T-type voltage-dependent calcium channel enhancers

Abstract

Described herein are T-type voltage-gated calcium channel enhancers that can increase thalamic function, e.g., reduce thalamocortical hyperactivity, in patients in need thereof. These enhancers may be useful in many diseases or conditions associated therewith, e.g., schizophrenia and neurodevelopmental disorders. Typically, C av The enhancer has the structure of formula (I) or formula (V). JPEG2025530763000653.jpg74170

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Patent Application No. 63 / 402,031, filed August 29, 2023, which is incorporated herein by reference in its entirety.

[0002] 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 this invention. [Background technology]

[0003] background Voltage-gated calcium channels (VGCCs) are channels that transport calcium (Ca 2+ ) ions into excitable cells, is defined as the rapid and selective Ca 2+ This is achieved by allowing the inflow of Ca. 2+ voltage-dependent Ca transients by converting them into 2+ The channel is Ca 2+ Not only do they contribute to active membrane properties such as spiking and dendritic cell integration, but they are also responsible for many cellular functions including neurotransmitter release, neurite outgrowth, cell survival, hormone release, and gene expression.

[0004] The functional core of VGCC is Ca V It is composed of an α1 subunit, which contains the ion pore, gating mechanism, and toxin-binding domain, and consists of four homologous transmembrane domains (I-IV), cytoplasmic amino and carboxyl termini, and intracellular loops connecting each transmembrane domain. In humans, 10 genes encode Ca V They encode the α1 subunit, which are divided into three major subgroups (Ca V 1. Ca V 2, and CaV They are divided into three families.

[0005] Ca V Because they are rapidly inactivated, they are also called T-type calcium channels (the T stands for transient). V 3 T-type channels do not interact with auxiliary β subunits and their biophysical properties can be completely reconstituted by only the α1 subunit in heterologous expression systems, whereas Ca V 1 or Ca V 2 Ca 2+ Channel α1 subunit (Ca V 1 / 2) require co-expression of an auxiliary β subunit to facilitate channel transport to the membrane surface. V 3 T-type current is Ca V 1 / 2 channels are inactivated and activated at more negative potentials than 1 / 2 channels, and 100 mM Ba 2+ It exhibits a relatively small single-channel conductance of 8-12 pS in Ca V 3 T-type Ca 2+ The channels exhibit overlapping voltage-dependent activation and inactivation curves and a "window current" where, at physiological resting membrane potentials, the majority of channels are inactivated but a minority remain constitutively open. V 3. T-type channels V Compared to the 1 / 2 family, they close slowly from the open state, allowing for a large amount of Ca release during repolarization. 2+ Influx of T-type Ca2+ initiates membrane depolarization. 2+ These unique biophysical properties of the channel allow Ca ions to be released during repolarization, which is responsible for the rhythmic rebound firing of thalamic neurons in the brain. 2+ Inflow occurs.

[0006] Three genes (CACNA1G, CACNA1H, and CACNA1I) regulate Ca V 3 Three types of α1 subunits (Ca V 3.1, Ca V 3.2, and Ca V3.3). Human genetics has linked these genes to neurological and neuropsychiatric disorders. V Rare mutations in CACNA1G, the gene encoding the 3.1α1 subunit, are associated with severe developmental disorders, e.g., associated with spinocerebellar ataxia, idiopathic generalized epilepsy, and cerebellar atrophy. Patients with loss-of-function mutations in CACNA1H have been shown to be pain tolerant and therefore require Ca2+ to treat pain. V 3.2 is the biological basis for blocking

[0007] Several clinical drugs, including the antihypertensive drug mibefradil (removed from the market due to potential off-target drug-drug interactions), certain neuroleptics, and anticonvulsants, have been shown to inhibit T-type Ca2+ receptors. 2+ However, none of the existing T-type inhibitors are subtype-selective within the CaV3 family. Furthermore, 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), blocks CaV3 channels. V However, in fluorescence imaging plate reader (FLIPR) and electrophysiological assays in HEK cells, SAK3-mediated Ca + -regulation was not observed. V 3.3 Activation was not measured. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] WO2013111799 [Non-patent literature]

[0009] [Non-Patent Document 1] Zhang, YL., et al., ACS Pharmacol Transl Sci 5.3 (2022): 156-168 [Non-licensed document 2] Pantelis, Christos, et al. Nature 511.7510 (2014): 421-427 [Non-licensed document 3] Gulsuner, Suleyman, et al. Cell 154.3 (2013): 518-529

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Non-licensed literature 9

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[0010] There is also an urgent need to identify potentiators for the Ca V (Especially Ca V There is also no focus on the correlation between enhancement of 3.3) and therapeutic benefit for diseases, disorders, or conditions associated with these mutations. [Means for solving the problem]

[0011] overview In accordance with the above and other objects, the present disclosure provides a method for detecting T-type voltage-gated calcium channels, particularly Ca V 3.3 Compounds that potentiate T-type voltage-gated calcium channels are provided. V 3.3 Enhancers (e.g., Ca V3.3 Potentiators) demonstrate efficacy against disease states and can be used to provide therapeutic treatment to subjects in need thereof. In some embodiments, the compounds of the present disclosure are Ca V 3.3 Selectively potentiate T-type voltage-gated calcium channels, e.g., α.1.I subunits and / or auxiliary subunits. In some embodiments, compounds of the present disclosure selectively potentiate T-type voltage-gated calcium channels, Ca V 3.1 and Ca V 3.3. In various embodiments, the compounds of the present disclosure enhance Ca V 3.2 No effect on channels (e.g., Ca V EC 3.2 50 is greater than 20 μM, and Ca V 3.2 current amplitude does not increase), whereas Ca V 3.1 and Ca V Make changes to 3.3.

[0012] Ca of the present disclosure V 3.3 The potentiator has the structure of formula (I):

[0013] [ka]

[0014] (wherein the dashed circle represents an optionally unsaturated ring (e.g., an aromatic ring); p is 0 or 1; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; X A1 is N, O, or C; X A2 is N or C; X A3 is N or CR A3 and; R A1is independently at each occurrence absent or hydrogen, alkyl (e.g., optionally unsaturated C1-C8 alkyl, lower alkyl, e.g., C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl, e.g., -CD3), -C(O)OR, -C(O)R, haloalkyl (e.g., C1-C8 haloalkyl, lower haloalkyl, e.g., C1-C4 haloalkyl, halomethyl, C1-C8 fluoroalkyl, lower fluoroalkyl, e.g., C1-C4 fluoroalkyl, fluoromethyl, difluoromethyl, perfluoroalkyl, C1-C8 perfluoroalkyl, lower perfluoroalkyl, e.g., C1-C4 perfluoroalkyl, perfluoromethyl), hydroxy, or amino (e.g., -NRR); two R A1 may be taken together to form =O or a 3- to 6-membered spiro ring; A1 may independently have one or more (e.g., two, three, four) optional substitution points at each occurrence; R A2 are independently at each occurrence hydrogen and alkyl (e.g., optionally unsaturated C1-C8 alkyl, lower alkyl, e.g., C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl, e.g., -CD3); A2 The groups may be taken together to form =O or a 3- to 6-membered spiro ring; where R A2 may independently have one or more (e.g., two, three, four) optional substitution points at each occurrence; R A3 is independently at each occurrence hydrogen, alkyl (e.g., optionally unsaturated C1-C8 alkyl, lower alkyl, e.g., C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl, e.g., -CD3), alkoxy (e.g., C1-C8 alkoxy, lower alkoxy, e.g., C1-C4 alkoxy, methoxy, alkoxy substituted with aryl, e.g., benzyloxy), cyano, -C(O)OR, -C(O)R, or halogen (e.g., F, Cl, Br); where R A3 may independently have one or more (e.g., two, three, four) optional substitution points at each occurrence; RL is -S(=O)2-, -S(=O)-, -S(=NR)(=O)-, or -C(R)(R)-; X B1 is N, S, or CR B1 and one X B1 may be absent (e.g., two adjacent groups may be joined by a bond, such as a single or double bond, to preserve aromaticity); X B2 is independently N or CR for each occurrence B2 and; R B1 is independently at each occurrence hydrogen, alkyl (e.g., C1-C8 alkyl, lower alkyl, e.g., C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl, e.g., -CD3), haloalkyl (e.g., C1-C8 haloalkyl, lower haloalkyl, e.g., C1-C4 haloalkyl, halomethyl, C1-C8 fluoroalkyl, lower fluoroalkyl, e.g., C1-C4 fluoroalkyl, fluoromethyl, difluoromethyl, perfluoroalkyl, C1-C8 perfluoroalkyl, lower perfluoroalkyl, e.g., C1-C4 perfluoroalkyl, perfluoromethyl), halogen (e.g., F, Cl, Br), and -R C where R is selected from B1 may independently have one or more (e.g., two, three, four) optional substitution points at each occurrence; R B2 is independently at each occurrence hydrogen, alkyl (e.g., optionally unsaturated and substituted C1-C8 alkyl, lower alkyl, e.g., C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl, e.g., -CD3), haloalkyl (e.g., C1-C8 haloalkyl, lower haloalkyl, e.g., C1-C4 haloalkyl, halomethyl, C1-C8 fluoroalkyl, lower fluoroalkyl, e.g., C1-C4 fluoroalkyl, fluoromethyl, difluoromethyl, perfluoroalkyl, C1-C8 perfluoroalkyl, lower perfluoroalkyl, e.g., C1-C4 perfluoroalkyl, perfluoromethyl), halogen (e.g., F, Cl, Br), and -R Cwhere R is selected from B2 may independently have one or more (e.g., two, three, four) optional substitution points at each occurrence; R B1 or R B2 At least one of the following has the structure:

[0015] [ka]

[0016] (In the formula,

[0017] [ka]

[0018] indicates the point of attachment to the compound, and the dashed circle indicates optional aromaticity; X C6 is C, CH, CR, or N; X C1 , X C2 , X C3 , X C4 , and X C5 are independently CH, CR, N, NH, NR, O, or S; when the group is a 5-membered ring, X C5 does not exist; R C1 , R C2 , R C3 , R C4 , and R C5are independently hydrogen, alkyl (e.g., C1-C8 alkyl, lower alkyl, e.g., C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl, e.g., -CD3), -C(O)R, -C(O)NRR, halogen (e.g., F, Cl, Br), haloalkylhaloalkyl (e.g., C1-C8 haloalkyl, lower haloalkyl, e.g., C1-C4 haloalkyl, halomethyl, C1-C8 fluoroalkyl, lower fluoroalkyl, e.g., C1-C4 fluoroalkyl, fluoromethyl, difluoromethyl, perfluoroalkyl, C1-C8 perfluoroalkyl, lower perfluoroalkyl, e.g., C1-C4 perfluoroalkyl, perfluoromethyl), or cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl); or may be taken together with the R groups to form oxo (=O); where R C1 , R C2 , R C3 , R C4 , and R C5 may independently have one or more (e.g., two, three, four) optional substitution points; R at each occurrence is independently hydrogen or alkyl (e.g., C1-C8 alkyl, lower alkyl, e.g., C1-C4 alkyl, methyl, deuterated alkyl, or deuterated lower alkyl, e.g., -CD3), with -R C a compound having a group In some embodiments, R (e.g., R L When -S(=NR)(=O)- can be hydrogen or lower alkyl (eg, C1-C4 alkyl), such as methyl.

[0019] The present disclosure also includes compounds in which the bicyclic ring system of formula (I) is opened to form sulfonamides in which the N geminal amino groups do not join together to form a ring. These sulfonamides are referred to herein as Ca V 3.3 potentiators. For example, compounds of the present disclosure have the structure of formula (V):

[0020] [ka]

[0021] (In the formula, R D1 is hydrogen, alkyl (e.g., C1-C8 alkyl, lower alkyl, e.g., C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl, e.g., -CD3), haloalkyl (e.g., C1-C8 haloalkyl, lower haloalkyl, e.g., C1-C4 haloalkyl, halomethyl, C1-C8 fluoroalkyl, lower fluoroalkyl, e.g., C1-C4 fluoroalkyl, fluoromethyl, difluoromethyl, perfluoroalkyl, C1-C8 perfluoroalkyl, lower perfluoroalkyl, e.g., C1-C4 perfluoroalkyl, perfluoromethyl), monocyclic or bicyclic heterocyclyl, monocyclic or bicyclic heteroaryl, or aryl; and R D1 may have one or more (e.g., two, three, four) optional substitution points (and R D1 is optionally substituted, and any two geminal or adjacent substituents may form a 5- or 6-membered ring; R D2 is hydrogen or alkyl (e.g., C1-C8 alkyl, lower alkyl, e.g., C1-C4 alkyl, methyl, deuterated alkyl, or deuterated lower alkyl, e.g., -CD3), and R D2 may have one or more (e.g., two, three, four) optional substitution points; X B1 is independently N or CR for each occurrence B1 and; R B1 is independently selected at each occurrence from hydrogen, alkyl (e.g., C1-C8 alkyl, lower alkyl, e.g., C1-C4 alkyl, methyl, deuterated alkyl, or deuterated lower alkyl, e.g., -CD3), and -R C and R B1 may have one or more (e.g., two, three, four) optional substitution points; R B2is independently selected at each occurrence from hydrogen, optionally unsaturated alkyl (e.g., C1-C8 alkyl, lower alkyl, e.g., C1-C4 alkyl, methyl, deuterated alkyl, or deuterated lower alkyl, e.g., -CD3), and -R C and R B2 may have one or more (e.g., two, three, four) optional substitution points; R B1 or R B2 At least one of the following has the structure:

[0022] [ka]

[0023] (In the formula,

[0024] [ka]

[0025] indicates the point of attachment to the compound, and the dashed circle indicates optional aromaticity; XC6 is C, CH, CR, or N; X C1 , X C2 , X C3 , X C4 , and X C5 are independently CH, CR, N, NH, NR, O, or S; when the group is a 5-membered ring, X C5 does not exist; R C1 , R C2 , R C3 , R C4 , and R C5are independently hydrogen, alkyl (e.g., C1-C8 alkyl, lower alkyl, e.g., C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl, e.g., -CD3), -C(O)R, -C(O)NRR, halogen (e.g., F, Cl, O), haloalkyl (e.g., C1-C8 haloalkyl, lower haloalkyl, e.g., C1-C4 haloalkyl, halomethyl, C1-C8 fluoroalkyl, lower fluoroalkyl, e.g., C1-C4 fluoroalkyl, fluoromethyl, difluoromethyl, perfluoroalkyl, C1-C8 perfluoroalkyl, lower perfluoroalkyl, e.g., C1-C4 perfluoroalkyl, perfluoromethyl), or cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl); or may be taken together with a geminal R group to form oxo (=O), where R C1 , R C2 , R C3 , R C4 , and R C5 may independently have one or more (e.g., two, three, four) optional substitution points; R at each occurrence is independently hydrogen or alkyl (e.g., C1-C8 alkyl, lower alkyl, e.g., C1-C4 alkyl, methyl, deuterated alkyl, or deuterated lower alkyl, e.g., -CD3), with -R C a compound having a group This includes pharmaceutically acceptable salts thereof.

[0026] The present disclosure also provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound disclosed herein, such as Ca V3.3 Enhancers, Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (III), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh) , (Vi), compounds having the structure of (Vj), 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, and 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 above.

[0027] Methods of using these compounds are also provided, e.g., a method of increasing sleep spindles or rescuing sleep spindle disorders in a subject in need thereof, comprising administering to a subject a dose of Ca V 3.3 Enhancers (e.g., Ca V3.3 Enhancers, Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (III), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg ), (Vh), (Vi), and (Vj), and compounds 1 to 69, 71 to 172, 174 to 176, 179 to 265, 269 to 285, 287 to 288, 290 to 291, 293 to 295, 297 to 298, 300 to 301, 305, 307, 312, 314 to 321, 324 to 325, 327 to 340, 342 to 343, 345, 348 to 357, and 360 to 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, 512-51

[0023] Methods for treating schizophrenia may include administering to the subject one or more of the compounds listed in Table 1, 518-520, 522-523, 525-529, 532-541, 543-551, 553-558, 560-570, 573-575, 577-583, 585, and 587-596, or one or more of compounds 1-69, 71-172, 174-176, and 179-255. In some embodiments, the subject is human. In certain embodiments, the subject has schizophrenia.

[0028] The method for decreasing thalamocortical hyperactivity and / or increasing thalamocortical hypoactivity in a subject in need thereof includes administering Ca V 3.3 Enhancers (e.g., Ca V3.3 Enhancers, Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (III), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf) , (Vg), (Vh), (Vi), (Vj), 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, 348-349, 57, 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- The method includes administering to a subject one or more of compounds 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, and one or more of compounds 1-69, 71-172, 174-176, and 179-255. In some embodiments, the subject is human. In certain embodiments, the subject has schizophrenia. Without wishing to be bound by theory, thalamocortical hyperactivity and / or hypoactivity in various regions of the subject's brain may be associated with changes in rebound burst firing in the thalamic reticular nucleus (TRN). Normalizing TRN function can independently increase this hyperactivity and / or hypoactivity (depending on location) in a subject, thereby reducing the progression of the disease, disorder, or condition. For example, methods for increasing rebound burst firing in the thalamic reticular nucleus (TRN) in a subject in need thereof can be used to increase Ca V3.3 The method includes administering an augmenting agent to the subject. In embodiments, the administering step reduces thalamocortical hyperactivity in brain regions that exhibit this hyperactivity. In some embodiments, the subject is human. In particular embodiments, the subject has schizophrenia. In some embodiments, the subject exhibits a neurodevelopmental disorder or a condition associated therewith. In some embodiments, the subject exhibits thalamic reticular nucleus (TRN) decline associated with aging or neurodegeneration, or a condition associated therewith. V 3.3 Administering an augmenting agent to said subject. In some embodiments, administering the compound can rescue cognitive and / or motor deficits (e.g., those associated with neurodevelopmental disorders).

[0029] A method for improving cognitive function in a subject in need thereof, comprising administering to a subject a compound of any one of claims 1 to 41, Ca V 3.3 Enhancers (e.g., Ca V3.3 Enhancers, Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (III), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), Compounds having the structures (Vi) and (Vj), compounds 1 to 69, 71 to 172, 174 to 176, 179 to 265, 269 to 285, 287 to 288, 290 to 291, 293 to 295, 297 to 298, 300 to 301, 305, 307, 312, 314 to 321, 324 to 325, 327 to 340, 342 to 343, 345, 348 to 357, 360 to 362, 364 to 375, 37 7-378, 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 The method may include administering to a subject 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 above. In certain embodiments, the subject has a brain dysfunction, e.g., a brain dysfunction caused by cerebrovascular disease, brain injury, brain tumor, viral encephalitis, hypoxic encephalopathy, or alcoholism. In various embodiments, the subject has a cognitive dysfunction. In certain aspects, the cognitive dysfunction is selected from memory impairment, attention deficit, executive dysfunction, social behavior disorder, neurodegenerative disease, psychiatric disorder, or pervasive developmental disorder.

[0030] In various embodiments, the subject has Ca V 3.3 mutation. For example, the subject may be a human and may have a Ca VIn some embodiments, the subject is a mouse and the CaV3.3 mutation is a R1346H mutation. In some embodiments, the subject is a mouse and the CaV3.3 mutation is a R1305H mutation. V 3.3 The mutation is homozygous or heterozygous in the subject.

[0031] The present disclosure also provides a method for treating or preventing schizophrenia, neurodevelopmental disorders, thalamic reticular nucleus (TRN) dysfunction (e.g., associated with aging or neurodegeneration), or a condition associated therewith (e.g., cognitive impairment) in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of Ca V 3.3 Enhancers (e.g., Ca V3.3 Enhancers, Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (III), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (V Compounds having the structures of (Vg), (Vh), (Vi), and (Vj), compounds 1 to 69, 71 to 172, 174 to 176, 179 to 265, 269 to 285, 287 to 288, 290 to 291, 293 to 295, 297 to 298, 300 to 301, 305, 307, 312, 314 to 321, 324 to 325, 327 to 340, 342 to 343, 345, 348 to 357, and 36 0-362, 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 The present invention provides methods for treating schizophrenia, including administering to the subject one or more of compounds 1-69, 71-172, 174-176, and 179-255. Examples of disorders include schizophrenia, or conditions or disorders related thereto, such as cognitive impairment, decreased sleep spindles, decreased TRN function, or thalamocortical hyperactivity, and combinations thereof. In some embodiments, the disorder can be a neurodevelopmental disorder, such as autism spectrum disorder (ASD), schizophrenia, attention deficit hyperactivity disorder (ADHD), schizoaffective disorder, and bipolar affective disorder. In some embodiments, the disease may be a neurodegenerative disease, such as Alzheimer's disease. For example, Alzheimer's disease has been shown to exhibit reduced sleep spindles, and compounds of the present disclosure may provide particular benefit to patients exhibiting Alzheimer's disease (or a disorder or condition related thereto).

[0032] 1. A method for monitoring target engagement and / or treatment efficacy in a subject, comprising: a) measuring spindle density and / or amplitude in a subject to establish a baseline; b) administering the compound to the subject; c) measuring spindle density and / or amplitude after said administering step wherein a comparison of spindle density and / or amplitude after said administering step to a baseline is used to monitor target engagement and / or treatment efficacy. V3.3 Enhancers (e.g., compounds of formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (III), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), (Vd), (Ve), Compounds having the structures (Vf), (Vg), (Vh), (Vi), and (Vj), compounds 1 to 69, 71 to 172, 174 to 176, 179 to 265, 269 to 285, 287 to 288, 290 to 291, 293 to 295, 297 to 298, 300 to 301, 305, 307, 312, 314 to 321, 324 to 325, 327 to 340, 342 to 343, and 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- and one or more of compounds 1-69, 71-172, 174-176, and 179-255). In some embodiments, the sleep spindle density is the density of slow wave sleep spindles (e.g., 9-12 Hz). In various embodiments, the sleep spindle density is the density of fast wave sleep spindles (e.g., 13-15 Hz). In certain embodiments, the subject has a brain dysfunction, such as a brain dysfunction caused by cerebrovascular disease, brain injury, brain tumor, viral encephalitis, hypoxic encephalopathy, or alcoholism. In various embodiments, the subject has a cognitive dysfunction. In certain aspects, the cognitive dysfunction is selected from memory impairment, attention deficit, executive dysfunction, social behavior disorder, neurodegenerative disease, psychiatric disorder, 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.

[0033] definition Unless otherwise specified, all terms used herein are intended to have their ordinary meaning in the art. Unless otherwise specified, all concentrations refer to the weight percent of the specified component relative to the total weight of the composition of interest.

[0034] As used herein, "a" or "an" shall mean one or more. As used herein, the terms "a" or "an," when used in combination with the word "comprising," means one or more than one. As used herein, "another" means at least a second or more. Unless specifically stated otherwise or clear from context, as used herein, the term "or" is understood to be inclusive.

[0035] All numerical ranges used herein include the endpoints and all possible values ​​therebetween. Also, all half-integer exact values ​​are intended to be specifically disclosed and are intended as limits for all subsets of the disclosed ranges. For example, a range of 0.1% to 3% specifically discloses percentages of 0.1%, 1%, 1.5%, 2.0%, 2.5%, and 3%. Furthermore, a range of 0.1% to 3% includes subsets of the original range, including 0.5% to 2.5%, 1% to 3%, or 0.1% to 2.5%. It is understood that the sum of all weight percents of individual components may not exceed 100%.

[0036] Throughout this specification, various components may be identified as exhibiting specific values ​​or parameters, but these items are presented as exemplary embodiments. Indeed, many equivalent parameters, sizes, ranges, and / or values ​​are possible, and the exemplary embodiments do not limit various aspects and concepts of the present disclosure. Unless otherwise specified, terms such as "first," "second," "primary," "secondary," etc. do not denote order, quantity, or importance, but rather are used to distinguish one element from another.

[0037] By "agent" is meant a small molecule compound, a polypeptide, or a polynucleotide.

[0038] "Ameliorate" means to reduce, inhibit, attenuate, diminish, arrest, or stabilize the occurrence or progression of a disease.

[0039] By "consisting essentially of," it is meant that the component contains only the listed ingredients, along with normal impurities present in commercially available materials, and along with any other additives present at levels that do not affect the practice of the present disclosure, for example, less than 5% by weight, or less than 1% by weight, or even less than 0.5% by weight.

[0040] "Disease" refers to any condition or disorder that damages or disrupts the normal function of a cell, tissue, or organ. Examples of diseases include schizophrenia, or conditions or disorders related thereto, such as cognitive impairment, reduced sleep spindles, reduced TRN function, or thalamocortical hyperactivity, and combinations thereof. In some embodiments, the disorder can be a neurodevelopmental disorder, such as autism spectrum disorder (ASD), schizophrenia, attention deficit hyperactivity disorder (ADHD), schizoaffective disorder, and bipolar affective disorder. In some embodiments, the disease can be a neurodegenerative disease, such as Alzheimer's disease. For example, Alzheimer's disease has been shown to exhibit reduced sleep spindles, and compounds of the present disclosure may provide particular benefit to patients exhibiting Alzheimer's disease (or disorders or conditions related thereto).

[0041] The term "effective amount" or "therapeutically effective amount" of an agent refers to the amount of an agent (e.g., a compound described herein) required to improve the symptoms of a disease compared to an untreated patient. The effective amount of an active compound used in practicing the present invention for the therapeutic treatment of a disease will vary depending on the mode of administration and the age, weight, and general health of the subject. Ultimately, the appropriate amount and administration regimen will be determined by your physician or veterinarian. This amount is referred to as an "effective" amount. The agents described herein are compounds of formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (III), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), (Vd), (Ve), , compounds having the structures (Vf), (Vg), (Vh), (Vi), and (Vj), compounds 1 to 69, 71 to 172, 174 to 176, 179 to 265, 269 to 285, 287 to 288, 290 to 291, 293 to 295, 297 to 298, 300 to 301, 305, 307, 312, 314 to 321, 324 to 325, 327 to 340, 342 to 343, 344 5, 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 and one or more of compounds 1-69, 71-172, 174-176, and 179-255. In some embodiments, the compound is administered in an amount effective to treat a disease, disorder, or condition.

[0042] As used herein, the term "pharmaceutical composition" refers to a composition comprising a compound described herein formulated with a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is manufactured or sold as part of a therapeutic regimen for the treatment of a disease in a mammal, with the approval of a government regulatory agency. The pharmaceutical composition may be formulated, for example, in a unit dosage form for oral administration (e.g., a tablet, capsule, caplet, gel capsule); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution in a solvent system suitable for intravenous use, free of particulate embolic material); or as any other formulation described herein (see below).

[0043] As used herein, the phrase "pharmaceutically acceptable" refers to ingredients that are generally safe for oral ingestion or contact with living tissue at the levels used. "Pharmaceutically acceptable" is used interchangeably with "physiologically compatible." Unless otherwise specified, it will be understood that pharmaceutical compositions of the present disclosure include functional food compositions (e.g., dietary supplements).

[0044] "Baseline" refers to a standard or control condition. In one embodiment, the baseline is an untreated control cell or control animal. In another embodiment, the effect of an agent on a cell or animal is compared to the same animal at an earlier time point or before treatment. This earlier time point or pre-treatment time point is considered the baseline.

[0045] Ranges set forth herein are understood to refer to all 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 subrange from the group consisting of 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.

[0046] As used herein, the terms "treat," "treating," "treatment," and the like refer to reducing or ameliorating a disorder and / or its associated symptoms. It will be recognized that treating a disorder or condition may not necessarily result in the complete elimination of the disorder, condition, or its associated symptoms, although this cannot be ruled out.

[0047] "Subject" means a mammal, including, but not limited to, a human or non-human mammal, such as a cow, horse, dog, sheep, or cat. Typical subjects include any animal (e.g., a mammal, such as a mouse, rat, rabbit, non-human primate, and a human). Typically, a subject in need thereof is one for whom it is desirable to treat a disease, disorder, or condition described herein. For example, a subject in need thereof may be seeking or in need of treatment, may be requesting treatment, may be receiving treatment, may be planning to receive treatment in the future, or may be a human or animal under the care of a skilled professional for a particular disease, disorder, or condition.

[0048] The term "substituent" refers to a group that is "substituted" for a hydrocarbon, e.g., alkyl, at any atom of the hydrocarbon group, replacing one or more atoms therein, including hydrogen atoms (e.g., the point of substitution). In some embodiments, substituents on a group are each independently any one or any combination of two or more of the permissible atoms or groups of atoms defined for the substituent. In other embodiments, a substituent may itself be substituted with any one of the substituents described herein. Substituents may be positioned pendant from the hydrocarbon chain.

[0049] Additionally, as used herein, the phrase "substituted with" means that the specified group may be substituted with one or more of any combination of substituents described in this application. For example, a group such as an alkyl group or a heteroaryl group may be substituted with an "unsubstituted C1-C 20When "substituted with alkyl or unsubstituted 2-20 membered heteroalkyl," the group is substituted with one or more unsubstituted C1-C 20 The group may include alkyl and / or one or more unsubstituted 2- to 20-membered heteroalkyl. Additionally, when a moiety is substituted with an R substituent, the group may be referred to as "R-substituted." When a moiety is R-substituted, the moiety is substituted with at least one R substituent, and each R substituent may be different (e.g., R is independently at each occurrence a C1-C6 alkyl group, each of which may contain one or more points of substitution). 10 Alkyl or C1-C 10 heteroalkyl).

[0050] Unless specifically stated otherwise or clear from the context, the term "about" as used herein is understood to mean within the normal tolerances in the art, for example, within two standard deviations of the mean. "About" may be understood to mean 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 the context, all numerical values ​​provided herein are modified by the term about.

[0051] "Ca V 3.3 Polypeptide" refers to a protein or fragment thereof that exhibits at least about 85% amino acid sequence identity to NCBI Reference Sequence NP_066919.2 and exhibits voltage-gated T-type calcium channel subunit alpha-1 activity. V 3.3 Polypeptides are members of a subfamily of calcium channels called low-voltage-activated T-type calcium channels. V 3.3 proteins are characterized by slow activation and inactivation compared to other T-type calcium channels. V 3.3 The amino acid sequence is as follows:

[0052] [ka]

[0053] Ca V 3.3 The polypeptide can be a protein or fragment thereof that exhibits at least about 85% amino acid sequence identity to NCBI reference sequence NP_001037773.2, which is the voltage-gated T-type calcium channel subunit alpha-1 from Mus musculus. V 3.3 The protein sequence is as follows:

[0054] [ka]

[0055] "CACNA1I polynucleotide" refers to Ca V 3.3 refers to a polynucleotide encoding a polypeptide. An exemplary CACNA1I polynucleotide sequence is provided in NCBI Accession No. NM_021096, and is the mRNA sequence for the human (Homo sapiens) voltage-gated calcium channel subunit α1 I, reproduced below.

[0056] [ka]

[0057] [ka]

[0058] [ka]

[0059] In any definition of a variable herein, a reference to a list of chemical groups includes a definition of that variable as any one group or any one combination of the listed groups. A reference herein to an embodiment of a variable or aspect includes that embodiment as any one embodiment or in combination with any other embodiment or portion thereof.

[0060] Any compound, composition, or method described herein can be combined with one or more of any other compositions and methods described herein. [Brief explanation of the drawings]

[0061] [Figure 1A] 1 shows a schematic diagram of a Fluorescence Imaging Plate Reader (FLIPR) high-throughput assay for enhanced measurements of T-type calcium channel subunits, similar to the assay disclosed in Zhang, YL., et al., ACS Pharmacol Transl Sci 5.3 (2022): 156-168, which is incorporated by reference herein in its entirety, particularly with respect to the FLIPR assay and its protocol. [Figure 1B] Exemplary EC10 and EC90 responses to KCl are shown. [Figure 2] FIG. 1 is a schematic diagram of an automated patch clamp electrophysiological assay that can be used to measure specific mechanisms of action and identify differential responses in each subunit. [Figure 3A] Electrophysiology measurements upon administration of Compound 131 are shown. [Figure 3B] Electrophysiology measurements upon administration of Compound 131 are shown. [Figure 3C] Electrophysiology measurements upon administration of Compound 131 are shown. [Figure 3D] Electrophysiology measurements upon administration of Compound 131 are shown. [Figure 4A] Electrophysiology measurements upon administration of Compound 7 are shown. [Figure 4B] Electrophysiology measurements upon administration of Compound 7 are shown. [Figure 4C] Electrophysiology measurements upon administration of Compound 7 are shown. [Figure 4D] Electrophysiology measurements upon administration of Compound 7 are shown. [Figure 5A] 1 shows ex vivo measurements of rebound burst firing of thalamic reticular nucleus (TRN) neurons following administration of Compound 7. [Figure 5B] 1 shows ex vivo measurements demonstrating a decrease in the rebound burst potential threshold following administration of Compound 7. [Figure 6A] 1 shows ex vivo measurements of rebound burst firing of thalamic reticular nucleus (TRN) neurons following administration of Compound 131. [Figure 6B] 1 shows ex vivo measurements demonstrating a decrease in the rebound burst potential threshold following administration of Compound 131. [Figure 7] Figure 1 shows in vivo pharmacokinetic measurements of relevant plasma (Cp), blood (Cb), unbound plasma (Cb,u), unbound blood (Cb,u), and cerebrospinal fluid (CSF) concentrations following intraperitoneal administration of Compound 57 at 10 mg / kg or 30 mg / kg to mice. [Figure 8A] FIG. 1 is a schematic diagram of the social interaction assay in mice. [Figure 8B] 1 shows that Cav3.3-deficient heterozygous and homozygous mice exhibit reduced social interaction as measured by social indices compared to littermate control mice. [Figure 8C] Cav3.3 R1305H / WT and R1305H / R1305H homozygous mice show a similar effect, exhibiting reduced social interaction compared to littermate controls. [Figure 8D] FIG. 1 is a schematic diagram of a novel object recognition assay in mice. [Figure 8E] 1 shows that Cav3.3 homozygous knockout mice exhibit reduced object recognition as measured by object discrimination ratio compared to littermate controls. [Figure 8F]Figure 1 shows that Cav3.3 R1305H / WT and R1305H / R1305H homozygous mice exhibit reduced object recognition compared to littermate controls. One-way ANOVA with multiple comparison post-hoc test was performed for each data set. *p<0.05; **p<0.01; ***p<0.001. N=number of mice. [Figure 9A] FIG. 1 is a schematic diagram of the social interaction assay in mice. [Figure 9B] We show that compound 57, administered intraperitoneally 60 min before the social interaction assay, can rescue the reduced social interaction in Cav3.3-deficient heterozygous mice, with the most effective dose being 10 mg / kg. [Figure 9C] We show that compound 57, administered intraperitoneally 60 min before the social interaction assay, can rescue the reduction in social interaction in Cav3.3 R1305H / R1305H homozygous mice, with the most effective dose being 10 mg / kg. [Figure 9D] Compound 57 administered intraperitoneally 60 minutes before the social interaction assay had no effect in Cav3.3 homozygous knockout mice. One-way ANOVA with multiple comparison post-hoc test was performed for each data set. *p<0.05; **p<0.01; ***p<0.001. N=number of mice. [Figure 10A] FIG. 1 is a schematic diagram of a novel object recognition assay in mice. [Figure 10B] We show that compound 57, administered intraperitoneally 60 min before the novel object recognition assay, can rescue the decrease in object recognition in Cav3.3 R1305H / WT heterozygous mice, with the most effective dose being 30 mg / kg. [Figure 10C] Figure 1 shows that compound 57 administered intraperitoneally 60 min before the object recognition assay had no effect in Cav3.3 homozygous knockout mice. One-way ANOVA with multiple comparison post-hoc test was performed for each data set. *p<0.05; **p<0.01. [Figure 10D]Figure 1 shows that intraperitoneally administered compound 57 has no effect on basal locomotor activity in wild-type male mice. N = number of mice. [Figure 11A] FIG. 1 is a schematic diagram of a novel object recognition assay in mice. [Figure 11B] This shows that compound 57, administered intraperitoneally 60 minutes before the novel object recognition assay, can rescue the reduction in object recognition in 5xFAD heterozygous mice, with the most effective dose being 30 mg / kg. One-way ANOVA was performed with multiple comparison post-hoc test. *p<0.05; N=number of mice. [Figure 12A] Schematic diagram of electrode placement for mouse electroencephalography (EEG), with one electrode in the frontal cortex, one electrode in the parietal cortex, one reference electrode, one ground electrode, and electrodes for electromyography (EMG). [Figure 12B] FIG. 1 is a schematic diagram of a sound-attenuated EEG recording device. [Figure 12C] This is a dosing paradigm in which mice are recorded for 12 hours during the light (sleep) cycle. On the first day, mice are acclimated to the room and recording apparatus. Following a baseline recording day, mice are recorded after intraperitoneal administration of vehicle the next day, followed by intraperitoneal administration of 3 mg / kg Compound 57 the next day, intraperitoneal administration of 10 mg / kg Compound 57 the next day, and finally, on the final day, after intraperitoneal administration of 30 mg / kg Compound 57. [Figure 12D] 1 shows that compound 57 increases 11 Hz sleep spindle density in WT male mice at 30 mg / kg. [Figure 12E] Similar findings are shown in which compound 57 increases 11 Hz sleep spindle density in male Cav3.3 R1305H / R1305H homozygous mice at both 10 mg / kg and 30 mg / kg doses. [Figure 12F] Compound 57 has no effect in male Cav3.3 homozygous mice (these mice do not express functional Cav3.3 channels). One-way ANOVA (*p<0.05 and ***p<0.001) with Holm-Sidak multiple comparison test; each circle represents one mouse. DETAILED DESCRIPTION OF THE INVENTION

[0062] Detailed Description The compounds of the present disclosure inhibit the Ca(II) channel of T-type channels. V The compounds enhance the 3.3 subtype, and their administration improves the disease, disorder, or condition described herein (e.g., schizophrenia, cognitive impairment, decreased sleep spindles, decreased thalamic reticular nucleus function, thalamocortical hyperactivity, neurodevelopmental disorders such as autism spectrum disorder (ASD), schizophrenia, attention deficit hyperactivity disorder (ADHD), schizoaffective disorder, and bipolar affective disorder, and neurodegenerative diseases such as Alzheimer's disease).

[0063] Recently, a genome-wide association study has linked CACNA1I to schizophrenia risk (Pantelis, Christos, et al. Nature 511.7510 (2014): 421-427, incorporated herein by reference in its entirety). Furthermore, exome sequencing has identified rare loss-of-function mutations in schizophrenia patients (Gulsuner, Suleyman, et al. Cell 154.3 (2013): 518-529, incorporated herein by reference in its entirety). The exact mechanism underlying CACNA1I in schizophrenia risk is unknown, but novel variants of CACNA1I derived from schizophrenia patients were 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, both of which are incorporated herein by reference in their entirety. While these studies implicate loss of function in disease risk or pathophysiology, they do not address the role of any selective T-type Ca channel. 2+It does not focus on whether channel enhancers will demonstrate therapeutic benefit in specific disorders. As described in Fukunaga et al. Journal of Pharmacological Sciences 139 (2019): 51-58 and WO2013111799, both of which are incorporated herein by reference in their entirety, only one chemical series, represented by 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 demonstrated potential Ca channel enhancers. V 3.3 enhancers have been identified. However, overall, SAK3, ST-101, and Ca V For the potentiation assay, Ca as shown in Zhang, Yan-Ling, et al. ACS Pharmacology & Translational Science 5.3 (2022): 156-168, which is incorporated herein by reference. V The binding or direct effect of this on Ca 3 channels has not been demonstrated, and compounds in this chemical series exhibit activity as potentiators. This disclosure is based, in part, on the discovery of Ca 3 channels that exhibit therapeutic benefits as shown herein. V While not wishing to be bound by theory, Ca V Enhancers (e.g., those described herein, or Ca V (identified by the potentiation assay) V It may be possible to demonstrate therapeutic benefit by directly binding to

[0064] Ca V 3.3 Enhancer framework Ca of the present disclosure V 3.3 The potentiator has the structure of formula (I):

[0065] [ka]

[0066] (wherein the dashed circle represents an optionally unsaturated ring (e.g., an aromatic ring); p is 0 or 1; m is 0 (each carbon is bonded to 1 or 2 hydrogens), 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; X A1 is N, O, or C; X A2 is N or C; X A3 is N or CR A3 and; R A1 are independently at each occurrence hydrogen, alkyl (e.g., optionally unsaturated C1-C8 alkyl, lower alkyl, e.g., C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl, e.g., -CD3), -C(O)OR, -C(O)R, haloalkyl (e.g., C1-C8 haloalkyl, lower haloalkyl, e.g., C1-C4 haloalkyl, halomethyl, C1-C8 fluoroalkyl, lower fluoroalkyl, e.g., C1-C4 fluoroalkyl, fluoromethyl, difluoromethyl, perfluoroalkyl, C1-C8 perfluoroalkyl, lower perfluoroalkyl, e.g., C1-C4 perfluoroalkyl, perfluoromethyl), hydroxy, or amino (e.g., -NRR); two R A1 may be taken together to form =O or a 3- to 6-membered spiro ring; A1 may independently have one or more (e.g., two, three, four) optional substitution points at each occurrence; R A2 are independently at each occurrence hydrogen and alkyl (e.g., optionally unsaturated C1-C8 alkyl, lower alkyl, e.g., C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl, e.g., -CD3); A2 The groups may be taken together to form =O or a 3- to 6-membered spiro ring; where R A2 may independently have one or more (e.g., two, three, four) optional substitution points at each occurrence; R A3is independently at each occurrence hydrogen, alkyl (e.g., optionally unsaturated C1-C8 alkyl, lower alkyl, e.g., C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl, e.g., -CD3), alkoxy (e.g., C1-C8 alkoxy, lower alkoxy, e.g., C1-C4 alkoxy, methoxy, alkoxy substituted with aryl, e.g., benzyloxy), cyano, -C(O)OR, -C(O)R, or halogen (e.g., F, Cl, Br); where R A3 may independently have one or more (e.g., two, three, four) optional substitution points at each occurrence; R L is -S(=O)2-, -S(=O)-, -S(=N)2-, -S(=N)(=O)-, or -C(R)(R)-; X B1 is independently N, S, or CR for each occurrence B1 and one X B1 may not exist; X B2 is independently N or CR for each occurrence B2 and; R B1 is independently at each occurrence hydrogen, alkyl (e.g., C1-C8 alkyl, lower alkyl, e.g., C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl, e.g., -CD3), haloalkyl (e.g., C1-C8 haloalkyl, lower haloalkyl, e.g., C1-C4 haloalkyl, halomethyl, C1-C8 fluoroalkyl, lower fluoroalkyl, e.g., C1-C4 fluoroalkyl, fluoromethyl, difluoromethyl, perfluoroalkyl, C1-C8 perfluoroalkyl, lower perfluoroalkyl, e.g., C1-C4 perfluoroalkyl, perfluoromethyl), halogen (e.g., F, Cl, Br), and -R C where R is selected from B1 may independently have one or more (e.g., two, three, four) optional substitution points at each occurrence; R B2is independently at each occurrence hydrogen, alkyl (e.g., optionally unsaturated and substituted C1-C8 alkyl, lower alkyl, e.g., C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl, e.g., -CD3), haloalkyl (e.g., C1-C8 haloalkyl, lower haloalkyl, e.g., C1-C4 haloalkyl, halomethyl, C1-C8 fluoroalkyl, lower fluoroalkyl, e.g., C1-C4 fluoroalkyl, fluoromethyl, difluoromethyl, perfluoroalkyl, C1-C8 perfluoroalkyl, lower perfluoroalkyl, e.g., C1-C4 perfluoroalkyl, perfluoromethyl), halogen (e.g., F, Cl, Br), and -R C where R is selected from B2 may independently have one or more (e.g., two, three, four) optional substitution points at each occurrence; R B1 or R B2 At least one of the following has the structure:

[0067] [ka]

[0068] (In the formula,

[0069] [ka]

[0070] indicates the point of attachment to the compound, and the dashed circle indicates optional aromaticity; X C6 is C, CH, CR, or N; X C1 , X C2 , X C3 , X C4 , and X C5 are independently CH, CR, N, NH, NR, O, or S; when the group is a 5-membered ring, X C5 does not exist; R C1 , R C2 , R C3, R C4 , and R C5 are independently hydrogen, alkyl (e.g., C1-C8 alkyl, lower alkyl, e.g., C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl, e.g., -CD3), -C(O)R, -C(O)NRR, halogen (e.g., F, Cl, Br), haloalkylhaloalkyl (e.g., C1-C8 haloalkyl, lower haloalkyl, e.g., C1-C4 haloalkyl, halomethyl, C1-C8 fluoroalkyl, lower fluoroalkyl, e.g., C1-C4 fluoroalkyl, fluoromethyl, difluoromethyl, perfluoroalkyl, C1-C8 perfluoroalkyl, lower perfluoroalkyl, e.g., C1-C4 perfluoroalkyl, perfluoromethyl), or cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl); or may be taken together with the R groups to form oxo (=O); where R C1 , R C2 , R C3 , R C4 , and R C5 may independently have one or more (e.g., two, three, four) optional substitution points; R at each occurrence is independently hydrogen or alkyl (e.g., C1-C8 alkyl, lower alkyl, e.g., C1-C4 alkyl, methyl, deuterated alkyl, or deuterated lower alkyl, e.g., -CD3), with -R C a compound having a group In some embodiments, -R C The structure:

[0071] [ka]

[0072] for example

[0073] [ka]

[0074] It has.

[0075] Typically, an alkyl or alkylene group as used herein refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon group of 1 to 30 carbon atoms (e.g., 1 to 16 carbon atoms, 6 to 20 carbon atoms, 8 to 16 carbon atoms, 4 to 18 carbon atoms, 4 to 12 carbon atoms). In some embodiments, the alkyl or alkylene group may be unsaturated, for example, to form an alkenyl or alkynyl group. In some embodiments, the alkyl group may be substituted with 1, 2, 3, or 4 substituents as defined herein. The alkyl or alkylene group may have 1 to 26 carbon atoms. In other embodiments, the alkyl group has 6 to 18, or 1 to 8, or 1 to 6, or 1 to 4, or 1 to 3 carbon atoms, including, for example, embodiments having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 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. A heteroalkyl or heteroalkylene group can refer to a branched or straight-chain monovalent saturated aliphatic hydrocarbon group having one or more heteroatoms (e.g., N, O, or S) in the carbon chain. A heteroalkyl group can have 1 to 30 carbon atoms (e.g., 1 to 16 carbon atoms, 6 to 20 carbon atoms, 8 to 16 carbon atoms, 4 to 18 carbon atoms, or 4 to 12 carbon atoms). In some embodiments, a heteroalkyl or heteroalkylene group can be substituted with 1, 2, 3, or 4 substituents as defined herein. A heteroalkyl or heteroalkylene group can have 1 to 26 carbon atoms (and, e.g., one or more heteroatoms). In other embodiments, the heteroalkyl or heteroalkylene group has 6 to 18, or 1 to 8, or 1 to 6, or 1 to 4, or 1 to 3 carbon atoms, including, for example, embodiments having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.In some embodiments, the heteroalkyl or heteroalkylene group may be further substituted with one, two, three, or four substituents as described herein for an alkyl group. An example of a heteroalkyl group is an alkoxy. The alkoxy substituent or alkoxy-containing substituent may be substituted, for example, with one or more alkyl groups.

[0076] The cycloalkyl or cycloalkylene group may refer to a cyclic aliphatic hydrocarbon group of 3 to 15 carbon atoms (e.g., 3 to 12 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, 3 to 5 carbon atoms, 3 to 4 carbon atoms). In some embodiments, the cycloalkyl group may be substituted with 1, 2, 3, or 4 substituents as defined herein. The cycloalkyl group may have 3 to 12 carbon atoms in the carbocyclic ring. Cycloalkyl groups include monocyclic and polycyclic ring systems, such as bicyclic and tricyclic groups. In other embodiments, the cycloalkyl group has 3 to 8, or 3 to 6, or 3 to 4, or 3 carbon atoms, including, for example, embodiments having 3, 4, 5, 6, 7, 8, 9, or 10 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. A heterocycloalkyl or heterocycloalkylene group can refer to a saturated alicyclic hydrocarbon group having one or more heteroatoms (e.g., N, O, S) in the ring. A heterocycloalkyl or heterocycloalkylene group can have 3 to 15 atoms (e.g., 3 to 12 atoms, 3 to 8 atoms, 3 to 6 atoms, 3 to 5 atoms, 3 to 4 atoms) in the ring. In some embodiments, a heterocycloalkyl or heterocycloalkylene group can be substituted with 1, 2, 3, or 4 substituents as defined herein.

[0077] An aryl or arylene group can be an aromatic monocyclic or polycyclic group of 6 to 12 carbon atoms having at least one aromatic ring. Examples of these groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalyl, 1,2-dihydronaphthalyl, indanyl, and 1H-indenyl. Typically, a heteroaryl or heteroarylene group comprises a monocyclic or polycyclic group 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 by a carbonyl group. Examples of heteroaryl groups include pyridyl, benzoxazolyl, benzimidazolyl, and benzothiazolyl.

[0078] Exemplary heterocycloalkyl or heteroaryl groups (e.g., R C As a base

[0079] [ka]

[0080] These groups (e.g., R C ) may contain one or more substituents as described herein (e.g., may be alkyl substituted).

[0081] A substituted hydrocarbon group may have one or more hydrocarbon groups or substituted hydrocarbon groups as substituents, and may contain one or more heteroatoms. Examples of substituted hydrocarbon groups include, but are not limited to, heterocycles such as heteroaryl. Unless otherwise specified, a hydrocarbon substituted with one or more heteroatoms contains 1 to 20 heteroatoms. In other embodiments, a hydrocarbon substituted with one or more heteroatoms contains 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 heteroatoms. Examples of heteroatoms include, but are not limited to, oxygen, nitrogen, sulfur, phosphorus, halogens (e.g., F, Cl, Br, I), boron, or silicon. In some embodiments, heteroatoms are selected from the group consisting of oxygen, nitrogen, sulfur, phosphorus, and halogens (e.g., F, Cl, Br, I). In some embodiments, a heteroatom or heterogroup can replace carbon (e.g., a substituted alkyl can include a heteroalkyl). In some embodiments, a heteroatom or heterogroup can replace hydrogen. In some embodiments, substituted hydrocarbons can include one or more heteroatoms present in the backbone or chain of the molecule (e.g., inserted between two carbon atoms, as in "oxa"), In some embodiments, substituted hydrocarbons can include one or more heteroatoms pendant from the backbone or chain of the molecule (e.g., covalently bonded to a carbon atom in the chain or backbone, as in "oxo").

[0082] Unless otherwise specified, all groups described herein (e.g., alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, R A , R B , R C , R A , R B , R C , R A1 , R A2 , R A3 , R B1 , R B2 , R B3 , R C1 , R C2 , RC3 , R C4 , R C5 , R1~R 10 ) may contain one or more substituents as allowed by the valence. Substituents include halogen (e.g., F, Cl), C 1~12 Straight or branched chain alkyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C 3~12 Cycloalkyl, C 6~12 Aryl, C 3~12 Heteroaryl, C 3~12 Heterocyclyl, C 1~12 alkylsulfonyl, nitro, cyano, -COOR, -C(O)NRR', -OR, -SR, -NRR', and oxo, including mono-, di-, or tri-substituted with moieties such as halogen, fluoroalkyl, perfluoroalkyl, perfluoroalkoxy, trifluoromethoxy, chlorine, bromine, fluorine, methyl, methoxy, pyridyl, furyl, triazyl, piperazinyl, pyrazoyl, imidazoyl, and the like, all of which may contain one or more heteroatoms such as halo, N, O, S, and P. R and R' are independently hydrogen, C 1~12 Alkyl, C 1~12 Haloalkyl, C 2~12 Alkenyl, C 2~12 Alkynyl, C 3~12 Cycloalkyl, C 4~24 Cycloalkylalkyl, C 6~12 Aryl, C 7~24 Aralkyl, C 3~12 Heterocyclyl, C 3~24 Heterocyclylalkyl, C 3~12 Heteroaryl, or C 4~24Heteroarylalkyl. Furthermore, the phrase "optionally substituted" as used herein indicates that the specified hydrocarbon group may be unsubstituted (e.g., substituted with H) or may be substituted. Typically, a substituted hydrocarbon is a hydrocarbon in which any hydrogen atom has been removed and replaced with a substituent (e.g., a common substituent).Any hydrocarbon in the present disclosure can be, for example, alkyl (e.g., C1-C8 alkyl, lower alkyl, e.g., C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl, e.g., -CD3), heteroalkyl (e.g., C1-C8 heteroalkyl, lower heteroalkyl, e.g., C1-C4 heteroalkyl), alkoxy-substituted alkyl (e.g., C1-C6 alkyl substituted with C1-C6 alkoxy such as methoxy), cycloalkyl (e.g., C3-C9 cycloalkyl, C3-C5 cycloalkyl, cyclopropyl), alkoxy (e.g., C1-C8 alkoxy, lower alkoxy, e.g., C1-C4 alkoxy, methoxy), alkoxy substituted with aryl (e.g., benzyloxy), spirocycloalkyl (C3-C9 cycloalkyl, C3-C5 cycloalkyl, cyclopropyl), haloalkyl (e.g., C1-C8 haloalkyl, lower haloalkyl, e.g., C1-C4 haloalkyl, halomethyl, C1-C8 fluoroalkyl). and hydroxy, cyano, nitroso, carboxylic acid (-COOH), ester (e.g., -COOR', where R' at each occurrence is selected from C1-C8 alkyl, lower alkyl, e.g., C1-C4 alkyl, fluoromethyl, difluoromethyl, perfluoroalkyl, C1-C8 perfluoroalkyl, lower perfluoroalkyl, e.g., C1-C4 perfluoroalkyl, perfluoromethyl), halogen (e.g., F, Cl, Br), oxo (=O), amino (e.g., NH, NR'R'', where R' and R'' at each occurrence are independently selected from H and lower alkyl), amido (e.g., -NHC(O)R, -C(O)NR'R'', where R' and R'' at each occurrence are independently selected from H and lower alkyl), hydroxy, cyano, nitroso, carboxylic acid (-COOH), ester (e.g., -COOR', where R' at each occurrence is selected from C1-C8 alkyl, lower alkyl, -C(O)NR'R'', where R' and R'' at each occurrence are independently selected from H and lower alkyl).

[0083] Those skilled in the chemical arts will understand that substitution at a given atom is limited by valence. Generally, unless otherwise indicated, the use of a substituent prefix such as alkyl or alkylene without the "optionally substituted" or "substituted" modifier is understood to mean that the particular substituent is unsubstituted. Nevertheless, the use of haloalkyl without the "optionally substituted" or "substituted" modifier is understood to mean an alkyl group in which at least one hydrogen atom has been replaced with halo. When a group can be substituted with one or more of several substituents, the substitution is selected to conform to the principles of chemical bonding with respect to valence and to result in a compound that is not inherently unstable. For example, any carbon atom may be bonded to two, three, or four other atoms, consistent with the carbon's four valence electrons. Furthermore, if a structure contains fewer than the desired number of designated functional groups, carbon atoms not bearing the designated functional group are bonded to as many hydrogen atoms as necessary to satisfy the valence of that carbon, unless otherwise indicated.

[0084] The compounds provided herein may have one or more asymmetric carbon atoms and may exist in the form of optically pure enantiomers, mixtures of enantiomers, e.g., racemates, optically pure diastereoisomers, mixtures of diastereoisomers, racemates of diastereoisomers, or racemic mixtures of diastereoisomers. Optically active forms can be obtained, for example, by resolution of racemates, asymmetric synthesis, or asymmetric chromatography (chromatography with a chiral adsorbent or eluent). Thus, some disclosed compounds may exist in various stereoisomeric forms, including stereoisomers, enantiomers, diastereomers, or racemates (i.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 the enantiomers from the racemate using one or more well-known techniques and methods, such as chiral chromatography and separation methods based thereon. Suitable techniques and / or methods for separating the enantiomers of the compounds described herein from a racemic mixture can be readily determined by one skilled in the art.

[0085] The compounds provided herein may also exist as geometric isomers that differ in the orientation of substituent atoms (e.g., relative to a carbon-carbon double bond, relative to a cycloalkyl ring, relative to a bridged bicyclic ring system). Atoms (other than H) on each side of a carbon-carbon double bond may be in the E configuration (substituents on both sides of the carbon-carbon double bond) or the Z configuration (substituents oriented on the same side). "R," "S," "S*," "R*," "E," "Z," "cis," and "trans" indicate configuration relative to the core molecule and may be used to indicate the geometric configuration of the compounds disclosed herein. Some of the disclosed compounds may exist in atropisomeric forms. Atropisomers are stereoisomers resulting from hindered rotation about a single bond, where the steric strain barrier to rotation is high enough to allow for the isolation of conformers.

[0086] The compounds disclosed herein can be prepared as individual isomers by isomer-specific synthesis or resolution from an isomeric mixture. Conventional resolution techniques include forming a salt of the 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 a 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 isomer 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 starting materials or final products using various well-known chromatographic methods. When the stereochemical configuration of a disclosed compound is named or depicted by structure, typically the named or depicted stereoisomer can be greater than 50% (e.g., at least 55%, 60%, 70%, 80%, 90%, 99%, or 99.9%) by mass (or mole fraction) relative to the other stereoisomer. When one enantiomer is named or depicted by structure, the depicted or named enantiomer is greater than 50% optically pure by mass (or mole fraction ratio) (e.g., at least 55%, 60%, 70%, 80%, 90%, 99%, or 99.9%). When one diastereomer is named or depicted by structure, the depicted or named diastereomer is greater than 50% optically pure by mass (or mole fraction ratio) (e.g., at least 55%, 60%, 70%, 80%, 90%, 99%, or 99.9%). Percent optical purity refers to the ratio of the masses of the enantiomers or the mass of the enantiomer plus the mass of its enantiomer. Diastereomeric purity by mass refers to the ratio of the mass of one diastereomer or the ratio of the masses of all diastereomers. Percent mole fraction purity refers to the ratio of moles of enantiomers or moles of enantiomer to moles of its optical isomer. Similarly, percent mole fraction purity refers to the ratio of moles of diastereomers or moles of diastereomer to moles of its isomer.When a disclosed compound is named or depicted by structure without indicating stereochemical configuration and is said to have at least one chiral center, the name or structure should be understood to encompass any enantiomer of the compound free of the corresponding optical isomer, a racemic mixture of the compound, or a mixture enriched in one enantiomer relative to the corresponding optical isomer. When a disclosed compound is named or depicted by structure without indicating stereochemical configuration and is said to have two or more chiral centers, the name or structure should be understood to encompass a diastereomer free of the other, several diastereomers free of other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers enriched in one diastereomer relative to the other, or mixtures of diastereomers enriched in one or more diastereomers relative to the other. The present disclosure encompasses all of these forms.

[0087] Solvates of the compounds described herein may form aggregates of the compound or ions of the compound with one or more solvents. These 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. Typically, solvates in which water is the solvent molecule are called hydrates. Hydrates include compositions containing stoichiometric amounts of water and compositions containing variable amounts of water.

[0088] The compounds described herein may exist as pharmaceutically acceptable salts. Typically, a salt is composed of a related number of cations and anions (at least one of which is formed from a compound described herein) paired such that the salt is electrically neutral (e.g., the pair can be ionically bonded). Pharmaceutically acceptable salts have the same activity as the parent compound (e.g., ED within 10%). 50), and exhibit a toxicity profile within a range consistent with utility in pharmaceutical compositions. For example, pharmaceutically acceptable salts can be suitable for use in contact with human and animal tissues, without undue toxicity, irritation, or allergic response, commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are described in Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and Pharmaceutically Acceptable Salts: Properties, Selection, and Use, (Eds. PH Stahl and CG Wermuth), Wiley-VCH, 2008. Salts can be prepared from pharmaceutically acceptable non-toxic acids and bases, including inorganic and organic acids and bases. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogensulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, dichloroacetate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glutamate, glycerophosphate, hemisulfate, heptonate, hexanoate, hippurate, hydrobromide, hydrochloride, hydroiodide, and 2-hydroxyethanesulfonate. , 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 base salts include alkali and alkaline earth metal salts, including sodium, lithium, potassium, calcium, and magnesium salts, aluminum salts, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, caffeine, and ethylamine.

[0089] Pharmaceutically acceptable acid addition salts of the present disclosure can be formed by reacting a compound of the present disclosure with an equimolar or excess amount of acid. Alternatively, hemi-salts can be formed by reacting a compound of the present disclosure with the desired acid in a 2:1 ratio (compound:acid). Typically, the reactants are combined in a mutual solvent such as diethyl ether, tetrahydrofuran, methanol, ethanol, isopropanol, or benzene. The salts will usually precipitate out of solution within, for example, 1 hour to 10 days and can be isolated by filtration or other conventional methods.

[0090] The compounds of the present invention include the compounds themselves, as well as their salts and prodrugs, if applicable. For example, salts can be formed between anions (e.g., halides such as chloride, fluoride, bromide, optionally substituted phosphate, optionally substituted sulfonate, optionally substituted acetate) and a positively charged substituent (e.g., optionally substituted ammonium) in the compounds described herein. Suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, and acetate. Similarly, salts can be formed between cations and negatively charged substituents (e.g., carboxylate) in the compounds described herein. Suitable cations include sodium, potassium, magnesium, calcium, and ammonium cations, such as tetramethylammonium. Generally, prodrugs are converted to active compounds after administration to a subject, for example, through in vivo hydrolysis. Examples of prodrugs include C-substituted carboxylic acid groups that can yield active compounds upon administration to a subject. 1~6 Alkyl esters are included.

[0091] In general, compounds of the present disclosure comprise, for example, an optionally substituted 5- or 6-membered nitrogen-containing heteroaryl, R C In some embodiments, R C The structure:

[0092] [ka]

[0093] (In the formula,

[0094] [ka]

[0095] is R L (or RL If does not exist, R B ) indicates the point of attachment; dashed circle indicates optional unsaturation (e.g., aromaticity); XC6 is C, CR, or N; X C1 , X C2 , X C3 , X C4 , and X C5 is independently at each occurrence CH, CR, N, NH, NR, O, or S; when the group is a 5-membered ring, X C5 does not exist (i.e., it is a bond); R C1 , R C2 , R C3 , R C4 , and R C5 is independently at each occurrence hydrogen, alkyl (e.g., C1-C8 alkyl, lower alkyl, e.g., C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl, e.g., -CD3), halogen (e.g., F, Cl, Br), haloalkyl (e.g., C1-C8 haloalkyl, lower haloalkyl, e.g., C1-C4 haloalkyl, halomethyl, C1-C8 fluoroalkyl, lower fluoroalkyl, e.g., C1-C4 fluoroalkyl, fluoromethyl, difluoromethyl, perfluoroalkyl). , C1-C8 perfluoroalkyl, lower perfluoroalkyl, e.g., C1-C4 perfluoroalkyl, perfluoromethyl), cycloalkyl (e.g., C3-C9 cycloalkyl, C3-C5 cycloalkyl, cyclopropyl), carboxylic acid (-COOH), ester (e.g., -COOR' (wherein R' at each occurrence is selected from C1-C8 alkyl, lower alkyl), -C(O)NR'R'' (wherein R' and R'' at each occurrence are independently selected from H and lower alkyl); R at each occurrence is independently hydrogen or lower alkyl (e.g., C1-C4 alkyl). In various embodiments, R C The structure:

[0096] [ka]

[0097] [ka]

[0098] (In the formula, R C1 is hydrogen, alkyl, halogen, haloalkyl, cycloalkyl, or —C(O)NRR′, where R and R′ are independently hydrogen or lower alkyl. In certain embodiments, R C The structure:

[0099] [ka]

[0100] For example, R C The structure:

[0101] [ka]

[0102] R C1 can be, for example, hydrogen, or lower alkyl (eg, C1-C4 alkyl, methyl), cycloalkyl (eg, C3-C5 cycloalkyl), haloalkyl (eg, C1-C4 haloalkyl, C1-C4 fluoroalkyl, fluoromethyl, difluoromethyl).

[0103] In certain embodiments, R C The group is R L The compounds of the present disclosure have the structure of formula (II):

[0104] [ka]

[0105] For example, the compound may have the structure of Formula (IIa), (IIb), (IIc), (IId), (IIe), (IIIf), (IIg), (IIh), (IIi), or (IIj):

[0106] [ka]

[0107] [ka]

[0108] may have.

[0109] For example, the compound

[0110] [ka]

[0111] [ka]

[0112] [ka]

[0113] [ka]

[0114] [ka]

[0115] [ka]

[0116] In some embodiments, the compound may be

[0117] [ka]

[0118] It is possible.

[0119] This compound

[0120] [ka]

[0121] [ka]

[0122] [ka]

[0123] The compound may be

[0124] [ka]

[0125] [ka]

[0126] In some embodiments, the compound may be selected from the group consisting of:

[0127] [ka]

[0128] is.

[0129] In some embodiments, the compound is

[0130] [ka]

[0131] In certain embodiments, the compound is

[0132] [ka]

[0133] is.

[0134] R C The group is R L The compound may be attached to the group in a meta configuration of the central six-membered ring. For example, the compound may have the structure of formula (III):

[0135] [ka]

[0136] For example, the compound may have the structure of formula (IIIa), (IIIb), (IIIc), (IIId), or (IIIe):

[0137] [ka]

[0138] may have.

[0139] In some embodiments, the compound is

[0140] [ka]

[0141] [ka]

[0142] [ka]

[0143] [ka]

[0144] For example, the compound can be

[0145] [ka]

[0146] It is possible.

[0147] Usually, R L is a -S(=O)2- group. In some embodiments, R in Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (III), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe) L The group is -S(=O)2-. For example, the compound has the structure of formula (IV):

[0148] [ka]

[0149] (wherein each dashed circle independently represents an optional unsaturation; X is N, C, or CR3; Y is =N-, -N=, -N(R9)-, -(C(R7)(R8)) p -, =C(R7)-, -C(R7)=, -N(R9)C(R7)(R8)-, -C(R7)(R8)N(R9)-, -N(R9)C(R7)=, =C(R7)N(R9)-, -C(R7)=C(R8)-, -N=C(R8)-, or -C(R7)=N-; p is 1, 2, or 3; Z is N, C, or CR6; R4 and R6 may together form =O; A1, 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; R1 is absent, hydrogen, or alkyl (e.g., C1-C8 alkyl, lower alkyl, e.g., C1-C4 alkyl, methyl, deuterated alkyl, or deuterated lower alkyl, e.g., -CD3); R2 to R6 are independently hydrogen or alkylalkyl (e.g., C1 to C8 alkyl, lower alkyl, e.g., C1 to C4 alkyl, methyl, deuterated alkyl, or deuterated lower alkyl, e.g., -CD3); wherein R2 to R6 independently may have one or more optional substitution points; R7-R9 at each occurrence can independently be hydrogen or alkylalkyl (e.g., C1-C8 alkyl, lower alkyl, e.g., C1-C4 alkyl, methyl, deuterated alkyl, or deuterated lower alkyl, e.g., -CD3); where R7-R9 can independently have one or more optional points of substitution; or or a pharmaceutically acceptable salt thereof, or a prodrug of any of the above. In some embodiments, the compound has the structure of Formula (IVa) or (IVb):

[0150] [ka]

[0151] (wherein n is 1 or 2; Y is N, CH, or CR 10 and; R 10 is hydrogen or alkyl (e.g., C1-C8 alkyl, lower alkyl, e.g., C1-C4 alkyl, methyl, deuterated alkyl, or deuterated lower alkyl, e.g., -CD3), and R 10 may have one or more optional substitution points).

[0152] This compound

[0153] [ka]

[0154] [ka]

[0155] [ka]

[0156] [ka]

[0157] In some embodiments, the compound may be

[0158] [ka]

[0159] is.

[0160] The compounds may exhibit variations of the bicyclic ring systems of formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIi), (III), (IIIa), (IIIb), (IIIc), (IIId), or (IIIe), for example, to give sulfonamides. Typically, these systems have a central ring (R B ) and R c For example, the Ca V 3.3 The enhancer has the structure of formula (V):

[0161] [ka]

[0162] (In the formula, R D1 is hydrogen, alkyl (e.g., C1-C8 alkyl, lower alkyl, e.g., C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl, e.g., -CD3), haloalkyl (e.g., C1-C8 haloalkyl, lower haloalkyl, e.g., C1-C4 haloalkyl, halomethyl, C1-C8 fluoroalkyl, lower fluoroalkyl, e.g., C1-C4 fluoroalkyl, fluoromethyl, difluoromethyl, perfluoroalkyl, C1-C8 perfluoroalkyl, lower perfluoroalkyl, e.g., C1-C4 perfluoroalkyl, perfluoromethyl), monocyclic or bicyclic heterocyclyl, monocyclic or bicyclic heteroaryl, or aryl; R D1 may have one or more (e.g., two, three, four) optional substitution points (and R D1 is optionally substituted, and any two geminal or adjacent substituents may form a 5- or 6-membered ring; R D2 is hydrogen or alkyl (e.g., C1-C8 alkyl, lower alkyl, e.g., C1-C4 alkyl, methyl, deuterated alkyl, or deuterated lower alkyl, e.g., -CD3), and R D2 may have one or more (e.g., two, three, four) optional substitution points; X B1 is independently N or CR for each occurrence B1 and; R B1 is independently selected at each occurrence from hydrogen, alkyl (e.g., C1-C8 alkyl, lower alkyl, e.g., C1-C4 alkyl, methyl, deuterated alkyl, or deuterated lower alkyl, e.g., -CD3), and -R C and R B1 may have one or more (e.g., two, three, four) optional substitution points; R B2is independently selected at each occurrence from hydrogen, optionally unsaturated alkyl (e.g., C1-C8 alkyl, lower alkyl, e.g., C1-C4 alkyl, methyl, deuterated alkyl, or deuterated lower alkyl, e.g., -CD3), and -R C and R B2 may have one or more (e.g., two, three, four) optional substitution points; R B1 or R B2 At least one of the following has the structure:

[0163] [ka]

[0164] (In the formula,

[0165] [ka]

[0166] indicates the point of attachment to the compound, and the dashed circle indicates optional aromaticity; XC6 is C, CH, CR, or N; X C1 , X C2 , X C3 , X C4 , and X C5 are independently CH, CR, N, NH, NR, O, or S; when the group is a 5-membered ring, X C5 does not exist; R C1 , R C2 , R C3 , R C4 , and R C5are independently hydrogen, alkyl (e.g., C1-C8 alkyl, lower alkyl, e.g., C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl, e.g., -CD3), -C(O)R, -C(O)NRR, halogen (e.g., F, Cl, O), haloalkyl (e.g., C1-C8 haloalkyl, lower haloalkyl, e.g., C1-C4 haloalkyl, halomethyl, C1-C8 fluoroalkyl, lower fluoroalkyl, e.g., C1-C4 fluoroalkyl, fluoromethyl, difluoromethyl, perfluoroalkyl, C1-C8 perfluoroalkyl, lower perfluoroalkyl, e.g., C1-C4 perfluoroalkyl, perfluoromethyl), or cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl); or may be taken together with a geminal R group to form oxo (=O), where R C1 , R C2 , R C3 , R C4 , and R C5 may independently have one or more (e.g., two, three, four) optional substitution points; R at each occurrence is independently hydrogen or alkyl (e.g., C1-C8 alkyl, lower alkyl, e.g., C1-C4 alkyl, methyl, deuterated alkyl, or deuterated lower alkyl, e.g., -CD3), with -R C an enhancer having a group In various embodiments, the compound has the structure of Formula (Va), (Vb), (Vc), (Vd), or (Ve), including pharmaceutically acceptable salts thereof:

[0167] [ka]

[0168] [ka]

[0169] may have.

[0170] In various embodiments, the compound is

[0171] [ka]

[0172] [ka]

[0173] It is possible.

[0174] The hydrocarbon groups identified in the compounds of the present disclosure (e.g., R A1 , R A2 , R A3 , R B1 , R B2 , R C1 , R C2 , R C3 , R C4 , R C5 , R D1 , and R D2 ) may be substituted one or more times with substituents described herein. For example, in some embodiments, R D1 is alkyl or aryl optionally substituted one or more times with substituents selected from alkyl, alkoxy, halogen, —NRR, —C(O)R, —NRC(O)R, and —C(O)NRR; any two adjacent substituents may be joined to form a 5- or 6-membered ring (e.g., dihydrobenzodioxinyl, e.g., dihydrobenzo[b][1,4]dioxin-5-yl). In various embodiments, R D1 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][1,4]dioxin-5-yl optionally substituted one or more times with alkyl. In some embodiments, R D2is hydrogen or lower alkyl (e.g., C1-C4 alkyl, e.g., methyl) optionally substituted with alkoxy or -NRR. Furthermore, when the identified group is alkyl, the alkyl group may be unsaturated (e.g., alkenyl). For example, in some embodiments, R B2 is selected from hydrogen or optionally unsaturated alkyl (eg, C2-C8 alkenyl, C2-C8 alkynyl, C2-C4 alkenyl, C2-C4 alkynyl, ethenyl).

[0175] Ca V 3.3 Potentiators (or activators) may exhibit activity as described in the assays set forth herein (e.g., Example 1). For example, potentiator compounds may exhibit Ca concentrations of less than 100 μM (or 0.1 nM to 100 μM) (e.g., less than 10 μM, less than 1 μM, less than 100 nM). V 3.3 Activation of EC 50 (e.g., as measured by a 1 hour incubation). In various embodiments, the compounds may exhibit a Ca V 3.3 can be selective for activation (e.g., Ca V 3.3 Activation of EC 50 is less than 20 μM (or 0.1 nM to 20 μM), for example, Ca V 3.2 Inactive for activation, e.g., Ca V 3.2 Activation of EC 50 The EC may be 20 μM or greater. 50can be measured by the assays described in the Examples, including, for example, a Fluorescence Imaging Plate Reader (FLIPR) assay. In some embodiments, the compounds can 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, KB 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, all of which are incorporated herein by reference in their entirety, particularly with respect to high-throughput assay protocols.

[0176] The compounds are the same as compounds 1 to 69, 71 to 172, 174 to 176, 179 to 265, 269 to 285, 287 to 288, 290 to 291, 293 to 295, 297 to 298, 300 to 301, 305, 307, 312, 314 to 321, 324 to 325, 327 to 340, 342 to 343, 345, 348 to 357, 360 to 362, 364 to 375, 377 to 378, 380 to 392, 395 to 396, 398 to 423, 425 to 435, 438 to 439, 441 to 446, 448, 450, 452 to 456, 45 5, 6, 7, 8, 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, a stereoisomer, tautomer, diastereomer, enantiomer, or mixture thereof, or a racemic mixture of any of the above. In some embodiments, the compound is any one of Compounds 1-69, 71-172, 174-176, and 179-255. In some embodiments, the compound can have a structure of Formula (I) or (V), and can 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, 4 25-435, 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.

[0177]

Table 1-1

[0178]

Table 1-2

[0179]

Table 1-3

[0180]

Table 1-4

[0181]

Table 1-5

[0182]

Table 1-6

[0183]

Table 1-7

[0184]

Table 1-8

[0185]

Table 1-9

[0186]

Table 1-10

[0187]

Table 1-11

[0188]

Table 1-12

[0189]

Table 1-13

[0190]

Table 1-14

[0191]

Table 1-15

[0192]

Table 1-16

[0193]

Table 1-17

[0194]

Table 1-18

[0195]

Table 1-19

[0196]

Table 1-20

[0197]

Table 1-21

[0198]

Table 1-22

[0199]

Table 1-23

[0200]

Table 1-24

[0201]

Table 1-25

[0202]

Table 1-26

[0203]

Table 1-27

[0204]

Table 1-28

[0205]

Table 1-29

[0206]

Table 1-30

[0207]

Table 1-31

[0208]

Table 1-32

[0209]

Table 1-33

[0210]

Table 1-34

[0211]

Table 1-35

[0212]

Table 1-36

[0213]

Table 1-37

[0214]

Table 1-38

[0215]

Table 1-39

[0216]

Table 1-40

[0217]

Table 1-41

[0218]

Table 1-42

[0219]

Table 1-43

[0220]

Table 1-44

[0221]

Table 1-45

[0222]

Table 1-46

[0223]

Table 1-47

[0224]

Table 1-48

[0225]

Table 1-49

[0226]

Table 1-50

[0227]

Table 1-51

[0228]

Table 1-52

[0229]

Table 1-53

[0230]

Table 1-54

[0231]

Table 1-55

[0232]

Table 1-56

[0233]

Table 1-57

[0234]

Table 1-58

[0235]

Table 1-59

[0236]

Table 1-60

[0237]

Table 1-61

[0238]

Table 1-62

[0239]

Table 1-63

[0240]

Table 1-64

[0241]

Table 1-65

[0242]

Table 1-66

[0243]

Table 1-67

[0244]

Table 1-68

[0245]

Table 1-69

[0246]

Table 1-70

[0247]

Table 1-71

[0248]

Table 1-72

[0249]

Table 1-73

[0250]

Table 1-74

[0251]

Table 1-75

[0252]

Table 1-76

[0253]

Table 1-77

[0254]

Table 1-78

[0255]

Table 1-79

[0256]

Table 1-80

[0257]

Table 1-81

[0258]

Table 1-82

[0259]

Table 1-83

[0260]

Table 1-84

[0261]

Table 1-85

[0262]

Table 1-86

[0263]

Table 1-87

[0264] Table 1-88

[0265]

Table 1-89

[0266]

Table 1-90

[0267]

Table 1-91

[0268]

Table 1-92

[0269]

Table 1-93

[0270]

Table 1-94

[0271]

Table 1-95

[0272]

Table 1-96

[0273]

Table 1-97

[0274]

Table 1-98

[0275]

Table 1-99

[0276]

Table 1-100

[0277]

Table 1-101

[0278]

Table 1-102

[0279] In some embodiments, the compound is selected from the group consisting 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, 438-440, 440-442, 442-443, 445-448, 448-449, 450-451, 452-453, 454-455, 456-457, 458-460, 459-461, 460-462, 461-462, 462-463, 463-464, 464-465, 465-466, 466-467, 467-468, 468-470, 469-471, 471-472, 472-473, 473-474, 474-475, 475-476, 476-477, 477-478, 478-480, 479-481, 479-482, 48 39, 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. 1 (Table 1), or a pharmaceutically acceptable salt or prodrug thereof, including its stereoisomers, tautomers, diastereomers, enantiomers, mixtures, or racemic mixtures of any of the above.

[0280] Generally, each stereochemical designation shown for a compound of the present disclosure in Table 1 and in the Synthetic Examples should be considered accompanied by an "or1" label. However, compounds in which the indicated stereochemical configuration is the absolute ("abs") stereochemical configuration of the compound are contemplated within the present disclosure (and all enantiomers and mixtures thereof may be encompassed by the indicated structure). Compounds can be characterized by their elution order in chiral separation processes, such as those described in the Synthetic Examples. For example, compounds can be chiral separated from a mixture of enantiomers and characterized by their elution order and properties (e.g., activity, increase in pharmacokinetic parameters). The present compounds (e.g., compounds 2, 10, 15, 36, 39, 46, 67, 90, 114, 126, 154, 156, 176, 182, 184, 193, 198, 207, 272, 522, 523, 561, 562) have the structure:

[0281] [ka]

[0282] or a mixture thereof, including a racemic mixture. In some embodiments, the compounds (e.g., compounds 21, 24, 27, 55, 59, 68, 83, 88, 91, 116, 120, 138, 153, 186, 262, 263, 264, 307, 389, 433, 555, 557) have the structure:

[0283] [ka]

[0284] or mixtures thereof, including racemic mixtures. The compounds (e.g., compounds 29, 81, 88, 100, 118, 165, 201, 261, 262, 265, 269, 307, 390, 391, 392, 434, 483, 518) have the structure:

[0285] [ka]

[0286] or a mixture thereof, including a racemic mixture. In certain embodiments, the compounds (e.g., compounds 135, 435) have the structure:

[0287] [ka]

[0288] or a mixture thereof, including a racemic mixture. In various embodiments, the compounds (e.g., compounds 63, 357) have the structure:

[0289] [ka]

[0290] or a mixture thereof, including a racemic mixture. In some embodiments, the compound has the structure:

[0291] [ka]

[0292] or a mixture thereof, including a racemic mixture. In some embodiments, the compound (e.g., compounds 210, 230) has the structure:

[0293] [ka]

[0294] or a mixture thereof, including a racemic mixture. In some embodiments, the compound (e.g., compound 404) has the structure:

[0295] [ka]

[0296] or a mixture thereof, including a racemic mixture.

[0297] 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.

[0298] [ka]

[0299] [ka]

[0300] In various embodiments, the compound is

[0301] [ka]

[0302] 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 is

[0303] [ka]

[0304] In some embodiments, the compound may be

[0305] [ka]

[0306] In some embodiments, the compound is

[0307] [ka]

[0308] [ka]

[0309] In some embodiments, the compound is

[0310] [ka]

[0311] is.

[0312] Pharmaceutical Composition The compounds described herein (e.g., Ca V 3.3 Enhancers, having the structure of formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb, (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (Iii), (IIj), (III), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IV), (IVa), or (IVb) 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, 3 77-378, 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, 51 and one or more of compounds 1-69, 71-172, 174-176, and 179-255) are useful for treating a subject in need thereof. The compounds described herein can 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.

[0313] Compounds of the present disclosure (e.g., Ca V 3.3 Enhancers, compounds having the structure of formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb, (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (Iii), (IIj), (III), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IV), (IVa), or (IVb), 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, Pharmaceutical dosage forms are also provided that may include one or more of the compounds listed in Table 1 below (e.g., 532-541, 543-551, 553-558, 560-570, 573-575, 577-583, 585, and 587-596, and one or more of compounds 1-69, 71-172, 174-176, and 179-255), and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0314] A unit dosage form, also referred to as a unitary dosage form, often refers to a form of pharmaceutical supplied such that no further weighing or measuring is required to provide a dosage form (e.g., tablet, capsule, caplet). The compositions of the present disclosure may exist as a unit dosage form. For example, a unit dosage form may refer to a physically discrete unit suitable as a unit dosage form for human subjects and other species, each unit containing a predetermined amount of an active agent calculated to produce a desired therapeutic effect, in combination with any suitable pharmaceutical excipient(s). Exemplary, non-limiting unit dosage forms include tablets (e.g., chewable tablets), caplets, capsules (e.g., hard or soft capsules), lozenges, films, strips, and gel capsules. In certain embodiments, the compounds described herein (including their crystalline forms, polymorphs, and solvates) may exist in a unit dosage form.

[0315] Pharmaceutical carriers, excipients, and diluents useful in preparing the compositions herein can be solid, liquid, or gaseous. These include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. Pharmaceutically acceptable carriers or excipients do not destroy the pharmacological activity of the disclosed compounds and are non-toxic when administered in dosages sufficient to deliver a therapeutic amount of the compound. Thus, the compositions may take the form of tablets, pills, capsules, suppositories, powders, enteric-coated or other protected formulations (e.g., bound to ion exchange resins or packaged in lipid-protein vesicles), sustained-release formulations, solutions, suspensions, elixirs, and aerosols. Carriers can be selected from a variety of oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, and sesame oil. Water, saline, aqueous dextrose, and glycols are examples of liquid carriers for injectable solutions (e.g., those that are isotonic with blood). For example, formulations for intravenous administration include sterile aqueous solutions of active ingredients, which are prepared by dissolving solid active ingredients in water to form an aqueous solution and sterilizing the solution. Suitable pharmaceutical excipients include starch, cellulose, chitosan, talc, glucose, lactose, gelatin, malt, rice, wheat flour, chalk, silica, magnesium stearate, sodium stearate, glyceryl monostearate, sodium chloride, dried skim milk, glycerin, propylene glycol, water, and ethanol. The composition may contain conventional pharmaceutical additives, such as preservatives, stabilizers, wetting agents or emulsifiers, salts for adjusting osmotic pressure, and buffers. Suitable pharmaceutical carriers and their formulation are described in Remington's Pharmaceutical Sciences by EW Martin. In any case, these compositions contain an effective amount of the active compound together with a suitable carrier to prepare a dosage form suitable for administration to the recipient.

[0316] 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 carboxymethylcellulose, 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; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffers; non-toxic, compatible lubricants such as sodium lauryl sulfate and magnesium stearate. sodium; colorants; release agents; coating agents; sweetening agents, flavoring agents, and fragrances; preservatives; antioxidants; ion exchangers; alumina; aluminum stearate; lecithin; self-emulsifying drug delivery systems (SEDDS), such as D-α-tocopherol polyethylene glycol 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; polyvinylpyrrolidone; cellulosic materials; polyacrylates; waxes; and polyethylene-polyoxypropylene-block polymers. Cyclodextrins, such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives, such as hydroxyalkyl cyclodextrins, including 2- and 3-hydroxypropyl-cyclodextrin, or other solubilizing derivatives, may be used to enhance delivery of the compounds described herein.

[0317] In various embodiments, the compositions of the present invention are formulated as pellets or tablets for oral administration. According to this type of formulation, the compositions contain lactose monohydrate, microcrystalline cellulose, crospovidone / povidone, flavor, compressible sugar, and magnesium stearate as excipients. When the compositions are in pellet or tablet form, they are, for example, 1 mg, 2 mg, or 4 mg pellets or tablets. These pellets or tablets are divisible so that they can be cut to accommodate once- or twice-daily administration of the dosage of the present invention. In a further embodiment, the compositions of the present disclosure are formulated as an injectable solution or suspension for parenteral administration. The injectable composition is produced by mixing a therapeutically effective amount of torasemide with a pH adjusting agent, a buffering agent, a suspending agent, a solubilizing agent, a stabilizer, an isotonicity agent, and / or a preservative, and converting the mixture into an intravenous, subcutaneous, or intramuscular injection or infusion solution according to conventional methods. In some cases, the injectable composition may be lyophilized according to conventional methods. Examples of suspending agents include methylcellulose, polysorbate 80, hydroxyethylcellulose, xanthan gum, sodium carboxymethylcellulose, and polyethoxylated sorbitan monolaurate. Examples of solubilizing agents include polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinamide, polyethoxylated sorbitan monolaurate, macrogol, and castor oil fatty acid ethyl ester. Furthermore, stabilizers include sodium sulfite, sodium metabisulfite, and ethers, while preservatives include methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, sorbic acid, phenol, cresol, and chlorocresol. An example of an isotonic agent is mannitol. When preparing injection suspensions or solutions, it is desirable to ensure that they are isotonic with blood.

[0318] In some embodiments, the pharmaceutical composition further comprises a viscosity enhancer. In some embodiments, viscosity enhancers include methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, and smart hydrogel. In some embodiments, the viscosity enhancer is hydroxyethylcellulose. In some embodiments, the pharmaceutical composition comprises 0.01-1.0% (w / v) of a viscosity enhancer. In other embodiments, the intranasal pharmaceutical composition comprises 0.05% (w / v) hydroxyethylcellulose.

[0319] In some embodiments, the pharmaceutical composition has a pH of 4.0 to 7.5. In other embodiments, the pharmaceutical composition has a pH of 4.0 to 6.5. In another embodiment, the pharmaceutical composition has a pH of 5.5 to 6.5. In a further embodiment, the pharmaceutical composition has a pH of 6.0 to 6.5. In various embodiments, the aqueous solution or liquid formulation has a pH of 3 to 7, 3 to 6, 4 to 6, or 5 to 6. These pH ranges can be achieved through the incorporation of one or more pH adjusting agents, buffering agents, etc. In some embodiments, a pH adjusting agent, such as acetic acid, is present at a final concentration of at least 0.001%, preferably at least 0.01%, and more preferably 0.01% to 0.2% by weight of the composition.

[0320] The compositions of the present invention may be in the form of solutions, emulsions (including microemulsions), suspensions, creams, lotions, gels, powders, or other typical solid or liquid compositions for application to the skin and other tissues to which the compositions are applicable. These compositions may contain additional antibacterial agents, moisturizers and hydrating agents, penetrating agents, preservatives, emulsifiers, natural or synthetic oils, solvents, surfactants, detergents, gelling agents, emollients, antioxidants, perfumes, fillers, thickeners, waxes, odor absorbers, pigments, colorants, powders, viscosity control agents, and water, and may optionally contain anesthetics, antipruritic actives, botanical extracts, conditioning agents, darkening or whitening agents, glitter, humectants, mica, minerals, polyphenols, silicones or their derivatives, sunscreens, vitamins, and botanicals. In certain embodiments, the compositions of the present invention are formulated with the above ingredients to exhibit long-term stability, which may be beneficial when continuous or long-term treatment is intended.

[0321] Methods for Treatment As shown herein, Ca V 3.3 Enhancers can induce significant therapeutic effects in patients in need thereof, including increasing sleep spindles, rescuing sleep spindle disorders, increasing rebound burst firing in the thalamic reticular nucleus (TRN), and / or reducing thalamocortical hyperactivity. V 3.3 Enhancers are shown herein to rescue social interaction and novel object recognition when administered to a subject. In some embodiments, Ca V Stimulation of channels (e.g., Ca delivery to the target V 3.3 by administration of an augmenting agent) may be effective in treating and / or preventing diseases, disorders, or conditions associated with declarative memory impairment and / or social impairment.

[0322] Typically, treatment of a disease, disorder, or condition (e.g., schizophrenia, cognitive impairment, decreased sleep spindles, decreased thalamic reticular nucleus function, thalamocortical hyperactivity, neurodevelopmental disorders such as autism spectrum disorder (ASD), schizophrenia, attention deficit hyperactivity disorder (ADHD), schizoaffective disorder, and bipolar affective disorder, neurodegenerative diseases such as Alzheimer's disease) is an approach to obtain beneficial or desired results, such as clinical results. V3.3 Potentiators, compounds having the structure of formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb, (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (Iii), (IIj), (III), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IV), (IVa), or (IVb); Compounds 1-69, 71-172, 174-176, 179-265, 269-285, 287-288, 290-291, 293-295, 297-298, 300-301, 3 05, 307, 312, 314~321, 324~325, 327~340, 342~343, 345, 348~357, 360~362, 364~375, 377~378, 38 0~392, 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, and one or more of compounds 1-69, 71-172, 174-176, and 176-255) can be used in the treatment of any disease, disorder, condition, or method described herein. In some embodiments, the compounds can be used in the preparation of a medicament for the treatment of any disease, disorder, condition, or method described herein. Beneficial or desired results may include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, whether detectable or undetectable; a reduction in the severity of the disease, disorder, or condition; a stable state of the disease, disorder, or condition (i.e., not worsening); prevention of the spread of the disease, disorder, or condition; a delay or slowing of the progression of the disease, disorder, or condition; an improvement or palliation of the disease, disorder, or condition; and remission (whether partial or complete).That a disease, disorder, or condition can be "alleviated" includes a decrease in the severity and / or undesirable clinical symptoms of the disease, disorder, or condition, and / or a slowing or prolongation of the time course of progression compared to the severity or time course in the absence of treatment.

[0323] Methods encompassing the treatment and / or prevention of neurodegenerative diseases, psychiatric disorders, cognitive impairment, and pervasive developmental disorders, comprising administering to a subject a compound (e.g., Ca V3.3 Enhancers, having the structure of formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb, (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (Iii), (IIj), (III), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IV), (IVa), or (IVb) 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,

[0023] Methods are provided for improving brain function in a subject, comprising administering a compound (e.g., one or more of compounds 518-520, 522-523, 525-529, 532-541, 543-551, 553-558, 560-570, 573-575, 577-583, 585, and 587-596, or one or more of compounds 1-69, 71-172, 174-176, and 176-255). In various embodiments, the cognitive impairment is a disorder selected from Alzheimer's disease, Parkinson's disease, Pick's disease, Huntington's disease, schizophrenia, bipolar disorder, depression, phobia, sleep disorder, drug addiction, autism, Asperger's syndrome, mental retardation, hyperactivity disorder, and tic disorder.

[0024] Methods are provided for improving brain function in a subject, comprising administering a compound (e.g., Ca V3.3 Enhancers, having the structure of formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb, (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (Iii), (IIj), (III), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IV), (IVa), or (IVb) 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, 3 77-378, 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, 51 and one or more of compounds 1-69, 71-172, 174-176, and 176-255) to a subject. The improvement of brain function in the present invention includes improving brain dysfunction, such as brain dysfunction caused by cerebrovascular disease, brain injury, brain tumor, viral encephalitis, hypoxic encephalopathy, and alcoholism. The present disclosure is particularly applicable to cognitive dysfunction, such as memory impairment, attention deficit, executive dysfunction, and social behavior disorder. Cognitive dysfunction includes, for example, neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, Pick's disease, and Huntington's disease), psychiatric disorders (e.g., schizophrenia, bipolar disorder, depression, phobias, sleep disorders, drug addiction, etc.), and pervasive developmental disorders (e.g., autism, Asperger's syndrome, mental retardation, hyperactivity disorder, tic disorder).

[0324] Methods for treating a subject in need thereof (e.g., a subject having or prone to developing schizophrenia, cognitive impairment, reduced sleep spindles, reduced thalamic reticular nucleus function, thalamocortical hyperactivity, a neurodevelopmental disorder 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) can be achieved by administering a compound of the present disclosure (e.g., Ca V 3.3 Enhancer, having the structure of formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb, (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (Iii), (IIj), (III), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IV), (IVa), or (IVb). 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, 5 The method includes administering to a subject one or more of the compounds 18 to 520, 522 to 523, 525 to 529, 532 to 541, 543 to 551, 553 to 558, 560 to 570, 573 to 575, 577 to 583, 585, and 587 to 596, and one or more of the compounds 1 to 69, 71 to 172, 174 to 176, and 176 to 255) or a composition.

[0325] The compounds of the present disclosure selectively modulate T-type calcium channels associated with schizophrenia, as well as other conditions disclosed herein (e.g., cognitive impairment, decreased sleep spindles, decreased thalamic reticular nucleus function, thalamocortical hyperactivity, neurodevelopmental disorders such as autism spectrum disorder (ASD), schizophrenia, attention deficit hyperactivity disorder (ADHD), schizoaffective disorder, and bipolar affective disorder, and neurodegenerative diseases such as Alzheimer's disease). These small molecules rescue the sleep spindle disturbances observed in schizophrenia patients. Sleep spindles are brain oscillations that are particularly important for memory consolidation during sleep, and Ca V The function of 3.3 is crucial for the formation of sleep spindles. A method for reducing the formation of sleep spindles is also provided. Sleep spindles can be classified into slow-wave sleep spindles and fast-wave sleep spindles. The difference in power distribution between mood disorder states and normal states can be particularly seen in certain types of sleep spindles, such as slow-wave sleep spindles. Therefore, by setting the frequency band of slow-wave sleep spindles as a special frequency band, it becomes possible to diagnose whether a test subject is in a mood disorder state. Based on the sleep spindle state or predominant sleep spindle state of a subject in need thereof, a compound of the present disclosure (e.g., Ca V3.3 Enhancer, a compound having the structure of formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb, (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (Iii), (IIj), (III), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IV), (IVa), or (IVb) Compounds having the formula: Compounds 1 to 69, 71 to 172, 174 to 176, 179 to 265, 269 to 285, 287 to 288, 290 to 291, 293 to 295, 297 to 298, 300 to 301, 305, 307, 312, 314 to 321, 324 to 325, 327 to 340, 342 to 343, 345, 348 to 357, 360 to 362, 364 to 365, 366 to 367, 368 to 369, 370 to 373, 374 to 375, 376 to 377, 378 to 379, 380 to 381, 382 to 383, 383 to 384, 385 to 386, 387 to 388, 389 to 390, 391 to 392, 393 to 394, 395 to 396, 400 to 401, 402 to 403, 404 to 405, 406 to 407, 408 to 409, 410 to 411, 412 to 413, 414 to 415, 416 to 417, 418 to 419, 420 to 421, 422 to 423, 424 to 425, 426 to 427, 428 to 429, 430 to 431, 432 to 4 75, 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 administration of one or more of compounds 1 to 69, 71 to 172, 174 to 176, and 179 to 255) can be selected.

[0326] The present disclosure is based, at least in part, on the discovery that T-type calcium channel modulators are useful as antipsychotic drugs, particularly for rescuing sleep spindle disorders and alleviating cognitive symptoms (e.g., working memory impairment, attention disorders, and learning disabilities).

[0327] 1. A method for reducing thalamocortical hyperactivity in a subject in need thereof, comprising: V3.3 Enhancers (e.g., compounds having the structure of formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb, (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (Iii), (IIj), (III), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IV), (IVa), or (IVb), 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, 57 In some embodiments, the subject is a human. In certain embodiments, the subject has schizophrenia. For example, a method for increasing rebound burst firing in the thalamic reticular nucleus (TRN) of a subject in need thereof can include administering to the subject a Ca V 3.3 may comprise administering an augmenting agent to the subject. In some embodiments, the subject is a human. In certain embodiments, the subject has schizophrenia.

[0328] The present disclosure also provides a method for treating or preventing schizophrenia, or a disease, disorder, or condition related thereto (e.g., cognitive impairment), in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of Ca V 3.3 A method is provided comprising the step of administering to said subject an augmenting agent.

[0329] To treat, prevent, or prevent the recurrence of a disease, disorder, or condition described herein (e.g., schizophrenia, or a disorder or condition related thereto, such as cognitive impairment, reduced sleep spindles, or reduced thalamocortical hyperactivity), a compound or composition of the present disclosure can be administered at least once daily for at least one week. In various embodiments, the composition is administered at least twice daily for at least two days. In certain embodiments, the composition is administered approximately daily, at least daily, twice weekly, once weekly, or monthly. In certain embodiments, the composition of the present invention is administered for several months, e.g., at least two months, at least six months, or at least one year or more. Furthermore, the present invention is suitable for long-term use, which may be particularly beneficial for preventing the recurrence of an infection or for preventing an infection or condition in at-risk or susceptible patients, including immunocompromised patients. This long-term use may include treatment for at least two years, at least three years, at least four years, or even at least five years or more.

[0330] Examples of other drugs that can be used in combination with the compounds described herein include pharmaceuticals for the treatment of schizophrenia or related conditions or disorders. Combination methods can include the use of two (or more) agents, formulated together or separately, as determined appropriate. In one example, two or more drugs are formulated together for simultaneous or near-simultaneous administration of the agents.

[0331] kit In another aspect, the compositions of the present invention comprise a composition disclosed herein (e.g., one or more Ca V3.3 Compositions comprising a potentiator, one or more of the following having the structure of formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb, (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (Iii), (IIj), (III), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IV), (IVa), or (IVb): Compositions containing a number of compounds, 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, 377-3 78, 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, 5 and compositions comprising one or more of the compounds 25-529, 532-541, 543-551, 553-558, 560-570, 573-575, 577-583, 585, and 587-596, and one or more of compounds 1-69, 71-172, 174-176, and 179-255. The packaging or dispenser may include a bottle, tube, spray bottle, or other dispenser. In certain embodiments of the present invention, the compositions are packaged in concentrated form and are diluted to the desired concentration by the end user at the time of use. Typically, in these embodiments, the compositions may be formulated and packaged in a manner suitable for long-term storage to maintain the effectiveness of the compositions.

[0332] synthesis The present disclosure also provides synthetic methods for preparing the active compounds of the present disclosure (e.g., compounds having a structure of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb, (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (Iii), (IIj), (III), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IV), (IVa), or (IVb)), as well as compounds useful as intermediates in the synthetic methods. The method for producing a compound of Formula (I) can be carried out by reacting a compound having a structure of Formula (V):

[0333] [ka]

[0334] (In the formula, Z B1 is independently selected at each occurrence from hydrogen, optionally unsaturated alkyl, halogen, and -Z1, and at least one Z B1 is a coupling group Z1) with a compound having a structure of formula (VI):

[0335] [ka]

[0336] wherein Z2 is a coupling group for coupling with Z1. In some embodiments, one of Z1 or Z2 is a boron-containing coupling moiety (e.g., a dioxaborolane, dioxaborinane, or

[0337] [ka]

[0338] wherein the other of Z1 or Z2 is a halide (e.g., Cl, Br, I). For example, the synthesis method can involve the synthesis of a compound having a structure of formula (I):

[0339] [ka]

[0340] to form a compound having a structure of formula (Va) or (Vb):

[0341] [ka]

[0342] and an intermediate having a structure of formula (VIa):

[0343] [ka]

[0344] wherein Z is a halogen (e.g., Cl, Br, I). In some embodiments, the synthesis method can include coupling an intermediate having a structure of formula (I):

[0345] [ka]

[0346] to form a compound having a structure of formula (Vc) or (Vd):

[0347] [ka]

[0348] wherein Z is a halogen (e.g., Cl, Br, I) with a compound having a structure of formula (VIb):

[0349] [ka]

[0350] The method may include coupling an intermediate having the formula:

[0351] The coupling can be carried out under metal exchange catalyzed coupling conditions, such as Buchwald-Hartwig coupling (e.g., with tBuXPhos, Pd2(dba)3, CuO, and combinations thereof), Negishi coupling, Suzuki coupling, Kumada coupling, or Stille coupling. For example, the intermediates can be reacted in the presence of a metal catalyst under alkaline conditions (e.g., basic conditions generated by an organic or inorganic base in a solvent). In some embodiments, the metal catalyst can be Pd(dppf)Cl2CH2Cl2, Pd(OAc)2, Pd(PPh3)4, Ni(cod2), or Ni(dppf)Cl2. The coupling can be carried out in a solvent selected from toluene, tetrahydrofuran, N,N-dimethylformamide, dioxane, water, and mixtures thereof. Alkaline conditions can be established through the use of a base dissolved in a solvent, where the base can be, for example, sodium carbonate, potassium carbonate, cesium carbonate, potassium carbonate, sodium hydroxide, barium hydroxide, potassium fluoride, cesium fluoride, and sodium tert-butoxide.

[0352] The following examples are put forward so as 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 treatment methods of the present invention, and are not intended to limit the scope of what the inventors regard as their invention. [Example]

[0353] Example 1 High-throughput Ca V 3.3 Enhancement measurements A high-throughput assay for screening compounds was developed that could identify both inhibitors and potentiators (activators). The assay targeted K, an inwardly rectifying potassium channel capable of hyperpolarizing cells to -70 mV. ir 2.3-expressing T-type Ca 2+This inwardly rectifying potassium channel is a type of channel that catalyzes the majority of T-type Ca channels. 2+ It creates a physiological membrane potential available for channel opening. Furthermore, the assay provides a stable and ultrasensitive Ca 2+ A membrane-bound form of the sensor GCaMP6s (GCaMP6s-CAAX) was included. Similar assays are described in their entirety, particularly with regard to high-throughput assay protocols, in Pan, J, et al., Methods Mol Biol 1787 (2018): 235-252 and Baez-Nieto, D, et al., Brain (2017):awab443, which are incorporated herein by reference.

[0354] A schematic of this assay is shown in Figure 1A, and the EC values ​​of representative stimulus responses used for activity analysis are shown. 10 KCl measurement value and EC90 K Cl The results are shown in Figure 1B. Measurements were performed in triplicate and the compounds were incubated with the cells for 1 hour, after which the cells were incubated at EC 10 Load the KCl trigger.

[0355] Table 2 shows the K ir 2.3 EC of various compounds of the present disclosure measured by a Fluorescence Imaging Plate Reader (FLIPR) assay utilizing cell lines and the GCamP6s-CAAX sensor 50 List the following: EC 50 The maximum response (Emax%) was determined by normalizing the response to the maximum response identified for KCl and fitting it to a four-parameter logistic equation to determine the minimum response, maximum response (Emax%), and concentration producing a half-maximal response (EC 50 ), and the slope coefficient of the response curve were determined.

[0356] [Table 2-1]

[0357] [Table 2-2]

[0358]

Table 2-3

[0359]

Table 2-4

[0360]

Table 2-5

[0361]

Table 2-6

[0362]

Table 2-7

[0363]

Table 2-8

[0364]

Table 2-9

[0365]

Table 2-10

[0366]

Table 2-11

[0367]

Table 2-12

[0368]

Table 2-13

[0369]

Table 2-14

[0370]

Table 2-15

[0371]

Table 2-16

[0372]

Table 2-17

[0373]

Table 2-18

[0374]

Table 2-19

[0375]

Table 2-20

[0376]

Table 2-21

[0377]

Table 2-22

[0378] [Table 2-23]

[0379] [Table 2-24]

[0380] [Table 2-25]

[0381] [Table 2-26]

[0382] [Table 2-27]

[0383] Example 2 Electrophysiological testing Three T-type Ca channels were measured using an automated planar patch clamp instrument (Syncropatch 384 PE) that provides a GΩ seal and precise voltage control, as described below and in Andrade, A. et al. Sci. Rep. 6 (2016): 34233, which is incorporated herein by reference in its entirety, particularly with regard to the patch clamp assay protocol. 2+ Channel (Ca V 3.1, Ca V 3.2, and Ca V 3.3) The electrophysiological profile of the stimuli was measured. A schematic diagram of this electrophysiological assay is shown in Figure 2. Electrophysiological parameters, such as voltage-current dependence indicative of ion movement across the membrane, were measured in relation to administration of Compound 131 and Compound 7.

[0384] [ka]

[0385] Figure 3A shows current-voltage measurements associated with administration of Compound 131 compared to DMSO, and Figures 3B-3D show the voltage-dependent activation, current amplitude, and deactivation kinetics for Compound 131, separated for each calcium channel. As can be seen, Compound 131 induces a left-shift voltage-dependent activation, and the current amplitude is significantly higher than that of DMSO. V 3.3 channels (but Ca V 3.1 or Ca V (No increase in 3.2 channels).

[0386] Figure 4A shows the current-voltage relationship measurements associated with administration of Compound 7 compared to DMSO, and Figures 4B-4D show the voltage-dependent activation, current amplitude, and deactivation kinetics for Compound 7, separated for each calcium channel. As can be seen, Compound 7 significantly increased current amplitude relative to the Ca V 3.1 and Ca V 3.3 channels (but Ca V (No increase in 3.2 channels).

[0387] Example 3 Ex vivo measurements: brain slice electrophysiological testing Ex vivo electrophysiological measurements were performed using a mouse brain slice electrophysiological assay, with analysis performed as described in Ghosal, A, et al., Transl Psychiatry 10.1 (2020): 29, which is incorporated herein by reference, particularly with respect to the brain slice electrophysiological assay. Briefly, the experiments measured the number of bursts in thalamic reticular nucleus (TRN) neurons from mouse brain slices exposed to an effective compound. In the experiments described herein, the structure:

[0388] [ka]

[0389] Compound 7, having a pH of 1.0, was measured for burst firing in TRNs. 1 μM of compound 7 was used in the assay. Figure 5A shows measurements of the number of bursts, identified as a large increase in signal observed across all holding potentials of the assay. Figure 5B shows the threshold for rebound bursting, identified by a decrease in the threshold potential for ion currents after administration of compound 7 to TRN neurons. These results suggest that Ca V 3.3 shows that potentiators increase rebound burst firing in the TRN.

[0390] As shown in Example 2, compound 7 has a different mechanism of action (Ca V Ca (due to the addition of 3.1 enhancement) V 3.3 activator, structure:

[0391] [ka]

[0392] Measurements were also performed on Compound 131, which has the following structure: Figure 6A shows the measured burst number, and Figure 6B shows the rebound burst threshold measured in TRN neurons exposed to 5 μM Compound 131. The concentration of each compound measured in the assay was calculated as the EC 50 As can be seen, the Ca V 3.3 activators regulate rebound burst firing in TRNs, even though they exhibit different mechanisms of action on T-type voltage-gated calcium channels.

[0393] Example 4 In vivo pharmacokinetic measurements The relationship between dose and pharmacokinetics was determined for intraperitoneal administration of Compound 57. Compound 57 was administered at 10 mg / kg or 30 mg / kg, and blood, plasma, unbound blood, unbound plasma, and cerebrospinal fluid concentrations were measured over 8 hours. Figure 7 shows the concentrations of each measured parameter. Table 3 shows the maximum brain concentration (C) at each dose. max ), area under the curve after administration (AUC), brain half-life (T1 / 2 ), plasma partition coefficient, and unbound plasma partition coefficient (K puu ) shows that tripling the dose allowed a 5-fold increase in maximum concentration and a 7-fold increase in brain AUC.

[0394] [Table 3]

[0395] Example 5 Ca V 3.3 Behavioral assays in mice administered augmenting agents Ca V 3.3 Knockout mice (Cacna1i - / - (KO) and Cacna1i + / - (Het)) and R1305H mutant knock-in mice (Cacna1i RH / RH (RH / RH) and Cacna1i + / RH (RH Het)) was generated. V The R1305H mutation in 3.3 corresponds to R1346H in the human channel.

[0396] [ka]

[0397] Overall, especially Ca V 3.3 Knockout mice and Ca V 3.3 Regarding the generation of RH knock-in mice, mice were generated as described in Ghosal et al. Translational Psychiatry 10 (2020): 29, which is incorporated herein by reference.

[0398] Test wild-type (WT), knockout, and knockin mice were subjected to a social interaction assay. Figure 8A shows a schematic diagram of the social interaction assay in mice. Briefly, mice were habituated in a three-chamber apparatus. After habituation, a cup was placed in the outermost chamber, and an unknown WT mouse matched in age, sex, and strain was placed under one of the cups. The social index of each test mouse was monitored as the ratio of the time each test mouse spent in proximity to the mouse under the cup (mouse-object / total time). Figure 8B shows the Ca V 3.3 Social index ratios of knockout mice (Het and KO) compared with littermate control mice (WT). Both heterozygous (Het) and homozygous (KO) knockout mice showed significantly reduced social index scores compared with WT controls. Figure 8C shows the Ca V 3.3 Social index scores of RH knockin mice (Het and KO) are shown in comparison with littermate control mice (WT). Both heterozygous (RH Het) and homozygous (RH / RH) RH knockin mice showed significantly reduced social index scores compared to WT controls. Furthermore, homozygous RH knockin mice showed significantly reduced social index scores compared to heterozygous RH knockin mice.

[0399] Test wild-type (WT), knockout, and knockin mice were also subjected to a novel object recognition assay. A schematic diagram is shown in Figure 8D. Briefly, mice were habituated to two identical objects (identified as boxes in Figure 8D) in a room. After 10 minutes of habituation, one of the familiar objects was replaced with a novel object (identified as a star in Figure 8D). The discrimination ratio was assessed as the difference in the time the mouse spent between the novel object (star) and the familiar object (box). Figure 8E shows the discrimination ratio of homozygous knockout (KO) mice, which is statistically different from WT. Figure 8F shows the discrimination ratio of RH knockin mice, which is statistically different from WT for both homozygous (RH / RH) and heterozygous (RH Het) mice.

[0400] Social interaction assays were performed on mice that received intraperitoneal (IP) administration of Compound 57 at 3 mg / kg, 10 mg / kg, or 30 mg / kg 60 min before habituation began. A schematic diagram of the assay protocol is shown in Figure 9A. Figure 9B compares the social index ratio measurements of heterozygous knockout mice, demonstrating that intraperitoneal administration of 10 mg / kg of Compound 57 significantly rescued the social index ratio. Figure 9B compares the social index ratio measurements of homozygous RH knockin mice (RH homo), demonstrating that administration of 10 mg / kg of Compound 57 significantly rescued the social index ratio. Figure 9D compares the social index ratios of each homozygous knockout mouse (KO / KO).

[0401] Novel object assays were also performed on mice that received intraperitoneal administration of Compound 57 at 3 mg / kg, 10 mg / kg, or 30 mg / kg 60 min prior to habituation. Figure 10A shows a schematic diagram of the assay protocol. Figure 10B compares the discrimination ratios of RH heterozygous knock-in mice (RH het), demonstrating a statistically significant rescue of the discrimination ratio at 30 mg / kg. Figure 10C compares the discrimination ratios of homozygous knock-out mice (KO hom). Basal locomotor activity was also measured in wild-type mice treated with each test concentration. Compound 57 administration at each concentration had no effect on basal locomotor activity beyond 80 min post-administration (Figure 10D).

[0402] A novel object recognition assay was also performed on 5xFAD heterozygous mice. 5xFAD heterozygous mice exhibited progressive neuronal loss accompanied by amyloid deposition, gliosis, and cognitive and motor impairments, recapitulating many features of human Alzheimer's disease (AD). A schematic diagram of the novel visual recognition assay is shown in Figure 11A. Sixty minutes before habituation, 5xFAD mice were administered 3 mg / kg, 10 mg / kg, or 30 mg / kg of Compound 57 by intraperitoneal injection. Figure 11B compares the discrimination ratios of these mice, demonstrating that the higher dose (30 mg / kg being the most effective dose) rescued the loss of object recognition in 5xFAD mice.

[0403] Example 6 Effect on spindle density Wild-type mice, homozygous RH knock-in (R1305H / R1305H) mice, and homozygous Ca V 3.3 Knockout (Ca V Mouse electroencephalography (EEG) measurements were performed on 3.3 KO / KO mice. Figure 12A shows a schematic diagram of the electrode placement for these measurements, showing one electrode placed in the frontal cortex (EEG2), one electrode placed in the parietal cortex (EEG1), the reference electrode placement, the ground electrode placement, and the electrode placement for electromyography (EMG). Mice were placed in a soundproof EEG chamber and recording apparatus as shown in Figure 12B. Figure 12C shows the administration paradigm. Mice were recorded for 12 hours during the light (sleep) cycle. Mice were first acclimated to the chamber and recording apparatus. Following one baseline recording day, mice were recorded for one day after intraperitoneal administration of vehicle, 3 mg / kg of Compound 57 intraperitoneally the next day, 10 mg / kg of Compound 57 intraperitoneally the next day, and 30 mg / kg of Compound 57 intraperitoneally the next day. The spindle density measured for each mouse was shown in Figure 12D (wild-type mice), Figure 12E (R1305H homozygous knock-in mice), and Figure 12F (Ca VAs can be seen from the figure, compound 57 increased the density of 11 Hz sleep spindles in WT male mice at 30 mg / kg. Similar effects were observed in R1305H homozygous knock-in mice at 10 mg / kg and 30 mg / kg, while Ca V No effect is seen in 3.3 knockout mice. These data demonstrate that the measurement protocol allows for the evaluation of compound treatments for disorders associated with spindle dysfunction.

[0404] Example 7 Compound synthesis The compounds of the present disclosure were synthesized as follows.

[0405] 4-[5-fluoro-2-methyl-4-(1-methyl-1H-pyrazol-4-yl)benzenesulfonyl]-1,5-dimethyl-1,2,3,4-tetrahydroquinoxaline (Broad_P_Cav3.3_303, Compound 1)

[0406] [ka]

[0407] To a stirred solution of 4-(4-bromo-5-fluoro-2-methylbenzenesulfonyl)-1,5-dimethyl-1,2,3,4-tetrahydroquinoxaline (0.95 g, 2.29 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (570 mg, 2.74 mmol) in 1,4-dioxane (6 mL), potassium carbonate (948 mg, 6.86 mmol) was added at room temperature, and the reaction mixture was degassed with argon for 20 minutes. After that, palladium(2+) bis(cyclopenta-1,3-dien-1-yldiphenylphosphane)methylene chloride iron dichloride (187 mg, 0.229 mmol) was added at room temperature, and the reaction mixture was heated at 100 °C for 6 hours. After completion, the reaction mixture was poured into water (40 mL) and extracted with EtOAc (3 × 30 mL). The organic layer was washed with brine solution (2 × 10 mL), dried over NaSO, and evaporated. The residue was purified by Biotage (50:1 CHCl / MeOH; 12S column) to give 4-[5-fluoro-2-methyl-4-(1-methyl-1H-pyrazol-4-yl)benzenesulfonyl]-1,5-dimethyl-1,2,3,4-tetrahydroquinoxaline (0.85 g, 89.5% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 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]+.

[0408] (3S)-5-Fluoro-3,7-dimethyl-1-[[4-methyl-6-(4-methylimidazol-1-yl)-3-pyridyl]sulfonyl]indoline and (3R)-5-Fluoro-3,7-dimethyl-1-[[4-methyl-6-(4-methylimidazol-1-yl)-3-pyridyl]sulfonyl]indoline (Broad_P_CaV3.3_673A and B) (Compound 2 and Compound 39)

[0409] [ka]

[0410] To a mixture of 1-[(6-bromo-4-methyl-3-pyridyl)sulfonyl]-5-fluoro-3,7-dimethyl-indoline (0.20 g, 0.501 mmol, 1.00 equiv.), 4-methyl-1H-imidazole (0.16 g, 2.00 mmol, 4.00 equiv.), and KPO (0.21 g, 1.00 mmol, 2.00 equiv.) in 1,4-dioxane (4 mL) was added tBuXPhos (0.043 g, 0.100 mmol, 0.200 equiv.) and Pd(dba) (0.046 g, 0.0501 mmol, 0.100 equiv.), and the mixture was degassed with argon for 15 min. The reaction mixture was then heated at 120 °C for 16 h. Upon completion, the reaction mixture was diluted with water (100 mL) and extracted into ethyl acetate (100 mL x 3). The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica column chromatography using 60%-80% ethyl acetate in hexane. The product fraction was evaporated under reduced pressure and purified by preparative HPLC using a Sunfire C8 (250*19) mm, 5μ column in 30%-45% acetonitrile in water with 0.1% formic acid as a modifier as the mobile phase. The product fraction was lyophilized to give the racemic mixture (Broad_P_CaV3.3_673). The racemic mixture was further purified by chiral preparative HPLC using a CHIRALCEL OX-H (250*21.0) mm, 5μ column in 25% IPA:ACN (70:30) with 0.1% DEA in hexane with 0.1% DEA as the mobile phase. The product fractions were evaporated under reduced pressure to give an off-white solid of Broad_P_CaV3.3_673B (27 mg, 14% yield) and an off-white solid of Broad_P_CaV3.3_673A (14 mg, 7% yield). 1H NMR (400 MHz, DMSO-d6) δ 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]+.

[0411] 1-[(6-bromo-4-methyl-3-pyridyl)sulfonyl]-5-fluoro-3,7-dimethyl-indoline

[0412] [ka]

[0413] To a solution of 5-fluoro-3,7-dimethyl-indoline (0.20 g, 1.21 mmol, 1.00 equiv.) in dichloromethane (5 mL), 6-bromo-4-methyl-pyridine-3-sulfonyl chloride (491 mg, 1.82 mmol, 1.50 equiv.) and pyridine (0.49 mL, 6.05 mmol, 5.00 equiv.) were added dropwise, and the reaction mixture was stirred at room temperature for 24 h. Upon completion, the reaction mixture was diluted with water (100 mL) and extracted into dichloromethane (100 mL x 3). The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica column chromatography using 1% to 2% ethyl acetate in hexane. Evaporation of the product fractions under reduced pressure afforded Int-1403 (0.25 g, 0.545 mmol, 45% yield), a brown semi-solid. MS (ESI): 401.4 [M+H]+.

[0414] 5-Fluoro-3,7-dimethyl-indoline

[0415] [ka]

[0416] To a solution of 5-fluoro-3,7-dimethyl-1H-indole (600 mg, 3.68 mmol, 1.00 equiv.) in acetic acid (6 mL) at 0 °C, sodium cyanoborohydride (693 mg, 11.0 mmol, 3.00 equiv.) was added portionwise, and the reaction mixture was stirred at room temperature for 16 hours. Upon completion, the reaction mixture was quenched with ice-cold water (150 mL), and the product was extracted into ethyl acetate (100 mL × 3). The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give a residue. The residue was purified by silica column chromatography using 5% ethyl acetate in hexane. The product fractions were evaporated under reduced pressure to give Int-1403 as a yellow oil (500 mg, 2.38 mmol, 65% yield). MS (ESI): 166.0 [M+H]+

[0417] 5-Fluoro-3,7-dimethyl-1H-indole

[0418] [ka]

[0419] To a solution of 5-fluoro-7-methyl-1H-indole-3-carbaldehyde (800 mg, 4.52 mmol, 1.00 equiv.) in tetrahydrofuran (25 mL) was added lithium aluminum hydride solution (1 M in tetrahydrofuran, 11.29 mL, 11.3 mmol, 2.50 equiv.) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. Upon completion, the reaction mixture was quenched with 2 mL of water and 5 mL of 2 M aqueous sodium hydroxide solution. The reaction mixture was filtered through Celite and washed with ethyl acetate (50 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give a residue. The residue was purified by silica column chromatography using 10%-20% ethyl acetate in hexane. Evaporation of the product fractions under reduced pressure gave Int-1388 (600 mg, 3.51 mmol, 78% yield), a brown semi-solid. MS(ESI): 162.0 [MH]-

[0420] 5-Fluoro-7-methyl-1H-indole-3-carbaldehyde

[0421] [ka]

[0422] To a solution of 5-fluoro-7-methyl-1H-indole (1.00 g, 6.70 mmol, 1.00 equiv.) in N,N-dimethylformamide (2.58 mL, 33.5 mmol, 5.00 equiv.) was added phosphorus(V) oxychloride (0.75 mL, 8.05 mmol, 1.20 equiv.) dropwise at 0 °C, and the reaction mixture was allowed to warm to room temperature and stirred for 2 h. Upon completion, the reaction mixture was quenched with ice-water (30 mL) and basified with 2 M aqueous sodium hydroxide. The resulting brown solid was filtered, washed with water (100 mL), and evaporated under reduced pressure to give Int-1387 (800 mg, 4.30 mmol, 64% yield). MS (ESI): 178.2 [M+H]+

[0423] 5-Fluoro-7-methyl-1H-indole

[0424] [ka]

[0425] A mixture of 7-bromo-5-fluoro-1H-indole (2.00 g, 9.34 mmol, 1.00 equiv.), methylboronic acid (839 mg, 14.0 mmol, 1.50 equiv.), and cesium carbonate (9134 mg, 28.0 mmol, 3.00 equiv.) in 1,4-dioxane (20 mL) was degassed for 5 minutes, and the reaction mixture was added with [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (763 mg, 0.934 mmol, 0.100 equiv.) and heated at 100 °C for 16 hours. Upon completion, the reaction mixture was diluted with water (150 mL), and the product was extracted into ethyl acetate (100 mL × 3). The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give a residue. The residue was purified by silica column chromatography using 10% ethyl acetate in hexane. The product fractions were evaporated in vacuo to give Int-1386 as a brown semi-solid (1.00 g, 6.70 mmol, 72% yield). 1H NMR (400 MHz, DMSO-d6) δ 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).

[0426] 7-Bromo-5-fluoro-1H-indole

[0427] [ka]

[0428] To a solution of 2-bromo-4-fluoro-1-nitro-benzene (3.00 g, 13.6 mmol, 1.00 equiv.) in tetrahydrofuran (30 mL) was added vinylmagnesium bromide (1 M in tetrahydrofuran, 68.18 mL, 68.2 mmol, 5.00 equiv.) at -70°C, and the reaction mixture was stirred for 1 hour. Upon completion, the reaction mixture was quenched with water (250 mL), filtered through a pad of Celite, and washed with ethyl acetate (100 mL). The organic layer in the filtrate was dried over sodium sulfate and evaporated under reduced pressure to give a residue. The residue was purified by silica column chromatography using 10% ethyl acetate in hexane. The product fractions were evaporated under reduced pressure to give Int-1385 as a brown oil (1.50 g, 6.93 mmol, 51% yield). MS(ESI): 212.0 [MH]-

[0429] Synthesis scheme of Broad_P_CaV3.3_565 (compound 3)

[0430] [ka]

[0431] tert-Butyl (2-((4-bromo-2-methylphenyl)sulfonamido)-3-methylphenyl)carbamate: Intermediate 1

[0432] [ka]

[0433] To a stirred solution of tert-butyl N-(2-amino-3-methyl-phenyl)carbamate (2.80 g, 12.6 mmol, 1.00 equiv.) and pyridine (5.09 mL, 63.0 mmol, 5.00 equiv.) in dichloromethane (30 mL) was added 4-bromo-2-methyl-benzenesulfonyl chloride (5.09 g, 18.9 mmol, 1.50 equiv.) at room temperature. The reaction mixture was stirred at the same temperature for 16 hours. Upon completion, the reaction was quenched with water and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine solution (2 × 50 mL), dried over NaSO, and evaporated. The residue was purified by silica gel column chromatography using (8% ethyl acetate:hexane) as the mobile phase to give 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. 1 H NMR (400 MHz, DMSO-d6) δ 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] +

[0434] tert-Butyl 4-((4-bromo-2-methylphenyl)sulfonyl)-5-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate: Intermediate 2

[0435] [ka]

[0436] 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 equiv.) and 1,2-dibromoethane (0.71 mL, 7.91 mmol, 1.20 equiv.) in DMF (20 mL) was added KCO (3.64 g, 26.4 mmol, 4.00 equiv.) 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 × 50 mL). The combined organic layers were washed with brine solution (2 × 50 mL), dried over NaSO, and evaporated under reduced pressure to give 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 a yellow solid. MS(ESI): 427.2 [M-56]+ 1H NMR (400 MHz, DMSO-d6) δ 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).

[0437] 1-((4-Bromo-2-methylphenyl)sulfonyl)-8-methyl-1,2,3,4-tetrahydroquinoxaline: Intermediate 3

[0438] [ka]

[0439] 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 equiv.) in dichloromethane (30 mL) was added HCl 1,4-dioxane solution (4 M in dioxane, 20 mL, 80.0 mmol, 12.4 equiv.) at 0 °C. The reaction mixture was stirred at room temperature. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was stripped three to four times with n-hexane, and the solid was dried under reduced pressure to give 4-(4-bromo-2-methyl-phenyl)sulfonyl-5-methyl-2,3-dihydro-1H-quinoxaline; hydrochloride salt (2.60 g, 5.85 mmol, 91% yield) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ 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 D2O (400 MHz, DMSO-d6) δ 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]+.

[0440] 4-((4-Bromo-2-methylphenyl)sulfonyl)-5-methyl-1-(methyl-d3)-1,2,3,4-tetrahydroquinoxaline: Intermediate 4

[0441] [ka]

[0442] To a stirred solution of 4-(4-bromo-2-methyl-phenyl)sulfonyl-5-methyl-2,3-dihydro-1H-quinoxaline (500 mg, 1.31 mmol, 1.00 equiv) and CD3I (1521 mg, 10.5 mmol, 8.00 equiv) in DMF (5 mL) was added K2CO3 (724 mg, 5.25 mmol, 4.00 equiv) at room temperature. The reaction mixture was heated at 80 °C. Upon completion, the reaction mixture was poured into ice-cold water (50 mL) (brown solid by-product), filtered, and dried. Purification was achieved by column chromatography in 4% ethyl acetate:hexanes eluting to give the desired 4-(4-bromo-2-methyl-phenyl)sulfonyl-5-methyl-1-(trideuteriomethyl)-2,3-dihydroquinoxaline (370 mg, 0.901 mmol, 69% yield) as a white solid. MS(ESI): 398.2 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 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).

[0443] 5-Methyl-1-(methyl-d3)-4-((2-methyl-4-(4-methyl-1H-imidazol-1-yl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoxaline (Compound 3)

[0444] [ka]

[0445] A stirred suspension of 4-(4-bromo-2-methyl-phenyl)sulfonyl-5-methyl-1-(trideuteriomethyl)-2,3-dihydroquinoxaline (330 mg, 0.828 mmol, 1.00 equiv.), 4-methyl-1H-imidazole (204 mg, 2.49 mmol, 3.00 equiv.), and potassium tert-butoxide (283 mg, 2.49 mmol, 3.00 equiv.) in DMF (10 mL) was degassed with nitrogen gas for 15 minutes. After 15 minutes, CuO (24 mg, 0.166 mmol, 0.200 equiv.) was added and heated to 80 °C. The progress of the reaction was monitored by TLC using 60% ethyl acetate:hexane as the mobile phase. Upon completion, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with brine solution (3 × 70 mL). The organic layer was dried over NaSO and evaporated under reduced pressure. The residue was purified by Combiflash using (80% ethyl acetate:hexane) as the mobile phase to give an impure product, which was then repurified by preparative HPLC in (A) water containing 0.1% FA and (B) 100% ACN as the mobile phase to give 5-methyl-4-[2-methyl-4-(4-methylimidazol-1-yl)phenyl]sulfonyl-1-(trideuteriomethyl)-2,3-dihydroquinoxaline (6.7 mg, 0.0159 mmol, 2% yield) as a brown solid. MS(ESI): 400.06 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 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).

[0446] 1,5-Dimethyl-4-[2-methyl-4-(2-methyl-1,3-oxazol-5-yl)benzenesulfonyl]-1,2,3,4-tetrahydroquinoxaline (Broad_P_Cav3.3_313, compound 4)

[0447] [ka]

[0448] To a stirred solution of 4-(4-bromo-2-methylbenzenesulfonyl)-1,5-dimethyl-1,2,3,4-tetrahydroquinoxaline (200 mg, 0.5059 mmol), 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) was added at room temperature. The reaction mixture was degassed with argon for 20 minutes, after which palladium(2+) bis(cyclopenta-1,3-dien-1-yldiphenylphosphane)methylene chloride iron dichloride (41.3 mg, 0.05059 mmol) was added at room temperature, and the reaction mixture was heated at 100 °C for 7 hours. After completion, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (3 × 30 mL). The organic layer was washed with brine solution (2 × 20 mL), dried over NaSO, and evaporated. The product was applied to a preparative HPLC column and eluted with a gradient of 35–40% ACN in water containing 0.1% formic acid to give 1,5-dimethyl-4-[2-me] (45 mg, 22.0% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 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]+.

[0449] 4-[2-fluoro-6-methyl-4-(1-methyl-1H-pyrazol-4-yl)benzenesulfonyl]-1,5-dimethyl-1,2,3,4-tetrahydroquinoxaline (Broad_P_Cav3.3_302, compound 5)

[0450] [ka]

[0451] To a stirred solution of 4-(4-bromo-2-fluoro-6-methylbenzenesulfonyl)-1,5-dimethyl-1,2,3,4-tetrahydroquinoxaline (0.8 g, 1.93 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (480 mg, 2.31 mmol), potassium carbonate (800 mg, 5.79 mmol) in 1,4-dioxane (8 mL) was added at room temperature, and the reaction mixture was degassed with argon for 20 minutes. After that, palladium(2+) bis(cyclopenta-1,3-dien-1-yldiphenylphosphane)methylene chloride iron dichloride (157 mg, 0.1930 mmol) was added at room temperature, and the reaction mixture was heated at 100 °C for 6 hours. After completion, the reaction mixture was poured into water (40 mL) and extracted with EtOAc (3 × 30 mL). The organic layer was washed with brine solution (2 × 10 mL), dried over NaSO, and evaporated. The residue was purified by Biotage (50:1 CHCl / MeOH; 12S column) to give 4-[2-fluoro-6-methyl]-4-(2-fluoro-6-methyl) ... H NMR (400 MHz, chloroform-d) δ 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].

[0452] 5-Fluoro-4,8-dimethyl-1-[2-methyl-4-(1-methyl-1H-pyrazol-4-yl)benzenesulfonyl]-1,2,3,4-tetrahydroquinoxaline (Broad_P_Cav3.3_299, compound 6)

[0453] [ka]

[0454] To a stirred solution of 1-(4-bromo-2-methylbenzenesulfonyl)-5-fluoro-4,8-dimethyl-1, (0.04 g, 0.09677 mmol, 1 equiv.) in dioxane (4 mL) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- (0.024 mg, 0.0001153 mmol, 0.001 equiv.) and potassium carbonate (13.3 mg, 0.09677 mmol, 1.0 equiv.) at room temperature. The reaction mixture was degassed with argon for 20 minutes, after which palladium(2+) bis(cyclopentyldiphenylphosphane)methylene ch (80.0 mg, 0.09677 mmol, 1.0 equiv.) was added at room temperature and the reaction mixture was heated at 80 °C for 16 h. Upon completion, the reaction mixture was poured into water (25 mL) and extracted with EtOAc (3 × 25 mL). The organic layer was washed with brine solution (2 × 10 mL), dried over NaSO, and evaporated. The product was applied to a preparative HPLC column and eluted with a gradient of 35–70% ACN in water containing 0.1% formic acid to give 5-fluoro-4,8-dimethyl-1-[2-methyl-4-(1-methyl-1H-pyrazole-4-yl)-y] (0.00568 g, 14.1% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ2.10 (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).

[0455] 1,5-Dimethyl-4-[2-methyl-4-(1-methyl-1H-pyrazol-4-yl)benzenesulfonyl]-1,2,3,4-tetrahydroquinoxaline (Broad_P_CaV3.3_259, compound 7)

[0456] [ka]

[0457] To a stirred solution of 8-methyl-1-[2-methyl-4-(1-methyl-1H-pyrazol-4-yl)benzenesulf (0.17 g, 444 μmol, 1 equiv.) in dichloromethane (5 mL) was added triethylamine (89.8 mg, 888 μmol, 2 equiv.) and methyl iodide (75.5 mg, 532 μmol, 1.2 equiv.) at room temperature, and the reaction mixture was stirred at room temperature for 12 h. After completion, the reaction mixture was poured into water (50 mL) and extracted with DCM (3 × 50 mL). The organic layer was washed with brine solution (2 × 10 mL), dried over NaSO, and evaporated. The crude product was purified by flash chromatography using [0–50% EtOAc / hexane] to give an impure product, which was further purified by preparative HPLC using (0.5–70% ACN in water with 0.1% formic acid as a modifier) ​​as the mobile phase to give 1,5-dimethyl-4-[2-methyl-4-(1-methyl-1H-pyrazol-4-yl)benzene] (0.004 g, 3% yield) as a white solid. 1H NMR (400 MHz, chloroform-d) δ 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).

[0458] 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)

[0459] [ka]

[0460] To a stirred solution of 1,5-dimethyl-4-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonyl]-1,2,3,4-tetrahydroquinoxaline (100 mg, 0.2260 mmol), 5-bromo-2-methyl-1,3-thiazole (48.2 mg, 0.2712 mmol) in 1,4-dioxane (3 mL) and water (0.3 mL) was added potassium carbonate (93.6 mg, 0.6779 mmol) at room temperature. The reaction mixture was degassed with argon for 20 minutes, after which palladium(2+) bis(cyclopenta-1,3-dien-1-yldiphenylphosphane)methylene chloride iron dichloride (18.4 mg, 0.02260 mmol) was added at room temperature, and the reaction mixture was heated at 100 °C for 5 hours. After completion, the reaction mixture was poured into water (30 mL) and extracted with EtOAc (3 × 20 mL). The organic layer was washed with brine solution (2 × 20 mL), dried over NaSO, and evaporated. The product was applied to a preparative HPLC column and eluted with a gradient of 40–50% ACN in water containing 0.1% formic acid to give 1,5-dimethyl-4-[2-me] (44 mg, 47.1% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 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]+.

[0461] Synthesis of compound 9

[0462] [ka]

[0463] 4-[4-(4-ethylimidazol-1-yl)-2-methyl-phenyl]sulfonyl-1,5-dimethyl-2,3-dihydroquinoxaline: (Broad_P_CaV3.3_347, compound 9)

[0464] [ka]

[0465] A stirred solution of 4-(4-bromo-2-methyl-phenyl)sulfonyl-1,5-dimethyl-2,3-dihydroquinoxaline (0.15 g, 0.379 mmol, 1.00 equiv.) and 4-ethyl-1H-imidazole (0.036 g, 0.379 mmol, 1.00 equiv.) in dimethylformamide (5 mL) was degassed with nitrogen gas for 15 minutes. After 15 minutes, copper(I) oxide (0.011 g, 0.0759 mmol, 0.200 equiv.) and potassium tert-butoxide (0.13 g, 1.14 mmol, 3.00 equiv.) were added, and the mixture was heated at 150 °C in a sealed tube for 96 hours. After 96 hours, the reaction mixture was poured into cold water (50 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were dried over NaSO and evaporated. The residue was purified by Combiflash using ethyl acetate:hexane (1:1) as the mobile phase to give 4-[4-(4-cyclopropylimidazol-1-yl)-2-methyl-phenyl]sulfonyl-1,5-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 1 H NMR (400 MHz, DMSO-d6) δ 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).

[0466] (3S)-5-Fluoro-3,7-dimethyl-1-[2-methyl-4-(4-methylimidazol-1-yl)phenyl]sulfonyl-indoline and (3R)-5-Fluoro-3,7-dimethyl-1-[2-methyl-4-(4-methylimidazol-1-yl)phenyl]sulfonyl-indoline (Broad_P_CaV3.3_661A and B) (Compound 10 and Compound 207)

[0467] [ka]

[0468] To a mixture of 1-(4-bromo-2-methyl-phenyl)sulfonyl-5-fluoro-3,7-dimethyl-indoline (250 mg, 0.628 mmol, 1.00 equiv.), 4-methylimidazole (206 mg, 2.51 mmol, 4.00 equiv.), and potassium tert-butoxide (211 mg, 1.88 mmol, 3.00 equiv.) in dimethylformamide (5 mL) was added copper(I) oxide (45 mg, 0.314 mmol, 0.500 equiv.), 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 into ethyl acetate (100 mL x 3). The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica column chromatography using 60%-80% ethyl acetate in hexane. The product fractions were evaporated under reduced pressure and purified by preparative HPLC using a Phenomenex C8 (250*21.2) mm, 5μ column in 30%-45% acetonitrile in water with 0.1% formic acid as a modifier. The product fractions were lyophilized to give the racemic mixture (Broad_P_CaV3.3_661). The racemic mixture was further purified by chiral preparative HPLC using a CHIRALCEL OX-H (250*21.0) mm, 5μ column in 40% hexane with 0.1% DEA in IPA:ACN (70:30) with 0.1% DEA as the mobile phase. The product fractions were evaporated under reduced pressure to give a light brown solid of Broad_P_CaV3.3_661A (19 mg, 0.0486 mmol, 100% purity, 8% yield) and a 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) δ 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) δ 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]+.

[0469] Synthesis of Compound 5 and Compound 134

[0470]

change

[0471] N-(3-フルオロ-2-メチル-フェニル)アセトアミド: Intermediate 790

[0472]

change

[0473] To a solution of 3-fluoro-2-methyl-aniline (7.00 g, 55.9 mmol, 1.00 equiv.) in dichloromethane (70 mL) was added acetic anhydride (7.92 mL, 83.9 mmol, 1.50 equiv.) dropwise at 0 °C, and the mixture was stirred at room temperature for 2 h. After 2 h, the mixture was quenched with cold water (500 mL) and extracted with MDC (2 × 60 mL). The organic layer was dried over Na2SO4 and evaporated. The residue was purified by Biotage (20:1 Hex / EtOAc; 12S column) to give N-(3-fluoro-2-methyl-phenyl)acetamide Broad_P_CaV3.3_400_Int_790 (8.20 g, 47.5 mmol, 85% yield, 16.4% yield) as a light yellow solid. MS: [M+H] + 167.18.

[0474] (2-Acetamido-4-fluoro-3-methyl-phenyl)-hydroxy-oxo-ammonium: Intermediate 791

[0475] [ka]

[0476] To a solution of N-(3-fluoro-2-methyl-phenyl)acetamide (8.20 g, 47.5 mmol, 1.00 equiv.) in sulfuric acid (3.8 mL, 71.2 mmol, 1.50 equiv.) was added nitric acid (5.94 mL, 142 mmol, 3.00 equiv.) dropwise at −5°C, and the mixture was stirred at that temperature for 1 h. The reaction was quenched with water (30 mL) to form a solid product, which was filtered. The solid product afforded (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.

[0477] (2-Amino-4-fluoro-3-methyl-phenyl)-hydroxy-oxo-ammonium: Intermediate 792

[0478] [ka]

[0479] A solution of (2-acetamido-4-fluoro-3-methyl-phenyl)-hydroxy-oxo-ammonium (7.00 g, 32.8 mmol, 1.00 equiv.) in tetrahydrofuran (35 mL) was added to a solution of sodium hydroxide (2.63 g, 65.7 mmol, 2.00 equiv.) in water (35 mL) at 0 °C, and the resulting mixture was stirred at room temperature for 5 h. The reaction mixture was diluted with water (50 mL), acidified with dilute HCl (20 mL), and extracted with EtOAc (3 × 120 mL). The organic layer was dried over Na2SO4 and evaporated. The residue was purified by Biotage (5:1 Hex / EtOAc; 12S column) to give (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 a brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 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).

[0480] 4-Fluoro-3-methyl-benzene-1,2-diamine: Intermediate 792A

[0481] [ka]

[0482] A solution of (2-amino-4-fluoro-3-methyl-phenyl)-hydroxy-oxo-ammonium (2.50 g, 14.6 mmol, 1.00 equiv.) in acetic acid (25 mL) was added to zinc dust (5.73 g, 87.6 mmol, 6.00 equiv.) in several portions at 25 °C, and the resulting mixture was stirred at room temperature for 6 h. The reaction mixture was diluted with water (30 mL), adjusted to pH 7 with sodium bicarbonate solution, and then extracted with EtOAc (3 × 30 mL). The organic layer was dried over Na2SO4 and evaporated. The residue was purified by Biotage (8:2 Hex / EtOAc; 24S column) to give 4-fluoro-3-methyl-benzene-1,2-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

[0483] tert-Butyl N-(2-amino-4-fluoro-3-methyl-phenyl)carbamate: Intermediate 793

[0484] [ka]

[0485] A solution of 4-fluoro-3-methyl-benzene-1,2-diamine (1.30 g, 7.51 mmol, 1.00 equiv.) in dichloromethane (10 mL) was added to triethylamine (1.05 mL, 7.51 mmol, 1.00 equiv.) at 0° C., followed by di-tert-butyl dicarbonate (0.86 mL, 3.76 mmol, 0.500 equiv.) at 0° C. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×20 mL). The organic layer was dried over Na2SO4 and evaporated. The residue was purified by Biotage (5:1 Hex / EtOAc; 12S column) to give 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. 1 H NMR (400 MHz, DMSO-d6) δ 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).

[0486] tert-Butyl N-[2-[(4-bromo-2-fluoro-6-methyl-phenyl)sulfonylamino]-4-fluoro-3-methyl-phenyl]carbamate: Intermediate 794

[0487] [ka]

[0488] A solution of tert-butyl N-(2-amino-4-fluoro-3-methyl-phenyl)carbamate (1.10 g, 4.58 mmol, 1.00 equiv.) in dichloromethane (10 mL) was added to pyridine (1.48 mL, 18.3 mmol, 4.00 equiv.) at room temperature, followed by the addition of 5-bromo-1-fluoro-3-methyl-2-methylsulfonyl-benzene (3.67 g, 13.7 mmol, 3.00 equiv.), and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 20 mL). The organic layer was dried over Na2SO4 and evaporated. The residue was purified by Biotage (8:2 Hex / EtOAc; 12S column) to give 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.

[0489] N-(6-amino-3-fluoro-2-methyl-phenyl)-4-bromo-2-fluoro-6-methyl-benzenesulfonamide: Intermediate 794A

[0490] [ka]

[0491] 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 equiv.) in dichloromethane (5 mL) was added to a 4.0 M solution of hydrogen chloride in dioxane (5 mL, 1.77 mmol, 1.00 equiv.) at 0 °C, and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (10 mL) and extracted with MDC (3 × 20 mL). The organic layer was dried over Na2SO4 and evaporated. The residue was purified by Biotage (8:2 Hex / EtOAc; 12S column) to give N-(6-amino-3-fluoro-2-methyl-phenyl)-4-bromo-2-fluoro-6-methyl-benzenesulfonamide (Broad_P_CaV3.3_400_Int_794A) (0.60 g, 1.53 mmol, 87% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 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).

[0492] 4-(4-Bromo-2-fluoro-6-methyl-phenyl)sulfonyl-6-fluoro-5-methyl-2,3-dihydro-1H-quinoxaline: Intermediate 795

[0493] [ka]

[0494] A solution of N-(6-amino-3-fluoro-2-methyl-phenyl)-4-bromo-2-fluoro-6-methyl-benzenesulfonamide (0.60 g, 1.53 mmol, 1.00 equiv.) in dimethylformamide (10 mL) was added to potassium carbonate (0.42 g, 3.07 mmol, 2.00 equiv.) at 25 °C, followed by the addition of 1,2-dibromoethane (0.16 mL, 1.84 mmol, 1.20 equiv.), and the resulting mixture was stirred at 100 °C for 3 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 25 mL). The organic layer was dried over Na2SO4 and evaporated. The residue was purified by Biotage (8:2 Hex / EtOAc; 12S column) to give 4-(4-bromo-2-fluoro-6-methyl-phenyl)sulfonyl-6-fluoro-5-methyl-2,3-dihydro-1H-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.

[0495] 6-Fluoro-4-[2-fluoro-6-methyl-4-(1-methylpyrazol-4-yl)phenyl]sulfonyl-5-methyl-2,3-dihydro-1H-quinoxaline: Broad_P_CaV3.3_453, compound 134

[0496] [ka]

[0497] A stirred suspension of 4-(4-bromo-2-fluoro-6-methyl-phenyl)sulfonyl-6-fluoro-5-methyl-2,3-dihydro-1H-quinoxaline (0.45 g, 0.927 mmol, 1.00 equiv.), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (0.29 g, 1.39 mmol, 1.50 equiv.), and potassium carbonate (0.38 g, 2.78 mmol, 3.00 equiv.) in 1,4-dioxane (8 mL) and water (2 mL) was degassed with nitrogen gas for 15 minutes. After 15 minutes, (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (0.014 g, 0.0185 mmol, 0.0200 equiv.) was added thereto and heated at 100°C for 4 hours. After 4 hours, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The organic layer was dried over NaSO and evaporated. The residue was purified by Biotage (5:1 Hex / EtOAc; 12S column) to give impure product, which was further purified by preparative HPLC using (25-70% ACN in water with 5 mM ammonium carbonate and 0.1% ammonia in water as modifier) ​​as the mobile phase to give 6-fluoro-4-[2-fluoro-6-methyl-4-(1-methylpyrazol-4-yl)phenyl]sulfonyl-5-methyl-2,3-dihydro-1H-quinoxaline 4-(4-bromo-2-fluoro-6-methyl-phenyl)sulfonyl-6-fluoro-5-methyl-2,3-dihydro-1H-quinoxaline (0.45 g, 0.927 mmol) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 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.

[0498] 6-Fluoro-4-[2-fluoro-6-methyl-4-(1-methylpyrazol-4-yl)phenyl]sulfonyl-1,5-dimethyl-2,3-dihydroquinoxaline: Broad_P_CaV3.3_400, compound 5

[0499] [ka]

[0500] A solution of 6-fluoro-4-[2-fluoro-6-methyl-4-(1-methylpyrazol-4-yl)phenyl]sulfonyl-5-methyl-2,3-dihydro-1H-quinoxaline (0.22 g, 0.519 mmol, 1.00 equiv.), dimethylformamide (5 mL), and methyl iodide (0.04 mL, 0.622 mmol, 1.20 equiv.) was stirred at 100° C. for 3 hours. After completion of the reaction, the reaction mixture was quenched in water (5 mL) and extracted with ethyl acetate (3×10 mL). The organic layer was dried over NaSO and evaporated. The residue was purified by Biotage (5:1 Hex / EtOAc; 12S column) to give an impure product, which was further purified by preparative HPLC using a mobile phase (25-70% ACN in water with 5 mM ammonium carbonate and 0.1% ammonia in water as a modifier) ​​to give 6-fluoro-4-[2-fluoro-6-methyl-4-(1-methylpyrazol-4-yl)phenyl]sulfonyl-1,5-dimethyl-2,3-dihydroquinoxaline Broad_P_CaV3.3_400 (0.014 g, 0.0301 mmol, 6% yield) as an off-white solid. MS:[M+H]+ 361.0. 1H NMR (400 MHz, DMSO-d6) δ 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).

[0501] 4-[4-(5-fluoro-1-methyl-1H-pyrazol-4-yl)-2-methylbenzenesulfonyl]-1,5-dimethyl-1,2,3,4-tetrahydroquinoxaline (Broad_P_Cav3.3_309, compound 12)

[0502] [ka]

[0503] To a stirred solution of 1,5-dimethyl-4-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonyl]-1,2,3,4-tetrahydroquinoxaline (90 mg, 0.2034 mmol), 4-bromo-5-fluoro-1-methyl-1H-pyrazole (43.6 mg, 0.2440 mmol) in 1,4-dioxane (3 mL) and water (0.3 mL) was added potassium carbonate (84.3 mg, 0.6102 mmol) at room temperature. The reaction mixture was degassed with argon for 20 minutes, after which palladium(2+) bis(cyclopenta-1,3-dien-1-yldiphenylphosphane)methylene chloride iron dichloride (16.6 mg, 0.02034 mmol) was added at room temperature and the reaction mixture was heated at 100 °C for 8 hours. After completion, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (3 × 20 mL). The organic layer was washed with brine solution (2 × 20 mL), dried over NaSO, and evaporated. The residue was purified by Biotage (50:1 CHCl / MeOH; 12S column) to give 4-[4-(5-fluoro-1-met) (60 mg, 69.2% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 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]+.

[0504] 1,5-Dimethyl-4-[[4-methyl-6-(4-methylimidazol-1-yl)-3-pyridyl]sulfonyl]-2,3-dihydroquinoxaline (Broad_P_CaV3.3_356, compound 13)

[0505] [ka]

[0506] To a stirred solution of 4-[(6-bromo-4-methyl-3-pyridyl)sulfonyl]-1,5-dimethyl-2,3-dihydroquinoxaline (200 mg, 0.505 mmol, 1.00 equiv.) in DMF (2 mL) was added 4-methylimidazole (83 mg, 1.01 mmol, 2.00 equiv.) at 0 °C and stirred at the same temperature for 30 min. After 30 min, a 60% suspension of sodium hydride in paraffin oil (26 mg, 0.757 mmol, 1.50 equiv.) was added and stirred at room temperature for 16 h. After completion, the reaction mixture was poured into cold water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over NaSO and evaporated. The residue was purified on a Combiflash apparatus using ethyl acetate:hexane (3:7) to give an impure compound, which was further purified by preparative HPLC purification using (25-50% ACN in water with 0.1% formic acid as a modifier) ​​as the mobile phase to give 1,5-dimethyl-4-[[4-methyl-6-(4-methylimidazol-1-yl)-3-pyridyl]sulfonyl]-2,3-dihydroquinoxaline (40 mg, 19.9% ​​yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 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]+.

[0507] 1,5-Dimethyl-4-[[4-methyl-6-(1-methylpyrazol-4-yl)-3-pyridyl]sulfonyl]-3H-quinoxalin-2-one (Broad_P_CaV3.3_407, compound 14)

[0508] [ka]

[0509] A stirred suspension of 4-[(6-bromo-4-methyl-3-pyridyl)sulfonyl]-1,5-dimethyl-3H-quinoxalin-2-one (310 mg, 0.356 mmol, 1.00 equiv.), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (111 mg, 0.534 mmol, 1.50 equiv.), and potassium carbonate (148 mg, 1.07 mmol, 3.00 equiv.) in dioxane (2.8254 mL) was degassed with nitrogen gas for 15 minutes. After 15 minutes, (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (26 mg, 0.0356 mmol, 0.100 equiv.) was added and heated at 100 °C for 16 hours. After 16 h, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The organic layer was dried over NaSO and evaporated. The residue was purified by Biotage (40 / 60 Hex / EtOAc; 12S column) to give an impure product, which was further purified by preparative HPLC using 20–55% ACN in water with 0.1% formic acid in water as a modifier as the mobile phase to give Broad_P_Cav3.3_407 (28 mg, 0.0677 mmol, 19% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 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 MS(ESI): 412.3[M+H]+.

[0510] 4-[(6-chloro-4-methyl-3-pyridyl)sulfonyl]-1,5-dimethyl-3H-quinoxalin-2-one

[0511] [ka]

[0512] To a stirred solution of 4-[(6-chloro-4-methyl-3-pyridyl)sulfonyl]-5-methyl-1,3-dihydroquinoxalin-2-one (350 mg, 0.872 mmol, 1.00 equiv.), potassium carbonate (362 mg, 2.62 mmol, 3.00 equiv.) in DMF (4.385 mL) was added iodomethane (0.08 mL, 1.31 mmol, 1.50 equiv.) at room temperature. The reaction mixture was heated to 50° C. and stirred for 15 hours. Upon completion, the reaction mixture was quenched with ice-water (50 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine solution (2×30 mL), dried over Na2SO4, 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 give Broad_P_Cav3.3_407_Int-825 (310 mg, 0.399 mmol, 46% yield) as an off-white solid. MS (ESI): 366.2 [M+H]+.

[0513] 4-[(6-chloro-4-methyl-3-pyridyl)sulfonyl]-5-methyl-1,3-dihydroquinoxalin-2-one

[0514] [ka]

[0515] 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 equiv.) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (236 mg, 1.23 mmol, 1.20 equiv.) in DMF (3.62 mL) was added at room temperature. The reaction mixture was stirred at 30° C. for 6 h. After completion, the reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine solution (3×20 mL), dried over Na2SO4, and evaporated. The residue was purified by Combi-Flash column chromatography eluting with 2-3% MeOH in DCM as a gradient to give 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]+.

[0516] 2-[2-amino-N-[(6-chloro-4-methyl-3-pyridyl)sulfonyl]-6-methyl-anilino]acetic acid

[0517] [ka]

[0518] 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 equiv) in MeOH (2.2737 mL), THF (2.2737 mL), and water (1.1369 mL) at room temperature, lithium hydroxide monohydrate (0.32 g, 7.62 mmol, 4.00 equiv) was added at the same temperature. The reaction mixture was stirred at 30 °C for 5 h. After completion, the reaction mixture was acidified with dilute HCl solution (5 mL), and the solvent was concentrated under reduced pressure. The residue was diluted with EtOAc (50 mL), and the organic layer was washed with water (3 × 40 mL) and brine solution (3 × 40 mL). The combined organic layers were dried over Na2SO4 and evaporated to give 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]+.

[0519] [ka]

[0520] Ethyl 2-[2-amino-N-[(6-chloro-4-methyl-3-pyridyl)sulfonyl]-6-methyl-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 equiv.), ethyl 2-bromoacetate (0.43 mL, 3.90 mmol, 1.20 equiv.), and potassium carbonate (1.35 g, 9.76 mmol, 3.00 equiv.) in DMF (11.328 mL) at room temperature. The reaction mixture was stirred at 30° C. for 3 hours. After completion, the reaction mixture was quenched with ice water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine solution (3×30 mL), dried over Na2SO4, and evaporated. The residue was purified by Combi-Flash column chromatography eluting with 70% EtOAc in hexane as a gradient to give 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]+.

[0521] N-(2-amino-6-methyl-phenyl)-6-chloro-4-methyl-pyridine-3-sulfonamide; hydrochloride

[0522] [ka]

[0523] 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 equiv.) in DCM (13.164 mL) was added 4 M HCl in dioxane (4 M, 6.13 mL, 24.5 mmol, 10.0 equiv.), which was stirred at room temperature for 3 h. After completion, the reaction mixture was evaporated to give Broad_P_Cav3.3_407_Int-728 (1.50 g, 3.25 mmol, quantitative) as an off-white solid. MS (ESI): 310.3 [M-HCl-1]+.

[0524] tert-Butyl N-[2-[(6-bromo-4-methyl-3-pyridyl)sulfonylamino]-3-methyl-phenyl]carbamate

[0525] [ka]

[0526] A solution of tert-butyl N-(2-amino-3-methyl-phenyl)carbamate (1.56 g, 7.02 mmol, 1.00 equiv.) in dichloromethane (10 mL) was added to pyridine (2.26 mL, 28.1 mmol, 4.00 equiv.) at 25 °C, followed by 6-bromo-4-methyl-pyridine-3-sulfonyl chloride (1.90 g, 7.02 mmol, 1.00 equiv.), and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 80 mL). The organic layer was dried over Na2SO4 and evaporated. The residue was purified by Biotage (8:2 Hex / EtOAc; 12S column) to give 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) δ 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[MH]-.

[0527] Synthesis of Compound 15 and Compound 46

[0528] [ka]

[0529] (4R)-4,8-Dimethyl-1-[2-methyl-4-(1-methylpyrazol-4-yl)phenyl]sulfonyl-3,4-dihydro-2H-quinoline and (4S)-4,8-Dimethyl-1-[2-methyl-4-(1-methylpyrazol-4-yl)phenyl]sulfonyl-3,4-dihydro-2H-quinoline: Broad_P_CaV3.3_430 and Broad_P_CaV3.3_431 (Compound 15 and its stereoisomers) 4,8-Dimethyl-1,2,3,4-tetrahydroquinoline (0.20 g, 1.24 mmol, 1.00 equiv.) and 2-methyl-4-(1-methylpyrazol-4-yl)benzenesulfonyl chloride (0.84 g, 3.10 mmol, 2.50 equiv.) were taken up in acetonitrile (4 mL) under a nitrogen atmosphere. Zinc oxide (0.20 g, 2.48 mmol, 2.00 equiv.) was added, and the reaction was stirred at room temperature for 72 hours. Upon completion, water was added, and the crude product was extracted with ethyl acetate (3 × 25 mL). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the crude product, which was first purified using column chromatography to give racemic compound 758E, which exhibited 96% LCMS purity (254 nm), followed by chiral preparative HPLC purification to give two fractions. The pure fractions were evaporated to give 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) δ 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) δ 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).

[0530] 6-Fluoro-1,5-dimethyl-4-[2-methyl-4-(1-methyl-1H-pyrazol-4-yl)benzenesulfonyl]-1,2,3,4-tetrahydroquinoxaline (Broad_P_Cav3.3_301, compound 16)

[0531] [ka]

[0532] To a stirred solution of 4-(4-bromo-2-methylbenzenesulfonyl)-6-fluoro-1,5-dimethyl-1,2,3,4-tetrahydroquinoxaline (350 mg, 0.8468 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (210 mg, 1.01 mmol), potassium carbonate (351 mg, 2.54 mmol) in 1,4-dioxane (5 mL) was added at room temperature, and the reaction mixture was degassed with argon for 20 minutes. After that, palladium(2+) bis(cyclopenta-1,3-dien-1-yldiphenylphosphane)methylene chloride iron dichloride (69.1 mg, 0.08468 mmol) was added at room temperature, and the reaction mixture was heated at 100 °C for 8 hours. After completion, the reaction mixture was poured into water (30 mL) and extracted with EtOAc (3 × 30 mL). The organic layer was washed with brine solution (2 × 20 mL), dried over NaSO, and evaporated. The residue was purified by Biotage (50:1 CHCl / MeOH; 12M column) to give 6-fluoro-1,5-dimethy (198 mg, 55.7% yield) as an off-white solid. 1H NMR (400 MHz, chloroform-d) δ 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) δ -128.76. MS (ESI): 415.0 [M+H]+.

[0533] Synthesis of compound 17

[0534] [ka]

[0535] 4-[4-(4-cyclopropylimidazol-1-yl)-2-methyl-phenyl]sulfonyl-1,5-dimethyl-2,3-dihydroquinoxaline: Broad_P_CaV3.3_346

[0536] [ka]

[0537] A stirred solution of 4-(4-bromo-2-methyl-phenyl)sulfonyl-1,5-dimethyl-2,3-dihydroquinoxaline (0.15 g, 0.379 mmol, 1.00 equiv.) and 4-cyclopropyl-1H-imidazole (0.082 g, 0.759 mmol, 2.00 equiv.) in dimethylformamide (5 mL) was degassed with nitrogen gas for 15 minutes. After 15 minutes, copper(I) oxide (0.054 g, 0.379 mmol, 1.00 equiv.) and potassium tert-butoxide (0.13 g, 1.14 mmol, 3.00 equiv.) were added, and the mixture was heated at 100 °C in a sealed tube for 16 hours. After 16 hours, the reaction mixture was poured into cold water (50 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were dried over NaSO and evaporated. The residue was purified by Combiflash using ethyl acetate:hexane (1:1) as the mobile phase to give 4-[4-(4-cyclopropylimidazol-1-yl)-2-methyl-phenyl]sulfonyl-1,5-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. 1H NMR (400 MHz, DMSO-d6) δ 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).

[0538] Synthesis of compound 18

[0539]

change

[0540] 1-((4-ブロモ-2-メチルフェニル)スルホニル)-7-メチルインドリン: Intermediate 1

[0541]

change

[0542] To a stirred solution of 7-methylindoline (50 mg, 0.375 mmol, 1.00 equiv.) and 4-bromo-2-methyl-benzenesulfonyl chloride (121 mg, 0.450 mmol, 1.20 equiv.) in pyridine (1 mL) under an inert atmosphere at room temperature, triethylamine (0.16 mL, 1.13 mmol, 3.00 equiv.) was added, followed by DMAP (46 mg, 0.375 mmol, 1.00 equiv.), followed by stirring at room temperature. The RM was quenched with water (20 mL) and extracted with ethyl acetate (30 mL × 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Purification was carried out by column chromatography in 0–10% ethyl acetate:hexane to afford 1-(4-bromo-2-methyl-phenyl)sulfonyl-7-methyl-indoline (90 mg, 0.241 mmol, 64% yield) as a light brown solid. MS(ESI): 366.27[M+H] 1 H NMR (400 MHz, chloroform-d) δ 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).

[0543] 7-Methyl-1-((2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfonyl)indoline

[0544] [ka]

[0545] To a stirred solution of 1-(4-bromo-2-methyl-phenyl)sulfonyl-7-methyl-indoline (80 mg, 0.218 mmol, 1.00 equiv.) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (91 mg, 0.437 mmol, 2.00 equiv.) in dioxane (3 mL) and water (1 mL) was added sodium carbonate (69 mg, 0.655 mmol, 3.00 equiv.) at room temperature. The reaction mixture was then purged with argon for 10 minutes, and then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (8.9 mg, 0.0109 mmol, 0.0500 equiv.) was added under an inert atmosphere, and the reaction mixture was stirred at 80°C. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to give 7-methyl-1-[2-methyl-4-(1-methylpyrazol-4-yl)phenyl]sulfonyl-indoline (51 mg, 0.137 mmol, 63% yield) as a brown solid. MS(ESI): 367.47[M+H] 1 H NMR (400 MHz, DMSO-d6) δ 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).

[0546] 1,5-Dimethyl-4-[2-methyl-4-(4-methylimidazol-1-yl)phenyl]sulfonyl-2,3-dihydroquinoxaline (Broad_P_Cav3.3_291, compound 19)

[0547] [ka]

[0548] A stirred suspension of 4-(4-bromo-2-methyl-phenyl)sulfonyl-1,5-dimethyl-2,3-dihydroquinoxaline (1.50 g, 3.64 mmol, 1.00 equiv.), 4-methyl-1H-imidazole (0.75 g, 9.09 mmol, 2.50 equiv.), and potassium tert-butoxide (0.82 g, 7.27 mmol, 2.00 equiv.) in DMF (15 mL) was degassed with nitrogen gas for 15 minutes. After 15 minutes, copper(I) oxide (0.14 g, 1.82 mmol, 0.500 equiv.) was added, and the mixture was heated at 120 °C for 16 hours. Upon completion, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with brine solution (3 × 70 mL). The organic layer was dried over NaSO and evaporated under reduced pressure. The residue was purified by Combiflash using (80% ethyl acetate:hexane) as the mobile phase to give impure product, which was then repurified by preparative HPLC using (10–30% ACN and water with 0.1% formic acid as a modifier) ​​as the mobile phase to give Broad_P_Cav3.3_291 (45 mg, 0.110 mmol, 3% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 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]+.

[0549] 4-(4-Bromo-2-methyl-phenyl)sulfonyl-1,5-dimethyl-2,3-dihydroquinoxaline

[0550] [ka]

[0551] To a stirred solution of 4-(4-bromo-2-methyl-phenyl)sulfonyl-5-methyl-2,3-dihydro-1H-quinoxaline (2.00 g, 4.93 mmol, 1.00 equiv.) and potassium carbonate (2.04 g, 14.8 mmol, 3.00 equiv.) in DMF (10.12 mL) was added iodomethane (0.46 mL, 7.40 mmol, 1.50 equiv.) at room temperature. The reaction mixture was heated at 80° C. and stirred for 16 hours. After completion, the reaction mixture was poured into ice water (100 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine solution (2×50 mL), dried over Na2SO4, and evaporated. The residue was purified by Biotage (40:60, Hex / EtOAc) to give 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]+.

[0552] 4-(4-Bromo-2-methyl-phenyl)sulfonyl-5-methyl-2,3-dihydro-1H-quinoxaline; Hydrochloride

[0553] [ka]

[0554] 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 equiv.) in dichloromethane (30 mL) was added HCl 1,4-dioxane solution (4 M in dioxane, 20 mL, 80.0 mmol, 12.4 equiv.) at 0 °C. The reaction mixture was stirred at room temperature for 5 h. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was stripped with n-hexane three to four times, and the solid was dried under reduced pressure to give 4-(4-bromo-2-methyl-phenyl)sulfonyl-5-methyl-2,3-dihydro-1H-quinoxaline; hydrochloride salt (2.60 g, 5.85 mmol, 91% yield) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ 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, MS(ESI): 381.2 [M+H]+.

[0555] tert-Butyl 4-(4-bromo-2-methyl-phenyl)sulfonyl-5-methyl-2,3-dihydroquinoxaline-1-carboxylate

[0556] [ka]

[0557] 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 equiv.) and 1,2-dibromoethane (0.71 mL, 7.91 mmol, 1.20 equiv.) in DMF (20 mL) was added KCO (3.64 g, 26.4 mmol, 4.00 equiv.) 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 × 50 mL). The combined organic layers were washed with brine solution (2 × 50 mL), dried over NaSO, and evaporated under reduced pressure to give 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 a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 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]+.

[0558] tert-Butyl N-[2-[(4-bromo-2-methyl-phenyl)sulfonylamino]-3-methyl-phenyl]carbamate

[0559] [ka]

[0560] To a stirred solution of tert-butyl N-(2-amino-3-methyl-phenyl)carbamate (2.80 g, 12.6 mmol, 1.00 equiv.) and pyridine (5.09 mL, 63.0 mmol, 5.00 equiv.) in dichloromethane (30 mL) was added 4-bromo-2-methyl-benzenesulfonyl chloride (5.09 g, 18.9 mmol, 1.50 equiv.) at room temperature. The reaction mixture was stirred at the same temperature for 16 hours. Upon completion, the reaction was quenched with water and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine solution (2 × 50 mL), dried over NaSO, and evaporated. The residue was purified by silica gel column chromatography using (8% ethyl acetate:hexane) as the mobile phase to give 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) δ 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]+.

[0561] Synthesis of compound 20

[0562] [ka]

[0563] 1-(4-Bromo-2-methyl-phenyl)sulfonyl-5-fluoro-7-methyl-indoline: Intermediate 1290

[0564] [ka]

[0565] To a stirred solution of 5-fluoro-7-methyl-indoline (0.20 g, 1.32 mmol, 1.00 equiv.) and pyridine (0.43 mL, 5.29 mmol, 4.00 equiv.) in DCM (5 mL) was added 4-bromo-2-methyl-benzenesulfonyl chloride (641.85 mg, 2.38 mmol, 2.00 equiv.) at room temperature. The reaction mixture was stirred at the same temperature for 12 hours. After completion, the reaction was quenched with 10% citric acid solution (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine solution (2 × 50 mL), dried over NaSO, and evaporated. The residue was purified by silica gel column chromatography using (6:4, ethyl acetate:hexane) as a mobile phase to give 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) δ 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).

[0566] 5-Fluoro-7-methyl-1-[2-methyl-4-(4-methylimidazol-1-yl)phenyl]sulfonyl-indoline: Broad_P_Cav3.3_625, compound 20

[0567] [ka]

[0568] A stirred suspension of 1-(4-bromo-2-methyl-phenyl)sulfonyl-5-fluoro-7-methyl-indoline (0.18 g, 0.47 mmol, 1.00 equiv.), 4-methyl-1H-imidazole (0.076 g, 0.94 mmol, 2.00 equiv.), and Ktb (0.157 g, 1.41 mmol, 3.00 equiv.) in DMF (5 mL) was degassed with nitrogen gas for 15 minutes. After 15 minutes, copper(I) oxide (0.020 g, 0.140 mmol, 0.3 equiv.) was added, and the mixture was heated in a microwave oven at 170 °C for 4 hours. After completion, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with brine solution (3 × 70 mL). The organic layer was dried over NaSO and evaporated under reduced pressure. The residue was purified by Combiflash using (1:1, ethyl acetate:hexane) as the mobile phase to give a mixture of isomers, which was further purified by preparative 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) δ 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) δ -115.92

[0569] Synthesis of Compound 21 and Compound 138

[0570] [ka]

[0571] 3,8-Dimethyl-2,3-dihydro-1H-quinolin-4-one: Intermediate 891C

[0572] [ka]

[0573] To a stirred solution of 3,8-dimethyl-1H-quinolin-4-one (2.00 g, 11.5 mmol, 1.00 equiv.) in THF (20 mL) was added phenylsilane (5.00 g, 46.2 mmol, 4.00 equiv.), followed by dibutyltin dichloride (7.02 g, 23.1 mmol, 2.00 equiv.); the reaction mixture was stirred at room temperature. Upon completion, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were dried over NaSO and evaporated. The residue was purified by Combiflash using ethyl acetate:hexane (3:7) to afford Int-891C (1.60 g, 9.13 mmol, 79% yield) as a bright yellow solid. MS: [M+H]+ 176.0

[0574] 4-Bromo-2-methylbenzenesulfonyl chloride: Broad_P_CaV3.3_449 and 450

[0575] [ka]

[0576] To a stirred solution of 3,8-dimethyl-2,3-dihydro-1H-quinolin-4-one (0.50 g, 2.85 mmol, 1.00 equiv.) and 2-methyl-4-(1-methylpyrazol-4-yl)benzenesulfonyl chloride (0.93 g, 3.42 mmol, 1.20 equiv.) in ACN (10 mL) was added zinc oxide (0.46 g, 5.71 mmol, 2.00 equiv.), which was stirred at room temperature for 48 h. After completion, the reaction mixture was filtered through a bed of Celite and washed with ethyl acetate (3 × 20 mL). The filtrate was evaporated under reduced pressure, and the residue was purified by Combiflash using ethyl acetate:hexane (3:7) to give the racemic product, which was further purified by chiral preparative HPLC to give 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) δ 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). [α]D 25 = -35.00° Chiral separation conditions: (CHIRALPAK IB-N (250*4.6mm) 5u, 0.1% DEA / hexane-containing IPA as mobile phase) and CO2 gas Elution order: Fraction 1 (retention time: 11.03 min); Fraction 2 (retention time: 12.91 min) Broad_P_CaV3.3_450 MS:[M+H]+ 410.2 1H NMR (400 MHz, DMSO-d6) δ 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). [α]D 25 = +33.40° Chiral separation conditions: (CHIRALPAK IB-N (250*4.6mm) 5u, 0.1% DEA / hexane-containing IPA as mobile phase) and CO2 gas Elution order: Fraction 1 (retention time: 11.03 min); Fraction 2 (retention time: 12.91 min)

[0577] 6-Fluoro-1,4-dimethyl-3-[[4-methyl-6-(4-methylimidazol-1-yl)-3-pyridyl]sulfonyl]indole (Broad_P_CaV3.3_676, compound 22)

[0578] [ka]

[0579] A stirred suspension of 3-[(6-bromo-4-methyl-3-pyridyl)sulfonyl]-6-fluoro-1,4-dimethyl-indole (3.60 g, 9.06 mmol, 1.00 equiv.), 4-methyl-1H-imidazole (2.98 g, 36.2 mmol, 4.00 equiv.), CuO (0.39 g, 2.72 mmol, 0.300 equiv.), and potassium tert-butoxide (3.05 g, 27.2 mmol, 3.00 equiv.) in dimethylformamide (72 mL) was heated at 150 °C for 2 h. After completion, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with brine solution (3 × 70 mL). The organic layer was dried over NaSO and evaporated under reduced pressure. The residue was purified by Combiflash using (1:9, MeOH:DCM) as the mobile phase to give a mixture of isomers, which was further purified by reverse-phase purification using 15–85% acetonitrile and water (0.1% formic acid as a 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) δ 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]+.

[0580] 3-[(6-bromo-4-methyl-3-pyridyl)sulfonyl]-6-fluoro-1,4-dimethyl-indole

[0581] [ka]

[0582] To a stirred solution of 3-[(6-bromo-4-methyl-3-pyridyl)sulfanyl]-6-fluoro-1,4-dimethyl-indole (300 mg, 0.821 mmol, 1.00 equiv) in tetrahydrofuran (3 mL) and water (3 mL) was added Oxone (757 mg, 2.46 mmol, 3.00 equiv) at 0 °C. The reaction mixture was stirred at 25 °C for 16 h. Upon completion, the reaction was quenched with water and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine solution (2 × 50 mL), dried over NaSO, and evaporated. The residue was purified by silica gel column chromatography using 40% ethyl acetate in hexane as the mobile phase to afford 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]+.

[0583] 3-[(6-bromo-4-methyl-3-pyridyl)sulfanyl]-6-fluoro-1,4-dimethyl-indole

[0584] [ka]

[0585] To a stirred solution of 6-fluoro-1,4-dimethyl-indole (450 mg, 2.76 mmol, 1.00 equiv.) and 6-bromo-4-methyl-pyridine-3-sulfonyl chloride (1492 mg, 5.52 mmol, 2.00 equiv.) in dimethylformamide (4.5 mL) was added tetrabutylammonium iodide (2037 mg, 5.52 mmol, 2.00 equiv.) at 25 °C. The reaction mixture was stirred at the same temperature for 2 h. Upon completion, the reaction was quenched with water and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine solution (2 × 50 mL), dried over NaSO, and evaporated. The residue was purified by silica gel column chromatography using 60% ethyl acetate in hexane as the mobile phase to give Broad_P_CaV3.3_676 (300 mg, 0.791 mmol, 29% yield) as a pale yellow semisolid. MS (ESI): 365.4 [M+H]+.

[0586] 5-chloro-1-methyl-4-[2-methyl-4-(1-methyl-1H-pyrazol-4-yl)benzenesulfonyl]-1,2,3,4-tetrahydroquinoxaline (Broad000415-105, compound 23)

[0587] [ka]

[0588] To a vial was added bromosulfonamide (100 mg, 0.2405 mmol, 1 equiv.), methylpyrazoleboronic acid (60.0 mg, 0.2885 mmol, 1.2 equiv.), XPhos Pd G2 (9.45 mg, 0.01202 mmol, 0.05 equiv.), and sodium carbonate (76.4 mg, 0.7214 mmol, 3 equiv.) in 4:1 dioxane / water (2.00 mL). The reaction mixture was stirred at 80 °C for 2 h. After cooling to room temperature, water was poured on and the product was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was purified by reverse-phase chromatography (ACN / water) to afford the desired chloro-N-methylsulfonamidomethylpyrazole (20 mg, 18.5% yield) as a white solid. 1H NMR (400 MHz, chloroform-d) δ 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]+.

[0589] Synthesis of Compound 24 and Compound 116

[0590] [ka]

[0591] 3,8-Dimethyl-3,4-dihydro-1H-quinoxalin-2-one:

[0592] [ka]

[0593] To a solution of 2-bromo-6-methyl-aniline (10.00 g, 53.7 mmol, 1.00 equiv.) in dimethyl sulfoxide (DMSO) (50 mL) was added DL-alanine (14.37 g, 161 mmol, 3.00 equiv.), 1,2-dimethylethylenediamine (DMEDA) (2.84 g, 32.2 mmol, 0.600 equiv.), copper(I) chloride (0.80 g, 8.06 mmol, 0.150 equiv.), and potassium phosphate tribasic (KPO) (34.23 g, 161 mmol, 3.00 equiv.) at room temperature. The reaction mixture was then heated for up to 18 hours. The reaction mixture was cooled to room temperature, poured into water (200 mL × 2), and extracted with ethyl acetate (100 mL × 2). The organic layer was separated. The organic layer was then evaporated under reduced pressure. The 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 a yellow solid. MS: [M+H]+ 177.0

[0594] 3,4,8-trimethyl-1,3-dihydroquinoxalin-2-one

[0595] [ka]

[0596] Next, to a solution of 3,8-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (7.00 g, 39.7 mmol, 1.00 equiv.) in methanol (50 mL) was added paraformaldehyde (4.77 g, 119 mmol, 3.00 equiv.) and sodium cyanoborohydride (NaCNBH4) (4.99 g, 79.4 mmol, 2.00 equiv.) at room temperature. The reaction mixture was stirred at room temperature for 24 hours. Methanol was evaporated under reduced pressure, and the residue was extracted with water (50 mL × 2) and ethyl acetate (50 mL × 2). The organic layer was separated and evaporated under reduced pressure. The residue was further purified by column chromatography (5% ethyl acetate in n-hexane) to give 3,4,8-trimethyl-1,3-dihydroquinoxalin-2-one (3.00 g, 13.7 mmol, 34% yield) as a yellow solid. MS: [M+H]+ 191.2

[0597] 3,4,8-trimethyl-2,3-dihydro-1H-quinoxaline:

[0598] [ka]

[0599] Next, 1M LAH in THF (30 mL, 31.5 mmol, 2.00 equiv.) was added dropwise to a solution of 3,4,8-trimethyl-1,3-dihydroquinoxalin-2-one (3.00 g, 15.8 mmol, 1.00 equiv.) in THF (30 mL) at -5 °C. The reaction mixture was then heated for up to 6 h. The reaction mixture was quenched into ice-cold water (100 mL × 2) and extracted with ethyl acetate (50 mL × 2). The organic layer was evaporated under reduced pressure. The residue was further purified by column chromatography (2% ethyl acetate in n-hexane) to give 3,4,8-trimethyl-2,3-dihydro-1H-quinoxaline (1.50 g, 8.42 mmol, 53% yield) as a yellowish-brown liquid. MS: [M+H]+ 176.26

[0600] 4-(4-bromo-2-methyl-phenyl)sulfonyl-1,2,5-trimethyl-2,3-dihydroquinoxaline:

[0601] [ka]

[0602] Next, to a solution of 3,4,8-trimethyl-2,3-dihydro-1H-quinoxaline (1.50 g, 8.51 mmol, 1.00 equiv.) in pyridine, triethylamine (3.56 mL, 25.5 mmol, 3.00 equiv.), 4-dimethylaminopyridine (1.04 g, 8.51 mmol, 1.00 equiv.), and 4-bromo-2-methyl-benzenesulfonyl chloride (6.88 g, 25.5 mmol, 3.00 equiv.) were added at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then poured into water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was further washed with citric acid solution and then with water. The organic layer was separated and evaporated under reduced pressure. The residue was purified by column chromatography (2% ethyl acetate in n-hexane) to give Int-686A (1.20 g, 2.76 mmol, 32% yield) as a brownish oily liquid. MS:[M+H]+ 411.5

[0603] 1,2,5-trimethyl-4-[2-methyl-4-(4-methylimidazol-1-yl)phenyl]sulfonyl-2,3-dihydroquinoxaline

[0604] [ka]

[0605] A solution of 4-(4-bromo-2-methyl-phenyl)sulfonyl-1,2,5-trimethyl-2,3-dihydroquinoxaline (1.20 g, 2.93 mmol, 1.00 equiv.) in 1,4-dioxane (10 mL) was treated with potassium phosphate tripotassium (K3PO4) (1.24 g, 5.86 mmol, 2.00 equiv.), tris(dibenzylideneacetone)dipalladium(0) (P d2(dba)3) (0.27 g, 0.293 mmol, 0.1000 equiv.), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (tBuXPhos) (0.25 g, 0.586 mmol, 0.200 equiv.), and 4-methyl-1H-imidazole (0.48 g, 5.86 mmol, 2.00 equiv.) were added at room temperature. The reaction mixture was then heated for up to 16 hours. The reaction mixture was then poured into water (50 mL × 2) and extracted with ethyl acetate (50 mL × 2). The organic layer was separated and evaporated under reduced pressure. The residue was purified by column chromatography (50% ethyl acetate in n-hexane) to give 0.25 g of compound, which was further purified by preparative HPLC (0.1% formic acid in water, gradient 0-100% ACN, 23 min) to give 0.06 g of compound, which was purified by chiral SFC (CHIRALPAK AD-H (250*4.6 mm) 5u) with 0.1% Further purification with DEA ​​in MeOH gave (2R)-1,2,5-trimethyl-4-[2-methyl-4-(4-methylimidazol-1-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-1-yl)phenyl]sulfonyl-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) δ 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) δ8.29 (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).

[0606] Synthesis of compound 25

[0607]

change

[0608] 1-((4-ブロモ-2-メチルフェニル)スルホニル)-7-メチルインドリン:

[0609]

change

[0610] To a stirred solution of 7-methylindoline (0.20 g, 1.50 mmol, 1.00 equiv) and pyridine (0.24 mL, 3.00 mmol, 2.00 equiv) in DCM (5 mL) was added 4-bromo-2-methyl-benzenesulfonyl chloride (809 mg, 3.00 mmol, 2.00 equiv) at room temperature. The reaction mixture was stirred at the same temperature for 12 h. Upon completion, the reaction was quenched with 10% citric acid solution (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine solution (2 × 50 mL), dried over NaSO, and evaporated. The residue was purified by silica gel column chromatography using (6:4, ethyl acetate:hexane) as the mobile phase to give Broad_P_CaV3.3_624_Int-933 (200 mg, 0.546 mmol, 36% yield) as an off-white solid. 1H NMR (400 MHz, chloroform-d) δ 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).

[0611] 7-methyl-1-((2-methyl-4-(4-methyl-1H-imidazol-1-yl)phenyl)sulfonyl)indoline:

[0612] [ka]

[0613] A stirred suspension of 1-(4-bromo-2-methyl-phenyl)sulfonyl-7-methyl-indoline (0.20 g, 0.546 mmol, 1.00 equiv.), 4-methyl-1H-imidazole (0.090 g, 1.09 mmol, 2.00 equiv.), and KOtBu (0.18 g, 1.64 mmol, 3.00 equiv.) in DMF (5 mL) was degassed with nitrogen gas for 15 minutes. Copper(I) oxide (0.023 g, 0.164 mmol, 0.300 equiv.) was added, and the mixture was heated at 140 °C for 16 hours. After completion, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with brine solution (3 × 70 mL). The organic layer was dried over NaSO and evaporated under reduced pressure. The residue was purified by Combiflash using (1:1, ethyl acetate:hexane) as the mobile phase to give a mixture of isomers, which was further purified by preparative 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-d6) δ 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-d4) δ 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).

[0614] 1,5-Dimethyl-4-[2-methyl-4-(5-methylpyridin-3-yl)benzenesulfonyl]-1,2,3,4-tetrahydroquinoxaline (Broad_P_CaV3.3_297)

[0615] [ka]

[0616] A stirred solution of 4-(4-bromo-2-methylbenzenesulfonyl)-1,5-dimethyl-1,2,3,4-tet (0.2 g, 505 μmol, 1 equiv.), (5-methylpyridin-3-yl)boronic acid (82.9 Mg, 606 μmol, 1.2 equiv.), and potassium carbonate (208 mg, 1.51 mmol, 3 equiv.) in 1,4-dioxane (3 mL) and water (0.5 mL) was degassed with nitrogen gas for 15 minutes, after which palladium(2+) bis(cy) (41.2 mg, 50.5 μmol, 0.1 equiv.) was added and the reaction mixture was heated at 80° C. for 16 hours. Upon completion, the reaction mixture was quenched into water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by [0-50% NMR (CDCl)]. The impure product was purified by flash chromatography using hexanes in 10% hexane / 3% ethyl acetate to give an impure product, which was purified by preparative HPLC using water (35-80% ACN with 0.1% formic acid as a modifier) ​​as the mobile phase to give 1,5-dimethyl-4-[2-methyl-4-(5-methylpyridin-3-yl)benzenesulfonate] (0.035 g, 17.0% yield) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ 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]+.

[0617] Synthesis of Broad_P_CaV3.3_506 and 507 (Compound 27 and Compound 55)

[0618] [ka]

[0619] 2-Bromo-6-methyl-N-(2-methylallyl)aniline: Intermediate 899B

[0620] [ka]

[0621] To a stirred solution of 2-bromo-6-methyl-aniline (6.00 g, 32.2 mmol, 1.00 equiv.) in DMF (60 mL) was added NaH (60% in mineral oil) (1.16 g, 48.4 mmol, 1.50 equiv.) at 0 °C and stirred at the same temperature for 20 min. 3-Bromo-2-methyl-prop-1-ene (4.79 g, 35.5 mmol, 1.10 equiv.) was added and stirred at room temperature. After 16 h, the reaction mixture was poured into cold water (600 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over NaSO and evaporated. The residue was purified by Combiflash using ethyl acetate:hexane (3:7) to give Int-899B (5.00 g, 20.7 mmol, 64% yield) as a yellow oil. MS: [M+H] + 242.0 1 H NMR (400 MHz, chloroform-d) δ 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).

[0622] 3,8-Dimethyl-1,2,3,4-tetrahydroquinoline and 3,3,7-trimethylindoline: Intermediates 899C and 899F

[0623] [ka]

[0624] To a stirred solution of 2-bromo-6-methyl-N-(2-methylallyl)aniline (5.00 g, 20.8 mmol, 1.00 equiv.) in toluene (50 mL) was added azobisisobutyronitrile (0.68 g, 4.16 mmol, 0.200 equiv.) and tributyltin hydride (6.67 g, 22.9 mmol, 1.10 equiv.). The reaction mixture was then heated at 80°C. Upon completion, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (3 x 80 mL). The combined organic layers were dried over NaSO and evaporated. The residue was purified by Combiflash using ethyl acetate:hexane (1:9) to give 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 yellow oils. Int-899C: MS: [M+H]+ 162.00 1 H NMR (400 MHz, DMSO-d6) δ 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). (The product contains aliphatic impurities). Int-899F: MS: [M+H]+ 162.00 1H NMR (400 MHz, DMSO-d6) δ 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).

[0625] (R)-3,8-dimethyl-1-((2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline and (S)-3,8-dimethyl-1-((2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoline: Broad_P_CaV3.3_506 and 507

[0626] [ka]

[0627] To a stirred solution of 3,8-dimethyl-1,2,3,4-tetrahydroquinoline (0.40 g, 2.26 mmol, 1.00 equiv.) in pyridine (4 mL) was added triethylamine (687 mg, 6.79 mmol, 3.00 equiv.) and 4-dimethylaminopyridine (276 mg, 2.26 mmol, 1.00 equiv.), which was then heated at 80°C. After 0.5 h, the reaction mixture was cooled to room temperature, and 2-methyl-4-(1-methylpyrazol-4-yl)benzenesulfonyl chloride (1225 mg, 4.52 mmol, 2.00 equiv.) was added in one lot to the reaction mixture. The reaction mixture was heated at 80°C for 3 h. Upon completion, the reaction mixture was poured into 5% citric acid solution (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over NaSO and evaporated under reduced pressure. The residue was purified by Combiflash using ethyl acetate:hexane (4:6) to give the pure product, which was further purified by chiral preparative HPLC using (CHIRALPAK IG (250*4.6 mm) 5u), MeOH containing 0.1% DEA) to give 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 off-white solids. Broad_P_CaV3.3_506: MS: [M+H]+ 396.2 1 H NMR (400 MHz, DMSO-d6) δ 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). [α]D 25 = -27.00° Chiral separation conditions: (CHIRALCEL IH (250*4.6mm) 5u), mobile phase: 0.1% DEA_hexane-containing IPA:MeOH (1:1)) and CO2 gas Elution order: Fraction 1 (retention time: 9.05 min); Fraction 2 (retention time: 9.76 min) Broad_P_CaV3.3_507: MS: [M+H]+ 396.2 1 H NMR (400 MHz, DMSO-d6) δ 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). [α]D 25 = +26.00° Chiral separation conditions: (CHIRALCEL IH (250*4.6mm) 5u), mobile phase: 0.1% DEA_hexane-containing IPA:MeOH (1:1)) and CO2 gas Elution order: Fraction 1 (retention time: 9.05 min); Fraction 2 (retention time: 9.76 min)

[0628] 4-[4-(1-ethyl-1H-pyrazol-4-yl)-2-methylbenzenesulfonyl]-1,5-dimethyl-1,2,3,4-tetrahydroquinoxaline (Broad000415 - 040, compound 28)

[0629] [ka]

[0630] To a vial was added N-methylbromosulfonamide (75 mg, 0.1897 mmol, 1 equiv.), ethylpyrazoleboronic acid pinacol ester (50.5 mg, 0.2276 mmol, 1.2 equiv.), sodium carbonate (60.3 mg, 0.5691 mmol, 3 equiv.), and XPhos Pd G2 (7.46 mg, 0.009485 mmol, 0.05 equiv.) in 4:1 dioxane / water (1.5 mL). The reaction mixture was stirred at 80 °C for 2 h. After cooling to room temperature, the reaction mixture was partitioned between water and EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel flash chromatography (hexane / EtOAc) to give the desired N-ethylpyrazole N-sulfonamide (67 mg, 97% purity, 83% yield). A second purification by reverse phase chromatography eluting with (water / ACN) removed the pinacol and gave N-ethylpyrazole N-sulfonamide (4.9 mg, 6.10% yield). 1H NMR (400 MHz, chloroform-d) δ 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]+.

[0631] Synthesis of Compound 31 and Compound 45

[0632] [ka]

[0633] tert-Butyl N-[2-[(4-bromo-2-methyl-phenyl)sulfonylamino]-3-methyl-phenyl]carbamate:

[0634] [ka]

[0635] To a stirred solution of tert-butyl N-(2-amino-3-methyl-phenyl)carbamate (6.00 g, 27.0 mmol, 1.00 equiv.) and pyridine (8.73 mL, 108 mmol, 4.00 equiv.) in DCM (5 mL) was added 4-bromo-2-methyl-benzenesulfonyl chloride (8.73 g, 32.4 mmol, 1.20 equiv.) at room temperature. The reaction mixture was stirred at the same temperature for 16 h. Upon completion, the reaction was quenched with 10% citric acid solution (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine solution (2 × 50 mL), dried over NaSO, and evaporated. The residue was purified by silica gel column chromatography using (6:4, ethyl acetate:hexane) as the mobile phase to give Broad_P_CaV3.3_495_Int-536 (12.00 g, 26.4 mmol, 98% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 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).

[0636] tert-Butyl 4-(4-bromo-2-methyl-phenyl)sulfonyl-5-methyl-2,3-dihydroquinoxaline-1-carboxylate:

[0637] [ka]

[0638] 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 equiv.) and 1,2-dibromoethane (2.73 mL, 31.6 mmol, 1.20 equiv.) in DMF (100 mL) was added potassium carbonate (7.28 g, 52.7 mmol, 2.00 equiv.) at room temperature. The reaction mixture was heated to 80 °C and stirred at the same temperature for 12 h. After completion, the reaction mixture was poured into ice-cold water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine solution (2 x 50 mL), dried over Na2SO4 and evaporated under reduced pressure to give Broad_P_CaV3.3_495_Int-540A (10.20 g, 21.2 mmol, 80% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 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, 0H), 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).

[0639] tert-Butyl 5-methyl-4-[2-methyl-4-(1-methylpyrazol-4-yl)phenyl]sulfonyl-2,3-dihydroquinoxaline-1-carboxylate:

[0640] [ka]

[0641] 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 equiv.), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (5.29 g, 25.4 mmol, 1.20 equiv.), and potassium carbonate (5.86 g, 42.4 mmol, 2.00 equiv.) in 1,4-dioxane (80 mL) and water (20 mL) was degassed with nitrogen for 15 minutes. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.87 g, 1.06 mmol, 0.0500 equiv.) was added and heated at 120 °C for 16 h. After completion, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with brine solution (3 × 70 mL). The organic layer was dried over NaSO and evaporated under reduced pressure. The residue was purified by CombiFlash using (1:1, ethyl acetate:hexane) as the mobile phase to give Broad_P_CaV3.3_495_Int-540B (10.00 g, 19.3 mmol, 91% yield) as a brown solid. MS: [M+H]+ 482.6

[0642] 5-methyl-4-[2-methyl-4-(1-methylpyrazol-4-yl)phenyl]sulfonyl-2,3-dihydro-1H-quinoxaline:

[0643] [ka]

[0644] To a stirred solution of tert-butyl 5-methyl-4-[2-methyl-4-(1-methylpyrazol-4-yl)phenyl]sulfonyl-2,3-dihydroquinoxaline-1-carboxylate (10.00 g, 20.7 mmol, 1.00 equiv.) in 1,4-dioxane (70 mL) was added 4.0 M hydrogen chloride in dioxane (10.07 mL, 290 mmol, 14.0 equiv.) at 0 °C. The reaction mixture was stirred at room temperature for 12 h. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was stirred with n-hexane (100 mL), and the free solid was filtered through a Buchner funnel and washed with ethyl acetate (2 × 30 mL). The solid was dried under reduced pressure, dissolved in saturated NaHCO3 solution (50 mL), and extracted into ethyl acetate (3 × 50 mL). The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure to give 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) δ 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).

[0645] 5-methyl-4-[2-methyl-4-(1-methylpyrazol-4-yl)phenyl]sulfonyl-1-(trifluoromethyl)-2,3-dihydroquinoxaline:

[0646] [ka]

[0647] To a stirred solution of 5-methyl-4-[2-methyl-4-(1-methylpyrazol-4-yl)phenyl]sulfonyl-2,3-dihydro-1H-quinoxaline (1.00 g, 2.61 mmol, 1.00 equiv.) in acetonitrile (8 mL) was added tetramethylammonium (trifluoromethyl)sulfanide (0.60 g, 3.40 mmol, 1.30 equiv.), and the reaction mixture was stirred at room temperature for 15 minutes. After that, silver(I) fluoride (1.66 g, 13.1 mmol, 5.00 equiv.) was added at room temperature. The reaction mixture was stirred at 50° C. for 24 hours. Upon completion, the reaction mixture was quenched by the addition of water (50 mL) and extracted with ethyl acetate (3×80 mL). The combined organic layers were washed with brine solution (3×50 mL), dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using (1:5, ethyl acetate:hexane) as the mobile phase to give an impure compound, which was subjected to preparative HPLC for further purification using (45-100% ACN in water and 0.1% NH3 in water as a modifier) ​​to give 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) δ 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) δ -58.50.

[0648] 1,5-Dimethyl-4-[2-methyl-3-(3-methyl-1,2-oxazol-5-yl)benzenesulfonyl]-1,2,3,4-tetrahydroquinoxaline (Broad000374 - 080, compound 32)

[0649] [ka]

[0650] A stirred solution of 8-methyl-1-[2-methyl-3-(3-methyl-1,2-oxazol-5-yl)benzenesulfonyl]-1,2,3,4-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) was added at room temperature. The reaction mixture was heated to 50 °C and stirred at the same temperature for 18 h. After completion, the reaction mixture was poured into ice water (20 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine solution (2 × 20 mL), dried over NaSO, and evaporated. The residue was purified by Biotage (5:1 Hex / EtOAc; 12S column) to give 1,5-dimethyl-4-[2-me (110 mg, 69.0% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 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]+.

[0651] 1-Ethyl-5-methyl-4-[2-methyl-4-(1-methyl-1H-pyrazol-4-yl)benzenesulfonyl]-1,2,3,4-tetrahydroquinoxaline (Broad000415 - 036. Compound 33)

[0652] [ka]

[0653] To a vial was added sulfonamidopyrazole (68.6 mg, 0.1793 mmol, 1 equiv.) and potassium carbonate (74.3 mg, 0.5379 mmol, 3 equiv.) in DMF (0.7 mL). After stirring for 15 min, iodoethane (100 μL, 1.25 mmol, 7 equiv.) was added. The reaction mixture was stirred at 60° C. for 1 h and 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 over MgSO4, filtered, and concentrated. The crude product was purified by silica gel flash chromatography (hexane / EtOAc) to give the desired N-ethylsulfonamidomethylpyrazole (27 mg, 36.2% yield). 1H NMR (400 MHz, chloroform-d) δ 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]+.

[0654] 6-Fluoro-1,4-dimethyl-3-[2-methyl-4-(4-methylimidazol-1-yl)phenyl]sulfonyl-indole (Broad_P_CaV3.3_640, compound 22)

[0655] [ka]

[0656] To a stirred suspension of 3-(4-bromo-2-methyl-phenyl)sulfonyl-6-fluoro-1,4-dimethyl-indole (185 mg, 0.467 mmol, 1.00 equiv.) in DMF, 4-methyl-1H-imidazole (153 mg, 1.87 mmol, 4.00 equiv.), copper(I) oxide (20 mg, 0.140 mmol, 0.300 equiv.), potassium t-butoxide (157 mg, 1.40 mmol, 3.00 equiv.) were added, and the reaction mass was stirred at 140° C. for 16 hours. After 16 hours, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over NaSO and evaporated under reduced pressure. The residue was purified by Combiflash using (25:1, DCM:MeOH) as the mobile phase to give an impure product, which was further purified by preparative HPLC using (20–60% ACN and water (with 0.1% formic acid as a modifier)) as the mobile phase to give Broad_P_CaV3.3_640 (8.4 mg, 0.0209 mmol, 4% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 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.

[0657] 3-(4-Bromo-2-methyl-phenyl)sulfonyl-6-fluoro-1,4-dimethyl-indole

[0658] [ka]

[0659] To a solution of 3-(4-bromo-2-methyl-phenyl)sulfanyl-6-fluoro-1,4-dimethyl-indole (310 mg, 0.851 mmol, 1.00 equiv.) in DCM (6 mL) was added 3-chloroperoxybenzoic acid (441 mg, 2.55 mmol, 3.00 equiv.), 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 × 70 mL). The organic layer was dried over NaSO and evaporated under reduced pressure. The residue was purified by Combiflash using (1:1, ethyl acetate:hexane) as the mobile phase to give Broad_P_CaV3.3_640_Int_1340 (185 mg, 0.467 mmol, 55% yield) as a yellow solid. MS (ESI): [M+H] 398.0.

[0660] 3-(4-Bromo-2-methyl-phenyl)sulfanyl-6-fluoro-1,4-dimethyl-indole

[0661] [ka]

[0662] To a solution of 6-fluoro-1,4-dimethyl-indole (300 mg, 1.84 mmol, 1.00 equiv) in DMF (3 mL) was added tetrabutylammonium iodide (1358 mg, 3.68 mmol, 2.00 equiv) and 4-bromo-2-methyl-benzenesulfonyl chloride (496 mg, 1.84 mmol, 1.00 equiv) at 25° C. and the reaction was stirred for 4 h at 25° C. Upon completion, the reaction was quenched with water (100 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with water (3 × 100 mL), brine, dried over anhydrous NaSO, and concentrated under reduced pressure to give the crude product, which was then purified by column chromatography using 25% ethyl acetate in hexane as the mobile phase to give Broad_P_CaV3.3_640_Int_1339 (310 mg, 0.851 mmol, 46% yield) as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ 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).

[0663] 8-Methyl-1-[2-methyl-3-(3-methyl-1,2-oxazol-5-yl)benzenesulfonyl]-1,2,3,4-tetrahydroquinoxaline (Broad_P_Cav3.3_272, compound 35)

[0664] [ka]

[0665] To a stirred solution of 1-(3-bromo-2-methylbenzenesulfonyl)-8-methyl-1,2,3,4-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, 3-methyl-5-(tributylstannyl)-1,2-oxazole (409 mg, 1.10 mmol) was added at the same temperature, and the reaction mixture was purged with argon for 10 minutes and heated at 100 °C for 8 hours. After completion, the reaction mixture was poured into water (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine solution (3 × 20 mL), dried over Na SO , and evaporated. The residue was purified by Biotage (5:1 Hex / EtOAc; 12S column) to give 8-methyl-1-[2-methyl] (250 mg, 71.2% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 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, MS (ESI): 384.2 [M+H]+.

[0666] (3S)-3,7-Dimethyl-1-[[4-methyl-6-(4-methylimidazol-1-yl)-3-pyridyl]sulfonyl]indoline (Broad_P_CaV3.3_660A) and (3R)-3,7-Dimethyl-1-[[4-methyl-6-(4-methylimidazol-1-yl)-3-pyridyl]sulfonyl]indoline (Broad_P_CaV3.3_660B) (Compounds 36 and 90)

[0667] [ka]

[0668] A mixture of 1-[(6-bromo-4-methyl-3-pyridyl)sulfonyl]-3,7-dimethyl-indoline (200 mg, 0.525 mmol, 1.00 equiv.), 4-methyl-1H-imidazole (172 mg, 2.10 mmol, 4.00 equiv.), tBuXPhos (45 mg, 0.105 mmol, 0.200 equiv.), and tribasic potassium phosphate (223 mg, 1.05 mmol, 2.00 equiv.) in 1,4-dioxane (5 mL) was degassed for 10 minutes, and tris(dibenzylideneacetone)dipalladium(0) (48 mg, 0.0525 mmol, 0.100 equiv.) was added to the reaction mixture and heated at 120 °C for 16 hours. After completion, the reaction mixture was diluted with water (100 mL), and the product was extracted into ethyl acetate (100 mL × 3). The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give a residue. The residue was purified by silica column chromatography using 60%-70% ethyl acetate in hexane. The product fraction was evaporated under reduced pressure to give an impure product. The impure product was purified by preparative HPLC purification on a SUNFIRE C18 (250*19) mm, 5μ column using 5%-55% acetonitrile in water with 0.1% formic acid as a modifier as the mobile phase. The product fraction was lyophilized to give the racemic mixture (Broad_P_CaV3.3_660). The racemic mixture was purified by chiral preparative HPLC on a CHIRALPAK IH (250*21) mm, 5μ column using 10% 0.1% DEA in IPA:methanol (50:50) with 0.1% DEA in n-hexane as the mobile phase. The product fractions were evaporated under reduced pressure and lyophilized to give an off-white solid of Broad_P_CaV3.3_660B (21 mg, 0.0533 mmol, 10% yield) and an 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) δ 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) δ 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]+.

[0669] 1-[(6-ブロモ-4-メチル-3-ピリジル)スルホニル]-3,7-ジメチル-インドリン

[0670]

change

[0671] To a solution of 3,7-dimethylindoline (600 mg, 4.08 mmol, 1.00 equiv.) in dichloromethane (12 mL) was added 6-bromo-4-methyl-pyridine-3-sulfonyl chloride (1654 mg, 6.11 mmol, 1.50 equiv.) followed by pyridine (1.65 mL, 20.4 mmol, 5.00 equiv.) at 0 °C, and the reaction mixture was stirred at room temperature for 16 h. Upon completion, the reaction mixture was diluted with water (100 mL), and the product was extracted into dichloromethane (100 mL × 3). The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give a residue. The residue was purified by silica column chromatography using 1% to 2% ethyl acetate in hexane. Evaporation of the product fractions under reduced pressure gave Int-1402 (500 mg, 0.837 mmol, 21% yield) as a reddish-brownish semi-solid. MS (ESI): 383.2 [M+H]+.

[0672] 3,7-Dimethylindoline

[0673] [ka]

[0674] To a solution of 3,7-dimethyl-1H-indole (1.00 g, 6.89 mmol, 1.00 equiv.) in acetic acid (10 mL) was added sodium cyanoborohydride (1.30 g, 20.7 mmol, 3.00 equiv.) in several portions at 0 °C, and the reaction mixture was stirred for 3 h. Upon completion, the reaction mixture was basified with 2 M aqueous sodium hydroxide and extracted with ethyl acetate (150 mL × 3). The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give the crude product. The crude product was purified by silica column chromatography using 0% to 5% ethyl acetate in hexane as the mobile phase. The product fractions were collected and evaporated under reduced pressure to give 3,7-dimethylindoline Int-1364 as a yellow oil (500 mg, 1.46 mmol, 21% yield). MS (ESI): 148.1 [M+H]+.

[0675] 7-Methyl-1-[[4-methyl-6-(4-methylimidazol-1-yl)-3-pyridyl]sulfonyl]indoline (Broad_P_CaV3.3_649, compound 37)

[0676] [ka]

[0677] A stirred suspension of 1-[(6-bromo-4-methyl-3-pyridyl)sulfonyl]-7-methyl-indoline (200 mg, 0.545 mmol, 1.00 equiv.), 4-methyl-1H-imidazole (89 mg, 1.09 mmol, 2.00 equiv.), and potassium t-butoxide (183 mg, 1.63 mmol, 3.00 equiv.) in DMF (5 mL) was degassed with nitrogen gas for 15 minutes. To this was added copper(I) oxide (23 mg, 0.163 mmol, 0.300 equiv.), and it was heated at 140 °C for 12 hours. Upon completion, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with brine solution (3 × 70 mL). The organic layer was dried over NaSO and evaporated under reduced pressure. The residue was purified by Combiflash using (1:1, ethyl acetate:hexane) as the mobile phase to give a mixture of isomers, which was further purified by preparative 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) δ 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]+.

[0678] 1-[(6-bromo-4-methyl-3-pyridyl)sulfonyl]-7-methyl-indoline

[0679] [ka]

[0680] To a stirred solution of 7-methylindoline (200 mg, 1.50 mmol, 1.00 equiv) and pyridine (0.49 mL, 6.01 mmol, 4.00 equiv) in DCM (5 mL) was added 6-bromo-4-methyl-pyridine-3-sulfonyl chloride (812 mg, 3.00 mmol, 2.00 equiv) at room temperature. The reaction mixture was stirred at the same temperature for 12 h. Upon completion, the reaction was quenched with 10% citric acid solution (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine solution (2 × 50 mL), dried over NaSO, and evaporated. The residue was purified by silica gel column chromatography using (6:4, ethyl acetate:hexane) as the mobile phase to afford Broad_P_CaV3.3_649_Int-1378 (390 mg, 0.722 mmol, 48% yield) as a brown solid. LCMS: 368.2 [M+H]+.

[0681] 1,5-Dimethyl-4-{[2-methyl-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]sulfonyl}-1,2,3,4-tetrahydroquinoxaline (Broad_P_Cav3.3_359, compound 38)

[0682] [ka]

[0683] To a stirred solution of 4-[(6-bromo-2-methylpyridin-3-yl)sulfonyl]-1,5-dimethyl-1,2,3,4-tetrahydroquinoxaline (0.6 g, 1.51 mmol), 4-methyl-1H-imidazole (247 mg, 3.02 mmol), potassium tert-butoxide (508 mg, 4.53 mmol) in DMF (5 mL) was added at room temperature. The reaction mixture was degassed with argon for 20 minutes, after which cuprous oxide (43.2 mg, 0.302 mmol) was added at room temperature and the reaction mixture was heated at 120 °C for 16 hours. After completion, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (3 × 30 mL). The organic layer was washed with brine solution (2 × 30 mL), dried over NaSO, and evaporated. The product was applied to a preparative HPLC column and eluted with a gradient of 35% to 50% ACN in water containing 0.1% formic acid to give 1,5-dimethyl-4-{[2-m] (178 mg, 29.3% yield) as an off-white solid. 1H NMR (400 MHz, chloroform-d) δ 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. (ESI): 398.3 [M+H]+.

[0684] Synthesis of 3,7-dimethyl-1-[2-methyl-4-(4-methylimidazol-1-yl)phenyl]sulfonyl-indole (compound 40)

[0685] [ka]

[0686] 2-Isopropenyl-6-methyl-aniline: Intermediate 1098A

[0687] [ka]

[0688] A mixture of 2-bromo-6-methyl-aniline (1500 mg, 8.06 mmol, 1.00 equiv.), 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1626 mg, 9.67 mmol, 1.20 equiv.), and cesium carbonate (7881 mg, 24.2 mmol, 3.00 equiv.) in tetrahydrofuran (15 mL) and water (1.5 mL) was degassed under nitrogen for 10 minutes, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (658 mg, 0.806 mmol, 0.100 equiv.) was added to the reaction mixture, and the reaction was heated at 80° C. for 4 hours. Upon completion, the reaction was diluted with water (100 mL), and the product was extracted into ethyl acetate (3×100 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by silica column chromatography using 5%-10% ethyl acetate in hexane as the mobile phase. The product fractions were evaporated under reduced pressure to give 2-isopropenyl-6-methyl-aniline Int-1098A as a yellow semi-solid (500 mg, 2.45 mmol, 30% yield). MS(ESI): 148.1 [M+1] +

[0689] 4-Bromo-N-(2-isopropenyl-6-methyl-phenyl)-2-methyl-benzenesulfonamide: Intermediate 1098B

[0690] [ka]

[0691] To a solution of 2-isopropenyl-6-methyl-aniline (500 mg, 2.45 mmol, 1.00 equiv.) and 4-bromo-2-methyl-benzenesulfonyl chloride (991 mg, 3.68 mmol, 1.50 equiv.) in dichloromethane (7.22 mL) was added pyridine (0.99 mL, 12.3 mmol, 5.00 equiv.) dropwise at room temperature, and the reaction was stirred at room temperature for 16 hours. Upon completion, the reaction mixture was concentrated under reduced pressure and purified by silica column chromatography using 10% to 15% ethyl acetate in hexane. Evaporation of the product fractions under reduced pressure afforded 4-bromo-N-(2-isopropenyl-6-methyl-phenyl)-2-methyl-benzenesulfonamide Int-1098B (500 mg, 0.864 mmol, 35% yield) as an off-white solid. MS(ESI): 382.0 [M+2H] +

[0692] N-(2-Isopropenyl-6-methyl-phenyl)-2-methyl-4-(4-methylimidazol-1-yl)benzenesulfonamide: Intermediate 1098C

[0693] [ka]

[0694] A mixture of 4-bromo-N-(2-isopropenyl-6-methylphenyl)-2-methyl-benzenesulfonamide (100 mg, 0.173 mmol, 1.00 equiv.), 4-methyl-1H-imidazole (57 mg, 0.691 mmol, 4.00 equiv.), tBuXPhos (15 mg, 0.0345 mmol, 0.200 equiv.), and potassium phosphate tribasic (73 mg, 0.345 mmol, 2.00 equiv.) in 1,4-dioxane (1.31 mL) was degassed for 10 min. After degassing, tris(dibenzylideneacetone)dipalladium(0) (16 mg, 0.0173 mmol, 0.100 equiv.) was added, and the reaction mixture was heated at 120 °C for 16 h. After 16 h, the reaction mixture was poured into a mixture of water (50 mL) and ethyl acetate (3 × 50 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by silica column chromatography using 80% to 90% ethyl acetate in hexane as the mobile phase. The product fractions were evaporated under reduced pressure to give N-(2-isopropenyl-6-methyl-phenyl)-2-methyl-4-(4-methylimidazol-1-yl)benzenesulfonamide Int-1098C (50 mg, 0.102 mmol, 59% yield) as a light brown semi-solid. 1 H NMR (400 MHz, methanol-d4) δ 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 = MS(ESI): 382.3 [M+H] +

[0695] 3,7-Dimethyl-1-[2-methyl-4-(4-methylimidazol-1-yl)phenyl]sulfonyl-indole (Compound 40)

[0696] [ka]

[0697] To a solution of N-(2-isopropenyl-6-methyl-phenyl)-2-methyl-4-(4-methylimidazol-1-yl)benzenesulfonamide (200 mg, 0.407 mmol, 1.00 equiv.) in dimethylformamide (1.55 mL) was added silver nitrate (138 mg, 0.815 mmol, 2.00 equiv.), and the reaction was heated at 120 °C for 16 h. Upon completion, the reaction mixture was diluted with water (100 mL) and extracted into ethyl acetate (3 × 100 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by silica column chromatography using 50%–60% ethyl acetate in hexane as the mobile phase. Evaporation of the product fractions under reduced pressure afforded impure product. The impure product was purified by preparative HPLC using a Phenomenex C8 (250*21.2) mm, 5μ column and 20%-45% acetonitrile in water with 0.1% formic acid as a mobile phase to give 3,7-dimethyl-1-[2-methyl-4-(4-methylimidazol-1-yl)phenyl]sulfonyl-indole Broad_P_CaV3.3_553 as an off-white solid (30 mg, 0.0777 mmol, 19% yield). 1 H NMR (400 MHz, DMSO-d6) δ 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). 1 H NMR (400 MHz, DMSO-d 6,D2O exchange) δ 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, MS(ESI): 379.9 [M] +

[0698] 1,5-Dimethyl-4-{[4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl]sulfonyl}-1,2,3,4-tetrahydroquinoxaline (Broad_P_CaV3.3_286, compound 41)

[0699] [ka]

[0700] To a stirred solution of 8-methyl-1-{[4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl]pyridin-3-yl (0.15 g, 391 μmol, 1 equiv.) in DMF (2 mL) was added potassium carbonate (215 mg, 1.56 mmol, 4 equiv.) at room temperature. After stirring for 30 min, methyl iodide (110 mg, 782 μmol, 2 equiv.) was added dropwise at room temperature, and the reaction mixture was stirred at 70 °C for 16 h. After completion, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (3 × 50 mL). The organic layer was washed with brine solution (2 × 50 mL), dried over NaSO, and evaporated. The impure product was purified by flash chromatography using [0–5% MeOH / DCM] to give the impure product. The impure product was purified by preparative HPLC using 20-70% ACN in water with 0.1% formic acid as a modifier as the mobile phase to give 1,5-dimethyl-4-{[4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridiyl]pyridin (0.032 g, 20.6% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 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]+.

[0701] 4-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-2-methylbenzenesulfonyl}-1,5-dimethyl-1,2,3,4-tetrahydroquinoxaline (Broad000415 - 088, compound 42)

[0702] [ka]

[0703] To a vial was added N-methylbromotetrahydroquinoxaline (45 mg, 0.1138 mmol, 1 equiv.), N-difluoromethylpyrazoleboronic acid (33.3 mg, 0.1365 mmol, 1.2 equiv.), sodium carbonate (36.1 mg, 0.3414 mmol, 3 equiv.), and XPhos Pd G2 (4.47 mg, 0.005690 mmol, 0.05 equiv.) in 4:1 dioxane:water (1.5 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 over MgSO4, filtered, and concentrated. The crude product was purified by reverse-phase chromatography (ACN / water) to give the desired difluoromethylpyrazole tetrahydroquinoxaline sulfonamide (20 mg, 37.8% yield). 1H NMR (400 MHz, chloroform-d) δ 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]+.

[0704] 1,5,6-trimethyl-4-[2-methyl-4-(1-methyl-1H-pyrazol-4-yl)benzenesulfonyl]-1,2,3,4-tetrahydroquinoxaline (Broad_P_Cav3.3_306, compound 43)

[0705] [ka]

[0706] To a stirred solution of 4-(4-bromo-2-methylbenzenesulfonyl)-1,5,6-trimethyl-1,2,3,4-tetrahydroquinoxaline (150 mg, 0.3664 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (91.4 mg, 0.4396 mmol) in 1,4-dioxane (3 mL), potassium carbonate (150 mg, 1.09 mmol) was added at room temperature, and the reaction mixture was degassed with argon for 20 minutes. After that, palladium(2+) bis(cyclopenta-1,3-dien-1-yldiphenylphosphane)methylene chloride iron dichloride (29.9 mg, 0.03664 mmol) was added at room temperature, and the reaction mixture was heated at 100 °C for 6 hours. After completion, the reaction mixture was poured into water (30 mL) and extracted with EtOAc (3 × 30 mL). The organic layer was washed with brine solution (2 × 20 mL), dried over NaSO, and evaporated. The residue was purified by Biotage (50:1 CHCl / MeOH; 12M column) to give 1,5,6-trimethyl-4-[2 (90 mg, 57.9% yield) as an off-white solid. 1H NMR (400 MHz, chloroform-d) δ 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]+.

[0707] Synthesis of compound 45

[0708] [ka]

[0709] 1-(4-Bromo-2-methylbenzenesulfonyl)-8-methyl-1,2,3,4-tetrahydroquinoline: Intermediate 55

[0710] [ka]

[0711] A solution of 8-methyl-1,2,3,4-tetrahydroquinoline (0.15 g, 1.01 mmol, 1 equiv.), 4-bromo-2-methylbenzene-1-sulfonyl chloride (816 mg, 3.03 mmol, 3 equiv.), triethylamine (102 mg, 1.01 mmol, 1.0 equiv.), and 2-dimethylaminopyridine (12.3 mg, 101 μmol, 0.1 equiv.) in pyridine (2 mL) was stirred at 110° C. for 16 h. Upon completion, the reaction mixture was evaporated, and the residue was purified by flash chromatography using 0–15% EtOAc / hexanes to afford 1-(4-bromo-2-methylbenzenesulfonyl)-8-methyl-1,2,3,4-tetrahydroquinoline (0.15 g, 39.0% yield) as a white solid. MS:[M+H]+ 382.00

[0712] 8-Methyl-1-[2-methyl-4-(1-methyl-1H-pyrazol-4-yl)benzenesulfonyl]-1,2,3,4-tetrahydroquinoline: Broad_P_CaV3.3_257 (Compound 45)

[0713] [ka]

[0714] A stirred solution of 1-(4-bromo-2-methylbenzenesulfonyl)-8-methyl-1,2,3,4-tetrahydrofuran (0.15 g, 394 μmol, 1 equiv.), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-(98.2 mg, 472 μmol, 1.2 equiv.), and potassium carbonate (163 mg, 1.18 mmol, 3 equiv.) in 1,4-dioxane (5 mL) and water (1 mL) was degassed with nitrogen gas for 15 minutes. After that, tetrakis(triphenylphosphine) (45.5 mg, 39.4 μmol, 0.1 equiv.) was added and the reaction mixture was heated at 90 °C for 16 hours. Upon completion, the reaction mixture was quenched into water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by [0-50% NMR (CDCl)]. Purification by flash chromatography using hexanes / EtOAc] gave an impure product, which was further purified by preparative HPLC using water (40-50% ACN with 0.1% formic acid as a modifier) ​​as the mobile phase to give 8-methyl-1-[2-methyl-4-(1-methyl-1H-pyrazol-4-yl)benzenesulfonate (0.053 g, 35.3% yield) as a white solid. MS:[M+H]+ 382.40. 1 H NMR (400 MHz, DMSO-d6) δ 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).

[0715] 5'-Fluoro-7'-methyl-1'-[[4-methyl-6-(4-methylimidazol-1-yl)-3-pyridyl]sulfonyl]spiro[cyclopropane-1,3'-indoline] (Broad_P_CaV3.3_684, compound 47)

[0716] [ka]

[0717] To a solution of 1'-[(6-bromo-4-methyl-3-pyridyl)sulfonyl]-5'-fluoro-7'-methyl-spiro[cyclopropane-1,3'-indoline] (0.35 g, 0.851 mmol, 1.00 equiv.) in dimethyl sulfoxide (3.5 mL), 4-methylimidazole (0.28 g, 3.40 mmol, 4.00 equiv.), potassium tert-butoxide (0.29 g, 2.55 mmol, 3.00 equiv.), and copper(I) oxide (0.037 g, 0.255 mmol, 0.300 equiv.) were added at room temperature, and the reaction mass was stirred at 140° C. for 1 hour. The reaction mass was quenched in water (250 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4 and evaporated to give the crude product, which was purified by column chromatography using 2% methanol in DCM as the mobile phase to give the compound, which was finally purified by reverse-phase preparative HPLC using 10-100% acetonitrile in water (0.1% formic acid as a 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) δ 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 [MH]-.

[0718] 1'-[(6-bromo-4-methyl-3-pyridyl)sulfonyl]-5'-fluoro-7'-methyl-spiro[cyclopropane-1,3'-indoline]

[0719] [ka]

[0720] To a solution of 5'-fluoro-7'-methyl-spiro[cyclopropane-1,3'-indoline] (0.18 g, 1.02 mmol, 1.00 equiv.) in dichloromethane (1.8 mL), 6-bromo-4-methylpyridine-3-sulfonyl chloride (0.55 g, 2.03 mmol, 2.00 equiv.) and pyridine (0.33 mL, 4.06 mmol, 4.00 equiv.) were added at room temperature, and the reaction mixture was stirred at the same temperature for 1 hour. The reaction mass was quenched with water (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous NaSO and evaporated to give 1'-[(6-bromo-4-methyl-3-pyridyl)sulfonyl]-5'-fluoro-7'-methyl-spiro[cyclopropane-1,3'-indoline] Broad_P_Cav3.3_684 (0.35 g, 0.851 mmol). MS(ESI): 413.0 [M+H]

[0721] 5'-Fluoro-7'-methyl-spiro[cyclopropane-1,3'-indoline]

[0722] [ka]

[0723] To a solution of 5'-fluoro-7'-methyl-spiro[cyclopropane-1,3'-indoline]-2'-one (0.55 g, 2.88 mmol, 1.00 equiv.) in tetrahydrofuran (11 mL) was added lithium aluminum hydride (1 M in THF) (14.39 mL, 14.4 mmol, 5.00 equiv.) dropwise at room temperature, and the reaction mass was stirred at the same temperature for 12 hours. The reaction was quenched in water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4 and evaporated to give 5'-fluoro-7'-methyl-spiro[cyclopropane-1,3'-indoline] (0.20 g, 0.858 mmol, 30% yield). 1H NMR (400 MHz, DMSO-d6) δ 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]+.

[0724] 5'-Fluoro-7'-methyl-spiro[cyclopropane-1,3'-indolin]-2'-one

[0725] [ka]

[0726] To a solution of trimethylsulfoxonium iodide (30710 mg, 140 mmol, 5.00 equiv.) in DMSO (40 mL) was added sodium hydride (60% in oil) (4019 mg, 167 mmol, 6.00 equiv.) in portions. The reaction mixture was stirred at room temperature for 5 minutes. 5-Fluoro-7-methyl-indoline-2,3-dione (5.00 g, 27.9 mmol, 1.00 equiv.) dissolved in DMSO (20 mL) was added and stirred at room temperature for 4 hours. The reaction mixture was quenched with saturated ammonium bromide solution (200 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were dried over anhydrous Na2SO4 and evaporated to give 5'-fluoro-7'-methyl-spiro[cyclopropane-1,3'-indolin]-2'-one (0.55 g, 2.79 mmol, 10% yield). MS(ESI): 192.0 [M+H]+.

[0727] 5-Fluoro-7-methyl-indoline-2,3-dione

[0728] [ka]

[0729] A solution of (2E)-N-(4-fluoro-2-methyl-phenyl)-2-hydroxyimino-acetamide (9.50 g, 48.4 mmol, 1.00 equiv) in H2SO4 (76 mL) was stirred at 50 °C for 3 h. The reaction was quenched in water (500 mL) and extracted with EtOAc (3 x 300 mL). The combined organic layers were dried over anhydrous Na2SO4 and evaporated to give 5-fluoro-7-methyl-indoline-2,3-dione (6.30 g, 34.8 mmol, 72% yield). MS (ESI): 180.0 [M+H]+.

[0730] (2E)-N-(4-fluoro-2-methyl-phenyl)-2-hydroxyimino-acetamide

[0731] [ka]

[0732] A solution of chloral hydrate (14.54 g, 87.9 mmol, 1.10 equiv) and sodium sulfate (11.35 g, 79.9 mmol, 1.00 equiv) in water (120 mL) was stirred at 50° C. for 15 minutes. To the reaction mixture was added 4-fluoro-2-methyl-aniline (10.00 g, 79.9 mmol, 1.00 equiv) in water (60 mL), 1,4-dioxane (60 mL), and concentrated HCl (8.5 mL), and the mixture was stirred at 70° C. for 15 minutes. To the reaction mixture was added a solution of hydroxylamine hydrochloride (11.11 g, 160 mmol, 2.00 equiv) in water (60 mL). The reaction was quenched with water (500 mL) and extracted with EtOAc (3×300 mL). The combined organic layers were dried over anhydrous Na2SO4 and evaporated to give (2E)-N-(4-fluoro-2-methyl-phenyl)-2-hydroxyimino-acetamide as a yellow solid. MS(ESI): 197.1 [M+H]+.

[0733] 1-Ethyl-6-fluoro-4-methyl-3-[[4-methyl-6-(4-methylimidazol-1-yl)-3-pyridyl]sulfonyl]indole (Broad_P_CaV3.3_683, compound 48)

[0734] [ka]

[0735] To a solution of 3-[(6-bromo-4-methyl-3-pyridyl)sulfonyl]-1-ethyl-6-fluoro-4-methyl-indole (0.41 g, 0.997 mmol, 1.00 equiv.) in dimethylformamide (4 mL) was added potassium tert-butoxide (0.34 g, 2.99 mmol, 3.00 equiv.) and purged with argon for 15 minutes. Copper(I) oxide, 99% (metal basis) (0.043 g, 0.299 mmol, 0.300 equiv.) was added and stirred at 140 °C for 6 hours. After 6 hours, the reaction mixture was diluted with water (15 mL) and extracted with EtOAc (3 × 20 mL). The organic layer was dried over NaSO and evaporated under reduced pressure. The residue was purified by Combiflash using DCM:MeOH (9:1) as the mobile phase to give an impure product, which was further purified by reverse-phase preparative HPLC using 40–100% ACN in water with 0.1% formic acid as the mobile phase to give Broad-P_CaV3.3_683 as a white solid (0.058 g, 0.141 mmol, 14% yield). 1H NMR (400 MHz, DMSO-d6) δ 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 MS(ESI): 413.0 [M+H]+.

[0736] 3-[(6-bromo-4-methyl-3-pyridyl)sulfonyl]-1-ethyl-6-fluoro-4-methyl-indole

[0737] [ka]

[0738] To a suspension of 3-[(6-bromo-4-methyl-3-pyridyl)sulfanyl]-1-ethyl-6-fluoro-4-methyl-indole (0.67 g, 1.77 mmol, 1.00 equiv.) in dichloromethane (6.7 mL) was added m-chloroperoxybenzoic acid (0.91 g, 5.30 mmol, 3.00 equiv.) and stirred at 25 °C for 12 h. Upon completion, the reaction was quenched with saturated NaHCO solution (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine solution (2 × 50 mL), dried over NaSO, and evaporated. The residue was purified by silica gel column chromatography using 20% ​​ethyl acetate in hexane as the mobile phase to afford Broad_P_CaV3.3_683 (0.41 g, 0.701 mmol, 40% yield) as a yellow solid. MS(ESI): 413.1 [M+H]+.

[0739] 3-[(6-bromo-4-methyl-3-pyridyl)sulfanyl]-1-ethyl-6-fluoro-4-methyl-indole

[0740] [ka]

[0741] To a stirred solution of 1-ethyl-6-fluoro-4-methyl-indole (0.61 g, 3.44 mmol, 1.00 equiv.) and 6-bromo-4-methyl-pyridine-3-sulfonyl chloride (1.86 g, 6.88 mmol, 2.00 equiv.) in DMF (10 mL) was added tetra-n-butylammonium iodide (2.54 g, 6.88 mmol, 2.00 equiv.). The reaction mixture was stirred at the same temperature for 4 hours. Upon completion, the reaction was quenched with saturated NaSO solution (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine solution (2 × 50 mL), dried over NaSO, and evaporated. The residue was purified by silica gel column chromatography using 15% ethyl acetate in hexane as the mobile phase to give 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]+.

[0742] 1-Ethyl-6-fluoro-4-methyl-indole

[0743] [ka]

[0744] To a solution of 4-bromo-1-ethyl-6-fluoroindole (0.90 g, 3.72 mmol, 1.00 equiv.) in 1,4-dioxane (9 mL) was added a solution of potassium carbonate (1539 mg, 11.2 mmol, 3.00 equiv.) in water (2 mL) and methylboronic acid (267 mg, 4.46 mmol, 1.20 equiv.). After purging the reaction with nitrogen, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride in dichloromethane (304 mg, 0.372 mmol, 0.100 equiv.) was added and stirred at 110 °C for 2 h. Upon completion, the reaction mixture was diluted with ethyl acetate (10 mL) and washed with brine solution (3 × 40 mL). The organic layer was dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by Combiflash using (1:20, ethyl acetate:hexane) as the mobile phase to give Broad_P_CaV3.3_683 (0.61 g, 2.99 mmol, 81% yield) as a light brown liquid. MS(ESI): 178.1 [M+H]+.

[0745] 4-Bromo-1-ethyl-6-fluoro-indole

[0746] [ka]

[0747] To a solution of 4-bromo-6-fluoro-1H-indole (1.00 g, 4.67 mmol, 1.00 equiv.) in DMF at 0 °C, sodium hydride (60% in mineral oil) (0.17 g, 7.01 mmol, 1.50 equiv.) was added in several portions, followed by stirring for 15 minutes. Ethyl iodide (1.46 g, 9.34 mmol, 2.00 equiv.) was then added at the same temperature. The reaction mixture was stirred at 25 °C for 2 hours. Upon completion, the reaction mixture was diluted with ethyl acetate (10 mL) and washed with brine solution (3 × 70 mL). The organic layer was dried over Na2SO4 and evaporated under reduced pressure to give Broad_P_CaV3.3_683 (0.90 g, 3.72 mmol, 80% yield) as the major product. MS (ESI): 244.0 [M+H]+.

[0748] 1,5-Dimethyl-4-[2-methyl-4-(1-methyl-1H-pyrazol-4-yl)benzenesulfonyl]-1,2,3,4-tetrahydroquinoxalin-2-one (Broad_P_Cav3.3_326, compound 49)

[0749] [ka]

[0750] To a stirred solution of 5-methyl-4-[2-methyl-4-(1-methyl-1H-pyrazol-4-yl)benzenesulfonyl]-1,2,3,4-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 to 50 °C and stirred at the same temperature for 5 h. After completion, the reaction mixture was poured into ice water (50 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine solution (2 × 30 mL), dried over Na SO , and evaporated. The residue was purified by Biotage (50:1 CH2Cl2 / MeOH; 12M column) to give 1,5-dimethyl-4-[2-me (0.7 g, 79.6% yield) as an off-white solid. 1H NMR (400 MHz, chloroform-d) δ 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]+.

[0751] 4-[2,6-dimethyl-4-(1-methyl-1H-pyrazol-4-yl)benzenesulfonyl]-1,5-dimethyl-1,2,3,4-tetrahydroquinoxaline (Broad_P_Cav3.3_305, compound 50)

[0752] [ka]

[0753] To a stirred solution of 4-(4-bromo-2,6-dimethylbenzenesulfonyl)-1,5-dimethyl-1,2,3,4-tetrahydroquinoxaline (0.85 g, 2.07 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (516 mg, 2.48 mmol), potassium carbonate (856 mg, 6.20 mmol) in 1,4-dioxane (6 mL) was added at room temperature, and the reaction mixture was degassed with argon for 20 minutes. After that, palladium(2+) bis(cyclopenta-1,3-dien-1-yldiphenylphosphane)methylene chloride iron dichloride (169 mg, 0.207 mmol) was added at room temperature, and the reaction mixture was heated at 100 °C for 6 hours. After completion, the reaction mixture was poured into water (40 mL) and extracted with EtOAc (3 × 30 mL). The organic layer was washed with brine solution (2 × 10 mL), dried over NaSO, and evaporated. The residue was purified by Biotage (50:1 CHCl / MeOH; 12S column) to give 4-[2,6-dimethyl-4-(1) (0.55 g, 64.7% yield) as an off-white solid. 1H NMR (400 MHz, chloroform-d) δ 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 MS (ESI): 411.4 [M+H]+.

[0754] 4-[4-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methylbenzenesulfonyl]-1,5-dimethyl-1,2,3,4-tetrahydroquinoxaline (Broad000415 - 041, compound 51)

[0755] [ka]

[0756] To a vial was added N-methylbromosulfonamide (75 mg, 0.1897 mmol, 1 equiv.), cyclopropylpyrazoleboronic acid pinacol ester (53.2 mg, 0.2276 mmol, 1.2 equiv.), sodium carbonate (60.3 mg, 0.5691 mmol, 3 equiv.), and XPhos Pd G2 (7.46 mg, 0.009485 mmol, 0.05 equiv.) in 4:1 dioxane / water (1.5 mL). The reaction mixture was stirred at 80 °C for 2 h. After cooling to room temperature, the reaction mixture was partitioned between water and EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel flash chromatography (hexane / EtOAc) to give the desired N-methylsulfonamidocyclopropylpyrazole (61 mg, 100% pure, 76% yield). A second purification by reverse phase chromatography eluting with (water / ACN with 0.1% formic acid) removed the pinacol and gave N-methylsulfonamidocyclopropylpyrazole (13.6 mg, 16.9% yield). 1H NMR (400 MHz, chloroform-d) δ 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]+.

[0757] 7-Fluoro-1,5-dimethyl-4-[2-methyl-4-(1-methyl-1H-pyrazol-4-yl)benzenesulfonyl]-1,2,3,4-tetrahydroquinoxaline (Broad_P_Cav3.3_300, compound 52)

[0758] [ka]

[0759] To a stirred solution of 4-(4-bromo-2-methylbenzenesulfonyl)-7-fluoro-1,5-dimethyl-1H-(0.15 g, 362 μmol, 1 equiv.) in 1,4-dioxane (4 mL) and water (1 mL), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-(0.0903 g, 433 μmol, 1.196 equiv.), and potassium carbonate (0.149 g, 1.07 mmol, 2.956 equiv.) was added at room temperature. The reaction mixture was degassed with argon for 20 minutes, after which bis(cyclopenta-1,3-dien-1-yldiphenylphosphane)methylene HCl (0.0592 g, 72.3 μmol, 0.2 equiv.) was added at room temperature, and the reaction mixture was heated at 100 °C for 16 hours. Upon completion, the reaction mixture was poured into water (25 mL) and extracted with EtOAc (3 × 25 mL). The organic layer was washed with brine solution (2 × 10 mL), dried over NaSO, and evaporated. The product was applied to a preparative HPLC column and eluted with a gradient of 15–55% ACN in water containing 0.1% formic acid to give 7-fluoro-1,5-dimethyl-4-[2-methyl-4-(1-methyl-1H-pyrazole-4-yl] (0.03125 g, 20.7% yield). 1H NMR (400 MHz, DMSO-d6) δ 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).

[0760] 6-Chloro-1,5-dimethyl-4-[2-methyl-4-(1-methyl-1H-pyrazol-4-yl)benzenesulfonyl]-1,2,3,4-tetrahydroquinoxaline (Broad_P_Cav3.3_307, compound 53)

[0761] [ka]

[0762] To a stirred solution of 4-(4-bromo-2-methylbenzenesulfonyl)-6-chloro-1,5-dimethyl-1,2,3,4-tetrahydroquinoxaline (45 mg, 0.1047 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (26.1 mg, 0.1256 mmol) in 1,4-dioxane (2 mL), potassium carbonate (43.4 mg, 0.3141 mmol) was added at room temperature, and the reaction mixture was degassed with argon for 20 minutes. After that, palladium(2+) bis(cyclopenta-1,3-dien-1-yldiphenylphosphane)methylene chloride iron dichloride (8.55 mg, 0.01047 mmol) was added at room temperature, and the reaction mixture was heated at 100 °C for 6 hours. After completion, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (3 × 10 mL). The organic layer was washed with brine solution (2 × 10 mL), dried over NaSO, and evaporated. The residue was purified by Biotage (1:1 Hex / EtOAc; 12S column) to give 6-chloro-1,5-dimethy (30 mg, 63.8% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 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]+.

[0763] 1,5-Dimethyl-4-[2-methyl-4-(3-methyl-1,2-oxazol-5-yl)benzenesulfonyl]-1,2,3,4-tetrahydroquinoxaline (Broad_P_CaV3.3_253, compound 54)

[0764] [ka]

[0765] To a stirred solution of 8-methyl-1-[2-methyl-4-(3-methyl-1,2-oxazol-5-yl)benzenesulf (0.145 g, 378 μmol, 1 equiv.) in dichloromethane (10 mL) was added triethylamine (76.5 mg, 756 μmol, 2 equiv.) and methyl iodide (64.2 mg, 453 μmol, 1.2 equiv.) at room temperature, and the reaction mixture was stirred at room temperature for 3 h. After completion, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (3×50 mL). The organic layer was washed with brine solution (2×10 mL), dried over Na2SO4, and evaporated. The crude product was purified by flash chromatography using [0–30% EtOAc / hexane] to give an impure product, which was further purified by preparative HPLC using (55–75% ACN in water with 0.1% formic acid as a modifier) ​​as the mobile phase to give 1,5-dimethyl-4-[2-methyl-4-(3-methyl-1,2-oxazol-5-yl)benzene] (0.0405 g, 27.0% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ8.02 (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).

[0766] 1-[2-ethyl-5-(1-methyl-1H-pyrazol-4-yl)benzenesulfonyl]-8-methyl-1,2,3,4-tetrahydroquinoxaline (Broad_P_Cav3.3_224, compound 56)

[0767] [ka]

[0768] To a stirred solution of N-(2-amino-6-methylphenyl)-2-ethyl-5-(1-methyl-1H-pyrazol-4-yl)benzene-1-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) was added at room temperature. The reaction mixture was heated to 100 °C and stirred at the same temperature for 12 h. After completion, the reaction mixture was poured into ice-water (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine solution (2 × 10 mL), dried over NaSO, and evaporated. The product was applied to a preparative HPLC column and eluted with a gradient of 45–65% ACN in water containing 0.1% formic acid to give 1-[2-ethyl-5-(1-methyl-1H-pyrazol-4-yl)-2-methyl-1H-pyrazol-4-yl]benzene-1-sulfonamide (12 mg, 32.0% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 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]+.

[0769] 1,4-Dimethyl-3-[[4-methyl-6-(4-methylimidazol-1-yl)-3-pyridyl]sulfonyl]indole (Broad_P_CaV3.3_639, compound 57)

[0770] [ka]

[0771] A stirred suspension of 3-[(6-bromo-4-methyl-3-pyridyl)sulfonyl]-1,4-dimethyl-indole (3.60 g, 9.49 mmol, 1.00 equiv.), 4-methyl-1H-imidazole (1.56 g, 19.0 mmol, 2.00 equiv.), and potassium tert-butoxide (3.20 g, 28.5 mmol, 3.00 equiv.) in dimethylformamide (36 mL) was degassed with nitrogen gas for 15 minutes. Copper(I) oxide (0.41 g, 2.85 mmol, 0.300 equiv.) was added, and the mixture was heated at 140 °C for 2 hours. After completion, the reaction mixture was diluted with ethyl acetate (40 mL) and washed with brine solution (3 × 20 mL). The organic layer was dried over NaSO and evaporated under reduced pressure. The residue was purified by Combiflash with DCM:methanol (20:1) as the mobile phase to give a mixture of isomers, which was further purified by preparative 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 (400 MHz, DMSO-d6) δ 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 MS(ESI): 381.0 [M+H]+.

[0772] 3-[(6-bromo-4-methyl-3-pyridyl)sulfonyl]-1,4-dimethyl-indole

[0773] [ka]

[0774] To a stirred solution of 3-[(6-bromo-4-methyl-3-pyridyl)sulfanyl]-1,4-dimethyl-indole (2.00 g, 5.76 mmol, 1.00 equiv) in tetrahydrofuran (11.079 mL) and water (11.079 mL) was added Oxone (7.08 g, 23.0 mmol, 4.00 equiv) at 25 °C. The reaction mixture was stirred at 25 °C for 16 h. Upon completion, the reaction mixture was dissolved in water (30 mL) and extracted into ethyl acetate (3 × 30 mL). The combined organic layers were dried over NaSO and evaporated under reduced pressure to give the crude product, which was purified by flash chromatography using ethyl acetate:hexane (2:8) as the mobile phase to give Broad_P_CaV3.3_639_1335 (1.30 g, 3.43 mmol, 60% yield) as a yellow solid. MS(ESI): 381.1 [M+H]+.

[0775] 3-[(6-bromo-4-methyl-3-pyridyl)sulfanyl]-1,4-dimethyl-indole

[0776] [ka]

[0777] To a stirred solution of 1,4-dimethylindole (3.00 g, 20.7 mmol, 1.00 equiv.) and 6-bromo-4-methyl-pyridine-3-sulfonyl chloride (11.18 g, 41.3 mmol, 2.00 equiv.) in dimethylformamide (39 mL) was added tetrabutylammonium iodide (15260 mg, 41.3 mmol, 2.00 equiv.) at 25 °C. The reaction mixture was stirred at the same temperature for 3 h. Upon completion, the reaction was quenched with saturated NaSO solution (50 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine solution (2 × 150 mL), dried over NaSO, and evaporated. The residue was purified by silica gel column chromatography using 10% ethyl acetate in hexane as the mobile phase to give 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]+.

[0778] 1,5-Dimethyl-4-[2-methyl-4-(2-methyl-2H-1,2,3-triazol-4-yl)benzenesulfonyl]-1,2,3,4-tetrahydroquinoxaline (Broad_P_Cav3.3_289, compound 58)

[0779] [ka]

[0780] To a stirred solution of 1,5-dimethyl-4-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxa-b] (0.1 g, 226 μmol, 1 equiv.), 4-bromo-2-methyl-2H-1,2,3-triazole (54.9 mg, 339 μmol, 1.5 equiv.), potassium carbonate (93.7 mg, 678 μmol, 3.0 equiv.) in 1,4-dioxane (3 mL) and water (0.5 mL) was added at room temperature. The reaction mixture was degassed with argon for 20 minutes, and then palladium(2+) was added. Bis(cyclopenta-1,3-dien-1-yldiphenylphosphane) (18.4 mg, 22.6 μmol, 0.1 equiv.) was added at room temperature, and the reaction mixture was heated at 80° C. for 16 h. After completion, the reaction mixture was poured into water (25 mL) and extracted with EtOAc (3×25 mL). The organic layer was washed with brine solution (2×30 mL), dried over NaSO, and evaporated. The residue was purified by Biotage (8:2 Hex / EtOAc; 12S column) to give 1,5-dimethyl-4-[2-methyl-4-(2-methyl-2H-1,2,3-triazol-4-yl)b (4.9 mg, 5.45% yield) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ 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).

[0781] (2S)-1,2,5-trimethyl-4-[2-methyl-4-(1-methyl-1H-pyrazol-4-yl)benzenesulfonyl]-1,2,3,4-tetrahydroquinoxaline (compound 59) and (2R)-1,2,5-trimethyl-4-[2-methyl-4-(1-methyl-1H-pyrazol-4-yl)benzenesulfonyl]-1,2,3,4-tetrahydroquinoxaline (compound 120) (330 and 331).

[0782] [ka]

[0783] To a stirred solution of 4-(4-bromo-2-methylbenzenesulfonyl)-1,2,5-trimethyl-1,2,3,4-tetrahydroquinoxaline (100 mg, 0.2442 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-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 minutes. Pd(dppf)Cl·DCM (9.97 mg, 0.01221 mmol) was added, and the mixture was heated at 100 °C for 3 hours. After completion, the reaction mixture was filtered through Celite and washed with ethyl acetate (10 mL). The resulting filtrate was dried over NaSO and evaporated. The residue was purified by Biotage (1:1 Hex / EtOAc; 12M column) to give the pure product, which was further purified by chiral preparative HPLC using CO and IPA:hexane (70:30) containing 0.1% diethylamine as the mobile phase to give (2S)-1,2,5-trimethyl-4-[2-methyl-4-(1-methyl-1H-pyrazol-4-yl)benzenesulfonyl]-1,2,3,4-tetrahydroquinoxaline (10 mg, 9.70%) as a brown semisolid and (2R)-1,2,5-trimethyl-4-[2-methyl-4-(1-methyl-1H-pyrazol-4-yl)benzenesulfonyl]-1,2,3,4-tetrahydroquinoxaline (35 mg, 34.9%) as an off-white solid. Broad_P_CaV3.3_330 1H NMR (400 MHz, DMSO-d6) δ 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) δ 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]+.

[0784] 1,5-ジジメチル-4-[2-メチル-4-(5-メチル-1,3,4-オキサジアゾール-2-イル)ベンゼンスルホニル]-1,2,3,4-テトラヒドロキノキサリン (Broad_P_Cav3.3_324, compound 60)

[0785]

change

[0786] To a stirred solution of 1,5-dimethyl-4-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonyl]-1,2,3,4-tetrahydroquinoxaline (150 mg, 0.3390 mmol), 2-bromo-5-methyl-1,3,4-oxadiazole (66.2 mg, 0.4068 mmol) in 1,4-dioxane (3 mL) and water (0.3 mL) was added potassium carbonate (139 mg, 1.01 mmol) at room temperature. The reaction mixture was degassed with argon for 20 minutes, after which palladium(2+) bis(cyclopenta-1,3-dien-1-yldiphenylphosphane)methylene chloride iron dichloride (27.6 mg, 0.03390 mmol) was added at room temperature, and the reaction mixture was heated at 100 °C for 6 hours. After completion, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (3 × 20 mL). The organic layer was washed with brine solution (2 × 20 mL), dried over NaSO, and evaporated. The residue was purified by Biotage (50:1 CHCl / MeOH; 12S column) to give 1,5-dimethyl-4-[2-me (15 mg, 10.9% yield) as a white solid. 1H NMR (400 MHz, chloroform-d) δ 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 = MS (ESI): 399.0 [M+H]+.

[0787] 8-Methyl-1-[2-methyl-4-(1-methylpyrazol-4-yl)phenyl]sulfonyl-2,3-dihydroquinolin-4-one (Broad_P_Cav3.3_389, compound 61)

[0788] [ka]

[0789] To a stirred solution of 8-methyl-2,3-dihydro-1H-quinolin-4-one (0.20 g, 1.23 mmol, 1.00 equiv) in pyridine (2 mL) was added 4-dimethylaminopyridine (0.075 g, 0.616 mmol, 0.500 equiv) and triethylamine (0.52 mL, 3.70 mmol, 3.00 equiv); the reaction mixture was heated at 60° C. for 1 hour. The reaction mixture was cooled to room temperature, and 2-methyl-4-(1-methylpyrazol-4-yl)benzenesulfonyl chloride (1.00 g, 3.70 mmol, 3.00 equiv) was added in several portions. The reaction mixture was heated at 100° C. for 16 hours. After completion, the reaction mixture was poured into 10% citric acid solution (20 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over NaSO and evaporated. The residue was purified by Combiflash using hexane:ethyl acetate (50:50) to give an impure compound, which was further purified by preparative HPLC purification using (25-45% ACN in water with formic acid as a modifier) ​​as the mobile phase to give 8-methyl-1-[2-methyl-4-(1-methylpyrazol-4-yl)phenyl]sulfonyl-2,3-dihydroquinolin-4-one (5 mg, 1% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 8.03 (s, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.64 (d, J = 8.6 Hz, 3H), 7.43 (t, J = 7.6 Hz, 1H), 4.20 (s, 1H), 3.90 (s, 2H), 2.36 (s, 4H), 2.24 (s, 2H), 2.11 (s, 2H). MS(ESI): 396.3 [M+H]+.

[0790] 8-Methyl-2,3-dihydro-1H-quinolin-4-one

[0791] [ka]

[0792] Triflic acid (14.82 mL, 167 mmol, 3.00 equiv.) was added dropwise to a stirred solution of 1-(o-tolyl)azetidin-2-one (9.00 g, 55.8 mmol, 1.00 equiv.) in 1,2-dichloroethane (90 mL) under a nitrogen atmosphere, which was stirred at room temperature for 1 h. After completion, the reaction mixture was poured into water (200 mL) and extracted with DCM (3 × 90 mL). The combined organic layers were dried over NaSO and evaporated. The residue was purified by Combiflash using hexane:ethyl acetate (30:70) to give 8-methyl-2,3-dihydro-1H-quinolin-4-one (5.4 g, 59.6% yield) as a yellow solid. H NMR (400 MHz, chloroform-d) δ 7.81 (dd, J = 8.0, 1.6 Hz, 1H), 7.24 (d, J = 7.1 Hz, 1H), 6.72 (t, J = 7.6 Hz, 1H), 4.36 (s, 1H), 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]+.

[0793] 1-(o-Tolyl)azetidin-2-one

[0794] [ka]

[0795] To a stirred suspension of sodium tert-butoxide (9.19 g, 95.6 mmol, 1.05 equiv) in DMF (90 mL) was added a solution of 3-chloro-N-(o-tolyl)propanamide (18.00 g, 91.1 mmol, 1.00 equiv) in DMF (90 mL) dropwise at room temperature and stirred at the same temperature for 16 h. The reaction mixture was poured into cold water (1000 mL) and extracted with ethyl acetate (3 × 150 mL). The combined organic layers were dried over NaSO and evaporated to give intermediate 755 (9.00 g, 54.3 mmol, 60% yield) as a brown oil. 1H NMR (400 MHz, chloroform-d) δ 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, 1H). MS(ESI): 162.0 [M+H]+.

[0796] 1,5-Dimethyl-4-[2-methyl-4-(4-methylimidazol-1-yl)phenyl]sulfonyl-3H-quinoxalin-2-one (Broad_P_CaV3.3_406, compound 62)

[0797] [ka]

[0798] To a stirred solution of ethyl 2-[2-methyl-6-(methylamino)-N-[2-methyl-4-(4-methylimidazol-1-yl)phenyl]sulfonyl-anilino]acetate (150 mg, 0.260 mmol, 1.00 equiv.) in THF (1 mL), methanol (1 mL), and water (0.5 mL) was added lithium hydroxide monohydrate (44 mg, 1.04 mmol, 4.00 equiv.) and stirred at room temperature for 16 hours. After completion, the reaction mixture was acidified with 1N HCl solution (pH = 2) and evaporated; subsequently, azeotropically washed with methanol. The residue was suspended in methanol (3 mL), filtered through a Buchner funnel, and dried under reduced pressure. The resulting solid (50 mg) was added to water (3 mL) and stirred at room temperature for 16 hours. After 16 h, the reaction mixture was filtered through a Buchner funnel and dried under vacuum to give Broad_P_CaV3.3_406 (5.0 mg, 0.0120 mmol, 5% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 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, MS(ES): 411.6 [M+H]+.

[0799] Ethyl 2-[2-methyl-6-(methylamino)-N-[2-methyl-4-(4-methylimidazol-1-yl)phenyl]sulfonyl-anilino]acetate

[0800] [ka]

[0801] To a stirred solution of ethyl 2-(2-amino-6-methyl-N-[2-methyl-4-(4-methylimidazol-1-yl)phenyl]sulfonyl-anilino)acetate (400 mg, 0.820 mmol, 1.00 equiv.) and paraformaldehyde (25 mg, 0.820 mmol, 1.00 equiv.) in methanol was added acetic acid (4.9 mg, 0.0820 mmol, 0.100 equiv.) and stirred at room temperature for 3 hours. After 3 hours, sodium cyanoborohydride (103 mg, 1.64 mmol, 2.00 equiv.) was added and stirred at room temperature for 16 hours. Upon completion, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic layers were dried over NaSO and evaporated. The residue was purified by Combiflash using ethyl acetate:hexane (1:3) to give Int-824D (150 mg, 0.260 mmol, 32% yield) as a yellow semi-solid. MS(ESI): 457.2 [M+H]+.

[0802] Ethyl 2-(2-amino-6-methyl-N-[2-methyl-4-(4-methylimidazol-1-yl)phenyl]sulfonyl-anilino)acetate

[0803] [ka]

[0804] To a stirred solution of ethyl 2-[2-(tert-butoxycarbonylamino)-6-methyl-N-[2-methyl-4-(4-methylimidazol-1-yl)phenyl]sulfonyl-anilino]acetate (1.15 g, 2.12 mmol, 1.00 equiv) in DCM (10 mL) was added 4 M HCl in dioxane (4 M, 5.3 mL, 21.2 mmol, 10.0 equiv) at 0 °C. The reaction mixture was warmed to 25 °C and stirred for 8 h. Upon completion, the reaction solvent was concentrated under reduced pressure, and the residue was washed with n-hexane (30 mL), stirred with n-hexane (30 mL), and the free solid was filtered and washed with n-hexane (2 × 20 mL). The solid was dried under vacuum to give Broad_P_Cav3.3_406_Int-822E (0.81 g, 1.66 mmol, 78% yield) as the hydrochloride salt as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 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]+.

[0805] Ethyl 2-[2-(tert-butoxycarbonylamino)-6-methyl-N-[2-methyl-4-(4-methylimidazol-1-yl)phenyl]sulfonyl-anilino]acetate

[0806] [ka]

[0807] To a stirred solution of tert-butyl N-[3-methyl-2-[[2-methyl-4-(4-methylimidazol-1-yl)phenyl]sulfonylamino]phenyl]carbamate (2.00 g, 4.12 mmol, 1.00 equiv.) was added ethyl 2-bromoacetate (0.55 mL, 4.94 mmol, 1.20 equiv.) and potassium carbonate (1.70 g, 12.4 mmol, 3.00 equiv.) in DMF (20 mL) at room temperature. The reaction mixture was stirred at 30 °C for 2 h. Upon completion, the reaction mixture was quenched with ice water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine solution (3 × 20 mL), dried over Na SO , and evaporated. The residue was purified by Combiflash column chromatography eluting with 1.2% MeOH in DCM as a gradient to give 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) δ 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]+.

[0808] tert-Butyl N-[3-methyl-2-[[2-methyl-4-(4-methylimidazol-1-yl)phenyl]sulfonylamino]phenyl]carbamate

[0809] [ka]

[0810] To a stirred solution of tert-butyl N-[2-[(4-bromo-2-methylphenyl)sulfonylamino]-3-methylphenyl]carbamate (14.00 g, 27.1 mmol, 1.00 equiv.) and 4-methyl-1H-imidazole (4.45 g, 54.2 mmol, 2.00 equiv.) in 1,4-dioxane (100 mL) under a nitrogen atmosphere at room temperature, potassium phosphate tribasic (11.51 g, 54.2 mmol, 2.00 equiv.), tBuXPhos (2.30 g, 5.42 mmol, 0.200 equiv.), and [Pd(dba)(III)] (2.48 g, 2.71 mmol, 0.100 equiv.) were added at the 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 × 100 mL). The combined organic layers were washed with brine solution (3 × 50 mL), dried over NaSO, and evaporated. The residue was purified by flash column chromatography eluting with 1.5% MeOH in DCM as a gradient to give 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].

[0811] tert-Butyl N-[2-[(4-bromo-2-methyl-phenyl)sulfonylamino]-3-methyl-phenyl]carbamate

[0812] [ka]

[0813] To a stirred solution of tert-butyl N-(2-amino-3-methyl-phenyl)carbamate (9.34 g, 42.0 mmol, 1.20 equiv) and pyridine (8.47 mL, 105 mmol, 3.00 equiv) in DCM (100 mL) was added 4-bromo-2-methyl-benzenesulfonyl chloride (9.44 g, 35.0 mmol, 1.00 equiv) at room temperature. The reaction mixture was stirred at 30 °C for 16 h. Upon completion, the reaction mixture was quenched with 10% citric acid solution (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine solution (3 × 100 mL), dried over Na SO , and evaporated. The crude product was purified by silica gel column chromatography using 20% ​​EtOAc in n-hexane as a gradient to give 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].

[0814] 4-Bromo-2-methyl-benzenesulfonyl chloride

[0815] [ka]

[0816] To a stirred solution of 1-bromo-3-methyl-benzene (30.00 g, 175 mmol, 1.00 equiv) in chloroform (300 mL) was added chlorosulfuric acid (58.4 mL, 877 mmol, 5.00 equiv) slowly at 0 °C. The reaction mixture was stirred at 30 °C for 10 h. After completion, the reaction mixture was carefully quenched into ice water (1000 mL) and extracted with DCM (3 × 500 mL). The combined organic layers were washed with brine solution (3 × 200 mL), dried over NaSO, and evaporated to give Broad_P_Cav3.3_406_Int-535 (35.00 g, 130 mmol, 74% yield) as a white solid. H NMR (400 MHz, chloroform-d) δ 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).

[0817] Synthesis of Compounds 63 and 135 and Their Enantiomers (Broad_P_CaV3.3_500, 501, 502, and 503)

[0818] [ka]

[0819] 2,3,5-Trimethylquinoxaline: Intermediate 997B To a solution of 3-methylbenzene-1,2-diamine (3.00 g, 24.6 mmol, 1.00 equiv.) and 3-chlorobutan-2-one (3.14 g, 29.5 mmol, 1.20 equiv.) in methanol (30 mL) was added CHCOONa (3.02 g, 36.8 mmol, 1.50 equiv.), and the reaction mixture was stirred at room temperature. After completion, water was added, and the product was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, and evaporated to give the crude product, which was further purified by column chromatography using silica gel. The desired product was eluted with 20% ethyl acetate in hexane to give 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) δ 7.87 - 7.75 (m, 1H), 7.59 - 7.46 (m, 2H), 2.78 (s, 3H), 2.74 (d, J = 6.5 Hz, 6H).

[0820] [ka]

[0821] 2,3,5-trimethyl-1,2,3,4-tetrahydroquinoxaline: Intermediate 997C To a solution of 2,3,5-trimethylquinoxaline (2.40 g, 13.9 mmol, 1.00 equiv.) in methanol (48 mL) was added NiCl2-6H2O (3.31 g, 13.9 mmol, 1.00 equiv.) at 0 °C and stirred for 10 min. Sodium borohydride (4.22 g, 111 mmol, 8.00 equiv.) was added slowly in lots to the reaction mixture within 1 h. The reaction mixture was stirred at room temperature. Upon completion, the reaction mixture was diluted with ethyl acetate (100 mL) and filtered through a pad of Celite. The filtrate was concentrated, water (100 mL) was added, and the mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, and evaporated to give the crude product, which was further purified by column chromatography using silica gel. The desired product was eluted with 50% ethyl acetate in hexane to give Int-997C (2.40 g, 13.6 mmol, 98% yield) as a solid compound. MS: [M+H] + 177.0 1H NMR (400 MHz, DMSO-d6) δ 6.25 (q, J = 4.6, 3.3 Hz, 3H), 5.14 (s, 1H), 4.53 (d, J = 2.9 Hz, 1H), 3.27 (dq, J = 6.5, 3.9, 3.2 Hz, 1H), 1.97 (s, 3H), 1.00 (dd, J = 10.6, 6.5 Hz, 6H).

[0822] tert-Butyl 2,3,5-trimethyl-3,4-dihydro-2H-quinoxaline-1-carboxylate: Intermediate 997D

[0823] [ka]

[0824] To a solution of 2,3,5-trimethyl-1,2,3,4-tetrahydroquinoxaline (2.40 g, 13.6 mmol, 1.00 equiv.) in tetrahydrofuran (48 mL) was added triethylamine (5.51 g, 54.5 mmol, 4.00 equiv.) at room temperature and stirred for 10 minutes. Boc anhydride (6.54 g, 30.0 mmol, 2.20 equiv.) was slowly added to the reaction mixture within 15 minutes. The reaction mixture was stirred at room temperature. After completion, water (100 mL) was added and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, and evaporated to give the crude product, which was further purified by column chromatography using silica gel. The desired product was eluted with 15% ethyl acetate in hexane to give 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) δ 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),...

Claims

1. Structure of equation (IV): 【Chemistry 1】 (In the equation, each dashed circle independently represents an arbitrarily chosen unsaturated line; X is N, C, or CR 3 and; Y is =N-, -N=, -N(R 9 )-, -(C(R 7 )(R 8 )) p -, =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 )-, -C(R 7 )=N-; p is 1, 2, or 3; Z is N, C, or CR 6 And; R 4 and R 6 They may come together to form =O; A 1 , A 2 , and A 3 These are independently N, C, or CH; G is C, CH, or N; J is N, C, or CH; E is either O or CH; R 1 It is either absent or is hydrogen or alkyl; R 2 ~R 6 These are independently hydrogen or alkyl; R 7 ~R 9 A compound having (where each occurrence is independently hydrogen or alkyl); or The pharmaceutically acceptable salt.

2. Structure of equation (IVa): 【Chemistry 2】 The compound according to claim 1, having (wherein n is 1 or 2). 【Request Item 3】 【Chemistry 3】 The compound according to claim 1.

4. Structure of equation (IVb): 【Chemistry 4】 (In the formula, Y is N, CH, or CR) 10 and; R 10 The compound according to claim 1, wherein ( is hydrogen or alkyl). 【Request Item 5】 【Chemistry 5A】 【Chem.5B】 The compound according to claim 1.

6. R 2 The compound according to claim 1, wherein the alkyl group is alkyl.

7. EC less than 100 μM 50 Strict Ca V 3.3 The compound according to claim 1, which is an enhancer.

8. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical product for use in a method of increasing sleep spindles or rescuing sleep spindle disorder in a subject requiring such action, comprising the compound described in claim 1, or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical for use in a method of increasing rebound burst firing in the thalamic reticular nucleus (TRN) of a subject requiring such action, comprising the compound described in claim 1, or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical product for use in a method of reducing hyperactivity of the thalamic cortex in subjects requiring such reduction, comprising the compound described in claim 1, or a pharmaceutically acceptable salt thereof.

12. The method according to any one of claims 9 to 11, wherein the subject is a human being who has or does not have schizophrenia.

13. A pharmaceutical product for use in methods for treating or preventing schizophrenia or related diseases, disorders, or conditions in subjects requiring the use thereof, comprising the compound described in claim 1, or a pharmaceutically acceptable salt thereof.

14. The pharmaceutical product according to any one of claims 9 to 11 or 13, wherein the subject has altered sleep spindle activity compared to a control subject having a Ca V 3.3 mutation and / or not showing impaired TRN function.

15. A pharmaceutical for use in a method for increasing rebound burst firing of TRNs in a neuron, wherein the method comprises a step of bringing a neuron and the pharmaceutical into contact, the pharmaceutical comprising a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.

16. A method for monitoring target involvement and / or treatment effectiveness in a subject, The method includes the steps of establishing a baseline by measuring the spindle density and / or amplitude in a subject before administering the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, and measuring the spindle density and / or amplitude after administering the compound or a pharmaceutically acceptable salt thereof to the subject, A method for monitoring target involvement and / or treatment efficacy, wherein a comparison of pre-administration spindle density and / or amplitude measured as baseline with spindle density and / or amplitude measured after administration of any of the compounds described in claims 1 to 7 or a pharmaceutically acceptable salt thereof is used.

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