completion, the reaction mixture was diluted with water (100 mL) and extracted in ethyl acetate (100 mL x 3). The organic layer was dried over sodium sulphate and vacuum evaporated. The residue obtained was purified by column chromatography in silica using 60%-80% ethyl acetate in hexane. The product fractions were vacuum evaporated and purified by Prep HPLC purification using Sunfire C8(250*19)mm, 5p column in 30%-45% acetonitrile in water containing 0.1% formic acid as modifier, as mobile phase. The product fractions were lyophilized to afford racemic mixture (Broad_P_CaV3.3_673).
  • the racemic mixture was further purified by Chiral Prep HPLC using CHIRALCEL OX-H (250*21.0)mm, 5p column in 25% of 0.1% DEA in IPA:ACN (70:30) in 0.1% DEA in hexane, as mobile phase.
  • the product fractions were vacuum evaporated to afford off white solid of Broad_P_CaV3.3_673B, (27 mg, 14% yield) and off white solid of Broad_P_CaV3.3_673A, (14 mg, 7% yield).
  • reaction was monitored by TLC using 60% Ethyl acetate: Hexane as mobile phase. After completion, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with brine solution (3 x 70 mL). The organic layer was dried over Na2SO4 and evaporated under vacuum.
  • reaction mixture was poured into water (30 mL) and extracted with EtOAc (3 x 20 mL). The organic layer was washed with brine solution (2 x 20 mL), dried over Na2SC>4 and evaporated.
  • the product was added to a Prep HPLC column and was eluted with 40 - 50 % ACN in 0.1 % formic acid in water as a gradient to provide 1,5- dimethyl-4-[2-me (44 mg, 47.1 % yield) as a white solid.
  • reaction mixture was diluted with water (100 mL) and extracted in ethyl acetate (100 mL x 3). The organic layer was dried over sodium sulphate and vacuum evaporated. The residue obtained was purified by column chromatography in silica using 60%-80% ethyl acetate in hexane. The product fractions were vacuum evaporated and purified by Prep HPLC purification using Phenomenex C8(250*21 ,2)mm, 5p column in 30%-45% acetonitrile in water containing 0.1% formic acid as modifier, as mobile phase. The product fractions were lyophilized to afford racemic mixture (Broad_P_CaV3.3_661).
  • the racemic mixture was further purified by Chiral Prep HPLC using CHIRALCEL OX-H (250*21.0)mm,5p column in 40% of 0.1% DEA in IPA:ACN (70:30) in 0.1% DEA in hexane, as mobile phase.
  • the product fractions were vacuum evaporated to afford light brown solid of Broad_P_CaV3.3_661A, (19 mg, 0.0486 mmol, 100% purity, 8% yield) and light brown solid of Broad_P_CaV3.3_661B, (9.4 mg, 0.0235 mmol, 4% yield).
  • N-(3-fluoro-2-methyl-phenyl)acetamide Intermediate-790 To a solution of 3-fluoro-2-methyl-aniline (7.00 g, 55.9 mmol, 1.00 eq) in Dichloromethane (70 mL), Acetic anhydride (7.92 mL, 83.9 mmol, 1.50 eq) was added drop wise at 0° C. and the mixture was stirred for 2 hour at RT. After 2 hour the mixture was quenched cold water (500 mL) and extracted with MDC (2 x 60 mL). The organics were dried with Na2SO4 and evaporated.
  • Solid product provide (2-acetamido-4-fluoro-3-methyl-phenyl)-hydroxy-oxo-ammonium Broad_P_CaV3.3_400_Int_791, (7.00 g, 32.8 mmol, 69% yield) as a white solid.
  • reaction mixtutre was allowed to stir at RT for 5 h. After completion, the reaction mixture was concentrated under vacuum. The residue was stripping with n-hexane 3-4 times and solid was dried under vacuum to provide 4-(4-bromo-2-methyl-phenyl)sulfonyl-5-methyl-2,3- dihydro-lH-quinoxaline;hydrochloride, (2.60 g, 5.85 mmol, 91% yield) as an light brown solid.
  • reaction mixture was poured into ice-cold water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organics were washed with brine solution (2 x 50 mL), dried over Na2SC>4 and evaporated under vacuum to provide tert-butyl 4-(4-bromo-2-methyl- phenyl)sulfonyl-5-methyl-2,3-dihydroquinoxaline-l-carboxylate, (3.10 g, 6.18 mmol, 94% yield) as an yellow solid.
  • Residue was further purified by column chromatography (2%ethyl acetate in n-hexane) gave 3,4,8-trimethyl-2,3-dihydro-lH-quinoxaline, (1.50 g, 8.42 mmol, 53% yield) as yellowish brown liquid.
  • reaction mixture was quenched in water (100 mL) and extracted with ethyl acetate (3 x 100 mL), combine organic layer was dried over sodium sulphate, filtered and concentrated under reduce pressure to obtained crude product which was purify by flash chromatography using [0-50% EtOAc/hexanes] to provide impure product.
  • the impure product was purify by prep HPLC using (35-80% ACN in water containing 0.1% formic acid as modifier) as mobile phase to provide l,5-dimethyl-4-[2-methyl-4-(5-methylpyridin-3- yl)benzenesulf (0.035 g, 17.0 % yield) as a light brown solid.
  • N-methyl bromo sulfonamide 75 mg, 0.1897 mmol, 1 eq
  • ethyl pyrazole boronic acid pinacol ester 50.5 mg, 0.2276 mmol, 1.2 eq
  • sodium carbonate 60.3 mg, 0.5691 mmol, 3 eq
  • XPhos Pd G2 7.46 mg, 0.009485 mmol, 0.05 eq
  • the racemic mixture was purified by Chiral Prep HPLC in CHIRALPAK IH(250*21)mm,5p column using 10% of 0.1% DEA in IPA:Methanol(50:50) in 0.1% DEA in n-hexane, as mobile phase.
  • the product fraction were vacuum evaportaed and lyophilized to afford off white solid of Broad_P_CaV3.3_660B, (21 mg, 0.0533 mmol, 10% yield) and off white solid of Broad_P_CaV3.3_660A, (21 mg, 0.0532 mmol, 10% yield).
  • Tris(dibenzylideneacetone)dipalladium(0) (16 mg, 0.0173 mmol, 0.100 eq) was added and the reaction mixture was heated at 120 °C for 16 h. After 16 h, the reaction mixture was poured in mixture of water (50 mL) and ethyl acetate (3 x 50 mL). The organic layer was dried over sodium sulphate and vacuum evaporated. The residue was purifed by column chromatography in silica using 80%-90% ethyl acetate in hexane as mobile phase.
  • the residue was purified by column chromatography in silica using 50%-60% ethyl acetate in hexane as mobile phase. The product fractions were vacuum evaporated to afford impure product.
  • the impure product was purified by Prep HPLC purification using Phenomenex C8(250*21.2)mm,5p column and 20%-45% acetonitrile in water containing 0.1% formic acid as modifier, as mobile phase, to provide off white solid of 3 ,7-dimethyl- 1 -[2-methyl-4-(4-methylimidazol- 1 -yl)phenyl] sulfonyl-indole Broad_P_CaV3.3_553 (30 mg, 0.0777 mmol, 19% yield).
  • the organic layer was washed with brine solution (2 x 50 mL), dried over Na2SC>4 and evaporated.
  • the impure product was purify by flash chromatography using [0-5% MeOH/DCM] to provide impure product.
  • the impure product was purify by prep HPLC using (20-70% ACN in water containing 0.1% formic acid as modifier) as mobile phase to provide l,5-dimethyl-4- ⁇ [4-methyl-6-(l-methyl-lH-pyrazol- 4-yl)pyridi (0.032 g, 20.6 % yield) as off white solid.
  • N-methyl bromo tetrahydroquinoxaline 45 mg, 0.1138 mmol, 1 eq
  • N- difluoromethyl pyrazole boronic acid (33.3 mg, 0.1365 mmol, 1.2 eq)
  • sodium carbonate 36.1 mg, 0.3414 mmol, 3 eq
  • XPhos Pd G2 4.47 mg, 0.005690 mmol, 0.05 eq
  • the reaction mixture was stirred at 80 °C for 1 day.
  • the reaction mixture was partitioned between water and EtOAc.
  • the combined organic layers were dried with MgSO4, filtered and concentrated.
  • the crude product was purified with reversed-phase chromatography (ACN/water) to afford the desired difluoromethyl pyrazol tetrahydroquinoxaline sulfonamide (20 mg, 37.8 % yield).
  • reaction mixture was quenched in water (50 mL) and extracted with ethyl acetate (3 x 50 mL), combine organic layer was dried over sodium sulphate, filtered and concentrated under reduce pressure to obtained crude product which was purify by flash chromatography using [0-50% EtOAc/Hexanes] to provide impure product, which was further purified by prep HPLC using (40-50% ACN in water containing 0.1% formic acid as modifier) as mobile phase to provide 8-methyl- l-[2-methyl-4-(l -methyl- lH-pyrazol-4-yl)benzenesulf (0.053 g, 35.3 % yield) as a white solid.
  • reaction was purged with nitrogen gas for and then added 1, 1 '-Bis (diphenylphosphino)ferrocene- palladium (Il)dichloride dichloromethane (304 mg, 0.372 mmol, 0.100 eq) and stirred at 110 °C for 2 h. After completion, the reaction mixture was diluted with ethyl acetate (10 mL) and washed with brine solution (3 x 40 mL). The organic layer was dried over Na2SC>4 and evaporated under vacuum.
  • 1, 1 '-Bis (diphenylphosphino)ferrocene- palladium (Il)dichloride dichloromethane 304 mg, 0.372 mmol, 0.100 eq
  • N-methyl bromo sulfonamide 75 mg, 0.1897 mmol, 1 eq
  • cyclopropyl pyrazole boronic acid pinacol ester 53.2 mg, 0.2276 mmol, 1.2 eq
  • sodium carbonate 60.3 mg, 0.5691 mmol, 3 eq
  • XPhos Pd G2 7.46 mg, 0.009485 mmol, 0.05 eq
  • the reaction mixture was stirred at 80 °C for 2 hours. After cooling down to room temperature, the reaction mixture was partitioned between water and EtOAc. The organic layer was dried with MgSO4, filtered and concentrated.
  • the crude product was purified with flash chromatography on silica gel (Hexane/EtOAc) to afford the desired N-methyl sulfonamide cyclopropyl pyrazole (61 mg, 100 % purity, 76% yield).
  • a second purification was made on reverse phase chromatography eluting with (water/ ACN with 0.1% of formic acid) to remove the pinacol and obtained the N-methyl sulfonamide cyclopropyl pyrazole (13.6 mg, 16.9 % yield).

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Abstract

L'invention concerne des potentialisateurs de canaux calciques voltage-dépendants de type T qui sont aptes à augmenter la fonction thalamique, par exemple, à diminuer l'hyperactivité thalamocorticale chez des patients qui le nécessitent. Ces potentialisateurs peuvent être utiles dans de nombreuses maladies ou affections associées telles que la schizophrénie et les troubles du développement neurologique. Les potentialisateurs de Cav ont typiquement la structure de formule (I) ou de formule (V).
PCT/US2023/073007 2022-08-29 2023-08-28 Potentialisateurs de canaux calciques voltage-dépendants de type t WO2024050312A2 (fr)

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FR2708608B1 (fr) * 1993-07-30 1995-10-27 Sanofi Sa Dérivés de N-sulfonylbenzimidazolone, leur préparation, les compositions pharmaceutiques en contenant.
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