T-TYPE VOLTAGE-GATED CALCIUM CHANNEL POTENTIATORS

CROSS REFERENCE TO RELATED APPLICATIONS

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.

STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH

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.

BACKGROUND

Voltage-gated calcium channels (VGCC) provide the primary pathway for calcium (Ca ²⁺ ) ions to enter excitable cells by allowing rapid and selective Ca ²⁺ entry upon membrane depolarization. By transducing natural voltage transients, such as action potentials, into intracellular Ca ²⁺ transients, voltage-gated Ca ²⁺ channels not only contribute to active membrane properties such as Ca ²⁺ spikes and dendritic information integration, but also underlie many cellular functions including neurotransmitter release, neurite outgrowth, cell survival, hormone release, and gene expression.

The functional core of the VGCC is comprised of the Cavai subunit, which contains the ion pore, gating mechanism, toxin-binding domains, and consists of four homologous transmembrane domains (I-IV), cytoplasmic amino- and carboxyl- termini, and intracellular loops connecting each transmembrane domain. 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).

Cav3 channels are also called T-type calcium channels (T for transient) because they inactivate rapidly. Cav3 T-type channels do not interact with the auxiliary P subunit, and their biophysical properties can be fully reconstituted with the ai subunit alone in heterologous expression system, whereas Cavl or Cav2 Ca ²⁺ channel ai subunits (Cavl/2) require coexpression of auxiliary P subunits facilitate channel trafficking to the membrane surface for expression. Cav3 T-type currents inactivate and activate at much negative potentials compared to Cavl/2 channels and have a smaller single channel conductance of 8-12 pS in 100 mM Ba ²⁺ . In addition, Cav3 T-type Ca ²⁺ channels have overlapping voltage dependent activation and inactivation curves, displaying “window currents” where a large fraction of the channels is inactivated but a small fraction of the channels remain constitutively open at physiological resting membrane potentials. Cav3 T-type channels also close slower from the open states compared to Cavl/2 families, allowing large amounts of Ca ²⁺ influx upon repolarization to trigger membrane depolarization. These unique biophysical properties of the T-type Ca ²⁺ channels produce Ca ²⁺ influx during repolarizations that underlie the rhythmic rebound firing of thalamic neurons in the brain.

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.

Several clinical drugs have been found to block T-type Ca ²⁺ 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.

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.

SUMMARY

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.

The Cav3.3 potentiators of the present disclosure comprise a compound having the structure of formula (I): wherein the dotted circle represents an optionally unsaturated e.g., aromatic) ring; p is 0 or 1; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4;

XAI is N, O, or C;

XA2 is N or C;

XA3 is N or CRAS;

RAI is independently at each occurence absent, hydrogen, alkyl (e.g., optionally unsaturated Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3), -C(O)OR, -C(O)R, haloalkyl (e.g., Ci-Cs haloalkyl, lower haloalkyl such as C1-C4 haloalkyl, halomethyl, Ci-Cs fluoroalkyl, lower fluoroalkyl such as C1-C4 fluoroalkyl, fluorom ethyl, difluoromethyl, perfluoroalkyl, Ci-Cs perfluoroalkyl, lower perfluoroalkyl such as C1-C4 perfluoroalkyl, perfluoromethyl), hydroxy, or amino (e.g., - NRR); and two RAI 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;

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;

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;

R ^L is -S(=0) ₂ -, -S(=0)-, -S(=NR)(=O)-, or -C(R)(R)-;

XBI is N, S, or CRBI, and one XBI may be absent (e.g., the two neighboring groups are joined by the bond such as a single or double bond to optionally preserve aromaticity);

XB2 is independently at each occurrence N, or CRB2;

RBI is independently selected at each occurrence from hydrogen, alkyl (e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as - CD3,), haloalkyl (e.g., Ci-Cs haloalkyl, lower haloalkyl such as C1-C4 haloalkyl, halomethyl, Ci-Cs fluoroalkyl, lower fluoroalkyl such as C1-C4 fluoroalkyl, fluoromethyl, difluoromethyl, perfluoroalkyl, Ci-Cs perfluoroalkyl, lower perfluoroalkyl such as C1-C4 perfluoroalkyl, perfluoromethyl), halogen (e.g., F, Cl, Br), and -Rc; wherein RBI may independently at each occurence have one or more (e.g., two, three, four) points of optional substititution;

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;

XC6 is C, CH, CR, or N;

Xci, Xc2, Xc3, Xc4, and Xcs are independently CH, CR, N, NH, NR, O, or S; and when the group is a five membered ring, Xcs is absent; and

Rci, RC2, RC3, RC4, and Res are independently hydrogen, alkyl (e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3,), -C(O)R, -C(O)NRR, halogen (e.g., F, Cl, Br), haloalkyl haloalkyl (e.g., Ci-Cs haloalkyl, lower haloalkyl such as C1-C4 haloalkyl, halomethyl, Ci-Cs fluoroalkyl, lower fluoroalkyl such as C1-C4 fluoroalkyl, fluoromethyl, difluoromethyl, perfluoroalkyl, Ci-Cs perfluoroalkyl, lower perfluoroalkyl such as C1-C4 perfluoroalkyl, perfluoromethyl), 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

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 R ^L is -S(=NR)(=0)-) may be hydrogen or lower alkyl (e.g., C1-C4 alkyl) such as methyl.

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);

R _D2 is hydrogen or alkyl (e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3) and RD2 may have one or more (e.g., two, three, four) optional points of substitution;

XBI is independently at each occurrence N or CRBI;

RBI is independently selected at each occurrence from hydrogen, alkyl (e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as - CD3), and -Rc and RBI may have one or more (e.g., two, three, four) optional points of substitution;

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:

_Z V wherein 7 indicates the point of attachment to the compound and the dotted circle indicates optional aromaticity;

XC ₆ is C, CH, CR, or N;

Xci, Xc2, Xc3, Xc4, and Xcs are independently CH, CR, N, NH, NR, O, or S; and when the group is a five membered ring, Xcs is absent; and

Rci, RC2, RC3, RC4, and Res are independently hydrogen, alkyl (e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3), -C(O)R, -C(O)NRR, halogen (e.g., F, Cl, O), haloalkyl (e.g., Ci-Cs haloalkyl, lower haloalkyl such as C1-C4 haloalkyl, halomethyl, Ci-Cs fluoroalkyl, lower fluoroalkyl such as C1-C4 fluoroalkyl, fluoromethyl, difluoromethyl, perfluoroalkyl, Ci-Cs perfluoroalkyl, lower perfluoroalkyl such as C1-C4 perfluoroalkyl, perfluoromethyl), or 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.

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.

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.

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).

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.

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).

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.

Definitions

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.

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.

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%.

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.

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

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

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.

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).

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.

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).

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.

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.

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.

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.

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.

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).

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.

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:

1 maesasppss saaapaaepg vtteqpgprs ppssppglee pldgadphvp hpdlapiaf f

61 clrqttsprn wcikmvcnpw f ecvsmlvil Incvtlgmyq pcddmdclsd rckilqvf dd

121 f if if f amem vlkmvalgif gkkcylgdtw nrldf f ivma gmveysldlq ninlsairtv

181 rvlrplkain rvpsmrilvn llldtlpmlg nvlllcf fvf f ifgiigvql wagllrnrcf

241 leenf tiqgd valppyyqpe eddempf ics Isgdngimgc heipplkeqg recclskddv

301 ydfgagrqdl nasglcvnwn ryynvcrtgs anphkgainf dnigyawivi f qvitlegwv

361 eimyyvmdah sfynf iyf il liivgsf fmi nlclvviatq f setkqrehr Imleqrqryl

421 ssstvasyae pgdcyeeif q yvchilrkak rralglyqal qsrrqalgpe apapakpgph

481 akeprhyhgk tkgqgdegrh Igsrhcqtlh gpaspgndhs grelcpqhsp Idatphtlvq

541 pipatlasdp ascpccqhed grrpsglgst dsgqegsgsg ssaggedead gdgarssedg

601 asselgkeee eeeqadgavw Icgdvwretr aklrgivdsk yfnrgimmai Ivntvsmgie

661 hheqpeeltn ileicnvvf t smf alemilk laafglf dyl rnpynif dsi iviisiweiv

721 gqadgglsvl rtf rllrvlk Ivrfmpalrr qlvvlmktmd nvatf cmllm If if if silg

781 mhifgckf si rtdtgdtvpd rknf dsllwa ivtvf qiltq edwnvvlyng mastspwasl

841 yfvalmtfgn yvlfnllvai Ivegf qaegd anrsysdedq sssnieef dk Iqegldssgd

901 pklcpipmtp nghldpslpl gghlgpagaa gpaprlslqp dpmlvalgsr kssvmslgrm

961 sydqrslsss rssyygpwgr saawasrrss wnslkhkpps aehesllsae rgggarvcev

1021 aadegppraa plhtphahhi hhgphlahrh rhhrrtlsld nrdsvdlael vpavgahpra

1081 awraagpapg hedcngrmps iakdvf tkmg drgdrgedee eidytlcf rv rkmidvykpd

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

1201 rif Itvsnyi f taifvgemt Ikvvslglyf geqaylrssw nvldgf Ivfv siidivvsla

1261 saggakilgv Irvlrllrtl rplrvisrap glklvvetli sslkpigniv liccaf f iif

1321 gilgvqlf kg kfyhclgvdt rnitnrsdcm aanyrwvhhk ynf dnlgqal mslfvlaskd

1381 gwvnimyngl davavdqqpv tnhnpwmlly f isf llivsf fvlnmfvgvv venf hkcrqh

1441 qeaeearrre ekrlrrlekk rrkaqrlpyy atychtrlli hsmctshyld if itf iicln

1501 vvtmslehyn qptsletalk ycnymf ttvf vleavlklva fglrrf f kdr wnqldlaivl

1561 Isvmgitlee ieinaalpin ptiirimrvl riarvlkllk matgmralld tvvqalpqvg

1621 nlgllfmllf f iyaalgvel fgklvcnden pcegmsrhat f enfgmaf It If qvstgdnw

1681 ngimkdtlrd cthderscls slqfvsplyf vsfvltaqfv linvvvavlm khlddsnkea

1741 qedaemdael elemahglgp gprlptgspg apgrgpggag gggdtegglc rrcyspaqen

1801 Iwldsvslii kdslegelti idnlsgsif h hysspagckk chhdkqevql aeteaf sins

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

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:

1 madsnlppss saapdpepgi teqpgprspp psppgleepl dgtnpdvphp dlapvaffcl

61 rqttsprnwc ikmvcnpwfe cvsmlvilln cvtlgmyqpc ddmeclsdrc kilqvfddfi

121 fiffamemvl kmvalgifgk kcylgdtwnr Idffivmagm veysldlqni nlsairtvrv

181 Irplkainrv psmrilvnll Idtlpmlgnv lllcffvffi fgiigvqlwa gllrnrcfle

241 enftiqgdva Ippyyqpeed dempficsls gdngimgche ipplkeqgre cclskddmyd

301 fgagrqdlna sglcvnwnry ynvcrtgnan phkgainfdn igyawivifq vitlegwvei

361 myyvmdahsf ynfiyfilli ivgsffminl clvviatqfs etkqrehrlm leqrqrylss

421 stvasyaepg dcyeeifqyv chilrkakrr alglyqalqn rrqatgpgtp apakpgphak

481 epshcklcpr hspldttpht Ivqpisaila sdpsscprcq heagrrpsgl gstdsgqegs

541 gsggsaeaea ngdgpqssed gvssglgkee eqedgaarlc gdvwretrak Irgivdskyf

601 nrgimmailv ntvsmgiehh eqpeeltnil eicnwftsm falemilkla afglfdylrn

661 pynifdsiiv iisiweivgq adgglsvlrt frllrvlklv rfmpalrrql vvlmktmdnv

721 atfcmllmlf ififsilgmh ifgckfslrt dtgdtvpdrk nfdsllwaiv tvfqiltqed

781 wnvvlyngma sttpwaslyf valmtfgnyv Ifnllvailv egfqaegdan rsysdedqss

841 snleeldklp egldssrdlk Icpipmtpng hldpslplgg hlgpagamga aprlslqpdp

901 vlvalesrks svmslgrmsy dqrslsssrs syygpwgrsg twasrrsswn slkhkppsae

961 hesllsgerg gscvracega redappraap lhaphthhah hgphlahrhr hhrrtlsldt

1021 rdsvdlaelv pvvgahsraa wraagqapgh edcngrmpni akdvftkmdd rrdrgedeee

1081 idytlcfrvr kmidvykpdw cevredwsvy Ifspenkfri Icqtiiahkl fdyvvlafif

1141 Incitialer pqieagster ifltvsnyif taifvgemtl kvvslglyfg eqaylrsswn

1201 vldgflvfvs iidivvsvas aggakilgvl rvlrllrtlr plrvisrapg Iklvvetlis

1261 slkpignivl iccaffiifg ilgvqlfkgk fyhclgvdtr nitnrsdcva anyrwvhhky

1321 nfdnlgqalm slfvlaskdg wvnimyngld avavdqqpvt nhnpwmllyf isfllivsff

1381 vlnmfvgwv enfhkcrqhq eaeearrree krlrrlekkr rkaqrlpyya tycptrllih

1441 smctshyldi fitfiiclnv vtmslehynq ptsletalky cnymfttvfv leavlklvaf

1501 glrrffkdrw nqldlaivll svmgitleei einaalpinp tiirimrvlr iarvlkllkm

1561 atgmralldt vvqalpqvgn Igllfmllff iyaalgvelf gklvcndenp cegmsrhatf

1621 enfgmafltl fqvstgdnwn gimkdtlrdc thdersclss Iqfvsplyfv sfvltaqfvl

1681 invvvavlmk hlddsnkeaq edaemdaeie lemahglgpg pgpcpcpcpc pcpcpcpgpr

1741 mptsspgapg rgsggagvgg dteshlcrhc yspaqetlwl dsvsliikds legeltiidn

1801 Isgsifhhys spagcdkchh dkqevqlaet eafslnsdrs ssvllgddls ledptacpqg

1861 pkeskgelep pepmqagdld ecffpfagep vsagpesllc emgaipfnpv qswlkhesnq

1921 appspfspdg sspllqmpae ffhpavsasq kgqepgmssg tlpkialqgs waslrspsvn

1981 ctllrqatvs dtsldaspss sagslqttle dsltlsdspr ralgppvqvp gpraslspat

2041 rrrlslrgrg Ifslrglrah qrshssggst spgctyhdsm dpsdeegrgg aggggagseh

2101 setlsslslt slfclpptlp ppgltparkf sstsslaagp grpgatvsvr glarspswaa

2161 drskdppgqa qlasgfgssa pepqpppges tdaaskrkr

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:

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

3781 tcagccgggg gagccaagat cttgggggtc ctccgagtct tgcggctcct gcgcacccta

3841 cgccccctgc gtgtcatcag ccgggcgccg ggcctgaagc tggtggtgga gacactcatc

3901 tcctccctca agcccatcgg caacatcgtg ctcatctgct gtgccttctt catcatcttt

3961 ggcatcctgg gagtgcagct cttcaagggc aagttctacc actgtctggg cgtggacacc

4021 cgcaacatca ccaaccgctc ggactgcatg gccgccaact accgctgggt ccatcacaaa

4081 tacaacttcg acaacctggg ccaggctctg atgtccctct ttgtcctggc atccaaggat

4141 ggttgggtga acatcatgta caatggactg gatgctgttg ctgtggacca gcagcctgtg

4201 accaaccaca acccctggat gctgctgtac ttcatctcct tcctgctcat cgtcagcttc

4261 tttgtgctca acatgtttgt gggtgtcgtg gtggagaact tccacaagtg ccggcagcac

4321 caggaggctg aagaggcacg gcggcgtgag gagaagcggc tgcggcgcct ggagaagaag

4381 cgccggaagg cccagcggct gccctactat gccacctatt gtcacacccg gctgctcatc

4441 cactccatgt gcaccagcca ctacctggac atcttcatca ccttcatcat ctgcctcaac

4501 gtggtcacca tgtccctgga gcactacaat cagcccacgt ccctggagac agccctcaag

4561 tactgcaact atatgttcac cactgtcttt gtgctggagg ctgtgctgaa gctggtggca

4621 tttggtctga ggcgcttctt caaggaccga tggaaccagc tggacctggc cattgtgcta

4681 ctgtcagtca tgggcatcac cctggaggag atcgagatca atgcggccct gcccatcaat

4741 cccaccatca tccgcatcat gagggttctg cgcattgccc gagtgctgaa gctgttgaag

4801 atggccacag gaatgcgggc cctgctggac acggtggtgc aagctttgcc ccaggtgggc

4861 aacctgggcc tcctcttcat gctgctcttc ttcatctatg ctgctctcgg ggtggagctc

4921 tttgggaagc tggtctgcaa cgacgagaac ccgtgcgagg gcatgagccg gcatgccacc

4981 ttcgagaact tcggcatggc cttcctcaca ctcttccagg tctccacggg tgacaactgg

5041 aacgggatca tgaaggacac gctgcgggac tgcacccacg acgagcgcag ctgcctgagc

5101 agcctgcagt ttgtgtcgcc gctgtacttc gtgagcttcg tgctcaccgc gcagttcgtg

5161 ctcatcaacg tggtggtggc tgtgctcatg aagcacctgg acgacagcaa caaggaggcg

5221 caggaggacg ccgagatgga tgccgagctc gagctggaga tggcccatgg cctgggccct

5281 ggcccgaggc tgcctaccgg ctccccgggc gcccctggcc gagggccggg

5341 ggcgggggcg acaccgaggg cggcttgtgc cggcgctgct actcgcctgc ccaggagaac

5401 ctgtggctgg acagcgtctc tttaatcatc aaggactcct tggaggggga gctgaccatc

5461 atcgacaacc tgtcgggctc catcttccac cactactcct cgcctgccgg ctgcaagaag

5521 tgtcaccacg acaagcaaga ggtgcagctg gctgagacgg aggccttctc cctgaactca

5581 gacaggtcct cgtccatcct gctgggtgac gacctgagtc tcgaggaccc cacagcctgc

5641 ccacctggcc gcaaagacag caagggtgag ctggacccac ctgagcccat gcgtgtggga

5701 gacctgggcg aatgcttctt ccccttgtcc tctacggccg tctcgccgga tccagagaac

5761 ttcctgtgtg agatggagga gatcccattc aaccctgtcc ggtcctggct gaaacatgac

5821 agcagtcaag cacccccaag tcccttctcc ccggatgcct ccagccctct cctgcccatg

5881 ccagccgagt tcttccaccc tgcagtgtct gccagccaga aaggcccaga aaagggcact

5941 ggcactggaa ccctccccaa gattgcgctg cagggctcct gggcatctct gcggtcacca

6001 agggtcaact gtaccctcct ccggcaggcc accgggagcg acacgtcgct ggacgccagc

6061 cccagcagct ccgcgggcag cctgcagacc acgctcgagg acagcctgac cctgagcgac

6121 agcccccggc gtgccctggg gccgcccgcg cctgctccag gaccccgggc cggcctgtcc

6181 cccgccgctc gccgccgcct gagcctgcgc ggccggggcc tcttcagcct gcgggggctg

6241 cgggcgcatc agcgcagcca cagcagcggg ggctccacca gcccgggctg cacccaccac

6301 gactccatgg acccctcgga cgaggagggc cgcggtggcg cgggcggcgg gggcgcgggc

6361 agcgagcact cggagaccct cagcagcctc tcgctcacct ccctcttctg cccgccgccc

6421 ccgccgccag cccccggcct cacgcccgcc aggaagttca gcagcaccag cagcctggcc

6481 gcccccggcc gcccccacgc cgccgccctg gcccacggcc tggcccggag cccctcgtgg

6541 gccgcggacc gcagcaagga cccccccggc cgggcaccgc tgcccatggg cctgggcccc

6601 ttggcgcccc cgccgcaacc gctccccgga gagctggagc cgggagacgc cgccagcaag

6661 aggaagagat gagggtcgca ggggcccccg gccgcccacc gcccgccccg tctcaccttc

6721 tttacctcag gagccaggag cagacagcaa tacttcgtcc acacctggga tcgcgcaggg

6781 cccgcagggc acaggcgccc gacagccggg ctgagcggag tctgggttag ccaggcctgc

6841 gtggcccatg gtggcccttc cagtgcatat acatacatat atatatatat atgcatatat

6901 atatatatat atatatatat gtgtatacac acacacatag acagacatat atatatatat

6961 ttattttttt tactgagagc ttatgacttc cagaaagtgc taaaggtggg aggtgggcca

7021 gggcctggac ggggcttttg tctgatgctc tgggattctg gccagaccca ccccagggca

7081 catgtcctgc gggggcgtcc cagctgtgtt ttttgatgtc tcctccctgg ttaagagtag

7141 cttggagagg accctcaggc ctctgagggc accaggccct ggagaagagg tgcaattcag

7201 ggtgtgtgtg tgtttttttt cctttaaaga agaaacgctg ctaagatccc acgtggctcc

7261 cacgtgtcgg ggtgtctgtc ctgtcatcct gactgtctcg ttattgtgaa gtctttcgta

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

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.

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

FIG. 1 A provides a schematic of the Fluorescence Imaging Plate Reader (FLIPR) high throughput assay for performing potentiation measurements on the T-type calcium channel subunits similar to the assay disclosed in Zhang, Y-L., et al., ACS Pharmacol Transl Sci 5.3 (2022): 156-168, which is hereby incorporated by reference in its entirety and particularly in relation to the FLIPR assay and protocol therefor. FIG. IB provides exemplary EC 10 and EC90 responses to KC1.

FIG. 2 is a schematic of the automated patch-clamp electrophysiology assay which may be used for specific Mechanism of Action measurements and identify differential response in each subunit.

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

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

FIG. 5 A shows ex vivo measurements of rebound bursting of thalamic reticular nucleus (TRN) neurons following administration of Compound 7. FIG. 5B shows ex vivo measurements illustrating the decrease in voltage threshold of rebound bursts following administration of Compound 7.

FIG. 6A shows ex vivo measurements of rebound bursting of thalamic reticular nucleus (TRN) neurons following administration of Compound 131. FIG. 6B shows ex vivo measurements illustrating the decrease in voltage threshold of rebound bursts following administration of Compound 131.

FIG. 7 provides in vivo pharmacokinetic measurements of relevant concentrations of plasma (Cp), blood (Cb), unbound plasma (Cb,u), unbound blood (Cb,u), and spinal fluid (CSF) following IP administration of Compound 57 to mice at either 10 mg/kg or 30 mg/kg.

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.

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.

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.

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.

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.

DETAILED DESCRIPTION

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).

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 Ca ²⁺ 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-spi ro [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.

Cav3,3 Potentiator Scaffolds

The Cav3.3 potentiators of the present disclosure may be a compound having the structure of formula (I): wherein the dotted circle represents an optionally unsaturated (e.g. aromatic) ring; p is 0 or 1; m is 0 (and each carbon is bonded to one or two hydrogens), 1, 2, 3, or 4; n is 0, 1, 2,3, or 4;

XAI is N, O, or C;

XA2 is N or C;

XA3 is N or CRAS; RAI is independently at each occurence hydrogen alkyl (e.g., optionally unsaturated Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3,), -C(O)OR, -C(O)R, haloalkyl e.g., Ci-Cs haloalkyl, lower haloalkyl such as C1-C4 haloalkyl, halomethyl, Ci-Cs fluoroalkyl, lower fluoroalkyl such as C1-C4 fluoroalkyl, fluoromethyl, difluoromethyl, perfluoroalkyl, Ci-Cs perfluoroalkyl, lower perfluoroalkyl such as C1-C4 perfluoroalkyl, perfluoromethyl), hydroxy, or amino (e.g., -NRR); 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;

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;

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;

R ^L is -S(=0) ₂ -, -S(=0)-, -S(=N) ₂ -, -S(=N)(=O)-, or -C(R)(R)-;

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

XB2 is independently at each occurrence N, or CRB2;

RBI is independently selected at each occurrence from hydrogen, alkyl (e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as - CD3,), haloalkyl (e.g., Ci-Cs haloalkyl, lower haloalkyl such as C1-C4 haloalkyl, halomethyl, Ci-Cs fluoroalkyl, lower fluoroalkyl such as C1-C4 fluoroalkyl, fluoromethyl, difluoromethyl, perfluoroalkyl, Ci-Cs perfluoroalkyl, lower perfluoroalkyl such as C1-C4 perfluoroalkyl, perfluoromethyl), halogen (e.g., F, Cl, Br), and -Rc; wherein RBI may independently at each occurence have one or more (e.g., two, three, four) points of optional substititution;

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;

XC6 is C, CH, CR, or N;

Xci, Xc2, Xc3, Xc4, and Xcs are independently CH, CR, N, NH, NR, O, or S; and when the group is a five membered ring, Xcs is absent; and

Rci, RC2, RC3, RC4, and Res are independently hydrogen, alkyl (e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3,), -C(O)R, -C(O)NRR, halogen (e.g., F, Cl, Br), haloalkyl haloalkyl (e.g., Ci-Cs haloalkyl, lower haloalkyl such as C1-C4 haloalkyl, halomethyl, Ci-Cs fluoroalkyl, lower fluoroalkyl such as C1-C4 fluoroalkyl, fluoromethyl, difluoromethyl, perfluoroalkyl, Ci-Cs perfluoroalkyl, lower perfluoroalkyl such as C1-C4 perfluoroalkyl, perfluoromethyl), 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

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

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.

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.

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.

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.

Exemplary heterocycloalkyl or heteroaryl groups (e.g., R ^c groups) include:

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

A substituted hydrocarbon group may have as a substituent one or more hydrocarbon radicals, substituted hydrocarbon radicals, or may comprise one or more heteroatoms. 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”).

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).

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.

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.

The compound provided herein may also be present as geometric isomer which differ in the orientation of substituent atoms (e.g., to a carbon-carbon double bond, to a cycloalkyl ring, to a bridged bicyclic system). Atoms (other than H) on each side of a carbon-carbon double bond may be in an E (substituents are on opposite sides of the carbon- carbon double bond) or Z (substituents are oriented on the same side) configuration. “R,” “S,” “S*,” “R*,” “E,” “Z,” “cis,” and “trans,” indicate configurations relative to the core molecule and may be used to indicate the geometric configuration of the presently disclosed compounds. Certain of the disclosed compounds may exist in atropisomeric forms. Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers.

The compounds disclosed herein may be prepared as individual isomers by either isomer-specific synthesis or resolved from an isomeric mixture. Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods. 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.

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.

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.

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.

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.

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);

XC ₆ is C, CR, or N;

Xci, Xc2, Xc3, Xc4, and Xcs are independently at each occurrence CH, CR, N, NH, NR, O, or S; and when the group is a five membered ring, Xcs is absent (z.e., it is a bond); and

Rci, RC2, RC3, RC4, and Res are independently occurrence hydrogen, alkyl (e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as - CD3,), halogen (e.g., F, Cl, Br), haloalkyl (e.g., Ci-Cs haloalkyl, lower haloalkyl such as Ci- C4 haloalkyl, halomethyl, Ci-Cs fluoroalkyl, lower fluoroalkyl such as C1-C4 fluoroalkyl, fluoromethyl, difluoromethyl, perfluoroalkyl, Ci-Cs perfluoroalkyl, lower perfluoroalkyl such as C1-C4 perfluoroalkyl, perfluoromethyl), cycloalkyl (e.g., C3-C9 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,

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:

For example, Rc may have the structure:

Rci may be, for example, hydrogen or lower alkyl (e.g., C1-C4 alkyl, methyl), cycloalkyl (e.g., C3-C5 cycloalkyl), haloalkyl (e.g., C1-C4 haloalkyl, C1-C4 fluoroalkyl, fluromethyl, difluoromethyl).

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

For example the comopund may be:

0

8

In some embodiments, the compound may be:

Compound 7 The compound may be:

Compound 2 Compound 10 Compound 18

Compound 22

Compound 48 Compound 71

Compound 57 Compound 69

Compound 99 Compound 104 Compound 122

The compound may be selected from the group consisting of:

Compound 22 Compound 34 Compound 57 Compound 71

Compound 74 Compound 77 Compound 82 Compound 92

Compound 101 Compound 104 Compound 130

Compound 132 Compound 133 Compound 144 Compound 208

Compound 220 Compound 235 Compound 238 Compound 255

In some embodiments, the compound is

Compound 22 Compound 57 Compound 82 Compound 104

Compound 131 Compound 208

In some embodiments, the comopund is

Compound 36 Compound 39

Compound 67

In a particular embodiment, the comopund is

Compound

25

The Rc group may also be conjugated in the meta configuration of the central six membered ring with respect to the R ^L group. 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):

In some aspects, the compound may be:

Compound 32 Compound 35 Compound 56 Compound 68

Compound 72 Compound 73 Compound 76 Compound 85

Compound 128 Comopund 131 Compound 137 Compound 147

Compound 157 Compound 163 Compound 164 Compound 168

Compound 181 Compound 183 Compound 186 Compound 188

Compound 189 Compound 190 Compound 192 Compound 196

Compound 197 Compound 199 Compound 203

Compound 212 Compound 213 Compound 214 Compound 216

Compound 234 Compound 236 Compound 237 Compound 241

Compound 242 Comopund 243 Compound 245 Compound 248

For example, the compound may be:

R ^L is typically an -S(=O)2- group. In some embodiments, the R ^L group 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;

X is N, C, or CR3;

Y is =N- -N=,-N(R ₉ )-, -(C(R ₇ )(R ₈ ) , =C(R ₇ ) -, -C(R ₇ )=, -N(R ₉ )C(R ₇ )(R ₈ )-, -C(R ₇ )(R ₈ )N(R ₉ )-, -N(R ₉ )C(R ₇ )=, =C(R ₇ )N(R ₉ )-, -C(R ₇ )=C(R ₈ )-, -N=C(R ₈ ) -, or -C(R ₇ ) =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 (e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3);

R2-R6 are independently hydrogen or alkyl alkyl (e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3); wherein R2-R6 may independently have one or more points of optional substititution;

R7-R9 are independently at each occurrence hydrogen or alkyl alkyl (e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3); wherein R7-R9 may independently have one or more points of optional substititution; or pharmaceutically acceptable salts thereof or prodrugs of any of the foregoing. 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

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.

The compound may be:

Comopund l31 Compound 137 Compound 147 Compound 157

Compound 163 Compound 164 Compound 168 Compound 170

Compound 171 Compound 175 Compound 180 Compound 181

Compound 190 Compound 192 Compound 196 Compound 197

Compound 199 Compound 203 Compound 205 Compound 212

Compound 213 Compound 214 Compound 216 Compound 217

Compound 221 Compound 222 Compound 225 Ccompound 229

Compound 231 Compound 232 Compound 233 Compound 234

Compound 236 Compound 237 Compound 241 Compound 242

In some embodiments, the compound is:

The compounds may have alterations on the bicyclic ring system of Formula (I), (II), (Ila), (lib), (lie), (Hd), (lie), (Ilf), (Ilg), (Ilh), (Hi), (III), (Illa), (Illb), (IIIc), (Hid), or (Ille) to result, in for example, sulfonamides. Typically, these systems may retain the features of the central ring (R ^B ) and R ^c . 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);

R _D2 is hydrogen or alkyl (e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3) and RD2 may have one or more (e.g., two, three, four) optional points of substitution;

XBI is independently at each occurrence N or CRBI;

RBI is independently selected at each occurrence from hydrogen, alkyl (e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as - CD3), and -Rc and RBI may have one or more (e.g., two, three, four) optional points of substitution;

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;

XC ₆ is C, CH, CR, or N;

Xci, Xc2, Xc3, Xc4, and Xcs are independently CH, CR, N, NH, NR, O, or S; and when the group is a five membered ring, Xcs is absent; and Rci, RC2, RC3, RC4, and Res are independently hydrogen, alkyl (e.g., Ci-Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3), -C(O)R, -C(O)NRR, halogen (e.g., F, Cl, O), haloalkyl (e.g., Ci-Cs haloalkyl, lower haloalkyl such as C1-C4 haloalkyl, halomethyl, Ci-Cs fluoroalkyl, lower fluoroalkyl such as C1-C4 fluoroalkyl, fluoromethyl, difluoromethyl, perfluoroalkyl, Ci-Cs perfluoroalkyl, lower perfluoroalkyl such as C1-C4 perfluoroalkyl, perfluoromethyl), or 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):

In various embodiments, the compound may be:

Compound 194 Compound 200 Compound 202

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).

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.

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-

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-

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.

Table 1

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.

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.,

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.,

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,

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

In various implementations, the compound is:

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,

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

Compound 131 Compound 181

In some embodiments, the compound is:

In some embodiments, the compound is:

Compound 22 Compound 34 Compound 57 Compound 71

In some embodiments, the compound is:

Compound 22 Compound 57 Compound 82 Compound 104

Compound 131 Compound 208

Pharmaceutical Compositions

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.

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.

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.

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.

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.

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.

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.

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.

Methods for Treatment

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.

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.

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).

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.

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).

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.

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.

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.

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

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.

Syntheses

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):

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):

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.

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.

EXAMPLES

Example 1 : High-Throughput Cay3, 3 Potentiation Measurements

High-throughput assays able to identify both inhibitors and potentiators (activators) were to screen compounds. The assays involved T-type Ca ²⁺ channel cell lines expressing Kir2.3, an inward rectifying potassium channel that can hyperpolarize the cells to -70 mV. This inward rectifying potassium channel creates a physiological membrane potential where most T-type Ca ²⁺ channels are available to open. Additionally, the assay involved a membrane bound version of the stable ultrasensitive Ca ²⁺ sensor GCaMP6s (GCaMP6s- CAAX). 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.

Table 2

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.

* 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.

Example 2: Electrophysiology

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

G seal and precise voltage control, the electrophysiological profiles of the three T-type Ca ²⁺ 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

Compound 131 Compound 7

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).

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).

Example 3: Ex vivo measurements: Brain slice electrophysiology

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:

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.

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

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

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.

Example 4: In vivo Pharmacokinetic Measurements

The relationship of dosing to pharmacokinetics was measured for intraperitoneal administration of Compound 57. Compound 57 was administered at either 10 mg/kg or 30 mg/kg and the blood, plasma, unbound blood, unbound plasma, and spinal fluid concentrations were measured over eight hours. FIG. 7 provides the concentrations of each measured parameter. Table 3 provides the brain maximum concentration (Cmax), area under curve (AUC) following administration, brain half-life (T1/2), plasma partition coefficient, and unbound plasma partition coefficient (K _pU u) for each dose. By tripling the dose, the maximum concentration was able to increase 5-fold and the brain AUC increased 7-fold.

Table 3

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

Cav3.3 knock-out (Cacnali' ¹ ' (KO) and Cacnalt ¹ ' (Het)) and R1305H mutation knock-in mice (Cacnal i ^mim (RH/RH) and Cacnali ^{+ R} (RH Het)) were generated. The R1305H mutation in murine Cav3.3 corresponds to R1346H in the human channel:

Hu_CACNAl I 1340 TRNITNRSDC 1349

Ms_CACNAl I 1299 TRNITNRSDC 1308

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.

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.

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).

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).

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).

Example 6: Effect on Spindle Density

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.

Example 7: Compound Synthesis

Compounds of the present disclosure were synthesized as follows.

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

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

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

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)benzenesulf onyl]-l,5-dimethyl-

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

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]+.

(3S)-5-fluoro-3,7-dimethyl-l-[[4-methyl-6-(4-methylimidaz ol-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)

To a mixture of l-[(6-bromo-4-methyl-3-pyridyl)sulfonyl]-5-fluoro-3,7-dimeth yl- 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).

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-dimeth yl-indoline

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]+.

5-fluoro-3,7-dimethyl-indoline

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]+

5 -fluoro-3 , 7 -dimethyl - 1 H-indol e

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]-

5-fluoro-7-methyl-lH-indole-3-carbaldehyde

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]+

5 -fluoro-7 -methyl - 1 H-indol e

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).

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).

7-bromo-5-fluoro-lH-indole

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)

Broad_P_CaV3.3_565

Compound 3 tert-butyl (2-((4-bromo-2-methylphenyl)sulfonamido)-3-methylphenyl)carb amate :

Intermediate- 1

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.

^X H 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-dihydroqui noxaline-l(2H)- carboxylate: Intermediate-2

Boc

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]+

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-tetrah ydroquinoxaline : intermediate-3

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.

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).

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]+.

4-((4-bromo-2-methylphenyl)sulfonyl)-5-methyl-l-(methyl-d 3)-l,2,3,4- tetrahydroquinoxaline : Intermediate-4

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]+

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).

5-methyl-l-(methyl-d3)-4-((2-methyl-4-(4-methyl-lH-imidaz ol-l-yl)phenyl)sulfonyl)-

1,2,3,4-tetrahydroquinoxaline (Compound 3)

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-dihydroquinoxal ine (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)benzene sulfonyl]-l,2,3,4- tetrahydroquinoxaline (Broad_P_Cav3.3_313, Compound 4)

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.

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)benzenesulf onyl]-l,5-dimethyl-

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

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]+.

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

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

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.

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)benzene sulfonyl]-l,2,3,4- tetrahydroquinoxaline (Broad_P_CaV3.3_259, Compound 7)

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).

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)

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-tetrahydroquinoxa line (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.

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

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

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.

MS :[M+H]+ 411.00

’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

(s, 3H), 1.21 (s, 3H).

(3S)-5-fluoro-3,7-dimethyl-l-[2-methyl-4-(4-methylimidazo l-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)

To a mixture of l-(4-bromo-2-methyl-phenyl)sulfonyl-5-fluoro-3,7-dimethyl-in doline (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).

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]+

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]+.

Synthesis of Compound 5 and Compound 134

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)ace tamide Broad_P_CaV3.3_400_Int_790, (8.20 g, 47.5 mmol85% yield) 16.4 % yield) as a light yellow oil.

MS: [M+H] + 167.18.

(2-acetamido-4-fluoro-3-methyl-phenyl)-hydroxy-oxo-ammoni um: Intermediate-791

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.

MS: [M+H] + 213.30.

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

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.

^X H 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).

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

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

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

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.

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

Boc

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.

^X H 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)sulfonylam ino]-4-fluoro-3-methyl- phenyl]carbamate: Intermediate-794

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.

N-(6-amino-3-fluoro-2-methyl-phenyl)-4-bromo-2-fluoro-6-m ethyl-benzenesulfonamide:

Intermediate-794 A

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-meth yl- benzenesulfonamide(Broad_P_CaV3.3_400_Int_794A, (0.60 g, 1.53 mmol, 87% yield) as a white solid.

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).

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

A solution of N-(6-amino-3-fhioro-2-methyl-phenyl)-4-bromo-2-fluoro-6-meth yl- 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.

MS :[M+H]+ 417.27.

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

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

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.

MS:[M+H]+ 361.0.

'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,

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).

4-[4-(5-fluoro-l-methyl-lH-pyrazol-4-yl)-2-methylbenzenes ulfonyl]-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-tetrahydroquinoxa line (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.

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-pyridy l]sulfonyl]-2,3- dihydroquinoxaline (Broad_P_CaV3.3_356, Compound 13)

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-dihydroquinoxal ine (40 mg, 19.9% yield) as a white solid.

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)

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.

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]+.

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

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]+.

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

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]+.

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

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-methy l-anilino]acetate

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]+.

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

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-ph enyl]carbamate

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.

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-

H]-.

Synthesis of Compound 15 and Compound 46 aV3.3 431 2

Compound 15

Compound 46

(4R)-4,8-dimethyl-l-[2-methyl-4-(l-methylpyrazol-4-yl)phe nyl]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)

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).

MS:[M+H]+ 396.10.

Fr-1 (Broad_P_CaV3.3_430):

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).

Fr-2 (Broad_P_CaV3.3_431):

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).

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)

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.

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

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

Synthesis of Compound 17 Compound 17

4-[4-(4-cyclopropylimidazol-l-yl)-2-methyl-phenyl]sulfony l-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.

MS:[M+H]+ 423.00.

’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).

Synthesis of Compound 18

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

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]

^X H 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).

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

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]

’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]sul fonyl-2,3- dihydroquinoxaline (Broad_P_Cav3.3_291, Compound 19)

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.

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]+.

4-(4-bromo-2-methyl-phenyl)sulfonyl-l,5-dimethyl-2,3-dihy droquinoxaline 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]+.

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.

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-dihydroquin oxaline-l- carb oxy late

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-carboxylat e, (3.10 g, 6.18 mmol, 94% yield) as an yellow solid.

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-pheny l]carbamate

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.

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]+.

Synthesis of Compound 20

Broad_P_CaV3.3_625

Compound 20 l-(4-bromo-2-methyl-phenyl)sulfonyl-5-fluoro-7-methyl-indoli ne: Intermediate- 1290

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.

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).

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

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

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).

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

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.

MS: [M+H]+ 176.0

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

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.

Broad_P_CaV3.3_449

MS :[M+H]+ 410.2

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).

[a]D ²⁵ = -35.00°

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

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

Broad_P_CaV3.3_450

MS :[M+H]+ 410.2

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 -

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 -

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).

[a]D ²⁵ = +33.40°

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

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

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

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.

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]+.

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

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]+.

3-[(6-bromo-4-methyl-3-pyridyl)sulfanyl]-6-fluoro-l,4-dim ethyl-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]+.

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

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.

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

Broad_P_Cav3.3_411 Broad_P_Cav3.3_412

Compound 24

Compound 116

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

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.

MS: [M+H]+ 177.0

3,4,8-trimethyl-l,3-dihydroquinoxalin-2-one

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

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

MS: [M+H]+ 191.2

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.

MS: [M+H]+ 176.26

4-(4-bromo-2-methyl-phenyl)sulfonyl-l,2,5-trimethyl-2,3-d ihydroquinoxaline:

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.

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

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]sulfon yl-2,3-dihydroquinoxaline, (4.6 mg, 0.0111 mmol, 0.38).

Broad_P_CaV3.3_411

MS: [M + H]+ 411.4

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).

Broad_P_CaV3.3_412

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).

Synthesis of Compound 25

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

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.

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=

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)su lfonyl)indoline:

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.

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

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).

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)

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.

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

(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]+.

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

Compound 27

Compound 55

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

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.

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).

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

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.

Int-899C:

MS: [M+H]+ 162.00

’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).

Int-899F:

MS: [M+H]+ 162.00

^X H 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).

(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

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.

Broad_P_CaV3.3_506:

MS: [M+H]+ 396.2

'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 =

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 =

6.7 Hz, 3H).

[a]D ²⁵ = -27.00°

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

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

MS: [M+H]+ 396.2

^X H 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).

[a]D ²⁵ = +26.00°

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

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

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

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),

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)

PdCI ₂ (dppf).DCM (0.1 eq), K ₂ CO ₃ (3 eq), dioxane:water (4:1 ) ,90 °

C, 16h

Broad P CaV3.3 495

Compound 31 Compound 45 tert-butyl N-[2-[(4-bromo-2-methyl-phenyl)sulfonylamino]-3-methyl-pheny l]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.

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-dihydroquin oxaline-l- carb oxy late:

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.

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 =

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,

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:

Boc i

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

5-methyl-4-[2-methyl-4-(l-methylpyrazol-4-yl)phenyl]sulfo nyl-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.

MS :[M+H]+ 382.48

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).

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

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.

MS:[M+H]+450.48

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).

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

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.

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)ben zenesulfonyl]-l,2,3,4- tetrahydroquinoxaline (Broad000415 - 036. Compound 33)

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).

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,

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)p henyl]sulfonyl-indole

(Broad_P_CaV3.3_640, Compound 22)

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.

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),

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.

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-in dole (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.

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

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.

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)benzenesulf onyl]-l,2,3,4- tetrahydroquinoxaline (Broad_P_Cav3.3_272, Compound 35)

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.

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]+.

(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)

The mixture of l-[(6-bromo-4-methyl-3-pyridyl)sulfonyl]-3,7-dimethyl-indoli ne (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).

Broad_P_CaV3.3 660A

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]+.

Broad_P_CaV3.3 660B

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-indoli ne

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

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]+.

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

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.

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

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)pyrid in-3-yl]sulfonyl}-l,2,3,4- tetrahydroquinoxaline (Broad_P_Cav3.3_359, Compound 38)

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.

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 =

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]+.

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

59% roa _ _ a . _ Compound 40 1098C

2-isopropenyl-6-methyl-aniline: Intermediate 1098 A

1098A

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]|

4-bromo-N-(2-isopropenyl-6-methyl-phenyl)-2-methyl-benzen esulfonamide: Intermediate 1098B

1098B

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 |

N-(2-isopropenyl-6-methyl-phenyl)-2-methyl-4-(4-methylimi dazol-l-yl)benzenesulfonamide: Intermediate 1098C

1098C

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-methylimidaz ol-l- yl)benzenesulfonamide Int-1098C, (50 mg, 0.102 mmol, 59% yield). ^X H 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] ⁺

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

Broad_P_CaV3.3_553 Compound 40

To the solution of N-(2-isopropenyl-6-methyl-phenyl)-2-methyl-4-(4-methylimidaz ol- 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).

'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,

1H), 2.34 (s, 3H), 2.28 (s, 3H), 2.15 (s, 3H).

’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)pyridi n-3-yl]sulfonyl}-l,2,3,4- tetrahydroquinoxaline (Broad_P_CaV3.3_286, Compound 41)

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]+.

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

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).

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)benz enesulfonyl]-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.

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]+.

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.

MS :[M+H]+ 382.00

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

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.

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).

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

To a solution of l'-[(6-bromo-4-methyl-3-pyridyl)sulfonyl]-5'-fluoro-7'-methy l- 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.

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'-methy l-spiro[cyclopropane-l,3'- indoline]

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]

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).

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]+.

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

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]+.

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

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]+.

(2E)-N-(4-fluoro-2-methyl-phenyl)-2-hydroxyimino-acetamid e

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)

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.

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]+.

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

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]+.

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

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]+.

1 -ethyl-6-fluoro-4-methyl-indole

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]+.

4-bromo- 1 -ethyl-6-fluoro-indole

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)benzene sulfonyl]-l,2,3,4- tetrahydroquinoxalin-2-one (Broad_P_Cav3.3_326, Compound 49)

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]+.

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

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]+.

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

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]+.

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

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

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).

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-y l)benzenesulfonyl]-

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

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]+.

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

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).

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)

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.

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-pyridy l]sulfonyl]indole (Broad_P_CaV3.3_639, Compound 57)

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.

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]+.

3-[(6-bromo-4-methyl-3-pyridyl)sulfonyl]-l,4-dimethyl-ind ole

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]+.

3-[(6-bromo-4-methyl-3-pyridyl)sulfanyl]-l,4-dimethyl-ind ole

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)b enzenesulfonyl]-l,2,3,4- tetrahydroquinoxaline (Broad_P_Cav3.3_289, Compound 58)

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.

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).

(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-tetrahydroqu inoxaline (Compound 120) (Broad_P_Cav3.3 330 and 331)

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-tetrahydroqu inoxaline (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

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]+.

Broad_P_CaV3.3_331

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)be nzenesulfonyl]-l,2,3,4- tetrahydroquinoxaline (Broad_P_Cav3.3_324, Compound 60)

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-tetrahydroquinoxa line (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]+.

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

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.

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]+.

8-methyl-2,3-dihydro-lH-quinolin-4-one

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.

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]+.

1 -(o-tolyl)azetidin-2-one

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.

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]sul fonyl-3H-quinoxalin-2- one (Broad_P_CaV3.3_406, Compound 62)

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.

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,

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

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,

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)phe nyl]sulfonyl- anilino)acetate

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.

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-me thylimidazol-l- yl)phenyl]sulfonyl-anilino]acetate

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

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-pheny l]carbamate

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]-.

4-bromo-2-methyl-benzenesulfonyl chloride

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,

2.1 Hz, 1H), 2.77 (s, 3H).

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

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.

MS: [M+H] ⁺ 173.0

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).

2,3,5-trimethyl-l,2,3,4-tetrahydroquinoxaline: Intermediate-997C

To a solution of 2,3,5-trimethylquinoxaline (2.40 g, 13.9 mmol, 1.00 eq) in methanol (48 mL) was added NiC12-6H2O (3.31 g, 13.9 mmol, 1.00 eq) at 0°C and allowed to stir for 10 min. Sodium borohydride (4.22 g, 111 mmol, 8.00 eq) was added slowly and lot wise to reaction mixture within Ih. Reaction was allowed to stir at room temperature. After completion, reaction mixture was diluted with ethyl acetate (100 mL) and filtered through celite bad. Filtrate was concentrated, water (100 mL) was added and extracted with ethyl acetate (3 x lOOmL). 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 50% ethyl acetate in hexanes to Int-997C, (2.40 g, 13.6 mmol, 98% yield) as a solid compound.

MS: [M+H] ⁺ 177.0

IH NMR (400 MHz, DMSO-d6) 5 6.25 (q, J = 4.6, 3.3 Hz, 3H), 5.14 (s, IH), 4.53 (d, J = 2.9 Hz, IH), 3.27 (dq, J = 6.5, 3.9, 3.2 Hz, IH), 1.97 (s, 3H), 1.00 (dd, J = 10.6, 6.5 Hz, 6H). tert-butyl 2, 3, 5-trimethyl-3,4-dihydro-2H-quinoxaline-l -carboxylate: Intermediate-997D Boc i

To a solution of 2,3,5-trimethyl-l,2,3,4-tetrahydroquinoxaline (2.40 g, 13.6 mmol, 1.00 eq) in tetrahydrofuran (48 mL) was added Triethylamine (5.51 g, 54.5 mmol, 4.00 eq) at room temperature and allowed to stir for 10 minutes. Boc anhydride (6.54 g, 30.0 mmol, 2.20 eq) was added slowly to reaction mixture within 15 minutes. Reaction was allowed to stir at room temperature. After completion, water (100 mL) was added and extracted with ethyl acetate (3 x 100ml). 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 15% ethyl acetate in hexanes to provide Int-997D, (2.50 g, 8.89 mmol, 65% yield) as a solid compound.

MS: [M+H] ⁺ 277.0

1H NMR (400 MHz, DMSO-d6) 5 7.18 (d, J = 8.1 Hz, 1H), 6.71 (d, J = 7.3 Hz, 1H), 6.44 (t, J = 7.7 Hz, 1H), 4.98 (s, 1H), 4.34 (d, J = 7.7 Hz, 1H), 2.08 (s, 3H), 1.42 (s, 8H), 1.16 (d, J = 6.5 Hz, 3H), 0.79 (d, J = 6.8 Hz, 3H). tert-butyl 2,3,5-trimethyl-4-[2-methyl-4-(l-methylpyrazol-4-yl)phenyl]s ulfonyl-2,3- dihydroquinoxaline-l-carboxylate: Intermediate-997E

Boc i

To a solution of tert-butyl 2,3,5-trimethyl-3,4-dihydro-2H-quinoxaline-l-carboxylate (1.20 g, 4.34 mmol, 1.00 eq) and 4-(l-methylpyrazol-4-yl)benzenesulfonyl chloride (1.17 g, 4.56 mmol, 1.05 eq) in acetonitrile (24 mL) was added Zinc oxide (0.71 g, 8.68 mmol, 2.00 eq) at room temperature and reaction mixture was allowed to stir at RT. After completion, reaction mixture was filtered through celite bed, washed with ethyl acetate (50 mL). Filtrate was conentrated under vacuum, water (50 mL) was added and extracted with ethyl acetate (3 x 50mL). 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 18% ethyl acetate in hexanes to provide Int-997E, (0.66 g, 1.11 mmol, 26% yield) as a solid compound.

MS: [M+H] ⁺ 455.0

1H NMR (400 MHz, DMSO-d6) 5 8.27 (s, 1H), 7.95 (s, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.63 - 7.50 (m, 2H), 7.27 - 7.15 (m, 2H), 7.06 (d, J = 7.3 Hz, 1H), 4.70 (p, J = 7.2 Hz, 1H), 4.19 (t, J = 7.6 Hz, 1H), 3.87 (s, 3H), 2.28 (s, 3H), 2.02 (d, J = 29.1 Hz, 3H), 1.44 - 1.14 (m, 9H), 0.93 (d, J = 7.0 Hz, 3H), 0.89 - 0.74 (m, 3H).

2,3,5-trimethyl-4-[2-methyl-4-(l-methylpyrazol-4-yl)pheny l]sulfonyl-2,3-dihydro-lH- quinoxaline: Intermediate-997

To a solution of tert-butyl 2,3,5-trimethyl-4-[2-methyl-4-(l-methylpyrazol-4- yl)phenyl]sulfonyl-2,3-dihydroquinoxaline-l-carboxylate (0.66 g, 1.29 mmol, 1.00 eq) in dichloromethane (6.6 mL) was added 4M HC1 in 1,4-Dioxane (4 M in , 2.5 mL, 10.0 mmol, 7.74 eq) at 0°C and reaction mixture was allowed to stir at RT. After completion, saturated sodium bicarbonate solution was added (up to -pH 8) and product was extracted with dichloromethane (2 x 50mL). Combined organic layer was washed with water, brine, dried over anhydrous sodium sulphate and evaporated to give crude product Int-997, (0.42 g, 0.854 mmol, 66% yield), which was used in next step without further purification.

MS: [M+H] ⁺ 411.0

(2S,3S)-l,2,3,5-tetramethyl-4-[2-methyl-4-(l-methylpyrazo l-4-yl)phenyl]sulfonyl-2,3- dihydroquinoxaline; (2S,3R)- 1,2,3, 5-tetramethyl-4-[2-methyl-4-(l -methylpyrazol-4- yl)phenyl]sulfonyl-2,3-dihydroquinoxaline; (2R,3S)-l,2,3,5-tetramethyl-4-[2-methyl-4-(l- methylpyrazol-4-yl)phenyl]sulfonyl-2,3-dihydroquinoxaline and (2R,3R)-1,2,3,5- tetramethyl-4-[2-methyl-4-(l-methylpyrazol-4-yl)phenyl]sulfo nyl-2,3-dihydroquinoxaline:

Broad_P_CaV3.3_500; Broad_P_CaV3.3_501; Broad_P_CaV3.3_502 and

Broad_P_CaV3.3_503

To a solution of 2,3,5-trimethyl-4-[2-methyl-4-(l-methylpyrazol-4- yl)phenyl]sulfonyl-2,3-dihydro-lH-quinoxaline (0.42 g, 1.02 mmol, 1.00 eq) in dimethylformamide (4.2 mL) was added Sodium hydride (60% in mineral oil) (0.074 g, 3.07 mmol, 3.00 eq) at 0°C and reaction mixture was allowed to stir at 0°C for 10 Minutes. Methyl iodide (0.87 g, 6.14 mmol, 6.00 eq) was added and reaction was heated at 60°C. After completion, reaction was quenched slowly with crushed ice and product was extracted with ethyl acetate (2 x 50mL). 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 products were eluted out in 12% ethyl acetate in hexanes to provide two diastereomers as spot-1 (50mg, 11.51%) and spot-2 (180mg, 41.44%).

Spot-1 was further purified by chiral SFC purification to provide Fraction-1 Broad_P_Cav3.3_500 (9.0 mg, 0.0202 mmol, 2% yield) and Fraction-2 Broad_P_Cav3.3_501 (8.7 mg, 0.0195 mmol, 2% yield).

Spot-2 was further purified by chiral SFC purification to provide Fraction-3 Broad_P_Cav3.3_502 (13 mg, 0.0294 mmol, 3% yield) and Fraction-4 Broad_P_Cav3.3_503 (22 mg, 0.0519 mmol, 5% yield).

Broad_P_CaV3.3_500

MS: [M+H] ⁺ 425.2 1H NMR (400 MHz, DMSO-d6) 5 8.30 (s, 1H), 8.00 (s, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.68 - 7.55 (m, 2H), 6.97 (dd, J = 16.2, 7.7 Hz, 2H), 6.72 (t, J = 7.8 Hz, 1H), 4.38 - 4.25 (m, 1H), 3.87 (s, 3H), 2.87 (t, J = 6.1 Hz, 1H), 2.40 (s, 3H), 2.26 (s, 3H), 2.16 (s, 3H), 1.25 (d, J = 8.0 Hz, 1H), 0.98 (d, J = 6.3 Hz, 3H), 0.90 (d, J = 6.9 Hz, 3H).

[a]D ²⁵ = +72.01°

Chiral separation conditions: (CHIRALCEL OX-H (250*4.6mm) 5u), 0.1% DEA in MeOH) and CO2 gas as a mobile phase

Order of elution: Fraction-1 (RT: 6.56 min); Fraction-2 (RT: 6.72 min)

Broad_P_CaV3.3_501

MS: [M+H] ⁺ 425.2

1H NMR (400 MHz, DMSO-d6) 5 8.30 (s, 1H), 8.00 (s, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.68 - 7.53 (m, 2H), 6.97 (dd, J = 16.1, 7.6 Hz, 2H), 6.72 (t, J = 7.8 Hz, 1H), 4.37 - 4.25 (m, 1H), 3.87 (s, 3H), 2.94 - 2.83 (m, 1H), 2.40 (s, 3H), 2.26 (s, 3H), 2.16 (s, 3H), 0.98 (d, J = 6.4 Hz, 3H), 0.90 (d, J = 6.9 Hz, 3H).

[a]D ²⁵ = -74.01°

Chiral separation conditions: (CHIRALCEL OX-H (250*4.6mm) 5u), 0.1% DEA in MeOH) and CO2 gas as a mobile phase

Order of elution: Fraction-1 (RT: 6.56 min); Fraction-2 (RT: 6.72 min)

Broad_P_CaV3.3_502

MS: [M+H] ⁺ 425.2

1H NMR (400 MHz, DMSO-d6) 5 8.29 (s, 1H), 7.98 (s, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 6.8 Hz, 2H), 6.99 (t, J = 7.8 Hz, 1H), 6.50 (dd, J = 22.8, 7.9 Hz, 2H), 4.38 - 4.27 (m, 1H), 3.86 (s, 3H), 3.06 - 2.94 (m, 1H), 2.37 (s, 3H), 2.21 (s, 3H), 1.99 (s, 3H), 0.88 (d, J = 6.7 Hz, 6H).

[a]D ²⁵ = +49.00°

Chiral separation conditions: (CHIRALCEL OX-H (250*4.6mm) 5u), 0.1% DEA in MeOH) and CO2 gas as a mobile phase

Order of elution: Fraction-1 (RT: 7.16 min); Fraction-2 (RT: 7.89 min)

Broad_P_CaV3.3_503 MS: [M+H] ⁺ 425.0

1H NMR (400 MHz, DMSO-d6) 5 8.29 (s, 1H), 7.98 (s, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 6.6 Hz, 2H), 6.99 (t, J = 7.8 Hz, 1H), 6.50 (dd, J = 22.9, 7.9 Hz, 2H), 4.32 (t, J = 6.8 Hz, 1H), 3.86 (s, 3H), 3.00 (t, J = 6.6 Hz, 1H), 2.37 (s, 3H), 2.21 (s, 3H), 1.99 (s, 3H), 0.88 (d, J = 6.7 Hz, 6H).

[a]D ²⁵ = -48.00°

Chiral separation conditions: (CHIRALCEL OX-H (250*4.6mm) 5u), 0.1% DEA in MeOH) and CO2 gas as a mobile phase

Order of elution: Fraction-1 (RT: 7.16 min); Fraction-2 (RT: 7.89 min) Synthesis of Compound 64

Broad_P_CaV3.3_258 Compound 64 2-methyl-4-(l -methyl- lH-pyrazol-4-yl)-N-(2-methyl-6-nitrophenyl)benzene-l -sulfonamide:

Intermediate-66

To a stirred solution of 5-bromo-2-methyl-N-(2-methyl-6-nitrophenyl)benzene-l- sulfona (1.1 g, 2.85 mmol, 1 eq) l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 1H- (711 mg, 3.42 mmol, 1.2 eq) and potassium carbonate (1.18 g, 8.55 mmol, 3 eq) in 1,4- di oxane (20 mL) and water (2 mL) was degassed for 15 minutes with Nitrogen gas followed by tetrakis(triphenylph (329 mg, 285 pmol, 0.1 eq) was added and heated the reaction mixture at 100°C for 16 h. 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 obtain crude product which was purified by flash chromatography using [0-50% EtOAc/Hexanes] to provide 2- methyl-5-(l-methyl-lH-pyrazol-4-yl)-N-(2-methyl-6-nitrophe (0.55 g, 42.7 % yield) as a yellow solid. MS:[M+H]+ 384.20 N-(2-amino-6-methylphenyl)-2-methyl-5-(l -methyl- lH-pyrazol-4-yl)benzene-l -sulfonamide:

Intermediate-67

A solution of 2-methyl-4-(l-methyl-lH-pyrazol-4-yl)-N-(2-methyl-6-nitrophe (0.125 g, 323 pmol, 1 eq) in acetic acid (1 mL) was added zinc (168 mg, 2.58 mmol, 8 eq) at room temperature and stirred at same temperature for 3 h. After completion, the reaction mixture was filtered off, concentrated under vacuum followed by saturated NaHCOs solution was added to residue and aqueous was extracted with ethyl acetate (50 mL) and washed with water (2 x 50 mL). The organic layer was dried over Na2SO4 and evaporated to provide N-(2- amino-6-methylphenyl)-2-methyl-4-(l-methyl-lH-pyrazol-4 (0.1 g, 86.9 % yield) as a yellow solid.

MS :[M+H]+ 357.44.

8-methyl-l-[2-methyl-4-(l-methyl-lH-pyrazol-4-yl)benzenes ulfonyl]-l,2,3,4- tetrahydroquinoxaline: Broad_P_CaV3.3_258 (Compound 64)

To a solution of N-(2-amino-6-methylphenyl)-2-methyl-4-(l-methyl-lH-pyrazol-4 (0.1 g, 280 pmol, 1 eq) and potassium carbonate (116 mg, 840 pmol, 3 eq) in DMF (1 mL) was drop wise added dibromoethane (78.9 mg, 420 pmol, 1.5 eq) at room temperature and stirred at 80 °C for 16 h. After completion, reaction was quenched with water and aqueous was extracted with EtOAc (3 x 25 mL).The combined organic layer was washed with brine solution and dried over sodium sulphate, evaporated and the residue was purify by flash chromatography using [0-25% EtOAc/Hexanes] to provide impure product, which was further purified by prep HPLC using (40-55% 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 (0.02 g, 18.6 % yield) as an off white solid.

MS:[M+H]+ 483.20.

’H NMR (400 MHz, DMSO-de) 5 8.22 (s, 1H), 7.98 (d, J = 2.0 Hz, 1H), 7.86 (s, 1H), 7.72 (dd, J = 7.9, 1.9 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 6.86 (t, J = 7.7 Hz, 1H), 6.36 (dd, J = 11.9, 7.6 Hz, 2H), 5.92 (s, 1H), 4.03 (s, 1H), 3.86 (s, 3H), 3.32 (s, 1H), 3.09 (s, 1H), 2.72 (s, 1H), 2.18 (d, J = 29.4 Hz, 6H). l,5-dimethyl-4-[[4-methyl-6-(4-methylimidazol-l-yl)-3-pyridy l]sulfonyl]-3H-quinoxalin- 2-one (Broad_P_CaV3.3_408, Compound 65)

To a stirred solution of ethyl 2-[2-methyl-6-(methylamino)-N-[[4-methyl-6-(4- methylimidazol-l-yl)-3-pyridyl]sulfonyl]anilino]acetate (40 mg, 0.0684 mmol, 1.00 eq) in THF (1 mL), Methanol (1 mL) and Water (0.5 mL) was added Lithium hydroxide monohydrate (14 mg, 0.342 mmol, 5.00 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. The residue was diluted with EtOAc (50 mL) and the organic layer was washed with water (3 x 20 mL) and brine solition (3 x 20 mL). The combined organics were dried over Na2SC>4 and evaporated and crude product was purified by combi-flash column chromatography and was eluted with 1.2% MeOH in DCM as a gradient to provide impure product. The impure product was further purified by prep-HPLC and was eluted with 10-35% ACN in 0.1% TFA in water as a gradient to provide Broad_P_CaV3.3_408 (9.2 mg, 0.0221 mmol, 32% yield) as an off white solid.

1H NMR (400 MHz, Methanol-d4) 5 9.56 (s, 1H), 8.72 (s, 1H), 8.07 (s, 1H), 7.81 (s, 1H), 7.37 (t, J = 7.9 Hz, 1H), 7.20 (d, J = 7.7 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 4.66 (d, J = 17.7 Hz, 1H), 4.19 (d, J = 17.7 Hz, 1H), 2.68 (s, 3H), 2.59 (s, 3H), 2.42 (s, 3H), 2.16 (s, 3H). MS(ES): 412.4 [M+H]+. 5-methyl-4-[2-methyl-4-(4-methylimidazol-l-yl)phenyl]sulfony l-2,3-dihydro-lH- quinoxaline (Broad_P_CaV3.3_423, Compound 66)

To a cool suspension of tert-butyl 5-methyl-4-[2-methyl-4-(4-methylimidazol-l- yl)phenyl]sulfonyl-2,3-dihydroquinoxaline-l-carboxylate (0.28 g, 0.584 mmol, 1.00 eq) in 1,4-Dioxane (3 mL) was added Hydrogen chloride solution 4.0 M in dioxane (.06 mL, 1.75 mmol, 3.00 eq) at 0 °C. After 3h, the reaction mixture was concentrated under reduced pressure. The residue was purified via Biotage (5: 1 Hex/EtOAc; 12S column) to provide impure product, which was further purified by prep HPLC using (15-100% ACN in water containing 0.1% FA in water as modifier) as mobile phase to provide 5-methyl-4-[2-methyl- 4-(4-methylimidazol-l-yl)phenyl]sulfonyl-2,3-dihydro-lH-quin oxaline (0.050 g, 0.131 mmol, 22% yield) as off white solid.

1H NMR (400 MHz, DMSO-d6) 5 8.31 (d, J = 7.9 Hz, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.73 - 7.54 (m, 3H), 6.86 (q, J = 7.8 Hz, 1H), 6.36 (dd, J = 12.5, 7.7 Hz, 2H), 5.92 (s, 1H), 4.00 (s, 1H), 3.10 (s, 2H), 2.72 (s, 1H), 2.24 - 2.02 (m, 9H). tert-butyl 5-methyl-4-[2-methyl-4-(4-methylimidazol-l-yl)phenyl]sulfony l-2,3- dihydroquinoxaline- 1 -carboxylate A stirred suspension of tert-butyl 4-(4-bromo-2-methyl-phenyl)sulfonyl-5-methyl-2,3- dihydroquinoxaline-1 -carboxylate (0.73 g, 1.51 mmol, 1.00 eq), 4-methyl-lH-imidazole (0.25 g, 3.01 mmol, 2.00 eq) and Potassium phosphate tribasic (0.64 g, 3.01 mmol, 2.00 eq) in 1,4-Dioxane (7 mL) was degassed with nitrogen gas for 15 min. tBuXPhos (0.064 g, 0.151 mmol, 0.100 eq) and Tris(dibenzylideneacetone)dipalladium(0) (0.069 g, 0.0753 mmol, 0.0500 eq) was added to it and heated at 120 °C for 16h. The reaction mixture was filtered through celite and wash with EtOAc (2 ^ 30 mL), the filtrate was evaporated. The residue was purified via Biotage (2: 1 Hex/EtOAc; 12M column) to provide tert-butyl 5-methyl-4-[2- methyl-4-(4-methylimidazol-l-yl)phenyl]sulfonyl-2,3-dihydroq uinoxaline-l -carboxylate, (0.28 g, 0.584 mmol, 39% yield) as a white solid. MS(ESI):483[M+H]+.

(3R)-3,7-dimethyl-l-[2-methyl-4-(4-methylimidazol-l-yl)ph enyl]sulfonyl-indolineand (3S)-3,7-dimethyl-l-[2-methyl-4-(4-methylimidazol-l-yl)pheny l]sulfonyl-indoline (Broad_P_CaV3.3_645A and B) (Compounds 67 and 83)

The mixture of l-(4-bromo-2-methyl-phenyl)sulfonyl-3,7-dimethyl-indoline (250 mg, 0.657 mmol, 1.00 eq), 4-methyl-lH-imidazole (216 mg, 2.63 mmol, 4.00 eq), Potassium phosphate tribasic (279 mg, 1.31 mmol, 2.00 eq), tBuXPhos (56 mg, 0.131 mmol, 0.200 eq) in 1,4-Dioxane (5 mL) was degassed for 10 minutes. After degassing, Tris(dibenzylideneacetone)dipalladium(0) (60 mg, 0.0657 mmol, 0.100 eq) was added and the reaction mixture was heated at 120 °C for 16 h. After completion, the reaction was diluted with water (100 mL) and the product was extracted in ethyl acetate (100 mL x 3). The organic layer was dried over sodium sulphate and vacuum evaporated. The residue was purified by column chromatography in silica using 80%-90% ethyl acetate in hexane as mobile phase. The product fractions were vacuum evaporated to afford off white solid of racemic mixture (Int-1366). The racemic mixture was further purified by chiral prep HPLC in Chiralpak IG (250*21.0)mm,5p column using 0.1%DEA in propan-2-ol: methanol (50:50) in n-hexane containg 0.1% DEA as mobile phase. Both product fractions were evaportated under vaccum and lyophilized to afford off white solid of Broad_P_CaV3.3_645B (14 mg, 0.0357 mmol, 97.87% purity, 5% yield) and light yellow solid of Broad_P_CaV3.3_645A (21 mg, 0.0549 mmol, 8% yield).

Broad_P_CaV3.3 645 A

1H NMR (400 MHz, DMSO-d6) 5 8.34 (s, 1H), 8.04 - 7.99 (m, 1H), 7.70 (dd, J = 6.3, 2.6 Hz, 2H), 7.60 (s, 1H), 7.21 - 7.11 (m, 2H), 7.04 (d, J = 6.9 Hz, 1H), 4.20 (dd, J = 12.7, 7.3 Hz, 1H), 3.45 - 3.39 (m, 1H), 2.67 - 2.62 (m, 1H), 2.41 (s, 3H), 2.16 (d, J = 12.4 Hz, 6H), 1.01 (d, J = 6.7 Hz, 3H). MS(ESI): 382.0 [M+H]+.

Broad_P_CaV3.3 645B

1H NMR (400 MHz, DMSO-d6) 5 8.34 (s, 1H), 8.07 - 7.98 (m, 1H), 7.69 (d, J = 6.3 Hz, 2H), 7.61 (s, 1H), 7.19 - 7.11 (m, 2H), 7.04 (d, J = 6.8 Hz, 1H), 4.20 (dd, J = 12.7, 7.3 Hz, 1H), 3.41 (dd, J = 12.7, 10.2 Hz, 1H), 2.66 (d, J = 6.8 Hz, 1H), 2.41 (s, 3H), 2.16 (d, J = 12.5 Hz, 6H), 1.25 (s, 1H), 1.01 (d, J = 6.7 Hz, 3H). MS(ESI): 382.0 [M+H]+.

(2S)-l,2,5-trimethyl-4-[2-methyl-5-(l-methylpyrazol-4-yl) phenyl]sulfonyl-2,3- dihydroquinoxaline and (2R)-l,2,5-trimethyl-4-[2-methyl-5-(l-methylpyrazol-4- yl)phenyl]sulfonyl-2,3-dihydroquinoxaline (Broad_P_Cav3.3_442 and 443) (Compound 68 and Compound 557)

A stirred solution of 4-(5-bromo-2-methyl-phenyl)sulfonyl-l,2,5-trimethyl-2,3- dihydroquinoxaline (300 mg, 0.701 mmol, 1.00 eq) and l-methyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyrazole (175 mg, 0.842 mmol, 1.20 eq) in 1,4 Dioxane (4.7855 mL) was degassed with nitrogen gas for 15 min. Potassium carbonate (291 mg, 2.10 mmol, 3.00 eq) and Pd(dppf)C12 • DCM (11 mg, 0.0140 mmol, 0.0200 eq) was added to it and heated it at lOOoC for 2 h. After completion, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with brine solution (3 x 50 mL). The organic layer was dried over Na2SC>4 and evaporated. The residue was purified by combi-flash chromatography using Ethyl acetate: Hexanes (8 : 3 ) as a mobile phase, which was further purified by chiral HPLC (SFC) (CHIRALPAK AD-H (250*4.6mm) 5u), 0.1% DEA in MeOH) to provide Broad_P_Cav3.3_443 (17 mg, 0.0401 mmol, 6% yield) and Broad_P_Cav3.3_442 (13 mg, 0.0307 mmol, 4% yield)

Broad_P_CaV3.3_442

1H NMR (400 MHz, DMSO-d6) 5 8.20 (s, 1H), 7.94 (d, J = 1.9 Hz, 1H), 7.83 (s, 1H), 7.67 (dd, J = 8.0, 2.0 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 7.01 (t, J = 7.8 Hz, 1H), 6.55 (d, J = 7.5 Hz, 1H), 6.38 (d, J = 8.2 Hz, 1H), 4.36 (q, J = 12.2 Hz, 1H), 3.87 (s, 3H), 3.06 - 2.92 (m, 2H), 2.29 (s, 3H), 2.21 (s, 3H), 1.97 (s, 3H), 0.84 (d, J = 5.0 Hz, 3H). MS(ESI): 411.2[M+H]+.

Broad_P_CaV3.3 443

1H NMR (400 MHz, DMSO-d6) 5 8.19 (s, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.83 (s, 1H), 7.67 (dd, J = 7.9, 2.0 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 7.01 (t, J = 7.8 Hz, 1H), 6.55 (d, J = 7.4 Hz, 1H), 6.37 (d, J = 8.0 Hz, 1H), 4.36 (q, J = 12.2 Hz, 1H), 3.87 (s, 3H), 2.98 (q, J = 6.6, 3.5 Hz, 2H), 2.29 (s, 3H), 2.21 (s, 3H), 1.97 (s, 3H), 0.84 (d, J = 5.0 Hz, 3H). MS(ESI): 411.2 [M+H]+.

4-(5-bromo-2-methyl-phenyl)sulfonyl-l,2,5-trimethyl-2,3-d ihydroquinoxaline

To a solution 3,4,8-trimethyl-2,3-dihydro-lH-quinoxaline (0.50 g, 2.81 mmol, 1.00 eq) in pyridine was added Triethylamine (1.18 mL, 8.42 mmol, 3.00 eq), 4- Dimethylaminopyridine (0.34 g, 2.81 mmol, 1.00 eq) and 5-bromo-2-methyl-benzenesulfonyl chloride (2.27 g, 8.42 mmol, 3.00 eq) at room temperature. Reaction mixture was then stirred for 16 h at room temperature. 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 using 5% ethyl acetate in n-hexane to obtained Broad_P_Cav3.3_442_Int-885, (0.70 g, 1.64 mmol, 58% yield) as brown sticky solid. MS(ESI): 411.1 [M+H]+.

3,4,8-trimethyl-2,3-dihydro-lH-quinoxaline

To a solution of 3,4,8-trimethyl-l,3-dihydroquinoxalin-2-one (3.00 g, 15.8 mmol, 1.00 eq) in THF (30 mL) was added, IM LAH in THF (30 mL, 31.5 mmol, 2.00 eq) dropwise at -5°C. Reaction mixture was then heated upto 70 °C for 6 h. Reaction mixture was quenched 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. MS(ESI): 177.2[M+H]+.

3,4,8-trimethyl-l,3-dihydroquinoxalin-2-one

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) 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 3,4,8-trimethyl-l,3- dihydroquinoxalin-2-one, (3.00 g, 13.7 mmol, 34% yield) as yellow solid. MS(ESI): 191.2 [M+H]+.

3 , 8-dimethyl-3 ,4-dihy dro- 1 H-quinoxalin-2-one

To a solution of 2-bromo-6-methyl-aniline (10.00 g, 53.7 mmol, 1.00 eq) in Dimethyl sulfoxide (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) at room temperature. Reaction mixture was then heated up to 110 °C for 16 h. 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!nt-683A, (7.00 g, 32.6 mmol, 61% yield) as yellow solid. MS(ESI): 177.0 [M+H]+. l-isopropyl-4-methyl-3-[2-methyl-4-(4-methylimidazol-l-yl)ph enyl]sulfonyl-indole (Broad_P_CaV3.3_663)

To a solution of Broad_P_CaV3.3_557 (100 mg, 1.00 eq) in dimethylformamide (1 mL), added 60% Sodium hydride in Mineral oil (0.0099 g, 0.410 mmol, 1.50 eq) at 0 °C followed by addition of 2-iodopropane (.08 mL, 0.684 mmol, 2.50 eq) and reaction was stirred at 0 °C for 1 h. After completion, the reaction was quenched with water (20 ml) and extracted with ethyl acetate (3 x 30 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 10% DCM in Methanol as a mobile phase to provide impure product, which on further purification by Reverse phase prep HPLC using 30-100% ACN in water with 0.1% formic acid as a modifier to get Broad_P_CaV3.3_663 (7.0 mg, 0.0168 mmol, 6% yield) as white solid.

1H NMR (400 MHz, DMSO-d6) 5 8.34 (s, 1H), 8.25 (s, 1H), 7.93 (d, J = 8.5 Hz, 1H), 7.73 - 7.61 (m, 2H), 7.61 - 7.49 (m, 2H), 7.19 (t, J = 7.8 Hz, 1H), 6.94 (d, J = 7.3 Hz, 1H), 4.90 (p, J = 6.7 Hz, 1H),2.45 (s, 3H), 2.39 (s, 3H), 2.15 (s, 3H), 1.54 (d, J = 6.6 Hz, 6H). MS(ESI): 408.0 [M+H]+. l-(fluoromethyl)-4-methyl-3-[2-methyl-4-(4-methylimidazol-l- yl)phenyl]sulfonyl-indole (Broad_P_CaV3.3_656, Compound 71)

To the solution of 4-methyl-3-[2-methyl-4-(4-methylimidazol-l-yl)phenyl]sulfony l- IH-indole (0.15 g, 0.410 mmol, 1.00 eq) in dimethylformamide (10 mL), added Sodium hydride 60% in mineral oil (15 mg, 0.616 mmol, 1.50 eq) at 0 °C followed by addition of Fluoroiodomethane (263 mg, 1.64 mmol, 4.00 eq) and reaction was stirred at 0 °C for 1 h. After completion, the reaction was quenched with water (20 ml) and extracted with ethyl acetate (3 x 30 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 10% DCM in Methanol as a mobile phase to provide impure product, which on further purification by Reverse phase prep HPLC using 40-100% ACN in water wirh 0.1% formic acid as a modifier to get Broad_P_CaV3.3_656 (18 mg, 0.0458 mmol, 11% yield) white solid.

1H NMR (400 MHz, DMSO-d6) 5 8.53 (s, 1H), 8.30 (d, J = 1.5 Hz, 1H), 8.00 (d, J = 8.7 Hz, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.72 (dd, J = 8.6, 2.4 Hz, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.57 (s, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.07 (d, J = 7.3 Hz, 1H), 6.55 (s, 1H), 6.41 (s, 1H), 2.55 (s, 3H), 2.46 (s, 3H), 2.17 (s, 3H). MS(ESI): 398.0 [M+H]+. l-[4-(l-ethyl-lH-pyrazol-4-yl)-2-methylbenzenesulfonyl]-8-me thyl-l,2,3,4- tetrahydroquinoxaline (Broad000415 - 017, Compound 72)

To a vial, tetrahydroquinoxaline (35 mg, 0.09179 mmol, 1 eq), ethylpyrazole boronic acid pinacol ester (24.4 mg, 0.1101 mmol, 1.2 eq), sodium carbonate (29.1 mg, 0.2753 mmol, 3 eq), XPhos Pd G2 (3.61 mg, 0.004589 mmol, 0.05 eq) were added in dioxane/water 4: 1 (0.8 mL). The reaction mixture was stirred at 90°C for 6 hours. The reaction mixture was partitioned between water and EtOAc. The organic layer was washed with brine, dried with MgSO4, filtered and concentrated. The crude product was purified with flash chromatography on silica gel eluting with hexane/EtOAc to afford the desired sulfonyl tetrahydroquinoxaline ethylpyrazole (14 mg, 36.6 % yield).

1H NMR (400 MHz, Chloroform-d) 5 7.93 (d, J = 8.1 Hz, 1H), 7.82 (s, 1H), 7.72 (s, 1H), 7.34 (d, J = 10.5 Hz, 2H), 6.93 (t, J = 7.7 Hz, 1H), 6.54 (d, J = 7.4 Hz, 1H), 6.31 (d, J = 7.9 Hz, 1H), 4.22 (q, J = 7.3 Hz, 3H), 3.13 (s, 3H), 2.29 (s, 3H), 2.28 (s, 3H), 1.53 (t, J = 7.3 Hz, 3H). MS (ESI): 397.4 [M+H]+.

Synthesis of Broad_P_CaV3.3 448 (Compound 73) and 451 (Compound 79) l-methyl-4-(p-tolyl)pyrazole: Intermediate-64 A A stirred solution of l-bromo-4-methyl-benzene (10.00 g, 58.5 mmol, 1.00 eq) and 1- methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazo le (14.60 g, 70.2 mmol, 1.20 eq) in 1,4-Dioxane (100 mL) and water (30 mL) was degassed with nitrogen gas for 15 min. Sodium carbonate (18.59 g, 175 mmol, 3.00 eq) and Pd(dppf)C12 - DCM (0.95 g, 1.17 mmol, 0.0200 eq) was added to it and heated it at 80C for 2h. After completion, the reaction mixture was diluted with ethyl acetate (200 mL) and washed eith brine solution (3 * 100 mL). The organic layer was dried over Na2SO4 and evaporated. The residue was purified by combi- flash chromatography using Ethyl acetae: Hexanes (3:7) as a mobile phase to provide Intermediate-64A, (7.00 g, 40.6 mmol, 70% yield) as a off white solid.

MS: [M+H]+ 173.2

2-methyl-5-(l-methylpyrazol-4-yl)benzenesulfonyl chloride: Intermediate-64B

To a stirred solution of l-methyl-4-(p-tolyl)pyrazole (7.00 g, 40.6 mmol, 1.00 eq) in Chloroform (50 mL) was drop wise added Chlorosulfuric acid (13.53 mL, 203 mmol, 5.00 eq) at 0C and allowed it to stir at RT for 3h. After completion of the reaction, the reaction mixture was poured into ice-cold water (100 mL) and extracted with DCM (3 x 70 mL). The combined organic layer was dried over Na2SO4 and evaporated to provide Intermediate-65 A, (8.00 g, 29.5 mmol, 73% yield) as an off-white solid.

^X H NMR (400 MHz, DMSO ) 5 11.66 - 10.92 (m, 4H), 8.16 (s, 1H), 7.89 (d, J = 3.1 Hz, 2H), 7.42 (dd, J = 7.7, 2.0 Hz, 1H), 7.14 (d, J = 7.7 Hz, 1H), 3.87 (s, 3H). methyl (E)-2-methyl-3-(2-methylanilino)prop-2-enoate: Intermediate-891

To a stirred solution of 2-methylaniline (13.00 g, 121 mmol, 1.00 eq) and methyl 3,3- dimethoxy-2-methyl-propanoate (19.68 g, 121 mmol, 1.00 eq) in Benzene (4 mL) was added p-Toluenesulfonic acid (6.26 g, 36.4 mmol, 0.300 eq) and heated it in a sealed tube for 48 h. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organics were dried over Na2SO4 and evaporated. The residue was purified by combiflash using Ethyl acetate: Hexane (1 :9) as a mobile phase to provide Int- 891, (11.00 g, 53.6 mmol, 44% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) 5 9.88 (d, J = 12.3 Hz, 1H), 7.69 (d, J = 12.3 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 7.18 (d, J = 7.3 Hz, 2H), 6.86 (t, J = 7.4 Hz, 1H), 3.69 (s, 3H), 2.21 (s, 3H), 1.83 (s, 3H).

3,8-dimethyl-lH-quinolin-4-one: Intermediate-89 IB

A solution of methyl (E)-2-methyl-3-(2-methylanilino)prop-2-enoate (11.00 g, 52.7 mmol, 1.00 eq) in Diphenyl ehter (100 mL) was heated in heating mentel at 240 °C for 45 min and allowed it to cool to RT. the resultant solid was filtered through buchner funnel and washed with hexane to provide Int-891B, (7.00 g, 40.4 mmol, 77% yield) as an off white solid.

1H NMR (400 MHz, DMSO-d6) 5 10.96 (s, 1H), 8.09 - 7.93 (m, 1H), 7.79 (q, J = 7.7, 5.6 Hz, 1H), 7.56 - 7.37 (m, 1H), 7.17 (q, J = 7.5 Hz, 1H), 2.46 (s, 3H, merged with DMSO), 1.98 (d, J = 5.3 Hz, 3H).

3,8-dimethyl-l-[2-methyl-5-(l-methylpyrazol-4-yl)phenyl]s ulfonyl-quinolin-4-one: Broad_P_CaV3.3_448 (Compound 73)

To a stirred solution of 3,8-dimethyl-lH-quinolin-4-one (25 mg, 0.144 mmol, 1.00 eq) in DCM (1 mL) was added Triethylamine (.04 mL, 0.289 mmol, 2.00 eq) and followed by lot wise addition of 2-methyl-5-(l-methylpyrazol-4-yl)benzenesulfonyl chloride (39 mg, 0.144 mmol, 1.00 eq). The reaction mixture was allowed to stir at RT. After completion, the reaction mixture was poured into water (15 mL) and extracted with DCM (3 x 10 mL). The combined organics were dried over Na2SO4 and evaporated. The residue was purified by prep HPLc purification using (40-85% ACN in water containing 0.1% formic acid as a modifier) as a mobile phase to provide Broad_P_CaV3.3_448 (10 mg, 0.0240 mmol, 17% yield) as an off-white solid.

MS:[M+H]+ 408.0

1H NMR (400 MHz, DMSO-d6) 5 8.89 (s, 1H), 8.26 (s, 1H), 7.98 (dd, J = 7.9, 2.0 Hz, 1H), 7.95 - 7.89 (m, 2H), 7.66 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 7.0 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.44 (t, J = 7.7 Hz, 1H), 3.82 (s, 3H), 2.77 (s, 3H), 2.71 (s, 3H), 2.19 (s, 3H).

3,8-dimethyl-l-[2-methyl-4-(l-methylpyrazol-4-yl)phenyl]s ulfonyl-quinolin-4-one: Broad_P_CaV3.3_451 (Compound 79)

To a stirred solution of 3,8-dimethyl-lH-quinolin-4-one (90 mg, 0.520 mmol, 1.00 eq) in DCM (3.6 mL) was added Triethylamine (.14 mL, 1.04 mmol, 2.00 eq) and followed by lot wise addition of 2-methyl-4-(l-methylpyrazol-4-yl)benzenesulfonyl chloride (141 mg, 0.520 mmol, 1.00 eq). The reaction mixture was allowed to stir at RT. After completion, the reaction mixtue was poured into water (15 mL) and extracted with DCM (3 x 10 mL). The combined organics were dried over Na2SO4 and evaporated. The residue was purified by prep HPLc purification using (40-55% ACN in water containing 0.1% formic acid as a modifier) as a mobile phase to provide Broad_P_CaV3.3_451 (25 mg, 0.0614 mmol, 12% yield) as an off white solid.

MS:[M+H]+ 408.2

1H NMR (400 MHz, DMSO-d6) 5 8.88 (d, J = 3.5 Hz, 1H), 8.39 (d, J = 3.4 Hz, 1H), 8.17 - 8.05 (m, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.76 (dd, J = 8.3, 3.2 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.63 - 7.57 (m, 1H), 7.56 - 7.50 (m, 1H), 7.42 (td, J = 7.9, 3.3 Hz, 1H), 3.90 (d, J = 3.4 Hz, 3H), 2.79 (d, J = 3.4 Hz, 3H), 2.71 (d, J = 3.3 Hz, 3H), 2.19 (d, J = 3.4 Hz, 3H). 4-methoxy-l-methyl-3-[2-methyl-4-(4-methylimidazol-l-yl)phen yl]sulfonyl-indole

(Broad_P_CaV3.3_669, Compound 74)

To a solution of 3-(4-bromo-2-methyl-phenyl)sulfonyl-4-methoxy-l-methyl-indol e (0.30 g, 0.761 mmol, 1.00 eq) in dimethylformamide (3 mL) was added Potassium tertbutylate (0.26 g, 2.28 mmol, 3.00 eq), Copper(I) oxide (0.054 g, 0.380 mmol, 0.500 eq) and 4-methyl-lH-imidazole (0.25 g, 3.04 mmol, 4.00 eq) and stirred at 140 °C for 16 h. After completion, the reaction mixture was diluted with water (15 mL) and extracted with EtOAc (3 x 20 mL). The organics were dried over Na2SC>4 and evaporated under vacuum. The residue was purified via combi flash using DCM:MeOH (9:1) as a mobile phase to provide product which was further purified by prep HPLC purification to get a white solid of Broad_P_CaV3.3_669 (40 mg, 0.10 mmol, 13% yield).

1H NMR (400 MHz, DMSO-d6) 5 8.24-8.21 (m, 3H), 7.73 (dd, J = 2 Hz, 1H), 7.59 (d, J = 1.6 Hz, 1H), 7.52 (s, 1H), 7.19 (t, 1H), 7.14 (d, J = 1.6 Hz, 1H) 6.61 (d, J = 7.6 Hz, 1H) 3.88 (s, 3H), 3.63 (s, 3H), 2.43 (s, 3H), 2.15 (s, 3H). MS(ESI): 396.0 [M+H]+.

3-(4-bromo-2-methyl-phenyl)sulfonyl-4-methoxy-l-methyl-in dole

To a solution of 3-(4-bromo-2-methyl-phenyl)sulfanyl-4-methoxy-l-methyl-indol e (1.80 g, 4.97 mmol, 1.00 eq) in Tetrahydrofuran (14 mL) and Water (4 mL), OXONE (3.02 g, 19.9 mmol, 4.00 eq) was added at room temperature and stirred at same temperature for 16 h. The reaction was quenched in water (100 mL) and extracted with EtOAc (3 * 100 mL). The combined organics were dride over anhydrous Na2SC>4 and evaporated to get 3-(4-bromo-2- methyl-phenyl)sulfonyl-4-methoxy-l-methyl-indole, (1.00 g, 2.38 mmol, 48% yield).

MS(ESI): 396.2 [M+H]+. 3-(4-bromo-2-methyl-phenyl)sulfanyl-4-methoxy-l-methyl-indol e

To a stirred solution of 4-methoxy-l -methyl -indole (2.00 g, 12.4 mmol, 1.00 eq) and 4-bromo-2-methyl-benzenesulfonyl chloride (6.69 g, 24.8 mmol, 2.00 eq) in Dimethylformamide (20 mL) was added Tetrabutylammonium iodide (9.16 g, 24.8 mmol, 2.00 eq) at 25 °C. The reaction mixture was stirred at same temperature for 4 h. After completion, the reaction was quenched with saturated solution of NaiSiCh (200 mL) and extracted ethyl acetate (3 x 100 mL). The combined organics were washed with brine solution (2 x 100 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 3-(4-bromo-2-methyl-phenyl)sulfanyl-4-methoxy-l-methyl-indol e, (1.80 g, 3.73 mmol, 30% yield). MS(ESI): 362.2 [M+H]+.

Synthesis of Compound 75

Compound 75 l-(4-bromo-2-methylbenzenesulfonyl)-8-methyl-l,2,3,4-tetrahy droquinoline: Intermediate-

310

A solution of 4-bromo-2-methylbenzene-l -sulfonyl chloride (1.47 g, 5.49 mmol, 3 eq), 8-methyl-l,2,3,4-tetrahydroquinoline (0.27 g, 1.83 mmol, 1 eq), triethylamine (555 mg, 5.49 mmol, 3 eq) and 4-dimethylaminopyridine (11.1 mg, 91.5 pmol, 0.05 eq) in pyridine (3 mL) was stirred at 110 °C for 1 h in microwave irradiation. The reaction mixture was evaporated and the residue was purify by flash chromatography using [0-10% EtOAc/Hexanes] to provide l-(4-bromo-2-methylbenzenesulfonyl)-8-methyl-l, 2,3,4- tetrahydroquline (0.2 g, 28.7 % yield) as a yellow solid.

MS :[M+H]+ 380.00.

8-methyl-l-[2-methyl-4-(3-methyl-l,2-oxazol-5-yl)benzenes ulfonyl]-l,2,3,4- tetrahydroquinoline: Broad_P_CaV3.3_187 (Compound 75)

To a stirred solution of l-(4-bromo-2-methylbenzenesulfonyl)-8-methyl-l, 2,3,4- tetrahydroquinoline (0.15 g, 394 pmol, 1 eq), xphos (26.2 mg, 55.1 pmol, 0.14 eq) and palladium(II) acetat (6.17 mg, 27.5 pmol, 0.07 eq) in 1,4-Dioxane (53mL), degassed for 15 minutes with Nitrogen gas then 3-methyl-5-(tributylstannyl)-l,2-oxazole (293 mg, 788 pmol, 2 eq) was added and heated the reaction mixture at 100°C for 3h. After completion, the reaction mixture was quenched in water (lOOmL) and extracted with ethyl acetate (3 x 100 mL), combine organic layer was dried over sodium sulphate, filtered and concentrated under reduce pressure up to crude, this was purify by flash chromatography using [0-25% EtOAc/Hexanes] to provide impure product, which was further purified by prep HPLC using (55-75% ACN : MeOH (1 : 1) in water containing 0.1% formic acid as modifier) as mobile phase to provide 8-methyl-l-[2-methyl-4-(3-methyl-l,2-oxazol-5-yl)benzenesulf onyl]- 1,2,3,4-tetrahydroquinoline (0.0147 g, 9.80 % yield) as a white solid.

MS :[M+H]+ 383.00.

1H NMR (400 MHz, DMSO-d6) 5 8.01 (d, J = 8.7 Hz, 1H), 7.85 (d, J = 6.9 Hz, 2H), 7.19 - 7.11 (m, 2H), 7.06 (s, 1H), 6.96 (dd, J = 6.1, 3.0 Hz, 1H), 4.04 (s, 1H), 3.24 (s, 1H), 2.38 (s, 1H), 2.30 (d, J = 7.1 Hz, 6H), 2.13 (s, 3H), 1.92 (s, 1H), 1.56 (d, J = 28.7 Hz, 2H). l,5-dimethyl-4-[2-methyl-5-(l-methyl-lH-pyrazol-4-yl)benzene sulfonyl]-l,2,3,4- tetrahydroquinoxaline (Broad_P_Cav3.3_363, Compound 76)

To a stirred solution of 4-(5-bromo-2-methylbenzenesulfonyl)-l,5-dimethyl-l, 2,3,4- tetrahydroquinoxaline (0.3 g, 0.7588 mmol) were added l-methyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-pyrazole (189 mg, 0.9105 mmol), potassium carbonate (313 mg,

2.27 mmol) in 1,4-Dioxane (10 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 (61.9 mg, 0.07588 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 30 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 (0.12 g, 39.0 % yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) 5 8.21 (s, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.84 (s, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.01 (t, J = 7.9 Hz, 1H), 6.53 (d, J = 7.5 Hz, 1H), 6.44 (d, J = 8.2 Hz, 1H), 4.18 (d, J = 11.0 Hz, 1H), 3.86 (s, 3H), 3.25 (s, 1H), 2.39 (s, 3H),

2.28 (s, 3H), 2.02 (s, 3H). MS (ESI): 397.4 [M+H]+. 5-fluoro-l,4-dimethyl-3-[2-methyl-4-(4-methylimidazol-l-yl)p henyl]sulfonyl-indole

(Broad_P_CaV3.3 634, Compound 77)

A stirred suspension of 3-(4-bromo-2-methyl-phenyl)sulfonyl-5-fluoro-l,4-dimethyl- indole (0.35 g, 0.883 mmol, 1.00 eq), 4-methyl-lH-imidazole (0.15 g, 1.77 mmol, 2.00 eq) and Potassium t-butoxide (0.30 g, 2.65 mmol, 3.00 eq) in DMF (7.5289 mL) was degassed with nitrogen gas for 15 min. Copper(I)oxide (0.038 g, 0.265 mmol, 0.300 eq) was added to it and heated it at 120 °C for 15 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 prep HPLC to give Broad_P_CaV3.3_634 (150 mg, 0.371 mmol, 42% yield) as an off white solid. MS (ESI): 398.6 [M+H]+.

3-(4-bromo-2-methyl-phenyl)sulfonyl-5-fluoro-l,4-dimethyl -indole

To a stirred solution of 3-(4-bromo-2-methyl-phenyl)sulfanyl-5-fluoro-l,4-dimethyl- indole (0.40 g, 1.10 mmol, 1.00 eq) in THF (5 mL) and Water (4 mL) was added OXONE (2.70 g, 4.39 mmol, 4.00 eq) at 0°C. The reaction mixtutre was allowed to stir at RT for 12 h. After completion, the reaction mixture was dissolved in saturated solution of NaHCOs (50 mL) and extracted in ethyl acetate (3 x 50 mL). The combined organics were dried over Na2SC>4 and evaporated under vacuum to provide Broad_P_CaV3.3_634_Int_1317, (0.35 g, 0.632 mmol, 58% yield) as a yellow solid. MS(ESI): 398.2 [M+H]+.

3-(4-bromo-2-methyl-phenyl)sulfanyl-5-fluoro-l,4-dimethyl -indole

To a stirred a solution of 5-fluoro-l,4-dimethyl-indole (0.51 g, 3.13 mmol, 1.00 eq) and 4-bromo-2-methyl-benzenesulfonyl chloride (1.68 g, 6.25 mmol, 2.00 eq) in DMF (5 mL) was added TBAI (2.31 g, 6.25 mmol, 2.00 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 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_634_Int_1316, (0.40 g, 0.953 mmol, 30% yield) as a pale yellow semi solid.

5-fluoro- 1 ,4-dimethyl-indole

To a stirred solution of 5-fluoro-4-methyl-lH-indole (0.55 g, 3.69 mmol, 1.00 eq) in Dimethylformamide (6 mL) was added Sodium hydride 60 % dispersion in mineral oil (0.13 g, 5.53 mmol, 1.50 eq) at 0°C. The reaction mixture was allowed to stir at RT for Ihr. lodomethane solution (1.05 g, 7.37 mmol, 2.00 eq) was added at same tempreture. The reaction mixtutre was allowed to stir at RT for 16 h. After completion, the reaction mixture was dissolved in ice cooled water (40 mL) and extracted in ethyl acetate (3 x 40 mL). The combined organics were dried over Na2SC>4 and evaporated under vacuum to provide Broad_P_CaV3.3_634_Int_1315, (0.51 g, 2.98 mmol, 81% yield) as a brown liquid. 1H NMR (400 MHz, Chloroform-d) 5 7.28 - 7.23 (m, 1H), 7.19 - 7.09 (m, 3H), 6.64 - 6.60 (m, 1H), 3.82 (s, 3H).

5-fluoro-4-methyl-lH-indole

7-chloro-5-fluoro-4-methyl-lH-indole (0.80 g, 4.36 mmol, 1.00 eq) was dissolved with Ethanol (10 mL). Triethylamine (.91 mL, 6.54 mmol, 1.50 eq) was added to the reaction mixture, and the reaction mixture was stirred at 35 °C. Under an atmosphere of argon, Palladium on carbon (10 wt. %) (0.080 g, 0.752 mmol, 0.173 eq) was added to the reaction mixture. The reaction mixture was made an atmosphere of hydrogen from an atmosphere of argon and stirred for 16 h. The reaction mixture was filtered with Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (hexane:ethyl aceta te=98:2-91 :9) to give the title compound Broad_P_CaV3.3_634_Int_1314, (0.55 g, 3.41 mmol, 78% yield).

7-chloro-5-fluoro-4-methyl-lH-indole

(2-chloro-4-fluoro-5-methyl-phenyl)-hydroxy-oxo-ammonium (1.90 g, 9.97 mmol, 1.00 eq) was dissolved with anhydrous Tetrahydrofuran (100 mL), and the reaction mixture was stirred at -50° C. Vinylmagnesium bromide solution 1.0 M in THF (1 M in THF, 39.88 mL, 39.9 mmol, 4.00 eq) was added to the reaction mixture. The reaction mixture was raised slowly to -20 °C. for 1 h. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and a saturated salt solution. The obtained extract was concentrated under reduced pressure after drying with sodium sulfate. The obtained residue was purified by column chromatography on silica gel (hexane:ethyl acetate=95:5-91 :9) to give Broad_P_CaV3.3_634_Int_1313, (0.80 g, 3.84 mmol, 39% yield) as colourless oil. l,5-dimethyl-4-{[2-methyl-6-(l-methyl-lH-pyrazol-4-yl)pyridi n-3-yl]sulfonyl}-l,2,3,4- tetrahydroquinoxaline (Broad_P_Cav3.3_262, Compound 80)

To a stirred solution of 8-methyl-l-{[2-methyl-6-(l-methyl-lH-pyrazol-4-yl)pyridin- 3- (0.04 g, 104 pmol, 1 eq) in DMF (1 mL) was added potassium carbonate (43.1 mg, 312 pmol, 3 eq) at room temperature and stirred for 30 minutes followed by drop wise addition of methyl iodide (17.6 mg, 124 pmol, 1.2 eq) in DMF (0.2 mL) at room temperature and reaction mixture was stirred at same temperature for 16h. After completion, the reaction mixture was poured in 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 prep HPLC using (20-60% ACN in water containing 0.1% formic acid as modifier) as mobile phase to provide l,5-dimethyl-4-{[2-methyl-6-(l-methyl- lH-pyrazol-4-yl)pyridi-3-yl]sulfonyl}-l,2,3,4-tetrahydroquin oxaline (0.01 g, 23.1 % yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) 5 8.38 (s, 1H), 8.14 (d, J = 8.4 Hz, 1H), 8.06 (s, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.04 (t, J = 7.9 Hz, 1H), 6.57 (d, J = 7.5 Hz, 1H), 6.44 (d, J = 8.1 Hz, 1H), 4.19 (dd, J = 14.7, 7.1 Hz, 1H), 3.89 (s, 3H), 3.25 (s, 1H), 2.97 (s, 1H), 2.86 (s, 1H), 2.32 (d, J = 13.5 Hz, 6H), 2.12 (s, 3H). MS(ESI): 398.4 [M+H]+. Synthesis of Compound 82 To a stirred solution of 4-methyl-lH-indole (5.00 g, 38.1 mmol, 1.00 eq) in DMF (50 mL) was added Sodium hydride 60% in minaral oil (0.82 g, 34.3 mmol, 0.901 eq) at 0°C. The reaction mixtutre was allowed to stir at RT for Ihr. Methyl iodide (10826 mg, 76.2 mmol, 2.00 eq) was added at same tempreture. The reaction mixtutre was allowed to stir at RT for 12hr. After completion, the reaction mixture was dissolved in ice cooled water (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_556-Int-l 105A, (2.00 g, 13.8 mmol, 36% yield) as a brown liquid.

MS(ESI): 145.2 [M+H]+

3-((4-bromo-2-methylphenyl)thio)-l,4-dimethyl-lH-indole: To a stirred a solution of 1,4-dimethylindole (1.00 g, 6.89 mmol, 1.00 eq) and 4- bromo-2-methyl-benzenesulfonyl chloride (3.71 g, 13.8 mmol, 2.00 eq) in DMF (10 mL) was added TBAI (16.88 g, 45.7 mmol, 3.00 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_556_Int-l 106, (500 mg, 1.44 mmol, 21% yield) as a pale yellow semi solid.

1H NMR (400 MHz, Chloroform-d) 5 7.22 (dd, J = 16.0, 8.8 Hz, 2H), 7.05 (td, J = 8.6, 7.9, 2.5 Hz, 1H), 6.91 (d, J = 7.0 Hz, 1H), 6.56 (d, J = 8.4 Hz, 1H), 3.83 (d, J = 13.7 Hz, 3H), 2.58 (s, 3H), 2.43 (s, 2H).

3-((4-bromo-2-methylphenyl)sulfonyl)-l,4-dimethyl-lH-indo le:

To a stirred solution of 3-(4-bromo-2-methyl-phenyl)sulfanyl-l,4-dimethyl-indole (0.45 g, 1.30 mmol, 1.00 eq) in DCM (5 mL) was added m-CPBA (0.90 g, 5.20 mmol, 4.00 eq) at 0°C. The reaction mixtutre was allowed to stir at RT for 12 h. After completion, the reaction mixture was 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_556_Int-l 107, (420 mg, 1.11 mmol, 85% yield) as a yellow semi solid.

MS(ESI): 271.0 [M+H]+ l,4-dimethyl-3-((2-methyl-4-(4-methyl-lH-imidazol-l-yl)pheny l)sulfonyl)-lH-indole

(Compound 82):

A stirred suspension of 3-(4-bromo-2-methyl-phenyl)sulfonyl-l,4-dimethyl-indole (0.42 g, 1.11 mmol, 1.00 eq) , 4-methyl-lH-imidazole (0.18 g, 2.22 mmol, 2.00 eq) and DMF

(3 mL) was degassed with nitrogen gas for 15 min. Copper(I)oxide (0.048 g, 0.333 mmol, 0.300 eq) was added to it and heated it at 140oC 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 (1 : 1, Ethyl acetate: Hexanes) as a mobile phase to provide Broad_P_CaV3.3_556 (67mg) as a white solid.

MS(ESI): 379.48 [M+H]+

1H NMR (400 MHz, DMSO-d6) 5 8.28 (d, J = 12.2 Hz, 2H), 7.91 (d, J = 8.5 Hz, 1H), 7.71 (s, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.54 (s, 1H), 7.44 (d, J = 8.3 Hz, 1H), 7.21 (t, J = 7.7 Hz, 1H), 6.96 (d, J = 7.2 Hz, 1H), 3.91 (s, 3H), 2.53 (s, 3H), 2.41 (s, 3H), 2.15 (s, 3H).

2,8-dimethyl-l-[2-methyl-4-(l-methylpyrazol-4-yl)phenyl]s ulfonyl-quinolin-4-one (AG 001 030, Compound 84) Sodium carbonate (241 mg, 2.25 mmol, 3.00 eq), l-(4-bromo-2-methyl- phenyl)sulfonyl-2,8-dimethyl-quinolin-4-one (305 mg, 0.751 mmol, 1.00 eq) and l-methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (187 mg, 0.899 mmol, 1.20 eq) were added in a microwave tube. The system was purged 3 times between vacuum and a balloon of Argon. Then 1.4 DIOXANE (6.3 mL) and water (2.3 mL) previously degassed with a balloon of argon respectively in a different flask were added. Then Pd (dppf) Ch (11 mg, 0.0150 mmol, 0.0200 eq) was added quickly and the microwave tube was sealed with a balloon of argon. The tube was heated at 100 °C during 4 h. After completion, the reaction mixture was poured into water (50 mL) and extracted with Ethyl acetate (3 x 50 mL). The combined organic layers were washed 2 times with brine (50 mL), dried over Na2SC>4 and evaporated. The crude material was purified by column chromatography using (EtOAc/Hexane) (90/100) to provide 2,8-dimethyl-l-[2-methyl-4-(l-methylpyrazol-4-yl)phenyl]sulf onyl-quinolin-4-one (284 mg, 0.698 mmol, 93% yield) as a white powder.

1H NMR (400 MHz, Chloroform-d) 5 7.89 (d, 1H), 7.80 (s, 1H), 7.77 (d, 1H), 7.68 (s, 1H), 7.48 (d, 1H), 7.44 (s, 1H), 7.35 (d, 1H), 7.31 (t, 1H), 7.05 (s, 1H), 3.93 (s, 3H), 2.77 (s, 3H), 2.73 (s, 3H), 2.65 (s, 3H). MS: [M+H]+ 408.16.

8-methyl-l-[2-methyl-3-(l-methyl-lH-pyrazol-4-yl)benzenes ulfonyl]-l,2,3,4- tetrahydroquinoxaline (Broad_P_Cav3.3_271, Compound 85)

To a stirred solution of N-(2-amino-6-methylphenyl)-2-methyl-3-(l-methyl-lH- pyrazol-4-yl)benzene-l -sulfonamide hydrochloride (130 mg, 0.3308 mmol), in DMF (3 mL) was added dibromoethane (74.5 mg, 0.3969 mmol) and potassium carbonate (137 mg, 0.9923 mmol) at room temperature. The reaction mixture was heated at 80°C and stirred at same temperature for 2 h. After completion, the reaction mixture was poured in to ice-water (30 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 8-m ethyl- l-[2-m ethyl (25 mg, 19.8 % yield) as an white solid.

1H NMR (400 MHz, DMSO-d6) 5 7.99 - 7.86 (m, 2H), 7.61 (d, J = 6.6 Hz, 2H), 7.40 (t, J = 7.8 Hz, 1H), 6.85 (t, J = 7.7 Hz, 1H), 6.41 - 6.29 (m, 2H), 6.00 (s, 1H), 3.95 (s, 1H), 3.87 (s, 3H), 3.11 (s, 2H), 2.74 (s, 1H), 2.24 (s, 3H), 2.16 (s, 3H). MS (ESI): 383.0 [M+H]+. l,5-dimethyl-4-{[2-methyl-6-(2-methyl-l,3-oxazol-5-yl)pyridi n-3-yl]sulfonyl}-l,2,3,4- tetrahydroquinoxaline (Broad_P_Cav3.3_358, Compound 86)

To a stirred solution of 4-[(6-bromo-2-methylpyridin-3-yl)sulfonyl]-l,5-dimethyl- 1,2,3,4-tetrahydroquinoxaline (200 mg, 0.5046 mmol) were added 2-methyl-5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3-oxazole (126 mg, 0.6055 mmol), potassium carbonate (208 mg, 1.51 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 (41.2 mg, 0.05046 mmol) was added at room temperature and reaction mixture was heated at 90°C for 16 h. After completion, the reaction mixture was poured in to water (50 mL) and extracted with EtOAc (3 x 30 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 (50: 1 C^Ch/MeOH; 12S column) to provide l,5-dimethyl-4-{[2-m (62 mg, 29.6 % yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) 5 8.32 (d, J = 8.4 Hz, 1H), 7.80 (s, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.06 (t, J = 7.8 Hz, 1H), 6.59 (d, J = 7.5 Hz, 1H), 6.46 (d, J = 8.0 Hz, 1H), 4.23 (dd, J = 14.6, 7.4 Hz, 1H), 3.25 (d, J = 6.6 Hz, 1H), 2.97 (t, J = 9.0 Hz, 1H), 2.87 (q, J = 11.1 Hz, 1H), 2.54 (s, 3H), 2.32 (d, J = 3.1 Hz, 6H), 2.14 (s, 3H). MS (ESI): 399.3 [M+H]+. Synthesis of Compound 87

Compound 87

8-ethyl-l -[2-ethyl-5-(l -methyl- lH-pyrazol-4-yl)benzenesulfonyl]- 1,2, 3,4- tetrahydroquinoline: Broad_P_CaV3.3_222 (Compound 87)

A solution of 8-ethyl-l, 2,3, 4-tetrahydroquinoline (0.17 g, 1.05 mmol, 1 eq), 2-ethyl-5- (l-methyl-lH-pyrazol-4-yl)benzene-l-sulfonyl chlor (597 mg, 2.10 mmol, 2 eq), tri ethylamine (318 mg, 3.15 mmol, 3.0 eq) and 2-dimethylaminopyrid (128 mg, 1.05 mmol, 1.0 eq) in pyridine (8 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 [0-25% EtOAc/Hexanes] to provide impure product, which was further purified by prep HPLC using (35-75% ACN in water containing 0.1% formic acid as modifier) as mobile phase to provide 8-ethyl-l -[2-ethyl-5-(l -methyl- lH-pyrazol-4-yl)benzenesulfonnyl]- 1,2, 3,4- tetrahydroquinoline (0.011 g, 2.5 % yield) as a white solid.

MS: [M+H]+ 410.50.

1H NMR (400 MHz, DMSO-d6) 5 8.23 (s, 1H), 7.94 (d, J = 1.9 Hz, 1H), 7.86 (s, 1H), 7.79 (dd, J = 8.1, 1.9 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.27 - 7.13 (m, 2H), 6.94 (dd, J = 7.0, 2.0 Hz, 1H), 4.10 (s, 1H), 3.86 (s, 3H), 3.25 (s, 1H), 3.03 - 2.87 (m, 1H), 2.71 - 2.58 (m, 1H), 2.33 (s, 3H), 1.90 (s, 1H), 1.67 - 1.41 (m, 2H), 1.10 (t, J = 7.5 Hz, 3H), 0.98 (t, J = 7.4 Hz, 3H). Synthesis of rac-(2R)-2,4,8-trimethyl-l-[2-methyl-4-(4-methylimidazol-l- yl)phenyl] sulfonyl-2,3-dihydroquinoxaline and rac-(2S)-2,4,8-trimethyl-l- [2-methyl-4-

(4-methylimidazol-l-yl)phenyl]sulfonyl-2,3-dihydroquinoxa line (Compound 88 and

Compound 116)

Compound 88

Compound 116

3,5-dimethyl-3,4-dihydro-lH-quinoxalin-2-one: Intermediate 694

To a solution of 2-bromo-3-methyl-aniline (2.00 g, 10.7 mmol, 1.00 eq), DL-Alanine (2.87 g, 32.2 mmol, 3.00 eq), 1,2-Dimethylethylenediamine (.69 mL, 6.45 mmol, 0.600 eq) in Dimethyl sulfoxide (20 mL), was added Tripotassium phosphate (6.85 g, 32.2 mmol, 3.00 eq) and Copper(I) chloride (0.16 g, 1.61 mmol, 0.150 eq) at room temperature and the reaction mixture was heated at 110 °C for 24 h. After completion, the reaction mixture was poured in water (250 mL), and extracted in ethyl acetate (250 mL x 3). The combined organic layer was dried over sodium sulphate and vacuum evaporated to get yellow-brown semisolid residue. The residue was purified by column chromatography in silica using 20%-30% ethyl acetate in hexane. The product fraction was vacuum evaporated to afford light brown solid of 3,5- dimethyl-3,4-dihydro-lH-quinoxalin-2-one Int-694, (500 mg, 2.29 mmol, 21% yield).

MS(ESI): 177.14 [M+H]+

4-(4-bromo-2-methyl-phenyl)sulfonyl-3,5-dimethyl-l,3-dihy droquinoxalin-2-one:

Intermediate 695

695

To a solution of 3,5-dimethyl-3,4-dihydro-lH-quinoxalin-2-one (10.00 g, 45.4 mmol, 1.00 eq) in Di chloromethane (160 mL), was added Pyridine (18.32 mL, 227 mmol, 5.00 eq) at room temperature and then 4-bromo-2-methyl-benzenesulfonyl chloride (36.71 g, 136 mmol, 3.00 eq) in portion wise at 0°C. The reaction was stirred at room temperature for 16 h. After completion, the reaction was diluted with water (250 mL) and extracted in dichloromethane (250 mL x 3). The combined organic layer dried over sodium sulphate and vacuum evaporated. The residue obtained was purified by column chromatography in silica using 10%-20% ethyl acetate in hexane. The product fractions were vacuum evaporated to afford yellow solid of 4-(4-bromo-2-methyl-phenyl)sulfonyl-3,5-dimethyl-l,3- dihydroquinoxalin-2-one Int-695, (8.00 g, 9.38 mmol, 21% yield).

1H NMR (400 MHz, DMSO-d6) 5 10.23 (s, 1H), 7.65 - 7.48 (m, 3H), 7.21 (t, J = 7.8 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.65 (d, J = 7.9 Hz, 1H), 4.46 (q, J = 7.3 Hz, 1H), 2.42 (s, 3H), 1.93 (s, 3H), 1.09 (d, J = 7.3 Hz, 3H). MS(ESI): 411.0 [M+2H]+

4-(4-bromo-2-methyl-phenyl)sulfonyl-3,5-dimethyl-2,3-dihy dro-lH-quinoxaline: Intermediate 698A

To a solution of 4-(4-bromo-2-methyl-phenyl)sulfonyl-3,5-dimethyl-l,3- dihydroquinoxalin-2-one (5.00 g, 5.86 mmol, 1.00 eq) in Tetrahydrofuran (48 mL) was added Borane dimethyl sulfide complex solution (2 M in THF, 14.66 mL, 29.3 mmol, 5.00 eq) at room temperature dropwise and the reaction was heated at 70°C for 16 h. After completion, the reaction mixture was quenched dropwise in cold water (500 mL) and the product was extracted in ethyl acetate (250 mL x 3). The combined organic layer was dried over sodium sulphate and vacuum evaporated. The residue was purified by column chromatography in silica using 10%-20% ethyl acetate in hexane. The product fraction was vacuum evaporated to afford off white solid of 4-(4-bromo-2-methyl-phenyl)sulfonyl-3,5-dimethyl-2,3-dihydro - IH-quinoxaline Int-698A, (2.50 g, 5.75 mmol, 98% yield). MS(ESI): 397.0 [M+2H]+ l-(4-bromo-2-methyl-phenyl)sulfonyl-2,4,8-trimethyl-2,3-dihy droquinoxaline: Intermediate 698 698

To a solution of 4-(4-bromo-2-methyl-phenyl)sulfonyl-3,5-dimethyl-2,3-dihydro -lH- quinoxaline (2.50 g, 5.75 mmol, 1.00 eq) in dimethylformamide (22.75 mL), was added Potassium carbonate (2.39 g, 17.3 mmol, 3.00 eq) at room temperature, followed by dropwise addition of Methyl iodide (.72 mL, 11.5 mmol, 2.00 eq) at room temperature. The reaction mixture was then heated at 70°C for 16 h. After completion, the reaction was diluted with water (250 mL), and the product was extracted in ethyl acetate (250 mL x 3). The combined organic layer was dried over sodium sulphate and vacuum evaporated. The residue was the purified by column chromatography in silica using 20%-30% ethyl acetate in hexane. The product fraction was vacuum evaporated to get brown semisolid of l-(4-bromo-2-methyl- phenyl)sulfonyl-2,4,8-trimethyl-2,3-dihydroquinoxaline Int-698, (1.20 g, 2.29 mmol, 40% yield). MS(ESI): 409.0 [M]+ rac-(2R)-2,4,8-trimethyl-l-[2-methyl-4-(4-methylimidazol-l-y l)phenyl]sulfonyl-2,3- dihydroquinoxaline and rac-(2S)-2,4,8-trimethyl-l-[2-methyl-4-(4-methylimidazol-l- yl)phenyl]sulfonyl-2,3-dihydroquinoxaline

To a solution of l-(4-bromo-2-methyl-phenyl)sulfonyl-2,4,8-trimethyl-2,3- dihydroquinoxaline (250 mg, 0.476 mmol, 1.00 eq) in 1,4-dioxane (3.9 mL), was added 4- methyl-lH-imidazole (156 mg, 1.91 mmol, 4.00 eq), Tripotassium phosphate (202 mg, 0.953 mmol, 2.00 eq), and tBuXPhos (40 mg, 0.0953 mmol, 0.200 eq) and the reaction mixture was degassed for 10 minutes. After degassing, Tris(dibenzylideneacetone)dipalladium(0) (44 mg, 0.0476 mmol, 0.100 eq) was added to reaction and the reaction mixture was heated to 120°C for 16 h . The reaction was diluted with water (100 mL) and the product was extracted in ethyl acetate (150 mL x 3). The combined organic layer was dried over sodium sulphate and vacuum evaporated. The residue obtained was purified by column chromatography in silica using 30%-70% ethyl acetate in hexane. The product fraction was vacuum evaporated to afford 100 mg pink solid of racemic mixture of the product (Int-826). The racemic mixture was purified by chiral prep HPLC purification using 0.1% DEA in methanol as cosolvent in CHIRALCEL OJ-H (250*4.6mm) 5p column. The product fractions were distilled and the lyophilized to afford light pink solid of (2R)-2,4,8-trimethyl-l-[2-methyl-4-(4- methylimidazol-l-yl)phenyl]sulfonyl-2,3-dihydroquinoxaline Broad_P_CaV3.3_409 (20 mg, 0.0473 mmol, 10% yield) and impure Broad_P_CaV3.3_410. The impure Broad_P_CaV3.3_410 was further purified by prep HPLC purification using acetonitrile and 0.1% formic acid in water (15%-50%) as mobile phase. The product fraction was lyophilized to afford light pink solid of (2S)-2,4,8-trimethyl-l-[2-methyl-4-(4-methylimidazol-l- yl)phenyl]sulfonyl-2,3-dihydroquinoxaline Broad_P_CaV3.3_410 (7.8 mg, 0.0186 mmol, 4% yield).

BROAD_P_CaV3 .3 409

1H NMR (400 MHz, DMSO-d6) 5 8.30 (s, 1H),7.89 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 8.6 Hz, 2H), 7.58 (s, 1H), 7.04 (t, J = 7.8 Hz, 1H), 6.59 (d, J = 7.5 Hz, 1H), 6.46 (d, J = 8.1 Hz, 1H), 4.51 - 4.39 (m, 1H), 2.87 (dd, J = 11.6, 7.2 Hz, 1H), 2.62 (d, J = 11.9 Hz, 1H), 2.39 (s, 3H), 2.28 (s, 3H), 2.16 (s, 3H), 2.01 (s, 3H), 0.95 (d, J = 6.8 Hz, 3H). MS(ESI):411.7[M+H]+. [a]D20 = -7.00°

Chiral separation conditions: (CHIRALPAK OJ-H (250*4.6mm) 5u), 0.1% DEA in MeOH) and CO2 gas as a mobile phase. Order of elution: Fraction- 1 (RT: 3.7 min); Fraction-2 (RT: 4.12 min)

BROAD_P_CaV3 .3 410

1H NMR (400 MHz, DMSO-d6) 5 8.30 (d, J = 7.0 Hz, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.60 (dd, J = 22.8, 7.6 Hz, 3H), 7.04 (t, J = 8.0 Hz, 1H), 6.53 (dd, J = 52.1, 7.8 Hz, 2H), 4.45 (t, J = 7.5 Hz, 1H), 2.87 (s, 1H), 2.63 (s, 1H), 2.38 (d, J = 7.2 Hz, 3H), 2.27 (d, J = 7.3 Hz, 3H), 2.15 (d, J = 7.2 Hz, 3H), 2.01 (d, J = 7.2 Hz, 3H), 0.96 (d, J = 7.1 Hz, 3H). MS(ESI):411.2[M+H]+. [a]D20 = +6.00°

Chiral separation conditions: (CHIRALPAK OJ-H (250*4.6mm) 5u), 0.1% DEA in MeOH) and CO2 gas as a mobile phase. Order of elution: Fraction- 1 (RT: 3.7 min); Fraction-2 (RT: 4.12 min).

l,5-dimethyl-4-[2-methyl-4-(2-methyl-lH-imidazol-4-yl)ben zenesulfonyl]-l,2,3,4- tetrahydroquinoxaline (Broad_P_Cav3.3_292, Compound 89)

To a stirred solution of tert-butyl 4-{4-[(4,8-dimethyl-l,2,3,4-tetrahydroquinoxalin-l- yl)sulfonyl]-3-methylphenyl}-2-methyl-lH-imidazole-l-carboxy late (0.3 g, 0.6040 mmol) in DCM (2 mL) was added 4.0 M HC1 in dioxane (330 mg, 9.06 mmol) at 0°C. The reaction mixture was warmed at room temperature and stirred for 4 h. After completion, the reaction mixture was poured in to saturated NaHCOs solution (30 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 40 - 50 % ACN in 0.1% formic acid in water as a gradient to provide l,5-dimethyl-4-[2-me (0.04 g, 16.6 % yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) 5 12.00 (s, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.65 (s, 3H), 7.00 (t, J = 7.8 Hz, 1H), 6.48 (dd, J = 22.2, 7.8 Hz, 2H), 4.08 (d, J = 12.3 Hz, 1H), 3.21 (s, 1H), 2.95 (s, 1H), 2.77 (s, 1H), 2.43 (s, 3H), 2.31 (s, 3H), 2.25 (s, 3H), 2.02 (s, 3H). LCMS: 397.3

[M+H]+.

Synthesis of Compound 91 and Compound 118

Broad_P_CaV3.3_463 Broad_P_CaV3.3_464

Compound 91 Compound 118

3 , 8-dimethyl-3 ,4-dihy dro- 1 H-quinoxalin-2-one : 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 uptol 10 °C for 16 h. 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.

1H NMR (400 MHz, DMSO-d6) 5 9.56 (s, 1H), 6.68 (t, J = 7.6 Hz, 1H), 6.56 (d, J = 7.8 Hz, 1H), 6.47 (d, J = 7.4 Hz, 1H), 5.93 (s, 1H), 3.67 (q, J = 6.6 Hz, 1H), 2.41 (s, 1H), 2.16 (s, 3H), 1.24 (d, J = 6.6 Hz, 3H).

4-[(4-methoxyphenyl)methyl]-3,8-dimethyl-l,3-dihydroquino xalin-2-one:

A stirred suspension of 3,8-dimethyl-3,4-dihydro-lH-quinoxalin-2-one (1.00 g, 5.67 mmol, 1.00 eq), 4-methoxybenzaldehyde (0.93 g, 6.81 mmol, 1.20 eq) and Dibutyltin dichloride (2.59 g, 8.51 mmol, 1.50 eq) in THF (10 mL). After 15 min, Phenylsilane (2.8 mL, 22.7 mmol, 4.00 eq) was added to it and stirred at room tempreture for 16h. After 16h, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 40 mL). The organic layer was dried over Na2SO4 and evaporated. The residue was purified via column 20% EtOAc in Hexane to provide 4-[(4-methoxyphenyl)methyl]-3,8-dimethyl-l,3- dihydroquinoxalin-2-one, (1.60 g, 5.24 mmol, 92% yield) as a Brown solid.

MS: [M+H]+ 296.37

1H NMR (400 MHz, DMSO-d6) 5 9.76 (s, 1H), 7.26 (d, J = 8.1 Hz, 2H), 6.90 (d, J = 8.0 Hz, 2H), 6.74 (q, J = 7.2, 6.6 Hz, 1H), 6.58 (d, J = 7.7 Hz, 2H), 4.46 (dd, J = 14.7, 6.3 Hz, 1H), 4.13 (dd, J = 14.5, 6.4 Hz, 1H), 3.72 (d, J = 6.2 Hz, 4H), 2.20 (d, J = 6.2 Hz, 3H), 0.95 (t, J = 6.5 Hz, 3H), 0.88 (t, J = 7.2 Hz, 1H).

4-[(4-methoxyphenyl)methyl]-3,8-dimethyl-2,3-dihydro-lH-q uinoxaline: .0.

A stirred suspension of 4-[(4-methoxyphenyl)methyl]-3,8-dimethyl-l,3- dihydroquinoxalin-2-one (1.60 g, 5.40 mmol, 1.00 eq), in THF (20 mL). After 15 min, Lithium aluminum hydride solution 1.0 M in THF (1 M in , 26.99 mL, 27.0 mmol, 5.00 eq) was added to it at room tempreture and heated at 70 °C for 2h. After 2h, the reaction mixture was diluted with water (100 mL) solid was formed filter and elute was extracted with ethyl acetate (3 x 40 mL). The organic layer was dried over Na2SO4 and evaporated. The residue was purified via column (50% EtOAc in Hexane to provide Broad_P_CaV3.3_463_Int-908, (1.40 g, 4.09 mmol, 76% yield) as a off white solid.

MS: [M+H]+ 282.39

4-(4-bromo-2-methyl-phenyl)sulfonyl-l-[(4-methoxyphenyl)m ethyl]-2,5-dimethyl-2,3- dihy droquinoxaline :

A stirred suspension of 4-[(4-methoxyphenyl)methyl]-3,8-dimethyl-2,3-dihydro-lH- quinoxaline (1.40 g, 4.96 mmol, 1.00 eq), 4-bromo-2-methyl-benzenesulfonyl chloride (2.67 g, 9.92 mmol, 2.00 eq) in Acetonitrile (14 mL). After 15 min, Zinc oxide (0.040 g, 0.496 mmol, 0.100 eq) was added to it and stirred at room tempreture for 48h. The reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (3 x 20 mL). The organic layer was dried over Na2SO4 and evaporated. The residue was purified via Column 10% ethyl acetate in hexane to provide Broad_P_CaV3.3_463_Int-915, (800 mg, 1.55 mmol, 31% yield) as a off white solid. 1H NMR (400 MHz, DMSO-d6) 5 7.83 (d, J = 8.5 Hz, 1H), 7.71 (s, 1H), 7.69 - 7.60 (m, 1H), 6.97 (d, J = 8.2 Hz, 2H), 6.91 (q, J = 7.3, 6.8 Hz, 1H), 6.83 (d, J = 8.3 Hz, 2H), 6.52 (d, J = 7.6 Hz, 1H), 6.33 (d, J = 8.3 Hz, 1H), 5.76 (s, 1H), 4.22 (dd, J = 22.4, 11.0 Hz, 1H), 4.04 (s, 2H), 3.72 (s, 4H), 3.18 (d, J = 8.0 Hz, 2H), 2.16 (s, 3H), 2.10 (s, 3H), 0.86 (d, J = 5.3 Hz, 3H). l-[(4-methoxyphenyl)methyl]-2,5-dimethyl-4-[2-methyl-4-(l-me thylpyrazol-4- yl)phenyl] sulfonyl-2, 3 -dihydroquinoxaline :

A stirred suspension of 4-(4-bromo-2-methyl-phenyl)sulfonyl-l-[(4- methoxyphenyl)methyl]-2,5-dimethyl-2,3-dihydroquinoxaline (0.80 g, 1.55 mmol, 1.00 eq), l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyra zole (0.39 g, 1.86 mmol, 1.20 eq) and Potassium carbonate (0.64 g, 4.66 mmol, 3.00 eq) in dioxane (4 mL) and Water (2 mL) was degassed with nitrogen gas for 15 min. After 15 min, [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with di chloromethane (0.13 g, 0.155 mmol, 0.100 eq) was added to it and heated at 120 °C for 16h. After 16h, the reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (3 x 40 mL). The organic layer was dried over Na2SO4 and evaporated. The residue was purified via column 50% ethyl acetate in hexane to provide Broad_P_CaV3.3_463_Int-916, (647 mg, 1.20 mmol, 78% yield) as a brown semisolid.

1H NMR (400 MHz, DMSO-d6) 5 8.34 (s, 1H), 8.04 (s, 1H), 7.85 - 7.80 (m, 1H), 7.66 (s, 1H), 7.63 - 7.55 (m, 2H), 6.94 (s, 3H), 6.77 (d, J = 8.0 Hz, 3H), 6.52 (s, 1H), 6.31 (d, J = 8.3 Hz, 1H), 4.17 (s, 1H), 4.03 (s, 2H), 3.89 (s, 3H), 3.66 (s, 3H), 2.19 (s, 3H), 2.14 (s, 3H), 0.85 (s, 5H). MS: [M+H]+ 516.6. 2,5-dimethyl-4-[2-methyl-4-(l-methylpyrazol-4-yl)phenyl]sulf onyl-2,3-dihydro-lH- quinoxaline:

A stirred suspension of l-[(4-methoxyphenyl)methyl]-2,5-dimethyl-4-[2-methyl-4-(l- methylpyrazol-4-yl)phenyl]sulfonyl-2,3-dihydroquinoxaline (0.60 g, 1.16 mmol, 1.00 eq), in DCM (10 mL) Trifluoroacetic acid (.62 mL, 8.13 mmol, 7.00 eq) was added to it at 0°C and reaction mixture was allowed to warmed at room tempreture and stirred for 16h. After 16h, the reaction mixture was diluted with sodium bicarbonate solution (80 mL) and extracted with ethyl acetate (3 x 40 mL). The organic layer was dried over Na2SO4 and evaporated. The residue was purified via column 50% ethyl acetate in hexane to provide impure product, which was further purified by prep HPLC using (40-100% ACN in water and 0.1% Formic acid in water as modifier) as mobile phase to provide recemic product (185 mg), which was further submitted (95 mg) for chiral SFC separetion to provide Broad_P_CaV3.3_463 (16 mg, 0.0398 mmol, 3% yield) and Broad_P_CaV3.3_464 (9.9 mg, 0.0247 mmol, 2% yield) as a off white solid.

Broad_P_CaV3.3_463:

MS : [M+H]+ 396.51

1H NMR (400 MHz, DMSO-d6) 5 8.29 (s, 1H), 7.99 (s, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.63 - 7.52 (m, 2H), 6.84 (t, J = 7.7 Hz, 1H), 6.34 (d, J = 7.7 Hz, 2H), 5.92 (s, 1H), 3.97 - 3.89 (m, 1H), 3.87 (s, 3H), 3.02 - 2.93 (m, 1H), 2.71 (d, J = 13.8 Hz, 1H), 2.19 (s, 3H), 2.16 (s, 3H), 0.91 (d, J = 6.1 Hz, 3H).

Broad_P_CaV3.3_464:

MS : [M+H]+ 396.51 1H NMR (400 MHz, DMSO-d6) 5 8.29 (s, 1H), 7.99 (s, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.62 - 7.51 (m, 2H), 6.84 (t, J = 7.7 Hz, 1H), 6.34 (d, J = 7.8 Hz, 2H), 5.91 (s, 1H), 3.92 (dd, J = 14.1, 4.8 Hz, 1H), 3.87 (s, 3H), 3.02 - 2.93 (m, 1H), 2.70 (s, 1H), 2.17 (d, J = 11.3 Hz, 6H), 0.91 (d, J = 6.1 Hz, 3H). l-ethyl-4-methyl-3-[2-methyl-4-(4-methylimidazol-l-yl)phenyl ]sulfonyl-indole (Broad_P_CaV3.3_662, Compound 92)

A stirred suspension of 3-(4-bromo-2-methyl-phenyl)sulfonyl-l-ethyl-4-methyl- indole (0.22 g, 0.561 mmol, 1.00 eq), 4-methyl-lH-imidazole (0.092 g, 1.12 mmol, 2.00 eq) and Potassium tert-butoxide (0.19 g, 1.68 mmol, 3.00 eq)in DMF (4 mL) was degassed with argon gas for 15 min. After 15 min, Copper(I)oxide (0.024 g, 0.168 mmol, 0.300 eq) was added to it and heated it at 140 °C for 16 h. The progress of reaction was monitored by TLC using Ethyl acetate: Hexanes (3:7) as mobile phase. After completion of the reaction, 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 impured compound which was further purified by prep HPLC using 10-100% ACN in water (containing 1% formic acid as modifier) as mode phase to give Broad_P_CaV3.3_662 (38 mg, 0.0926 mmol, 17% yield) as an off white solid.

1H NMR (400 MHz, DMSO-d6) 5 8.33 (s, 1H), 8.25 (s, 1H), 7.92 (d, J = 8.6 Hz, 1H), 7.76 - 7.61 (m, 2H), 7.59 - 7.45 (m, 2H), 7.20 (t, J = 7.8 Hz, 1H), 6.94 (d, J = 7.2 Hz, 1H), 4.36 (q, J = 7.2 Hz, 2H), 2.54 (s, 3H), 2.40 (s, 3H), 2.15 (s, 3H), 1.40 (t, J = 7.2 Hz, 3H). MS(ESI): 394.0 [M+H]+.

3-(4-bromo-2-methyl-phenyl)sulfonyl-l-ethyl-4-methyl-indo le

To a stirred solution of 3-(4-bromo-2-methyl-phenyl)sulfonyl-4-methyl-lH-indole (0.21 g, 0.577 mmol, 1.00 eq) in Dimethylformamide (0.9381 mL) was added Sodium hydride 60 % dispersion in mineral oil (0.028 g, 1.15 mmol, 2.00 eq) at 0°C. The reaction mixtutre was allowed to stir at RT for Ihr. lodoethane solution (.12 mL, 1.44 mmol, 2.50 eq) was added at same tempreture. The reaction mixtutre was allowed to stir at RT for 16 h. After completion, the reaction mixture was dissolved in ice cooled water (40 mL) and extracted in ethyl acetate (3 x 40 mL). The combined organics were dried over Na2SC>4 and evaporated under vacuum to provide Broad_P_CaV3.3_662_Int_l 107A, (0.22 g, 0.561 mmol, 97% yield) as an brown liquid. MS ESI: 394.2 [M+H]+.

3-(4-bromo-2-methyl-phenyl)sulfonyl-4-methyl-lH-indole

To a stirred solution of 3-(4-bromo-2-methyl-phenyl)sulfanyl-4-methyl-lH-indole (0.77 g, 2.30 mmol, 1.00 eq) in DCM (10 mL) was added MCPBA (1.59 g, 9.21 mmol, 4.00 eq) at 0°C. The reaction mixtutre was allowed to stir at RT for 12 h. After completion, the reaction mixture was dissolved in saturated solution of NaHCOs (50 mL) and extracted in ethyl acetate (3 x 50 mL). The combined organics were dried over Na2SC>4 and evaporated under vacuum to provide 3-(4-bromo-2-methyl-phenyl)sulfonyl-4-methyl-lH-indole, (786 mg, 2.16 mmol, 94% yield) as an yellow semi solid.

1H NMR (400 MHz, DMSO-d6) 5 12.38 (s, 1H), 8.23 (d, J = 3.2 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.68 - 7.60 (m, 2H), 7.38 (d, J = 8.2 Hz, 1H), 7.15 (t, J = 7.7 Hz, 1H), 6.91 (d, J = 7.3 Hz, 1H), 5.77 (s, 1H), 3.76 (s, 1H), 2.47 (s, 3H), 2.37 (s, 3H). 3-(4-bromo-2-methyl-phenyl)sulfanyl-4-methyl-lH-indole

To a stirred a solution of 4-methyl-lH-indole (2.00 g, 15.2 mmol, 1.00 eq) and 4- bromo-2-methyl-benzenesulfonyl chloride (8.22 g, 30.5 mmol, 2.00 eq) in DMF (20 mL) was added TBAI (16.88 g, 45.7 mmol, 3.00 eq) at RT. The reaction mixture was stirred at same temperature for 6 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 3-(4-bromo-2-methyl-phenyl)sulfanyl-4-methyl-lH-indole, (765 mg, 2.30 mmol, 15% yield) as an pale yellow semi solid. MS(ESI): 330.1 [M-H]-.

4-[3-fluoro-2-methyl-4-(l-methyl-lH-pyrazol-4-yl)benzenes ulfonyl]-l,5-dimethyl- 1,2,3,4-tetrahydroquinoxaline (Broad_P_Cav3.3_304, Compound 94)

To a stirred solution of 4-(4-bromo-3-fluoro-2-methylbenzenesulfonyl)-l,5-dimethyl- 1,2,3,4-tetrahydroquinoxaline (0.52 g, 1.25 mmol) were added l-methyl-4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (312 mg, 1.50 mmol), potassium carbonate (518 mg, 3.75 mmol) in 1,4-Dioxane (10 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 (102 mg, 0.125 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 (50 mL) and extracted with EtOAc (3 x 30 mL). The organic layer was washed with brine solution (2 x 30 mL), dried over Na2SC>4 and evaporated. The product was added to a prep HPLC column and was eluted with 55% - 65% ACN in 0.1% formic acid in water as a gradient to provide 4-[3-fluoro-2-methyl (0.07 g, 13.5 % yield) as an off white solid.

1H NMR (400 MHz, Chloroform-d) 5 7.95 - 7.76 (m, 3H), 7.44 (t, J = 7.5 Hz, 1H), 7.06 (t, J = 7.9 Hz, 1H), 6.62 (d, J = 7.9 Hz, 1H), 6.39 (d, J = 8.3 Hz, 1H), 4.29 (s, 1H), 3.97 (d, J = 2.0 Hz, 3H), 3.27 (s, 1H), 2.95 (d, J = 8.2 Hz, 2H), 2.47 (d, J = 2.0 Hz, 3H), 2.43 - 2.33 (m, 3H), 2.01 (t, J = 2.7 Hz, 3H). MS (ESI): 415.3 [M+H]+. l,5-dimethyl-4-[2-methyl-4-(2-methylpyridin-4-yl)benzenesulf onyl]-l,2,3,4- tetrahydroquinoxaline (Broad_P_CaV3.3_298, Compound 95)

To a stirred solution of 4-(4-bromo-2-methylbenzenesulfonyl)-l,5-dimethyl-l, 2,3,4- tet (0.2 g, 0.5059 mmol, 1 eq), were added 2-methylpyridin-4-ylboronic acid (83.1 mg, 0.6070 mmol, 1.2 eq) and potassium carbonate (139 mg, 1.01 mmol, 2 eq) in 1,4-Dioxane (5 mL) at room temperature and reaction mixture was degassed with argon for 20 min followed by palladium(2+) bis(cyclopentyldiphenylphosphane) methylene ch (41.8 mg, 0.05059 mmol, 0.1 eq) was added at room temperature and 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 Na2SO4 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 l,5-dimethyl-4-[2- methyl-4-(2-methylpyridin-4-yl)benzenesulf (0.0685 g, 33.2 % yield)as a white solid.

1H NMR (400 MHz, DMSO-d6) 5 8.56 (d, J = 5.3 Hz, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.84 - 7.74 (m, 2H), 7.60 - 7.52 (m, 1H), 7.04 (t, J = 7.8 Hz, 1H), 6.56 (d, J = 7.6 Hz, 1H), 6.47 (d, J = 8.1 Hz, 1H), 4.18 (d, J = 11.5 Hz, 1H), 3.27 (s, 1H), 2.98 (s, 1H), 2.83 (s, 1H), 2.56 (s, 3H), 2.40 (s, 3H), 2.30 (s, 3H), 2.12 (s, 3H).

5-methyl-4-[2-methyl-4-(4-methylimidazol-l-yl)phenyl]sulf onyl-2,3-dihydro-l,4- benzoxazine (Broad_P_CaV3.3_426, Compound 96)

A stirred suspension of 4-(4-bromo-2-methyl-phenyl)sulfonyl-5-methyl-2,3-dihydro- 1,4-benzoxazine (0.40 g, 1.05 mmol, 1.00 eq), 4-methyl-lH-imidazole (0.17 g, 2.09 mmol, 1.99 eq) and Potassium tert-butoxide (0.24 g, 2.10 mmol, 2.00 eq) in DMF (5 mL) was degassed with nitrogen gas for 15 min. After 15 min, Copper(I) oxide (0.030 g, 0.210 mmol, 0.200 eq) was added to it and heated at 120 °C for 16h. After 16h, the reaction mixture was diluted with water (80 mL) andextracted with ethyl acetate (3 x 40 mL). The organic layers was dried over Na2SC>4 and evaporated. The residue was purified via Biotage (5: 1 Hex/EtOAc; 12S column) toprovide impure product, which was further purified by prep HPLC using (15-100% ACN in water containing 0.1% Formic acid in water as modifier) as mobile phase to provide 5-methyl-4-[2-methyl-4-(4-methylimidazol-l-yl)phenyl]sulfony l- 2,3-dihydro-l,4-benzoxazine (0.018 g, 0.0469 mmol, 4% yield) as a off white solid.

1H NMR (400 MHz, DMSO-d6) 5 9.21(s, 1H), 8.05(d, J = 8.8 Hz, , 1H), 7.91 (d, , J = 12.4 Hz, 2H), 7.79 (d, J = 8.2 Hz 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.00 (t, J = 8.4 Hz 1H), 6.78 (t, J = 8.0 Hz 1H), 4.02 (d, J = 5.2, 2H), 3.87 (s, 2H), 2.44 (s,5H), 2.28 (s, 3H), 2.11 (s, 3H). MS(ESI):384.6 [M+H]+.

4-(4-bromo-2-methyl-phenyl)sulfonyl-5-methyl-2,3-dihydro- l,4-benzoxazine

A solution of 4-bromo-N-(2-hydroxy-6-methyl-phenyl)-2-methyl- benzenesulfonamide (0.75 g, 2.11 mmol, 1.00 eq) in DMF (4 mL) was added to a solution ofl,2-Dibromoethane (.22 mL, 2.53 mmol, 1.20 eq) and Potassium carbonate (0.58 g, 4.22 mmol, 2.00 eq) at room temperature and the resulting mixture was stirred at 80°C for 6 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 50 mL). The organics were dried over Na2SC>4 and evaporated. The residue was purified via Biotage (5: 1 Hex/EtOAc; 12S column) to provided4-(4-bromo-2-methyl-phenyl)sulfonyl-5- methyl-2,3-dihydro-l,4-benzoxazine, (0.40 g, 1.05 mmol, 50% yield).

1H NMR (400 MHz, DMSO-d6) 5 7.79 (d, J = 8.5 Hz, 1H), 7.75 (s, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.17 (d, J = 8.3 Hz, 1H), 6.98 (d, J = 7.4 Hz, 1H), 6.77 (t, J = 7.8 Hz, 1H), 4.03 - 3.94 (m, 2H), 3.82 (t, J = 4.5 Hz, 2H), 2.35 (s, 3H), 2.11 (s, 3H).

4-bromo-N-(2-hydroxy-6-methyl-phenyl)-2-methyl-benzenesul fonamide

To a stirred suspension of 2-amino-3-methyl-phenol (0.50 g, 4.06 mmol, 1.00 eq), in DCM (5 mL), was added 4-bromo-2-methyl-benzenesulfonyl chloride (2.10 g, 7.79 mmol, 2.00 eq) and Pyridine (1.8 mL, 22.3 mmol, 4.00 eq) stirred at 35°C. After 16h, the reaction mixture was diluted with Citric acid solution (50 mL) and extracted with ethyl acetate (3 x 40 mL). The organic layers was dried over Na2SC>4 and evaporated. The residue was purified via column chrometography (50:50 Hexane/EtOAc),to provide 4-bromo-N-(2-hydroxy-6-methyl- phenyl)-2-methyl-benzenesulfonamide, (0.75 g, 2.11 mmol) as a red solid. MS(ESI): 358.2[M+H]+.

8-ethyl-l-[2-methyl-5-(l-methyl-lH-pyrazol-4-yl)benzenesu lfonyl]-l, 2,3,4- tetrahydroquinoxaline (Broad_P_CaV3.3_225, Compound 97)

To a stirred solution of N-(2-amino-6-ethylphenyl)-2-methyl-5-(l-methyl-lH- pyrazol-4- (0.038 g, 0.1025 mmol, 1 eq), were added potassium carbonate (28.3 mg, 0.205 mmol, 2 eq) and dibromoethane (23.0 mg, 0.1229 mmol, 1.2 eq) in DMF (3 mL) at room temperature and reaction mixture was heated at 80°C for Ih. 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 (55-65% ACN in water containing 0.1% formic acid as modifier) as mobile phase to provide 8-ethyl-l-[2-methyl-5- (l-methyl-lH-pyrazol-4-yl)benzenesulfo (0.0098 g, 24.1 % yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) 5 8.21 (s, IH), 7.97 (d, J = 1.9 Hz, IH), 7.85 (s, IH), 7.71 (dd, J = 7.8, 2.0 Hz, IH), 7.31 (d, J = 8.0 Hz, IH), 6.91 (t, J = 7.7 Hz, IH), 6.43 (d, J = 7.3 Hz, IH), 6.33 (d, J = 8.0 Hz, IH), 5.87 (d, J = 4.1 Hz, IH), 4.07 (d, J = 14.2 Hz, IH), 3.86 (s, 3H), 3.09 (d, J = 11.3 Hz, 2H), 2.90 (dd, J = 14.6, 7.4 Hz, IH), 2.76 - 2.65 (m, IH), 2.56 (d, J = 7.5 Hz, IH), 2.09 (s, 3H), 1.07 (t, J = 7.5 Hz, 3H). N-(2,3-dihydro-l,4-benzodioxin-6-yl)-N,2-dimethyl-4-(l-methy lpyrazol-4- yl)benzenesulfonamide (AG 001 021, Compound 98)

N-(2, 3 -dihydro- 1 ,4-benzodioxin-6-yl)-2-methyl-4-(l -methylpyrazol-4- yl)benzenesulfonamide (100 mg, 0.259 mmol, 1.00 eq) and K2CO3 (108 mg, 0.782 mmol, 3.00 eq) were introduced in a vial. The vial headspace was purged with an argon balloon. DRY DMF (1.74 mL) was introduced before iodomethane (.02 mL, 0.313 mmol, 1.20 eq). The reaction mixture was set up at room temperature overnight. The crude mixture was concentraded. Then the residue was dissolved in Ethyl Acetate (10 mL). Water was added (15 mL). The aqueous phase was extracted with Ethyl Acetate (4 x 25 mL) and then washed with a 5 % LiCl solution (25 mL) and finally dried over Na2SC>4. The crude material was purified by column chromatography using (EtOAc/Hexane) (80/20) to provideN-(2, 3 -dihydro- 1,4- benzodioxin-6-yl)-N,2-dimethyl-4-(l-methylpyrazol-4-yl)benze nesulfonamide (82 mg, 0.205 mmol, 79% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) 5 7.78 (d, 1H), 7.68 (s, 1H), 7.33 (d, 1H), 6.74 (d, 1H), 6.63 (dd, 1H), 4.22 (s, 4H), 3.95 (s, 3H), 3.16 (s, 3H), 2.37 (s, 3H). MS: 400.19 [M+H]+.

Broad_P_CaV3.3_471

Synthesis of Compound 99 Compound 99

7-methyl-l-[2-methyl-4-(l-methylpyrazol-4-yl)phenyl]sulfo nyl-indole:

Broad_P_CaV3.3_471 (Compound 99)

To a stirred solution of 7-methyl-lH-indole (500 mg, 3.81 mmol, 1.00 eq) in DMF (10 mL) was added 60% Sodium hydride in mineral oil (183 mg, 7.62 mmol, 2.00 eq) at 10 °C and stirred at same temperature for 20 min. After 20 min, 2-methyl-4-(l-methylpyrazol-4- yl)benzenesulfonyl chloride (3096 mg, 11.4 mmol, 3.00 eq) was added to it and allowed it to stir at RT for . After 16h, the reaction mixture was poured into ice-cold water (100 mL). The resultant solid was filtered through buchner funnel. The residue was purified by comib-flash using DCM:Methanol (10: 1) to provide impure product which was furhter purified by prep HPLC purification using (55-65% ACN in water containing 0.1% formic acid as a modifier) to provide Broad_P_CaV3.3_471 (30 mg, 0.0817 mmol, 2% yield) as an off white solid.

MS: [M+H]+ 366.0 1H NMR (400 MHz, Chloroform-d) 5 8.28 (s, 1H), 7.98 (s, 1H), 7.85 (d, J = 3.9 Hz, 1H),

7.71 (s, 1H), 7.56 (dd, J = 20.1, 8.2 Hz, 2H), 7.44 (d, J = 8.4 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 7.04 (d, J = 7.3 Hz, 1H), 6.89 (d, J = 3.9 Hz, 1H), 3.86 (s, 3H), 2.40 (s, 3H), 2.34 (s, 3H). Synthesis of (3R)-l,3,5-trimethyl-4-[2-methyl-4-(4-methylimidazol-l-yl)ph enyl]sulfonyl- 3H-quinoxalin-2-one and (3S)-l,3,5-trimethyl-4-[2-methyl-4-(4-methylimidazol-l- yl)phenyl]sulfonyl-3H-quinoxalin-2-one (Compounds 100 and 392)

695 1071 Step-2 t-butyl Xphos(0.2eq), Chiral Separation Pd ₂ (dba) ₃ (0.1eq),K ₃ PO ₄ (2eq), 1 ,4-dioxane, 120°C,16 h

Compound 100

Compound 392

4-(4-bromo-2-methyl-phenyl)sulfonyl-l,3,5-trimethyl-3H-qu inoxalin-2-one: Intermediate 1071

To a mixture of 4-(4-bromo-2-methyl-phenyl)sulfonyl-3,5-dimethyl-l,3- dihydroquinoxalin-2-one (1.00 g, 1.17 mmol, 1.00 eq) and Potassium carbonate (486 mg, 3.52 mmol, 3.00 eq) in dimethylformamide (10 mL) was added Methyl Iodide (333 mg, 2.35 mmol, 2.00 eq) at room temperature and the reaction mixture was heated at 120 °C for 16 h. After completion, the reaction mixture was diluted with water (200 mL) and extracted in ethyl acetate (100 mL x 3). The combined organic layer was dried over sodium sulphate and evaporated under vacuum. The residue obtained was purified by column chromatography in silica using 5%-l 0% ethyl acetate in hexane. The product fraction was vacuum evaporated to afford yellow solid of 4-(4-bromo-2-methyl-phenyl)sulfonyl-l,3,5-trimethyl-3H-quino xalin- 2-one Int-1071, (900 mg, 1.15 mmol, 98% yield). MS(ESI): 425.2 [M+2H]+

(3R)-l,3,5-trimethyl-4-[2-methyl-4-(4-methylimidazol-l-yl )phenyl]sulfonyl-3H-quinoxalin-

2-one (Compound 100) and (3S)-l,3,5-trimethyl-4-[2-methyl-4-(4-methylimidazol-l- yl)phenyl]sulfonyl-3H-quinoxalin-2-one

The mixture of 4-(4-bromo-2-methyl-phenyl)sulfonyl-l,3,5-trimethyl-3H-quino xalin- 2-one (1000 mg, 1.28 mmol, 1.00 eq), tert-Butyl XPhos (109 mg, 0.256 mmol, 0.200 eq), 4- methyl-lH-imidazole (420 mg, 5.12 mmol, 4.00 eq), and Potassium phosphate (543 mg, 2.56 mmol, 2.00 eq) in 1,4-dioxane (5.42 mL) was degassed for 15 minutes under nitrogen. After degassing, Tris(dibenzylideneacetone)dipalladium(0) (117 mg, 0.128 mmol, 0.1000 eq) was added and the reaction mixture was heated to 120 °C for 16 h. After completion, the reaction mixture was diluted with water (100 mL) and the product was extracted in ethyl acetate (150 mL x 3). The combined organic layer was dried over sodium sulphate and vacuum evaporated. The residue was purified by column chromatography in silica using 90%-100% ethyl acetate in hexane. The product fraction was vacuum evaporated to afford impure Int- 1071 A (racemic mixture of product). The Int-1071 A was purified by prep HPLC Purification using 10%-35% acetonitrile in water containing 0.1% formic acid as mobile phase (Column: Sunfire C18(250*19)mm,5p). The product fraction was lyophilized to afford off white solid of Int-1071 A. The Int-1071 A was purified by chiral Prep SFC purification using 20% of 0.1% DEA in methanol: acetonitrile (50:50), in liquid carbon dioxide as mobile phase (Column: Chiralcel OXH (250*21)mm, 5p). The both isolated product fractions were distilled and lyophilized to afford off white solid of (3S)-l,3,5-trimethyl-4-[2-methyl-4-(4- methylimidazol-l-yl)phenyl]sulfonyl-3H-quinoxalin-2-one Broad_P_CaV3.3_539 (23 mg, 0.0547 mmol, 4% yield) and off white solid of (3R)-l,3,5-trimethyl-4-[2-methyl-4-(4- methylimidazol-l-yl)phenyl]sulfonyl-3H-quinoxalin-2-one Broad_P_CaV3.3_538 (22 mg, 0.0522 mmol, 4% yield).

Broad_P_CaV3.3_538

1H NMR (400 MHz, Methanol-d4) 5 8.22 (s, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.52 (s, 2H), 7.43 (s, 1H), 7.37 (t, J = 7.9 Hz, 1H), 7.20 (d, J = 7.7 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 4.78 (t, J = 7.3 Hz, 1H), 2.67 (s, 3H), 2.59 (s, 3H), 2.27 (s, 3H), 2.05 (s, 3H), 1.17 (d, J = 7.3 Hz, 3H). MS(ESI): 425.1 [M+H]+. [a]D ²⁵ = -88.01°

Chiral separation conditions: (CHIRALCEL OX-H (250*4.6mm) 5u), 0.1%DEA in MeOH: ACN (50:50) and CO2 gas as a mobile phase. Order of elution: Fraction-1 (RT: 5.79 min); Fraction-2 (RT: 6.28 min).

Broad_P_CaV3.3_539

1H NMR (400 MHz, Methanol-d4) 5 8.21 (s, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.52 (s, 2H), 7.43 (s, 1H), 7.37 (t, J = 7.9 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 6.92 (d, J = 8.1 Hz, 1H), 4.80 (t, J = 7.3 Hz, 1H), 2.67 (s, 3H), 2.59 (s, 3H), 2.27 (s, 3H), 2.05 (s, 3H), 1.17 (d, J = 7.3 Hz, 3H). MS(ESI): 425.2 [M+H]+. [a]D ²⁵ = +90.21° Chiral separation conditions: (CHIRALCEL OX-H (250*4.6mm) 5u), 0.1%DEA in MeOH: ACN (50:50) and CO2 gas as a mobile phase. Order of elution: Fraction-1 (RT: 5.79 min); Fraction-2 (RT: 6.28 min). l-cyclopropyl-4-methyl-3-[2-methyl-4-(4-methylimidazol-l-yl) phenyl]sulfonyl-indole (Broad_P_CaV3.3_664, Compound 101)

To a stirred a solution of 4-methyl-3-[2-methyl-4-(4-methylimidazol-l- yl)phenyl]sulfonyl-lH-indole (0.18 g, 0.493 mmol, 1.00 eq), in dichloromethane (5 mL) was added cyclopropylboronic acid (0.051 g, 0.591 mmol, 1.20 eq), 2,2'-Bipyridyl (0.077 g, 0.493 mmol, 1.00 eq) and Copper(I) acetate (0.060 g, 0.493 mmol, 1.00 eq) The reaction mixture was stirred at 80 °C same temperature for 7 h. After completion, the reaction was quenched with water (50 mL) and extracted with dichloromethane (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 crude product, which was further purified by reverse phase prep HPLC using 20% - 100% ACN in water (containing 0.1% Formic acid in water as modifier) as mobile phase to provide Broad_P_CaV3.3_664 (28 mg, 0.0695 mmol, 14% yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) 5 8.27 (s, 1H), 8.15 (s, 1H), 7.92 (d, J = 8.6 Hz, 1H), 7.74 - 7.52 (m, 4H), 7.24 (t, J = 7.8 Hz, 1H), 6.98 (d, J = 7.3 Hz, 1H), 3.62 (tt, J = 7.1, 3.9 Hz, 1H), 2.59 - 2.52 (m, 3H), 2.43 (d, J = 31.2 Hz, 3H), 2.15 (s, 3H), 1.19 - 1.04 (m, 6H). MS: [M+H]+ 406.0. 4-[4-(3-fluoro-l-methyl-lH-pyrazol-4-yl)-2-methylbenzenesulf onyl]-l,5-dimethyl-

1,2,3,4-tetrahydroquinoxaline (Broad_P_Cav3.3_308, Compound 102)

To a stirred solution of l,5-dimethyl-4-[2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxab (0.15 g, 339 pmol, 1 eq), was added 4-bromo-3-fluoro-l-methyl-lH-pyrazole (0.072 g, 402 pmol, 1.186 eq) and potassium carbonate (0.139 g, 1.00 mmol, 2.95 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 (0.0277 g, 33.8 pmol, 0.1 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 4-[4-(3-fluoro-l-methyl-lH-pyrazol-4-yl)-2-methylbenzenesulf (29% yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) 5 8.28 (d, J = 2.3 Hz, 1H), 7.91 (d, J = 8.3 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.45 (s, 1H), 7.00 (t, J = 7.8 Hz, 1H), 6.52 (d, J = 7.5 Hz, 1H), 6.45 (d, J = 8.1 Hz, 1H), 4.18 - 4.05 (m, 1H), 3.77 (s, 3H), 3.22 (s, 1H), 2.96 (s, 1H), 2.78 (s, 1H), 2.41 (s, 3H), 2.26 (s, 3H), 2.02 (s, 3H). MS (ESI): 414.5. 3-methyl-5-(4-methyl-3-((8-methyl-3,4-dihydroquinolin-l(2H)- yl)sulfonyl)phenyl)isoxazole (Broad_P_Cav3.3_112, Compound 103)

To a stirred solution of 8-m ethyl- 1,2,3, 4-tetrahydroquinoline (194 mg, 1.32 mmol), 4- (Dimethylamino)pyridine (67.1 mg, 0.55 mmol) in Pyridine (5.0 mL) was added 2-methyl-5- (3-methylisoxazol-5-yl)benzene-l-sulfonyl chloride (300 mg, 1.10 mmol) at room temperature. The reaction mixture was stirred at 70°C for 10 h. After completion, the reaction mixture was poured in to water (40 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with 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 3- methyl-5-(4-methyl (125 mg, 29.5 % yield) as an off white solid.

1H NMR (400 MHz, DMSO-d6) 5 8.20 (d, J = 1.9 Hz, 1H), 7.97 (dd, J = 7.9, 2.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.21 - 7.10 (m, 2H), 6.96 (dd, J = 5.9, 3.2 Hz, 1H), 6.89 (s, 1H), 3.74 (s, 2H), 2.31 (d, J = 2.8 Hz, 6H), 2.25 (s, 3H), 2.14 (s, 2H), 1.78 (s, 2H). MS (ESI) : 383.0 [M+H]+.

7-methyl-l-[2-methyl-4-(l-methylpyrazol-4-yl)phenyl]sulfo nyl-benzimidazole (Broad_P_CaV3.3_470, Compound 104)

A stirred suspension of l-(4-bromo-2-methyl-phenyl)sulfonyl-7-methyl- benzimidazole (0.20 g, 0.550 mmol, 1.00 eq), l-methyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazole (0.14 g, 0.660 mmol, 1.20 eq) and Potassium carbonate (0.15 g, 1.10 mmol, 2.00 eq) in 1,4-Dioxane (5 mL) was degassed with nitrogen gas for 15 min. After 15 min, [l,l'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.045 g, 0.0550 mmol, 0.100 eq) was added to it and heated at 110 °C for 16h. The reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (3 x 40 mL). The organic layers was 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 (30-100% ACN in water containing 0.1% Formic acid in water as modifier) as mobile phase to provide 7-methyl-l-[2-methyl-4-(l-methylpyrazol-4- yl)phenyl]sulfonyl-benzimidazole (86 mg, 0.234 mmol, 43% yield) as a Brown solid.

1H NMR (400 MHz, DMSO-d6) 5 8.85 (s, 1H), 8.32 (s, 1H), 8.01 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.74 (s, 1H), 7.67 (t, J = 5.7 Hz, 2H), 7.30 (t, J = 7.8 Hz, 1H), 7.15 (d, J = 7.4 Hz, 1H), 3.87 (s, 3H), 2.38 (s, 3H), 2.34 (s, 3H). MS(ESI): 367[M+H]+. l-(4-bromo-2-methyl-phenyl)sulfonyl-7-methyl -benzimidazole

A stirred suspension of N-(2-amino-6-methyl-phenyl)-4-bromo-2-methyl- benzenesulfonamide (0.50 g, 1.41 mmol, 1.00 eq) in 2-methoxyethanol (5 mL) was added Formamidine acetate (0.59 g, 5.63 mmol, 4.00 eq), the reaction mixture was heated at 80 °C for 16h. The reaction mixture was diluted with water(100 mL) and wash with EtOAc (2 x 50 mL), the filtrate was evaporated. The residue was purified via Biotage (2:1 Hex/EtOAc; 12M column) to provide l-(4-bromo-2-methyl-phenyl)sulfonyl-7-methyl-benzimidazole, (0.20 g, 0.548 mmol, 39% yield) as a off white solid. MS(ESI): 367.1[M+H]+.

N-(2-amino-6-methyl-phenyl)-4-bromo-2-methyl-benzenesulfo namide

To a cool suspension of tert-butyl N-[2-[(4-bromo-2-methyl-phenyl)sulfonylamino]- 3-methyl-phenyl]carbamate (1.30 g, 2.85 mmol, 1.00 eq) in 1,4-Dioxane (3 mL). Hydrogen chloride solution 4M in HC1 (0.31 g, 8.56 mmol, 3.00 eq) was added dropwise in to reaction suspensoin at 0 °C. After 5h, the reaction mixture was concentrated under reduced pressure. The residue was purified via Biotage (5: 1 Hex/EtOAc; 12S column) to provide N-(2-amino- 6-methyl-phenyl)-4-bromo-2-methyl-benzenesulfonamide, (1.00 g, 2.81 mmol, 99% yield) as a off white solid. MS(ESI): 357[M+H]+. tert-butyl N-[2-[(4-bromo-2-methyl-phenyl)sulfonylamino]-3-methyl-pheny l]carbamate

A stirred suspension of tert-butyl N-(2-amino-3-methyl-phenyl)carbamate (1.00 g, 4.50 mmol, 1.00 eq) and Pyridine (1.46 mL, 18.0 mmol, 4.00 eq) in Dichloromethane (10 mL) was added 4-bromo-2-methyl-benzenesulfonyl chloride (2.43 g, 9.00 mmol, 2.00 eq) and reaction was stirred at 25 °C for 16h. The reaction mixture was diluted with citric acid solution (100 mL), the reaction mixture was extracted with EtOAc (3 x 100 mL), the filtrate was evaporated. The residue was purified via Biotage (2: 1 Hex/EtOAc; 12M column) to provide tert-butyl N-[2-[(4-bromo-2-methyl-phenyl)sulfonylamino]-3-methyl- phenyl]carbamate, (0.98 g, 2.15 mmol, 48% yield) as a yellow semi-solid.

1H NMR (400 MHz, DMSO-d6) 5 9.36 (s, 1H), 7.65 (d, J = 20.0 Hz, 2H), 7.56 (d, J = 13.4 Hz, 3H), 7.15 (t, J = 7.9 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H), 2.43 (s, 3H), 2.08 (s, 3H), 1.99 (s, 1H), 1.40 (s, 9H). Synthesis of Compound 157

5-bromo-2-methyl-N-(2-methyl-6-nitrophenyl)benzene-l -sulfonamide: Intermediate-348 A A solution of 2-methyl-6-nitroaniline (1 g, 6.57 mmol, 1 eq), 5-bromo-2- m ethylbenzene- 1 -sulfonyl chloride (5.30 g, 19.7 mmol, 3 eq) and 2-dimethylaminopyrid (1.60 g, 13.1 mmol, 2 eq) in pyridine (20 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 [0-25% EtOAc/Hexanes] to provide 5-bromo-2-methyl-N-(2-methyl- 6-nitrophenyl)benzene-l-sulfona (1.1 g, 19.0 % yield) as a yellow solid.

MS :[M+H]+ 385.00 2-methyl-5-(l -methyl- lH-pyrazol-4-yl)-N-(2-methyl-6-nitrophenyl)benzene-l -sulfonamide:

Intermediate-348B

To a stirred solution of 5-bromo-2-methyl-N-(2-methyl-6-nitrophenyl)benzene-l- sulfona (l. l g, 2.85 mmol, 1 eq) l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 1H- (711 mg, 3.42 mmol, 1.2 eq) and potassium carbonate (1.18 g, 8.55 mmol, 3 eq) in 1,4- di oxane (20 mL) and water (2 mL) was degassed for 15 minutes with Nitrogen gas followed by tetrakis(triphenylph (329 mg, 285 pmol, 0.1 eq) was added and heated the reaction mixture at 100°C for 16 h. 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 2-methyl-5-(l-methyl-lH-pyrazol-4-yl)-N-(2-methyl-6-nitrophe (0.55 g, 42.7 % yield) as a yellow solid.

MS :[M+H]+ 387.00.

N-(2-amino-6-methylphenyl)-2-methyl-5-(l -methyl- lH-pyrazol-4-yl)benzene-l -sulfonamide:

Intermediate-349

A solution of 2-methyl-5-(l-methyl-lH-pyrazol-4-yl)-N-(2-methyl-6-nitrophe (0.35 g, 903 pmol, 1 eq) in acetic acid (1 mL) was added zinc (472 mg, 7.22 mmol, 8 eq) at room temperature and stirred at same temperature for 2 h. After completion of the reaction, the reaction mixture was filtered off, concentrated under vacuum followed by saturated NaHCOs solution was added to residue and aqueous was extracted with ethyl acetate (50 mL) and washed with water (2 x 50 mL). The organic layer was dried over Na2SO4 and evaporated to provide N-(2-amino-6-methylphenyl)-2-methyl-5-(l-methyl-lH-pyrazol-4 (0.17 g, 45.1 % yield) as a yellow solid.

MS :[M+H]+ 357.00.

8-methyl-l-[2-methyl-5-(l-methyl-lH-pyrazol-4-yl)benzenes ulfonyl]-l,2,3,4- tetrahydroquinoxaline: Broad_P_CaV3.3_223 (Compound 157)

A solution of N-(2-amino-6-methylphenyl)-2-methyl-5-(l -methyl- IH-pyrazol -4 (0.165 g, 462 pmol, 1 eq) and potassium carbonate (190 mg, 1.38 mmol, 3 eq) in DMF (1 mL) was drop wise added dibromoethane (130 mg, 693 pmol, 1.5 eq) at room temperature and stir at 80 °C for 16 h. After completion, reaction mass was quenched with water and aqueous was extracted with EtOAc (3 x 25 mL). The combined organic layer was washed with brine solution and dried over sodium sulphate, evaporated and the residue was purify by flash chromatography using [0-25% EtOAc/Hexanes] to provide impure product, which was further purified by prep HPLC using (40-55% ACN in water containing 0.1% formic acid as modifier) as mobile phase to provide 8-methyl-l-[2-methyl-5-(l-methyl-lH-pyrazol-4- yl)benzenesulf (0.048 g, 27.2 % yield) as a off white solid.

MS:[M+H]+ 483.20.

1H NMR (400 MHz, DMSO-d6) 5 8.22 (s, 1H), 7.98 (d, J = 2.0 Hz, 1H), 7.86 (s, 1H), 7.72 (dd, J = 7.9, 1.9 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 6.86 (t, J = 7.7 Hz, 1H), 6.36 (dd, J = 11.9, 7.6 Hz, 2H), 5.92 (s, 1H), 4.03 (s, 1H), 3.86 (s, 3H), 3.32 (s, 1H), 3.09 (s, 1H), 2.72 (s, 1H), 2.18 (d, J = 29.4 Hz, 6H). 1 ,5-dimethyl-4- [2-methyl-4-(2-methyl- 1 ,3-thiazol-4-yl)benzenesulfonyl] - 1 ,2,3,4- tetrahydroquinoxaline (Broad_P_Cav3.3_322, Compound 106)

To a stirred solution of l,5-dimethyl-4-[2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxab (0.15 g, 339 pmol, 1 eq), were added 4-bromo-2-methyl-l,3-thiazole (0.0722 g, 405 pmol,

1.195 eq) and potassium carbonate (0.139 g, 1.00 mmol, 2.95 eq) in 1,4-Dioxane (4 mL) and Water (1 mL) at room temperature and reaction mixture was degassed with argon for 20 min followed by bis(cyclopenta-l,3-dien-l-yldiphenylphosphane) methylene chi (0.0277 g, 33.8 pmol, 0.1 eq) was added at room temperature and 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 1,5- dimethyl-4-[2-methyl-4-(2-methyl- 1 ,3 -thiazol-4-yl)benzenesulfonyl]- 1 ,2,3,4- tetrahydroquinoxaline (0.02818 g, 20.0 % yield).

1H NMR (400 MHz, DMSO-d6) 5 8.16 (s, 1H), 8.01 - 7.86 (m, 3H), 7.01 (t, J = 7.8 Hz, 1H), 6.52 (d, J = 7.5 Hz, 1H), 6.45 (d, J = 8.0 Hz, 1H), 4.14 (dd, J = 14.7, 6.8 Hz, 1H), 3.23 (s, 1H), 2.96 (s, 1H), 2.79 (d, J = 7.7 Hz, 1H), 2.73 (s, 3H), 2.40 (s, 3H), 2.26 (s, 3H), 2.06 (s, 3H). MS (ESI): 413.6. l,5-dimethyl-4-{[2-methyl-4-(l-methyl-lH-pyrazol-4-yl)phenyl ]methyl}-l,2,3,4- tetr ahydroquinoxaline (Broad P Ca V3.3 317)

To a stirred solution of 4-[(4-bromo-2-methylphenyl)methyl]-l,5-dimethyl-l, 2,3,4- tetrahydroquinoxaline (0.2 g, 0.5792 mmol), were added l-methyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-lH- (0.144 g, 0.6920 mmol, 1.195 eq) and potassium carbonate (0.239 g, 1.72 mmol, 2.97 eq) in 1,4-Dioxane (4 mL) and water (1 mL) at room temperature and reaction mixture was degassed with argon for 20 min followed by bis(cyclopenta-l,3- dien-l-yldiphenylphosphane) methylene chi (0.0947 g, 0.1156 mmol, 0.2 eq) were 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 10 mL), dried over Na2SC>4 and evaporated. The product was purified by Column Chromatography to provide the pure product l,5-dimethyl-4-{[2-methyl-4-(l-methyl-lH-pyrazol-4-yl)phenyl (0.05 g, 25.0 % yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) 5 8.10 (d, J = 7.7 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.53 - 7.31 (m, 2H), 6.79 (q, J = 7.9 Hz, 1H), 6.59 (t, J = 8.1 Hz, 1H), 6.47 (t, J = 7.7 Hz, 1H), 3.87 (d, J = 7.7 Hz, 3H), 3.79 (d, J = 7.7 Hz, 2H), 3.18 (q, J = 5.7, 4.6 Hz, 2H), 2.92 (d, J = 8.1 Hz, 5H), 2.24 (d, J = 7.7 Hz, 3H), 2.13 (d, J = 7.7 Hz, 3H).

5-methyl-4-[2-methyl-4-(l-methyl-lH-pyrazol-4-yl)benzenes ulfonyl]-l-(2,2,2- trifluoroethyl)-l,2,3,4-tetrahydroquinoxaline (Broad000415 - 063, Compound 108) To a vial, N trifluoroethyl bromo sulfonamide (21 mg, 0.04532 mmol, 1 eq), sodium carbonate (14.4 mg, 0.1359 mmol, 3 eq), XPhos Pd G2 (1.78 mg, 0.002266 mmol, 0.05 eq) and methyl boronic acid pinacol ester (11.3 mg, 0.05438 mmol, 1.2 eq) were added in dioxane/water 4: 1 (0.3 mL). The reaction mixture was stirred at 80 °C for 2h30. After cooling down to room temperature, the reaction mixture was partitioned between water and EtOAc. The organic layer was washed with brine, dried with MgSO4, filtered and concentrated. The crude product was purified with reversed-phase chromatography (ACN/water) to afford the desired N trifluoroethyl methyl pyrazole sulfonamide (6.8 mg, 32.3 % yield).

1H NMR (400 MHz, Chloroform-d) 5 7.90 (d, J = 8.3 Hz, 1H), 7.79 (s, 1H), 7.68 (s, 1H), 7.38 - 7.33 (m, 1H), 7.31 (s, 1H), 7.06 (t, J = 7.9 Hz, 1H), 6.70 (d, J = 7.4 Hz, 1H), 6.55 (d, J = 8.1 Hz, 1H), 4.34 - 4.24 (m, 1H), 3.96 (s, 3H), 3.40 - 3.24 (m, 3H), 3.09 (s, 2H), 2.33 (s, 3H), 2.16 (s, 3H). MS (ESI): 465.3 [M+H]+.

8-methyl-l-[2-methyl-4-(3-methyl-l,2-oxazol-5-yl)benzenes ulfonyl]-l,2,3,4- tetrahydroquinoxaline (Broad_P_CaV3.3_252, Compound 109)

To a stirred solution of N-(2-amino-6-methylphenyl)-2-methyl-4-(3-methyl-l,2- oxazol-5 (0.071 g, 198 pmol, 1 eq), were added potassium carbonate (54.7 mg, 396 pmol, 2.0 eq) and ethylene dichloride (23.4 mg, 237 pmol, 1.2 eq) in DMF (2 mL) at room temperature and reaction mixture was heated at 80°C for Ih. 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 Na2SO4 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 (55-65% ACN in water containing 0.1% formic acid as modifier) as mobile phase to provide 8-methyl-l-[2-methyl-4-(3-methyl- l,2-oxazol-5-yl)benzenesulf (0.025 g, 32.9 % yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) 5 8.04 (d, J = 8.1 Hz, 1H), 7.84 (s, 2H), 7.06 (s, 1H), 6.87 (t, J = 7.7 Hz, 1H), 6.36 (dd, J = 13.7, 7.7 Hz, 2H), 5.92 (d, J = 3.2 Hz, 1H), 4.02 (s, 1H), 3.11 (s, 2H), 2.30 (s, 3H), 2.21 (d, J = 4.4 Hz, 6H).

N-(2-amino-6-methylphenyl)-2-methyl-4-(3-methyl-l,2-oxazo l-5-yl)benzene-l -sulfonamide

To a stirred solution of 2-methyl-4-(3-methyl-l,2-oxazol-5-yl)-N-(2-methyl-6- nitrophe (0.116 g, 299 pmol, 1 eq), was added zinc (156 mg, 2.39 mmol, 8 eq) in Acetic acid (5 mL) and reaction mixture was stirred at room temperature for 2h. After completion, the reaction mixture was poured in to NaHCOs (30 mL) and extracted with EtOAc (3 x 40 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 combiflash using [0-30% EtOAc/Hexanes] to provide pure product, N-(2-amino-6-methylphenyl)-2-methyl-4-(3 -methyl- l,2-oxazol-5 (0.071 g, 66.8 % yield) as a yellow oil. MS (ESI) : 358.0 [M+H]+.

2-methyl-4-(3-methyl-l,2-oxazol-5-yl)-N-(2-methyl-6-nitro phenyl)benzene-l -sulfonamide

To a stirred solution of 4-bromo-2-methyl-N-(2-methyl-6-nitrophenyl)benzene-l- sulfona (0.18 g, 467 pmol, 1 eq), was added 3-methyl-5-(tributylstannyl)-l,2-oxazole (347 mg, 934 pmol, 2 eq) in 1,4-Dioxane (5 mL) at room temperature and reaction mixture was degassed with argon for 20 min followed by palladium(II) acetate (7.31 mg, 32.6 pmol, 0.07 eq) and xphos (31.1 mg, 65.3 pmol, 0.14 eq) were added at room temperature and 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 crude product was purify by combiflash using [0-20% EtOAc/Hexanes] to provide pure product, 2-methyl-4-(3- methyl-l,2-oxazol-5-yl)-N-(2-methyl-6-nitrophe (0.116 g, 64.4 % yield) as a yellow solid. MS (ESI) : 386.0 [M-H]-.

4-bromo-2-methyl-N-(2-methyl-6-nitrophenyl)benzene-l -sulfonamide

To a stirred solution of 2-methyl-6-nitroaniline (0.3 g, 1.97 mmol, 1 eq) were added 4-bromo-2-methylbenzene-l -sulfonyl chloride (2.12 g, 7.88 mmol), 4-dimethylaminopyridine (240 mg, 1.97 mmol, 1 eq) and triethylamine (598 mg, 5.91 mmol, 3 eq) in Pyridine (6 mL) at room temperature and reaction mixture was heated at 100°C for 16 h. After completion, the reaction mixture was poured in to Citric acid solution in 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 Na2SO4 and evaporated. The crude product was purify by combiflash using [0-10% EtOAc/Hexanes] to provide pure product, 4-bromo-2-methyl-N-( (0.18 g, 23.7 % yield) as a yellow solid. MS (ESI) : 386 [M+H]+. 8-ethyl-l-[2-methyl-5-(3-methyl-l,2-oxazol-5-yl)benzenesulfo nyl]-l,2,3,4- tetrahydroquinoline (Broad_P_Cav3.3_165, Compound 110)

To a Stirred solution of 2-methyl-5-(3-methyl-l,2-oxazol-5-yl)benzene-l-sulfonyl chloride (1.01 g, 3.72 mmol), 8-ethyl-l,2,3,4-tetrahydroquinoline (0.2 g, 1.24 mmol) in Pyridine (2 mL) at RT, then triethylamine (250 mg, 2.48 mmol) and 4- dimethylaminopyridine (15.1 mg, 124 pmol) then Irradiated the reaction mixture at 100°C for Ih. After completion, the reaction mixture was quenched in 20% citric acid aqueous solution (20 mL) and then extracted with Ethyl acetate (3 x 15 mL), combined organic layer was dried over sodium sulphate and then filtered and concentrated under reduced pressure up to crude, this was purify by flash chromatography using [0-15% EtOAc/Hexanes] to provide impure product, which was further purified by prep HPLC using (45-55% ACN in water containing 0.1% formic acid as modifier) as mobile phase to provide 8-ethyl-l-[2-methyl- (52 mg, purity, 10.5 % yield).

1H NMR (400 MHz, DMSO-d6) 5 8.22 (d, J = 1.9 Hz, IH), 8.02 (dd, J = 7.9, 1.9 Hz, IH), 7.53 (d, J = 8.0 Hz, IH), 7.29 - 7.13 (m, 2H), 7.04 (s, IH), 6.96 (dd, J = 6.7, 2.2 Hz, IH), 4.13 (s, IH), 2.92 (dq, J = 15.1, 7.5 Hz, IH), 2.61 (dt, J = 14.6, 7.5 Hz, IH), 2.37 (d, J = 9.6 Hz, IH), 2.29 (s, 3H), 2.07 (s, 3H), 1.92 (s, IH), 1.52 (s, 2H), 1.11 (t, J = 7.5 Hz, 3H). MS(ESI):397[M+H]+.

8-ethyl-l-[2-methyl-5-(l-methyl-lH-pyrazol-4-yl)benzenesu lfonyl]-l,2,3,4- tetrahydroquinoline (Broad_P_CaV3.3_221, Compound 111)

To a stirred solution of 2-methyl-5-(l-methyl-lH-pyrazol-4-yl)benzene-l-sulfonyl chloride (750 mg, 2.77 mmol), 4-dimethylaminopyridine (676 mg, 5.54 mmol) in Pyridine (5 mL) at room temperature. The reaction mixture was stirred for 20 min. at room temperature. After 20 min., was added 2-methyl-5-(l-methyl-lH-pyrazol-4-yl)benzene-l-sulfonyl chloride (750 mg, 2.77 mmol) at same temperature. The reaction mixture was heated at 100°C and stirred for 15 h. After completion, the reaction mixture was poured in to citric acid solution (30 mL) and extracted with EtOAc (3 x 30 mL). The combined 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 55 - 65 % ACN in 0.1 % formic acid in water as a gradient to provide 8-ethyl-l-[2-methyl- (15 mg, 1.35 % yield) as a white solid.

1H NMR (400 MHz, Chloroform-d) 5 7.93 (d, J = 2.0 Hz, 1H), 7.72 (s, 1H), 7.60 (s, 1H), 7.51 (dd, J = 8.0, 2.0 Hz, 1H), 7.22 - 7.12 (m, 3H), 6.87 (d, J = 7.3 Hz, 1H), 4.18 (d, J = 7.3 Hz, 1H), 3.95 (s, 3H), 3.42 - 3.30 (m, 1H), 3.04 (dd, J = 15.1, 7.5 Hz, 1H), 2.72 (dd, J = 14.8, 7.6 Hz, 1H), 2.33 (d, J = 12.1 Hz, 1H), 2.17 (s, 3H), 2.10 (s, 1H), 1.76 (d, J = 11.1 Hz, 2H), 1.17 (t, J = 7.6 Hz, 3H). MS (ESI) : 396.2 [M+H]+.

8-methyl-l-[2-methyl-5-(2-methyl-lH-imidazol-4-yl)benzene sulfonyl]-l,2,3,4- tetrahydroquinoline (Broad_P_CaV3.3_210, Compound 112)

To a stirred solution of 8-methyl-l-[2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborol (100 mg, 233 pmol, 1 eq), 4-bromo-2-methyl-lH-imidazole (44.9 mg, 279 pmol, 1.2 eq) and potassium carbonate (96.6 mg, 699 pmol) in 1,4-Dioxane (2 mL) and Water (1 mL) at room temperature and reaction mixture was degassed with argon for 20 min followed by tetrakis(triphenylphosphine) palladium (26.9 mg, 23.3 pmol) was added at room temperature and reaction mixture was heated at 110°C for 16 h. 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 Na2SO4 and evaporated. The crude product was purify by flash chromatography using [0-50% EtOAc/Hexanes] to provide impure product, which was further purified by prep HPLC using (15-45% ACN in water containing 0.1% formic acid as modifier) as mobile phase to provide 8-methyl-l-[2-methyl-5- (2-methyl-lH-imidazol-4-yl)benzenesul (46.630 mg, 52.4 % yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) 5 12.08 (s, 1H), 8.25 (d, J = 1.9 Hz, 1H), 7.84 (dd, J = 7.9, 1.9 Hz, 1H), 7.54 (s, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 6.3 Hz, 2H), 6.94 (dd, J = 6.2, 2.8 Hz, 1H), 4.05 (s, 1H), 3.41 (s, 1H), 2.45 (s, 1H), 2.30 (d, J = 13.1 Hz, 6H), 2.00 (s, 3H), 1.90 (s, 1H), 1.58 (d, J = 67.3 Hz, 2H). MS (ESI): 382.0 [M+H]+. l,5-dimethyl-4-[2-methyl-4-(l-methyl-lH-l,2,3-triazol-4-yl)b enzenesulfonyl]-l,2,3,4- tetrahydroquinoxaline (Broad_P_CaV3.3_290, Compound 113)

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-tetrahydroquinoxa line (100 mg, 0.2260 mmol) were added 4-bromo-l-methyl-lH-l,2,3-triazole (54.8 mg, 0.3389 mmol), potassium carbonate (93.6 mg, 0.6779 mmol, 3 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) methylene chloride iron dichloride (18.4 mg, 0.02260 mmol) 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 (10: 1 Hex/EtOAc; 12S column) to provide l,5-dimethyl-4-[2-me (17 mg, 18.2 % yield) as a light brown solid.

1H NMR (400 MHz, DMSO-d6) 5 8.66 (s, 1H), 7.96 (d, J = 8.3 Hz, 1H), 7.87 - 7.74 (m, 2H), 7.01 (t, J = 7.9 Hz, 1H), 6.53 (d, J = 7.4 Hz, 1H), 6.45 (d, J = 8.2 Hz, 1H), 4.11 (s, 4H), 3.24 (s, 1H), 2.96 (s, 1H), 2.81 (s, 1H), 2.40 (s, 3H), 2.27 (s, 3H), 2.06 (s, 3H). MS (ESI) : 398.2 [M+H]+.

Synthesis of Broad_P_CaV3.3_434 and 435 (Compounds 114 and 523)

Step-2 63%

Na ₂ CO ₃ (3 eq), PdCI ₂ (dppf) (0.02 eq), Dioxane (10V), water (5V), 100°C, 3h

Broad_P_CaV3.3_434 Broad_P_CaV3.3_435

Compound 114

Compound 523 l-(5-bromo-2-methyl-phenyl)sulfonyl-4,8-dimethyl-3,4-dihydro -2H-quinoline: Intermediate-

879 To a stirred solution of 4,8-dimethyl-l,2,3,4-tetrahydroquinoline (250 mg, 1.55 mmol,

1.00 eq) in Pyridine (2.5 mL) was added Triethylamine (.65 mL, 4.65 mmol, 3.00 eq) and stir for 5 min. After 5 min, 5-bromo-2-methyl-benzenesulfonyl chloride (836 mg, 3.10 mmol, 2.00 eq) was lot wise added to it followed by addition of 4-Dimethylaminopyridine (189 mg, 1.55 mmol, 1.00 eq). The reaction mixute was heated in microwave for Ih. After completion of the reaction, the reaction mixture was poured into 5% citric acid solution (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layer was dried over Na2SO4 and evaporated. The residue was purified by Combi-flash machine using Ethyl acetate: Hexanes (2:8) to provide Int-879, (250 mg, 0.634 mmol, 41% yield) as light brown solid.

MS: [M+H]+ 395.0 rac-(4R)-4,8-dimethyl-l-[2-methyl-5-(l-methylpyrazol-4-yl)ph enyl]sulfonyl-3,4-dihydro-2H- quinoline and rac-(4S)-4,8-dimethyl-l-[2-methyl-5-(l-methylpyrazol-4-yl)ph enyl]sulfonyl-

3,4-dihydro-2H-quinoline: Broad_P_CaV3.3_434 and Broad_P_CaV3.3_435

To a stirred solution of l-(5-bromo-2-methyl-phenyl)sulfonyl-4,8-dimethyl-3,4- dihydro-2H-quinoline (150 mg, 0.380 mmol, 1.00 eq) and l-methyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyrazole (95 mg, 0.456 mmol, 1.20 eq) in 1,4-dioxane (3 mL) and Water (1 mL) was added Sodium carbonate (121 mg, 1.14 mmol, 3.00 eq) and degassed it with nitrogen for 5 min; after 5 min, Pd(dppf)C12 - DCM (6.2 mg, 0.00761 mmol, 0.0200 eq) was added to it and heated it at 100°C for 16 h. After completion, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic were washed with brine solution (70 mL), dried over Na2SO4 and evaporated. The residue was purified by Combi-flash machine using Ethyl acetate :Hexanes (5:5) to provide Broad_P_CaV3.3_434 (25 mg, 0.0632 mmol, 17% yield) as an off white solid and Broad_P_CaV3.3_435 (25 mg, 0.0610 mmol, 16% yield) as an off white solid.

Broad_P_CaV3.3_434

MS: [M+H]+ 396.0 1H NMR (400 MHz, DMSO-d6) 5 8.09 (s, 1H), 7.91 (d, J = 1.9 Hz, 1H), 7.77 (s, 1H), 7.69 (dd, J = 8.0, 2.0 Hz, 1H), 7.34 (d, J = 7.9 Hz, 1H), 7.16 (dt, J = 13.7, 7.2 Hz, 2H), 7.06 (d, J = 7.4 Hz, 1H), 3.92 (s, 1H), 3.87 (s, 3H), 3.54 (s, 1H), 2.28 (s, 3H), 2.22 (s, 3H), 2.05 - 1.97 (m, 1H), 1.27 (s, 2H), 1.08 (d, J = 6.8 Hz, 3H). [a]D ²⁵ = -70.81°

Chiral separation conditions: (CHIRALPAK IG (250*4.6mm) 5u), 0.1% DEA in MeOH: ACN (1 : 1)) and CO2 gas as a mobile phase

Order of elution: Fraction-1 (RT: 3.84 min); Fraction-2 (RT: 4.14 min)

Broad_P_CaV3.3_435 MS: [M+H]+ 396.0

1H NMR (400 MHz, DMSO-d6) 5 8.10 (s, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.77 (s, 1H), 7.69 (dd, J = 7.9, 2.0 Hz, 1H), 7.34 (d, J = 7.9 Hz, 1H), 7.22 - 7.12 (m, 2H), 7.06 (d, J = 7.4 Hz, 1H), 3.92 (s, 1H), 3.87 (s, 3H), 3.54 (s, 1H), 2.28 (s, 3H), 2.21 (s, 3H), 2.02 (dt, J = 13.0, 6.4 Hz, 1H), 1.26 (d, J = 6.9 Hz, 2H), 1.08 (d, J = 6.8 Hz, 3H). [a]D ²⁵ = +69.01°

Chiral separation conditions: (CHIRALPAK IG (250*4.6mm) 5u), 0.1% DEA in MeOH: ACN (1 : 1)) and CO2 gas as a mobile phase

Order of elution: Fraction-1 (RT: 3.84 min); Fraction-2 (RT: 4.14 min).

Synthesis of Compound 115

Broad_P_Cav3.3_168 Compound 115

5-(4-ethylphenyl)-3-methyl-l,2-oxazole: Intermediate-247 A solution of 2-methyl-5-(3-methyl-l,2-oxazol-5-yl)benzene-l-sulfonyl chlo (0.5 g,

1.84 mmol, 1 eq), 2-methyl-6-nitroaniline (839 mg, 5.52 mmol, 3 eq) and potassium tert- butox (619 mg, 5.52 mmol, 3.0 eq) in DMF (5 ml) was stirred at room temperature for 2 h. After completion, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (2 x 50 mL). The organic layer was dried over Na2SO4 and evaporated. The residue was purified via Biotage (5: 1 Hex/EtOAc; 12S column) to provide 2-methyl-5-(3- methyl (0.16 g, 9.67 % yield) as a solid.

MS: [M+H]+ 388.20

N-(2-amino-6-methylphenyl)-2-methyl-5-(3-methyl-l,2-oxazo l-5-yl)benzene-l -sulfonamide: Intermediate-248

A solution of 2-methyl-5-(3-methyl-l,2-oxazol-5-yl)-N-(2-methyl-6-nitrophe (0.16 g, 412 pmol, 1 eq) in acetic acid (2 ml) was added Zn (dust) at room temperature and stirred at same temperature for 5 h. After completion, the reaction mixture was filtered off, concentrated under vacuum followed by saturated NaHCOs solution was added to residue and aqueous was extracted with ethyl acetate (50 mL) and washed with water (2 x 50 mL). The organic layer was dried over Na2SO4 and evaporated to provide N-(2-amino-6- methylphenyl)-2-methyl-5-(3-methyl-l,2-oxazol-5 (0.12 g, 78.2 % yield) as a yellow solid.

MS:[M+H]+ 358.30.

8-methyl-l-[2-methyl-5-(3-methyl-l,2-oxazol-5-yl)benzenes ulfonyl]-l,2,3,4- tetrahydroquinoxaline: Broad_P_CaV3.3_168 (Compound 115)

A solution of N-(2-amino-6-methylphenyl)-2-methyl-5-(3-methyl-l,2-oxazol-5 (0.11 g, 307 pmol, 1 eq) and potassium carbonate (127 mg, 921 pmol, 3 eq) in DMF (5 ml) was drop wise added dibromoethane (86.4 mg, 460 pmol, 1.5 eq) at room temperature and stir at 80 °C for 5 h. After completion, reaction mass was quenched with water and aqueous was extracted with EtOAc (3 x 25 mL).The combined organic layer was washed with brine solution and dried over sodium sulphate, evaporated and the residue was purify by flash chromatography using [0-25% EtOAc/Hexanes] to provide impure product, which was further purified by prep HPLC using (45-53% ACN in water containing 0.1% formic acid as modifier) as mobile phase to provide 8-methyl-l-[2-methyl-5-(3-methyl-l,2-oxazol-5- yl)benzenesulf (0.01 g, 8.17 % yield) as a off white solid. MS:[M+H]+ 384.00. 1H NMR (400 MHz, DMSO-d6) 5 8.27 (d, J = 1.9 Hz, 1H), 7.98 (dd, J = 7.9, 1.9 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.00 (s, 1H), 6.87 (t, J = 7.7 Hz, 1H), 6.37 (dd, J = 17.7, 7.7 Hz, 2H), 5.90 (d, J = 3.4 Hz, 1H), 4.09 (s, 1H), 3.12 (s, 2H), 2.68 (s, 1H), 2.29 (s, 3H), 2.20 (d, J = 16.6 Hz, 6H).

1 ,5-dimethyl-4- [ 2-in et hy l-5-(3-m et hy 1- 1 ,2-oxazol-5-yl)benzenesulfonyl] - 1 ,2,3,4- tetrahydroquinoxaline: Broad_P_CaV3.3_169 (Compound 115)

Broad_P_Cav3.3_169 Compound 115

A solution of 8-methyl-l-[2-methyl-5-(3-methyl-l,2-oxazol-5-yl)benzenesulf (0.1 g, 0.2607 mmol, 1 eq) in DMF (1 mL) was added sodium hydride (31.1 mg, 0.7821 mmol, 3 eq) at room temparature and stirred for 15 min. To this reaction mixture methyl iodide (111 mg, 0.7821 mmol, 3 eq) was dropwise added and stirred for 16 h at room temparature. 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 up to crude, this was purify by flash chromatography using [0-50% EAOAc/Hexanes] to provide impure compound, which was further purified by prep HPLC using (55-80% ACN in water containing 0.1% formic acid as modifier) as mobile phase to provide l,5-dimethyl-4-[2-methyl-5-(3-methyl-l,2-oxazol-5-yl)benzene (0.016 g, 15.5 % yield) as a Off white solid.

MS:[M+H]+ 397.49.

1H NMR (400 MHz, DMSO-d6) 5 8.26 (d, J = 1.9 Hz, 1H), 7.97 (dd, J = 8.0, 1.9 Hz, 1H), 7.47 (d, J = 7.9 Hz, 1H), 7.09 - 6.93 (m, 2H), 6.55 (d, J = 7.5 Hz, 1H), 6.44 (d, J = 8.1 Hz, 1H), 4.23 (dd, J = 14.7, 7.0 Hz, 1H), 3.27 (s, 1H), 2.96 (dd, J = 11.4, 6.1 Hz, 1H), 2.76 (s, 1H), 2.35 (s, 3H), 2.29 (d, J = 3.8 Hz, 6H), 2.04 (s, 3H). l,5-dimethyl-4-[2-methyl-4-(6-methylpyridin-2-yl)benzenesulf onyl]-l,2,3,4- tetrahydroquinoxaline (Broad_P_Cav3.3_360, Compound 117)

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-tetrahydroquinoxa line (100 mg, 0.2260 mmol) were added 2-bromo-6-methylpyridine (46.6 mg, 0.2712 mmol), potassium carbonate (93.6 mg, 0.6779 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 (18.4 mg, 0.02260 mmol) was added at room temperature and reaction mixture was heated at 100°C for 10 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 product was added to a Prep HPLC column and was eluted with 45% - 60% ACN in 0.1% formic acid in water as a gradient to provide l,5-dimethyl-4-[2-me (10 mg, 10.4 % yield) as an off white solid.

1H NMR (400 MHz, Chloroform-d) 5 8.05 (d, J = 8.2 Hz, 1H), 7.88 (d, J = 9.2 Hz, 2H), 7.66 (t, J = 7.7 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 7.05 (t, J = 7.9 Hz, 1H), 6.60 (d, J = 7.6 Hz, 1H), 6.40 (d, J = 8.0 Hz, 1H), 4.28 (s, 1H), 3.27 (s, 1H), 3.03 (s, 1H), 2.96 (s, 1H), 2.63 (d, J = 8.3 Hz, 3H), 2.48 (s, 3H), 2.37 (s, 3H), 2.23 (s, 3H). MS (ESI) : 408.4 [M+H]+.

(3R)-3,5-dimethyl-4-[2-methyl-4-(l-methylpyrazol-4-yl)phe nyl]sulfonyl-2,3-dihydro-lH- quinoxaline and (3S)-3,5-dimethyl-4-[2-methyl-4-(l-methylpyrazol-4-yl)phenyl ]sulfonyl- 2,3-dihydro-lH-quinoxaline (Broad_P_Cav3.3_461 and 462) (Compound 118 and Compound 262)

To a stirred solution of 3,5-dimethyl-4-[2-methyl-4-(l-methylpyrazol-4- yl)phenyl]sulfonyl-l,3-dihydroquinoxalin-2-one (450 mg, 1.10 mmol, 1.00 eq) in THF (4 mL) was added Borane dimethyl sulfide (2 M in , 2.74 mL, 5.48 mmol, 5.00 eq) at OoC under nitrogen atmosphere. The reaction mixture was heated at 70 °C and stirred it at same temperature for 12 h The progress of reaction was monitored by TLC using Ethyl acetate: Hexanes (4: 1) as mobile phase. After completion, the reaction mixture was quenched with NH4Br solution (50 mL) and extracted with EtOAc (3 x 50 mL). The organics were washed with water (2 x 30 mL), brine solution (30 mL), 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 impure compound; which was further purified by prep HPLC using (0-65% ACN and water containing 0.1% formic acid as a modifier) as a mobile phase to provide 0.06 g of compound which was further purified by chiral HPLC using (CHIRALPAK IC (250*4.6mm) 5u), 0.1% DEA in MeOH) to provide Broad_P_Cav3.3_462 (21 mg, 0.0525 mmol, 5% yield) as an off white solid and Broad_P_Cav3.3_461 (17 mg, 0.0420 mmol, 4% yield) as an off white solid.

Broad_P_Cav3.3_461 (Compound 118)

1H NMR (400 MHz, DMSO-d6) 5 8.28 (s, 1H), 7.98 (s, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.56 (d, J = 10.0 Hz, 2H), 6.86 (t, J = 7.7 Hz, 1H), 6.36 (dd, J = 21.1, 7.7 Hz, 2H), 5.93 (d, J = 4.6 Hz, 1H), 4.12 (q, J = 6.5 Hz, 1H), 3.87 (s, 3H), 2.81 (dd, J = 12.0, 4.9 Hz, 1H), 2.74 - 2.65 (m, 1H), 2.20 (s, 3H), 2.13 (s, 3H), 0.90 (d, J = 6.8 Hz, 3H). MS(ESI) : 397.3 [M+H]+.

Broad_P_Cav3.3 462 1H NMR (400 MHz, DMSO-d6) 5 8.28 (s, 1H), 7.98 (s, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.56 (d, J = 10.3 Hz, 2H), 6.86 (t, J = 7.7 Hz, 1H), 6.36 (dd, J = 21.2, 7.7 Hz, 2H), 5.93 (d, J = 4.8 Hz, 1H), 4.12 (t, J = 6.7 Hz, 1H), 3.87 (s, 3H), 2.81 (dd, J = 11.5, 4.8 Hz, 1H), 2.70 (d, J = 5.5 Hz, 1H), 2.20 (s, 3H), 2.13 (s, 3H), 0.90 (d, J = 6.8 Hz, 3H). MS(ESI) : 397.3 [M+H]+. l,5-dimethyl-4-{[2-methyl-5-(l-methyl-lH-pyrazol-4-yl)thioph en-3-yl]sulfonyl}-l,2,3,4- tetrahydroquinoxaline (Broad_P_CaV3.3_279, Compound 119)

To a stirred solution of 4-[(5-bromo-2-methylthiophen-3-yl)sulfonyl]-l,5-dimethyl- 1,2 (0.110 g, 0.2740 mmol, 1 eq), were added l-methyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH- (68.4 mg, 0.3288 mmol, 1.2 eq) and potassium carbonate (75.7 mg, 0.548 mmol, 2 eq) in Dioxane (3 mL) at room temperature and reaction mixture was degassed with argon for 20 min followed by xphos (13.0 mg, 0.02740 mmol, 0.1 eq) and palladium(II) acetate (3.07 mg, 0.01370 mmol, 0.05 eq) were 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 10 mL), dried over Na2SC>4 and evaporated. The product was added to a Prep HPLC column and was eluted with 40 - 52% ACN in 5mM ammonium bicarbonate+ 0.1% NH3 in water as a gradient to provide l,5-dimethyl-4-{[2-methyl-5-(l- methyl-lH-pyrazol-4-yl)thioph (0.0216 g, 19.6 % yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) 5 8.05 (s, 1H), 7.71 (s, 1H), 7.16 (s, 1H), 7.02 (t, J = 7.8 Hz, 1H), 6.54 (d, J = 7.5 Hz, 1H), 6.44 (d, J = 8.2 Hz, 1H), 4.20 (dd, J = 14.6, 6.5 Hz, 1H), 3.83 (s, 3H), 3.31 - 3.23 (m, 1H), 3.05 (ddd, J = 17.8, 11.0, 6.5 Hz, 2H), 2.44 (s, 3H), 2.33 (s, 3H), 1.96 (s, 3H). l,4-dimethyl-3-[2-methyl-4-(4-methylimidazol-l-yl)phenyl]sul fonyl-pyrrolo[2,3- bjpyridine (LDECULTO_003-103, Compound 122)

A vial fitted with a stir bar was charged with 3-(4-bromo-2-methyl-phenyl)sulfonyl- l,4-dimethyl-pyrrolo[2,3-b]pyridine (20 mg, 0.0527 mmol, 1.00 eq), 4-methyl-lH-imidazole (8.7 mg, 0.105 mmol, 2.00 eq), and potassium phosphate tribasic (22 mg, 0.105 mmol, 2.00 eq). The vial was capped with a septum and the headspace was evacuated and refilled with nitrogen. 1,4-dioxane (1.0547 mL), sparged with nitrogen for 15 min prior to use, was added, followed by the addition of Me4 t-BuXPhos-Pd-G3 (6.7 mg, 0.00791 mmol, 0.150 eq). The headspace was evacuated and refilled with nitrogen (3 x). The vial was sealed with a green teflon-coated cap and the reaction mixture was stirred at 120 °C for 17 h (start: 10.14.20, 5.30 pm). The reaction mixture was allowed to cool to rt, diluted with 1,4-dioxane (2 mL) and the solides were filtered off using a nylon syringe filter. Volatiles were removed in vacuo. Crude material was purified by reverse phase prep HPLC (column: XBridge Prep C18 5 pM OBD 19 x 250 mm, load: DMSO (2.5 mL), flow: 18 mL/min, tubes: 13 x 100 mm, 5mL/tube, DAD = 254 nm, A: water 0.1% FA / B: MeCN 0.1% FA, gradient: 5 to 21.8% B over 0.3 min then 21.8 to 29.8% B over 22.9 min then 29.8 to 95% B over 1.4 min then 95% B for 5 min then 95 to 50% B over 5 min) to afford m = 4.77 mg (11.9 pmol, 23%) of the desired imidazole, as a white fluffy solid (lyophilized).

1H NMR (400 MHz, DMSO) 5 8.48 (s, 1H), 8.28 (d,J= 4.8 Hz, 1H), 8.25 (d,J= 1.4 Hz, 1H), 7.97 (d,J= 8.6 Hz, 1H), 7.72 (d,J= 2.4 Hz, 1H), 7.66 (dd,J= 8.6, 2.4 Hz, 1H), 7.53 (t,J= 1.3 Hz, 1H), 7.06 (dd, J = 4.5, 0.6 Hz, 1H), 3.92 (s, 3H), 2.54 (s, 3H), 2.47 (s, 3H), 2.15 (d, J = 0.6 Hz, 3H). MS (ESI): 381.19 [M+H]+.

3-(4-bromo-2-methyl-phenyl)sulfonyl-l,4-dimethyl-pyrrolo[ 2,3-b]pyridine

To a solution of 3-(4-bromo-2-methyl-phenyl)sulfanyl-l,4-dimethyl-pyrrolo[2,3 - b]pyridine (140 mg, 0.403 mmol, 1.00 eq) in a 4: 1 mixture of THF and water (8.1 mL) at 0 °C, was added oxone (991 mg, 3.23 mmol, 8.00 eq). The resulting mixture was stirred at RT for 17 h. Upon complete conversion showed by LCMS, the reaction mixture was poured in a sep funnel containing EtOAc (20 mL) and a NaHCOs sat. aq. solution (20 mL). The layers were separated and the aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated. Crude material was purified by silica gel chromatography (load: CH2CI2, column: Teledyne Isco RediSep Rf Gold 12 g, flow: 24 mL/min, tubes: 13 x 100 mm, gradient: CELCh/MeOEl 0% for 2 min then 0 to 10% over 25 min) to afford the desired sulfone (145 mg, 0.382 mmol, 95%) as an amorphous white solid.

1H NMR (400 MHz, CDC13) 5 8.29 (d,J= 4.9 Hz, 1H), 8.03 (s, 1H), 7.86 - 7.81 (m, 1H), 7.45 - 7.41 (m, 2H), 6.97 (dd,J= 4.9, 0.9 Hz, 1H), 3.98 (s, 3H), 2.56 (s, 3H), 2.52 (s, 3H). 3-(4-bromo-2-methyl-phenyl)sulfanyl-l,4-dimethyl-pyrrolo[2,3 -b]pyridine

To a solution of l,4-dimethylpyrrolo[2,3-b]pyridine (100 mg, 0.684 mmol, 1.00 eq) and 4-bromo-2-methyl-benzenesulfonyl chloride (369 mg, 1.37 mmol, 2.00 eq) in dimethylformamide (0.9772 mL) at RT, was added tetrabutylammonium iodide (505 mg, 1.37 mmol, 2.00 eq). The resulting mixture was stirred at 40 °C for 17 h. Upon complete conversion observed by LCMS, the volatiles were removed in vacuo. Crude material was purified by silica gel chromatography (load: CH2CI2, column: Teledyne Isco RediSep Rf Gold 12 g, flow: 24 mL/min, tubes: 13 x 100 mm, gradient: hexanes/EtOAc 2% for 2 min then 2 to 40% over 28 min) to afford the desired thioether (78 mg, 0.22 mmol, 33%) as light yellow solid.

1H NMR (400 MHz, CDC13) 5 8.27 (d,J= 5.0 Hz, 1H), 7.41 (s, 1H), 7.29 - 7.27 (m, 1H), 7.05 (dd,J= 8.6, 2.2 Hz, 1H), 6.90 (br d,J= 5.0 Hz, 1H), 6.49 (d,J= 8.5 Hz, 1H), 3.99 (s, 3H), 2.56 (s, 3H), 2.41 (s, 3H). MS (ESI): 348.45 [M+H]+.

8-ethyl-l-[2-ethyl-5-(l-methyl-lH-pyrazol-4-yl)benzenesul fonyl]-l,2,3,4- tetrahydroquinoxaline (Broad_P_CaV3.3_226, Compound 124)

To a stirred solution of N-(2-amino-6-ethylphenyl)-2-ethyl-5-(l-methyl-lH-pyrazol- 4-y (0.02 g, 0.05201 mmol, 1 eq), were added potassium carbonate (14.3 mg, 0.1040 mmol, 2 eq) and dibromoethane (11.7 mg, 0.06241 mmol, 1.2 eq) in DMF (2 mL) at room temperature and reaction mixture was heated at 80°C for Ih. 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 (50-65% ACN in water containing 0.1% formic acid as modifier) as mobile phase to provide 8-ethyl-l-[2-ethyl-5-(l -methyl- 1H- pyrazol-4-yl)benzenesulfon (0.002 g, 9.38 % yield) as a white solid.

IH NMR (400 MHz, DMSO-d6) 5 8.20 (s, IH), 7.94 (d, J = 2.0 Hz, IH), 7.84 (s, IH), 7.76 (dd, J = 8.0, 2.0 Hz, IH), 7.38 (d, J = 8.1 Hz, IH), 6.91 (t, J = 7.7 Hz, IH), 6.43 (d, J = 7.4 Hz, 1H), 6.34 (d, J = 7.9 Hz, 1H), 5.88 (d, J = 3.8 Hz, 1H), 3.86 (s, 3H), 3.09 (s, 2H), 2.88 (dd, J = 14.8, 7.4 Hz, 1H), 2.68 (s, 2H), 1.04 (dt, J = 21.2, 7.5 Hz, 6H).

Synthesis of Broad_P_CaV3.3_570 (Compound 125)

Compound 125

8-bromo-2,4-dichloro-5-methylquinoline: Intermediate-115 IB

To a mixture of 2-bromo-5-methyl-aniline (10.00 g, 53.7 mmol, 1.00 eq) and malonic acid (8.39 g, 80.6 mmol, 1.50 eq) was carefully added POCk (49.99 mL, 537 mmol, 10.0 eq) and heated in a sealed tube at 25 °C for 16h. After 16h, the reaction mixture was heated at 140 °C for Ih. After completion, the reaction mixture was concentrated to brown oil under vacuum and poured into cold water (200 mL) and extracted with DCM (3 * 150 mL). The organics were neutralized by NaHCOs solution until neutral pH. The mixture was filtered through celite. The organics were dried over Na2SO4 and eavporated. The residue was purified via combi flash using (1 :9, Ethyl acetate: Hexanes) as a mobile phase to provide Int- 115 IB, (6.00 g, 20.6 mmol, 38% yield) as a yellow solid.

MS: [M+H]+ 292.0

1H NMR (400 MHz, Chloroform-d) 5 8.15 (d, J = 7.8 Hz, IH), 7.98 (s, IH), 7.47 (d, J = 7.8 Hz, IH), 2.94 (s, 3H).

2,4-dichloro-5-methylquinoline: Intermediate-1151

To a solution of 8-bromo-2,4-dichloro-5-methyl-quinoline (6.00 g, 20.6 mmol, 1.00 eq) in Diethyl ether (120 mL) and THF (60 mL) was added a 2.5 M n-Butyllithium in THF (2.5 M in , 16.5 mL, 41.2 mmol, 2.00 eq) all at once at and stirred it at same temperature for 3h. After completion, the reaction mixture was quenched with water (150 mL) and extracted with ethyl acetate (3 x 70 mL). The combined organics were dried over Na2SO4 and evaporated. The residue was purified by combi-flash using Ethyl acetate: Hexanes (4:6) to provide Int-1151, (3.00 g, 11.8 mmol, 57% yield) as a white solid.

MS: [M+H]+ 214.2

IH NMR (400 MHz, DMSO-d6) 5 7.91 - 7.82 (m, 2H), 7.75 (t, J = 7.8 Hz, IH), 7.56 (d, J = 7.2 Hz, IH), 2.99 (s, 3H).

4-chloro-5-methylquinolin-2(lH)-one: Intermediate- 1152

To a stirred solution of 2,4-dichloro-5-methyl-quinoline (3.00 g, 11.8 mmol, 1.00 eq) in 1,4-Dioxane (30 mL) was added Con. HC1 (30.22 mL, 1234 mmol, 105 eq) and heated it at 110 °C for 16h. After completion, the reaction mixture was poured into ice cold water (50 mL) and filtered through buchner funnel. The obtained solid was suspended in methanol and filtered throgh buchner funnel (to remove undesired regio-siomer of product in filtrate) to provide Int-1152, (1.60 g, 8.20 mmol, 70% yield) as an off white solid.

MS: [M+H]+ 194.2

1H NMR (400 MHz, DMSO-d6) 5 12.01 (s, 1H), 7.45 (t, J = 7.8 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.07 (d, J = 7.4 Hz, 1H), 6.72 (d, J = 1.9 Hz, 1H), 2.82 (s, 3H).

4-chloro-l,5-dimethylquinolin-2(lH)-one: Intermediate-1153

To a stirred solution of 4-chloro-5-methyl-lH-quinolin-2-one (1.60 g, 8.20 mmol, 1.00 eq) in DMF (16 mL) was added Potassium carbonate (2263 mg, 16.4 mmol, 2.00 eq) and Potassium carbonate (2263 mg, 16.4 mmol, 2.00 eq) at RT. The reaction mixture was allowed to stir at same temperature for 16h. After completion, the reaction mixture was poured into ice cold water (150 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organics were dried over Na2SO4 and evaporated to provide Int-1153, (1.20 g, 5.47 mmol, 67% yield) as an off white solid.

MS:[M+H]+ 208.1

1H NMR (400 MHz, DMSO-d6) 5 7.55 (t, J = 8.0 Hz, 1H), 7.48 (d, J = 8.7 Hz, 1H), 7.15 (d, J = 7.3 Hz, 1H), 6.82 (s, 1H), 3.59 (s, 3H), 3.43 (s, 1H), 2.83 (s, 3H).

S-(6-bromo-4-methylpyridin-3-yl) O-ethyl carb onodi thioate: Intermediate- 1145 To a stirred suspension of 6-bromo-4-methyl-pyridin-3-amine (10.00 g, 53.5 mmol, 1.00 eq) in Con. HC1 (10 mL) was added Water (20 mL) and cooled to 0 °C. A solution of Sodium nitrite (4.43 g, 64.2 mmol, 1.20 eq) in Water (40 mL) was added to it and stirred it at same temperature for 5 min. After 5 min, a solution of potassium;ethoxymethanedithioate (10.28 g, 64.2 mmol, 1.20 eq) in Ethanol (40 mL) and Water (40 mL) was added to it and heated it at 60 °C for 2h. After completion, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (3 * 100 mL). The combined organics were dried over Na2SO4 and evaporated. The residue was purified by combi-flash using Hexanes to provide Int-1145, (5.00 g, 16.2 mmol, 30% yield) as a light yellow crystline material.

MS:[M+H]+ 294.1

1H NMR (400 MHz, DMSO-d6) 5 8.43 (s, 1H), 7.84 (s, 1H), 4.62 (q, J = 7.1 Hz, 2H), 2.36 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H).

4-[(6-bromo-4-methyl-3-pyridyl)sulfanyl]-l,5-dimethyl-qui nolin-2-one: Intermediate- 1154

To a stirred solution of O-ethyl (6-bromo-4-methyl-3-pyridyl)sulfanylmethanethioate (5.36 g, 17.3 mmol, 3.00 eq) in Methanol (24 mL) was added IN KOH (1 M in , 24.27 mL, 24.3 mmol, 4.20 eq) and allowed to stir it at RT for 2h. After 2h, the reaction mixture was evaporated to dryness. The residue was suspended in DMA (24 mL) and 4-chloro-l,5- dimethyl-quinolin-2-one (1.20 g, 5.78 mmol, 1.00 eq) was added to it followed by addition of Copper(I) bromide (1.24 g, 8.67 mmol, 1.50 eq) and Copper(I) oxide (1.24 g, 8.67 mmol, 1.50 eq). The reaction mixture was heated at 60 °C for 3h. After completion, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (3 * 70 mL). The combined organics were dried over Na2SO4 and evaporated. The residue was purified via combi flash using (1 : 1, Ethyl acetate: Hexanes) as a mobile phase to provide Int-1154, (200 mg, 0.491 mmol, 8% yield) as a light yellow solid.

MS:[M+H]+ 377.0 1H NMR (400 MHz, DMSO-d6) 5 8.52 (s, 1H), 7.92 (s, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H), 7.20 (d, J = 7.3 Hz, 1H), 5.51 (s, 1H), 3.55 (s, 3H), 3.01 (s, 3H), 2.36 (s, 3H).

4-[(6-bromo-4-methyl-3-pyridyl)sulfinyl]-l,5-dimethyl-qui nolin-2-one: Intermediate- 1155 A

To a stirred solution of 4-[(6-bromo-4-methyl-3-pyridyl)sulfanyl]-l,5-dimethyl- quinolin-2-one (200 mg, 0.491 mmol, 1.00 eq) in THF (2 mL) and Water (2 mL) was added Oxone (603 mg, 0.982 mmol, 2.00 eq) and allowed it to stir at RT for 16h. After completion, the reaction mixture was poured into water (30 mL and extracted with ethyl acetate (3 x 20 mL). The combined organics were dried over Na2SO4 and evaporated to provide Int-1155, (150 mg, 0.272 mmol, 55% yield) as a light yellow semi-solid.

MS :[M+H]+ 393.2 l,5-dimethyl-4-[[4-methyl-6-(4-methylimidazol-l-yl)-3-pyridy l]sulfmyl]quinolin-2-one: Broad_P_CaV3.3_570 (Compound 125)

To a stirred solution of 4-[(6-bromo-4-methyl-3-pyridyl)sulfinyl]-l,5-dimethyl- quinolin-2-one (150 mg, 0.272 mmol, 1.00 eq) and 4-methyl-lH-imidazole (22 mg, 0.272 mmol, 1.00 eq) in 1,4-Dioxane (3 mL) was added Tripotassium phosphate (115 mg, 0.544 mmol, 2.00 eq) and degassed with nitrogen for 5 min. After 5 min, tBuXPhos (23 mg, 0.0544 mmol, 0.200 eq) and Pd2(dba)3 (25 mg, 0.0272 mmol, 0.100 eq) was added to it and heated at 120 °C for 2h in MW. After completion, the reaction mixture was filtered through celite bed and filtrate was evaporated. The residue was purified via combi flash using (1 :1, Ethyl acetate: Hexanes) as a mobile phase to provide impure compound; which was further purified by prep HPLC using (0-30% ACN and water containing 0.1% formic acid as a modifier) as a mobile phase to provide Broad_P_CaV3.3_570 (4.0 mg, 0.0102 mmol, 4% yield) as a light yellow solid.

1H NMR (400 MHz, DMSO-d6) 5 8.39 (s, 1H), 7.93 (d, J = 13.7 Hz, 2H), 7.67 - 7.51 (m, 3H), 7.48 (s, 1H), 7.06 (t, J = 4.2 Hz, 1H), 3.74 (s, 3H), 2.85 (s, 3H), 2.39 (s, 3H), 2.14 (s, 3H). MS : [M+H]+ 393.0.

Synthesis of Broad_P_CaV3.3_383 (Compound 184) and 387 (Compound 198)

Broad_P_Cav3.3_387 Broad_P_Cav3.3_383 Compound 198 Compound 184 2-methyl-N-[rac-(4R)-8-methyl-l-[2-methyl-4-(l-methylpyrazol -4-yl)phenyl]sulfonyl-3,4- dihydro-2H-quinolin-4-yl]propane-2-sulfinamide: Intermediate-760

To a stirred solution of 8-methyl-l-[2-methyl-4-(l-methylpyrazol-4- yl)phenyl]sulfonyl-2,3-dihydroquinolin-4-one (0.50 g, 1.25 mmol, 1.00 eq) and rac-(R)-2- methylpropane-2-sulfmamide (0.60 g, 4.99 mmol, 4.00 eq) in THF (10 mL) was added Titanium(IV) ethoxide (1.71 g, 7.48 mmol, 6.00 eq) and heated at 80 °C in a sealed tube. After 48h, the reaction mixture was drop-wise added to a suspension of Sodium borohydride (0.28 g, 7.48 mmol, 6.00 eq) in THF (10 mL) at -78 °C and allowed to stir it at RT for 16h. After completion, the reaction mixture was poured into brine solution (70 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organics were dried over Na2SO4 and evaporated. The residue was purified by Combi-flash machine using MethanokDCM (3:97) to provide 2-methyl-N-[rac-(4R)-8-methyl-l-[2-methyl-4-(l-methylpyrazol -4- yl)phenyl]sulfonyl-3,4-dihydro-2H-quinolin-4-yl]propane-2-su lfinamide (400mg, 52.55% yield) as a yellow semi-solid.

MS: [M+H]+ 501.2 rac-(4S)-8-methyl-l-[2-methyl-4-(l-methylpyrazol-4-yl)phenyl ]sulfonyl-3,4-dihydro-2H- quinolin-4-amine: Broad_P_CaV3.3_383

To a stirred solution of 2-methyl-N-[rac-(4R)-8-methyl-l-[2-methyl-4-(l- methylpyrazol-4-yl)phenyl]sulfonyl-3,4-dihydro-2H-quinolin-4 -yl]propane-2-sulfinamide (300 mg, 0.491 mmol, 1.00 eq) in 1,4-Dioxane (6 mL) was added Concentrated HC1 (.64 mL, 19.7 mmol, 40.0 eq) and allowed it to stir at RT for 2h. After completion, the reaction mixture was evaporated, suspended in DCM (15 mL) and filtered through buchner funnel to provide a pure product, which was 94% chiral purity so we have purified it by chiral prep HPLC using 0.1% DEA in methanol as a co-solvent to provide rac-(4S)-8-methyl-l-[2- methyl-4-( 1 -methylpyrazol-4-yl)phenyl] sulfonyl-3 ,4-dihy dro-2H-quinolin-4-amine (13 Omg, 66.31 % yield) as a light yellow solid.

1H NMR (400 MHz, DMSO-d6) 5 8.18 (s, 1H), 7.91 (s, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.61 - 7.49 (m, 2H), 7.35 (d, J = 7.5 Hz, 1H), 7.25 - 7.08 (m, 2H), 3.94 (dd, J = 14.3, 7.5 Hz, 1H), 3.89 (s, 3H), 3.43 (dd, J = 12.7, 6.4 Hz, 1H), 3.25 (t, J = 8.2 Hz, 1H), 2.27 (s, 3H), 2.22 (s, 3H), 2.19 - 2.12 (m, 1H), 1.65 (s, 2H), 1.32 (dd, J = 20.2, 10.9 Hz, 1H). MS:[M+H]+ 396.0. [a]D ²⁵ = +74.21°.

Chiral separation conditions: (CHIRALPAK IG (250*4.6mm) 5u), 0.1% DEA in MeOH) rac-(4S)-N,N,8-trimethyl-l-[2-methyl-4-(l-methylpyrazol-4-yl )phenyl]sulfonyl-3,4-dihydro- 2H-quinolin-4-amine: Broad_P_CaV3.3_387

To a stirred solution of rac-(4S)-8-methyl-l-[2-methyl-4-(l-methylpyrazol-4- yl)phenyl]sulfonyl-3,4-dihydro-2H-quinolin-4-amine (100 mg, 0.251 mmol, 1.00 eq) in Methanol (2 mL) was added Sodium cyanoborohydride (32 mg, 0.501 mmol, 2.00 eq) and stirred at RT for 5 min. After 5 min, Paraformaldehyde (15 mg, 0.501 mmol, 2.00 eq) was added to it followed by addition of rac-(4S)-8-methyl-l-[2-methyl-4-(l-methylpyrazol-4- yl)phenyl]sulfonyl-3,4-dihydro-2H-quinolin-4-amine (100 mg, 0.251 mmol, 1.00 eq)Methanol (2 mL) was added Sodium cyanoborohydride (32 mg, 0.501 mmol, 2.00 eq) and stirred for 5 min at RT. After 5 min, Paraformaldehyde (15 mg, 0.501 mmol, 2.00 eq) was added to it followed by addition of Acetic acid (1.5 mg, 0.0251 mmol, 0.100 eq). The reaction mixture was allowed to stir at RT for 16h. After completion, the reaction mixture was poured into saturated NaHCOs solution (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organics were dried over Na2SO4 and evaporated. The residue was purified by Combi-flash machine using Ethyl acetate:Hexanes (1 : 1) to provide impure compound; which was further purified by prep HPLC purification using (10-30% ACN in water containing formic acid as an modifier) as a mobile phase to provide pure product. We observed 10-15% racemization of product; so the product was purified by chiral prep HPLC purification to provide Broad_P_CaV3.3_387, (30 mg, 0.0707 mmol, 28% yield) as an off white solid.

1H NMR (400 MHz, DMSO-d6) 5 8.18 (s, 1H), 7.90 (s, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.54 (d, J = 9.7 Hz, 2H), 7.29 (d, J = 7.2 Hz, 1H), 7.22 - 7.12 (m, 2H), 3.88 (s, 4H), 3.49 (dd, J = 18.5, 5.3 Hz, 1H), 2.32 (s, 3H), 2.15 (s, 3H), 2.00 (s, 6H), 1.93 - 1.86 (m, 1H), 1.63 (s, 1H). MS:[M+H]+ 425.2. [a]D ²⁵ = -92.01°.

Chiral separation conditions: (CHIRALPAK IG (250*4.6mm) 5u), 0.1% DEA in MeOH). l,5-dimethyl-4-[2-methyl-4-(3-methyl-l,2,4-oxadiazol-5-yl)be nzenesulfonyl]-l,2,3,4- tetrahydroquinoxaline (Broad_P_Cav3.3_314, Compound 127)

To a stirred solution of l,5-dimethyl-4-[2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxab (0.15 g, 339 pmol, 1 eq), were added 5-bromo-3-methyl-l,2,4-oxadiazole (0.066 g, 404 pmol, 1.192 eq) and potassium carbonate (0.139 g, 1.00 mmol, 2.95 eq) in 1,4-Dioxane (4 mL) and water (1 mL) at room temperature and reaction mixture was degassed with argon for 20 min followed by bis(cyclopenta-l,3-dien-l-yldiphenylphosphane) methylene chi (0.03 g, 36.6 pmol, 0.108 eq) was added at room temperature and 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 1,5- dimethyl-4-[2-methyl -4-(3-methyl- 1,2, 4-oxadiazol-5-yl)benzenesulfonyl]-l, 2,3,4- tetrahydroquinoxaline (10.1 mg, 7.5 % yield).

1H NMR (400 MHz, DMSO-d6) 5 8.14 (d, J = 8.2 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 8.02 (s, 1H), 7.04 (t, J = 7.8 Hz, 1H), 6.56 (d, J = 7.6 Hz, 1H), 6.45 (d, J = 8.2 Hz, 1H), 4.25 - 4.15 (m, 1H), 3.23 (s, 1H), 2.95 (d, J = 7.2 Hz, 1H), 2.44 (s, 3H), 2.35 (s, 3H), 2.28 (s, 3H), 2.09 (s, 3H). MS (ESI): 398.48. l,2,2,5-tetramethyl-4-[2-methyl-4-(l-methyl-lH-pyrazol-4-yl) benzenesulfonyl]-l,2,3,4- tetrahydroquinoxaline (Broad_P_Cav3.3_332, Compound 129)

A stirred solution of 4-(4-bromo-2-methylbenzenesulfonyl)-l,2,2,5-tetramethyl- 1,2,3,4-tetrahydroquinoxaline (150 mg, 0.3543 mmol) and l-methyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-pyrazole (73.7 mg, 0.3543 mmol) in 1,4-Dioxane (3 mL) and Water (1 mL) was degassed with nitrogen for 5 min. After 5 min, Pd(dppf)C12 • DCM (292 mg, 0.3543 mmol) was added to it and heated at 100 °C for 3h. After completion, the reaction mixture was filtered through celite and washed with ethyl acetate (15 mL). The filtrate was dried over Na2SC>4 and evaporated. The residue was purified via Biotage (2: 1 CJLCh/EtOAc; 12M column) to provide impure product; which was further purified by prep HPLC purification using (35 - 65% ACN in water containing 0.1% formic acid as a modifier) as a mobile phase to provide l,2,2,5-tetramethyl-4-[2-methyl-4-(l-methyl-lH-pyrazol-4- yl)benzenesulfonyl]- 1,2,3,4-tetrahydroquinoxaline (40 mg, 25.7 %) as a white solid. 1H NMR (400 MHz, DMSO-d6) 6 8.28 (s, 1H), 7.98 (s, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.56 (s, 2H), 7.05 (t, J = 7.8 Hz, 1H), 6.61 (d, J = 7.6 Hz, 1H), 6.53 (d, J = 8.0 Hz, 1H), 4.16 (s, 1H), 3.87 (s, 3H), 2.38 (s, 3H), 2.18 (s, 3H), 2.01 (s, 3H), 1.01 (s, 6H). MS(ESI): 425.2 [M+H]+.

4-chloro-l-methyl-3-[2-methyl-4-(4-methylimidazol-l-yl)ph enyl]sulfonyl-indole

(Broad_P_CaV3.3_633), Compound 130

A stirred suspension of 3-(4-bromo-2-methyl-phenyl)sulfonyl-4-chloro-l-methyl- indole (0.20 g, 0.502 mmol, 1.00 eq) , 4-methyl-lH-imidazole (0.082 g, 1.00 mmol, 2.00 eq) and DMF (5 mL) was degassed with nitrogen gas for 15 min. After 15 min, CuO (0.022 g, 0.150 mmol, 0.300 eq) and kotbu (0.17 g, 1.50 mmol, 3.00 eq) were added to it and heated it at 140 oC 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 (1 : 1, Ethyl acetate: Hexanes) as a mobile phase to provide Broad_P_CaV3.3_633 (12 mg, 0.0280 mmol, 6% yield) as an white solid.

1H NMR (400 MHz, DMSO-d6) 5 8.49 (s, 1H), 8.26 (s, 1H), 8.08 (d, J = 8.5 Hz, 1H), 7.72 - 7.59 (m, 3H), 7.54 (s, 1H), 7.31 (t, J = 8.0 Hz, 1H), 7.23 (d, J = 7.7 Hz, 1H), 3.97 (s, 3H), 2.17 (s, 3H). MS(ESI): 399.89 [M+H]+.

3-(4-bromo-2-methyl-phenyl)sulfonyl-4-chloro-l-methyl-ind ole To a stirred solution of 3-(4-bromo-2-methyl-phenyl)sulfanyl-4-chloro-l-methyl- indole (0.20 g, 0.545 mmol, 1.00 eq) in DCM (10 mL) was added MCPBA (0.38 g, 2.18 mmol, 4.00 eq) at 0°C. The reaction mixtutre was allowed to stir at RT for 12 h. After completion, the reaction mixture was dissolved in saturated solution of NaHCOs (50 mL) and extracted in ethyl acetate (3 x 50 mL). The combined organics were dried over Na2SC>4 and evaporated under vacuum to provide Broad_P_CaV3.3_633_Int-1311, (0.20 g, 0.358 mmol, 66% yield) as a yellow semi solid. MS(ESI): 398.70 [M+H]+.

3-(4-bromo-2-methyl-phenyl)sulfanyl-4-chloro-l-methyl-ind ole

To a stirred a solution of 4-chloro-l-methyl-indole (0.50 g, 3.02 mmol, 1.00 eq) and 4-bromo-2-methyl-benzenesulfonyl chloride (1.63 g, 6.04 mmol, 2.00 eq) in DMF (5 mL) was added TBAI (3.34 g, 9.06 mmol, 3.00 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_633_Int-1310, (0.50 g, 1.36 mmol, 45% yield) as a pale yellow semi solid. 1H NMR (400 MHz, Chloroform-d) 5 7.40 - 7.31 (m, 2H), 7.23 (t, J = 7.9 Hz, 1H), 7.20 - 7.13 (m, 1H), 7.08 (dd, J = 8.4, 2.2 Hz, 1H), 6.61 (d, J = 8.4 Hz, 1H), 3.88 (s, 3H), 2.47 (s, 3H). Synthesis of Compound 131

Compound 131 tert-butyl N-[2-[(5-bromo-2-methyl-phenyl)sulfonylamino]-3-methyl-pheny l]carbamate: A stirred suspension of tert-butyl N-(2-amino-3-methyl-phenyl)carbamate (1.00 g,

4.50 mmol, 1.00 eq) and Pyridine (1.46 mL, 18.0 mmol, 4.00 eq) in Dichloro methane (10 mL) was added 5-bromo-2-methyl-benzenesulfonyl chloride (2.43 g, 9.00 mmol, 2.00 eq) and reaction was stirred at 25 °C. After 16h, the reaction mixture was diluted with citric acid solution (100 mL), the reaction mixture was extracted with EtOAc (3 x 100 mL), the filtrate was evaporated. The residue was purified via Biotage (2: 1 Hex/EtOAc; 12M column) to provide tert-butyl N-[2-[(5-bromo-2-methyl-phenyl)sulfonylamino]-3-methyl- phenyl]carbamate, (0.98 g, 2.15 mmol, 48% yield) as a yellow semi-solid. MS: [M+H]+ 357.4 tert-butyl 4-(5-bromo-2-methyl-phenyl)sulfonyl-5-methyl-2,3-dihydroquin oxaline-l- carb oxy late:

Boc i

A stirred suspension of tert-butyl N-[2-[(5-bromo-2-methyl-phenyl)sulfonylamino]-3- methyl-phenyl]carbamate (0.50 g, 1.10 mmol, 1.00 eq) in dioxane (50 mL) was added Potassium carbonate (0.30 g, 2.20 mmol, 2.00 eq) and 1,2-Dibromoethane (.11 mL, 1.32 mmol, 1.20 eq). The reaction mixture was heated at 80 °C. After 6h, the reaction mixture was dilute with water (100 mL) and wash with EtOAc (2 x 50 mL), the filtrate was evaporated. The residue was purified via Biotage (2: 1 Hex/EtOAc; 12M column) to provide tert-butyl 4- (5-bromo-2-methyl-phenyl) sulfonyl-5-methyl-2,3-dihydroquinoxaline-l -carboxylate, (0.45 g, 0.929 mmol, 85% yield) as a off white solid. MS: [M+H]+ 427.4. tert-butyl 5-methyl-4-[2-methyl-5-(4-methylimidazol-l-yl)phenyl]sulfony l-2,3- dihydroquinoxaline-l-carboxylate:

Boc i

A stirred suspension of tert-butyl 4-(5-bromo-2-methyl-phenyl)sulfonyl-5-methyl-2,3- dihydroquinoxaline-1 -carboxylate (0.45 g, 0.930 mmol, 1.00 eq), 4-methyl-lH-imidazole (0.15 g, 1.86 mmol, 2.00 eq) and Potassium tert-butoxide (0.21 g, 1.86 mmol, 2.00 eq) in DMF (4 mL) was degassed with nitrogen gas for 15 min. Copper(I) oxide (0.040 g, 0.279 mmol, 0.300 eq) was added to it and heated at 120 °C for 16h. The reaction mixture was filtered through celite and wash with EtOAc (2 ^ 30 mL), the filtrate was evaporated. The residue was purified via Biotage (2: 1 Hex/EtOAc; 12M column) to provide tert-butyl 5- methyl-4-[2-methyl-5-(4-methylimidazol-l-yl)phenyl]sulfonyl- 2,3-dihydroquinoxaline-l- carboxylate, (0.38 g, 0.792 mmol, 85% yield) as a white solid. MS: [M+H]+ 483.8.

8-methyl-l -((2-methyl-5-(4-methyl-lH-imidazol-l-yl)phenyl)sulfonyl)-l, 2,3,4- tetrahydroquinoxaline

To a cool suspension of tert-butyl 5-methyl-4-[2-methyl-5-(4-methylimidazol-l- yl)phenyl]sulfonyl-2,3-dihydroquinoxaline-l-carboxylate (0.38 g, 0.792 mmol, 1.00 eq) in 1,4-Dioxane (3 mL) Hydrogen chloride solution 4.0 M in dioxane (.09 mL, 2.37 mmol, 3.00 eq) was added dropwise in to reaction suspension at 0 °C. After 2h, the reaction mixture was concentrated under reduced pressure. The residue was purified via Biotage (5: 1 Hex/EtOAc;

12S column) to provide impure product, which was further purified by prep HPLC using (15- 100% ACN in water containing 0.1% FA in water as modifier) as mobile phase to provide 5- methyl-4-[2-methyl-5-(4-methylimidazol-l-yl)phenyl]sulfonyl- 2,3-dihydro-lH-quinoxaline, (24 mg, 0.0624 mmol, 8% yield) as a off white solid. 1H NMR (400 MHz, DMS0-d6) 5 8.14 (s, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.79 (dd, J = 8.2, 2.5 Hz, 1H), 7.55 - 7.40 (m, 2H), 6.88 (t, J = 7.7 Hz, 1H), 6.38 (dd, J = 17.7, 7.7 Hz, 2H), 5.90 (s, 1H), 4.14 (s, 1H), 3.11 (s, 2H), 2.26 (s, 3H), 2.16 (d, J = 2.3 Hz, 6H). MS:[M+H]+ 383.0.

7-fluoro-l,4-dimethyl-3-[2-methyl-4-(4-methylimidazol-l-y l)phenyl]sulfonyl-indole

(Broad_P_CaV3.3 635, Compound 132)

A stirred solution of 3-(4-bromo-2-methyl-phenyl)sulfonyl-7-fluoro-l,4-dimethyl- indole (120 mg, 0.303 mmol, 1.00 eq), 4-methyl-lH-imidazole (75 mg, 0.908 mmol, 3.00 eq) and potassium ter-butoxide (102 mg, 0.908 mmol, 3.00 eq) in DMF (4 mL) C O (8.7 mg, 0.0606 mmol, 0.200 eq) was added to it 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 Na2SC>4 and evaporated under vacuum. The residue was purified via combi flash using (60% Ethyl acetate: Hexanes) as a mobile phase to provide mixture then repurified by Prep HPLC in (A) 0.1% Formic acid in water, (B) 100% ACN , after lyophilization provided 7-fluoro-l,4-dimethyl-3-[2-methyl-4-(4-methylimidazol- l-yl)phenyl]sulfonyl-indole (37 mg, 0.0938 mmol, 31% yield) as a off white solid.

1H NMR (400 MHz, DMSO-d6) 5 8.48 (s, 1H), 8.30 (d, J = 12.6 Hz, 2H), 7.93 (d, J = 8.6 Hz, 1H), 7.75 (d, J = 2.4 Hz, 1H), 7.67 (dd, J = 8.6, 2.4 Hz, 1H), 7.56 (s, 1H), 7.03 (dd, J = 12.3, 8.0 Hz, 1H), 6.88 (dd, J = 8.3, 4.5 Hz, 1H), 4.08 (d, J = 2.9 Hz, 3H), 2.56 (s, 3H), 2.37 (s, 3H), 2.17 (s, 3H). MS(ESI): 398.3 [M+H]+.

3-(4-bromo-2-methyl-phenyl)sulfonyl-7-fluoro-l,4-dimethyl -indole

A stirred solution of 3-(4-bromo-2-methyl-phenyl)sulfanyl-7-fluoro-l,4-dimethyl- indole (150 mg, 0.412 mmol, 1.00 eq) in THF (5 mL)water (2 mL) Oxone (1266 mg, 2.06 mmol, 5.00 eq) was added to it and stirred 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 to provided crude 3-(4- bromo-2-methyl-phenyl)sulfonyl-7-fhioro-l,4-dimethyl-indole, (120 mg, 0.291 mmol, 71% yield) as a light red solid and used as such for next step.

1H NMR (400 MHz, DMSO-d6) 5 8.32 (s, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.68 - 7.63 (m, 1H), 7.04 (dd, J = 12.3, 8.1 Hz, 1H), 6.90 (dd, J = 8.2, 4.6 Hz, 1H), 4.08

(d, J = 2.9 Hz, 3H), 2.37 (s, 3H), 2.33 (s, 3H), 2.20 - 2.14 (m, 1H), 1.25 (s, 1H). MS(ESI): 396.27[M+H]+.

3-(4-bromo-2-methyl-phenyl)sulfanyl-7-fluoro-l,4-dimethyl -indole To a stirred solution of 7 -fluoro- 1,4-dimethyl-indole (220 mg, 1.35 mmol, 1.00 eq) and 4-bromo-2-methyl-benzenesulfonyl chloride (727 mg, 2.70 mmol, 2.00 eq) in DMF (10 mL) under inert atmosphere Tetrabutylammonium iodide (996 mg, 2.70 mmol, 2.00 eq) was added and stirred reaction mixture for 16 h at RT. 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 hexane as a mobile phase to provide 3-(4-bromo-2-methyl-phenyl)sulfanyl- 7-fluoro-l,4-dimethyl-indole (150 mg, 0.395 mmol, 29% yield) as white solid.

1H NMR (400 MHz, Chloroform-d) 5 7.30 (s, 1H), 7.24 (s, 1H), 7.08 (dd, J = 8.4, 2.1 Hz, 1H), 6.86 (dd, J = 12.4, 7.9 Hz, 1H), 6.76 (dd, J = 8.0, 4.5 Hz, 1H), 6.55 (d, J = 8.5 Hz, 1H), 4.07 (d, J = 2.3 Hz, 3H), 2.52 (s, 3H), 2.44 (s, 3H). MS(ESI): 364.28 [M+H]+.

7-fluoro- 1 ,4-dimethyl-indole

To a stirred solution of 7-fluoro-4-methyl-lH-indole (310 mg, 2.08 mmol, 1.00 eq) and iodomethane (442 mg, 3.12 mmol, 1.50 eq) in DMF (5 mL) at 0 °C Sodium hydride (442 mg, 18.4 mmol, 8.86 eq) was added portion wise then stirred reaction for 6h at RT. After completion cool to 0 °C and quenched slowly with ice water (50 mL) and extracted with ethyl acetate (3 x 30mL) the organic layer was dried over Na2SC>4 and evaporated under vacuum. The residue was purified via combi flash using (10% Ethyl acetate: Hexanes) as a mobile phase to provide 7-fluoro- 1,4-dimethyl-indole, (220 mg, 1.28 mmol, 62% yield) as colourless liquid.

1H NMR (400 MHz, Chloroform-d) 5 7.00 (d, J = 3.1 Hz, 1H), 6.83 - 6.71 (m, 2H), 6.47 (t, J = 2.9 Hz, 1H), 4.01 (d, J = 1.8 Hz, 3H), 2.50 (s, 3H), 1.28 (s, 15H), 0.98 - 0.77 (m, 6H).

MS(ESI): 163.20 [M+H]+.

7-fluoro-4-methyl-lH-indole tassL PJSaVS.3 jmj „ 1

To a stirred solution of bromo(vinyl)magnesium (1 M in THF, 45.12 mL, 45.1 mmol, 3.50 eq) in THF (40 mL) under inert atmosphere at -45 °C dropwise l-fluoro-4-methyl-2- nitro-benzene (2.00 g, 12.9 mmol, 1.00 eq) was added and stirred reaction mass for 3h at same temperature. After completion, reaction mass was quenched with water (lOOmL) and extracted with ethyl acetate (50mL x 3), combined organic layer and dried over anhydrous Na2SC>4, filter and evaporated under vacuum. The residue was purified via combi flash using (10% Ethyl acetate: Hexanes) as a mobile phase to provide 7-fluoro-4-methyl-lH-indole (310 mg, 2.08 mmol, 16% yield) as an brown liquid. 1H NMR (400 MHz, Chloroform-d) 5 8.36 (s, 1H), 7.27 (d, J = 11.7 Hz, 2H), 6.90 - 6.74 (m, 2H), 6.60 (q, J = 2.9 Hz, 1H), 2.54 (s, 3H). MS(ESI): 149.17 [M+H]+.

4-(fluoromethyl)-l-methyl-3-[[4-methyl-6-(4-methylimidazo l-l-yl)-3- pyridyljsulfonyljindole (Broad_P_CaV3.3_675, Compound 133) To a solution of [l-methyl-3-[[4-methyl-6-(4-methylimidazol-l-yl)-3- pyridyl]sulfonyl]indol-4-yl]methanol (0.20 g, 0.504 mmol, 1.00 eq) in dichloromethane (2 mL) cooled to -50°C. to the reaction mixture XtalFluor-M® (0.37 g, 1.51 mmol, 3.00 eq) was added and stirred for 3 h. The reaction mass was quenched in water (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organics were dride over anhydrous Na2SC>4 and evaporated to get 4-(fluoromethyl)-l-methyl-3-[[4-methyl-6-(4-methylimidazol-l -yl)-3- pyridyl]sulfonyl]indole Broad_P_CaV3.3_675 (0.021 g, 0.0480 mmol, 10% yield).

1H NMR (400 MHz, DMSO-d6) 5 8.78 (s, 1H), 8.48 (d, J = 11.9 Hz, 2H), 7.84 (s, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7.69 (s, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.34 (d, J = 7.4 Hz, 1H), 5.81 (s,

1H), 5.69 (s, 1H), 3.97 (s, 3H), 2.58 (s, 3H), 2.16 (s, 3H). MS(ESI): 399.6 [M+H]

[l-methyl-3-[[4-methyl-6-(4-methylimidazol-l-yl)-3-pyridy l]sulfonyl]indol-4-yl]methanol

To a solution of methyl l-methyl-3-[[4-methyl-6-(4-methylimidazol-l-yl)-3- pyridyl]sulfonyl]indole-4-carboxylate (0.30 g, 0.707 mmol, 1.00 eq) in Dichloromethane (3 mL) cooled to -78°C, IM DIBAL in toluene (0.30 g, 2.12 mmol, 3.00 eq) was added in the reaction at same temperature and gradually warm up to 0°C. The reaction mass was stirred at same temperature for 3 h. The reaction mass was quenched in water (500 mL) and extracted with EtOAc (3 x 300 mL). The combined organics were dride over anhydrous Na2SO4 and evaporated to get [l-methyl-3-[[4-methyl-6-(4-methylimidazol-l-yl)-3- pyridyl]sulfonyl]indol-4-yl]methanol, (0.28 mg, 0.650 mmol, 92% yield). MS(ESI): 397.0 [M+H]+. methyl l-methyl-3-[[4-methyl-6-(4-methylimidazol-l-yl)-3-pyridyl]su lfonyl]indole-4- carb oxy late

To a solution of methyl 3-[(6-bromo-4-methyl-3-pyridyl)sulfonyl]-l-methyl-indole-4- carboxylate (1.50 g, 3.54 mmol, 1.00 eq) in 1,4 Dioxane (15 mL) at room temperature, 4- methyl-lH-imidazole (1.16 g, 14.2 mmol, 4.00 eq) Pd2dba3 (0.32 g, 0.354 mmol, 0.100 eq), t-Bu-Xphos (.31 mL, 0.709 mmol, 0.200 eq) and K3PO4 (1.54 mL, 7.09 mmol, 2.00 eq) was added portion wise and stirred it at 120°C for 16 h. The reaction mass was quenched in water (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organics were dride over anhydrous Na2SC>4 and evaporated to get methyl l-methyl-3-[[4-methyl-6-(4- methylimidazol-l-yl)-3-pyridyl]sulfonyl]indole-4-carboxylate , (1.10 g, 2.15 mmol, 61% yield). MS(ESI): 425.2 [M+H]+. methyl 3-[(6-bromo-4-methyl-3-pyridyl)sulfonyl]-l-methyl-indole-4-c arboxylate

To a solution of methyl 3-[(6-bromo-4-methyl-3-pyridyl)sulfanyl]-l-methyl-indole-4- carboxylate (3.00 g, 7.67 mmol, 1.00 eq) in Tetrahydrofuran (20 mL) and Water (10 mL), OXONE (4.67 g, 30.7 mmol, 4.00 eq) was added at room temperature and stirred at same temperature for 16 h. The reaction mass was quenched in water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organics were dried over anhydrous Na2SO4 and evaporated to get methyl 3-[(6-bromo-4-methyl-3-pyridyl)sulfonyl]-l-methyl-indole-4- carboxylate, (2.70 g, 5.61 mmol, 73% yield). MS(ESI): 425 [M+H]+. methyl 3-[(6-bromo-4-methyl-3-pyridyl)sulfanyl]-l-methyl-indole-4-c arboxylate To a stirred a solution of methyl l-methylindole-4-carboxylate (3.80 g, 20.1 mmol,

1.00 eq) and 6-bromo-4-methyl-pyridine-3-sulfonyl chloride (10.87 g, 40.2 mmol, 2.00 eq) in dimethylformamide (38 mL) was added Tetrabutylammonium iodide (14.83 g, 40.2 mmol, 2.00 eq) at 25 °C. The reaction mixture was stirred at same temperature for 16 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 100 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_675_1440, (3.50 g, 4.29 mmol, 21% yield) as an white solid. MS(ESI): 393.2 [M+H]+. Synthesis of Compound 137

8-methyl-l-[2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxabo rolan-2-yl)benzenesulfonyl]-

1,2,3,4-tetrahydroquinoline: Intermediate-325

To a stirred solution of l-(5-bromo-2-methylbenzenesulfonyl)-8-methyl-l,2,3,4- tetrahydroquinoline (1.8 g, 4.73 mmol, 1 eq), bis(pinacolato)diboron (2.40 g, 9.46 mmol, 2 eq) and potassium acetate (1.85 g, 18.9 mmol, 4 eq) in dioxane (6 mL) was degassed for 15 minutes with Nitrogen gas then lambda2-iron(2+) palladium(2+) bis(2- (diphenylphosphanyl)cyc (172 mg, 236 pmol, 0.05 eq) was added and heated the reaction mixture at 90°C for 3h. After completion, the reaction mixture was quenched in water (lOOmL) and extracted with ethyl acetate (3 / | 00 mL), combine organic layer was dried over sodium sulphate, filtered and concentrated under reduce pressure up to crude, this was purify by flash chromatography using [0-25% EtOAc/Hexanes] to provide 8-methyl-l-[2- methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzen esulfonyl]-l,2,3,4- tetrahydroquinoline (1.4 g, 69.3 % yield) as a yellow solid.

1H NMR (400 MHz, DMSO-d6) 5 8.08 (s, 1H), 7.80 (dd, J = 7.5, 1.3 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.18 - 7.08 (m, 2H), 6.93 (dd, J = 6.2, 2.9 Hz, 1H), 3.95 (s, 1H), 3.30 (s, 1H), 2.37 (s, 1H), 2.25 (s, 3H), 2.11 (s, 3H), 1.90 - 1.79 (m, 1H), 1.60 - 1.44 (m, 2H), 1.30 (s, 12H), 1.26 - 1.22 (m, 1H), 1.16 (s, 6H).

8-methyl-l-[2-methyl-5-(l-methyl-lH-pyrazol-3-yl)benzenes ulfonyl]-l,2,3,4- tetrahydroquinoline: Broad_P_CaV3.3 207

To a stirred solution of 8-methyl-l-[2-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)benzenesulfonyl]-l,2,3,4-tetrahydroquinoli ne (0.1 g, 233 pmol, 1 eq), 3- bromo-l-methyl-lH-pyrazole (37.5 mg, 233 pmol, 1 eq) and potassium carbonate (64.4 mg, 466 pmol, 2 eq) in 1,4 dioxane (4 mL) and water (1 mL) was degassed for 15 minutes with Nitrogen gas then tetrakis(tri phenylphosphine) palladium (26.9 mg, 23.3 pmol, 0.1 eq) was added and heated the reaction mixture at 90°C for 3h. 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 (50-70% ACN in water containing 0.1% ammonia as modifier) as mobile phase to provide 8- m ethyl- 1 -[2-methyl-5-(l -methyl- lH-pyrazol-3 -yl)benzenesulfonyl]- 1 ,2,3,4- tetrahydroquinoline (0.018 g, 20.2 % yield) as a white solid.

MS :[M+H]+ 382.40.

1H NMR (400 MHz, DMSO-d6) 5 8.28 (d, J = 1.9 Hz, 1H), 7.93 (dd, J = 7.9, 2.0 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.14 (q, J = 4.4, 3.5 Hz, 2H), 6.94 (dd, J = 6.2, 2.8 Hz, 1H), 6.74 (d, J = 2.3 Hz, 1H), 4.03 (s, 1H), 3.89 (s, 3H), 3.29 (s, 1H), 2.37 (s, 1H), 2.28 (s, 3H), 2.05 (s, 3H), 1.89 (s, 1H), 1.58 (d, J = 62.3 Hz, 2H). l,5-dimethyl-4-[2-methyl-4-(5-methylthiophen-2-yl)benzenesul fonyl]-l,2,3,4- tetrahydroquinoxaline (Broad_P_Cav3.3_311, Compound 139)

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-tetrahydroquinoxa line (100 mg, 0.2260 mmol) were added 2-bromo-5-methylthiophene (48.0 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 in to 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 30 - 35 % ACN in 0.1 % formic acid in water as a gradient to provide 1,5- dimethyl-4-[2-me (20 mg, 21.4 % yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) 5 7.87 (d, J = 8.3 Hz, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.53 (s, 1H), 7.50 (d, J = 3.6 Hz, 1H), 7.01 (t, J = 7.8 Hz, 1H), 6.88 (d, J = 3.6 Hz, 1H), 6.52 (d, J = 7.5 Hz, 1H), 6.45 (d, J = 8.1 Hz, 1H), 4.11 (d, J = 11.5 Hz, 1H), 3.22 (s, 1H), 2.96 (s, 1H), 2.81 (s, 1H), 2.42 (s, 3H), 2.26 (s, 3H), 2.03 (s, 3H). MS (ESI): 413.2 [M+H]+. l-{4-[(4,8-dimethyl-l,2,3,4-tetrahydroquinoxalin-l-yl)sulfon yl]-3-methylphenyl}-lH- imidazole-4-carbonitrile (Broad_P_Cav3.3_345, Compound 140)

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 lH-imidazole-4-carbonitrile (94.0 mg, 1.01 mmol), potassium tert-butoxide (169 mg, 1.51 mmol) in DMF (4 mL) at room temperature and reaction mixture was degassed with argon for 20 min followed by cuprous oxide (14.4 mg, 0.1011 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 (50 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 40% - 65% ACN in 0.1% formic acid in water as a gradient to provide l-{4-[(4,8-dimethyl- (10 mg, 5 % yield) as an off white solid.

1H NMR (400 MHz, DMSO-d6) 5 8.88 (s, 1H), 8.66 (s, 1H), 8.07 (d, J = 8.6 Hz, 1H), 7.76 (s, 2H), 7.03 (t, J = 7.9 Hz, 1H), 6.55 (d, J = 7.5 Hz, 1H), 6.46 (d, J = 8.2 Hz, 1H), 4.18 (dd, J = 14.9, 6.9 Hz, 1H), 3.26 (s, 1H), 2.97 (s, 1H), 2.83 (s, 1H), 2.40 (s, 3H), 2.28 (s, 3H), 2.05 (s, 3H). MS (ESI): 408.5 [M+H]+.

5-methyl-4-[[4-methyl-6-(4-methylimidazol-l-yl)-3-pyridyl ]sulfonyl]-l,3- dihydroquinoxalin-2-one (Broad_P_CaV3.3_482, Compound 141)

To a stirred solution of ethyl 2-[2-amino-6-methyl-N-[[4-methyl-6-(4- methylimidazol-l-yl)-3-pyridyl]sulfonyl]anilino]acetate (200 mg, 0.362 mmol, 1.00 eq) in MeOH (1 mL), THF (1 mL) and Water (0.5 mL) at room temperature, was added Lithium hydroxide monohydrate (76 mg, 1.81 mmol, 5.00 eq) at same temperature. The reaction mixture was stirred at 30 °C for 5 h. After completion, the reaction mixture was acidify with dilut HC1 solition (5 mL) and the solvent was concentrated under vaccum. The residue was diluted with EtOAc (50 mL) and the organic layer was washed with water (3 x 20 mL) and brine solition (3 x 20 mL). The combined organics were dried over Na2SC>4 and evaporated and crude product was purified by combi-flash column chrometography and was eluted with 1.5% MeOH in DCM as a gradient to provide impure product. The impure product was further purified by prep-HPLC column and was eluted with 0-28% ACN in 0.1% formic acid in water as a gradient to provide Broad_P_Cav3.3_482 (8.0 mg, 0.0200 mmol, 6% yield) as an off white solid.

1H NMR (400 MHz, DMSO-d6) 5 10.25 (s, 1H), 8.52 (d, J = 6.4 Hz, 2H), 7.76 (d, J = 25.2 Hz, 2H), 7.23 (t, J = 7.8 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.63 (d, J = 7.8 Hz, 1H), 4.30 (q, J = 17.6 Hz, 2H), 2.46 (s, 3H), 2.18 (s, 3H), 1.98 (s, 3H). MS (ESI): 398.6 [M+H]+. 7-methyl-l-[2-methyl-4-(4-methylimidazol-l-yl)phenyl]sulfony l-benzimidazole

(Broad_P_CaV3.3_550, Compound 142)

A stirred suspension of N-(2-amino-6-methyl-phenyl)-2-methyl-4-(4-methylimidazol- l-yl)benzenesulfonamide;hydrochloride (150 mg, 0.382 mmol, 1.00 eq) in 2-methoxyethanol (4 mL) was added Formamidine acetate (159 mg, 1.53 mmol, 4.00 eq). The reaction mixture was heated at 80 °C for 16 h. After completion, the reaction mixture was dilute with water(30 mL) and wash with EtOAc (2 x 50 mL), the filtrate was evaporated. The residue was purified via combi flash using (0.5:9.5, MeOH: DCM) as a mobile phase to provide impure product; which was further purified by prep HPLC using (5-45% ACN and water containing 0.1% Formic acid as a modifier) as a mobile phase to provide Broad_P_CaV3.3_550 (27 mg, 0.0728 mmol, 19% yield) as a off white solid.

1H NMR (400 MHz, DMSO-d6) 5 8.87 (s, 1H), 8.34 (s, 1H), 7.97 - 7.85 (m, 2H), 7.75 (dd, J = 8.7, 2.5 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.59 (s, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.17 (d, J = 7.5 Hz, 1H), 2.44 (s, 3H), 2.34 (s, 3H), 2.15 (s, 3H). MS(ESI): 367.1[M+H]+. l,5-dimethyl-4-{[4-methyl-6-(2-methyl-l,3-oxazol-5-yl)pyridi n-3-yl]sulfonyl}-l,2,3,4- tetrahydroquinoxaline (Broad_P_CaV3.3_355, Compound 143) To a stirred solution of 4-[(6-bromo-4-methylpyridin-3-yl)sulfonyl]-l,5-dimethyl- 1,2,3,4-tetrahydroquinoxaline (0.2 g, 0.5046 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l,3 (0.126 g, 0.6027 mmol, 1.194 eq) and potassium carbonate (0.208 g, 1.50 mmol, 2.973 eq) in 1,4-Dioxane (4 mL) and Water (1 mL) was degassed for 15 minutes with Nitrogen gas followed by potassium carbonate (0.208 g, 1.50 mmol, 2.973 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 [0-70% EtOAc/hexanes] to provide l,5-dimethyl-4-{[4-methyl-6-(2-methyl-l,3-oxazol-5- yl)pyridi (0.05 g, 24.8 %yield) as a yellow solid.

1H NMR (400 MHz, DMSO-d6) 5 8.94 (s, 1H), 7.82 (s, 1H), 7.63 (s, 1H), 7.05 (t, J = 7.7 Hz, 1H), 6.59 (d, J = 7.6 Hz, 1H), 6.44 (d, J = 8.2 Hz, 1H), 4.28 (dd, J = 14.5, 7.4 Hz, 1H), 3.28 (d, J = 11.0 Hz, 1H), 2.96 (t, J = 8.6 Hz, 1H), 2.83 (t, J = 10.0 Hz, 1H), 2.53 (s, 3H), 2.31 (d, J = 5.6 Hz, 6H), 1.97 (s, 3H). MS(ESI): 398.48 [M+H]+.

4-(fluoromethyl)-l-methyl-3-[2-methyl-4-(4-methylimidazol -l-yl)phenyl]sulfonyl-indole (Broad_P_CaV3.3_638, Compound 144)

To the stirred suspension of [l-methyl-3-[2-methyl-4-(4-methylimidazol-l- yl)phenyl]sulfonyl-indol-4-yl]methanol (0.11 g, 0.278 mmol, 1.00 eq) in DCM at -50 °C under Nitrogen, added 50% Deoxoflour in THF (0.25 g, 0.556 mmol, 2.00 eq) drop wise. The reaction was stirred at same temprature for 3 h. After completion, the reaction mass was evaporated. The residue was purified by silica gel column chromatography using 60% ethyl acetate in hexanes as a mobile phase which was further purified by prep HPLC purification to provide Broad_P_CaV3.3_638 (9.3 mg, 0.0233 mmol, 8% yield) as an off white solid. 1H NMR (400 MHz, DMSO-d6) 5 8.41 (s, 1H), 8.32 - 8.22 (m, 1H), 7.90 (d, J = 8.6 Hz, 1H), 7.71 (dd, J = 8.0, 5.2 Hz, 2H), 7.64 (dd, J = 8.7, 2.4 Hz, 1H), 7.54 (s, 1H), 7.44 - 7.36 (m, 1H), 7.32 (d, J = 7.3 Hz, 1H), 5.77 (d, J = 3.0 Hz, 1H), 5.65 (d, J = 3.1 Hz, 1H), 3.97 (d, J = 5.2 Hz, 3H), 2.57 (s, 3H), 2.16 (d, J = 5.8 Hz, 3H). MS(ESI): 398.0 [M+H]+. 7-methoxy-l-[2-methyl-4-(4-methylimidazol-l-yl)phenyl]sulfon yl-benzimidazole (Broad_P_CaV3.3 577, Compound 145)

A stirred suspension of N-(2-amino-6-methoxy-phenyl)-2-methyl-4-(4- methylimidazol-l-yl)benzenesulfonamide hydrochloride (750 mg, 1.83 mmol, 1.00 eq) in 2- methoxyethanol (10 mL) was added Formamidine acetate (765 mg, 7.34 mmol, 4.00 eq). The reaction mixture was heated at 80 °C for 16 h. After completion, the reaction mixture was dilute with water(30 mL) and wash with EtOAc (2 / 50 mL), the filtrate was evaporated. The residue was purified via combi flash using (0.5:9.5, MeOH: DCM) as a mobile phase to provide impure product; which was further purified by prep HPLC using (5-35% ACN and water containing 0.1% Formic acid as a modifier) as a mobile phase to provide Broad_P_CaV3.3_577 (56 mg, 0.140 mmol, 8% yield) as a off white solid.

1H NMR (400 MHz, DMSO-d6) 5 8.90 (s, 1H), 8.49 - 8.21 (m, 2H), 8.04 - 7.75 (m, 2H), 7.61 (s, 1H), 7.51 - 7.19 (m, 2H), 6.93 (d, J = 8.0 Hz, 1H), 3.68 (s, 3H), 2.39 (s, 3H), 2.18 (s, 3H). MS(ESI): 382.9 [M+H]+. l,5-dimethyl-4-{[2-methyl-6-(3-methyl-l,2-oxazol-5-yl)pyridi n-3-yl]sulfonyl}-l,2,3,4- tetrahydroquinoxaline (Broad_P_Cav3.3_256, Compound 145)

To a stirred solution of 8-methyl-l-{[2-methyl-6-(3-methyl-l,2-oxazol-5-yl)pyridin- 3- (0.05 g, 130 pmol, 1 eq) in DMF (2 mL) was added potassium carbonate (89.8 mg, 650 pmol, 5 eq) at room temperature and stirred for 30 minutes followed by drop wise addition of methyl iodide (55.2 mg, 389 pmol, 3 eq) at room temperature and reaction mixture was stirred at same temperature 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 [0-10% EtOAc/Hexane] to provide l,5-dimethyl-4-{[2- methyl-6-(3-methyl-l,2-oxazol-5-yl)pyridi (0.035 g, 65.0 % yield) as a light yellow solid.

1H NMR (400 MHz, DMSO-d6) 5 8.42 (d, J = 8.3 Hz, 1H), 7.92 (d, J = 8.3 Hz, 1H), 7.13 - 7.02 (m, 2H), 6.61 (d, J = 7.5 Hz, 1H), 6.45 (d, J = 8.1 Hz, 1H), 4.25 (dd, J = 14.7, 7.5 Hz, 1H), 3.21 (s, 1H), 2.96 (t, J = 9.0 Hz, 1H), 2.86 (s, 1H), 2.32 (s, 6H), 2.28 (s, 3H), 2.16 (s,

3H). MS(ESI): 399.5 [M+H]+.

8-methyl-l-[2-methyl-3-(l-methylpyrazol-4-yl)phenyl]sulfo nyl-2,3-dihydroquinolin-4- one (Broad_P_Cav3.3_445, Compound 147) To a stirred solution of8-methyl-l-[2-methyl-3-(l-methylpyrazol-4- yl)phenyl]sulfonyl-3,4-dihydro-2H-quinoline (80 mg, 0.189 mmol, 1.00 eq) in Acetone (4.504 mL) and Water (2.7024 mL) was added Magnesium sulfate (113 mg, 0.945 mmol, 5.00 eq) at 0°C and stirred for 5 min. After 5 min, Potassium permanganate (164 mg, 1.04 mmol, 5.50 eq) was lot wise added to it and allowed to stir it at RT for 16 h. After 16h, the reaction mixture was poured into water (30 mL) and extracted with wthyl acetate (3 x 25 mL). The combined organics were washed with sat. NaHCCh solution (3 x 50 mL). The organic layer was dried over Na2SC>4 and evaporated. The residue was purified by combi- flash purification using DCM:MeOH (10: 1) as a mobile phase to provide impure product which was further purified by prep HPLC purification using (30-45% Acetonitrile in water containing 0.1% formic acid as an modifier) as mobile phase to provide Broad_P_Cav3.3_445 (16 mg, 0.0398 mmol, 21% yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) 5 7.92 (d, J = 8.0 Hz, 1H), 7.80 (s, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.56 (d, J = 7.5 Hz, 1H), 7.51 (s, 1H), 7.41 (dt, J = 20.3, 7.7 Hz, 2H), 4.05 (t, J = 6.6 Hz, 2H), 2.45 (t, J = 6.6 Hz, 3H), 2.45 (t, 2H), 2.32 (s, 3H), 2.25 (s, 3H). MS(ESI): 396.6 [M+H]+.

5-methyl-4-[2-methyl-4-(4-methylimidazol-l-yl)phenyl]sulf onyl-l,3-dihydroquinoxalin- 2-one (Broad_P_Cav3.3_481, Compound 148)

To a stirred solution of 2-(2-amino-6-methyl-N-[2-methyl-4-(4-methylimidazol-l- yl)phenyl]sulfonyl-anilino)acetic acid (0.60 g, 1.34 mmol, 1.00 eq) and N-(3- Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.31 g, 1.61 mmol, 1.20 eq) in DMF (6 mL) at room temperature. The reaction mixture was stirred at 30 °C for 8h. After completion, the reaction mixture was qhunched 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_481 (0.20 g, 0.504 mmol, 38% yield) as an off white solid.

1H NMR (400 MHz, DMSO_d6) 5 10.17 (s, 1H), 8.35 (s, 1H), 7.72-7.58 (m, 4H), 7.19 (t, J = 7.8 Hz, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.62 (d, J = 7.8 Hz, 1H), 4.34-4.13 (m, 2H), 2.45 (s, 3H), 2.16 (s, 3H), 2.00 (s, 3H). MS (ESI): 397.6 [M+H]+.

7-methoxy-l-[[4-methyl-6-(4-methylimidazol-l-yl)-3-pyridy l]sulfonyl]benzimidazole (Broad_P_CaV3.3 578, Compound 149)

A stirred suspension of N-(2-amino-6-methoxy-phenyl)-4-methyl-6-(4- methylimidazol-l-yl)pyridine-3 -sulfonamide hydrochloride (750 mg, 1.83 mmol, 1.00 eq) in 2-methoxyethanol (10 mL) was added Formamidine acetate (763 mg, 7.32 mmol, 4.00 eq). The reaction mixture was heated at 80 °C for 16 h. After completion, the reaction mixture was diluted with water(30 mL) and wash with EtOAc (2 / 50 mL), the filtrate was evaporated. The residue was purified via combi flash using (0.5:9.5, MeOH: DCM) as a mobile phase to provide impure product; which was further purified by prep HPLC using (5- 35% ACN and water containing 0.1% Formic acid as a modifier) as a mobile phase to provide Broad_P_CaV3.3_578 (43 mg, 0.108 mmol, 6% yield) as a off white solid.

1H NMR (400 MHz, DMSO-d6) 5 9.13 (s, 1H), 8.91 (s, 1H), 8.52 (s, 1H), 7.90 (s, 1H), 7.73 (s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.31 (t, J = 8.0 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 3.70 (s, 3H), 2.41 (s, 3H), 2.17 (s, 3H). MS(ESI): 383.8 [M+H]+. Synthesis of Compound 152 Step-3

CuO (0.3 eq), t-BuOK (3 eq), DMSO (10V), 140°C, 16h

Broad_P_CaV3.3_557 Compond 152

3-((4-bromo-2-methylphenyl)thio)-4-methyl-lH-indole: To a stirred a solution of 4-methyl-lH-indole (2.00 g, 15.2 mmol, 1.00 eq) and 4- bromo-2-methyl-benzenesulfonyl chloride (8.22 g, 30.5 mmol, 2.00 eq) in DMF (20 mL) was added TBAI (16.88 g, 45.7 mmol, 3.00 eq) at RT. The reaction mixture was stirred at same temperature for 6 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 3-(4-bromo-2-methyl-phenyl)sulfanyl-4-methyl-lH-indole, (765 mg, 2.30 mmol, 15% yield) as an pale yellow semi solid.

MS(ESI): 332.26 [M+H]+

3-((4-bromo-2-methylphenyl)sulfonyl)-4-methyl-lH-indole:

To a stirred solution of 3-(4-bromo-2-methyl-phenyl)sulfanyl-4-methyl-lH-indole (0.77 g, 2.30 mmol, 1.00 eq) in DCM (10 mL) was added MCPBA (1.59 g, 9.21 mmol, 4.00 eq) at 0°C. The reaction mixtutre was allowed to stir at RT for 12 h. After completion, the reaction mixture was 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 3-(4-bromo-2-methyl-phenyl)sulfonyl-4-methyl-lH-indole, (786 mg, 2.16 mmol, 94% yield) as an yellow semi solid.

1H NMR (400 MHz, DMSO-d6) 5 12.38 (s, 1H), 8.23 (d, J = 3.2 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.68 - 7.60 (m, 2H), 7.38 (d, J = 8.2 Hz, 1H), 7.15 (t, J = 7.7 Hz, 1H), 6.91 (d, J = 7.3 Hz, 1H), 5.77 (s, 1H), 3.76 (s, 1H), 2.47 (s, 3H), 2.37 (s, 3H).

4-methyl-3 -((2-methyl-4-(4-m ethyl- IH-imidazol- 1 -yl)phenyl)sulfonyl)- IH-indole (Compound 152):

A stirred suspension of 3-(4-bromo-2-methyl-phenyl)sulfonyl-4-methyl-lH-indole (0.79 g, 2.16 mmol, 1.00 eq), 4-methyl-lH-imidazole (0.35 g, 4.32 mmol, 2.00 eq) and Kotbu (0.73 g, 6.47 mmol, 3.00 eq) in DMF (7 mL) was degassed with nitrogen gas for 15 min. After 15 min, copper oxide (0.093 g, 0.647 mmol, 0.300 eq) was added to it and heated it at 140oC 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_557 (12 mg, 0.0319 mmol, 1% yield) as an white solid. MS(ESI): 365.45[M+H]+

Synthesis of Broad_P_CaV3.3_385 (Compound 176)

N,2-dimethyl-N-[rac-(4R)-8-methyl-l-[2-methyl-4-(l-methyl pyrazol-4-yl)phenyl]sulfonyl- 3,4-dihydro-2H-quinolin-4-yl]propane-2-sulfinamide: Intermediate-762

To a stirred solution of 2-methyl-N-[rac-(4R)-8-methyl-l-[2-methyl-4-(l- methylpyrazol-4-yl)phenyl]sulfonyl-3,4-dihydro-2H-quinolin-4 -yl]propane-2-sulfinamide (100 mg, 0.200 mmol, 1.00 eq) in DMF (2 mL) was added 60% Sodium hydride in mineral oil (16 mg, 0.666 mmol, 3.33 eq) at 0 °C and stirred at same temperature for 20 min. After 20 min, iodomethane (.02 mL, 0.300 mmol, 1.50 eq) was added to it and allowed it to stir at RT for 3h. 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 Na2SO4 and evaporated. The residue was purified by Combi-flash using Ethyl acetate:Hexanes (1 : 1) to provide Intermediate-762, (80 mg, 0.126 mmol, 63% yield) as a yellow semi-solid.

MS: [M+H]+ 515.2 rac-(4R)-N,8-dimethyl-l-[2-methyl-4-(l-methylpyrazol-4-yl)ph enyl]sulfonyl-3,4-dihydro- 2H-quinolin-4-amine: Broad_P_CaV3.3_385

To a stirred solution of N,2-dimethyl-N-[rac-(4R)-8-methyl-l-[2-methyl-4-(l- methylpyrazol-4-yl)phenyl]sulfonyl-3,4-dihydro-2H-quinolin-4 -yl]propane-2-sulfinamide (80 mg, 0.155 mmol, 1.00 eq) in 1,4-Dioxane (2 mL) was added Concentrated HC1 (.15 mL, 6.12 mmol, 39.4 eq) and allowed it to stir at RT for Ih. After completion, the reaction mixture was diluted with water (15 mL) and extracted with DCM (3 x 15 mL) to remove impurities. The aqueous layer was basified with NaHCOs and extracted with DCM (3 x 20 mL). The combined organics were dried over Na2SO4 and evaporated to provide pure compound. We observed 10-15% racemization of the compound; so we purified it by chiral prep HPLC purification (CHIRALPAK IG (250*4.6mm) 5u), 0.1% DEA in MeOH) to provide Broad_P_CaV3.3_385 (15 mg, 0.0358 mmol, 23% yield) as yellow semi-solid.

MS :[M+H]+ 411.0

1H NMR (400 MHz, DMSO-d6) 5 8.18 (s, IH), 7.90 (s, IH), 7.80 (d, J = 8.2 Hz, IH), 7.55 (d, J = 8.3 Hz, 2H), 7.24 (d, J = 7.1 Hz, IH), 7.21 - 7.13 (m, 2H), 5.67 (s, IH), 3.95 (dd, J = 14.4, 7.2 Hz, IH), 3.88 (s, 3H), 3.52 - 3.43 (m, IH), 2.80 (s, IH), 2.31 (s, 3H), 2.18 (s, 3H), 2.13 (s, 3H), 1.33 (s, IH).

[a]D ²⁵ = +58.81° 6-fluoro-l,4-dimethyl-3-[[2-methyl-6-(4-methylimidazol-l-yl) -3-pyridyl]sulfonyl]indole

(Broad_P_CaV3.3_688, Compound 155)

To the solution of 3-[(6-bromo-2-methyl-3-pyridyl)sulfonyl]-6-fluoro-l,4-dimeth yl- indole (0.25 g, 0.629 mmol, 1.00 eq) in dimethylformamide (2.5 mL) was added Potassium tert-butoxide (212 mg, 1.89 mmol, 3.00 eq), and degased with N2 for 15 min. CmO (31 mg, 0.219 mmol, 0.300 eq) and 4-methyl-lH-imidazole (0.24 g, 2.92 mmol, 4.00 eq) was added and stirred at 120 °C for 6 h. After 6 h, the reaction mixture was diluted with water (15 mL) and extracted with EtOAc (3 x 20 mL). The organics were dried over Na2SC>4 and evaporated under vacuum. The residue was purified via combi flash using DCM:MeOH (9: 1) as a mobile phase to provide imure product, which on further purification using reverse phase prep HPLS, with ACN and Water as mobile phase (40-100%) and 0.1% formic acid as a modifier, to get a white solid of Broad_P_CaV3.3_690 (51 mg, 0.131 mmol, 18% yield).

1H NMR (400 MHz, DMSO-d6) 5 8.50 (s, 1H), 8.42 - 8.29 (m, 2H), 7.78 (d, J = 8.6 Hz, 1H), 7.71 (s, 1H), 7.40 (dd, J = 9.2, 2.1 Hz, 1H), 6.98 - 6.88 (m, 1H), 3.89 (s, 3H), 2.70 (s,

3H),2.50 (s, 3H), 2.44 (s, 3H), 2.18 (s, 3H). MS(ESI): 399.0[M+H]+.

3-[(6-bromo-2-methyl-3-pyridyl)sulfonyl]-6-fluoro-l,4-dim ethyl-indole To the solution of 3-[(6-bromo-2-methyl-3-pyridyl)sulfanyl]-6-fluoro-l,4-dimeth yl- indole (0.28 g, 0.767 mmol, 1.00 eq) in tetrahydrofuran (3 mL) and water (2 mL), added oxone (943 mg, 3.07 mmol, 4.00 eq) and stirred at 25 °C for 24 h. After completion, the reaction was 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 3-[(6-bromo-2-methyl-3-pyridyl)sulfonyl]-6-fluoro-l,4-dimeth yl-indole Broad- P_CaV3.3_688_1501, (0.25 g, 0.629 mmol, 82% yield) as an pale yellow solid.

MS(ESI): 399.1 [M+H]+.

3-[(6-bromo-2-methyl-3-pyridyl)sulfanyl]-6-fluoro-l,4-dim ethyl-indole

To a stirred a solution of Broad-P_CaV3.3_688_1500, (0.28 g, 0.767 mmol, 33% yield) and 6-bromo-2-methyl-pyridine-3-sulfonyl chloride (1260 mg, 4.66 mmol, 2.00 eq) in DMF (4 mL) was added tetrabutyl ammonium iodide (1720 mg, 4.66 mmol, 2.00 eq) at 25 °C. 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 10% ethyl acetate in hexanes as a mobile phase to provide Broad-P_CaV3.3_688_1500, (0.28 g, 0.767 mmol, 33% yield) as a pale yellow solid. MS(ESI): 367.0 [M+H]+. Synthesis of Compound 157 l-(5-bromo-2-methylbenzenesulfonyl)-8-methyl-l,2,3,4-tetrahy droquinoline: Intermediate-

312

To a stirred solution of 8-m ethyl- 1,2,3, 4-tetrahydroquinoline (100 mg, 679 pmol), triethylamine (1.35 mmol, 2.0 eq), 4-dimethylaminopyrid (164 mg, 1.35 mmol, 2.0 eq) in pyridine (1 mL) then 5-bromo-2-methylbenz (363 mg, 1.35 mmol, 2 eq) was added in the reaction and heated the reaction mixture at 80° C for 3h. After completion, quenched the reaction mixture in 20% citric acid solution and extracted with Ethyl acetate (3 x 10 mL), dried over sodium sulphate and concentrated under reduce pressure up to crude, The product was added to a silica gel column and was eluted with Hex/EtOAc(15%) to get l-(5-bromo-2- methylb (90 mg, 31.7 % yield). MS:[M+H]+ 382.00.

8-methyl-l-[2-methyl-5-(l-methyl-lH-pyrazol-4-yl)benzenes ulfonyl]-l,2,3,4- tetrahydroquinoline: Broad_P_CaV3.3_189 (Compound 157)

To a stirred solution of l-(5-bromo-2-methylbenzenesulfonyl)-8-methyl-l, 2,3,4- tetrahydroquinoline (0.25 g, 657 pmol), (l-methyl-lH-pyrazol-4-yl)boronic acid (99.2 mg, 788 pmol), potassium carbonate (272 mg, 1.97 mmol) in 1,4-Dioxane and water, degased for 15 minutes with Nitrogen gas then bis(cyclopenta-l,3-dien-l-yldiphenylphosphane) dihydrochloride iron palladium (48.2 mg, 65.7 pmol) was added and heated the reaction mixture at 90°C for 3h. After completion, the reaction mixture was quenched in water(25mL) and extracted with ethyl acetate (3 ^ 10 mL), combine organic layer was dried over sodium sulphate, filtered and concentrated under reduce pressure up to crude, this was purify by flash chromatography using [0-25% EtOAc/Hexanes] to provide impure product, which was further purified by prep HPLC using (45-55% ACN in water containing 0.1% formic acid as modifier) as mobile phase to provide 8-methyl-l-[2-methyl (30 mg, 12.0 % yield) as a off white solid.

1H NMR (400 MHz, DMSO-d6) 5 8.26 (s, 1H), 7.96 (d, J = 1.9 Hz, 1H), 7.88 (s, 1H), 7.74 (dd, J = 7.9, 1.9 Hz, 1H), 7.33 (d, J = 7.9 Hz, 1H), 7.14 (s, 2H), 7.00 - 6.86 (m, 1H), 4.09 (s, 1H), 3.86 (s, 3H), 2.31 (s, 3H), 2.03 (s, 3H), 1.91 (s, 1H), 1.56 (d, J = 45.4 Hz, 2H).

MS :[M+H]+ 382.00. l,4-dimethyl-3-[4-methyl-2-(4-methylimidazol-l-yl)pyrimidin- 5-yl]sulfonyl-indole (Broad_P_CaV3.3_678, Compound 161)

To a stirred solution of l,4-dimethyl-3-[4-methyl-2-(4-methylimidazol-l- yl)pyrimidin-5-yl]sulfanyl-indole (0.32 g, 0.916 mmol, 1.00 eq) in tetrahydrofuran (1.6 mL)and water (1.6 mL) was added Oxone (1.13 g, 3.66 mmol, 4.00 eq) and the reaction mixture was allowed to stir at 25 °C for 1 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 (50 mL), dried over Na2SO4 and evaporated. The residue was purified by silica gel column chromatography using 2% methanol in dichloromethane as a mobile phase to provide comparative pure product which was further purified by reverse phase prep HPLC using 5-100% ACN in water (containing 0.1% Formic acid in water as modifier) as mobile phase to provide Broad_P_Cav3.3_678 (31 mg, 0.0813 mmol, 9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) 5 9.10 (s, 1H), 8.50 (s, 1H), 8.41 (s, 1H), 7.66 (s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.24 (t, J = 7.8 Hz, 1H), 7.01 (d, J = 7.2 Hz, 1H), 3.91 (s, 3H), 2.70 (s, 3H), 2.47 - 2.37 (m, 3H), 2.17 (s, 3H). MS(ESI): 382.0 [M+H]+. l,4-dimethyl-3-[4-methyl-2-(4-methylimidazol-l-yl)pyrimidin- 5-yl]sulfanyl-indole

To a solution of l,4-dimethylindole-3 -thiol (0.35 g, 1.97 mmol, 1.00 eq) and 5- bromo-4-methyl-2-(4-methylimidazol-l-yl)pyrimidine (0.60 g, 2.37 mmol, 1.20 eq) in dimethylformamide (0.8745 mL) was added Cesium carbonate (1.29 g, 3.95 mmol, 2.00 eq) and reaction mixture was heated at 100 °C for 0.5 h. After completion, the reaction was quenched with water (50 mL) and extracted ethyl acetate (3 x 25 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_678_Int-1453C, (0.32 g, 0.916 mmol, 46% yield) as a white solid. MS: [M+H]+ 350.3. 5-bromo-4-methyl-2-(4-methylimidazol-l-yl)pyrimidine

To a solution of 5-bromo-2-chloro-4-methyl-pyrimidine (2.00 g, 9.64 mmol, 1.00 eq) in dimethylformamide (20 mL) was added 4-methyl-lH-imidazole (1.58 g, 19.3 mmol, 2.00 eq)and K2CO3 (2.66 g, 19.3 mmol, 2.00 eq) at room temperature and reaction was heated at 100 °C for 1 h. After completion, the reaction was quenched with water (50 mL) and extracted ethyl acetate (3 x 50 mL). The combined organics were washed brine solution (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 Broad_P_CaV3.3_678_Int-1450F, (2.00 g, 7.90 mmol, 82% yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) 5 8.02 (d, J = 8.1 Hz, 1H), 7.29 (d, J = 8.1 Hz, 1H), 2.67 (s, 3H). MS(ESI): [M+H]+ 255.3.

Broad P Cav3.3 220

Compound 163

4-(4-ethylphenyl)-l -methyl- IH-pyrazole: Intermediate-343 To a stirred solution of l-bromo-4-ethylbenzene (2 g, 10.8 mmol, 1 eq), l-methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- (2.68 g, 12.9 mmol, 1.2 eq) and sodium carbonate (3.43 g, 32.4 mmol, 3 eq) in 1,4-dioxane (16 mL) and water (4 mL) was degassed for 15 minutes with Nitrogen gas then tetrakis(triphenylph (624 mg, 540 pmol, 0.05 eq) was added and heated the reaction mixture at 100°C for 16 h. 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 4-(4-ethylphenyl)-l -methyl- IH-pyrazole (1.5 g, 61.1 % yield) as a Off white solid.

MS:[M+H]+ 187.26.

2-ethyl-5-(l -methyl- lH-pyrazol-4-yl)benzene-l -sulfonyl chloride: Intermediate-344

A solution of 4-(4-ethylphenyl)-l -methyl- IH-pyrazole (1.5 g, 8.05 mmol, 1 eq) in chlorosulfonic acid (26.2 g, 224 mmol, 27.826 eq) at 0 °C and stirred at 65 °C for 2 h. After completion, reaction mass was quenched carefully with cold water and aqueous was extracted with ethyl acetate (3X100 mL). The combined organic layer was washed with brine solution and dried over sodium sulphate, evaporated to provide 2-ethyl-5-(l-methyl-lH-pyrazol-4- yl)benzene-l -sulfonyl chloride (1.4 g, 61.1 % yield) as a yellow sticky.

1H NMR (400 MHz, Chloroform-d) 5 12.18 (s, 2H), 8.09 (s, 1H), 7.88 (d, J = 2.1 Hz, 1H), 7.77 (s, 1H), 7.58 - 7.52 (m, 1H), 7.43 (dd, J = 7.8, 2.1 Hz, 1H), 7.16 (d, J = 7.8 Hz, 1H), 3.88 (s, 3H), 2.99 (q, J = 7.5 Hz, 2H), 1.16 (t, J = 7.5 Hz, 4H). l-[2-ethyl-5-(l -methyl- lH-pyrazol-4-yl)benzenesulfonyl]-8-methyl- 1,2, 3,4- tetrahydroquinoline: Broad_P_CaV3.3 220

A solution of 8-methyl-l,2,3,4-tetrahydroquinoline (0.15 g, 1.01 mmol, 1 eq), 2-ethyl- 5-(l -methyl- lH-pyrazol-4-yl)benzene-l -sulfonyl chloride (575 mg, 2.02 mmol, 2 eq), tri ethylamine (306 mg, 3.03 mmol, 3 eq) and 2-dimethylaminopyridine (123 mg, 1.01 mmol, 1.0 eq) in Pyridine (5 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 [0-25% EtOAc/Hexanes] to provide impure product, which was further purified by prep HPLC using (40-65% ACN in water containing 0.1% formic acid as modifier) as mobile phase to provide l-[2-ethyl-5-(l -methyl- lH-pyrazol-4-yl)benzenesulfonyl]-8-methyl- 1,2, 3,4- tetrahydroquinoline (0.012 g, 2.9 % yield) as a white solid.

MS:[M+H]+ 396.40.

1H NMR (400 MHz, DMSO-d6) 5 8.25 (s, 1H), 7.95 (d, J = 2.0 Hz, 1H), 7.87 (s, 1H), 7.79 (dd, J = 8.0, 2.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.25 - 7.08 (m, 2H), 6.94 (dd, J = 6.8, 2.1 Hz, 1H), 4.04 (s, 1H), 3.86 (s, 3H), 3.33 (s, 1H), 2.41 (s, 2H), 2.31 (s, 3H), 2.13 - 1.10 (m, 4H), 1.00 (t, J = 7.4 Hz, 3H).

4-((2-ethyl-5-(3-methylisoxazol-5-yl)phenyl)sulfonyl)-5-m ethyl-3,4-dihydro-2H- benzo[b][l,4]oxazine (Broad_P_Cav3.3_096, Compound 164)

To a stirred solution of 2-ethyl-N-(2-hydroxy-6-methylphenyl)-5-(3-methylisoxazol- 5-yl)benzenesulfonamide (500 mg, 1.34 mmol), Potassium carbonate (555 mg, 4.02 mmol) in THF (8 mL) was added 1,2-dibromoethane (377 mg, 2.01 mmol) at room temperature. The reaction mixture was stirred at 70°C under microwave irradiation for 1 h. After completion, the reaction mixture was poured in to water (35 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with brine solution (2 x 20 mL), dried over Na2SO4 and evaporated. The product was added to a Prep HPLC column (YMC ACTUS TRIART C18 (150*20)mm, 5p) and was eluted with 55 - 63 % ACN in 0.1 % formic acid in water as a gradient to provide 4-((2-ethyl-5-(3-met (170 mg, 31.8 % yield) as an off white solid.

1H NMR (400 MHz, DMSO-d6) 5 8.32 (d, J = 2 Hz, 1H), 8.11 (dd, J = 1.6, 8 Hz, 1H), 7.69

(d, J = 8 Hz, 1H), 7.14 - 7.08 (m, 2H), 6.85 (d, J = 7.6 Hz, 1H), 6.73 (d, J = 8 Hz, 1H), 3.96 (s, 2H), 3.84 (s, 2H), 2.66 (t, J = 7.4 Hz, 2H), 2.31 (s, 3H), 2.25 (s, 3H), 1.12 (t, J = 7.4 Hz,

3H). MS (ESI): 399.2 [M+H]+.

Synthesis of Broad_P_CaV3.3_468 and 469 (Compound 165 and Compound 391) rel-(2R)-2,8-dimethyl-l-[2-methyl-4-(l-methylpyrazol-4-yl)ph enyl]sulfonyl-2,3- dihydroquinolin-4-one and rel-(2S)-2,8-dimethyl-l-[2-methyl-4-(l-methylpyrazol-4- yl)phenyl]sulfonyl-2,3-dihydroquinolin-4-one: Broad_P_CaV3.3_468 and 469 To a solution of 2,8-dimethyl-2,3-dihydro-lH-quinolin-4-one (1.00 g, 5.71 mmol, 1.00 eq) and 2-methyl-4-(l-methylpyrazol-4-yl)benzenesulfonyl chloride (4.64 g, 17.1 mmol, 3.00 eq) in ACN (20 mL) was added Zinc oxide (0.93 g, 11.4 mmol, 2.00 eq) and heated it 80 °C for 48h. After completion, the reaction mixture was filtered through celite bed and washed with ethyl acetate (30 mL). The filtrate was evaporated under vacuum. The residue was purified via combi flash using (3:7, Ethyl acetate: Hexanes) as a mobile phase to provide impure compound, which was further purified by prep HPLC using (10-55% ACN and water containing 0.1% formic acid as a modifier) as a mobile phase to provide 0.09 g of racemic compound which was further purified by chiral HPLC using (CHIRALPAK IG (250*4.6mm) 5u), 0.1% DEA in MeOH) to provide Broad_P_CaV3.3_468 (20 mg, 0.0488 mmol, 100% purity, 0.86) and Broad_P_CaV3.3_469 (20 mg, 0.0488 mmol) as an off white solid.

Broad_P_CaV3.3_468

MS: [M+H]+ 410.6

1H NMR (400 MHz, Chloroform-d) 5 8.32 (s, 1H), 8.01 (s, 1H), 7.81 (d, J = 8.1 Hz, 1H),

7.63 (dd, J = 13.9, 8.0 Hz, 4H), 7.42 (t, J = 7.6 Hz, 1H), 4.59 (q, J = 6.9 Hz, 1H), 3.87 (s, 3H), 2.42 - 2.31 (m, 4H), 2.22 (d, J = 19.3 Hz, 1H), 2.05 (s, 3H), 1.12 (d, J = 6.9 Hz, 3H).

[a]D ²⁵ = +24.00°

Chiral separation conditions: (CHIRALPAK IH (250*4.6mm) 5u), 0.1% DEA in IPA:ACN (1 : 1)) and CO2 gas as a mobile phase

Order of elution: Fraction-1 (RT: 6.84 min); Fraction-2 (RT: 7.91 min)

Broad_P_CaV3.3_469

MS: [M+H]+ 410.6

IH NMR (400 MHz, Chloroform-d) 5 8.32 (s, IH), 8.02 (s, IH), 7.81 (d, J = 8.2 Hz, IH),

7.64 (dd, J = 13.8, 8.0 Hz, 4H), 7.42 (t, J = 7.6 Hz, IH), 4.61 (p, J = 6.9 Hz, IH), 3.88 (s, 3H), 2.36 (s, 4H), 2.23 (d, J = 19.4 Hz, IH), 2.06 (s, 3H), 1.12 (d, J = 6.9 Hz, 3H).

[a]D ²⁵ = -25.00°

Chiral separation conditions: (CHIRALPAK IH (250*4.6mm) 5u), 0.1% DEA in IPA:ACN (1 : 1)) and CO2 gas as a mobile phase

Order of elution: Fraction-1 (RT: 6.84 min); Fraction-2 (RT: 7.91 min) 6-fluoro-l,4-dimethyl-3-[4-methyl-2-(4-methylimidazol-l-yl)p yrimidin-5-yl]sulfonyl- indole (Broad_P_CaV3.3_689, Compound 166)

To a stirred solution of 6-fluoro-l,4-dimethyl-3-[4-methyl-2-(4-methylimidazol-l- yl)pyrimidin-5-yl]sulfanyl-indole (0.22 g, 0.599 mmol, 1.00 eq) in tetrahydrofuran (1.0461 mL) and water (1.0461 mL) was added Oxone (0.74 g, 2.39 mmol, 4.00 eq) and the reaction mixture was allowed to stir at 25 °C for 1 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 (50 mL), dried over Na2SO4 and evaporated. The residue was purified by silica gel column chromatography using 2% methanol in dichloromethane as a mobile phase to provide comparative pure product which was further purified by reverse phase prep HPLC using 5-100% ACN in water (containing 0.1% Formic acid in water as modifier) as mobile phase to provide Broad_P_Cav3.3_689 (32 mg, 0.0801 mmol, 13% yield) as a off white solid.

1H NMR (400 MHz, DMSO-d6) 5 9.09 (s, 1H), 8.50 (s, 1H), 8.39 (s, 1H), 7.66 (s, 1H), 7.39 (dd, J = 9.5, 2.4 Hz, 1H), 6.93 (d, J = 10.6 Hz, 1H), 3.86 (s, 3H), 2.69 (s, 3H), 2.17 (s, 3H). MS(ESI): 400 [M+H]+. l-{5-[3-(fluoromethyl)-l,2-oxazol-5-yl]-2-methylbenzenesulfo nyl}-8-methyl-l,2,3,4- tetrahydroquinoline (Broad_P_Cav3.3_185, Compound 168) To a stirred solution of 8-m ethyl- 1,2, 3, 4-tetrahydroquinoline (71.1 mg, 0.4832 mmol) in Pyridine (5 mL) was added 5-[3-(fluoromethyl)-l,2-oxazol-5-yl]-2-methylbenzene-l- sulfonyl chloride (280 mg, 0.9664 mmol) at room temperature. The reaction mixture was stirred at 100°C in microwave irradiation for 2 h. After completion, the reaction mixture was poured in to ice water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organics were dried over Na2SC>4 and evaporated. The product was added to a Prep HPLC column (X - BRIDGE C18 (250*19)MM, 5p) and was eluted with 45 - 60 % ACN in 0.1 % formic acid in water as a gradient to provide l-{5-[3-(fluoromethyl)-l,2-oxazol-5-yl]-2- methylbenzenesulfonyl} -8-m ethyl- 1, 2, 3, 4-tetrahydroquinoline (30 mg, 8 % yield) as a white solid.

1H NMR (400 MHz, Chloroform-d) 5 8.30 (d, J = 2.0 Hz, 1H), 7.86 (dd, J = 7.9, 2.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.18 - 7.08 (m, 2H), 6.88 (d, J = 7.0 Hz, 1H), 6.67 (s, 1H), 5.57 (s, 1H), 5.45 (s, 1H), 4.16 (s, 1H), 3.40 (s, 1H), 2.38 (s, 4H), 2.23 (s, 3H), 2.02 (s, 1H), 1.80 (s, 1H), 1.62 (s, 1H). MS (ESI): 401.0 [M+H]+.

5-[3-(fluoromethyl)-l,2-oxazol-5-yl]-2-methylbenzene-l -sulfonyl chloride

A solution of 3-(fluoromethyl)-5-(4-methylphenyl)-l,2-oxazole (300 mg, 1.56 mmol) in sulfurochloridric acid (3.63 g, 31.2 mmol) was stirred at 80 °C for 3 h. After completion, the reaction mixture was poured onto ice and extracted with DCM (3 x 20 mL). The organic layer was washed with NaHCOs solution (2 x 20 mL) and brine solution (2 x 20 mL), dried over Na2SC>4 and evaporated. The residue was purified via Biotage (10: 1 Hex/EtOAc; 12S column) to provide 5-[3-(fluoromethyl)-l,2-oxazol-5-yl]-2-methylbenzene-l-sulfo nyl chloride (280 mg, 62.0 % yield) as a white solid.

1H NMR (400 MHz, Chloroform-d) 5 8.45 (d, J = 1.9 Hz, 1H), 8.03 (dd, J = 8.0, 1.9 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 6.78 (s, 1H), 5.58 (s, 1H), 5.47 (s, 1H), 2.85 (s, 3H).

3-(fluoromethyl)-5-(4-methylphenyl)-l,2-oxazole

To a stirred a solution of diethyl(trifluoro-lambda4-sulfanyl)amine (1.22 g, 7.60 mmol) in DCM (20 mL) was added [5-(4-methylphenyl)-l,2-oxazol-3-yl]methanol (1.2 g, 6.34 mmol) at -78°C. the reaction mixture was stirred at -78°C for 2 h. After completion, the reaction mixture was quenched in saturated NaHCOs solution (20 mL) and extracted with DCM (3 x 30 mL). The combined 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 Hex/EtOAc; 12M column) to provide 3-(fluoromethyl)-5-( (300 mg, 22.5 % yield) as a white solid. MS (ESI) : 192.0 [M+H]+.

(6-fluoro-l,4-dimethyl-indol-3-yl)-imino-[4-methyl-6-(4-m ethylimidazol-l-yl)-3- pyridyl]-oxo-k ⁶ -sulfane and (6-fluoro-l,4-dimethyl-indol-3-yl)-imino-[4-methyl-6-(4- methylimidazol-l-yl)-3-pyridyl]-oxo- k ⁶ -sulfane (Broad_P_CaV3.3_682A and B) (Compounds 169 and 223)

The a solution of (6-bromo-4-methyl-3-pyridyl)-(6-fluoro-l,4-dimethyl-indol-3- yl)- imino-oxo-X ⁶ -sulfane (0.40 g, 1.01 mmol, 1.00 eq), 4-methyl-lH-imidazole (0.33 g, 4.04 mmol, 4.00 eq), Potassium tert-butoxide (340 mg, 3.03 mmol, 3.00 eq) in DMF was purged with Nitrogen for 15 min followed by addition of Copper Oxide (43 mg, 0.303 mmol, 0.300 eq) and the reaction was stirred at 120 °C for 4 h. After 4 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 impure product which on further purification by reverse phase Prep HPLC using ACN:Water (40-100%) as mobile phase and 0.1% formic acid as modifier to get of pure racemic mixture of Broad_P_CaV3.3_682.

1H NMR (400 MHz, DMSO-d6) 5 8.91 (s, 1H), 8.47 (s, 1H), 8.21 (s, 1H), 7.74 (d, J = 34.5 Hz, 2H), 7.39 - 7.22 (m, 1H), 6.82 (d, J = 10.7 Hz, 1H), 5.15 (s, 1H), 3.86 (s, 3H),2.53 (s, 3H), 2.47 (s, 3H), 2.17 (s, 3H). MS(ESI): 398.0[M+H]+.

The recemic mixture was purified by Chiral HPLC using Isopropyl Alcohol and hexane as mobile phase to get Broad_P_CaV3.3_682B (31 mg, 0.0778 mmol, 8% yield) and Broad_P_CaV3.3_682A (29 mg, 0.0712 mmol, 7% yield).

Broad_P_CaV3.3 682B

1H NMR (400 MHz, DMSO-d6) 5 8.92 (s, 1H), 8.48 (s, 1H), 8.22 (s, 1H), 7.79 (s, 1H), 7.71 (s, 1H), 7.33 (dd, J = 9.4, 2.4 Hz, 1H), 6.83 (dd, J = 10.5, 2.4 Hz, 1H), 5.17 (s, 1H), 3.86 (s, 3H), 2.59 (s, 3H), 2.47 (s, 3H), 2.18 (s, 3H).

Broad_P_CaV3.3 682A

1H NMR (400 MHz, DMSO-d6) 5 8.92 (s, 1H), 8.48 (s, 1H), 8.22 (s, 1H), 7.79 (s, 1H), 7.71 (s, 1H), 7.33 (dd, J = 9.5, 2.4 Hz, 1H), 6.83 (dd, J = 10.5, 2.4 Hz, 1H), 5.17 (s, 1H), 3.86 (s, 3H), 2.54 (s, 3H), 2.47 (s, 3H), 2.18 (s, 3H).

(6-bromo-4-methyl-3-pyridyl)-(6-fluoro-l,4-dimethyl-indol -3-yl)-imino-oxo-X ⁶ -sulfane

To the suspension of 3-[(6-bromo-4-methyl-3-pyridyl)sulfanyl]-6-fluoro-l,4- dimethyl-indole (0.60 g, 1.64 mmol, 1.00 eq) in Methanol (5ml), added

(Di acetoxy iodo)benzene (1.59 g, 4.93 mmol, 3.00 eq) at 0 °C and stirred for 15 min, then added Methanolic ammonia (5 M in , 3.29 mL, 16.4 mmol, 10.0 eq) and stirred at same temprature for 1 h. Reaction was monitored over TLC. 20-25 % sm remain unreacted so added (Di acetoxy iodo)benzene (500 mg) and methonlic ammonia (1 ml) and stirred at same temprature for 1 hr. After completion, the reaction was diluted 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 30% ethyl acetate in hexanes as a mobile phase to provide Broad_P_CaV3.3_682_1473 (0.40 g, 0.797 mmol, 49% yield) as a pale yellow solid. MS(ESI): 398.2 [M+H]+. l,5-dimethyl-4-[5-(3-methyl-l,2-oxazol-5-yl)-2-(trifluoromet hyl)benzenesulfonyl]- 1,2,3,4-tetrahydroquinoxaline (Broad_P_CaV3.3_247, Compound 170)

To a stirred solution of 8-methyl-l-[5-(3-methyl-l,2-oxazol-5-yl)-2- (trifluoromethyl)benzenesulfonyl]-l,2,3,4-tetrahydroquinoxal ine (120 mg, 0.2743 mmol), methyl iodide (77.8 mg, 0.5486 mmol) and potassium carbonate (113 mg, 0.8229 mmol) in DMF (3 mL) at room temperature. The reaction mixture was heated at 50°C and stirred at same temperature for 15 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 l,5-dimethyl-4-[5-(3 (65 mg, 52.2 % yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) 5 8.26 (d, J = 8.3 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.97 (s, 1H), 7.05 (t, J = 7.7 Hz, 1H), 7.01 (d, J = 1.6 Hz, 1H), 6.61 (d, J = 7.5 Hz, 1H), 6.43 (d, J = 8.2 Hz, 1H), 4.25 (s, 1H), 3.44 (s, 1H), 3.00 (s, 1H), 2.85 (t, J = 10.0 Hz, 1H), 2.67 - 2.56 (m, 1H), 2.31 (dd, J = 5.1, 1.6 Hz, 6H), 2.27 (s, 3H). MS (ESI): 452.3 [M+H]+. l-[2-ethyl-5-(3-methyl-l,2-oxazol-5-yl)benzenesulfonyl]-8-me thyl-l,2,3,4- tetrahydroquinoline: Broad_P_CaV3.3_166 (Compound 171)

A solution of 2-ethyl-5-(3-methyl-l,2-oxazol-5-yl)benzene-l-sulfonyl chlor (385 mg, 1.35 mmol, 2 eq), 8-methyl-l,2,3,4-tetrahydroquinoline (0.1 g, 679 pmol, 1 eq), triethylamine (136 mg, 1.35 mmol, 2 eq) and 2-dimethylaminopyridine (829 pg, 6.79 pmol, 0.01 eq) in pyridine (3 mL) was stirred at 80 °C for 3 h. The reaction mixture was evaporated and the residue was purify by flash chromatography using [0-25% EtOAc/Hexanes] to provide impure product, which was further purified by prep HPLC using (65-70% MeOH in water containing 0.1% formic acid as modifier) as mobile phase to provide l-[2-ethyl-5-(3-methyl- l,2-oxazol-5-yl)benzenesulfonyl]-8-me (0.012 g, 5 % yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) 5 8.23 (d, J = 1.9 Hz, 1H), 8.06 (dd, J = 8.0, 2.0 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.21 - 7.09 (m, 2H), 7.04 (s, 1H), 6.96 (dd, J = 6.9, 2.2 Hz, 1H), 4.03 (s, 1H), 3.48 (s, 1H), 2.40 (s, 2H), 2.30 (s, 6H), 1.90 (s, 1H), 1.59 (d, J = 55.6 Hz, 2H), 1.02 (t, J = 7.4 Hz, 3H). MS:[M+H]+ 397.30. l,4-dimethyl-3-[[2-methyl-6-(4-methylimidazol-l-yl)-3-pyridy l]sulfonyl]indole (Broad_P_CaV3.3 677, Compound 172)

A stirred suspension of 3-[(6-bromo-2-methyl-3-pyridyl)sulfonyl]-l,4-dimethyl- indole (0.40 g, 1.05 mmol, 1.00 eq), 4-methyl-lH-imidazole (0.17 g, 2.11 mmol, 2.00 eq) and K3PO4 (0.36 g, 3.16 mmol, 3.00 eq) in dioxane (4 mL) as degassed with nitrogen gas for 15 min. After 15 min, Tris(dibenzylideneacetone)dipalladium(0) (0.045 g, 0.316 mmol, 0.300 eq) was added to it and heated it at 160 °C for 3 h. After completion, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with brine solution (3 x 30 mL). The organic layer was dried over Na2SC>4 and evaporated under vacuum. The residue was burified by combi flash using (1 :9, MeOH: DCM) as a mobile phase to provide mixture of isomers which was further purified by prep HPLC to giveBroad_P_CaV3.3_677 (42 mg, 0.108 mmol, 10% yield) as an off white solid.

1H NMR (400 MHz, DMSO-d6) 5 8.47 (s, 1H), 8.42 - 8.17 (m, 2H), 7.76 (d, J = 8.6 Hz, 1H), 7.68 (s, 1H), 7.46 (d, J = 8.3 Hz, 1H), 7.23 (t, J = 7.8 Hz, 1H), 6.99 (d, J = 7.2 Hz, 1H), 3.92 (s, 3H), 2.69 (s, 3H), 2.43 (s, 3H), 2.17 (s, 3H). MS(ESI): 381.2 [M+H]+.

6-fluoro-4-methyl-3-[[4-methyl-6-(4-methylimidazol-l-yl)- 3-pyridyl]sulfonyl]-lH-indole (Broad_P_CaV3.3_690, Compound 174)

To the solution of 3-[(6-bromo-4-methyl-3-pyridyl)sulfonyl]-6-fluoro-4-methyl-l H- indole (0.28 g, 0.731 mmol, 1.00 eq) in dimethylformamide (3 mL) was added Potassium tert-butoxide (246 mg, 2.19 mmol, 3.00 eq), Q12O (31 mg, 0.219 mmol, 0.300 eq) and 4- methyl-lH-imidazole (0.24 g, 2.92 mmol, 4.00 eq) and stirred at 140 °C for 6 h. After 6 h, the reaction mixture was diluted with water (15 mL) and extracted with EtOAc (3 x 20 mL). The organics were dried over Na2SC>4 and evaporated under vacuum. The residue was purified via combi flash using DCM:MeOH (9: 1) as a mobile phase to provide a white solid of Broad_P_CaV3.3_690 (51 mg, 0.131 mmol, 18% yield).

1H NMR (400 MHz, DMSO-d6) 5 12.72 (s, 1H), 8.82 (s, 1H), 8.48 (s, 1H), 8.26 (s, 1H), 7.86 (s, 1H), 7.70 (s, 1H), 7.19 (dd, J = 9.1, 2.4 Hz, 1H), 6.85 (dd, J = 10.6, 2.3 Hz, 1H), 2.46 (s, 3H),2.46 (s, 3H), 2.17 (s, 3H). MS(ESI): 384.9[M+H]+.

3-[(6-bromo-4-methyl-3-pyridyl)sulfonyl]-6-fluoro-4-methy l-lH-indole

To the solution of 3-[(6-bromo-4-methyl-3-pyridyl)sulfanyl]-6-fluoro-4-methyl-l H- indole (0.45 g, 1.28 mmol, 1.00 eq) in tetrahydrofuran (4 mL), added water (6 mL) and oxone (1575 mg, 5.12 mmol, 4.00 eq) and stirred at 25 °C for 6 h. After 6 h the reaction mixture was diluted with water (5 mL) and extracted with Ethyl acetate (3 x 20 mL). The combined organics were dried over Na2SC>4 and evaporated under vacuum. The residue was purified via combi flash using (5: 1, Hex:EtOAc) as a mobile phase to provide 3-[(6-bromo-4-methyl-3- pyridyl)sulfonyl]-6-fluoro-4-methyl-lH-indole, (0.28 g, 0.731 mmol, 57% yield) as a off white solid. MS(ESI): 384.9 [M+H]+. 3-[(6-bromo-4-methyl-3-pyridyl)sulfanyl]-6-fluoro-4-methyl-l H-indole

To a stirred a solution of 6-fhioro-4-methyl-lH-indole (0.50 g, 3.35 mmol, 1.00 eq) and 6-bromo-4-methyl-pyridine-3-sulfonyl chloride (1.81 g, 6.70 mmol, 2.00 eq) in dimethylformamide (10 mL) was added Tetrabutylammonium iodide (2.48 g, 6.70 mmol, 2.00 eq) at 25 °C. The reaction mixture was stirred at same temperature for4 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 20% ethyl acetate in hexanes as a mobile phase to provide Broad_P_CaV3.3_690_1506 (0.35 g, 0.996 mmol, 30% yield) as a pale yellow solid. MS(ESI): 353.1 [M+H]+.

Synthesis of Compound 175

K ₃ PO ₄ (2 eq), t-Butyl X-phos Step-3 (0.1 eq), Pd ₂ (dba) ₃ (0.05 10.27% eq), Dioxane (5V), 120°C, 15h

Broad_P_CaV3.3_425 Compound 175

5-bromo-N-(2-hydroxy-6-methyl-phenyl)-2-methyl-benzenesul fonamide: Intermediate-879A To a stirred suspension of 2-amino-3-methyl-phenol (5.00 g, 40.6 mmol, 1.00 eq), in DCM (5 mL), was added 5-bromo-2-methyl-benzenesulfonyl chloride (16.42 g, 60.9 mmol, 1.50 eq) and Pyridine (13.14 mL, 162 mmol, 4.00 eq) stirred at RT. After 16h, the reaction mixture was diluted with Citric acid solution (50 mL) and extracted with ethyl acetate (3 x 40 mL). The organic layer was dried over Na2SO4 and evaporated. The residue was purified via column chrometography (50:50 Hexane/EtOAc),to provide 5-bromo-N-(2-hydroxy-6-methyl- phenyl)-2-methyl-benzenesulfonamide (3.10 g, 6.44 mmol, 16% yield) as a red solid.

MS:[M+2H]+ 358.20.

4-(5-bromo-2-methyl-phenyl)sulfonyl-5-methyl-2,3-dihydro- l,4-benzoxazine: Intermediate- 879B

A solution of 5-bromo-N-(2-hydroxy-6-methyl-phenyl)-2-methyl- benzenesulfonamide (3.10 g, 8.70 mmol, 1.00 eq) in DMF (16 mL) was added to a solution of 1,2-Dibromoethane (.9 mL, 10.4 mmol, 1.20 eq) and Potassium carbonate (2.41 g, 17.4 mmol, 2.00 eq) at room temperature and the resulting mixture was stirred at 80°C for 6 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 50 mL). The organics were dried over Na2SO4 and evaporated. The residue was purified via Biotage (5: 1 Hex/EtOAc; 12S column) to provided 4-(5-bromo-2-methyl-phenyl)sulfonyl-5- methyl-2,3-dihydro-l,4-benzoxazine Broad_P_CaV3.3_425_Int_879B, (2.40 g, 5.19 mmol, 60% yield).

MS:[M+H]+ 432.30.

5-methyl-4-[2-methyl-5-(4-methylimidazol-l-yl)phenyl]sulf onyl-2,3-dihydro-l,4- benzoxazine: Broad_P_CaV3.3_425 (Compound 175)

A stirred solution of 4-(5-bromo-2-methyl-phenyl)sulfonyl-5-methyl-2,3-dihydro-l,4 - benzoxazine (2.40 g, 5.19 mmol, 1.00 eq) and 4-methyl-lH-imidazole (0.85 g, 10.4 mmol, 2.00 eq) in 1,4-Dioxane (24 mL) was degassed with nitrogen gas for 15 min. After 15 min, t- BuXPhos (0.22 g, 0.519 mmol, 0.100 eq) and Tris(dibenzylideneacetone)dipalladium(0) (0.24 g, 0.259 mmol, 0.0500 eq) was added to it and heated it in a sealed tube for 15h at 120°C . After 15h, the reaction mixture was poured into cold water (20 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 5-methyl-4-[2-methyl-5-(4-methylimidazol-l-yl)phenyl]sulfony l- 2,3-dihydro-l,4-benzoxazine (9.5 mg, 0.0249 mmol, 1%) as an off white solid.

1H NMR (400 MHz, DMSO-d6) 5 8.07 (s, 1H), 7.96 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 8.3 Hz, 1H), 7.39 (s, 1H), 7.10 (t, J = 7.9 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 6.69 (d, J = 8.2 Hz, 1H), 3.98 (t, J = 5.8 Hz, 2H), 3.86 (t, J = 5.7 Hz, 2H), 2.29 (s, 6H), 2.18 (s, 3H). MS :[M+H]+ 484.10.

Synthesis of Broad_P_CaV3.3_384 (Compound 154)

Compound 154 N,2-dimethyl-N-[rac-(4S)-8-methyl-l-[2-methyl-4-(l-methylpyr azol-4-yl)phenyl]sulfonyl-

3,4-dihydro-2H-quinolin-4-yl]propane-2-sulfinamide: Intermediate-761

To a stirred solution of 2-methyl-N-[rac-(4S)-8-methyl-l-[2-methyl-4-(l- methylpyrazol-4-yl)phenyl]sulfonyl-3,4-dihydro-2H-quinolin-4 -yl]propane-2-sulfinamide (100 mg, 0.200 mmol, 1.00 eq) in DMF (2 mL) was added 60% Sodium hydride in mineral oil (9.6 mg, 0.399 mmol, 2.00 eq) at 0 °C and stirred at same temperature for 20 min. After 20 min, iodomethane (.02 mL, 0.300 mmol, 1.50 eq) was added to it and allowed it to stir at RT for 3h. 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 Na2SO4 and evaporated. The residue was purified by Combi-flash using Ethyl acetate:Hexanes (1 : 1) to provide Intermediate-761, (80 mg, 0.128 mmol, 64% yield) as a yellow semi-solid.

MS: [M+H]+ 515.2 rac-(4S)-N,8-dimethyl-l-[2-methyl-4-(l-methylpyrazol-4-yl)ph enyl]sulfonyl-3,4-dihydro- 2H-quinolin-4-amine: Broad_P_CaV3.3_384 To a stirred solution ofN,2-dimethyl-N-[rac-(4S)-8-methyl-l-[2-methyl-4-(l- methylpyrazol-4-yl)phenyl]sulfonyl-3,4-dihydro-2H-quinolin-4 -yl]propane-2-sulfinamide (80 mg, 0.155 mmol, 1.00 eq) in 1,4-Dioxane (2 mL) was added Concentrated HC1 (.15 mL, 6.12 mmol, 39.4 eq) and allowed it to stir at RT for Ih. After completion, the reaction mixture was diluted with water (15 mL) and extracted with DCM (3 x 15 mL) to remove impurities. The aqueous layer was basified with NaHCOs and extracted with DCM (3 x 20 mL). The combined organics were dried over Na2SC>4 and evaporated to provide pure compound. We observed 10-15% racemization of the compound; so we purified it by chiral prep HPLC (CHIRALPAK IG (250*4.6mm) 5u), 0.1% DEA in MeOH) to provide Broad_P_CaV3.3_384 (15 mg, 0.0351 mmol) as yellow semi-solid.

MS:[M+H]+ 411.0

1H NMR (400 MHz, DMSO-d6) 5 8.19 (s, IH), 7.90 (s, IH), 7.80 (d, J = 8.3 Hz, IH), 7.55 (d, J = 7.8 Hz, 2H), 7.25 (d, J = 7.1 Hz, IH), 7.18 (h, J = 5.5 Hz, 2H), 4.00 - 3.92 (m, IH), 3.88 (s, 3H), 3.44 (s, IH), 2.83 (s, IH), 2.31 (s, 3H), 2.18 (s, 3H), 2.14 (s, 3H).

[a]D ²⁵ = -73.01°

8-methyl-l-{[4-methyl-6-(l-methyl-lH-pyrazol-4-yl)pyridin -3-yl]sulfonyl}-l,2,3,4- tetrahydroquinoxaline (Broad_P_CaV3.3_285, Compound 179)

To a stirred solution of l-[(6-chloro-4-methylpyridin-3-yl)sulfonyl]-8-methyl-l,2,3,4 (0.2 g, 592 pmol, 1 eq), l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- (147 mg, 710 pmol, 1.2 eq) and potassium carbonate (244 mg, 1.77 mmol, 3 eq) in 1,4 dioxane (5 mL) and water (1 mL) was degassed for 15 minutes with Nitrogen gas followed by palladium(2+) bis(cy (48.3 mg, 59.2 pmol, 0.1 eq) was added and heated the reaction mixture at 80°C for 3h. 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 [0-5% MeOH/DCM] to provide impure product.The impure product was purify by prep HPLC using (30-58% ACN in water containing 0.1% formic acid as modifier) as mobile phase to provide 8-methyl-l-{[4-methyl- 6-(l-methyl-lH-pyrazol-4-yl)pyridin-3- (0.2 g, 88.1 % yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) 5 8.84 (s, 1H), 8.39 (s, 1H), 8.08 (s, 1H), 7.65 (s, 1H), 6.88 (t, J = 7.7 Hz, 1H), 6.40 (d, J = 7.3 Hz, 1H), 6.33 (d, J = 8.1 Hz, 1H), 5.88 (d, J = 3.3 Hz, 1H), 4.09 (s, 1H), 3.89 (s, 3H), 3.13 (s, 2H), 2.71 (s, 1H), 2.27 (s, 3H), 2.05 (s, 3H). MS(ESI): 384.3 [M+H]+.

Synthesis of Compound 180 Compound 180 l-[(5-bromo-2-methylpyridin-3-yl)sulfonyl]-8-methyl-l,2,3,4- tetrahydroquinoline:

Intermediate-231

A solution of 8-methyl- 1,2,3, 4-tetrahydroquinoline (0.2 g, 1.35 mmol, 1 eq), 5- bromo-2-methylpyridine-3-sulfonyl chloride (1.09 g, 4.05 mmol, 3 eq), triethylamine (409 mg, 4.05 mmol, 3 eq) and 4-dimethylaminopyrid (16.4 mg, 0.135 mmol, 0.1 eq) in pyridine (3 mL) was stirred at 110 °C for 1 h in microwave irriadiation. The reaction mixture was evaporated and the residue was purify by flash chromatography using [0-15% EtOAc/Hexanes] to provide l-[(5-bromo-2-methylpyridin-3-yl)sulfonyl]-8-methyl-l, 2,3,4- (0.12 g, 23.3 % yield) as a yellow oil. MS: [M+2H]+ 383.50.

8-methyl-l-{[2-methyl-5-(3-methyl-l,2-oxazol-5-yl)pyridin -3-yl]sulfonyl}-l, 2,3,4- tetrahydroquinoline: Broad_P_CaV3.3 154

To a stirred solution of l-[(5-bromo-2 -methylpyridin-3-yl)sulfonyl]-8-methyl-l, 2,3,4- (0.13 g, 0.3409 mmol, 1 eq), xphos (22.7 mg, 0.04772 mmol, 0.14 eq) and palladium(II) acetat (5.35 mg, 0.02386 mmol, 0.07 eq) in 1,4-Di oxane (3 mL), degassed for 15 minutes with Nitrogen gas then 3-methyl-5-(tributylstannyl)-l,2-oxazole (317 mg, 0.8522 mmol, 2.5 eq) was added and heated the reaction mixture at 100°C for 5h. After completion, the reaction mixture was quenched in water (lOOmL) and extracted with ethyl acetate (3 * 100 mL), combine organic layer was dried over sodium sulphate, filtered and concentrated under reduce pressure up to crude, this was purify by flash chromatography using [0-50% EtOAc/Hexanes] to provide impure compound, which was further purified by prep HPLC using (30-60% ACN in water containing 0.1% formic acid as modifier) as mobile phase to provide 8-methyl-l-{[2-methyl-5-(3-methyl-l,2-oxazol-5-yl)pyridin-3- (0.043 g, 33.0 % yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) 5 9.17 (d, J = 6.9 Hz, 1H), 8.50 (d, J = 6.9 Hz, 1H), 7.19 (ddd, J = 14.3, 7.4, 3.6 Hz, 3H), 6.98 (t, J = 5.8 Hz, 1H), 4.09 (s, 1H), 3.34 (s, 2H), 2.30 (dd, J = 9.3, 5.8 Hz, 9H), 1.92 (s, 1H), 1.54 (s, 2H). MS:[M+H]+ 384.20.

5-methyl-4-((2-methyl-5-(3-methylisoxazol-5-yl)phenyl)sul fonyl)-3,4-dihydro-2H- benzo[b][l,4]oxazine (Broad_P_Cav3.3_029, Compound 181)

To a stirred solution of 5-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazine (300 mg, 2.01 mmol), Diisopropylethylamine (778 mg, 6.02 mmol) in Acetonitrile (5.0 mL) was added 2- methyl-5-(3-methylisoxazol-5-yl)benzene-l-sulfonyl chloride (654 mg, 2.41 mmol) at room temperature. Then the reaction mixture was stirred 2 h at same temperature. After completion, the reaction mixture was poured in water (40 mL) and extracted with EtOAc (3 x 30 mL). The combined organics were washed with brine solution (2 x 20 mL), dried over Na2SC>4 and evaporated. The residue was purified by prep HPLC column (X-BRIDGE Cl 8 (250*19) mm, 5p) and was eluted with 55% ACN in 100% water as a gradient to provide 5- methyl-4-((2-methyl-5-(3-methylisoxazol-5-yl)phenyl)sulfonyl )-3,4-dihydro-2H- benzo[b][l,4]oxazine (120 mg, 15.5 % yield) as a Light yellow solid.

1H NMR (400 MHz, Chloroform-d) 5 8.33 (d, J = 1.9 Hz, 1H), 7.88 (dd, J = 7.9, 1.9 Hz, 1H), 7.41 (d, J = 7.9 Hz, 1H), 7.10 (t, J = 7.9 Hz, 1H), 6.84 (d, J = 7.5 Hz, 1H), 6.71 (d, J = 8.0 Hz,

1H), 6.41 (s, 1H), 4.02 (s, 2H), 3.84 (s, 2H), 2.44 - 2.27 (m, 9H). MS (ESI): 385.2 [M+H]+.

Synthesis of Broad_P_CaV3.3_428 and 429 (Compounds 182 and 193)

Compound 182

Compound 193 rac-(4R)-8-methyl-l-[2-methyl-4-(l-methylpyrazol-4-yl)phenyl ]sulfonyl-3,4-dihydro-2H- quinolin-4-ol and rac-(4S)-8-methyl-l-[2-methyl-4-(l-methylpyrazol-4-yl)phenyl ]sulfonyl- 3,4-dihydro-2H-quinolin-4-ol: Broad_P_CaV3.3_428 and 429

To a stirred solution of 8-methyl-l-[2-methyl-4-(l-methylpyrazol-4- yl)phenyl]sulfonyl-2,3-dihydroquinolin-4-one (100 mg, 0.249 mmol, 1.00 eq) in THF (1 mL) and Methanol (1 mL) was added Sodium borohydride (14 mg, 0.374 mmol, 1.50 eq) and allowed to stir it at RT for Ih. After completion, the reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organics were dried over Na2SO4 and evaporated to provide racemic compound; which was further purified by chiral SFC (CHIRALPAK IG (250*4.6mm) 5u), 0.1% DEA in MeOH) using 0.1% DEA in methanol and CO2 gas as a mobile phase to provide rac-(4R)-8-methyl-l-[2-methyl-4-(l- methylpyrazol-4-yl)phenyl]sulfonyl-3,4-dihydro-2H-quinolin-4 -ol (30 mg, 29.81% yield) and rac-(4S)-8-methyl-l-[2-methyl-4-(l-methylpyrazol-4-yl)phenyl ]sulfonyl-3,4-dihydro-2H- quinolin-4-ol (30 mg, 30.27% yield) as off white solid. Broad_P_CaV3.3_428

MS: [M+H]+ 398.2

1H NMR (400 MHz, DMSO-d6) 5 8.30 (s, 1H), 8.00 (s, 1H), 7.80 (d, J = 8.6 Hz, 1H), 7.60 (d, J = 6.8 Hz, 2H), 7.22 (ddd, J = 17.5, 13.2, 6.8 Hz, 3H), 5.34 (d, J = 5.6 Hz, 1H), 3.87 (s, 4H), 3.69 (s, 1H), 3.49 - 3.36 (m, 1H), 2.30 (s, 3H), 2.16 (s, 1H), 2.04 (s, 3H), 1.35 (t, J = 10.2 Hz, 1H).

1H NMR (77 °C, 400 MHz, DMSO-d6) 5 8.19 (s, 1H), 7.91 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 6.6 Hz, 2H), 7.31 (d, J = 7.3 Hz, 1H), 7.19 (dd, J = 14.0, 6.7 Hz, 2H), 5.02 (d, J = 5.7 Hz, 1H), 3.95 (dt, J = 15.0, 7.8 Hz, 2H), 3.89 (s, 3H), 3.38 (dt, J = 14.0, 7.2 Hz, 1H), 2.29 (s, 3H), 2.20 (s, 4H), 1.43 (dt, J = 15.8, 7.8 Hz, 1H).

[a]D ²⁵ = +92.01°

Broad_P_CaV3.3_429

MS: [M+H]+ 398.2

1H NMR (400 MHz, DMSO-d6) 5 8.30 (s, 1H), 8.00 (s, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.60 (d, J = 7.0 Hz, 2H), 7.22 (ddd, J = 17.6, 13.1, 7.0 Hz, 3H), 5.34 (d, J = 5.8 Hz, 1H), 3.87 (s, 4H), 3.68 (s, 1H), 3.40 (s, 1H), 2.30 (s, 3H), 2.16 (s, 1H), 2.04 (s, 3H), 1.35 (t, J = 10.4 Hz, 1H).

1H NMR (77 °C, 400 MHz, DMSO-d6) 5 8.19 (s, 1H), 7.91 (s, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.60 - 7.49 (m, 2H), 7.31 (d, J = 7.3 Hz, 1H), 7.24 - 7.09 (m, 2H), 5.03 (d, J = 5.6 Hz, 1H), 3.95 (td, J = 8.2, 4.1 Hz, 2H), 3.89 (s, 3H), 3.38 (ddd, J = 14.0, 8.2, 5.7 Hz, 1H), 2.30 (s, 3H), 2.24 (dd, J = 7.6, 5.5 Hz, 1H), 2.20 (s, 3H), 1.45 (dt, J = 13.1, 7.7 Hz, 1H).

[a]D ²⁵ = -84.71°

l-[2-fluoro-5-(l-methyl-lH-pyrazol-4-yl)benzenesulfonyl]- 8-methyl-l, 2,3,4- tetrahydroquinoline (Broad_P_CaV3.3_228, Compound 183)

To a stirred solution of l-(5-bromo-2-fluorobenzenesulfonyl)-8-methyl-l,2,3,4- tetrahydroquinoline (90 mg, 0.2342 mmol), l-methyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (48.7 mg, 0.2342 mmol) in 1,4 - Dioxane (5.0 mL) at room temperature was added potassium carbonate (32.3 mg, 0.2342 mmol) and Water (1 mL), the reaction mixture was purged with argon for 20 min. After completion of purging was added tetrakis(triphenylphosphine) palladium (270 mg, 0.2342 mmol) at same temperature. Then again purging with argon for 10 min. The reaction was heated at 100°C for 8 h. After completion, the reaction mixture was poured in to ice-water (35 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 l-[2-fluoro-5-(l-met (55 mg, 60.9 % yield) as a white solid. MS (ESI) : 386.2 [M+H]+.

7-methyl-l-[2-methyl-5-(4-methylimidazol-l-yl)phenyl]sulf onyl-indoline (Broad_P_CaV3.3_658, Compound 185) To the solution of l-(5-bromo-2-methyl-phenyl)sulfonyl-7-methyl-indoline (200 mg, 0.546 mmol, 1.00 eq) in Dimethylformamide (5 mL) was added 4-Methylimidazole (179 mg, 2.18 mmol, 4.00 eq), Copper(I) oxide (23 mg, 0.164 mmol, 0.300 eq), and Potassium tert- butoxide (184 mg, 1.64 mmol, 3.00 eq), and the reaction was heated at 140 °C for 16 h. After completion, the reaction was diluted with water (100 mL) and the product was extracted in ethyl acetate (100 mL x 3). The organic layer was dried over sodium sulphate and vacuum evaporated. The residue was purified by column chromatography in silica using 90%-100% ethyl acetate in hexane. The product fractions were vaccum evaporated to afford impure product. The impure product was purified by Prep HPLC using Column PHENOMENEX C8 (250*21.2)mm, 5p, in 10%-38% Acetonitrile in water containg 0.1% formic acid as modifier. The product fractions were lyophilized to afford white solid of 7-methyl-l-[2-methyl-5-(4- methylimidazol-l-yl)phenyl]sulfonyl-indoline Broad_P_CaV3.3_658 (53 mg, 0.145 mmol, 27% yield).

1H NMR (400 MHz, DMSO-d6) 5 8.15 (d, J = 1.4 Hz, 1H), 7.95 (d, J = 2.4 Hz, 1H), 7.83 (dd, J = 8.2, 2.5 Hz, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.19 - 7.10 (m, 2H), 7.05 (dd, J = 5.8, 2.9 Hz, 1H), 4.03 (t, J = 7.2 Hz, 2H), 2.46 (s, 3H), 2.29 (t, J = 7.1 Hz, 2H), 2.18 (s, 3H), 2.05 (s, 3H). MS(ESI): 368.3 [M+l]+.

(2R)-l,2,5-trimethyl-4-[2-methyl-5-(4-methylimidazol-l-yl )phenyl]sulfonyl-2,3- dihydroquinoxaline and (2S)-l,2,5-trimethyl-4-[2-methyl-5-(4-methylimidazol-l- yl)phenyl]sulfonyl-2,3-dihydroquinoxaline (Broad_P_Cav3.3_440 and 441) (Compounds 186 and 555)

A stirred solution of 4-(5-bromo-2-methyl-phenyl)sulfonyl-l,2,5-trimethyl-2,3- dihydroquinoxaline (400 mg, 0.935 mmol, 1.00 eq) and 4-methyl-lH-imidazole (92 mg, 1.12 mmol, 1.20 eq) in DMF (5 mL) was degassed with nitrogen gas for 15 min. After 15 min, Copper(I) oxide (37 mg, 0.468 mmol, 0.500 eq) and Potassium tert-butoxide (0.23 g, 2.07 mmol, 2.00 eq) was added to it and heated it in a sealed tube for 16 h. After 16 h, the reaction mixture was poured into cold water (50 mL) and extracted with ethyl acetate (3 x 30 mL). Organic layer was seperated and evaporated under reduced pressure. Residue was purified by column chromatography (80% ethyl acetate in n-hexane) to obtained 0.07 g of compound which was further purified by Preparative HPLC (0.1%Formic acid in water, gradient 20 to 35% ACN ) gave 0.045m g of compound which was further purified by chiral HPLC (SFC) (CHIRALPAK AD-H (250*4.6mm) 5u), 0.1% DEA in MeOH) gave Broad_P_Cav3.3_441 (10 mg, 0.0245 mmol, 3% yield) and Broad_P_Cav3.3_440 (6.5 mg, 0.0154 mmol, 2% yield).

Broad_P_CaV3.3_440

1H NMR (400 MHz, DMSO-d6) 5 8.16 (d, J = 7.7 Hz, 1H), 7.94 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.45 (q, J = 8.5 Hz, 2H), 7.03 (t, J = 8.0 Hz, 1H), 6.58 (d, J = 7.8 Hz, 1H), 6.38 (d, J =

8.4 Hz, 1H), 4.49 (s, 1H), 2.97 (d, J = 7.9 Hz, 2H), 2.32 (d, J = 8.1 Hz, 3H), 2.19 (d, J = 13.3 Hz, 6H), 1.97 (d, J = 8.1 Hz, 3H), 0.84 (t, J = 6.4 Hz, 3H). MS(ESI): 411.4[M+H]+.

Broad_P_CaV3.3_441

1H NMR (400 MHz, DMSO-d6) 5 8.14 (s, 1H), 7.93 (d, J = 2.6 Hz, 1H), 7.74 (dd, J = 8.1,

2.5 Hz, 1H), 7.51 - 7.34 (m, 2H), 7.03 (t, J = 7.9 Hz, 1H), 6.58 (d, J = 7.5 Hz, 1H), 6.38 (d, J = 8.1 Hz, 1H), 4.54 - 4.38 (m, 1H), 2.96 (dd, J = 13.3, 7.4 Hz, 2H), 2.31 (s, 3H), 2.19 (d, J = 14.3 Hz, 6H), 1.97 (s, 3H), 0.84 (d, J = 4.9 Hz, 3H). MS(ESI): 411.4[M+H]+.

8-methyl-l-{[2-methyl-6-(l-methyl-lH-pyrazol-4-yl)pyridin -3-yl]sulfonyl}-l,2,3,4- tetrahydroquinoline (Broad_P_CaV3.3_260, Compound 187) A solution of 8-methyl- 1,2,3, 4-tetrahydroquinoline (0.15 g, 1.01 mmol, 1 eq), 2- methyl-6-(l-methyl-lH-pyrazol-4-yl)pyridine-3-sulfonyl chi (823 mg, 3.03 mmol, 3 eq), triethylamine (306 mg, 3.03 mmol, 3 eq) and 2-dimethylaminopyrid (123 mg, 1.01 mmol, 1.0 eq) in pyridine (10 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 [0-80% EtOAc/Hexanes] to provide impure product, which was further purified by prep HPLC using (35-45% ACN in water containing 0.1% formic acid as modifier) as mobile phase to provide 8-methyl-l-{[2-methyl-6-(l-methyl-lH-pyrazol-4-yl)pyridin-3- (0.012 g, 3 % yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) 5 8.39 (s, 1H), 8.14 (d, J = 8.4 Hz, 1H), 8.08 (s, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.25 - 7.09 (m, 2H), 6.97 (dd, J = 6.2, 2.8 Hz, 1H), 4.02 (s, 1H), 3.89 (s, 3H), 3.27 (s, 1H), 2.41 (s, 1H), 2.31 (s, 3H), 2.22 (s, 3H), 1.94 (s, 1H), 1.73 - 1.43 (m, 2H). MS(ESI): 383.4 [M+H]+.

Synthesis of Compound 188

Compound 188

8-methyl- 1 -[2-methyl-5-(4-methyl- IH-imidazol- 1 -yl)benzenesulfonyl]- 1 ,2,3,4- tetrahydroquinoline: Broad_P_CaV3.3_211

To a stirred solution of l-(5-bromo-2-methylbenzenesulfonyl)-8-methyl-l, 2,3,4- tetrahy (0.2 g, 525 pmol, 1 eq), 4-methyl-lH-imidazol (51.7 mg, 630 pmol, 1.2 eq) and potassium tert-butoxide (88.3 mg, 787 pmol, 1.5 eq) in DMF (5 mL) was degassed for 15 minutes with Nitrogen gas then cuprous oxide (15.0 mg, 105 pmol, 0.2 eq) was added and heated the reaction mixture at 110°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 (0-44% ACN in water containing 0.1% formic acid as modifier) as mobile phase to provide 8-methyl-l-[2-methyl-5-(4-methyl-lH-imidazol-l-yl)benzenesul (0.019 g, 9.49 % yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) 5 8.22 (d, J = 1.4 Hz, 1H), 7.97 (d, J = 2.5 Hz, 1H), 7.84 (dd, J = 8.2, 2.5 Hz, 1H), 7.61 - 7.45 (m, 2H), 7.25 - 7.07 (m, 2H), 6.97 (dd, J = 6.6, 2.3 Hz, 1H), 4.19 (s, 1H), 3.46 (s, 1H), 2.49 - 2.38 (m, 1H), 2.35 (s, 3H), 2.18 (s, 3H), 2.05 (s, 3H), 1.94 (s, 1H), 1.54 (s, 2H). MS: [M+2H]+ 382.20.

N-methyl-l-[2-methyl-5-(3-methyl-l,2-oxazol-5-yl)benzenes ulfonyl]-l,2,3,4- tetrahydroquinolin-8-amine (Compound 189):

To a cooled solution of tert-butyl N-methyl-N-{ l-[2-methyl-5-(3-methyl-l,2-oxazol- 5- (0.175 g, 349 pmol, 1 eq) in DCM (15 mL) was added trifluoroacetic acid (118 mg, 1.04 mmol, 3 eq) at room temperature and reaction mixture was stirred at room tempreture for 16h. After completion, the reaction mixture was poured in to sodium bicarbonate solution (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 (35-80% ACN in water containing 0.1% formic acid as modifier) as mobile phase to provide N-methyl-l-[2-methyl-5-(3-methyl-l,2-oxazol-5- yl)benzenesulf (0.0676 g, 49 % yield) as a white solid.

1H NMR (400 MHz, Methanol-d4) 5 8.28 (d, J = 2.0 Hz, 1H), 7.92 (dd, J = 8.0, 2.0 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.10 (t, J = 7.8 Hz, 1H), 6.77 - 6.58 (m, 2H), 6.37 (d, J = 7.4 Hz, 1H), 4.81 (s, 1H), 3.78 (s, 2H), 2.82 (s, 3H), 2.35 (s, 3H), 2.22 (s, 3H), 1.80 (s, 3H). 8-methyl-l-[2-methyl-5-(l-methyl-lH-l,2,3-triazol-4-yl)benze nesulfonyl]-l,2,3,4- tetrahydroquinoline (Broad_P_Cav3.3_188, Compound 190)

To a stirred solution of 8-m ethyl- 1,2, 3, 4-tetrahydroquinoline (108 mg, 0.736 mmol) in Pyridine (4 mL) was added 2-methyl-5-(l-methyl-lH-l,2,3-triazol-4-yl)benzene-l- sulfonyl chloride (200 mg, 0.7360 mmol) at room temperature. The reaction mixture was stirred at 100°C for 12 h. After completion, the reaction mixture was poured in to ice water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organics were dried over Na2SC>4 and evaporated. The product was added to a Prep HPLC column (X - BRIDGE Cl 8 (250*19)MM, 5p) and was eluted with 55 - 60 % ACN in 0.1 % formic acid in water as a gradient to provide 8-methyl-l-[2-methyl-5-(l-methyl-lH-l,2,3-triazol-4- yl)benzenesulfonyl]-l, 2, 3, 4-tetrahydroquinoline (15 mg, 5.33 % yield) as a white solid.

1H NMR (400 MHz, Chloroform-d) 5 8.20 (d, J = 1.9 Hz, 1H), 8.03 (dd, J = 7.8, 2.0 Hz, 1H), 7.76 (s, 1H), 7.31 (t, J = 7.0 Hz, 1H), 7.16 - 7.06 (m, 2H), 6.87 (d, J = 7.3 Hz, 1H), 4.16 (s, 4H), 3.37 (s, 1H), 2.37 (s, 4H), 2.20 (s, 3H), 2.01 (s, 1H), 1.84 (s, 2H). MS (ESI): 383.0 [M+H]+. l,3,3,5-tetramethyl-4-[2-methyl-4-(l-methylpyrazol-4-yl)phen yl]sulfonyl-2H- quinoxaline (Broad_P_CaV3.3_335, Compound 191)

To a stirred solution of 2,2,4, 8-tetramethyl-l,3-dihydroquinoxaline (0.25 g, 1.31 mmol, 1.00 eq), 4-(Dimethylamino)pyridine (0.16 g, 1.31 mmol, 1.00 eq) and Triethylamine (.55 mL, 3.94 mmol, 3.00 eq) in Pyridine (5 mL) at room temperature. The reaction mixture was stirred for 30 min. was added 2-methyl-4-(l-methylpyrazol-4-yl)benzenesulfonyl chloride (1.07 g, 3.94 mmol, 3.00 eq) at same temperature. The reaction was stirred at same temperature for 24 h. After completion, the reaction concentrated under vacuum. The residue was quince with 10 % citric acid solution (50 mL) and extracted with EtOAc (3 x 30 mL).

The combined organic were washed with brine solution (3 x 20 mL), dried over Na2SO4 and evaporated. The product was purified by prep-HPLC column chromatography and the product was eluted with 65 - 75% in ACN in 0.1% formic acid in water as a gradient to provide l,3,3,5-tetramethyl-4-[2-methyl-4-(l-methylpyrazol-4-yl)phen yl]sulfonyl-2H- quinoxaline Broad_P_Cav3.3_335 (15 mg, 0.0353 mmol, 3% yield) as an of white solid.

1H NMR (400 MHz, DMSO-d6) 5 8.15 (s, 1H), 8.01 - 7.83 (m, 2H), 7.63 - 7.44 (m, 2H), 6.91 (d, J = 2.1 Hz, 1H), 6.75 (d, J = 2.1 Hz, 1H), 5.26 (s, 1H), 3.87 (s, 3H), 2.86 (d, J = 11.7 Hz, 5H), 2.06 (s, 3H), 1.22 (s, 6H). MS (ESI) : 425.6 [M+H]+.

Synthesis of Compound 192 Compound 192

3-ethyl-5-(4-methylphenyl)-l,2-oxazole: Intermediate :-296 To a stirred solution of di-tert-butyl dicarbonate (3.36 g, 15.4 mmol), l-ethynyl-4- methylbenzene (600 mg, 5.16 mmol) in ACN (10 mL) was added 4-dimethylaminopyridine (315 mg, 2.58 mmol) and 1 -nitropropane (1.37 g, 15.4 mmol) at room temperature. The reaction mixture was stirred at same temperature for 3 h. After completion, the reaction mixture was poured in to water (40 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with brine solution (2 x 30 mL), dried over Na2SO4, and evaporated. The residue was purified via Biotage (10:1 Hex/EtOAc; 12M column) to provide 3-ethyl-5-(4-methylp (270 mg, 26.7 % yield) as a white solid.

MS: [M+H]+ 188.30.

5-(3-ethyl-l,2-oxazol-5-yl)-2-methylbenzene-l-sulfonyl chloride: Intermediate :-297

A solution of 3-ethyl-5-(4-methylphenyl)-l,2-oxazole (270 mg, 1.44 mmol) in sulfurochloridic acid (3.34 g, 28.7 mmol) was stirred at 80 °C for 3 h. After completion, the reaction mixture was poured onto ice and extracted with DCM (3 x 30 mL). The organic layer was washed with NaHCOs solution (2 x 20 mL) and brine solution (2 x 20 mL), dried over Na2SO4 and evaporated. The residue was purified via Biotage (5: 1 Hex/EtOAc; 12S column) to provide 5-(3-ethyl-l,2-oxazo (170 mg, 41.3 % yield) as an off white solid.

1 -[5-(3-ethyl- 1 , 2-oxazol-5-yl)-2-methylbenzenesulfonyl]-8-methyl-l, 2,3,4- tetrahydroquinoline: Broad_P_CaV3.3_183 (Compound 192)

To a stirred solution of 8-m ethyl- 1,2,3, 4-tetrahydroquinoline (105 mg, 0.7138 mmol) in Pyridine (5 mL) was added 5-(3-ethyl-l,2-oxazol-5-yl)-2-methylbenzene-l-sulfonyl chloride (170 mg, 0.5949 mmol) at room temperature. The reaction mixture was stirred at same temperature for 12 h. After completion, the solvent was evaporated and quenched with water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organics were dried over Na2SC>4 and evaporated. The product was added to a Prep HPLC column and was eluted with 30 - 60 % ACN in 0.1 % formic acid in water as a gradient to provide 1 -[5-(3 -ethyl- 1 ,2- ox (12 mg, 5 % yield) as a white solid.

MS: [M+2H]+ 397.20.

1H NMR (400 MHz, Chloroform-d) 5 8.26 (d, J = 1.9 Hz, 1H), 7.84 (dd, J = 7.9, 1.9 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.17 - 7.09 (m, 2H), 6.87 (d, J = 7.1 Hz, 1H), 6.41 (s, 1H), 4.16 (s, 1H), 3.39 (s, 1H), 2.75 (q, J = 7.6 Hz, 2H), 2.37 (s, 3H), 2.22 (s, 3H), 2.01 (s, 1H), 1.80 (s, 2H), 1.33 (t, J = 7.6 Hz, 3H), 1.28 (s, 1H). l,4-dimethyl-3-[3-methyl-5-(4-methylimidazol-l-yl)pyrazin-2- yl]sulfonyl-indole (Broad_P_CaV3.3 679, Compound 195)

To the solution of 3-(5-chloro-3-methyl-pyrazin-2-yl)sulfonyl-l,4-dimethyl-indo le (0.20 g, 0.596 mmol, 1.00 eq) in Dimethylformamide (2 mL) was added Potassium tert- butoxide (0.20 g, 1.79 mmol, 3.00 eq), C O (0.026 g, 0.179 mmol, 0.300 eq) and 4-methyl- IH-imidazole (0.098 g, 1.19 mmol, 2.00 eq) and stirred at 140 °C for 16 h. After completion, the reaction was quenched with water (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 to provide crude product, which was purified by silica gel column chromatography using 4% methanol in DCM as a mobile phase to provide comparative pure product, which was further purified by reverse phase prep HPLC using 5-100% ACN in water (containing 0.1% Formic acid in water as modifier) as mobile phase to provide Broad_P_CaV3.3_679 (25 mg, 0.0649 mmol, 11% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) 5 8.87 (d, J = 4.6 Hz, 1H), 8.51 (d, J = 4.8 Hz, 1H), 8.34 (d, J = 4.5 Hz, 1H), 7.71 (d, J = 4.7 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.25 (dd, J = 10.0, 5.4 Hz, 1H), 7.01 (d, J = 7.0 Hz, 1H), 3.93 (d, J = 4.6 Hz, 3H), 2.92 (d, J = 4.6 Hz, 3H), 2.37 (d, J = 4.6 Hz, 3H), 2.18 (d, J = 4.7 Hz, 3H). MS(ESI): 382.0 [M+H]+. 3-(5-chloro-3-methyl-pyrazin-2-yl)sulfonyl-l,4-dimethyl-indo le

To a solution of 3-(5-chloro-3-methyl-pyrazin-2-yl)sulfanyl-l,4-dimethyl-indo le (0.23 g, 0.757 mmol, 1.00 eq) in Tetrahydrofuran (2 mL) added Water (1 mL) was added Oxone (0.35 g, 1.14 mmol, 1.50 eq) and stirred at 37 °C for 48 h. After 48 h the reaction mixture was diluted with water (50 mL) and extracted with Ethyl acetate (3x 50 mL) The combined organics were dried over Na2SO4 and evaporated under vacuum to provide crude product, which was purified by combiO-flash chromatography using 20% EtOAc in hexanes as mobile phase to provide Broad_P_CaV3.3_679_1457, (0.23 g, 0.473 mmol, 62% yield) as white solid. MS (ESI): [M+H]+ 336.1. 3-(5-chloro-3-methyl-pyrazin-2-yl)sulfanyl-l,4-dimethyl-indo le

To a solution of l,4-dimethylindole-3 -thiol (0.70 g, 3.95 mmol, 1.00 eq) in

Dimethylformamide (7 mL) was stirred at room temperature and Cesium carbonate (2.57 g, 7.90 mmol, 2.00 eq), 2-bromo-5-chloro-3-methylpyrazine (0.98 g, 4.74 mmol, 1.20 eq) was added at same temperature and reaction mass was stirred at 100°C for 2 h. The reaction mass was quenched in water (100 mL) and extracted with EtOAc (3 * 50 mL). The combined organics were dride over anhydrous Na2SC>4 and evaporated to get impure mixture of product. The mixuture was purified by reverse phase chromatography using 10-100% ACN in water with 0.1% formic acid as modifier to get pure Broad_P_CaV3.3_679_1456 (0.23 g, 0.757 mmol, 19% yield). MS(ESI): 306.0 [M+H]+.

3-methyl-5-(4-methyl-3-((7-methyl-3,4-dihydroquinolin-l(2 H)- yl)sulfonyl)phenyl)isoxazole (Broad_P_Cav3.3_017, Compound 196)

To a stirred solution of 7-methyl-l,2,3,4-tetrahydroquinoline (97.5 mg, 0.6624 mmol) and Diisopropylethylamine (213 mg, 1.65 mmol) in Acetonitrile (4 mL) was added 2-methyl- 5-(3-methylisoxazol-5-yl)benzene-l-sulfonyl chloride (150 mg, 0.5520 mmol) at RT and stirred for 2 h at same temperature. The reaction mixture was poured in to water (25 mL) and the extracted with EtOAc (3 x 30 mL). The combined organic layer was dried over Na2SO4 and evaporated. The residue was purified by Biotage (5: 1 Hex/EtOAc; 12S column) to provide the 3-methyl-5-(4-methyl-3-((7-methyl-3, 4-dihydroquinolin- 1(214)- yl)sulfonyl)phenyl)isoxazole (118 mg, 56 % yield) as an off white solid.

1H NMR (400 MHz, Chloroform-d) 5 8.28 (d, J = 1.8 Hz, 1H), 7.85 (dd, J = 7.9, 1.9 Hz, 1H),

7.39 (d, J = 8.0 Hz, 1H), 7.30 (s, 1H), 6.98 (d, J = 7.7 Hz, 1H), 6.91 (dd, J = 8.1, 1.6 Hz, 1H),

6.39 (s, 1H), 3.84 - 3.75 (m, 2H), 2.64 (t, J = 6.7 Hz, 2H), 2.44 (s, 3H), 2.38 (s, 3H), 2.28 (s, 3H), 1.80 (p, J = 6.6 Hz, 2H). MS ESI : 383.2 [M+H]+. (4S)-N,N,8-trimethyl-l-[2-methyl-4-(l-methylpyrazol-4-yl)phe nyl]sulfonyl-3,4-dihydro-

2H-quinolin-4-amine: Broad_P_CaV3.3_386

To a stirred solution of (4S)-8-methyl-l-[2-methyl-4-(l-methylpyrazol-4- yl)phenyl]sulfonyl-3,4-dihydro-2H-quinolin-4-amine (100 mg, 0.252 mmol, 1.00 eq) in Methanol (2 mL) was added Sodium cyanoborohydride (32 mg, 0.504 mmol, 2.00 eq) and stirred at RT for 5 min. After 5 min, Paraformaldehyde (15 mg, 0.504 mmol, 2.00 eq) was added to it followed by addition of Acetic acid (1.5 mg, 0.0252 mmol, 0.100 eq). The reaction mixture was allowed to stir at RT for 16h. After completion, the reaction mixture was poured into saturated NaHCOs solution (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organics were dried over Na2SO4 and evaporated. The residue was purified by Combi-flash using Ethyl acetate: Hexanes (1 : 1) to provide impure compound; which was further purified by prep HPLC purification using (10-30% ACN in water containing formic acid as an modifier) as a mobile phase to provide pure product. We observed 10-15% racemization of product; so we purified it by chiral prep HPLC purification (CHIRALPAK IG (250*4.6mm) 5u), 0.1% DEA in MeOH) to provide Broad_P_CaV3.3_386 (25 mg, 0.0589 mmol, 23% yield) as an off white solid.

1H NMR (400 MHz, DMSO-d6) 5 8.18 (s, 1H), 7.90 (s, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.53 (s, 2H), 7.29 (d, J = 7.3 Hz, 1H), 7.21 - 7.12 (m, 2H), 3.88 (s, 4H), 3.51 (d, J = 24.4 Hz, 1H), 2.32 (s, 4H), 2.15 (s, 3H), 2.00 (s, 6H), 1.63 (s, 1H), 1.27 (s, 1H). MS:[M+H]+ 425.2. [a]D ²⁵ = +80.21°.

General Methods

Construction of stable single copy inducible Flpin TREx 293 cell lines constitutively expressing both the inward rectifying K ⁺ channel KCNJ4 and membrane-tethered genetic calcium sensors Inducible Flpin TREx cell lines that express a single isogenic copy of Cav3.1, Cav3.2, or Cav3.3 cDNA were generated and validated. 3 pg of pLenti-KCNJ4-P2A-puroR was transfected with Lipofectamine 2000 at a 1 :2 ratio in Optimem into these cell lines and selected with 1.25 pg/mL of puromycin to generate a polyclonal line for each Cav3 channel. Next, 3 pg of CMV-GCamp6s/m/f with a C-terminal CAAX motif (from Addgene) were transfected as above into these cell lines and selected with 300 pg/mL of neomycin. Clonal lines were selected under a fluorescent picking scope for proper membrane localization and expanded before testing. Cells were passaged once in 15 pg/mL blasticidin S and 200 ug/mL hygromycin B, once in 300 ug/mL neomycin, and then in 1.25 pg/mL puromycin for less than 20 passages. Cells plated for experiments were plated in the absence of selection antibiotics.

Fluorescence Imaging Plate Reader (FLIPR) assay for T-type calcium channels using GCaMP6s-CAAX

FLIPR assay protocol is described in Zhang, Y-L, et al, ACS Pharmacol and Transl Sci 5.3 (2022): 156-168, which is hereby incorporated by reference in its entirety, and particularly in relation to FLIPR assay protocol. Briefly, cells were maintained in DMEM/F- 12+GlutaMAX™+ 10% FB S+0.5 pg/mL puromycin. Two days prior to conducting the assay, Cav3/Kir2.3/GCaMP6 cells were seeded at 16K/well density in the presence of 1 pg/mL doxycycline into poly -D-ly sine-coated 384-well clear-bottom plates using Multidrop Combi dispenser (Thermal Fisher) at medium speed. The cell plates were incubated in a 5% CO2 humidified incubator at 37°C for 2 days. On the day of the assay, medium was aspirated using plate washer, and 25pL equilibrium buffer was added to each well following aspiration. The assay plates were incubated for 60min at room temp in the dark. The assay plates were incubated for ~60min at room temperature in the dark and then placed in the FLIPR Tetra™ instrument (Molecular Devices). Changes in fluorescence were measured over time with excitation 470-495 nm and emission 515-575 nm using two depolarization stimulations at 1Hz sampling rate.

After 30 seconds baseline reading, 25 pL of the first stimulation, Buffer 1, containing the EC10 concentration of KC1 in equilibrium buffer was added for evaluation of agonist activity. The fluorescence emission was recorded for additional 120 seconds. To evaluate antagonist activity, 25 pL of the second stimulation, Buffer 2, containing the EC90 concentration of KC1 in equilibrium buffer was added and recorded for another 120 seconds. The equilibrium buffer containing 133 mM NaCl; 10 mM HEPES; 10 mM D-Glucose; 2 mM KC1, 1 mM CaCh and adjusted to pH 7.3 using NaOH. The assay was performed at room temperature. The peak response over baseline from FLIPR ¹ ^ ¹ ^ after each KC1 addition was used for data analysis. For agonist evaluation, the fluorescence response to the low KC1 (ECio) stimulation is used as the baseline, and the fluorescence response to the high KC1 ((ECio) stimuatlion is used asl00% activation. For antagonist evaluation, the channel activity measured by the fluorescence response to the EC90KCI stimulation is used as the baseline, and the fluorescence response in the presence TTA-A2 (10 mM) is used as 100% inhibition.

The first stimulation involved addition 25 pl stimulation buffer 1 (KC1 or CaCh to generate ECio in equilibrium buffer) in each well. The second stimulation involved addition of 25 l stimulation buffer 2 (EC90 concentration in equilibrium buffer) in each well. The assay was performed at 25°C. Baseline normalized data were used for data analysis.

The Equilibrium buffer used was 133 mM NaCl; 10 mM HEPES; 10 mM D-Glucose; 2 mM KC1 ; 1 mM CaCh; using NaOH to adjust to pH=7.3.

Automated patch-clamp electrophysiology

Measurements were performed using the automated patch-clamp electrophysiology assay described in Baez-Nieto, D, et al. Brain 145.5 (2022): 1839-1853, which is hereby incorporated by reference in its entirety and particularly in relation to the patch clamp assay protocol. Briefly, experiments were performed using the SyncroPatch 384PE platform (Nanion Technologies®) that can record simultaneously up to 384 independent cells with GQ resistance seals. Cells were harvested, pelleted, and re-suspended in 10 mL of serum-free media and pelleted at 1000 rpm for 3 min at RT. The supernatant is discarded and cells are re-suspended in serum-free DMEM F12-GlutaMAX (ThermoFisher Scientific) and pECS 50% (v:v). The cells were kept until the moment of the experiment in a temperature controlled dedicated reservoir at 10° C and shaken at 200 rpm. The experiments were performed within one hour after the harvesting process. The assays were carried in singlehole chips with resistances between 4-5 MQ after priming the chip with the following solutions (in mM), physiological extracellular solution (pECS) 10 HEPES, 140 NaCl, 5 Glucose, 4 KC1, 2 CaCh, 1 MgCh, 295-305 mOsm pH 7.4 (NaOH). Internal recording solution (in mM) 20 EGTA, 10 HEPES, 50 CsCl, 10 NaCl, 60 CsF, 285 mOsm pH 7.2 (by IN CsOH). The junction potential (~ 12 mV) and the fast capacitive component were compensated, then 15 pL of the cell suspension (50% v/v pECS/DMEM no serum) was added to each well to a final density of 50-80K cells/mL. All recording solutions were prepared with ultrapure MilliQ water (18 MQ-cm) and test compound added at either O. lpM, 0.3pM, IpM, 3pM, or lOpM, and filtered with 0.22 pm PES membrane and stored at 4°C until use. The whole-cell configuration was achieved by a brief negative pressure pulse of -250 mbar. The holding potential was set at -100 mV for all the voltage protocols. Once in whole-cell configuration, the slow capacitive component (Cslow) was canceled, and the series resistance (Rs) compensation was set at 80%. The data were acquired at 20 kHz and filtered at 10 kHz using Nani on proprietary software PatchControl 384 software (v.1.4.5). The data was processed on DataControl384 Version 1.5.0 in real time using the quality checkpoints along the experiment, using the seal resistance, capacitance, and series resistance as qualitative parameters.

The peak current and the activation steady-state parameters were obtained from currents elicited by a two-pulse protocol. The voltage dependent activation and voltage dependent inactivation protocols have been described in Heyne, H. O., et al. Set TranslMed 12 (2020): eaay6848, which is hereby incorporated by reference in its entirety and particularly in relation to voltage activation and inactivation protocols. Cells were initially held at -lOOmV for 100 ms then held for Is at a range of voltages from -120 to 20 mV with a 10 mV increase per sweep (TP1), followed by a 300 ms test pulse at -20 mV (TP2), concluding with 300 ms at -lOOmV before the next step. The peak current density value was calculated as the maximum peak current from the preconditioning pulse normalized by the capacitance. The normalized chord conductance (G/Gmax) was calculated from the I-V relationship constructed with the peak current values for each voltage during TP1, using the following equation:

Where Vrev is the reversal potential obtained using a linear extrapolation of the last four points of the I-V relationship mentioned above. The voltage activation process was fitted using a single Boltzmann function:

Gmax was defined as the maximum value of G when the first derivative of G is minimal, zd corresponds to the slope of the function and represent the voltage dependency of the activation, Vh is the voltage at which half of the Gmax. R corresponds to the universal gas constant, T is the absolute temperature in Kelvin, and F is the Faraday constant. The steadystate inactivation parameters were obtained from the peak current values during TP2 which represent the fraction of channels able to be opened at the end of TP1. The voltage inactivation was fitted by the sum of two Boltzmann distributions according to the following equation:

Statistical analysis

Electrophysiology data were analyzed using Clampfit 10 (Molecular Devices), Excel (Microsoft), and GraphPad Prism 9.0 (GraphPad Software, La Jolla, CA), and were presented as mean ± SEM and statistically analyzed with one-way ANOVA with Dunnett’s post hoc test. For fluorescence in vitro cell based experiments, baseline and 100% activation or inhibition %, corresponding to its experimental settings. The data were fit to a 4-parameter logistic equation to determine the minimum response, maximum response (%Emax), the concentration giving the half-maximal response (ECso or ICso), and the slope factor of the curve using Origin 2018b (from OriginLab) or Prism 9.0.

Other Embodiments

From the foregoing description, it will be apparent that variations and modifications may be made to the invention described herein to adopt it to various usages and conditions. Such embodiments are also within the scope of the following claims.

The recitation of a listing of elements in any definition of a variable herein includes definitions of that variable as any single element or combination (or subcombination) of listed elements. The recitation of an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.

All patents and publications mentioned in this specification are herein incorporated by reference to the same extent as if each independent patent and publication was specifically and individually indicated to be incorporated by reference.