Amino quinoline compounds and uses thereof

Abstract

Provided herein are compounds of formula (I) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein R1, R2, n, L, R4, R5, R6, R7, and R8 are as defined elsewhere herein. Also provided are methods of preparing compounds of formula (I). Also provided herein are methods of modulating TDP-43 and methods of treating a disease or condition mediated by TDP-43 in an individual in need thereof.

Description

[0001] Attorney Docket No.: 185992002040 AMINO QUINOLINE COMPOUNDS AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority benefit of United States Provisional PatentApplication No. 63 / 618,220 filed January 5, 2024, which is hereby incorporated herein byreference in its entirety.FIELD OF THE INVENTION Aspects of the invention generally relate to amino quinoline compounds, pharmaceutical compositions, kits comprising the same, their use as biomolecular condensate modifying drugs (c-mods), and their use in the treatment of a disease or condition. BACKGROUND OF THE INVENTION TAR DNA-binding protein 43 (TDP-43) is a highly conserved and ubiquitously- expressed RNA / DNA-binding protein involved in RNA processing. Cytoplasmic aggregates of TDP-43 occur in >97% of amyotrophic lateral sclerosis (ALS) cases. Stress-induced formation of cytoplasmic TDP-43 biological condensates represent an intermediate, reversible, pre-pathological state in neurons. Over time, TDP-43-containing condensates losetheir fluid-like properties and potentially convert into irreversible, toxic aggregates [Ling, etal., Neuron 79, 416–438 (2013); Markmiller, et al. Cell Reports 36, 109685 (2021); and Lu etal. Nat Cell Biol 1–16 (2022)].The role of condensate dysfunction in ALS pathogenesis is supported by thediscovery of condensate genes as genetic modifiers of ALS (e.g., TAF15, EWSR1, TIA1,HNRNPA1, HNRNPA2B1), as well as co-localization of C9ORF72 ALS G4C2expansion- derived dipeptide repeats (DPRs) and stress granule proteins with TDP-43 inclusions in preclinical models. Nuclear depletion of TDP-43 into cytoplasmic condensates leads to toxic loss of splicing function in motor neurons. Small molecule condensate modifying drugs (c-mods) that directly modulate TDP-43 condensates can treat diverse forms of ALS [Chew, J.et al., Mol. Neurodegener. 14, 9 (2019); and Taylor, J. P., et al., Nature 539, 197–206(2016)]. Attorney Docket No.: 185992002040 BRIEF SUMMARY OF THE INVENTION In one aspect, provided herein is a compound of formula (I): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, orsolvent of any of the foregoing, wherein:R1is H, C1-6alkyl, C2-6alkenyl, -C(=O)R11, -C(=O)OR11, -C(=O)N(R10)(R11), -S(=O)2R11, - S(=O)2N(R10)(R11), C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl,or 5- to 10-membered heteroaryl, whereinthe C1-6alkyl of R1is optionally substituted with one or more R1a, the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to10-membered heteroaryl of R1is optionally substituted with one or more R1b, and optionally, two substituents of the C1-6alkyl, C2-6alkenyl, -C(=O)R11, -C(=O)OR11, - C(=O)N(R10)(R11), -S(=O)2R11, -S(=O)2N(R10)(R11), or C3-8cycloalkyl group of R1are taken together with the atoms to which they are attached to form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-memberedheteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl,or 5- to 10-membered heteroaryl is optionally substituted with one or moreR1b; each R2is independently halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR9, -SR9, -SF5, -N(Rx)(Ry), -NO2, -CN, -N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, - OC(=O)R11, -OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), - C(=O)OR11, -C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, - N(R10)S(=O)2R11, -S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=NR12)R11, -S(=NR12)N(R10)R11, -S(=NR12)OR11, -S(=O)2R11, -S(=O)2N(R10)(R11), C3-8cycloalkyl, 3- to8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, whereinthe C1-6alkyl of R2is optionally substituted by one or more R2a, Attorney Docket No.: 185992002040 the C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R2is optionally substituted with one or more R2b, and the 3- to 8-membered heterocyclyl of R2comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; n is 0, 1, 2, or 3; L is a bond, C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R3)(C1-6alkyl)- wherein the C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R3)(C1-6alkyl)- is optionally substituted by one or more RL; each RLis independently halo, -N(Rx)(Ry), -OR9, -SR9, -SF5, -NO2, -CN, -N(R10)C(=O)R11, - N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, -OC(=O)N(R10)R11, - OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, C3-8cycloalkyl, 3- to 8- membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, or two RLare taken together along with the atoms to which they are attached to form a C3-8cycloalkyl or 3- to 8-membered heterocyclyl; R3is H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C(=O)R11, -S(=O)2R11, -S(=O)2N(R10)(R11), or C3-8cycloalkyl, wherein the C1-6alkyl of R3is optionally substituted with one or more halo, -N(Rx)(Ry), -OR9, - SR9, -SF5, -N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, - OC(=O)R11, -OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), - C(=O)OR11, -C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, - N(R10)S(=O)2R11, -S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=NR12)R11, - S(=NR12)N(R10)R11, -S(=NR12)OR11, -S(=O)2R11, or -S(=O)2N(R10)(R11), and the C3-8cycloalkyl is optionally substituted with one or more R3b; R4is H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR9, -SR9, -SF5, -N(Rx)(Ry), -NO2, -CN, - N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, - OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, - C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, -N(R10)S(=O)2R11, - S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=NR12)R11, -S(=NR12)N(R10)R11, - S(=NR12)OR11, -S(=O)2R11, -S(=O)2N(R10)(R11), C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R4is optionally substituted by one or more R4a, the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R4is optionally substituted with one or more R4b, - C(=O)R11, -C(=O)N(R10)(R11), or -C(=O)OR11, and Attorney Docket No.: 185992002040 the 3- to 12-membered heterocyclyl of R4comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S, and optionally, two substituents of R4are taken together with the atoms to which they are attached form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R4b, -C(=O)R11, -C(=O)N(R10)(R11), or -C(=O)OR11; R5, R6, R7, and R8are each independently H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR9, - OR13, -SR9, -SF5, -N(Rx)(Ry), -NO2, -CN, -N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, - N(R10)C(=O)OR11, -OC(=O)R11, -OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, - C(=O)N(R10)(R11), -C(=O)OR11, -C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, - C(=NR12)OR11, -N(R10)S(=O)2R11, -S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=NR12)R11, -S(=NR12)N(R10)R11, -S(=NR12)OR11, -S(=O)2R11, -S(=O)2N(R10)(R11), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R5, R6, R7, or R8is optionally substituted by one or more R5a, the 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R5, R6, R7, or R8is optionally substituted with one or more R5b, and the 3- to 8-membered heterocyclyl of R5, R6, R7, or R8comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S, and optionally, two substituents of R5, R6, R7, or R8are taken together with the atoms to which they are attached form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R5b; or R6and R7are taken together with the carbon atoms to which they are attached to form a 4- to 8-membered heterocyclyl; each R1a, R2a, R4a, or R5ais independently halo, -N(Rx)(Ry), -OR9, -SR9, -NO2, -CN, - N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, - OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, - C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, -N(R10)S(=O)2R11, - S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=NR12)R11, -S(=NR12)N(R10)R11, - Attorney Docket No.: 185992002040 S(=NR12)OR11, -S(=O)2R11, -S(=O)2N(R10)(R11), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R1a, R2a, R4a, or R5ais optionally substituted with one or more R1b, and the 3- to 12-membered heterocyclyl of R1a, R2a, R4a, or R5acomprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; each R1b, R2b, R3b, R4b, or R5bis independently halo, C1-6alkyl, -OR13, -N(Rx)(Ry), oxo, -CN, C3-8cycloalkyl, or 3- to 8-membered heterocyclyl, wherein wherein the C1-6alkyl of R1b, R2b, R3b, R4b, or R5bis optionally substituted by -OR9, - N(Rx)(Ry), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; each R9is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R9is optionally substituted with one or more halo, deuterium, C1-6alkoxy, -N(Rx)(Ry), or 3- to 8-membered heterocyclyl; each R10is independently H, C1-6alkyl, or C3-8cycloalkyl; each R11is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-6alkyl of R11is optionally substituted by one or more halo, -OH, -O(C1-6alkyl), -O(phenyl), -SH, -S(C1-6alkyl), -(C=O)NH2, -(C=O)OH, -O(C=O)C1-8alkyl), - NH(C=NH)NH2, -N(Rx)(Ry), C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10- membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the 6- to 10-membered aryl is optionally substituted by -OH, and the C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl of R11is optionally substituted with halo, C1-6alkyl, -OH, or -N(Rx)(Ry); each R12is independently H or C1-6alkyl; each R13is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R13is optionally substituted with 6- to 10-membered aryl, or 5- to 10- membered heteroaryl, wherein Attorney Docket No.: 185992002040 the 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionallysubstituted with halo, C1-3alkyl, C1-3alkoxy, -N(Rx)(Ry), or 3- to 12-memberedheterocyclyl, and the 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R13 is optionallysubstituted with halo, C1-3alkyl, C1-3alkoxy, or -N(Rx)(Ry); and each Rxand Ryis independently H, C1-6alkyl, C3-8cycloalkyl, -C(=O)(C1-6alkyl), or - C(=O)O(C1-6alkyl), wherein the C1-6alkyl of Rx or Ry is optionally substituted with 6- to 10-membered aryl, 5- to10-membered heteroaryl, or -NH2, NH(C1-6alkyl), or -N(C1-6alkyl)(C1-6alkyl), and the C1-6alkyl of -C(=O)(C1-6alkyl) or -C(=O)O(C1-6alkyl) is optionally substituted with -O(C=O)C1-8alkyl), wherein when are each H, R1 is not -CH2CH2CH2N(CH3)(CH3). In some embodiments, the compound of formula (I) is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Any embodiments provided herein of a compound of formula (I), or a stereoisomer ortautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of theforegoing, apply where applicable to any other formula detailed herein, the same as if each and every embodiment were specifically and individually listed. Thus, it is understood and described that each embodiment provided herein of a compound of formula (I), or astereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate ofany of the foregoing, such as embodiments related to R1, R2, n, L, RL, R3, R4, R5, R6, R7, R8,R1a, R2a, R4a, R5a, R1b, R2b, R3b, R4b, R5b, R9, R10, R11, R12, R13, Rx, and Ry, apply to formula(II) or (III), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt,hydrate, or solvate of any of the foregoing, the same as if each and every embodiment werespecifically and individually listed. It is also understood and described that all such embodiments may be used in any of the pharmaceutical compositions, methods, kits, uses, orother aspects detailed herein.In one aspect, provided is a pharmaceutical composition comprising a compound offormula (I) or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, ora pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, and one or Attorney Docket No.: 185992002040more pharmaceutically acceptable excipients. This aspect in some embodiments may employa compound of any of formulas (II) or (III), or a stereoisomer or tautomer thereof, or apharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing. In anotheraspect, provided is a pharmaceutical composition comprising a compound of formula (I) orany variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceuticallyacceptable excipients. This aspect in some embodiments may employ a compound of any offormulas (II) or (III), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptablesalt of any of the foregoing. In one aspect, provided is a method for treating a disease or condition mediated byTDP-43, comprising administering to an individual in need thereof a compound of formula(I) or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or apharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, or apharmaceutical composition comprising a compound of formula (I) or any variation orembodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptablesalt, hydrate, or solvate of any of the foregoing, and one or more pharmaceutically acceptableexcipients. This aspect in some embodiments may employ a compound of any of formulas(II) or (III), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt,hydrate, or solvate of any of the foregoing. In another aspect, provided is a method fortreating a disease or condition mediated by TDP-43, comprising administering to anindividual in need thereof a compound of formula (I) or any variation or embodiment thereof,or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of theforegoing, or a pharmaceutical composition comprising a compound of formula (I) or anyvariation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptableexcipients. This aspect in some embodiments may employ a compound of any of formulas(II) or (III), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing. In one aspect, provided herein is a method of modulating TDP-43, comprisingcontacting a cell with an effective amount of a compound of formula (I), or a stereoisomer ortautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of theforegoing. This aspect in some embodiments may employ a compound of any of formulas (II)or (III), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate,or solvate of any of the foregoing. In another aspect, provided herein is a method of Attorney Docket No.: 185992002040modulating TDP-43, comprising contacting a cell with an effective amount of a compound offormula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt ofany of the foregoing. This aspect in some embodiments may employ a compound of any offormulas (II) or (III), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptablesalt of any of the foregoing.In one aspect, provided herein is a method of modulating TDP-43 target geneexpression levels, comprising contacting a cell with an effective amount of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt,hydrate, or solvate of any of the foregoing. This aspect in some embodiments may employ acompound of any of formulas (II) or (III), or a stereoisomer or tautomer thereof, or apharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing. In anotheraspect, provided herein is a method of modulating TDP-43 target gene expression levels,comprising contacting a cell with an effective amount of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of theforegoing. This aspect in some embodiments may employ a compound of any of formulas (II)or (III), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In one aspect, provided herein is a compound of formula (I), or a stereoisomer ortautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of theforegoing, or a pharmaceutical composition comprising a compound of formula (I) or anyvariation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceuticallyacceptable salt, hydrate, or solvate of any of the foregoing, and one or more pharmaceuticallyacceptable excipients, for use in the treatment of a disease or condition mediated by TDP-43.This aspect in some embodiments may employ a compound of any of formulas (II) or (III), ora stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvateof any of the foregoing. In another aspect, provided herein is a compound of formula (I), or astereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of theforegoing, or a pharmaceutical composition comprising a compound of formula (I) or anyvariation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptableexcipients, for use in the treatment of a disease or condition mediated by TDP-43. This aspectin some embodiments may employ a compound of any of formulas (II) or (III), or astereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Attorney Docket No.: 185992002040 In one aspect, provided herein is the use of a compound of formula (I), or astereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate ofany of the foregoing, or a pharmaceutical composition comprising a compound of formula (I) or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or apharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, and one or morepharmaceutically acceptable excipients, in the manufacture a medicament for the treatment ofa disease or condition mediated by TDP-43. This aspect in some embodiments may employ acompound of any of formulas (II) or (III), or a stereoisomer or tautomer thereof, or apharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing. In anotheraspect, provided herein is the use of a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceuticalcomposition comprising a compound of formula (I) or any variation or embodiment thereof,or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients, in the manufacture amedicament for the treatment of a disease or condition mediated by TDP-43. This aspect insome embodiments may employ a compound of any of formulas (II) or (III), or astereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In one aspect, provided herein is a kit, comprising (i) a compound of formula (I), or astereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate ofany of the foregoing, and (ii) instructions for use in treating a TDP-43 mediated disease orcondition in an individual in need thereof. This aspect in some embodiments may employ acompound of any of formulas (II) or (III), or a stereoisomer or tautomer thereof, or apharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing. In anotheraspect, provided herein is a kit, comprising (i) a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (ii)instructions for use in treating a TDP-43 mediated disease or condition in an individual inneed thereof. This aspect in some embodiments may employ a compound of any of formulas (II) or (III), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. All pharmaceutical compositions, methods, kits, uses, or other aspects described herein with reference to formula (I), or stereoisomer or tautomer thereof, or apharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, are also hereby Attorney Docket No.: 185992002040 described and embraced for any one of the other formulas detailed herein such as formula (II) or (III), the same as if each and every embodiment were specifically and individually listed. DETAILED DESCRIPTION OF THE INVENTION “Individual” refers to mammals and includes humans and non-human mammals. Examples of individuals include, but are not limited to, mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cows, and humans. In some embodiments, individual refers to a human. As used herein, “about” a parameter or value includes and describes that parameter or value per se. For example, “about X” includes and describes X per se. “Treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired results may include one or more of the following: decreasing one or more symptom resulting from the disease or condition; diminishing the extent of the disease or condition; slowing or arresting the development of one or more symptom associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition); and relieving the disease, such as by causing the regression of clinical symptoms (e.g., ameliorating the disease state, enhancing the effect of another medication, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival). As used herein, “delaying” development of a disease or condition means to defer, hinder, slow, retard, stabilize and / or postpone development of the disease or condition. Thisdelay can be of varying lengths of time, depending on the history of the disease and / orindividual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease or condition. As used herein, the term “therapeutically effective amount” or “effective amount” intends such amount of a compound of the disclosure or a pharmaceutically salt thereof sufficient to effect treatment when administered to an individual. As is understood in the art, an effective amount may be in one or more doses, e.g., a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved. Attorney Docket No.: 185992002040 As used herein, “unit dosage form” refers to physically discrete units, suitable as unit dosages, each unit containing a predetermined quantity of active ingredient, or compound, which may be in a pharmaceutically acceptable carrier. As used herein, by “pharmaceutically acceptable” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to an individual without causing significant undesirable biological effects. The term “alkyl”, as used herein, refers to an unbranched or branched saturated univalent hydrocarbon chain. As used herein, alkyl has 1-20 carbons (i.e., C1-20alkyl), 1-16 carbons (i.e., C1-16alkyl), 1-12 carbons (i.e., C1-12alkyl), 1-10 carbons (i.e., C1-10alkyl), 1-8 carbons (i.e., C1-8alkyl), 1-6 carbons (i.e., C1-6alkyl), 1-4 carbons (i.e., C1-4alkyl), or 1-3 carbons (i.e., C1-3alkyl). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, iso-pentyl, neo-pentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or molecular formula, all positional isomers having that number of carbon atoms may be encompassed—for example, “butyl” includes n-butyl, sec-butyl, iso-butyl, and tert-butyl; and “propyl” includes n-propyl and iso- propyl. Certain commonly used alternative names may be used and will be understood by those of ordinary skill in the art. For instance, a divalent group, such as a divalent “alkyl” group, may be referred to as an “alkylene”. The term “alkenyl”, as used herein, refers to a branched or unbranched univalent hydrocarbon chain comprising at least one carbon-carbon double bond. As used herein, alkenyl has 2-20 carbons (i.e., C2-20alkenyl), 2-16 carbons (i.e., C2-16alkenyl), 2-12 carbons (i.e., C2-12alkenyl), 2-10 carbons (i.e., C2-10alkenyl), 2-8 carbons (i.e., C2-8alkenyl), 2-6 carbons (i.e., C2-6alkenyl), 2-4 carbons (i.e., C2-4alkenyl), or 2-3 carbons (i.e., C2-3alkenyl). Examples of alkenyl include, but are not limited to, ethenyl, prop-1-enyl, prop-2-enyl 1,2- butadienyl, and 1,3-butadienyl. When an alkenyl residue having a specific number of carbons is named by chemical name or molecular formula, all positional isomers having that number of carbon atoms may be encompassed—for example, “propenyl” includes prop-1- enyl and prop-2-enyl. Certain commonly used alternative names may be used and will be understood by those of ordinary skill in the art. For instance, a divalent group, such as a divalent “alkenyl” group, may be referred to as an “alkenylene”. The term “alkynyl”, as used herein, refers to a branched or unbranched univalent hydrocarbon chain comprising at least one carbon-carbon triple bond. As used herein, Attorney Docket No.: 185992002040 alkynyl has 2-20 carbons (i.e., C2-20alkynyl), 2-16 carbons (i.e., C2-16alkynyl), 2-12 carbons (i.e., C2-12alkynyl), 2-10 carbons (i.e., C2-10alkynyl), 2-8 carbons (i.e., C2-8alkynyl), 2-6 carbons (i.e., C2-6alkynyl), 2-4 carbons (i.e., C2-4alkynyl), or 2-3 carbons (i.e., C2-3alkynyl). Examples of alkynyl include, but are not limited to, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1- ynyl, but-2-ynyl, and but-3-ynyl. When an alkynyl residue having a specific number of carbons is named by chemical name or molecular formula, all positional isomers having that number of carbon atoms may be encompassed—for example, “propynyl” includes prop-1- ynyl and prop-2-ynyl. Certain commonly used alternative names may be used and will be understood by those of ordinary skill in the art. For instance, a divalent group, such as a divalent “alkynyl” group, may be referred to as an “alkynylene”. The term “alkoxy”, as used herein, refers to an -O-alkyl moiety. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. The term “aryl”, as used herein, refers to a fully unsaturated carbocyclic ring moiety. The term “aryl” encompasses monocyclic and polycyclic fused-ring moieties. As used herein, aryl encompasses ring moieties comprising, for example, 6 to 20 annular carbonatoms (i.e., 6- to 20-membered aryl), 6 to 16 annular carbon atoms (i.e., 6- to 16-memberedaryl), 6 to 12 annular carbon atoms (i.e., 6- to 12-membered aryl), or 6 to 10 annular carbonatoms (i.e., 6- to 10-membered aryl). Examples of aryl moieties include, but are not limitedto, phenyl, naphthyl, fluorenyl, and anthryl. The term “cycloalkyl”, as used herein, refers to a saturated or partially unsaturated carbocyclic ring moiety. The term “cycloalkyl” encompasses monocyclic and polycyclic ring moieties, wherein the polycyclic moieties may be fused, branched, or spiro. Cycloalkyl includes cycloalkenyl groups, wherein the ring moiety comprises at least one annular double bond. Cycloalkyl includes any polycyclic carbocyclic ring moiety comprising at least one non-aromatic ring, regardless of the point of attachment to the remainder of the molecule. As used herein, cycloalkyl includes rings comprising, for example, 3 to 20 annular carbon atoms (i.e., a C3-20cycloalkyl), 3 to 16 annular carbon atoms (i.e., a C3-16cycloalkyl), 3 to 12 annular carbon atoms (i.e., a C3-12cycloalkyl), 3 to 10 annular carbon atoms (i.e., a C3-10cycloalkyl), 3 to 8 annular carbon atoms (i.e., a C3-8cycloalkyl), 3 to 6 annular carbon atoms (i.e., a C3-6cycloalkyl), or 3 to 5 annular carbon atoms (i.e., a C3-5cycloalkyl). Monocyclic cycloalkyl ring moieties include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbonyl, decalinyl, 7,7-dimethyl -bicyclo [2.2.1]heptanyl, Attorney Docket No.: 185992002040 and the like. Still further, cycloalkyl also includes spiro cycloalkyl ring moieties, for example, spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro [5.5]undecanyl. The term “halo”, as used herein, refers to atoms occupying groups VIIA of The Periodic Table and includes fluorine (fluoro), chlorine (chloro), bromine (bromo), and iodine (iodo). Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “C1-4haloalkyl” is mean to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, difluoromethyl, and the like. The term “heteroaryl”, as used herein, refers to an aromatic (fully unsaturated) ringmoiety that comprises one or more annular heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The term “heteroaryl” includes both monocyclic and polycyclic fused-ring moieties. As used herein, a heteroaryl comprises, forexample, 5 to 20 annular atoms (i.e., a 5- to 20-membered heteroaryl), 5 to 16 annular atoms(i.e., a 5- to 16-membered heteroaryl), 5 to 12 annular atoms (i.e., a 5- to 12-memberedheteroaryl), 5 to 10 annular atoms (i.e., a 5- to 10-membered heteroaryl), 5 to 8 annular atoms(i.e., a 5- to 8-membered heteroaryl), or 5 to 6 annular atoms (i.e., a 5- to 6-memberedheteroaryl). Any monocyclic or polycyclic aromatic ring moiety comprising one or more annular heteroatoms is considered a heteroaryl, regardless of the point of attachment to the remainder of the molecule (i.e., the heteroaryl moiety may be attached to the remainder of the molecule through any annular carbon or any annular heteroatom of the heteroaryl moiety). Examples of heteroaryl groups include, but are not limited to, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, and pyridazinyl. The term “heterocyclyl”, as used herein, refers to a saturated or partially unsaturated cyclic moiety that encompasses one or more annular heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The term “heterocyclyl” includes both monocyclic and polycyclic ring moieties, wherein the polycyclic ring moieties may be fused, bridged, or spiro. Any non-aromatic monocyclic or polycyclic ring moiety comprising at least one annular heteroatom is considered a heterocyclyl, regardless of the point of attachment to the remainder of the molecule (i.e., the heterocyclyl moiety may be attached to the remainder of the molecule through any annular carbon or any annular heteroatom of the heterocyclyl moiety). Further, the term heterocyclyl is intended to encompass any polycyclic ring moiety comprising at least one annular heteroatom wherein the polycyclic ring moiety comprises at least one non-aromatic ring, regardless of the point of attachment to the remainder of the molecule. As used herein, a heterocyclyl comprises, for example, 3 to 20annular atoms (i.e., a 3- to 20-membered heterocyclyl), 3 to 16 annular atoms (i.e., a 3- to 16- Attorney Docket No.: 185992002040membered heterocyclyl), 3 to 12 annular atoms (i.e., a 3- to 12-membered heterocyclyl), 3 to10 annular atoms (i.e., a 3- to 10-membered heterocyclyl), 3 to 8 annular atoms (i.e., a 3- to8-membered heterocyclyl), 3 to 6 annular atoms (i.e., a 3- to 6-membered heterocyclyl), 3 to5 annular atoms (i.e., a 3- to 5-membered heterocyclyl), 5 to 8 annular atoms (i.e., a 5- to 8-membered heterocyclyl), or 5 to 6 annular atoms (i.e., a 5- to 6-membered heterocyclyl).Examples of heterocyclyl groups include, e.g., azetidinyl, piperidinyl, piperazinyl,pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrofuryl, or tetrahydropyranyl. Examples of spiro heterocyclyl rings include, but are not limited to, bicyclic and tricyclic ring systems, such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1- azaspiro[3.3]heptanyl. Examples of fused heterocyclyl rings include, but are not limited to, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidinyl, 5,7- dihydrofuro[3,4-d]pyrimidinyl, and 5,7-dihydrothieno[3,4-d]pyrimidinyl, where theheterocyclyl can be bound via either ring of the fused system.The term “oxo”, as used herein, refers to a =O moiety. The terms “spiro”, “spirocycle” and “spirocyclic”, as used herein, refer to a polycyclic moiety in which two of the rings share one atom in common. The terms “spiro”, “spirocycle”and “spirocyclic” may refer to a saturated or partially unsaturated carbocycle, or a saturatedor partially unsaturated heterocycle.The term “fused”, as used herein, refers to a polycyclic moiety in which two of the rings share two adjacent atoms in common. The term “fused” may refer to a saturated orpartially unsaturated carbocycle, or a saturated or partially unsaturated heterocycle.The term “bridged”, as used herein, refers to a polycyclic moiety in which two of the rings share three or more atoms in common, and the bridgehead atoms are separated by at least one atom. The term “bridged” may refer to a saturated or partially unsaturatedcarbocycle, or a saturated or partially unsaturated heterocycle.The terms “optional” and “optionally”, as used herein, mean that the subsequently described event or circumstance may or may not occur and that the description includes instances where the event or circumstance occurs and instances where it does not. Accordingly, the term “optionally substituted” infers that any one or more (e.g., 1, 2, 1 to 5, 1 to 3, 1 to 2, etc.) hydrogen atoms on the designated atom or moiety or group may be replaced or not replaced by an atom or moiety or group other than hydrogen. By way of illustration and not limitation, the phrase “methyl optionally substituted with one or more chloro” encompasses -CH3, -CH2Cl, -CHCl2, and -CCl3moieties. Attorney Docket No.: 185992002040 It is understood that aspects and embodiments described herein as “comprising” include “consisting of” and “consisting essentially of” embodiments. The term “pharmaceutically acceptable salt”, as used herein, of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and which are not biologically or otherwise undesirable. “Pharmaceutically acceptable salts” include, for example, salts with inorganic acids, and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. See, e.g., Handbook of Pharmaceutical Salts Properties, Selection, and Use, International Union of Pure and Applied Chemistry, John Wiley & Sons (2008), which isincorporated herein by reference in its entirety. Those skilled in the art will recognize varioussynthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic or organic acids. Salts derived from inorganic acids include, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include, e.g., acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, trifluoroacetic acid, and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic or organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines. Specific examples of suitable amines include, by way of example only,isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine,ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N- ethylpiperidine, and the like. Isotopically labeled forms of the compounds depicted herein may be prepared. Isotopically labeled compounds have structures depicted herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, Attorney Docket No.: 185992002040 carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as2H,3H,11C,13C,14C,13N,15N,15O,17O,18O,31P,32P,35S,18F,36Cl,123I, and125I, respectively. In someembodiments, a compound of formula (I) is provided wherein one or more hydrogen isreplaced by deuterium or tritium. Some of the compounds provided herein may exist as tautomers. Tautomers are in equilibrium with one another. By way of illustration, amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown and regardless of the nature of the equilibrium among tautomers, the compounds of this disclosure are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, for example, amide-containing compounds are understood to include their imidic acid tautomers. Likewise, imidic-acid containing compounds are understood to include their amide tautomers. Also provided herein are prodrugs of the compounds depicted herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvatethereof. In some embodiments, provided herein are prodrugs of the compounds depictedherein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof. Prodrugs are compounds that may be administered to an individual and release, in vivo, a compound depicted herein as the parent drug compound. It is understood that prodrugs may be prepared by modifying a functional group on a parent drug compound in such a way thatthe modification is cleaved in vitro or in vivo to release the parent drug compound. See, e.g.,Rautio, J., Kumpulainen, H., Heimbach, T. et al. Prodrugs: design and clinical applications.Nat Rev Drug Discov 7, 255–270 (2008), which is incorporated herein by reference in itsentirety. The compounds of the present disclosure, or their pharmaceutically acceptable salts,hydrates, or solvates may include an asymmetric center and may thus give rise toenantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms ofabsolute stereochemistry, as (R)- or (S)- (or as (D)- or (L)- for amino acids). The presentdisclosure is meant to include all such possible isomers, as well as their racemic and opticallypure forms and mixtures thereof in any ratio. Optically active (+) and (-), (R)- and (S)-, or(D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or may beresolved using conventional techniques, for example, chromatography and / or fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or the resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high Attorney Docket No.: 185992002040 pressure liquid chromatography (HPLC), and chiral supercritical fluid chromatography (SFC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless specified otherwise, it is intended that the present disclosureincludes both E and Z geometric isomers. Likewise, cis- and trans- are used in theirconventional sense to describe relative spatial relationships. A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds, but having different three-dimensional structures, which are not interchangeable.The present disclosure contemplates various stereoisomers, or mixtures thereof, and includes“enantiomers,” which refers to two stereoisomers whose structures are non-superimposable mirror images of one another. “Diastereomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror images of each other. Where enantiomeric and / or diastereomeric forms exist of a given structure, flat bondsindicate a mixture of stereoisomeric forms of the depicted structure may be present. Wherethe composition is made up of at least 90%, by weight, dashes or wedges with or without thepresence of an “(S)” or “(R)” designation indicate a single enantiomer or diastereomer withknown relative or absolute stereochemistry.COMPOUNDS In one aspect, provided herein is a compound of formula (I): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, orsolvent of any of the foregoing, wherein:R1is H, C1-6alkyl, C2-6alkenyl, -C(=O)R11, -C(=O)OR11, -C(=O)N(R10)(R11), -S(=O)2R11, - S(=O)2N(R10)(R11), C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl,or 5- to 10-membered heteroaryl, whereinthe C1-6alkyl of R1is optionally substituted with one or more R1a, the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to10-membered heteroaryl of R1 is optionally substituted with one or more R1b, and Attorney Docket No.: 185992002040 optionally, two substituents of the C1-6alkyl, C2-6alkenyl, -C(=O)R11, -C(=O)OR11, - C(=O)N(R10)(R11), -S(=O)2R11, -S(=O)2N(R10)(R11), or C3-8cycloalkyl group of R1are taken together with the atoms to which they are attached to form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R1b; each R2is independently halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR9, -SR9, -SF5, - N(Rx)(Ry), -NO2, -CN, -N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, - OC(=O)R11, -OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), - C(=O)OR11, -C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, - N(R10)S(=O)2R11, -S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=NR12)R11, - S(=NR12)N(R10)R11, -S(=NR12)OR11, -S(=O)2R11, -S(=O)2N(R10)(R11), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R2is optionally substituted by one or more R2a, the C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R2is optionally substituted with one or more R2b, and the 3- to 8-membered heterocyclyl of R2comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; n is 0, 1, 2, or 3; L is a bond, C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R3)(C1-6alkyl)- wherein the C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R3)(C1-6alkyl)- is optionally substituted by one or more RL; each RLis independently halo, -N(Rx)(Ry), -OR9, -SR9, -SF5, -NO2, -CN, -N(R10)C(=O)R11, - N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, -OC(=O)N(R10)R11, - OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, C3-8cycloalkyl, 3- to 8- membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, or two RLare taken together along with the atoms to which they are attached to form a C3-8cycloalkyl or 3- to 8-membered heterocyclyl; R3is H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C(=O)R11, -S(=O)2R11, -S(=O)2N(R10)(R11), or C3-8cycloalkyl, wherein the C1-6alkyl of R3is optionally substituted with one or more halo, -N(Rx)(Ry), -OR9, - SR9, -SF5, -N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, - Attorney Docket No.: 185992002040 OC(=O)R11, -OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), - C(=O)OR11, -C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, - N(R10)S(=O)2R11, -S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=NR12)R11, - S(=NR12)N(R10)R11, -S(=NR12)OR11, -S(=O)2R11, or -S(=O)2N(R10)(R11), and the C3-8cycloalkyl is optionally substituted with one or more R3b; R4is H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR9, -SR9, -SF5, -N(Rx)(Ry), -NO2, -CN, - N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, - OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, - C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, -N(R10)S(=O)2R11, - S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=NR12)R11, -S(=NR12)N(R10)R11, - S(=NR12)OR11, -S(=O)2R11, -S(=O)2N(R10)(R11), C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R4is optionally substituted by one or more R4a, the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R4is optionally substituted with one or more R4b, - C(=O)R11, -C(=O)N(R10)(R11), or -C(=O)OR11, and the 3- to 12-membered heterocyclyl of R4comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S, and optionally, two substituents of R4are taken together with the atoms to which they are attached form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R4b, -C(=O)R11, -C(=O)N(R10)(R11), or -C(=O)OR11; R5, R6, R7, and R8are each independently H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR9, - OR13, -SR9, -SF5, -N(Rx)(Ry), -NO2, -CN, -N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, - N(R10)C(=O)OR11, -OC(=O)R11, -OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, - C(=O)N(R10)(R11), -C(=O)OR11, -C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, - C(=NR12)OR11, -N(R10)S(=O)2R11, -S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=NR12)R11, -S(=NR12)N(R10)R11, -S(=NR12)OR11, -S(=O)2R11, -S(=O)2N(R10)(R11), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R5, R6, R7, or R8is optionally substituted by one or more R5a, the 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R5, R6, R7, or R8is optionally substituted with one or more R5b, and Attorney Docket No.: 185992002040 the 3- to 8-membered heterocyclyl of R5, R6, R7, or R8comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S, and optionally, two substituents of R5, R6, R7, or R8are taken together with the atoms to which they are attached form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R5b; or R6and R7are taken together with the carbon atoms to which they are attached to form a 4- to 8-membered heterocyclyl; each R1a, R2a, R4a, or R5ais independently halo, -N(Rx)(Ry), -OR9, -SR9, -NO2, -CN, - N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, - OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, - C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, -N(R10)S(=O)2R11, - S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=NR12)R11, -S(=NR12)N(R10)R11, - S(=NR12)OR11, -S(=O)2R11, -S(=O)2N(R10)(R11), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R1a, R2a, R4a, or R5ais optionally substituted with one or more R1b, and the 3- to 12-membered heterocyclyl of R1a, R2a, R4a, or R5acomprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; each R1b, R2b, R3b, R4b, or R5bis independently halo, C1-6alkyl, -OR13, -N(Rx)(Ry), oxo, -CN, C3-8cycloalkyl, or 3- to 8-membered heterocyclyl, wherein the C1-6alkyl of R1b, R2b, R3b, R4b, or R5bis optionally substituted by -OR9, - N(Rx)(Ry), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; each R9is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R9is optionally substituted with one or more halo, deuterium, C1-6alkoxy, -N(Rx)(Ry), or 3- to 8-membered heterocyclyl; each R10is independently H, C1-6alkyl, or C3-8cycloalkyl; Attorney Docket No.: 185992002040each R11 is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 6- to 10-membered aryl,5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, whereinthe C1-6alkyl of R11 is optionally substituted by one or more halo, -OH, -O(C1-6alkyl),-O(phenyl), -SH, -S(C1-6alkyl), -(C=O)NH2, -(C=O)OH, -O(C=O)C1-8alkyl), -NH(C=NH)NH2, -N(Rx)(Ry), C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, whereinthe 6- to 10-membered aryl is optionally substituted by -OH, andthe C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to12-membered heterocyclyl of R11is optionally substituted with halo, C1-6alkyl, -OH, or -N(Rx)(Ry); each R12is independently H or C1-6alkyl;each R13 is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 3- to 8-memberedheterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, whereinthe C1-6alkyl of R13 is optionally substituted with 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionallysubstituted with halo, C1-3alkyl, C1-3alkoxy, or -N(Rx)(Ry), and the 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R13 is optionallysubstituted with halo, C1-3alkyl, C1-3alkoxy, -N(Rx)(Ry), or 3- to 12-memberedheterocyclyl; andeach Rx and Ry is independently H, C1-6alkyl, C3-8cycloalkyl, -C(=O)(C1-6alkyl), or -C(=O)O(C1-6alkyl), whereinthe C1-6alkyl of Rx or Ry is optionally substituted with 6- to 10-membered aryl, 5- to10-membered heteroaryl, or -NH2, NH(C1-6alkyl), or -N(C1-6alkyl)(C1-6alkyl), and the C1-6alkyl of -C(=O)(C1-6alkyl) or -C(=O)O(C1-6alkyl) is optionally substituted with-O(C=O)C1-8alkyl). In some embodiments of the above, the compound is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments of a compound of formula (I), or any variation or embodimentthereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate,or salt of any of the foregoing:R1 is C1-6alkyl, C2-6alkenyl, -C(=O)R11, -C(=O)OR11, -C(=O)N(R10)(R11), -S(=O)2R11, - S(=O)2N(R10)(R11), or C3-8cycloalkyl, wherein Attorney Docket No.: 185992002040 the C1-6alkyl of R1is optionally substituted with one or more R1a, the C3-8cycloalkyl of R1is optionally substituted with one or more R1b, and optionally, two substituents of the C1-6alkyl, C2-6alkenyl, -C(=O)R11, -C(=O)OR11, - C(=O)N(R10)(R11), -S(=O)2R11, -S(=O)2N(R10)(R11), or C3-8cycloalkyl group of R1are taken together with the atoms to which they are attached to form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R1b; each R2is independently halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR9, -SR9, -SF5, - N(Rx)(Ry), -NO2, -CN, -N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, - OC(=O)R11, -OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), - C(=O)OR11, -C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, - N(R10)S(=O)2R11, -S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=NR12)R11, - S(=NR12)N(R10)R11, -S(=NR12)OR11, -S(=O)2R11, -S(=O)2N(R10)(R11), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R2is optionally substituted by one or more R2a, the C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R2is optionally substituted with one or more R2b, and the 3- to 8-membered heterocyclyl of R2comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; n is 0, 1, 2, or 3; L is a bond, C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R3)(C1-6alkyl)- wherein the C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R3)(C1-6alkyl)- is optionally substituted by one or more RL; each RLis independently halo, -N(Rx)(Ry), -OR9, -SR9, -SF5, -NO2, -CN, -N(R10)C(=O)R11, - N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, -OC(=O)N(R10)R11, - OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, C3-8cycloalkyl, 3- to 8- membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, or two RLare taken together along with the atoms to which they are attached to form a C3-8cycloalkyl or 3- to 8-membered heterocyclyl; R3is H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C(=O)R11, -S(=O)2R11, -S(=O)2N(R10)(R11), or C3-8cycloalkyl, wherein Attorney Docket No.: 185992002040 the C1-6alkyl of R3is optionally substituted with one or more halo, -N(Rx)(Ry), -OR9, - SR9, -SF5, -N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, - OC(=O)R11, -OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), - C(=O)OR11, -C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, - N(R10)S(=O)2R11, -S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=NR12)R11, - S(=NR12)N(R10)R11, -S(=NR12)OR11, -S(=O)2R11, or -S(=O)2N(R10)(R11), and the C3-8cycloalkyl is optionally substituted with one or more R3b; R4is -N(Rx)(Ry), -N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, - OC(=O)N(R10)R11, -C(=O)(C1-6alkyl)N(Rx)(Ry), -C(=O)N(R10)(R11), -N(R10)S(=O)2R11, - S(=O)N(R10)R11, -S(=O)2N(R10)(R11), or 3- to 8-membered N-containing heterocyclyl, wherein the 3- to 8-membered N-containing heterocyclyl of R4is optionally substituted with one or more R4b, -C(=O)R11, -C(=O)N(R10)(R11), or -C(=O)OR11, and the 3- to 8-membered N-containing heterocyclyl of R4comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; R5, R6, R7, and R8are each independently H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR9, - OR13, -SR9, -SF5, -N(Rx)(Ry), -NO2, -CN, -N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, - N(R10)C(=O)OR11, -OC(=O)R11, -OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, - C(=O)N(R10)(R11), -C(=O)OR11, -C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, - C(=NR12)OR11, -N(R10)S(=O)2R11, -S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=NR12)R11, -S(=NR12)N(R10)R11, -S(=NR12)OR11, -S(=O)2R11, -S(=O)2N(R10)(R11), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R5, R6, R7, or R8is optionally substituted by one or more R5a, the 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R5, R6, R7, or R8is optionally substituted with one or more R5b, and the 3- to 8-membered heterocyclyl of R5, R6, R7, or R8comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S, and optionally, two substituents of R5, R6, R7, or R8are taken together with the atoms to which they are attached form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R5b; Attorney Docket No.: 185992002040 or R6and R7are taken together with the carbon atoms to which they are attached to form a 4- to 8-membered heterocyclyl; each R1a, R2a, R4a, or R5ais independently halo, -N(Rx)(Ry), -OR9, -SR9, -NO2, -CN, - N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, - OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, - C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, -N(R10)S(=O)2R11, - S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=NR12)R11, -S(=NR12)N(R10)R11, - S(=NR12)OR11, -S(=O)2R11, -S(=O)2N(R10)(R11), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R1a, R2a, R4a, or R5ais optionally substituted with one or more R1b, and the 3- to 12-membered heterocyclyl of R1a, R2a, R4a, or R5acomprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; each R1b, R2b, R3b, R4b, or R5bis independently halo, C1-6alkyl, -OR13, -N(Rx)(Ry), oxo, -CN, C3-8cycloalkyl, or 3- to 8-membered heterocyclyl, wherein the C1-6alkyl of R1b, R2b, R3b, R4b, or R5bis optionally substituted by -OR9, - N(Rx)(Ry), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; each R9is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl is optionally substituted with one or more halo, deuterium, C1- 6alkoxy, -N(Rx)(Ry), or 3- to 8-membered heterocyclyl; each R10is independently H, C1-6alkyl, or C3-8cycloalkyl; each R11is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-6alkyl of R11is optionally substituted by one or more halo, -OH, -O(C1-6alkyl), -SH, -S(C1-6alkyl), -(C=O)NH2, -(C=O)OH, -O(C=O)C1-8alkyl), -NH(C=NH)NH2, - N(Rx)(Ry), C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the 6- to 10-membered aryl is optionally substituted by -OH, and Attorney Docket No.: 185992002040 the C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to12-membered heterocyclyl of R11is optionally substituted with halo, C1-6alkyl, -OH, or -N(Rx)(Ry); each R12is independently H or C1-6alkyl;each R13 is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 3- to 8-memberedheterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, whereinthe C1-6alkyl of R13 is optionally substituted with 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionallysubstituted with halo, C1-3alkyl, C1-3alkoxy, or -N(Rx)(Ry), and the 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R13 is optionallysubstituted with halo, C1-3alkyl, C1-3alkoxy, -N(Rx)(Ry), or 3- to 12-memberedheterocyclyl; andeach Rx and Ry is independently H, C1-6alkyl, C3-8cycloalkyl, -C(=O)(C1-6alkyl), or -C(=O)O(C1-6alkyl), whereinthe C1-6alkyl of Rx or Ry is optionally substituted with 6- to 10-membered aryl, 5- to10-membered heteroaryl, or -NH2, NH(C1-6alkyl), or -N(C1-6alkyl)(C1-6alkyl), and the C1-6alkyl of -C(=O)(C1-6alkyl) or -C(=O)O(C1-6alkyl) is optionally substituted with-O(C=O)C1-8alkyl). In some embodiments of the above, the compound is a compoundof formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or salt of any of the foregoing:R1 is C1-6alkyl, -C(=O)R11, -C(=O)OR11, -C(=O)N(R10)(R11), or C3-8cycloalkyl, wherein the C1-6alkyl of R1is optionally substituted with one or more R1a, the C3-8cycloalkyl of R1is optionally substituted with one or more R1b; optionally, two substituents of the C1-6alkyl, C2-6alkenyl, -C(=O)R11, -C(=O)OR11, - C(=O)N(R10)(R11), or C3-8cycloalkyl group of R1are taken together with the atoms to which they are attached to form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6-to 10-membered aryl, or 5- to 10-membered heteroaryl, whereinthe C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl,or 5- to 10-membered heteroaryl is optionally substituted with one or moreR1b; Attorney Docket No.: 185992002040 each R2is independently halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR9, -SR9, -N(Rx)(Ry), - NO2, -CN, -N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, - OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, - C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, -N(R10)S(=O)2R11, - S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=O)2R11, -S(=O)2N(R10)(R11), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, wherein the C1-6alkyl of R2is optionally substituted by one or more R2a, the C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl of R2is optionally substituted with one or more R2b, and the 3- to 8-membered heterocyclyl of R2comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; n is 0, 1, 2, or 3; L is a bond, C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R3)(C1-6alkyl)- wherein the C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R3)(C1-6alkyl)- is optionally substituted by one or more RL; each RLis independently halo, -N(Rx)(Ry), -OR9, -SR9, -SF5, -NO2, -CN, -N(R10)C(=O)R11, - N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, -OC(=O)N(R10)R11, - OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, C3-8cycloalkyl, 3- to 8- membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, or two RLare taken together along with the atoms to which they are attached to form a C3-8cycloalkyl or 3- to 8-membered heterocyclyl; R3is H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C(=O)R11, -S(=O)2R11, -S(=O)2N(R10)(R11), or C3-8cycloalkyl, wherein the C1-6alkyl of R3is optionally substituted with one or more halo, -N(Rx)(Ry), -OR9, - SR9, -N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, - OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, - C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, - N(R10)S(=O)2R11, -S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=O)2R11, or - S(=O)2N(R10)(R11), and the C3-8cycloalkyl is optionally substituted with one or more R3b; R4is H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR9, -SR9, -SF5, -N(Rx)(Ry), -NO2, -CN, - N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, - OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, - C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, -N(R10)S(=O)2R11, - Attorney Docket No.: 185992002040 S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=NR12)R11, -S(=NR12)N(R10)R11, - S(=NR12)OR11, -S(=O)2R11, -S(=O)2N(R10)(R11), C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R4is optionally substituted by one or more R4a, the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R4is optionally substituted with one or more R4b, - C(=O)R11, -C(=O)N(R10)(R11), or -C(=O)OR11, and the 3- to 12-membered heterocyclyl of R4comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S, and optionally, two substituents of R4are taken together with the atoms to which they are attached form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R4b, -C(=O)R11, -C(=O)N(R10)(R11), or -C(=O)OR11; R5is H; R6and R7are each independently H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR9, -OR13, - SR9, -N(Rx)(Ry), -NO2, -CN, -N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, -OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), - C(=O)OR11, -C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, - N(R10)S(=O)2R11, -S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=O)2R11, - S(=O)2N(R10)(R11), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6- membered heteroaryl, wherein the C1-6alkyl of R6or R7is optionally substituted by one or more R5a, the 3- to 8-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl of R6or R7is optionally substituted with one or more R5b, and the 3- to 8-membered heterocyclyl of R6or R7comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; or R6and R7are taken together with the carbon atoms to which they are attached to form a 4- to 8-membered heterocyclyl; R8is H; each R1a, R2a, R4a, and R5ais independently halo, -N(Rx)(Ry), -OR9, -SR9, -NO2, -CN, - N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, - OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, - Attorney Docket No.: 185992002040 C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, -N(R10)S(=O)2R11, - S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=O)2R11, -S(=O)2N(R10)(R11), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl of R1a, R2a, R4a, or R5ais optionally substituted with one or more R1b, and the 3- to 12-membered heterocyclyl of R1a, R2a, R4a, or R5acomprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; each R1b, R2b, R3b, R4b, or R5bis independently halo, C1-6alkyl, -OR13, -N(Rx)(Ry), oxo, -CN, C3-8cycloalkyl, or 3- to 8-membered heterocyclyl, wherein the C1-6alkyl of R1b, R2b, R3b, R4b, or R5bis optionally substituted by -OR9, - N(Rx)(Ry), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6- membered heteroaryl; each R9is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl is optionally substituted with one or more halo, deuterium, C1-6alkoxy, -N(Rx)(Ry), or 3- to 8-membered heterocyclyl; each R10is independently H, C1-6alkyl, or C3-8cycloalkyl; each R11is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-6alkyl of R11is optionally substituted by one or more halo, -OH, -O(C1-6alkyl), -SH, -S(C1-6alkyl), -(C=O)NH2, -(C=O)OH, -O(C=O)C1-8alkyl), -NH(C=NH)NH2, - N(Rx)(Ry), C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the 6- to 10-membered aryl is optionally substituted by -OH, and the C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl of R11is optionally substituted with halo, C1-6alkyl, -OH, or -N(Rx)(Ry); each R12is independently H or C1-6alkyl; each R13is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R13is optionally substituted with 6- to 10-membered aryl, or 5- to 10- membered heteroaryl, wherein Attorney Docket No.: 185992002040 the 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionallysubstituted with halo, C1-3alkyl, C1-3alkoxy, -N(Rx)(Ry), or 3- to 12-memberedheterocyclyl, and the 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R13 is optionallysubstituted with halo, C1-3alkyl, C1-3alkoxy, or -N(Rx)(Ry); and each Rxand Ryis independently H, C1-6alkyl, C3-8cycloalkyl, -C(=O)(C1-6alkyl), or - C(=O)O(C1-6alkyl), wherein the C1-6alkyl of Rx or Ry is optionally substituted with 6- to 10-membered aryl, 5- to10-membered heteroaryl, or -NH2, NH(C1-6alkyl), or -N(C1-6alkyl)(C1-6alkyl), and the C1-6alkyl of -C(=O)(C1-6alkyl) or -C(=O)O(C1-6alkyl) is optionally substituted with -O(C=O)C1-8alkyl); wherein when L is -OCH2CH2CH2-, R4 is , and R5 and R6 are each H, R1 is not -CH2CH2CH2N(CH3)(CH3). In some embodiments of the above, the compound is a compoundof formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments of a compound of formula (I), or any variation or embodimentthereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate,or salt of any of the foregoing:R1 is C1-6alkyl, -C(=O)R11, -C(=O)OR11, -C(=O)N(R10)(R11), or C3-8cycloalkyl, wherein the C1-6alkyl of R1is optionally substituted with one or more R1a, the C3-8cycloalkyl of R1is optionally substituted with one or more R1b; optionally, two substituents of the C1-6alkyl, C2-6alkenyl, -C(=O)R11, -C(=O)OR11, - C(=O)N(R10)(R11), or C3-8cycloalkyl of R1are taken together with the atoms to which they are attached to form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, whereinthe C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl,or 5- to 10-membered heteroaryl is optionally substituted with one or moreR1b; andeach R2is independently halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR9, -SR9, -N(Rx)(Ry), - NO2, -CN, -N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, - OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, - C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, -N(R10)S(=O)2R11, - Attorney Docket No.: 185992002040 S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=O)2R11, -S(=O)2N(R10)(R11), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, wherein the C1-6alkyl of R2is optionally substituted by one or more R2a, the C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl of R2is optionally substituted with one or more R2b, and the 3- to 8-membered heterocyclyl of R2comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; n is 0, 1, 2, or 3; L is a bond, C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R3)(C1-6alkyl)-; R3is H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C(=O)R11, -S(=O)2R11, -S(=O)2N(R10)(R11), or C3-8cycloalkyl, wherein the C1-6alkyl of R3is optionally substituted with one or more halo, -N(Rx)(Ry), -OR9, - SR9, -N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, - OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, - C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, - N(R10)S(=O)2R11, -S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=O)2R11, or - S(=O)2N(R10)(R11), and the C3-8cycloalkyl is optionally substituted with one or more R3b; R4is -N(Rx)(Ry), -N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, - OC(=O)N(R10)R11, -C(=O)N(R10)(R11), -N(R10)S(=O)2R11, -S(=O)N(R10)R11, - S(=O)2N(R10)(R11), or 3- to 8-membered N-containing heterocyclyl, wherein the C1-6alkyl of R4is optionally substituted by one or more R4a, the 3- to 8-membered N-containing heterocyclyl of R4is optionally substituted with one or more R4b, -C(=O)R11, -C(=O)N(R10)(R11), or -C(=O)OR11, and the 3- to 8-membered N-containing heterocyclyl of R4comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; R5is H; R6and R7are each independently H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR9, -SR9, - N(Rx)(Ry), -NO2, -CN, -N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, - OC(=O)R11, -OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), - C(=O)OR11, -C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, - N(R10)S(=O)2R11, -S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=O)2R11, - S(=O)2N(R10)(R11), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6- membered heteroaryl, wherein Attorney Docket No.: 185992002040 the C1-6alkyl of R6or R7is optionally substituted by one or more R5a, the 3- to 8-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl of R6or R7is optionally substituted with one or more R5b, and the 3- to 8-membered heterocyclyl of R6or R7comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; or R6and R7are taken together with the carbon atoms to which they are attached to form a 4- to 8-membered heterocyclyl; R8is H; each R1a, R2a, R4a, and R5ais independently halo, -N(Rx)(Ry), -OR9, -SR9, -NO2, -CN, - N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, - OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, - C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, -N(R10)S(=O)2R11, - S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=O)2R11, -S(=O)2N(R10)(R11), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl is optionally substituted with of R1a, R2a, R4a, or R5ais optionally substituted with one or more R1b, and the 3- to 12-membered heterocyclyl of R1a, R2a, R4a, or R5acomprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; each R1b, R2b, R3b, R4b, or R5bis independently halo, C1-6alkyl, -OR13, -N(Rx)(Ry), oxo, -CN, C3-8cycloalkyl, or 3- to 8-membered heterocyclyl; each R9is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl is optionally substituted with one or more halo, deuterium, C1-6alkoxy, -N(Rx)(Ry), or 3- to 8-membered heterocyclyl; each R10is independently H, C1-6alkyl, or C3-8cycloalkyl; each R11is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-6alkyl of R11is optionally substituted by halo, -OH, -O(C1-6alkyl), -O(C=O)C1- 8alkyl), -N(Rx)(Ry), C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, and the C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl of R11is optionally substituted with halo, C1-6alkyl, or - N(Rx)(Ry); Attorney Docket No.: 185992002040 each R12is independently H or C1-6alkyl;each R13 is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 3- to 8-memberedheterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, whereinthe C1-6alkyl of R13 is optionally substituted with 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionallysubstituted with halo, C1-3alkyl, C1-3alkoxy, or -N(Rx)(Ry), and the 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R13 is optionallysubstituted with halo, C1-3alkyl, C1-3alkoxy, or -N(Rx)(Ry); andeach Rx and Ry is independently H, C1-6alkyl, C3-8cycloalkyl, -C(=O)(C1-6alkyl), or -C(=O)O(C1-6alkyl), whereinthe C1-6alkyl of Rx or Ry is optionally substituted with 6- to 10-membered aryl, 5- to10-membered heteroaryl, or -NH2, NH(C1-6alkyl), or -N(C1-6alkyl)(C1-6alkyl), and the C1-6alkyl of -C(=O)(C1-6alkyl) or -C(=O)O(C1-6alkyl) is optionally substituted with-O(C=O)C1-8alkyl); wherein when L is -OCH2CH2CH2-, R4 is , and R5 and R6 are each H, R1 is not -CH2CH2CH2N(CH3)(CH3). In some embodiments of the above, the compound is a compoundof formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments of a compound of formula (I), or any variation or embodimentthereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate,or salt of any of the foregoing: R1is C1-6alkyl optionally substituted with one or more R1a; each R2is independently halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR9, -SR9, -N(Rx)(Ry), - NO2, -CN, -N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, - OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, - C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, -N(R10)S(=O)2R11, -S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=O)2R11, -S(=O)2N(R10)(R11), C3-8cycloalkyl, 3-to 8-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, whereinthe C1-6alkyl of R2is optionally substituted by one or more R2a, the C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6-memberedheteroaryl of R2is optionally substituted with one or more R2b, and Attorney Docket No.: 185992002040 the 3- to 8-membered heterocyclyl of R2comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; n is 0, 1, 2, or 3; L is a bond, C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R3)(C1-6alkyl)- wherein the C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R3)(C1-6alkyl)- is optionally substituted by one or more RL; each RLis independently halo, -N(Rx)(Ry), -OR9, -SR9, -SF5, -NO2, -CN, -N(R10)C(=O)R11, - N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, -OC(=O)N(R10)R11, - OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, C3-8cycloalkyl, 3- to 8- membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, or two RLare taken together along with the atoms to which they are attached to form a C3-8cycloalkyl or 3- to 8-membered heterocyclyl; R3is H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C(=O)R11, -S(=O)2R11, -S(=O)2N(R10)(R11), or C3-8cycloalkyl, wherein the C1-6alkyl of R3is optionally substituted with one or more halo, -N(Rx)(Ry), -OR9, - SR9, -N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, - OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, - C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, - N(R10)S(=O)2R11, -S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=O)2R11, or - S(=O)2N(R10)(R11), and the C3-8cycloalkyl is optionally substituted with one or more R3b; R4is -N(Rx)(Ry), -N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, - OC(=O)N(R10)R11, -C(=O)(C1-6alkyl)N(Rx)(Ry), -C(=O)N(R10)(R11), or 3- to 8-membered N- containing heterocyclyl, wherein the 3- to 8-membered N-containing heterocyclyl of R4is optionally substituted with one or more R4b, -C(=O)R11, -C(=O)N(R10)(R11), or -C(=O)OR11, and the 3- to 8-membered N-containing heterocyclyl of R4comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; R5is H; R6and R7are each independently H, halo, C1-6alkyl, -OR9, -OR13, -N(Rx)(Ry), - N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, - OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, - C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, -N(R10)S(=O)2R11, - S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=O)2R11, or -S(=O)2N(R10)(R11), wherein Attorney Docket No.: 185992002040 the C1-6alkyl of R6or R7is optionally substituted by one or more R5a; or R6and R7are taken together with the carbon atoms to which they are attached to form a 4- to 8-membered heterocyclyl; R8is H; each R1a, R2a, R4a, and R5ais independently halo, -N(Rx)(Ry), -OR9, -SR9, -NO2, -CN, - N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, - OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, - C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, -N(R10)S(=O)2R11, - S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=O)2R11, -S(=O)2N(R10)(R11), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl of R1a, R2a, R4a, or R5ais optionally substituted with one or more R1b, and the 3- to 12-membered heterocyclyl of R1a, R2a, R4a, or R5acomprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; each R1b, R2b, R3b, R4b, or R5bis independently halo, C1-6alkyl, -OR13, -N(Rx)(Ry), oxo, -CN, C3-8cycloalkyl, or 3- to 8-membered heterocyclyl, wherein the C1-6alkyl of R1b, R2b, R3b, R4b, or R5bis optionally substituted by -OR9, - N(Rx)(Ry), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6- membered heteroaryl; each R9is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl is optionally substituted with one or more halo, deuterium, C1- 6alkoxy, -N(Rx)(Ry), or 3- to 8-membered heterocyclyl; each R10is independently H, C1-6alkyl, or C3-8cycloalkyl; each R11is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-6alkyl of R11is optionally substituted by one or more halo, -OH, -O(C1-6alkyl), -SH, -S(C1-6alkyl), -(C=O)NH2, -(C=O)OH, -O(C=O)C1-8alkyl), -NH(C=NH)NH2, - N(Rx)(Ry), C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the 6- to 10-membered aryl is optionally substituted by -OH, and the C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl of R11is optionally substituted with halo, C1-6alkyl, -OH, or -N(Rx)(Ry); Attorney Docket No.: 185992002040 each R12is independently H or C1-6alkyl;each R13 is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 3- to 8-memberedheterocyclyl, phenyl, or 5- to 6-membered heteroaryl, whereinthe C1-6alkyl of R13 is optionally substituted with phenyl, or 5- to 6-memberedheteroaryl, wherein the phenyl, or 5- to 6-membered heteroaryl is optionally substituted with halo,C1-3alkyl, C1-3alkoxy, -N(Rx)(Ry), or 3- to 8-membered heterocyclyl, andthe phenyl, or 5- to 6-membered heteroaryl of R13 is optionally substituted with halo,C1-3alkyl, C1-3alkoxy, or -N(Rx)(Ry); and each Rxand Ryis independently H, C1-6alkyl, C3-8cycloalkyl, -C(=O)(C1-6alkyl), or - C(=O)O(C1-6alkyl), wherein the C1-6alkyl of Rx or Ry is optionally substituted with 6- to 10-membered aryl, 5- to10-membered heteroaryl, or -NH2, NH(C1-6alkyl), or -N(C1-6alkyl)(C1-6alkyl), and the C1-6alkyl of -C(=O)(C1-6alkyl) or -C(=O)O(C1-6alkyl) is optionally substituted with -O(C=O)C1-8alkyl); wherein when L is -OCH2CH2CH2-, R4is , and R5and R6are each H, R1is not -CH2CH2CH2N(CH3)(CH3). In some embodiments of the above, the compound is a compoundof formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments of a compound of formula (I), or any variation or embodimentthereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate,or salt of any of the foregoing: R1is C1-6alkyl optionally substituted with one or more R1a; each R2is independently halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR9, -SR9, -N(Rx)(Ry), - NO2, -CN, -N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, - OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, - C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, -N(R10)S(=O)2R11, -S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=O)2R11, -S(=O)2N(R10)(R11), C3-8cycloalkyl, 3-to 8-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, whereinthe C1-6alkyl of R2is optionally substituted by one or more R2a, the C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6-memberedheteroaryl of R2is optionally substituted with one or more R2b, and Attorney Docket No.: 185992002040 the 3- to 8-membered heterocyclyl of R2comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; n is 0, 1, 2, or 3; L is a bond, C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R3)(C1-6alkyl)-; R3is H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C(=O)R11, -S(=O)2R11, -S(=O)2N(R10)(R11), or C3-8cycloalkyl, wherein the C1-6alkyl of R3is optionally substituted with one or more halo, -N(Rx)(Ry), -OR9, - SR9, -N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, - OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, - C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, - N(R10)S(=O)2R11, -S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=O)2R11, or - S(=O)2N(R10)(R11), and the C3-8cycloalkyl is optionally substituted with one or more R3b; R4is -N(Rx)(Ry), -N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, - OC(=O)N(R10)R11, -C(=O)N(R10)(R11), or 3- to 8-membered N-containing heterocyclyl, wherein the C1-6alkyl of R4is optionally substituted by one or more R4a, the 3- to 8-membered N-containing heterocyclyl of R4is optionally substituted with one or more R4b, -C(=O)R11, -C(=O)N(R10)(R11), or -C(=O)OR11, and the 3- to 8-membered N-containing heterocyclyl of R4comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; and R5is H; R6and R7are each independently H, halo, C1-6alkyl, -OR9, -N(Rx)(Ry), -N(R10)C(=O)R11, - N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, -OC(=O)N(R10)R11, - OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, -C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, -N(R10)S(=O)2R11, -S(=O)R11, -S(=O)2R11, - S(=O)N(R10)R11, -S(=O)OR11, or -S(=O)2N(R10)(R11), wherein the C1-6alkyl of R6or R7is optionally substituted by one or more R5a; or R6and R7are taken together with the carbon atoms to which they are attached to form a 4- to 8-membered heterocyclyl; R8is H; each R1a, R2a, R4a, and R5ais independently halo, -N(Rx)(Ry), -OR9, -SR9, -NO2, -CN, - N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, - OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, - Attorney Docket No.: 185992002040 C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, -N(R10)S(=O)2R11, - S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=O)2R11, -S(=O)2N(R10)(R11), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl is optionally substituted with of R1a, R2a, R4a, or R5ais optionally substituted with one or more R1b, and the 3- to 12-membered heterocyclyl of R1a, R2a, R4a, or R5acomprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; each R1b, R2b, R3b, R4b, or R5bis independently halo, C1-6alkyl, -OR13, -N(Rx)(Ry), oxo, -CN, C3-8cycloalkyl, or 3- to 8-membered heterocyclyl; each R9is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl is optionally substituted with one or more halo, deuterium, C1- 6alkoxy, -N(Rx)(Ry), or 3- to 8-membered heterocyclyl; each R10is independently H, C1-6alkyl, or C3-8cycloalkyl; each R11is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-6alkyl of R11is optionally substituted by halo, -OH, -O(C1-6alkyl), -O(C=O)C1-8alkyl), -N(Rx)(Ry), C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, and the C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl of R11is optionally substituted with halo, C1-6alkyl, or - N(Rx)(Ry); each R12is independently H or C1-6alkyl; each R13is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R13is optionally substituted with 6- to 10-membered aryl, or 5- to 10- membered heteroaryl, wherein the 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with halo, C1-3alkyl, C1-3alkoxy, or -N(Rx)(Ry), and the 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R13is optionally substituted with halo, C1-3alkyl, C1-3alkoxy, or -N(Rx)(Ry); and each Rxand Ryis independently H, C1-6alkyl, C3-8cycloalkyl, -C(=O)(C1-6alkyl), or - C(=O)O(C1-6alkyl), wherein Attorney Docket No.: 185992002040 the C1-6alkyl of Rx or Ry is optionally substituted with 6- to 10-membered aryl, 5- to10-membered heteroaryl, or -NH2, NH(C1-6alkyl), or -N(C1-6alkyl)(C1-6alkyl), and the C1-6alkyl of -C(=O)(C1-6alkyl) or -C(=O)O(C1-6alkyl) is optionally substituted with-O(C=O)C1-8alkyl), wherein when are each H, R1 is not -CH2CH2CH2N(CH3)(CH3). In some embodiments of the above, the compound is a compoundof formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or salt of any of the foregoing: L is a bond or -O(C1-6alkyl);R4 is 3- to 12-membered N-containing heterocyclyl optionally substituted by R4b, -C(=O)R11,-C(=O)N(R10)(R11), or -C(=O)OR11; andR1is C1-4alkyl optionally substituted with one or more substituents selected from the groupconsisting of -OH, -NH(CH3), and -N(CH3)(CH3). In some embodiments of the above, thecompound is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments of formula (I), or any variation or embodiment thereof, or astereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or salt of anyof the foregoing, when L is -OCH2CH2CH2-, R4 is , and R5 and R6 are each H, R1is not -CH2CH2CH2N(CH3)(CH3). In some embodiments of the above, the compound is acompound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate,or solvate of any of the foregoing, R1 is C1-6alkyl substituted with one or more R1a. In someembodiments of the above, the compound is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, Attorney Docket No.: 185992002040or solvate of any of the foregoing, each R1a is independently -OH, -NH(C1-6alkyl), -N(C1-6alkyl)(C1-6alkyl), or phenyl, wherein the phenyl is optionally substituted by halo. In someembodiments, each R1a is independently -OH, -NH(CH3), -N(CH3)(CH3), or fluorophenyl. Insome embodiments of the above, the compound is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments of a compound of formula (I), or any variation or embodimentthereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, R1is selected from the group consisting of compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate,or solvate of any of the foregoing, L is a bond or -O(C1-6alkyl)-. In some embodiments, L is abond or -O(C1-4alkyl)-. In some embodiments, L is a bond or -O(CH2CH2)-. In someembodiments of the above, the compound is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments of a compound of formula (I), or any variation or embodimentthereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, R4is -N(Rx)(Ry). In some embodiments, R4is -NH(C1-6alkyl), -N(C1-6alkyl)(C1-6alkyl), wherein each C1-6alkyl is independently optionallysubstituted by one or more R4a. In some embodiments, R4 is -N(R10)C(O)R11. In someembodiments, R4is -NHC(O)(C1-6alkyl). In some embodiments, R4 is -NHC(O)(CH3). Insome embodiments, R4 is 3- to 12-membered N-containing heterocyclyl optionallysubstituted by R4b, -C(=O)R11, -C(=O)N(R10)(R11), or -C(=O)OR11. In some embodiments, R4is azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, wherein the piperazinyl is optionally substituted by R4b, -C(=O)R11, -C(=O)N(R10)(R11), or -C(=O)OR11. In some embodiments, R4is azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, wherein the piperazinyl is optionally Attorney Docket No.: 185992002040substituted by R4b or -C(=O)R11. In some embodiments of the above, the compound is acompound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, some embodiments of the above, the compound is a compound offormula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, Attorney Docket No.: 185992002040or solvate of any of the foregoing, R6 and R7 are each independently H, halo, C1-6alkyl, -N(Rx)(Ry), -OR9, -N(R10)C(O)R11, or -N(R10)C(O)OR11. In some embodiments, R6and R7are each independently H, halo, C1-6alkyl, -NH(C1-6alkyl), -N(C1-6alkyl)(C1-6alkyl), -O(C1-6alkyl),-O(5- to 6-membered aryl), -O(5- to 6-membered heteroaryl), -NHC(O)(C1-6alkyl), -NHC(O)(5- to 6-membered aryl), or -NHC(O)O(C1-6alkyl), wherein the -O(C1-6alkyl) of R6or R7 is optionally substituted with phenyl or halo; the -O(5- to 6-membered aryl) of R6 or R7is optionally substituted with 4- to 6-membered heterocyclyl; the -NHC(O)(C1-6alkyl) of R6or R7 is optionally by -O(5- to 6-membered aryl); and the -NHC(O)(5- to 6-membered aryl)of R6 or R7 is optionally substituted with -N(Rx)(Ry). In some embodiments, R6 and R7 aretaken together with the carbon atoms to which they are attached to form a 4- to 8-memberedheterocyclyl. In some embodiments, R6 and R7 are taken together with the carbon atoms towhich they are attached to form a 5- to 6-membered heterocyclyl. In some embodiments, R6and R7are taken together with the carbon atoms to which they are attached to form a 5-membered heterocyclyl. In some embodiments, R6 and R7 are taken together with the carbonatoms to which they are attached to form a 6-membered heterocyclyl. In some embodiments, R6and R7are taken together with the carbon atoms to which they are attached to form. In some embodiments of the above, the compound is a compound of formula (I), or astereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, R6and R7are each independently selected from the group consisting of H, -CH3, F, -NH(CH3), -N(CH3)(CH3), -OCF3, -OCH3, are each independently selected from the group consisting of H, -CH3, F, -OCH3, Attorney Docket No.: 185992002040 embodiments of the above, the compound is a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments of a compound of formula (I), or any variation or embodimentthereof, or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, orsolvate of any of the foregoing, R11 is selected from the group consisting configuration. In some embodiments, the aforementioned R14groups have the (S)- Attorney Docket No.: 185992002040configuration. In some embodiments of the above, the compound is a compound of formula(I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments of a compound of formula (I), the compound is a compound of formula (II) any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate ofany of the foregoing, wherein R1, R4, R5, R6, R7, and R8 are as defined elsewhere herein. Inanother variation, R1, R4, R5, R6, R7, and R8are as defined for a compound of formula (I), ora stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of theforegoing, or any variation or embodiment thereof. In some embodiments of a compound offormula (II), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt,hydrate, or solvate of any of the foregoing, the compound is a compound of formula (II), or astereoisomer or tautomer thereof, or a pharmaceutically acceptable salt any of the foregoing. In some embodiments of a compound of formula (I), the compound is a compound offormula (III) any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein R1, R4, R5, R6, R7, and R8are as defined elsewhereherein. In another variation, R1, R4, R5, R6, R7, and R8 are as defined for a compound offormula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of Attorney Docket No.: 185992002040any of the foregoing, or any variation or embodiment thereof. In some embodiments of acompound of formula (III), or a stereoisomer or tautomer thereof, or a pharmaceuticallyacceptable salt, hydrate, or solvate of any of the foregoing, the compound is a compound offormula (III), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt any of the foregoing. In some embodiments, the compounds of formula (I), or any variation or embodimentthereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any ofthe foregoing, selectively modulate TDP-43. In some embodiments, the compounds offormula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, ora pharmaceutically acceptable salt of any of the foregoing, reduce TDP-43 cytoplasmicinclusions, improve nuclear TDP-43 function, or reduce neurodegeneration. In someembodiments, the compounds of formula (I), or any variation or embodiment thereof, or astereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of theforegoing, reduce TDP-43 cytoplasmic inclusions. In some embodiments, the compounds offormula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, ora pharmaceutically acceptable salt of any of the foregoing, improve nuclear TDP-43 function.In some embodiments, the compounds of formula (I), or any variation or embodimentthereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any ofthe foregoing, reduce neurodegeneration. In some embodiments, the compounds of formula(I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or apharmaceutically acceptable salt of any of the foregoing, mitigate TDP-43 cytoplasmiccondensates in motor neurons. In some embodiments, the motor neurons are iPSC-derivedmotor neurons. In some embodiments, STMN2 and POLDIP3 splicing in iPSC-derived motorneurons is restored. In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate,or solvate of any of the foregoing, the compound is selected from Table 1. In someembodiments of a compound of formula (I), or any variation or embodiment thereof, or astereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate ofany of the foregoing, the compound is selected from compounds 1-40 of Table 1. In someembodiments of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, the compound is selected from Table 1, or a pharmaceuticallyacceptable salt of any of the foregoing. In some embodiments of a compound of formula (I), Attorney Docket No.: 185992002040 or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, the compound is selected from compounds 1-40 of Table 1, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments of a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, the compound is selected from compounds 1- 28, or 30-40 of Table 1, or a pharmaceutically acceptable salt of any of the foregoing. Table 1 Attorney Docket No.: 185992002040 Attorney Docket No.: 185992002040 Attorney Docket No.: 185992002040 Attorney Docket No.: 185992002040 Attorney Docket No.: 185992002040 Attorney Docket No.: 185992002040 In some embodiments, provided herein is a compound of formula (I), or any variation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein the compound is selectedfrom the group consisting of: N1,N1-dimethyl-N3-(2-(6-(pyrrolidin-1-yl) pyridin-3-yl) quinolin-4-yl) propane-1,3-diamine; N1-(2-(6-(azetidin-1-yl) pyridin-3-yl)-6,7-dimethoxyquinolin-4-yl)-N3,N3-dimethylpropane- 1,3-diamine; 1-(4-(5-(4-((3-(dimethylamino) propyl) amino)-6,7-dimethoxyquinolin-2-yl) pyridin-2-yl) piperazin-1-yl) ethan-1-one; N1-(2-(6-(4-benzylpiperazin-1-yl) pyridin-3-yl)-7-methoxyquinolin-4-yl)-N3,N3- dimethylpropane-1,3-diamine; N1-(2-(6-(dimethylamino) pyridin-3-yl)-7-methoxyquinolin-4-yl)-N3,N3-dimethylpropane-1,3- diamine; N1-(2-(6-(benzyl(methyl)amino) pyridin-3-yl)-7-methoxyquinolin-4-yl)-N3,N3- dimethylpropane-1,3-diamine; N1-(2-(6-(azetidin-1-yl) pyridin-3-yl)-7-fluoro-6-methoxyquinolin-4-yl)-N3,N3- dimethylpropane-1,3-diamine; N1,N1-dimethyl-N3-(2-(6-(piperazin-1-yl)pyridin-3-yl)quinolin-4-yl)propane-1,3-diamine; N1-(6,7-dimethoxy-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl)-N3, N3- dimethylpropane-1,3-diamine; N1-(2-(6-(azetidin-3-yl) pyridin-3-yl)-6,7-dimethoxyquinolin-4-yl)-N3,N3-dimethylpropane- 1,3-diamine; N1-(7-methoxy-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl)-N3,N3-dimethylpropane-1,3- diamine; N1-(6-methoxy-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl)-N3,N3-dimethylpropane-1,3- diamine; N-(4-((3-(dimethylamino) propyl) amino)-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-6-yl) acetamide; Attorney Docket No.: 185992002040 3-((2-(6-(azetidin-1-yl) pyridin-3-yl)-6,7-dimethoxyquinolin-4-yl) amino)-2- ((dimethylamino)methyl) propan-1-ol; N1-(7-methoxy-2-(6-(2-(methylamino) ethoxy) pyridin-3-yl) quinolin-4-yl)-N3- methylpropane-1,3-diamine; 2-(4-(5-(4-((3-(dimethylamino) propyl) amino)-6,7-dimethoxyquinolin-2-yl) pyridin-2-yl) piperazin-1-yl) ethan-1-ol; (R)-1-(dimethylamino)-3-((7-methoxy-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl) amino) propan-2-ol; (S)-1-(dimethylamino)-3-((7-methoxy-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl) amino) propan-2-ol; ethyl (4-((3-(dimethylamino) propyl) amino)-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-7- yl) carbamate; N4-(3-(dimethylamino) propyl)-6-methoxy-N7,N7-dimethyl-2-(6-(piperazin-1-yl) pyridin-3-yl) quinoline-4,7-diamine; N1,N1-dimethyl-N3-(2-(6-(piperazin-1-yl) pyridin-3-yl)-7-(pyridin-3-yloxy) quinolin-4-yl) propane-1,3-diamine; N1, N1-dimethyl-N3-(2-(6-(piperazin-1-yl) pyridin-3-yl)-7-(trifluoromethoxy) quinolin-4-yl) propane-1,3-diamine; N1-(7-(methoxy-d3)-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl)-N3, N3- dimethylpropane-1,3-diamine; N1,N1-dimethyl-N3-(7-methyl-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl) propane-1,3- diamine; 2-amino-1-(4-(5-(4-((3-(dimethylamino) propyl) amino)-7-methoxyquinolin-2-yl) pyridin-2- yl) piperazin-1-yl) propan-1-one; N1-(2-(6-(4-benzylpiperazin-1-yl) pyridin-3-yl) quinolin-4-yl)-N3, N3-dimethylpropane-1,3- diamine; N-(2-(6-(azetidin-1-yl) pyridin-3-yl)-4-((3-(dimethylamino) propyl) amino) quinolin-7-yl)-2- phenoxyacetamide; 2-(6-(azetidin-1-yl) pyridin-3-yl)-N4-(3-(dimethylamino) propyl)-6-methoxy-N7- methylquinoline-4,7-diamine; N1,N1-dimethyl-N3-(7-(3-phenylpropoxy)-2-(pyridin-3-yl)quinolin-4-yl)propane-1,3-diamine; N4-[3-(dimethylamino) propyl]-N7,N7-dimethyl-2-(6-piperazin-1-yl-3-pyridyl) quinoline-4,7- diamine; Attorney Docket No.: 185992002040 N1-(7-methoxy-2-(6-(methylamino)pyridin-3-yl)quinolin-4-yl)-N3,N3-dimethylpropane-1,3- diamine; N-[2-[6-(azetidin-1-yl)-3-pyridyl]-4-[3-(dimethylamino) propylamino]-6-quinolyl]-4- (diethylamino) benzamide; 3-((7-methoxy-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl) amino) propan-1-ol; N-[3-(4-fluorophenyl) propyl]-2-(6-piperazin-1-yl-3-pyridyl) quinolin-4-amine; N1-(6-fluoro-7-methoxy-2-(6-(piperazin-1-yl)pyridin-3-yl)quinolin-4-yl)-N3,N3- dimethylpropane-1,3-diamine; N1,N1-dimethyl-N3-(2-(6-(piperazin-1-yl)pyridin-3-yl)-7-(4-(pyrrolidin-1- yl)phenoxy)quinolin-4-yl)propane-1,3-diamine; N1-(7-fluoro-2-(6-(piperazin-1-yl)pyridin-3-yl)quinolin-4-yl)-N3,N3-dimethylpropane-1,3- diamine; N1,N1-dimethyl-N3-(2-(6-morpholinopyridin-3-yl)quinolin-4-yl)propane-1,3-diamine;3-[[2-(6-piperazin-1-yl-3-pyridyl)-4-quinolyl] amino] propan-1-ol; andN-(5-(4-((3-(dimethylamino) propyl) amino) quinolin-2-yl) pyridin-2-yl) acetamide. In some embodiments, provided herein is a compound of formula (I), or any variationor embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein the compound is selected from the group consisting of: N1,N1-dimethyl-N3-(2-(6-(pyrrolidin-1-yl) pyridin-3-yl) quinolin-4-yl) propane-1,3-diamine; N1-(2-(6-(azetidin-1-yl) pyridin-3-yl)-6,7-dimethoxyquinolin-4-yl)-N3,N3-dimethylpropane- 1,3-diamine; 1-(4-(5-(4-((3-(dimethylamino) propyl) amino)-6,7-dimethoxyquinolin-2-yl) pyridin-2-yl) piperazin-1-yl) ethan-1-one; N1-(2-(6-(4-benzylpiperazin-1-yl) pyridin-3-yl)-7-methoxyquinolin-4-yl)-N3,N3- dimethylpropane-1,3-diamine; N1-(2-(6-(dimethylamino) pyridin-3-yl)-7-methoxyquinolin-4-yl)-N3,N3-dimethylpropane-1,3- diamine; N1-(2-(6-(benzyl(methyl)amino) pyridin-3-yl)-7-methoxyquinolin-4-yl)-N3,N3- dimethylpropane-1,3-diamine; N1-(2-(6-(azetidin-1-yl) pyridin-3-yl)-7-fluoro-6-methoxyquinolin-4-yl)-N3,N3- dimethylpropane-1,3-diamine; Attorney Docket No.: 185992002040 N1,N1-dimethyl-N3-(2-(6-(piperazin-1-yl)pyridin-3-yl)quinolin-4-yl)propane-1,3-diamine; N1-(6,7-dimethoxy-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl)-N3, N3- dimethylpropane-1,3-diamine; N1-(2-(6-(azetidin-3-yl) pyridin-3-yl)-6,7-dimethoxyquinolin-4-yl)-N3,N3-dimethylpropane- 1,3-diamine; N1-(7-methoxy-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl)-N3,N3-dimethylpropane-1,3- diamine; N1-(6-methoxy-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl)-N3,N3-dimethylpropane-1,3- diamine; N-(4-((3-(dimethylamino) propyl) amino)-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-6-yl) acetamide; 3-((2-(6-(azetidin-1-yl) pyridin-3-yl)-6,7-dimethoxyquinolin-4-yl) amino)-2- ((dimethylamino)methyl) propan-1-ol; N1-(7-methoxy-2-(6-(2-(methylamino) ethoxy) pyridin-3-yl) quinolin-4-yl)-N3- methylpropane-1,3-diamine; 2-(4-(5-(4-((3-(dimethylamino) propyl) amino)-6,7-dimethoxyquinolin-2-yl) pyridin-2-yl) piperazin-1-yl) ethan-1-ol; 1-(dimethylamino)-3-((7-methoxy-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl) amino) propan-2-ol; 1-(dimethylamino)-3-((7-methoxy-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl) amino) propan-2-ol; ethyl (4-((3-(dimethylamino) propyl) amino)-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-7- yl) carbamate; N4-(3-(dimethylamino) propyl)-6-methoxy-N7,N7-dimethyl-2-(6-(piperazin-1-yl) pyridin-3-yl) quinoline-4,7-diamine; N1,N1-dimethyl-N3-(2-(6-(piperazin-1-yl) pyridin-3-yl)-7-(pyridin-3-yloxy) quinolin-4-yl) propane-1,3-diamine; N1, N1-dimethyl-N3-(2-(6-(piperazin-1-yl) pyridin-3-yl)-7-(trifluoromethoxy) quinolin-4-yl) propane-1,3-diamine; N1-(7-(methoxy-d3)-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl)-N3, N3- dimethylpropane-1,3-diamine; N1,N1-dimethyl-N3-(7-methyl-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl) propane-1,3- diamine; Attorney Docket No.: 185992002040 2-amino-1-(4-(5-(4-((3-(dimethylamino) propyl) amino)-7-methoxyquinolin-2-yl) pyridin-2- yl) piperazin-1-yl) propan-1-one; N1-(2-(6-(4-benzylpiperazin-1-yl) pyridin-3-yl) quinolin-4-yl)-N3, N3-dimethylpropane-1,3- diamine; N-(2-(6-(azetidin-1-yl) pyridin-3-yl)-4-((3-(dimethylamino) propyl) amino) quinolin-7-yl)-2- phenoxyacetamide; 2-(6-(azetidin-1-yl) pyridin-3-yl)-N4-(3-(dimethylamino) propyl)-6-methoxy-N7- methylquinoline-4,7-diamine; N1,N1-dimethyl-N3-(7-(3-phenylpropoxy)-2-(pyridin-3-yl)quinolin-4-yl)propane-1,3-diamine; N4-[3-(dimethylamino) propyl]-N7,N7-dimethyl-2-(6-piperazin-1-yl-3-pyridyl) quinoline-4,7- diamine; N1-(7-methoxy-2-(6-(methylamino)pyridin-3-yl)quinolin-4-yl)-N3,N3-dimethylpropane-1,3- diamine; N-[2-[6-(azetidin-1-yl)-3-pyridyl]-4-[3-(dimethylamino) propylamino]-6-quinolyl]-4- (diethylamino) benzamide; 3-((7-methoxy-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl) amino) propan-1-ol; N-[3-(4-fluorophenyl) propyl]-2-(6-piperazin-1-yl-3-pyridyl) quinolin-4-amine; N1-(6-fluoro-7-methoxy-2-(6-(piperazin-1-yl)pyridin-3-yl)quinolin-4-yl)-N3,N3- dimethylpropane-1,3-diamine; N1,N1-dimethyl-N3-(2-(6-(piperazin-1-yl)pyridin-3-yl)-7-(4-(pyrrolidin-1- yl)phenoxy)quinolin-4-yl)propane-1,3-diamine; N1-(7-fluoro-2-(6-(piperazin-1-yl)pyridin-3-yl)quinolin-4-yl)-N3,N3-dimethylpropane-1,3- diamine; N1,N1-dimethyl-N3-(2-(6-morpholinopyridin-3-yl)quinolin-4-yl)propane-1,3-diamine;3-[[2-(6-piperazin-1-yl-3-pyridyl)-4-quinolyl] amino] propan-1-ol; andN-(5-(4-((3-(dimethylamino) propyl) amino) quinolin-2-yl) pyridin-2-yl) acetamide. PHARMACEUTICAL COMPOSITIONS Provided herein are pharmaceutical compositions comprising a compound of formula(I), or any variation or embodiment thereof, such as (II) or (III), or a stereoisomer or tautomerthereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, as described elsewhere herein. In some embodiments, provided herein is a pharmaceutical composition comprising (i) a compound of formula (I), or any variation or embodiment thereof, such as (II) or (III), or a stereoisomer or tautomer thereof, or a pharmaceutically Attorney Docket No.: 185992002040 acceptable salt, hydrate, or solvate of any of the foregoing, and (ii) one or morepharmaceutically acceptable excipients. In another variation, provided herein is apharmaceutical composition comprising (i) a compound of formula (I), or any variation orembodiment thereof, or a stereoisomer or tautomer thereof, such as (II) or (III), or apharmaceutically acceptable salt of any of the foregoing, and (ii) one or morepharmaceutically acceptable excipients. In some embodiments, the composition comprises atherapeutically effective amount of the compound, or a stereoisomer or tautomer thereof, or apharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing. In someembodiments, the composition comprises a therapeutically effective amount of thecompound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt ofany of the foregoing. In some embodiments, provided herein are pharmaceutical compositions comprising(i) a compound of formula (I), stereoisomer or tautomer thereof, or apharmaceutically acceptable salt thereof, and (ii) one or more pharmaceutically acceptableexcipients, wherein R1is C1-6alkyl optionally substituted with one or more R1a; each R2is independently halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR9, -SR9, -N(Rx)(Ry), - NO2, -CN, -N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, - OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, - C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, -N(R10)S(=O)2R11, -S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=O)2R11, -S(=O)2N(R10)(R11), C3-8cycloalkyl, 3-to 8-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, whereinthe C1-6alkyl of R2is optionally substituted by one or more R2a, the C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6-memberedheteroaryl of R2is optionally substituted with one or more R2b, and Attorney Docket No.: 185992002040 the 3- to 8-membered heterocyclyl of R2comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; n is 0, 1, 2, or 3; L is a bond, C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R3)(C1-6alkyl)-; R3is H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C(=O)R11, -S(=O)2R11, -S(=O)2N(R10)(R11), or C3-8cycloalkyl, wherein the C1-6alkyl of R3is optionally substituted with one or more halo, -N(Rx)(Ry), -OR9, - SR9, -N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, - OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, - C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, - N(R10)S(=O)2R11, -S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=O)2R11, or - S(=O)2N(R10)(R11), and the C3-8cycloalkyl is optionally substituted with one or more R3b; R4is -N(Rx)(Ry), -N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, - OC(=O)N(R10)R11, -C(=O)(C1-6alkyl)N(Rx)(Ry), -C(=O)N(R10)(R11), or 3- to 8-membered N- containing heterocyclyl, wherein the 3- to 8-membered N-containing heterocyclyl of R4is optionally substituted with one or more R4b, -C(=O)R11, -C(=O)N(R10)(R11), or -C(=O)OR11, and the 3- to 8-membered N-containing heterocyclyl of R4comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; R5is H; R6and R7are each independently H, halo, C1-6alkyl, -OR9, -N(Rx)(Ry), -N(R10)C(=O)R11, - N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, -OC(=O)N(R10)R11, - OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, -C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, -N(R10)S(=O)2R11, -S(=O)R11, -S(=O)N(R10)R11, - S(=O)OR11, -S(=O)2R11, or -S(=O)2N(R10)(R11), wherein the C1-6alkyl of R6or R7is optionally substituted by one or more R5a; or R6and R7are taken together with the carbon atoms to which they are attached to form a 4- to 8-membered heterocyclyl; each R1a, R2a, R4a, and R5ais independently halo, -N(Rx)(Ry), -OR9, -SR9, -NO2, -CN, - N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, - OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, - C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, -N(R10)S(=O)2R11, - Attorney Docket No.: 185992002040 S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=O)2R11, -S(=O)2N(R10)(R11), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl is optionally substituted with of R1a, R2a, R4a, or R5ais optionally substituted with one or more R1b, and the 3- to 12-membered heterocyclyl of R1a, R2a, R4a, or R5acomprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; each R1b, R2b, R3b, R4b, or R5bis independently halo, C1-6alkyl, -OR13, -N(Rx)(Ry), oxo, -CN, C3-8cycloalkyl, or 3- to 8-membered heterocyclyl, wherein the C1-6alkyl of R1b, R2b, R3b, R4b, or R5bis optionally substituted by -OR9, - N(Rx)(Ry), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6- membered heteroaryl; each R9is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R9is optionally substituted with one or more halo, deuterium, C1-6alkoxy, -N(Rx)(Ry), or 3- to 8-membered heterocyclyl; each R10is independently H, C1-6alkyl, or C3-8cycloalkyl; each R11is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-6alkyl of R11is optionally substituted by halo, -OH, -O(C1-6alkyl), -O(phenyl), - O(C=O)C1-8alkyl), -N(Rx)(Ry), C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10- membered heteroaryl, or 3- to 12-membered heterocyclyl, and the C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl of R11is optionally substituted with halo, C1-6alkyl, or - N(Rx)(Ry); each R12is independently H or C1-6alkyl; each R13is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, wherein the C1-6alkyl of R13is optionally substituted with phenyl, or 5- to 6-membered heteroaryl, wherein the phenyl, or 5- to 6-membered heteroaryl is optionally substituted with halo, C1-3alkyl, C1-3alkoxy, -N(Rx)(Ry), or 3- to 8-membered heterocyclyl, and Attorney Docket No.: 185992002040 the phenyl, or 5- to 6-membered heteroaryl of R13 is optionally substitutedwith halo, C1-3alkyl, C1-3alkoxy, or -N(Rx)(Ry); andeach Rx and Ry is independently H, C1-6alkyl, C3-8cycloalkyl, -C(=O)(C1-6alkyl), or -C(=O)O(C1-6alkyl), whereinthe C1-6alkyl of Rx or Ry is optionally substituted with 6- to 10-membered aryl, 5- to10-membered heteroaryl, or -NH2, NH(C1-6alkyl), or -N(C1-6alkyl)(C1-6alkyl), and the C1-6alkyl of -C(=O)(C1-6alkyl) or -C(=O)O(C1-6alkyl) is optionally substituted with-O(C=O)C1-8alkyl), wherein when are each H, R1 is not -CH2CH2CH2N(CH3)(CH3). Suitable pharmaceutically acceptable excipients may include, for example, fillers, diluents, sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants. Various substances may be embraced by the term excipient, including without limitation any substance used as a binder, disintegrant, coating, compression / encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending / gelling agent, or wet granulation agent. Examples of suitable excipients are well-known to those skilled in the art. See, e.g., Handbook of Pharmaceutical Excipients, Pharmaceutical Press (2017), which is incorporated herein by reference in its entirety. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington’s Pharmaceutical Sciences, Academic Press, 23rded. (2020), which is incorporated herein byreference in its entirety.METHODS OF TREATMENT Traumatic brain injury (TBI) is a risk factor for ALS as demonstrated by the significantly higher incidence of disease in professional athletes and military veterans [See,e.g., Lehman et al. Neurology 79, 1970-1974 (2012); McKee et al. J. Neuropathol. Exp.Neurol. 69, 989-929 (2010); Chio et al. Brain 128, 472-476 (2005), and Sagiraju et al. Mil.Med. 185 e501-e509 (2020), each of which is incorporated herein by reference in its entirety].Cytoplasmic accumulation of TDP-43 has been shown in ~80% brains of patients withrepeated head traumas [McKee et al. J. Neuropathol. Exp. Neurol. 69, 989-929 (2010), whichis incorporated herein by reference in its entirety]. TDP-43 proteinopathy and loss-of- function has been shown to be a driver of neurodegeneration and pathology in preclinical Attorney Docket No.: 185992002040models of brain injury and ALS [Lai et al. Cell Stem Cell 31, 519-536 (2024); Dogan et al.Acta Neuropathol Commun 11, 206 (2023); and Kahriman et al. Brain 146, 5139-5152(2023), each of which is incorporated herein by reference in its entirety].Neurofilament lightchain (NfL) and glial fibrillary acid protein (GFAP) are prognostic neurodegeneration biomarkers for both TBI [Shahim et al. Neurology 95, e610-e622 (2020); Shahim et al. SciRep 6, 36791 (2016) and Abdelhak et al. Nat Rev Neuro 18, 158-172 (2022), each of which isincorporated herein by reference in its entirety] and ALS [Lu et al. Neurology 84, 2247-2257); and Benninger et al. J Clin Neurosci 26, 75-78 (2016), each of which is incorporatedherein by reference in its entirety]. In one aspect, provided is a method for treating a disease or condition mediated byTDP-43, comprising administering to an individual in need thereof a compound of formula(I) or any variation or embodiment thereof, such as (II) or (III), or a stereoisomer or tautomerthereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, or apharmaceutical composition comprising a compound of formula (I) or any variation orembodiment thereof, such as (II) or (III), or a stereoisomer or tautomer thereof, or apharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, and one or morepharmaceutically acceptable excipients. In some embodiments, provided is a method fortreating a disease or condition mediated by TDP-43, comprising administering to anindividual in need thereof a compound of formula (I) or any variation or embodiment thereof,such as (II) or (III), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptablesalt of any of the foregoing, or a pharmaceutical composition comprising a compound offormula (I) or any variation or embodiment thereof, such as (II) or (III), or a stereoisomer ortautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one ormore pharmaceutically acceptable excipients. In some embodiments, a therapeuticallyeffective amount of a compound of formula (I) or any variation or embodiment thereof, suchas (II) or (III), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt,hydrate, or solvate of any of the foregoing, or a pharmaceutical composition comprising acompound of formula (I) or any variation or embodiment thereof, such as (II) or (III), or astereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate ofany of the foregoing, and one or more pharmaceutically acceptable excipients isadministered. In some embodiments, a therapeutically effective amount of a compound offormula (I) or any variation or embodiment thereof, such as (II) or (III), or a stereoisomer ortautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or apharmaceutical composition comprising a compound of formula (I) or any variation or Attorney Docket No.: 185992002040 embodiment thereof, such as (II) or (III), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceuticallyacceptable excipients is administered. In some embodiments, the methods selectivelymodulate TDP-43. In some embodiments, the methods reduce TDP-43 cytoplasmic inclusions, improve nuclear TDP-43 function, or reduce neurodegeneration. In some embodiments, the methods reduce TDP-43 cytoplasmic inclusions. In some embodiments, the methods improve nuclear TDP-43 function. In some embodiments, the methods reduce neurodegeneration. In some embodiments, the methods mitigate TDP-43 cytoplasmic condensates in motor neurons. In some embodiments, the motor neurons are iPSC-derivedmotor neurons. In some embodiments, STMN2 and POLDIP3 splicing in iPSC-derivedmotor neurons is restored. In some embodiments, provided herein is a method for treating a disease or conditionmediated by TDP-43, comprising administering to an individual in need thereof a compoundof formula (I), stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R1is C1-6alkyl optionally substituted with one or more R1a; each R2is independently halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR9, -SR9, -N(Rx)(Ry), - NO2, -CN, -N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, - OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, - C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, -N(R10)S(=O)2R11, -S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=O)2R11, -S(=O)2N(R10)(R11), C3-8cycloalkyl, 3-to 8-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, whereinthe C1-6alkyl of R2is optionally substituted by one or more R2a, Attorney Docket No.: 185992002040 the C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl of R2is optionally substituted with one or more R2b, and the 3- to 8-membered heterocyclyl of R2comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; n is 0, 1, 2, or 3; L is a bond, C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R3)(C1-6alkyl)-; R3is H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C(=O)R11, -S(=O)2R11, -S(=O)2N(R10)(R11), or C3-8cycloalkyl, wherein the C1-6alkyl of R3is optionally substituted with one or more halo, -N(Rx)(Ry), -OR9, - SR9, -N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, - OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, - C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, - N(R10)S(=O)2R11, -S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=O)2R11, or - S(=O)2N(R10)(R11), and the C3-8cycloalkyl is optionally substituted with one or more R3b; R4is -N(Rx)(Ry), -N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, - OC(=O)N(R10)R11, -C(=O)(C1-6alkyl)N(Rx)(Ry), -C(=O)N(R10)(R11), or 3- to 8-membered N- containing heterocyclyl, wherein the 3- to 8-membered N-containing heterocyclyl of R4is optionally substituted with one or more R4b, -C(=O)R11, -C(=O)N(R10)(R11), or -C(=O)OR11, and the 3- to 8-membered N-containing heterocyclyl of R4comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; R5is H; R6and R7are each independently H, halo, C1-6alkyl, -OR9, -N(Rx)(Ry), -N(R10)C(=O)R11, - N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, -OC(=O)N(R10)R11, - OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, -C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, -N(R10)S(=O)2R11, -S(=O)R11, -S(=O)N(R10)R11, - S(=O)OR11, -S(=O)2R11, or -S(=O)2N(R10)(R11), wherein the C1-6alkyl of R6or R7is optionally substituted by one or more R5a; or R6and R7are taken together with the carbon atoms to which they are attached to form a 4- to 8-membered heterocyclyl; each R1a, R2a, R4a, and R5ais independently halo, -N(Rx)(Ry), -OR9, -SR9, -NO2, -CN, - N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, - OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, - Attorney Docket No.: 185992002040 C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, -N(R10)S(=O)2R11, - S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=O)2R11, -S(=O)2N(R10)(R11), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl is optionally substituted with of R1a, R2a, R4a, or R5ais optionally substituted with one or more R1b, and the 3- to 12-membered heterocyclyl of R1a, R2a, R4a, or R5acomprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; each R1b, R2b, R3b, R4b, or R5bis independently halo, C1-6alkyl, -OR13, -N(Rx)(Ry), oxo, -CN, C3-8cycloalkyl, or 3- to 8-membered heterocyclyl, wherein the C1-6alkyl of R1b, R2b, R3b, R4b, or R5bis optionally substituted by -OR9, - N(Rx)(Ry), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6- membered heteroaryl; each R9is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R9is optionally substituted with one or more halo, deuterium, C1-6alkoxy, -N(Rx)(Ry), or 3- to 8-membered heterocyclyl; each R10is independently H, C1-6alkyl, or C3-8cycloalkyl; each R11is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-6alkyl of R11is optionally substituted by halo, -OH, -O(C1-6alkyl), -O(phenyl), - O(C=O)C1-8alkyl), -N(Rx)(Ry), C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10- membered heteroaryl, or 3- to 12-membered heterocyclyl, and the C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl of R11is optionally substituted with halo, C1-6alkyl, or - N(Rx)(Ry); each R12is independently H or C1-6alkyl; each R13is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, wherein the C1-6alkyl of R13is optionally substituted with phenyl, or 5- to 6-membered heteroaryl, wherein the phenyl, or 5- to 6-membered heteroaryl is optionally substituted with halo, C1-3alkyl, C1-3alkoxy, -N(Rx)(Ry), or 3- to 8-membered heterocyclyl, and Attorney Docket No.: 185992002040 the phenyl, or 5- to 6-membered heteroaryl of R13 is optionally substitutedwith halo, C1-3alkyl, C1-3alkoxy, or -N(Rx)(Ry); andeach Rx and Ry is independently H, C1-6alkyl, C3-8cycloalkyl, -C(=O)(C1-6alkyl), or -C(=O)O(C1-6alkyl), whereinthe C1-6alkyl of Rx or Ry is optionally substituted with 6- to 10-membered aryl, 5- to10-membered heteroaryl, or -NH2, NH(C1-6alkyl), or -N(C1-6alkyl)(C1-6alkyl), and the C1-6alkyl of -C(=O)(C1-6alkyl) or -C(=O)O(C1-6alkyl) is optionally substituted with-O(C=O)C1-8alkyl), wherein when are each H, R1 is not -CH2CH2CH2N(CH3)(CH3). In some embodiments, the disease or condition is a neurological disease or condition.In some embodiments, the disease or condition is selected from the group consisting ofAlzheimer’s disease, Parkinson’s disease, Huntington’s disease, traumatic brain injury (TBI), chronic traumatic encephalopathy (CTE), frontotemporal dementia (FTD), inclusion body myositis, Perry syndrome, corticobasaldegeneration, spinocerebellar ataxia type 3, and amyotrophic lateral sclerosis (ALS). In some embodiments, the disease or condition is traumatic brain injury (TBI).In some embodiments, the disease or condition is frontotemporal dementia (FTD).In some embodiments, the disease or condition is amyotrophic lateral sclerosis (ALS).In some variations, the amyotrophic lateral sclerosis is sporadic amyotrophic lateral sclerosisor C9ORF72 amyotrophic lateral sclerosis. In some embodiments, the individual is a human.In one aspect, provided herein is a method of reducing neurodegeneration, comprisingadministering to an individual in need thereof a compound of formula (I) or any variation orembodiment thereof, such as (II) or (III), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, or apharmaceutical composition comprising a compound of formula (I) or any variation orembodiment thereof, such as (II) or (III), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, and one or morepharmaceutically acceptable excipients. In some embodiments, provided herein is a methodof reducing neurodegeneration, comprising administering to an individual in need thereof acompound of formula (I) or any variation or embodiment thereof, such as (II) or (III), or a Attorney Docket No.: 185992002040 stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of theforegoing, or a pharmaceutical composition comprising a compound of formula (I) or anyvariation or embodiment thereof, such as (II) or (III), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or morepharmaceutically acceptable excipients. In some embodiments, the individual has aneurological disease or condition. In some embodiments, the individual has a disease or condition selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, traumatic brain injury (TBI), chronic traumatic encephalopathy (CTE), frontotemporal dementia (FTD), inclusion body myositis, Perry syndrome, corticobasal degeneration, spinocerebellar ataxia type 3, and amyotrophic lateral sclerosis (ALS). In some embodiments, the individual has frontotemporal dementia (FTD). In some embodiments, theindividual has a traumatic brain injury or ALS. In some embodiments, the individual has atraumatic brain injury. In some embodiments, the individual has ALS. In some variations, theamyotrophic lateral sclerosis is sporadic amyotrophic lateral sclerosis or C9ORF72amyotrophic lateral sclerosis. In one aspect, provided herein is a method of reducing neurodegeneration fromtraumatic brain injury, comprising administering to an individual in need thereof a compoundof formula (I) or any variation or embodiment thereof, such as (II) or (III), or a stereoisomeror tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of theforegoing, or a pharmaceutical composition comprising a compound of formula (I) or anyvariation or embodiment thereof, such as (II) or (III), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, and one ormore pharmaceutically acceptable excipients. In some embodiments, provided herein is amethod of reducing neurodegeneration from traumatic brain injury, comprising administeringto an individual in need thereof a compound of formula (I) or any variation or embodimentthereof, such as (II) or (III), or a stereoisomer or tautomer thereof, or a pharmaceuticallyacceptable salt of any of the foregoing, or a pharmaceutical composition comprising acompound of formula (I) or any variation or embodiment thereof, such as (II) or (III), or astereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients. In one aspect, provided herein is a method of modulating TDP-43, comprisingcontacting a cell with an effective amount of a compound of formula (I) or any variation orembodiment thereof, such as (II) or (III), or a stereoisomer or tautomer thereof, or apharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, or a Attorney Docket No.: 185992002040pharmaceutical composition comprising a compound of formula (I) or any variation orembodiment thereof, such as (II) or (III), or a stereoisomer or tautomer thereof, or apharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, and one or morepharmaceutically acceptable excipients. In some embodiments, provided herein is a methodof modulating TDP-43, comprising contacting a cell with an effective amount of a compoundof formula (I) or any variation or embodiment thereof, such as (II) or (III), or a stereoisomeror tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or apharmaceutical composition comprising a compound of formula (I) or any variation orembodiment thereof, such as (II) or (III), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceuticallyacceptable excipients. In some embodiments, modulating TDP-43 comprises modulatingTDP-43 incorporation into condensates, modulating TDP-43 binding to RNA in condensates,modulating TDP-43 aggregation, or modulating TDP-43 protein-protein interactions. In someembodiments, modulating TDP-43 comprises modulating TDP-43 incorporation intocondensates. In some embodiments, modulating TDP-43 comprises modulating TDP-43binding to RNA in condensates. In some embodiments, modulating TDP-43 comprisesmodulating TDP-43 aggregation. In some embodiments, modulating TDP-43 comprisesinhibiting TDP-43 protein-protein interactions. In some embodiments, modulating TDP-43comprises mitigating TDP-43 interaction to RNA condensates, mitigating TDP-43 aggregation, or mitigating TDP-43 protein-protein interactions. In some embodiments, modulating TDP-43 comprises mitigating TDP-43 interaction to RNA condensates. In some embodiments, modulating TDP-43 comprises mitigating TDP-43 aggregation. In some embodiments, modulating TDP-43 comprises mitigating TDP-43 protein-protein interactions. In one aspect, provided herein is a method of modulating TDP-43 driven geneexpression levels, comprising contacting a cell with an effective amount of a compound offormula (I) or any variation or embodiment thereof, such as (II) or (III), or a stereoisomer ortautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of theforegoing, or a pharmaceutical composition comprising a compound of formula (I) or anyvariation or embodiment thereof, such as (II) or (III), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, and one ormore pharmaceutically acceptable excipients. In some embodiments, provided herein is amethod of modulating TDP-43 driven gene expression levels, comprising contacting a cellwith an effective amount of a compound of formula (I) or any variation or embodimentthereof, such as (II) or (III), or a stereoisomer or tautomer thereof, or a pharmaceutically Attorney Docket No.: 185992002040 acceptable salt of any of the foregoing, or a pharmaceutical composition comprising acompound of formula (I) or any variation or embodiment thereof, such as (II) or (III), or astereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of theforegoing, and one or more pharmaceutically acceptable excipients. In some embodiments,the gene expression levels are for STMN2 or POLDIP3. In some embodiments, the geneexpression levels are for STMN2. In some embodiments, the gene expression levels are forPOLDIP3. In some embodiments, the methods selectively modulate TDP-43. In someembodiments, the methods reduce TDP-43 cytoplasmic inclusions, improve nuclear TDP-43 function, or reduce neurodegeneration. In some embodiments, the methods reduce TDP-43 cytoplasmic inclusions. In some embodiments, the methods improve nuclear TDP-43 function. In some embodiments, the methods reduce neurodegeneration. In some embodiments, the methods mitigate TDP-43 cytoplasmic condensates in motor neurons. In some embodiments, the motor neurons are iPSC-derived motor neurons. In someembodiments, STMN2 and POLDIP3 splicing in iPSC-derived motor neurons is restored.In one aspect, provided herein is a compound of formula (I), or any variation orembodiment thereof, such as (II) or (III), or a stereoisomer or tautomer thereof, or apharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, or apharmaceutical composition comprising a compound of formula (I), or any variation orembodiment thereof, such as (II) or (III), or a stereoisomer or tautomer thereof, or apharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing and one or morepharmaceutically acceptable excipients, for use in the treatment of a disease or conditionmediated by TDP-43. In some embodiments, provided herein is a compound of formula (I),or any variation or embodiment thereof, such as (II) or (III), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceuticalcomposition comprising a compound of formula (I), or any variation or embodiment thereof,such as (II) or (III), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients, for usein the treatment of a disease or condition mediated by TDP-43. In some embodiments, themethods selectively modulate TDP-43. In some embodiments, the methods reduce TDP-43 cytoplasmic inclusions, improve nuclear TDP-43 function, or reduce neurodegeneration. In some embodiments, the methods reduce TDP-43 cytoplasmic inclusions. In some embodiments, the methods improve nuclear TDP-43 function. In some embodiments, the methods reduce neurodegeneration. In some embodiments, the methods mitigate TDP-43 cytoplasmic condensates in motor neurons. In some embodiments, the motor neurons are Attorney Docket No.: 185992002040iPSC-derived motor neurons. In some embodiments, STMN2 and POLDIP3 splicing iniPSC-derived motor neurons is restored. In one aspect, provided herein is the use of a compound of formula (I) or anyvariation or embodiment thereof, such as (II) or (III), or a stereoisomer or tautomer thereof,or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, or apharmaceutical composition comprising a compound of formula (I) or any variation orembodiment thereof, such as (II) or (III), or a stereoisomer or tautomer thereof, or apharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, and one or morepharmaceutically acceptable excipients, in the manufacture a medicament for the treatment ofa disease or condition mediated by TDP-43. In some embodiments, provided herein is the useof a compound of formula (I) or any variation or embodiment thereof, such as (II) or (III), ora stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of theforegoing, or a pharmaceutical composition comprising a compound of formula (I) or anyvariation or embodiment thereof, such as (II) or (III), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients, in the manufacture a medicament for the treatment of a disease or condition mediated by TDP-43. KITS The present disclosure further provides kits for carrying out the methods disclosedherein. The kits may comprise a compound, or stereoisomer or tautomer thereof, orpharmaceutically acceptable salt, hydrate, or solvate thereof as described herein and suitablepackaging. The kits may comprise one or more containers comprising any compounddescribed herein. In one aspect, a kit includes a compound of the disclosure, or stereoisomeror tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and alabel and / or instructions for use of the compound in the treatment of a disease or disorderdescribed herein. The kits may comprise a unit dosage form of the compound. In someembodiments, the kits may comprise a compound, or stereoisomer or tautomer thereof, orpharmaceutically acceptable salt thereof. Provided herein are kits, comprising (i) an effective amount of a compound offormula (I) or any variation or embodiment thereof, such as (II) or (III), or a stereoisomer ortautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of theforegoing, and (ii) instructions for use in treating a TDP-43 mediated disease, disorder, orcondition in an individual in need thereof. In some embodiments, the kits comprise (i) a Attorney Docket No.: 185992002040compound of formula (I) or any variation or embodiment thereof, such as (II) or (III), or astereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of theforegoing, and (ii) instructions for use in treating a TDP-43 mediated disease, disorder, orcondition in an individual in need thereof. In some embodiments, the kits comprise (i) aneffective amount of a compound of formula (I) or any variation or embodiment thereof, suchas (II) or (III), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt ofany of the foregoing, and (ii) instructions for use in treating a TDP-43 mediated disease,disorder, or condition in an individual in need thereof. Also provided herein are kits,comprising (i) a pharmaceutical composition comprising an effective amount of a compoundof formula (I) or any variation or embodiment thereof, such as (II) or (III), or a stereoisomeror tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of theforegoing, and one or more pharmaceutically acceptable excipients; and (ii) instructions foruse in treating a TDP-43 mediated disease, disorder, or condition in an individual in needthereof. In some embodiments, the kits comprise (i) a pharmaceutical compositioncomprising an effective amount of a compound of formula (I) or any variation or embodimentthereof, such as (II) or (III), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptableexcipients; and (ii) instructions for use in treating a TDP-43 mediated disease, disorder, orcondition in an individual in need thereof. In some embodiments, the individual is a human. Articles of manufacture are also provided, wherein the article of manufacturecomprises a compound of formula (I) or any variation or embodiment thereof, such as (II) or(III), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, orsolvate of any of the foregoing, in a suitable container. In some embodiments, the article ofmanufacture comprises a compound of formula (I) or any variation or embodiment thereof,such as (II) or (III), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptablesalt of any of the foregoing, in a suitable container. Also provided herein are articles ofmanufacture, comprising a pharmaceutical composition comprising a compound of formula(I) or any variation or embodiment thereof, such as (II) or (III), or a stereoisomer or tautomerthereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, in asuitable container. In some embodiments, the articles of manufacture comprise apharmaceutical composition comprising a compound of formula (I) or any variation orembodiment thereof, such as (II) or (III), or a stereoisomer or tautomer thereof, or a Attorney Docket No.: 185992002040 pharmaceutically acceptable salt of any of the foregoing, in a suitable container. The container may be a vial, jar, ampoule, preloaded syringe, or intravenous bag. METHODS OF PREPARING The present disclosure further provides processes for preparing the compounds of present invention. In some aspects, provided herein are processes of preparing a compound offormula (I), or any variation or embodiment thereof or a stereoisomer or tautomer thereof, ora pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing. In someembodiments, provided herein are processes of preparing a compound of formula (I), or anyvariation or embodiment thereof, or a stereoisomer or tautomer thereof, or a pharmaceuticallyacceptable salt of any of the foregoing. In some embodiments, provided herein are processesof preparing a compound of formula (I), or any variation or embodiment thereof, or astereoisomer or tautomer thereof. The following synthetic reaction schemes, which are detailed in the Schemes and Examples, are merely illustrative of some of the methods by which the compounds of the present disclosure, or an embodiment or aspect thereof, can be synthesized. Various modifications to these synthetic reaction schemes can be made, as will be apparent to those of ordinary skill in the art. As depicted in the Schemes and Examples below, in certain exemplary embodiments, compounds of formula (I), or any variation or embodiment thereof, as described elsewhere herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate,or solvate of any of the foregoing, are prepared according to the general procedures. Thegeneral methods below, and other methods known to synthetic chemists of ordinary skill in the art, can be applied to all formulae, embodiments, and species described herein. The starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data. Although certain exemplary embodiments are depicted and described herein, the compounds of the present disclosure, or any variation or embodiment thereof, may be prepared using appropriate starting materials according to the methods described generally herein and / or by methods available to one of ordinary skill in the art. All the products generated from the following reactions can be isolated and purified employing standard techniques, such as extraction, ion exchange chromatography, Attorney Docket No.: 185992002040 chromatography on silica gel, prep-HPLC. Specific purification steps and methods were set up and will be referred to in the text as follows. Compounds may be prepared by methods known in the art of organic chemistry as set forth in part by the following synthesis schemes. In all the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Green and P.G.M. Wuts (1991) Protecting Groups in Organic Synthesis, John Wiley et Sons, hereby incorporated by reference in its entirety). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The compound may be represented as a mixture of enantiomers, which may be resolved intothe individual pure R- or S-enantiomers.Commercial nitrobenzene and aniline were used as starting material A.1 (Schemes 1,2, 3 and 4) for the synthesis of 6,7-disubstituted 2,4-dichloroquinoline A.4. Commercialmaterials were used as such for cyclization step (step 3) to form the quinolines A.4 orunderwent two former steps: a first step to further substitute compound A.1 in position 3 byreductive amination, aromatic nucleophilic substitution, or methylation, and a second step for the reduction of nitro-groups or deacylation of methylamide to get the free aniline A.3. Thederivative 2,4-dichloroquinoline A.4 was then formed by cyclization of A.3 with malonicacid in phosphoryl chloride. The 2,4-dichloroquinoline A.4 underwent a Suzuki cross coupling reaction withcommercially available or synthesized boronic ester or boronic acids derivatives (Scheme 1).Quinolines A.4 were selectively substituted in position 2 to give compounds A.5. Thesubstitution of position 4 of compound A.5 was realized by Buchwald cross coupling or byaromatic nucleophilic substitution with commercial or synthesized amines and allowed the formation of FP (Final Product).

[0002] Attorney Docket No.: 185992002040 SCHEME 1. Similarly to Scheme 1, others FP were synthesized applying first the Buchwaldcoupling or the nucleophilic aromatic substitution on quinolines A.4 to give derivatives B.5(Scheme 2). This step was then followed by a Suzuki coupling to give FP.SCHEME 2. In some cases, the substituted (hetero)aromatic ring added during the Suzuki couplingon quinolines A.4 contains a protecting group (PG, Schemes 3 and 4). In these cases, FPwere obtained after an additional step of deprotection. Scheme 3 describes the syntheticsequence similar to Scheme 1, with a Suzuki cross coupling realized first on quinolines A.4,followed by the substitution of quinolines C.5 using a Buchwald reaction or a nucleophilicaromatic substitution to give compounds C6. Compound C.6 underwent then a deprotectionstep to give FP. Attorney Docket No.: 185992002040 SCHEME 3. Scheme 4 describes a synthetic sequence similar to Scheme 2, with first a Buchwaldor aromatic nucleophilic substitution realized on quinolines A.4 to give derivatives B.5 andfollowed by a Suzuki cross coupling to obtain C.6 derivatives which upon a finaldeprotection step will afford the desired FPs. SCHEME 4. Scheme 5 describes a synthetic sequence similar to Scheme 1, with first a Suzuki cross coupling realized on position 2 of quinolines A.4. This step is followed by thesubstitution of position 4 of quinolines A.5 using a nucleophilic aromatic substitution or aBuchwald coupling with amines bearing a protective group to obtain D.6 intermediates. FP isobtained after an additional step of deprotection. Attorney Docket No.: 185992002040 SCHEME 5. Scheme 6 describes a synthetic sequence where both boronic ester derivatives used for the Suzuki coupling and the amine used for the Buchwald coupling or aromatic substitution held a protecting group, PG and PG’ respectively. Compound E.6 is then fully deprotected to give FP. SCHEME 6.

[0003] Attorney Docket No.: 185992002040 ENUMERATED EMBODIMENTS Enumerated Embodiment 1. A compound of formula (I): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvent of any of the foregoing, wherein: R1is H, C1-6alkyl, C2-6alkenyl, -C(=O)R11, -C(=O)OR11, -C(=O)N(R10)(R11), -S(=O)2R11, - S(=O)2N(R10)(R11), C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl,or 5- to 10-membered heteroaryl, whereinthe C1-6alkyl of R1is optionally substituted with one or more R1a, the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to10-membered heteroaryl of R1is optionally substituted with one or more R1b, and optionally, two substituents of the C1-6alkyl, C2-6alkenyl, -C(=O)R11, -C(=O)OR11, - C(=O)N(R10)(R11), -S(=O)2R11, -S(=O)2N(R10)(R11), or C3-8cycloalkyl group of R1are taken together with the atoms to which they are attached to form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-memberedheteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl,or 5- to 10-membered heteroaryl is optionally substituted with one or moreR1b; each R2is independently halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR9, -SR9, -SF5, - N(Rx)(Ry), -NO2, -CN, -N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, - OC(=O)R11, -OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), - C(=O)OR11, -C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, - N(R10)S(=O)2R11, -S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=NR12)R11, - S(=NR12)N(R10)R11, -S(=NR12)OR11, -S(=O)2R11, -S(=O)2N(R10)(R11), C3-8cycloalkyl, 3- to8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, whereinthe C1-6alkyl of R2is optionally substituted by one or more R2a, Attorney Docket No.: 185992002040 the C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R2is optionally substituted with one or more R2b, and the 3- to 8-membered heterocyclyl of R2comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; n is 0, 1, 2, or 3; L is a bond, C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R3)(C1-6alkyl)- wherein the C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R3)(C1-6alkyl)- is optionally substituted by one or more RL; each RLis independently halo, -N(Rx)(Ry), -OR9, -SR9, -SF5, -NO2, -CN, -N(R10)C(=O)R11, - N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, -OC(=O)N(R10)R11, - OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, C3-8cycloalkyl, 3- to 8- membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, or two RLare taken together along with the atoms to which they are attached to form a C3-8cycloalkyl or 3- to 8-membered heterocyclyl; R3is H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C(=O)R11, -S(=O)2R11, -S(=O)2N(R10)(R11), or C3-8cycloalkyl, wherein the C1-6alkyl of R3is optionally substituted with one or more halo, -N(Rx)(Ry), -OR9, - SR9, -SF5, -N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, - OC(=O)R11, -OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), - C(=O)OR11, -C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, - N(R10)S(=O)2R11, -S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=NR12)R11, - S(=NR12)N(R10)R11, -S(=NR12)OR11, -S(=O)2R11, or -S(=O)2N(R10)(R11), and the C3-8cycloalkyl is optionally substituted with one or more R3b; R4is H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR9, -SR9, -SF5, -N(Rx)(Ry), -NO2, -CN, - N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, - OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, - C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, -N(R10)S(=O)2R11, - S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=NR12)R11, -S(=NR12)N(R10)R11, - S(=NR12)OR11, -S(=O)2R11, -S(=O)2N(R10)(R11), C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R4is optionally substituted by one or more R4a, the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R4is optionally substituted with one or more R4b, - C(=O)R11, -C(=O)N(R10)(R11), or -C(=O)OR11, and Attorney Docket No.: 185992002040 the 3- to 12-membered heterocyclyl of R4comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S, and optionally, two substituents of R4are taken together with the atoms to which they are attached form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R4b, -C(=O)R11, -C(=O)N(R10)(R11), or -C(=O)OR11; R5, R6, R7, and R8are each independently H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR9, - OR13, -SR9, -SF5, -N(Rx)(Ry), -NO2, -CN, -N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, - N(R10)C(=O)OR11, -OC(=O)R11, -OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, - C(=O)N(R10)(R11), -C(=O)OR11, -C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, - C(=NR12)OR11, -N(R10)S(=O)2R11, -S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=NR12)R11, -S(=NR12)N(R10)R11, -S(=NR12)OR11, -S(=O)2R11, -S(=O)2N(R10)(R11), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R5, R6, R7, or R8is optionally substituted by one or more R5a, the 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R5, R6, R7, or R8is optionally substituted with one or more R5b, and the 3- to 8-membered heterocyclyl of R5, R6, R7, or R8comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S, and optionally, two substituents of R5, R6, R7, or R8are taken together with the atoms to which they are attached form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R5b; or R6and R7are taken together with the carbon atoms to which they are attached to form a 4- to 8-membered heterocyclyl; each R1a, R2a, R4a, or R5ais independently halo, -N(Rx)(Ry), -OR9, -SR9, -NO2, -CN, - N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, - OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, - C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, -N(R10)S(=O)2R11, - S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=NR12)R11, -S(=NR12)N(R10)R11, - Attorney Docket No.: 185992002040 S(=NR12)OR11, -S(=O)2R11, -S(=O)2N(R10)(R11), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R1a, R2a, R4a, or R5ais optionally substituted with one or more R1b, and the 3- to 12-membered heterocyclyl of R1a, R2a, R4a, or R5acomprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; each R1b, R2b, R3b, R4b, or R5bis independently halo, C1-6alkyl, -OR13, -N(Rx)(Ry), oxo, -CN, C3-8cycloalkyl, or 3- to 8-membered heterocyclyl, wherein the C1-6alkyl of R1b, R2b, R3b, R4b, or R5bis optionally substituted by -OR9, - N(Rx)(Ry), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; each R9is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl is optionally substituted with one or more halo, deuterium, C1-6alkoxy, - N(Rx)(Ry), or 3- to 8-membered heterocyclyl; each R10is independently H, C1-6alkyl, or C3-8cycloalkyl; each R11is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-6alkyl of R11is optionally substituted by one or more halo, -OH, -O(C1-6alkyl), -SH, -S(C1-6alkyl), -(C=O)NH2, -(C=O)OH, -O(C=O)C1-8alkyl), -NH(C=NH)NH2, - N(Rx)(Ry), C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the 6- to 10-membered aryl is optionally substituted by -OH, and the C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl of R11is optionally substituted with halo, C1- 6alkyl, -OH, or -N(Rx)(Ry); each R12is independently H or C1-6alkyl; each R13is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl of R13is optionally substituted with 6- to 10-membered aryl, or 5- to 10- membered heteroaryl, wherein the 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is optionally substituted with halo, C1-3alkyl, C1-3alkoxy, or -N(Rx)(Ry), and Attorney Docket No.: 185992002040 the 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R13 is optionallysubstituted with halo, C1-3alkyl, C1-3alkoxy, -N(Rx)(Ry), or 3- to 12-memberedheterocyclyl; and each Rxand Ryis independently H, C1-6alkyl, C3-8cycloalkyl, -C(=O)(C1-6alkyl), or - C(=O)O(C1-6alkyl), wherein the C1-6alkyl of Rx or Ry is optionally substituted with 6- to 10-membered aryl,5- to 10-membered heteroaryl, or -NH2, NH(C1-6alkyl), or -N(C1-6alkyl)(C1-6alkyl), and the C1-6alkyl of -C(=O)(C1-6alkyl) or -C(=O)O(C1-6alkyl) is optionally substituted with -O(C=O)C1-8alkyl). Enumerated Embodiment 2. The compound of Enumerated Embodiment 1, or astereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein:R1 is C1-6alkyl, C2-6alkenyl, -C(=O)R11, -C(=O)OR11, -C(=O)N(R10)(R11), -S(=O)2R11, - S(=O)2N(R10)(R11), or C3-8cycloalkyl, wherein the C1-6alkyl of R1is optionally substituted with one or more R1a, the C3-8cycloalkyl of R1is optionally substituted with one or more R1b, and optionally, two substituents of the C1-6alkyl, C2-6alkenyl, -C(=O)R11, -C(=O)OR11, - C(=O)N(R10)(R11), -S(=O)2R11, -S(=O)2N(R10)(R11), or C3-8cycloalkyl group of R1are taken together with the atoms to which they are attached to form a C3-8cycloalkyl, 3-to 12-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-memberedheteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl,or 5- to 10-membered heteroaryl is optionally substituted with one or moreR1b; andR4is -N(Rx)(Ry), -N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)N(R10)R11, -C(=O)(C1-6alkyl)N(Rx)(Ry), -C(=O)N(R10)(R11), -N(R10)S(=O)2R11, -S(=O)N(R10)R11, -S(=O)2N(R10)(R11), or 3- to 8-membered N-containing heterocyclyl,wherein the 3- to 8-membered N-containing heterocyclyl of R4 is optionally substituted withone or more R4b, -C(=O)R11, -C(=O)N(R10)(R11), or -C(=O)OR11, andthe 3- to 8-membered N-containing heterocyclyl of R4 comprises 1, 2, or 3 atomsselected from the group consisting of N, O, and S. Attorney Docket No.: 185992002040 Enumerated Embodiment 3. The compound of Enumerated Embodiment 1 or 2, or astereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein:R1 is C1-6alkyl, -C(=O)R11, -C(=O)OR11, -C(=O)N(R10)(R11), or C3-8cycloalkyl, wherein the C1-6alkyl of R1is optionally substituted with one or more R1a, the C3-8cycloalkyl of R1is optionally substituted with one or more R1b; optionally, two substituents of the C1-6alkyl, C2-6alkenyl, -C(=O)R11, -C(=O)OR11, - C(=O)N(R10)(R11), or C3-8cycloalkyl group of R1are taken together with the atoms to which they are attached to form a C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6-to 10-membered aryl, or 5- to 10-membered heteroaryl, whereinthe C3-8cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl,or 5- to 10-membered heteroaryl is optionally substituted with one or moreR1b; each R2is independently halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR9, -SR9, -N(Rx)(Ry), - NO2, -CN, -N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, - OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, - C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, -N(R10)S(=O)2R11, -S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=O)2R11, -S(=O)2N(R10)(R11), C3-8cycloalkyl, 3-to 8-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, whereinthe C1-6alkyl of R2is optionally substituted by one or more R2a, the C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6-memberedheteroaryl of R2is optionally substituted with one or more R2b, and the 3- to 8-membered heterocyclyl of R2 comprises 1, 2, or 3 atoms selected from thegroup consisting of N, O, and S; R3is H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C(=O)R11, -S(=O)2R11, -S(=O)2N(R10)(R11), or C3-8cycloalkyl, wherein the C1-6alkyl of R3is optionally substituted with one or more halo, -N(Rx)(Ry), -OR9, - SR9, -N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, - OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, - C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, - N(R10)S(=O)2R11, -S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=O)2R11, or - S(=O)2N(R10)(R11), and the C3-8cycloalkyl is optionally substituted with one or more R3b; R5is H; Attorney Docket No.: 185992002040 R6and R7are each independently H, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR9, -SR9, - N(Rx)(Ry), -NO2, -CN, -N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, - OC(=O)R11, -OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), - C(=O)OR11, -C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, - N(R10)S(=O)2R11, -S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=O)2R11, - S(=O)2N(R10)(R11), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6- membered heteroaryl, wherein the C1-6alkyl of R6or R7is optionally substituted by one or more R5a, the 3- to 8-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl of R6or R7is optionally substituted with one or more R5b, and the 3- to 8-membered heterocyclyl of R6or R7comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; or R6and R7are taken together with the carbon atoms to which they are attached to form a 4- to 8-membered heterocyclyl; R8is H; each R1a, R2a, R4a, and R5ais independently halo, -N(Rx)(Ry), -OR9, -SR9, -NO2, -CN, - N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, - OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, - C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, -N(R10)S(=O)2R11, - S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=O)2R11, -S(=O)2N(R10)(R11), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl of R1a, R2a, R4a, or R5ais optionally substituted with one or more R1b, and the 3- to 12-membered heterocyclyl of R1a, R2a, R4a, or R5acomprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; each R1b, R2b, R3b, R4b, or R5bis independently halo, C1-6alkyl, -OR13, -N(Rx)(Ry), oxo, -CN, C3-8cycloalkyl, or 3- to 8-membered heterocyclyl, wherein the C1-6alkyl of R1b, R2b, R3b, R4b, or R5bis optionally substituted by -OR9, - N(Rx)(Ry), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; wherein when L is -OCH2CH2CH2-, R2 is , and R5 and R6 are each H, R1 is not -CH2CH2CH2N(CH3)(CH3). Attorney Docket No.: 185992002040 Enumerated Embodiment 4. The compound of any of Enumerated Embodiments 1-3,or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein: R1is C1-6alkyl optionally substituted with one or more R1a; R4is -N(Rx)(Ry), -N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, - OC(=O)N(R10)R11, -C(=O)(C1-6alkyl)N(Rx)(Ry), -C(=O)N(R10)(R11), or 3- to 8-membered N-containing heterocyclyl, whereinthe 3- to 8-membered N-containing heterocyclyl of R4 is optionally substituted withone or more R4b, -C(=O)R11, -C(=O)N(R10)(R11), or -C(=O)OR11, andthe 3- to 8-membered N-containing heterocyclyl of R4 comprises 1, 2, or 3 atomsselected from the group consisting of N, O, and S;R6 and R7 are each independently H, halo, C1-6alkyl, -OR9, -N(Rx)(Ry), -N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, -OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, -C(=NR12)R11, -C(=NOR11)R11,-C(=NR12)N(R10)R11, -C(=NR12)OR11, -N(R10)S(=O)2R11, -S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=O)2R11, or -S(=O)2N(R10)(R11), wherein the C1-6alkyl of R6or R7is optionally substituted by one or more R5a; or R6and R7are taken together with the carbon atoms to which they are attached to form a 4- to 8-membered heterocyclyl; andeach R13 is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 3- to 8-memberedheterocyclyl, phenyl, or 5- to 6-membered heteroaryl, whereinthe C1-6alkyl of R13 is optionally substituted with phenyl, or 5- to 6-memberedheteroaryl, wherein the phenyl, or 5- to 6-membered heteroaryl is optionally substituted with halo,C1-3alkyl, C1-3alkoxy, -N(Rx)(Ry), or 3- to 8-membered heterocyclyl, andthe phenyl, or 5- to 6-membered heteroaryl of R13 is optionally substitutedwith halo, C1-3alkyl, C1-3alkoxy, or -N(Rx)(Ry); wherein when L is -OCH2CH2CH2-, R2 is , and R5 and R6 are each H, R1 is not -CH2CH2CH2N(CH3)(CH3). Enumerated Embodiment 5. The compound of any of Enumerated Embodiments 1-4,or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein L is a bond or -O(C1-6alkyl)-. Attorney Docket No.: 185992002040 Enumerated Embodiment 6. The compound of Enumerated Embodiment 5, or astereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein L is a bond or -O(C1-4alkyl)-. Enumerated Embodiment 7. The compound of Enumerated Embodiment 6, or astereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein L is a bond or -O(CH2CH2)-. Enumerated Embodiment 8. The compound of any of Enumerated Embodiments 1-7,wherein the compound is a compound of formula (II): stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing. Enumerated Embodiment 9. The compound of any of Enumerated Embodiments 1-7,wherein the compound is a compound of formula (III): stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing. Enumerated Embodiment 10. The compound of any of Enumerated Embodiments 1-9,or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein R1is C1-6alkyl substituted with one or more R1a. Enumerated Embodiment 11. The compound of any of Enumerated Embodiments 1-10, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or Attorney Docket No.: 185992002040 solvate of any of the foregoing, wherein each R1ais independently -OH, -NH(C1-6alkyl), - N(C1-6alkyl)(C1-6alkyl), or phenyl, wherein the phenyl is optionally substituted by halo. Enumerated Embodiment 12. The compound of Enumerated Embodiment 11, or astereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein each R1ais independently -OH, -NH(CH3), -N(CH3)(CH3), or fluorophenyl. Enumerated Embodiment 13. The compound of any of Enumerated Embodiments 1-10, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein R1is selected from the group consisting of Enumerated Embodiment 14. The compound of any of Enumerated Embodiments 1-13, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein R4is -N(Rx)(Ry). Enumerated Embodiment 15. The compound of Enumerated Embodiment 14, or astereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate ofany of the foregoing, wherein R4 is -NH(C1-6alkyl), -N(C1-6alkyl)(C1-6alkyl), wherein each C1-6alkyl is independently optionally substituted by one or more R4a. Enumerated Embodiment 16. The compound of Enumerated Embodiment 15, or astereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein R4is selected from the group consisting of -NH(CH3), - Enumerated Embodiment 17. The compound of any of Enumerated Embodiments 1-13, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein R4is -N(R10)C(O)R11. Attorney Docket No.: 185992002040 Enumerated Embodiment 18. The compound of Enumerated Embodiment 17, or astereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein R4is -NHC(O)(C1-6alkyl). Enumerated Embodiment 19. The compound of Enumerated Embodiment 18, or astereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein R4is -NHC(O)(CH3). Enumerated Embodiment 20. The compound of any of Enumerated Embodiments 1-13, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, orsolvate of any of the foregoing, wherein R4 is 3- to 12-membered N-containing heterocyclyloptionally substituted by R4b, -C(=O)R11, -C(=O)N(R10)(R11), or -C(=O)OR11. Enumerated Embodiment 21. The compound of Enumerated Embodiment 20, or astereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein R4is azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, wherein the piperazinyl is optionally substituted by R4b, -C(=O)R11, -C(=O)N(R10)(R11), or - C(=O)OR11. Enumerated Embodiment 22. The compound of Enumerated Embodiment 21, or astereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of Enumerated Embodiment 23. The compound of any of Enumerated Embodiments 1-22, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein R6and R7are each independently H, halo, C1-6alkyl, -N(Rx)(Ry), -OR9, -N(R10)C(O)R11, or -N(R10)C(O)OR11. Enumerated Embodiment 24. The compound any of Enumerated Embodiments 1-23,or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein R6and R7are each independently H, halo, C1-6alkyl, Attorney Docket No.: 185992002040-NH(C1-6alkyl), -N(C1-6alkyl)(C1-6alkyl), -O(C1-6alkyl), -O(5- to 6-membered aryl), -O(5- to6-membered heteroaryl), -NHC(O)(C1-6alkyl), -NHC(O)(5- to 6-membered aryl), or -NHC(O)O(C1-6alkyl), wherein the -O(C1-6alkyl) is optionally substituted with phenyl or halo; the -O(5- to 6-membered aryl) is optionally substituted with 4- to 6-memberedheterocyclyl; the -NHC(O)(C1-6alkyl) is optionally by -O(5- to 6-membered aryl); andthe -NHC(O)(5- to 6-membered aryl) is optionally substituted with -N(Rx)(Ry).Enumerated Embodiment 25. The compound of any of Enumerated Embodiments 1-24, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein R6and R7are each independently selected from the group consisting of H, -CH3, F, -NH(CH3), -N(CH3)(CH3), -OCF3, -OCH3, Enumerated Embodiment 26. The compound of any of Enumerated Embodiments 1-23, wherein R6and R7are each independently selected from the group consisting of H, -CH3, Enumerated Embodiment 27. The compound of any of Enumerated Embodiments 1-4,or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein: L is a bond or -O(C1-6alkyl); R4 is 3- to 12-membered N-containing heterocyclyl optionally substituted by R4b, -C(=O)R11, -C(=O)N(R10)(R11), or -C(=O)OR11; and R1is C1-4alkyl optionally substituted with one or more substituents selected from the group consisting of -OH, -NH(CH3), and -N(CH3)(CH3). Attorney Docket No.: 185992002040 Enumerated Embodiment 28. The compound of Enumerated Embodiment 1, or astereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, wherein the compound is selected from Table 1. Enumerated Embodiment 29. A pharmaceutical composition comprising a compoundof any of Enumerated Embodiments 1-28, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, and one or more pharmaceutically acceptable excipients or carriers. Enumerated Embodiment 30. A method for treating a disease or condition mediatedby TDP-43, comprising administering to a subject in need thereof a compound of any of Enumerated Embodiments 1-28, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, or the pharmaceutical compositionof Enumerated Embodiment 29.Enumerated Embodiment 31. The method of Enumerated Embodiment 30, wherein atherapeutically effective amount of the compound is administered. Enumerated Embodiment 32. The method of Enumerated Embodiment 30 or 31,wherein said disease or condition mediated by TDP-43 is a neurological disease or condition. Enumerated Embodiment 33. The method of Enumerated Embodiment 32, whereinthe neurological disease is selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, traumatic brain injury (TBI), chronic traumatic encephalopathy (CTE), frontotemporal dementia (FTD), inclusion body myositis, Perrysyndrome, corticobasal degeneration, spinocerebellar ataxia type 3, and amyotrophic lateralsclerosis (ALS). Enumerated Embodiment 34. The method of Enumerated Embodiment 32 or 33,wherein the neurological disease or condition is traumatic brain injury (TBI). Enumerated Embodiment 35. The method of Enumerated Embodiment 32 or 33,wherein the neurological disease or condition is frontotemporal dementia (FTD). Enumerated Embodiment 36. The method of Enumerated Embodiment 32 or 33,wherein the neurological disease or condition is amyotrophic lateral sclerosis (ALS). Enumerated Embodiment 37. The method of any of Enumerated Embodiments 32, 33,or 36, wherein the neurological disease or condition is sporadic amyotrophic lateral sclerosis or C9ORF72 amyotrophic lateral sclerosis. Attorney Docket No.: 185992002040 Enumerated Embodiment 38. The method of any of Enumerated Embodiments 30-37,wherein the subject is a human. Enumerated Embodiment 39. A method of modulating TDP-43, comprisingcontacting a cell with an effective amount of a compound of any of Enumerated Embodiments 1-28, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, or the pharmaceutical composition ofEnumerated Embodiment 29, wherein modulating TDP-43 comprises modulating TDP-43incorporation into condensates, modulating TDP-43 binding to RNA in condensates, modulating TDP-43 aggregation, or modulating TDP-43 protein-protein interactions. Enumerated Embodiment 40. A method of modulating TDP-43 driven geneexpression levels, comprising contacting a cell with an effective amount of a compound of any of Enumerated Embodiments 1-28, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, or thepharmaceutical composition of Enumerated Embodiment 29.Enumerated Embodiment 41. The method of Enumerated Embodiment 40, whereinthe gene expression levels are for STMN2.Enumerated Embodiment 42. The method of Enumerated Embodiment 40, whereinthe gene expression levels are for POLDIP3.Enumerated Embodiment 43. The compound of any of Enumerated Embodiments 1-28, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, orsolvate thereof, or the pharmaceutical composition of Enumerated Embodiment 34 for use inthe treatment of a disease or condition mediated by TDP-43. Enumerated Embodiment 44. Use of a compound of any of Enumerated Embodiments1-28, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof in the manufacture of a medicament for the treatment of a disease or disorder mediated by TDP-43. Enumerated Embodiment 45. A kit, comprising (i) a compound of any one ofEnumerated Embodiments 1-28, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate of any of the foregoing, or the pharmaceutical compositionof Enumerated Embodiment 29 and (ii) instructions for use in treating a TDP-43 mediateddisease or condition in an individual in need thereof. Attorney Docket No.: 185992002040 EXAMPLES The reagents and starting materials are commercially available and / or, using well- known techniques, can be readily synthesized by one of ordinary skill in the art. Unless otherwise noted, all commercially starting materials were used without further purification. Specifically, the following abbreviations may be used in the examples and throughout the specification. Table 2 Attorney Docket No.: 185992002040 SCX general protocol. The hydrochloride salt product was neutralized by StrongCation Exchange Resin. The resin was first washed with two volumes of deionized water. The compound to neutralize was absorbed to the resin by washing the resin with a solution of the compound in methanol. The resin was then washed with deionized water until the pH of the solution is neutral. A solution of ammonium hydroxide and methanol was used to cleave Attorney Docket No.: 185992002040 compound from the resin. Solvents were then concentrated and lyophilized to get the desired product. Prep-HPLC. Experiments were carried out at room temperature and detection wasdone by UV at 220 and 254 nm. The different methods used are described as follows: 1: ACSWH-GX-N; YMC triart C18 column 150 x 25 mm x 5 mm; mobile phase: water (HCl)-ACN 2: ACSWH-GX-N; Phenomenex Luna C18 column 150 x 25 mm x 10 mm; mobile phase: water (FA)-ACN 3: ACSWH-GX-N; Phenomenex Luna C18 column 150 x 25 mm x 10 mm; mobile phase: water (TFA)-ACN 4: ACSWH-GX-N; Unisil 3-100 C18 ultra column 150 x 50 mm x 3 mm; mobile phase: water (0.23% FA)-ACN 5: Agilent Infinity II 1260 / 1290, Agilent Infinity Lab Poroshell 1204; HPH-C18column 21.2 x 150 mm; mobile phase: water (0.1% FA)-ACN (0.1% FA) 6 (basic system): Agilent Infinity II 1260 / 1290, Agilent Infinity Lab Poroshell 1204; HPH-C18 column 21.2 x 150 mm; mobile phase: water-ACN (0.1 % NH3) 7: ACSWH-GX-N; Waters Xbridge 150 x 25 mm x 5 mm; mobile phase: water (ammonia hydroxide v / v)-ACN 8: ACSWH-GX-O; Phenomenex luna C18150 x 25 mm x 10mm; mobile phase: water (HCl)-ACN Flash chromatography. Puri Flash XS520Plus, Interchim, PF-30SIHP-JP-F00xx, 30μm. NMR and LCMS. The analytical characterization of synthesized compounds wasdone by NMR and LCMS.1H NMR spectra were recorded on a Bruker AVANCE III 400, Bruker AVANCE NEO 400, Bruker AVANCE III HD 400 or on a Jeol ECZ 400 spectrometer at 400 MHz Data are reported as follows: chemical shift in ppm, deuterated solvent (CDCl3for deuterated chloroform, DMSO-d6for deuterated dimethylsulfoxide and methanol-d4 for deuterated methanol), multiplicity (s = singulet, d = doublet, t = triplet, q = quartet, m = multiplet or overlap of non-equivalent resonances, integration, br = broad singulet, dd = doublet of doublet, dt = doublet of triplet, td = triplet of doublet, dq = doubletof quintuplet). Coupling constants J were measured in Hertz.LCMS spectra were recorded according to the following conditions: SHIMADZU LCMS-2020 using LabSolution software Version 5.89 and 5.93; HALO C18 column 3.0 x 30 mm x 5.0 um or Kinetex EVO C18 column 2.1 x 30 mm x 5 um; mobile Attorney Docket No.: 185992002040 phase: water (0.04% TFA)-ACN (0.02% TFA), at 50 °C on a 1 to 2 minutes gradient (flow rate 1.5 to 2.0 mL / min) with UV detection at 220 and 254 nm; ESI for mass spectra. Agilent 1260 Infinity II, Agilent Poroshell 120 EC C18 or HPH C18 column 2.7 μm 2.1 x 50 mm; mobile phase: water (0.1% FA)-ACN on a two-minute gradient (flow rate 0.6 mL / min) or mobile phase: water (0.1% FA)-ACN on a five-minute gradient (flow rate 0.6 mL / min) or water (0.1% NH3)-ACN (flow rate 0.7 mL / min) with UV detection at 220 and 254 nm; ESI for mass spectra.Synthesis of non-commercially available boronic ester derivative reagentsbor.1’: [6-(1-tert-butoxycarbonylazetidin-3-yl)-3-pyridyl] boronic acid To a solution of 2,5-dibromopyridine 7.1 (3.0 g, 13 mmol, 1.0 equiv), tert-butyl 3-iodoazetidine-1-carboxylate (4.7 g, 16.5 mmol, 1.3 equiv) in DME (30 mL) were addedIr[dF(CF3)ppy]2(bpy)PF6(0.14 g, 0.13 mmol, 0.01 equiv), NiCl2,dtbbpy (25 mg, 0.06 mmol,0.005 equiv), TTMSS (3.15 g, 13 mmol, 1.0 equiv) and Na2CO3 (2.7 g, 25 mmol, 2.0 equiv)at 25 °C. After stirring at 25 °C for 16 h irradiated with a 455 nm blue LED, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residuewas purified by flash chromatography (20 g column, Eluent of 0~60% EtOAc / PE gradient at40 mL / min) to give tert-butyl 3-(5-bromo-2-pyridyl) azetidine-1-carboxylate 7.2 (1.0 g, 2.75mmol, 22% yield, 86% purity) as yellow oil. MS m / z (ESI) [M-55] + = 259.0.To a solution of 7.2 (1.0 g, 2.75 mmol, 1.0 equiv), B2pin2 (0.91 g, 3.6 mmol, 1.3equiv) in dioxane (25 mL) was added Pd(dppf)Cl2 (0.20 g, 0.28 mmol, 0.10 equiv) and KOAc (1.1 g, 11 mmol, 4.0 equiv) at 20 °C. After stirring at 80 °C for 24 h, the reaction mixture was diluted with water (30 mL) and then extracted with ethyl acetate (30 mL, three times), the combined organic phase was washed with brine (10 mL, three times), dried with Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (12 g column, Eluent of 0~50% EtOAc / PE gradient at 40 mL / min) togive bor.1’ (0.45 g, 1.5 mmol, 54% yield, 91% purity) as a yellow gum. MS m / z (ESI) [M-80] + = 223.3. Attorney Docket No.: 185992002040bor.2: 2-(azetidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) thiazole To a solution of 2,5-dibromothiazole 8.1 (1.0 g, 4.1 mmol, 1.0 equiv) in N, N-dimethylformamide (10 mL) was added K2CO3(1.1 g, 8.2 mmol, 2.0 equiv) and azetidine (0.60 g, 6.4 mmol, 0.71 mL, 1.6 equiv, HCl salt) at 25 °C. After stirring at 80 °C for 16 h, the reaction mixture was added into water (50 mL) and extracted with ethyl acetate 60 mL (20 mL, three times). The combined organic layers were washed with brine 60 mL (20 mL, three times), dried over Na2SO4 , filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (24g column, Eluent of 0~15% EtOAc / PE gradient at45 mL / min) to give 2-(azetidin-1-yl)-5-bromo-thiazole 8.2 (0.50 g, 2.3 mmol, 55% yield,99% purity) as a white solid. MS m / z (ESI) [M+H] + = 221.0.To a solution of 8.2 (0.25 g, 1.1 mmol, 1.0 equiv) in THF (10 mL) was added n-BuLi(2.5 M, 1.0 mL, 2.2 equiv) at – 60 °C under stirring, after 0.5 h, the 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.32 g, 1.7 mmol, 0.35 mL, 1.5 equiv) was added into themixture at – 60 °C .Then, the mixture was stirred at – 60 °C for 2 h. The reaction mixture wasadded into saturated aqueous solution of ammonium chloride (20 mL) and extracted withEtOAc (15 mL, three times). The combined organic layers were washed with brine 15 mL,dried over Na2SO4, filtered, and concentrated under reduced pressure to give boronic esterbor.2 (0.20 g, 0.38 mmol, 33% yield, 50% purity) as a brown solid. MS m / z (ESI) [M+H] + =267.1.bor.3: tert-butyl N-methyl-N-[2-[[5-(4,4,5,5-tetramethyl- dioxaborolan-2-yl)-2-pyridyl] oxy] ethyl] carbamate To a solution of 5-bromopyridin-2-ol 9.1 (1.0 g, 5.8 mmol, 1.0 equiv), tert-butyl N-(2-hydroxyethyl)-N-methylcarbamate (1.2 g, 6.9 mmol, 1.2 equiv) in THF (20 mL) was addedPPh3 (1.8 g, 6.9 mmol, 1.2 equiv) and DIAD (1.4 g, 6.9 mmol, 1.3 mL, 1.2 equiv) at 25 °C. Attorney Docket No.: 185992002040 After stirring at 25 °C for 16 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (40 g column, Eluent of 0~15% EtOAc / PE gradient at 30 mL / min) to give tert-butyl N-[2-[(5-bromo-2-pyridyl) oxy] ethyl]-N-methylcarbamate 9.2 (1.0 g, 2.9 mmol, 50% yield, 95% purity) as colorless oil. MS m / z(ESI) [M-55] + = 241.0.A mixture of 9.2 (0.50 g, 1.5 mmol, 1.0 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (0.42 g, 1.7 mmol, 1.1 equiv),Pd(dppf)Cl2 (0.11 g, 0.15 mmol, 0.10 equiv), KOAc (0.30 g, 3.0 mmol, 2.0 equiv) in dioxane(10 mL, degassed and purged with nitrogen for 3 times at 25 °C) was heated at 80 °C for 16 hunder nitrogen atmosphere and stirring. Then, the reaction mixture was concentrated underreduced pressure. The residue was purified by flash chromatography (12 g column, Eluent of 0~10% EtOAc / PE gradient at 50 mL / min) to give bor.3 (0.50 g, 1.15 mmol, 76% yield, 87% purity) as colorless oil. MS m / z (ESI) [M-100+H]+= 297.1.bor.4: tert-butyl N-cyclopropyl-N-[2-[[5-(4,4,5,5-tetramethyl- dioxaborolan-2-yl)-2- pyridyl] oxy] ethyl] carbamate To a solution of 5-bromopyridin-2-ol 10.1 (2.0 g, 11.5 mmol, 1.0 equiv), 2,2-diethoxyethanol (1.9 g, 14 mmol, 1.2 equiv) in THF (20 mL) were added PPh3 (3.6 g, 14mmol, 1.2 equiv) and diisopropyl azodiformate (2.8 g, 14 mmol, 1.2 equiv) at 0 °C. Afterstirring at 20 °C for 12 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (40 g column, Eluent of 0~40% EtOAc / PEgradient at 40 mL / min) to give 5-bromo-2-(2,2-diethoxyethoxy) pyridine 10.2 (3.0 g, 10mmol, 90% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) d (ppm): 7.87 (d, J =2.8 Hz, 1H) ,7.54 (dd, J = 10, 2.8 Hz, 1H), 6.38 (d, J = 9.8 Hz, 1H), 4.71 - 4.66 (m, 1H), 3.94(d, J = 5.5 Hz, 2H), 3.70 - 3.55 (m, 4H), 1.05 (t, J = 7.0 Hz, 6H). Attorney Docket No.: 185992002040 To a solution of 10.2 (2.8 g, 10 mmol, 1.0 equiv) in ACN (20 mL) was added HCl (4M, 6.0 mL, 2.5 equiv) at 20 °C. The mixture was stirred at 20 °C for 4 h. The reactionmixture was diluted with water (20 mL) and then extracted with EtOAc (30.0 mL, threetimes), the combined organic phase was washed with brine (10 mL, three times), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give 2-[(5- bromo-2-pyridyl) oxy] acetaldehyde 10.3 (2.2 g, crude) as an off-white solid. To a solution of 10.3 (1.1 g, 5.1 mmol, 1.0 equiv) and cyclopropanamine (0.26 g, 4.6mmol, 0.90 equiv) in MeOH (15 mL) were added AcOH (0.92 g, 15 mmol, 3.0 equiv) andNaBH3CN (0.48 g, 7.6 mmol, 1.5 equiv) at 20 °C. After stirring at 20 °C for 12 h, thereaction mixture was concentrated under reduce presser, the residue was diluted with water(15 mL) and then extracted with EtOAc (15 mL, three times), the combined organic phasewas washed with brine (5.0 mL, three times), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give N-[2-[(5-bromo-2-pyridyl)oxy]ethyl]cyclopropanamine 10.4 (0.80 g, 2.4 mmol, 47% yield, 77% purity) as ayellow solid. MS m / z (ESI) [M+H] + = 259.1.To a solution of 10.4 (0.80 g, 2.4 mmol, 1.0 equiv) in DMF (10 mL) were added TEA(0.73 g, 7.2 mmol, 1.0 mL, 3.0 equiv) and Boc2O (1.1 g, 4.8 mmol, 1.1 mL, 2.0 equiv) at 20°C, the mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with water (20mL) and then extracted with EtOAc (20.0 mL, three times), the combined organic phase waswashed with brine (10 mL, three times), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (12 g column, Eluent of 0~25% EtOAc / PE gradient at 40 mL / min) to give tert-butyl N-[2-[(5-bromo-2-pyridyl) oxy] ethyl]-N-cyclopropyl-carbamate 10.5 (0.60 g, 1.4 mmol, 60% yield,86% purity) as a yellow solid. MS m / z (ESI) [M-100]+= 257.2. To a mixture of 10.5 (0.60 g, 1.4 mmol, 1.0 equiv) and B2pin2 (0.44 g, 1.7 mmol, 1.2equiv) in dioxane (10 mL) were added Pd(dppf)Cl2 (53 mg, 0.07 mmol, 0.05 equiv) andKOAc (0.28 g, 2.9 mmol, 2.0 equiv) at 25 °C, the mixture was degassed and purged withnitrogen for 3 times, and then the mixture was stirred at 60 °C for 4 h under nitrogenatmosphere. The reaction mixture was diluted with EtOAc (10 mL), then the mixture wasfiltered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (12 g column, Eluent of 0~25% EtOAc / PE gradient at 40 mL / min) tobor.4 (0.40 g, 0.73 mmol, 51% yield, 74% purity) as a brown solid. MS m / z (ESI) [M+H] + =405.3. Attorney Docket No.: 185992002040bor.5: tert-butyl N-[1-methyl-2-oxo-2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl] ethyl] carbamate To a solution of 2-(tert-butoxycarbonylamino) propanoic acid 11.1 (10 g, 53 mmol,1.0 equiv) in DMF (100 mL) was added HATU (25 g, 66 mmol, 1.2 equiv), the reactionmixture was stirred at 25 °C for 10 min. Then the mixture was added DIEA (19 g, 0.14 mol,25 mL, 2.7 equiv) and N-methoxymethanamine (6.0 g, 62 mmol, 1.2 equiv, HCl). Themixture was stirred at 25 °C for another 5 h. The reaction mixture was extracted with EtOAc(400 mL) and H2O (300 mL). The combined organic layers were washed with saturatedaqueous NH4Cl (300 mL), saturated aqueous NaHCO3 (300 mL) and brine (300 mL), driedover Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified byflash chromatography (80 g column, Eluent of 0~50% EtOAc / PE gradient at 100 mL / min) togive tert-butyl N-[2-[methoxy(methyl)amino]-1-methyl-2-oxo-ethyl] carbamate 11.2 (9.0 g,37 mmol, 70% yield, 95% purity) as a white solid.To a solution of 5-bromo-2-iodo-pyridine 11.3 (9.7 g, 34 mmol, 1.0 equiv) in THF(150 mL) was added 11.2 (8.0 g, 34 mmol, 1.0 equiv) , the reaction mixture was degassedand purged with N2 for three times, then i-PrMgCl (2 M, 35 mL, 2.0 equiv) was added to thereaction mixture at 0 °C, the reaction mixture was stirred at 25 °C for 1 h under N2atmosphere. The reaction mixture was quenched with saturated aqueous NH4Cl (300 mL)and extracted with EtOAc (500 mL, twice). The combined organic layers were washed withbrine (400 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. Theresidue was purified by flash chromatography (80 g column, Eluent of 0~9% EtOAc / PEgradient at 100 mL / min) to give desired compound as a yellow solid, which was furtherpurified by reversed-phase MPLC (0.1%FA condition) to give tert-butyl N-[2-(5-bromo-2-pyridyl)-1-methyl-2-oxo-ethyl]carbamate 11.4 (4.0 g, 12 mmol, 36% yield, 100% purity) as awhite solid. Attorney Docket No.: 185992002040 To a solution of 11.4 (0.36 g, 1.1 mmol, 1.0 equiv) and B2pin2 (0.44 g, 1.7 mmol, 1.6equiv) in dioxane (5.0 mL) was added Pd(dppf)Cl2 (72 mg, 98 μmol, 0.09 equiv) and KOAc(0.33 g, 3.3 mmol, 3.0 equiv), the reaction mixture was degassed and purged with N2 forthree times. The mixture was stirred at 80 °C for 5 h under N2 atmosphere. The crudeproduct bor.5 (0.42 g, crude) was directly used into the next step without further purificationas a black liquid.bor.6: [6-(azetidin-1-yl)-3-pyridyl] boronic acid To a solution of 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine12.1 (4.5 g, 20 mmol, 1.0 equiv) and azetidine (2.3 g, 24 mmol, 2.7 mL, 1.2 equiv, HCl) inDMSO (40 mL) was added K2CO3 (8.4 g, 61 mmol, 3.0 equiv) at 25 °C. The mixture was stirred at 100 °C for 16 h. The mixture was diluted with water (50 mL) and extracted withEtOAc (60 mL, three times). The organic phase was washed with brine (150 mL), dried overNa2SO4, filtered and the filtrate was concentrated. The residue was purified by prep-HPLC 3’(gradient: 0%-30% ACN over 10 min) to give [6-(azetidin-1-yl)-3-pyridyl] boronic acid bor.6(2.2 g, 12 mmol, 61% yield, 99% purity) as a yellow solid. MS m / z (ESI) [M+H] + = 178.9.bor.7: (6-(4-((tert-butoxycarbonyl) alanyl) piperazin-1-yl) pyridin-3-yl) boronic acid To a solution of tert-butyl 4-(5-bromo-2-pyridyl) piperazine-1-carboxylate 13.1 (1.0g, 2.9 mmol, 1.0 equiv) in dioxane (0.5 mL) was added HCl / dioxane (2.0 M, 2.0 mL) at 25 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated underreduced pressure to give 1-(5-bromo-2-pyridyl) piperazine 13.2 (0.80 g, 2.8 mmol, 96%yield, 98% purity, HCl). MS m / z (ESI) [M+H] + = 242.0.To a solution of 13.2 (0.80 g, 2.9 mmol, 1.0 eq, HCl) in DMF (3.0 mL) was addedBoc-DL-Ala-OH (0.65 g, 3.4 mmol, 1.2 equiv), HATU (2.2 g, 5.7 mmol, 2.0 equiv) andDIEA (1.5 g, 11 mmol, 2.0 mL, 4 equiv). The mixture was stirred at 25 °C for 16 h. The Attorney Docket No.: 185992002040 reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl N-[2-[4-(5-bromo-2-pyridyl) piperazin-1-yl]-1-methyl-2-oxo-ethyl] carbamate 13.3 (1.1 g, 2.6mmol, 92% yield, 99% purity). MS m / z (ESI) [M+H] + = 413.1.A mixture of 13.3 (1.1 g, 2.7 mmol, 1 equiv), B2pin2 (1.0 g, 4.0 mmol, 1.5 equiv),Pd(dppf)Cl2(0.20 g, 0.27 mmol, 0.10 equiv), AcOK (0.79 g, 8.0 mmol, 3.0 equiv) in dioxane (3.0 mL) was degassed and purged with N2 three times at 25 °C, and then the mixture was stirred at 80 °C for 16 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with EtOAc (35 mL, three times). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. Theresidue was purified by prep-HPLC 2 (gradient:10%-40% over 15 min) to give bor.7 (0.48 g,1.3 mmol, 48% yield, 100% purity). MS m / z (ESI) [M+H] + = 379.2.bor.8: tert-butyl (3-methyl-1-oxo-1-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl)amino) butan-2-yl) carbamate To a solution of 4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline 14.1 (1.0g, 4.6 mmol, 1.0 equiv) and Boc-DL-Val (1.0 g, 4.6 mmol, 1.0 equiv) in DMF (20 mL) wasadded HATU (2.6 g, 6.9 mmol, 1.5 equiv) and DIEA (2.0 g, 15 mmol, 2.7 mL, 3.4 equiv) in turns, then the resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was dilutedwith EtOAc (50 mL), washed with sat. NH4Cl (50 mL, twice), sat. NaHCO3 (50 mL, twice),brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentratedto give crude material. The residue was purified by flash chromatography 2 (40 g Column,Eluent of 0 to 40% EtOAc / PE gradient at 40 mL / min) to give product bor.8 (1.2 g, 2.2 mmol,48% yield, 76% purity) as white solid. MS m / z (ESI) [M+H] + = 419.3. Attorney Docket No.: 185992002040 Synthesis of amine intermediates amine.1: 1, 2, 3, 3a, 4, 5, 7, 7a-octahydropyrrolo [3, 4-c] pyridin-6-one Tert-butyl 5-oxo-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxylate 15.1(5.0 g, 22 mmol, 1.0 equiv) was added to HCl / dioxane (2 M, 40 mL, 3.6 equiv). The reactionsolution was stirred at 25 °C for 1 h. The reaction solution was concentrated under vacuum togive 2,3,3a,4,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-one 15.2 (5.0 g, crude, HCl) as ayellow solid which was used for next step without further purification. To a solution of 15.2 (3.6 g, 22 mmol, 1.0 equiv, HCl) and TEA (7.3 g, 72 mmol, 10mL, 3.2 equiv) in DCM (40 mL) was added CbzCl (4.6 g, 27 mmol, 3.8 mL, 1.2 equiv) at 0°C, The reaction solution was stirred at 25 °C for 1 h. The residue was partitioned betweenEtOAc (50 mL) and water (50 mL). The organic phase was washed by sat. NaCl (50 mL).The combined organic layers were dried over Na2SO4and evaporated to give a crudematerial. The residue was purified by flash chromatography (12 g column, Eluent of 0~20%EtOAc / PE gradient at 40 mL / min) to afford benzyl 5-oxo-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxylate 15.3 (1.2 g, 3.4 mmol, 15% yield, 73%purity) as a light-yellow oil.To a solution of 15.3 (1.2 g, 4.6 mmol, 1.0 equiv) in MeOH (20 mL) / H2O (5 mL) wasadded NH2OH.HCl (0.72 g, 10 mmol, 2.2 equiv) and NaOAc (1.1 g, 13 mmol, 2.8 equiv) ,The reaction solution was stirred at 25 °C for 1 h. The residue was partitioned betweenEtOAc (500 mL) and water (500 mL). The organic phase was washed by sat. NaCl (500 mL).The combined organic layers were dried over Na2SO4 and evaporated. The residue was purified by flash silica gel chromatography (12 g column, Eluent of 0~20% EtOAc / PEgradient at 40 mL / min) to afford benzyl 5-hydroxyimino-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxylate 15.4 (1.2 g, 4.4 mmol, 95% yield) as a light- Attorney Docket No.: 185992002040yellow oil. 1H NMR (400 MHz, CDCl3) d (ppm): 7.38 - 7.33 (m, 5H), 5.14 (d, J = 4.9 Hz,2H), 3.71 - 3.63 (m, 2H), 3.33 - 3.18 (m, 2H), 2.83 - 2.65 (m, 4H), 2.44 - 2.34 (m, 2H).To a solution of 15.4 (1.2 g, 4.4 mmol, 1.0 equiv) in THF (10 mL) was added SOCl2(1.6 g, 14 mmol, 1.0 mL, 3.2 equiv) at 0 °C, the reaction solution was stirred at 25 °C for 2 h.The residue was partitioned between EtOAc (500 mL) and water (500 mL). The organicphase was washed by sat. NaCl (500 mL). The combined organic layers were dried overNa2SO4 and evaporated. The residue was purified by prep-HPLC 2 (gradient: 23%-53% ACNover 15 min). After Prep-HPLC purification, the eluent was concentrated to remove organicsolvents. The residual aqueous solution was lyophilized to give benzyl 6-oxo-3,3a,4,5,7,7a-hexahydro-1H-pyrrolo[3,4-c] pyridine-2-carboxylate 15.5 (0.60 g, 2.2 mmol, 50% yield,100% purity) as a yellow oil. 1H NMR (400 MHz, CDCl3) d (ppm): 7.40 - 7.37 (m, 5H), 5.16(s, 2H), 3.79 - 3.62 (m, 3H), 3.45 - 3.28 (m, 3H), 2.94 - 2.60 (m, 3H), 2.47 (br dd, J = 3.7,17.9 Hz, 1H). MS m / z (ESI) [M+H] + = 275.2.To a solution of Pd / C (20 mg, 10% purity) in EtOAc (5.0 mL) was added 15.5 (0.10g, 0.36 mmol, 1.0 equiv) under N2, the reaction solution was degassed and purged under H2for three times, The reaction solution was stirred at 25 °C for 12 h. The reaction solution wasfiltered, and filtrate was concentrated under vacuum to give amine.1 (50 mg, crude) as ayellow oil was used for next step without purification. Synthesis of dichloroquinoline intermediatesA.4a (R6 = F; R7 = OMe): 2, 4-dichloro-7-fluoro-6-methoxy-quinoline To a solution of 3-fluoro-4-methoxy-aniline A.3a (2.0 g, 14 mmol, 1.0 equiv) andmalonic acid (1.6 g, 15 mmol, 1.6 mL, 1.1 equiv) in POCl3 (33 g, 215 mmol, 20 mL, 15equiv) at 25 °C. The mixture was stirred at 25 °C for 3 h, then stirred at 90 °C for 12 h. Thereaction mixture was added into H2O and held the temperature at 20 °C ~ 30 °C, washed withaq. NaHCO3 then was partitioned between EtOAc (30 mL) and water (50 mL). The aqueouslayer was extracted with EtOAc (30 mL) twice. The combined organic layers were dried over Na2SO4and evaporated to give a crude material. The water phase was added aq. NaOH andadjusted to pH = 7 then put into waste liquid tank. The residue was purified by flash Attorney Docket No.: 185992002040chromatography (40 g column, Eluent of 0~10% EtOAc / PE gradient at 40 mL / min) to afford2, 4-dichloro-7-fluoro-6-methoxy-quinoline A.4a (1.9 g, 7.7 mmol, 54% yield, 100% purity)as white solid. 1H NMR (400 MHz, DMSO-d6) d (ppm): 7.89 (m, 2H), 7.59 (d, J = 8.9 Hz,1H), 4.06 (s, 3H). MS m / z (ESI) [M+H] + = 246.0.A.4b (R6-R7 = NHCH2CH2O): 7,9-dichloro-3,4-dihydro-2H-pyrido[2,3-g] [1,4] benzoxazine To a solution of 6-nitro-3,4-dihydro-2H-1,4-benzoxazine A.1b (4.2 g, 23 mmol, 1.0equiv) and NaOH (2.8 g, 70 mmol, 1.3 mL, 3.0 equiv) in THF (40 mL) was added Fmoc-Cl (7.2 g, 28 mmol, 1.2 equiv) at 0 °C. The mixture was stirred at 25 °C for 1 h. The mixturewas diluted with water (100 mL) and extracted with EtOAc (100 mL, three times). Theorganic phase was washed with brine (300 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated. The residue was purified by flash chromatography (Eluent of 0~100% EtOAc / PE gradient at 50 mL / min) to give 9H-fluoren-9-ylmethyl 6-nitro-2,3-dihydro-1,4-benzoxazine-4-carboxylate A.2b (7.6 g, 17 mmol, 71% yield, 88% purity) as ayellow solid. MS m / z (ESI) [M+Na]+= 425.1. To a solution of A.2b (7.6 g, 19 mmol, 1.0 equiv) and NH4Cl (6.1 g, 113 mmol, 6.0eq) in EtOH (60 mL) / H2O (60 mL) was added Fe (5.3 g, 94 mmol, 5.0 equiv) at 60 °C, the mixture was stirred at 60 °C for 16 h. The mixture was diluted with water (200 mL) andextracted with EtOAc (200 mL, three times). The organic phase was washed with brine (300mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated. The residue was purified by flash chromatography (Eluent of 0~100% EtOAc / PE gradient at 50 mL / min) to give 9H-fluoren-9-ylmethyl 6-amino-2,3-dihydro-1,4-benzoxazine-4-carboxylate A.3b(6.0 g, 13 mmol, 68% yield, 80% purity) as a yellow solid. MS m / z (ESI) [M+H] + = 373.2.A mixture of A.3b (5.0 g, 13 mmol, 1.0 eq) and malonic acid (1.6 g, 15 mmol, 1.6mL, 1.1 eq) in POCl3(50 mL) was stirred at 100 °C for 16 h. The reaction mixture was concentrated under reduced pressure to remove POCl3, the reaction mixture was quenched with water (200 mL) at 25 °C, the mixture was adjusted to pH = 7~8 with NaHCO3.Themixture was diluted with water (200 mL) and extracted with EtOAc (200 mL, three times).The organic phase was washed with brine (400 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to give a residue. The mixture was concentrated. The residue was purified by flash chromatography (25 g column, Eluent of 0~100% EtOAc / PE gradient at Attorney Docket No.: 185992002040 50 mL / min) to give 9H-fluoren-9-ylmethyl 7,9-dichloro-2,3-dihydropyrido[2,3-g] [1,4]benzoxazine-4-carboxylate A.4b’ (1.0 g, 1.3 mmol, 9.8% yield, 63% purity) as a yellowsolid. MS m / z (ESI) [M+H] + = 477.1.Intermediate A.4b’ underwent an additional step of deprotection. To a solution ofA.4b’ (0.90 g, 1.9 mmol, 1.0 equiv) in DCM (5.0 mL) was added diethylamine (3.2 g, 44 mmol, 4.5 mL, 23 equiv) at 25 °C. The mixture was stirred at 60 °C for 2 h. The mixture wasdiluted with water (20 mL) and extracted with EtOAc (30 mL, three times). The organicphase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated. The residue was purified by flash chromatography (20 g column, Eluent of0~50% EtOAc / PE gradient at 40 mL / min) to give quinoline A.4b (0.15 g, 0.59 mmol, 31%yield) was obtained as yellow oil. 1H NMR (400 MHz, DMSO-d6) d (ppm): 7.45 (s, 1H), 7.29(s, 1H), 7.24 (s, 1H), 4.33 - 4.29 (m, 2H), 3.59 - 3.54 (m, 2H).A.4c (R6 = O- R7 = H): 2,4-dichloro-7-(3- To a mixture of 1-fluoro-3-nitrobenzene A.1c (10 g, 71 mmol, 7.6 mL, 1.0 equiv) andpyridin-3-ol (8.1 g, 85 mmol, 1.2 equiv) in DMF (100 mL) was added potassium carbonate(20 g, 0.14 mol, 2.0 equiv) at 20 °C. The reaction mixture was stirred at 130 °C for 48 h. The reaction mixture was quenched with water (500 mL) and extracted with EtOAc (500 mL, twice). The combined organic phase was washed with brine (500 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo. The crude product was purified by column chromatography (SiO2, PE / EtOAc = 10:1 to 3:1) to give 3-(3-nitrophenoxy)pyridine A.2.c (7.0 g, 45% yield) as a yellow oil. MS m / z (ESI) [M+H] + = 216.9.To a mixture of A.2c (7.0 g, 32 mmol, 1.0 equiv) in a mixed solution of EtOH (80mL) and water (10 mL) was added NH4Cl (14 g, 0.26 mol, 8.0 equiv) at 20 °C. The reactionmixture was stirred at 80 °C and Fe (9.0 g, 0.16 mol, 5.0 equiv) was added to the reaction mixture in batches at 80 °C. Then the reaction mixture was stirred at 80 °C for 3 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentratedin vacuo to give a crude product. The crude product was purified by flash chromatography(SiO2, PE / EtOAc = 5:1 to 1:1) to give 3-(3-pyridyloxy) aniline A.3c (4.0 g, 66% yield) asyellow oil. Attorney Docket No.: 185992002040 Amixture of A.3c (4.0 g, 22 mmol, 1.0 eq) and malonic acid (2.5 g, 24 mmol, 2.5mL, 1.1 equiv) in POCl3 (40 mL) as stirred at 110 °C for 16 h. The reaction mixture was cooled to room temperature and most of the POCl3 was removed by decompress distillation to give a residue. The residue was quenched with saturated NaHCO3solution (500 mL) andextracted with EtOAc (500 mL, twice). The combined organic phase was washed with brine(500 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuoto. The crude product was purified by column chromatography (SiO2, PE / EtOAc = 10:1 to3:1) and preparative TLC (SiO2, PE / EtOAc = 3:1) quinoline A.4c (0.20 g, 3% yield) as ayellow solid. MS m / z (ESI) [M+H] + = 290.9.A.4d (R6 = Me2N; R7 = H): 2,4-dichloro-N, N-dimethyl-quinolin-7-amine To a solution of N1, N1-dimethylbenzene-1,3-diamine A.3d (10 g, 73 mmol, 1.0equiv) in POCl3(90 mL) was added malonic acid (10 g, 96 mmol, 10 mL, 1.3 equiv) at 25 °C. After stirring at 110 °C for 16 h, the reaction mixture was added into saturated NaHCO3solution (200 mL) and extracted with EtOAc 300 mL (3 x 100 mL). The combined organiclayers were washed with brine 300 mL (3 x 100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (80g column, Eluent of 0~7% EtOAc / PE gradient at 30 mL / min) to give quinoline A.4d (1.5 g,5.9 mmol, 8.1% yield, 95% purity) as a yellow solid. MS m / z (ESI) [M+H] + = 241.0.A.4e (R6 = MeNH; R7 = OMe): 2,4-dichloro-6-methoxy-N-methyl-quinolin-7-amine To a solution of N-(3-amino-4-methoxy-phenyl) acetamide A.1e (12 g, 67 mmol, 1.0equiv) in MeOH (100 mL) / acetic acid (10 mL) was added formaldehyde (2.0 g, 67 mmol,1.8 mL, 1.0 equiv) and NaBH3CN (13 g, 0.20 mol, 3.0 equiv) at 25 °C. After stirring at 25 °Cfor 16 h, the reaction mixture was added into water (200 mL) and adjusted the pH = 7-8 then,extracted with EtOAc 300 mL (3 x 100 mL). The combined organic layers were washed withbrine 300 mL (3 x 100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography (80 g column, Attorney Docket No.: 185992002040 Eluent of 0~50% EtOAc / PE gradient at 60 mL / min) to give N-[4-methoxy-3-(methylamino)phenyl] acetamide A.2e’ (7.0 g, 24 mmol, 36% yield, 66% purity) as a yellow solid. MS m / z(ESI) [M+H] + = 195.0.Intermediate A.2e’ underwent an additional step of protection. To a solution of N-[4-methoxy-3-(methylamino) phenyl] acetamide A.2e’ (6.5 g, 22 mmol, 1.0 equiv) in dioxane(100 mL) was added NaHCO3 (5.6 g, 66 mmol, 2.6 mL, 3.0 equiv) and Fmoc-Cl (6.3 g, 24mmol, 1.1 equiv) at 0 °C. After stirring at 25 °C for 16 h, the reaction mixture was added into water (100 mL) and extracted with ethyl acetate 120 mL (3 x 40 mL). The combined organic layers were washed with brine 120 mL (3 x 40 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (80 g column, Eluent of 0~50% EtOAc / PE gradient at 60 mL / min) to give 9H-fluoren-9-ylmethylN-(5-acetamido-2-methoxy-phenyl)-N-methylcarbamate A.2e (10 g, 19 mmol, 87% yield,80% purity) as a yellow solid. MS m / z (ESI) [M+H] + = 417.2.To a solution A.2e (9.9 g, 24 mmol, 1.0 equiv) in methanol (100 mL) was addedsulfuric acid (12 M, 20 mL, 10 equiv) at 25 °C. After stirring at 60 °C for 16 h, the reaction mixture was added into water and adjusted the pH to 7-8, extracted with ethyl acetate 120 mL (3 x 40 mL). The combined organic layers were washed with brine 120 mL (3 x 40 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 9H-fluoren-9-ylmethyl N-(5-amino-2-methoxy-phenyl)-N-methylcarbamate A.3e (11 g, 24 mmol, 99%yield, 80% purity) as a yellow gum. MS m / z (ESI) [M+H] + = 375.1.To a solution of A.3e (10 g, 27 mmol, 1.0 equiv) in POCl3 (90 mL) was addedmalonic acid (3.5 g, 34 mmol, 3.5 mL, 1.3 equiv) at 25 °C. After stirring at 110°C for 16 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residuewas added into saturated NaHCO3 solution (200 mL) and extracted with EtOAc 300 mL (3 x100 mL). The combined organic layers were washed with water (100 mL) and brine 300 mL (3 x 100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography (40 g column, Eluent of 0~20% EtOAc / PE gradient at 60 mL / min) to give 9H-fluoren-9-ylmethyl N-(2,4-dichloro-6-methoxy-7-quinolyl)-N-methylcarbamate A.4e’ (2.0 g, 3.3 mmol, 12% yield, 78% purity) asa yellow solid. MS m / z (ESI) [M+H] + = 479.1.Intermediate A.4e’ underwent an additional step of deprotection. To a solution ofA.4e’ (2.0 g, 4.2 mmol, 1.0 equiv) in DCM (20 mL) was added piperidine (8.6 g, 0.10 mol,10 mL, 24 equiv) at 25 °C. After stirring at 60 °C for 2 h, the reaction mixture was added intowater and extracted with EtOAc 60 mL (3 x 20 mL). The combined organic layers were Attorney Docket No.: 185992002040 washed with brine 60 mL (3 x 20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (12 g column, Eluent of0~30% EtOAc / PE gradient at 45 mL / min) to give quinoline A.4e (0.60 g, 1.6 mmol, 39%yield, 70% purity) as a yellow solid. MS m / z (ESI) [M+H] + = 256.9.A.4f (R6 = OCF3; R7 = H): 2,4-dichloro-7-(trifluoromethoxy) quinoline To a solution of 3-(trifluoromethoxy) aniline A.3f (10 g, 56 mmol, 7.6 mL, 1.0 equiv)in POCl3 (90 mL) was added malonic acid (7.5 g, 72 mmol, 7.5 mL, 1.3 equiv) at 20 °C. Thereaction mixture was stirred at 20 °C for 2 h, then the reaction mixture was stirred at 110 °Cfor 12 h. The reaction mixture was concentrated under reduced pressure to remove solvent.The residue was diluted with saturated aqueous NaHCO3 (500 mL). The mixture was thenextracted with EtOAc (1000 mL, three times), the combined organic phase was washed withbrine (1000 mL, three times), dried with anhydrous Na2SO4, filtered and the filtrate wasconcentrated under reduced pressure. The residue was purified by flash chromatography (80gcolumn, Eluent of 0~10% EtOAc / PE gradient at 40 mL / min) to afford quinoline A.4f (5.2 g,18 mmol, 33% yield) as colorless oil. 1H NMR (400 MHz, CDCl3) d (ppm): 8.28 (d, J = 9.2Hz, 1H), 7.91 (d, J = 0.7 Hz, 1H), 7.59 - 7.50 (m, 2H).A.4g (R6 = F; R7 = Me): 2,4-dichloro-6-fluoro-N, N-dimethyl-quinolin-7-amine To a solution of 2-fluoro-5-nitro-aniline A.1g (10 g, 64 mmol, 1.0 equiv) in MeOH(100 mL) / AcOH (10 mL) was added HCHO (5.8 g, 192 mmol, 5.3 mL, 3.0 equiv) at 25 °C. After stirring at 25 °C for 48 h. The reaction mixture was added into saturated aqueoussolution of NH4Cl (200 mL) and extracted with EtOAc 300 mL (100 mL, three times). Thecombined organic layers were washed with brine 300 mL (100 mL, three times), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (40 g column, Eluent of 0~5% EtOAc / PE gradient at 45mL / min) to give 2- Attorney Docket No.: 185992002040fluoro-N, N-dimethyl-5-nitro-aniline A.2g (7.0 g, 36 mmol, 56% yield, 95% purity) as yellowoil. MS m / z (ESI) [M+H] + = 185.1.To a solution of Pd / C (0.10 g, 10% purity) in EtOAc (20 mL) was added A.2g (1.0 g,5.4 mmol, 1.0 equiv) under N2atmosphere at 25 °C. The suspension was degassed and purged with H2three times at 25 °C. After stirring under H2(15 Psi) at 25 °C for 16 h, the reaction mixture was filtered and concentrated under reduced pressure to give 4-fluoro-N3,N3-dimethyl-benzene-1,3-diamine A.3g (0.70 g, 4.1 mmol, 75% yield, 90% purity) as brownoil. MS m / z (ESI) [M+H] + = 155.1.To a solution of A.3g (0.70 g, 4.5 mmol, 1.0 equiv), malonic acid (0.5 g, 4.8 mmol,0.50 mL, 1.1 equiv) in POCl3 (7.0 mL) at 25 °C. After stirring at 100 °C for 16 h, the reactionmixture was added into saturated NaHCO3 aqueous solution (100 mL) and extracted withEtOAc 60 mL (20 mL, three times). The combined organic layers were washed with brine 60mL (20 mL, three times), dried over Na2SO4 filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (40 g column, Eluent of 0~5%EtOAc / PE gradient at 45 mL / min) to give quinoline A.4g (0.17 g, 0.59 mmol, 13% yield,90% purity) as a yellow solid. MS m / z (ESI) [M+H] + = 259.1.A.4h (R6 = Br; R7 = H): 7-bromo-2,4-dichloro-quinoline To a solution of 3-bromoaniline A.3h (10 g, 58 mmol, 6.3 mL, 1 equiv) and malonicacid (6.7 g, 64 mmol, 6.7 mL, 1.1 equiv) in POCl3(100 mL) at 25 °C. The mixture was stirred at 25 °C for 1 h. Then the mixture was stirred at 100 °C for 16 h. The reaction mixture was concentrated under reduced pressure to remove POCl3. The reaction mixture was quenched with water (200 mL) at 25 °C, the mixture was adjusted to pH=7~8 withNaHCO3.The mixture was diluted with water (200 mL) and extracted with EtOAc (200 mL,three times). The organic phase was washed with brine (600 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to give a residue. The mixture was concentrated. The residue was purified by column chromatography (SiO2, PE / EtOAc).Quinoline A.4h (3.0 g, 11 mmol, 19% yield, 100% purity) was obtained as a white solid. MSm / z (ESI) [M+H] + = 277.9. Attorney Docket No.: 185992002040 A.4i (R6 = OCD3; R7 = H): 2,4-dichloro-7-(trideuteriomethoxy) quinoline To a solution of 2,4-dichloro-7-methoxy-quinoline (1.0 g, 4.4 mmol, 1.0 equiv) inDCM (15 mL) was added BBr3 (2.6 g, 10 mmol, 2.4 equiv) at 0 °C. The mixture was stirredat 0 °C for 2 h. The reaction mixture was quenched by MeOH (20 mL), the mixture wasdiluted with water (50 mL) and then to the mixture was added NaHCO3until the pH = 7. Theabove mixture was then extracted with DCM (50 mL, three times), washed with brine (20mL, three times), dried with anhydrous Na2SO4, filtered and the filtrate was concentratedunder reduced pressure to give a residue. The residue was purified by flash silica gelchromatography (20 g column, Eluent of 0~30% EtOAc / PE gradient at 40 mL / min) to give2,4-dichloroquinolin-7-ol 16.2 (0.85 g, 3.7 mmol, 84% yield, 93% purity) as a white solid.MS m / z (ESI) [M+H] + = 214.1.To a solution of 16.2 (0.40 g, 1.9 mmol, 1.0 equiv) in ACN (8.0 mL) was addedK2CO3 (0.52 g, 3.7 mmol, 2.0 equiv) and CD3I (0.35 g, 2.4 mmol, 1.3 equiv) at 20 °C. Themixture was stirred at 20 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (12g column, Eluent of 0~20% EtOAc / PE gradient at 30 mL / min) to give quinoline A.4i (0.30 g,1.3 mmol, 70% yield, 100% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) d(ppm): 8.11 - 8.03 (m, 1H), 7.73 (s, 1H), 7.46 - 7.37 (m, 2H). MS m / z (ESI) [M+H] + = 231.2.A.4j (R6 = OMe; R7 = F): 2,4-dichloro-6-fluoro-7-methoxy-quinoline To a solution of 4-fluoro-3-methoxy-aniline (10 g, 71 mmol, 1.0 equiv) in POCl3 (165g, 1.1 mol, 0.10 L, 15 equiv) was added malonic acid (7.4 g, 71 mmol, 7.4 mL, 1.0equiv). The reaction solution was stirred at 105 °C for 12 h. The reaction solution was quenched by H2O (0.10 L). The pH of the residue was adjusted to 8 by adding sat. NaHCO3. The residue was extracted by EtOAc (0.30 L, twice), The organic phase was washed by sat. NaHCO3 (0.20 L, three times). The combined organic layers were dried over Na2SO4 andevaporated. The residue was purified by flash chromatography 2 (12 g column, Eluent of Attorney Docket No.: 1859920020400~20% EtOAc / PE gradient at 40 mL / min) to afford A.4j (13 g, 52 mmol, 74% yield, 99%purity) as a light green solid. MS m / z (ESI) [M+H] + = 246.0. 1H NMR (400 MHz, CDCl3) d(ppm): 7.79 (d, J = 11.4 Hz, 1H), 7.44 (d, J = 7.9 Hz, 1H), 7.41 (s, 1H), 4.03 (s, 3H).A.4k (R6 = O-Ph-pyrrolidine; R7 = H): 2, 4-dichloro-7-(4-pyrrolidin-1-ylphenoxy)quinoline To a solution of 4-iodophenol 17.1 (19 g, 86 mmol, 1.2 equiv) in DMA (0.15 L) wasadded Cs2CO3(47 g, 0.14 mol, 2.0 equiv) and 1-fluoro-3-nitrobenzene (10 g, 71 mmol, 7.6mL, 1.0 equiv). The mixture was stirred at 130 °C for 16 h. The reaction mixture wasquenched by water (0.15 L), and then the resulting organic phase was extracted with EtOAc (0.10 L, three times). The combined organic layers were washed with brine (0.10 L), dried over Na2SO4, filtered and the filtrate was concentrated in vacuum. The residue was purifiedby flash chromatography (120 g, PE / EtOAc) to afford 1-(4-iodophenoxy) -3-nitrobenzene17.2 (15 g, 44 mmol, 62% yield) as yellow solid. 1H NMR (400 MHz, methanol-d4) d (ppm):7.99 (ddd, J = 0.9, 2.1, 8.2 Hz, 1H), 7.80 - 7.71 (m, 3H), 7.60 (t, J = 8.3 Hz, 1H), 7.40 (ddd, J= 0.8, 2.4, 8.3 Hz, 1H), 6.93 - 6.87 (m, 2H).To a solution of 17.2 (13 g, 38 mmol, 1.0 equiv) in DMSO (0.15 L) was addedpyrrolidine (3.9 g, 55 mmol, 1.4 equiv), L-Proline (0.88 g, 7.6 mmol, 0.20 equiv), K2CO3 (12g, 87 mmol, 2.3 equiv) and CuI (0.78 g, 4.1 mmol, 0.10 equiv). The mixture was degassed and purged with N2three times, and then the mixture was stirred at 90 °C for 16 h under N2atmosphere. The reaction mixture was quenched by water (0.20 L), and then the resultingorganic phase was extracted with EtOAc (0.20 L, twice). The combined organic layers werewashed with brine (0.10 L, twice), dried over Na2SO4, filtered and the filtrate wasconcentrated in vacuum. The residue was purified by flash chromatography (80 g, PE / EtOAc)to afford 1-[4-(3-nitrophenoxy) phenyl] pyrrolidine 17.3 (6.7 g, 24 mmol, 62% yield) as Attorney Docket No.: 185992002040orange solid. 1H NMR (400 MHz, CDCl3) d (ppm): 7.83 (dd, J = 1.6, 8.1 Hz, 1H), 7.69 (t, J =2.3 Hz, 1H), 7.41 (t, J = 8.3 Hz, 1H), 7.25 (d, J = 2.4 Hz, 1H), 7.00 - 6.93 (m, 2H), 6.57 (d, J= 8.9 Hz, 2H), 3.30 (br t, J = 6.5 Hz, 4H), 2.08 - 2.01 (m, 4H).To a solution of (6.7 g, 24 mmol, 1.0 equiv) in EtOH (70 mL) and H2O (30 mL) wasadded NH4Cl (8.0 g, 0.15 mol, 6.3 equiv). Then mixture was added Fe (7.0 g, 0.13 mol, 5.3 equiv) in batches at 50 °C. Then the mixture was stirred at 80 °C for 2 h. The reaction mixture was filtered through celite, and the filtrate was concentrated in vacuum. The residuewas extracted with EtOAc (0.10 L, twice). The combined organic layers were washed withbrine (0.10 L), dried over Na2SO4, filtered and the filtrate was concentrated in vacuum. Theresidue was purified by flash chromatography (PE / EtOAc) to afford 3-(4-pyrrolidin-1-ylphenoxy) aniline 17.4 (5.1 g, 20 mmol, 86% yield) as off-white solid. 1H NMR (400 MHz,CDCl3) d (ppm): 7.03 (t, J = 8.0 Hz, 1H), 6.99 - 6.94 (m, 2H), 6.57 - 6.52 (m, 2H), 6.32 (dd, J= 2.2, 8.1 Hz, 2H), 6.26 - 6.21 (m, 1H), 3.63 (br s, 2H), 3.28 (br t, J = 6.6 Hz, 4H), 2.01 (td, J= 3.3, 6.6 Hz, 4H). To a solution of POCl3(50 mL) was added malonic acid (2 g, 19.2 mmol, 1.2 eq) and17.4 (4.1 g, 16 mmol, 1.0 equiv) carefully at 20 °C. The mixture was stirred at 20~90 °C for15 min and 90 °C for 6 h. The reaction mixture was concentrated in vacuum, then the residue was diluted with EtOAc (0.10 L), then quenched by water (0.10 L) and adjusted pH to 8 with NaHCO3 solution, and then the resulting organic phase was extracted with EtOAc (0.10 L, three times), the un-dissolved solid was abandoned. The combined organic layers were washed with brine (0.10 L), dried over Na2SO4, filtered and the filtrate was concentrated invacuum to give a residue. The residue was purified by flash chromatography (PE / EtOAc) toafford A.4k (0.80 g, 2.2 mmol, 14% yield) as yellow solid. 1H NMR (400 MHz, CDCl3) d(ppm): 8.11 (d, J = 9.2 Hz, 1H), 7.42 (dd, J = 2.6, 9.2 Hz, 1H), 7.34 (s, 1H), 7.24 (d, J = 2.4Hz, 1H), 7.04 - 6.96 (m, 2H), 6.62 - 6.52 (m, 2H), 3.30 (br t, J = 6.5 Hz, 4H), 2.04 (td, J =3.3, 6.5 Hz, 4H).A.4l (R6 = F; R7 = H): 2,4-dichloro-7-fluoro-quinoline To a solution of 3-fluoroaniline A.3l (25 g, 0.22 mol, 22 mL, 1.0 equiv) in POCl3(0.20 L) was added malonic acid (28 g, 0.27 mol, 28 mL, 1.2 equiv) at 25 °C. The mixture Attorney Docket No.: 185992002040 was stirred at 110 °C for 16 h. The reaction mixture was concentrated under reduced pressure to remove POCl3. The residue was diluted with NaHCO3 solution (0.10 L) and extracted withEtOAc 0.60 L (0.20 L, three times). The combined organic layers were washed with brine(0.30 L), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure.The residue was purified by flash chromatography 2 (120 g column, Eluent of 0~10%EtOAc / PE gradient at 40 mL / min) to give A.4l (12 g, 57 mmol, 25% yield, 100% purity) wasobtained as a white solid. 1H NMR (400 MHz, DMSO-d6) d (ppm): 8.23 (dd, J = 6.0, 9.3 Hz,1H), 7.90 (s, 1H), 7.80 (dd, J = 2.6, 9.9 Hz, 1H), 7.70 (dt, J = 2.6, 8.8 Hz, 1H). 1H NMR (400MHz, CDCl3) d (ppm): 8.19 - 8.10 (m, 1H), 7.61 (dd, J = 2.1, 9.4 Hz, 1H), 7.46 - 7.34 (m,2H). MS m / z (ESI) [M+H] + = 215.9.Synthesis of Suzuki Coupling Products A.5 and C.5 – (Schemes 1, 3, 5 and 6; step 4),(Scheme 4; step 5) General conditions for Suzuki Coupling. A mixture of 2,4-dichloroquinolinederivative A.4 (1.0 equiv), boronic ester derivatives (bor. When not commercially available)(1.2 equiv), Na2CO3 (3.0 equiv), Pd(PPh3)4 (0.10 equiv) in S1: dioxane / H2O (0.85:0.15;0.16M) or S2: EtOH / toluene / H2O (0.45:0.45:0.10; 0.17M) was degassed and purged with N2for three times at 25 °C, and then the mixture was stirred at 80 °C for 16 h under N2atmosphere. The mixture was diluted with water and extracted with EtOAc (three times).The organic phase was washed with brine (three times), dried over anhydrous Na2SO4,filtered and the filtrate was concentrated.A.5a: 2-[6-(azetidine-1-yl)-3-pyridyl]-4-chloro-6,7-dimethoxy-quinoline According to scheme 1 and 5, step 4, 2,4-Dichloro-6,7-dimethoxy-quinoline (0.40 g,1.6 mmol, 1.0 equiv) and boronic acid bor.6 (0.33 g, 1.9 mmol, 1.2 equiv) reacted under thegeneral conditions for Suzuki coupling. The residue was purified by flash silica gel chromatography (20g column, Eluent of 0~100% EtOAc / PE gradient at 40mL / min) to givecompound A.5a (0.22 g, 0.42 mmol, 27% yield, 68% purity) as a yellow solid. MS m / z (ESI)[M+H] + = 356.0. Attorney Docket No.: 185992002040A.5b: 1-[4-[5-(4-chloro-6,7-dimethoxy-2-quinolyl)-2-pyridyl] piperazin-1-yl] ethanone According to scheme 1 and 5, step 4, 2,4-Dichloro-6,7-dimethoxy-quinoline (0.25 g,0.97 mmol, 1.0 equiv). The residue was purified by prep-TLC (SiO2, PE / EtOAc = 1:1) togive compound A.5b (0.27 g, 0.59 mmol, 61% yield, 94% purity) was obtained as a brownsolid. MS m / z (ESI) [M+H] + = 427.1.A.5c: 2-[6-(4-benzylpiperazin-1-yl)-3-pyridyl]-4-chloro-7-methoxy-quinoline According to scheme 1 and 5, step 4, 2,4-Dichloro-7-methoxy-quinoline (0.20 g, 0.88mmol, 1.0 equiv). The crude product was triturated with MeOH (25 mL) at 25 °C for 30 minto give compound A.5c (0.35 g, 0.61 mmol, 69% yield, 77% purity) was obtained as a whitesolid. MS m / z (ESI) [M+H] + = 445.2.A.5d: 5-(4-chloro-7-methoxy-2-quinolyl)-N, N-dimethyl-pyridin-2-amine According to scheme 1 and 5, step 4, 2,4-Dichloro-7-methoxy-quinoline (0.30 g, 1.3mmol, 1.0 equiv). The residue was purified by prep-TLC (SiO2, DCM / MeOH = 10:1) to givecompound A.5d (0.15 g, 0.45 mmol, 35% yield, 95% purity) as a yellow solid. MS m / z (ESI)[M+H] + = 314.1. Attorney Docket No.: 185992002040A.5e: N-benzyl-5-(4-chloro-7-methoxy-2-quinolyl) -N- methyl-pyridin-2-amine According to scheme 1 and 5, step 4, 2, 4-Dichloro-7-methoxy-quinoline (0.20 g, 0.88mmol, 1.0 equiv). The residue was purified by prep-TLC (Plate 1: PE / EtOAc = 3:1) to givecompound 1.5l (0.13 g, 0.30 mmol, 34% yield, 90% purity) as a white solid.A.5f: 2-[6-(azetidin-1-yl) -3-pyridyl]-4-chloro-7-fluoro-6-methoxy-quinoline According to scheme 1 and 5, step 4, 2, 4-Dichloro-7-fluoro-6-methoxy-quinolineA.4a (0.30 g, 1.2 mmol, 1.0 equiv), boronic acid bor.6. The residue was purified by flashsilica gel chromatography (40 g column, Eluent of 0~30% EtOAc / PE gradient at 40 mL / min)to afford compound A.5f (0.28 g, 0.63 mmol, 51% yield, 77% purity) as white solid. 1HNMR (400 MHz, CDCl3) d (ppm): 8.82 (d, J = 2.1 Hz, 1H), 8.28 (dd, J = 2.4, 8.8 Hz, 1H),7.80 (s, 1H), 7.74 (d, J = 12.0 Hz, 1H), 7.51 - 7.48 (m, 1H), 6.37 (d, J = 8.8 Hz, 1H), 4.16 (t,J = 7.4 Hz, 4H), 4.07 (s, 3H), 2.51 - 2.41 (m, 2H). MS m / z (ESI) [M+H] + = 344.1.A.5g: 7- [6-(azetidin-1-yl)-3-pyridyl]- 9-chloro -3,4-dihydro -2H -pyrido[2,3-g] [1,4]benzoxazine According to scheme 1 and 5, step 4, 7,9-Dichloro-3,4-dihydro-2H-pyrido[2,3-g][1,4] benzoxazine A.4b (0.13 g, 0.51 mmol, 1.0 equiv), boronic acid bor.6. The residue waspurified by prep-TLC (SiO2, PE / EtOAc = 0:1) to give compound A.5g (70 mg, 0.18 mmol,36% yield, 92% purity) as a yellow solid. MS m / z (ESI) [M+H] + = 353.2. Attorney Docket No.: 185992002040A.5h: 2-[6-(azetidin-1-yl)-3-pyridyl]-4-chloro-6-methoxy-N-methyl-quinolin-7-amine According to scheme 1 and 5, step 4, 2,4-Dichloro-6-methoxy-N-methyl-quinolin-7-amine A.4e (0.60 g, 1.9 mmol, 1.0 equiv), boronic acid bor.6. The residue was triturated withethyl acetate at 25 oC for 25 minutes to give compound A.5h (0.35 g, 0.59 mmol, 32% yield,60% purity) was obtained as a yellow solid. MS m / z (ESI) [M+H] + = 355.1.A.5i: 2-[6-(azetidin-1-yl)-3-pyridyl]-4-chloro-6-fluoro-7-methoxy-quinoline According to scheme 1 and 5, step 4, 2,4-Dichloro-6-fluoro-7-methoxy-quinoline (0.20 g, 0.81 mmol, 1.0 equiv), boronic acid bor.6. The crude product was triturated withethyl acetate (5.0 mL) at 25 °C for 10 min to give compound A.5i (0.15 g, 0.41 mmol, 50%yield, 93% purity) as a yellow solid. MS m / z (ESI) [M+H] + = 344.0.A.5j: 2-(azetidin-1-yl)-5-(4-chloro-6-fluoro-7-methoxy-2-quinolyl) thiazole According to scheme 1 and 5, step 4, 2,4-Dichloro-6-fluoro-7-methoxy-quinoline(0.30 g, 1.2 mmol, 1.0 equiv), boronic ester bor.2. The residue was purified by prep-TLC(SiO2, PE / EtOAc = 3:1) to give compound A.5j (50 mg, 0.10 mmol, 8.2% yield, 70% purity)as yellow oil. MS m / z (ESI) [M+H] + = 350.0.A.5k: 2-[6-(azetidin-1-yl)-3-pyridyl]-4-chloro-6-fluoro-N, N-dimethyl-quinolin-7-amine Attorney Docket No.: 185992002040 According to scheme 1 and 5, step 4, 2,4-Dichloro-6-fluoro-N, N-dimethyl-quinolin- 7-amine (0.17 g, 0.66 mmol, 1.0 equiv), boronic acid bor.6. The residue was purified by flash silica gel chromatography (12 g column, Eluent of 0~20% EtOAc / PE gradient at 45 mL / min)to give compound A.5k (0.12 g, 0.30 mmol, 46% yield, 90% purity) as a yellow solid. MSm / z (ESI) [M+H] + = 357.1.A.5l: 2-[6-(azetidin-1-yl)-3-pyridyl]-7-bromo-4-chloro-quinoline According to scheme 1 and 5, step 4, 2,4-Dichloro-7-bromo-quinoline A4.h (1.0 g,3.6 mmol, 1.0 equiv). Boronic acid bor.6. The crude product was triturated with EtOAc (10mL) 25 °C for 10 min. Product A.5l (1.0 g, 2.4 mmol, 67% yield, 91% purity) was obtainedas a white solid. MS (ESI) m / z. 374.0 [M+H]+.A.5m: 2-(6-(4-benzylpiperazin-1-yl) 114zetidin-3-yl)-4-chloroquinoline Asolution of substrate C.5b (33 g, 78 mmol, 1.0 equiv) in EtOAc (0.10 L) wasdegassed and purged with N2 three times. HCl / EtOAc (2.0 M, 0.50 mL, 13 equiv) was added dropwise under N2. The reaction mixture was stirred at room temperature for 1 h under N2. The reaction mixture was filtered and gave the HCl.salt (40.0 g, crude) as a yellow solid. To the crude (70 g from two batches) was added H2O (1.0 L) at room temperature. pH was adjusted to 11~12 with saturated K2CO3aqueous solution. The mixture was extracted with EtOAc (1.0 L, four times) and concentrated under vacuum. The crude product (around 40 g) was triturated with MTBE (1V) at room temperature for 12 h. The free amine (34 g, 0.10mol, 60% yield, 96% purity) was obtained as a light yellow solid. MS m / z (ESI) [M+H] + =325.0. 1H NMR (400 MHz, CDCl3) d (ppm): 8.92 (d, J = 2.4 Hz, 1H), 8.35 (dd, J = 2.4, 8.8Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.88 (s, 1H), 7.7-7.8 (m, 1H), 7.57 (t, J = 7.6 Hz, 1H), 6.76 (d, J = 9.2 Hz, 1H), 3.6-3.7 (m, 4H), 3.0-3.1 (m, 4H). Attorney Docket No.: 185992002040 Free amine (1.5 g, 4.6 mmol, 1.0 equiv) was mixed with cesium carbonate (3.0 g, 9.2 mmol, 2.0 equiv) and (chloromethyl)benzene (0.64 mL, 5.5 mmol, 1.2 equiv) in 100 mLflask. DMF (37 mL) was added, and the reaction was stirred at room temperature for 3 days.The reaction mixture was transferred to a 0.50 L flask and diluted with EtOAc (0.20 L) and washed with water (0.20 L) and brine (0.20 L). The crude material was obtained as 2.7 g of yellow oil. The oil was diluted with DCM (4.0 mL) and subjected to purification by fully automated flash chromatography (heptane / EtOAc, 0–40% in 0–15 CV). Compound A.5m (0.71 g, 1.7 mmol, 37% yield) was obtained as yellow solid.1H NMR (400 MHz, CDCl3) d(ppm): 8.96 (d, J = 2.4 Hz, 1H), 7.50–8.05 (m, 6H), 7.39 (s, 5H), 6.79 (d, J = 9.0 Hz, 1H),3.73 (t, J = 5.6 Hz, 4H), 3.63 (s, 2H), 2.63 (t, J = 5.1 Hz, 4H).A.5n: 4-chloro-2-phenyl-6-(3-phenylpropoxy) quinoline 2,4-dichloroquinolin-6-ol (0.18 g, 0.84 mmol, 1.0 equiv), Cs2CO3(0.55 g, 1.7 mmol, 2.0 equiv) were transferred to a Schlenk tube, 5 A / V cycles were performed and DMF (3.8 mL, 5.2 mL / mmol) were added in counter flow, 3-(chloropropyl)benzene (0.16 g, 0.144 μL, 1.2 Eq, 1.01 mmol) was added taken up in DMF (0.8 mL), the mixture was heated to reflux for 2.5 h. 2,4-dichloroquinolin-6-ol (0.18 g, 0.84 mmol, 1.0 equiv), Cs2CO3(0.55 g, 1.7 mmol, 2.0 equiv) were transferred to a Schlenk tube, 5 A / V cycles were performed. DMF (3.8 mL, 5.2 mL / mmol) were added in counter flow and (3-chloropropyl)benzene (0.16 g, 0.14 mL, 1.0 mmol, 1.2 equiv) was added taken up in DMF (0.8 mL). The mixture was heated to reflux for 2.5 h. After work-up, residue was purified by flash chromatography using DCM / MeOH to give 2,4-dichloro-6-(3-phenylpropoxy)quinoline (0.10 g, 0.84 mmol, 37%). According to scheme 1 and 5, 2,4-dichloro-6-(3-phenylpropoxy) quinoline (69 mg,0.21 mmol, 1.0 equiv), phenylboronic acid (20 mg, 0.17 mmol, 0.80 equiv), Na2CO3 (66 mg, 0.62 mmol, 3.0 equiv) were transferred to a Schlenk tube, 5 A / V cycles were performed,degassed Toluene (3.4 mL, 1.6 mL / mmol) EtOH (3.4 mL) water (1.0 mL) were added incounter flow. Pd(PPh3)4 (24 mg, 21 μmol, 0.10 equiv) was added in counterflow, the mixture was heated to 65 °C (external temp), the mixture was filtered through a syringe filter, diluted with H2O and DCM (25 mL), phases were separated and evaporated to dryness. The samplewas purified using flash chromatography to give A.5n (52 mg, 0.14 mmol, 67 %) as a yellowsolid. Attorney Docket No.: 185992002040 A.5o: 4-chloro-7-(3-phenylpropoxy)-2-(3-pyridyl) quinoline According to scheme 1 and 5, a mixture of 2,4-dichloro-7-(3-phenylpropoxy)quinoline (0.20 g, 0.60 mmol, 1.0 equiv) , 3-pyridylboronic acid (59 mg, 0.48mmol, 0.80 equiv) , Pd(PPh3)4(70 mg, 60 μmol, 0.10 equiv), Na2CO3(0.19 g, 1.8 mmol, 3.0 equiv) in toluene (2.0 mL) / EtOH (2.0 mL) / H2O (0.40 mL) was degassed and purged with N2 three times at 25 °C, and then the mixture was stirred at 60 °C for 16 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue.The residue was diluted with water (30 mL) and extracted with EtOAc (40 mL, three times).The combined organic layers were washed with brine (35 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue waspurified by flash silica gel chromatography 2 (12 g column, Eluent of 0~30% EtOAc / PEgradient at 60 mL / min) to give A.5o (0.16 g, 0.41 mmol, 68% yield, 96% purity) wasobtained as a yellow solid. MS m / z (ESI) [M+H] + = 375.1.A.5p: 2-[6-(116zetidine-1-yl)-3-pyridyl]-6-bromo-4-chloro-quinoline According to scheme 1 and 5, step 4, to a solution 6-bromo-2,4-dichloro-quinoline(1.0 g, 3.6 mmol, 1.0 equiv) in dioxane (50 mL) / H2O (5.0 mL) was added bor.6 (0.80 g, 4.5mmol, 1.2 equiv), Na2CO3 (1.2 g, 11 mmol, 3.0 equiv) and Pd(PPh3)2Cl2 (0.26 g, 0.37 mmol,0.10 equiv). The reaction solution was degassed and purged under N2 three times; thereaction mixture was stirred at 60 °C for 12 h. The reaction mixture was concentrated to givea residue. The crude product was triturated with EtOAc (20 mL) at 25 °C for 20 min and theresulting solid was filtered and washed with EtOAc (2.0 mL), the filter cake was concentratedto give A.5p (1.8 g, crude) as yellow solid. Attorney Docket No.: 185992002040 C.5a: tert-butyl 4-[4-(4-chloro-2-quinolyl) phenyl] piperazine-1-carboxylate According to scheme 3 and 6, step 4, 2,4-Dichloroquinoline (2.0 g, 10 mmol, 1.0equiv). The residue was purified by flash chromatography (SiO2, PE / EtOAc = 20 / 1 to 3 / 1) toafford compound C.5a (3.0 g, 7.1 mmol, 70% yield) as a yellow solid. MS m / z (ESI) [M+H]+= 424.2.C.5b: tert-butyl 4-[5-(4-chloro-2-quinolyl) -2-pyridyl] piperazine-1-carboxylate According to scheme 3 and 6, step 4, 2,4-Dichloroquinoline (0.35 g, 1.8 mmol, 1.0equiv). The crude product was purified by flash silica gel chromatography (40 g column,Eluent of 0-21% EtOAc / PE gradient at 40 mL / min) to give compound C.5b (0.65 g, 1.5mmol, 87% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) d (ppm): 8.95 - 8.92 (m,1H), 8.41 - 8.36 (m, 1H), 8.23 - 8.18 (m, 1H), 8.14 - 8.09 (m, 1H), 7.90 - 7.88 (m, 1H), 7.78 -7.73 (m, 1H), 7.62 - 7.56 (m, 1H), 6.80 - 6.75 (m, 1H), 3.72 - 3.65 (m, 4H), 3.63 - 3.56 (m,4H), 1.53 - 1.49 (m, 9H).C.5c: tert-butyl 4- [5-(4-chloro-6, 7-dimethoxy-2-quinolyl) -2-pyridyl] piperazine-1-carboxylate According to scheme 3 and 6, step 4, 2, 4-Dichloro-6, 7-dimethoxy-quinoline (0.20 g,0.77 mmol, 1.0 equiv) The residue was purified by flash silica gel chromatography (20 g Attorney Docket No.: 185992002040column, Eluent of 0~50% EtOAc / PE gradient at 30 mL / min) to afford compound C.5c (0.35g, 0.59 mmol, 76% yield, 82% purity) as yellow gum. MS m / z (ESI) [M+H] + = 485.2.C.5d: 3-[5-(4-chloro-6,7-dimethoxy-2-quinolyl)-2-pyridyl] azetidine-1-carboxylate According to scheme 3 and 6, step 4, 2,4-Dichloro-6,7-dimethoxy-quinoline (0.20 g,0.78 mmol, 1.0 equiv), boronic acid bor.a’ (0.28 g, 0.93 mmol, 1.2 equiv). The residue waspurified by flash silica gel chromatography (12 g column, Eluent of 0~60% EtOAc / PEgradient at 30 mL / min) to give compound C.5d (0.20 g, 0.39 mmol, 50% yield, 88% purity)as a yellow solid. MS m / z (ESI) [M+H] + = 456.3.C.5e: tert-butyl 4-[5-(4-chloro-7-methoxy-2-quinolyl)-2-pyridyl] piperazine-1-carboxylate According to scheme 3 and 6, step 4, 2,4-Dichloro-7-methoxy-quinoline (0.30 g, 1.3mmol, 1.0 equiv). The residue was purified by prep-TLC (SiO2, PE / EtOAc = 2:1) to givecompound C.5e (0.50 g, 1.0 mmol, 77% yield, 92% purity) was obtained as yellow oil. MSm / z (ESI) [M+H] + = 455.2.C.5f: tert-butyl 4-[5-(4-chloro-6-methoxy-2-quinolyl)-2-pyridyl] piperazine-1-carboxylate According to scheme 3 and 6, step 4, 2,4-Dichloro-6-methoxy-quinoline (0.30 g, 1.3mmol, 1.0 equiv). The crude was used next step without purification. Compound C.5f (0.60 Attorney Docket No.: 185992002040g, 1.1 mmol, 82% yield, 82% purity) was obtained as a white solid. MS m / z (ESI) [M+H] + =455.2.C.5g: tert-butyl 4-[5-(6-bromo-4-chloro-2-quinolyl)-2-pyridyl] piperazine-1-carboxylate According to scheme 3 and 6, step 4, 6-Bromo-2,4-dichloro-quinoline (2.0 g, 7.2mmol, 1.0 equiv). The residue was purified by flash silica gel chromatography (25 g column,Eluent of 0~35% EtOAc / PE gradient at 55 mL / min) to give compound C.5g (2.0 g, 3.6mmol, 49% yield, 90% purity) as a yellow solid. MS m / z (ESI) [M+H] + = 505.1.C.5h: tert-butyl 4-[5-(7-bromo-4-chloro-2-quinolyl)-2-pyridyl] piperazine-1-carboxylate According to scheme 3 and 6, step 4, 7-Bromo-2,4-dichloro-quinoline A.4h (0.60 g,2.2 mmol, 1.0 equiv). The residue was purified by flash silica gel chromatography (20 gcolumn, Eluent of 0~40% EtOAc / PE gradient at 80 mL / min) to give compound C.5h (0.76 g,1.2 mmol, 54% yield, 78% purity) was obtained as a yellow solid. MS m / z (ESI) [M+H] + =505.1.C.5i: tert-butyl 4-[4-(4-chloro-7-methoxy-2-quinolyl) phenyl] piperazine-1-carboxylate According to scheme 3 and 6, step 4, 2,4-Dichloro-7-methoxy-quinoline (0.40 g, 1.8mmol, 1.0 equiv). The residue was purified by flash silica gel chromatography (12 g column,Eluent of 20~30% EtOAc / PE gradient at 40 mL / min) to afford compound C.5i (0.60 g, 1.3mmol, 75% yield, 99% purity) as yellow oil. MS m / z (ESI) [M+H] + = 454.2. Attorney Docket No.: 185992002040C.5j: tert-butyl 3-[5-(4-chloro-7-methoxy-2-quinolyl)-2-pyridyl] azetidine-1-carboxylate According to scheme 3 and 6, step 4, 2,4-Dichloro-7-methoxy-quinoline (0.40 g, 1.8mmol, 1.0 equiv), boronic acid bor.1’. The residue was purified by flash silica gel chromatography (40g column, Eluent of 0~10% EtOAc / PE gradient at 40 mL / min) toafford compound C.5j (0.36 g, 0.74 mmol, 42% yield, 88% purity) as yellow oil. MS m / z(ESI) [M+H] + = 426.1.C.5k: tert-butyl 4-[5-[4-chloro-7-(dimethylamino)-6-methoxy-2-quinolyl]-2-pyridyl]piperazine-1-carboxylate According to scheme 3 and 6, step 4, 2,4-Dichloro-6-methoxy-N, N-dimethyl-quinolin-7-amine (0.15 g, 0.55 mmol, 1.0 equiv). The residue was purified by prep-TLC(SiO2, PE / EtOAc = 2:1) to give compound C.5k (0.20 g, 0.40 mmol, 73% yield, 100%purity) as a yellow solid. MS m / z (ESI) [M+H] + = 498.3.C.5l: tert-butyl N- [2- [4- [4-chloro-7-(dimethylamino)-6-methoxy-2-quinolyl] phenoxy]ethyl]-N-methylcarbamate According to scheme 3 and 6, step 4, 2,4-Dichloro-6-methoxy-N, N-dimethyl-quinolin-7-amine (0.15 g, 0.55 mmol, 1.0 equiv), boronic ester bor.3. The residue waspurified by prep-TLC (SiO2, PE / EtOAc = 2:1) to give compound C.5l (0.16 g, 0.33 mmol,60% yield, 100% purity) as a yellow oil. MS m / z (ESI) [M+H] + = 486.3. Attorney Docket No.: 185992002040C.5m: tert-butyl 4-[4-chloro-7-(3-pyridyloxy)-2-quinolyl]-2-pyridyl] piperazine-1-carboxylate According to scheme 3 and 6, step 4, 2,4-Dichloro-7-(3-pyridyloxy) quinoline A.4c(0.20 g, 0.69 mmol, 1.0 equiv). The residue was purified by preparative TLC (SiO2,PE / EtOAc = 3:1) to give compound C.5m (0.18 g, 0.35 mmol, 35% yield) as a white solid.MS m / z (ESI) [M+H] + = 518.3.C.5n: tert-butyl 4-[5-[4-chloro-7-(dimethylamino)-2-quinolyl]-2-pyridyl] piperazine-1-carboxylate According to scheme 3 and 6, step 4, 2,4-Dichloro-N, N-dimethyl-quinolin-7-amineA.4d (0.50 g, 2.1 mmol, 1.0 equiv). The crude was not purified. Compound C.5n (0.80 g, 1.2mmol, 58% yield, 70% purity) was obtained as a yellow solid. MS m / z (ESI) [M+H] + =468.2.C.5o: tert-butyl N-[2- chloro-7-(dimethylamino)-2-quinolyl]-2-pyridyl] oxy] ethyl]-N- methylcarbamate According to scheme 3 and 6, step 4, 2,4-Dichloro-N, N-dimethyl-quinolin-7-amineA.4d (0.30 g, 1.2 mmol, 1.0 equiv), boronic ester bor.3. The crude was not purified.Compound C.5o (0.80 g, 1.2 mmol, 98% yield, 70% purity) as a yellow solid. MS m / z (ESI)[M+H] + = 457.2. Attorney Docket No.: 185992002040C.5p: tert-butyl 4-[5-[4-chloro-7-(trifluoromethoxy)-2-quinolyl]-2-pyridyl] piperazine-1-carboxylate According to scheme 3 and 6, step 4, 2,4-Dichloro-7-(trifluoromethoxy) quinolineA.4f (0.20 g, 0.71 mmol, 1.0 equiv). The residue was purified by flash chromatography (12 gcolumn, Eluent of 0~30% EtOAc / PE gradient at 40 mL / min) to afford compound C.5p (0.41g, 0.55 mmol, 78% yield, 69% purity) as yellow solid. MS m / z (ESI) [M+H] + = 509.1.C.5q: tert-butyl N-[5-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)-2-pyridyl]-N-methylcarbamate According to scheme 3 and 6, step 4, 2,4-Dichloro-6-fluoro-7-methoxy-quinoline(0.45 g, 1.8 mmol, 1.0 equiv). The residue was purified by flash silica gel chromatography(12 g column, Eluent of 0~20% EtOAc / PE gradient at 40 mL / min) to afford compound C.5q(0.60 g, 1.2 mmol, 64% yield, 82% purity) as a light green solid. MS m / z (ESI) [M+H] + =418.1.C.5r: tert-butyl 4-[5-[4-chloro-7-(trideuteriomethoxy)-2-quinolyl]-2-pyridyl] piperazine-1-carboxylate According to scheme 3 and 6, step 4, 2,4-Dichloro-7-(trideuteriomethoxy) quinolineA.4i (0.30 g, 1.3 mmol, 1.0 equiv). The residue was purified by flash silica gel Attorney Docket No.: 185992002040 chromatography (12 g column, Eluent of 0 to 30% EtOAc / PE gradient at 30 mL / min) to givecompound C.5r (0.45 g, 0.91 mmol, 70% yield, 93% purity) as a yellow solid. 1H NMR (400MHz, DMSO-d6) d (ppm): 9.08 - 8.98 (m, 1H), 8.44 (dd, J = 9.00, 2.40 Hz, 1H) 8.15 (s, 1H),8.04 (d, J = 9.12 Hz, 1H), 7.44 (d, J = 2.52 Hz, 1H), 7.30 (dd, J = 9.12, 2.52 Hz, 1H), 6.98 (d,J = 9.12 Hz, 1H), 3.70 - 3.60 (m, 4H), 3.45 (s, 4H), 1.43 (s, 9H). MS m / z (ESI) [M+H] + =458.3.C.5s: tert-butyl 4-[5-[4-chloro-7-(dimethylamino)-6-fluoro-2-quinolyl]-2-pyridyl]piperazine-1-carboxylate According to scheme 3, step 4, 2,4-Dichloro-6-fluoro-N, N-dimethyl-quinolin-7-amine (0.30 g, 1.2 mmol, 1.0 equiv) and 6. The residue was purified by flash silica gelchromatography (12 g column, Eluent of 0 to 15% EtOAc / PE gradient at 45 mL / min) to givecompound C.5s (0.50 g, 0.84 mmol, 73% yield, 82% purity) as a yellow solid. MS m / z (ESI)[M+H] + = 486.2.C.5t: tert-butyl N-[2-[4-(4-chloro-6-fluoro-7-methoxy-2-quinolyl) phenoxy] ethyl]-N-methylcarbamate According to scheme 3 and 6, step 4, 2,4-Dichloro-6-fluoro-7-methoxy-quinoline(0.30 g, 1.2 mmol, 1.0 equiv), boronic ester bor.3. The residue was purified by silica gelchromatography (Biotage, 100-200 mesh silica gel, product came out at B = 25% EtOAc / PE)to afford product compound C.5t (0.50 g, 1.1 mmol, 89% yield) as off-white solid. Attorney Docket No.: 185992002040C.5u: tert-butyl N-[2-[[5-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)-2-pyridyl] oxy] ethyl]-N-cyclopropyl-carbamate According to scheme 3 and 6, step 4, 2,4-Dichloro-6-fluoro-7-methoxy-quinoline(0.18 g, 0.73 mol, 1.0 equiv), boronic ester bor.4. The residue was purified by flash silica gel chromatography (20 g column, Eluent of 0~30% EtOAc / PE gradient at 30 mL / min) to givecompound C.5u (0.12 g, 0.17 mmol, 23% yield, 69% purity) as a yellow solid. MS m / z (ESI)[M+H] + = 488.2.C.5v: tert-butyl N-[2-[5-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)-2-pyridyl]- 1-methyl-2-oxo-ethyl] carbamate According to scheme 3 and 6, step 4, 2,4-Dichloro-6-fluoro-7-methoxy-quinoline(0.30 g, 1.2 mmol, 1.0 equiv), boronic ester bor.5. The residue was purified by flash silica gelchromatography (20 g column, Eluent of 0~23% EtOAc / PE gradient at 60 mL / min) togive desired compound as a yellow solid, which was further triturated with EtOAc (50 mL) at25 °C for 10 min, the resulting solid was filtered and washed by EtOAc (50 mL), the filtercake was concentrated to give compound C.5v (0.30 g, 0.65 mmol, 53% yield, 99% purity) asan off-white solid.C.5w: tert-butyl N-[5-(7-bromo-4-chloro-2-quinolyl) -2-pyridyl]-N-methylcarbamate According to scheme 3 and 6, step 4, 7-Bromo-2,4-dichloro-quinoline A.4h (0.30 g,1.1 mmol, 1.0 equiv). The residue was purified by flash silica gel chromatography (12 g Attorney Docket No.: 185992002040column, Eluent of 0~10% EtOAc / PE gradient at 40 mL / min) to afford compound C.5w (0.30g, 0.66 mmol, 60% yield, 98% purity) as a white solid. MS m / z (ESI) [M+H] + = 450.0.C.5x: tert-butyl N-[2-[4-[5-(4-chloro-7-methoxy-2-quinolyl)-2-pyridyl] piperazin-1-yl]-1-methyl-2-oxo-ethyl] carbamate According to scheme 3 and 6, step 4, 2,4-Dichloro-7-methoxy-quinoline (0.25 g, 1.1mmol, 1.0 equiv), boronic acid bor.7 (0.48 g, 1.3 mmol, 1.2 equiv). The crude product wastriturated with EtOAc (30 mL) at 25 °C for 30 min to give compound C.5x (0.23 g, 0.41mmol, 37% yield, 94% purity). MS m / z (ESI) [M+H] + = 526.2.C.5y: tert-butyl 4-[5-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)-2-pyridyl] piperazine-1-carboxylate According to scheme 3 and 6, step 4, 2,4-Dichloro-6-fluoro-7-methoxy-quinoline(0.30 g, 1.2 mmol, 1.0 equiv). The residue was purified by flash silica gel chromatography(40g column, Eluent of 0~25% EtOAc / PE gradient at 40 mL / min) to afford compound C.5y(0.55 g, 0.95 mmol, 78% yield, 82% purity) as yellow oil. MS m / z (ESI) [M+H] + = 473.2.C.5z: tert-butyl (2-((5-(4-chloro-7-methoxyquinolin-2-yl) pyridin-2-yl) oxy) ethyl)(methyl)carbamate According to scheme 3 and 6, step 4, 2,4-Dichloro-7-methoxy-quinoline (0.30 g, 1.3mmol, 1.0 equiv). The residue was purified by flash silica gel chromatography (20 g column, Attorney Docket No.: 185992002040EtOAc / PE 0 to 21% at 60 mL / min) to give product C.5z (0.60 g, 0.81 mmol, 62% yield, 60%purity) as a colourless gum.C.5aa: tert-butyl (1-(4-(4-(4-chloro-7-methoxyquinolin-2-yl) phenyl) piperazin-1-yl)-1- oxopropan-2-yl) carbamate According to scheme 3 and 6, step 4, 2,4-Dichloro-7-methoxy-quinoline (0.10 mg,0.44 mmol, 1.0 equiv eq), boronic acid bor.7. The crude product was triturated with Ethyl acetate (20 mL) at 25 °C for 20 min to give tert-butyl N-[2-[4-[4-(4-chloro-7-methoxy-2-quinolyl) phenyl] piperazin-1-yl]-1-methyl-2-oxo-ethyl] carbamate C.5aa (0.13 mg, 0.25mmol, 56% yield, 100% purity) was obtained as a yellow solid. MS m / z (ESI) [M+H] + =525.2. C.5ab: tert-butyl-[2-[4-[5-(4-chloro-6,7-dimethoxy-2-quinolyl)-2-pyridyl] piperazin-1-yl] ethoxy]-dimethyl-silane To a solution of compound C.5c (0.70 g, 1.4 mmol, 1.0 equiv) in dioxane (2.0 mL)was added HCl / dioxane (4.0 M, 5.0 mL) at 25 °C. The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give 4-chloro-6,7- dimethoxy-2-(6-piperazin-1-yl-3-pyridyl) quinoline (0.17 g, 0.44 mmol, 77% yield, 100%purity) was obtained as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.56 (s,2H), 9.00 (d, J = 2.1 Hz, 1H), 8.64 (d, J = 7.8 Hz, 1H), 8.32 (s, 1H), 7.78 (s, 1H), 7.40 (s,1H), 7.27 (d, J = 9.3 Hz, 1H), 4.00 (s, 10H), 3.24 (s, 4H). MS m / z (ESI) [M+H] + = 385.1.To a solution of 4-chloro-6,7-dimethoxy-2-(6-piperazin-1-yl-3-pyridyl) quinoline (0.14 g, 0.36 mmol, 1.0 equiv) in DMF (2.0 mL) was added 2-bromoethoxy-tert-butyl- dimethyl-silane (0.14 g, 0.59 mmol, 1.6 equiv) and K2CO3 (0.21 g, 1.5 mmol, 4.2 equiv) at 25 Attorney Docket No.: 185992002040 °C. The mixture was stirred at 60 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (20 mL) and extractedwith EtOAc (25 mL, three times). The combined organic layers were washed with brine (25mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, PE / EtOAc = 1:1) to give compound C.5ab (0.14 g, 0.25 mmol, 69% yield, 98% purity) was obtained as a yellow oil. MS m / z (ESI)[M+H] + = 543.3.C.5ac: tert-butyl-[2-[4-[5-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)-2-pyridyl] piperazin-1-yl] ethoxy]-dimethyl-silane To a solution of tert-butyl 4-[5-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)-2-pyridyl]piperazine-1-carboxylate C.5y (0.19 g, 0.40 mmol, 1.0 equiv) in dioxane (2.0 mL) was addedHCl / dioxane (2.0 M, 5.0 mL, 25 equiv). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated to give 4-chloro-6-fluoro-7-methoxy-2-(6-piperazin-1-yl-3-pyridyl) quinoline (0.14 g, 0.38 mmol, 93% yield) as a white solid. The crude was used next stepwithout purification. MS m / z (ESI) [M+H] + = 373.1.To a solution of 4-chloro-6-fluoro-7-methoxy-2-(6-piperazin-1-yl-3-pyridyl) quinoline (0.13 g, 0.35 mmol, 1.0 equiv) and 2-bromoethoxy-tert-butyl-dimethyl-silane (0.17 g, 0.71 mmol, 2.0 equiv) in DMF (5.0 mL) was added K2CO3 (0.10 g, 0.75 mmol, 2.2 equiv) at 25 °C. The mixture was stirred at 60 °C for 5 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL, three times). The organic phase was washed with brine (50 mL, three times), dried over anhydrous sodium sulfate, filtered and the filtratewas concentrated to give a residue. The residue was purified by prep-HPLC 2 (gradient:34%-64% B over 10 min) to give compound C.5ac (0.15 g, 0.19 mmol, 55% yield, 68%purity) as a white solid. MS m / z (ESI) [M+H] + = 531.3. Attorney Docket No.: 185992002040 C.5ad: tert-butyl (1-((4-(4-chloro-6-fluoro-7-methoxyquinolin-2-yl) phenyl) amino)-3- methyl-1-oxobutan-2-yl) carbamate According to scheme 3 and 6, step 4, A.4j (0.20 g, 0.81 mmol, 1.0 equiv), bor.8 (1.0equiv), S1, Pd (PPh3)4(0.10 equiv), Na2CO3(2.3 equiv). Purification was done by flashchromatography 2 (4.0 g Column, Eluent of 0 to 100% EtOAc / PE gradient at 20 mL / min) togive C.5ad (0.29 g, 0.56 mmol, 69% yield, 97% purity) as colorless gum. MS m / z (ESI)[M+H]+= 502.4.C.5ae: tert-butyl (1-(4-(5-(4-chloro-6-fluoro-7-methoxyquinolin-2-yl) pyridin-2-yl)piperazin-1-yl)-2-methyl-1-oxopropan-2-yl) carbamate To a solution of tert-butyl 4-[5-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)-2-pyridyl]piperazine-1-carboxylate C.5y (0.19 g, 0.40 mmol, 1.0 equiv) in dioxane (2.0 mL) was addedHCl / dioxane (2 M, 5.0 mL, 25 equiv). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated to give 4-chloro-6-fluoro-7-methoxy-2-(6-piperazin-1-yl-3-pyridyl) quinoline (0.14 g, 0.38 mmol, 93%) as a white solid. The crude was used next step withoutpurification. MS m / z (ESI) [M+H] + = 373.1.To a solution of 4-chloro-6-fluoro-7-methoxy-2-(6-piperazin-1-yl-3-pyridyl)quinoline(0.20 g, 0.54 mmol, 1.0 equiv) in DMF (10 mL) was added 2-(tert-butoxycarbonylamino)-2-methyl-propanoic acid (0.17 g, 0.84 mmol, 1.6 equiv), HATU (0.32 g, 0.84 mmol, 1.6equiv) and DIEA (0.22 g, 1.7 mmol, 0.30 mL, 3.2 equiv) , the reaction mixture was stirred at25 °C for 12 h. The reaction was poured into water (100 mL), extracted with EtOAc (50 mL, three times). The combined organic phase was washed with saturated brine (50 mL, twice), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purifiedby flash silica gel chromatography 2 (40 g column, Eluent of 0 to 10% EtOAc / PE gradient at Attorney Docket No.: 18599200204040 mL / min) to afford C.5ae (0.20 g, 0.34 mmol, 63% yield, 94% purity) as red oil. MS m / z(ESI) [M+H] + = 558.2.C.5af: tert-butyl N-[5-(4-chloro-7-methoxy-2-quinolyl) -2-pyridyl]-N-methyl-carbamate According to scheme 3 and 6, step 4, to a solution of 2, 4-dichloro-7-methoxy-quinoline (0.30 g, 1.3 mmol, 1.0 equiv), tert-butyl N-methyl-N-[5-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2-pyridyl]carbamate (0.39 g, 1.2 mmol, 0.90 equiv) in EtOH (0.50 mL), toluene (0.50 mL), H2O (0.10 mL) were added Pd(PPh3)4(0.15 g, 0.13 mmol, 0.10 equiv) and sodium carbonate (0.28 g, 2.6 mmol, 2.0 equiv) at 20 °C. The mixture was degassed and purged with N2 three times, and then the mixture was stirred at 60 °C for 12 h under N2atmosphere. The reaction mixture was filtered and concentrated under reducedpressure to give a residue. The residue was purified by prep-TLC (PE / EtOAc = 3:1) to giveC.5af (0.30 g, 0.68 mmol, 51% yield, 90% purity) as a white solid.C.5ag: tert-butyl 4-[5-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)-2-pyridyl] piperazine-1-carboxylate According to scheme 3 and 6, step 4, To a solution of A.4j (1.0 g, 4.1 mmol, 1.0equiv) in the mixture solvent of H2O (1.0 mL), EtOH (5.0 mL) and toluene (5.0 mL) wasadded tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]piperazine-1-carboxylate (1.4 g, 3.6 mmol, 0.90 equiv), Pd(PPh3)4 (0.50 g, 0.43 mmol, 0.10equiv) and Na2CO3 (0.86 g, 8.1 mmol, 2.0 equiv). The mixture was degassed and purged withN2three times, then the resulting mixture was stirred at 80 °C for 12 h. The reaction solution was concentrated under vacuum. The residue was purified by flash silica gel chromatography2 (12 g column, Eluent of 0~20% EtOAc / PE gradient at 40 mL / min) to afford C.5ag (1.5 g,2.6 mmol, 64% yield, 82% purity) as a light green solid. MS m / z (ESI) [M+H] + = 473.2. 1H Attorney Docket No.: 185992002040NMR (400 MHz, CDCl3) d (ppm): 8.88 (d, J = 2.3 Hz, 1H), 8.30 (dd, J = 2.4, 9.0 Hz, 1H),7.80 (d, J = 11.6 Hz, 1H), 7.76 (s, 1H), 7.52 (d, J = 8.1 Hz, 1H), 6.76 (d, J = 9.0 Hz, 1H),4.06 (s, 3H), 3.71 - 3.63 (m, 4H), 3.63 - 3.53 (m, 4H), 1.51 (s, 9H).C.5ah: tert-butyl 4-[5-[4-chloro-7-(4-pyrrolidin-1-ylphenoxy)-2-quinolyl]-2-pyridyl]piperazine-1-carboxylate According to scheme 3 and 6, step 4, To a screw-cap vial equipped with a magneticstir bar was added 2, 4-dichloro-7-(4-pyrrolidin-1-ylphenoxy) quinoline A.4k (0.30 g, 0.84mmol, 1.0 equiv) and tert-butyl 4-[5-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2- pyridyl]piperazine-1-carboxylate (0.33 g, 0.83 mmol, 1.0 equiv), Na2CO3 (0.27 g, 2.6 mmol, 3.0 equiv), dioxane (5.0 mL), H2O (1.0 mL) and Pd(PPh3)4(0.10 g, 87 μmol, 0.10 equiv) sequentially. The vial was sealed with a Teflon-lined septum, evacuated, and backfilled with nitrogen. Then the mixture was stirred at 90 °C for 16 h under nitrogen atmosphere. The reaction mixture was quenched by water (10 mL), and then the resulting organic phase was extracted with ethyl acetate (10 mL, three times). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and the filtrate was concentrated invacuum to give a residue. The residue was purified by silica gel chromatography (PE / EtOAc)to afford C.5ah (0.50 g, crude) as yellow solid.C.5ai: tert-butyl 4-[5-(4-chloro-7-fluoro-2-quinolyl)-2-pyridyl] piperazine-1-carboxylate According to scheme 3 and 6, step 4, a mixture of 2,4-dichloro-7-fluoro-quinolineA.4l (0.30 g, 1.4 mmol, 1.0 equiv), tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]piperazine-1-carboxylate (0.49 g, 1.3 mmol, 0.90 equiv), Na2CO3 (0.30 g, 2.8 mmol, 2.0 equiv), Pd(t-Bu3P)2 (0.16 g, 0.14 mmol, 0.10 equiv) in toluene (3.0 mL) / ethanol (3.0 mL) / H2O (0.60 mL) was degassed and purged with N2three times at 25 °C, and then Attorney Docket No.: 185992002040 the mixture was stirred at 80 °C for 16 h under N2atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (25 mL) and extracted with ethyl acetate (30 mL, three times). The combined organic layers werewashed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentratedunder reduced pressure to give a residue. The residue was purified by flash silica gelchromatography 2 (40 g column, Eluent of 0~50% EtOAc / PE gradient at 80 mL / min) to giveC.5ai (0.33 g, 0.74 mmol, 53% yield, 99% purity) was obtained as a yellow solid. MS m / z(ESI) [M+H] + = 443.1.Synthesis of Buchwald coupling and SNAr products – Intermediates B.5 (Schemes 2 and 4;step 4), C.6 (Scheme 3; step 5), D.6 (Scheme 5; step 5), E.6 (Scheme 6; step 5) & Suzukicoupling products – Intermediates C.6 (Scheme 4; step 5)Conditions 1 Buchwald: A mixture of derivative A.5 or C.5 (1.0 equiv), amine (2.0equiv), BrettPhos Pd G3 (0.10 equiv), t-BuONa (3.0 equiv) in dioxane (0.10 M) was degassed and purged with N2 for three times at 25 °C, and then the mixture was stirred at 80 °C for 16 h under N2atmosphere. The mixture was diluted with water and extracted with EtOAc (three times). The organic phase was washed with brine, dried over anhydrousNa2SO4, filtered and the filtrate was concentrated in vacuo to give a residue.Conditions 2 Buchwald: A mixture of derivative A.5 or C.5 (1.0 equiv), amine (1.3equiv), PdP(t-Bu)3(0.10 equiv), t-BuONa (3.0 equiv) in dioxane (0.15 M) was degassed and purged with N2 for three times at 25 °C, and then the mixture was stirred at 80 °C for 16 h under N2 atmosphere. The mixture was diluted with water and extracted with EtOAc (three times). The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered andthe filtrate was concentrated in vacuo to give a residue.Conditions 3 Buchwald: A mixture of derivative A.5 or C.5 (1.0 equiv), amine (3.0equiv), CPhos Pd G3 (0.10 equiv), CsCO3(2.0 equiv) in dioxane (0.10 M) was degassed and purged with N2 for three times at 25 °C, and then the mixture was stirred at 80 °C for 16 h under N2 atmosphere. The mixture was diluted with water and extracted with EtOAc (three times). The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered andthe filtrate was concentrated in vacuo to give a residue.Conditions 4 Buchwald: A mixture of derivative A.5 or C.5 (1.0 equiv), amine (1.2equiv), SPhos Pd G3(0.10 equiv), Cs2CO3(3.0 equiv) in dioxane was degassed and purged with N2for three times, and then the mixture was stirred at 80 °C for 16 hours under N2 Attorney Docket No.: 185992002040 atmosphere. The mixture was diluted with water and extracted with ethyl acetate (three times). The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give a residue. Conditions 1 SNAr: To a solution of quinoline A.4 or C.5 (1.0 equiv), amine (1.5equiv) in dimethyl sulfoxide (0.40 M) was added cesium fluoride (2.0 equiv) at 25 °C. After stirring at 130 °C for 16 h, the reaction mixture was added into water (0.08 M) and extracted with ethyl acetate (three times). The combined organic layers were washed with brine (three times), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Conditions 2 SNAr: To a screw-cap vial equipped with a magnetic stir bar was addedA.4 or C.5 (1.0 equiv), and amine (> 10 equiv) sequentially. The vial was sealed with aTeflon-lined septum. Then the mixture was stirred at 130 °C for 16 h. The reaction mixture was diluted with EtOAc and water, and then the resulting organic phase was extracted with ethyl acetate (three times). The combined organic layers were washed with brine, dried oversodium sulfate, filtered and the filtrate was concentrated in vacuum to give the product.Conditions 3 SNAr: To a solution of A.4 or C.5 (1.0 equiv) in DMSO (0.40 M) wasadded amine (3.0 equiv) and DIEA (1.7 equiv) at 25 °C. The mixture was stirred at 100 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water and extracted with ethyl acetate (three times). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue.B.5a: N1-(2-chloroquinolin-4-yl)-N3, N3-dimethylpropane-1,3-diamine According to schemes 2 and 4, step4, conditions 2 SNAr. 2,4-Dichloroquinoline (2.0g, 0.01 mol, 1.0 equiv) was treated with N1, N1-dimethylpropane-1,3-diamine (9.7 g, 12 mL, 95 mmol, 9.0 equiv). The reaction was stirred at room temperature overnight. The crude material was divided in multiple fractions and purified by PuriFlash XS520Plus reversed phase (H2O / ACN):0.1% FA = (97.5:2.5 to 90:10), PF-C18HP, 15 μm, 80g). Product B.5a (1.3 g, 4.9 mmol, 50 %) was isolated as a white solid and the regioisomer (0.86 g, 3.3 mmol, 30 %) was isolated as a yellow oil. Attorney Docket No.: 185992002040C.6a: tert-butyl 4-(4-(4-((3-(dimethylamino) propyl) amino) quinolin-2-yl) phenyl)piperazine-1-carboxylate According to scheme 3, step 5, to a solution of C.5a (3.0 g, 7.1 mmol, 1.0 equiv),N',N'-dimethylpropane-1,3-diamine (2.2 g, 21 mmol, 2.7 mL, 3.0 equiv), [Pd(OAc)2]3 (0.16 g, 0.71 mmol, 0.10 equiv), BINAP (0.88 g, 1.4 mmol, 0.20 equiv) in 1,4-dioxane (30 mL) was added K3PO4 (3.0 g, 14 mmol, 2.0 equiv) at 20 °C. The reaction mixture was degassed and purged with nitrogen atmosphere three times. After stirring at 100 °C for 16 h under nitrogen atmosphere, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2,PE / EtOAc = 10:1 to 1:1) to afford product C.6a (3.0 g, 4.6 mmol, 65% yield, 75% purity) asa yellow solid. MS m / z (ESI) [M+H] + = 490.1.C.6b: tert-butyl 4-[5-[4-[3-(dimethylamino) propylamino]-2-quinolyl]-2-pyridyl] piperazine- 1-carboxylate According to scheme 3, step 5, conditions 2 Buchwald. Tert-butyl 4-[5-(4-chloro-2-quinolyl) -2-pyridyl] piperazine-1-carboxylate C.5b (0.20 g, 0.47 mmol, 1.0 equiv). Thecrude product was purified by prep-HPLC 1 (B%: 18%-48%, 10 min) After Prep-HPLCpurification, the eluent was concentrated to remove organic solvents. The residual aqueoussolution was lyophilized to give compound C.6b (0.12 g, 0.24 mmol, 52% yield) as a yellowsolid. 1H NMR (400 MHz, DMSO-d6) d (ppm): 8.42 (s, 1H) 8.06 (d, J = 9.2 Hz, 1H) 7.59 (s,1H) 7.26 - 7.31 (m, 2H) 6.31 (br s, 1H) 4.13 (t, J = 6.4 Hz, 2H) 3.24 (br t, J = 6.8 Hz, 2H)2.59 (t, J = 7.2 Hz, 2H) 2.49 (br d, J = 4 Hz, 4H) 2.39 (t, J = 6.8 Hz, 2H) 2.19 (s, 6H) 1.95 (br t, J = 6.8 Hz, 2H) 1.82 (quin, J = 6.8 Hz, 2H) 1.69 (dt, J = 6.4, 3.13 Hz, 4H). Attorney Docket No.: 185992002040 C.6c: tert-butyl 4-[5-[4-[3-(dimethylamino) propylamino]-6, 7-dimethoxy-2-quinolyl]-2- pyridyl] piperazine-1-carboxylate According to scheme 3, step 5, conditions 1 Buchwald. Tert-butyl 4-[5-(4-chloro-6, 7-dimethoxy-2-quinolyl) -2-pyridyl]piperazine-1-carboxylate C.5c (0.10 g, 0.21 mmol, 1.0equiv). The reaction mixture was concentrated to give a residue. The filter liquor was purifiedby Prep-HPLC 4 (gradient: 1%-30%, 10 min). The elute was directly lyophilized to givecompound C.6c (30 mg, 54 μmol, 26% yield, N / A purity) as yellow solid. MS m / z (ESI)[M+H] + = 551.4.C.6d: tert-butyl 3-[5-[4-[3-(dimethylamino) propylamino]-6,7-dimethoxy-2-quinolyl]-2- pyridyl] azetidine-1-carboxylate According to scheme 3, step 5, conditions 3 Buchwald. Tert-butyl 3-[5-(4-chloro-6,7-dimethoxy-2-quinolyl)-2-pyridyl] azetidine-1- carboxylate C.5d (0.18 g, 0.35 mmol, 1.0equiv). The reaction mixture was filtered, and the filtrate was concentrated under reducedpressure to give a residue. The residue was purified by prep-HPLC 1 (gradient: 11%-31%over 9 min) to give compound C.6d (0.11 g, 0.21 mmol, 64% yield, 100% purity) as a yellowsolid. MS m / z (ESI) [M+H] + = 522.3.C.6e: tert-butyl 4-[5-[4-[3-(dimethylamino) propylamino]-7-methoxy-2-quinolyl]-2-pyridyl] piperazine-1-carboxylate Attorney Docket No.: 185992002040 According to scheme 3, step 5, conditions 2 Buchwald. Tert-butyl 4-[5-(4-chloro-7-methoxy-2-quinolyl)-2-pyridyl] piperazine-1-carboxylate C.5e (0.15 g, 0.33 mmol, 1.0equiv). The residue was purified by prep-HPLC 1 (gradient: 11%-41% over 10 min) to givecompound C.6e (75 mg, 0.14 mmol, 43% yield, 98% purity) was obtained as a yellow solid.MS m / z (ESI) [M+H] + = 521.3.C.6f: tert-butyl 4- [5- [4-[3-(dimethylamino) propylamino]-6-methoxy-2-quinolyl]-2-pyridyl]piperazine-1-carboxylate According to scheme 3, step 5, conditions 2 Buchwald. Tert-butyl 4-[5-(4-chloro-6-methoxy-2-quinolyl)-2-pyridyl] piperazine-1-carboxylate C.5f (0.30 g, 0.66 mmol, 1.0equiv). Amine 1.0 equiv. The residue was purified by prep-HPLC 2 (gradient: 10%-40% over10 min). Compound C.6f (0.21 g, 0.40 mmol, 60% yield, 98% purity) was obtained as awhite solid. MS m / z (ESI) [M+H] + = 521.5.C.6g: N-[2-[6-[4-[2-[tert-butyl(dimethyl)silyl] oxyethyl] piperazin-1-yl]-3-pyridyl]-6,7- dimethoxy-4-quinolyl]-N’, N'-dimethyl-propane-1,3-diamine According to scheme 3, step 5, conditions 2 Buchwald. Tert-butyl-[2-[4-[5-(4-chloro-6,7-dimethoxy-2-quinolyl)-2-pyridyl] piperazin-1-yl] ethoxy]-dimethyl-silane C.5ab (0.18 g,0.33 mmol, 1.0 equiv). The residue was purified by prep-HPLC 2 (gradient: 8%-38% over 10min) to give compound C.6g (40 mg, 43 μmol, 13% yield, 65% purity) was obtained as ayellow oil. MS m / z (ESI) [M+H] + = 609.4. Attorney Docket No.: 185992002040 C.6h: tert-butyl 4-[5-[4-[3-(dimethylamino) propyl amino]-7-methoxy-2-quinolyl]-2-pyridyl] piperazine-1-carboxylate According to scheme 3, step 5, conditions 2 Buchwald. Tert-butyl 4-[5-(4-chloro-7-methoxy-2-quinolyl)-2-pyridyl] piperazine-1-carboxylate C.5e (0.30 g, 0.66 mmol, 1.0equiv). The residue was purified by prep-HPLC 2 (gradient: 5%-35% over 10 min) to givecompound C.6h (0.21 g, 0.40 mmol, 61% yield, 99% purity) was obtained as a yellow solid.MS m / z (ESI) [M+H] + = 521.3.C.6i: tert-butyl 4-[5-[7-(dimethylamino)-4-[3-(dimethylamino) propylamino]-6-methoxy-2- quinolyl]-2-pyridyl] piperazine-1-carboxylate According to scheme 3, step 5, conditions 1 Buchwald. Tert-butyl 4-[5-[4-chloro-7-(dimethylamino)-6-methoxy-2-quinolyl]-2-pyridyl] piperazine-1-carboxylate C.5k (0.16 g,0.32 mmol, 1.0 equiv). The residue was purified by prep-HPLC 2 (gradient: 11%-41% over10 min) to give compound C.6i (0.10 g, 0.18 mmol, 55% yield, 100% purity) as a yellowsolid. MS (ESI) m / z. 564.4. C.6j: tert-butyl 4-[5-[4-[3-(dimethylamino) propylamino]-7-(3-pyridyloxy)-2-quinolyl]-2- pyridyl] piperazine-1-carboxylate According to scheme 3, step 5, conditions 2 Buchwald. Tert-butyl 4-[5-[4-chloro-7-(3-pyridyloxy)-2-quinolyl]-2-pyridyl] piperazine-1-carboxylate C.5m (0.15 g, 0.29 mmol, 1.0 Attorney Docket No.: 185992002040equiv). The filtrate was concentrated in vacuo to give compound C.6j (0.15 g, 0.26 mmol,59% yield) as a white solid. MS m / z (ESI) [M+H] + = 584.3.C.6k: tert-butyl 4-[5-[4-[3-(dimethylamino) propylamino]-7-(trifluoromethoxy)-2-quinolyl]- 2-pyridyl] piperazine-1-carboxylate According to scheme 3, step 5, conditions 1 Buchwald. 4-[5-[4-chloro-7-(trifluoromethoxy)-2-quinolyl]-2-pyridyl] piperazine-1-carboxylate C.5p (0.41 g, 0.81 mmol,1.0 equiv). The residue was purified by flash silica gel chromatography (40 g, Eluent of0~10% EtOAc / PE gradient at 40 mL / min) to afford compound C.6k (0.23 g, 0.38 mmol,47% yield, 95% purity) as yellow oil. MS m / z (ESI) [M+H] + = 575.3.C.6l: tert-butyl 4- [5- [4- [3-(dimethylamino) propylamino] -7-(trideuteriomethoxy)-2-quinolyl]-2-pyridyl] piperazine-1-carboxylate According to scheme 3, step 5, conditions 1 Buchwald. tert-butyl 4-[5-[4-chloro-7-(trideuteriomethoxy)-2-quinolyl]-2-pyridyl] piperazine-1-carboxylate C.5r (0.22 g, 0.45mmol, 1.0 equiv). BrettPhos Pd G4 (0.10 equiv). No work-up, only filtration. The reaction mixture was diluted with methanol (5.0 mL) and then the reaction mixture was filtered, the filtrate was concentrated under reduced pressure to give a residue. The residue was purifiedby prep-TLC (PE / EtOAc = 0:1) to give compound C.6l (0.18 g, 0.27 mmol, 61% yield, 79%purity) as a yellow solid. MS m / z (ESI) [M+H] + = 524.3. Attorney Docket No.: 185992002040C.6m: tert-butyl 4-[5-[6-bromo-4-[3-(dimethylamino) propylamino]-2-quinolyl]-2-pyridyl]piperazine-1-carboxylate According to scheme 3, step 5, conditions 1 SNAr. tert-butyl 4-[5-(6-bromo-4-chloro-2-quinolyl)-2-pyridyl] piperazine-1-carboxylate C.5g (1.9 g, 3.8 mmol, 1.0 equiv).Compound C.6m(1.9 g, 3.0 mmol, 80% yield, 90% purity) as a white solid. MS m / z (ESI)[M+H] + = 571.2.(R)-C.6n: tert-butyl 4-[5-[4-[[(2S)-3-(dimethylamino)-2-hydroxy-propyl] amino]-7-methoxy- 2-quinolyl]-2-pyridyl] piperazine-1-carboxylate AND(S)-C.6n: tert-butyl (S)-4-(5-(4-((3-(dimethylamino)-2-hydroxypropyl) amino)-7-methoxyquinolin-2-yl) pyridin-2-yl) piperazine-1-carboxylate According to scheme 3, step 5, conditions 1 SNAr. tert-butyl 4-[5-(4-chloro-7-methoxy-2-quinolyl)-2-pyridyl] piperazine-1-carboxylate C.5e (0.40 g, 0.62 mmol, 1.0equiv). The residue was purified by prep-HPLC 2 (gradient: 10%-40% over 10 min). Theresidue was further separated by SFC (B: 60%, isocratic elution mode) to give (S)-C.6n (40 mg, 75 μmol, 12% yield, 100% purity) as a yellow gum and give (R)-C.6n (60 mg, 0.11mmol, 18% yield, 100% purity) as a yellow gum. (S)-C.6n: MS m / z (ESI) [M+H] + = 537.5.(R)-C.6n: MS m / z (ESI) [M+H] + = 537.5. Attorney Docket No.: 185992002040 C.6o: tert-butyl 4-[5-[7-bromo-4-[3-(dimethylamino) propylamino]-2-quinolyl]-2-pyridyl] piperazine-1-carboxylate According to scheme 3, step 5, conditions 2 SNAr. tert-butyl 4-[5-(7-bromo-4-chloro-2-quinolyl)-2-pyridyl] piperazine-1-carboxylate C.5w (0.92 g, 1.5 mmol, 1.0 equiv). N’, N'-dimethylpropane-1,3-diamine (31 equiv). The residue was purified by prep-HPLC 2 (gradient: 6%-36% over 10 min) to give compound C.6o (0.45 g, 0.74 mmol, 51% yield, 94%purity) was obtained as a yellow solid. MS m / z (ESI) [M+H] + = 571.0.C.6p: tert-butyl 4-[5-[6-acetamido-4-[3-(dimethylamino) propylamino]-2-quinolyl]-2- pyridyl] piperazine-1-carboxylate To a solution of tert-butyl 4-[5-[6-bromo-4-[3-(dimethylamino)propylamino]-2-quinolyl]-2-pyridyl]piperazine-1-carboxylate C.6m (1.7 g, 3.0 mmol, 1.0 equiv),diphenylmethanimine (2.7 g, 15 mmol, 2.5 mL, 5.0 equiv) in dioxane (20 mL) was added cesium carbonate (2.0 g, 6.0 mmol, 2.0 equiv) and [2-(2-aminophenyl)phenyl]- methylsulfonyloxy-palladium;(5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl- phosphane (0.28 g, 0.30 mmol, 0.10 equiv) at 25 °C. After stirring at 80 °C for 16 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE / EtOAc = 0:1, then EtOAc / MeOH = 10:1) to Attorney Docket No.: 185992002040 give tert-butyl 4-[5-[6-(benzhydrylideneamino)-4-[3-(dimethylamino) propylamino]-2-quinolyl]-2-pyridyl] piperazine-1-carboxylate 18.1 (1.5 g, 1.6 mmol, 53% yield, 70% purity)as a yellow solid. MS m / z (ESI) [M+H] + = 670.4.A solution of 18.1 (0.20 g, 0.30 mmol, 1.0 equiv) in AcOH (0.52 g, 8.7 mmol, 0.50mL, 29 equiv) was stirred at 25 °C for 16 h, the mixture was used as such for the next step(no work-up). MS m / z (ESI) [M+H] + = 506.3 (18.2).To a solution of tert-butyl 4-[5-[6-amino-4-[3-(dimethylamino) propylamino]-2-quinolyl]-2-pyridyl] piperazine-1-carboxylate 18.2 (0.10 g, 0.20 mmol, 1.0 equiv) in aceticacid (0.50 mL) was added acetic anhydride (0.54 g, 5.3 mmol, 0.50 mL, 27 equiv) and triethylamine (0.36 g, 3.6 mmol, 0.50 mL, 18 equiv) at 25 °C. After stirring at 25 °C for 1.5h, the reaction mixture was filtered to give a solution. The solution was purified by prep-HPLC (FA condition) to give tert-butyl 4-[5-[6-acetamido-4-[3-(dimethylamino)propylamino]-2-quinolyl]-2-pyridyl] piperazine-1-carboxylate C.6p (80 mg, 0.13 mmol, 66%yield, 90% purity) as a yellow solid. MS m / z (ESI) [M+H] + = 548.3.C.6q: tert-butyl 4-(5-(4-((3-(dimethylamino) propyl) amino)-7-methylquinolin-2-yl) pyridin-2-yl) piperazine-1-carboxylate To a solution of tert-butyl 4-[5-[7-bromo-4-[3-(dimethylamino)propylamino]-2-quinolyl]-2-pyridyl]piperazine-1-carboxylate C.6o (0.30 g, 0.53 mmol, 1.0 equiv) in dioxane(5.0 mL) / H2O (1.0 mL) was added 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (3.5 M, 0.34mL, 2.3 equiv) , Pd(dppf)Cl2 (40 mg, 55 μmol, 0.10 equiv) and K2CO3 (0.22 g, 1.6 mmol, 3.0equiv) at 20 °C. The mixture was degassed and purged with N2 three times, and then themixture was stirred at 90°C for 4 h under N2 atmosphere. The reaction was poured into water(100 mL), extracted with EtOAc (50 mL, three times). The combined organic phase waswashed with saturated brine (50 mL, twice), dried over anhydrous Na2SO4, filtered, andconcentrated in vacuo. The residue was purified by prep-HPLC 2 (gradient: 8%-38% B over10 min). After Prep-HPLC purification, the eluent was concentrated to remove organicsolvents. The residual aqueous solution was lyophilized to give tert-butyl 4-[5-[4-[3- Attorney Docket No.: 185992002040 (dimethylamino) propylamino]-7-methyl-2-quinolyl]-2-pyridyl] piperazine-1-carboxylateC.6q (0.11 g, 0.22 mmol, 41% yield, 99% purity) as a yellow solid. MS m / z (ESI) [M+H] + =505.3. C.6r: tert-butyl 4-[5-[7-(dimethylamino)-4-[3-(dimethylamino) propylamino]-2-quinolyl]-2- pyridyl] piperazine-1-carboxylate According to scheme 3, step 5, to a solution of tert-butyl 4-[5-[4-chloro-7-(dimethylamino)-2-quinolyl]-2-pyridyl]piperazine-1-carboxylate C.5n (0.27 g, 0.58 mmol,1.0 equiv) in DMSO (2.0 mL) was added CsF (0.18 g, 1.2 mmol, 43 μL, 2.0 equiv) and N',N'- dimethylpropane-1,3-diamine (1.6 g, 16 mmol, 2.0 mL, 28 equiv) at 25 °C. After stirring at 130 °C for 16 h, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (gradient: 12%-42% over 10 min) togive C.6r (0.15 g, 0.27 mmol, 46% yield, 95% purity) as a yellow solid. MS m / z (ESI)[M+H] + = 534.3.C.6s: tert-butyl N-[5-[4-[3-(dimethylamino) propylamino]-7-methoxy-2-quinolyl]-2-pyridyl]-N-methylcarbamate According to scheme 3, step 5, to a solution of tert-butyl N-[5-(4-chloro-7-methoxy-2-quinolyl) -2-pyridyl]-N-methyl-carbamate C.5g (0.30 g, 0.75 mmol, 1.0 equiv), N', N'-dimethylpropane-1, 3-diamine (0.10 g, 0.98 mmol, 0.12 mL, 1.3 equiv) in dioxane (4.0 mL) was added Pd(t-Bu3P)2 (40 mg, 78 μmol, 0.10 equiv) and t-BuONa (0.15 g, 1.6 mmol, 2.1 equiv). The mixture was degassed and purged with N2 three times, and then the mixture was stirred at 80 °C for 12 h under N2atmosphere. The reaction mixture was filtered andconcentrated under reduced pressure to give C.6s (0.30 g, crude) as a yellow solid. Attorney Docket No.: 185992002040C.6t: tert-butyl 4-[5-[4-(3-hydroxypropylamino)-7-methoxy-2-quinolyl]-2-pyridyl]piperazine-1-carboxylate According to scheme 3, step 5, to a solution of tert-butyl 4-[5-(4-chloro-7-methoxy-2-quinolyl)-2-pyridyl]piperazine-1-carboxylate (0.20 g, 0.44 mmol, 1.0 equiv) in dioxane (6.0mL) was added 3-aminopropan-1-ol (0.10 g, 1.3 mmol, 0.10 mL, 3.0 equiv), Pd(t-Bu3P)2(30 mg, 59 μmol, 0.10 equiv), t-BuONa (0.15 g, 1.6 mmol, 3.6 equiv), then the resulting mixture was purged with N2 for three times and stirred at 80 °C for 12 h. The reaction mixture waspartitioned between EtOAc (0.15 L) and water (80 mL), washed with brine (70 mL), diedover Na2SO4, filtered, and evaporated under reduced pressure. The crude product waspurified by flash chromatography 2 (20 g column, Eluent of 0~30% EtOAc / PE gradient at 40mL / min) to give C.6t (0.17 g, 0.31 mmol, 71% yield, 90% purity) as a yellow solid. MS m / z(ESI) [M+H] + = 494.3.C.6u: tert-butyl 4-[5-[4-[3-(4-fluorophenyl) propylamino]-2-quinolyl]-2-pyridyl] piperazine-1-carboxylate According to scheme 3, step 5, a mixture of tert-butyl 4-[5-(4-chloro-2-quinolyl)-2-pyridyl]piperazine-1-carboxylate (0.10 g, 0.19 mmol, 1.0 equiv) , 3-(4-fluorophenyl)propan- 1-amine (29 mg, 0.19 mmol, 1.0 equiv), t-BuONa (54 mg, 0.56 mmol, 3.0 equiv) , BrettPhos- Pd-G3 (17 mg, 19 μmol, 0.10 equiv) in dioxane (0.10 mL) was degassed and purged with N2three times at 25 °C, and then the mixture was stirred at 80 °C for 16 h under N2 atmosphere. The reaction mixture was extracted with ethyl acetate (30 mL, three times). The combined organic layer was washed with saturated salt water (30 mL), dried on anhydrous Na2SO4, filtered, and reduced pressure concentrated. The residue was purified by prep-TLC (SiO2, Attorney Docket No.: 185992002040 PE / EtOAc = 0:1). The residue was purified by prep-TLC (SiO2, PE / EA = 0:1) to give C.6u(80 mg, 0.15 mmol, 78% yield) as a yellow solid. MS m / z (ESI) [M+H] + = 542.3.C.6v: tert-butyl 4-[5-[4-[3-(dimethylamino) propylamino]-6-fluoro-7-methoxy-2-quinolyl]-2-pyridyl] piperazine-1-carboxylate According to scheme 3, step 5, to a solution of tert-butyl 4-[5-(4-chloro-6-fluoro-7-methoxy-2-quinolyl)-2-pyridyl]piperazine-1-carboxylate C.5g (0.40 g, 0.85 mmol, 1.0equiv) in DMSO (5.0 mL) was added N',N'-dimethylpropane-1,3-diamine (0.12 g, 1.2 mmol,0.15 mL, 1.4 equiv) and TEA (0.29 g, 2.9 mmol, 0.40 mL, 3.4 equiv). The reaction mixturewas stirred at 120 °C for 12 h. The residue was partitioned between EtOAc (50 mL) and water (50 mL). The organic phase was washed by sat. NaCl (50 mL). The combined organiclayers were dried over (Na2SO4) and evaporated to give C.6v (0.90 g, 0.82 mmol, 97%yield) which was used for next step without further purification.C.6w: tert-butyl 4-[5-[4-[3-(dimethylamino) propylamino]-7-(4-pyrrolidin-1-ylphenoxy)-2-quinolyl]-2-pyridyl] piperazine-1-carboxylate According to scheme 3, step 5, to a screw-cap vial equipped with a magnetic stir barwas added tert-butyl 4-[5-[4-chloro-7-(4-pyrrolidin-1-ylphenoxy)-2-quinolyl]-2-pyridyl]piperazine-1-carboxylate C.5h (0.46 g, 0.78 mmol, 1.0 equiv) and dioxane (10 mL)and N', N'-dimethylpropane-1, 3-diamine (0.12 g, 1.2 mmol, 1.5 equiv) and t-BuONa (0.23 g, 2.4 mmol, 3.0 equiv) and Pd(t-Bu3P)2 (40 mg, 78 μmol, 0.10 equiv) sequentially. The vial was sealed with a teflon-lined septum, evacuated, and backfilled with nitrogen. Then themixture was stirred at 80 °C for 16 h under nitrogen atmosphere. The reaction mixture wasquenched by water (20 mL), and then the resulting organic phase was extracted with ethyl acetate (20 mL, twice). The combined organic layers were washed with brine (20 mL), dried Attorney Docket No.: 185992002040 over Na2SO4, filtered and the filtrate was concentrated in vacuum to give a residue. Theresidue was purified by silica gel chromatography (EtOAc / MeOH) to afford C.6w (0.26 g,0.40 mmol, 51% yield) as yellow solid. C.6x: tert-butyl 4-[5-[4-[3-(dimethylamino) propylamino]-7-fluoro-2-quinolyl]-2-pyridyl] piperazine-1-carboxylate According to scheme 3, step 5, a mixture of C.5l (0.33 g, 0.75 mmol, 1.0 equiv),N',N'-dimethylpropane-1,3-diamine (90 mg, 0.88 mmol, 0.11 mL, 1.2 equiv), Pd(t-Bu3P)2 (38 mg, 74 μmol, 0.10 equiv), sodium 2-methylpropan-2-olate (0.22 g, 2.2 mmol, 3.0 equiv) in dioxane (3.0 mL) was degassed and purged with N2three times at 25 °C, and then the mixture was stirred at 80 °C for 16 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (30 mL) and extracted with ethyl acetate (40 mL, three times). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentratedunder reduced pressure to give C.6x (0.45 g, crude) as yellow gum. MS m / z (ESI) [M+H] + =509.3.D.6a: N-[2-[6-(azetidin-1-yl) -3-pyridyl]-6, 7-dimethoxy-4-quinolyl]-2- [tert-butyl (dimethyl)silyl] oxymethyl]-N', N'-dimethyl-propane-1, 3-diamine According to scheme 5, step 5, conditions 1 Buchwald. 2-[[Tert-butyl (dimethyl)silyl]oxymethyl]-N', N'-dimethyl-propane-1, 3-diamine C.5c (50 mg, 0.20 mmol, 1.0 equiv).The residue was purified by prep-HPLC 3 (gradient: 3-10 min 21-51%). Compound D.6a (80mg, 0.14 mmol, 70% yield) was obtained as a yellow solid. MS m / z (ESI) [M+H] + = 566.4. Attorney Docket No.: 185992002040E.6a: tert-butyl N- [3- [[2- [6- [2- [tert-butoxycarbonyl(methyl)amino] ethoxy]-3-pyridyl]-7-methoxy-4-quinolyl] amino] propyl]-N-methylcarbamate According to scheme 6, step 5, conditions 2 Buchwald. Tert-butyl N-[2-[[5-(4-chloro-7-methoxy-2-quinolyl)-2-pyridyl] oxy] ethyl]-N-methyl-carbamate C.5aa (0.20 g, 0.45mmol, 1.0 equiv). The reaction mixture was filtered and concentrated under reduced pressureto give the residue. The residue was purified by prep-HPLC 2 (gradient: 25%-55% over 10min). The eluent was lyophilized to give compound E.6a (0.13 g, 0.20 mmol, 44% yield,90% purity) as a brown gum.Synthesis of Final Products Final products from Suzuki coupling (Scheme 2; step 5), Buchwald coupling or SNAr(Scheme 1; step 5) – See above protocols.Final products from deprotection step (Schemes 3, 4, 5 and 6; step 6) – Protocolsbelow Conditions 1 HCl. To a solution of substrate C.6 or D.6 or E.6 (1.0 equiv) in dioxane(0.06M) was added HCl / dioxane (> 20 equiv). The mixture was stirred at 25 °C for 2 h. The mixture was concentrated to give a residue. Conditions 2 TFA. To a solution of substrate C.6 or D.6 or E.6 (1.0 equiv) in DCM(0.15M) was added TFA (> 10 equiv) at 25 °C. After stirring at 25 °C for 4 h, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. Example 1: N1,N1-dimethyl-N3-(2-(6-(pyrrolidin-1-yl) pyridin-3-yl) quinolin-4-yl) propane- 1,3-diamine According to scheme 2, step 5, quinoline B.5a (70 mg, 0.27 mmol, 1.0 equiv), 2-(pyrrolidin-1-yl)-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (87 mg, 0.32 Attorney Docket No.: 185992002040 mmol, 1.2 equiv), XPhos Pd G2 (10 mg, 13 μmol, 0.05 equiv), and K2CO3(73 mg, 0.53 mmol, 2.0 equiv) were suspended in MeOH (2.7 mL) and heated to 65 °C for two days, not fully converted. XPhos Pd G2 (10 mg, 13 μmol, 0.05 equiv) and potassium carbonate (73 mg,0.53 mmol, 2.0 equiv) were added and the reaction was stirred for another day. The crudewas concentrated and purified by prep-HPLC 6 and then 7 to give Example 1 (35 mg, 93μmol, 35 %) as a yellow solid.Example 2: N1-(2-(6-(azetidin-1-yl) pyridin-3-yl)-6,7-dimethoxyquinolin-4-yl)-N3,N3-dimethylpropane-1,3-diamine According to scheme 1, step 5, conditions 2 Buchwald. Substrate A.5a (80 mg, 0.22mmol, 1.0 equiv) N', N'-dimethylpropane-1,3-diamine (28 mg, 0.27 mmol, 34 μL, 1.2 equiv).The residue was purified by prep-HPLC 2 (gradient:1%-30% over 10 min) to give Example2 (40 mg, 86 μmol, 38% yield, 100% purity, FA) was obtained as a yellow solid. Then thecrude product was purified with SCX (see general protocol).1H NMR (400 MHz, DMSO-d6)δ (ppm): 8.83 (d, J = 2.0 Hz, 1H), 8.26 (dd, J = 2.3, 8.7 Hz, 1H), 7.41 (s, 1H), 7.19 (s, 1H),7.10 (d, J = 4.5 Hz, 1H), 6.78 (s, 1H), 6.43 (d, J = 8.6 Hz, 1H), 4.00 (t, J = 7.4 Hz, 4H), 3.89(d, J = 1.3 Hz, 6H), 3.43 - 3.38 (m, 2H), 2.43 (t, J = 6.8 Hz, 2H), 2.38 - 2.31 (m, 2H), 2.23 (s,6H), 1.85 (q, J = 6.8 Hz, 2H). MS m / z (ESI) [M+H] + = 422.2.Example 3: 1-(4-(5-(4-((3-(dimethylamino) propyl) amino)-6,7-dimethoxyquinolin-2-yl) pyridin-2-yl) piperazin-1-yl) ethan-1-one According to scheme 1, step 5, conditions 2 Buchwald. Substrate A.5b (0.10 g, 0.23mmol, 1.0 equiv). The residue was purified by prep-HPLC 2 (gradient: 1%-30% over 10 min)to give Example 3 (40 mg, 74 μmol, 32% yield, 100% purity, FA) was obtained as a yellowsolid. Then the salt was neutralized with SCX (see general protocol).1H NMR (400 MHz,DMSO-d6) δ (ppm): 8.90 (d, J = 2.2 Hz, 1H), 8.32 (dd, J = 2.3, 8.9 Hz, 1H), 7.43 (s, 1H), Attorney Docket No.: 1859920020407.20 (s, 1H), 7.11 (s, 1H), 6.94 (d, J = 8.9 Hz, 1H), 6.82 (s, 1H), 3.89 (d, J = 1.1 Hz, 6H),3.64 (d, J = 3.1 Hz, 2H), 3.57 (s, 6H), 3.41 (s, 2H), 2.46 (t, J = 6.8 Hz, 2H), 2.25 (s, 6H), 2.06(s, 3H), 1.86 (q, J = 7.0 Hz, 2H). MS m / z (ESI) [M+H] + = 493.3.Example 4: N1-(2-(6-(4-benzylpiperazin-1-yl) pyridin-3-yl)-7-methoxyquinolin-4-yl)-N3,N3- dimethylpropane-1,3-diamine According to scheme 1, step 5, conditions 2 Buchwald. Substrate A.5c (0.10 g, 0.17mmol, 1.0 equiv). The crude product was triturated with MeOH (20 mL) at 25oC for 40 minto give Example 4 (69 mg, 0.13 mmol, 76% yield, 98% purity) was obtained as an off-whitesolid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.91 (d, J = 2.1 Hz, 1H), 8.31 (dd, J = 2.3,8.9 Hz, 1H), 8.01 (d, J = 9.1 Hz, 1H), 7.35 (d, J = 4.3 Hz, 4H), 7.30 - 7.24 (m, 1H), 7.23 -7.16 (m, 2H), 6.98 (dd, J = 2.6, 9.1 Hz, 1H), 6.90 (d, J = 9.0 Hz, 1H), 6.79 (s, 1H), 3.88 (s,3H), 3.62 - 3.56 (m, 4H), 3.53 (s, 2H), 3.41 - 3.36 (m, 2H), 2.49 - 2.46 (m, 4H), 2.37 (t, J =6.8 Hz, 2H), 2.18 (s, 6H), 1.82 (t, J = 6.8 Hz, 2H). MS m / z (ESI) [M+H] + = 511.3.Example 5: N1-(2-(6-(4-benzylpiperazin-1-yl) pyridin-3-yl)-7-methoxyquinolin-4-yl)-N3,N3-dimethylpropane-1,3-diamine According to scheme 1, step 5, conditions 2 Buchwald. Substrate A.5d (0.15 g, 0.48mmol, 1.0 equiv). The residue was purified by prep-TLC (SiO2, DCM / MeOH = 10:1(NH3.H2O), then, DCM / MeOH = 5:1 (NH3.H2O) to give Example 5 (0.11 g, 0.28 mmol,59% yield, 99% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.90 (d, J= 2.4 Hz, 1H), 8.30 (dd, J = 8.9, 2.4 Hz, 1H), 8.02 (d, J = 9.1 Hz, 1H), 7.24 (s, 1 H), 7.18 (d, J = 2.6 Hz, 1H), 6.99 (dd, J = 9.1, 2.6 Hz, 1H), 6.80 (s, 1H), 6.73 (d, J = 9.0 Hz, 1H), 3.88 (s, 3H), 3.41 (d, J = 5.6 Hz, 2H), 3.10 (s, 6H), 2.45 (t, J = 6.8 Hz, 2H), 2.24 (s, 6H), 1.84 (q, J =6.9 Hz, 2H). MS m / z (ESI) [M+H] + = 380.2. Attorney Docket No.: 185992002040 Example 6: N1-(2-(6-(benzyl(methyl)amino) pyridin-3-yl)-7-methoxyquinolin-4-yl)-N3,N3- dimethylpropane-1,3-diamine According to scheme 1, step 5, conditions 2 Buchwald. Substrate A.5e (0.10 g, 0.26mmol, 1.0 equiv); Amine (16 equiv). The reaction mixture was filtered and concentrated under reduced pressure to give residue. The residue was purified by prep-TLC (Plate 1DCM / MeOH = 10:1) to give Example 6 (25 mg, 54 μmol, 21% yield, 99% purity) as a whitesolid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.91 (d, J = 2 Hz, 1H), 8.30 (dd, J = 2.4, 8.8Hz, 1H), 8.00 (d, J = 9.2 Hz, 1H), 7.35 - 7.30 (m, 2H), 7.27 - 7.21 (m, 3H), 7.20 - 7.15 (m,2H), 6.97 (dd, J = 2.6, 9.2 Hz, 1H), 6.81 - 6.73 (m, 2H), 4.88 (s, 2H), 3.87 (s, 3H), 3.43 - 3.37(m, 2H), 3.10 (s, 3H), 2.36 (t, J = 6.8 Hz, 2H), 2.17 (s, 6H), 1.81 (t, J = 6.8 Hz, 2H). MS m / z(ESI) [M+H] + = 456.3.Example 7: N1-(2-(6-(azetidin-1-yl) pyridin-3-yl)-7-fluoro-6-methoxyquinolin-4-yl)-N3,N3- dimethylpropane-1,3-diamine According to scheme 1, step 5, conditions 1 Buchwald. Substrate A.5g (60 mg, 0.17mmol, 1.0 equiv). The residue was purified by prep-HPLC 2 (gradient: 2%-32% over 10min). The residue was purified by strong cation exchange resin SCX (see general protocol) togive Example 7 (38 mg, 91 μmol, 54% yield, 100% purity) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ (ppm) 8.74 (d, J = 2.4 Hz, 1H), 8.15 (dd, J = 2.4, 8.8 Hz, 1H), 7.41 (s,1H), 7.25 - 7.12 (m, 1H), 6.87 (s, 1H), 6.70 ( s, 1H), 6.59 (s, 1H), 6.43 (d, J = 8.8 Hz, 1H),4.20 ( t, J = 4.0 Hz, 2H), 4.01 (t, J = 7.6 Hz, 4H), 3.38 ( d, J = 4.4 Hz, 4H), 2.36 (q, J = 6.8Hz, 4H), 2.18 (s, 6H), 1.82- 1.75 (m, 2H). MS m / z (ESI) [M+H] + = 419.2. Attorney Docket No.: 185992002040 Example 8: N1,N1-dimethyl-N3-(2-(6-(piperazin-1-yl)pyridin-3-yl)quinolin-4-yl)propane-1,3- diamine According to scheme 3, step 6, conditions 1 HCl. Substrate C.6b (0.10 g, 0.20 mmol,1.0 equiv) in EtOH (2.0 mL). Neutralization was done using SCX (see general protocol).After Lyophilization, Example 8 (25 mg, 64 μmol, 31% yield, 100% purity) was obtained asa yellow solid. 1H NMR (400 MHz, methanol-d4) δ (ppm): 8.66 - 8.63 (m, 1H), 8.11 - 8.06(m, 1H), 7.96 - 7.91 (m, 1H), 7.81 - 7.76 (m, 1H), 7.57 - 7.50 (m, 1H), 7.34 - 7.28 (m, 1H),6.85 - 6.80 (m, 1H), 6.72 - 6.68 (m, 1H), 3.56 - 3.49 (m, 4H), 3.44 - 3.37 (m, 2H), 3.25 - 3.17(m, 6H), 2.89 - 2.82 (m, 4H), 2.46 - 2.40 (m, 2H), 1.93 - 1.84 (m, 2H). MS m / z (ESI) [M+H]+= 391.3.Example 9: N1-(6,7-dimethoxy-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl)-N3, N3-dimethylpropane-1,3-diamine According to scheme 3, step 6, conditions 1 HCl. Substrate C.6c (30 mg, 54 mmol,1.0 equiv) in MeOH (0.50 mL). The filter liquor was purified by Prep-HPLC 2 (gradient: 8%-38% B over 9 min). The elute was directly lyophilized to give Example 9 (20 mg, 45 mmol,82% yield, 100% purity) as off-white solid. 1H NMR (400 MHz, methanol-d4) δ (ppm) : 8.84(d, J = 2.4 Hz, 1H), 8.52 (dd, J = 2.4, 9.4 Hz, 1H), 7.84 (s, 1H), 7.48 - 7.43 (m, 2H), 7.09 (s,1H), 4.13 - 4.10 (m, 4H), 4.07 (s, 3H), 4.05 (s, 3H), 3.83 (t, J = 7.1 Hz, 2H), 3.49 - 3.46 (m,4H), 3.40 - 3.36 (m, 2H), 2.94 (s, 6H), 2.34 - 2.27 (m, 2H). MS m / z (ESI) [M+H] + = 451.3. Attorney Docket No.: 185992002040Example 10: N1-(2-(6-(azetidin-3-yl) pyridin-3-yl)-6,7-dimethoxyquinolin-4-yl)-N3,N3-dimethylpropane-1,3-diamine According to scheme 3, step 6, conditions 1 HCl. Substrate C.6d (0.10 g, 0.19 mmol,1.0 equiv) in HCl / MeOH (4.0 M, 10 mL). After lyophilization, Example 10 (70 mg, 0.16mmol, 86% yield, 99% purity) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) : 14.32 (s, 1H), 10.96 (s, 1H), 9.96 (d, J = 6.1 Hz, 1H), 9.75 - 9.64 (m, 1H), 9.62 -9.49 (m, 1H), 9.40 (d, J = 2.0 Hz, 1H), 8.75 - 8.65 (m, 1H), 8.17 (s, 1H), 8.01 (s, 1H), 7.73(d, J = 8.2 Hz, 1H), 7.08 (s, 1H), 4.47 - 4.35 (m, 1H), 4.32 - 4.18 (m, 4H), 3.98 (s, 3H), 3.89(s, 3H), 3.75 (d, J = 5.6 Hz, 2H), 3.30 - 3.15 (m, 2H), 2.76 (d, J = 4.8 Hz, 6H), 2.26 - 2.11 (m,2H). MS m / z (ESI) [M+H] + = 422.2.Example 11: N1-(7-methoxy-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4- dimethylpropane-1,3-diamine According to scheme 3, step 6, conditions 1 HCl. Substrate C.6e (75 mg, 0.14 mmol,1.0 equiv). The residue was purified by prep-HPLC 1 (gradient: 8%-38% over 10 min) togive Example 11 (23 mg, 54 μmol, 38% yield, 100% purity) was obtained as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ (ppm) : 13.76 (s, 1H), 10.94 (s, 1H), 9.71 (s, 2H), 9.49 -9.41 (m, 1H), 8.99 (s, 1H), 8.63 (d, J = 9.4 Hz, 1H), 8.50 (d, J = 9.3 Hz, 1H), 7.92 (s, 1H),7.30 - 7.22 (m, 1H), 7.16 (d, J = 9.3 Hz, 1H), 7.01 (s, 1H), 3.98 (s, 4H), 3.92 (s, 3H), 3.75 (d,J = 5.8 Hz, 2H), 3.19 (s, 6H), 2.74 (d, J = 4.8 Hz, 6H), 2.20 - 2.10 (m, 2H). MS m / z (ESI)[M+H] + = 421.2. Attorney Docket No.: 185992002040Example 12: N1-(6-methoxy-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4- dimethylpropane-1,3-diamine According to scheme 3, step 6, conditions 1 HCl. Substrate C.6f (0.20 g, 0.38 mmol,1.0 equiv). The residue was purified by prep-HPLC 1 (gradient: 9%-39% over 10 min).Example 12 (0.13 g, 0.32 mmol, 83% yield, 100% purity) was obtained as a white solid. 1HNMR (400 MHz, DMSO-d6) δ (ppm) : 13.97 (s, 1H), 10.91 (br s, 1H), 9.73 (br s, 2H), 9.60(br t, J = 5.6 Hz, 1H), 8.98 (d, J = 2.8 Hz, 1H), 8.49 (dd, J = 9.2, 2.5 Hz, 1H), 8.35 (d, J = 9.6Hz, 1H), 8.20 (d, J = 2.4 Hz, 1H), 7.56 (dd, J = 9.2, 2.5 Hz, 1H), 7.15 (d, J = 9.2 Hz, 1H),7.05 (s, 1H), 3.99 - 3.94 (m, 7H), 3.78 (q, J = 6.4 Hz, 2H), 3.25 - 3.21 (m, 2H), 3.21 - 3.15(m, 4H), 2.76 (d, J = 5.2 Hz, 6H), 2.18 (quin, J = 7.6 Hz, 2H). MS m / z (ESI) [M+H] + =421.3. Example 13: N-(4-((3-(dimethylamino) propyl) amino)-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-6-yl) acetamide According to schemes 3 and 4, step 6, conditions 2 TFA. Substrate C.6p (50 mg, 91mmol, 1.0 equiv). The residue was purified by prep-HPLC 2 to give Example 13 (29 mg, 63μmol, 69% yield, 97% purity) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ (ppm) :10.16 (s, 1H), 8.97 (d, J = 1.9 Hz, 1H), 8.30 - 8.48 (m, 2H), 8.20 (s, 2H), 7.77 (d, J = 9.0 Hz,1H), 7.61 (br d, J = 8.9 Hz, 1H), 7.34 - 7.50 (m, 1H), 7.03 (d, J = 8.9 Hz, 1H), 6.91 (s, 1H),3.79 (s, 4H), 3.48 (s, 2H), 3.19 (s, 4H), 2.87 (t, J = 6.5 Hz, 2H), 2.56 (s, 6H), 2.11 (s, 3H),1.90 - 2.02 (m, 2H). MS m / z (ESI) [M+H] + = 448.2. Attorney Docket No.: 185992002040Example 14: 3-((2-(6-(azetidin-1-yl) pyridin-3-yl)-6,7-dimethoxyquinolin-4-yl) amino)-2-((dimethylamino)methyl) propan-1-ol According to scheme 5, step 6, conditions 1 HCl. Substrate D.6a (75 mg, 0.13 mmol,1.0 equiv) in EtOAc (1.0 mL). At 0 °C for 1 h. The residue was purified by prep-HPLC 8(gradient: 2-9 min 0-30% ACN). Then the product was purified with SCX (see generalprotocol). Example 14 (24 mg, 53 μmol, 65% yield, 99% purity) was obtained as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) : 8.83 - 8.82 (m, 1H), 8.25 - 8.25 (m,1H), 7.43 - 7.42 (m, 1H), 7.38 (s, 1H), 7.19 (s, 1H), 6.87 (s, 1H), 6.44 - 6.42 (m, 1H), 4.02 -4.01 (m, 4H), 3.90 (s, 6H), 3.50 - 3.47 (m, 4H), 2.33 - 2.31 (m, 4H), 2.23 (s, 6H), 2.05 - 2.03(m, 1H). MS m / z (ESI) [M+H] + = 452.2.Example 15: N1-(7-methoxy-2-(6-(2-(methylamino) ethoxy) pyridin-3-yl) quinolin-4-yl)-N3- methylpropane-1,3-diamine According to scheme 6, step 6, conditions 1 HCl. Substrate E.6a (0.12 g, 0.20 mmol,1.0 equiv) in MeOH (1.0 mL). The residue was purified by prep-HPLC 8 (gradient:1%-25%ACN over 8 min). The eluent was lyophilized to give Example 15 (27 mg, 69 μmol, 34%yield, 99% purity) as a yellow gum. Then the crude product was purified with SCX (seegeneral protocol). 1H NMR (400 MHz, methanol-d4) δ (ppm): 8.72 (d, J = 2.3 Hz, 1H), 8.27(dd, J = 2.4, 8.7 Hz, 1H), 7.98 (d, J = 9.2 Hz, 1H), 7.29 (d, J = 2.4 Hz, 1H), 7.06 (dd, J = 2.6,9.3 Hz, 1H), 6.96 (d, J = 8.6 Hz, 1H), 6.73 (s, 1H), 4.49 (t, J = 5.3 Hz, 2H), 3.93 (s, 3H), 3.50(t, J = 7.0 Hz, 2H), 3.03 (t, J = 5.3 Hz, 2H), 2.80 (t, J = 7.2 Hz, 2H), 2.49 (s, 3H), 2.46 (s,3H), 2.04 - 1.95 (m, 2H). MS m / z (ESI) [M+H] + = 396.3. Attorney Docket No.: 185992002040 Example 16: 2-(4-(5-(4-((3-(dimethylamino) propyl) amino)-6,7-dimethoxyquinolin-2-yl) pyridin-2-yl) piperazin-1-yl) ethan-1-ol According to schemes 3 and 4, step 6, conditions 1 HCl. Substrate C.6g (40 mg, 66μmol, 1.0 equiv) in dioxane (1.0 mL). Then the residue was purified with SCX (see generalprotocol) to give Example 16 (14 mg, 27 μmol, 41% yield, 99% purity) was obtained as ayellow solid. Then the crude product was purified with SCX (see general protocol).1H NMR(400 MHz, DMSO-d6) δ (ppm): 8.88 (d, J = 2.3 Hz, 1H), 8.28 (dd, J = 2.4, 8.9 Hz, 1H), 7.42(s, 1H), 7.20 (s, 1H), 7.11 (s, 1H), 6.90 (d, J = 9.0 Hz, 1H), 6.81 (s, 1H), 3.89 (d, J = 1.5 Hz,6H), 3.58 - 3.53 (m, 6H), 3.44 - 3.39 (m, 2H), 2.53 (d, J = 4.9 Hz, 4H), 2.47 - 2.42 (m, 4H),2.24 (s, 6H), 1.85 (q, J = 6.8 Hz, 2H). MS m / z (ESI) [M+H] + = 495.3.Example 17: (R)-1-(dimethylamino)-3-((7-methoxy-2-(6-(piperazin-1-yl) pyridin-3-yl) quinolin-4-yl) amino) propan-2-ol According to schemes 3 and 4, step 6, conditions 1 HCl. Substrate R-C.6n (60 mg,0.11 mmol, 1.0 equiv). The residue was purified by prep-HPLC 8 (gradient: 2%-30% over 9min). Then the residue was purified with SCX (see general protocol) to give Example 17 (7.8mg, 18 μmol, 16% yield, 99% purity) was obtained as a white solid. 1H NMR (400 MHz,methanol-d4) δ (ppm): 8.73 (d, J = 2.4 Hz, 1H), 8.16 (dd, J = 8.8, 2.4 Hz, 1H), 7.96 (d, J ...

Claims

Attorney Docket No.: 185992002040 CLAIMS What is claimed is:

1. A compound of formula (I)or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is C1-6alkyl optionally substituted with one or more R1a; each R2is independently halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -OR9, -SR9, -N(Rx)(Ry), - NO2, -CN, -N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, - OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, - C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, -N(R10)S(=O)2R11, - S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=O)2R11, -S(=O)2N(R10)(R11), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, wherein the C1-6alkyl of R2is optionally substituted by one or more R2a, the C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl of R2is optionally substituted with one or more R2b, and the 3- to 8-membered heterocyclyl of R2comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; n is 0, 1, 2, or 3; L is a bond, C1-6alkyl, -O-(C1-6alkyl)-, -S-(C1-6alkyl)-, or -N(R3)(C1-6alkyl)-; R3is H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C(=O)R11, -S(=O)2R11, -S(=O)2N(R10)(R11), or C3-8cycloalkyl, wherein the C1-6alkyl of R3is optionally substituted with one or more halo, -N(Rx)(Ry), -OR9, - SR9, -N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, - OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, - C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, - N(R10)S(=O)2R11, -S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=O)2R11, or - S(=O)2N(R10)(R11), andAttorney Docket No.: 185992002040 the C3-8cycloalkyl is optionally substituted with one or more R3b; R4is -N(Rx)(Ry), -N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, - OC(=O)N(R10)R11, -C(=O)(C1-6alkyl)N(Rx)(Ry), -C(=O)N(R10)(R11), or 3- to 8-membered N- containing heterocyclyl, wherein the 3- to 8-membered N-containing heterocyclyl of R4is optionally substituted with one or more R4b, -C(=O)R11, -C(=O)N(R10)(R11), or -C(=O)OR11, and the 3- to 8-membered N-containing heterocyclyl of R4comprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; R5is H; R6and R7are each independently H, halo, C1-6alkyl, -OR9, -N(Rx)(Ry), -N(R10)C(=O)R11, - N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, -OC(=O)N(R10)R11, - OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, -C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, -N(R10)S(=O)2R11, -S(=O)R11, -S(=O)N(R10)R11, - S(=O)OR11, -S(=O)2R11, or -S(=O)2N(R10)(R11), wherein the C1-6alkyl of R6or R7is optionally substituted by one or more R5a; or R6and R7are taken together with the carbon atoms to which they are attached to form a 4- to 8-membered heterocyclyl; each R1a, R2a, R4a, and R5ais independently halo, -N(Rx)(Ry), -OR9, -SR9, -NO2, -CN, - N(R10)C(=O)R11, -N(R10)C(=O)N(R10)R11, -N(R10)C(=O)OR11, -OC(=O)R11, - OC(=O)N(R10)R11, -OC(=O)OR11, -C(=O)R11, -C(=O)N(R10)(R11), -C(=O)OR11, - C(=NR12)R11, -C(=NOR11)R11, -C(=NR12)N(R10)R11, -C(=NR12)OR11, -N(R10)S(=O)2R11, - S(=O)R11, -S(=O)N(R10)R11, -S(=O)OR11, -S(=O)2R11, -S(=O)2N(R10)(R11), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, wherein the C3-8cycloalkyl, 3- to 12-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl is optionally substituted with of R1a, R2a, R4a, or R5ais optionally substituted with one or more R1b, and the 3- to 12-membered heterocyclyl of R1a, R2a, R4a, or R5acomprises 1, 2, or 3 atoms selected from the group consisting of N, O, and S; each R1b, R2b, R3b, R4b, or R5bis independently halo, C1-6alkyl, -OR13, -N(Rx)(Ry), oxo, -CN, C3-8cycloalkyl, or 3- to 8-membered heterocyclyl, wherein the C1-6alkyl of R1b, R2b, R3b, R4b, or R5bis optionally substituted by -OR9, - N(Rx)(Ry), C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6- membered heteroaryl;Attorney Docket No.: 185992002040 each R9is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 3- to 8-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the C1-6alkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl of R9is optionally substituted with one or more halo, deuterium, C1-6alkoxy, -N(Rx)(Ry), or 3- to 8-membered heterocyclyl; each R10is independently H, C1-6alkyl, or C3-8cycloalkyl; each R11is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-6alkyl of R11is optionally substituted by halo, -OH, -O(C1-6alkyl), -O(phenyl), - O(C=O)C1-8alkyl), -N(Rx)(Ry), C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10- membered heteroaryl, or 3- to 12-membered heterocyclyl, and the C3-8cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl of R11is optionally substituted with halo, C1-6alkyl, or - N(Rx)(Ry); each R12is independently H or C1-6alkyl; each R13is independently H, C1-6alkyl, C2-6alkenyl, C3-8cycloalkyl, 3- to 8-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, wherein the C1-6alkyl of R13is optionally substituted with phenyl, or 5- to 6-membered heteroaryl, wherein the phenyl, or 5- to 6-membered heteroaryl is optionally substituted with halo, C1-3alkyl, C1-3alkoxy, -N(Rx)(Ry), or 3- to 8-membered heterocyclyl, and the phenyl, or 5- to 6-membered heteroaryl of R13is optionally substituted with halo, C1-3alkyl, C1-3alkoxy, or -N(Rx)(Ry); and each Rxand Ryis independently H, C1-6alkyl, C3-8cycloalkyl, -C(=O)(C1-6alkyl), or - C(=O)O(C1-6alkyl), wherein the C1-6alkyl of Rxor Ryis optionally substituted with 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -OH, -NH2, NH(C1-6alkyl), or -N(C1-6alkyl)(C1-6alkyl), and the C1-6alkyl of -C(=O)(C1-6alkyl) or -C(=O)O(C1-6alkyl) is optionally substituted with -O(C=O)C1-8alkyl), wherein whenare each H, R1 is not -CH2CH2CH2N(CH3)(CH3).Attorney Docket No.: 185992002040 2. The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is a bond or -O(C1- 6alkyl)-.

3. The compound of claim 2, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is a bond or -O(C1- 4alkyl)-.

4. The compound of claim 3, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is a bond or - O(CH2CH2)-.

5. The compound of any of claims 1-4, wherein the compound is a compound of formula (II)stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

6. The compound of any of claims 1-4, wherein the compound is a compound of formula (III)tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.Attorney Docket No.: 185992002040 7. The compound of any of claims 1-6, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is C1-6alkyl substituted with one or more R1a.

8. The compound of any of claims 1-7, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein each R1ais independently - OH, -NH(C1-6alkyl), -N(C1-6alkyl)(C1-6alkyl), or phenyl, wherein the phenyl is optionally substituted by halo.

9. The compound of claim 8, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein each R1ais independently - OH, -NH(CH3), -N(CH3)(CH3), or fluorophenyl.

10. The compound of any of claims 1-7, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is selected from the11. The compound of any of claims 1-10, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R4is -N(Rx)(Ry).

12. The compound of claim 11, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R4is -NH(C1-6alkyl), - N(C1-6alkyl)(C1-6alkyl), wherein each C1-6alkyl is independently optionally substituted by one or more R4a.Attorney Docket No.: 185992002040 13. The compound of claim 12, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R4is selected from thegroup consisting14. The compound of any of claims 1-10, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R4is -N(R10)C(O)R11.

15. The compound of claim 14, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R4is -NHC(O)(C1-6alkyl).

16. The compound of claim 15, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R4is -NHC(O)(CH3).

17. The compound of any of claims 1-10, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R4is 3- to 12-membered N- containing heterocyclyl optionally substituted by R4b, -C(=O)R11, -C(=O)N(R10)(R11), or - C(=O)OR11.

18. The compound of claim 17, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R4is azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, wherein the piperazinyl is optionally substituted by R4b, -C(=O)R11, -C(=O)N(R10)(R11), or -C(=O)OR11.

19. The compound of claim 18, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R4is selected from thegroup consistingAttorney Docket No.: 185992002040.

20. The compound of any of claims 1-19, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R6and R7are each independently H, halo, C1-6alkyl, -N(Rx)(Ry), -OR9, -N(R10)C(O)R11, or -N(R10)C(O)OR11.

21. The compound any of claims 1-20, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R6and R7are each independently H, halo, C1-6alkyl, -NH(C1-6alkyl), -N(C1-6alkyl)(C1-6alkyl), -O(C1-6alkyl), - O(5- to 6-membered aryl), -O(5- to 6-membered heteroaryl), -NHC(O)(C1-6alkyl), - NHC(O)(5- to 6-membered aryl), or -NHC(O)O(C1-6alkyl), wherein the -O(C1-6alkyl) is optionally substituted with phenyl or halo; the -O(5- to 6-membered aryl) is optionally substituted with 4- to 6-membered heterocyclyl; the -NHC(O)(C1-6alkyl) is optionally by -O(5- to 6-membered aryl); and the -NHC(O)(5- to 6-membered aryl) is optionally substituted with -N(Rx)(Ry).

22. The compound of any of claims 1-21, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R6and R7are each independently selected from the group consisting of H, -CH3, F, -NH(CH3), -N(CH3)(CH3), -Attorney Docket No.: 185992002040 23. The compound of any of claims 1-20, wherein R6and R7are each independently selected from the group consisting of H, -CH3, F, -OCH3,,24. The compound of any of claims 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: L is a bond or -O(C1-6alkyl); R4is 3- to 12-membered N-containing heterocyclyl optionally substituted by R4b, - C(=O)R11, -C(=O)N(R10)(R11), or -C(=O)OR11; and R1is C1-4alkyl optionally substituted with one or more substituents selected from the group consisting of -OH, -NH(CH3), and -N(CH3)(CH3).

25. The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is selected from Table 1.

26. A compound selected from compounds 1 to 40 of Table 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

27. A pharmaceutical composition comprising a compound of any of claims 1-26, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and one or more pharmaceutically acceptable excipients or carriers.

28. A method for treating a disease or condition mediated by TDP-43, comprising administering to an individual in need thereof a compound of any of claims 1-26, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 27.

29. The method of claim 28, wherein said disease or condition mediated by TDP-43 is a neurological disease or condition.Attorney Docket No.: 185992002040 30. The method of claim 29, wherein the neurological disease is selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, traumatic brain injury (TBI), chronic traumatic encephalopathy (CTE), frontotemporal dementia (FTD), inclusion body myositis, Perry syndrome, corticobasal degeneration, spinocerebellar ataxia type 3, and amyotrophic lateral sclerosis (ALS).

31. The method of claim 29 or 30, wherein the neurological disease or condition is traumatic brain injury (TBI).

32. The method of claim 29 or 30, wherein the neurological disease or condition is frontotemporal dementia (FTD).

33. The method of claim 29 or 30, wherein the neurological disease or condition is amyotrophic lateral sclerosis (ALS).

34. The method of any of claims 29, 30, or 33, wherein the neurological disease or condition is sporadic amyotrophic lateral sclerosis or C9ORF72 amyotrophic lateral sclerosis.

35. The method of any of claims 28-34, wherein the individual is a human.

36. A method of modulating TDP-43, comprising contacting a cell with an effective amount of a compound of any of claims 1-26, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 27, wherein modulating TDP-43 comprises modulating TDP-43 incorporation into condensates, modulating TDP-43 binding to RNA in condensates, modulating TDP-43 aggregation, or modulating TDP-43 protein-protein interactions.

37. A method of modulating TDP-43 driven gene expression levels, comprising contacting a cell with an effective amount of a compound of any of claims 1-26, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 27.Attorney Docket No.: 185992002040 38. The method of claim 37, wherein the gene expression levels are for STMN2.

39. The method of claim 37, wherein the gene expression levels are for POLDIP3.

40. The compound of any of claims 1-26, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 27 for use in the treatment of a disease or condition mediated by TDP-43.

41. Use of a compound of any of claims 1-26, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease or disorder mediated by TDP-43.

42. A kit, comprising (i) a compound of any one of claims 1-26, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 27 and (ii) instructions for use in treating a TDP-43 mediated disease or condition in an individual in need thereof.

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