T-type voltage-gated calcium channel potentiators

Abstract

T-type voltage-gated calcium channel potentiators are described herein which are able to augment thalamic function, for example, decrease thalamocortical hyperactivity in patients in need thereof. These potentiators may be useful in many diseases or conditions associated therewith such as schizophrenia and neurodevelopmental disorders. The Cav potentiators typically have the structure of Formula (I) or Formula (V).

Description

[0001] T-TYPE VOLTAGE-GATED CALCIUM CHANNEL POTENTIATORS

[0002] CROSS REFERENCE TO RELATED APPLICATIONS

[0003] The present application claims priority to and the benefit of U.S. App. No. 63 / 402,031, filed August 29, 2023, which is hereby incorporated by reference in its entirety.

[0004] STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH

[0005] This invention was made with government support under Grant No. MH115045 awarded by the National Institutes of Health. The government has certain rights in the invention.

[0006] BACKGROUND

[0007] Voltage-gated calcium channels (VGCC) provide the primary pathway for calcium (Ca2+) ions to enter excitable cells by allowing rapid and selective Ca2+entry upon membrane depolarization. By transducing natural voltage transients, such as action potentials, into intracellular Ca2+transients, voltage-gated Ca2+channels not only contribute to active membrane properties such as Ca2+spikes and dendritic information integration, but also underlie many cellular functions including neurotransmitter release, neurite outgrowth, cell survival, hormone release, and gene expression.

[0008] 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. Ten genes encode Cavai subunits in humans and are divided into three major sub-groups based on structural, functional and pharmacological similarities (Cavl, Cav2 and Cav3 families).

[0009] 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 Ca2+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 Ba2+. In addition, Cav3 T-type Ca2+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 Ca2+influx upon repolarization to trigger membrane depolarization. These unique biophysical properties of the T-type Ca2+channels produce Ca2+influx during repolarizations that underlie the rhythmic rebound firing of thalamic neurons in the brain.

[0010] 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.

[0011] Several clinical drugs have been found to block T-type Ca2+channels, including the antihypertensive agent mibefradil (withdrawn from the market due to potential off-target drug-drug interactions), certain neuroleptics and anticonvulsants. However, none of the existing T-type inhibitor drugs is subtype-selective within the Cav3 family. In addition, only one chemical series, represented by the compound SAK3 (ethyl-8’-methyl-2’,4-dioxo-2- (piperidin- 1 -yl)-2’H-spiro [cyclopentane- 1 ,3 '-imidazo [ 1 ,2-a]pyridin]-2-ene-3 -carboxylate), has been reported as an alleged Cav3.3 enhancer. However, no Cav3.3 activation with SAK3 was was measured in Fluorescence Imaging Plate Reader (FLIPR) and electrophysiology assays in HEK cells.

[0012] The critical need to identify potentiators has not been addressed, nor has any correlation between Cav (particularly Cav3.3 potentiation from drug administration) and therapeutic benfit to disease, disorder, or conditions associated with these mutations.

[0013] SUMMARY

[0014] In accordance with the foregoing objectives and others, 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. In some embodiments, 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. In some embodiments, the compounds of the present disclosure potentiate the T-type voltage gated calcium channels Cav3.1 and Cav3.3. In various implementations 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.

[0015] 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;

[0016] XAI is N, O, or C;

[0017] XA2 is N or C;

[0018] XA3 is N or CRAS;

[0019] 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 may together form =0 or a three to six membered spiro ring; wherein RAI may independently at each occurence have one or more (e.g., two, three, four) points of optional substititution;

[0020] RA2 is independently at each occurrence hydrogen, and 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,); wherein any two geminal RA2 groups may together form =0 or a three to six membered spiro ring; wherein RA2 may independently at each occurence have one or more (e.g., two, three, four) points of optional substititution;

[0021] 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;

[0022] RLis -S(=0)2-, -S(=0)-, -S(=NR)(=O)-, or -C(R)(R)-;

[0023] 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);

[0024] XB2 is independently at each occurrence N, or CRB2;

[0025] 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) points of optional substititution;

[0026] 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 more (e.g., two, three, four) points of optional substititution; 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;

[0027] XC6 is C, CH, CR, or N;

[0028] 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

[0029] 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), or cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cyclyalkyl); or may together with an R group form oxo (=0); wherein Rci, Rc2, Rc3, Rc4, and Res may independently have one or more (e.g., two, three, four) points of optional substititution; and

[0030] 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. In some embodiments, R (such as when RLis -S(=NR)(=0)-) may be hydrogen or lower alkyl (e.g., C1-C4 alkyl) such as methyl.

[0031] 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. For example, 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 more (e.g., two, three, four) optional points of substitution (and RDI may be optionally substituted and any two geminal or vicinal substituents may optionally form a five or six membered ring);

[0032] RD2is 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;

[0033] XBI is independently at each occurrence N or CRBI;

[0034] 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;

[0035] 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:

[0036] ZV wherein 7 indicates the point of attachment to the compound and the dotted circle indicates optional aromaticity;

[0037] XC6is C, CH, CR, or N;

[0038] 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

[0039] 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 cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cyclyalkyl); or may together with a geminal R group form oxo (=0), wherein Rci, Rc2, Rc3, Rc4, and Res may independently have one or more (e.g., two, three, four) points of optional substititution; and

[0040] 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.

[0041] The disclosure also provides pharmaceutical 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, 360-362, 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, and 587-596 , one or more of compounds 1-69, 71-172, 174-176, and 179-255), or a pharmaceutically acceptable salt thereof, or a prodrug of any of the foregoing.

[0042] Methods of use of these compounds are also provided. For example, methods of increasing sleep spindles or rescuing sleep spindle deficits in a subject in need thereof are provided which may comprise administering to said subject 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, 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, and 587-596, one or more of compounds 1-69, 71-172, 174-176, and 179-255). In some embodiments, the subject is a human. In certain embodiments, the subject has schizophrenia.

[0043] 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, 314-321, 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, and 587-596, one or more of compounds 1-69, 71-172, 174-176, and 179-255). In some embodiments, the subject is a human. In certain embodiments, the subject has schizophrenia. Without wishing to be bound by theory, 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. For example, 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. In some embodiments, 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).

[0044] 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, 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, and 587-596, one or more of compounds 1-69, 71- 172, 174-176, and 179-255) to the subject , wherein the Cav3.3 potentiator is the compound according to any one of claims 1-41, or a pharmaceutically acceptable salt thereof, or a prodrug of any of the foregoing. In certain implementations, 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. In various implementations, the subject has a cognitive dysfunction. In certain aspects, the cognitive dysfunction is selected from dysmnesia, attentional deficit, executive function deficit, social behavior disorder, neurogedegenerative disease, mental disease, or pervasive developmental disorder.

[0045] In various implentations, the subject has a Cav3.3 mutation. For example, the subject may be human and the Cav3.3 mutation is an R1346H mutation. In some embodiments, the subject is murine and said the CaV3.3 mutation is and R1305H mutation. In some embodiments, 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, 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, and 587-596, one or more of compounds 1-69, 71-172, 174-176, and 179-255). Examples of 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. In some embodiments, 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. In some embodiments, 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).

[0046] 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. In various implementations 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, 380-392, 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, and 587-596, one or more of compounds 1-69, 71-172, 174-176, and 179-255). In some embodiments, the 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). In certain implementations, 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. In various implementations, the subject has a cognitive dysfunction. In certain aspects, the cognitive dysfunction is selected from dysmnesia, attentional deficit, executive function deficit, social behavior disorder, neurogedegenerative disease, mental disease, or pervasive developmental disorder. In some embodiments the subject has autism spectrum disorder (ASD), schizophrenia, attention deficit hyperactivity disorder (ADHD), schizoaffective disorder, bipolar affective disorder, or Alzheimer’s Disease.

[0047] Definitions

[0048] All terms used herein are intended to have their ordinary meaning in the art unless otherwise provided. All concentrations are in terms of percentage by weight of the specified component relative to the entire weight of the topical composition, unless otherwise defined.

[0049] As used herein, “a” or “an” shall mean one or more. As used herein when used in conjunction with the word “comprising,” the words “a” or “an” mean one or more than one. As used herein “another” means at least a second or more. Unless specifically stated or obvious from context, as used herein, the term “or” is understood to be inclusive.

[0050] As used herein, all ranges of 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. For example, a range of from 0.1% to 3% specifically discloses a percentage of 0.1%, 1%, 1.5%, 2.0%, 2.5%, and 3%. Additionally, 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%.

[0051] Throughout this description, various components may be identified having specific values or parameters, however, these items are provided as exemplary embodiments. Indeed, the exemplary embodiments do not limit the various aspects and concepts of the present disclosure as many comparable parameters, sizes, ranges, and / or values may be implemented. Unless otherwise specified, the terms “first,” “second,” and the like, “primary,” “secondary,” and the like, do not denote any order, quantity, or importance, but rather are used to distinguish one element from another.

[0052] By “agent” is meant a small compound, polypeptide or polynucleotide.

[0053] By “ameliorate” is meant decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease.

[0054] By “consist essentially” it is meant that the 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.

[0055] By “disease” is meant any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ. Examples of 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. In some embodiments, 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. In some embodiments, 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).

[0056] The term “effective amount” or “therapeutically effective amount” of an agent is meant the amount of an agent (e.g., a compound described herein) required to ameliorate the symptoms of a disease relative to an untreated patient. 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, 425-435, 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, and 587-596, one or more of compounds 1-69, 71-172, 174-176, and 179-255). In some embodiments, the compounds are administered in an effective amount for the treatment of a disease disorder or condition.

[0057] The term “pharmaceutical composition,” as used herein, represents a composition containing a compound described herein formulated with a pharmaceutically acceptable excipient. In some embodiments, 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).

[0058] As used herein, 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.

[0059] By “reference” is meant a standard or control condition. In one embodiment, the reference is an untreated control cell or animal. In another embodiment, 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. For example, 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.

[0060] As used herein, 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.

[0061] By “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. For example, 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.

[0062] The term “substituent” 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. In some aspects, 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. In another aspect, a substituent may itself be substituted with any one of the substituents described herein. Substituents may be located pendant to the hydrocarbon chain.

[0063] In addition, the phrase “substituted with a[n],” as used herein, means the specified group may be substituted with one or more of any combination substituents as described in the present application. For example, where a group, such as an alkyl or heteroaryl group, is “substituted with an unsubstituted C1-C20 alkyl, or unsubstituted 2 to 20 membered heteroalkyl,” the group may contain one or more unsubstituted C1-C20 alkyls, and / or one or more unsubstituted 2 to 20 membered heteroalkyls. Moreover, where a moiety is substituted with an R substituent, the group may be referred to as “R-substituted.” Where a moiety is 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).

[0064] Unless specifically stated or obvious from context, as used herein, 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.

[0065] By “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:

[0066] 1 maesasppss saaapaaepg vtteqpgprs ppssppglee pldgadphvp hpdlapiaf f

[0067] 61 clrqttsprn wcikmvcnpw f ecvsmlvil Incvtlgmyq pcddmdclsd rckilqvf dd

[0068] 121 f if if f amem vlkmvalgif gkkcylgdtw nrldf f ivma gmveysldlq ninlsairtv

[0069] 181 rvlrplkain rvpsmrilvn llldtlpmlg nvlllcf fvf f ifgiigvql wagllrnrcf

[0070] 241 leenf tiqgd valppyyqpe eddempf ics Isgdngimgc heipplkeqg recclskddv

[0071] 301 ydfgagrqdl nasglcvnwn ryynvcrtgs anphkgainf dnigyawivi f qvitlegwv

[0072] 361 eimyyvmdah sfynf iyf il liivgsf fmi nlclvviatq f setkqrehr Imleqrqryl

[0073] 421 ssstvasyae pgdcyeeif q yvchilrkak rralglyqal qsrrqalgpe apapakpgph

[0074] 481 akeprhyhgk tkgqgdegrh Igsrhcqtlh gpaspgndhs grelcpqhsp Idatphtlvq

[0075] 541 pipatlasdp ascpccqhed grrpsglgst dsgqegsgsg ssaggedead gdgarssedg

[0076] 601 asselgkeee eeeqadgavw Icgdvwretr aklrgivdsk yfnrgimmai Ivntvsmgie

[0077] 661 hheqpeeltn ileicnvvf t smf alemilk laafglf dyl rnpynif dsi iviisiweiv

[0078] 721 gqadgglsvl rtf rllrvlk Ivrfmpalrr qlvvlmktmd nvatf cmllm If if if silg

[0079] 781 mhifgckf si rtdtgdtvpd rknf dsllwa ivtvf qiltq edwnvvlyng mastspwasl

[0080] 841 yfvalmtfgn yvlfnllvai Ivegf qaegd anrsysdedq sssnieef dk Iqegldssgd

[0081] 901 pklcpipmtp nghldpslpl gghlgpagaa gpaprlslqp dpmlvalgsr kssvmslgrm

[0082] 961 sydqrslsss rssyygpwgr saawasrrss wnslkhkpps aehesllsae rgggarvcev

[0083] 1021 aadegppraa plhtphahhi hhgphlahrh rhhrrtlsld nrdsvdlael vpavgahpra

[0084] 1081 awraagpapg hedcngrmps iakdvf tkmg drgdrgedee eidytlcf rv rkmidvykpd

[0085] 1141 wcevredwsv ylf spenrf r vlcqtiiahk If dyvvlaf i f Incitiale rpqieagste

[0086] 1201 rif Itvsnyi f taifvgemt Ikvvslglyf geqaylrssw nvldgf Ivfv siidivvsla

[0087] 1261 saggakilgv Irvlrllrtl rplrvisrap glklvvetli sslkpigniv liccaf f iif

[0088] 1321 gilgvqlf kg kfyhclgvdt rnitnrsdcm aanyrwvhhk ynf dnlgqal mslfvlaskd

[0089] 1381 gwvnimyngl davavdqqpv tnhnpwmlly f isf llivsf fvlnmfvgvv venf hkcrqh

[0090] 1441 qeaeearrre ekrlrrlekk rrkaqrlpyy atychtrlli hsmctshyld if itf iicln

[0091] 1501 vvtmslehyn qptsletalk ycnymf ttvf vleavlklva fglrrf f kdr wnqldlaivl

[0092] 1561 Isvmgitlee ieinaalpin ptiirimrvl riarvlkllk matgmralld tvvqalpqvg

[0093] 1621 nlgllfmllf f iyaalgvel fgklvcnden pcegmsrhat f enfgmaf It If qvstgdnw

[0094] 1681 ngimkdtlrd cthderscls slqfvsplyf vsfvltaqfv linvvvavlm khlddsnkea

[0095] 1741 qedaemdael elemahglgp gprlptgspg apgrgpggag gggdtegglc rrcyspaqen

[0096] 1801 Iwldsvslii kdslegelti idnlsgsif h hysspagckk chhdkqevql aeteaf sins

[0097] 1861 drsssillgd dlsledptac ppgrkdskge Idppepmrvg dlgecf fpls stavspdpen 1921 flcemeeipf npvrswlkhd ssqappspfs pdasspllpm paeffhpavs asqkgpekgt 1981 gtgtlpkial qgswaslrsp rvnctllrqa tgsdtsldas psssagslqt tledsltlsd 2041 sprralgppa papgpragls paarrrlslr grglfslrgl rahqrshssg gstspgcthh 2101 dsmdpsdeeg rggaggggag sehsetlssl sltslfcppp pppapgltpa rkfsstssla 2161 apgrphaaal ahglarspsw aadrskdppg raplpmglgp lapppqplpg elepgdaask 2221 rkr

[0098] 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:

[0099] 1 madsnlppss saapdpepgi teqpgprspp psppgleepl dgtnpdvphp dlapvaffcl

[0100] 61 rqttsprnwc ikmvcnpwfe cvsmlvilln cvtlgmyqpc ddmeclsdrc kilqvfddfi

[0101] 121 fiffamemvl kmvalgifgk kcylgdtwnr Idffivmagm veysldlqni nlsairtvrv

[0102] 181 Irplkainrv psmrilvnll Idtlpmlgnv lllcffvffi fgiigvqlwa gllrnrcfle

[0103] 241 enftiqgdva Ippyyqpeed dempficsls gdngimgche ipplkeqgre cclskddmyd

[0104] 301 fgagrqdlna sglcvnwnry ynvcrtgnan phkgainfdn igyawivifq vitlegwvei

[0105] 361 myyvmdahsf ynfiyfilli ivgsffminl clvviatqfs etkqrehrlm leqrqrylss

[0106] 421 stvasyaepg dcyeeifqyv chilrkakrr alglyqalqn rrqatgpgtp apakpgphak

[0107] 481 epshcklcpr hspldttpht Ivqpisaila sdpsscprcq heagrrpsgl gstdsgqegs

[0108] 541 gsggsaeaea ngdgpqssed gvssglgkee eqedgaarlc gdvwretrak Irgivdskyf

[0109] 601 nrgimmailv ntvsmgiehh eqpeeltnil eicnwftsm falemilkla afglfdylrn

[0110] 661 pynifdsiiv iisiweivgq adgglsvlrt frllrvlklv rfmpalrrql vvlmktmdnv

[0111] 721 atfcmllmlf ififsilgmh ifgckfslrt dtgdtvpdrk nfdsllwaiv tvfqiltqed

[0112] 781 wnvvlyngma sttpwaslyf valmtfgnyv Ifnllvailv egfqaegdan rsysdedqss

[0113] 841 snleeldklp egldssrdlk Icpipmtpng hldpslplgg hlgpagamga aprlslqpdp

[0114] 901 vlvalesrks svmslgrmsy dqrslsssrs syygpwgrsg twasrrsswn slkhkppsae

[0115] 961 hesllsgerg gscvracega redappraap lhaphthhah hgphlahrhr hhrrtlsldt

[0116] 1021 rdsvdlaelv pvvgahsraa wraagqapgh edcngrmpni akdvftkmdd rrdrgedeee

[0117] 1081 idytlcfrvr kmidvykpdw cevredwsvy Ifspenkfri Icqtiiahkl fdyvvlafif

[0118] 1141 Incitialer pqieagster ifltvsnyif taifvgemtl kvvslglyfg eqaylrsswn

[0119] 1201 vldgflvfvs iidivvsvas aggakilgvl rvlrllrtlr plrvisrapg Iklvvetlis

[0120] 1261 slkpignivl iccaffiifg ilgvqlfkgk fyhclgvdtr nitnrsdcva anyrwvhhky

[0121] 1321 nfdnlgqalm slfvlaskdg wvnimyngld avavdqqpvt nhnpwmllyf isfllivsff

[0122] 1381 vlnmfvgwv enfhkcrqhq eaeearrree krlrrlekkr rkaqrlpyya tycptrllih

[0123] 1441 smctshyldi fitfiiclnv vtmslehynq ptsletalky cnymfttvfv leavlklvaf

[0124] 1501 glrrffkdrw nqldlaivll svmgitleei einaalpinp tiirimrvlr iarvlkllkm

[0125] 1561 atgmralldt vvqalpqvgn Igllfmllff iyaalgvelf gklvcndenp cegmsrhatf

[0126] 1621 enfgmafltl fqvstgdnwn gimkdtlrdc thdersclss Iqfvsplyfv sfvltaqfvl

[0127] 1681 invvvavlmk hlddsnkeaq edaemdaeie lemahglgpg pgpcpcpcpc pcpcpcpgpr

[0128] 1741 mptsspgapg rgsggagvgg dteshlcrhc yspaqetlwl dsvsliikds legeltiidn

[0129] 1801 Isgsifhhys spagcdkchh dkqevqlaet eafslnsdrs ssvllgddls ledptacpqg

[0130] 1861 pkeskgelep pepmqagdld ecffpfagep vsagpesllc emgaipfnpv qswlkhesnq

[0131] 1921 appspfspdg sspllqmpae ffhpavsasq kgqepgmssg tlpkialqgs waslrspsvn

[0132] 1981 ctllrqatvs dtsldaspss sagslqttle dsltlsdspr ralgppvqvp gpraslspat

[0133] 2041 rrrlslrgrg Ifslrglrah qrshssggst spgctyhdsm dpsdeegrgg aggggagseh

[0134] 2101 setlsslslt slfclpptlp ppgltparkf sstsslaagp grpgatvsvr glarspswaa

[0135] 2161 drskdppgqa qlasgfgssa pepqpppges tdaaskrkr

[0136] By “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:

[0137] 1 atggctgaga gcgcctcccc gccctcctca tctgcagcag ccccagccgc tgagccagga 61 gtcaccacgg agcagcccgg accccggagc cccccatcct ccccgccagg cctggaggag 121 cctctggatg gagctgatcc tcatgtccca cacccagacc tggcgcctat tgccttcttc 181 tgcctgcgac agaccaccag cccccggaac tggtgcatca agatggtgtg caacccgtgg 241 tttgaatgtg tcagcatgct ggtgatcctg ctgaactgcg tgacacttgg catgtaccag 301 ccgtgcgacg acatggactg cctgtccgac cgctgcaaga tcctgcaggt ctttgatgac 361 ttcatcttta tcttctttgc catggagatg gtgctcaaga tggtggccct ggggattttt 421 ggcaagaagt gctacctcgg ggacacatgg aaccgcctgg atttcttcat cgtcatggca 481 gggatggtcg agtactccct ggaccttcag aacatcaacc tgtcagccat ccgcaccgtg 541 cgcgtcctga ggcccctcaa agccatcaac cgcgtgccca gtatgcggat cctggtgaac 601 ctgctcctgg acacactgcc catgctgggg aatgtcctgc tgctctgctt ctttgtcttc 661 ttcatctttg gcatcatagg tgtgcagctc tgggcgggcc tgctgcgtaa ccgctgcttc 721 ctggaggaga acttcaccat acaaggggat gtggccttgc ccccatacta ccagccggag 781 gaggatgatg agatgccctt catctgctcc ctgtcgggcg acaatgggat aatgggctgc 841 catgagatcc ccccgctcaa ggagcagggc cgtgagtgct gcctgtccaa ggacgacgtc 901 tacgactttg gggcggggcg ccaggacctc aatgccagcg gcctctgtgt caactggaac 961 cgttactaca atgtgtgccg cacgggcagc gccaaccccc acaagggtgc catcaacttt 1021 gacaacatcg gttatgcttg gattgtcatc ttccaggtga tcactctgga aggctgggtg 1081 gagatcatgt actacgtgat ggatgctcac tccttctaca acttcatcta cttcatcctg 1141 cttatcatag tgggctcctt cttcatgatc aacctgtgcc tcgttgtcat agcgacccag 1201 ttctcggaga ccaagcaacg ggagcaccgg ctgatgctgg agcagcggca gcgctacctg 1261 tcctccagca cggtggccag ctacgccgag cctggcgact gctacgagga gatcttccag 1321 tatgtctgcc acatcctgcg caaggccaag cgccgcgccc tgggcctcta ccaggccctg 1381 cagagccggc gccaggccct gggcccggag gccccggccc ccgccaaacc tgggccccac 1441 gccaaggagc cccggcacta ccatgggaag actaagggtc agggagatga agggagacat 1501 ctcggaagcc ggcattgcca gactttgcat gggcctgcct cccctggaaa tgatcactcg 1561 ggaagagagc tgtgcccgca acatagcccc ctggatgcga cgccccacac cctggtgcag 1621 cccatccccg ccacgctggc ttccgatccc gccagctgcc cttgctgcca gcatgaggac 1681 ggccggcggc cctcgggcct gggcagcacc gactcgggcc aggagggctc gggctccggg 1741 agctccgctg gtggcgagga cgaggcggat ggggacgggg cccggagcag cgaggacgga 1801 gcctcctcag aactggggaa ggaggaggag gaggaggagc aggcggatgg ggcggtctgg 1861 ctgtgcgggg atgtgtggcg ggagacgcga gccaagctgc gcggcatcgt ggacagcaag 1921 tacttcaacc ggggcatcat gatggccatc ctggtcaaca ccgtcagcat gggcatcgag 1981 caccacgagc agccggagga gctgaccaac atcctggaga tctgcaatgt ggtcttcacc 2041 agcatgtttg ccctggagat gatcctgaag ctggctgcat ttgggctctt cgactacctg 2101 cgtaacccct acaacatctt cgacagcatc attgtcatca tcagcatctg ggagattgtg 2161 gggcaggcgg acggtgggct gtcggtgctg cggaccttcc ggctgctgcg cgtgctgaaa 2221 ctggtgcgct tcatgcctgc cctgcggcgc cagctcgtgg tgctcatgaa gaccatggac 2281 aacgtggcca ccttctgcat gctgctcatg ctcttcatct tcatcttcag catccttggg 2341 atgcatattt ttggctgcaa gttcagcctc cgcacggaca ctggagacac ggtgcccgac 2401 aggaagaact tcgactccct gctgtgggcc atcgtcactg tgttccagat cctcacccag 2461 gaggactgga acgtcgttct ctacaatggc atggcctcca cttctccctg ggcctccctc 2521 tactttgtcg ccctcatgac cttcggcaac tatgtgctct tcaacctgct ggtggccatc 2581 ctggtggagg gcttccaggc ggagggtgac gccaatcgct cctactcgga cgaggaccag 2641 agctcatcca acatagaaga gtttgataag ctccaggaag gcctggacag cagcggagat 2701 cccaagctct gcccaatccc catgaccccc aatgggcacc tggaccccag tctcccactg 2761 ggtgggcacc taggtcctgc tggggctgcg ggacctgccc cccgactctc actgcagccg 2821 gaccccatgc tggtggccct gggctcccga aagagcagtg tcatgtctct agggaggatg 2881 agctatgacc agcgctccct gtccagctcc cggagctcct actacgggcc atggggccgc 2941 agcgcggcct gggccagccg tcgctccagc tggaacagcc tcaagcacaa gccgccgtcg 3001 gcggagcatg agtccctgct ctctgcggag cgcggcggcg gcgcccgggt ctgcgaggtt 3061 gccgcggacg aggggccgcc gcgggccgca cccctgcaca ccccacacgc ccaccacatt 3121 catcacgggc cccatctggc gcaccgccac cgccaccacc gccggacgct gtccctcgac 3181 aacagggact cggtggacct ggccgagctg gtgcccgcgg tgggcgccca cccccgggcc 3241 gcctggaggg cggcaggccc ggcccccggg catgaggact gcaatggcag gatgcccagc 3301 atcgccaaag acgtcttcac caagatgggc gaccgcgggg atcgcgggga ggatgaggag 3361 gaaatcgact acaccctgtg cttccgcgtc cgcaagatga tcgacgtcta taagcccgac 3421 tggtgcgagg tccgcgaaga ctggtctgtc tacctcttct ctcccgagaa caggttccgg 3481 gtcctgtgtc agaccattat tgcccacaaa ctcttcgact acgtcgtcct ggccttcatc 3541 tttctcaact gcatcaccat cgccctggag cggcctcaga tcgaggccgg cagcaccgaa 3601 cgcatctttc tcaccgtgtc caactacatc ttcacggcca tcttcgtggg cgagatgaca 3661 ttgaaggtag tctcgctggg cctgtacttc ggcgagcagg cgtacctacg cagcagctgg 3721 aacgtgctgg atggctttct tgtcttcgtg tccatcatcg acatcgtggt gtccctggcc

[0138] 3781 tcagccgggg gagccaagat cttgggggtc ctccgagtct tgcggctcct gcgcacccta

[0139] 3841 cgccccctgc gtgtcatcag ccgggcgccg ggcctgaagc tggtggtgga gacactcatc

[0140] 3901 tcctccctca agcccatcgg caacatcgtg ctcatctgct gtgccttctt catcatcttt

[0141] 3961 ggcatcctgg gagtgcagct cttcaagggc aagttctacc actgtctggg cgtggacacc

[0142] 4021 cgcaacatca ccaaccgctc ggactgcatg gccgccaact accgctgggt ccatcacaaa

[0143] 4081 tacaacttcg acaacctggg ccaggctctg atgtccctct ttgtcctggc atccaaggat

[0144] 4141 ggttgggtga acatcatgta caatggactg gatgctgttg ctgtggacca gcagcctgtg

[0145] 4201 accaaccaca acccctggat gctgctgtac ttcatctcct tcctgctcat cgtcagcttc

[0146] 4261 tttgtgctca acatgtttgt gggtgtcgtg gtggagaact tccacaagtg ccggcagcac

[0147] 4321 caggaggctg aagaggcacg gcggcgtgag gagaagcggc tgcggcgcct ggagaagaag

[0148] 4381 cgccggaagg cccagcggct gccctactat gccacctatt gtcacacccg gctgctcatc

[0149] 4441 cactccatgt gcaccagcca ctacctggac atcttcatca ccttcatcat ctgcctcaac

[0150] 4501 gtggtcacca tgtccctgga gcactacaat cagcccacgt ccctggagac agccctcaag

[0151] 4561 tactgcaact atatgttcac cactgtcttt gtgctggagg ctgtgctgaa gctggtggca

[0152] 4621 tttggtctga ggcgcttctt caaggaccga tggaaccagc tggacctggc cattgtgcta

[0153] 4681 ctgtcagtca tgggcatcac cctggaggag atcgagatca atgcggccct gcccatcaat

[0154] 4741 cccaccatca tccgcatcat gagggttctg cgcattgccc gagtgctgaa gctgttgaag

[0155] 4801 atggccacag gaatgcgggc cctgctggac acggtggtgc aagctttgcc ccaggtgggc

[0156] 4861 aacctgggcc tcctcttcat gctgctcttc ttcatctatg ctgctctcgg ggtggagctc

[0157] 4921 tttgggaagc tggtctgcaa cgacgagaac ccgtgcgagg gcatgagccg gcatgccacc

[0158] 4981 ttcgagaact tcggcatggc cttcctcaca ctcttccagg tctccacggg tgacaactgg

[0159] 5041 aacgggatca tgaaggacac gctgcgggac tgcacccacg acgagcgcag ctgcctgagc

[0160] 5101 agcctgcagt ttgtgtcgcc gctgtacttc gtgagcttcg tgctcaccgc gcagttcgtg

[0161] 5161 ctcatcaacg tggtggtggc tgtgctcatg aagcacctgg acgacagcaa caaggaggcg

[0162] 5221 caggaggacg ccgagatgga tgccgagctc gagctggaga tggcccatgg cctgggccct

[0163] 5281 ggcccgaggc tgcctaccgg ctccccgggc gcccctggcc gagggccggg

[0164] 5341 ggcgggggcg acaccgaggg cggcttgtgc cggcgctgct actcgcctgc ccaggagaac

[0165] 5401 ctgtggctgg acagcgtctc tttaatcatc aaggactcct tggaggggga gctgaccatc

[0166] 5461 atcgacaacc tgtcgggctc catcttccac cactactcct cgcctgccgg ctgcaagaag

[0167] 5521 tgtcaccacg acaagcaaga ggtgcagctg gctgagacgg aggccttctc cctgaactca

[0168] 5581 gacaggtcct cgtccatcct gctgggtgac gacctgagtc tcgaggaccc cacagcctgc

[0169] 5641 ccacctggcc gcaaagacag caagggtgag ctggacccac ctgagcccat gcgtgtggga

[0170] 5701 gacctgggcg aatgcttctt ccccttgtcc tctacggccg tctcgccgga tccagagaac

[0171] 5761 ttcctgtgtg agatggagga gatcccattc aaccctgtcc ggtcctggct gaaacatgac

[0172] 5821 agcagtcaag cacccccaag tcccttctcc ccggatgcct ccagccctct cctgcccatg

[0173] 5881 ccagccgagt tcttccaccc tgcagtgtct gccagccaga aaggcccaga aaagggcact

[0174] 5941 ggcactggaa ccctccccaa gattgcgctg cagggctcct gggcatctct gcggtcacca

[0175] 6001 agggtcaact gtaccctcct ccggcaggcc accgggagcg acacgtcgct ggacgccagc

[0176] 6061 cccagcagct ccgcgggcag cctgcagacc acgctcgagg acagcctgac cctgagcgac

[0177] 6121 agcccccggc gtgccctggg gccgcccgcg cctgctccag gaccccgggc cggcctgtcc

[0178] 6181 cccgccgctc gccgccgcct gagcctgcgc ggccggggcc tcttcagcct gcgggggctg

[0179] 6241 cgggcgcatc agcgcagcca cagcagcggg ggctccacca gcccgggctg cacccaccac

[0180] 6301 gactccatgg acccctcgga cgaggagggc cgcggtggcg cgggcggcgg gggcgcgggc

[0181] 6361 agcgagcact cggagaccct cagcagcctc tcgctcacct ccctcttctg cccgccgccc

[0182] 6421 ccgccgccag cccccggcct cacgcccgcc aggaagttca gcagcaccag cagcctggcc

[0183] 6481 gcccccggcc gcccccacgc cgccgccctg gcccacggcc tggcccggag cccctcgtgg

[0184] 6541 gccgcggacc gcagcaagga cccccccggc cgggcaccgc tgcccatggg cctgggcccc

[0185] 6601 ttggcgcccc cgccgcaacc gctccccgga gagctggagc cgggagacgc cgccagcaag

[0186] 6661 aggaagagat gagggtcgca ggggcccccg gccgcccacc gcccgccccg tctcaccttc

[0187] 6721 tttacctcag gagccaggag cagacagcaa tacttcgtcc acacctggga tcgcgcaggg

[0188] 6781 cccgcagggc acaggcgccc gacagccggg ctgagcggag tctgggttag ccaggcctgc

[0189] 6841 gtggcccatg gtggcccttc cagtgcatat acatacatat atatatatat atgcatatat

[0190] 6901 atatatatat atatatatat gtgtatacac acacacatag acagacatat atatatatat

[0191] 6961 ttattttttt tactgagagc ttatgacttc cagaaagtgc taaaggtggg aggtgggcca

[0192] 7021 gggcctggac ggggcttttg tctgatgctc tgggattctg gccagaccca ccccagggca

[0193] 7081 catgtcctgc gggggcgtcc cagctgtgtt ttttgatgtc tcctccctgg ttaagagtag

[0194] 7141 cttggagagg accctcaggc ctctgagggc accaggccct ggagaagagg tgcaattcag

[0195] 7201 ggtgtgtgtg tgtttttttt cctttaaaga agaaacgctg ctaagatccc acgtggctcc

[0196] 7261 cacgtgtcgg ggtgtctgtc ctgtcatcct gactgtctcg ttattgtgaa gtctttcgta

[0197] 7321 gacaccccag agcacacaca tccccttagt ccaccggtta gatgtctctc tttagaaaaa 7381 tcaggggtga gtagctgtgt ttccttaggc ctggggtagg ggatggagag cagctccaag 7441 gctgagctgg ggctctggcc ccaggtgagg tccccagctc ctgagcactt ctgagggggt 7501 gggttccacc cccaggaggg cgggggtggg tggagcagga gtggaggcag cctgcagagg 7561 aagggtgcgg gagactgagc cggcagtggc ttgcttggag gggctagggt acccgcctgg 7621 tctcggctgg ctccagctgc cctgcaggtg cccctgggct caggtagtta gttgttcagc 7681 cactaatgcc ttttatcccc catatgggcg ctgagctgtg gctgttcctg gacactgtgc 7741 tgtccccgtc ctgagcaact atgcccccgc cccagtaggt tcaaggcaaa gcagctctga 7801 ccgaattcta ggcaggggtg ggggcacctg cctgggccct gggtccagcc gcatccccat 7861 gcccagcctt tcgcgtcacc tggaggccac atcttcccac cccacctgcc agcccctgtc 7921 tctcctcccc gctgccccta actgcagctc agctttcact atagcagtgc ttcccaaacg 7981 ggttctagac ttgggtgttt gatttgaaga gttacgcatt tatttcacta tttattggga 8041 aaaaaatgca ttgaacccgt gatttcacag acattttgct taggtcaagg ctacttttta 8101 aaaagggagt gactttcatg aagtcagttt gaagaaggag gttgggagca tgttggtggc 8161 agtgatctgg agaggctgca ggggccacga gtttgcagat gctgtacttc agcaataacc 8221 ttgcctttgc taagaccccc tccgagggct tcaggggggc ctgccaaggg ggggccttgt 8281 tcttgttccc aaactctgac ttggaagaac tcagcttgtg gccgggctgg tgagggtgtg 8341 gggtgcgccc ttcccttttg ggctgaggga gagggggccg ggaggggttg tcaagcccac 8401 ccgggaaact gagccctgga gaggggaagc agccagccca ggatgcttca gggccctggc 8461 agcaaagaag ctggggtggt gtggagggcc ctactccaca ccctagagct gtgatgctga 8521 gcaaggtgcc tgtggcggaa ggaactgccc agtcctccct gggggcaggt agacctgtgg 8581 ggatggctcg gtccaagccc aacactgccc gctccagaga gcctcagccc tgcctccctt 8641 tccacagagg tggttttatg tggaacgagg taccttgtct ggggaagaag tggagctggg 8701 caggcttgac tgctcctggc tgaccctgag ctctcgcagt tggagggaag cagacagact 8761 tgactttttg caagtccgcg tgttgctgga gggacacgtg tattggagcc cagaagaggg 8821 gctgtgtggc ctgggaatac catgtggaag gttgggcttc aagttaacag gatcagacac 8881 cagtcaagca gcctcaggtc atcttgcgac tccactgagc agcctttcct gttgtcacat 8941 gggttcagag cagctgagca gggaacacgt cctaggcagg tctgacgtga aacctcccct 9001 taccctgaac cgtgtgactc tgcaagcaga cacctcgagg caggtgttct aggcaaaggg 9061 atgggcatga gcgaaggctc cagggtccac agagcaggga gtgtggagaa ggtggaagag 9121 ctgagctcag aggcagagaa gctccttgca gggagcactg ggagatggcc tggcccgtcc 9181 caggctcctg gaggccccac ctgccgatcc caggcacttg accttgttcc tgtgggtgac 9241 agagatgaga accagggaag ctgtgatcca ctggccagga caagtcaaca tgggtgaggg 9301 ttgggcaaag ggcccttcct tcctccccaa ccctgtggtc tggggccatg gcctcaggct 9361 tgtgtctatc acaaaagcac aaacttgccc taacccacat gggcctggct gtggggaaag 9421 tggggaccca ggtccctgag ctgtctgctg ggctccgtag agcggtggtg ggcaggcacc 9481 ttggcatctg tgcagagacg gcccagtctg gccaaatcct cttcctctcc cctgctctac 9541 cttctccggc accaggcagc cccttaaagg aggacaaagt gtgtaaagcc cgtctgctgt 9601 cttcccccaa atcctcagct cagagccttc cgcttccagg gccaacccca gccccgtttg 9661 ctgcgttgtg taagggcttg gggtcttaga agctgctctt tagcccagat acacatactc 9721 ttttttgtct ttgtgcaata atcagtgttc ctggcagagc ctgggccaag ctgcagccta 9781 ctgaggaggc agaggccacc tcctccagaa agccctcggc ctgggccgcc gccgtgactc 9841 tagcactctc agtcgctgta cagtttctat ggtgtgaatg aacttccctc ctagttgctg 9901 atggcgctgg tacctgctgg cccatggccc gggtgtagag aaaccaagcg gcagccacca 9961 ccagtgttgt tttgaataaa agcccagaag cctatttaag aa

[0198] The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable or aspect herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.

[0199] Any compound, compositions, or methods provided herein can be combined with one or more of any of the other compositions and methods provided herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0200] 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.

[0201] 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.

[0202] FIGS. 3A-3D provide electrophysiology measurements relating administration of Compound 131.

[0203] FIGS. 4A-4D provide electrophysiology measurements relating administration of Compound 7.

[0204] 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.

[0205] 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.

[0206] 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.

[0207] 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. 8F shows that Cav3.3 R1305H / WT and R1305H / R1305H homozygous mice have decreased object recognition compared to littermate controls. For each data set, a one-way ANOVA was performed with a multiple comparison posthoc test. *p<0.05; **p<0.01; ***p<0.001. N=number of mice.

[0208] 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. 9D demonstrates that Compound 57 administered IP 60 minutes before the social interaction 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; ***p<0.001. N=number of mice.

[0209] 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. 10D demonstrates that Compound 57 dosed IP to wildtype male mice has no effect on basal locomotion. N=number of mice.

[0210] 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. One-way ANOVA was performed with a multiple comparison posthoc test *p<0.05; N=number of mice.

[0211] 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. Then there is one day of baseline recording, then one day in which the mice are recorded following being dosed IP with vehicle, then one day recorded following being dosed IP with 3mg / kg Compound 57, then one day recorded following being dosed IP with lOmg / kg Compound 57, then finally one day recorded following being dosed IP with 30mg / kg Compound 57. 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. FIG. 12F demonstrates that Compound 57 has no effect in male Cav3.3 homozygous mice (these mice do not express any functional Cav3.3 channels). One way ANOVA (*p<0.05 and ***p<0.001) with Holm-Sidak's multiple comparisons test; each circle is one mouse.

[0212] DETAILED DESCRIPTION

[0213] 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).

[0214] Recently, 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). In addition, 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). While the exact mechanism underlying CACNA1I in schizophrenia risk is unknown, 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. et al. Sci. Rep. 6, (2016): 34233, each of which are hereby incorporated by reference in their entirety. These studies implicate loss of function in disease risk or pathophysiology but do not address whether any selective T-type Ca2+channel potentiators provide therapeutic benefit in certain disorders. Only one chemical series, represented by the compound SAK3 (ethyl-8’-methyl-2’,4-dioxo-2-(piperidin-l-yl)-2’H-spiro [cyclopentane-l,3'-imidazo [l,2-a]pyridin]-2-ene-3-carboxylate) has been identified as a potential Cav3.3 enhancer as described in Fukunaga et al. Journal of Pharmacological Sciences 139 (2019): 51-58 and WO2013111799, which are hereby incorporated by reference in its entirety. However, its binding or direct effect on Cav3 channels had not been established and compounds in this chemical series have potentiator activity as shown in Zhang, Yan-Ling, et al. ACS Pharmacology & Translational Science 5.3 (2022): 156-168, which is hereby incorporated by reference in its entiery and particularly in relation to SAK3, ST-101, and Cav potentiation assays. The present disclosure is partially premised on the identification and characterization of Cav potentiators that, as shown herein, offer therapeutic benefit. Without wishing to be bound by theory Cav potentiators (such as those described herein or those identified by Cav potentiation assays) may be able to directly bind to Cav to provide therapeutic benefit.

[0215] Cav3,3 Potentiator Scaffolds

[0216] 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;

[0217] XAI is N, O, or C;

[0218] XA2 is N or C;

[0219] 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); and two RAI may together form =0 or a three to six membered spiro ring; wherein RAI may independently at each occurence have one or more (e.g., two, three, four) points of optional substititution;

[0220] RA2 is independently at each occurrence hydrogen, and 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,); wherein any two geminal RA2 groups may together form =0 or a three to six membered spiro ring; wherein RA2 may independently at each occurence have one or more (e.g., two, three, four) points of optional substititution;

[0221] 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;

[0222] RLis -S(=0)2-, -S(=0)-, -S(=N)2-, -S(=N)(=O)-, or -C(R)(R)-;

[0223] XBI is independently at each occurrence N, S, or CRBI, and one XBI may be absent;

[0224] XB2 is independently at each occurrence N, or CRB2;

[0225] 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) points of optional substititution;

[0226] 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 more (e.g., two, three, four) points of optional substititution; 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;

[0227] XC6 is C, CH, CR, or N;

[0228] 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

[0229] 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), or cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cyclyalkyl); or may together with an R group form oxo (=0); wherein Rci, Rc2, Rc3, Rc4, and Res may independently have one or more (e.g., two, three, four) points of optional substititution; and

[0230] 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. In some embodiments, -Rc has the structure

[0231] Typically, 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). In some embodiments, the alkyl or alkylene group may be unsaturated such as to form alkenyl or alkynyl groups. In some embodiments, 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. In other embodiments, 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). In other embodiments, 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. In some embodiments, the heteroalkyl group or heteroalkylene group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkyl groups. Examples of heteroalkyl groups are an alkoxy. Alkoxy substituent groups or alkoxy-containing substituent groups may be substituted by, for example, one or more alkyl groups.

[0232] 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). In some embodiments, 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. In other embodiments, 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.

[0233] 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). In some embodiments, the hetercyclooalkyl group or heterocycloalkylene group may be substituted with 1, 2, 3, or 4 substituent groups as defined herein.

[0234] Aryl or aryelene groups may be aromatic mono-or polycyclic radicals of 6 to 12 carbon atoms having at least one aromatic ring. Examples of such groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalyl, 1,2-dihydronaphthalyl, indanyl, and IH-indenyl. Typically, 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. Examples of heteroaryl groups are pyridyl, benzooxazolyl, benzoimidazolyl, and benzothiazolyl.

[0235] Exemplary heterocycloalkyl or heteroaryl groups (e.g., Rcgroups) include:

[0236]

[0237] These groups (e.g., Rc) may include one or more substituents as described herein e.g., alkyl substituted).

[0238] A substituted hydrocarbon group may have as a substituent one or more hydrocarbon radicals, substituted hydrocarbon radicals, or may comprise one or more heteroatoms. Examples of substituted hydrocarbon radicals include, without limitation, heterocycles, such as heteroaryls. Unless otherwise specified, a hydrocarbon substituted with one or more heteroatoms will comprise from 1-20 heteroatoms. In other embodiments, 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. Examples of heteroatoms include, but are not limited to, oxygen, nitrogen, sulfur, phosphorous, halogen (e.g., F, Cl, Br, I), boron, or silicon. In some embodiments, heteroatoms will be selected from the group consisting of oxygen, nitrogen, sulfur, phosphorous, and halogen (e.g., F, Cl, Br, I). In some embodiments, a heteroatom or group may substitute a carbon (e.g., substituted alkyl may include heteroalkyl). In some embodiments, a heteroatom or group may substitute a hydrogen. In some embodiments, 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”). In some embodiments, 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”).

[0239] Unless otherwise noted, all groups described herein (e.g., alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylene, heteroalkylene, cylcoalkylene, heterocycloalkylene, RA, RB, RC, RA, RB, RC, RAI, RA2, RA3, RBI, RB2, RB3, RCI, Rc2, Rc3, Rc4, Res, RI-RIO) 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 heteroatoms such as halo, N, O, S, and P. 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. Further, as used herein, the phrase optionally substituted indicates the designated hydrocarbon group may be unsubstituted (e.g., substituted with H) or substituted. Typically, substituted hydrocarbons are hydrocarbons with a hydrogen atom removed and replaced by 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 (e.g., Ci-Cs alkoxy, lower alkoxy such as C1-C4 alkoxy, methoxy), alkoxy substituted with, for example, aryl (e.g., benzyloxy), spiro cycloalkyl (C3-C9 cycloalkyl, C3-C5 cycloalkyl, cyclopropyl), 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), oxo (=0), amino (e.g., NHz, NR’R”, where R’ and R” are independently selected at each occurrence from H and lower alkyl), amide (e.g., - NHC(0)R, -C(0)NR’R”, where R’ and R” are independently selected at each occurrence from H and lower alkyl), hydroxy, cyano, nitroso, carboxylic acid (-C00H), ester (e.g., - COOR’, where R’ is selected at each occurrence from Ci-Cs alkyl, lower alkyl), - C(0)NR’R”, where R’ and R” are independently selected at each occurrence from H and lower alkyl).

[0240] It is understood by one of ordinary skill in the chemistry art that substitution at a given atom is limited by valency. Typically, the use of 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. However, the use of 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. For example, 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.

[0241] 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). That is, 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.

[0242] 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.

[0243] 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. When the stereochemistry of a disclosed compound is named or depicted by structure, 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. When a single enantiomer is named or depicted by structure, 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. When a single diastereomer is named or depicted by structure, 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. Similarly, 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. When a disclosed compound is named or depicted by structure without indicating the stereochemistry, and the compound has at least one chiral center, it is to be understood that the name or structure encompasses either enantiomer of the compound free from the corresponding optical isomer, a racemic mixture of the compound or mixtures enriched in one enantiomer relative to its corresponding optical isomer. When a disclosed compound is named or depicted by structure without indicating the stereochemistry and has two or more chiral centers, it is to be understood that the name or structure encompasses a diastereomer free of other diastereomers, a number of diastereomers free from other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers in which one diastereomer is enriched relative to the other diastereomer(s) or mixtures of diastereomers in which one or more diastereomer is enriched relative to the other diastereomers. The disclosure embraces all of these forms.

[0244] 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. Examples of 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.

[0245] The compounds described herein may be present as a pharmaceutically acceptable salt. Typically, 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. For example, 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. Pharmaceutically acceptable 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, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pantothenate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and valerate salts. 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.

[0246] 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. Alternatively, 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.

[0247] 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. Likewise, 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.

[0248] 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. In some embodiments, 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);

[0249] XC6is C, CR, or N;

[0250] 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

[0251] 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 cycloalkyl, C3-C5 cycloalkyl, cyclopropyl), carboxylic acid (-COOH), ester (e.g., -COOR’, where R’ is selected at each occurrence from Ci-Cs alkyl, lower alkyl), -C(O)NR’R”, where R’ and R” are independently selected at each occurrence from H and lower alkyl); and R is independently at each occurrence hydrogen or lower alkyl (e.g., C1-C4 alkyl). In various implementations,

[0252] 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. In particular embodiments, Rc has the structure:

[0253] For example, Rc may have the structure:

[0254] 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).

[0255] In certain embodiments, the Rc group is conjugated to a central six membered ring in the para configuration with respect to the RLgroup. The compounds of the present disclosure may have the structure of formula (II): or a pharmaceutically acceptable salt thereof. For example, the compound may have the structure of formula (Ila), (lib), (lie), (lid), (lie), (Ilf), (Ilg), (Ilg), (Ili), or (Ilj ):

[0256] For example the comopund may be:

[0257]

[0258]

[0259]

[0260] 0

[0261] 8

[0262] In some embodiments, the compound may be:

[0263] Compound 7 The compound may be:

[0264] Compound 2 Compound 10 Compound 18

[0265] Compound 22

[0266] Compound 48 Compound 71

[0267] Compound 57 Compound 69

[0268]

[0269] Compound 99 Compound 104 Compound 122

[0270] The compound may be selected from the group consisting of:

[0271]

[0272] Compound 22 Compound 34 Compound 57 Compound 71

[0273] Compound 74 Compound 77 Compound 82 Compound 92

[0274] Compound 101 Compound 104 Compound 130

[0275] Compound 132 Compound 133 Compound 144 Compound 208

[0276]

[0277] Compound 220 Compound 235 Compound 238 Compound 255

[0278] In some embodiments, the compound is

[0279] Compound 22 Compound 57 Compound 82 Compound 104

[0280] Compound 131 Compound 208

[0281] In some embodiments, the comopund is

[0282] Compound 36 Compound 39

[0283] Compound 67

[0284] In a particular embodiment, the comopund is

[0285] Compound

[0286] 25

[0287] The Rc group may also be conjugated in the meta configuration of the central six membered ring with respect to the RLgroup. For example, the compound may have the structure of formula (III): For example, the compound may have the structure of formula (Illa), (Illb), (IIIc), (Hid), or (Ille):

[0288]

[0289] In some aspects, the compound may be:

[0290] Compound 32 Compound 35 Compound 56 Compound 68

[0291] Compound 72 Compound 73 Compound 76 Compound 85

[0292] Compound 128 Comopund 131 Compound 137 Compound 147

[0293] Compound 157 Compound 163 Compound 164 Compound 168

[0294] Compound 181 Compound 183 Compound 186 Compound 188

[0295] Compound 189 Compound 190 Compound 192 Compound 196

[0296] Compound 197 Compound 199 Compound 203

[0297] Compound 212 Compound 213 Compound 214 Compound 216

[0298] Compound 234 Compound 236 Compound 237 Compound 241

[0299] Compound 242 Comopund 243 Compound 245 Compound 248

[0300] For example, the compound may be:

[0301] RLis typically an -S(=O)2- group. In some embodiments, the RLgroup in Formula (I), (II), (Ila), (lib), (lie), (lid), (lie), (Ilf), (Ilg), (Ilh), (Hi), (III), (Illa), (Illb), (IIIc), (Illd), or (Ille) is -S(=O)2- For example, the compound may have the structure of formula (IV): wherein each dotted circle independently indicates optionally unsaturation;

[0302] X is N, C, or CR3;

[0303] Y is =N- -N=,-N(R9)-, -(C(R7)(R8) , =C(R7) -, -C(R7)=, -N(R9)C(R7)(R8)-, -C(R7)(R8)N(R9)-, -N(R9)C(R7)=, =C(R7)N(R9)-, -C(R7)=C(R8)-, -N=C(R8) -, or -C(R7) =N-; p is 1, 2, or 3; Z is N, C, or CRe; and R4 and Re may together form =0;

[0304] Ai, A2, and A3 are independently N, C, or CH; G is C, CH or N;

[0305] J is N, C, or CH;

[0306] E is O or CH;

[0307] 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);

[0308] 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;

[0309] 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. In some embodiments, the compound has the structure of formula (IVa) or (IVb): wherein n is 1 or 2; Y is N, CH, or CRio; and

[0310] 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.

[0311] The compound may be:

[0312] Comopund l31 Compound 137 Compound 147 Compound 157

[0313] Compound 163 Compound 164 Compound 168 Compound 170

[0314] Compound 171 Compound 175 Compound 180 Compound 181

[0315] Compound 190 Compound 192 Compound 196 Compound 197

[0316] Compound 199 Compound 203 Compound 205 Compound 212

[0317] Compound 213 Compound 214 Compound 216 Compound 217

[0318] Compound 221 Compound 222 Compound 225 Ccompound 229

[0319] Compound 231 Compound 232 Compound 233 Compound 234

[0320] Compound 236 Compound 237 Compound 241 Compound 242

[0321] In some embodiments, the compound is:

[0322] 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. Typically, these systems may retain the features of the central ring (RB) and Rc. For example, 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 RDI may have one or more (e.g., two, three, four) optional points of substitution (and RDI may be optionally substituted and any two geminal or vicinal substituents may optionally form a five or six membered ring);

[0323] RD2is 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;

[0324] XBI is independently at each occurrence N or CRBI;

[0325] 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;

[0326] 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;

[0327] XC6is C, CH, CR, or N;

[0328] 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 cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cyclyalkyl); or may together with a geminal R group form oxo (=0), wherein Rci, Rc2, Rc3, Rc4, and Res may independently have one or more (e.g., two, three, four) points of optional substititution; and 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. In various implementations, the compound may have the structure of formula (Va), (Vb), (Vc), (Vd), or (Ve):

[0329]

[0330] In various embodiments, the compound may be:

[0331]

[0332] Compound 194 Compound 200 Compound 202

[0333] The identified hydrocarbon groups in the compounds of the present disclosure (e.g., RAI, RA2, RA3, RBI, RB2, RCI, Rc2, Rc3, Rc4, Res, RDI, and RD2) may be optionally substituted one or more times with a substituent as described herein. For example, in some embodiments, 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. dihydrobenzodioxinyl such as dihydrobenzo[b][l,4]dioxin-5-yl). In various implementations, 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. In some embodiments, RD2 is hydrogen or lower alkyl (e.g., C1-C4 alkyl such as methyl) optionally substituted with alkoxy or -NRR. Additionally, when the identified group is alkyl, the alkyl group may be optionally unsaturated (e.g., alkenyl). For example, in some embodiments, RB2 is selected from hydrogen or optionally unsaturated alkyl (e.g., C2-C8 alkenyl, C2-C8 alkynyl, C2-C4 alkenyl, C2-C4 alkynyl, ethenyl).

[0334] The Cav3.3 potentiator (or activator) may have activity as described in an assay presented herein (e.g., in Example 1). For example, 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). In various implementations, 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. In some embodiments, the compounds may be characterized by the assays described in Pan, J, et al, Methods Mol Biol 1787 (2018): 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.

[0335] 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-

[0336] 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, and 587-596 as disclosed in Table 1, stereoisomers, tautomers, diastereomers, enantiomers, mixtures thereof, or racemix mixtures of any of the foregoing. In some embodiments, the comound is any one of compounds 1-69, 71-172, 174-176, and 179-255. In some embodiments, 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-

[0337] 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, and 587-596.

[0338] Table 1

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378] In some embodiments, 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, and 587-596, or a pharmaceutically salt or prodrug thereof, including stereoisomers, tautomers, diastereomers, enantiomers, mixtures thereof, or racemix mixtures of any of the foregoing.

[0379] Typically, 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. However, 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. For example, 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. In some embodiments, 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. In certain aspects, the compound (e.g.,

[0380] Compound 135, 435) may have the structure: be a mixture, including racemic mixture, thereof. In various implementations, the compound (e.g., Compound 63, 357) may have the structure be a mixture, including racemic mixture, thereof. In some embodiments, the compound may have the structure: be a mixture, including racemic mixture, thereof. In some embodiments, the compound (e.g.,

[0381] Compound 210, 230) may have the structure: be a mixture, including a racemic mixture, thereof. In some embodiments, the compound (e.g., Compound 404) may have the structure: be a mixture, including a racemic mixture, thereof. In some embodiments, the compound is Compound 22, 34, 40, 48, 57, 71, 74, 77, 79,

[0382] 82, 84, 92, 99, 101, 104, 122, 130, 132, 133, 142, 144, 145, 149, 152, 155, 161, 166, 169, 172, 174, 195, 208, 220, 223, 230, 235, 238, 244, 246, 247, 249, 255, or 317. In various implementations, the compound is

[0383]

[0384] In various implementations, the compound is:

[0385] In some embodiments, 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. In some embodiments, the compound is Compound 32, 35, 56, 68, 70,

[0386] 73, 76, 85, 87, 93, 97, 105, 110, 112, 114-115, 119, 124, 128, 131, 137, 147, 157, 163-164, 171, 175, 177, 181, 183, 185, 186, 188-190, 192, 196-197, 199, 203, 205, 213, 214, 216, 221- 222, 225, 229, 231-232, 234, 236-237, 241-243, 245, 248, 250-253, 256, or 259. For example, the compound may be

[0387] Compound 131 Compound 181

[0388] In some embodiments, the compound is:

[0389] In some embodiments, the compound is:

[0390] Compound 22 Compound 34 Compound 57 Compound 71

[0391]

[0392] In some embodiments, the compound is:

[0393] Compound 22 Compound 57 Compound 82 Compound 104

[0394] Compound 131 Compound 208

[0395] Pharmaceutical Compositions

[0396] 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, 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, and 587-596, one or more of Compounds 1-69, 71-172, 174-176, and 179-255) are useful for the treatment of in a subject in need thereof. The compounds described herein may also be compounds for use in the preparation of a medicament for the treatment of (e.g., a disease caused by) in a subject in need thereof.

[0397] 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, 398-423, 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, and 587- 596, one or more of Compounds 1-69, 71-172, 174-176, and 179-255) and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0398] 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. For example, 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. In certain embodiments, the compounds described herein, including crystallized forms, polymorphs, and solvates thereof, may be present in a unit dosage form.

[0399] 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. Thus, the 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. For example, 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. The 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.

[0400] 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; releasing agents; coating agents; sweetening, flavoring and perfuming agents; preservatives; antioxidants; ion exchangers; alumina; aluminum stearate; lecithin; self-emulsifying drug delivery systems (SEDDS) such as d-atocopherol polyethyleneglycol 1000 succinate; surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices; serum proteins such as human serum albumin; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts; colloidal silica; magnesium trisilicate; polyvinyl pyrrolidone; cellulose-based substances; polyacrylates; waxes; and polyethylene-polyoxypropylene-block polymers. 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.

[0401] In various embodiments, 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. When 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. In a further embodiment, 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. Examples of suspension agents include methylcellulose, polysorbate 80, hydroxyethylcellulose, xanthan gum, sodic carboxymethylcellulose and polyethoxylated sorbitan monolaurate. Examples of solubilization agent include polyoxy ethylene- solidified castor oil, polysorbate 80, nicotinamide, polyethoxylated sorbitan monolaurate, macrogol and ethyl ester of caste oil fatty acid. Moreover, 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. When preparing injectable suspensions or solutions, it is desirable to make sure that they are blood isotonic.

[0402] In some embodiments, the pharmaceutical composition further comprises a viscosity enhancing agent. In some embodiments, the viscosity enhancing agent includes methylcellulose, hydroxy ethylcellulose, hydroxypropylmethylcellulose and smart hydrogel. In some embodiments, the viscosity enhancing agent is hydroxyethylcellulose. In some embodiments, the pharmaceutical composition comprises 0.01-1.0% (w / v) viscosity enhancing agent. In other embodiments, the intranasal pharmaceutical composition comprises 0.05% (w / v) hydroxyethylcellulose.

[0403] In some embodiments, 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. In some embodiments, a pH modifier such as acetic acid, is present in a final concentration of at least 0.001%, preferably at least 0.01%, more preferably between 0.01%- 0.2% by weight of the composition. In terms of their form, 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. Such 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. In certain embodiments, 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.

[0404] Methods for Treatment

[0405] As shown herein, 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. In some embodiments, agonization of the Cav channel (e.g., by administration of a Cav3.3 potentiator to a subject) may be effective for the treatment and / or prophylaxis of diseases, disorders, or conditions associated with declarative memor deficits and / or social deficits.

[0406] Typically, the treatment of 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)) is an approach for obtaining beneficial or desired results, such as clinical results. 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, 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, and 587-596, one or more of Compounds 1-69, 71-172, 174-176, 176-255) may be used for the treatment of any disease, disorder, condition, or method described herein. In some embodiments, 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.

[0407] Methods are provided involving the treatment and / or prophylaxis of a neurodegenerative disease, mental disease, cognitive dysfunction, and pervasive developmental disorder involving administration of a compound (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, 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, and 587-596, one or more of Compounds 1-69, 71-172, 174- 176, 176-255). In various implementations, 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. Methods for the improvement of brain function in a subject are provided involving administration of 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, 398-423, 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, and 587-596, one or more of Compounds 1-69, 71-172, 174-176, 176-255) to the subject. 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).

[0408] The method of treatment of a subject in need thereof (e.g., one having or having a propensity to develop 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) comprise 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, 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, and 587-596, one or more of Compounds 1-69, 71-172, 174-176, 176-255) or composition of the present disclosure. 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). 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. Administration of 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, 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, and 587-596, one or more of Compounds 1-69, 71-172, 174-176, 179-255) may be chosen based on the sleep spindle state or the predominant sleep spindle state of the subject in need thereof.

[0409] The present disclosure is based, at least in part, on the discovery that 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).

[0410] 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, 380-392, 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, and 587-596, one or more of Compounds 1-69, 71-172, 174-176, 179-255). In some embodiments, the subject is a human. In certain embodimenst, the subject has schizophrenia. For example, 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. In some embodiments, the subject is a human. In certain embodiments, the subject has schizophrenia.

[0411] 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.

[0412] In order to treat, prevent, or prevent recurrence of diseases, disorders, or conditions (e.g., schnizophrenia or disorders or conditions associated therewith such as cognitive deficit, decreased sleep spindles, decreased thalamocortical hyperactivity) as discussed herein, the compounds or compositions of the present disclosure may be administered at least once a day for at least one week. In various embodiments, the composition is administered at least twice a day for at least two days. In certain embodiments, the composition is administered approximately daily, at least daily, twice a week, weekly, or for once a month. In certain embodiments, 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.

[0413] 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

[0414] In another aspect, the 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, 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, and 587-596, one or more of Compounds 1-69, 71-172, 174-176, 179-255). The packaging or dispenser may include a bottle, tube, spray bottle, or other dispenser. In certain embodiments of the invention, the composition is packaged in a concentrated form, and diluted to a desired concentration upon use by the end user. Typically, in these aspects, the composition may be formulated and packaged in a manner suitable for long-term storage to maintain efficacy of the composition.

[0415] Syntheses

[0416] 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. 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. In some embodiments, 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). For example, 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):

[0417] In some embodiments, 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):

[0418] 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. For example, 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. In some embodiments 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.

[0419] The following examples are put forth to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the assay, screening, and therapeutic methods of the invention, and are not intended to limit the scope of what the inventors regard as their invention.

[0420] EXAMPLES

[0421] Example 1 : High-Throughput Cay3, 3 Potentiation Measurements

[0422] High-throughput assays able to identify both inhibitors and potentiators (activators) were to screen compounds. The assays involved T-type Ca2+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 Ca2+channels are available to open. Additionally, the assay involved a membrane bound version of the stable ultrasensitive Ca2+sensor GCaMP6s (GCaMP6s- CAAX). Similar assays have been described in Pan, J, et al, Methods Mol Biol 1787 (2018): 235-252, and Baez-Nieto, D, et al., Brain (2017):awab443, which are hereby incorporated by reference in their entirety and particularly in relation to high-throughput assay protocols. 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 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. 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.

[0423] Table 2

[0424] fit will be understood that in the event of any inconsistency between the SMILES string provided in Tables 1-2, allstereoisomers and mixtures of stereoisomers of the indicated structures will be considered embraced by the present disclosure.

[0425] * 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.

[0426] Example 2: Electrophysiology

[0427] Using an automated planar-patach claim instrument (Syncropatch 384 PE) that offers

[0428] G seal and precise voltage control, the electrophysiological profiles of the three T-type Ca2+channels (Cav3.1, Cav3.2, and Cav3.3) were measured as described below and in Andrade, A. et al. Sci. Rep. 6 (2016): 34233, which is hereby incorporated by reference in its entirety and particularly in relation to the patch clamp assay protocol. A schematic of this electrophysiological assay is provided in FIG. 2. Electrophysiological parameters such as voltage current dependence signifying ion migration through the membrane was measured as associated with administration of Compound 131 and Compound 7

[0429] Compound 131 Compound 7

[0430] 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. As can be seen, 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).

[0431] 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. As can be seen, Compound 7 increases the current amplitude in the Cav3.1 and Cav3.3 channels (but not Cav3.2 channels).

[0432] Example 3: Ex vivo measurements: Brain slice electrophysiology

[0433] Ex vivo electrophysiology measurements were performed using a mouse brain slice electrophysiology assay analyzing as described in Ghosal, A, et al., Transl Psychiatry 10.1 (2020): 29, which is hereby incorporated by reference in its entirety and particularly in relation to the brain slice electrophysiology assays. Briefly, experiments measured the number of bursts in thalamic reticular nucelus (TRN) neurons from mouse brain slices exposed to an active compound. For the experiments described herein, Compound 7 having the structure:

[0434] was measured relative to TRN bursting. 1 pM of Compound 7 was used in the assay. 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. These results demonstrate that Cav3.3 potentiator increases TRN rebround bursting.

[0435] Measurements were also performed on Compound 131 which, as shown in Example

[0436] 2, is a Cav3.3 activator with a different mechanism of action than Compound 7 (due to additional Cav3.1 potentiation) having the structure:

[0437] 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.

[0438] Example 4: In vivo Pharmacokinetic Measurements

[0439] 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 (KpUu) for each dose. By tripling the dose, the maximum concentration was able to increase 5-fold and the brain AUC increased 7-fold.

[0440] Table 3

[0441] Example 5: Behavioral Assays in Mice Administered Cav3,3 potentiators

[0442] Cav3.3 knock-out (Cacnali'1' (KO) and Cacnalt1' (Het)) and R1305H mutation knock-in mice (Cacnal imim(RH / RH) and Cacnali+ R(RH Het)) were generated. The R1305H mutation in murine Cav3.3 corresponds to R1346H in the human channel:

[0443] Hu_CACNAl I 1340 TRNITNRSDC 1349

[0444] Ms_CACNAl I 1299 TRNITNRSDC 1308

[0445] 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.

[0446] Test wild type (WT), knock out, and knock-in mice were subjected to a social interaction assay. 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). Knock out mice, both heterozygous (Het) and homozygous (KO), had significantly decreased social index scores as compared to WT control. 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. Furthermore, 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. Briefly, 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.

[0447] The social interaction assay was performed with on mice administered Compound 57 intraperitoneally (IP) 60 minutes at either 3 mg / kg, 10 mg / kg, or 30 mg / kg before habituation began. A schematic of the assay protocol is provided in FIG. 9A. FIG. 9B 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).

[0448] The novel object assay was also performed on mice having Compound 57 administered at 3 mg / kg, 10 mg / kg, or 30 mg / kg via IP 60 minutes before habituation. 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).

[0449] 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).

[0450] Example 6: Effect on Spindle Density

[0451] Mouse electroencephalogram (EEG) measurements were performed on Wild Type, homozygous RH knock in (R1305H / R1305H), and homozygous Cav3.3 knock out (Cav3.3 KO / KO) mice. 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. Following a day of baseline recording, 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. As can be seen, Compound 57 increases 11 Hz sleep spindle density at 30 mg / kg in WT male mice. A similar effect is seen in R1305H homozygous knock in mice at 10 mg / kg and 30 mg / kg, while no effect is seen on the Cav3.3 knock out mice. These data illustrate a measurement protocol that allows for the assessment of compound treatment on disorders associated with spindle deficits.

[0452] Example 7: Compound Synthesis

[0453] Compounds of the present disclosure were synthesized as follows.

[0454] 4-[5-fluoro-2-methyl-4-(l-methyl-lH-pyrazol-4-yl)benzenesulfonyl]-l,5-dimethyl-

[0455] 1,2,3,4-tetrahydroquinoxaline (Broad_P_Cav3.3_303, Compound 1)

[0456] To a stirred solution of 4-(4-bromo-5-fluoro-2-methylbenzenesulfonyl)-l,5-dimethyl-

[0457] 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. After completion, the reaction mixture was poured in water (40 mL) and extracted with EtOAc (3 x 30 mL). The organic layer was washed with brine solution (2 x 10 mL), dried over Na2SC>4 and evaporated. The residue was purified via Biotage (50: 1 CHzCh / MeOH; 12S column) to provide 4-[5-fluoro-2-methyl-4-(l-methyl-lH-pyrazol-4-yl)benzenesulfonyl]-l,5-dimethyl-

[0458] 1,2,3,4-tetrahydroquinoxaline (0.85 g, 89.5 % yield) as an off white solid.

[0459] 1H NMR (400 MHz, CDC13) 5 7.88 (s, 1H), 7.84 (m, 1H), 7.73 (d, J = 10.1 Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.06 (t, J = 8.2 Hz, 1H), 6.61 (d, J = 8.1 Hz, 1H), 6.40 (d, J = 8.2 Hz, 1H), 4.35-4.25 (m, 1H), 3.97 (s, 1H), 3.33-3.23 (m, 1H), 3.10-2.95 (m, 2H), 2.48 (s, 3H), 2.37 (s, 3H), 2.07 (s, 3H). MS(ESI): 415.3 [M+H]+.

[0460] (3S)-5-fluoro-3,7-dimethyl-l-[[4-methyl-6-(4-methylimidazol-l-yl)-3- pyridyljsulfonyljindoline and (3R)-5-fluoro-3,7-dimethyl-l-[[4-methyl-6-(4- methylimidazol-l-yl)-3-pyridyl] sulfonyl] indoline (Broad_P_CaV3.3_673A and B) (Compound 2 and Compound 39)

[0461] To a mixture of l-[(6-bromo-4-methyl-3-pyridyl)sulfonyl]-5-fluoro-3,7-dimethyl- indoline (0.20 g, 0.501 mmol, 1.00 eq), 4-methyl-lH-imidazole (0.16 g, 2.00 mmol, 4.00 eq) and K3PO4 (0.21 g, 1.00 mmol, 2.00 eq) in 1,4-di oxane (4 mL) was added tBuXPhos (0.043 g, 0.100 mmol, 0.200 eq) and Pd2(dba)3 (0.046 g, 0.0501 mmol, 0.100 eq) and it was degassed with argon for 15 min. The 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).

[0462] 1H NMR (400 MHz, DMSO-d6) 5 8.87 (s, 1H), 8.55 - 8.47 (m, 1H), 7.81 (s, 1H), 7.71 (s, 1H), 7.03 (dd, J = 10.1, 2.7 Hz, 1H), 6.94 (dd, J = 8.2, 2.7 Hz, 1H), 4.32 (dd, J = 13.0, 7.3 Hz, 1H), 3.46 (dd, J = 13.0, 10.5 Hz, 1H), 2.60 (q, J = 5.5, 3.5 Hz, 1H), 2.42 (s, 3H), 2.18 (s, 3H), 2.12 (s, 3H), 1.01 (d, J = 6.6 Hz, 3H). MS(ESI): 401.0 [M+H]+. l-[(6-bromo-4-methyl-3-pyridyl)sulfonyl]-5-fluoro-3,7-dimethyl-indoline

[0463]

[0464] To a solution of 5-fluoro-3,7-dimethyl-indoline (0.20 g, 1.21 mmol, 1.00 eq) in di chloromethane (5 mL) was added 6-bromo-4-methyl-pyridine-3 -sulfonyl chloride (491 mg, 1.82 mmol, 1.50 eq) and Pyridine (.49 mL, 6.05 mmol, 5.00 eq) dropwise, and the reaction mixture was stirred at room temperature for 24 h. After completion, the reaction mixture was diluted with water (100 mL) and extracted in dichloromethane (lOOmL x 3). The organic layer was dried over sodium sulphate and vacuum evaporated. The residue obtained purified by column chromatography in silica using l%-2% ethyl acetate in hexane. The product fractions vacuum evaporated to afford brown semisolid of Int-1403, (0.25 g, 0.545 mmol, 45% yield). MS(ESI): 401.4 [M+H]+.

[0465] 5-fluoro-3,7-dimethyl-indoline

[0466] To a solution of 5-fluoro-3,7-dimethyl-lH-indole (600 mg, 3.68 mmol, 1.00 eq) in Acetic acid (6 mL) at 0°C was added Sodium cyanoborohydride (693 mg, 11.0 mmol, 3.00 eq) in portion and the reaction mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was quenched with icecold water (150 mL) and the product was extracted in ethyl acetate (100 mL x 3). The organic layer layer was dried over sodium sulphate and vacuum evaporated to get residue. The residue was purified by column chromatography in silica using 5% ethyl acetate in hexane. The product fraction were vacuum evaorated to afford yellow oil of Int-1403, (500 mg, 2.38 mmol, 65% yield). MS(ESI): 166.0 [M+H]+

[0467] 5 -fluoro-3 , 7 -dimethyl - 1 H-indol e

[0468] To a solution of 5-fluoro-7-methyl-lH-indole-3-carbaldehyde (800 mg, 4.52 mmol, 1.00 eq) in Tetrahydrofuran (25 mL) was added Lithium aluminum hydride solution (1 M in Tetrahydrofuran, 11.29 mL, 11.3 mmol, 2.50 eq) at 0°C and the reaction mixture was warmed and stirred to room temperature for 16 h. After completion, the reaction mixture was quenched with 2 mL water and 5 mL aqueous solution of 2M sodium hydroxide. The reaction mixture was filtered through celite and washed with ethyl acetate (50 mL). The organic layer was dried over sodium sulphate and vacuum evaporated to afford residue. The residue was purified by column chromatography in silica using 10%-20% ethyl acetate in hexane. The product fractions were vacuum evaporated to affor brown semisolid of Int-1388, (600 mg, 3.51 mmol, 78% yield). MS(ESI): 162.0 [M-H]-

[0469] 5-fluoro-7-methyl-lH-indole-3-carbaldehyde

[0470] To a solution of 5-fluoro-7-methyl-lH-indole (1.00 g, 6.70 mmol, 1.00 eq) in N,N- Dimethylformamide (2.58 mL, 33.5 mmol, 5.00 eq) was added Phosphorus(V) oxychloride (.75 mL, 8.05 mmol, 1.20 eq) dropwise at 0°C and the reaction mixture was warmed to room temperature and stirred for 2 h. After completion, the reaction mixture was quenched with ice-water (30 mL) and basified by 2M aqueous solution of sodium hydroxide. The brown solid obtained was filtered and washed with water (100 mL) and vacuum dried to afford Int- 1387, (800 mg, 4.30 mmol, 64% yield). MS(ESI): 178.2 [M+H]+

[0471] 5 -fluoro-7 -methyl - 1 H-indol e

[0472] A mixture of 7-bromo-5-fluoro-lH-indole (2.00 g, 9.34 mmol, 1.00 eq), Methylboronic acid (839 mg, 14.0 mmol, 1.50 eq) and Cesium carbonate (9134 mg, 28.0 mmol, 3.00 eq) in 1,4-di oxane (20 mL) was degassed for 5 minutes and [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with di chloromethane (763 mg, 0.934 mmol, 0.100 eq) was added to reaction mixture and heated at 100 °C for 16 h. After completion, the reaction mixture was diluted with water (150 mL) and the product was extracted in ethyl acetate (100 mL x 3). The organic layer was dried over sodium sulphate and vacuum evaporated to afford residue. The resiude was purified by column chromatography in silica using 10% ethyl acetate in hexane. The product fractions were vacuum evaporated to afford brown semisolid of Int-1386, (1.00 g, 6.70 mmol, 72% yield).

[0473] 1H NMR (400 MHz, DMSO-d6) 5 11.16 (s, 1H), 7.45 - 7.35 (m, 1H), 7.11 (dd, J = 9.9, 2.5 Hz, 1H), 6.77 (dd, J = 10.2, 2.4 Hz, 1H), 6.48 - 6.36 (m, 1H), 2.48 (s, 3H).

[0474] 7-bromo-5-fluoro-lH-indole

[0475] To a solution of 2-bromo-4-fluoro-l -nitro-benzene (3.00 g, 13.6 mmol, 1.00 eq) in Tetrahydrofuran (30 mL) was added Vinylmagnesium bromide (1 M in Tetrahydrofuran, 68.18 mL, 68.2 mmol, 5.00 eq) at -70°C and the reaction mixture was stirred for 1 h. After completion, the reaction mixture was quenched with water (250 mL) and filtered through celite pad and washed with ethyl acetate (100 mL). The organic layer in filtrate was dried over sodium sulphate and vacuum evaporated to afford residue. The residue was purified by column chromatography in silica using 10% ethyl acetate in hexane. The product fraction was vacuum evaporated to afford brown oil of Int-1385, (1.50 g, 6.93 mmol, 51% yield). MS(ESI): 212.0 [M-H]- Synthetic Scheme for Broad_P_CaV3.3_565 (Compound 3)

[0476] Broad_P_CaV3.3_565

[0477] Compound 3 tert-butyl (2-((4-bromo-2-methylphenyl)sulfonamido)-3-methylphenyl)carbamate :

[0478] Intermediate- 1

[0479] To a stirred a solution of tert-butyl N-(2-amino-3-methyl-phenyl)carbamate (2.80 g, 12.6 mmol, 1.00 eq) and Pyridine (5.09 mL, 63.0 mmol, 5.00 eq) in dichloromethane (30 mL) was added 4-bromo-2-methyl-benzenesulfonyl chloride (5.09 g, 18.9 mmol, 1.50 eq) at RT. The reaction mixture was stirred at same temperature for 16 h. After completion, the reaction was quenched with water and extracted ethyl acetate (3 x 50 mL). The combined organics were washed brine solution (2 x 50 mL), dried over Na2SC>4 and evaporated. The residue was purified by silica gel column chromatography (8% Ethyl acetate: Hexanes) as a mobile phase to provide tert-butyl N-[2-[(4-bromo-2-methyl-phenyl)sulfonylamino]-3-methyl- phenyl]carbamate, (5.00 g, 10.6 mmol, 84% yield) as an off white solid.

[0480] XH NMR (400 MHz, DMSO ) 5 9.36 (s, 1H), 7.67 (s, 1H), 7.62 (s, 1H), 7.56 (d, J= 13.2 Hz, 3H), 7.15 (t, J= 7.8 Hz, 1H), 6.92 (d, J= 7.7 Hz, 1H), 2.43 (s, 3H), 2.08 (s, 3H), 1.49 - 1.32 (m, 9H). MS(ESI): 455.3 [M+H]+tert-butyl 4-((4-bromo-2-methylphenyl)sulfonyl)-5-methyl-3,4-dihydroquinoxaline-l(2H)- carboxylate: Intermediate-2

[0481] Boc

[0482] To a stirred solution of tert-butyl N-[2-[(4-bromo-2-methyl-phenyl)sulfonylamino]-3- methyl-phenyl]carbamate (3.00 g, 6.59 mmol, 1.00 eq) and 1,2-dibromoethane (.71 mL, 7.91 mmol, 1.20 eq) in DMF (20 mL) was added K2CO3 (3.64 g, 26.4 mmol, 4.00 eq) at room temperature. The reaction mixture was heated at 80°C. After completion, the 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 Na2SO4 and evaporated under vacuum to provide tert-butyl 4-(4-bromo-2-methyl-phenyl)sulfonyl-5- methyl-2,3 -dihydroquinoxaline- 1 -carboxylate, (3.10 g, 6.18 mmol, 94% yield) as an yellow solid. MS(ESI): 427.2 [M-56]+

[0483] 1H NMR (400 MHz, DMSO-t / 6) 5 7.90 (d, J= 8.6 Hz, 1H), 7.67 - 7.53 (m, 2H), 7.39 (s, 1H), 7.20 (t, J= 7.9 Hz, 1H), 7.04 (d, J= 7.6 Hz, 1H), 4.29 (d, J= 13.6 Hz, 1H), 3.30 (d, J= 10.7 Hz, 2H), 2.89 (s, 1H), 2.73 (s, 1H), 2.37 (s, 3H), 2.00 (s, 3H), 1.37 (s, 9H). l-((4-bromo-2-methylphenyl)sulfonyl)-8-methyl-l,2,3,4-tetrahydroquinoxaline : intermediate-3

[0484] To a stirred solution of tert-butyl 4-(4-bromo-2-methyl-phenyl)sulfonyl-5-methyl-2,3- dihydroquinoxaline-1 -carboxylate (3.10 g, 6.44 mmol, 1.00 eq) in dichloromethane (30 mL) was added HC1 in 1,4-dioxane (4 M in Dioxane, 20 mL, 80.0 mmol, 12.4 eq) at 0°C. The reaction mixtutre was allowed to stir at RT. 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.

[0485] 1H NMR (400 MHz, DMSO-t / 6) 5 7.84 (d, J= 8.5 Hz, 1H), 7.69 - 7.56 (m, 2H), 6.87 (t, J= 7.7 Hz, 1H), 6.37 (t, J= 8.9 Hz, 2H), 5.86 (s, 4H), 4.00 (s, 1H), 3.57 (s, 1H), 3.11 (s, 2H), 2.20 (s, 3H), 2.12 (s, 3H).

[0486] 1H NMR D20 (400 MHz, DMSO-t / 6) 5 7.84 (d, J= 8.6 Hz, 1H), 7.69 - 7.53 (m, 2H), 6.87 (t, J= 7.9 Hz, 1H), 6.37 (t, J= 9.7 Hz, 2H), 3.99 (s, 1H), 3.10 (s, 2H), 2.18 (d, J= 5.4 Hz, 3H), 2.11 (s, 3H), 1.24 (s, 1H). MS(ESI): 381.2 [M+H]+.

[0487] 4-((4-bromo-2-methylphenyl)sulfonyl)-5-methyl-l-(methyl-d3)-l,2,3,4- tetrahydroquinoxaline : Intermediate-4

[0488] To a stirred solution of 4-(4-bromo-2-methyl-phenyl)sulfonyl-5-methyl-2,3-dihydro- IH-quinoxaline (500 mg, 1.31 mmol, 1.00 eq) and CD3I (1521 mg, 10.5 mmol, 8.00 eq) in DMF (5 mL) was added K2CO3 (724 mg, 5.25 mmol, 4.00 eq) at room temperature. The reaction mixture was heated at 80 °C. After completion, the reaction mixture was poured into ice-cold water (50 mL) brown color solid fallout, filter and dried. Purification was done by column chromatography in 4% Ethyl acetate: Hexanes desired eluted to provide 4-(4-bromo- 2-methyl-phenyl)sulfonyl-5-methyl-l -(trideuteri omethyl)-2,3-dihydroquinoxaline, (370 mg, 0.901 mmol, 69% yield) as an white solid. MS(ESI): 398.2 [M+H]+

[0489] 1H NMR (400 MHz, DMSO-t / 6) 5 7.88 - 7.79 (m, 1H), 7.61 (dd, J= 5.9, 2.5 Hz, 2H), 7.03 (t, J= 7.9 Hz, 1H), 6.55 (d, J= 7.5 Hz, 1H), 6.47 (d, J= 8.2 Hz, 1H), 4.15 (dd, J= 15.2, 6.8 Hz, 1H), 3.25 (s, 1H), 2.98 (s, 1H), 2.80 (s, 1H), 2.26 (s, 3H), 2.00 (s, 3H).

[0490] 5-methyl-l-(methyl-d3)-4-((2-methyl-4-(4-methyl-lH-imidazol-l-yl)phenyl)sulfonyl)-

[0491] 1,2,3,4-tetrahydroquinoxaline (Compound 3)

[0492] A stirred suspension of 4-(4-bromo-2-methyl-phenyl)sulfonyl-5-methyl-l- (trideuteriomethyl)-2,3-dihydroquinoxaline (330 mg, 0.828 mmol, 1.00 eq), 4-methyl-lH- imidazole (204 mg, 2.49 mmol, 3.00 eq) and potassium ter-butoxide (283 mg, 2.49 mmol, 3.00 eq) in DMF (10 mL) was degassed with nitrogen gas for 15 min. After 15 min, Q12O (24 mg, 0.166 mmol, 0.200 eq) was added to it and heated it at 80°C. The progress of 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. The residue was purified via combi flash using (80% Ethyl acetate: Hexanes) as a mobile phase to provide impure product then repurified by Prep HPLC in (A) 0.1% FA in water (B)100% ACN as mobile phase to provided 5-methyl-4-[2-methyl-4-(4-methylimidazol-l- yl)phenyl]sulfonyl-l-(trideuteriomethyl)-2,3-dihydroquinoxaline (6.7 mg, 0.0159 mmol, 2% yield) as an Brown solid. MS(ESI): 400.06 [M+H]+. 1H NMR (400 MHz, DMSO-t / 6) 5 8.33 (s, 1H), 7.97 (d, J= 8.2 Hz, 1H), 7.62 (m, 3H), 7.02 (t, J= 7.7 Hz, 1H), 6.54 (d, J= 7.4 Hz, 1H), 6.45 (d, J= 8.1 Hz, 1H), 4.15 (d, J= 13.1 Hz, 1H), 3.25 (s, 1H), 2.97 (s, 1H), 2.81 (s, 1H), 2.28 (s, 3H), 2.17 (s, 3H), 2.06 (s, 3H). l,5-dimethyl-4-[2-methyl-4-(2-methyl-l,3-oxazol-5-yl)benzenesulfonyl]-l,2,3,4- tetrahydroquinoxaline (Broad_P_Cav3.3_313, Compound 4)

[0493] To a stirred solution of 4-(4-bromo-2-methylbenzenesulfonyl)-l,5-dimethyl-l, 2,3,4- tetrahydroquinoxaline (200 mg, 0.5059 mmol) were added 2-methyl-5-(4,4,5,5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl)- 1,3 -oxazole (126 mg, 0.6070 mmol), potassium carbonate (208 mg, 1.51 mmol) in 1,4- Dioxane (4 mL) and Water (0.3 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 di chloride (41.3 mg, 0.05059 mmol) was added at room temperature and reaction mixture was heated at 100°C for 7 h. After completion, the reaction mixture was poured in to water (20 mL) and extracted with EtOAc (3 x 30 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 35 - 40% ACN in 0.1% formic acid in water as a gradient to provide l,5-dimethyl-4-[2-me (45 mg, 22.0 % yield) as a white solid.

[0494] 1H NMR (400 MHz, DMSO-d6) 5 7.96 (d, J = 8.3 Hz, 1H), 7.73 (s, 1H), 7.64 (m, 2H), 7.01 (t, J = 7.8 Hz, 1H), 6.53 (d, J = 7.5 Hz, 1H), 6.45 (d, J = 8.1 Hz, 1H), 4.13 (s, 1H), 3.31 (s, 4H), 2.96 (s, 1H), 2.80 (s, 1H), 2.40 (s, 3H), 2.26 (s, 3H), 2.03 (s, 3H). MS (ESI) : 398.3 [M+H]+. 4-[2-fluoro-6-methyl-4-(l-methyl-lH-pyrazol-4-yl)benzenesulfonyl]-l,5-dimethyl-

[0495] 1,2,3,4-tetrahydroquinoxaline (Broad_P_Cav3.3_302, Compound 5)

[0496] To a stirred solution of 4-(4-bromo-2-fluoro-6-methylbenzenesulfonyl)-l,5-dimethyl- 1,2,3,4-tetrahydroquinoxaline (0.8 g, 1.93 mmol) were added l-methyl-4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (480 mg, 2.31 mmol), potassium carbonate (800 mg, 5.79 mmol) in 1,4-Dioxane (8 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 (157 mg, 0.1930 mmol) was added at room temperature and reaction mixture was heated at 100°C for 6 h. After completion, the reaction mixture was poured in water (40 mL) and extracted with EtOAc (3 x 30 mL). The organic layer was washed with brine solution (2 x 10 mL), dried over Na2SC>4 and evaporated. The residue was purified via Biotage (50: 1 CLLCh / MeOH; 12S column) to provide 4-[2-fluoro-6-methyl (0.3 g, 36.7 % yield) as an off white solid. 1H NMR (400 MHz, Chloroform-d) 5 7.77 (s, 1H), 7.66 (s, 1H), 7.13 - 6.98 (m, 3H), 6.62 (d, J = 7.5 Hz, 1H), 6.40 (d, J = 8.0 Hz, 1H), 4.50 (s, 1H), 3.96 (s, 3H), 3.33 (s, 2H), 3.03 (s, 1H), 2.51 (s, 3H), 2.32 (s, 3H), 2.22 (s, 3H). MS (ESI) : 415.5 [M+H]+.

[0497] 5-fluoro-4,8-dimethyl-l-[2-methyl-4-(l-methyl-lH-pyrazol-4-yl)benzenesulfonyl]-

[0498] 1,2,3,4-tetrahydroquinoxaline (Broad_P_Cav3.3_299, Compound 6)

[0499] To a stirred solution of l-(4-bromo-2-methylbenzenesulfonyl)-5-fluoro-4,8-dimethyl- 1, (0.04 g, 0.09677 mmol, 1 eq) were added l-methyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH- (0.024 mg, 0.0001153 mmol, 0.001 eq) and potassium carbonate (13.3 mg, 0.09677 mmol, 1.0 eq) in Dioxane (4 mL) at room temperature and reaction mixture was degassed with argon for 20 min followed by palladium(2+) bis(cyclopentyldiphenylphosphane) methylene ch (80.0 mg, 0.09677 mmol, 1.0 eq) was added at room temperature and reaction mixture was heated at 80°C for 16 h. After completion, the reaction mixture was poured in water (25 mL) and extracted with EtOAc (3 x 25 mL). The organic layer was washed with brine solution (2 x 10 mL), dried over Na2SC>4 and evaporated. The product was added to a Prep HPLC column and was eluted with 35 - 70% ACN in 0.1 % formic acid in water as a gradient to provide 5-fluoro-4,8-dimethyl-l-[2- methyl-4-(l-methyl-lH-pyrazol-4-y (0.00568 g, 14.1 % yield) as a white solid.

[0500] 1H NMR (400 MHz, DMSO-d6) 52.10 (s, 3H), 2.20 (s, 3H), 2.46 (d, J = 4.3 Hz, 3H), 2.62 (s, 1H), 3.10 (s, 1H), 3.24 (s, 1H), 3.87 (s, 3H), 4.18 (s, 1H), 6.58 (dd, J = 8.6, 5.3 Hz, 1H), 6.96 (dd, J = 13.4, 8.4 Hz, 1H), 7.55 - 7.67 (m, 2H), 7.85 (d, J = 8.2 Hz, 1H), 7.99 (s, 1H), 8.30 (s, 1H). l,5-dimethyl-4-[2-methyl-4-(l-methyl-lH-pyrazol-4-yl)benzenesulfonyl]-l,2,3,4- tetrahydroquinoxaline (Broad_P_CaV3.3_259, Compound 7)

[0501] To a stirred solution of 8-methyl-l-[2-methyl-4-(l-methyl-lH-pyrazol-4- yl)benzenesulf (0.17 g, 444 pmol, 1 eq), were added triethylamine (89.8 mg, 888 pmol, 2 eq) and methyl iodide (75.5 mg, 532 pmol, 1.2 eq) in Di chloromethane (5 mL) at room temperature and reaction mixture was stirred at Room tempreture for 12h. After completion, the reaction mixture was poured in to water (50 mL) and extracted with DCM (3 x 50 mL). The organic layer was washed with brine solution (2 x 10 mL), dried over Na2SC>4 and evaporated. The crude product was purify by flash chromatography using [0-50% EtOAc / Hexane] to provide impure product, which was further purified by prep HPLC using (05-70% ACN in water containing 0.1% formic acid as modifier) as mobile phase to provide l,5-dimethyl-4-[2-methyl-4-(l-methyl-lH-pyrazol-4-yl)benzene (0.004 g, 3 % yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) 5 7.93 (d, J = 8.2 Hz, 1H), 7.80 (s, 1H), 7.68 (s, 1H), 7.33 (dd, J = 8.3, 1.9 Hz, 1H), 7.27 (s, 1H), 7.04 (t, J = 7.9 Hz, 1H), 6.59 (d, J = 7.6 Hz, 1H), 6.39 (d, J = 8.1 Hz, 1H), 4.34 - 4.19 (m, 1H), 3.96 (s, 3H), 3.25 (s, 1H), 2.98 (q, J = 9.0, 7.4 Hz, 2H), 2.47 (s, 3H), 2.35 (s, 3H), 2.13 (s, 3H).

[0502] 1 ,5-dimethyl-4- [2-methyl-4-(2-methyl- 1 ,3-thiazol-5-yl)benzenesulfonyl] - 1 ,2,3,4- tetrahydroquinoxaline (Broad_P_Cav3.3_312, Compound 8)

[0503] To a stirred solution of l,5-dimethyl-4-[2-methyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzenesulfonyl]-l,2,3,4-tetrahydroquinoxaline (100 mg, 0.2260 mmol) were added 5-bromo-2-methyl-l,3-thiazole (48.2 mg, 0.2712 mmol), potassium carbonate (93.6 mg, 0.6779 mmol) in 1,4- Dioxane (3 mL) and Water (0.3 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 (18.4 mg, 0.02260 mmol) was added at room temperature and reaction mixture was heated at 100°C for 5 h. After completion, the 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.

[0504] 1H NMR (400 MHz, DMSO-d6) 5 8.21 (s, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.61 (d, J = 7.5 Hz, 2H), 7.01 (t, J = 7.9 Hz, 1H), 6.53 (d, J = 7.5 Hz, 1H), 6.45 (d, J = 8.1 Hz, 1H), 4.13 (d, J = 9.9 Hz, 1H), 3.23 (s, 1H), 2.97 (s, 1H), 2.82 (d, J = 8.1 Hz, 1H), 2.70 (s, 3H), 2.40 (s, 3H), 2.26 (s, 3H), 2.04 (s, 3H). MS (ESI) : 414.0 [M+H]+. Synthesis of Compound 9 Compound 9

[0505] 4-[4-(4-ethylimidazol-l-yl)-2-methyl-phenyl]sulfonyl-l,5-dimethyl-2,3-dihydroquinoxaline: (Broad_P_CaV3.3_347, Compound 9)

[0506] A stirred solution of 4-(4-bromo-2-methyl-phenyl)sulfonyl-l,5-dimethyl-2,3- dihydroquinoxaline (0.15 g, 0.379 mmol, 1.00 eq) and 4-ethyl-lH-imidazole (0.036 g, 0.379 mmol, 1.00 eq) in Dimethylformamide (5 mL) was degassed with nitrogen gas for 15 min. After 15 min, Copper (I) oxide (0.011 g, 0.0759 mmol, 0.200 eq) and Potassium tert-butoxide (0.13 g, 1.14 mmol, 3.00 eq) was added to it and heated it in a sealed tube for 96 h at 150 °C. After 96h, the reaction mixture was poured into cold water (50 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organics were dried over Na2SO4 and evaporated. The residue was purified by combiflash using Ethyl acetate: Hexane (1 : 1) as a mobile phase to provide 4-[4-(4-cyclopropylimidazol-l-yl)-2-methyl-phenyl]sulfonyl-l,5-dimethyl-2,3- dihydroquinoxaline Broad_P_CaV3.3_347, (0.017 g, 0.0422 mmol, 11% yield) as an off white solid.

[0507] MS :[M+H]+ 411.00

[0508] ’H NMR (400 MHz, DMSO-t / e) 5 8.56 (s, 1H), 7.99 (s, 1H), 7.69 (s, 3H), 7.02 (s, 1H), 6.50 (d, J= 33.2 Hz, 2H), 3.25 (s, 2H), 2.97 (s, 2H), 2.81 (s, 2H), 2.41 (s, 4H), 2.27 (s, 3H), 2.05

[0509] (s, 3H), 1.21 (s, 3H).

[0510] (3S)-5-fluoro-3,7-dimethyl-l-[2-methyl-4-(4-methylimidazol-l-yl)phenyl]sulfonyl- indoline and (3R)-5-fluoro-3,7-dimethyl-l-[2-methyl-4-(4-methylimidazol-l- yl)phenyl]sulfonyl-indoline (Broad_P_CaV3.3_661A and B) (Compound 10 and Compound 207)

[0511] To a mixture of l-(4-bromo-2-methyl-phenyl)sulfonyl-5-fluoro-3,7-dimethyl-indoline (250 mg, 0.628 mmol, 1.00 eq), 4-Methylimidazole (206 mg, 2.51 mmol, 4.00 eq), Potassium tert-butoxide (211 mg, 1.88 mmol, 3.00 eq) in Dimethylformamide (5 mL) was added Copper(I) oxide (45 mg, 0.314 mmol, 0.500 eq) and the reaction mixture was heated at 140 °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 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).

[0512] Broad_P_CaV3.3_661A 1H NMR (400 MHz, DMSO-d6) 5 8.33 (s, 1H), 7.98 (d, J = 8.3 Hz, 1H), 7.69 (d, J = 8.5 Hz, 2H), 7.59 (s, 1H), 6.96 (ddd, J = 23.4, 9.2, 2.7 Hz, 2H), 4.20 (dd, J = 12.8, 7.3 Hz, 1H), 3.41 (dd, J = 12.0, 8.0 Hz, 1H), 3.41 (d, J = 2.5 Hz, 1H), 2.39 (s, 3H), 2.16 (d, J = 5.5 Hz, 6H), 0.99 (d, J = 6.7 Hz, 3H). MS(ESI): 400.0 [M+H]+

[0513] Broad_P_CaV3.3_661B 1H NMR (400 MHz, DMSO-d6) 5 8.35 (s, 1H), 7.99 (t, J = 8.2 Hz, 1H), 7.71 (d, J = 8.5 Hz, 2H), 7.61 (s, 1H), 6.98 (ddd, J = 23.4, 9.2, 2.7 Hz, 2H), 4.22 (dd, J = 12.8, 7.3 Hz, 1H), 3.46 - 3.40 (m, 1H), 2.63 (s, 1H), 2.41 (s, 3H), 2.18 (d, J = 5.4 Hz, 6H), 1.01 (d, J = 6.7 Hz, 3H). MS(ESI): 400.0 [M+H]+.

[0514] Synthesis of Compound 5 and Compound 134

[0515] 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. The residue was purified via Biotage (20:1 Hex / EtOAc;12Scolumn)toprovideN-(3-fluoro-2-methyl-phenyl)acetamide Broad_P_CaV3.3_400_Int_790, (8.20 g, 47.5 mmol85% yield) 16.4 % yield) as a light yellow oil.

[0516] MS: [M+H] + 167.18.

[0517] (2-acetamido-4-fluoro-3-methyl-phenyl)-hydroxy-oxo-ammonium: Intermediate-791

[0518] To a solution of N-(3-fluoro-2-methyl-phenyl)acetamide (8.20 g, 47.5 mmol, 1.00 eq) in Sulfuric acid (3.8 mL, 71.2 mmol, 1.50 eq), Nitric acid (5.94 mL, 142 mmol, 3.00 eq) was added drop wise at -5° C. and the mixture was stirred for 1 hour at the temperature. The mixture was quenched with water (30 ml) so solid product formation and filter it. 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.

[0519] MS: [M+H] + 213.30.

[0520] (2-amino-4-fluoro-3-methyl-phenyl)-hydroxy-oxo-ammonium: Intermediate-792

[0521] A solution of (2-acetamido-4-fluoro-3-methyl-phenyl)-hydroxy-oxo-ammonium (7.00 g, 32.8 mmol, 1.00 eq) in Tetrahydrofuran (35 mL) was added to a solution of Sodium hydroxide (2.63 g, 65.7 mmol, 2.00 eq) in Water (35 mL) at 0 ° C and the resulting mixture was stirred at RT for 5 h. The reaction mixture was diluted with water (50 mL) and acidify by dillute HCL (20 ml) and extracted with EtOAc (3 x 120 mL). The organics were dried over Na2SO4 and evaporated. The residue was purified via Biotage (5: 1 Hex / EtOAc; 12S column) to provide (2-amino-4-fluoro-3-methyl-phenyl)-hydroxy-oxo-ammonium (Broad_P_CaV3.3_400_Int_792, (2.50 g, 14.6 mmol, 44% yield) as brown solid.

[0522] XH NMR (400 MHz, DMSO-cfc) 5 7.97 (dd, J = 9.7, 5.9 Hz, 1H), 7.41 (s, 2H), 6.53 (t, J = 9.0 Hz, 1H), 2.07 (t, J = 4.4 Hz, 3H).

[0523] 4-fluoro-3-methyl-benzene-l,2-diamine: Intermediate-792 A

[0524] A solution of (2-amino-4-fluoro-3-methyl-phenyl)-hydroxy-oxo-ammonium (2.50 g,

[0525] 14.6 mmol, 1.00 eq) in Acetic acid (25 mL) was added to a portionwise Zinc powder (5.73 g,

[0526] 87.6 mmol, 6.00 eq) at 25°C temperature and the resulting mixture was stirred at RT for 6h. The reaction mixture was diluted with water (30 mL) and then set ph=7 by sodium bicarbonate solution and then extracted with EtOAc (3 x 30 mL). The organics were dried over Na2SO4 and evaporated. The residue was purified via Biotage (8:2 Hex / EtOAc; 24S column) to provided 4-fluoro-3-methyl-benzene-l,2-diamine (Broad_P_CaV3.3_400_Int_792A, (1.30 g, 7.51 mmol, 51% yield) as a yellowish oil.

[0527] MS:[M+H]+ 141.10 tert-butyl N-(2-amino-4-fluoro-3-methyl-phenyl)carbamate: Intermediate-793

[0528] Boc

[0529] A solution of 4-fluoro-3-methyl-benzene-l,2-diamine (1.30 g, 7.51 mmol, 1.00 eq) in Dichloromethane (10 mL) was added to Triethylamine (1.05 mL, 7.51 mmol, 1.00 eq) at 0 °C and then add Di-tert-butyl dicarbonate (0.86 mL, 3.76 mmol, 0.500 eq) at 0°C and the resulting mixture was stirred at RT for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 20 mL). The organics were dried over Na2SO4 and evaporated. The residue was purified via Biotage (5:1 Hex / EtOAc; 12S column) to provided tert-butyl N-(2-amino-4-fluoro-3-methyl-phenyl)carbamate (Broad_P_CaV3 ,3_400_Int_793, (1.10 g, 4.58 mmol, 61% yield) as a white solid.

[0530] XH NMR (400 MHz, DMSO-cfc) 5 8.23 (s, 1H), 6.94 (t, J = 7.4 Hz, 1H), 6.32 (t, J = 9.0 Hz, 1H), 4.85 (s, 2H), 1.98 (s, 3H), 1.44 (s, 9H). tert-butylN-[2-[(4-bromo-2-fluoro-6-methyl-phenyl)sulfonylamino]-4-fluoro-3-methyl- phenyl]carbamate: Intermediate-794

[0531] A solution of tert-butyl N-(2-amino-4-fluoro-3-methyl-phenyl)carbamate (1.10 g, 4.58 mmol, 1.00 eq) in Dichloromethane (10 mL) was added to Pyridine (1.48 mL, 18.3 mmol, 4.00 eq) at RT and then add 5-bromo-l-fluoro-3-methyl-2-methylsulfonyl-benzene (3.67 g, 13.7 mmol, 3.00 eq) the resulting mixture was stirred at RT for 16h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 20 mL). The organics were dried over Na2SO4 and evaporated. The residue was purified via Biotage (8:2 Hex / EtOAc; 12S column) to provided tert-butyl N-[2-[(4-bromo-2-fluoro-6-methyl- phenyl)sulfonylamino]-4-fluoro-3-methyl-phenyl]carbamate (Broad_P_CaV3.3_400_Int_794, (1.00 g, 1.77 mmol, 39% yield) as a yellow solid. MS:[M+H]+ 391.3.

[0532] N-(6-amino-3-fluoro-2-methyl-phenyl)-4-bromo-2-fluoro-6-methyl-benzenesulfonamide:

[0533] Intermediate-794 A

[0534] A solution of tert-butyl N-[2-[(4-bromo-2-fluoro-6-methyl-phenyl)sulfonylamino]-4- fluoro-3-methyl-phenyl]carbamate (1.00 g, 1.77 mmol, 1.00 eq) in Dichloromethane (5 mL) was added to a solution of Hydrogen chloride solution 4.0 M in dioxane (5 mL, 1.77 mmol, 1.00 eq) at 0 ° C and the resulting mixture was stirred at RT for 3h. The reaction mixture was diluted with water (10 mL) and extracted with MDC (3 x 20 mL). The organics were dried over Na2SO4 and evaporated. The residue was purified via Biotage (8:2 Hex / EtOAc; 12S column) to provided N-(6-amino-3-fluoro-2-methyl-phenyl)-4-bromo-2-fluoro-6-methyl- benzenesulfonamide(Broad_P_CaV3.3_400_Int_794A, (0.60 g, 1.53 mmol, 87% yield) as a white solid.

[0535] 1H NMR (400 MHz, DMSO-d6) 5 10.14 (s, 1H), 7.64 (dd, J = 10.5, 2.0 Hz, 1H), 7.51 (s, 1H), 7.05 (t, J = 8.9 Hz, 1H), 6.88 (d, J = 6.6 Hz, 1H), 2.37 (s, 3H), 1.74 (d, J = 2.6 Hz, 3H).

[0536] 4-(4-bromo-2-fluoro-6-methyl-phenyl)sulfonyl-6-fluoro-5-methyl-2,3-dihydro-lH- quinoxaline: Intermediate-795

[0537] A solution of N-(6-amino-3-fhioro-2-methyl-phenyl)-4-bromo-2-fluoro-6-methyl- benzenesulfonamide (0.60 g, 1.53 mmol, 1.00 eq) in Dimethylformamide (10 mL) was added to Potassium carbonate (0.42 g, 3.07 mmol, 2.00 eq) at 25 °C temperature and then add 1,2- Dibromoethane (.16 mL, 1.84 mmol, 1.20 eq) the resulting mixture was stirred at 100°C for 3h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 25 mL). The organics were dried over Na2SO4 and evaporated. The residue was purified via Biotage (8:2 Hex / EtOAc; 12S column) to provided 4-(4-bromo-2-fluoro-6-methyl- phenyl)sulfonyl-6-fluoro-5-methyl-2,3-dihydro-lH-quinoxaline Broad_P_CaV3.3_400_Int_795_, (0.45 g, 0.927 mmol, 60% yield) as a white solid.

[0538] MS :[M+H]+ 417.27.

[0539] 6-fluoro-4-[2-fluoro-6-methyl-4-(l-methylpyrazol-4-yl)phenyl]sulfonyl-5-methyl-2,3- dihydro-lH-quinoxaline: Broad_P_CaV3.3_453, Compound 134

[0540] A stirred suspension of 4-(4-bromo-2-fluoro-6-methyl-phenyl)sulfonyl-6-fluoro-5- methyl-2,3-dihydro-lH-quinoxaline (0.45 g, 0.927 mmol, 1.00 eq), l-methyl-4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (0.29 g, 1.39 mmol, 1.50 eq) and Potassium carbonate (0.38 g, 2.78 mmol, 3.00 eq) in 1,4-Di oxane (8 mL) and Water (2 mL) was degassed with nitrogen gas for 15 min. After 15 min, (1,1 - Bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.014 g, 0.0185 mmol, 0.0200 eq) was added to it and heated at 100°C for 4h. After 4h, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 ^ 10 mL). The organic layer was dried over Na2SO4 and evaporated. The residue was purified via Biotage (5:1 Hex / EtOAc; 12S column) to provide impure product, which was further purified by prep HPLC using (25-70% ACN in water containing 5 mM ammonium carbonate and 0.1% ammonia in water as modifier) as mobile phase to provide 6-fluoro-4-[2-fluoro-6-methyl-4-(l-methylpyrazol-4- yl)phenyl]sulfonyl-5-methyl-2,3-dihydro-lH-quinoxaline 4-(4-bromo-2-fluoro-6-methyl- phenyl)sulfonyl-6-fluoro-5-methyl-2,3-dihydro-lH-quinoxaline (0.45 g, 0.927 mmol) as a off white solid. ’H NMR (400 MHz, DMSO-de) 5 8.34 (s, 1H), 8.04 (s, 1H), 7.47 (d, J = 12.1 Hz, 2H), 6.84 (t, J = 9.2 Hz, 1H), 6.36 (dd, J = 9.0, 5.5 Hz, 1H), 5.86 (s, 1H), 4.06 (s, 1H), 3.87 (s, 3H), 3.13 (s, 2H), 2.82 (s, 1H), 2.33 (s, 3H), 2.14 - 2.03 (m, 3H). MS :[M+H]+ 419.6. 6-fluoro-4-[2-fluoro-6-methyl-4-(l-methylpyrazol-4-yl)phenyl]sulfonyl-l,5-dimethyl-2,3- dihydroquinoxaline: Broad_P_CaV3.3_400, Compound 5

[0541]

[0542] A solution of 6-fluoro-4-[2-fluoro-6-methyl-4-(l-methylpyrazol-4-yl)phenyl]sulfonyl- 5-methyl-2,3-dihydro-lH-quinoxaline (0.22 g, 0.519 mmol, 1.00 eq), Dimethylformamide (5 mL), and Methyl iodide (.04 mL, 0.622 mmol, 1.20 eq) was stirred at 100°C temperature for 3h. After completion of reaction, the reaction mixture was quenched in water (5 mL) and extracted with ethyl acetate (3 ^ 10 mL). organics were dried over Na2SC>4 and evaporated. The residue was purified via Biotage (5: 1 Hex / EtOAc; 12S column) to provide impure product, which was further purified by prep HPLC using (25-70% ACN in water containing 5 mM ammonium carbonate and 0.1% ammonia in water as modifier) as mobile phase to provide 6-fluoro-4-[2-fluoro-6-methyl-4-(l-methylpyrazol-4-yl)phenyl]sulfonyl-l,5- dimethyl-2, 3 -dihydroquinoxaline Broad_P_CaV3.3_400, (0.014 g, 0.0301 mmol, 6% yield) as a off white solid.

[0543] MS:[M+H]+ 361.0.

[0544] 'H N R (400 MHz, DMSO-t / e) 5 8.34 (s, 1H), 8.04 (s, 1H), 7.51 - 7.35 (m, 2H), 6.98 (t, J= 9.2 Hz, 1H), 6.47 (dd, J= 9.1, 5.3 Hz, 1H), 4.24 (d, J= 25.5 Hz, 1H), 3.86 (s, 3H), 3.00 (s,

[0545] 1H), 2.91 (d, J= 9.9 Hz, 1H), 2.43 (s, 3H), 2.24 (s, 3H), 2.16 (d, J= 2.5 Hz, 3H).

[0546] 4-[4-(5-fluoro-l-methyl-lH-pyrazol-4-yl)-2-methylbenzenesulfonyl]-l,5-dimethyl- 1,2,3,4-tetrahydroquinoxaline (Broad_P_Cav3.3_309, Compound 12) To a stirred solution of l,5-dimethyl-4-[2-methyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzenesulfonyl]-l,2,3,4-tetrahydroquinoxaline (90 mg, 0.2034 mmol) were added 4-bromo-5-fluoro-l-methyl-lH-pyrazole (43.6 mg, 0.2440 mmol), potassium carbonate (84.3 mg, 0.6102 mmol) in 1,4- Dioxane (3 mL) and Water (0.3 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 (16.6 mg, 0.02034 mmol) was added at room temperature and reaction mixture was heated at 100°C for 8 h. After completion, the reaction mixture was poured in to water (20 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 residue was purified via Biotage (50:1 CFLCb / MeOH; 12S column) to provide 4- [4-(5 -fluoro- 1 -met (60 mg, 69.2 % yield) as a white solid.

[0547] 1H NMR (400 MHz, DMSO-d6) 5 7.99 (d, J = 3.1 Hz, 1H), 7.91 (d, J = 8.3 Hz, 1H), 7.57 - 7.45 (m, 2H), 7.00 (t, J = 7.8 Hz, 1H), 6.52 (d, J = 7.5 Hz, 1H), 6.45 (d, J = 8.1 Hz, 1H), 4.15 - 4.06 (m, 1H), 3.76 (s, 3H), 3.22 (s, 1H), 2.96 (s, 1H), 2.78 (d, J = 9.4 Hz, 1H), 2.41 (s, 3H), 2.26 (s, 3H), 2.03 (s, 3H). MS (ESI) : 415.2 [M+H]+. l,5-dimethyl-4-[[4-methyl-6-(4-methylimidazol-l-yl)-3-pyridyl]sulfonyl]-2,3- dihydroquinoxaline (Broad_P_CaV3.3_356, Compound 13)

[0548] To a stirred solution of 4-[(6-bromo-4-methyl-3-pyridyl)sulfonyl]-l,5-dimethyl-2,3- dihydroquinoxaline (200 mg, 0.505 mmol, 1.00 eq)in DMF (2 mL) was added 4- Methylimidazole (83 mg, 1.01 mmol, 2.00 eq) at 0°C and stirred at same temperature for 30 min. After 30 min, 60% suspension of Sodium hydride in parafin oil (26 mg, 0.757 mmol, 1.50 eq) was added to it and stirred at RT for 16h. After completion, the reaction mixture was poured into cold water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organics were dried over Na2SC>4 and evaporated. The residue was purified by Combi-flash machine using Ethyl acetate :Hexanes (3:7) to provide impure compound, which was further purified by prep HPLC purification using (25-50% ACN in water containing 0.1% formic acid as a modifier) as a mobile phase to provide l,5-dimethyl-4-[[4-methyl-6-(4- methylimidazol-l-yl)-3-pyridyl]sulfonyl]-2,3-dihydroquinoxaline (40 mg, 19.9% yield) as a white solid.

[0549] 1H NMR (400 MHz, DMSO-d6) 5 8.83 (s, 1H), 8.48 (s, 1H), 7.72 (d, J = 11.8 Hz, 2H), 7.05 (t, J = 7.9 Hz, 1H), 6.59 (d, J = 7.5 Hz, 1H), 6.45 (d, J = 8.1 Hz, 1H), 4.28 (dd, J = 14.8, 7.4 Hz, 1H), 3.27 (dd, J = 14.4, 7.2 Hz, 1H), 2.97 (dd, J = 11.4, 6.5 Hz, 1H), 2.86 (dd, J = 11.5, 8.0 Hz, 1H), 2.33 (d, J = 3.1 Hz, 6H), 2.17 (s, 3H), 1.97 (s, 3H). MS(ESI): 398.0 [M+H]+. l,5-dimethyl-4-[[4-methyl-6-(l-methylpyrazol-4-yl)-3-pyridyl]sulfonyl]-3H-quinoxalin- 2-one (Broad_P_CaV3.3_407, Compound 14)

[0550] A stirred suspension of 4-[(6-bromo-4-methyl-3-pyridyl)sulfonyl]-l,5-dimethyl-3H- quinoxalin-2-one (310 mg, 0.356 mmol, 1.00 eq), l-methyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazole (111 mg, 0.534 mmol, 1.50 eq) and Potassium carbonate (148 mg, 1.07 mmol, 3.00 eq) in Dioxane (2.8254 mL) was degassed with nitrogen gas for 15 min. After 15 min, (l,T-Bis(diphenylphosphino)ferrocene)palladium(II) dichloride (26 mg, 0.0356 mmol, 0.100 eq) was added to it and heated at 100 °C for 16 h. After 16 h, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 / 50 mL). The organic layers was dried over Na2SC>4 and evaporated. The residue was purified via Biotage (40 / 60 Hex / EtOAc; 12S column) to provide impure product, which was further purified by prep HPLC using (20-55% ACN in water containing 0.1% formic acid in water as modifier) as mobile phase to provideBroad_P_Cav3.3_407, (28 mg, 0.0677 mmol, 19% yield) as off white solid.

[0551] 1H NMR (400 MHz, DMSO-d6) 5 8.43 (d, J = 14.4 Hz, 2H), 8.08 (d, J = 26.5 Hz, 1H), 7.63 (s, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 4.52 - 4.25 (m, 2H), 3.89 (s, 3H),2.52 (s, 6H), 1.95 (s, 3H). MS(ESI): 412.3[M+H]+.

[0552] 4-[(6-chloro-4-methyl-3-pyridyl)sulfonyl]-l,5-dimethyl-3H-quinoxalin-2-one

[0553] To a stirred solution of 4-[(6-chloro-4-methyl-3-pyridyl)sulfonyl]-5-methyl-l,3- dihydroquinoxalin-2-one (350 mg, 0.872 mmol, 1.00 eq), Potassium carbonate (362 mg, 2.62 mmol, 3.00 eq) in DMF (4.385 mL) was added iodomethane (.08 mL, 1.31 mmol, 1.50 eq) at room temperature. The reaction mixture was heated at 50 °C and stirred for 15 h. After completion, the reaction mixture was quenched with ice-water (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organics were washed with brine solution (2 x 30 mL), dried over Na2SC>4 and evaporated. The residue was purified by flash column chromatography and the product was eluted with 30% EtOAc in n-hexane as a gradient to provide Broad_P_Cav3.3_407_Int-825, (310 mg, 0.399 mmol, 46% yield) as off white solid. MS (ESI) : 366.2 [M+H]+.

[0554] 4-[(6-chloro-4-methyl-3-pyridyl)sulfonyl]-5-methyl-l,3-dihydroquinoxalin-2-one

[0555]

[0556] To a stirred solution of 2-[2-amino-N-[(6-chloro-4-methyl-3-pyridyl)sulfonyl]-6- methyl-anilino]acetic acid (470 mg, 1.03 mmol, 1.00 eq) and l-Ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrchloride (236 mg, 1.23 mmol, 1.20 eq) in DMF (3.62 mL) at room temperature. The reaction mixture was stirred at 30 °C for 6h. After completion, the reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with brine solution (3 x 30 mL), dried over Na2SC>4 and evaporated. The residue was purified by combi-flash column chrometography and was eluted with 2-3 % MeOH in DCM as a gradient to provide Broad_P_Cav3.3_407_int-824, (350 mg, 0.872 mmol, 85% yield) as an off white solid. MS (ESI) : 352.4 [M+H]+.

[0557] 2-[2-amino-N-[(6-chloro-4-methyl-3-pyridyl)sulfonyl]-6-methyl-anilino]acetic acid

[0558] To a stirred solution of ethyl 2-[2-amino-N-[(6-chloro-4-methyl-3-pyridyl)sulfonyl]- 6-methyl-anilino]acetate (1.00 g, 1.90 mmol, 1.00 eq) in MeOH (2.2737 mL), THF (2.2737 mL) and Water (1.1369 mL) at room temperature, was added Lithium hydroxide monohydrate (0.32 g, 7.62 mmol, 4.00 eq) at same temperature. The reaction was stirred at 30 °C for 5h. After completion, the reaction mixture was acidify with dilut HC1 solition (5 mL) and the solvent was concentrated under vaccuo. The residue was diluted with EtOAc (50 mL) and the organic layer was washed with water (3 x 40 mL) and brine solition (3 x 40 mL). The combined organics were dried over Na2SC>4 and evaporated to provide Broad_P_Cav3.3_407_Int-823, (470 mg, 1.03 mmol, 54% yield) as an off white solid. MS (ESI): 370.1 [M+H]+. ethyl 2-[2-amino-N-[(6-chloro-4-methyl-3-pyridyl)sulfonyl]-6-methyl-anilino]acetate

[0559] To a stirred solution of N-(2-amino-6-methyl-phenyl)-6-chloro-4-methyl-pyridine-3- sulfonamide;hydrochloride (1.50 g, 3.25 mmol, 1.00 eq), ethyl 2-bromoacetate (.43 mL, 3.90 mmol, 1.20 eq) and Potassium carbonate (1.35 g, 9.76 mmol, 3.00 eq) in DMF (11.328 mL) at room temperature. The raction mixture was stirred at 30 °C for 3h. After completion, the reaction mixture was quenched with ice-water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with brine solution (3 x 30 mL), dried over Na2SC>4 and evaporated. The residue was purified by combi-flash column chromatography and was eluted with 70% EtOAc in Hexane as a gradient to provide Broad_P_Cav3.3_407_Int-822, (1.00 g, 2.16 mmol, 66% yield) as a white solid. MS (ESI): 398.2 [M+H]+.

[0560] N-(2-amino-6-methyl-phenyl)-6-chloro-4-methyl-pyridine-3-sulfonamide;hydrochloride

[0561] To a stirred solution of tert-butyl N-[2-[(6-bromo-4-methyl-3-pyridyl)sulfonylamino]- 3-methyl-phenyl]carbamate (1.70 g, 2.45 mmol, 1.00 eq) in DCM (13.164 mL) was added 4M HC1 in dioxane (4 M in , 6.13 mL, 24.5 mmol, 10.0 eq) and allowed to stir it at RT for 3 h. After compeltion, the reaction mixture was evaporated to provide Broad_P_Cav3.3_407_Int-728, (1.50 g, 3.25 mmol, quant) as an off white solid. MS(ESI): 310.3 [M-HC1-1]+. tert-butyl N-[2-[(6-bromo-4-methyl-3-pyridyl)sulfonylamino]-3-methyl-phenyl]carbamate

[0562] A solution of tert-butyl N-(2-amino-3-methyl-phenyl)carbamate (1.56 g, 7.02 mmol, 1.00 eq) in Dichloromethane (10 mL) was added to Pyridine (2.26 mL, 28.1 mmol, 4.00 eq) at 25 °C temperature and then add 6-bromo-4-methyl-pyridine-3-sulfonyl chloride (1.90 g, 7.02 mmol, 1.00 eq) the resulting mixture was stirred at RT for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 80 mL). The organics were dried over Na2SO4 and evaporated. The residue was purified via Biotage (8:2 Hex / EtOAc; 12S column) to provided tert-butyl N-[2-[(4-bromo-2-fluoro-6-methyl- phenyl)sulfonylamino]-4-fluoro-3-methyl-phenyl]carbamate (Broad_P_Cav3.3_407_Int-727, (1.70 g, 2.45 mmol, 35% yield) as a brown solid.

[0563] 1H NMR (400 MHz, DMSO-d6) 5 9.43 (s, 1H), 8.47 (d, J = 16.0 Hz, 1H), 7.90 (s, 1H), 7.74 (d, J = 54.6 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.18 (t, J = 7.9 Hz, 1H), 6.99 (d, J = 7.6 Hz, 1H), 2.38 (d, J = 3.9 Hz, 3H), 2.22 (s, 3H), , 1.39 (d, J = 3.4 Hz, 9H). MS(ESI): 454.24[M-

[0564] H]-.

[0565] Synthesis of Compound 15 and Compound 46 aV3.3 431 2

[0566] Compound 15

[0567] Compound 46

[0568] (4R)-4,8-dimethyl-l-[2-methyl-4-(l-methylpyrazol-4-yl)phenyl]sulfonyl-3,4-dihydro-2H- quinoline & (4S)-4,8-dimethyl-l-[2-methyl-4-(l-methylpyrazol-4-yl)phenyl]sulfonyl-3,4- dihydro-2H-quinoline: Broad_P_CaV3.3_430 & Broad_P_CaV3.3_431 (Compound 15 and its stereoisomer)

[0569] 4,8-dimethyl-l,2,3,4-tetrahydroquinoline (0.20 g, 1.24 mmol, 1.00 eq) and 2-methyl- 4-(l-methylpyrazol-4-yl)benzenesulfonyl chloride (0.84 g, 3.10 mmol, 2.50 eq) taken in acetonitrile (4 mL) under nitrogen atmosphere. Zinc oxide (0.20 g, 2.48 mmol, 2.00 eq) was added and reaction was allowed to stir at RT for 72h. After completion, water was added and crude product was extracted with ethyl acetate (3 x 25 mL). Organic layers combined and washed with brine, dried over anhydrous sodium sulphate and concentrated to give crude product, which was purified by first using column chromatography to give racemic compound 758E having LCMS purity 96% (254nm), followed by chiral prep HPLC purification to provide two fractions. Pure fractions were evaporated to provide Broad_P_CaV3.3_430, (7.6 mg, 0.0191 mmol, 2% yield) (Fr-1) and Broad_P_CaV3.3_431, (3.5 mg, 0.00876 mmol, 100% purity, 0.71) (Fr-2).

[0570] MS:[M+H]+ 396.10.

[0571] Fr-1 (Broad_P_CaV3.3_430):

[0572] 1H NMR (400 MHz, Chloroform-d) 5 7.88 (d, J = 8.2 Hz, 1H), 7.80 (s, 1H), 7.69 (s, 1H), 7.39 - 7.33 (m, 1H), 7.32 (s, 1H), 7.14 (s, 2H), 7.01 (d, J = 7.0 Hz, 1H), 4.21 - 4.04 (m, 1H), 3.96 (s, 3H), 3.40 (s, 1H), 2.33 (s, 3H), 2.21 (s, 3H), 2.06 (s, 2H), 1.31 - 1.17 (m, 1H), 1.11 (d, J = 6.4 Hz, 3H).

[0573] Fr-2 (Broad_P_CaV3.3_431):

[0574] 1H NMR (400 MHz, Chloroform-d) 5 7.87 (d, J = 8.2 Hz, 1H), 7.80 (s, 1H), 7.69 (s, 1H), 7.39 - 7.33 (m, 1H), 7.31 (s, 1H), 7.15 (d, J = 7.4 Hz, 2H), 7.00 (d, J = 6.8 Hz, 1H), 4.13 (s, 1H), 3.95 (s, 3H), 3.40 (s, 1H), 2.33 (s, 3H), 2.21 (s, 3H), 2.06 (s, 2H), 1.23 (d, J = 14.1 Hz, 1H), 1.11 (d, J = 6.4 Hz, 3H).

[0575] 6-fluoro-l,5-dimethyl-4-[2-methyl-4-(l-methyl-lH-pyrazol-4-yl)benzenesulfonyl]- 1,2,3,4-tetrahydroquinoxaline (Broad_P_Cav3.3_301, Compound 16)

[0576] To a stirred solution of 4-(4-bromo-2-methylbenzenesulfonyl)-6-fluoro-l,5-dimethyl- 1,2,3,4-tetrahydroquinoxaline (350 mg, 0.8468 mmol) were added l-methyl-4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (210 mg, 1.01 mmol), potassium carbonate (351 mg, 2.54 mmol) in 1,4-Dioxane (5 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 (69.1 mg, 0.08468 mmol) was added at room temperature and reaction mixture was heated at 100°C for 8 h. After completion, the reaction mixture was poured in to water (30 mL) and extracted with EtOAc (3 x 30 mL). The organic layer was washed with brine solution (2 x 20 mL), dried over Na2SO4 and evaporated. The residue was purified via Biotage (50: 1 CH^Ch / MeOH; 12M column) to provide 6-fluoro-l,5-dimethy (198 mg, 55.7 % yield) as an off white solid.

[0577] 1H NMR (400 MHz, Chloroform-d) 5 2.16 (s, 3H), 2.26 (d, J = 2.7 Hz, 3H), 2.46 (s, 3H), 2.92 (d, J = 6.9 Hz, 2H), 3.23 (s, 1H), 3.96 (s, 3H), 4.28 (d, J = 13.8 Hz, 1H), 6.32 (dd, J = 9.0, 5.0 Hz, 1H), 6.87 (t, J = 9.0 Hz, 1H), 7.28 (s, 1H), 7.33 (d, J = 8.2 Hz, 1H), 7.68 (s, 1H), 7.80 (s, 1H), 7.91 (d, J = 8.3 Hz, 1H). 19F NMR (377 MHz, Chloroform-d) 5 -128.76. MS

[0578] (ESI) : 415.0 [M+H]+.

[0579] Synthesis of Compound 17 Compound 17

[0580] 4-[4-(4-cyclopropylimidazol-l-yl)-2-methyl-phenyl]sulfonyl-l,5-dimethyl-2,3- dihydroquinoxaline: Broad_P_CaV3.3_346 A stirred solution of 4-(4-bromo-2-methyl-phenyl)sulfonyl-l,5-dimethyl-2,3- dihydroquinoxaline (0.15 g, 0.379 mmol, 1.00 eq) and 4-cyclopropyl-lH-imidazole (0.082 g, 0.759 mmol, 2.00 eq) in Dimethylformamide (5 mL) was degassed with nitrogen gas for 15 min. After 15 min, Copper(I) oxide (0.054 g, 0.379 mmol, 1.00 eq) and Potassium tert- butoxide (0.13 g, 1.14 mmol, 3.00 eq) was added to it and heated it in a sealed tube for 16 h at 100°C. After 16h, the reaction mixture was poured into cold water (50 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organics were dried over Na2SO4 and evaporated. The residue was purified by combiflash using Ethyl acetate: Hexane (1 : 1) as a mobile phase to provide 4-[4-(4-cyclopropylimidazol-l-yl)-2-methyl-phenyl]sulfonyl-l,5- dimethyl-2,3-dihydroquinoxaline Broad_P_CaV3.3_346, (0.015 g, 0.0364 mmol, 10% yield) as an off white solid.

[0581] MS:[M+H]+ 423.00.

[0582] ’H NMR (400 MHz, DMSO-cfc) 5 8.28 (s, 1H), 7.96 (d, J = 8.9 Hz, 1H), 7.63 (d, J = 7.1 Hz, 3H), 7.02 (t, J = 8.0 Hz, 1H), 6.54 (d, J = 7.5 Hz, 1H), 6.45 (d, J = 8.2 Hz, 1H), 4.15 (d, J = 8.7 Hz, 1H), 2.97 (s, 1H), 2.81 (s, 2H), 2.41 (s, 3H), 2.27 (s, 3H), 2.04 (s, 3H), 1.84 (s, 2H), 0.81 (d, J = 7.2 Hz, 2H), 0.69 (s, 2H).

[0583] Synthesis of Compound 18

[0584] Broad_P_CaV3.3_472 Compund 18 l-((4-bromo-2-methylphenyl)sulfonyl)-7-methylindoline : Intermediate 1

[0585] To a stirred solution of 7-m ethylindoline (50 mg, 0.375 mmol, 1.00 eq) and 4-bromo- 2-methyl-benzenesulfonyl chloride (121 mg, 0.450 mmol, 1.20 eq) in pyridine (1 mL) at rt under inert atmosphere added a Triethyl amine (0.16 mL, 1.13 mmol, 3.00 eq) followed by DMAP (46 mg, 0.375 mmol, 1.00 eq) was added and then allowed to stirred at rt. RM was quenched with water (20mL) and extracted with ethyl acetate (30m x 3), organic layer was dried over anhydrous Na2SC>4, Filter and concentrated under vaccum. Purification was done by column chromatography in 0-10% Ethyl acetate: Hexane, to provide a l-(4-bromo-2- methyl-phenyl)sulfonyl-7-methyl-indoline, (90 mg, 0.241 mmol, 64% yield) as light brown solid. MS(ESI): 366.27[M+H]

[0586] XH NMR (400 MHz, Chloroform-d) 5 7.82 (d, J = 8.5 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.35 (s, 1H), 7.07 (d, J = 4.5 Hz, 2H), 6.96 (t, J = 4.5 Hz, 1H), 3.94 (t, J = 7.2 Hz, 2H), 2.51 (s, 3H), 2.36 (t, J = 7.2 Hz, 2H), 2.09 (s, 3H).

[0587] 7-methyl- 1 -((2-methyl-4-( 1 -methyl- lH-pyrazol-4-yl)phenyl)sulfonyl)indoline

[0588] To a stirred solution of l-(4-bromo-2-methyl-phenyl)sulfonyl-7-methyl-indoline (80 mg, 0.218 mmol, 1.00 eq) and l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyrazole (91 mg, 0.437 mmol, 2.00 eq) in Dioxane (3 mL) Water (1 mL) at rt ,then followed by addition of sodium carbonate (69 mg, 0.655 mmol, 3.00 eq) purging reaction mixture by argon for 10 min then [l,l'-Bis(diphenylphosphino)ferrocene] dichloropalladium(II), complex with dichloromethane (8.9 mg, 0.0109 mmol, 0.0500 eq) was added under inert atmosphere and stirred reaction mixture at 80°C. Reaction was quenched with water (30mL) and extracted with ethyl acetate (30mL X3), organic layer was dried over anhydrous sodium sulphate, filter and concentrated under vaccuo. Crude was purified by column chromatography to provided 7-methyl-l-[2-methyl-4-(l-methylpyrazol-4- yl)phenyl]sulfonyl-indoline (51 mg, 0.137 mmol, 63% yield) as brown solid. MS(ESI): 367.47[M+H]

[0589] ’H NMR (400 MHz, DMSO-t / e) 5 8.29 (s, 1H), 7.98 (s, 1H), 7.86 (d, J= 8.3 Hz, 1H), 7.58 (dd, J= 8.3, 1.9 Hz, 1H), 7.52 (d, J= 1.9 Hz, 1H), 7.14 - 7.07 (m, 2H), 7.06 - 6.99 (m, 1H), 3.90 (t, J= 7.2 Hz, 2H), 3.86 (s, 3H), 2.44 (s, 3H), 2.26 (t, J= 7.2 Hz, 2H), 1.99 (s, 3H). l,5-dimethyl-4-[2-methyl-4-(4-methylimidazol-l-yl)phenyl]sulfonyl-2,3- dihydroquinoxaline (Broad_P_Cav3.3_291, Compound 19)

[0590] A stirred suspension of 4-(4-bromo-2-methyl-phenyl)sulfonyl-l,5-dimethyl-2,3- dihydroquinoxaline (1.50 g, 3.64 mmol, 1.00 eq), 4-methyl-lH-imidazole (0.75 g, 9.09 mmol, 2.50 eq) and Potassium tert-butoxide (0.82 g, 7.27 mmol, 2.00 eq) in DMF (15 mL) was degassed with nitrogen gas for 15 min. After 15 min, Copper(I) oxide (0.14 g, 1.82 mmol, 0.500 eq) was added to it and heated it at 120 °C for 16 h. 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 Na2SC>4 and evaporated under vacuum. The residue was purified via combi flash using (80% Ethyl acetate: Hexanes) as a mobile phase to provide impure product then repurified by prep HPLC using (10-30% ACN and water containing 0.1% Formic acid as a modifier) as a mobile phase to provided Broad_P_Cav3.3_291,(45 mg, 0.110 mmol, 3% yield), as an Brown solid.

[0591] 1H NMR (400 MHz, DMSO-d6) 5 8.32 (s, 1H), 7.98 (d, J = 8.5 Hz, 1H), 7.65 (d, J = 7.8 Hz, 2H), 7.60 (s, 1H), 7.03 (t, J = 7.8 Hz, 1H), 6.55 (d, J = 7.5 Hz, 1H), 6.47 (d, J = 8.2 Hz, 1H), 4.16 (dd, J = 14.9, 6.9 Hz, 1H), 3.25 (s, 1H), 2.98 (t, J = 8.6 Hz, 1H), 2.83 (s, 1H), 2.43 (s, 3H), 2.29 (s, 3H), 2.17 (s, 3H), 2.06 (s, 3H). MS(ESI): 397.2 [M+H]+.

[0592] 4-(4-bromo-2-methyl-phenyl)sulfonyl-l,5-dimethyl-2,3-dihydroquinoxaline To a stirred a solution of 4-(4-bromo-2-methyl-phenyl)sulfonyl-5-methyl-2,3- dihydro-lH-quinoxaline (2.00 g, 4.93 mmol, 1.00 eq) and Potassium carbonate (2.04 g, 14.8 mmol, 3.00 eq) in DMF (10.12 mL) was added iodomethane (.46 mL, 7.40 mmol, 1.50 eq) at room temperature. The reaction mixture was heated at 80 °C and stirred for 16 h. After completion, the reaction mixture was poured in to ice-water (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organics were washed with brine solution (2 x 50 mL), dried over Na2SC>4 and evaporated. The residue was purified via biotage (40:60, HexZEtOAc) to provide Broad_P_Cav3.3_291_Int-538C, (1.50 g, 3.64 mmol, 74% yield) as a white solid. MS (ESI) : 397.2 [M+H]+.

[0593] 4-(4-bromo-2-methyl-phenyl)sulfonyl-5-methyl-2,3-dihydro-lH-quinoxaline;hydrochloride To a stirred solution of tert-butyl 4-(4-bromo-2-methyl-phenyl)sulfonyl-5-methyl-2,3- dihydroquinoxaline-1 -carboxylate (3.10 g, 6.44 mmol, 1.00 eq) in dichloromethane (30 mL) was added HC1 in 1,4-dioxane (4 M in Dioxane, 20 mL, 80.0 mmol, 12.4 eq) at 0°C. The 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.

[0594] 1H NMR (400 MHz, DMSO-d6) 5 7.84 (d, J = 8.5 Hz, 1H), 7.69 - 7.56 (m, 2H), 6.87 (t, J = 7.7 Hz, 1H), 6.37 (t, J = 8.9 Hz, 2H), 5.86 (s, 4H), 4.00 (s, 1H), 3.57 (s, 1H), 3.11 (s, 2H), 2.20 (s, 3H), 2.12 (s, 3H). MS(ESI): 381.2 [M+H]+. tert-butyl 4-(4-bromo-2-methyl-phenyl)sulfonyl-5-methyl-2,3-dihydroquinoxaline-l- carb oxy late

[0595] To a stirred solution of tert-butyl N-[2-[(4-bromo-2-methyl-phenyl)sulfonylamino]-3- methyl-phenyl]carbamate (3.00 g, 6.59 mmol, 1.00 eq) and 1,2-dibromoethane (.71 mL, 7.91 mmol, 1.20 eq) in DMF (20 mL) was added K2CO3 (3.64 g, 26.4 mmol, 4.00 eq) at room temperature. The reaction mixture was heated at 90 °C for 16 h. After completion, the 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.

[0596] 1H NMR (400 MHz, DMSO-d6) 5 7.90 (d, J = 8.6 Hz, 1H), 7.67 - 7.53 (m, 2H), 7.39 (s, 1H), 7.20 (t, J = 7.9 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 4.29 (d, J = 13.6 Hz, 1H), 3.30 (d, J = 10.7 Hz, 2H), 2.89 (s, 1H), 2.73 (s, 1H), 2.37 (s, 3H), 2.00 (s, 3H), 1.37 (s, 9H). MS(ESI): 427.2 [M-56]+. tert-butyl N-[2-[(4-bromo-2-methyl-phenyl)sulfonylamino]-3-methyl-phenyl]carbamate

[0597]

[0598] To a stirred a solution of tert-butyl N-(2-amino-3-methyl-phenyl)carbamate (2.80 g, 12.6 mmol, 1.00 eq) and Pyridine (5.09 mL, 63.0 mmol, 5.00 eq) in dichloromethane (30 mL) was added 4-bromo-2-methyl-benzenesulfonyl chloride (5.09 g, 18.9 mmol, 1.50 eq) at RT. The reaction mixture was stirred at same temperature for 16 h. After completion, the reaction was quenched with water and extracted ethyl acetate (3 x 50 mL). The combined organics were washed brine solution (2 x 50 mL), dried over Na2SC>4 and evaporated. The residue was purified by silica gel column chromatography(8% Ethyl acetate: Hexanes) as a mobile phase to provide tert-butyl N-[2-[(4-bromo-2-methyl-phenyl)sulfonylamino]-3-methyl- phenyl]carbamate, (5.00 g, 10.6 mmol, 84% yield) as an off white solid.

[0599] 1H NMR (400 MHz, DMSO-d6) 5 9.36 (s, 1H), 7.67 (s, 1H), 7.62 (s, 1H), 7.56 (d, J = 13.2 Hz, 3H), 7.15 (t, J = 7.8 Hz, 1H), 6.92 (d, J = 7.7 Hz, 1H), 2.43 (s, 3H), 2.08 (s, 3H), 1.49 - 1.32 (m, 9H). MS(ESI): 455.3 [M+H]+.

[0600] Synthesis of Compound 20

[0601] Broad_P_CaV3.3_625

[0602] Compound 20 l-(4-bromo-2-methyl-phenyl)sulfonyl-5-fluoro-7-methyl-indoline: Intermediate- 1290

[0603] To a stirred a solution of 5-fluoro-7-methyl-indoline (0.20 g, 1.32 mmol, 1.00 eq) and Pyridine (0.43 mL, 5.29 mmol, 4.00 eq) in DCM (5 mL) was added4-bromo-2-methyl- benzenesulfonyl chloride (641.85 mg, 2.38 mmol, 2.00 eq) at RT. The reaction mixture was stirred at same temperature for 12 h. After completion, the reaction was quenched with 10% citric acid solution (50 mL) and extracted ethyl acetate (3 x 50 mL). The combined organics were washed brine solution (2 x 50 mL), dried over Na2SO4 and evaporated. The residue was purified by silica gel column chromatography (6:4, Ethyl acetate: Hexanes) as a mobile phase to provide Broad_P_CaV3.3_625_Int-1290, (180 mg, 0.47 mmol, 35% yield) as an off white solid.

[0604] 1H NMR (400 MHz, Chloroform-d) 5 7.85 (d, J = 8.5 Hz, 1H), 7.49 (dd, J = 8.5, 2.1 Hz, 1H), 7.43 (d, J = 2.0 Hz, 1H), 6.83 (dd, J = 9.8, 2.6 Hz, 1H), 6.73 (dd, J = 7.7, 2.6 Hz, 1H), 3.99 (t, J = 7.2 Hz, 2H), 2.54 (s, 3H), 2.40 (t, J = 7.3 Hz, 2H), 2.21 (s, 3H).

[0605] 5-fluoro-7-methyl-l-[2-methyl-4-(4-methylimidazol-l-yl)phenyl]sulfonyl-indoline: Broad_P_Cav3.3_625, Compound 20

[0606] A stirred suspension of l-(4-bromo-2-methyl-phenyl)sulfonyl-5-fluoro-7-methyl- indoline (0.18 g, 0.47 mmol, 1.00 eq) , 4-methyl-lH-imidazole (0.076 g, 0.94 mmol, 2.00 eq) and Ktb (0.157 g, 1.41 mmol, 3.00 eq) in DMF (5 mL) was degassed with nitrogen gas for 15 min. After 15 min, Copper(I)oxide (0.020 g, 0.140 mmol, 0.3 eq) was added to it and heated it at 170oC for 4 h in Microwave. 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. The residue was purified via combi flash using (1 :1, Ethyl acetate: Hexanes) as a mobile phase to provide mixture of isomers which was further purified by prep HPLC to give Broad_P_CaV3.3_625, (20 mg, 0.05 mmol, 10% yield) as an off white solid. MS: [M+H]+385.9

[0607] 1H NMR (400 MHz, DMSO-d6) 5 8.35 (s, 1H), 7.99 (d, J = 9.2 Hz, 1H), 7.71 (dd, J = 6.2, 2.6 Hz, 2H), 7.61 (s, 1H), 6.98 (ddd, J = 23.8, 9.2, 2.7 Hz, 2H), 3.96 (t, J = 7.2 Hz, 2H), 2.45 (s, 3H), 2.30 (t, J = 7.3 Hz, 2H), 2.15 (d, J = 19.7 Hz, 6H).

[0608] 19F NMR (376 MHz, DMSO-d6) 5 -115.92 Synthesis of Compound 21 and Compound 138

[0609] 3,8-dimethyl-2,3-dihydro-lH-quinolin-4-one: Intermediate-891C To a stirred solution of 3,8-dimethyl-lH-quinolin-4-one (2.00 g, 11.5 mmol, 1.00 eq) in THF (20 mL) was added Phenylsilane (5.00 g, 46.2 mmol, 4.00 eq) and followed by addition of Dibutyltin dichloride (7.02 g, 23.1 mmol, 2.00 eq); the reaction mixture was allowed to stir at RT. After completion, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organics were dried over Na2SO4 and evaporated. The residue was purified by combi-flash using Ethyl acetate:Hexanes (3:7) to provide Int-891C, (1.60 g, 9.13 mmol, 79% yield) as a bright yellow solid.

[0610] MS: [M+H]+ 176.0

[0611] 4-bromo-2-methylbenzenesulfonyl chloride: Broad_P_CaV3.3_449 and 450

[0612] To a stirred solution of 3,8-dimethyl-2,3-dihydro-lH-quinolin-4-one (0.50 g, 2.85 mmol, 1.00 eq) and 2-methyl-4-(l-methylpyrazol-4-yl)benzenesulfonyl chloride (0.93 g, 3.42 mmol, 1.20 eq) in ACN (10 mL) was added Zinc Oxide (0.46 g, 5.71 mmol, 2.00 eq) and allow to stir it at RT for 48h. After completion, the reaction mixture was filtered through celite bed and wahsed with ethyl acetate (3 x 20 mL). The filtrate was evaporated under vacuum and residue was purified by combi-flash using Ethyl acetate :Hexanes (3:7) to provide racemic product, which was further purified by chiral prep HPLC to provide Broad_P_CaV3.3_449, (20 mg, 0.0488 mmol, 100% purity, 2% yield) as an off white solid and Broad_P_CaV3.3_450, (20 mg, 0.0477 mmol, 2% yield) as an off white solid.

[0613] Broad_P_CaV3.3_449

[0614] MS :[M+H]+ 410.2

[0615] 1H NMR (400 MHz, DMSO-d6) 5 8.32 (s, 1H), 8.01 (s, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.72 - 7.57 (m, 4H), 7.40 (t, J = 7.6 Hz, 1H), 4.23 (dd, J = 14.8, 6.3 Hz, 1H), 3.87 (s, 3H), 3.61 (dd, J = 14.7, 12.5 Hz, 1H), 2.47 - 2.42 (m, 1H), 2.30 (s, 3H), 2.14 (s, 3H), 0.92 (d, J = 7.0 Hz, 3H).

[0616] [a]D25= -35.00°

[0617] Chiral separation conditions: (CHIRALPAK IB-N (250*4.6mm) 5u), 0.1% DEA / Hexan in IP A) and CO2 gas as a mobile phase

[0618] Order of elution: Fraction-1 (RT: 11.03 min); Fraction-2 (RT: 12.91 min)

[0619] Broad_P_CaV3.3_450

[0620] MS :[M+H]+ 410.2

[0621] 1H NMR (400 MHz, DMSO-d6) 5 8.32 (s, 1H), 8.01 (s, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.69 -

[0622] 7.57 (m, 4H), 7.40 (t, J = 7.6 Hz, 1H), 4.23 (dd, J = 14.8, 6.3 Hz, 1H), 3.87 (s, 3H), 3.67 -

[0623] 3.57 (m, 1H), 2.44 (d, J = 6.7 Hz, 1H), 2.30 (s, 3H), 2.14 (s, 3H), 0.92 (d, J = 7.0 Hz, 3H).

[0624] [a]D25= +33.40°

[0625] Chiral separation conditions: (CHIRALPAK IB-N (250*4.6mm) 5u), 0.1% DEA / Hexan in IP A) and CO2 gas as a mobile phase

[0626] Order of elution: Fraction-1 (RT: 11.03 min); Fraction-2 (RT: 12.91 min)

[0627] 6-fluoro-l,4-dimethyl-3-[[4-methyl-6-(4-methylimidazol-l-yl)-3-pyridyl]sulfonyl]indole (Broad_P_CaV3.3 676, Compound 22)

[0628] A stirred suspension of 3-[(6-bromo-4-methyl-3-pyridyl)sulfonyl]-6-fluoro-l,4- dimethyl-indole (3.60 g, 9.06 mmol, 1.00 eq), 4-methyl-lH-imidazole (2.98 g, 36.2 mmol, 4.00 eq) Q12O (0.39 g, 2.72 mmol, 0.300 eq) and Potassium tert-butoxide (3.05 g, 27.2 mmol, 3.00 eq) in dimethylformamide (72 mL) was heated it 150 °C for 2 h. 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 Na2SC>4 and evaporated under vacuum. The residue was purified via combi flash using (1 :9, MeOH: DCM) as a mobile phase to provide mixture of isomers which was further purified by reverse phase purification using 15 to 85% of Acetonitrile and water (0.1 % formic acid as modifier) to give Broad_P_CaV3.3_676, (1.02 g, 2.48 mmol, 27% yield) as an off white solid.

[0629] 1H NMR (400 MHz, DMSO-d6) 5 8.80 (s, 1H), 8.48 (s, 1H), 8.34 (s, 1H), 7.87 (s, 1H), 7.70 (s, 1H), 7.38 (dd, J = 9.4, 2.4 Hz, 1H), 6.91 (dd, J = 10.5, 2.4 Hz, 1H), 3.87 (s, 3H), 2.54 (s, 3H), 2.46 (s, 3H), 2.16 (s, 3H). MS (ESI): 399.5 [M+H]+.

[0630] 3-[(6-bromo-4-methyl-3-pyridyl)sulfonyl]-6-fluoro-l,4-dimethyl-indole

[0631] To a stirred solution of 3-[(6-bromo-4-methyl-3-pyridyl)sulfanyl]-6-fluoro-l,4- dimethyl-indole (300 mg, 0.821 mmol, 1.00 eq) in tetrahydrofuran (3 mL) and water (3 mL) was added OXONE (757 mg, 2.46 mmol, 3.00 eq) at 0°C. The reaction mixture was allowed to stir at 25 °C for 16 h. After completion, the reaction was quenched with water and extracted with ethyl acetate (3 x 50 mL). The combined organics were washed brine solution (2 x 50 mL), dried over Na2SO4 and evaporated. The residue was purified by silica gel column chromatography using 40% Ethyl acetate in Hexanes as a mobile phase to provide Broad_P_CaV3.3_676_Int-1445, (200 mg, 0.423 mmol, 51% yield) as a pale yellow semi solid. MS(ESI): 399.1 [M+H]+.

[0632] 3-[(6-bromo-4-methyl-3-pyridyl)sulfanyl]-6-fluoro-l,4-dimethyl-indole To a stirred a solution of 6-fluoro-l,4-dimethyl-indole (450 mg, 2.76 mmol, 1.00 eq) and 6-bromo-4-methyl-pyridine-3-sulfonyl chloride (1492 mg, 5.52 mmol, 2.00 eq) in dimethylformamide (4.5 mL) was added tetra butyl ammonium iodide (2037 mg, 5.52 mmol, 2.00 eq) at 25 °C. The reaction mixture was stirred at same temperature for 2 h. After completion, the reaction was quenched with water and extracted ethyl acetate (3 x 50 mL). The combined organics were washed brine solution (2 x 50 mL), dried over Na2SC>4 and evaporated. The residue was purified by silica gel column chromatography using 60% Ethyl acetate in hexane as a mobile phase to provide Broad_P_CaV3.3_676, (300 mg, 0.791 mmol, 29% yield) as an pale yellow semi solid. MS (ESI): 365.4 [M+H]+.

[0633] 5-chloro-l-methyl-4-[2-methyl-4-(l-methyl-lH-pyrazol-4-yl)benzenesulfonyl]-l,2,3,4- tetrahydroquinoxaline (Broad000415 - 105, Compound 23)

[0634] To a vial, were added bromo sulfonamide (100 mg, 0.2405 mmol, 1 eq), methyl pyrazole boronic acid (60.0 mg, 0.2885 mmol, 1.2 eq), XPhos Pd G2 (9.45 mg, 0.01202 mmol, 0.05 eq) and sodium carbonate (76.4 mg, 0.7214 mmol, 3 eq) in Dioxane / Water 4: 1 (2.00 mL). The reaction mixture was stirred at 80 °C for 2 hours. After cooling down to room temperature, water was poured and the product was extracted with 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 chloro N methyl sulfonamide methyl pyrazole (20 mg, 18.5 % yield) as white solid.

[0635] 1H NMR (400 MHz, Chloroform-d) 5 7.97 - 7.91 (m, 1H), 7.82 (d, J = 0.9 Hz, 1H), 7.70 (s, 1H), 7.35 (d, J = 7.3 Hz, 2H), 7.03 (t, J = 8.1 Hz, 1H), 6.67 (dd, J = 8.0, 1.3 Hz, 1H), 6.56 (dd, J = 8.4, 1.3 Hz, 1H), 4.25 (s, 1H), 3.97 (s, 3H), 3.34 (d, J = 89.8 Hz, 3H), 2.82 (s, 3H), 2.50 (s, 3H). MS (ESI): 417.0 [M+H]+. Synthesis of Compound 24 and Compound 116. -3

[0636] Broad_P_Cav3.3_411 Broad_P_Cav3.3_412

[0637] Compound 24

[0638] Compound 116

[0639] 3 , 8-dimethyl-3 ,4-dihy dro- 1 H-quinoxalin-2-one :

[0640] To a solution of 2-bromo-6-methyl-aniline (10.00 g, 53.7 mmol, 1.00 eq) in Dimethyl sulfoxide (DMSO) (50 mL), DL-Alanine (14.37 g, 161 mmol, 3.00 eq) was added, 1,2- Dimethylethylenediamine (DMEDA) (2.84 g, 32.2 mmol, 0.600 eq), Copper(I) chloride. (0.80 g, 8.06 mmol, 0.150 eq) and Tripotassium phosphate (K3PO4) (34.23 g, 161 mmol, 3.00 eq) were added at room temperature. Reaction mixture was then heated up to for 18h. Reaction mixture was cooled to room temperature and poured into water (200mL x 2) and extracted with ethyl acetate (lOOmL x 2). Organic layer was seperated. Organic layer was then evaporated under reduced pressure. Product was purified by column chromatography (10-20%Ethyl acetate in n-Hexane) to give Int-683A, (7.00 g, 32.6 mmol, 61% yield) as yellow solid.

[0641] MS: [M+H]+ 177.0

[0642] 3,4,8-trimethyl-l,3-dihydroquinoxalin-2-one

[0643] To a solution of 3,8-dimethyl-3,4-dihydro-lH-quinoxalin-2-one (7.00 g, 39.7 mmol, 1.00 eq) in Methanol (50 mL) was added, Paraformaldehyde (4.77 g, 119 mmol, 3.00 eq) and Sodium cyanoborohydride (NaCNBH4) (4.99 g, 79.4 mmol, 2.00 eq) were then added at room temperature. Reaction mixture was stirred for 24h at room temperature. Methanol was evaporated under reduced pressure and residue was extracted in water (50 mL x 2) and ethyl acetate (50 mL x 2). Organic layer was seperated and evaporated under reduced pressure. Residue was further purified by column chromatography (5%ethyl acetate in n-hexane) gave

[0644] 3,4,8-trimethyl-l,3-dihydroquinoxalin-2-one, (3.00 g, 13.7 mmol, 34% yield) as yellow solid.

[0645] MS: [M+H]+ 191.2

[0646] 3 ,4, 8-trimethyl-2,3 -dihy dro- 1 H-quinoxaline : To a solution 3,4,8-trimethyl-l,3-dihydroquinoxalin-2-one (3.00 g, 15.8 mmol, 1.00 eq) in THF (30 mL), IM LAH in THF (30 mL, 31.5 mmol, 2.00 eq) was then added dropwise at -5°C. Reaction mixture was then heated up to for 6h. Reaction mixture was quinched into ice cold water (100 mLx2) and extracted with ethyl acetate (50 mLx2). Organic layer was evaporated under reduced pressure. 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.

[0647] MS: [M+H]+ 176.26

[0648] 4-(4-bromo-2-methyl-phenyl)sulfonyl-l,2,5-trimethyl-2,3-dihydroquinoxaline:

[0649] To a solution 3,4,8-trimethyl-2,3-dihydro-lH-quinoxaline (1.50 g, 8.51 mmol, 1.00 eq) in pyridine was added, Triethylamine (3.56 mL, 25.5 mmol, 3.00 eq), 4- Dimethylaminopyridine (1.04 g, 8.51 mmol, 1.00 eq) and 4-bromo-2-methyl-benzenesulfonyl chloride (6.88 g, 25.5 mmol, 3.00 eq) were then added at room temperature. Reaction mixture was then stirred at room temperature for 16h. Reaction mixture was then poured into water (50 mL) and extracted with ethyl acetate (50 mL). Organic layer was further washed with citric acid solution and then water. Organic layer was seperated and evaporated under reduced pressure. Residue was purified by column chromatography (2% ethyl acetate in n- hexane) gave Int-686A, (1.20 g, 2.76 mmol, 32% yield) as brownish oily liquid.

[0650] MS:[M+H]+ 411.5 l,2,5-trimethyl-4-[2-methyl-4-(4-methylimidazol-l-yl)phenyl]sulfonyl-2,3- dihydroquinoxaline

[0651]

[0652] To a solution 4-(4-bromo-2-methyl-phenyl)sulfonyl-l,2,5-trimethyl-2,3- dihydroquinoxaline (1.20 g, 2.93 mmol, 1.00 eq) in 1,4-Dioxane (10 mL) was added, Tripotassium phosphate (K3PO4) (1.24 g, 5.86 mmol, 2.00 eq), Tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) (0.27 g, 0.293 mmol, 0.1000 eq), 2-Di- tert-butylphosphino-2',4',6'-triisopropylbiphenyl (tBuXPhos) (0.25 g, 0.586 mmol, 0.200 eq), and 4-methyl-lH-imidazole (0.48 g, 5.86 mmol, 2.00 eq) were added at room temperature. Reaction mixture was then heated up to for 16h. Reaction mixture was then poured into water (50mLx2) and extracted with ethyl acetate (50mL x 2). Organic layer was seperated and evaporated under reduced pressure. Residue was purified by column chromatography (50%ethyl acetate in n-hexane) gave 0.25 g of compound which was further purified by Preparative HPLC (0.1%Formic acid in water, gradient 0 to 100%ACN 23min) gave 0.06 g of compound which was further purified by chiral SFC (CHIRALPAK AD-H (250*4.6mm) 5u), 0.1% DEA in MeOH) gave (2R)-l,2,5-trimethyl-4-[2-methyl-4-(4-methylimidazol-l- yl)phenyl]sulfonyl-2,3-dihydroquinoxaline, (4.0 mg, 0.00977 mmol, 0.33) and (2S)-1,2,5- trimethyl-4-[2-methyl-4-(4-methylimidazol-l-yl)phenyl]sulfonyl-2,3-dihydroquinoxaline, (4.6 mg, 0.0111 mmol, 0.38).

[0653] Broad_P_CaV3.3_411

[0654] MS: [M + H]+ 411.4

[0655] 1H NMR (400 MHz, DMSO-d6) 5 8.08 (d, J= 8.5 Hz, 1H), 7.91 (s, 1H), 7.24 (d, J= 2.1 Hz, 1H), 7.17 (d, J= 2.2 Hz, 1H), 7.05 (t, J= 7.8 Hz, 2H), 6.63 (d, J= 7.7 Hz, 1H), 6.33 (d, J= 8.2 Hz, 1H), 4.43 (dd, J= 14.6, 7.3 Hz, 1H), 3.22 - 3.12 (m, 1H), 3.04 - 2.96 (m, 1H), 2.38 (s, 3H), 2.30 (s, 6H), 2.08 (s, 3H), 0.93 (d, J= 5.9 Hz, 3H).

[0656] Broad_P_CaV3.3_412

[0657] MS: [M + H]+ 411.4 1H NMR (400 MHz, DMSO-d6) 58.29 (s, 1H), 7.97(d, J= 7.1, , 1H), 7.62 (s,2H), 7.57 (s, 1H), 7.02 (t, J= 8.0 Hz, 1H), 6.55 (d, J= 8.4 Hz 1H), 6.38 (d, J= 8.4 Hz 1H), 4.32 (dd, J= 13.2, 5.2 Hz, 1H), 2.92 - 2.98 (m, 2H), 2.29 (s,3H), 2.23 (s, 3H), 2.16 (s, 3H), 1.97 (s,3H), 0.84 (t, J = 7.2 Hz, 3H).

[0658] Synthesis of Compound 25

[0659] Broad_P_CaV3.3_624 Compound 25 l-((4-bromo-2-methylphenyl)sulfonyl)-7-methylindoline:

[0660] To a stirred a solution of 7-m ethylindoline (0.20 g, 1.50 mmol, 1.00 eq) and Pyridine (.24 mL, 3.00 mmol, 2.00 eq) in DCM (5 mL) was added 4-bromo-2-methyl-benzenesulfonyl chloride (809 mg, 3.00 mmol, 2.00 eq) at RT. The reaction mixture was stirred at same temperature for 12 h. After completion, the reaction was quenched with 10% citric acid solution (50 mL) and extracted ethyl acetate (3 x 50 mL). The combined organics were washed with brine solution (2 x 50 mL), dried over Na2SO4 and evaporated. The residue was purified by silica gel column chromatography (6:4, Ethyl acetate: Hexanes) as a mobile phase to provide Broad_P_CaV3.3_624_Int-933, (200 mg, 0.546 mmol, 36% yield) as an off white solid.

[0661] 1H NMR (400 MHz, Chloroforms / ) 5 7.84 (d, J= 8.4 Hz, 1H), 7.45 (dd, J= 8.5, 2.1 Hz, 1H), 7.37 (d, J= 2.0 Hz, 1H), 7.10 (d, J= 4.5 Hz, 2H), 6.99 (t, J= 4.4 Hz, 1H), 3.97 (t, J=

[0662] 7.2 Hz, 2H), 2.54 (s, 3H), 2.38 (t, J= 7.2 Hz, 2H), 2.11 (s, 3H). 7-methyl-l-((2-methyl-4-(4-methyl-lH-imidazol-l-yl)phenyl)sulfonyl)indoline:

[0663] A stirred suspension of l-(4-bromo-2-methyl-phenyl)sulfonyl-7-methyl-indoline (0.20 g, 0.546 mmol, 1.00 eq) , 4-methyl-lH-imidazole (0.090 g, 1.09 mmol, 2.00 eq) and KOtBu (0.18 g, 1.64 mmol, 3.00 eq) in DMF (5 mL) was degassed with nitrogen gas for 15 min. Copper(I)oxide (0.023 g, 0.164 mmol, 0.300 eq) was added and heated it at 140°C for 16 h. 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. The residue was purified via combi flash using (1 : 1, Ethyl acetate: Hexanes) as a mobile phase to provide mixture of isomers which was further purified by prep HPLC to give Broad_P_CaV3.3_624, (47 mg, 0.128 mmol, 23% yield) as a white solid.

[0664] MS(ESI): 367.47 [M+H]+

[0665] 1H NMR (400 MHz, DMSO-t / 6) 5 8.35 (s, 1H), 8.01 (d, J= 8.6 Hz, 1H), 7.80 - 7.50 (m, 3H), 7.09 (dd, J= 29.3, 4.6 Hz, 3H), 3.94 (t, J= 7.2 Hz, 2H), 2.45 (s, 3H), 2.31 (t, J= 7.3 Hz, 2H), 2.17 (s, 3H), 2.06 (s, 3H).

[0666] 1H NMR (400 MHz, Methanol-6 / 4) 5 8.20 (s, 1H), 8.08 (d, J= 8.6 Hz, 1H), 7.57 (d, J= 8.6 Hz, 1H), 7.50 (s, 1H), 7.42 (s, 1H), 7.10 (d, J= 4.5 Hz, 2H), 6.99 (d, J= 5.1 Hz, 1H), 3.98 (t, J= 7.3 Hz, 2H), 2.50 (s, 3H), 2.34 (t, J= 7.2 Hz, 2H), 2.25 (s, 3H), 2.12 (s, 3H). l,5-dimethyl-4-[2-methyl-4-(5-methylpyri din-3-yl)benzenesulfonyl]-l, 2,3,4- tetrahydroquinoxaline (Broad_P_CaV3.3 297)

[0667]

[0668] To a stirred solution of 4-(4-bromo-2-methylbenzenesulfonyl)-l,5-dimethyl-l,2,3,4- tet (0.2 g, 505 pmol, 1 eq), (5-methylpyridin-3-yl)boronic acid (82.9 mg, 606 pmol, 1.2 eq) and potassium carbonate (208 mg, 1.51 mmol, 3 eq) in 1,4 dioxane (3 mL) and water (0.5 mL) was degassed for 15 minutes with Nitrogen gas followed by palladium(2+) bis(cy (41.2 mg, 50.5 pmol, 0.1 eq) was added and heated the reaction mixture at 80°C for 16h. After completion, the 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.

[0669] 1H NMR (400 MHz, DMSO-d6) 5 8.75 (d, J = 2.3 Hz, 1H), 8.47 (d, J = 2.0 Hz, 1H), 7.98 (d, J = 8.2 Hz, 2H), 7.78 - 7.68 (m, 2H), 7.02 (t, J = 7.8 Hz, 1H), 6.54 (d, J = 7.5 Hz, 1H), 6.46

[0670] (d, J = 8.1 Hz, 1H), 4.16 (d, J = 8.2 Hz, 1H), 3.26 (s, 1H), 2.97 (s, 1H), 2.82 (s, 1H), 2.39 (d, J = 7.6 Hz, 6H), 2.28 (s, 3), 2.10 (s, 3H). MS(ESI): 408.2 [M+H]+.

[0671] Synthesis of Broad_P_CaV3.3_506 and 507 (Compound 27 and Compound 55)

[0672] Compound 27

[0673] Compound 55

[0674] 2-bromo-6-methyl-N-(2-methylallyl)aniline: Intermediate-899B To a stirred solution of 2-bromo-6-methyl-aniline (6.00 g, 32.2 mmol, 1.00 eq) in

[0675] DMF (60 mL) was added 60% NaH oin mineral oil (1.16 g, 48.4 mmol, 1.50 eq) at 0 °C and stirred at same temperature for 20 min. 3-bromo-2-methyl-prop-l-ene (4.79 g, 35.5 mmol, 1.10 eq) was added to it and allowed to stir at RT. After 16h, the reaction mixture was poured into cold water (600 mL) and extracted with ethyl acetate (3 * 100 mL). The combined organics were dried over Na2SOi and evaporated. The residue was purified by combi-flash using Ethyl acetate:Hexanes (3:7) to provide Int-899B, (5.00 g, 20.7 mmol, 64% yield) as an yellow oil.

[0676] MS: [M+H]+242.0 ’H NMR (400 MHz, Chloroform-d) 5 7.39 (t, J = 7.1 Hz, 1H), 7.13 (t, J = 6.9 Hz, 1H), 6.77 (q, J = 7.6, 7.2 Hz, 1H), 4.98 (d, J = 6.1 Hz, 1H), 4.86 (d, J = 6.0 Hz, 1H), 4.30 (q, J = 6.9 Hz, 1H), 3.66 (t, J = 6.9 Hz, 2H), 2.32 (d, J = 6.2 Hz, 3H), 1.78 (d, J = 6.1 Hz, 3H).

[0677] 3,8-dimethyl-l,2,3,4-tetrahydroquinoline and 3,3,7-trimethylindoline: Intermediate-899C and 899F

[0678] To a stirred solution of 2-bromo-6-methyl-N-(2-methylallyl)aniline (5.00 g, 20.8 mmol, 1.00 eq) in Toluene (50 mL) was added Azobisisobutyronitrile (0.68 g, 4.16 mmol, 0.200 eq) and Tributyltin hydride (6.67 g, 22.9 mmol, 1.10 eq). The reaciton mixtue was then heated at 80C. After completion, the reaction mixture was poured into water (100 mL) and extracted eith ethyl acetate (3 x 80 mL). The combined organics were dried over Na2SO4 and evaported. The residue was purified by combi-flash using Ethyl acetate:Hexanes (1 :9) to provide Int-899C, (0.40 g, 2.26 mmol, 91.18% purity, 11% yield) and Int-899F, (1.50 g, 8.33 mmol, 40% yield) as a yellow oil.

[0679] Int-899C:

[0680] MS: [M+H]+ 162.00

[0681] ’H NMR (400 MHz, DMSO ) 5 6.71 (dd, J = 7.2 Hz, 2H), 6.35 (t, J = 7.4 Hz, 1H), 5.01 (s, 1H), 3.26 (m, 1H), 2.78 (t, J = 6.4 Hz, 1H), 2.66 (m, 1H), 2.33 (dd, J = 10.4 Hz, 1H), 1.98 (s, 3H), 1.59 (m, 1H), 1.29 (m, 3H), 1.10 (t, J = 8.0 Hz, 1H), 0.97 (d, J = 6.4 Hz, 1H), 0.87 (t, J = 7.6 Hz, 3H). (Product contains aliphatic impurities).

[0682] Int-899F:

[0683] MS: [M+H]+ 162.00

[0684] XH NMR (400 MHz, DMSO ) 5 6.81 (d, J = 7.2 Hz, 1H), 6.74 (d, J = 7.3 Hz, 1H), 6.49 (t, J = 7.4 Hz, 1H), 5.18 (s, 1H), 3.17 (s, 2H), 2.05 (s, 3H), 1.60 (p, J = 7.7 Hz, 1H), 1.32 (dt, J = 14.7, 7.2 Hz, 1H), 1.20 (s, 6H), 1.12 (d, J = 8.2 Hz, 1H), 0.88 (t, J = 7.3 Hz, 1H).

[0685] (R)-3 , 8-dimethyl- 1 -((2-methyl-4-( 1 -methyl- lH-pyrazol-4-yl)phenyl)sulfonyl)- 1 ,2,3,4- tetrahydroquinoline and (S)-3,8-dimethyl-l-((2-methyl-4-(l-methyl-lH-pyrazol-4- yl)phenyl)sulfonyl)-l,2,3,4-tetrahydroquinoline: Broad_P_CaV3.3_506 and 507

[0686] To a stirred solution of 3,8-dimethyl-l,2,3,4-tetrahydroquinoline (0.40 g, 2.26 mmol, 1.00 eq) in Pyridine (4 mL) was added Triethylamine (687 mg, 6.79 mmol, 3.00 eq), 4- Dimethylaminopyridine (276 mg, 2.26 mmol, 1.00 eq) and heated it at 80C. After 0.5 h, the reaction mixture was allowed to cool at RT and 2-methyl-4-(l-methylpyrazol-4- yl)benzenesulfonyl chloride (1225 mg, 4.52 mmol, 2.00 eq) was lot wise added to the reaction mixture. The reaction mixture was heated at 80° C for 3h. After completion, the reaction mixture was poured into 5% citric acid solution (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organics were dried over Na2SO4 and evaporated under vacuum. The residue was purified by combi-flash using Ethyl acetate: Hexanes (4:6) to provide pure product which was further purified by chiral prep HPLC purificaiton using (CHIRALPAK IG (250*4.6mm) 5u), 0.1% DEA in MeOH) to provide Broad_P_CaV3.3_506 (30 mg, 0.0758 mmol, 3% yield) and Broad_P_CaV3.3_507 (30 mg, 0.0758 mmol, 3% yield) as an off white solid.

[0687] Broad_P_CaV3.3_506:

[0688] MS: [M+H]+ 396.2

[0689] 'H N R (400 MHz, DMSO ) 5 8.21 (s, 1H), 7.92 (s, 1H), 7.83 - 7.76 (m, 1H), 7.56 (d, J =

[0690] 6.6 Hz, 2H), 7.12 (q, J = 3.7, 2.8 Hz, 2H), 6.94 (dd, J = 6.0, 3.1 Hz, 1H), 3.88 (s, 4H), 2.33 (d, J = 5.9 Hz, 1H), 2.29 (s, 3H), 2.16 (s, 3H), 1.98 (s, 1H), 1.73 (s, 1H), 1.26 (s, 1H), 0.81 (d, J =

[0691] 6.7 Hz, 3H).

[0692] [a]D25= -27.00°

[0693] Chiral separation conditions: (CHIRALCEL IH (250*4.6mm) 5u), 0.1% DEA HEXANE in IPAMeOH (1 : 1)) and CO2 gas as a mobile phase

[0694] Order of elution: Fraction-1 (RT: 9.05 min); Fraction-2 (RT: 9.76 min) Broad_P_CaV3.3_507:

[0695] MS: [M+H]+ 396.2

[0696] XH NMR (400 MHz, DMSO-r / r,) 5 8.21 (s, 1H), 7.92 (s, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.56 (d, J = 6.5 Hz, 2H), 7.12 (q, J = 3.8, 2.8 Hz, 2H), 6.94 (dd, J = 5.9, 3.1 Hz, 1H), 3.88 (s, 4H), 2.33 (d, J = 5.8 Hz, 1H), 2.29 (s, 3H), 2.16 (s, 3H), 1.98 (s, 1H), 1.74 (s, 1H), 1.26 (s, 1H), 0.81 (d, J = 6.7 Hz, 3H).

[0697] [a]D25= +26.00°

[0698] Chiral separation conditions: (CHIRALCEL IH (250*4.6mm) 5u), 0.1% DEA HEXANE in IPAMeOH (1 : 1)) and CO2 gas as a mobile phase

[0699] Order of elution: Fraction-1 (RT: 9.05 min); Fraction-2 (RT: 9.76 min)

[0700] 4-[4-(l-ethyl-lH-pyrazol-4-yl)-2-methylbenzenesulfonyl]-l, 5-dimethyl-l, 2,3,4- tetrahydroquinoxaline (Broad000415 - 040, Compound 28)

[0701] To a vial, 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) were added in Dioxane / water 4: 1 (1.5 mL). 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 MgSCU, filtered and concentrated. The crude product was purified with flash chromatography on silica gel (HexaneZEtOAc) to afford the desired N-ethyl pyrazole N-sulfonamide (67 mg, 97 % purity, 83% yield). A second purification was performed on reverse phase chromatography eluting with (water / ACN) to remove the pinacol and obtained N-ethyl pyrazole N-sulfonamide (4.9 mg, 6.10 % yield). 1H NMR (400 MHz, Chloroform-d) 5 7.92 (d, J = 8.3 Hz, 1H), 7.80 (s, 1H), 7.71 (s, 1H),

[0702] 7.33 (dd, J = 8.3, 1.8 Hz, 1H), 7.28 (s, 1H), 7.04 (t, J = 7.9 Hz, 1H), 6.59 (d, J = 7.5 Hz, 1H), 6.39 (d, J = 8.1 Hz, 1H), 4.22 (q, J = 7.3 Hz, 3H), 3.24 (s, 1H), 2.97 (m, 2H), 2.47 (s, 3H), 2.35 (s, 3H), 2.13 (s, 3H), 1.54 (t, J = 7.3 Hz, 3H). MS (ESI): 411.8 [M+H]+. Synthesis of Compound 31 and Compound 45 eq)

[0703] PdCI2(dppf).DCM (0.1 eq), K2CO3(3 eq), dioxane:water (4:1 ) ,90 °

[0704] C, 16h

[0705] Broad P CaV3.3 495

[0706] Compound 31 Compound 45 tert-butyl N-[2-[(4-bromo-2-methyl-phenyl)sulfonylamino]-3-methyl-phenyl]carbamate: To a stirred solution of tert-butyl N-(2-amino-3-methyl-phenyl)carbamate (6.00 g, 27.0 mmol, 1.00 eq) and Pyridine (8.73 mL, 108 mmol, 4.00 eq) in DCM (5 mL) was added 4-bromo-2-methyl-benzenesulfonyl chloride (8.73 g, 32.4 mmol, 1.20 eq) at RT. The reaction mixture was stirred at same temperature for 16 h. After completion, the reaction was quenched with 10% citric acid solution (50 mL) and extracted ethyl acetate (3 x 50 mL). The combined organics were washed brine solution (2 x 50 mL), dried over Na2SO4 and evaporated. The residue was purified by silica gel column chromatography (6:4, Ethyl acetate: Hexanes) as a mobile phase to provide Broad_P_CaV3.3_495_Int-536, (12.00 g, 26.4 mmol, 98% yield) as a yellow solid.

[0707] 1H NMR (400 MHz, DMSO-t / 6) 5 9.36 (s, 1H), 7.67 (s, 1H), 7.62 (s, 1H), 7.56 (d, J= 13.2 Hz, 3H), 7.15 (t, J= 7.9 Hz, 1H), 6.92 (d, J= 7.7 Hz, 1H), 2.43 (s, 3H), 2.08 (s, 3H), 1.40 (s, 9H). tert-butyl 4-(4-bromo-2-methyl-phenyl)sulfonyl-5-methyl-2,3-dihydroquinoxaline-l- carb oxy late:

[0708] To a stirred solution of tert-butyl N-[2-[(4-bromo-2-methyl-phenyl)sulfonylamino]-3- methyl-phenyl]carbamate (12.00 g, 26.4 mmol, 1.00 eq) and 1,2-Dibromoethane (2.73 mL, 31.6 mmol, 1.20 eq) in DMF (100 mL) was added Potassium carbonate (7.28 g, 52.7 mmol, 2.00 eq) at room temperature. The reaction mixture was heated at 80 °C and stirred at same temperature for 12 h. After completion, the 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 Na2SO4 and evaporated under vacuum to provide Broad_P_CaV3.3_495_Int-540A, (10.20 g, 21.2 mmol, 80% yield) as an brown solid.

[0709] 1H NMR (400 MHz, DMSO-d6) 5 7.90 (d, J = 8.5 Hz, 1H), 7.65 - 7.54 (m, 1H), 7.40 (d, J =

[0710] 8.2 Hz, 1H), 7.20 (t, J = 7.9 Hz, 1H), 7.04 (d, J = 7.5 Hz, 1H), 5.76 (s, OH), 4.30 (dt, J = 13.1,

[0711] 4.3 Hz, 1H), 3.29 (h, J = 6.0 Hz, 2H), 2.37 (s, 2H), 2.00 (s, 2H), 1.37 (s, 6H), 1.32 (s, 2H). tert-butyl 5-methyl-4-[2-methyl-4-(l-methylpyrazol-4-yl)phenyl]sulfonyl-2,3- dihydroquinoxaline-l-carboxylate:

[0712] Boc i

[0713] A stirred suspension of tert-butyl 4-(4-bromo-2-methyl-phenyl)sulfonyl-5-methyl-2,3- dihydroquinoxaline- 1 -carboxylate (10.20 g, 21.2 mmol, 1.00 eq), l-methyl-4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (5.29 g, 25.4 mmol, 1.20 eq) and Potassium carbonate (5.86 g, 42.4 mmol, 2.00 eq) in 1,4-Dioxane (80 mL) and water (20 mL) was degassed with nitrogen for 15 min. [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.87 g, 1.06 mmol, 0.0500 eq) was added and heated it at 120°C for 16 h. 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. The residue was purified via combi flash using (1 : 1, Ethyl acetate: Hexanes) as a mobile phase to provide Broad_P_CaV3.3_495_Int-540B, (10.00 g, 19.3 mmol, 91% yield) as an brown solid. MS: [M+H]+ 482.6

[0714] 5-methyl-4-[2-methyl-4-(l-methylpyrazol-4-yl)phenyl]sulfonyl-2,3-dihydro-lH-quinoxaline: To a stirred solution of tert-butyl 5-methyl-4-[2-methyl-4-(l-methylpyrazol-4- yl)phenyl]sulfonyl-2,3-dihydroquinoxaline-l-carboxylate (10.00 g, 20.7 mmol, 1.00 eq) in 1,4-Dioxane (70 mL) was added Hydrogen chloride solution 4.0 M in dioxane (10.07 mL, 290 mmol, 14.0 eq) at 0°C. The reaction mixture was allowed to stir at RT for 12 h. After completion, the reaction mixture was concentrated under vacuum. The residue was stirred with n-hexane (100 mL) and the free solid was filtered through Buchner funnel and washed with Ethyl acetate (2 x 30 mL). The solid was dried under vacuum and dissolved in saturated solution of NaHCOs (50 mL) and extracted in ethyl acetate (3 x 50 mL). The combined organics were dried over Na2SO4 and evaporated under vacuum to provide Broad_P_CaV3.3_495_Int-540C, (7.00 g, 17.8 mmol, 86% yield) as an off white solid.

[0715] MS :[M+H]+ 382.48

[0716] 1H NMR (400 MHz, DMSO-d6) 5 8.29 (s, 1H), 7.99 (s, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.60 - 7.50 (m, 2H), 6.85 (t, J = 7.7 Hz, 1H), 6.35 (t, J = 8.7 Hz, 2H), 5.92 (s, 1H), 3.96 (s, 1H), 3.87 (s, 4H), 3.53 (s, 2H), 3.07 (s, 2H), 2.68 (s, 2H), 2.21 (s, 3H), 2.15 (s, 3H).

[0717] 5-methyl-4-[2-methyl-4-(l-methylpyrazol-4-yl)phenyl]sulfonyl-l-(trifluoromethyl)-2,3- dihydroquinoxaline :

[0718] To a stirred solution of 5-methyl-4-[2-methyl-4-(l-methylpyrazol-4- yl)phenyl]sulfonyl-2,3-dihydro-lH-quinoxaline (1.00 g, 2.61 mmol, 1.00 eq) in Acetonitrile (8 mL) was added Tetramethylammonium (trifluoromethyl)sulfanide (0.60 g, 3.40 mmol, 1.30 eq), and reaction mixture was sirred at RT for 15min. followed by addition of Silver(I) fluoride (1.66 g, 13.1 mmol, 5.00 eq) at RT. The reaction mixture was stirred at 50 °C for 24h. After completion, the reaction mixture was quenched with the addition of water (50 mL) and extracted with ethyl acetate (3 x 80 mL). The combined organics were washed with brine solution (3 x 50 mL), dried over Na2SC>4 and evaporated under vacuum. The residue was purified by silica gel column chromatography using (1 :5, Ethyl acetate: Hexanes) as a mobile phase to provide impure compound which was sumitted for prep HPLC for further purification using (45-100% ACN in water and 0.1% NH3 in water as modifier) Broad_P_CaV3.3_495, (135 mg, 0.299 mmol, 11% yield) as a white solid.

[0719] MS:[M+H]+450.48

[0720] 1H NMR (400 MHz, DMSO-d6) 5 8.28 (s, 1H), 7.97 (s, 1H), 7.88 (d, J = 8.3 Hz, 1H), 7.61 - 7.49 (m, 2H), 7.21 (t, J = 8.0 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 4.35 (d, J = 13.9 Hz, 1H), 3.87 (s, 3H), 3.48 - 3.37 (m, 1H), 3.28 (d, J = 7.0 Hz, 2H), 2.34 (s, 3H), 2.04 (s, 3H).

[0721] 19F NMR (376 MHz, DMSO-d6) 5 -58.50. l,5-dimethyl-4-[2-methyl-3-(3-methyl-l,2-oxazol-5-yl)benzenesulfonyl]-l,2,3,4- tetrahydroquinoxaline (Broad000374 - 080, Compound 32)

[0722] To a stirred solution of 8-methyl-l-[2-methyl-3-(3-methyl-l,2-oxazol-5- yl)benzenesulfonyl]-l,2,3,4-tetrahydroquinoxaline (150 mg, 0.3911 mmol), methyl iodide (83.2 mg, 0.5866 mmol) and potassium carbonate (161 mg, 1.17 mmol) in DMF (4 mL) at room temperature. The reaction mixture was heated at 50°C and stirred at same temperature for 18 h. After completion, the reaction mixture was poured in to ice-water (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layer was washed brine solution (2 x 20 mL), dried over Na2SC>4 and evaporated. The residue was purified via Biotage (5: 1 Hex / EtOAc; 12S column) to provide 1,5 -dimethyl -4- [2-me (110 mg, 69.0 % yield) as a white solid.

[0723] 1H NMR (400 MHz, DMSO-d6) 5 8.18 (d, J = 7.9 Hz, 1H), 7.83 (d, J = 7.7 Hz, 1H), 7.55 (t, J = 7.9 Hz, 1H), 7.02 (t, J = 7.8 Hz, 1H), 6.61 (s, 1H), 6.54 (d, J = 7.5 Hz, 1H), 6.46 (d, J = 8.2 Hz, 1H), 4.20 - 4.05 (m, 1H), 3.27 (s, 1H), 2.96 (s, 1H), 2.67 (d, J = 8.3 Hz, 1H), 2.41 (s, 3H), 2.28 (d, J = 8.7 Hz, 6H), 2.03 (s, 3H). MS (ESI): 398.4 [M+H]+. l-ethyl-5-methyl-4-[2-methyl-4-(l-methyl-lH-pyrazol-4-yl)benzenesulfonyl]-l,2,3,4- tetrahydroquinoxaline (Broad000415 - 036. Compound 33)

[0724] To a vial, sulfonamide pyrazole (68.6 mg, 0.1793 mmol, 1 eq) and potassium carbonate (74.3 mg, 0.5379 mmol, 3 eq) were added in DMF (0.7 mL). After 15 min of stirring, iodoethane (100 pL, 1.25 mmol, 7 eq) was added. The reaction mixture was stirred at 60 °C for 1 hour, at 70 °C for 65 h. The reaction mixture was poured into water and the product was extracted with EtOAc. The organic layer was washed with LiCl (5%), dried with MgSO4, filtered and concentrated. The crude product was purified with flash chromatography (Hexane / EtOAc) on silica gel to afford the desired N-ethyl sulfonamide methyl pyrazole (27 mg, 36.2 % yield).

[0725] 1H NMR (400 MHz, Chloroform-d) 5 7.92 (d, J = 8.2 Hz, 1H), 7.78 (s, 1H), 7.66 (s, 1H), 7.33 (d, J = 8.3 Hz, 1H), 7.02 (t, J = 7.8 Hz, 1H), 6.57 (d, J = 7.5 Hz, 1H), 6.44 (d, J = 8.2 Hz,

[0726] 1H), 4.29 (d, J = 16.3 Hz, 1H), 3.96 (s, 3H), 3.24 (m, J = 15.9 Hz, 1H), 3.01 (m, J = 6.4 Hz, 4H), 2.36 (s, 3H), 2.13 (s, 3H), 0.84 (t, J = 7.1 Hz, 3H). MS (ESI): 411.40 [M+H]+. 6-fluoro-l,4-dimethyl-3-[2-methyl-4-(4-methylimidazol-l-yl)phenyl]sulfonyl-indole

[0727] (Broad_P_CaV3.3_640, Compound 22)

[0728] To the stirred suspension of 3-(4-bromo-2-methyl-phenyl)sulfonyl-6-fluoro-l,4- dimethyl-indole (185 mg, 0.467 mmol, 1.00 eq) in DMF, added 4-methyl-lH-imidazole (153 mg, 1.87 mmol, 4.00 eq) and Copper(I) oxide (20 mg, 0.140 mmol, 0.300 eq), Potassium t- butoxide (157 mg, 1.40 mmol, 3.00 eq) and the reaction mass was stirred at 140 °C for 16 h. After 16 h, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organics were dried over Na2SC>4 and evaporated under vacuum. The residue was purified via combi flash using (25: 1, DCM : MeOH) as a mobile phase to provide impure product; which was further purified by prep HPLC using (20-60% ACN and water (containing 0.1% formic acid as a modifier) as a mobile phase to provide Broad_P_CaV3.3_640, (8.4 mg, 0.0209 mmol, 4% yield) as a white solid.

[0729] 1H NMR (400 MHz, DMSO-d6) 5 8.28 (d, J = 6.5 Hz, 2H), 7.92 (d, J = 8.6 Hz, 1H), 7.73 (d, J = 2.3 Hz, 1H), 7.65 (dd, J = 8.6, 2.4 Hz, 1H), 7.55 (s, 1H), 7.37 (dd, J = 9.4, 2.3 Hz, 1H),

[0730] 6.89 (dd, J = 10.5, 2.4 Hz, 1H), 3.88 (s, 3H), 2.54 (s, 3H), 2.42 (s, 3H), 2.16 (s, 3H). MS(ESI): [M+H]+ 398.0.

[0731] 3-(4-bromo-2-methyl-phenyl)sulfonyl-6-fluoro-l,4-dimethyl-indole To the solution of 3-(4-bromo-2-methyl-phenyl)sulfanyl-6-fluoro-l,4-dimethyl-indole (310 mg, 0.851 mmol, 1.00 eq) inDCM (6 mL) added 3 -Chloroperoxybenzoic acid (441 mg, 2.55 mmol, 3.00 eq) and the reaction mass was stirred at 25 °C for 12 h. After completion, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with sodium bicarbonate solution (3 x 70 mL). The organic layer was dried over Na2SC>4 and evaporated under vacuum. The residue was purified via combi flash using (1 : 1, Ethyl acetate: Hexanes) as a mobile phase to provide Broad_P_CaV3.3_640_Int_1340, (185 mg, 0.467 mmol, 55% yield) as yellow solid. MS(ESI): [M+H]+ 398.0.

[0732] 3-(4-bromo-2-methyl-phenyl)sulfanyl-6-fluoro-l,4-dimethyl-indole

[0733] To the solution of 6-fluoro-l,4-dimethyl-indole (300 mg, 1.84 mmol, 1.00 eq) in DMF (3 mL) added Tetrabutylammonium iodide (1358 mg, 3.68 mmol, 2.00 eq) and 4-bromo-2- methyl-benzenesulfonyl chloride (496 mg, 1.84 mmol, 1.00 eq) at 25 °C and reaction was stirred at 25 °C for 4 h. After completion, reaction was quenched with water (lOOmL) and extracted with ethyl acetate (3 xl5 mL). Combined organic layers was washed with water (3 x lOOmL), brine, dried over anhydrous Na2SC>4 and concentrated under vaccum to get crude product, which was then purified by column chromatography using 25% ethyl Acetate in hexane as a mobile phase to provide Broad_P_CaV3.3_640_Int_1339, (310 mg, 0.851 mmol, 46% yield) as yellow solid.

[0734] 1H NMR (400 MHz, Chloroform-d) 5 7.92 (s, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.46 (d, J = 7.8 Hz, 2H), 6.94 (dd, J = 8.7, 2.3 Hz, 1H), 6.81 (dd, J = 10.3, 2.4 Hz, 1H), 3.87 (s, 3H), 2.61 (s, 3H), 2.51 (d, J = 8.8 Hz, 3H). 8-methyl-l-[2-methyl-3-(3-methyl-l,2-oxazol-5-yl)benzenesulfonyl]-l,2,3,4- tetrahydroquinoxaline (Broad_P_Cav3.3_272, Compound 35)

[0735] To a stirred solution of l-(3-bromo-2-methylbenzenesulfonyl)-8-methyl-l, 2,3,4- tetrahydroquinoxaline (350 mg, 0.9179 mmol), xphos (61.2 mg, 0.1285 mmol) and palladium(II) acetate (14.4 mg, 0.06425 mmol) in 1,4-Dioxane (5 mL) at room temperature was added 3-methyl-5-(tributylstannyl)-l,2-oxazole (409 mg, 1.10 mmol) at same temperature, and the reaction mixture was purged with argon for 10 min., and heated at 100°C for 8 h. After completion, the reaction mixture was poured in to water (30 mL), and extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with brine solution (3 x 20 mL), dried over Na2SC>4 and evaporated. The residue was purified via Biotage (5: 1 Hex / EtOAc; 12S column) to provide 8-m ethyl- l-[2-m ethyl (250 mg, 71.2 % yield) as a white solid.

[0736] 1H NMR (400 MHz, DMSO-d6) 5 8.17 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 7.7 Hz, 1H), 7.56 (t, J = 7.9 Hz, 1H), 6.86 (t, J = 7.7 Hz, 1H), 6.67 (s, 1H), 6.42 - 6.31 (m, 2H), 5.98 (s, 1H), 3.98 (s, 1H), 3.12 (s, 2H), 2.68 (s, 1H), 2.30 (s, 3H), 2.24 (s, 3H), 2.19 (s, 3H). MS (ESI) : 384.2 [M+H]+.

[0737] (3S)-3,7-dimethyl-l-[[4-methyl-6-(4-methylimidazol-l-yl)-3-pyridyl]sulfonyl]indoline (Broad_P_CaV3.3_660A) and (3R)-3,7-dimethyl-l-[[4-methyl-6-(4-methylimidazol-l- yl)-3-pyridyl] sulfonyl] indoline (Broad_P_CaV3.3_660B) (Compounds 36 and 90)

[0738] The mixture of l-[(6-bromo-4-methyl-3-pyridyl)sulfonyl]-3,7-dimethyl-indoline (200 mg, 0.525 mmol, 1.00 eq), 4-methyl-lH-imidazole (172 mg, 2.10 mmol, 4.00 eq), tBuXPhos (45 mg, 0.105 mmol, 0.200 eq), and Potassium phosphate tribasic (223 mg, 1.05 mmol, 2.00 eq) in 1,4-di oxane (5 mL) was degassed for 10 minutes and Tris(dibenzylideneacetone)dipalladium(0) (48 mg, 0.0525 mmol, 0.100 eq) was added to the reaction mixture and heated at 120 °C for 16 h. After completion, the reaction mixture was diluted with water (lOOmL) and product was extracted in ethyl acetate (100 mL x 3). The organic layer was dried over sodium sulphate and vacuum evaporated to afford residue. The residue was purified by column chromatography in silica using 60%-70% ethyl acetate in hexane. The product fraction were vacuum evaporated to afford impure product. The impure product was further purified by Prep HPLC purification in SIJNFIRE C18(250*19)mm,5p column using 5%-55% 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_660). 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).

[0739] Broad_P_CaV3.3 660A

[0740] 1H NMR (400 MHz, DMSO-d6) 5 8.87 (s, 1H), 8.50 (d, J = 1.4 Hz, 1H), 7.78 (s, 1H), 7.71 (s, 1H), 7.24 - 7.08 (m, 2H), 7.03 (d, J = 6.8 Hz, 1H), 4.31 (dd, J = 12.9, 7.3 Hz, 1H), 3.44 (dd, J = 12.9, 10.4 Hz, 1H), 2.60 (dq, J = 15.3, 5.8, 5.0 Hz, 1H), 2.42 (s, 3H), 2.17 (s, 3H), 2.06 (s, 3H), 1.01 (d, J = 6.7 Hz, 3H). MS(ESI): 383.0 [M+H]+.

[0741] Broad_P_CaV3.3 660B

[0742] 1H NMR (400 MHz, DMSO-d6) 5 8.87 (s, 1H), 8.57 - 8.43 (m, 1H), 7.74 (d, J = 28.0 Hz, 2H), 7.24 - 7.11 (m, 2H), 7.03 (d, J = 6.8 Hz, 1H), 4.30 (dd, J = 12.9, 7.3 Hz, 1H), 3.43 (dd, J = 12.9, 10.4 Hz, 1H), 2.60 (dt, J = 10.1, 6.9 Hz, 1H), 2.41 (s, 3H), 2.17 (s, 3H), 2.06 (s, 3H), 1.00 (d, J = 6.7 Hz, 3H). MS(ESI):383.0 [M+H]+. l-[(6-bromo-4-methyl-3-pyridyl)sulfonyl]-3,7-dimethyl-indoline

[0743] To the solution of 3,7-dimethylindoline (600 mg, 4.08 mmol, 1.00 eq) in Dichloromethane (12 mL) was added 6-bromo-4-methyl-pyridine-3 -sulfonyl chloride (1654 mg, 6.11 mmol, 1.50 eq) followed by Pyridine (1.65 mL, 20.4 mmol, 5.00 eq) at 0°C and the reaction mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was diluted with water (100 mL) and product was extracted in di chloromethane (lOOmL * 3). The organic layer was dried over sodium sulphate and vacuum evaporated to afford residue. The residue was purified by column chromatography in silica using l%-2% ethyl acetate in hexane. The product fractions were vacuum evaporated to afford reddish brown semisolid of Int-1402, (500 mg, 0.837 mmol, 21% yield). MS(ESI): 383.2 [M+H]+. 3,7-dimethylindoline

[0744] To the solution of 3,7-dimethyl-lH-indole (1.00 g, 6.89 mmol, 1.00 eq) in Acetic acid (10 mL) was added Sodium cyanoborohydride (1.30 g, 20.7 mmol, 3.00 eq) in portion at 0 °C and the reaction mixture was stirred for 3 h. After completion, the reaction was basified by 2M aqueous solution of sodium hydroxide and extracted with ethyl acetate (150 mL x 3). The organic layer was dried over sodium sulphate and vacuum evaporated to afford crude. The crude product was purified by column chromatography in silica using 0%-5% ethyl acetate in hexane as mobile phase. The product fraction was collected and vacuum evaporated to afford yellow oil of 3,7-dimethylindoline Int-1364, (500 mg, 1.46 mmol, 21% yield). MS(ESI): 148.1 [M+H]+.

[0745] 7-methyl-l-[[4-methyl-6-(4-methylimidazol-l-yl)-3-pyridyl]sulfonyl]indoline (Broad_P_CaV3.3_649, Compound 37)

[0746] A stirred suspension of l-[(6-bromo-4-methyl-3-pyridyl)sulfonyl]-7-methyl-indoline (200 mg, 0.545 mmol, 1.00 eq) 4-methyl-lH-imidazole (89 mg, 1.09 mmol, 2.00 eq) and Potassium t-butoxide (183 mg, 1.63 mmol, 3.00 eq) in DMF (5 mL) was degassed with nitrogen gas for 15 min. Copper(I)oxide (23 mg, 0.163 mmol, 0.300 eq) was added to it and heated it at 140oC for 12 h. 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 Na2SC>4 and evaporated under vacuum. The residue was purified via combi flash using (1 : 1, Ethyl acetate: Hexanes) as a mobile phase to provide mixture of isomers which was further purified by prep HPLC to give Broad_P_CaV3.3_649, (20 mg, 0.0543 mmol, 10% yield) as an off white solid.

[0747] 1H NMR (400 MHz, DMSO-d6) 5 8.88 (s, 1H), 8.54 (s, 1H), 7.76 (d, J = 20.9 Hz, 2H), 7.16 (d, J = 4.5 Hz, 2H), 7.06 (t, J = 4.4 Hz, 1H), 4.03 (t, J = 7.2 Hz, 2H), 2.46 (s, 3H), 2.33 (t, J = 7.2 Hz, 2H), 2.19 (s, 3H), 2.01 (s, 3H). MS(ESI): 369.2 [M+H]+. l-[(6-bromo-4-methyl-3-pyridyl)sulfonyl]-7-methyl-indoline

[0748]

[0749] To a stirred a solution of 7-m ethylindoline (200 mg, 1.50 mmol, 1.00 eq) and Pyridine (.49 mL, 6.01 mmol, 4.00 eq) in DCM (5 mL) was added 6-bromo-4-methyl-pyridine-3- sulfonyl chloride (812 mg, 3.00 mmol, 2.00 eq), at RT. The reaction mixture was stirred at same temperature for 12 h. After completion, the reaction was quenched with 10% citric acid solution (50 mL) and extracted ethyl acetate (3 x 50 mL). The combined organics were washed brine solution (2 x 50 mL), dried over Na2SC>4 and evaporated. The residue was purified by silica gel column chromatography (6:4, Ethyl acetate: Hexanes) as a mobile phase to provide Broad_P_CaV3.3_649_Int-1378, (390 mg, 0.722 mmol, 48% yield) as a brown solid. LCMS: 368.2 [M+H]+. l,5-dimethyl-4-{[2-methyl-6-(4-methyl-lH-imidazol-l-yl)pyridin-3-yl]sulfonyl}-l,2,3,4- tetrahydroquinoxaline (Broad_P_Cav3.3_359, Compound 38)

[0750] To a stirred solution of 4-[(6-bromo-2-methylpyridin-3-yl)sulfonyl]-l,5-dimethyl- 1,2,3,4-tetrahydroquinoxaline (0.6 g, 1.51 mmol) were added 4-methyl-lH-imidazole (247 mg, 3.02 mmol), potassium tert-butoxide (508 mg, 4.53 mmol) in DMF (5 mL) at room temperature and reaction mixture was degassed with argon for 20 min followed by cuprous oxide (43.2 mg, 0.302 mmol) was added at room temperature and reaction mixture was heated at 120°C for 16 h. After completion, the reaction mixture was poured in to water (100 mL) and extracted with EtOAc (3 x 30 mL). The organic layer was washed with brine solution (2 x 30 mL), dried over Na2SO4 and evaporated. The product was added to a Prep HPLC column and was eluted with 35% - 50% ACN in 0.1% formic acid in water as a gradient to provide l,5-dimethyl-4-{[2-m (178 mg, 29.3 % yield) as an off white solid.

[0751] 1H NMR (400 MHz, Chloroform-d) 5 8.55 (s, 1H), 8.27 (d, J = 8.8 Hz, 1H), 7.40 (s, 1H), 7.22 (d, J = 8.6 Hz, 1H), 7.09 (dd, J = 9.3, 6.5 Hz, 1H), 6.67 (d, J = 7.6 Hz, 1H), 6.40 (d, J =

[0752] 8.2 Hz, 1H), 4.42 - 4.28 (m, 1H), 3.07 - 2.92 (m, 2H), 2.40 (d, J = 2.9 Hz, 6H), 2.32 (s, 2H). MS (ESI): 398.3 [M+H]+.

[0753] Synthesis of 3,7-dimethyl-l-[2-methyl-4-(4-methylimidazol-l-yl)phenyl]sulfonyl-indole (Compound 40) tep-3

[0754] 59% roa _ _ a . _ Compound 40 1098C

[0755] 2-isopropenyl-6-methyl-aniline: Intermediate 1098 A

[0756] 1098A

[0757] The mixture of 2-bromo-6-methyl-aniline (1500 mg, 8.06 mmol, 1.00 eq), 2- isopropenyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1626 mg, 9.67 mmol, 1.20 eq) and Cesium carbonate (7881 mg, 24.2 mmol, 3.00 eq) in Tetrahydrofuran (15 mL) and Water (1.5 mL) was degassed for 10 minutes under nitrogen and [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (658 mg, 0.806 mmol, 0.100 eq) was added to the reaction mixture and the reaction was heated at 80 °C for 4 h. After completion, the reaction was diluted with water (100 mL) and the product was extracted in ethyl acetate (3 * 100 mL). The organic layer was dried over sodium sulphate and vacuum evaporated. The residue was purified by column chromatography in silica using 5%-l 0% ethyl acetate in hexane as mobile phase. The product fractions were vacuum evaporated to afford yellow semisolid of 2-isopropenyl-6-methyl-aniline Int-1098A, (500 mg, 2.45 mmol, 30% yield). MS(ESI): 148.1 [M+l]|

[0758] 4-bromo-N-(2-isopropenyl-6-methyl-phenyl)-2-methyl-benzenesulfonamide: Intermediate 1098B

[0759] 1098B

[0760] To the solution of 2-isopropenyl-6-methyl-aniline (500 mg, 2.45 mmol, 1.00 eq) and 4-bromo-2-methyl-benzenesulfonyl chloride (991 mg, 3.68 mmol, 1.50 eq) in Dichloromethane (7.22 mL) was added Pyridine (.99 mL, 12.3 mmol, 5.00 eq) dropwise at room temperature, and the reaction was stirred at room temperature for 16 h. After completion, the reaction mixture was concentrated under vacuum and purified by column chromatography in silica using 10%- 15% ethyl acetate in hexane. The product fractions were vacuum evaporated to afford off white solid of 4-bromo-N-(2-isopropenyl-6-methyl-phenyl)- 2-methyl-benzenesulfonamide Int-1098B, (500 mg, 0.864 mmol, 35% yield). MS(ESI): 382.0 | 2H |

[0761] N-(2-isopropenyl-6-methyl-phenyl)-2-methyl-4-(4-methylimidazol-l-yl)benzenesulfonamide: Intermediate 1098C

[0762] 1098C

[0763] The mixture of 4-bromo-N-(2-isopropenyl-6-methyl-phenyl)-2-methyl- benzenesulfonamide (100 mg, 0.173 mmol, 1.00 eq), 4-methyl-lH-imidazole (57 mg, 0.691 mmol, 4.00 eq), tBuXPhos (15 mg, 0.0345 mmol, 0.200 eq), and Potassium phosphate tribasic (73 mg, 0.345 mmol, 2.00 eq) in 1,4-Dioxane (1.31 mL) was degassed for 10 minutes. After degassing 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 product fraction was vacuum evaporated to afford light brown semisolid of N-(2-isopropenyl-6-methyl-phenyl)-2-methyl-4-(4-methylimidazol-l- yl)benzenesulfonamide Int-1098C, (50 mg, 0.102 mmol, 59% yield).XH NMR (400 MHz, Methanol-^) 5 8.20 (d, J= 1.6 Hz, 1H), 7.81 (d, J= 8.5 Hz, 1H), 7.62 (d, J= 2.3 Hz, 1H), 7.51 - 7.40 (m, 2H), 7.16 (d, J= 4.7 Hz, 2H), 6.98 (t, J= 4.6 Hz, 1H), 4.80 - 4.62 (m, 2H), 2.72 (s, 3H), 2.29 (d, J= 6.2 Hz, 6H), 1.74 (s, 3H). MS(ESI): 382.3 [M+H]+

[0764] 3,7-dimethyl-l-[2-methyl-4-(4-methylimidazol-l-yl)phenyl]sulfonyl-indole (Compound 40)

[0765]

[0766] Broad_P_CaV3.3_553 Compound 40

[0767] To the solution of N-(2-isopropenyl-6-methyl-phenyl)-2-methyl-4-(4-methylimidazol- l-yl)benzenesulfonamide (200 mg, 0.407 mmol, 1.00 eq) in Dimethylformamide (1.55 mL) was added Silver nitrate (138 mg, 0.815 mmol, 2.00 eq) and the reaction was heated at 120 °C for 16 h. After completion, the reaction mixture was diluted with the water (100 mL), and extracted in ethyl acetate (3 x 100 mL). The organic layer was dried over sodium sulphate and vacuum evaporated. 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).

[0768] 'H N R (400 MHz, DMSO ) 5 8.29 (s, 1H), 7.84 (d, J= 2.3 Hz, 1H), 7.65 (d, J= 9.4 Hz, 2H), 7.56 (s, 1H), 7.48 (dd, J= 8.3, 4.8 Hz, 2H), 7.22 (t, J= 7.5 Hz, 1H), 7.09 (d, J= 7.4 Hz,

[0769] 1H), 2.34 (s, 3H), 2.28 (s, 3H), 2.15 (s, 3H).

[0770] ’H NMR (400 MHz, DMSO-t / 6, D2O Exchange) 5 8.25 (s, 1H), 7.76 (s, 1H), 7.61 (d, J= 8.6 Hz, 2H), 7.57 - 7.49 (m, 2H), 7.46 (d, J= 7.9 Hz, 1H), 7.21 (t, J= 7.6 Hz, 1H), 7.07 (d, J= 7.4 Hz, 1H), 2.46 (s, 3H), 2.31 (s, 3H), 2.25 (s, 3H), 2.13 (s, 3H). MS(ESI): 379.9 [M]+ l,5-dimethyl-4-{[4-methyl-6-(l-methyl-lH-pyrazol-4-yl)pyridin-3-yl]sulfonyl}-l,2,3,4- tetrahydroquinoxaline (Broad_P_CaV3.3_286, Compound 41)

[0771] To a stirred solution of 8-methyl-l-{[4-methyl-6-(l-methyl-lH-pyrazol-4-yl)pyridin- 3- (0.15 g, 391 pmol, 1 eq) in DMF (2 mL) was added potassium carbonate (215 mg, 1.56 mmol, 4 eq) at room temperature and stirred for 30 minutes followed by drop wise addition of methyl iodide (110 mg, 782 pmol, 2 eq) at room temperature and reaction mixture was stirred at 70 °C for 16h. After completion, the reaction mixture was poured in to water (50 mL) and extracted with EtOAc (3 x 50 mL). 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. 1H NMR (400 MHz, DMSO-d6) 5 8.84 (s, 1H), 8.39 (s, 1H), 8.08 (s, 1H), 7.60 (s, 1H), 7.03 (t, J = 7.8 Hz, 1H), 6.57 (d, J = 7.5 Hz, 1H), 6.44 (d, J = 8.2 Hz, 1H), 4.24 (dd, J = 14.8, 7.2 Hz, 1H), 3.89 (s, 3H), 2.97 (dd, J = 11.4, 6.5 Hz, 1H), 2.84 (t, J = 9.6 Hz, 1H), 2.32 (d, J = 5.2 Hz, 6H), 1.92 (s, 3H). MS(ESI): 398.3 [M+H]+.

[0772] 4-{4-[l-(difluoromethyl)-lH-pyrazol-4-yl]-2-methylbenzenesulfonyl}-l,5-dimethyl- 1,2,3,4-tetrahydroquinoxaline (Broad000415 - 088, Compound 42)

[0773] To a vial, 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) and XPhos Pd G2 (4.47 mg, 0.005690 mmol, 0.05 eq) were added in dioxane:water 4: 1 (1 mL). 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).

[0774] 1H NMR (400 MHz, Chloroform-d) 5 8.11 (s, 1H), 8.02 - 7.93 (m, 2H), 7.42 - 7.31 (m, 2H), 7.10 - 7.00 (m, 1H), 6.62 (d, J = 7.6 Hz, 1H), 6.42 (d, J = 8.1 Hz, 1H), 4.30 (s, 1H), 3.28 (s, 1H), 3.00 (s, 2H), 2.48 (s, 3H), 2.35 (s, 3H), 2.17 (s, 3H). MS (ESI): 433.3 [M+H]+. l,5,6-trimethyl-4-[2-methyl-4-(l-methyl-lH-pyrazol-4-yl)benzenesulfonyl]-l,2,3,4- tetrahydroquinoxaline (Broad_P_Cav3.3_306, Compound 43) To a stirred solution of 4-(4-bromo-2-methylbenzenesulfonyl)-l,5,6-trimethyl-l,2,3,4- tetrahydroquinoxaline (150 mg, 0.3664 mmol) were added l-methyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-pyrazole (91.4 mg, 0.4396 mmol), potassium carbonate (150 mg, 1.09 mmol) in 1,4-Dioxane (3 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 (29.9 mg, 0.03664 mmol) was added at room temperature and reaction mixture was heated at 100°C for 6 h. After completion, the reaction mixture was poured in to water (30 mL) and extracted with EtOAc (3 x 30 mL). The organic layer was washed with brine solution (2 x 20 mL), dried over Na2SO4 and evaporated. The residue was purified via Biotage (50: 1 CHzCh / MeOH; 12M column) to provide l,5,6-trimethyl-4-[2 (90 mg, 57.9 % yield) as an off white solid.

[0775] 1H NMR (400 MHz, Chloroform-d) 5 7.91 (d, J = 8.2 Hz, 1H), 7.79 (s, 1H), 7.68 (s, 1H), 7.36 - 7.30 (m, 1H), 7.28 (s, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.31 (d, J = 8.2 Hz, 1H), 4.36 - 4.26 (m, 1H), 3.96 (s, 3H), 3.26 (ddd, J = 14.5, 10.7, 7.4 Hz, 1H), 2.99 - 2.86 (m, 2H), 2.41 (s, 3H), 2.27 (s, 3H), 2.19 (s, 3H), 2.09 (s, 3H). MS (ESI): 411.2 [M+H]+.

[0776] Synthesis of Compound 45 A solution of 8-methyl- 1,2,3, 4-tetrahydroquinoline (0.15 g, 1.01 mmol, 1 eq), 4- bromo-2-methylbenzene-l -sulfonyl chloride (816 mg, 3.03 mmol, 3 eq), triethylamine (102 mg, 1.01 mmol, 1.0 eq) and 2-dimethylaminopyridine (12.3 mg, 101 pmol, 0.1 eq) in pyridine (2 mL) was stirred at 110 °C for 16 h. after completion, the reaction mixture was evaporated and the residue was purify by flash chromatography using [0-15% EtOAc / Hexanes] to provide l-(4-bromo-2-methylbenzenesulfonyl)-8-methyl-l,2,3,4-tetrahy (0.15 g, 39.0 % yield) as a white solid.

[0777] MS :[M+H]+ 382.00

[0778] 8-methyl-l-[2-methyl-4-(l-methyl-lH-pyrazol-4-yl)benzenesulfonyl]-l,2,3,4- tetrahydroquinoline: Broad_P_CaV3.3_257 (Compound 45)

[0779] To a stirred solution of l-(4-bromo-2-methylbenzenesulfonyl)-8-methyl-l, 2,3,4- tetrahy (0.15 g, 394 pmol, 1 eq), l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 1H- (98.2 mg, 472 pmol, 1.2 eq) and potassium carbonate (163 mg, 1.18 mmol, 3 eq) in 1,4 dioxane (5 mL) and water (1 mL) was degassed for 15 minutes with Nitrogen gas then tetrakis(triphenylph (45.5 mg, 39.4 pmol, 0.1 eq) was added and heated the reaction mixture at 90°C for 16 h. After completion, the 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.

[0780] MS :[M+H]+ 382.40. ’H NMR (400 MHz, DMSO-d6) 5 8.30 (s, 1H), 8.00 (s, 1H), 7.81 (d, J = 8.7 Hz, 1H), 7.59 (d, J = 7.0 Hz, 2H), 7.14 (s, 2H), 6.97 - 6.91 (m, 1H), 4.01 (s, 1H), 3.29 (s, 1H), 3.87 (s, 4H), 2.30 (s, 3H), 2.04 (s, 3H), 1.91 (s, 1H), 1.63 (s, 1H), 1.50 (s, 1H).

[0781] 5'-fluoro-7'-methyl-l'-[[4-methyl-6-(4-methylimidazol-l-yl)-3- pyridyl]sulfonyl]spiro[cyclopropane-l,3'-indoline] (Broad_P_CaV3.3_684, Compound 47)

[0782] To a solution of l'-[(6-bromo-4-methyl-3-pyridyl)sulfonyl]-5'-fluoro-7'-methyl- spirofcy cl opropane- 1,3 '-indoline] (0.35 g, 0.851 mmol, 1.00 eq) in Dimethyl sulfoxide (3.5 mL) was added 4-methyl imidazole (0.28 g, 3.40 mmol, 4.00 eq), Potasium tert butoxide (0.29 g, 2.55 mmol, 3.00 eq), and Copper(I)Oxide (0.037 g, 0.255 mmol, 0.300 eq) at room temperature and reaction mass was stirred at 140°C for 1 hr. The reaction mass was quenched in water (250 mL) and extracted with EtOAc (3 x 50 mL). The combined organics were dride over anhydrous Na2SC>4 and evaporated to get crude product which was purified by column chromatography using 2% methanol in DCM as mobile phase to provide compound, which was finally purified by reverse phase prep HPLC using 10-100% Acetonitrile in water (0.1% formic acid as modifier to give Broad_P_CaV3.3_684, (45 mg, 0.106 mmol, 12% yield) as a light orange solid.

[0783] 1H NMR (400 MHz, DMSO-d6) 5 8.84 (s, 1H), 8.50 (s, 1H), 7.79 (s, 1H), 7.71 (s, 1H), 6.99 (dd, J = 10.1, 2.7 Hz, 1H), 6.55 (dd, J = 8.3, 2.7 Hz, 1H), 4.00 (s, 2H), 2.48 (s, 3H), 2.19 (s, 3H), 1.97 (s, 3H), 0.52 (s, 4H). MS(ESI): 411 [M-H]-. l'-[(6-bromo-4-methyl-3-pyridyl)sulfonyl]-5'-fluoro-7'-methyl-spiro[cyclopropane-l,3'- indoline]

[0784]

[0785] To a solution of 5'-fluoro-7'-methyl-spiro[cyclopropane-l,3'-indoline] (0.18 g, 1.02 mmol, 1.00 eq) in Dichloromethane (1.8 mL) was added 6-bromo-4-methylpyridine-3- sulfonyl chloride (0.55 g, 2.03 mmol, 2.00 eq) and Pyridine (.33 mL, 4.06 mmol, 4.00 eq) at room temperature and reaction was stirred at same temperature for 1 hr. The reaction mass was quenched in water (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organics were dride over anhydrous Na2SO4 and evaporated to get l'-[(6-bromo-4-methyl-3- pyridyl)sulfonyl]-5'-fluoro-7'-methyl-spiro[cyclopropane-l,3'-indoline], (0.35 g, 0.851 mmol) Broad_P_Cav3.3_684. MS(ESI): 413.0 [M+H]+ 5'-fluoro-7'-methyl-spiro[cyclopropane-l,3'-indoline]

[0786] To a solution of 5'-fluoro-7'-methyl-spiro[cyclopropane-l,3'-indoline]-2'-one (0.55 g, 2.88 mmol, 1.00 eq) in Tetrahydrofuran (11 mL) was added Lithium aluminium hydride (IM in THF) (14.39 mL, 14.4 mmol, 5.00 eq) dropwise at room temperature and reaction mass was stirred at same temperature for 12 hr. The reaction was quenched in water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organics were dride over anhydrous Na2SC>4 and evaporated to get 5'-fluoro-7'-methyl-spiro[cyclopropane-l,3'-indoline], (0.20 g, 0.858 mmol, 30% yield).

[0787] 1H NMR (400 MHz, DMSO-d6) 5 6.55 (dd, J = 10.3, 2.6 Hz, 1H), 6.30 (dd, J = 8.7, 2.6 Hz, 1H), 5.20 (s, 1H), 3.45 (d, J = 2.7 Hz, 2H), 2.04 (s, 3H), 0.90 (s, 4H). MS(ESI): 178.0 [M+H]+.

[0788] 5'-fluoro-7'-methyl-spiro[cyclopropane-l,3'-indoline]-2'-one

[0789] To a solution of Trimethylsulfoxonium iodide (30710 mg, 140 mmol, 5.00 eq) in DMSO (40 mL) Sodium hydride (60% in oil) (4019 mg, 167 mmol, 6.00 eq) was added portion wise. The reaction mixture was stirred for 5 min at room temperature. 5-fluoro-7- methyl-indoline-2, 3-dione (5.00 g, 27.9 mmol, 1.00 eq) was added by dissolving in DMSO (20 mL) and stirred for 4 hr at room temperature. The reaction was quenched in saturated ammonium bromide solution (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organics were dride over anhydrous Na2SO4 and evaporated to get 5'-fluoro-7'- methyl-spiro[cyclopropane-l,3'-indoline]-2'-one, (0.55 g, 2.79 mmol, 10% yield). MS(ESI): 192.0 [M+H]+.

[0790] 5 -fluoro-7-m ethyl -indoline-2, 3 -di one

[0791] A solution of (2E)-N-(4-fluoro-2-methyl-phenyl)-2-hydroxyimino-acetamide (9.50 g, 48.4 mmol, 1.00 eq) in H2SO4 (76 mL) was stirred at 50°C for 3 hrs. The reaction was quenched in water (500 mL) and extracted with EtOAc (3 x 300 mL). The combined organics were dride over anhydrous Na2SC>4 and evaporated to get 5-fluoro-7-methyl-indoline-2, 3-dione, (6.30 g, 34.8 mmol, 72% yield). MS(ESI): 180.0 [M+H]+.

[0792] (2E)-N-(4-fluoro-2-methyl-phenyl)-2-hydroxyimino-acetamide

[0793] A solution of Chloral hydrate (14.54 g, 87.9 mmol, 1.10 eq) and Sodium sulphate (11.35 g, 79.9 mmol, 1.00 eq) in Water (120 mL) was stirred at 50°C for 15 min. To the reaction mixture was added 4-fluoro-2-methyl-aniline (10.00 g, 79.9 mmol, 1.00 eq) in water (60 mL), 1,4 Dioxane (60 mL), Cone. HC1 (8.5 mL) and stirred at 70°C for 15 min. To the reaction mixture was added Hydroxylamine hydrochloride (11.11 g, 160 mmol, 2.00 eq) in Water (60 mL). The reaction was quenched in water (500 mL) and extracted with EtOAc (3 x 300 mL). The combined organics were dride over anhydrous Na2SC>4 and evaporated to get (2E)-N-(4-fluoro-2-methyl-phenyl)-2-hydroxyimino-acetamide as yellow solid. MS(ESI): 197.1 [M+H]+. l-ethyl-6-fluoro-4-methyl-3-[[4-methyl-6-(4-methylimidazol-l-yl)-3- pyridyljsulfonyljindole (Broad_P_CaV3.3_683, Compound 48)

[0794] To the solution of 3-[(6-bromo-4-methyl-3-pyridyl)sulfonyl]-l-ethyl-6-fluoro-4- methyl-indole (0.41 g, 0.997 mmol, 1.00 eq) in dimethylformamide (4 mL) was added Potassium tert-butoxide (0.34 g, 2.99 mmol, 3.00 eq) and purged with argon for 15 min. COPPER(I) OXIDE, 99% (METALS BASIS) (0.043 g, 0.299 mmol, 0.300 eq) was added and stirred at 140 °C for 6 h. After6 h, the reaction mixture was diluted with water (15 mL) and extracted with EtOAc (3 x 20 mL). The organics were dried over Na2SO4 and evaporated under vacuum. The residue was purified via combi flash using DCM:MeOH (9: 1) as a mobile phase to provide an impure product which on further pufification by reverse phase prep. HPLC using 40-100 % ACN in water as mobile phase with 0.1% Formic acid as modifier. A white solid of Broad-P_CaV3.3_683, (0.058 g, 0.141 mmol, 14% yield) was obtained.

[0795] 1H NMR (400 MHz, DMSO-d6) 5 8.82 (s, 1H), 8.50 (s, 1H), 8.40 (s, 1H), 7.88 (s, 1H), 7.71 (s, 1H), 7.49 (d, J = 9.7 Hz, 1H), 6.91 (d, J = 10.5 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 2.52 (s, 3H), 2.47 (s, 3H), 2.18 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H). MS(ESI): 413.0 [M+H]+.

[0796] 3-[(6-bromo-4-methyl-3-pyridyl)sulfonyl]-l-ethyl-6-fluoro-4-methyl-indole fssss<. ? „C« VS „8SS .. U?

[0797] To the suspension of 3-[(6-bromo-4-methyl-3-pyridyl)sulfanyl]-l-ethyl-6-fluoro-4- methyl-indole (0.67 g, 1.77 mmol, 1.00 eq) in dichloromethane (6.7 mL), added meta- Chloroperoxybenzoic acid (0.91 g, 5.30 mmol, 3.00 eq) and stirred at 25 °Cfor 12 h. After completion, the reaction was quenched with saturated solution of NaHCOs (50 mL) and extracted ethyl acetate (3 x 50 mL). The combined organics were washed brine solution (2 x 50 mL), dried over Na2SC>4 and evaporated. The residue was purified by silica gel column chromatography using 20% ethyl acetate in hexanes as a mobile phase to provide Broad_P_CaV3.3_683 (0.41 g, 0.701 mmol, 40% yield) as a yellow solid. MS(ESI): 413.1 [M+H]+.

[0798] 3-[(6-bromo-4-methyl-3-pyridyl)sulfanyl]-l-ethyl-6-fluoro-4-methyl-indole

[0799] To a stirred a solution of l-ethyl-6-fluoro-4-methyl-indole (0.61 g, 3.44 mmol, 1.00 eq) and 6-bromo-4-methyl-pyridine-3-sulfonyl chloride (1.86 g, 6.88 mmol, 2.00 eq) in DMF (10 mL) was added Tetra-n-butylammonium iodide (2.54 g, 6.88 mmol, 2.00 eq). The reaction mixture was stirred at same temperature for 4 h. After completion, the reaction was quenched with saturated solution of NaiSiCh (50 mL) and extracted ethyl acetate (3 x 50 mL). The combined organics were washed brine solution (2 x 50 mL), dried over Na2SC>4 and evaporated. The residue was purified by silica gel column chromatography using 15% ethyl acetate in hexanes as a mobile phase to provide Broad_P_Cav3.3_683_1476, (0.67 g, 1.77 mmol, 51% yield) as a pale yellow solid. MS(ESI): 381.2 [M+H]+.

[0800] 1 -ethyl-6-fluoro-4-methyl-indole

[0801] To the solution of 4-bromo-l-ethyl-6-fluoro-indole (0.90 g, 3.72 mmol, 1.00 eq)in 1,4-dioxane (9 mL), added Potassium carbonate (1539 mg, 11.2 mmol, 3.00 eq) solublised in water (2 mL) and Methyl Boronic acid (267 mg, 4.46 mmol, 1.20 eq). The 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. The residue was purified via combi flash using (1 :20, Ethyl acetate: Hexanes) as a mobile phase to provide Broad_P_CaV3.3_683 (0.61 g, 2.99 mmol, 81% yield) as a light brown liquid. MS(ESI): 178.1 [M+H]+.

[0802] 4-bromo- 1 -ethyl-6-fluoro-indole

[0803] To a solution of 4-bromo-6-fluoro-lH-indole (1.00 g, 4.67 mmol, 1.00 eq) in DMF at 0 °C was added sodium hydride (60% in mineral oil) (0.17 g, 7.01 mmol, 1.50 eq) portion wise and then stirred it for 15 min followed by addition of Ethyl Iodide (1.46 g, 9.34 mmol, 2.00 eq) at same tempreture. Reaction was stirred at 25 °C for2 h. After completion, the reaction mixture was diluted with ethyl acetate (10 mL) and washed with brine solution (3 x 70 mL). The organic layer was dried over Na2SC>4 and evaporated under vacuum to get Broad_P_CaV3.3_683 (0.90 g, 3.72 mmol, 80% yield) as major product. MS(ESI): 244.0 [M+H]+. l,5-dimethyl-4-[2-methyl-4-(l-methyl-lH-pyrazol-4-yl)benzenesulfonyl]-l,2,3,4- tetrahydroquinoxalin-2-one (Broad_P_Cav3.3_326, Compound 49)

[0804] To a stirred solution of 5-methyl-4-[2-methyl-4-(l-methyl-lH-pyrazol-4- yl)benzenesulfonyl]-l,2,3,4-tetrahydroquinoxalin-2-one (0.85 g, 2.14 mmol), was added methyl iodide (455 mg, 3.21 mmol) and potassium carbonate (887 mg, 6.42 mmol) in DMF (8 mL) at room temperature. The reaction mixture was heated at 50°C and stirred at same temperature for 5 h. After completion, the reaction mixture was poured in to ice-water (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layer was washed brine solution (2 x 30 mL), dried over Na2SC>4 and evaporated. The residue was purified via Biotage (50:1 CEBCh / MeOEl; 12M column) to provide l,5-dimethyl-4-[2-me (0.7 g, 79.6 % yield) as an off white solid. 1H NMR (400 MHz, Chloroform-d) 5 7.77 (s, 1H), 7.67 (t, J = 4.1 Hz, 2H), 7.33 (dd, J = 8.2, 1.9 Hz, 1H), 7.26 - 7.21 (m, 2H), 7.09 (d, J = 7.6 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 4.75 (d, J = 17.8 Hz, 1H), 3.96 (s, 3H), 3.89 (d, J = 17.7 Hz, 1H), 2.61 (s, 3H), 2.58 (s, 3H), 2.04 (s, 3H). MS (ESI): 411.4 [M+H]+.

[0805] 4-[2,6-dimethyl-4-(l-methyl-lH-pyrazol-4-yl)benzenesulfonyl]-l,5-dimethyl-l,2,3,4- tetrahydroquinoxaline (Broad_P_Cav3.3_305, Compound 50)

[0806] To a stirred solution of 4-(4-bromo-2,6-dimethylbenzenesulfonyl)-l,5-dimethyl- 1,2,3,4-tetrahydroquinoxaline (0.85 g, 2.07 mmol) were added l-methyl-4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (516 mg, 2.48 mmol), potassium carbonate (856 mg, 6.20 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 (169 mg, 0.207 mmol) was added at room temperature and reaction mixture was heated at 100°C for 6 h. After completion, the reaction mixture was poured in to water (40 mL) and extracted with EtOAc (3 x 30 mL). The organic layer was washed with brine solution (2 x 10 mL), dried over Na2SC>4 and evaporated. The residue was purified via Biotage (50: 1 CLLCh / MeOH; 12S column) to provide 4-[2,6-dimethyl-4-(l (0.55 g, 64.7 % yield) as an off white solid. 1H NMR (400 MHz, Chloroform-d) 5 7.80 (s, 1H), 7.68 (s, 1H), 7.19 (s, 2H), 7.02 (t, J = 7.9 Hz, 1H), 6.47 (dd, J = 7.9, 2.8 Hz, 2H), 4.33 (d, J = 8.4 Hz, 1H), 3.96 (s, 3H), 3.37 - 3.20 (m, 2H), 3.13 (s, 1H), 2.73 (s, 3H), 2.43 (s, 6H), 1.92 (s, 3H). MS (ESI): 411.4 [M+H]+.

[0807] 4-[4-(l-cyclopropyl-lH-pyrazol-4-yl)-2-methylbenzenesulfonyl]-l, 5-dimethyl-l, 2,3,4- tetrahydroquinoxaline (Broad000415 - 041, Compound 51)

[0808] To a vial, 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) and XPhos Pd G2 (7.46 mg, 0.009485 mmol, 0.05 eq) were added in Dioxane / Water 4: 1 (1.5 mL). 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). 1H NMR (400 MHz, Chloroform-d) 5 7.92 (d, J = 8.3 Hz, 1H), 7.77 (d, J = 5.4 Hz, 2H), 7.33 (dd, J = 8.3, 1.7 Hz, 1H), 7.27 (s, 1H), 7.05 (t, J = 7.9 Hz, 1H), 6.61 (d, J = 7.5 Hz, 1H), 6.41 (d, J = 8.1 Hz, 1H), 4.28 (s 1H), 3.64 (m, 1H), 3.27 (s, 1H), 2.99 (s, 2H), 2.49 (s, 3H), 2.34 (s, 3H), 2.15 (s, 3H), 1.18 (s, 2H), 1.07 (s, 2H). MS (ESI): 424.8 [M+H]+.

[0809] 7-fluoro-l,5-dimethyl-4-[2-methyl-4-(l-methyl-lH-pyrazol-4-yl)benzenesulfonyl]-

[0810] 1,2,3,4-tetrahydroquinoxaline (Broad_P_Cav3.3_300, Compound 52)

[0811] To a stirred solution of 4-(4-bromo-2-methylbenzenesulfonyl)-7-fluoro-l,5-dimethyl- 1, (0.15 g, 362 pmol, 1 eq), was added l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-lH- (0.0903 g, 433 pmol, 1.196 eq) and potassium carbonate (0.149 g, 1.07 mmol, 2.956 eq) in 1,4-Dioxane (4 mL) and Water (1 mL) at room temperature and the reaction mixture was degassed with argon for 20 min followed by bis(cyclopenta-l,3-dien-l- yldiphenylphosphane) methylene chi (0.0592 g, 72.3 pmol, 0.2 eq) was added at room temperature and the reaction mixture was heated at 100°C for 16 h. After completion, the reaction mixture was poured in to water (25 mL) and extracted with EtOAc (3 x 25 mL). The organic layer was washed with brine solution (2 x 10 mL), dried over Na2SC>4 and evaporated. The product was added to a Prep HPLC column and was eluted with 15 - 55% ACN in 0.1 % formic acid in water as a gradient to provide 7-fluoro-l,5-dimethyl-4-[2- methyl-4-(l-methyl-lH-pyrazol-4-y (0.03125 g, 20.7 % yield).

[0812] 1H NMR (400 MHz, DMSO-d6) 5 8.29 (s, 1H), 7.99 (s, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.56 (d, J = 7.6 Hz, 2H), 6.37 - 6.25 (m, 2H), 4.09 (dd, J = 14.5, 6.5 Hz, 1H), 3.87 (s, 3H), 3.21 (d, J = 13.6 Hz, 1H), 2.98 (dd, J = 11.6, 5.5 Hz, 1H), 2.78 (d, J = 6.8 Hz, 1H), 2.44 (s, 3H), 2.23 (s, 3H), 2.09 (s, 3H). 6-chloro-l,5-dimethyl-4-[2-methyl-4-(l-methyl-lH-pyrazol-4-yl)benzenesulfonyl]-

[0813] 1,2,3,4-tetrahydroquinoxaline (Broad_P_Cav3.3_307, Compound 53)

[0814] To a stirred solution of 4-(4-bromo-2-methylbenzenesulfonyl)-6-chl oro-1, 5-dimethyl- 1,2,3,4-tetrahydroquinoxaline (45 mg, 0.1047 mmol) were added 1 -methyl-4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (26.1 mg, 0.1256 mmol), potassium carbonate (43.4 mg, 0.3141 mmol) in 1,4-Dioxane (2 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 (8.55 mg, 0.01047 mmol) was added at room temperature and reaction mixture was heated at 100°C for 6 h. After completion, the reaction mixture was poured in to water (20 mL) and extracted with EtOAc (3 x 10 mL). The organic layer was washed with brine solution (2 x 10 mL), dried over Na2SC>4 and evaporated. The residue was purified via Biotage (1 : 1 Hex / EtOAc; 12S column) to provide 6-chloro-l,5-dimethy (30 mg, 63.8 % yield) as an off white solid. 1H NMR (400 MHz, DMSO-d6) 5 8.30 (s, 1H), 7.99 (s, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.57 (d, J = 7.1 Hz, 2H), 7.17 (d, J = 8.9 Hz, 1H), 6.52 (d, J = 8.9 Hz, 1H), 4.10 (dd, J = 14.9, 6.7 Hz, 1H), 3.87 (s, 3H), 3.23 (dd, J = 14.7, 5.8 Hz, 1H), 2.98 (dd, J = 11.7, 5.5 Hz, 1H), 2.74 - 2.66 (m, 1H), 2.46 (s, 3H), 2.25 (s, 3H), 2.05 (s, 3H). MS (ESI): 431.4 [M+H]+.

[0815] l,5-dimethyl-4-[2-methyl-4-(3-methyl-l,2-oxazol-5-yl)benzenesulfonyl]-l,2,3,4- tetrahydroquinoxaline (Broad_P_CaV3.3_253, Compound 54)

[0816] To a stirred solution of 8-methyl-l-[2-methyl-4-(3-methyl-l,2-oxazol-5- yl)benzenesulf (0.145 g, 378 pmol, 1 eq), were added triethylamine (76.5 mg, 756 pmol, 2 eq) and methyl iodide (64.2 mg, 453 pmol, 1.2 eq) in Dichloromethane (10 mL) at room temperature and reaction mixture was stirred at Room tempreture for 3h. After completion, the reaction mixture was poured in to water (50 mL) and extracted with EtOAc (3 x 50 mL). The organic layer was washed with brine solution (2 x 10 mL), dried over Na2SC>4 and evaporated. The crude product was purify by flash chromatography using [0-30% EtOAc / Hexane] to provide impure product, which was further purified by prep HPLC using (55-75% ACN in water containing 0.1% formic acid as modifier) as mobile phase to provide l,5-dimethyl-4-[2-methyl-4-(3-methyl-l,2-oxazol-5-yl)benzene (0.0405 g, 27.0 % yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) 58.02 (d, J = 8.2 Hz, 1H), 7.85 - 7.77 (m, 2H), 7.05 (s, 1H), 7.02 (t, J = 7.9 Hz, 1H), 6.54 (d, J = 7.4 Hz, 1H), 6.45 (d, J = 8.2 Hz, 1H), 4.17 (dd, J = 14.7, 6.9 Hz, 1H), 3.25 (s, 1H), 2.80 (t, J = 10.4 Hz, 1H), 2.36 (s, 3H), 2.28 (d, J = 12.5 Hz, 6H), 2.06 (s, 3H).

[0817] l-[2-ethyl-5-(l-methyl-lH-pyrazol-4-yl)benzenesulfonyl]-8-methyl-l,2,3,4- tetrahydroquinoxaline (Broad_P_Cav3.3_224, Compound 56)

[0818] To a stirred solution of N-(2-amino-6-methylphenyl)-2-ethyl-5-(l-methyl-lH- pyrazol-4-yl)benzene-l -sulfonamide (35 mg, 0.09447 mmol), dibromoethane (21.2 mg, 0.1133 mmol) and potassium carbonate (39.1 mg, 0.2834 mmol) in DMF (2 mL) at room temperature. The reaction mixture was heated at 100°C and stirred at same temperature for 12h. After completion, the reaction mixture was poured in to ice water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layer was washed brine solution (2 x 10 mL), dried over Na2SC>4 and evaporated. The product was added to a Prep HPLC column and was eluted with 45-65 % ACN in 0.1% formic acid in water as a gradient to provide l-[2- ethyl-5-(l-meth (12 mg, 32.0 % yield) as a white solid.

[0819] 1H NMR (400 MHz, DMSO-d6) 5 8.22 (s, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.85 (s, 1H), 7.77 (dd, J = 8.0, 2.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 6.86 (t, J = 7.7 Hz, 1H), 6.37 (t, J = 8.1 Hz, 2H), 5.93 (s, 1H), 3.97 (s, 1H), 3.86 (s, 3H), 3.10 (s, 2H), 2.71 (s, 1H), 2.54 (s, 2H), 2.21 (s, 3H), 1.04 (t, J = 7.4 Hz, 3H). MS (ESI): 397.2 [M+H]+. l,4-dimethyl-3-[[4-methyl-6-(4-methylimidazol-l-yl)-3-pyridyl]sulfonyl]indole (Broad_P_CaV3.3_639, Compound 57)

[0820] A stirred suspension of 3-[(6-bromo-4-methyl-3-pyridyl)sulfonyl]-l,4-dimethyl- indole (3.60 g, 9.49 mmol, 1.00 eq) , 4-methyl-lH-imidazole (1.56 g, 19.0 mmol, 2.00 eq) and Potassium tert-butoxide (3.20 g, 28.5 mmol, 3.00 eq) in dimethylformamide (36 mL) was degassed with nitrogen gas for 15 min. Copper(I)oxide (0.41 g, 2.85 mmol, 0.300 eq) was added and heated it at 140 °C for 2 h. After completion, the reaction mixture was diluted with ethyl acetate (40 mL) and washed with brine solution (3 x 20 mL). The organic layer was dried over Na2SC>4 and evaporated under vacuum. The residue was purified via combi flash DCM: Methanol (20: 1) as mobile phase as a mobile phase to provide mixture of isomers which was further purified by prep HPLC using ACN:Water(10-100%) with 0.1% Formic acid in water as a modifier to give Broad_P_CaV3.3_639 (1.11 g, 2.86 mmol, 30% yield) as a white solid.

[0821] 1H NMR (4OO MHz, DMSO-d6) 5 8.80 (s, 1H), 8.48 (s, 1H), 8.35 (s, 1H), 7.86 (s, 1H), 7.69 (s, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.23 (t, J = 7.8 Hz, 1H), 6.98 (d, J = 7.3 Hz, 1H), 3.91 (s, 3H), 2.54 (s, 3H), 2.45 (s, 3H), 2.16 (s, 3H). MS(ESI): 381.0 [M+H]+.

[0822] 3-[(6-bromo-4-methyl-3-pyridyl)sulfonyl]-l,4-dimethyl-indole

[0823] To a stirred solution of 3-[(6-bromo-4-methyl-3-pyridyl)sulfanyl]-l,4-dimethyl-indole (2.00 g, 5.76 mmol, 1.00 eq) in tetrahydrofuran (11.079 mL) and water (11.079 mL) was added Oxone (7.08 g, 23.0 mmol, 4.00 eq) at 25 °C. The reaction mixtutre was allowed to stir at 25 °C for 16 h. After completion, the reaction mixture was dissolved in Water (30 mL) and extracted in ethyl acetate (3 x 30 mL). The combined organics were dried over Na2SO4 and evaporated under vacuum to provide crude which was purified by flash chromatography using Ethyl acetate: Hexanes (2:8) as mobile phase Broad_P_CaV3.3_639_1335, (1.30 g, 3.43 mmol, 60% yield) as an yellow solid. MS(ESI): 381.1 [M+H]+.

[0824] 3-[(6-bromo-4-methyl-3-pyridyl)sulfanyl]-l,4-dimethyl-indole

[0825]

[0826] To a stirred a solution of 1,4-dimethylindole (3.00 g, 20.7 mmol, 1.00 eq) and 6- bromo-4-methyl-pyridine-3-sulfonyl chloride (11.18 g, 41.3 mmol, 2.00 eq) in dimethylformamide (39 mL) was added Tetrabutylammonium iodide (15260 mg, 41.3 mmol, 2.00 eq) at 25 °C. The reaction mixture was stirred at same temperature for 3 h. After completion, the reaction was quenched with saturated solution of Na2S2Ch (50 mL) and extracted ethyl acetate (3 * 100 mL). The combined organics were washed brine solution (2 x 150 mL), dried over Na2SC>4 and evaporated. The residue was purified by silica gel column chromatography using 10% ethyl acetate in hexanes as a mobile phase to provide Broad_P_CaV3.3_639_Int-1334, (3.00 g, 8.64 mmol, 42% yield) as a pale yellow solid. MS(ESI): 349.2 [M+H]+. l,5-dimethyl-4-[2-methyl-4-(2-methyl-2H-l,2,3-triazol-4-yl)benzenesulfonyl]-l,2,3,4- tetrahydroquinoxaline (Broad_P_Cav3.3_289, Compound 58)

[0827] To a stirred solution of l,5-dimethyl-4-[2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxab (0.1 g, 226 pmol, 1 eq) were added 4-bromo-2-methyl-2H- 1,2, 3 -triazole (54.9 mg, 339 pmol, 1.5 eq), potassium carbonate (93.7 mg, 678 pmol, 3.0 eq) in 1,4-Dioxane (3 mL) and Water (0.5 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) (18.4 mg, 22.6 nmol, 0.1 eq) was added at room temperature and reaction mixture was heated at 80°C for 16 h. After completion, the reaction mixture was poured in to water (25 mL) and extracted with EtOAc (3 x 25 mL). The organic layer was washed with brine solution (2 x 30 mL), dried over Na2SC>4 and evaporated. The residue was purified via Biotage (8:2 Hex / EtOAc; 12S column) to l,5-dimethyl-4-[2-methyl-4-(2-methyl-2H-l,2,3-triazol-4-yl)b (4.9 mg, 5.45 % yield) as a light brown solid.

[0828] 1H NMR (400 MHz, DMSO-d6) 5 8.36 (s, 1H), 7.97 (d, J = 8.3 Hz, 1H), 7.84 - 7.78 (m, 2H), 7.01 (t, J = 7.8 Hz, 1H), 6.53 (d, J = 7.4 Hz, 1H), 6.45 (d, J = 8.2 Hz, 1H), 4.22 (s, 3H), 4.15 (d, J = 10.2 Hz, 1H), 2.96 (s, 1H), 2.39 (s, 3H), 2.27 (s, 3H), 2.06 (s, 3H).

[0829] (2S)-l,2,5-trimethyl-4-[2-methyl-4-(l-methyl-lH-pyrazol-4-yl)benzenesulfonyl]-l,2,3,4- tetrahydroquinoxaline (Compound 59) and (2R)-l,2,5-trimethyl-4-[2-methyl-4-(l- methyl-lH-pyrazol-4-yl)benzenesulfonyl]-l,2,3,4-tetrahydroquinoxaline (Compound 120) (Broad_P_Cav3.3 330 and 331)

[0830] To a stirred solution of 4-(4-bromo-2-methylbenzenesulfonyl)-l,2,5-trimethyl-l,2,3,4- tetrahydroquinoxaline (100 mg, 0.2442 mmol) and l-methyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (50.8 mg, 0.2442 mmol) in 1,4-Dioxane (2 mL) and Water (1 mL) was added sodium carbonate (77.6 mg, 0.7326 mmol) and degassed with nitrogen for 5 min. Pd(dppf)C12 • DCM (9.97 mg, 0.01221 mmol) was added and heated it at 100 °C for 3h. After completion, the reaction mixture was filtered through celite and washed with ethyl acetate (10 mL). The obtained filtrate was dried over Na2SC>4 and evaporated. The residue was purified via Biotage (1 : 1 Hex / EtOAc; 12M column) to provide pure product, which was further purified by chiral prep HPLC purification using CO2 and 0.1% Diethylamine in IPA:Hexane (70:30) as a mobile phase to provide (2S)-l,2,5-trimethyl-4-[2-methyl-4-(l- methyl-lH-pyrazol-4-yl)benzenesulfonyl]-l,2,3,4-tetrahydroquinoxaline (10 mg, 9.70 %) as a brown semi-solid and (2R)-l,2,5-trimethyl-4-[2-methyl-4-(l-methyl-lH-pyrazol-4- yl)benzenesulfonyl]-l,2,3,4-tetrahydroquinoxaline (35 mg, 34.9 %) as off white solid. Broad_P_CaV3.3_330

[0831] 1H NMR (400 MHz, DMSO-d6) 5 8.28 (s, 1H), 7.98 (s, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.61 - 7.46 (m, 2H), 7.00 (t, J = 7.8 Hz, 1H), 6.53 (d, J = 7.5 Hz, 1H), 6.38 (d, J = 8.1 Hz, 1H), 4.34 - 4.17 (m, 1H), 3.86 (s, 3H), 3.04 - 2.87 (m, 2H), 2.25 (d, J = 14.5 Hz, 6H), 1.95 (s, 3H), 0.84 (d, J = 4.8 Hz, 3H). MS(ESI): 411.2 [M+H]+.

[0832] Broad_P_CaV3.3_331

[0833] 1H NMR (400 MHz, DMSO-d6) 5 8.28 (s, 1H), 7.98 (s, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.54 (dd, J = 10.9, 2.9 Hz, 2H), 7.00 (t, J = 7.8 Hz, 1H), 6.53 (d, J = 7.5 Hz, 1H), 6.38 (d, J = 8.2 Hz, 1H), 4.27 (d, J = 8.8 Hz, 1H), 3.86 (s, 3H), 2.96 (s, 2H), 2.27 (s, 3H), 2.23 (s, 3H), 1.94 (s, 3H), 0.84 (d, J = 4.9 Hz, 3H). MS(ESI): 411.2 [M+H]+. l,5-dimethyl-4-[2-methyl-4-(5-methyl-l,3,4-oxadiazol-2-yl)benzenesulfonyl]-l,2,3,4- tetrahydroquinoxaline (Broad_P_Cav3.3_324, Compound 60)

[0834] To a stirred solution of l,5-dimethyl-4-[2-methyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzenesulfonyl]-l,2,3,4-tetrahydroquinoxaline (150 mg, 0.3390 mmol) were added 2-bromo-5-methyl-l,3,4-oxadiazole (66.2 mg, 0.4068 mmol), potassium carbonate (139 mg, 1.01 mmol) in 1,4- Dioxane (3 mL) and Water (0.3 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 (27.6 mg, 0.03390 mmol) was added at room temperature and reaction mixture was heated at 100°C for 6 h. After completion, the reaction mixture was poured in to water (20 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 residue was purified via Biotage (50:1 C^Ch / MeOH; 12S column) to provide l,5-dimethyl-4-[2-me (15 mg, 10.9 % yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) 5 8.10 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 11.6 Hz, 2H), 7.06 (t, J = 8 Hz, 1H), 6.63 (d, J = 7.2 Hz, 1H), 6.38 (d, J = 8 Hz, 1H), 4.35 (d, J = 12.8 Hz, 1H), 3.29 (s, 1H), 2.97 (d, J = 7.4 Hz, 2H), 2.65 (s, 3H), 2.39 (s, 6H), 2.16 (s, 3H). MS (ESI): 399.0 [M+H]+.

[0835] 8-methyl-l-[2-methyl-4-(l-methylpyrazol-4-yl)phenyl]sulfonyl-2,3-dihydroquinolin-4- one (Broad_P_Cav3.3_389, Compound 61)

[0836] To a stirred solution of 8-methyl-2,3-dihydro-lH-quinolin-4-one (0.20 g, 1.23 mmol, 1.00 eq) in Pyridine (2 mL) was added 4-Dimethylaminopyridine (0.075 g, 0.616 mmol, 0.500 eq) and Triethylamine (.52 mL, 3.70 mmol, 3.00 eq); the reaction mixture was heated at 60 °C for Ih. The reaction mixture was cooled to RT and 2-methyl-4-(l-methylpyrazol-4- yl)benzenesulfonyl chloride (1.00 g, 3.70 mmol, 3.00 eq) was added portion wise to it. The reaction mixture was heated at 100 °C for 16 h. After completion, the reaction mixture was poured into 10% citric acid solution (20 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organics were dried over Na2SC>4 and evaporated. The residue was purified by combi-flash using Hexane:ethyl acetate (50:50) to provide impure compound; which was further purified by prep HPLC purification using (25-45 % ACN in water containing formic acid as a modifier) as a mobile phase to provide 8-methyl-l-[2-methyl-4-(l-methylpyrazol-4- yl)phenyl]sulfonyl-2,3-dihydroquinolin-4-one (5 mg, 1% yield) as an off white solid.

[0837] IH NMR (400 MHz, DMSO-d6) 5 8.34 (s, IH), 8.03 (s, IH), 7.85 (d, J = 8.2 Hz, IH), 7.64 (d, J = 8.6 Hz, 3H), 7.43 (t, J = 7.6 Hz, IH), 4.20 (s, IH), 3.90 (s, 2H), 2.36 (s, 4H), 2.24 (s, 2H), 2.11 (s, 2H). MS(ESI): 396.3 [M+H]+.

[0838] 8-methyl-2,3-dihydro-lH-quinolin-4-one

[0839] To a stirred solution of l-(o-tolyl)azetidin-2-one (9.00 g, 55.8 mmol, 1.00 eq) in 1,2- Di chloroethane (90 mL) was drop wise added Triflic acid (14.82 mL, 167 mmol, 3.00 eq) under nitrogen atmosphere and allowed it to stir at RT for Ih. After completion, the reaction mixture was poured into water (200 mL) and ectracted with DCM (3 x 90 mL). The combined organics were dried over Na2SC>4 and evaporated. The residue was purified by combi-flash using Hexane:ethyl acetate (30:70) to provide 8-methyl-2,3-dihydro-lH- quinolin-4-one (5.4g, 59.6 % yield) as a yellow solid.

[0840] IH NMR (400 MHz, Chloroform-d) 5 7.81 (dd, J = 8.0, 1.6 Hz, IH), 7.24 (d, J = 7.1 Hz, IH), 6.72 (t, J = 7.6 Hz, IH), 4.36 (s, IH), 3.67 (t, J = 7.0 Hz, 2H), 2.74 (t, J = 7.0 Hz, 2H), 2.20 (s, 3H). MS(ESI): 162.0 [M+H]+.

[0841] 1 -(o-tolyl)azetidin-2-one

[0842] To a stirred suspension of Sodium tert-butoxide (9.19 g, 95.6 mmol, 1.05 eq) in DMF (90 mL) was drop wise added solution of 3-chloro-N-(o-tolyl)propanamide (18.00 g, 91.1 mmol, 1.00 eq) in DMF (90mL) at RT and allowed to stir at same temperature for 16h. The reaction mixture was poured into cold water (1000 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic layer was dried over Na2SC>4 and evaporated to provide Intermediate-755, (9.00 g, 54.3 mmol, 60% yield) as a brown oil.

[0843] IH NMR (400 MHz, Chloroform-d) 5 7.44 - 7.36 (m, 2H), 7.23 (t, J = 6.9 Hz, 4H), 7.23 - 7.11 (m, 2H), 3.79 (t, J = 4.4 Hz, 4H), 3.16 (t, J = 4.4 Hz, 4H), 2.42 (s, 6H), 0.91 - 0.85 (m, IH). MS(ESI): 162.0 [M+H]+. l,5-dimethyl-4-[2-methyl-4-(4-methylimidazol-l-yl)phenyl]sulfonyl-3H-quinoxalin-2- one (Broad_P_CaV3.3_406, Compound 62)

[0844] To a stirred solution of ethyl 2-[2-methyl-6-(methylamino)-N-[2-methyl-4-(4- methylimidazol-l-yl)phenyl]sulfonyl-anilino]acetate (150 mg, 0.260 mmol, 1.00 eq) in THF (1 mL), Methanol (1 mL) and Water (0.5 mL) was added Lithium hydroxide monohydrate (44 mg, 1.04 mmol, 4.00 eq) and allowed to stir at RT for 16 h. After completion, the reaction mixture was acidified with IN HC1 solution (pH=2) and evaporatred; followed by azeotrop wash by methanol. The residue was suspended in methanol (3 mL) and filtered through buchner funnel and dried under vaccum. To the resultant solid (50 mg) was added water (3 mL) and stirred at RT for 16h. After 16h, the reaction mixture was filtered through buchner funnel and dried under vacuum to provide Broad_P_CaV3.3_406, (5.0 mg, 0.0120 mmol, 5% yield) as an off white solid.

[0845] 1H NMR (400 MHz, DMSO-d6) 5 8.32 (s, 1H), 7.71 - 7.52 (m, 4H), 7.34 (t, J = 7.8 Hz, 1H), 7.13 (d, J = 7.6 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 4.44 - 4.26 (m, 2H), 2.55 (s, 3H), 2.49 (s,

[0846] 3H), 2.16 (s, 3H), 1.96 (s, 3H). MS(ES): 411.6 [M+H]+. ethyl 2-[2-methyl-6-(methylamino)-N-[2-methyl-4-(4-methylimidazol-l-yl)phenyl]sulfonyl- anilino]acetate

[0847]

[0848] To a stirred solution of ethyl 2-(2-amino-6-methyl-N-[2-methyl-4-(4-methylimidazol- l-yl)phenyl]sulfonyl-anilino)acetate (400 mg, 0.820 mmol, 1.00 eq) and Paraformaldehyde (25 mg, 0.820 mmol, 1.00 eq) in methanol was added Aceic acid (4.9 mg, 0.0820 mmol, 0.100 eq) and stirred at RT for 3h. After 3h, Sodium cyanoborohydride (103 mg, 1.64 mmol,

[0849] 2.00 eq) was added and allowed to stir at RT for 16 h. After completion, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organics were dried over Na2SC>4 and evaporated. The residue was purified by combi-flash using Ethyl acetate: Hexanes (1 :3) to provide Int-824D, (150 mg, 0.260 mmol, 32% yield) as a yellow semi-solid. MS(ESI): 457.2 [M+H]+. ethyl 2-(2-amino-6-methyl-N-[2-methyl-4-(4-methylimidazol-l-yl)phenyl]sulfonyl- anilino)acetate

[0850] To a stirred solution of ethyl 2-[2-(tert-butoxycarbonylamino)-6-methyl-N-[2-methyl- 4-(4-methylimidazol-l-yl)phenyl]sulfonyl-anilino]acetate (1.15 g, 2.12 mmol, 1.00 eq) in DCM (10 mL) was added 4M HC1 in dioxane (4 M in , 5.3 mL, 21.2 mmol, 10.0 eq) at 0°C. The reaction mixture was warmed at 25 °Cand stirred for 8 h. After completion, the reaction solvent was concentrated under vaccuo, and the residue washed with stirred with n-hexane (30 mL) and the free solid was filtered and washed with n-hexane (2 x 20 mL). The solid was dried under vacuum to provide Broad_P_Cav3.3_406_Int-822E, (0.81 g, 1.66 mmol, 78% yield) as a hydrochloride salt of an off white solid.

[0851] 1H NMR (400 MHz, DMSO-d6) 5 8.33 (s, 1H), 7.89 (d, J = 9.3 Hz, 1H), 7.68 (dt, J = 4.3, 2.2 Hz, 2H), 7.60 (s, 1H), 6.91 (t, J = 7.7 Hz, 1H), 6.49 (d, J = 8.1 Hz, 1H), 6.33 (d, J = 7.4 Hz, 1H), 5.24 (s, 2H), 4.60 (d, J = 18.0 Hz, 1H), 4.20 - 4.07 (m, 3H), 2.17 (d, J = 7.7 Hz, 6H), 1.84 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H). MS (ESI): 443.4 [M+H]+. ethyl 2-[2-(tert-butoxycarbonylamino)-6-methyl-N-[2-methyl-4-(4-methylimidazol-l- yl)phenyl]sulfonyl-anilino]acetate

[0852] To a stirred solution of tert-butyl N-[3-methyl-2-[[2-methyl-4-(4-methylimidazol-l- yl)phenyl]sulfonylamino]phenyl]carbamate (2.00 g, 4.12 mmol, 1.00 eq), was added ethyl 2- bromoacetate (.55 mL, 4.94 mmol, 1.20 eq) and Potassium carbonate (1.70 g, 12.4 mmol, 3.00 eq) in DMF (20 mL) at room temperature. The raction mixture was stirred at 30 °C for 2h. After completion, the reaction mixture was quenched with ice-water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with brine solution (3 x 30 mL), dried over Na2SC>4 and evaporated. The residue was purified by combi- flash column chromatography and was eluted with 1.2% MeOH in DCM as a gradient to provide Broad_P_Cav3.3_406_Int-822D, (1.80 g, 3.32 mmol, 81% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) 5 8.62 (s, 1H), 8.01-7.80 (m, 3H), 7.26-7.14 (m, 3H), 7.06 (s, 1H), 6.84 (d, J = 7.6 Hz, 1H), 4.96 (d, J = 18.2 Hz, 1H), 4.29 (dh, J = 11.1, 3.8 Hz, 2H), 3.75 (d, J = 18.1 Hz, 1H), 2.30 (s, 3H), 2.24 (s, 3H), 2.06 (s, 3H), 1.38 (s, 9H), 1.32 (t, J = 7.0 Hz, 3H). MS (ESI): 543.3 [M+H]+. tert-butyl N-[3-methyl-2-[[2-methyl-4-(4-methylimidazol-l- yl)phenyl]sulfonylamino]phenyl]carbamate

[0853] To a stirred solution of tert-butyl N-[2-[(4-bromo-2-methyl-phenyl)sulfonylamino]-3- methyl-phenyl]carbamate (14.00 g, 27.1 mmol, 1.00 eq), 4-methyl-lH-imidazole (4.45 g, 54.2 mmol, 2.00 eq) in 1,4-Dioxane (100 mL) under nitrogen atmosphere at room temperature, was added Potassium phosphate tribasic (11.51 g, 54.2 mmol, 2.00 eq), tBuXPhos (2.30 g, 5.42 mmol, 0.200 eq) and [Pd2(dba)3] (2.48 g, 2.71 mmol, 0.100 eq) at same temperature. The reaction mixture was heated at 120 °C under microwave irradiation for 2 h. After completion, the reaction mixture was quenched in water (200 mL) and extracted with EtOAc (3 x 100 mL). The combined organics were washed with brine solution (3 x 50 mL), dried over Na2SC>4 and evaporated. The residue was purified by flash column chromatography and was eluted with 1.5% MeOH in DCM as a gradient to provide Broad_P_Cav3.3_406_Int-822C, (2.00 g, 4.12 mmol, 15% yield) as an off white solid. MS (ESI): 457.2 [M+H]+. tert-butyl N-[2-[(4-bromo-2-methyl-phenyl)sulfonylamino]-3-methyl-phenyl]carbamate

[0854] To a stirred solution of tert-butyl N-(2-amino-3-methyl-phenyl)carbamate (9.34 g, 42.0 mmol, 1.20 eq) and Pyridine (8.47 mL, 105 mmol, 3.00 eq) in DCM (100 mL) was added 4-bromo-2-methyl-benzenesulfonyl chloride (9.44 g, 35.0 mmol, 1.00 eq) at room temperature. The reaction mixture was stirred at 30 °C for 16 h. After completion, the reaction mixture was quenched with 10% citric acid solution (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layer was washed with brine solution (3 * 100 mL), dried over Na2SC>4 and evaporated. The crude product was purified by silica gel column chromatography using 20% EtOAc in n-hexane as a gradient to provide Broad_P_Cav3.3_406_Int-536, (14.00 g, 27.1 mmol, 88.2% purity, 77% yield) as an off white solid. MS (ESI) : 455.5 [M-H]-.

[0855] 4-bromo-2-methyl-benzenesulfonyl chloride

[0856] To a stirred solution of l-bromo-3-methyl-benzene (30.00 g, 175 mmol, 1.00 eq) in Chloroform (300 mL) was slowly added Chlorosulfuric acid (58.4 mL, 877 mmol, 5.00 eq) at 0°C. The reaction mixture was stirred at 30 °C for lOh. After completion, the reaction mixture was quenched carefully in ice water (1000 mL) and extracted with DCM (3 x 500 mL). The combined organics were washed with brine solution (3 x 200 mL), dried over Na2SC>4 and evaporated to provide Broad_P_Cav3.3_406_Int-535, (35.00 g, 130 mmol, 74% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) 5 7.92 (d, J = 8.5 Hz, 1H), 7.60 (s, 1H), 7.56 (dd, J = 8.6,

[0857] 2.1 Hz, 1H), 2.77 (s, 3H).

[0858] Synthesis of Compound 63 and 135 and enantiomers thereof (Broad_P_CaV3.3_500, 501, 502 and 503)

[0859] 2,3,5-trimethylquinoxaline: Intermediate-997B To a solution of 3 -methylbenzene- 1,2-diamine (3.00 g, 24.6 mmol, 1.00 eq) and 3- chlorobutan-2-one (3.14 g, 29.5 mmol, 1.20 eq) in methanol (30 mL) was added CH3COONa (3.02 g, 36.8 mmol, 1.50 eq) and reaction mixture was allowed to stir at room temperature. After completion, water was added and product was extracted by ethyl acetate (3 ^ 50 mL). Combined organic layer was washed with water, brine, dried over anhydrous sodium sulphate and evaporated to give crude product, which was further purified by column chromatography using silica gel. Desired product was eluted out in 20% ethyl acetate in hexanes to provide Int-997B, (2.45 g, 13.5 mmol, 55% yield) as a solid compound.

[0860] MS: [M+H]+173.0

[0861] 1H NMR (400 MHz, DMSO-d6) 5 7.87 - 7.75 (m, 1H), 7.59 - 7.46 (m, 2H), 2.78 (s, 3H), 2.74 (d, J = 6.5 Hz, 6H).

[0862] 2,3,5-trimethyl-l,2,3,4-tetrahydroquinoxaline: Intermediate...

Claims

1. CLAIMSWhat is claimed is:

1. A compound having the structure of formula (I):wherein the dotted circle represents an optionally unsaturated 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, -C(O)OR, -C(O)R, haloalkyl, hydroxy, or amino; and two RAI may together form =0 or a three to six membered spiro ring;RA2 is independently at each occurrence hydrogen, alkyl; wherein any two geminal RA2 groups may together form =0 or a three to six membered spiro ring;RA3 is independently at each occurrence hydrogen, alkyl, alkoxy, cyano, -C(0)0R, -C(0)R, or halogen;RLis -S(=O)2-, -S(=O)-,-S(=NR)(=O)-, or -C(R)(R)-;XBI is 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, optionally unsaturated alkyl, halogen, and -Rc;RB2 is independently selected at each occurrence from hydrogen, optionally unsaturated alkyl, halogen, and -Rc; 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;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, -C(O)R, -C(O)NRR, halogen, haloalkyl, or cycloalkyl; or may together with an R group form oxo (=0); andR is independently at each occurrence hydrogen or alkyl; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein Rc has the structure:wherein Rci is hydrogen, alkyl, halogen, haloalkyl, or cycloalkyl.

3. The compound according to claims 1 or 2, wherein Rc has the structure:wherein Rci is hydrogen, alkyl, halogen, haloalkyl, cycloalkyl.

4. The compound according to any one of claims 1-3, wherein Rci is hydrogen or lower alkyl, cycloalkyl, or haloalkyl.

5. The compound according to any one of claims 1-4, wherein said compound has the structure of formula (II):or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 5, wherein said compound has the structure of formula (Ila):

7. The compound according to claim 5 or 6, wherein said compound has the structure formula (lib), (lie), (lid), or (lie):The compound according to any one of claims 1-7, wherein said compound is:Compound 71Compound 69Compound 99 Compound 104 Compound 122or enantiomers or diastereomers thereof, mixtures of enantiomers or diastereomers, or racemic mixtures thereof.

9. The compound according to any one of claims 1-7, wherein said compound is:Compound 22 Compound 34 Compound 57 Compound 71Compound 74 Compound 77 Compound 82 Compound 92Compound 133 Compound 144 Compound 208or enantiomers or diastereomers thereof, mixtures of enantiomers or diastereomers, or racemic mixtures thereof.

10. The compound according to any one of claims 1-7, wherein said compound is:or enantiomers or diastereomers thereof, mixtures of enantiomers or diastereomers, or racemic mixtures thereof.

11. The compound according to claim 6, wherein said compound has the structure of formula (Ilf) or (Ilg):

12. The compound according to any one of claims 1-6 and 11, wherein said compound is:Compound 6713. The compound according to claim 11, wherein said compound is Compound 25 having the structure:Compound2514. The compound according to claim 5, wherein said compound has the structure of formula (Ilh):

15. The compound according to claim 14, wherein said compound has the structure of formula (Hi) or (Ilj):or enantiomers or diastereomers thereof, mixtures of enantiomers or diastereomers, or racemic mixtures thereof.

16. The compound according to any one of claims 1-5, and 14-15, wherein said compound is:or enantiomers or diastereomers thereof, mixtures of enantiomers or diastereomers, or racemic mixtures thereof.

17. The compound according to any one of claims 1-5, and 14-15, wherein said compound is Compound 7:Compound 718. The compound according to any one of claims 1-4, wherein said compound has the structure of formula (III):

19. The compound according to claim 18, wherein said compound has the structure of formula (Illa):

20. The compound according to claim 18 or 19, wherein said compound has the structure of formula (Illb), (IIIc), (Hid), or (Ille):

21. The compound according to any one of claims 1-4 and 19-20, wherein said compound is:Compound 87 Compound 93 Compound 97 Compound 103Compound 105 Compound 110 Compound 111 Compound 112Compound 128 Comopund l31 Compound 137 Compound 147Compound 157 Compound 163 Compound 164 Compound 168Compound 189 Compound 190 Compound 192 Compound 196Compound 197 Compound 199 Compound 203 Compound 205Compound 212 Compound 213 Compound 214 Compound 216Compound 217 Compound 221 Compound 222 Compound 225Compound 250 Compound 251 Compound 252 Compound 253or enantiomers or diastereomers thereof, mixtures of enantiomers or diastereomers, or racemic mixtures thereof.

22. The compound according to any one of claims 1-4 and 19-20, wherein said compound23. The compound according to claim 1 having the structure of formula (IV):wherein each dotted circle independently indicates optional unsaturation;X is N, C, or CR3;Y is =N- -N=,-N(R9)-, -(C(R7)(R8) , =C(R7) -C(R7)=, -N(R9)C(R7)(R8)-, -C(R7)(R8)N(R9)-, -N(R9)C(R7)=, =C(R7)N(R9)-, -C(R7)=C(R8)-, -N=C(R8) -C(R7) =N-; p is 1, 2, or 3;Z is N, C, or CRe; and R4 and Re may together form =0;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;R2-R6 are independently hydrogen or alkyl;R7-R9 are independently at each occurrence hydrogen or alkyl; or pharmaceutically acceptable salts thereof or prodrugs of any of the foregoing.

24. The compound according to claim 23, wherein said compound has the structure of Formula (IVa):wherein n is 1 or 2.

25. The compound according to claim 23 or 24, wherein said compound is:Compound 7 Compound 25 Compound 131 Compound 18126. The compound according to claim 23, wherein said compound has the structure of Formula (IVb):wherein Y is N, CH, or CRio; andRio is hydrogen or alkyl.

27. The compound according to claim 23 or 26, wherein said compound is:Compound 22 Compound 34 Compound 57 Compound 71Compound 74 Compound 77 Compound 82 Compound 92ing to claim 23 or 26, wherein said compound is:

29. The compound according to any one of claims 23-26, wherein R2 is alkyl.

30. A compound having the structure of formula (V):RDI is hydrogen, alkyl, haloalkyl, mono or bicyclic heterocyclyl, mono or bicyclic heteroaryl, or aryl (and RDI may be optionally substituted and any two vicinal substituents may optionally form a five or six membered ring);RD2 is hydrogen or alkyl;XBI is independently at each occurrence N or CRBI;RBI is independently selected at each occurrence from hydrogen, alkyl, and -Rc;RB2 is independently selected at each occurrence from hydrogen, optionally unsaturated alkyl, and -Rc; and at least one of RBI or RB2, is a group -Rc having the structure:wherein 2 indicates the point of attachment to the compound and the dotted circle indicates optional aromaticity;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; andRci, RC2, RC3, RC4, and Res are independently hydrogen, alkyl, -C(O)R, -C(O)NRR, halogen, haloalkyl, or cycloalkyl; or may together with a geminal R group form oxo (=0); andR is independently at each occurrence hydrogen or optionally unsaturated alkyl; or a pharmaceutically acceptable salt thereof.

31. The compound according to claim 30, wherein 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.

32. The compound according to claim 30 or 31, wherein 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.

33. The compound according to any one of claims 30-32, wherein RD2 is hydrogen or lower alkyl optionally substituted with alkoxy or -NRR.

34. The compound according to any one of claims 30-33, wherein RB2 is selected from hydrogen or optionally unsaturated alkyl.

35. The compound according to any one of claims 30-34, wherein Xci is absent.

36. The compound according to any one of claims 30-35, wherein Rc has the structure:wherein Rci is hydrogen, or alkyl.

37. The compound according to any one of claims 30-36, wherein said compound has the structure of formula (Va) or (Vb):

38. The compound according to any one of claims 30-37, wherein said compound has the structure of formula (Vc) or (Vd):

39. The compound according to any one of claims 30-37, wherein said compound has the structure of formula (Ve), (Vf), (Vg), V(h), V(i) or (Vj):

40. The compound according to any one of claims 30-39, wherein said compound is selected from:Compound 194Compound 22841. The compound according to any one of claims 1-40, wherein said compound is a Cav3.3 potentiator having an ECso of less than 100 pM.

42. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound according to any one of claims 1-41, or a pharmaceutically acceptable salt thereof, or a prodrug of any of the foregoing.

43. A method of increasing sleep spindles or rescuing sleep spindle deficits in a subject in need thereof comprising administering to said subject a Cav3.3 potentiator.

44. A method of increasing sleep spindles or rescuing sleep spindle deficits in a subject in need thereof comprising administering to said subject a Cav3.3 potentiator, wherein said Cav3.3 potentiator is the compound according to any one of claims 1-41, or a pharmaceutically acceptable salt thereof, or a prodrug of any of the foregoing.

45. A method of increasing rebound bursting and optionally restore spindle deficits in the reticular thalamus (TRN) of a subject in need thereof comprising administering to said subject a Cav3.3 potentiator.

46. A method of increasing rebound bursting in the reticular thalamus (TRN) a subject in need thereof comprising administering to said subject a Cav3.3 potentiator, wherein said Cav3.3 potentiator is the compound according to any one of claims 1-41, or a pharmaceutically acceptable salt thereof, or a prodrug of any of the foregoing.

47. A method of decreasing thalamocortical hyperactivity and / or increasing thalmocoritical hypoactivity in a subject in need thereof comprising administering to said subject a Cav3.3 potentiator.

48. A method of decreasing thalamocortical hyperactivity in a subject in need thereof comprising administering to said subject a Cav3.3 potentiator wherein said Cav3.3 potentiator is the compound according to any one of claims 1-41, or a pharmaceutically acceptable salt thereof, or a prodrug of any of the foregoing.

49. The method of any one of claims claim 43-46, wherein the subject is a human.

50. The method of any one of claims 43-49, wherein said subject has schizophrenia.

51. A method for the treatment or prophylaxis of schizophrenia, or a disease, disorder, or condition associated therewith in a subject in need thereof comprising administering to said subject a Cav3.3 potentiator.

52. A method for the treatment or prophylaxis of schizophrenia, or a disease, disorder, or condition associated therewith in a subject in need thereof comprising administering to said subject a Cav3.3 potentiator, wherein said Cav3.3 potentiator is the compound according to any one of claims 1-41, or a pharmaceutically acceptable salt thereof, or a prodrug of any of the foregoing.

53. A method for the treatment or prophylaxis of a neurodevel opmental disoder or condition associated therewith in a subject in need thereof comprising administering to said subject a Cav3.3 potentiator.

54. A method for the treatment or prophylaxis of a neurodevelopmental disoder or condition associated therewith in a subject in need thereof comprising administering to said subject a Cav3.3 potentiator, wherein said Cav3.3 potentiator is the compound according to any one of claims 1-41, or a pharmaceutically acceptable salt thereof, or a prodrug of any of the foregoing.

55. The method according to claim 53 or 54, wherein said neurodevelopmental disorder is Alzheimer’s Disease.

56. The method according to any one of claims 53-55, wherein said administering rescues cognitive and / or motor deficiences associated with said neurodevelopmental disorder.

57. A method for the treatment or prophylaxis of 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.

58. A method for the treatment or prophylaxis of of 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, wherein said Cav3.3 potentiator is the compound according to any one of claims 1-41, or a pharmaceutically acceptable salt thereof, or a prodrug of any of the foregoing.

59. The method according to any one of claims 43-58, wherein said subject has altered sleep spindle activity as compared to a a control subject that does not have TRN hypofunction.

60. A method of improving cognitive function in a subject in need thereof comprising administering a Cav3.3 potentiator to the subject.

61. A method of improving cognitive function in a subject in need thereof comprising adminstration of a Cav3.3 potentiator to the subject, wherein the Cav3.3 potentiator is the compound according to any one of claims 1-41, or a pharmaceutically acceptable salt thereof, or a prodrug of any of the foregoing.

62. The method according to claim 60 or 61, wherein said subject has a brain dysfunction.

63. The method according to claim 62, wherein said brain dysfunction is caused by cerebrovascular disease, brain damage, brain tumor, viral encephalitis, hypoxic encephalopathy, or alcoholism.

64. The method according to claim 60 or 61, wherein said subject has a cognitive dysfunction.

65. The method according to claim 64, wherein said cognitive dysfunction is selected from dysmnesia, attentional deficit, executive function deficit, social behavior disorder, neurogedegenerative disease, mental disease, or pervasive developmental disorder.

66. The method according to any one of claims 43-65, wherein said subject has a Cav3.3 mutation.

67. The method according to claim 66, wherein said subject is human and the Cav3.3 mutation is an R1346H mutation or said subject is murine and said the CaV3.3 mutation is and R1305H mutation.

68. The method according to claim 66 or 67, wherein said Cav3.3 mutation is homozygous.

69. A method of increasing TRN rebound bursting in a neuron comprising contacting the neuron with a Cav3.3 potentiator.

70. A method of increasing TRN rebound bursting in a neuron comprising contacting the neuron with a Cav3.3 potentiator, wherein said Cav3.3 potentiator is the compound according to any one of claims 1-41, or a pharmaceutically acceptable salt thereof, or a prodrug of any of the foregoing.

71. A method for producing the compound of Formula (I) according to any one of claims 1-29 comprising: reacting a compound having the structure of Fomula (V)with a compound having the structure of Formula (VI):Reawherein ZBI is independently selected at each occurrence from hydrogen, optionally unsaturated alkyl, halogen, and -Zi, and at least one ZBI is a coupling group Zi; and Z2 is a coupling group for coupling with Zi.

72. A method of monitoring target engagement and / or treatment efficacy 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.

73. The method according to claim 63, wherein the compound is a Cav3.3 potentiator.

74. The method according to claim 64, wherein the Cav3.3 potentiator is the compound according to any one of claims 1-41, or a pharmaceutically acceptable salt thereof, or a prodrug of any of the foregoing.

75. The method according to any one of claims 72-74, wherein the sleep spindle density is the density of slow sleep spindles.

76. The method according to any one of claims 72-74, wherein the sleep spindle density is the density of fast sleep spindles.

77. The method according to any one of claims 72-76, wherein the subject has autism spectrum disorder (ASD), schizophrenia, attention deficit hyperactivity disorder (ADHD), schizoaffective disorder, bipolar affective disorder, or Alzheimer’s Disease.

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