Fused quinone compounds

Abstract

The present disclosure describes fused quinone compounds, and compositions and methods thereof. Such compounds can be useful in treating mitochondrial diseases in a subject, such as a human.

Description

Attorney Docket No.058367-510001WO FUSED QUINONE COMPOUNDS CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. provisional application 63 / 609,598 filed December 13, 2023, which is herein incorporated by reference in its entirety for all purposes. BACKGROUND

[0002] Ferroptosis is an iron-dependent form of regulated cell death that is believed to be caused by the toxic buildup of lipid peroxides on cellular membranes. Studies have linked ferroptosis to various pathological conditions and diseases, such as neurodegenerative diseases.

[0003] One class of ferroptosis inhibitors includes radical-trapping antioxidants, which can trap chain-carrying radicals and thereby block propagation of the radical chain reactions during lipid peroxidation. For example, α-tocopherol and ubiquinol are two naturally occurring radical- trapping antioxidants that are capable of inhibiting ferroptosis. Ferrostatin-1 and liproxstatin-1 are radical-trapping antioxidants that were identified from screenings as potent ferroptosis inhibitors.

[0004] Phenothiazine quinones have been previously described as potentially useful for treating diseases with decreased mitochondrial function, such as neurodegenerative diseases. See, US Patents 10,472,340 and 10,745,366. For instance, in vitro evaluation of such compounds suggests that certain phenothiazine quinones may be useful in increasing frataxin levels in Freidreich’s ataxia cells. See, Khdour, et al. Med. Chem. Commun.2018, 9, 1491.

[0005] There is a need to develop ferroptosis inhibitors that have favorable physicochemical and pharmacokinetic properties in order to treat diseases associated with excessive ferroptosis. BRIEF SUMMARY

[0006] In some embodiments, a compound of the present disclosure is a compound of Formula J:J), or a pharmaceutically acceptab whereineach R1 and R2 is independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6hydroxyalkyl, C1-6aminoalkyl, (C0-6alkyl)(C3-8cycloalkyl), (C0-6alkyl)(heterocyclyl), (C0-6alkyl)(C6-10aryl), (C0-6alkyl)(heteroaryl), halogen, ORa, SRa, NRaRb, NO2, or CN, wherein the alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0, 1, 2, 3, or 4 R1a; or R1and R2taken together with the carbon atoms to which they are attached form a C5-10cycloalkyl, heterocyclyl, C6-10 aryl, or heteroaryl ring each substituted with 0, 1, 2, 3, or 4 R1b; each R1aand R1bis independently D, halogen, ORa, SRa, NRaRb, oxo, NO2, or CN;each Ra and Rb is independently H or C1-6 alkyl;each R3a, R3b, R4a, R4b, R5a, R5b, R6a, and R6bis independently H, C1-6 alkyl, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6aminoalkyl; or two of R3a, R3b, R4a, R4b, R5a, R5b, R6a, and R6btaken together with the atoms to which they are attached form a C3-8 cycloalkyl or a heterocyclyl; X is –C(R7a)(R7b)-, -N(R8)-, -O-, or –S-; R7ais (C0-6alkyl)-N(R7a1)(R7a2), (C0-6alkyl)-OR7a1, or (C0-6alkyl)-SR7a1; R7bis H or C1-6 alkyl; or R7aand R7btaken together form an oxo; each R7a1and R7a2is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C2-6alkoxyalkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, (C2-6 alkyl)-N(R7c)C(O)-(R7d), (C2- 6 alkyl)-N(R7c)C(O)(OR7d), (C2-6 alkyl)-N(R7c)S(O)2R7d, (C0-6 alkyl)(C3-8 cycloalkyl), (C0- 6 alkyl)(heterocyclyl), (C0-6alkyl)(C6-10aryl), (C0-6alkyl)(heteroaryl), (C0-6alkyl)-C(O)-R7c, (C0-6alkyl)-C(O)O-R7c, (C0-6alkyl)-C(O)-N(R7c)(R7d), (C0-6alkyl)-S(O)R7c, (C0-6 alkyl)-S(O)(NH)R7c, (C0-6 alkyl)-S(O)2R7c, (C0-6 alkyl)-S(O)2N(R7c)(R7d), or (C0-6 alkyl)- S(O)(NR7c)R7d, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0, 1, 2, or 3 R7e; or R7a1and R7a2taken together with the atoms to which they are attached form a heterocyclyl, which is substituted with 0, 1, 2, or 3 R7e; R8is H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C2-6alkoxyalkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6 aminoalkyl, (C2-6 alkyl)-N(R8a)C(O)-(R8b), (C2-6 alkyl)-N(R8a)C(O)(OR8b), (C2- 6 alkyl)-N(R8a)S(O)2R8b, (C0-6 alkyl)(C3-8 cycloalkyl), (C0-6 alkyl)(heterocyclyl), (C0- 6 alkyl)(C6-10aryl), (C0-6alkyl)(heteroaryl), (C0-6alkyl)-C(O)-R8a, (C0-6alkyl)-C(O)O-R8a, (C0-6alkyl)-C(O)-N(R8a)(R8b), (C0-6alkyl)-S(O)R8a, (C0-6alkyl)-S(O)(NH)R8a, (C0-6alkyl)- S(O)2R8a, (C0-6 alkyl)-S(O)2N(R8a)(R8b), or (C0-6 alkyl)-S(O)(NR8a)R8b, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0, 1, 2, or 3 R8c; each R7eand R8cis independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C2-6alkoxyalkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, C3-8 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, (C0-6 alkyl)-C(O)-R9a, (C0-6 alkyl)-C(O)O-R9a, (C0-6 alkyl)-C(O)-N(R9a)(R9b), (C0-6alkyl)-S(O)R9a, -S(O)(NH)R9a, -S(O)2R9a, -S(O)2N(R9a)(R9b), or -S(O)(NR9a)R9b; each R7c, R7d, R8a, R8b, R9a, and R9bis independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2- 6 alkoxyalkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, (C0-6 alkyl)(C3-8 cycloalkyl), (C0-6alkyl)(heterocyclyl), (C0-6alkyl)(C6-10aryl), or (C0-6alkyl)(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0 to 4 Z1; each Z1is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-6 alkoxyalkyl, C1-6 haloalkyl, C3- 8 cycloalkyl, heterocyclyl, C6-10aryl, heteroaryl, halogen, oxo, -OH, -CN, -NO2, -NH2, - N3, -SH, -O(C1-6 alkyl), -O(C1-6 haloalkyl), -NH(C1-6 alkyl), -NH(C1-6 haloalkyl), -N(C1-6 alkyl)2, -N(C1-6 haloalkyl)2, -N(C1-6 alkyl)(C1-6 haloalkyl), -C(O)(C1-6 alkyl), -C(O)(C1-6 haloalkyl), -C(O)O(C1-6alkyl), -C(O)O(C1-6haloalkyl), -C(O)NH2, -C(O)NH(C1-6alkyl), -C(O)NH(C1-6 haloalkyl), -C(O)N(C1-6 alkyl)2, -C(O)N(C1-6 haloalkyl)2, -NHC(O)(C1-6 alkyl), -NHC(O)(C1-6 haloalkyl), -NHC(O)O(C1-6 alkyl), -NHC(O)O(C1-6haloalkyl), -NHC(O)NH(C1-6alkyl), -NHC(O)NH(C1-6haloalkyl), -NHS(O)(C1-6alkyl), -N(C1-6alkyl)(S(O)(C1-6alkyl), -S(C1-6alkyl), -S(C1-6haloalkyl), -S(O)N(C1-6alkyl)2, -S(O)(C1-6alkyl), -S(O)(C1-6haloalkyl), -S(O)2(C1-6alkyl), -S(O)2(C1-6 haloalkyl), -S(O)(NH)(C1-6 alkyl), -S(O)2NH(C1-6 alkyl), or -S(O)2N(C1-6 alkyl)2; each heterocyclyl is a 4- to 10-membered ring having 1, 2, 3, or 4 heteroatoms selected from N, O, and S; and each heteroaryl is a 5- to 10-membered ring having 1, 2, 3, or 4 heteroatoms selected from N, O, and S.

[0007] In some embodiments, a pharmaceutical composition comprises a compound of the present disclosure or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0008] In some embodiments, a method of inhibiting ferroptosis in a cell comprises administering to the cell an effective amount of a compound of the present disclosure or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0009] In some embodiments, a method of treating a mitochondrial disease of the present disclosure comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. DETAILED DESCRIPTIONI. GENERAL

[0010] The present disclosure describes novel quinone compounds fused to a seven-membered heterocyclic ring, and compositions and methods thereof. Such compounds can be useful in treating mitochondrial diseases in a subject, such as a human.

[0011] The compounds of the present disclosure are quinones fused to a seven-membered heterocyclic ring. Such compounds are generally useful in inhibiting ferroptosis, thereby inhibiting cell death associated with certain mitochondrial diseases. Without wishing to be bound by theory, a compound of the present disclosure, such as a compound of Formula J, possesses structural features that are believed to afford superior properties such as improved solubility,permeability, bioavailability, and / or toxicity, while retaining ferroptosis inhibiting activity, compared to known ferroptosis inhibitors. Standard techniques known in the art can be used to quantify properties of the compounds of the present disclosure. For example, an Ames test can test whether a given compound can cause mutations in DNA, thereby giving a convenient assay to estimate the carcinogenic potential of a compound as part of a determination of toxicity.

[0012] The compounds of the present disclosure, e.g., the compounds synthesized in Examples 1 through 127, demonstrated potent inhibition of ferroptosis, e.g., in a cell viability rescue model from RSL3 challenge. See, Example 128 and Table 4. Without being bound by theory, the ferroptosis inhibition of the compounds of the present disclosure is believed to be achieved through inhibition of 15-lipoxygenase (15-LO) and thereby LRRK2 inhibition.

[0013] The compounds of the present disclosure are believed to exhibit superior neuroprotective properties compared to literature LRRK2 kinase inhibitors. In an in vivo rat model of Parkinson’s disease, Compound 2 exhibited a dose-dependent prevention of rotenone- induced LRRK2 kinase hyperactivity, leading to protection of TH-positive dopaminergic neuron viability from rotenone challenge at a 1.5 mg / kg dose. See, Example 129. In illustrative in vitro experiments, Compound 2 demonstrated rescue from RSL3-induced neurite loss in Parkinson’s disease patient neurons, whereas the literature LRRK2 kinase inhibitor MLi-2 failed to deliver such protection under the same conditions. See, Example 130. In Parkinson’s disease patient- derived fibroblasts, IKE-induced cell death was completely rescued by Compound 2 in a co- dosing experiment, while co-dosing with literature LRRK2 kinase inhibitors PFE-360 and MLi-2 exhibited a comparably modest rescue at best. In an interventional context, e.g., administering a compound of the present disclosure after IKE-induced cell death had already begun, Compound 2 also exhibited dose-dependent cell rescue. See, Example 131 and Table 11.II. DEFINITIONS

[0014] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0015] The prefix “Cu-Cv” or “Cu-v”indicates that the following group has from u to v carbon atoms. For example, “C1-8 alkyl” indicates that the alkyl group has from 1 to 8 carbon atoms.

[0016] “Alkyl” is a linear or branched saturated monovalent or divalent hydrocarbon. For example, an alkyl group can have 1 to 10 carbon atoms (i.e., C1-10 alkyl) or 1 to 8 carbon atoms (i.e., C1-8 alkyl) or 1 to 6 carbon atoms (i.e., C1-6 alkyl) or 1 to 4 carbon atoms (i.e., (C1-4 alkyl). Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1- butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3, and octyl (-(CH2)7CH3).

[0017] “Alkenyl” refers to a straight chain or branched hydrocarbon having at least 2 carbon atoms and at least one double bond. Alkenyl can include any number of carbons, such as C2, C2-3, C2-4, C2-5, C2-6, C2-7, C2-8, C2-9, C2-10, C3, C3-4, C3-5, C3-6, C4, C4-5, C4-6, C5, C5-6, and C6. Alkenyl groups can have any suitable number of double bonds, including, but not limited to, 1, 2, 3, 4, 5 or more. Examples of alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl. Alkenyl groups can be substituted or unsubstituted.

[0018] “Alkynyl” refers to either a straight chain or branched hydrocarbon having at least 2 carbon atoms and at least one triple bond. Alkynyl can include any number of carbons, such as C2, C2-3, C2-4, C2-5, C2-6, C2-7, C2-8, C2-9, C2-10, C3, C3-4, C3-5, C3-6, C4, C4-5, C4-6, C5, C5-6, and C6. Examples of alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentynyl, 1,3-pentadiynyl, 1,4-pentadiynyl,1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl, or 1,3,5-hexatriynyl. Alkynyl groups can be substituted or unsubstituted.

[0019] “Alkoxy” means a group having the formula –O-alkyl, in which an alkyl group, as defined above, is attached to the parent molecule via an oxygen atom. The alkyl portion of an alkoxy group can have 1 to 20 carbon atoms (i.e., C1-C20 alkoxy), 1 to 12 carbon atoms (i.e., C1-C12 alkoxy), 1 to 8 carbon atoms (i.e., C1-C8 alkoxy), 1 to 6 carbon atoms (i.e., C1-C6 alkoxy) or 1 to 3 carbon atoms (i.e., C1-C3alkoxy). Examples of suitable alkoxy groups include, but are not limited to, methoxy (-O-CH3or –OMe), ethoxy (-OCH2CH3or -OEt), isopropoxy (-O- CH(CH3)2), t-butoxy (-O-C(CH3)3 or –OtBu) and the like. Other examples of suitable alkoxy groups include, but are not limited to, sec-butoxy, tert-butoxy, pentoxy, hexoxy, and the like.

[0020] “Alkoxyalkyl” refers an alkoxy group linked to an alkyl group which is linked to the remainder of the compound. Alkoxyalkyl can have any suitable number of carbons, such as from 2 to 6 (C2-6 alkoxyalkyl), 2 to 5 (C2-5 alkoxyalkyl), 2 to 4 (C2-4 alkoxyalkyl), or 2 to 3 (C2-3 alkoxyalkyl). Alkoxy and alkyl are as defined above. Examples of “alkoxyalkyl” include, but are not limited to, methoxymethyl (CH3OCH2-), and methoxyethyl (CH3OCH2CH2).

[0021] “Hydroxyalkyl” refers to a hydroxy group, -OH, linked to an alkyl group which is linked to the remainder of the compound such that the alkyl group is divalent. Hydroxyalkyl can have any suitable number of carbons, such as from 1 to 8 (C1-8hydroxyalkyl), 1 to 6 (C1-6hydroxyalkyl), 2 to 6 (C2-6 hydroxyalkyl), 2 to 4 (C2-4 hydroxyalkyl), or 2 to 3 (C2-3 hydroxyalkyl). Alkyl is as defined above where the alkyl is divalent.

[0022] “Aminoalkyl” is an alkyl group, as defined above, in which one or more hydrogen atoms of the alkyl group is replaced with an amine group (-NR2, where R = H or alkyl). The alkyl portion of an aminoalkyl group can have 1 to 20 carbon atoms (i.e., C1-C20 aminoalkyl), 1 to 12 carbon atoms (i.e., C1-C12aminoalkyl), 1 to 8 carbon atoms (i.e., C1-C8aminoalkyl), 1 to 6 carbon atoms (i.e., C1-C6 aminoalkyl) or 1 to 3 carbon atoms (i.e., C1-C3 aminoalkyl). The alkyl groups can be substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9 or more amines. Examples of suitable aminoalkyl groups include, but are not limited to, -CH2NH2, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, -CH2CH2N(CH3)2, and -CH2CH2CH2N(CH3)2.

[0023] “Halo” or “halogen” as used herein refers to fluoro (-F), chloro (-Cl), bromo (-Br) and iodo (-I).

[0024] “Haloalkyl” is an alkyl group, as defined above, in which one or more hydrogen atoms of the alkyl group is replaced with a halogen atom. The alkyl portion of a haloalkyl group can have 1 to 20 carbon atoms (i.e., C1-C20 haloalkyl), 1 to 12 carbon atoms (i.e., C1-C12 haloalkyl), 1 to 8 carbon atoms (i.e., C1-C8 haloalkyl), 1 to 6 carbon atoms (i.e., C1-C6 alkyl) or 1 to 3 carbon atoms (i.e., C1-C3alkyl). The alkyl groups can be substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9 or more halogens. Examples of suitable haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CFH2, -CH2CF3, fluorochloromethyl, difluorochloromethyl, 1,1,1-trifluoroethyl and pentafluoroethyl.

[0025] “Cycloalkyl” refers to a single saturated or partially unsaturated all carbon ring having 3 to 20 annular carbon atoms (i.e., C3-20 cycloalkyl), for example from 3 to 12 annular atoms, for example from 3 to 10 annular atoms, or 3 to 8 annular atoms, or 3 to 6 annular atoms, or 3 to 5 annular atoms, or 3 to 4 annular atoms. The term “cycloalkyl” also includes multiple condensed, saturated and partially unsaturated all carbon ring systems (e.g., ring systems comprising 2, 3 or 4 carbocyclic rings). Accordingly, cycloalkyl includes multicyclic carbocycles such as a bicyclic carbocycles (e.g., bicyclic carbocycles having about 6 to 12 annular carbon atoms such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane), and polycyclic carbocycles (e.g. tricyclic and tetracyclic carbocycles with up to about 20 annular carbon atoms). The rings of a multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3- enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl and 1-cyclohex-3-enyl.

[0026] “Alkyl-cycloalkyl” refers to a radical having an alkyl component and a cycloalkyl component, where the alkyl component links the cycloalkyl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene, to link to the cycloalkyl component and to the point of attachment. In some instances, the alkyl component can be absent. The alkyl component can include any number of carbons, such as C1-6, C1-2, C1-3, C1-4, C1-5, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6 and C5-6. The cycloalkyl component is as defined within. Exemplary alkyl-cycloalkyl groups include, butare not limited to, methyl-cyclopropyl, methyl-cyclobutyl, methyl-cyclopentyl and methyl- cyclohexyl.

[0027] “Heterocyclyl” or “heterocycle” or “heterocycloalkyl” as used herein refers to a single saturated or partially unsaturated non-aromatic ring or a non-aromatic multiple ring system that has at least one heteroatom in the ring (i.e., at least one annular heteroatom selected from oxygen, nitrogen, and sulfur). Unless otherwise specified, a heterocyclyl group has from 3 to about 20 annular atoms, for example from 3 to 12 annular atoms, for example from 3 to 10 annular atoms, or 3 to 8 annular atoms, or 3 to 6 annular atoms, or 3 to 5 annular atoms, or 4 to 6 annular atoms, or 4 to 5 annular atoms. Thus, the term includes single saturated or partially unsaturated rings (e.g., 3, 4, 5, 6 or 7-membered rings) having from about 1 to 6 annular carbon atoms and from about 1 to 3 annular heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring. The rings of the multiple condensed ring (e.g. bicyclic heterocyclyl) system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. Heterocycles include, but are not limited to, azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane, thietane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine,, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 6-oxa-1- azaspiro[3.3]heptan-1-yl, 2-thia-6-azaspiro[3.3]heptan-6-yl, 2,6-diazaspiro[3.3]heptan-2-yl, 2- azabicyclo[3.1.0]hexan-2-yl, 3-azabicyclo[3.1.0]hexanyl, 2-azabicyclo[2.1.1]hexanyl, 2- azabicyclo[2.2.1]heptan-2-yl, 4-azaspiro[2.4]heptanyl, 5-azaspiro[2.4]heptanyl, and the like. The heterocycle can be unsubstituted or substituted.

[0028] “Alkyl-heterocycloalkyl” refers to a radical having an alkyl component and a heterocycloalkyl component, where the alkyl component links the heterocycloalkyl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene, to link to the heterocycloalkyl component and to the point of attachment. The alkyl component can include any number of carbons, such as C0-6, C1-2, C1-3, C1-4, C1-5, C1-6, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6and C5-6. In some instances, the alkyl component can be absent. The heterocycloalkyl component is as defined above.

[0029] “Aryl” means an aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. For example, an aryl group canhave 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms. Exemplary aryl groups include, but are not limited to, radicals derived from benzene (e.g., phenyl), naphthalene, anthracene, biphenyl, and the like.

[0030] “Alkyl-aryl” refers to a radical having an alkyl component and an aryl component, where the alkyl component links the aryl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene, to link to the aryl component and to the point of attachment. The alkyl component can include any number of carbons, such as C0-6, C1-2, C1-3, C1-4, C1-5, C1-6, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6 and C5-6. In some instances, the alkyl component can be absent. The aryl component is as defined above. Examples of alkyl-aryl groups include, but are not limited to, benzyl and ethyl-benzene.

[0031] “Heteroaryl” as used herein refers to a single aromatic ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; “heteroaryl” also includes multiple condensed ring systems that have at least one such aromatic ring, which multiple condensed ring systems are further described below. Thus, “heteroaryl” includes single aromatic rings of from about 1 to 6 carbon atoms and about 1- 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. The sulfur and nitrogen atoms may also be present in an oxidized form provided the ring is aromatic. Exemplary heteroaryl ring systems include but are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl. “Heteroaryl” also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) wherein a heteroaryl group, as defined above, is condensed with one or more rings selected from heteroaryls (to form for example 1,8-naphthyridinyl), heterocycles, (to form for example 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycles (to form for example 5,6,7,8-tetrahydroquinolyl) and aryls (to form for example indazolyl) to form the multiple condensed ring system. Thus, a heteroaryl (a single aromatic ring or multiple condensed ring system) has about 1-20 carbon atoms and about 1-6 heteroatoms within the heteroaryl ring. Such multiple condensed ring systems may be optionally substituted with one or more (e.g., 1, 2, 3 or 4) oxo groups on the carbocycle or heterocycle portions of the condensed ring. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the individual rings ofthe multiple condensed ring system may be connected in any order relative to one another. It is to be understood that the point of attachment for a heteroaryl or heteroaryl multiple condensed ring system can be at any suitable atom of the heteroaryl or heteroaryl multiple condensed ring system including a carbon atom and a heteroatom (e.g., a nitrogen). It also to be understood that when a reference is made to a certain atom-range membered heteroaryl (e.g., a 5 to 10 membered heteroaryl), the atom range is for the total ring atoms of the heteroaryl and includes carbon atoms and heteroatoms. For example, a 5-membered heteroaryl would include a thiazolyl and a 10- membered heteroaryl would include a quinolinyl. Exemplary heteroaryls include but are not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl benzofuranyl, benzimidazolyl, thianaphthenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, phenothiazinyl, and triazolyl. The heteroaryl can be substituted or unsubstituted.

[0032] “Alkyl-heteroaryl” refers to a radical having an alkyl component and a heteroaryl component, where the alkyl component links the heteroaryl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene, to link to the heteroaryl component and to the point of attachment. The alkyl component can include any number of carbons, such as C0-6, C1-2, C1-3, C1-4, C1-5, C1-6, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6 and C5-6. In some instances, the alkyl component can be absent. The heteroaryl component is as defined within.

[0033] “Oxo” refers to the group (=O) or (O).

[0034] A “compound of the disclosure” or “compound of the present disclosure” includes compounds described herein, for example a compound of the present disclosure includes compounds of Formula J, I, Ia, Ib, II, and / or III, including the compounds of the Examples.III. COMPOUNDS

[0035] The compounds of the present disclosure, e.g., compounds of Formula J, Formula I, Ia, Ib, II, and / or III, are substituted quinones fused to a seven-membered ring that contains a heteroatom. Such compounds are generally useful in inhibiting ferroptosis, thereby inhibiting cell death associated with certain mitochondrial diseases.

[0036] In some embodiments, a compound of the present disclosure is a compound of Formula J: , or a pharmaceuticallywhereineach R1 and R2 is independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, (C0-6 alkyl)(C3-8 cycloalkyl), (C0-6 alkyl)(heterocyclyl), (C0-6alkyl)(C6-10aryl), (C0-6alkyl)(heteroaryl), halogen, ORa, SRa, NRaRb, NO2, or CN, wherein the alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0, 1, 2, 3, or 4 R1a; or R1and R2taken together with the carbon atoms to which they are attached form a C5-10 cycloalkyl, heterocyclyl, C6-10aryl, or heteroaryl ring each substituted with 0, 1, 2, 3, or 4 R1b; each R1aand R1bis independently D, halogen, ORa, SRa, NRaRb, oxo, NO2, or CN;each Ra and Rb is independently H or C1-6 alkyl;each R3a, R3b, R4a, R4b, R5a, R5b, R6a, and R6bis independently H, C1-6 alkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl; or two of R3a,R3b,R4a,R4b,R5a,R5b,R6a,and R6btaken together with the atoms to which they are attached form a C3-8cycloalkyl or a heterocyclyl; X is –C(R7a)(R7b)-, -N(R8)-, -O-, or –S-; R7ais (C0-6 alkyl)-N(R7a1)(R7a2), (C0-6 alkyl)-OR7a1, or (C0-6 alkyl)-SR7a1; R7bis H or C1-6alkyl; or R7aand R7btaken together form an oxo;each R7a1and R7a2is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C2-6alkoxyalkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, (C2-6 alkyl)-N(R7c)C(O)-(R7d), (C2- 6 alkyl)-N(R7c)C(O)(OR7d), (C2-6 alkyl)-N(R7c)S(O)2R7d, (C0-6 alkyl)(C3-8 cycloalkyl), (C0- 6 alkyl)(heterocyclyl), (C0-6alkyl)(C6-10aryl), (C0-6alkyl)(heteroaryl), (C0-6alkyl)-C(O)- R7c, (C0-6 alkyl)-C(O)O-R7c, (C0-6 alkyl)-C(O)-N(R7c)(R7d), (C0-6 alkyl)-S(O)R7c, (C0- 6 alkyl)-S(O)(NH)R7c, (C0-6 alkyl)-S(O)2R7c, (C0-6 alkyl)-S(O)2N(R7c)(R7d), or (C0-6 alkyl)- S(O)(NR7c)R7d, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0, 1, 2, or 3 R7e; or R7a1and R7a2taken together with the atoms to which they are attached form a heterocyclyl, which is substituted with 0, 1, 2, or 3 R7e; R8is H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C2-6alkoxyalkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6 aminoalkyl, (C2-6 alkyl)-N(R8a)C(O)-(R8b), (C2-6 alkyl)-N(R8a)C(O)(OR8b), (C2- 6 alkyl)-N(R8a)S(O)2R8b, (C0-6 alkyl)(C3-8 cycloalkyl), (C0-6 alkyl)(heterocyclyl), (C0- 6 alkyl)(C6-10aryl), (C0-6alkyl)(heteroaryl), (C0-6alkyl)-C(O)-R8a, (C0-6alkyl)-C(O)O-R8a, (C0-6 alkyl)-C(O)-N(R8a)(R8b), (C0-6 alkyl)-S(O)R8a, (C0-6 alkyl)-S(O)(NH)R8a, (C0-6 alkyl)- S(O)2R8a, (C0-6 alkyl)-S(O)2N(R8a)(R8b), or (C0-6 alkyl)-S(O)(NR8a)R8b, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0, 1, 2, or 3 R8c; each R7eand R8cis independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-6 alkoxyalkyl, C1- 6 haloalkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, C3-8 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, (C0-6alkyl)-C(O)-R9a, (C0-6alkyl)-C(O)O-R9a, (C0-6alkyl)-C(O)-N(R9a)(R9b), (C0-6alkyl)-S(O)R9a, -S(O)(NH)R9a, -S(O)2R9a, -S(O)2N(R9a)(R9b), or -S(O)(NR9a)R9b; each R7c, R7d, R8a, R8b, R9a, and R9bis independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2- 6 alkoxyalkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, (C0-6 alkyl)(C3-8 cycloalkyl), (C0-6alkyl)(heterocyclyl), (C0-6alkyl)(C6-10aryl), or (C0-6alkyl)(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0 to 4 Z1; each Z1is independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C2-6alkoxyalkyl, C1-6haloalkyl, C3-8 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, halogen, oxo, -OH, -CN, -NO2, -NH2, - N3, -SH, -O(C1-6 alkyl), -O(C1-6 haloalkyl), -NH(C1-6 alkyl), -NH(C1-6 haloalkyl), -N(C1-6 alkyl)2, -N(C1-6haloalkyl)2, -N(C1-6alkyl)(C1-6haloalkyl), -C(O)(C1-6alkyl), -C(O)(C1-6haloalkyl), -C(O)O(C1-6alkyl), -C(O)O(C1-6haloalkyl), -C(O)NH2, -C(O)NH(C1-6alkyl), -C(O)NH(C1-6haloalkyl), -C(O)N(C1-6alkyl)2, -C(O)N(C1-6haloalkyl)2, -NHC(O)(C1-6 alkyl), -NHC(O)(C1-6 haloalkyl), -NHC(O)O(C1-6 alkyl), -NHC(O)O(C1-6 haloalkyl), -NHC(O)NH(C1-6 alkyl), -NHC(O)NH(C1-6 haloalkyl), -NHS(O)(C1-6alkyl), -N(C1-6alkyl)(S(O)(C1-6alkyl), -S(C1-6alkyl), -S(C1-6haloalkyl), -S(O)N(C1-6 alkyl)2, -S(O)(C1-6 alkyl), -S(O)(C1-6 haloalkyl), -S(O)2(C1-6 alkyl), -S(O)2(C1-6 haloalkyl), -S(O)(NH)(C1-6 alkyl), -S(O)2NH(C1-6 alkyl), or -S(O)2N(C1-6alkyl)2; each heterocyclyl is a 4- to 10-membered ring having 1, 2, 3, or 4 heteroatoms selected from N, O, and S; and each heteroaryl is a 5- to 10-membered ring having 1, 2, 3, or 4 heteroatoms selected from N, O, and S.

[0037] In some embodiments, the compound of the present disclosure is a compound of Formula I: , or a pharmaceuticallywhereineach R1 and R2 is independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, (C0-6 alkyl)(C3-8 cycloalkyl), (C0-6 alkyl)(heterocyclyl), (C0-6 alkyl)(C6-10 aryl), (C0-6 alkyl)(heteroaryl), halogen, ORa, SRa, NRaRb, NO2, or CN, wherein the alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0, 1, 2, or 3 R1a; or R1and R2taken together with the carbon atoms to which they are attached form a C5-10 cycloalkyl, heterocyclyl, C6-10aryl, or heteroaryl ring each substituted with 0, 1, 2, or 3 R1b;each R1aand R1bis independently ORa, SRa, NRaRb, oxo, NO2, or CN;each Ra and Rb is independently H or C1-6 alkyl;each R3a, R3b, R4a, R4b, R5a, R5b, R6a, and R6bis independently H, C1-6 alkyl, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6aminoalkyl; or two of R3a, R3b, R4a, R4b, R5a, R5b, R6a, and R6btaken together with the atoms to which they are attached form a C3-8 cycloalkyl or a heterocyclyl; X is –C(R7a)(R7b)-, -N(R8)-, -O-, or –S-; R7ais (C0-6 alkyl)-N(R7a1)(R7a2), (C0-6 alkyl)-OR7a1, or (C0-6 alkyl)-SR7a1; R7bis H or C1-6 alkyl; or R7aand R7btaken together form an oxo; each R7a1and R7a2is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C2-6alkoxyalkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, (C2-6 alkyl)-N(R7c)C(O)-(R7d), (C2- 6 alkyl)-N(R7c)C(O)(OR7d), (C2-6 alkyl)-N(R7c)S(O)2R7d, (C0-6 alkyl)(C3-8 cycloalkyl), (C0- 6 alkyl)(heterocyclyl), (C0-6alkyl)(C6-10aryl), (C0-6alkyl)(heteroaryl), (C0-6alkyl)-C(O)- R7c, (C0-6 alkyl)-C(O)O-R7c, (C0-6 alkyl)-C(O)-N(R7c)(R7d), (C0-6 alkyl)-S(O)R7c, (C0- 6 alkyl)-S(O)(NH)R7c, (C0-6 alkyl)-S(O)2R7c, (C0-6 alkyl)-S(O)2N(R7c)(R7d), or (C0-6 alkyl)- S(O)(NR7c)R7d, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0, 1, 2, or 3 R7e; or R7a1and R7a2taken together with the atoms to which they are attached form a heterocyclyl, which is substituted with 0, 1, 2, or 3 R7e; R8is H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C2-6alkoxyalkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6 aminoalkyl, (C2-6 alkyl)-N(R8a)C(O)-(R8b), (C2-6 alkyl)-N(R8a)C(O)(OR8b), (C2- 6 alkyl)-N(R8a)S(O)2R8b, (C0-6 alkyl)(C3-8 cycloalkyl), (C0-6 alkyl)(heterocyclyl), (C0- 6 alkyl)(C6-10aryl), (C0-6alkyl)(heteroaryl), (C0-6alkyl)-C(O)-R8a, (C0-6alkyl)-C(O)O-R8a, (C0-6 alkyl)-C(O)-N(R8a)(R8b), (C0-6 alkyl)-S(O)R8a, (C0-6 alkyl)-S(O)(NH)R8a, (C0-6 alkyl)- S(O)2R8a, (C0-6 alkyl)-S(O)2N(R8a)(R8b), or (C0-6 alkyl)-S(O)(NR8a)R8b, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0, 1, 2, or 3 R8c; each R7eand R8cis independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-6 alkoxyalkyl, C1- 6 haloalkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, C3-8 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, (C0-6alkyl)-C(O)-R9a, (C0-6alkyl)-C(O)O-R9a, (C0-6alkyl)-C(O)-N(R9a)(R9b), (C0-6alkyl)-S(O)R9a, -S(O)(NH)R9a, -S(O)2R9a, -S(O)2N(R9a)(R9b), or -S(O)(NR9a)R9b;each R7c, R7d, R8a, R8b, R9a, and R9bis independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C2-6 alkoxyalkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, (C0-6 alkyl)(C3-8 cycloalkyl), (C0-6 alkyl)(heterocyclyl), (C0-6 alkyl)(C6-10 aryl), or (C0-6 alkyl)(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0 to 4 Z1; each Z1is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-6 alkoxyalkyl, C1-6 haloalkyl, C3- 8 cycloalkyl, heterocyclyl, C6-10aryl, heteroaryl, halogen, oxo, -OH, -CN, -NO2, -NH2, - N3, -SH, -O(C1-6 alkyl), -O(C1-6 haloalkyl), -NH(C1-6 alkyl), -NH(C1-6 haloalkyl), -N(C1-6 alkyl)2, -N(C1-6 haloalkyl)2, -N(C1-6 alkyl)(C1-6 haloalkyl), -C(O)(C1-6 alkyl), -C(O)(C1-6 haloalkyl), -C(O)O(C1-6alkyl), -C(O)O(C1-6haloalkyl), -C(O)NH2, -C(O)NH(C1-6alkyl), -C(O)NH(C1-6haloalkyl), -C(O)N(C1-6alkyl)2, -C(O)N(C1-6haloalkyl)2, -NHC(O)(C1-6 alkyl), -NHC(O)(C1-6 haloalkyl), -NHC(O)O(C1-6 alkyl), -NHC(O)O(C1-6 haloalkyl), -NHC(O)NH(C1-6 alkyl), -NHC(O)NH(C1-6 haloalkyl), -NHS(O)(C1-6alkyl), -N(C1-6alkyl)(S(O)(C1-6alkyl), -S(C1-6alkyl), -S(C1-6haloalkyl), -S(O)N(C1-6 alkyl)2, -S(O)(C1-6 alkyl), -S(O)(C1-6 haloalkyl), -S(O)2(C1-6 alkyl), -S(O)2(C1-6 haloalkyl), -S(O)(NH)(C1-6 alkyl), -S(O)2NH(C1-6 alkyl), or -S(O)2N(C1-6alkyl)2; each heterocyclyl is a 4- to 10-membered ring having 1, 2, 3, or 4 heteroatoms selected from N, O, and S; and each heteroaryl is a 5- to 10-membered ring having 1, 2, 3, or 4 heteroatoms selected from N, O, and S.

[0038] In some embodiments of the compound of the present disclosure or a pharmaceutically acceptable salt thereof, each R1is independently C1-6 alkyl, F, Cl, Br, I, ORa, SRa, NRaRb, or CN.

[0039] In some embodiments of the compound of the present disclosure or a pharmaceutically acceptable salt thereof, each R2is independently C1-6 alkyl, F, Cl, Br, I, ORa, SRa, NRaRb, or CN.

[0040] In some embodiments of the compound of the present disclosure or a pharmaceuticallyacceptable salt thereof, each R1 and R2 is independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl,C1-6 haloalkyl, wherein the alkyl, alkenyl, alkynyl, or haloalkyl is substituted with 0, 1, 2, or 3R1a. In some embodiments, each R1 and R2 is independently C1-6 alkyl. In some embodiments,each R1 and R2 is methyl.

[0041] In some embodiments of the compound of the present disclosure or a pharmaceutically acceptable salt thereof, each R1ais independently ORa, NRaRb, oxo, or CN.

[0042] In some embodiments of the compound of the present disclosure or a pharmaceutically acceptable salt thereof, each R1bis independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6 haloalkyl, halogen, or CN.

[0043] In some embodiments of the compound of the present disclosure or a pharmaceutically acceptable salt thereof, each Rais independently H or C1-3alkyl.

[0044] In some embodiments of the compound of the present disclosure or a pharmaceutically acceptable salt thereof, each Rbis independently H or C1-3 alkyl.

[0045] In some embodiments of the compound of the present disclosure or a pharmaceutically acceptable salt thereof, each R3a,R3b,R6a,and R6bis H.

[0046] In some embodiments, the compound of Formula J and / or I, or a pharmaceutically acceptable salt thereof, has the structure of Formula Ia: .

[0047] In someI, or a pharmaceutically acceptable salt thereof, has the structure of Formula Ib: O R4a,wherein n is 0, 1, 2, or 3.

[0048] In some embodiments of the compound of Formula J, I, Ia, and / or Ib, or a pharmaceutically acceptable salt thereof, each R4aand R4bis independently H or C1-6 alkyl. In some embodiments, one of R4aand R4bis H, and the other is methyl. In some embodiments, R4aand R4bare each H. In some embodiments, R4aand R4bare each methyl.

[0049] In some embodiments of the compound of Formula J, I, Ia, and / or Ib, or a pharmaceutically acceptable salt thereof, R4aand R4btaken together with the carbon to which they are attached form C3-8cycloalkyl or a heterocyclyl. In some embodiments, R4aand R4btaken together with the carbon to which they are attached form cyclohexyl. In some embodiments, R4aand R4btaken together with the carbon to which they are attached form tetrahydropyranyl.

[0050] In some embodiments of the compound of Formula J, I, Ia, and / or Ib, or a pharmaceutically acceptable salt thereof, each R5aand R5bis independently H or C1-6alkyl. In some embodiments, one of R5aand R5bis H, and the other is methyl. In some embodiments, R5aand R5bare each H. In some embodiments, R5aand R5bare each methyl.

[0051] In some embodiments of the compound of the present disclosure or a pharmaceutically acceptable salt thereof, each R3a, R3b, R4a, R4b, R5a, R5b, R6a, and R6bis H.

[0052] In some embodiments, the compound of Formula J , I, and / or Ia, or a pharmaceutically acceptable salt thereof, has the structure of Formula II: .

[0053] In some embodimentsdisclosure or a pharmaceutically acceptable salt thereof, R1and R2taken together with the carbon atoms to which they are attached form C6-10 aryl or heteroaryl ring substituted with 0, 1, 2, or 3 R1b.

[0054] In some embodiments, the compound of Formula J , I, and / or Ib, or a pharmaceutically acceptable salt thereof, has the structure of Formula III:I), wherein n is 0, 1, 2,

[0055] In some embodiments of the compound of the present disclosure or a pharmaceutically acceptable salt thereof, n is 1, 2, or 3. In some embodiments, n is 3. In some embodiments, n is 2. In some embodiments, n is 0 or 1. In some embodiments, n is 1. In some embodiments, n is 0.

[0056] In some embodiments of the compound of the present disclosure, e.g., the compound of Formula J , I, Ia, Ib, and / or III, or a pharmaceutically acceptable salt thereof, each R1bis independently halogen or ORa. In some embodiments, each R1bis independently halogen. In some embodiments, each R1bis Br. In some embodiments, each R1bis independently ORa. In some embodiments, each R1bis OMe.

[0057] In some embodiments of the compound of the present disclosure or a pharmaceutically acceptable salt thereof, X is –C(R7a)(R7b)- or -N(R8)-. In some embodiments, X is –C(R7a)(R7b)- . In some embodiments, X is -N(R8)-.

[0058] In some embodiments of the compound of the present disclosure or a pharmaceutically acceptable salt thereof, R7ais -N(R7a1)(R7a2); and R7bis H.

[0059] In some embodiments of the compound of the present disclosure or a pharmaceutically acceptable salt thereof, each R7a1and R7a2is independently H, C1-6alkyl, C2-6alkoxyalkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, (C2-6 alkyl)-N(R7c)C(O)-(R7d), (C2- 6 alkyl)-N(R7c)C(O)(OR7d), (C2-6 alkyl)-N(R7c)S(O)2R7d, (C0-6 alkyl)(C3-8 cycloalkyl), (C0-6alkyl)(heterocyclyl), (C0-6alkyl)(C6-10aryl), (C0-6alkyl)(heteroaryl), (C0-6alkyl)-C(O)-R7c, (C0-6 alkyl)-C(O)O-R7c, (C0-6 alkyl)-C(O)-N(R7c)(R7d), (C0-6 alkyl)-S(O)R7c, (C0-6 alkyl)- S(O)(NH)R7c, (C0-6 alkyl)-S(O)2R7c, (C0-6 alkyl)-S(O)2N(R7c)(R7d), or (C0-6 alkyl)-S(O)(NR7c)R7d, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0, 1, or 2 R7e.

[0060] In some embodiments of the compound of the present disclosure or a pharmaceutically acceptable salt thereof, each R7a1and R7a2is independently H, C1-6 alkyl, C2-6 alkoxyalkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6aminoalkyl, (C2-6alkyl)-N(R7c)C(O)-(R7d), (C2-6 alkyl)-N(R7c)C(O)(OR7d), (C2-6 alkyl)-N(R7c)S(O)2R7d, (C0-6 alkyl)(C3-8 cycloalkyl), (C0- 6 alkyl)(heterocyclyl), (C0-6 alkyl)(C6-10 aryl), (C0-6 alkyl)(heteroaryl), (C0-6 alkyl)-C(O)-R7c, (C0-6alkyl)-C(O)O-R7c, (C0-6alkyl)-C(O)-N(R7c)(R7d), (C0-6alkyl)-S(O)R7c, (C0-6alkyl)- S(O)(NH)R7c, (C0-6 alkyl)-S(O)2R7c, (C0-6 alkyl)-S(O)2N(R7c)(R7d), or (C0-6 alkyl)-S(O)(NR7c)R7d. In some embodiments, each R7a1and R7a2is independently H, C1-3 alkyl, C2-3 alkoxyalkyl, C1-3haloalkyl, C1-3hydroxyalkyl, C1-3aminoalkyl, (C2-3alkyl)-N(R7c)C(O)-(R7d), (C2-3 alkyl)-N(R7c)C(O)(OR7d), (C2-3 alkyl)-N(R7c)S(O)2R7d, (C0-3 alkyl)(C3-8 cycloalkyl), (C0- 3 alkyl)(heterocyclyl), (C0-3 alkyl)(C6 aryl), (C0-3 alkyl)(heteroaryl), (C0-3 alkyl)-C(O)-R7c, (C0-3alkyl)-C(O)O-R7c, (C0-3alkyl)-C(O)-N(R7c)(R7d), (C0-3alkyl)-S(O)R7c, (C0-3alkyl)- S(O)(NH)R7c, (C0-3alkyl)-S(O)2R7c, (C0-3alkyl)-S(O)2N(R7c)(R7d), or (C0-3alkyl)-S(O)(NR7c)R7d. In some embodiments, each R7a1and R7a2is independently H, C1-3 alkyl, C2-3 alkoxyalkyl, C1- 3 haloalkyl, C1-3 hydroxyalkyl, C1-3 aminoalkyl, (C2-3 alkyl)-N(R7c)C(O)-(R7d), (C2-3alkyl)-N(R7c)C(O)(OR7d), (C2-3alkyl)-N(R7c)S(O)2R7d, C3-8cycloalkyl, heterocyclyl, phenyl, heteroaryl, -C(O)-R7c, -C(O)O-R7c, -C(O)-N(R7c)(R7d), -S(O)R7c, -S(O)(NH)R7c, -S(O)2R7c, -S(O)2N(R7c)(R7d), or -S(O)(NR7c)R7d.

[0061] In some embodiments of the compound of the present disclosure or a pharmaceutically acceptable salt thereof, R7a1and R7a2taken together with the atoms to which they are attached form a heterocyclyl, which is substituted with 0, 1, 2, or 3 R7e.

[0062] In some embodiments of the compound of the present disclosure or pharmaceutically acceptable salt thereof, each R7eis independently C1-6alkyl, C2-6alkoxyalkyl, C1-6haloalkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, C3-8 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, (C0-3 alkyl)- C(O)-R9a, (C0-3 alkyl)-C(O)O-R9a, (C0-3 alkyl)-C(O)-N(R9a)(R9b), (C0-3 alkyl)-S(O)R9a, - S(O)(NH)R9a, -S(O)2R9a, -S(O)2N(R9a)(R9b), or -S(O)(NR9a)R9b.

[0063] In some embodiments of the compound of the present disclosure, e.g., a compound of Formula J, I, Ia, and / or Ib, or a pharmaceutically acceptable salt thereof, R8is H, C1-6 alkyl, C2-6alkoxyalkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6aminoalkyl, (C2-6alkyl)-N(R8a)C(O)-(R8b), (C2-6 alkyl)-N(R8a)C(O)(OR8b), (C2-6 alkyl)-N(R8a)S(O)2R8b, (C0-6 alkyl)(C3-8 cycloalkyl), (C0- 6 alkyl)(heterocyclyl), (C0-6 alkyl)(C6-10 aryl), (C0-6 alkyl)(heteroaryl), (C0-6 alkyl)-C(O)-R8a, (C0-6alkyl)-C(O)O-R8a, (C0-6alkyl)-C(O)-N(R8a)(R8b), (C0-6alkyl)-S(O)R8a, (C0-6alkyl)-S(O)(NH)R8a,(C0-6alkyl)-S(O)2R8a, (C0-6alkyl)-S(O)2N(R8a)(R8b), or (C0-6alkyl)-S(O)(NR8a)R8b, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0, 1, or 2 R8c.

[0064] In some embodiments of the compound of the present disclosure or a pharmaceutically acceptable salt thereof, each R8cis independently C1-6alkyl, C2-6alkoxyalkyl, C1-6haloalkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, C3-8 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, (C0-6 alkyl)- C(O)-R9a, (C0-6 alkyl)-C(O)O-R9a, (C0-6 alkyl)-C(O)-N(R9a)(R9b), (C0-6 alkyl)-S(O)R9a, - S(O)(NH)R9a, -S(O)2R9a, -S(O)2N(R9a)(R9b), or -S(O)(NR9a)R9b.

[0065] In some embodiments of the compound of the present disclosure, e.g., a compound of Formula J, I, Ia, Ib, II, and / or III, or a pharmaceutically acceptable salt thereof, R8is H, C1-6alkyl, C2-6alkoxyalkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6aminoalkyl, (C2-6alkyl)-N(R8a)C(O)-(R8b), (C2-6alkyl)-N(R8a)C(O)(OR8b), (C2-6alkyl)-N(R8a)S(O)2R8b, (C0-6 alkyl)(C3-8 cycloalkyl), (C0-6 alkyl)(heterocyclyl), (C0-6 alkyl)(C6-10 aryl), (C0- 6 alkyl)(heteroaryl), (C0-6 alkyl)-C(O)-R8a, (C0-6 alkyl)-C(O)O-R8a, (C0-6 alkyl)-C(O)-N(R8a)(R8b), (C0-6alkyl)-S(O)R8a, (C0-6alkyl)-S(O)(NH)R8a, (C0-6alkyl)-S(O)2R8a, (C0-6 alkyl)-S(O)2N(R8a)(R8b), or (C0-6 alkyl)-S(O)(NR8a)R8b. In some embodiments, R8is H, C1- 3 alkyl, C2-3 alkoxyalkyl, C1-3 haloalkyl, C1-3 hydroxyalkyl, C1-3 aminoalkyl, (C2-3alkyl)-N(R8a)C(O)-(R8b), (C2-3alkyl)-N(R8a)C(O)(OR8b), (C2-3alkyl)-N(R8a)S(O)2R8b, (C0-3alkyl)(C3-6cycloalkyl), (C0-3alkyl)(heterocyclyl), (C0-3alkyl)(C6aryl), (C0-3alkyl)(heteroaryl), (C0-3 alkyl)-C(O)-R8a, (C0-3 alkyl)-C(O)O-R8a, (C0-3 alkyl)-C(O)-N(R8a)(R8b), (C0-3 alkyl)-S(O)R8a, (C0-3alkyl)-S(O)(NH)R8a, (C0-3alkyl)-S(O)2R8a, (C0-3alkyl)-S(O)2N(R8a)(R8b), or (C0-3alkyl)- S(O)(NR8a)R8b. In some embodiments, R8is H, C1-3alkyl, C2-3alkoxyalkyl, C1-3haloalkyl, C1-3 hydroxyalkyl, C1-3 aminoalkyl, (C2-3 alkyl)-N(R8a)C(O)-(R8b), (C2-3 alkyl)-N(R8a)C(O)(OR8b), (C2-3 alkyl)-N(R8a)S(O)2R8b, C3-6 cycloalkyl, heterocyclyl, phenyl, heteroaryl, -C(O)-R8a, -C(O)O- R8a, -C(O)-N(R8a)(R8b), -S(O)R8a, -S(O)(NH)R8a, -S(O)2R8a, -S(O)2N(R8a)(R8b), or -S(O)(NR8a)R8b.

[0066] In some embodiments of the compound of the present disclosure or a pharmaceutically acceptable salt thereof, each R7c, R7d, R8a, R8b, R9a, and R9bis independently H, C1-6alkyl, C2-6 alkoxyalkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, (C0-6 alkyl)(C3-8 cycloalkyl), (C0-6 alkyl)(heterocyclyl), (C0-6 alkyl)(C6-10 aryl), or (C0-6 alkyl)(heteroaryl), wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0 to 4 Z1. In some embodiments ofthe compound of the present disclosure or a pharmaceutically acceptable salt thereof, each R7c, R7d, R8a, R8b, R9a, and R9bis independently H, C1-6 alkyl, C2-6 alkoxyalkyl, C1-6 haloalkyl, C1- 6 hydroxyalkyl, C1-6 aminoalkyl, (C0-6 alkyl)(C3-8 cycloalkyl), (C0-6 alkyl)(heterocyclyl), (C0-6alkyl)(C6-10aryl), or (C0-6alkyl)(heteroaryl). In some embodiments of the compound of the present disclosure or a pharmaceutically acceptable salt thereof, each R7c, R7d, R8a, R8b, R9a, and R9bis independently H, C1-3 alkyl, C2-3 alkoxyalkyl, C1-3 haloalkyl, C1-3 hydroxyalkyl, C1-3aminoalkyl, (C0-3alkyl)(C3-6cycloalkyl), (C0-3alkyl)(heterocyclyl), (C0-3alkyl)(C6aryl), or (C0-3 alkyl)(heteroaryl).

[0067] In some embodiments of the compound of the present disclosure or a pharmaceutically acceptable salt thereof, R7ais NH2, N(CH2CH3)2, NHCH(CH3)2, NHCH2CH2OCH3, NHCH2CH2F, NHCH2CH2OH, NHCH2CH2CF3, NHCH2CH2Ph, ,

[0068] In some embodiments of the compound of the present disclosure, e.g., a compound of Formula J, I, Ia, Ib, II, and / or III, or a pharmaceutically acceptable salt thereof, R8is H, CH3, CH2CH3, CH(CH3)2, CH(CH2CH3)2, CH2CH2OCH3, CH2CH2F, CH2CH2OH, CH2CH2CF3, CH2CH2N(CH3)2, CH2CH2CH2NHCH3, CH2CH2CH2N(CH3)2, CH2CH2CH2N(CH3)C(O)(C(CH3)3), cyclopentyl, CH2CH2Ph, or

[0069] In some embodiments of the compound of the present disclosure or a pharmaceutically acceptable salt thereof, R8is H, CH3, CH2CH3, CH(CH3)2, CH(CH2CH3)2, CH2CH2OCH3, CH2CH2F, CH2CH2OH, CH2CH2CF3, CH2CH2N(CH3)2, CH2CH2CH2NHCH3, CH2CH2CH2N(CH3)2, CH2CH2CH2N(CH3)C(O)(C(CH3)3), cyclopentyl, CH2CH2Ph, ,

[0070] In some embodiments of the compound of the present disclosure or a pharmaceutically acceptable salt thereof, the heterocyclyl has 1, 2, or 3 atoms selected from N, O, and S.

[0071] In some embodiments of the compound of the present disclosure or a pharmaceutically acceptable salt thereof, the heteroaryl has 1, 2, or 3 atoms selected from N, O, and S.

[0072] In some embodiments of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, e.g., a compound of Formula J, I, Ia, Ib, II, and / or III, the compound has a structure as shown in Table 1 or Table 2. Table 1. Compounds Compound Structure / NameCompound Structure / Name2Compound Structure / Name8Compound Structure / Name8-(isopropylamino)-78910-tetrahydro-5H-cyclohepta[b]naphthalene-511(6H)- e-Compound Structure / Name19 -Compound Structure / Name23 -Compound Structure / Name28Compound Structure / Name34 eCompound Structure / NameN-(511-dioxo-67891011-hexahydro-5H-cyclohepta[b]naphthalen-8- -Compound Structure / Name45Compound Structure / Name50 c -Compound Structure / Name55Compound Structure / Name60Compound Structure / Name66 - -Compound Structure / Name71 -Compound Structure / Name76 '-Compound Structure / Name82 e e-Compound Structure / Name89-dibromo-3-(2-hydroxyethyl)-2345-tetrahydro-1H-naphtho[23-d]azepine- -Compound Structure / Name710-dimethoxy-2345-tetrahydro-1H-naphtho[23-d]azepine-611-dioneTable 2. Compounds Compound Structure / NameCompound Structure / Nametert-butyl 78-dimethyl-69-dioxo-124569-hexahydro-3H-benzo[d]azepine-3-Compound Structure / Name210Compound Structure / Name215 n-Compound Structure / Name220Compound Structure / Name225Compound Structure / Name230 OCompound Structure / Name78-dimethyl-12'33'455'6'-octahydrospiro[benzo[d]azepine-24'-pyran]-69-, ne or more stereocenters. Stereoisomers include enantiomers and diastereomers. The compounds may exist in stereoisomeric form if they possess one or more asymmetric centers or a double bond with asymmetric substitution and, therefore, can be produced as individual stereoisomers or as mixtures. Unless otherwise indicated, the description is intended to include individual stereoisomers as well as mixtures. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see, e.g., Chapter 4 of Advanced Organic Chemistry, 4th ed., J. March, John Wiley and Sons, New York, 1992).

[0074] The present invention also includes tautomers of compounds of the disclosure, e.g., a compound of Formula J. As known in the art, a tautomer refers to an alternate form of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a ring atom attached to both a ring -NH- and a ring =N- such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.

[0075] The compounds described herein may be prepared and / or formulated as pharmaceutically acceptable salts or when appropriate as a free base. Pharmaceutically acceptable salts are non-toxic salts of a free base form of a compound that possess the desired pharmacological activity of the free base. These salts may be derived from inorganic or organic acids or bases. For example, a compound that contains a basic nitrogen may be prepared as a pharmaceutically acceptable salt by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6- dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates,methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates, besylates, xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, and mandelates. Lists of other suitable pharmaceutically acceptable salts are found in Remington: The Science and Practice of Pharmacy, 21stEdition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.

[0076] Examples of pharmaceutically acceptable salts of the compounds disclosed herein also include salts derived from an appropriate base, such as an alkali metal (for example, sodium, potassium), an alkaline earth metal (for example, magnesium), ammonium and NM4+(wherein M is C1^C4alkyl). Also included are base addition salts, such as sodium or potassium salts.

[0077] Provided are also compounds described herein or pharmaceutically acceptable salts, isomers, or a mixture thereof, in which from 1 to n hydrogen atoms attached to a carbon atom can be replaced by a deuterium atom or D, in which n is the number of hydrogen atoms in the molecule. As known in the art, the deuterium atom is a non-radioactive isotope of the hydrogen atom. Such compounds can increase resistance to metabolism, and thus can be useful for increasing the half-life of the compounds described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof when administered to a mammal. See, e.g., Foster, “DeuteriumIsotope Effects in Studies of Drug Metabolism,” TRENDS PHARMACOL. SCI., 5(12):524-527(1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0078] Examples of isotopes that can be incorporated into the disclosed compounds also include isotopes of hydrogen, 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. Substitution with positron emitting isotopes, such as11C,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of Formulas J, I, Ia, Ib, II, and III can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.

[0079] The compounds of the present disclosure, such as a compound of Formula J or pharmaceutically acceptable salt thereof, possess structural features that are believed to afford superior properties such as improved solubility, permeability, bioavailability, and / or toxicity, while retaining ferroptosis inhibiting activity, compared to known ferroptosis inhibitors. Standard techniques known in the art can be used to quantify properties of the compounds of the present disclosure.

[0080] The compounds of the present disclosure generally possess sufficient solubility to permit dissolution in biological media, such as blood or plasma. Kinetic solubility assays can be assessed by diluting a solution of the compound of the present disclosure prepared in DMSO into aqueous buffer, simulated intestinal fluid (SIF), or simulated gastric fluid (SGF). See, United States Pharmacopeia, USP40-NF35 (2017). In some embodiments, a compound of Formula J, or a pharmaceutically acceptable salt thereof, has a solubility of greater than about 5 µM, such as greater than about 10 µM, greater than about 20 µM, greater than about 30 µM, greater than about 40 µM, greater than about 50 µM, greater than about 100 µM, greater than about 200 µM, or greater than about 300 µM. In some embodiments, a compound of Formula J, or a pharmaceutically acceptable salt thereof, has a solubility of from about 5 µM to about 300 µM, such as from about 10 µM to about 200 µM or from about 20 µM to about 200 µM.

[0081] The compounds of the present disclosure, such as a compound of Formula J or pharmaceutically acceptable salt thereof, generally possess sufficient permeability to permit passive permeability across cell membranes in a biologically relevant timeframe. In vitro permeability assays known in the art, e.g., with Caco-2, MDR1-MDCK, MDCKII-MDR1, or MDCKII-BCRP cells, can assess compound permeability. For instance, a Caco-2 cell permeability assay is similar to the design of a P-gp substrate assay. The assay is conducted in a transwell plate, which can be thought of as a cup within a cup with a polarized monolayer of Caco-2 cells grown on a permeable membrane that separates the two compartments. This creates a basal section and an apical section on either side of the monolayer of cells. Test compound is added, either to the apical side or the basal side, and the efflux of the compound in either direction is measured. In some embodiments, an acceptable permeability value is a high apparent permeability coefficient (Papp) that indicates a substance can be easily transported across the Caco-2 monolayer and absorbed by the human body. In some embodiments, a compound ofFormula J, or a pharmaceutically acceptable salt thereof, has a permeability of from about 1 x 10-6cm / sec to about 100 x 10-6cm / sec, such as from about from about 1 x 10-6cm / sec to about 10 x 10-6cm / sec or from about from about 10 x 10-6cm / sec to about 100 x 10-6cm / sec.

[0082] An Ames test can test whether a given compound can cause mutations in DNA, thereby giving a convenient assay to estimate genotoxicity. The Ames Test is an in vitro genetic toxicology test designed to detect mutagenicity of chemicals by various mechanisms. The Ames Test detects bacterial reverse mutations.

[0083] An Ames test is performed by using different bacterial strains like Salmonella typhimurium / Escherichia coli to assure mutagenic capabilities. An Ames test mainly focuses on the induction of a new mutation to an already mutating gene that replaces the previous mutation providing a restoring effect to the gene function. Due to this newly induced mutation, the new mutant cells are formed without histidine forming colonies, so this test is also called the Reversion Assay / Test.

[0084] In some embodiments, the compound of the present disclosure, e.g., a compound of Formula J or pharmaceutically acceptable salt thereof, is not positive in an Ames test.IV. COMPOSITIONS

[0085] In some embodiments, the pharmaceutical composition of the present invention is a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt as described herein, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of Formula I or pharmaceutically acceptable salt as described herein, and a pharmaceutically acceptable excipient.

[0086] The compound can be administered by any useful route and means, such as by oral or parenteral (e.g., intravenous) administration. Therapeutically effective amounts of the compound may include from about 0.00001 mg / kg body weight per day to about 10 mg / kg body weight per day, such as from about 0.0001 mg / kg body weight per day to about 10 mg / kg body weight per day, or such as from about 0.001 mg / kg body weight per day to about 1 mg / kg body weight perday, or such as from about 0.01 mg / kg body weight per day to about 1 mg / kg body weight per day, or such as from about 0.05 mg / kg body weight per day to about 0.5 mg / kg body weight per day, or such as from about 0.3 mg to about 30 mg per day, or such as from about 30 mg to about 300 mg per day.

[0087] As understood in the art, the term “about” means approximately. In some embodiments, the term “about” when referring to a value includes the stated value + / - 10% of the stated value. For example, about 50% can include a range of from 45% to 55%, while about 20 molar equivalents can include a range of from 18 to 22 molar equivalents. Accordingly, in some embodiments, when referring to a range, “about” refers to each of the stated values + / - 10% of the stated value of each end of the range. For instance, a ratio of from about 1 to about 3 (weight / weight) can include a range of from 0.9 to 3.3. A. Formulation

[0088] For preparing pharmaceutical compositions from the compound or pharmaceutically acceptable salt of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, cachets, and dispersible granules. A solid carrier can be one or more substances, which may also act as diluents, binders, preservatives, disintegrating agents, or an encapsulating material. Details on techniques for formulation and administration are well described in the scientific and patent literature, see, e.g., the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton PA ("Remington's").

[0089] In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from 5% or 10% to 70% of the conjugates of the present invention.

[0090] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

[0091] Aqueous solutions suitable for oral use can be prepared by dissolving the compound or pharmaceutically acceptable salt of the present invention in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitol mono-oleate), or a condensation product of ethylene oxide with a partial ester derived from fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate). The aqueous suspension can also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, aspartame or saccharin. Formulations can be adjusted for osmolality.

[0092] Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

[0093] Oil suspensions can be formulated by suspending the compound or pharmaceutically acceptable salt of the present invention in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin; or a mixture of these. The oil suspensions can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents can be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose. These formulations can be preserved by the addition of an antioxidant such as ascorbic acid. As an example of an injectable oil vehicle, see Minto, J. Pharmacol. Exp. Ther. 281 :93-102, 1997. The pharmaceutical formulations of the invention can also be in the form of oil-in- water emulsions. The oily phase can be a vegetable oil or a mineral oil, described above,or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan mono-oleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan mono-oleate. The emulsion can also contain sweetening agents and flavoring agents, as in the formulation of syrups and elixirs. Such formulations can also contain a demulcent, a preservative, or a coloring agent.

[0094] The compositions of the present invention can also be delivered as microspheres for slow release in the body. For example, microspheres can be formulated for administration via intradermal injection of drug-containing microspheres, which slowly release subcutaneously (see Rao, J. Biomater Sci. Polym. Ed.7:623-645, 1995; as biodegradable and injectable gel formulations (see, e.g., Gao Pharm. Res.12:857-863, 1995); or, as microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol.49:669-674, 1997). Both transdermal and intradermal routes afford constant delivery for weeks or months.

[0095] In another embodiment, the compositions of the present invention can be formulated for parenteral administration into a body cavity. The formulations for administration will commonly comprise a solution of the compositions of the present invention dissolved in a pharmaceutically acceptable carrier. Among the acceptable vehicles and solvents that can be employed are water and Ringer's solution, an isotonic sodium chloride. In addition, sterile fixed oils can conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can likewise be used in the preparation of injectables. These solutions are sterile and generally free of undesirable matter. These formulations may be sterilized by conventional, well known sterilization techniques. The formulations may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. The concentration of the compositions of the present invention in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight, and the like, in accordance with the particular mode of administration selected and the patient's needs. For IV,intratumoral, or intravitreal administration, the formulation can be a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally-acceptable diluent or solvent, such as a solution of 1,3- butanediol.

[0096] In another embodiment, the formulations of the compositions of the present invention can be delivered by the use of liposomes which fuse with the cellular membrane or are endocytosed, i.e., by employing ligands attached to the liposome, or attached directly to the oligonucleotide, that bind to surface membrane protein receptors of the cell resulting in endocytosis. By using liposomes, particularly where the liposome surface carries ligands specific for target cells, or are otherwise preferentially directed to a specific organ, one can focus the delivery of the compositions of the present invention into the target cells in vivo. (See, e.g., Al- Muhammed, J. Microencapsul.13:293-306, 1996; Chonn, Curr. Opin. Biotechnol.6:698-708, 1995; Ostro, Am. J. Hosp. Pharm.46: 1576-1587, 1989).

[0097] Lipid-based drug delivery systems include lipid solutions, lipid emulsions, lipid dispersions, self-emulsifying drug delivery systems (SEDDS) and self-microemulsifying drug delivery systems (SMEDDS). In particular, SEDDS and SMEDDS are isotropic mixtures of lipids, surfactants and co-surfactants that can disperse spontaneously in aqueous media and form fine emulsions (SEDDS) or microemulsions (SMEDDS). Lipids useful in the formulations of the present invention include any natural or synthetic lipids including, but not limited to, sesame seed oil, olive oil, castor oil, peanut oil, fatty acid esters, glycerol esters, Labrafil®, Labrasol®, Cremophor®, Solutol®, Tween®, Capryol®, Capmul®, Captex®, and Peceol®. B. Administration

[0098] The compound or pharmaceutically acceptable salt and compositions of the present invention can be delivered by any suitable means, including oral, parenteral and topical methods.

[0099] A compound or composition of the present disclosure may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, atleast about 6 months, or at least about 12 months or longer. In one variation, the compound is administered on a daily or intermittent schedule for the duration of the individual’s life.

[0100] The dosage or dosing frequency of a compound or composition of the present disclosure may be adjusted over the course of the treatment, based on the judgment of the administering physician.

[0101] The compound or composition may be administered to an individual (e.g., a human) in an effective amount. In some embodiments, the compound is administered once daily.

[0102] The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the compounds and compositions of the present invention. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.

[0103] The compounds and compositions of the present invention can be co-administered with other agents. Co-administration includes administering the compound or composition of the present invention within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of the other agent. Co- administration also includes administering simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. Moreover, the compounds and compositions of the present invention can each be administered once a day, or two, three, or more times per day so as to provide the preferred dosage level per day.

[0104] In some embodiments, co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including the compounds and compositions of the present invention and any other agent. Alternatively, the various components can be formulated separately.

[0105] The compounds and compositions of the present invention, and any other agents, can be present in any suitable amount, and can depend on various factors including, but not limited to, weight and age of the subject, state of the disease, etc. Suitable dosage ranges include from about 0.1 mg to about 10,000 mg, or about 1 mg to about 1000 mg, or about 10 mg to about 750 mg, or about 25 mg to about 500 mg, or about 50 mg to about 250 mg. Suitable dosages alsoinclude about 1 mg, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1000 mg. The composition can also contain other compatible therapeutic agents. The compounds described herein can be used in combination with one another, with other active agents known to be useful in modulating ferroptosis, or with adjunctive agents that may not be effective alone, but may contribute to the efficacy of the active agent.V. METHODS AND / OR USESA. Methods of Reducing Expression and / or Activity

[0106] Ferroptosis is an iron-dependent form of cell death that occurs as a consequence of lipid reactive oxygen species (ROS) production. Cells undergoing ferroptosis exhibit subtle morphological features, including smaller-than-normal mitochondria with increased density. The presence of ferroptosis can be confirmed by looking at whether cell death is prevented byinhibitors, and by measuring lipid peroxides. Dysregulation of mitochondrial metabolism isconsidered a biochemical feature of diseases, such as neurodegenerative diseases, linked to ferroptosis. Accordingly, it is believed that certain mitochondrial diseases can be treated by inhibiting ferroptosis.

[0107] Cellular assays for measuring ferroptosis, such as those that use RAS-selective lethal (RSL) compounds, such as RSL3, to induce ferroptosis, are known in the art. See, e.g., Dixon, S. J. et al. Cell 2012, vol.149 (5), pages 1060-1072; Chen, X. et al. Frontiers in Cell and Development Biology January 2021, vol.9, article 637162; and references cited therein, as well as the biological assay described in Example 128 herein.

[0108] As described in Example 128 herein, compounds or compositions of the present disclosure, e.g., a compound of Formula I, are useful for inhibiting ferroptosis in a cell. Accordingly, in some embodiments, a method of inhibiting ferroptosis in a cell comprises administering to the cell an effective amount of a compound of the present disclosure or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. In some embodiments, the method comprises administering the compound of the present disclosure or pharmaceutically acceptable salt thereof in vitro, ex vivo, or in vivo.

[0109] The compounds or compositions of the present disclosure are believed to be useful for inhibiting ferroptosis in the treatment of mitochondrial diseases. Accordingly, in some embodiments, a method of treating a mitochondrial disease in a subject in need thereof comprises administering to the subject a therapeutically effective amount of a compound of the present disclosure or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0110] A ferroptosis inhibitor of the present disclosure may also be useful for inhibiting Miro1 and / or Miro2. Accordingly, in some embodiments, a method of the present disclosure is a method of reducing a Miro1 and / or Miro2 level in a cell, comprising contacting the cell with an effective amount of a compound of Formula J or pharmaceutically acceptable salt thereof.

[0111] In some embodiments, reduction of a Miro1 and / or Miro2 level in a method as described herein is a reduction in the amount of a Miro1 and / or Miro2 nucleic acid, e.g., RNA and / or DNA, and / or a reduction in the activity of a Miro1 and / or Miro2 protein. In some embodiments, the reduction of a Miro1 and / or Miro2 level is a reduction in the amount of a Miro1 and / or Miro2 DNA as determined by any assay method, including assays known in the art and the assays described in the present disclosure. In some embodiments, the reduction of a Miro1 and / or Miro2 level is a reduction in the amount of a Miro1 and / or Miro2 RNA as determined by any assay method, including assays known in the art and the assays described in the present disclosure.

[0112] In some embodiments, reduction of a Miro1 and / or Miro2 level in a method as described herein is a reduction in the amount of a Miro1 and / or Miro2 protein and / or a reduction in the activity of a Miro1 and / or Miro2 protein. In some embodiments, the reduction of a Miro1 and / or Miro2 level is a reduction in the amount of a Miro1 and / or Miro2 protein as determined by any assay method, including assays known in the art and the assays described in the present disclosure, that results in a reduction in the Miro1 and / or Miro2 activity.

[0113] Any suitable cell can be used in a method of reducing, or downregulating, Miro1 and / or Miro2 level described herein. Cultured cells may be derived from a subject (e.g., a patient) or control samples; and may be modified to generate genetically-modified cells, in vitro differentiated cells, cells exposed to a candidate therapeutic agent; and the like. In some embodiments, the cell is a skin cell. In some embodiments, the cell is a muscle cell. For example,the muscle cell can be a cardiac cell, that is, a cardiomyocyte. In some embodiments, the cell is a renal cell. In some embodiments, the cell is a liver cell. In some embodiments, the cell is a neuronal cell. The method can be performed in a cell in vitro, ex vivo, or in vivo. In some embodiments, the reducing Miro1 and / or Miro2 level is in vitro or ex vivo. In some embodiments, the reducing Miro1 and / or Miro2 level is in vivo.

[0114] Any suitable biological sample described herein, including urine, tissue, cerebrospinal fluid (CSF), or blood, can be used in the methods. In some embodiments, the biological sample and the control biological sample comprise fibroblasts. For example, skin fibroblasts can be directly obtained from the subject. In some embodiments, the biological sample and the control biological sample comprise iPSCs or cells differentiated from iPSCs.

[0115] iPSCs can be directly obtained from a subject or be cultured from other cell types obtained from a subject according to any method known in the art. See, Shi, Y. et al. Nature Reviews Drug Discovery vol.16, pages 115-130 (2017), and references cited therein. For example, iPSCs can be dedifferentiated from fibroblast cells that were directly obtained from a subject. Additionally, iPSCs can be redifferentiated into a variety of different cell types, including neuronal cells, glial cells, skin cells, blood cells, muscle cells, such as cardiac muscle cells, and liver cells.

[0116] Such cells differentiated from iPSCs of a subject can be used to determine a personalized therapy in a convenient manner without directly obtaining a target cell type directly from a subject. In an illustrative example, a skin fibroblast can be obtained from a subject at risk for developing Parkinson’s disease. The skin fibroblast can be dedifferentiated into iPSCs, which can then be redifferentiated into motor neurons. The motor neurons differentiated from iPSCs can be tested in an assay described herein for Miro1 deficit with and without treatment of a mitochondrial stressor in order to identify whether the subject may be responsive to a Miro1 and / or Miro2 reducing therapy, such as one containing a compound of the disclosure.

[0117] A Miro1 and / or Miro2 level measured in a method described herein can be compared to a control Miro1 and / or Miro2 level by any method known in the art. See, for example, the ELISA assay described in Hsieh C-H, et al. Cell Metab.2019; 1131–1140. See also, the Miro2 assays described in Cao, Y. et al. Circulation Research 2019; 125(8):728-743; Oeding, S. J. et alJournal of Cell Science 2018; 131(17): jcs219469; and Furnish, M. et al. Molecular Cancer Research 2022; 20(4): 607-621.

[0118] In some embodiments, a compound of the present disclosure, e.g., a compound of Formula J or pharmaceutically acceptable salt thereof, reduces the level of Miro1 and / or Miro2 to a normal range. For example, in some embodiments, a Miro1 and / or Miro2 normal range can be the range observed between untreated or naïve healthy fibroblast or iPSC dopaminergic (DA) neuron cells (top of the range) and mitochondrial stressor-challenged healthy fibroblast or iPSC DA neuron cells (bottom of the range).

[0119] Any mitochondrial stressor known in the art may be used in the methods described herein. Suitable mitochondrial stressors include mitochondrial depolarizing agents, such as carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP) and carbonyl cyanide 3- chlorophenylhydrazone (CCCP); mitochondrial electron transport chain inhibitors, including Complex I inhibitors, such as rotenone, piericidin A, 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP), and paraquat, Complex III inhibitors, such as antimycin A, Complex V inhibitors, such as oligomycin A, and mitochondrial membrane potassium ionophores, such as valinomycin; metabolic modulators, including modulators of insulin signaling, such as metformin, and inhibitors of mTOR master signaling pathway required for cell growth and metabolism, such as rapamycin. In some embodiments, the mitochondrial stressor comprises antimycin A or carbonyl cyanide 3-chlorophenylhydrazone (CCCP). In some embodiments, the mitochondrial stressor comprises carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP).

[0120] In some embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces, or downregulates, the level of Miro1 and / or Miro2 to within about 50%, about 40%, about 30%, or about 20% relative to a control level of Miro1 and / or Miro2. In some embodiments, the control level of Miro1 and / or Miro2 is measured in a control cell from a control subject that does not have or is not suspected of having a disease or disorder mediated by an aberrant Miro1 and / or Miro2 level. For example, a compound of Formula J or pharmaceutically acceptable salt thereof can downregulate the Miro1 and / or Miro2 level in a neuronal cell from a Parkinson’s disease patient to within about 50% relative to a control level ofMiro1 and / or Miro2 in a control neuronal cell from an age-matched patient that does not have or is not suspected of having Parkinson’s disease.

[0121] The level of Miro1 in a cell after contacting with the compound of Formula J or pharmaceutically acceptable salt thereof can be higher or lower than the control level of Miro1 in the control cell. In some embodiments, the level of Miro1 in a cell after contacting with the compound of Formula J or pharmaceutically acceptable salt thereof is about 20%, about 30%, about 40%, or about 50% higher than the control level of Miro1 in the control cell. In some embodiments, the level of Miro1 in a cell after contacting with the Compound of Formula J or pharmaceutically acceptable salt thereof is from about 20% to about 50% higher than the control level of Miro1 in the control cell. In some embodiments, the level of Miro1 in a cell after contacting with the compound of Formula J or pharmaceutically acceptable salt thereof is about 20%, about 30%, about 40%, or about 50% lower than the control level of Miro1 in the control cell. In some embodiments, the level of Miro1 in a cell after contacting with the Compound of Formula J or pharmaceutically acceptable salt thereofi s from about 20% to about 50% lower than the control level of Miro1 in the control cell.

[0122] Any suitable concentration of a compound of Formula J or pharmaceutically acceptable salt thereof in a cell can be used to effect reducing the Miro1 level in the cell to a desired level. In some embodiments, the concentration of Compound of Formula J or pharmaceutically acceptable salt thereof in the cell can be from about 1 nM to about 100 µM, such as from about 1 nM to about 10 µM, from about 1 nM to about 1 µM, from about 10 nM to about 100 µM, from about 10 nM to about 10 µM, from about 10 nM to about 1 µM, from about 100 nM to about 100 µM, from about 100 nM to about 10 µM, from about 100 nM to about 1 µM, from about 1 µM to about 100 µM, or from about 1 µM to about 10 µM.

[0123] In some embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro1 by about 20% or more, for example, about 30% or more, about 40% or more, or about 50% or more, about 60% or more, about 70% or more, or about 80% or more, e.g. about 90%, about 95%, or about 100%, relative to an untreated control not contacted with the compound of Formula J or pharmaceutically acceptable salt thereof. In some embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro1 by about 20% relative to an untreatedcontrol not contacted with the compound of Formula J or pharmaceutically acceptable salt thereof. In some embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro1 by about 25% relative to an untreated control not contacted with the compound of Formula J or pharmaceutically acceptable salt thereof. In some embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro1 by about 30% relative to an untreated control not contacted with the compound of Formula J or pharmaceutically acceptable salt thereof. In some embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro1 by about 35% relative to an untreated control not contacted with the compound of Formula J or pharmaceutically acceptable salt thereof. In some embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro1 by about 40% relative to an untreated control not contacted with the compound of Formula J or pharmaceutically acceptable salt thereof. In some embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro1 by about 45% relative to an untreated control not contacted with the compound of Formula J or pharmaceutically acceptable salt thereof. In some embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro1 by about 50% relative to an untreated control not contacted with the compound of Formula J or pharmaceutically acceptable salt thereof. In some embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro1 by about 55% relative to an untreated control not contacted with the compound of Formula J or pharmaceutically acceptable salt thereof. In some embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro1 by about 60% relative to an untreated control not contacted with the compound of Formula J or pharmaceutically acceptable salt thereof. In some embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro1 by about 70% relative to an untreated control not contacted with the Miro1 reducer and / or Miro1-reducing agent. In some embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro1 by about 80% relative to an untreated control not contacted with the compound of Formula J or pharmaceutically acceptable salt thereof. In someembodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro1 by about 90% relative to an untreated control not contacted with the compound of Formula J or pharmaceutically acceptable salt thereof. In some embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro1 by about 95% relative to an untreated control not contacted with the compound of Formula J or pharmaceutically acceptable salt thereof.

[0124] In some embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro1 by about 20% to about 100% relative to an untreated control not contacted with the Miro1 reducer and / or Miro1-reducing agent. In embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro1 by about 20% to about 90% relative to an untreated control not contacted with the Miro1 reducer and / or Miro1-reducing agent. In embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro1 by about 20% to about 80% relative to an untreated control not contacted with the Miro1 reducer and / or Miro1-reducing agent. In embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro1 by about 20% to about 70% relative to an untreated control not contacted with the Miro1 reducer and / or Miro1-reducing agent. In embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro1 by about 20% to about 60% relative to an untreated control not contacted with the Miro1 reducer and / or Miro1-reducing agent. In embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro1 by about 20% to about 50% relative to an untreated control not contacted with the Miro1 reducer and / or Miro1-reducing agent. In embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro1 by about 20% to about 40% relative to an untreated control not contacted with the Miro1 reducer and / or Miro1-reducing agent. In embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro1 by about 30% to about 50% relative to an untreated control not contacted with the Miro1 reducer and / or Miro1-reducing agent. In embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level orbiological activity of Miro1 by about 40% to about 60% relative to an untreated control not contacted with the Miro1 reducer and / or Miro1-reducing agent.

[0125] The level of Miro2 in a cell after contacting with the compound of Formula J or pharmaceutically acceptable salt thereof can be higher or lower than the control level of Miro2 in the control cell. In some embodiments, the level of Miro2 in a cell after contacting with the compound of Formula J or pharmaceutically acceptable salt thereof is about 20%, about 30%, about 40%, or about 50% higher than the control level of Miro2 in the control cell. In some embodiments, the level of Miro2 in a cell after contacting with the Compound of Formula J or pharmaceutically acceptable salt thereof is from about 20% to about 50% higher than the control level of Miro2 in the control cell. In some embodiments, the level of Miro2 in a cell after contacting with the Compound of Formula J or pharmaceutically acceptable salt thereof is about 20%, about 30%, about 40%, or about 50% lower than the control level of Miro2 in the control cell. In some embodiments, the level of Miro2 in a cell after contacting with the Compound of Formula J or pharmaceutically acceptable salt thereof is from about 20% to about 50% lower than the control level of Miro2 in the control cell.

[0126] Any suitable concentration of a compound of Formula J or pharmaceutically acceptable salt thereof in a cell can be used to effect reducing the Miro2 level in the cell to a desired level. In some embodiments, the concentration of compound of Formula J or pharmaceutically acceptable salt thereof in the cell can be from about 1 nM to about 100 µM, such as from about 1 nM to about 10 µM, from about 1 nM to about 1 µM, from about 10 nM to about 100 µM, from about 10 nM to about 10 µM, from about 10 nM to about 1 µM, from about 100 nM to about 100 µM, from about 100 nM to about 10 µM, from about 100 nM to about 1 µM, from about 1 µM to about 100 µM, or from about 1 µM to about 10 µM.

[0127] In some embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro2 by about 20% or more, for example, about 30% or more, about 40% or more, or about 50% or more, about 60% or more, about 70% or more, or about 80% or more, e.g. about 90%, about 95%, or about 100%, relative to an untreated control not contacted with the compound of Formula J or pharmaceutically acceptable salt thereof. In some embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro2 by about 20% relative to an untreatedcontrol not contacted with the compound of Formula J or pharmaceutically acceptable salt thereof. In some embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro2 by about 25% relative to an untreated control not contacted with the compound of Formula J or pharmaceutically acceptable salt thereof. In some embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro2 by about 30% relative to an untreated control not contacted with the compound of Formula J or pharmaceutically acceptable salt thereof. In some embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro2 by about 35% relative to an untreated control not contacted with the compound of Formula J or pharmaceutically acceptable salt thereof. In some embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro2 by about 40% relative to an untreated control not contacted with the compound of Formula J or pharmaceutically acceptable salt thereof. In some embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro2 by about 45% relative to an untreated control not contacted with the compound of Formula J or pharmaceutically acceptable salt thereof. In some embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro2 by about 50% relative to an untreated control not contacted with the compound of Formula J or pharmaceutically acceptable salt thereof. In some embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro2 by about 55% relative to an untreated control not contacted with the compound of Formula J or pharmaceutically acceptable salt thereof. In some embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro2 by about 60% relative to an untreated control not contacted with the compound of Formula J or pharmaceutically acceptable salt thereof. In some embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro2 by about 70% relative to an untreated control not contacted with the Miro2 reducer and / or Miro2-reducing agent. In some embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro2 by about 80% relative to an untreated control not contacted with the compound of Formula J or pharmaceutically acceptable salt thereof. In someembodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro2 by about 90% relative to an untreated control not contacted with the compound of Formula J or pharmaceutically acceptable salt thereof. In some embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro2 by about 95% relative to an untreated control not contacted with the compound of Formula J or pharmaceutically acceptable salt thereof.

[0128] In some embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro2 by about 20% to about 100% relative to an untreated control not contacted with the Miro2 reducer and / or Miro2-reducing agent. In embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro2 by about 20% to about 90% relative to an untreated control not contacted with the Miro2 reducer and / or Miro2-reducing agent. In embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro2 by about 20% to about 80% relative to an untreated control not contacted with the Miro2 reducer and / or Miro2-reducing agent. In embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro2 by about 20% to about 70% relative to an untreated control not contacted with the Miro2 reducer and / or Miro2-reducing agent. In embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro2 by about 20% to about 60% relative to an untreated control not contacted with the Miro2 reducer and / or Miro2-reducing agent. In embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro2 by about 20% to about 50% relative to an untreated control not contacted with the Miro2 reducer and / or Miro2-reducing agent. In embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro2 by about 20% to about 40% relative to an untreated control not contacted with the Miro2 reducer and / or Miro2-reducing agent. In embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro2 by about 30% to about 50% relative to an untreated control not contacted with the Miro2 reducer and / or Miro2-reducing agent. In embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level orbiological activity of Miro2 by about 40% to about 60% relative to an untreated control not contacted with the Miro2 reducer and / or Miro2-reducing agent.

[0129] In some embodiments, a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro1 and Miro2 as described above. B. Methods and / or Uses of Treatment with Compounds of Disclosure

[0130] The compounds of the present disclosure are capable of acting as ferroptosis inhibitors, and are believed to be useful for treatment of diseases or disorders associated with mitochondrial dysfunction.

[0131] In some embodiments, treatment refers to an approach for obtaining beneficial or desired results. For purposes of the present disclosure, beneficial or desired results include, but are not limited to, alleviation of a symptom and / or diminishment of the extent of a symptom and / or preventing a worsening of a symptom associated with a disease or condition. In one embodiment, treatment or treating includes one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and / or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, delaying the worsening or progression of the disease or condition); and c) relieving the disease or condition, e.g., causing the regression of clinical symptoms, ameliorating the disease state, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival.

[0132] Generally, a therapeutically effective amount refers to an amount that is effective to elicit the desired biological or medical response, including the amount of the compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The effective amount will vary depending on the compound, the disease, and its severity and the age, weight, etc., of the subject to be treated. The effective amount can include a range of amounts. As is understood in the art, an effective amount may be in one or more doses, i.e., 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, inconjunction with one or more other agents, a desirable or beneficial result may be or is achieved. Suitable doses of any co-administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.

[0133] The treatment can be in a subject in need thereof. In some embodiments, the subject is any mammal, such as a mouse, a rat, a dog, a cat, including veterinary animals, such as a goat, a pig, a horse, a cow, or a donkey, and primates, such as non-human primates, e.g., a cynomolgous monkey, rhesus monkey, or chimpanzee, as well as humans. In some embodiments, the subject is a human. In some embodiments, a subject is a patient.

[0134] Mitochondrial dysfunction contributes to various disease states. Some mitochondrial diseases are due to mutations or deletions in the mitochondrial genome. If a threshold proportion of mitochondria in the cell is defective, and if a threshold proportion of such cells within a tissue have defective mitochondria, symptoms of tissue or organ dysfunction can result. Practically any tissue can be affected, and a large variety of symptoms may be present, depending on the extent to which different tissues are involved. Some examples of mitochondrial diseases include Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, Friedreich's ataxia (FRDA), Leber's Hereditary Optic Neuropathy (LHON), mitochondrial myopathy, encephalopathy, lactacidosis, and stroke (MELAS), Myoclonus Epilepsy Associated with Ragged-Red Fibers (MERRF) syndrome, Maternally Inherited Diabetes and Deafness (MIDD), and respiratory chain disorders. Mitochondrial diseases can involve children who manifest the signs and symptoms of accelerated aging, including neurodegenerative diseases, stroke, blindness, hearing or balance impairment, diabetes, and heart failure. Accordingly, in some embodiments, the mitochondrial disease comprises a neurodegenerative disease.

[0135] Neurodegenerative diseases that are believed to benefit from treatment using a compound of the present disclosure include, but are not limited to, traumatic brain injury (TBI); spinal cord injury (SCI); stroke; Parkinson's Disease (PD); Parkinson’s Disease with Dementia (PDD); Lewy Body Disease (LBD); Alzheimer's Disease (AD); Huntington’s Disease (HD); spinocerebellar ataxia (SCA); amyotrophic lateral sclerosis (ALS); multiple systems atrophy (MSA); multiple sclerosis, including primary progressive multple sclerosis (PPMS), secondary progressive multiple sclerosis (SPMS), and relapsing remitting multple sclerosis (RRMS);frontotemporal dementia (FTD), of which there are many subtypes (progranulin, tau, C9ORF72, TDP43); Leigh's syndrome (LS); progressive Supranuclear Palsy (PSP); Friedreich's Ataxia (FA); mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS); macular degeneration (MD), including wet-type and dry-type MD; Leber's Hereditary Optic Neuropathy (LHON); PLA2G6-associated neurodegeneration (PLAN); infantile neuroaxonal dystrophy (INAD); and neurodegeneration with brain iron accumulation (NBIA).

[0136] Friedreich's ataxia is an autosomal recessive neurodegenerative and cardiodegenerative disorder caused by decreased levels of the protein Frataxin. The disease causes the progressive loss of voluntary motor coordination (ataxia) and cardiac complications. Symptoms typically begin in childhood, and the disease progressively worsens as the patient grows older; patients eventually become wheelchair-bound due to motor disabilities.

[0137] Leber's Hereditary Optic Neuropathy (LHON) is a disease characterized by blindness which occurs on average between 27 and 34 years of age. Other symptoms may also occur, such as cardiac abnormalities and neurological complications.

[0138] Mitochondrial myopathy, encephalopathy, lactacidosis, and stroke (MELAS) can manifest itself in infants, children, or young adults. Strokes, accompanied by vomiting and seizures, are one of the most serious symptoms; it is postulated that the metabolic impairment of mitochondria in certain areas of the brain is responsible for cell death and neurological lesions, rather than the impairment of blood flow as occurs in ischemic stroke.

[0139] Myoclonus Epilepsy Associated with Ragged-Red Fibers (MERRF) syndrome is one of a group of rare muscular disorders that are called mitochondrial encephalomyopathies. Mitochondrial encephalomyopathies are disorders in which a defect in the genetic material arises from a part of the cell structure that releases energy (mitochondria). This can cause a dysfunction of the brain and muscles (encephalomyopathies). The most characteristic symptom of MERRF syndrome is myoclonic seizures that are usually sudden, brief, jerking, spasms that can affect the limbs or the entire body, difficulty speaking (dysarthria), optic atrophy, short stature, hearing impairment, dementia, and involuntary jerking of the eyes (nystagmus) may also occur.

[0140] Leigh's disease is a rare inherited neurometabolic disorder characterized by degeneration of the central nervous system where the symptoms usually begin between the agesof 3 months to 2 years and progress rapidly. In most children, the first signs may be poor sucking ability and loss of head control and motor skills. These symptoms may be accompanied by loss of appetite, vomiting, irritability, continuous crying, and seizures. As the disorder progresses, symptoms may also include generalized weakness, lack of muscle tone, and episodes of lactic acidosis, which can lead to impairment of respiratory and kidney function. Heart problems may also occur.

[0141] Other diseases or disorders that are believed to benefit from treatment using a ferroptosis inhibitor of the present disclosure include, but are not limited to, asthma; allergy; chronic rhinosinusitis with nasal polyps (CRSwNP); myocardial ischemia-reperfusion injury; acute kidney injury; fatty liver disease, including alcohol-related liver disease (ARLD), non- alcoholic steatohepatitis (NASH), and non-alcoholic fatty liver disease (NAFLD); type 2 diabetes; osteoporosis; osteoarthritis; and radiation exposure.

[0142] Maternally Inherited Diabetes and Deafness (MIDD) is caused by a mutation in mitochondrial DNA (3243 tRNA). The diabetes is a non insulin dependent type that usually presents before the age of 40 years; it is due to a defect in beta cell function with normal insulin sensitivity. The associated deafness is sensorineural and develops in most of the diabetic subjects. In keeping with other mitochondrial disorders, MIDD may have other multi-organ features: for example, elevated serum lactate, neuromuscular and cardiac problems, pigmented retinopathy, and nephropathy with proteinuria.

[0143] Co-Enzyme Q10 Deficiency is a respiratory chain disorder, with syndromes such as myopathy with exercise intolerance and recurrent myoglobin in the urine manifested by ataxia, seizures or mental retardation and leading to renal failure, childhood-onset cerebellar ataxia and cerebellar atrophy; and infantile encephalomyopathy associated with nephrosis. Biochemical measurement of muscle homogenates of patients with CoQ10 deficiency showed severely decreased activities of respiratory chain complexes I and II+III, while complex IV (COX) was moderately decreased.

[0144] Complex I Deficiency or NADH dehydrogenase NADH-CoQ reductase deficiency is a respiratory chain disorder, with symptoms classified by three major forms: (1) fatal infantile multisystem disorder, characterized by developmental delay, muscle weakness, heart disease, congenital lactic acidosis, and respiratory failure; (2) myopathy beginning in childhood or inadult life, manifesting as exercise intolerance or weakness; and (3) mitochondrial encephalomyopathy (including MELAS), which may begin in childhood or adult life and consists of variable combinations of symptoms and signs, including ophthalmoplegia, seizures, dementia, ataxia, hearing impairment, pigmentary retinopathy, sensory neuropathy, and uncontrollable movements.

[0145] Complex II Deficiency or Succinate dehydrogenase deficiency is a respiratory chain disorder with symptoms including encephalomyopathy and various manifestations, including failure to thrive, developmental delay, hyoptonia, lethargy, respiratory failure, ataxia, myoclonus and lactic acidosis.

[0146] Complex III Deficiency or Ubiquinone-cytochrome C oxidoreductase deficiency is a respiratory chain disorder with symptoms categorized in four major forms: (1) fatal infantile encephalomyopathy, congenital lactic acidosis, hypotonia, dystrophic posturing, seizures, and coma; (2) encephalomyopathies of later onset (childhood to adult life): various combinations of weakness, short stature, ataxia, dementia, hearing impairment, sensory neuropathy, pigmentary retinopathy, and pyramidal signs; (3) myopathy, with exercise intolerance evolving into fixed weakness; and (4) infantile histiocytoid cardiomyopathy.

[0147] Complex IV Deficiency or Cytochrome C oxidase deficiency is a respiratory chain disorder with symptoms categorized in two major forms: (1) encephalomyopathy, which is typically normal for the first 6 to 12 months of life and then show developmental regression, ataxia, lactic acidosis, optic atrophy, ophthalmoplegia, nystagmus, dystonia, pyramidal signs, respiratory problems and frequent seizures; and (2) myopathy with two main variants: (a) fatal infantile myopathy—may begin soon after birth and accompanied by hypotonia, weakness, lactic acidosis, ragged-red fibers, respiratory failure, and kidney problems: and (b) benign infantile myopathy—may begin soon after birth and accompanied by hypotonia, weakness, lactic acidosis, ragged-red fibers, respiratory problems, but (if the child survives) followed by spontaneous improvement.

[0148] Complex V Deficiency or ATP synthase deficiency is a respiratory chain disorder including symptoms such as slow, progressive myopathy.

[0149] CPEO or Chronic Progressive External Ophthalmoplegia Syndrome is a respiratory chain disorder including symptoms such as visual myopathy, retinitis pigmentosa, or dysfunction of the central nervous system.

[0150] Kearns-Sayre Syndrome (KSS) is a mitochondrial disease characterized by a triad of features including: (1) typical onset in persons younger than age 20 years; (2) chronic, progressive, external ophthalmoplegia; and (3) pigmentary degeneration of the retina. In addition, KSS may include cardiac conduction defects, cerebellar ataxia, and raised cerebrospinal fluid (CSF) protein levels (e.g., >100 mg / dL). Additional features associated with KSS may include myopathy, dystonia, endocrine abnormalities (e.g., diabetes, growth retardation or short stature, and hypoparathyroidism), bilateral sensorineural deafness, dementia, cataracts, and proximal renal tubular acidosis.

[0151] In addition to congenital disorders involving inherited defective mitochondria, acquired mitochondrial dysfunction contributes to diseases, particularly neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), or Huntington's disease. The incidence of somatic mutations in mitochondrial DNA rises exponentially with age; diminished respiratory chain activity is found universally in aging people. Mitochondrial dysfunction is also implicated in excitoxic, neuronal injury, such as that associated with cerebral vascular accidents, seizures and ischemia.

[0152] Parkinson’s disease has been associated with mitochondrial dysfunction since 1983, when 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was found to cause parkinsonian- like symptoms in intravenous drug users. When MPTP penetrates the blood-brain barrier, the compound is bio-transformed into its toxic form 1-methyl-4-phenylpyridinium (MPP+) by glial monoamine oxidase (MAO). MPP+ specifically interferes with the activity of respiratory chain (RC) complex I (NADH: Ubiquinone oxidoreductase) in dopaminergic (DA) neurons, causingselective neurodegeneration in both human and mouse substantia nigra (SN). In post-mortemstudies, varying degrees of Complex I and complex II (succinate dehydrogenase, SDH) deficiency have been found in individual SN neurons from PD patients (~60% Complex I and ~65% Complex II deficiency).

[0153] Mitochondria may mediate, drive, or contribute to a variety of Alzheimer’s disease (AD) pathologies. Amyloid-β (Aβ) may induce AD mitochondrial dysfunction. Alternatively,data indicate mitochondrial dysfunction exists independent of Aβ, potentially lies upstream of Aβ deposition, and suggest a primary mitochondrial cascade hypothesis that assumes mitochondrial pathology hierarchically supersedes Aβ pathology. Mitochondria, therefore, appear at least to mediate or possibly even initiate pathologic molecular cascades in AD.

[0154] Amyotrophic lateral sclerosis (ALS) is caused by selective degeneration of motor neurons in the brain and spinal cord, which may be mediated by mitochondrial dysfunction. Studies suggest that ferroptosis mediates selective motor neuron death in amyotrophic lateral sclerosis. See, Wang, T. et al. Cell Death Differ 29, 1187–1198 (2022).

[0155] Compounds of the disclosure or pharmaceutically acceptable salts thereof are also useful for methods of aiding the treatment of a disease, a disorder, and / or a health condition associated with a mitochondrial disease, such as Parkinson’s disease. As used herein, a “method of aiding” generally refers to methods of assisting in performing or practicing a method disclosed herein, for example, methods of assisting in (i) performing, (ii) practicing, and / or (iii) making a determination concerning the detection, classification, treatment regiment, or nature, of a mitochondrial disease (e.g., Parkinson’s disease), a disease, a disorder, and / or a health condition.

[0156] Accordingly, in some embodiments, a method of aiding in the treatment of a mitochondrial disease in a subject in need thereof comprises administering to the subject a therapeutically effective amount of a compound of the present disclosure or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. In some embodiments, the method of aiding in the treatment comprises administering a pharmaceutical composition of the compound of Formula I as described herein.

[0157] In some embodiments, a use of the present disclosure comprises a compound of the present disclosure or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure for the manufacture of a medicament for aiding in the treatment of a mitochondrial disease in a subject in need thereof. In some embodiments, the use comprises a pharmaceutical composition of the compound of Formula I as described herein.

[0158] In some embodiments, a compound of the present disclosure or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure is for use in aiding in the treatment of a mitochondrial disease in a subject in need thereof. In someembodiments, the compound for use comprises a pharmaceutical composition of the compound of Formula I as described herein.

[0159] In some embodiments, a use of the present disclosure comprises a compound of the present disclosure or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure for the manufacture of a medicament for treating a mitochondrial disease in a subject in need thereof. In some embodiments, the use comprises a pharmaceutical composition of the compound of Formula I as described herein.

[0160] In some embodiments, a compound of the present disclosure or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure is for use in treating a mitochondrial disease in a subject in need thereof. In some embodiments, the compound for use comprises a pharmaceutical composition of the compound of Formula I as described herein.

[0161] Kits that comprise a compound of the present disclosure, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing any of the above, are also included in the present disclosure. In some embodiments, a kit further includes instructions for use. In some embodiments, a kit includes a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and a label and / or instructions for use of the compounds in the treatment of the indications, such as the diseases or conditions, described herein. In some embodiments,kits comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents are provided.

[0162] Provided herein are also articles of manufacture that include a compound of the present disclosure or a pharmaceutically acceptable salt thereof in a suitable container. The container may be a vial, jar, ampoule, preloaded syringe, and intravenous bag.VI. EXAMPLES

[0163] The following examples are provided to further aid in understanding the embodiments disclosed in the application, and presuppose an understanding of conventional methods well known to those persons having ordinary skill in the art to which the examples pertain. Theparticular materials and conditions described hereunder are intended to exemplify particular aspects of embodiments disclosed herein and should not be construed to limit the reasonable scope thereof.

[0164] Many general references providing commonly known chemical synthetic schemes and conditions useful for synthesizing the disclosed compounds are available (see, e.g., Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7thedition, Wiley-Interscience, 2013.)

[0165] Compounds as described herein can be purified by any of the means known in the art, including chromatographic means, such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reversed phases as well as ionic resins. For example, disclosed compounds can be purified via silica gel chromatography. See, e.g., Introduction to Modern Liquid Chromatography, 3rded., ed. L. R. Snyder, J. J. Kirkland, J. W. Dolan. John Wiley and Sons, 2011; and Thin Layer Chromatography, E. Stahl (ed.), Springer-Verlag, New York, 1969.

[0166] Compounds were characterized using standard instrumentation methods. Identification of the compound was carried out by hydrogen nuclear magnetic resonance spectrum (1H-NMR) and mass spectrum (MS).1H-NMR was measured at 400 MHz, unless otherwise specified. In some cases, exchangeable hydrogen could not be clearly observed depending on the compound and measurement conditions. The designation br. or broad, used herein, refers to a broad signal. HPLC preparative chromatography was carried out by a commercially available ODS column in a gradient mode using water / methanol (containing formic acid) as eluents, unless otherwise specified.

[0167] The Examples provided herein describe the synthesis of compounds disclosed herein as well as intermediates used to prepare the compounds. It is to be understood that individual steps described herein may be combined. It is also to be understood that separate batches of a compound may be combined and then carried forth in the next synthetic step.

[0168] Representative syntheses of compounds of the present disclosure are described in schemes below, and the particular examples that follow.

[0169] Abbreviations. Certain abbreviations and acronyms are used in describing the experimental details. Although most of these would be understood by one skilled in the art, the following table contains a list of many of these abbreviations and acronyms. Table 3. List of abbreviations and acronyms. Abbreviation MeaningACN acetonitrileTHF tetrahydrofuran δ parts per million referenced to residual non-deuterated solvent peak

[0170] HPLCMS Method A: LC / MS: The gradient was 5% B in 0.40 min and 5-95% B in 2.60 min, hold on 95% B in 1.00 min, and then 95-5% B in 0.01 min, the flow rate was 1.0 mL / min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. The column used for chromatography was a Kinetex C18 2.1*50 mm, 5 um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.

[0171] HPLCMS Method B: LC / MS: The gradient was 5%B in 0.40min and 5-95% B at 0.40- 3.40 min, hold on 95% B for 0.45min, and then 95-5%B in 0.01min, the flow rate was 0.8 ml / min. Mobile phase A was H2O+10mM NH4HCO3, mobile phase B was Acetonitrile. The column used for chromatography was a Xbridge C182.1*50mm column (5um particles). Detection methods are diode array (DAD) evaporative light scattering (ELSD) detection .MS mode was negative electrospray ionization. MS range was 100-1000.

[0172] LCMS method C: LC / MS( The gradient was 5%B in 0.40min and 5-95% B in 2.60 min, hold on 95% B in 1.00min, and then 95-5%B in 0.01min, the flow rate was 1.0 ml / min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Luna C18 50*2.0mm column (5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection .MS mode was positive electrospray ionization. MS range was 100-1000.

[0173] LCMS method D: LC / MS (The column used for chromatography was a Halo C18 3.0*30mm, 5um. Detection methods are diode array (DAD). MS mode was positive electrospray ionization. MS range was 50-2000. Mobile phase A was 0.04% TFA in water, and mobile phase B was 0.02% TFA in HPLC grade acetonitrile. The gradient was 10-100% B in 0.90 min .10% B in 0.01 min, 10-100% B (0.01-0.50 min) with a hold at 100% B for 0.40 min. The flow rate was 2.0 mL / min.

[0174] LCMS method E: LC / MS (The column used for chromatography was a Xtimate C18 2.1*30mm, 5μm. Detection methods are diode array (DAD). MS mode was positive electrospray ionization and negative electrospray ionization acquisition simultaneously. MS range was 50- 2000. Mobile phase A was 10 mM Ammonium bicarbonate in water, and mobile phase B was HPLC grade acetonitrile. The gradient was 10-100% B in 0.90 min .10% B in 0.01 min, 10- 100% B (0.01-0.50 min) with a hold at 100% B for 0.40 min. The flow rate was 1.5 mL / min (0.00-0.90 min). Example 1. Compound 1: tert-butyl 6,11-dioxo-1,2,4,5,6,11-hexahydro-3H-naphtho[2,3- d]azepine-3-carboxylate O O O O HO N OH

[0175] To a solution of 3-[tert-butoxycarbonyl(2-carboxyethyl)amino]propanoic acid (4.13 g, 9.48 mmol, 1.5 eq) and naphthalene-1,4-dione (1 g, 6.32 mmol, 1 eq) in H2O (25 mL) and MeCN (50 mL) was added AgNO3(1.29 g, 7.59 mmol, 1.2 eq) at 20°C. The mixture was stirred at 100°C for 10 min. Then to the mixture a reaction mixture was added the solution of ammonium persulfate (5.77 g, 25.29 mmol, 5.50 mL, 4 eq) in H2O (10 mL) and MeCN (20 mL) dropwise over 30 min at 20°C. The mixture was stirred at 100°C for 3 hrs. LCMS showed the starting material was consumed, and desired mass was detected. Then the mixture was cooled to 25°C and adjust to pH=8 with NaHCO3. The mixture was diluted with THF (50 mL). Then Boc2O (2.76 g, 12.65 mmol, 2.91 mL, 2 eq) was added to the mixture at 25°C. Then the mixture was stirred for 3 hrs at 25°C. LCMS showed the reaction worked well. The mixture was diluted with water (100 mL), the mixture was extracted with EtOAc (80 mL*3). The combined organic phase was washed with brine (50mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash column on silica gel (petroleum ether: ethyl acetate=93:7) and the eluent was concentrated under reduced pressure to give Compound 1 (335 mg, 992.60 μmol, 15.70% yield, 97% purity) obtained as light-yellow solid:1H NMR (400 MHz, CHLOROFORM-d) δ 8.15 - 8.05 (m, 2H), 7.77 - 7.68 (m, 2H), 3.60 (br d, J = 4.8 Hz, 4H), 3.09 - 2.98 (m, 4H), 1.48 (s, 9H); Method A LCMS (ESI+): 2.881 min, m / z 350 (M+Na). Example 2. Compound 2: 2,3,4,5-tetrahydro-1H-naphtho[2,3-d]azepine-6,11-dione

[0176] To amL) was added HCl / EtOAc (4 M, 12.88 mL, 53.67 eq) at 25°C. The mixture was stirred at 25 °C for 8 hrs. LCMS showed the starting material was consumed, and one major peak with desired Mass was detected. The reaction mixture was concentrated under reduced pressure. The residue was triturated with ethyl acetate (5 mL) and filtered. The cake was washed with ethyl acetate (5 mL). The cake was dried by high vacuum to give Compound 2 (205 mg, 777.34 μmol, 80.97% yield, HCl salt) was obtained as light-yellow solid:1H NMR (400 MHz, DMSO-d6) δ 9.26 (br s, 2H), 8.12 - 7.94 (m, 2H), 7.92 - 7.77 (m, 2H), 3.22 (br s, 4H), 3.17 - 3.08 (m, 4H). Example 3. Compound 3: 3-isopropyl-2,3,4,5-tetrahydro-1H-naphtho[2,3-d]azepine-6,11- dione

[0177] To a solution of Compound 2 (200 mg, 697.71 μmol, 1 eq, HCl) in IPA (10 mL) was added acetone (202.61 mg, 3.49 mmol, 256.47 μL, 5 eq), AcOH (41.90 mg, 697.71 μmol, 39.94 μL, 1 eq) and NaOAc (171.70 mg, 2.09 mmol, 3 eq) at 25°C. Then the mixture was stirred for 1 hr at 40°C. Then NaBH3CN (131.53 mg, 2.09 mmol, 3 eq) was added to the mixture at 25°C.The mixture was stirred for 12 hrs at 40°C. LCMS showed the reaction worked well. The mixture was added saturated Na2CO3 (aqueous) to pH = 8, then the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (neutral condition, column: Waters Xbridge BEH C18100*30 mm*10 um; mobile phase: [H2O (10 mM NH4HCO3)-MeCN]; gradient: 25%-55% B over 8.0 min) and lyophilized to give Compound 3 (64 mg, 225.50 μmol, 32.32% yield, 94.9% purity) as light purple solid:1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.01 - 8.23 (m, 2 H), 7.58 - 7.82 (m, 2 H), 2.86 - 3.16 (m, 5 H), 2.66 (br s, 4 H), 1.05 (br d, J=6.50 Hz, 6 H); Method A LCMS (ESI+): 1.687 min, m / z 268 (M+H). Example 4. Compound 4: 3-cyclopentyl-2,3,4,5-tetrahydro-1H-naphtho[2,3-d]azepine-6,11- dione

[0178] a mg, eq, (20 mL) was added cyclopentanone (293.44 mg, 3.49 mmol, 308.89 μL, 5 eq), AcOH (41.90 mg, 697.71 μmol, 39.94 μL, 1 eq) and NaOAc (171.70 mg, 2.09 mmol, 3 eq) at 25°C. The mixture was stirred for 1 hr at 40°C. Then NaBH3CN (131.53 mg, 2.09 mmol, 3 eq) was added to the mixture at 25°C. The mixture was stirred for 2 hrs at 40°C. LCMS showed the reaction worked well. The mixture was added saturated Na2CO3 (aqueous) to pH = 8. Then the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. One additional vial in 200 mg scale was set up as described above, the residue was combined. The crude product was triturated with MeOH 5 mL, filtered. The filter cake was dried in high vacuo to give Compound 4 (86 mg, 287.66 μmol, 20.61% yield, 98.8% purity) as light brownsolid:1H NMR (400 MHz, DMSO-d6) δ ppm 7.97 - 8.05 (m, 2 H), 7.84 (dd, J=5.69, 3.31 Hz, 2 H), 2.86 - 2.92 (m, 4 H), 2.82 (br d, J=8.38 Hz, 1 H), 2.57 - 2.64 (m, 4 H), 1.71 - 1.83 (m, 2 H), 1.55 - 1.66 (m, 2 H), 1.48 (br dd, J=7.44, 4.82 Hz, 2 H), 1.29 - 1.41 (m, 2 H); Method A LCMS (ESI+): 1.832 min, m / z 296 (M+H). Example 5. Compound 5: 3-(pentan-3-yl)-2,3,4,5-tetrahydro-1H-naphtho[2,3-d]azepine- 6,11-dione5 was prepared according to the general procedures described in other Examples in the application. Example 6. Compound 6: 3-phenethyl-2,3,4,5-tetrahydro-1H-naphtho[2,3-d]azepine-6,11- dione

[0180] To a solution of Compound 2 (200 mg, 697.71 μmol, 1 eq, HCl salt) and 2- phenylacetaldehyde (419.14 mg, 3.49 mmol, 272.17 μL, 5 eq) in MeOH (20 mL) was added NaOAc (171.70 mg, 2.09 mmol, 3 eq) and AcOH (41.90 mg, 697.71 μmol, 39.94 μL, 1 eq) at 25°C. Then the mixture was stirred for 1 hr at 25°C. Then NaBH3CN (131.53 mg, 2.09 mmol, 3 eq) was added in portions to the mixture at 25°C. The mixture was stirred for 2 hrs at 25°C. One additional vial in 20 mg scale was set up as described above and these two reactions were combined. The combined mixture was added saturated Na2CO3(aqueous) to pH = 8. Then the mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic phaseswere washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate in Petroleum ether gradient @ 60 mL / min) to give crude product. Then the crude product was triturated with MeOH (2 mL) and then filtered. The filter cake was dried in high vacuum to give Compound 6 (48 mg, 141.94 μmol, 18.49% yield, 98.0% purity) as a light brown solid:1H NMR (400 MHz, DMSO-d6) δ ppm 7.98 - 8.06 (m, 2 H), 7.84 (dd, J=5.69, 3.31 Hz, 2 H), 7.20 - 7.29 (m, 4 H), 7.14 - 7.20 (m, 1 H), 2.87 - 2.94 (m, 4 H), 2.72 - 2.78 (m, 2 H), 2.62 - 2.71 (m, 6 H); Method A LCMS (ESI+): 2.042 min, m / z 332 (M+H). Example 7. Compound 7: 3-(3,3,3-trifluoropropyl)-2,3,4,5-tetrahydro-1H-naphtho[2,3- d]azepine-6,11-dioneDMF (10 mL) was added K2CO3 (534.54 mg, 3.87 mmol, 4 eq) at 25°C. The mixture was stirred for 0.5 hr at 25°C. Then 1,1,1-trifluoro-3-iodo-propane (649.68 mg, 2.90 mmol, 339.97 μL, 3 eq) was added to the mixture at 25°C and stirred for 8 hrs at 50°C. LCMS showed the reaction worked and desired mass was detected. One additional vial in 50 mg scale was set up as described above. The mixture was combined and diluted with water (20 mL) and extracted with ethyl acetate (3 x 8 mL). The combined organic phases were washed with brine (3 x 10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (neutral condition, column: Waters Xbridge Prep OBD C18150*40 mm*10 um; mobile phase: [H2O (10 mM NH4HCO3)-MeCN]; gradient: 45%-75% B over 8.0 min) and lyophilization to give crude product. The crude product was triturated with methanol (1 mL), filtered and the filter cake was dried in high vacuum to give Compound 7 (23 mg, 68.15 μmol, 6.59% yield, 95.8% purity) as a deep-purple solid:1H NMR (400 MHz, METHANOL-d4) δ ppm 8.08 (dd, J=5.69, 3.31 Hz, 2 H), 7.77 (dd, J=5.69, 3.31 Hz, 2 H), 2.95 - 3.10 (m, 4 H),2.74 - 2.85 (m, 2 H), 2.65 - 2.74 (m, 4 H), 2.33 - 2.53 (m, 2 H); Method A LCMS (ESI+): 1.815 min, m / z 324 (M+H). Example 8. Compound 8: 3-(4-(trifluoromethyl)benzoyl)-2,3,4,5-tetrahydro-1H- naphtho[2,3-d]azepine-6,11-dione

[0182] was added 4-(trifluoromethyl)benzoic acid (216.27 mg, 1.14 mmol, 1.5 eq), NMI (186.80 mg, 2.28 mmol, 181.36 μL, 3 eq) and TCFH (425.57 mg, 1.52 mmol, 2 eq) at 25°C in order. The mixture was stirred at 25°C for 12 hours. The mixture was diluted with ethyl acetate (10 mL) and water (10 mL). The mixture was extracted with ethyl acetate (3 x 10 mL). The organic layer was dried with Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=92%) and then triturated with ethyl acetate (2 mL). The solid was dried in high vacuum to give Compound 8 (101 mg, 247.59 μmol, 32.65% yield, 97.9% purity) as yellow solid:1H NMR (DMSO-d6, 400 MHz) δ (ppm) 8.02 (br dd, J = 10.8, 4.6 Hz, 1H), 7.78-7.90 (m, 2H), 7.65 (d, J = 8.0 Hz, 1H), 3.82 (br s, 1H), 3.46 (br s, 1H), 3.10 (br s, 1H), 2.94 (br s, 1H); Method A LCMS (ESI+): 2.832 min, m / z 400 (M+H). Example 9. Compound 9: 1,2,4,5-tetrahydronaphtho[2,3-d]oxepine-6,11-dione

[0183] To a solution of naphthalene-1,4-dione (400 mg, 2.53 mmol, 1 eq) and 3,3'-oxydipropionic acid (410.08 mg, 2.53 mmol, 1 eq) in acetonitrile (40 mL) and H2O (20 mL) was added AgNO3 (515.57 mg, 3.04 mmol, 1.2 eq) in portions at 25°C under N2. The mixture was stirred at 100°C under N2for 30 minutes. Then the mixture was cooled to 25°C and to a reaction mixture was added the solution of ammonium persulfate (1.85 g, 8.09 mmol, 1.76 mL, 3.2 eq) in acetonitrile (40 mL) and H2O (20 mL) dropwise at 25°C under N2. The mixture was stirred at 100°C under N2for 3 hours. The mixture was cooled to 25°C. The mixture was quenched with aqueous of saturated sodium sulfite (300 mL). The aqueous phase was extracted with ethyl acetate (3 x 300 mL). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give the residue. The residue was purified by prep-HPLC (NH4HCO3condition; Column: Waters Xbridge BEH C18100*30mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:24%-56% B over 8.0 min) and the desired eluent was lyophilized to give Compound 9 (45.6 mg, 177.61 μmol, 7.02% yield, 88.9% purity) as light brown solid:1H NMR (400 MHz, DMSO-d6) δ 2.96-3.03 (m, 4H), 3.65-3.71 (m, 4H), 7.81-7.88 (m, 2H), 7.98-8.06 (m, 2H); Method B LCMS (ESI-): 2.798 min. Example 10. Compound 10: 3-(pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-naphtho[2,3- d]azepine-6,11-dione

[0184] To a solution of Compound 2 (250 mg, 853.18 μmol, 1 eq, HCl salt) and 4- chloropyrimidine (195.43 mg, 1.71 mmol, 2 eq) in THF (6 mL) was added TEA (259.00 mg, 2.56 mmol, 356.26 μL, 3 eq) in one portion at 25°C under N2. The mixture was stirred at 60°C for 12 hours under N2. One additional vial in 100 mg scale was set up as described above and these two reactions were combined. The mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue.The residue was purified by prep-HPLC (neutral condition, column: Waters Xbridge Prep OBD C18150*40mm*10um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient:30%-60% B over 8.0 min) and the desired eluent was lyophilized to give Compound 10 (34 mg, 110.24 μmol, 9.23% yield, 99% purity) as a light yellow solid:1H NMR (400 MHz, DMSO-d6) δ ppm 2.07 (s, 1 H) 2.96 - 3.10 (m, 4 H) 3.89 (br s, 4 H) 6.85 (dd, J=6.32, 1.19 Hz, 1 H) 7.78 - 7.89 (m, 2 H) 7.97 - 8.05 (m, 2 H) 8.18 (d, J=6.13 Hz, 1 H) 8.51 (s, 1 H); Method A LCMS (ESI+): 1.896 min, m / z 306 (M+H). Example 11. Compound 11: 3-(pyrimidin-2-yl)-2,3,4,5-tetrahydro-1H-naphtho[2,3- d]azepine-6,11-dione

[0185] To a solution of Compound 2 (250 mg, 853.18 μmol, 1 eq, HCl salt) and 4- chloropyrimidine (195.43 mg, 1.71 mmol, 2 eq) in THF (6 mL) was added TEA (259.00 mg, 2.56 mmol, 356.26 μL, 3 eq) in one portion at 25°C under N2. The mixture was stirred at 60°C for 12 hours under N2. One additional vial in 100 mg scale was set up as described above and these two reactions were combined. The mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (neutral condition, column: Waters Xbridge Prep OBD C18150*40mm*10um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient:30%-60% B over 8.0 min) and the desired eluent was lyophilized to give Compound 11 (16 mg, 50.78 μmol, 4.25% yield, 96.9% purity) as a purple solid:1H NMR (400 MHz, DMSO-d6) δ 2.95 - 3.07 (m, 4 H) 3.91 - 4.05 (m, 4 H) 6.61 (t, J=4.75 Hz, 1 H) 7.84 (dd, J=5.57, 3.31 Hz, 2 H) 8.01 (dd, J=5.75, 3.25 Hz, 2 H) 8.39 (d, J=4.75 Hz, 2 H); Method A LCMS (ESI+): 2.404 min, m / z 306 (M+H).Example 12. Compound 12: 6,7,9,10-tetrahydro-5H-cyclohepta[b]naphthalene-5,8,11- trionea g, acid (2.20 g, 12.65 mmol, 1 eq) in acetonitrile (200 mL) and H2O (100 mL) was added AgNO3(2.58 g, 15.18 mmol, 1.2 eq) in portions at 25°C under N2. The reaction was stirred at 100°C for 30 minutes. Then the mixture was cooled to 25°C and to a reaction mixture was added the solution of ammonium persulfate (9.23 g, 40.47 mmol, 8.79 mL, 3.2 eq) in acetonitrile (200 mL) and H2O (100 mL) dropwise at 25°C under N2. The mixture was stirred at 100°C under N2 for 3 hours. The mixture was cooled to 25°C. The mixture was quenched with aqueous of saturated sodium sulfite (500 mL). The aqueous phase was extracted with ethyl acetate (3 x 200 mL). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give the residue. The residue was purified by prep-HPLC (NH4HCO3 condition; column: Welch Xtimate C18250*70mm#10um;mobile phase: [H2O(10mM NH4HCO3)- ACN];gradient:30%-60% B over 17.0 min) and the desired eluent was lyophilized to give the Compound 1 (211.6 mg, 830.53 μmol, 6.57% yield, 94.3% purity) as light yellow solid:1H NMR (400 MHz, DMSO-d6) δ 2.55-2.60 (m, 4H), 2.94 (br d, J=5.00 Hz, 4H), 7.86 (br dd, J=5.25, 3.25 Hz, 2H), 8.04 (dd, J=5.57, 3.31 Hz, 2H); Method B LCMS (ESI-): 2.599 min, m / z 239 (M-1). Example 13. Compound 13: 8-(isopropylamino)-7,8,9,10-tetrahydro-5H- cyclohepta[b]naphthalene-5,11(6H)-dioneNH2O (3 eq) O

[0187] To a mixture of Compound 12 (60 mg, 224.76 μmol, 1 eq, purity 90%) and propan-2- amine (39.86 mg, 674.29 μmol, 57.93 μL, 3 eq) in dichloromethane (1 mL) was added AcOH (13.50 mg, 224.76 μmol, 12.87 μL, 1 eq) dropwise at 25°C. Then the reaction was stirred at 25°C for 30 minutes. The sodium triacetoxyboranuide (119.09 mg, 561.91 μmol, 2.5 eq) was added to the mixture at 25°C. The reaction mixture was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure to give the residue. The residue was purified by prep- HPLC (HCl condition; column: Phenomenex luna C18100*40mm*5 um;mobile phase: [H2O(0.04% HCl)-ACN];gradient:1%-35% B over 8.0 min) and the desired eluent was lyophilized to give Compound 13 (63.8 mg, 197.49 μmol, 67.59% yield, 99% purity, HCl salt) as yellow solid:1H NMR (400 MHz, DMSO-d6) δ 1.48 (q, J=11.42 Hz, 2H), 2.23-2.34 (m, 2H), 2.40 (br dd, J=14.76, 11.63 Hz, 2H), 2.98 (br dd, J=10.32, 6.32 Hz, 2H), 3.12-3.24 (m, 2H), 3.29 (br d, J=7.63 Hz, 2H), 3.47 (br d, J=1.00 Hz, 1H), 7.21-7.40 (m, 5H), 7.80-7.90 (m, 2H), 7.97- 8.07 (m, 2H), 9.02 (br s, 2H); Method A LCMS (ESI+): 1.896 min, m / z 284 (M+1). Example 14. Compound 14: 8-hydroxy-7,8,9,10-tetrahydro-5H-cyclohepta[b]naphthalene- 5,11(6H)-dione

[0188] To a mixture of Compound 12 (500 mg, 1.98 mmol, 1 eq, purity 95%) in methanol (10 mL) was added NaBH4 (149.60 mg, 3.95 mmol, 2 eq) in portions at 0°C. The mixture was stirred for 10 minutes at 25°C. The mixture was quenched with ice saturated aqueous ofammonium chloride (100 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with brine (30mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give Compound 14 (572 mg, 2.31 mmol, 97.53% yield, 98% purity) as yellow solid:1H NMR (400 MHz, DMSO-d6) δ 1.27-1.40 (m, 2H), 1.77-1.89 (m, 2H), 2.42 (br dd, J=14.26, 10.38 Hz, 2H), 3.07 (br dd, J=14.38, 9.26 Hz, 2H), 3.79 (td, J=8.13, 3.88 Hz, 1H), 4.76 (d, J=4.13 Hz, 1H), 7.75-7.89 (m, 2H), 7.93-8.07 (m, 2H); Method A LCMS (ESI+): 2.222 min, m / z 243 (M+1). Example 15. Compound 15: 3-(2-(pyrrolidin-1-yl)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H- naphtho[2,3-d]azepine-6,11-dione

[0189] To a solution of Compound 2 (150 mg, 568.79 μmol, 1 eq, HCl) in HFIP (4 mL) was added 4-chloro-2-(pyrrolidin-1-yl)pyrimidine (164.92 mg, 853.18 μmol, 1.5 eq) dropwise at 25°C under N2. The mixture was stirred at 50°C for 12 hours under N2. Then the mixture was concentrated under reduced pressure to remove the solvent. The crude was purified by prep- HPLC (neutral condition, column: Waters Xbridge Prep OBD C18150*40mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:40%-80% B over 8.0 min) and the desired eluent was lyophilized to give Compound 15 (17 mg, 39.30 μmol, 6.91% yield, 95% purity, HCl) as a yellow solid:1H NMR (400 MHz, DMSO-d6) δ 1.82 - 2.11 (m, 4 H) 2.99 - 3.15 (m, 4 H) 3.43 - 3.67 (m, 4 H) 3.81 - 4.21 (m, 4 H) 6.57 (d, J=7.50 Hz, 1 H) 7.78 - 7.91 (m, 3 H) 8.02 (dd, J=5.69, 3.31 Hz, 2 H) 12.14 (br d, J=1.75 Hz, 1 H); Method A LCMS (ESI+): 2.238 min, m / z 375 (M+H). Example 16. Compound 16: 3-(4-(pyrrolidin-1-yl)pyrimidin-2-yl)-2,3,4,5-tetrahydro-1H- naphtho[2,3-d]azepine-6,11-dione

[0190] To a solution of Compound 2 (150 mg, 568.79 μmol, 1 eq, HCl) in HFIP (5 mL) wasadded 2-chloro-4-(pyrrolidin-1-yl)pyrimidine (164.92 mg, 853.18 μmol, 1.5 eq) in one portion at25°C under N2. The mixture was stirred at 50°C for 72 hours under N2. Then the mixture was concentrated under reduced pressure to remove the solvent. The crude was purified by prep- HPLC (neutral condition, column: Waters Xbridge Prep OBD C18150*40mm*10um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient:15%-75% B over 8.0 min) and the desired eluent was lyophilized to give Compound 16 (25 mg, 62.89 μmol, 11.06% yield, 94.29% purity) as an orange solid:1H NMR (400 MHz, DMSO-d6) δ 1.91 (br s, 4 H) 2.91 - 3.04 (m, 4 H) 3.32 - 3.62 (m, 4 H) 3.84 - 3.99 (m, 4 H) 5.72 (d, J=5.75 Hz, 1 H) 7.78 - 7.88 (m, 3 H) 7.96 - 8.04 (m, 2 H); Method A LCMS (ESI+): 2.244 min, m / z 375 (M+H). Example 17. Compound 17: 8-(4-isopropylpiperazin-1-yl)-7,8,9,10-tetrahydro-5H- cyclohepta[b]naphthalene-5,11(6H)-dione

[0191] To a mixture of Compound 12 (80 mg, 299.68 μmol, 1 eq, purity 90%) and 1- isopropylpiperazine (115.27 mg, 899.05 μmol, 128.65 μL, 3 eq) in dichloromethane (1 mL) was added AcOH (18.00 mg, 299.68 μmol, 17.16 μL, 1 eq) dropwise at 25°C. Then the reaction was stirred at 25°C for 30 minutes. Then sodium triacetoxyboranuide (158.79 mg, 749.21 μmol, 2.5 eq) was added to the mixture at 25°C. The reaction mixture was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure to give the residue. The residue was purifiedby prep-HPLC (HCl condition; column: Phenomenex luna C18100*40mm*5 um;mobile phase: [H2O(0.04% HCl)-ACN];gradient:1%-30% B over 8.0 min) and the desired eluent was lyophilized to give Compound 17 (78.4 mg, 201.58 μmol, 61.15% yield, 100% purity, HCl) as off-white solid:1H NMR (400 MHz, METHANOL-d4) δ 1.43 (d, J=6.63 Hz, 6H), 1.64 (q, J=11.92 Hz, 2H), 2.33-2.49 (m, 4H), 3.56-3.87 (m, 12H), 7.76-7.83 (m, 2H), 8.06-8.13 (m, 2H); Method A LCMS (ESI+): 1.749 min, m / z 353 (M+1). Example 18. Compound 18: 3-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-naphtho[2,3- d]azepine-6,11-dione

[0192] To a solution of Compound 2 (30 mg, 113.76 μmol, 1 eq, HCl) in DCM (3 mL) was added methoxysulfinyl methyl sulfite (29.72 mg, 170.64 μmol, 1.5 eq) and TEA (23.02 mg, 227.51 μmol, 31.67 μL, 2 eq) at 0°C. The mixture was stirred at 25°C for 2 hours. The mixture was diluted with water (10 mL). The aqueous phase was extracted with dichloromethane (3 x 10 mL). The organic layer was washed with HCl solution (1 M, 10 mL), dried with Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The crude product was triturated with methyl alcohol (5 mL) at 25oC for 10 min and then filtered. The solid was dried in high vacuum to give Compound 18 (6.5 mg, 20.84 μmol, 18.32% yield, 97.9% purity) as yellow solid: 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 8.03 (dd, J = 5.7, 3.3 Hz, 2H), 7.82-7.91 (m, 2H), 3.37-3.44 (m, 4H), 2.98-3.05 (m, 4H), 2.90 (s, 3H); Method A LCMS (ESI+): 2.359 min, m / z 306(M+H). Example 19. Compound 19: 8-(pyrrolidin-1-yl)-7,8,9,10-tetrahydro-5H- cyclohepta[b]naphthalene-5,11(6H)-dione

[0193] To a mixture of Compound 12 (80 mg, 299.68 μmol, 1 eq) and pyrrolidine (63.94 mg, 899.05 μmol, 75.05 μL, 3 eq, purity 90%) in dichloromethane (2 mL) was added AcOH (18.00 mg, 299.68 μmol, 17.16 μL, 1 eq) dropwise at 25°C. Then the reaction was stirred at 25°C for 30 minutes. Then sodium triacetoxyboranuide (158.79 mg, 749.21 μmol, 2.5 eq) was added to the mixture at 25°C. The reaction mixture was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure to give the residue. The residue was purified by prep- HPLC (HCl condition; column: Phenomenex luna C18100*40mm*5 um;mobile phase: [H2O(0.04% HCl)-ACN];gradient:1%-30% B over 8.0 min) and the desired eluent was lyophilized to give Compound 19 (45.7 mg, 137.31 μmol, 45.82% yield, 99.7% purity, HCl) as brown solid:1H NMR (400 MHz, DMSO-d6) δ 1.56 (q, J=11.51 Hz, 2H), 1.80-2.00 (m, 4H), 2.29 (br t, J=8.94 Hz, 2H), 2.40 (br dd, J=14.95, 11.44 Hz, 2H), 3.08 (br dd, J=10.69, 7.19 Hz, 2H), 3.29 (br s, 1H), 3.33-3.37 (m, 1H), 3.43 (br dd, J=10.07, 4.69 Hz, 2H), 3.48-3.58 (m, 1H), 7.80-7.90 (m, 2H), 7.97-8.07 (m, 2H), 10.80 (br d, J=1.75 Hz, 1H); Method A LCMS (ESI+): 1.878 min, m / z 296 (M+1). Example 20. Compound 20: 8-(phenethylamino)-7,8,9,10-tetrahydro-5H- cyclohepta[b]naphthalene-5,11(6H)-dione NH2O O

[0194] To a mixture of Compound 12 (60 mg, 224.76 μmol, 1 eq, purity 90%) and 2- phenylethanamine (81.71 mg, 674.29 μmol, 84.67 μL, 3 eq) in dichloromethane (2 mL) wasadded AcOH (13.50 mg, 224.76 μmol, 12.87 μL, 1 eq) dropwise at 25°C. Then the reaction was stirred at 25°C for 30 minutes. Then sodium triacetoxyboranuide (119.09 mg, 561.91 μmol, 2.5 eq) was added to the mixture at 25°C. The reaction mixture was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure to give the residue. The residue was purified by prep-HPLC (HCl condition; column: Phenomenex luna C18100*40mm*5 um;mobile phase: [H2O(0.04% HCl)-ACN];gradient:1%-40% B over 8.0 min) and the desired eluent was lyophilized to give Compound 20 (58.9 mg, 152.69 μmol, 58.56% yield, 99% purity, HCl) as light yellow solid:1H NMR (400 MHz, DMSO-d6) δ 1.48 (q, J=11.42 Hz, 2H), 2.23-2.34 (m, 2H), 2.40 (br dd, J=14.76, 11.63 Hz, 2H), 2.98 (br dd, J=10.32, 6.32 Hz, 2H), 3.12-3.24 (m, 2H), 3.29 (br d, J=7.63 Hz, 2H), 3.47 (br d, J=1.00 Hz, 1H), 7.21-7.40 (m, 5H), 7.80-7.90 (m, 2H), 7.97-8.07 (m, 2H), 9.02 (br s, 2H); Method A LCMS (ESI+): 2.186 min, m / z 346 (M+1). Example 21. Compound 21: 8-((3,3,3-trifluoropropyl)amino)-7,8,9,10-tetrahydro-5H- cyclohepta[b]naphthalene-5,11(6H)-dione

[0195] To a solution of Compound 12 (80 mg, 299.68 μmol, 1 eq, purity 90%) and 3,3,3- trifluoropropan-1-amine (134.45 mg, 899.05 μmol, 3 eq, HCl) in dichloromethane (1 mL) was added AcOH (18.00 mg, 299.68 μmol, 17.16 μL, 1 eq) dropwise at 25°C. Then the reaction was stirred at 25°C for 30 minutes. The sodium triacetoxyboranuide (158.79 mg, 749.21 μmol, 2.5 eq) was added to the mixture at 25°C. The reaction mixture was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure to give the residue. The residue was triturated with methanol. Then the filter cake was collected and the cake was concentrated under reduced pressure to give Compound 21 (9 mg, 24.03 μmol, 8.02% yield, 99.8% purity, HCl) as light yellow solid. The rest of the residue was purified by prep-HPLC (HCl condition; column: Phenomenex luna C18100*40mm*5 um;mobile phase: [H2O(0.04% HCl)-ACN];gradient:1%- 40% B over 8.0 min) and the desired eluent was lyophilized to give Compound 21 (29.1 mg,71.23 μmol, 23.77% yield, 91.5% purity, HCl) as light yellow solid:1H NMR (400 MHz, DMSO-d6) δ 1.48 (q, J=11.46 Hz, 2H), 2.27 (br t, J=8.63 Hz, 2H) 2.39 (br dd, J=14.63, 11.63Hz, 2H), 2.71-2.89 (m, 2H), 3.15-3.25 (m, 2H), 3.28 (br d, J=7.75 2H), 3.49 (br s, 1H), 7.77- 7.93 (m, 2H), 8.02 (dd, J=5.69, 3.31 Hz, 2H), 9.28 (br d, J=1.63 Hz, 2H);19F NMR (377 MHz, DMSO-d6) δ -64.07 (s, 3F); Method A LCMS (ESI+): 1.995 min, m / z 338 (M+1). Example 22. Compound 22: 8-((4-(trifluoromethyl)phenyl)amino)-7,8,9,10-tetrahydro-5H- cyclohepta[b]naphthalene-5,11(6H)-dione F F F (3

[0196] To a mixture of Compound 12 (35 mg, 138.40 μmol, 1 eq, purity 95%) and 4- (trifluoromethyl)aniline (66.90 mg, 415.19 μmol, 51.62 μL, 3 eq) in dichloromethane (1 mL) was added AcOH (8.31 mg, 138.40 μmol, 7.92 μL, 1 eq) dropwise at 25°C and stirred at 25°C for 30 minutes. Then sodium triacetoxyboranuide (73.33 mg, 345.99 μmol, 2.5 eq) was added to the mixture at 25°C. The reaction mixture was stirred at 25°C for 3 hours. The mixture was concentrated under reduced pressure to give the residue. The residue was purified by prep- HPLC (HCl condition; column: Phenomenex luna C18100*40mm*5 um;mobile phase: [H2O(0.04% HCl)-ACN];gradient:45%-75% B over 8.0 min) and the desired eluent was lyophilized to give Compound 22 (8.4 mg, 19.91 μmol, 6.31% yield, 100% purity, HCl) as yellow solid:1H NMR (400 MHz, CHLOROFORM-d) δ 1.28-1.41 (m, 2H), 2.22-2.35 (m, 2H), 2.42 (br dd, J=14.38, 12.01 Hz, 2H), 3.44 (dd, J=15.13, 7.88 Hz, 2H), 3.63-3.77 (m, 1H), 6.65 (br d, J=2.63 Hz, 2H), 7.44 (br d, J=8.25 Hz, 2H), 7.68-7.78 (m, 2H), 8.07-8.18 (m, 2H);19F NMR (377 MHz, CHLOROFORM-d) δ -61.10 (br s, 3F); Method A LCMS (ESI+): 3.220 min, m / z 386 (M+1). Example 23. Compound 23: tert-butyl (3-(6,11-dioxo-1,2,4,5,6,11-hexahydro-3H- naphtho[2,3-d]azepin-3-yl)propyl)(methyl)carbamate

[0197] To a solution of Compound 2 (200 mg, 758.38 μmol, 1 eq, HCl) and tert-butyl N- methyl-N-(3-oxopropyl)carbamate (425.99 mg, 2.28 mmol, 3 eq) in MeOH (8 mL) was added NaOAc (186.63 mg, 2.28 mmol, 3 eq) and AcOH (45.54 mg, 758.38 μmol, 43.41 μL, 1 eq) in order at 25°C. The mixture was stirred for 1 hr at 40°C. Then NaBH3CN (142.97 mg, 2.28 mmol, 3 eq) was added to the mixture in portions and stirred for 12 hrs at 25°C. The mixture was added saturated NaHCO3(aqueous) to pH = 8. Then the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Ethyl acetate in Petroleum ether = 0-45%) togive a crude product. The crude product was purified by prep-HPLC (HCl condition, column:Phenomenex luna C18100*40 mm*5 um; mobile phase: [H2O (0.04% HCl)-ACN]; gradient:1%-40% B over 8.0 min) to give Compound 23 (30 mg, 66.01 μmol, 8.70% yield, 95.7% purity, HCl) as an off-white solid:1H NMR (400 MHz, METHANOL-d4) δ ppm 8.12 (dd, J=5.75, 3.38 Hz, 2 H), 7.82 (dd, J=5.75, 3.38 Hz, 2 H), 3.70 - 3.84 (m, 2 H), 3.53 - 3.68 (m, 2 H), 3.38 (t, J=6.69 Hz, 2 H), 3.13 - 3.29 (m, 4 H), 2.78 - 3.09 (m, 5 H), 1.99 - 2.10 (m, 2 H), 1.48 (s, 9 H); Method A LCMS (ESI+): 2.130 min, m / z 399.2 (M+H). Example 24. Compound 24: 3-(3-(methylamino)propyl)-2,3,4,5-tetrahydro-1H- naphtho[2,3-d]azepine-6,11-dione

[0198] A solution of Compound 23 (30 mg, 75.28 μmol, 1 eq) in EtOAc (1 mL) and HCl / EtOAc (1 mL, 4 mol / L) was stirred for 2 hrs at 25°C. The residue was purified by prep-HPLC (HCl condition, column: Phenomenex luna C18100*40 mm*5 um;mobile phase: [H2O (0.04% HCl)-ACN]; gradient: 1%-20% B over 8.0 min) and lyophilized to give Compound 24 (11 mg, 28.91 μmol, 38.41% yield, 97.6% purity, 2HCl) as a light yellow solid:1H NMR (400 MHz, DMSO-d6) δ ppm 11.34 - 11.53 (m, 1 H), 8.96 (br s, 2 H), 7.99 - 8.12 (m, 2 H), 7.88 (dd, J=5.69, 3.31 Hz, 2 H), 3.63 (br d, J=1.00 Hz, 2 H), 3.34 - 3.35 (m, 2 H), 3.24 (br s, 2 H), 3.05 - 3.19 (m, 4 H), 3.00 (br s, 2 H), 2.54 (br s, 3 H), 2.10 (br s, 2 H); Method A LCMS (ESI+): 1.40 min, m / z 299.1 (M+H). Example 25. Compound 25: 3-acetyl-2,3,4,5-tetrahydro-1H-naphtho[2,3-d]azepine-6,11- dione

[0199] To a solution of Compound 2 (100 mg, 379.19 μmol, 1 eq, HCl) in DCM (3 mL) was added TEA (115.11 mg, 1.14 mmol, 158.34 μL, 3 eq) and acetyl chloride (59.53 mg, 758.38 μmol, 53.92 μL, 2 eq) in portions at 25°C under N2. The mixture was stirred at 25°C under N2 for 2 hours. One additional vial in 20 mg scale was set up as described above and these two reactions were combined. Then the mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude. The crudeproduct was triturated with tert-butyl methyl ether (10 mL) at 25°C for 30 minutes. The mixture was filtered and the filter cake was concentrated under reduced pressure to give Compound 25 (57 mg, 211.03 μmol, 46.38% yield, 99.7% purity) as a yellow solid:1H NMR (400 MHz, DMSO-d6) δ ppm 2.06 (s, 3 H) 2.82 - 3.07 (m, 4 H) 3.62 (td, J=5.16, 2.56 Hz, 4 H) 7.78 - 7.91 (m, 2 H) 7.96 - 8.07 (m, 2 H); Method A LCMS (ESI+): 2.140 min, m / z 270 (M+H). Example 26. Compound 26: 3-(2-(dimethylamino)ethyl)-2,3,4,5-tetrahydro-1H- naphtho[2,3-d]azepine-6,11-dione prepared according to the general procedures described in otherExample 27. Compound 27: 3-(3-(dimethylamino)propyl)-2,3,4,5-tetrahydro-1H- naphtho[2,3-d]azepine-6,11-dione

[0201] To a solution of Intermediate 27-2 (20 mg, 55.98 μmol, 1 eq, 2HCl) in MeOH (1 mL) was added NaOAc (13.78 mg, 167.94 μmol, 3 eq), (HCHO)n (10.09 mg, 335.88 μmol, 6 eq) and AcOH (3.36 mg, 55.98 μmol, 3.20 μL, 1 eq) in order at 25°C. The mixture was stirred for 1 hr at 25°C. Then NaBH3CN (10.55 mg, 167.94 μmol, 3 eq) was added to the mixture at 25°C. The mixture was stirred for 12 hrs at 25°C. One additional vial in 5 mg scale was set up as described above. The mixtures were combined and filtered. The filtrate was purified by prep- HPLC (HCl condition, column: Phenomenex Luna C1875*30 mm*3 um; mobile phase: [H2O (0.04% HCl)-ACN]; gradient: 1%-25% B over 8.0 min) and lyophilized to give Compound 27(8.9 mg, 22.66 μmol, 32.38% yield, 98.1% purity, 2HCl) as a yellow solid:1H NMR (400 MHz, DMSO-d6) δ ppm 8.04 (dd, J=5.69, 3.31 Hz, 2 H), 7.87 (dd, J=5.69, 3.31 Hz, 2 H), 3.61 (br d,J=1.00 Hz, 2 H), 3.29 - 3.40 (m, 2 H), 3.05 - 3.25 (m, 6 H), 2.90 - 3.02 H), 2.78 (s, 6 H), 2.00 - 2.13 (m, 2 H); Method A LCMS (ESI+): 1.48 min, m / z 313.1 (M+H). Example 28. Compound 28: 8-amino-7,8,9,10-tetrahydro-5H-cyclohepta[b]naphthalene- 5,11(6H)-dione

[0202] To a solution of Compound 12 (300 mg, 1.25 mmol, 1 eq) and NH4Cl (80.15 mg, 1.50 mmol, 1.2 eq) in DCM (6 mL) was added HOAc (74.98 mg, 1.25 mmol, 71.48 μL, 1 eq) at 25°C. The mixture was stirred at 25°C for 1 hour. Then NaBH(OAc)3 (661.61 mg, 3.12 mmol, 2.5 eq) was added to the mixture. The mixture was stirred at 25°C for 12 hours. The mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by prep-HPLC (column: Phenomenex luna C18100*40mm*5 um; mobile phase: [H2O (0.04% HCl)-ACN]; gradient:5%-30% B over 8.0 min) and lyophilized to give Compound 28 (24.9 mg, 103.20 μmol, 8.26% yield) as a yellow solid:1H NMR (DMSO-d6, 400 MHz) δ (ppm) 8.07 (br s, 2H), 7.97-8.04 (m, 2H), 7.80-7.91 (m, 2H), 3.37-3.48 (m, 1H), 3.23-3.30 (m, 2H), 2.41 (br dd, J = 14.4, 12.1 Hz, 2H), 2.05-2.19 (m, 2H), 1.28-1.43 (m, 2H); Method A LCMS (ESI+): 1.709 min, m / z 242 (M+1). Example 29. Compound 29: 8-(diethylamino)-7,8,9,10-tetrahydro-5H- cyclohepta[b]naphthalene-5,11(6H)-dione

[0203] To a mixture of Compound 12 (200 mg, 790.83 μmol, 1 eq, purity 95%) and N- ethylethanamine (578.39 mg, 7.91 mmol, 814.63 μL, 10 eq) in dichloromethane (4 mL) was added AcOH (47.49 mg, 790.83 μmol, 45.27 μL, 1 eq) dropwise at 25°C. Then the reaction was stirred at 40°C for 12 hours in a 40 mL of sealed tube. Then sodium triacetoxyboranuide (419.02 mg, 1.98 mmol, 2.5 eq) was added to the mixture at 25°C. The reaction mixture was stirred at 25°C for 16 hours in a 40 mL of sealed tube. The mixture was concentrated under reduced pressure to give the residue. The residue was purified by prep-HPLC (HCl condition; column: Phenomenex luna C18100*40mm*5 um;mobile phase: [H2O(0.04% HCl)-ACN]; gradient:1%- 45% B over 8.0 min) and the desired eluent was lyophilized to give the product. The product was further purified again by prep-HPLC (HCl condition; column: Phenomenex luna C18 100*40mm*5 um;mobile phase: [H2O(0.04% HCl)-ACN];gradient:1%-35% B over 8.0 min) and the desired eluent was lyophilized to give Compound 29 (26.3 mg, 77.20 μmol, 9.76% yield, 98% purity, HCl) as yellow solid:1H NMR (400 MHz, DMSO-d6) δ 1.27 (br t, J=7.19 Hz, 6H), 1.52 (q, J=11.97 Hz, 2H), 2.22-2.30 (m, 2H), 2.36-2.43 (m, 2H), 3.04 (dt, J=13.26, 6.63 Hz, 2H), 3.11-3.18 (m, 2H), 3.38 (br s, 2H), 3.67-3.77 (m, 1H), 7.82-7.90 (m, 2H), 8.03 (td, J=3.60, 1.56 Hz, 2H), 9.55 (br s, 1H); Method A LCMS (ESI+): 1.919 min, m / z 298 (M+1). Example 30. Compound 30: 3-methyl-2,3,4,5-tetrahydro-1H-naphtho[2,3-d]azepine-6,11- dione 1. (HCHO)n(2 eq) O AcOH (1 eq) O NaOAc (3

[0204] To a solution of Compound 2 (150 mg, 568.79 μmol, 1 eq, HCl) and (HCHO)n(51.24 mg, 1.71 mmol, 47.00 μL, 3 eq) in MeOH (4 mL) was added AcOH (34.16 mg, 568.79 μmol, 32.56 μL, 1 eq) and NaOAc (139.97 mg, 1.71 mmol, 3 eq) in portions at 25°C under N2. The mixture was stirred at 40°C under N2for 1 hour. Then to the mixture was added NaBH3CN (107.23 mg, 1.71 mmol, 3 eq) in one portion at 25°C under N2. The mixture was stirred at 40°C under N2 for 1 hour. The combined mixture was added saturated aqueous Na2CO3 to adjusted to pH=8. Then the mixture was extracted with ethyl acetate (3 x 40 mL). The combined organic phases were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude. The crude was purified by prep-HPLC (neutral condition, column: Waters Xbridge Prep OBD C18150*40mm*10um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient:30%-70% B over 8.0 min) and the desired eluent was lyophilized to give Compound 30 (69 mg, 277.10 μmol, 48.72% yield, 96.9% purity) as a dark purple solid:1H NMR (400 MHz, DMSO-d6) δ ppm 2.25 (s, 3 H) 2.41 - 2.47 (m, 4 H) 2.85 - 2.93 (m, 4 H) 7.84 (br dd, J=5.50, 3.38 Hz, 2 H) 7.96 - 8.07 (m, 2 H); Method A LCMS (ESI+): 1.622 min, m / z 242 (M+H). Example 31. Compound 31: 3-ethyl-2,3,4,5-tetrahydro-1H-naphtho[2,3-d]azepine-6,11- dione

[0205] To a solution of Compound 2 (100 mg, 379.19 μmol, 1 eq, HCl) in DMF (3 mL) was added TEA (115.11 mg, 1.14 mmol, 158.34 μL, 3 eq) and iodoethane (295.70 mg, 758.38 μmol, 151.64 μL, 2 eq) in portions at 25°C under N2. The mixture was stirred at 25°C under N2 for 2 hours. One additional vial in 10 mg scale was set up as described above and these two reactions were combined. The combined mixture was diluted with H2O (30 mL) and extracted with ethyl acetate (3 x 40 mL). Then the combined organic phases were washed with brine (3 x 30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude. The crudewas purified by prep-HPLC (HCl condition, column: Phenomenex luna C18100*40mm*5 um;mobile phase: [H2O(0.04% HCl)-ACN];gradient:1%-30% B over 8.0 min) and the desired eluent was lyophilized to give Compound 31 (22 mg, 74.35 μmol, 17.82% yield, 98.6% purity, HCl) as a light-yellow solid:1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (t, J=7.25 Hz, 3 H) 2.85 - 3.03 (m, 2 H) 3.04 - 3.23 (m, 4 H) 3.37 - 3.38 (m, 2 H) 3.39 - 3.49 (m, 2 H) 3.54 - 3.72 (m, 2 H) 7.83 - 7.93 (m, 2 H) 8.00 - 8.10 (m, 2 H) 10.08 - 10.72 (m, 1 H); Method A LCMS (ESI+): 1.672 min, m / z 256 (M+H). Example 32. Compound 32: 3-(2-methoxyethyl)-2,3,4,5-tetrahydro-1H-naphtho[2,3- d]azepine-6,11-dione

[0206] To a solution of Compound 2 (150 mg, 568.79 μmol, 1 eq, HCl) in DMF (3 mL) was added TEA (172.67 mg, 1.71 mmol, 237.50 μL, 3 eq) and 1-bromo-2-methoxy-ethane (158.11 mg, 1.14 mmol, 106.90 μL, 2 eq) in portions at 25°C under N2. The mixture was stirred at 25°C under N2for 12 hours. The mixture was diluted with H2O (40 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine (3 x 40 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (HCl condition, column: Phenomenex luna C18 100*40mm*5 um;mobile phase: [H2O(0.04% HCl)-ACN];gradient:1%-40% B over 8.0 min) and the desired eluent was lyophilized to give Compound 32 (13 mg, 39.99 μmol, 7.03% yield, 99% purity, HCl) as a light-yellow solid:1H NMR (400 MHz, DMSO-d6) δ ppm 2.95 - 3.10 (m, 2 H) 3.14 - 3.26 (m, 2 H) 3.37 (br d, J=5.00 Hz, 7 H) 3.58 - 3.68 (m, 2 H) 3.71 (br t, J=4.82 Hz, 2 H) 7.82 - 7.94 (m, 2 H) 7.99 - 8.11 (m, 2 H) 10.55 (br s, 1 H); Method A LCMS (ESI+): 1.720 min, m / z 286 (M+H).Example 33. Compound 33: 3-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-naphtho[2,3- d]azepine-6,11-dionea mg, eq, was added TEA (172.67 mg, 1.71 mmol, 237.50 μL, 3 eq) and 2-iodoethanol (195.62 mg, 1.14 mmol, 88.92 μL, 2 eq) in portions at 25°C under N2. The mixture was stirred at 25°C under N2for 12 hours. One additional vial in 10 mg scale was set up as described above and these two reactions were combined. The mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (3 x 60 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (HCl condition, column: Phenomenex luna C18 100*40mm*5 um;mobile phase: [H2O(0.04% HCl)-ACN];gradient:1%-30% B over 8.0 min) and the desired eluent was lyophilized to give Compound 33 (23 mg, 73.98 μmol, 12.27% yield, 99% purity, HCl) as a light-yellow solid:1H NMR (400 MHz, DMSO-d6) δ ppm 2.99 - 3.12 (m, 2 H) 3.14 - 3.32 (m, 6 H) 3.67 (br dd, J=12.01, 7.75 Hz, 2 H) 3.79 (br s, 2 H) 5.28 - 5.47 (m, 1 H) 7.82 - 7.94 (m, 2 H) 7.99 - 8.10 (m, 2 H) 10.47 (br d, J=2.13 Hz, 1 H); Method A LCMS (ESI+): 1.598 min, m / z 272 (M+H). Example 34. Compound 34: 3-(2-fluoroethyl)-2,3,4,5-tetrahydro-1H-naphtho[2,3- d]azepine-6,11-dione

[0208] To a solution of Compound 2 (150 mg, 568.79 μmol, 1 eq, HCl) in DMF (3 mL) was added TEA (172.67 mg, 1.71 mmol, 237.50 μL, 3 eq) and 1-fluoro-2-iodo-ethane (197.89 mg, 1.14 mmol, 2 eq) in portions at 25°C under N2. The mixture was stirred at 25°C under N2 for 12 hours. The mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (3 x 60 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (HCl condition, column: Phenomenex luna C18100*40mm*5 um;mobile phase: [H2O(0.04% HCl)-ACN];gradient:1%-30% B over 8.0 min) and the desired eluent was lyophilized to give Compound 34 (45 mg, 145.27 μmol, 25.54% yield, 100% purity, HCl) as a light yellow solid:1H NMR (400 MHz, DMSO-d6) δ ppm 2.94 - 3.10 (m, 2 H) 3.19 - 3.29 (m, 2 H) 3.35 - 3.46 (m, 2 H) 3.50 - 3.77 (m, 4 H) 4.75 - 5.02 (m, 2 H) 7.82 - 7.94 (m, 2 H) 8.00 - 8.10 (m, 2 H) 10.93 (br d, J=1.13 Hz, 1 H);19F NMR (376 MHz, DMSO-d6) δ ppm - 218.76 (s, 1 F); Method A LCMS (ESI+): 1.673 min, m / z 274 (M+H). Example 35. Compound 35: 8-morpholino-7,8,9,10-tetrahydro-5H- cyclohepta[b]naphthalene-5,11(6H)-dione

[0209] To a mixture of Compound 12 (100 mg, 395.42 μmol, 1 eq, purity 95%) and morpholine (103.35 mg, 1.19 mmol, 104.39 μL, 3 eq) in dichloromethane (2 mL) was added AcOH (23.75 mg, 395.42 μmol, 22.64 μL, 1 eq) dropwise at 25°C. The reaction mixture was stirred at 25°C for 30 minutes. Then NaBH(OAc)3(209.51 mg, 988.54 μmol, 2.5 eq) was added to the mixture at 25°C. The reaction mixture was stirred at 25°C for 3 hours. The mixture was added saturated NaHCO3 (aqueous) to pH = 8. Then the mixture was extracted with ethyl acetate (3 x 40 mL). The combined organic phases were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (NH4HCO3 condition; column: Waters Xbridge Prep OBD C18150*40mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:30%-60% B over 8.0 min) and the desired eluent was lyophilized to give Compound 35 (100.4 mg, 315.99 μmol, 66.60% yield, 98% purity) as yellow solid:1H NMR (400 MHz, DMSO-d6) δ 1.28-1.41 (m, 2H), 1.85-1.96 (m, 2H), 2.07 (s, 1H), 2.22-2.34 (m, 2H), 2.43-2.48 (m, 4H), 2.61 (ddd, J=10.41, 7.54, 3.06 Hz, 1H), 3.23 (dd, J=14.45, 7.69 Hz, 2H), 3.49-3.59 (m, 4H), 7.83 (dd, J=5.69, 3.31 Hz, 2H), 7.97-8.04 (m, 2H); Method A LCMS (ESI+): 1.817 min, m / z 312 (M+1). Example 36. Compound 36: 8-((2-methoxyethyl)amino)-7,8,9,10-tetrahydro-5H- cyclohepta[b]naphthalene-5,11(6H)-dione

[0210] To a solution of Compound 12 (100 mg, 395.42 μmol, 1 eq) and 2- methoxyethanamine (89.10 mg, 1.19 mmol, 103.12 μL, 3 eq) in DCM (2 mL) was added AcOH (23.74 mg, 395.42 μmol, 22.64 μL, 1 eq) in one portion at 25°C under N2. The reaction mixture was stirred at 25°C for 30 minutes. Then NaBH(OAc)3(209.51 mg, 988.54 μmol, 2.5 eq) was added to the mixture in one portion at 25°C under N2. The mixture was stirred at 25°C under N2 for 1 hour. One additional vial in 20 mg scale was set up as described above and these two reactions were combined. The combined mixture was added saturated aqueous Na2CO3to adjusted to pH=8. Then the mixture was extracted with ethyl acetate (3 x 40 mL). The combined organic phases were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with tert-butyl methyl ether (10 mL) at 25°C for 30 minutes. The mixture was filtered and the filter cake was concentrated under reduced pressure to give Compound 36 (49 mg, 157.13 μmol, 33.12% yield, 96.4% purity) as a yellow solid:1H NMR (400 MHz, DMSO-d6) δ ppm 1.31 - 1.53 (m, 2 H) 2.14 - 2.31 (m, 2 H) 2.38 (br dd, J=14.57, 11.57 Hz, 2 H) 3.04 - 3.14 (m, 2 H) 3.23 - 3.32 (m, 6 H) 3.60 (t, J=5.13 Hz, 2 H) 7.79 - 7.92 (m, 2 H) 7.97 - 8.08 (m, 2 H) 8.53 - 9.07 (m, 1 H); Method A LCMS (ESI+): 1.864 min, m / z 300 (M+H).Example 37. Compound 37: 8-((2-hydroxyethyl)amino)-7,8,9,10-tetrahydro-5H- cyclohepta[b]naphthalene-5,11(6H)-dioneaminoethan-1-ol (72.46 mg, 1.19 mmol, 71.60 μL, 3 eq) in dichloromethane (1 mL) was added AcOH (23.75 mg, 395.42 μmol, 22.64 μL, 1 eq) dropwise at 25°C. The reaction mixture was stirred at 25°C for 30 minutes. Then sodium triacetoxyboranuide (209.51 mg, 988.54 μmol, 2.5 eq) was added to the mixture at 25°C. The reaction mixture was stirred at 25°C for 3 hours. The combined mixture was added saturated Na2CO3(aqueous) to pH = 8. Then the mixture was extracted with ethyl acetate (3 x 40 mL). The combined organic phases were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with tert-butyl methyl ether: ethyl acetate = 5:1. The mixture was filtered and the filter cake was collected. The filter cake was dried by high vacuum to give the Compound 37 (65.4 mg, 221.41 μmol, 46.66% yield, 96.6% purity) as orange solid:1H NMR (400 MHz, DMSO-d6) δ 1.15-1.28 (m, 2H), 1.85-1.96 (m, 2H), 2.41 (br dd, J=14.38, 10.76 Hz, 2H), 2.63 (t, J=5.75 Hz, 2H), 2.73-2.84 (m, 1H), 3.07-3.19 (m, 2H), 3.45 (br d, J=2.25 Hz, 2H), 4.51 (br s, 1H), 7.80-7.86 (m, 2H), 7.97-8.04 (m, 2H); Method A LCMS (ESI+): 1.776 min, m / z 286 (M+1). Example 38. Compound 38: 8-((2-fluoroethyl)amino)-7,8,9,10-tetrahydro-5H- cyclohepta[b]naphthalene-5,11(6H)-dione

[0212] To a solution of Compound 12 (100 mg, 395.42 μmol, 1 eq, purity 95%) and 2- fluoroethanamine (118.07 mg, 1.19 mmol, 3 eq, HCl) in dichloromethane (2 mL) was added AcOH (23.75 mg, 395.42 μmol, 22.64 μL, 1 eq) dropwise at 25°C. The reaction mixture was stirred at 25°C for 1 hour. Then sodium triacetoxyboranuide (209.51 mg, 988.54 μmol, 2.5 eq) was added to the mixture at 25°C. The reaction mixture was stirred at 25°C for 3 hours. The combined mixture was added saturated NaHCO3 (aqueous) to pH = 8. Then the mixture was extracted with ethyl acetate (3 x 40 mL). The combined organic phases were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (NH4HCO3 condition; column: Waters Xbridge Prep OBD C18150*40mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:15%-45% B over 8.0 min) and the desired eluent was lyophilized to give the product, which was purified again by prep-HPLC (HCl condition; column: Phenomenex luna C18100*40mm*5 um;mobile phase: [H2O(0.04% HCl)-ACN];gradient:5%-50% B over 8.0 min) and the desired eluent was lyophilized to give the Compound 38 (47.6 mg, 145.54 μmol, 30.67% yield, 99% purity, HCl) was as light yellow solid:1H NMR (400 MHz, DMSO-d6) δ 1.39 (q, J=11.72 Hz, 2H), 2.20-2.30 (m, 2H), 2.37 (br dd, J=14.70, 11.94 Hz, 2H), 3.25-3.34 (m, 3H), 3.35-3.40 (m, 1H), 3.47 (ddd, J=11.07, 7.63, 3.44 Hz, 1H), 4.63-4.80 (m, 2H), 7.80-7.88 (m, 2H), 8.01 (dd, J=5.75, 3.38 Hz, 2H);19F NMR (376 MHz, DMSO-d6) δ -222.39 (s, 1F); Method A LCMS (ESI+): 1.812 min, m / z 288 (M+1). Example 39. Compound 39: N-(5,11-dioxo-6,7,8,9,10,11-hexahydro-5H- cyclohepta[b]naphthalen-8-yl)acetamide

[0213] To a solution of Compound 28 (40 mg, 133.94 μmol, 1 eq, HCl) in DMF (2 mL) was added TEA (40.66 mg, 401.81 μmol, 55.93 μL, 3 eq) and acetyl chloride (21.03 mg, 267.87 μmol, 19.05 μL, 2 eq) in portions at 0°C under N2. The mixture was stirred at 0°C under N2for2 hours. One additional vial in 20 mg scale was set up as described above and these two reactions were combined. Then the mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the residue. The residue was purified by prep-HPLC (HCl condition, column: Phenomenex luna C18100*40mm*5 um;mobile phase: [H2O(0.04% HCl)-ACN];gradient:15%-55% B over 8.0 min) and the desired eluent was lyophilized to give Compound 39 (10 mg, 33.53 μmol, 18.21% yield, 95% purity) as a yellow solid:1H NMR (400 MHz, DMSO-d6) δ ppm 1.11 - 1.34 (m, 2 H) 1.79 (s, 3 H) 1.85 - 1.97 (m, 2 H) 2.40 (br dd, J=14.45, 11.07 Hz, 2 H) 3.16 (dd, J=14.76, 7.75 Hz, 2 H) 3.84 - 4.01 (m, 1 H) 7.83 (dd, J=5.69, 3.31 Hz, 2 H) 7.88 (br s, 1 H) 8.01 (dd, J=5.69, 3.31 Hz, 2 H); Method A LCMS (ESI+): 2.179 min, m / z 284 (M+H). Example 40. Compound 40: N-(5,11-dioxo-6,7,8,9,10,11-hexahydro-5H- cyclohepta[b]naphthalen-8-yl)methanesulfonamideprepared in a similar manner as Compound 39.1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.01 (br dd, J = 5.3, 3.4 Hz, 2H), 7.84 (br s, 2H), 7.22 (br s, 1H), 3.55 (br t, J = 9.6 Hz, 1H), 3.14 (br dd, J = 14.7, 8.2 Hz, 2H), 2.96 (s, 3H), 2.44 (br t, J = 12.3 Hz, 2H), 1.94- 2.06 (m, 2H), 1.26-1.44 (m, 2H). Method B LCMS (ESI+): rt = 2.634 min, m / z 318 (M-H). Example 41. Compound 41: 2,2-dimethyl-2,3,4,5-tetrahydro-1H-naphtho[2,3-d]azepine- 6,11-dione

[0215] To a suspension of Pd / C (200.00 mg, 939.67 μmol, 50% purity, 4.07 eq) in MeOH (10 mL) was added Compound 48 (0.1 g, 231.10 μmol, 1 eq) and HCl (1 M, 231.10 μL, 1 eq) under an N2 atmosphere. The suspension was degassed and purged with H23 times. The mixture was stirred under H2(465.85 μg, 231.10 μmol, 1 eq) (15 Psi) for 12 hrs at 20°C. Upon reaction completion, the suspension was filtered through celite and the filtrate was concentrated under reduced pressure. One additional reaction on 20 mg scale was set up as described above. The product was purified by prep-HPLC and lyophilized to give Compound 41 (30.2 mg, 99.37 μmol, 35.83% yield, 96% purity, HCl) as yellow solid. Prep-HPLC method: Column: Phenomenex luna C18100*40mm*5 um; mobile phase: [H2O (0.04% HCl)-ACN]; gradient: 1%-30% B over 8.0 min.1H NMR (METHANOL-d4, 400 MHz) δ (ppm) 8.07-8.23 (m, 2H), 7.76-7.92 (m, 2H), 3.37-3.43 (m, 2H), 3.24-3.31 (m, 2H), 3.23 (s, 2H), 1.45 (s, 6H). Method C LCMS (ESI+): rt = 1.710 min, m / z 256 (M+H). Example 42. Compound 42: 1',3',4',5'-tetrahydrospiro[cyclohexane-1,2'-naphtho[2,3- d]azepine]-6',11'-dione

[0216] To a solution g, (50 mL) was addedSOCl2 (7.57 g, 63.61 mmol, 4.62 mL, 2 eq) dropwise at 0°C under N2. The mixture was stirred at 40°C for 12 hours under N2. Upon completion, the reaction mixture was concentrated underreduced pressure to give Intermediate 42-2 (6.6 g, 25.42 mmol, 79.93% yield, 80% purity, HCl)as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 1.21 - 1.51 (m, 4 H) 1.53 - 1.79 (m, 6 H) 2.76 (s, 2 H)8.18 (br s, 3 H).

[0217] To a solution of Intermediate 42-2 (4 g, 15.41 mmol, 1HCl) in methyl prop-2-enoate(7.96 g, 92.44 mmol, 8.32 mL, 6 eq) was added TEA (4.68 g, 46.22 mmol, 6.43 mL, 3 eq) dropwise at 20°C under N2. The mixture was stirred at 70°C for 24 hours under N2. One additional reaction on 1 g scale was set up as described above and these two reactions were combined. The resulting mixture was filtered and the filter cake was washed with petroleum ether (50 mL). The filtrate was concentrated under reduced pressure. The crude residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=99 / 1to 1 / 1) and thedesired eluent was concentrated under reduced pressure to give Intermediate 42-3 (3 g, 10.49mmol, 54.48% yield, 90% purity) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ ppm 1.12 - 1.39 (m, 5 H) 1.40 - 1.59 (m, 5 H) 2.30 - 2.42 (m, 4 H) 2.65 (br t, J=6.32 Hz, 2 H) 3.57 (d, J=10.63 Hz, 5 H).

[0218] To a g, and THF (15mL) was added NaHCO3(1.76 g, 20.99 mmol, 816.56 μL, 3 eq) and benzyl chloroformate (2.39 g, 13.99 mmol, 2.00 mL, 2 eq) in portions at 0°C. The mixture was stirred at 70°C for 12 hours. One additional reaction on 1 g scale was set up as described above and these two reactions were combined. The resulting mixture was diluted with H2O (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic phase was washed with brine (2 x 30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=99 / 1 to 1 / 1) and the desired eluentwas concentrated under reduced pressure to give Intermediate 42-4 (4.9 g, 9.39 mmol, 89.47%yield, 75% purity) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ ppm 1.24 - 1.55 (m, 7 H) 1.76 (br t, J=10.13 Hz, 2 H) 2.11 (br d, J=12.76 Hz, 2 H) 2.52 - 2.60 (m, 2 H) 2.91 (s, 2 H) 3.46 - 3.60 (m, 7 H) 5.06 (s, 2 H) 7.28 - 7.40 (m, 7 H).

[0219] To a solution of Intermediate 42-4 (4.4 g, 8.43 mmol, 1 eq) in THF (30 mL), MeOH (10mL) and H2O (10 mL) was added LiOH (1.42 g, 33.72 mmol, 4 eq) in one portion at 20°C. The mixture was stirred at 20°C for 12 hours. Upon completion, the mixture was diluted with H2O (30 mL) and extracted with ethyl acetate (2 x 60 mL). The aqueous phase was adjusted to pH=3 with aqueous of 1N HCl (20 mL) and extracted with ethyl acetate (3 x 60 mL). The combined organic phase was washed with brine (2 x 40 mL), dried over Na2SO4, filtered and concentratedunder reduced pressure to give Intermediate 42-5 (3.7 g, 8.15 mmol, 96.62% yield, 80% purity)as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 - 1.54 (m, 6 H) 1.74 (br t, J=10.19 Hz, 2 H) 2.18 (br d, J=13.01 Hz, 2 H) 2.44 - 2.49 (m, 2 H) 2.85 (s, 2 H) 3.45 - 3.56 (m, 2 H) 5.06 (s, 2 H) 7.23 - 7.43 (m, 5 H) 11.83 - 12.41 (m, 2 H).

[0220] To a solution of naphthalene-1,4-dione (0.1 g, 632.30 μmol, 1 eq) and Intermediate 42-5 (344.67 mg, 758.76 μmol, 1.2 eq) in ACN (4 mL) and H2O (2 mL) was added AgNO3 (139.63 mg, 821.99 μmol, 1.3 eq) in one portion at 20°C. The mixture was stirred at 90°C for 0.5 hours.Then the mixture was cooled to 20°C. A solution of ammonium persulfate (461.73 mg, 2.02 mmol, 439.75 μL, 3.2 eq) in H2O (2 mL) and ACN (4 mL) was added dropwise at 20°C. The mixture was stirred at 90°C for 3.5 hours. Upon completion, the mixture was cooled to 20°C and quenched with aqueous of saturated sodium sulfite (30 mL). The aqueous phase was extracted with ethyl acetate (3 x 50 mL). The combined organic phase was washed with brine (2 x 30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by prep-HPLC (neutral condition) and the desired eluent was lyophilized give the product Compound 42 (8.5 mg, 18.94 μmol, 3.00% yield, 95.7% purity) as a yellow solid. column: Waters Xbridge Prep OBD C18150*40mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:35%-85% B over 8.0 min.1H NMR (400 MHz, DMSO-d6) δ ppm 1.04 - 1.19 (m, 1 H) 1.39 - 1.54 (m, 6 H) 1.59 (br d, J=13.38 Hz, 1 H) 2.52 - 2.63 (m, 2 H) 2.87 (br t, J=5.50 Hz, 2 H) 3.37 (s, 2 H) 3.96 (t, J=5.82 Hz, 2 H) 5.04 (s, 2 H) 7.27 - 7.42 (m, 5 H) 7.80 - 7.88 (m, 2 H) 7.94 - 8.07 (m, 2 H). Method C LCMS (ESI+): rt = 3.249 min, m / z 430 (M+H). Example 43. Compound 43: 1,2',3,3',4,5,5',6'-octahydrospiro[naphtho[2,3-d]azepine-2,4'- pyran]-6,11-dione

[0221] Compound 43 was prepared in a similar manner as Compound 41 using Compound 78 as starting material.1H NMR (400 MHz, DMSO-d6) δ ppm 1.65 - 1.80 (m, 2 H) 1.82 - 1.93 (m, 2 H) 2.07 (s, 1 H) 3.16 (br s, 2 H) 3.26 (br s, 4 H) 3.52 (br t, J=11.13 Hz, 2 H) 3.80 (br d, J=11.13 Hz, 2 H) 7.83 - 7.94 (m, 2 H) 8.00 - 8.12 (m, 2 H) 9.35 (br s, 2 H). Method C LCMS (ESI+): rt = 1.694 min, m / z 298 (M+H). Example 44. Compound 44: tert-butyl (2-(5,11-dioxo-6,7,8,9,10,11-hexahydro-5H- cyclohepta[b]naphthalen-8-yl)ethyl)carbamate

[0222] To a mixture of NaH (5.21 g, 130.29 mmol, 60% purity, 1.5 eq) in THF (300 mL) was added 2-diethoxyphosphorylacetonitrile (18.46 g, 104.23 mmol, 16.86 mL, 1.2 eq) in THF (50 mL) dropwise at 0°C under N2. The mixture was stirred for 60 min at 20°C under N2.Then Intermediate 44-1 (20 g, 86.86 mmol, 18.64 mL, 1 eq) in THF (50 mL) was added to themixture at 20°C under N2. The mixture was stirred for 12 hrs at 20°C. LCMS showed the starting material was consumed. The mixture was quenched by adding NH4Cl (aqueous, 600 mL) dropwise at 0°C. Then the mixture was extracted with ethyl acetate (3 x 300 mL). The combined organic phases were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Ethyl acetate in Petroleum ether = 20-30%, Rf = 0.49) to give Intermediate 44-2 (10.9 g, 42.77 mmol, 49.25% yield, 99.4% purity) as a colorless oil.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.19 (s, 1 H), 4.16 (qd, J=7.13, 4.50 Hz, 4 H), 2.70 - 2.80 (m, 2 H), 2.43 - 2.62 (m, 6 H), 1.27 (td, J=7.10, 4.94 Hz, 6 H). Method A LCMS (ESI+): rt = 2.221 min, m / z 254 (M+H).

[0223] To a mixture of nickel (231.72 mg, 3.95 mmol, 1 eq) in MeOH (40 mL) was added Intermediate 44-2 (1 g, 3.95 mmol, 1 eq) and Boc2O (1.72 g, 7.90 mmol, 1.81 mL, 2 eq) at 20°C under N2. The mixture was degassed and purged with H23 times. The mixture was stirred for 5 hrs at 30°C under H2(30 psi). LCMS showed the starting material was consumed. The mixture was filtered through celite and the filtrate was concentrated under reduced pressure.The crude residue was purified by column chromatography (SiO2, Ethyl acetate in Petroleum ether =5-15%) to give Intermediate 44-3 (1.3 g, 3.62 mmol, 91.61% yield, 100% purity) as a colorless oil.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.60 (br s, 1 H), 4.13 (q, J=7.13 Hz, 4 H), 3.15 (br d, J=5.63 Hz, 2 H), 2.31 (t, J=7.75 Hz, 4 H), 1.57 - 1.68 (m, 5 H), 1.41 - 1.49 (m, 11 H), 1.26 (t, J=7.19 Hz, 6 H). Method A LCMS (ESI+): rt = 2.587 min, m / z 260 (M+H- 100).a g, , MeOH (30 mL) and H2O (15 mL) was added LiOH.H2O (2.45 g, 58.42 mmol, 3 eq) in portions at 20°C. The mixture was stirred for 12 hrs at 20°C. LCMS showed the starting material consumed. The mixture was cooled to 0oC and the pH was adjusted to 4 by the dropwise addition of 2M HCl. The mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure to give Intermediate 44-4 (5.8 g, 19.12 mmol, 98.18% yield) as a white solid which was used for next step without further purification.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.72 (br s, 1 H), 3.16 (br s, 2 H), 2.30 - 2.50 (m, 4 H), 1.62 (q, J=6.42 Hz, 4 H), 1.45 (br s, 12 H). Method A LCMS (ESI+): rt = 1.885 min, m / z 204 (M+H-100).

[0225] To a mixture of naphthalene-1,4-dione (1 g, 6.32 mmol, 1 eq) and Intermediate 44-4 (2.88 g, 9.48 mmol, 1.5 eq) in MeCN (100 mL) and H2O (50 mL) was added AgNO3 (1.29 g, 7.59 mmol, 1.2 eq) in portions at 20°C. The mixture was stirred for 30 min at 100°C. Then asolution of ammonium persulfate (4.62 g, 20.23 mmol, 4.40 mL, 3.2 eq) in MeCN (100 mL) and H2O (50 mL) was added to the mixture dropwise at 25°C. The mixture was stirred for 3 hrs at 100°C. LCMS showed desired product was generated. The reaction solution was cooled to rt. Then THF (50 mL), NaHCO3(6.36 g, 75.74 mmol, 2.95 mL, 12 eq) and Boc2O (2.76 g, 12.62 mmol, 2.90 mL, 2 eq) were added. The mixture was stirred for 12 hrs at 20°C. LCMS showed the desired product. The mixture was partitioned between ethyl acetate (50 mL) and water (100 mL). The mixture was extracted with ethyl acetate (3 x 100 mL). The organic layer was washed with saturated sodium sulfite solution (50 mL), dried with Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (SiO2, Ethyl acetate in Petroleum ether = 5%) and then perp-HPLC (FA condition, column: Phenomenex luna C18 100*40 mm*5 um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 50%-85% B over 8.0 min), lyophilized to give Compound 44 (90 mg, 235.81 μmol, 3.74% yield, 96.8% purity) as a light yellow solid.1H NMR (400 MHz, DMSO-d6) δ ppm 8.00 (dd, J=5.63, 3.38 Hz, 2 H), 7.83 (dd, J=5.63, 3.38 Hz, 2 H), 6.77 (br t, J=4.82 Hz, 1 H), 3.29 (s, 1 H), 3.19 (br dd, J=14.57, 7.32 Hz, 2 H), 2.96 (q, J=6.42 Hz, 2 H), 2.30 - 2.40 (m, 2 H), 1.79 - 1.90 (m, 2 H), 1.72 (br d, J=2.38 Hz, 1 H), 1.37 (s, 9 H), 1.31 (q, J=6.96 Hz, 2 H), 0.90 - 1.05 (m, 2 H). Method A LCMS (ESI+): rt = 2.817 min, m / z 270 (M+H-100), 392 (M+23). Example 45. Compound 45: 8-(2-aminoethyl)-7,8,9,10-tetrahydro-5H- cyclohepta[b]naphthalene-5,11(6H)-dione

[0226] A mixture of Compound 44 (60 mg, 157.21 μmol, 1 eq) in HCl / EtOAc (10 mL) was stirred for 3 hrs at 20°C. LCMS showed the reaction was complete. One additional in 5 mg scale was set up as described above and combined. The mixture was concentrated under reduced pressure to give Compound 45 (52.5 mg, 165.50 μmol, 97.48% yield, 96.4% purity, HCl) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ ppm 8.01 (dd, J=5.75, 3.25 Hz, 2 H), 7.82 - 7.87(m, 2 H), 7.78 (br s, 3 H), 3.21 (br dd, J=14.26, 7.25 Hz, 2 H), 2.76 - 2.92 (m, 2 H), 2.37 (dd, J=13.70, 11.94 Hz, 2 H), 1.74 - 1.92 (m, 3 H), 1.42 - 1.55 (m, 2 H), 0.91 - 1.09 (m, 2 H). Method A LCMS (ESI+): rt = 1.909 min, m / z 270 (M+H). Example 46. Compound 46: 3-(dimethylglycyl)-2,3,4,5-tetrahydro-1H-naphtho[2,3- d]azepine-6,11-dioneprepared in a similar manner as Compound 8.1H NMR (400 MHz, DMSO-d6) δ ppm 2.82 (br s, 6 H) 2.94 - 3.02 (m, 2 H) 3.02 - 3.10 (m, 2 H) 3.53 - 3.61 (m, 2 H) 3.69 - 3.77 (m, 2 H) 4.35 (br s, 2 H) 7.79 - 7.94 (m, 2 H) 7.96 - 8.11 (m, 2 H) 9.61 (br d, J=0.88 Hz, 1 H). Method C LCMS (ESI+): rt = 1.744 min, m / z 313 (M+H). Example 47. Compound 47: 3-(2-(piperidin-1-yl)acetyl)-2,3,4,5-tetrahydro-1H-naphtho[2,3- d]azepine-6,11-dionein a similar manner as Compound 8.1H NMR (400 MHz, DMSO-d6) δ ppm 1.32 - 1.47 (m, 1 H) 1.62 - 1.85 (m, 5 H) 2.89 - 3.01 (m, 4 H) 3.02 - 3.10 (m, 2 H) 3.40 (br d, J=1.13 Hz, 2 H) 3.54 - 3.65 (m, 2 H) 3.68 - 3.81 (m, 2 H) 4.32 (br d, J=4.75 Hz, 2 H) 7.82 - 7.93 (m, 2 H) 7.95 - 8.12 (m, 2 H) 9.40 (br d, J=2.50 Hz, 1 H). Method C LCMS (ESI+): rt = 1.848 min, m / z 353 (M+H). Example 48. Compound 48: benzyl 2,2-dimethyl-6,11-dioxo-1,2,4,5,6,11-hexahydro-3H- naphtho[2,3-d]azepine-3-carboxylate

[0229] To a solution of Intermediate 48-1 (5.4 g, 29.73 mmol, 1 eq) in methyl prop-2-enoate (7.68 g, 89.18 mmol, 8.03 mL, 3 eq) was added TEA (3.01 g, 29.73 mmol, 4.14 mL, 1 eq) dropwise at 25°C under N2. The mixture was stirred at 70°C for 12 hours under N2. Upon completion, the mixture was filtered and the filter cake was washed with ethyl acetate (100 mL). Then the filtrate was concentrated under reduced pressure to give the Intermediate 48-2 (4.8 g,18.68 mmol, 62.83% yield, 90% purity) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ ppm1.06 (s, 6 H) 1.17 (t, J=7.13 Hz, 3 H) 2.29 - 2.41 (m, 4 H) 2.69 (t, J=6.75 Hz, 2 H) 3.58 (s, 3 H) 4.04 (q, J=7.05 Hz, 2 H).

[0230] To a solution of Intermediate 48-2 (2.5 g, 9.73 mmol, 1 eq) in H2O (10 mL) and THF (10 mL) was added NaHCO3 (2.45 g, 29.18 mmol, 1.14 mL, 3 eq) and benzyl chloroformate (1.83 g, 10.70 mmol, 1.53 mL, 1.1 eq) in portions at 0°C under N2. The mixture was stirred at 25°C for 4 hours under N2. LCMS showed the starting material was consumed completely and one main peak with desired mass was detected. One additional reaction on 1.5 g scale was set up as described above and these two reactions were combined. The mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with brine (3 x 40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=99 / 1 to 1 / 1) and the desired eluent was concentrated under reduced pressure to give Intermediate 48-3 (5.6 g, 13.79 mmol, 88.61% yield, 90% purity) as a yellow oil.1HNMR (400 MHz, DMSO-d6) δ ppm 1.12 (t, J=7.13 Hz, 3 H) 1.42 (s, 6 H) 2.53 (br d, J=7.75 Hz,2 H) 2.88 (s, 2 H) 3.49 - 3.59 (m, 5 H) 3.99 (q, J=7.13 Hz, 2 H) 4.49 (d, J=5.75 Hz, 1 H) 5.06 (s, 2 H) 7.27 - 7.40 (m, 6 H).

[0231] To a solution of Intermediate 48-3 (4.6 g, 11.33 mmol, 1 eq) in THF (30 mL), MeOH (10 mL) and H2O (10 mL) was added LiOH (1.09 g, 45.32 mmol, 4 eq) in one portion at 25°C. The mixture was stirred at 25°C for 12 hours. LCMS showed the starting material was consumed completely and one main peak with the desired mass was detected. The mixture was diluted with H2O (30 mL) and extracted with ethyl acetate (2 x 60 mL). The aqueous phase was adjusted to pH=3 with aqueous 1N HCl (20 mL) and extracted with ethyl acetate (3 x 60 mL). The combined organic phases were washed with brine (2 x 40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give Intermediate 48-4 (3.6 g, 10.02 mmol, 88.45% yield, 90% purity) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (s, 6 H) 2.42 - 2.49 (m, 2 H) 2.82 (s, 2 H) 3.44 - 3.59 (m, 2 H) 5.07 (s, 2 H) 7.19 - 7.49 (m, 5 H) 11.91 - 12.33 (m, 2 H).48-4 (408.89 mg, 1.14 mmol, 1.2 eq) in ACN (5 mL) and H2O (3 mL) was added AgNO3 (209.45 mg, 1.23 mmol, 1.3 eq) in portions at 25°C. The mixture was stirred at 100°C for 0.5 hours. Then the mixture was cooled to 25°C, and a solution of ammonium persulfate (692.60 mg, 3.04 mmol, 659.62 μL, 3.2 eq) in ACN (5 mL) and H2O (3 mL) was added dropwise at 25°C. The resulting mixture was stirred at 100°C under N2for 3 hours. LCMS showed the starting material was consumed completely and 26% of desired mass was detected. The mixture wascooled to 25°C, and quenched with aqueous saturated sodium sulfite (30 mL). The aqueous phase was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with brine (2 x 30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by prep-HPLC (HCl condition) and the desired eluent was lyophilized to give the product Compound 48 (33.7 mg, 77.88 μmol, 8.21% yield, 91.6% purity)as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.40 (s, 6 H) 2.88 (br t, J=5.75 Hz, 2H) 3.16 (s, 2 H) 3.94 (t, J=5.88 Hz, 2 H) 5.04 (s, 2 H) 7.24 - 7.43 (m, 5 H) 7.78 - 7.89 (m, 2 H) 7.95 - 8.06 (m, 2 H). Method C LCMS (ESI+): rt = 3.025 min, m / z 390 (M+H). Example 49. Compound 49: Ethyl 2-(5,11-dioxo-5,6,7,9,10,11-hexahydro-8H- cyclohepta[b]naphthalen-8-ylidene)acetateμmol, 82.58 μL, 2 eq) in THF (3 mL) was added t-BuOK (46.70 mg, 416.23 μmol, 2 eq) at 0°C. The mixture was stirred at 20°C for 1 hour. Then Compound 12 (50 mg, 208.11 μmol, 1 eq) was added to the mixture. The mixture was stirred at 25°C for 2 hours. Eighteen additional reactions on 50 mg scale were set up as described above. LCMS showed the reaction worked. The mixture was diluted with ethyl acetate (15 mL) and water (15 mL). The aqueous phase was extracted with ethyl acetate (3 x 10 mL). The organic layer was dried with Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The crude product was combined and purified by prep-HPLC and lyophilized to give Compound 49 (0.34 g, 1.10 mmol, 27.71% yield) as yellow solid.1H NMR (CHLOROFORM-d, 400 MHz) δ (ppm) 8.05-8.16 (m, 2H), 7.66-7.77 (m, 2H), 5.76 (s, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.05-3.15 (m, 2H), 2.95-3.03 (m, 4H), 2.45-2.54 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H). Method C LCMS (ESI+): 2.759 min, m / z 311 (M+1). Example 50. Compound 50: Ethyl 2-(5,11-dioxo-6,7,8,9,10,11-hexahydro-5H- cyclohepta[b]naphthalen-8-yl)acetate

[0234] To a suspension of Pd / C (85.73 mg, 80.56 μmol, 10% purity, 0.1 eq) in THF (10 mL) was added Compound 49 (250 mg, 805.56 μmol, 1 eq) at 25°C. The mixture was charged with H23 times. The mixture was stirred at 25°C for 12 hours under H2 (15 psi). Upon completion, the reaction mixture was filtered and the filtrate was concentrated. The crude product was purified by prep-HPLC and lyophilized to give Compound 50 (4 mg, 12.68 μmol, 1.57% yield, 99% purity) as a yellow solid.1H NMR (DMSO-d6, 400 MHz) δ (ppm) 8.00 (dd, J = 5.7, 3.3 Hz, 2H), 7.83 (dd, J = 5.7, 3.3 Hz, 2H), 4.06 (q, J = 7.1 Hz, 2H), 3.21 (dd, J = 14.6, 7.2 Hz, 2H), 2.33-2.44 (m, 2H), 2.21-2.26 (m, 2H), 2.11-2.19 (m, 1H), 1.77-1.90 (m, 2H), 1.18 (t, J = 7.1 Hz, 3H), 0.97-1.12 (m, 2H). Method C LCMS (ESI+): rt = 2.897 min, m / z 312 (M+1). Example 51. Compound 51: 2-(5,11-Dioxo-6,7,8,9,10,11-hexahydro-5H- cyclohepta[b]naphthalen-8-yl)acetic Acidprepared in a similar manner as Compound 50.1H NMR (DMSO- d6, 400 MHz) δ (ppm) 12.07 (s, 1H), 7.93-8.05 (m, 2H), 7.76-7.90 (m, 2H), 3.20 (dd, J = 14.5, 7.1 Hz, 2H), 2.32-2.44 (m, 2H), 2.14 (s, 3H), 1.85 (br dd, J = 12.8, 8.3 Hz, 2H), 0.96-1.10 (m, 2H). Method B LCMS (ESI+): rt = 2.329 min, m / z 283 (M-1). Example 52. Compound 52: cis-2,4-Dimethyl-2,3,4,5-tetrahydro-1H-naphtho[2,3-d]azepine- 6,11-dione

[0236] To a solution of Intermediate 52-1 (40 g, 207.21 mmol, 28.53 mL, 1 eq) in acetone (200 mL) was added Na2S (8.09 g, 103.61 mmol, 4.35 mL, 0.5 eq) at 20°C. The mixture was stirred for 12 hrs at 60°C. TLC (petroleum ether: ethyl acetate =5:1, Rf = 0.39) showed the desired product. Two additional reactions on 40 g scale were set up as described above and combined. The filtrate was purified by column chromatography (SiO2, Ethyl acetate in Petroleum ether = 5-25%, Rf = 0.39) to give Intermediate 52-2 (33.3 g, 128.90 mmol, 20.74% yield) as a colorless oil.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.76 - 6.97 (m, 2 H), 5.81 - 5.96 (m, 2 H), 4.17 - 4.30 (m, 4 H), 3.13 - 3.43 (m, 4 H), 1.31 (t, J=7.13 Hz, 6 H).

[0237] To a mixture of Intermediate 52-2 (18.3 g, 70.84 mmol, 1 eq) in EtOH (92 mL) was added PMBNH2(29.15 g, 212.52 mmol, 27.58 mL, 3 eq) at 20°C. The mixture was stirred for 20 hrs at 60°C. LCMS showed the reaction worked. One additional reaction on 15 g scale was set up as described above and combined. Without work up the mixture was purified by column chromatography (SiO2, eluent of 5-10% ethyl acetate in petroleum ether) to give Intermediate 52-3 (15 g, 37.93 mmol, 29.42% yield) as a light orange oil.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.18 (d, J=8.50 Hz, 2 H), 6.84 (d, J=8.63 Hz, 2 H), 4.10 (qd, J=7.09, 3.13 Hz, 4 H), 3.80 (s, 3 H), 3.67 - 3.78 (m, 2 H), 3.58 - 3.67 (m, 2 H), 2.60 - 2.80 (m, 6 H), 2.43 (dd, J=13.51, 6.88 Hz, 2 H), 1.22 (t, J=7.13 Hz, 6 H).mL) was added Intermediate 52-3 (4 g, 10.11 mmol, 1 eq) in 10 mL EtOH at 20°C. The mixture was degassed and purged with H23 times and stirred for 5 hrs at 80°C under H2 (30 psi). LCMS showed the reaction was complete. The mixture was filtered through celite. One additionalreaction on 3 g scale was set up as described above and the filtrate was combined and concentrated under reduced pressure to give Intermediate 52-4 (5 g, 13.68 mmol, 77.30% yield) as a light orange oil which was used for next step directly.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.21 (d, J=8.50 Hz, 2 H), 6.83 (d, J=8.63 Hz, 2 H), 4.00 - 4.21 (m, 4 H), 3.80 (s, 3 H), 3.68 (d, J=14.13 Hz, 1 H), 3.50 (d, J=14.26 Hz, 1 H), 3.36 (sxt, J=6.85 Hz, 2 H), 2.51 (dd, J=14.45, 6.82 Hz, 2 H), 2.29 (dd, J=14.38, 7.75 Hz, 2 H), 1.23 (t, J=7.13 Hz, 6 H), 1.11 (d, J=6.63 Hz, 6 H).a g, 0.1 eq) (100 mL) was added Intermediate 52-4 (5 g, 13.68 mmol, 1 eq) at 20°C. The mixture was degassedand purged with H23 times. The mixture was stirred for 3 hrs at 70°C under H2 (50 psi). LCMSshowed the starting material was consumed. The mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give a residue of Intermediate 52-5 (3.3 g, 13.45 mmol, 98.32% yield) as a colorless oil.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.14 (q, J=7.13 Hz, 4 H), 3.12 - 3.28 (m, 2 H), 2.27 - 2.45 (m, 4 H), 1.27 (t, J=7.13 Hz, 6 H), 1.10 (d, J=6.38 Hz, 6 H).

[0240] To a mixture of Intermediate 52-5 (2.6 g, 11.24 mmol, 1 eq) in THF (15 mL) and H2O (15 mL) was added NaHCO3 (5.67 g, 67.45 mmol, 2.62 mL, 6 eq) and Boc2O (12.27 g, 56.21 mmol, 12.91 mL, 5 eq) in order at 20°C. The mixture was stirred for 12 hrs at 20°C. LCMS showed the reaction was complete. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by column chromatography (SiO2, Ethyl acetate in Petroleum ether = 0-15%) to give Intermediate 52-6 (1.85 g, 5.83 mmol, 51.85% yield) as a colorless oil. 1H NMRCHLOROFORM- δ 4.23 - 4.50 1 3.86 - 4.01 1 3.58 - 3.74

[0241] To a mixture of Intermediate 52-6 (1.85 g, 5.83 mmol, 1 eq) in THF (8 mL) and MeOH (8 mL) was added a solution of LiOH.H2O (733.82 mg, 17.49 mmol, 3 eq) in H2O (4 mL) dropwise at 20°C. The mixture was stirred for 2 hrs at 20°C. LCMS showed the starting material was consumed. The pH of the reaction mixture was adjusted to 5 with the dropwise addition of 1M HCl. The resulting solution was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure to give Intermediate 52-7 (1 g, 3.46 mmol, 59.30% yield) as a colorless oil.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.30 - 4.67 (m, 1 H), 3.88 - 4.08 (m, 1 H), 2.87 - 3.10 (m, 2 H), 2.44 (br dd, J=16.26, 4.63 Hz, 2 H), 1.48 (s, 9 H), 1.25 - 1.29 (m, 6 H). O NH

[0242] To a mixture of naphthalene-1,4-dione (200 mg, 1.26 mmol, 1 eq) and Intermediate 52-7 (548.82 mg, 1.90 mmol, 1.5 eq) in MeCN (12 mL) and H2O (10 mL) was added AgNO3(257.78 mg, 1.52 mmol, 1.2 eq) in portions at 20°C. The mixture was stirred for 40 min at 100°C. Then a solution of (NH4)2S2O8 (923.47 mg, 4.05 mmol, 879.49 μL, 3.2 eq) in MeCN (12 mL) and H2O (10 mL) was added to the mixture dropwise at 25°C. The mixture was stirred for 4hrs at 100°C. LCMS showed the desired product was generated. One additional reaction on 0.1 g scale was set up as described above and combined. Then the pH was adjusted to 8 with the dropwise addition of saturated aqueous NaHCO3. The resulting solution was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18100*40 mm*5 um; mobile phase: [H2O (0.04% HCl)-ACN]; gradient: 10%-30% B over 8.0 min) and lyophilized to give crude product. The crude product was purified by prep-HPLC (column: Phenomenex luna C18100*40 mm*5 um; mobile phase: [H2O (0.04% HCl)-ACN]; gradient: 1%-25% B over 8.0 min) and lyophilized to give Compound 52 (56 mg, 181.37 μmol, 9.56% yield, 94.5% purity, HCl salt) as a light yellow solid.1H NMR (400 MHz, DMSO-d6) δ ppm 9.34 (br s, 2 H), 8.04 (dd, J=5.69, 3.31 Hz, 2 H), 7.83 - 7.94 (m, 2 H), 3.70 (br s, 2 H), 2.99 - 3.21 (m, 4 H), 1.29 (d, J=6.63 Hz, 6 H). Method B LCMS (ESI+): rt = 1.700 min, m / z 256 (M+H). Example 53. Compound 53: benzyl, cis-2,4-dimethyl-6,11-dioxo-1,2,4,5,6,11-hexahydro-3H- naphtho[2,3-d]azepine-3-carboxylate Example 54. Compound 54: benzyl, trans-2,4-dimethyl-6,11-dioxo-1,2,4,5,6,11-hexahydro- 3H-naphtho[2,3-d]azepine-3-carboxylatein EtOH (9 mL) was added NH3·H2O (910.00 mg, 6.49 mmol, 1 mL, 25% purity, 0.247 eq) dropwise at 20°C. The mixture was stirred at 65°C for 12 hours. LCMS indicated desired mass was detected. Then the mixture was purified by prep-HPLC (HCl condition) directly and the desired eluent was concentrated under reduced pressure to give Intermediate 53-2 (0.8 g, 2.84 mmol, 10.80% yield, HCl) as a white solid. Method D LCMS (ESI+): rt = 0.280 min, m / z 246 (M+H).5 mL) and THF (3 mL) was added NaHCO3 (715.55 mg, 8.52 mmol, 331.43 μL, 3 eq) and benzyl chloroformate (968.67 mg, 5.68 mmol, 810.61 μL, 2 eq) in portions at 0°C. The mixture was stirred at 20°C for 12 hours. LCMS showed 10% of starting material remained and the desired compound mass was detected. The mixture was diluted with H2O (30 mL) and extracted with ethyl acetate (2 x 40 mL). The combined organic phases were washed with brine (2 x 40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / 1 to 1 / 1, Rf = 0.54) and the desired eluent was concentrated under reduced pressure to give the product Intermediate 53-3 (0.7 g, 1.66 mmol, 58.48% yield, 90% purity) as a yellow oil.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.13 - 1.42 (m, 12 H) 2.47 - 2.86 (m, 4 H) 3.98 - 4.35 (m, 6 H) 5.01 - 5.24 (m, 2 H) 7.29 - 7.43 (m, 5 H).

[0245] To a solution of Intermediate 53-3 (0.6 g, 1.42 mmol, 1 eq) in MeOH (2 mL), H2O (2 mL) and THF (4 mL) was added LiOH·H2O (238.86 mg, 5.69 mmol, 4 eq) in one portion at 20°C. The mixture was stirred at 20°C for 12 hours. LCMS showed starting material was consumed completely and two main peaks with desired mass were detected. One additional reaction on 0.1 g scale was set up as described above and these two reactions were combined. The mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (2 x 30 mL). The aqueous phase was adjusted to pH = 3 with aqueous of 1N HCl (5 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with brine (2 x 20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the compoundIntermediate 53-4 (0.6 g, 1.67 mmol, 90.27% yield, 90% purity) as a yellow oil. 1H NMR (400MHz, CHLOROFORM-d) δ ppm 1.06 - 1.52 (m, 7 H) 2.29 - 2.65 (m, 2 H) 2.79 - 3.37 (m, 2 H) 4.18 - 4.44 (m, 1 H) 4.99 - 5.31 (m, 2 H) 7.28 - 7.46 (m, 4 H).

[0246] To a solution of naphthalene-1,4-dione (0.1 g,53-4 (340.75 mg, 948.45 μmol, 1.5 eq) in MeCN (6 mL) and H2O (5 mL) was added AgNO3 (139.63 mg, 821.99 μmol, 1.2 eq) in one portion at 20°C. The mixture was stirred at 100°C for 1 hour. Then the mixture was cooled to 20°C, and a solution of ammonium persulfate (461.73 mg, 2.02 mmol, 439.75 μL, 3.2 eq) in MeCN (6 mL) and H2O (5 mL) was added to the mixture dropwise at 20°C. The mixture was stirred at 100°C for 3 hours. LCMS showed the starting material was consumed completely and 15% of desired mass was detected. The mixture was cooled to 20°C. The mixture was quenched with aqueous of saturated sodium sulfite (30 mL). The aqueous phase was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with brine (2 x 30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by prep-HPLC (HCl condition) and the desired eluent was lyophilized give the products Compound 53 (P1, 3.1 mg, 7.77 μmol, 1.23% yield, 97.6% purity) and Compound 54 (P2, 5.8 mg, 13.58 μmol, 2.15% yield, 91.2% purity) as yellow soilds. P11H NMR (400 MHz, DMSO-d6) δ ppm 1.32 (br d, J=6.50 Hz, 6 H) 2.84 - 3.13 (m, 4 H) 4.07 - 4.30 (m, 2 H) 4.75 - 5.10 (m, 2 H) 6.92 - 7.18 (m, 5 H) 7.72 - 8.14 (m, 4 H). P1Method C LCMS (ESI+): 2.963 min, m / z 390 (M+H). P21H NMR (400 MHz, DMSO-d6) δ ppm 1.19 (d, J=7.00 Hz, 6 H) 2.85 - 3.17 (m, 4 H) 4.58 (br dd, J=11.82, 6.57 Hz, 2 H) 5.04 (s, 2 H) 7.24 (s, 5H) 7.87 (dd, J=5.75, 3.38 Hz, 2 H) 7.97 - 8.11 (m, 2 H). P2 Method C LCMS (ESI+): rt = 3.004min, m / z 390 (M+H).Example 55. Compound 55: benzyl-cis-7,10-dibromo-2,4-dimethyl-6,11-dioxo-1,2,4,5,6,11- hexahydro-3H-naphtho[2,3-d]azepine-3-carboxylate in a similar manner as Compound 53.1H NMR (400J=5.13 Hz, 6H), 2.77-3.12 (m, 4H), 4.11-4.27 (m, 2H), 4.83-5.07 (m, 2H), 7.04-7.19 (m, 5H), 7.91 (s, 2H). Method C LCMS (ESI+): rt = 3.142 min, m / z 546 / 548 (M+1 / +3). Example 56. Compound 56: trans-2,4-dimethyl-2,3,4,5-tetrahydro-1H-naphtho[2,3- d]azepine-6,11-dionein THF (10 mL) was added Compound 54 (60 mg, 138.66 μmol, 1 eq) and HCl (2 M, 300.00 μL, 4.33 eq) under N2 atmosphere. The suspension was degassed and purged with H23 times. The mixture was stirred under H2 (15Psi) for 12 hours at 20°C. LCMS showed the starting material was consumed completely and one main peak with desired mass was detected. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The crude material was purified by prep-HPLC (HCl condition) and the desired eluent was lyophilized to give Compound 56 (18.9 mg, 73.58 μmol, 53.07% yield, 99.4% purity) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ ppm 1.42 (d, J=6.50 Hz, 6 H) 2.86 (br dd, J=15.82, 10.44 Hz, 2 H) 3.29 (br d, J=15.51 Hz, 4 H) 7.82 - 7.95 (m, 2 H) 7.99 - 8.11 (m, 2 H) 8.79 - 9.00 (m, 1 H) 9.33 (br d, J=9.51 Hz, 1 H). Method C LCMS (ESI+): rt = 1.686 min, m / z 256 (M+H).Example 57. Compound 57: cis-7,10-dibromo-2,4-dimethyl-2,3,4,5-tetrahydro-1H- naphtho[2,3-d]azepine-6,11-dione 57 was prepared in a similar manner as Compound 56.1H NMR (4001.29 (d, J=6.63 Hz, 6H), 2.93-3.10 (m, 4H), 3.67 (br s, 2H), 7.93 (s, 2H), 9.14 (br s, 2H). Method C LCMS (ESI+): rt = 1.975 min, m / z 412 / 414 (M+1 / +3). Example 58. Compound 58: 2,3,4,5,7,10-hexahydro-1H-7,10-ethanonaphtho[2,3-d]azepine- 6,11-dione

[0250] To a solution of Intermediate 58-1 (0.13 g, 468.78 μmol, 1 eq) in DCM (3 mL) was added cyclohexa-1,3-diene (75.12 mg, 937.56 μmol, 89.33 μL, 2 eq) at 20°C. The mixture was stirred at 20°C for 12 hours. This reaction was monitored by TLC. Upon completion, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by prep-TLC to give Intermediate 58-2 (0.1 g, 279.77 μmol, 59.68% yield) as a white solid.1H NMR (DMSO-d6, 400 MHz) δ (ppm) 6.14 (t, J = 3.6 Hz, 2H), 3.33-3.43 (m, 4H), 3.08 (s, 2H), 3.04 (br s, 2H), 2.64 (br t, J = 5.1 Hz, 4H), 1.67 (br d, J = 7.4 Hz, 2H), 1.38 (s, 9H), 1.22 (br d, J = 8.0 Hz, 2H).

[0251] To a solution of Intermediate 58-2 (95 mg, 265.78 μmol, 1 eq) in MeOH (5 mL) was added NaOAc (65.41 mg, 797.33 μmol, 3 eq) at 25°C. The mixture was charged with N23 times. The mixture was stirred at 50°C for 3 hours. TLC showed starting material consumed and two new spots formed (Rf=0.81 and Rf=0.39). The mixture was concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=80%) to give Intermediate 58-3 (50 mg, 125.89 μmol, 47.37% yield, 90% purity) as a white solid and Intermediate 58-4 (25 mg, 70.34 μmol, 26.47% yield, 100% purity) as a yellow solid.1H NMR (DMSO-d6, 400 MHz) Intermediate 58-4 δ (ppm) 6.37-6.45 (m, 2H), 4.23 (br s, 2H), 3.37-3.53 (m, 4H), 2.73 (br s, 4H), 1.32-1.40 (m, 11H), 1.26 (br d, J = 6.5 Hz, 2H). Method C LCMS (ESI+): rt = 2.990 min, m / z 378 (M+23).1H NMR (DMSO-d6, 400 MHz) Intermediate 58-3 δ (ppm) 7.74 (s, 2H), 6.43 (dd, J = 4.4, 3.3 Hz, 2H), 4.31 (br s, 2H), 3.40-3.52 (m, 2H), 3.23-3.30 (m, 2H), 2.74-2.92 (m, 4H), 1.35-1.40 (m, 11H), 1.25 (br d, J = 6.1 Hz, 2H).eq) in EtOAc (10 mL) was added HCl / EtOAc (4 M, 2.09 mL, 258.49 eq) at 20°C. The mixture was stirred at 20°C for 12 hours. LCMS showed the reaction was complete. The mixture was concentrated under reduced pressure to give Compound 58 (10 mg, 28.55 μmol, 88.24% yield, 83.3% purity, HCl) as a light green solid.1H NMR (DMSO-d6, 400 MHz) δ (ppm) 9.16 (br s, 2H), 6.53 (dd, J = 4.3, 3.1 Hz, 2H), 4.34 (br s, 2H), 3.15-3.33 (m, 4H), 2.94-3.10 (m, 4H), 1.49 (br d, J = 6.5 Hz, 2H), 1.36 (br d, J = 6.5 Hz, 2H). Method C LCMS (ESI+): rt = 1.79 min, m / z 256 (M+1). Example 59. Compound 59: 3-methyl-2,3,4,5,7,8,9,10-octahydro-1H-7,10- ethanonaphtho[2,3-d]azepine-6,11-dione

[0253] To a solution of Compound 58 (0.13 g, 509.18 μmol, 1 eq) in DMF (5 mL) was added iodomethane (79.50 mg, 560.10 μmol, 34.87 μL, 1.1 eq) and TEA (103.05 mg, 1.02 mmol, 141.74 μL, 2 eq) at 20°C. The mixture was stirred at 20°C for 12 hours. LCMS showed the reaction was complete. One additional reaction on 10 mg scale was set up as described above. The combined reaction mixture was concentrated under reduced pressure to give the crude product. The mixture was purified by prep-HPLC and lyophilized to give Intermediate59-1 (0.1 g, 371.28 μmol, 68.15% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δppm 1.27 (br d, J=6.25 Hz, 2 H) 1.41 (br d, J=6.63 Hz, 2 H) 2.71 (br s, 3 H) 2.93 - 3.13 (m, 8 H) 4.25 (br s, 2 H) 6.44 (br s, 2 H).mL) was added Intermediate 59-1 (0.1 g, 371.28 μmol, 1 eq) at 20°C. The mixture was charged with H23 times. The mixture was stirred at 20 °C for 2 hours at 15 psi. LCMS showed the reaction worked. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a mixture of Compound 59 (60 mg, 22.11 μmol, 5.96% yield, 10% purity) and Intermediate 59-2 (60 mg, 116.33 μmol, 31.33% yield, 53% purity) as a yellow solid. Method A LCMS (ESI+): rt = 0.931 / 1.150 min, m / z 272 / 274 (M+H).O OH O MnO2(2 eq) HCl

[0255] To a solution of Compound 59 (60 mg, 22.11 μmol, 0.19 eq) and Intermediate 59-2 (60 mg, 116.33 μmol, 1 eq) in acetone (5 mL) was added MnO2 (10.11 mg, 116.33 μmol, 1 eq) at 20°C. The mixture was stirred at 20°C for 2 hours. LCMS showed the reaction was complete. The reaction mixture was filtered and the filtrate was concentrated. The crude product was purified by prep-HPLC and lyophilized to give Compound 59 (8 mg, 27.42 μmol, 19.80% yield, 93% purity) as a yellow solid.1H NMR (400 MHz, METHANOL-d4) δ ppm 1.28 (br d, J=7.25 Hz, 4 H) 1.77 (br d, J=7.38 Hz, 4 H) 2.75 (br dd, J=17.32, 11.19 Hz, 2 H) 2.95 (s, 3 H) 3.09 (br t, J=12.19 Hz, 2 H) 3.26 (br s, 2 H) 3.45 (br dd, J=17.32, 6.69 Hz, 2 H) 3.66 (br dd, J=13.13, 6.88 Hz, 2 H). Method A LCMS (ESI+): rt = 1.840 min, m / z 272 (M+H). Example 60. Compound 60: 2,3,4,5,7,8,9,10-octahydro-1H-7,10-ethanonaphtho[2,3- d]azepine-6,11-dioneadded Intermediate 58-4 (49.72 mg, 139.88 μmol, 1 eq) at 20°C. The mixture was charged with H23 times. The mixture was stirred at 20°C for 12 hours under H2(15 psi). LCMS showed two peaks were detected. The reaction mixture was filtered and the filtrate was concentrated to give mixture of Intermediate 60-1 (18 mg, 50.08 μmol, 35.80% yield) and Intermediate 60-2 (20 mg, 55.95 μmol, 40.00% yield) as a yellow solid. Method C LCMS (ESI+): rt = 2.46 min / 2.98 min.

[0257] A suspension of Intermediate 60-1 (20 mg, 55.95 μmol, 1 eq) and Intermediate 60-2 (18 mg, 50.08 μmol, 8.95e-1 eq) in acetone (5 mL) and MeOH (1 mL) was added MnO2 (9.73 mg, 111.91 μmol, 2 eq) at 20°C. The mixture was stirred at 20°C for 1 hour. LCMS showed the reaction was complete. The reaction mixture was filtered and the filtrate was concentrated to give Intermediate 60-2 (20 mg, 54.11 μmol, 96.70% yield, 96.7% purity) as a yellow solid.1H NMR (DMSO-d6, 400 MHz) δ (ppm) 3.45 (br s, 4H), 3.20 (br s, 2H), 2.77 (br t, J = 5.0 Hz, 4H), 1.68 (br d, J = 7.3 Hz, 4H), 1.18 (br d, J = 7.1 Hz, 4H). Method C LCMS (ESI+): rt = 3.0 min, m / z 380 (M+23).

[0258] To a solution of Intermediate 60-2 (9 mg, 25.18 μmol, 1 eq) in EtOAc (2 mL) was added HCl / EtOAc (4 M, 0.5 mL, 79.43 eq) at 20°C. The mixture was stirred at 20°C for 1 hour. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to give the crude product. The mixture was purified by prep-HPLC (Phenomenex Luna C18 75*30mm*3um; mobile phase: [ H2O (0.04% HCl)-ACN]; gradient:20%-62% B over 8.0 min) and lyophilized to give Compound 60 (6 mg, 20.42 μmol, 81.11% yield, HCl) as a yellow solid.1H NMR (DMSO-d6, 400 MHz) δ (ppm) 9.03 (br s, 2H), 3.30 (br d, J = 15.5 Hz, 6H), 2.98-3.12 (m, 4H), 1.81 (br d, J = 7.3 Hz, 4H), 1.17-1.37 (m, 4H). Method C LCMS (ESI+): rt = 1.80 min, m / z 258 (M+1). Example 61. Compound 61: 4-((((benzyloxy)carbonyl)amino)methyl)heptanedioic acid

[0259] To a solution of tert-butyl 2-diethoxyphosphorylacetate (41.08 g, 162.86 mmol, 1.5 eq) in tetrahydrofuran (250 mL) was added NaH (8.69 g, 217.15 mmol, 60% purity, 2 eq) in portions at 0°C under N2. The reaction was stirred at 20°C for 1 hour under N2. Then Intermediate 44-1 (25 g, 108.57 mmol, 23.30 mL, 1 eq) in tetrahydrofuran (250 mL) was added to the reaction mixture dropwise at 0°C under N2. The reaction was stirred at 20°C for 2 hours under N2. TLC showed the starting material was consumed and one main spot (Rf= 0.64, UV=254 nm) with lower polarity was formed. One additional reaction on 8 g scale and three additional reactions on 25 g scale were set up as described above and these five reactions were combined. And the combined reaction mixture was poured into ice saturated aqueous of NH4Cl (3 L) slowly and extracted with ethyl acetate (3 x 1 L). The combined organic layers were washed with brine (1 L), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10: 1) and the desired eluent was concentrated under reduced pressure to give the Intermediate 61-1 (55.8 g, 169.91 mmol, 36.23% yield) as a yellow oil.1H NMR (400 MHz, CHLOROFORM-d) δ 1.26 (t, J=7.13 Hz, 6H), 1.47 (s, 9H), 2.45-2.54 (m, 6H), 2.80-2.88 (m, 2H), 4.14 (qd, J=7.13, 3.25 Hz, 4H), 5.59 (s, 1H).

[0260] To the mixture of Pd / C (3 g, 14.10 mmol, 50% purity, 0.46 eq) in tetrahydrofuran (100 mL) was added a solution of Intermediate 61-1 (10 g, 30.45 mmol, 1 eq) in tetrahydrofuran (100 mL) in portions under an Ar atmosphere. The suspension was degassed and purged with H2three times. The mixture was stirred at 20°C for 12 hours under H2(15 Psi). LCMS showed the starting material was consumed and one main peak with the desired mass was detected. Two additional reactions on 10 g scale were set up as described above and these three reactions were combined. The combined reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give the Intermediate 61-2 (30.13 g, 91.19 mmol, 99.82% yield) as gray oil.1H NMR (400 MHz, CHLOROFORM-d) δ 1.26 (t, J=7.13 Hz, 6H), 1.45 (s, 9H), 1.61-1.74 (m, 4H), 1.89 (dt, J=13.04, 6.55 Hz, 1H), 2.19 (d, J=6.63 Hz, 2H), 2.33 (t, J=7.94 Hz, 4H), 4.13 (q, J=7.13 Hz, 4H).

[0261] To a solution of Intermediate 61-2 (15.13 g, 45.79 mmol, 1 eq) in dichloromethane (150 mL) was added TFA (230.25 g, 2.02 mol, 150 mL, 44.10 eq) dropwise at 20°C. The reaction was stirred at 20°C for 2 hours. LCMS showed the starting material was consumed and one main peak with the desired mass was detected. One additional reaction on 15 g scale was set up as described above and these two reactions were combined. The reaction mixture was concentrated under reduced pressure to give the Intermediate 61-3 (27.1 g, 88.91 mmol, 97.58% yield, 90% purity) as a brown oil.1H NMR (400 MHz, CHLOROFORM-d) δ 1.27 (t, J=7.13 Hz, 6H), 1.67-1.76 (m, 4H), 1.88-2.01 (m, 1H), 2.30-2.41 (m, 6H), 4.14 (q, J=7.13 Hz, 4H).

[0262] To a solution of Intermediate 61-3 (10.81 g, 35.47 mmol, 1 eq) in toluene (100 mL) was added TEA (10.77 g, 106.40 mmol, 14.81 mL, 3 eq), DPPA (24.40 g, 88.67 mmol, 19.14 mL, 2.5 eq) and BnOH (5.75 g, 53.20 mmol, 5.51 mL, 1.5 eq) in order at 20°C under N2. The reaction was stirred at 120°C for 12 hours under N2. TLC showed the starting material was consumed and one main spot (Rf= 0.41, PMA) with lower polarity was formed. Two additional reactions on 10.81 g scale were set up as described above and these three reactions were combined. The combined reaction mixture was diluted with water (300 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine 100 mL, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=6:1) and the desired eluent was concentrated under reduced pressure to give the Intermediate 61-4 (9.4 g, 24.77 mmol, 32.04% yield) as a yellow oil.1H NMR (400 MHz, CHLOROFORM-d) δ 1.22-1.30 (m, 6H), 1.55-1.71 (m, 6H), 2.37 (br t, J=7.38 Hz, 3H), 3.15 (br t, J=5.57 Hz, 2H), 4.13 (q, J=7.13 Hz, 4H), 5.03 (br s, 1H), 5.11 (s, 2H), 7.30-7.41 (m, 5H).

[0263] To a solution of Intermediate 61-4 (9.4 g, 24.77 mmol, 1 eq) in tetrahydrofuran (90 mL), methanol (25 mL) and H2O (25 mL) was added lithium hydroxide hydrate (4.16 g, 99.09 mmol, 4 eq) in portions at 20°C. The reaction mixture was stirred at 20°C for 12 hours. LCMS showed the starting material was consumed and one main peak with the desired mass was detected. The reaction mixture was diluted with water (300 mL) and extracted with ethyl acetate (3 x 100 mL). The aqueous phase was adjusted to pH = 2 with 1M HCl. Then the aqueous phase was diluted with water (300 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine 150 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give Intermediate 61 (7.55 g, 23.33 mmol, 94.19% yield) as a white solid.1H NMR (400 MHz, CHLOROFORM-d) δ 1.62 (br s, 6H), 2.47 (br d, J=5.25 Hz, 3H), 3.20 (br s, 2H), 4.89-4.99 (m, 1H), 5.11 (s, 2H), 7.30-7.43 (m, 5H).Example 62. Compound 62: benzyl ((5,11-dioxo-6,7,8,9,10,11-hexahydro-5H- cyclohepta[b]naphthalen-8-yl)methyl)carbamate

[0264] To a solution of naphthalene-1,4-dione (158 mg, 999.03 μmol, 1 eq) and Intermediate 61 (484.54 mg, 1.20 mmol, 1.2 eq) in acetonitrile (10 mL) and H2O (5 mL) was added AgNO3 (203.65 mg, 1.20 mmol, 1.2 eq) in portions at 20°C under N2. The reaction was stirred at 100°C for 1 hour. Then the mixture was cooled to 20°C and to the reaction mixture was added a solution of ammonium persulfate (729.54 mg, 3.20 mmol, 694.80 μL, 3.2 eq) in acetonitrile (10 mL) and H2O (5 mL) dropwise at 20°C under N2. The mixture was stirred at 100°C under N2 for 3 hours. TLC showed the starting material was consumed and one major new spot (Rf = 0.38, Petroleum ether: Ethyl acetate = 3:1) was detected. The mixture was cooled to 20°C. The mixture was quenched with aqueous of saturated sodium sulfite (100 mL). The aqueous phase was extracted with ethyl acetate (3 x 30 mL). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated under vacuum. The crude residue was purified by prep-TLC (SiO2, Petroleum ether / Ethyl acetate = 3:1). This material was further purified by prep-HPLC (NH4HCO3 condition) and the desired eluent was lyophilized to give Compound 62 (12 mg, 30.81 μmol, 3.08% yield) as a light yellow solid.1H NMR (400 MHz, CHLOROFORM- d) δ 0.96-1.11 (m, 2H), 1.87-2.06 (m, 3H), 2.32 (br t, J=13.13 Hz, 2H), 3.09 (br t, J=6.50 Hz, 2H), 3.46 (br dd, J=14.51, 7.75 Hz, 2H), 4.78-4.87 (m, 1H), 5.11 (s, 2H), 7.29-7.41 (m, 5H), 7.71 (dd, J=5.69, 3.31 Hz, 2H), 8.07-8.14 (m, 2H). Method C LCMS (ESI+): 2.905 min, m / z 390 (M+1). Example 63. Compound 63: 8-(aminomethyl)-7,8,9,10-tetrahydro-5H- cyclohepta[b]naphthalene-5,11(6H)-dione

[0265] To a mixture of Pd / C (185.82 mg, 873.04 μmol, 50% purity, 1 eq) in tetrahydrofuran (35 mL) was added a solution of Compound 62 (340 mg, 873.04 μmol, 1 eq) in tetrahydrofuran (35 mL) and HCl (6M, 10 mL, 68.73 eq) under an Ar atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred at 20°C for 12 hours under H2 (15 Psi). LCMS showed the starting material was consumed and one main peak with the desired mass was detected. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give the Intermediate 63-1 which was used for the next step. To a solution of Intermediate 63-1 in acetone (3 mL) and methanol (1 mL) was added MnO2(44.78 mg, 515.12 μmol, 2 eq) at 20°C. The reaction mixture was stirred at 20°C for 2 hours. LCMS showed the starting material was consumed and one main peak with the desired mass was detected. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The crude material was triturated with ethyl acetate: methanol = 5:1. Then the mixture was filtered and the filter cake was collected. The filter cake was dried under vacuum to give Compound 63 (260 mg, 867.94 μmol, 99.42% yield, 97.4% purity, HCl) as a light yellow solid.1H NMR (400 MHz, DMSO-d6) δ 1.06 (q, J=11.80 Hz, 2H), 1.84-1.97 (m, 2H), 2.02 (br dd, J=5.63, 2.25 Hz, 1H), 2.34-2.44 (m, 2H), 2.67 (br d, J=4.75 Hz, 2H), 3.21 (br dd, J=14.20, 7.07 Hz, 2H), 7.85 (br d, J=4.13 Hz, 2H), 8.01 (br d, J=3.25 Hz, 4H). Method C LCMS (ESI+): rt = 1.742 min, m / z 256 (M+1). Example 64. Compound 64: 8-(2-(dimethylamino)ethyl)-7,8,9,10-tetrahydro-5H- cyclohepta[b]naphthalene-5,11(6H)-dioneO 1. (HCHO)n, AcOH (1 eq) O HCl NH2NaOAc (3 eq), MeOH, 40°C, 1 h Nmg, 126.10 μmol, 3.47 μL, 4 eq) in MeOH (1 mL) was added AcOH (1.89 mg, 31.52 μmol, 1.80 μL, 1 eq) and NaOAc (7.76 mg, 94.57 μmol, 3 eq) in portions at 20°C under N2. The mixture was stirred at 40°C under N2 for 1 hour. Then to the mixture was added NaBH3CN (5.94 mg, 94.57 μmol, 3 eq) in one portion at 20°C under N2. The mixture was stirred at 40°C under N2 for 1 hour. LCMS showed the starting material was consumed completely and one main peak with the desired mass was detected. One additional reaction on 10 mg scale was set up as described above and these two reactions were combined. Then the mixture was adjusted to pH = 3 with 2N HCl (2 mL) and concentrated under reduced pressure. The crude material was purified by prep- HPLC (HCl condition) and the desired eluent was lyophilized to give the product Compound 64(2.3 mg, 6.89 μmol, 10.93% yield, HCl) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δppm 0.96 - 1.14 (m, 2 H) 1.51 - 1.64 (m, 2 H) 1.72 - 1.93 (m, 3 H) 2.35 - 2.45 (m, 2 H) 2.74 (s, 6 H) 3.01 - 3.13 (m, 2 H) 3.22 (br dd, J=14.45, 7.32 Hz, 2 H) 7.79 - 7.90 (m, 2 H) 7.96 - 8.07 (m, 2 H) 9.76 (br s, 1 H). Method C LCMS (ESI+): rt = 1.989 min, m / z 298 (M+H). Example 65. Compound 65: 8-((dimethylamino)methyl)-7,8,9,10-tetrahydro-5H- cyclohepta[b]naphthalene-5,11(6H)-dionewas prepared in a similar manner as Compound 64.1H NMR (400 MHz, DMSO-d6) δ 1.01-1.15 (m, 2H), 1.89-2.00 (m, 2H), 2.22 (br d, J=3.00 Hz, 1H), 2.44 (br d, J=14.38 Hz, 2H), 2.76 (br s, 6H), 2.92 (br d, J=5.25 Hz, 2H), 3.21 (br dd, J=14.70, 7.57 Hz, 2H),7.84 (dd, J=5.69, 3.31 Hz, 2H), 8.01 (dd, J=5.63, 3.38 Hz, 2H), 9.52-9.82 (m, 1H). Method C LCMS (ESI+): rt = 1.778 min, m / z 284 (M+1). Example 66. Compound 66: 8-(2-(isopropylamino)ethyl)-7,8,9,10-tetrahydro-5H- cyclohepta[b]naphthalene-5,11(6H)-dione prepared in a similar manner as Compound 64.1H NMR (DMSO-d6, 400 MHz) δ (ppm) 8.66 (br s, 2H), 8.01 (br dd, J = 5.4, 3.3 Hz, 2H), 7.84 (br dd, J = 5.5, 3.3 Hz, 2H), 3.16-3.27 (m, 3H), 2.89 (br s, 2H), 2.32-2.44 (m, 2H), 1.76-1.93 (m, 3H), 1.50-1.60 (m, 2H), 1.23 (br d, J = 6.4 Hz, 6H), 0.97-1.12 (m, 2H). Method C LCMS (ESI+):rt = 2.008 min, m / z 312 (M+H). Example 67. Compound 67: 8-(2-(diethylamino)ethyl)-7,8,9,10-tetrahydro-5H- cyclohepta[b]naphthalene-5,11(6H)-dioneprepared in a similar manner as Compound 64.1H NMR (DMSO- d6, 400 MHz) δ (ppm) 9.69 (br d, J = 0.8 Hz, 1H), 8.01 (dd, J = 5.6, 3.4 Hz, 2H), 7.84 (dd, J = 5.7, 3.3 Hz, 2H), 3.21 (br dd, J = 14.4, 7.3 Hz, 2H), 2.99-3.13 (m, 6H), 2.34-2.44 (m, 2H), 1.83- 1.93 (m, 2H), 1.80 (br d, J = 3.3 Hz, 1H), 1.52-1.62 (m, 2H), 1.19 (t, J = 7.2 Hz, 6H), 1.01-1.12 (m, 2H). Method C LCMS (ESI+): rt = 2.034 min, m / z 326 (M+H). Example 68. Compound 68: 8-((isopropylamino)methyl)-7,8,9,10-tetrahydro-5H- cyclohepta[b]naphthalene-5,11(6H)-dionewas prepared in a similar manner as Compound 64.1H NMR (400 MHz, DMSO-d6) δ 1.05-1.17 (m, 2H), 1.24 (d, J=6.38 Hz, 6H), 1.91-2.02 (m, 2H), 2.08-2.19 (m, 1H), 2.43 (br dd, J=13.95, 11.94 Hz, 2H), 2.73-2.82 (m, 2H), 3.17-3.31 (m, 3H), 7.85 (dd, J=5.69, 3.31 Hz, 2H), 8.02 (dd, J=5.69, 3.31 Hz, 2H), 8.48 (br s, 2H). Method C LCMS (ESI+): rt = 1.361 min, m / z 278 (M+1). Example 69. Compound 69: 8-((diethylamino)methyl)-7,8,9,10-tetrahydro-5H- cyclohepta[b]naphthalene-5,11(6H)-dionewas added TEA (83.23 mg, 822.56 μmol, 114.49 μL, 3 eq) and iodoethane (427.64 mg, 2.74 mmol, 219.30 μL, 10 eq) in portions at 20°C under N2. The mixture was stirred at 20°C under N2 for 2 hours. LCMS showed the starting material was consumed and one main peak with desired mass was detected. One additional reaction on 10 mg scale was set up as described above and these two reactions were combined. The reaction mixture was filtered and the filtrate was purified by prep-HPLC (NH4HCO3condition). The desired eluent was lyophilized to give the product. The product was not pure enough on LCMS. The residue was purified again by prep- HPLC (HCl condition) and the desired eluent was lyophilized to give Compound 69 (13.2 mg, 40.86 μmol, 13.31% yield, 96.4% purity, HCl salt) as yellow solid.1H NMR (400 MHz, DMSO- d6) δ 1.05-1.18 (m, 2H), 1.23 (br t, J=7.13 Hz, 6H), 1.96-2.07 (m, 2H), 2.15-2.29 (m, 1H), 2.42- 2.49 (m, 2H), 2.91 (br t, J=5.69 Hz, 2H), 3.15 (br d, J=3.50 Hz, 4H), 3.24 (br dd, J=14.51, 7.50 Hz, 2H), 7.86 (dd, J=5.50, 3.25 Hz, 2H), 8.03 (br dd, J=5.57, 3.31 Hz, 2H), 9.11-9.26 (m, 1H). Method C LCMS (ESI+): rt = 1.876 min, m / z 312 (M+1).Example 70. Compound 70: 3-ethyl-2,3,4,5,7,8,9,10-octahydro-1H-7,10-ethanonaphtho[2,3- d]azepine-6,11-dione 70 was prepared in a similar manner as Compound 69.1H NMR (DMSO-3.58 (br dd, J = 11.9, 7.0 Hz, 2H), 3.23 (br s, 2H), 3.14-3.21 (m, 4H), 3.02-3.12 (m, 2H), 2.85 (br dd, J = 17.0, 10.5 Hz, 2H), 1.67-1.78 (m, 4H), 1.25 (br t, J = 7.3 Hz, 3H), 1.20 (br d, J = 7.0 Hz, 4H). Method C LCMS (ESI+): rt = 1.835 min, m / z 286 (M+H). Example 71. Compound 71: 7,10-dibromo-2,3,4,5-tetrahydro-1H-naphtho[2,3-d]azepine- 6,11-dione

[0273] To a solution of ceric ammonium sulfate (26.67 g, 104.91 mmol, 6 eq) in ACN (80 mL) and H2SO4(400 mL) was added a solution of Intermediate 71-1 (5 g, 17.48 mmol, 1 eq) in ACN (240 mL) dropwise at 20°C. The mixture was stirred at 65°C for 48 hours. LCMS showed 50% of the product was detected. One additional reaction on 1.1 g scale and one additional reaction on 5 g were set up as described above. The combined mixture was extracted with ethyl acetate (3 x 800 mL). The organic layer was dried with Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=93%) to give Intermediate 71-2 (0.82 g, 2.60 mmol, 6.75% yield) as yellow solid.1H NMR (DMSO-d6, 400 MHz) δ (ppm) 7.94 (s, 2H), 7.04 (s, 2H).

[0274] To a solution of Intermediate 71-2 (0.5 g, 1.58 mmol, 1 eq) and 3- [benzyloxycarbonyl(2-carboxyethyl)amino]propanoic acid (514.04 mg, 1.74 mmol, 1.1 eq) in ACN (15 mL) and H2O (10 mL) was added AgNO3(322.59 mg, 1.90 mmol, 1.2 eq) at 20°C. The mixture was stirred at 100°C for 1 hour. Then a solution of ammonium persulfate (1.16 g, 5.06 mmol, 1.10 mL, 3.2 eq) in ACN (15 mL) and H2O (10 mL) was added to the mixture dropwise at 20°C. The mixture was stirred at 100°C for 3 hours. TLC showed the reaction was complete (petroleum ether: ethyl acetate=4:1, Rf=0.43). The mixture was quenched with saturated sodium sulfite solution (10 mL). The mixture was extracted with ethyl acetate (3 x 10 mL). The organic layer was dried with Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The crude material was purified by prep-TLC to give Intermediate 71-3 (0.1 g, 192.61 μmol, 12.17% yield) as yellow solid.1H NMR (DMSO-d6, 400 MHz) δ (ppm) 7.89 (s, 2H), 7.32-7.40 (m, 5H), 5.08-5.14 (m, 2H), 3.60 (br s, 4H), 2.85-2.91 (m, 4H).

[0275] To a solution of Intermediate 71-3 (100 mg, 192.61 μmol, 1 eq) in ACN (5 mL) was added TMSI (115.62 mg, 577.83 μmol, 78.65 μL, 3 eq) at 20°C. The mixture was stirred at 20°C for 3 hours. LCMS showed the reaction was complete. One additional reaction on 5 mg scale was set up as described above. The combined mixture was diluted with methanol (3 mL). The mixture was concentrated under reduced pressure to give the crude product. The product was purified by prep-HPLC and lyophilized to give Compound 71 (30 mg, 71.17 μmol, 36.95% yield, HCl) was obtained as yellow solid.1H NMR (DMSO-d6, 400 MHz) δ (ppm) 9.10 (br s,2H), 7.93 (s, 2H), 3.17-3.25 (m, 4H), 3.01-3.09 (m, 4H). Method C LCMS (ESI+): 1.820 min, m / z 386 (M+H). Example 72. Compound 72: benzyl 7,10-dibromo-2,2-dimethyl-6,11-dioxo-1,2,4,5,6,11- hexahydro-3H-naphtho[2,3-d]azepine-3-carboxylate in a similar manner as Intermediate 71-3. Method DLCMS (ESI+): rt = 0.662 min, m / z 546 / 548 / 550 (M+1 / +3 / +5). Example 73. Compound 73: 7,10-dibromo-2,2-dimethyl-2,3,4,5-tetrahydro-1H- naphtho[2,3-d]azepine-6,11-dione 73 was prepared in a similar manner as Compo1und 71. H NMR (400 MHz, DMSO-d6) δ 1.33 (s, 6H), 3.00 (s, 2H), 3.02-3.10 (m, 2H), 3.23 (br s, 2H), 7.94 (s, 2H), 9.13 (br s, 2H). Method C LCMS (ESI+): rt = 1.991 min, m / z 412 / 414 / 416 (M+1 / +3 / +5). Example 74. Compound 74: 8-(2-morpholinoethyl)-7,8,9,10-tetrahydro-5H- cyclohepta[b]naphthalene-5,11(6H)-dione

[0278] To a solution of Compound 45 (0.1 g, 371.28 μmol, 1 eq) in THF (5 mL) was added 1- bromo-2-(2-bromoethoxy)ethane (94.72 mg, 408.41 μmol, 51.34 μL, 1.1 eq), KI (6.16 mg, 37.13 μmol, 0.1 eq) and TEA (37.57 mg, 371.28 μmol, 51.68 μL, 1 eq) at 20°C. The mixture was stirred at 65°C for 12 hours. LCMS showed a major peak with the desired mass. The mixture was concentrated under reduced pressure. The crude product was purified by prep-HPLC (column: Phenomenex luna C18100*40mm*5 um;mobile phase: [H2O(0.04% HCl)- ACN];gradient:15%-45% B over 8.0 min) and lyophilized to give Compound 74 (17.5 mg,46.56 μmol, 12.54% yield, HCl) as a yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ (ppm)10.48-10.77 (m, 1H), 7.94-8.07 (m, 2H), 7.73-7.89 (m, 2H), 3.87-4.03 (m, 2H), 3.75 (br t, J = 11.5 Hz, 2H), 3.40-3.49 (m, 2H), 3.20 (br dd, J = 14.5, 7.1 Hz, 2H), 3.11 (dt, J = 10.9, 5.2 Hz, 2H), 2.94-3.06 (m, 2H), 2.33-2.44 (m, 2H), 1.74-1.92 (m, 3H), 1.57-1.70 (m, 2H), 0.97-1.14 (m, 2H).Method C LCMS (ESI+): rt = 1.910 min, m / z 340 (M+H). Example 75. Compound 75: 8-(morpholinomethyl)-7,8,9,10-tetrahydro-5H- cyclohepta[b]naphthalene-5,11(6H)-dione prepared i1n a similar manner as Compound 74. H NMR (DMSO- d6, 400 MHz) δ (ppm) 10.27 (br d, J = 2.5 Hz, 1H), 8.02 (dd, J = 5.7, 3.3 Hz, 2H), 7.81-7.88 (m, 2H), 3.83-4.01 (m, 4H), 3.46 (br d, J = 12.6 Hz, 2H), 3.22 (br dd, J = 14.7, 7.6 Hz, 2H), 3.02- 3.14 (m, 2H), 2.99 (br t, J = 5.9 Hz, 2H), 2.40-2.49 (m, 2H), 2.23-2.35 (m, 1H), 1.96-2.08 (m, 2H), 1.05-1.20 (m, 2H). Method C LCMS (ESI+): rt = 1.807 min, m / z 326 (M+H). Example 76. Compound 76: 8-(2-(pyrrolidin-1-yl)ethyl)-7,8,9,10-tetrahydro-5H- cyclohepta[b]naphthalene-5,11(6H)-dione

[0280] Compound 76 was prepared in a similar manner as Compound 74.1H NMR (DMSO- d6, 400 MHz) δ (ppm) 10.08 (br s, 1H), 7.96-8.06 (m, 2H), 7.78-7.88 (m, 2H), 3.48 (br dd, J = 10.6, 5.3 Hz, 2H), 3.11-3.26 (m, 4H), 2.88-3.01 (m, 2H), 2.33-2.43 (m, 2H), 1.93-2.07 (m, 2H), 1.73-1.92 (m, 5H), 1.53-1.63 (m, 2H), 0.95-1.11 (m, 2H). Method C LCMS (ESI+): rt = 2.064 min, m / z 324 (M+H). Example 77. Compound 77: 8-(pyrrolidin-1-ylmethyl)-7,8,9,10-tetrahydro-5H- cyclohepta[b]naphthalene-5,11(6H)-dione w1as prepared in a similar manner as Compound 74. H NMR (DMSO- d6, 400 MHz) δ (ppm) 9.63 (br dd, J = 5.5, 3.4 Hz, 1H), 7.95-8.08 (m, 2H), 7.78-7.91 (m, 2H), 3.58 (br d, J = 4.5 Hz, 2H), 3.21 (br dd, J = 14.7, 7.6 Hz, 2H), 2.93-3.08 (m, 4H), 2.44 (br d, J = 13.9 Hz, 2H), 2.13-2.22 (m, 1H), 2.00 (br d, J = 6.8 Hz, 4H), 1.84-1.93 (m, 2H), 1.11 (q, J = 11.6 Hz, 2H). Method C LCMS (ESI+): rt = 1.888 min, m / z 310 (M+H). Example 78. Compound 78: benzyl 6,11-dioxo-2',3',4,5,5',6,6',11- octahydrospiro[naphtho[2,3-d]azepine-2,4'-pyran]-3(1H)-carboxylatemmol, 1 eq) in NH3 / EtOH (25 mL) was stirred at 90°C in a 100 mL sealed tube for 24 hours. LCMS showed the starting material was consumed and desired mass was detected. Three additional reactions on 2.5 g scale were set up as described above and these four reactions were combined. Then N2 was bubbled into the mixture to remove the excess of the ammonia gas. Then the mixture was adjusted to pH = 3 with 2N HCl (30 mL) and concentrated under reduced pressure to give the product Intermediate 78-2 (12 g, 42.92 mmol, 73.04% yield, 80% purity, HCl) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ ppm 1.21 (t, J=7.07 Hz, 3 H) 1.81 (br t, J=5.19 Hz, 4 H) 2.89 (s, 2 H) 3.49 - 3.68 (m, 5 H) 3.70 - 3.82 (m, 2 H) 8.43 (br s, 2 H). O OO O OO (8 eq) O

[0283] To a solution of Intermediate 78-2 (6 g, 21.46 mmol, 1 eq, HCl) in methyl prop-2- enoate (14.78 g, 171.66 mmol, 15.46 mL, 8 eq) was added TEA (6.51 g, 64.37 mmol, 8.96 mL, 3 eq) dropwise at 20°C under N2. The mixture was stirred at 70°C for 12 hours under N2. LCMS showed the 15% of starting material remained and 60% of desired mass was detected. One additional reaction on 6 g scale was set up as described above and these two reactions were combined. The mixture was filtered and the filter cake was washed with petroleum ether (100 mL). Then the filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=99 / 1 to 1 / 1, Rf=0.1) and the desired eluent was concentrated under reduced pressure to give the compound Intermediate 78- 3 (4 g, 13.17 mmol, 30.69% yield, 90% purity) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ ppm 1.18 (t, J=7.13 Hz, 3 H) 1.44 - 1.59 (m, 4 H) 2.33 - 2.44 (m, 5 H) 2.62 - 2.72 (m, 3 H) 3.47 (dt, J=11.19, 3.97 Hz, 2 H) 3.54 - 3.66 (m, 7 H) 4.04 (q, J=7.13 Hz, 2 H).was added K2CO3(3.64 g, 26.34 mmol, 4 eq) and benzyl chloroformate (3.37 g, 19.76 mmol, 2.82 mL, 3 eq) in portions at 0°C. The mixture was stirred at 80°C for 12 hours. LCMS showed 10% of starting material remained and 60% of desired mass was detected. One additional reaction on 2 g scale was set up as described above and these two reactions were combined. The mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with brine (2 x 40 mL), dried over Na2SO4, filtered and concentrated underreduced pressure. The crude material was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=99 / 1 to 1 / 1, Rf=0.4) and the desired eluent was concentrated under reduced pressure to give the compound Intermediate 78-4 (3.1 g, 6.85 mmol, 51.99% yield, 90% purity)as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07 - 1.14 (m, 3 H) 1.82 - 1.98 (m, 2 H)2.22 (br d, J=13.51 Hz, 2 H) 2.53 - 2.60 (m, 2 H) 2.99 (s, 2 H) 3.44 - 3.53 (m, 4 H) 3.54 - 3.58 (m, 5 H) 3.63 - 3.72 (m, 2 H) 3.97 (q, J=7.13 Hz, 2 H) 5.07 (s, 2 H) 7.24 - 7.44 (m, 5 H).

[0285] To a solution of Intermediate 78-4 (2.5 g, 5.52 mmol, 1 eq) in THF (15 mL), MeOH (5 mL) and H2O (10 mL) was added LiOH (1.42 g, 33.72 mmol, 4 eq) in one portion at 20°C. The mixture was stirred at 20°C for 12 hours. LCMS showed the starting material was consumed completely and one main peak with desired mass was detected. One additional reaction on 0.6 g scale was set up as described above and these two reactions were combined. The mixture was diluted with H2O (30 mL) and extracted with ethyl acetate (2 x 60 mL). The aqueous phase was adjusted to pH=3 with aqueous of 1N HCl (10 mL) and extracted with ethyl acetate (3 x 60 mL). The combined organic phases were washed with brine (2 x 40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the compound Intermediate 78-5 (2.1 g, 5.17 mmol, 78.06% yield, 90% purity) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ ppm 1.81 - 1.91 (m, 2 H) 2.27 (br d, J=13.26 Hz, 2 H) 2.45 - 2.49 (m, 2 H) 2.95 (s, 2 H) 3.42 - 3.56 (m, 4 H) 3.62 - 3.72 (m, 2 H) 5.07 (s, 2 H) 7.23 - 7.44 (m, 5 H) 12.17 (br s, 2 H).

[0286] To a solution of naphthalene-1,4-dione (0.1 g, 632.30 μmol, 1 eq) and Intermediate78-5 (308.04 mg, 758.76 μmol, 1.2 eq) in ACN (3 mL) and H2O (2 mL) was added AgNO3 (128.89 mg, 758.76 μmol, 1.2 eq) in one portion at 20°C. The mixture was stirred at 100°C for 0.5 hours. Then the mixture was cooled to 20°C, and a solution of ammonium persulfate (461.73 mg, 2.02 mmol, 439.75 μL, 3.2 eq) in ACN (3 mL) and H2O (2 mL) was added dropwise at 20°C. The mixture was stirred at 100°C under N2 for 3.5 hours. LCMS showed the starting material was consumed completely and 20% of the desired mass was detected. The mixture was cooled to 20°C. The mixture was quenched with aqueous of saturated sodium sulfite (30 mL). The aqueous phase was extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with brine (3 x 20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by prep-HPLC (neutral condition) and the desired eluent was lyophilized give the product Compound 78 (4.3 mg, 9.55 μmol, 1.51% yield, 95.8% purity) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ ppm 1.42 (br d, J=13.38 Hz, 2 H) 2.78 (td, J=12.60, 5.19 Hz, 2 H) 2.89 (br t, J=5.57 Hz, 2 H) 3.47 (s, 2 H) 3.52 - 3.62 (m, 2 H) 3.72 (br dd, J=11.69, 3.81 Hz, 2 H) 3.98 (t, J=5.82 Hz, 2 H) 5.05 (s, 2 H) 7.27 - 7.43 (m, 4 H) 7.80 - 7.89 (m, 2 H) 7.94 - 8.07 (m, 2 H). Method C LCMS (ESI+): rt = 2.837 min, m / z 431 (M+H). Example 79. Compound 79: 6,7-dibromonaphthalene-1,4-dione

[0287] To a 500 mL three-neck round-bottom flask fitted with a dropping funnel and a thermometer was added H2O2 (20.62 g, 181.87 mmol, 17.47 mL, 30% purity, 8.8 eq) and the mixture was stirred at -15°C to -20 °C. Then TFAA (64.24 g, 305.87 mmol, 42.52 mL, 14.8 eq) in dichloromethane (15 mL) was added to the mixture dropwise at 0-5 °C. The solution was stirred at 0-5°C for 30 minutes. A solution of Intermediate 79-1 (5 g, 20.67 mmol, 2.26 mL, 1 eq) in dichloromethane (25 mL) was added to the mixture in one portion at 0-5°C. The reaction mixture was stirred at 20°C for 3 hours. TLC showed the starting material was consumed andone new spot (Rf=0.6, UV) was formed. One additional reaction on 5 g scale was set up as described above and these two reactions were combined. The reaction mixture was adjusted to pH = 5 with 300 mL of saturated sodium carbonate at 0°C. The mixture was extracted with dichloromethane (3 x 200 mL). Then the combined organics were washed with saturated aqueous sodium sulfite (300 mL). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give Intermediate 79-2 (10 g, 36.51 mmol, 88.32% yield) as a yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ 6.84 (s, 2H).mmol, 1 eq) in AcOH (50 mL) was added 1,4-benzoquinone (19.73 g, 182.53 mmol, 41.10 mL, 10 eq) in one portion at 20°C. The reaction was stirred at 110°C for 12 hours. LCMS showed the starting material was consumed and one main peak was detected. One additional reaction on 2 g scale and another additional reaction on 2.5 g scale were set up as described above. The combined reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated under vacuum to give the residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=19: 1) and the desired eluent was concentrated under reduced pressure to give Intermediate 79 (2 g, 6.33 mmol, 18.26% yield) as a yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ 7.01 (s, 2H), 8.31 (s, 2H). Example 80. Compound 80: 8,9-dibromo-2,3,4,5-tetrahydro-1H-naphtho[2,3-d]azepine- 6,11-dione

[0289] Compound 80 was prepared in a similar manner as Compound 71 using Intermediate 79 as starting material.1H NMR (400 MHz, DMSO-d6) δ 3.02-3.12 (m, 4H), 3.17-3.26 (m, 4H), 8.23 (s, 2H). Method C LCMS (ESI+): rt = 2.050 min, m / z 384 / 386 / 388 (M+1 / +3 / +5). Example 81. Compound 81: 8,9-dibromo-2,2-dimethyl-2,3,4,5-tetrahydro-1H-naphtho[2,3- d]azepine-6,11-dione was prepared in a similar manner as Compound 71 using Intermediate79 as starting material.1H NMR (400 MHz, DMSO-d6) δ 1.31 (s, 6H), 3.05 (s, 2H), 3.10 (br d, J=0.75 Hz, 2H), 3.25 (br s, 2H), 8.25 (s, 1H), 8.27 (s, 1H), 9.07 (br s, 2H). Method C LCMS (ESI+): rt = 2.155 min, m / z 412 / 414 / 416 (M+1 / +3 / +5). Example 82. Compound 82: cis-8,9-dibromo-2,4-dimethyl-2,3,4,5-tetrahydro-1H- naphtho[2,3-d]azepine-6,11-dionewas prepared in a similar manner as Compound 71 using Intermediate 79 as starting material.1H NMR (400 MHz, DMSO-d6) δ 1.25 (d, J=6.63 Hz, 6H), 2.92-3.14 (m, 4H), 3.62-3.74 (m, 2H), 8.23 (s, 2H). LCMS (ESI+): rt = 2.150 min, m / z 412 / 414 / 416 (M+1 / +3 / +5). Example 83. Compound 83: 8,9-dibromo-3-methyl-2,3,4,5-tetrahydro-1H-naphtho[2,3- d]azepine-6,11-dione

[0292] Compound 83 was prepared in a similar manner as Compound 3.1H NMR (400 MHz, DMSO-d6) δ 2.82 (s, 3H), 2.87-2.99 (m, 2H), 3.00-3.13 (m, 2H), 3.38 (br s, 2H), 3.51-3.70 (m, 2H), 8.26 (s, 2H), 10.62-10.80 (m, 1H). Method C LCMS (ESI+): rt = 2.055 min, m / z 398 / 400 / 402 (M+1 / +3 / +5). Example 84. Compound 84: 8,9-dibromo-3-ethyl-2,3,4,5-tetrahydro-1H-naphtho[2,3- d]azepine-6,11-dione was prepared in a similar manner as Compound 3.1H NMR (400 MHz,DMSO-d6) δ 1.24 (t, J=7.25 Hz, 3H), 2.81-2.95 (m, 2H), 3.10 (br t, J=11.94 Hz, 2H), 3.18 (q, J=7.25 Hz, 2H), 3.34 (br dd, J=17.26, 7.13 Hz, 2H), 3.59-3.65 (m, 2H), 8.24 (s, 2H). Method C LCMS (ESI+): rt = 2.094 min, m / z 412 / 414 / 416 (M+1 / +3 / +5). Example 85. Compound 85: 7,10-dibromo-3-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H- naphtho[2,3-d]azepine-6,11-dioneprepared in a similar manner as Compound 7.1H NMR (400 MHz, DMSO+D2O-d6) δ ppm 2.86 - 3.01 (m, 2 H) 3.14 - 3.29 (m, 6 H) 3.62 (br dd, J=12.51, 7.75 Hz, 2 H) 3.71 - 3.76 (m, 2 H) 7.90 (s, 2 H). Method A LCMS (ESI+): rt = 1.857 min, m / z 430 (M+H). Example 86. Compound 86: 7,10-dibromo-3-(2-methoxyethyl)-2,3,4,5-tetrahydro-1H- naphtho[2,3-d]azepine-6,11-dionewas prepared in a similar manner as Compound 7.1H NMR (400 MHz, DMSO+D2O-d6) δ ppm 2.82 - 2.98 (m, 2 H) 3.21 (br s, 4 H) 3.31 (s, 3 H) 3.36 (br s, 2 H) 3.66 (br s, 4 H) 7.90 (s, 2 H). Method A LCMS (ESI+): rt = 1.958 min, m / z 444 (M+H). Example 87. Compound 87: 8,9-dibromo-3-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H- naphtho[2,3-d]azepine-6,11-dionein a similar manner as Compound 7.1H NMR (400 MHz, DMSO-d6) δ 2.89-3.04 (m, 2H), 3.15-3.33 (m, 6H), 3.56-3.64 (m, 2H), 3.74 (br s, 2H), 8.22 (s, 2H). Method C LCMS (ESI+): rt = 2.024 min, m / z 428 / 430 / 432 (M+1 / +3 / +5). Example 88. Compound 88: 8,9-dibromo-3-(2-methoxyethyl)-2,3,4,5-tetrahydro-1H- naphtho[2,3-d]azepine-6,11-dioneprepared in a similar manner as Compound 7.1H NMR (400 MHz, DMSO-d6) δ 2.87-3.01 (m, 2H), 3.10-3.43 (m, 9H), 3.65 (br d, J=4.88 Hz, 4H), 8.23 (s, 2H). Method C LCMS (ESI+): rt = 2.121 min, m / z 442 / 444 / 446 (M+1 / +3 / +5). Example 89. Compound 89: 3-(2-(pyrrolidin-1-yl)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H- naphtho[2,3-d]azepine-6,11-dioneprepared in a similar manner as Compound 16.1H NMR (400 MHz, DMSO-d6) δ ppm 1.82 - 2.11 (m, 4 H) 2.99 - 3.15 (m, 4 H) 3.43 - 3.67 (m, 4 H) 3.81 - 4.21 (m, 4 H) 6.57 (d, J=7.50 Hz, 1 H) 7.78 - 7.91 (m, 3 H) 8.02 (dd, J=5.69, 3.31 Hz, 2 H) 12.14 (br d, J=1.75 Hz, 1 H). Method C LCMS (ESI+): rt = 2.238 min, m / z 375 (M+H) Example 90. Compound 90: 2,3,4,5-tetrahydro-1H-naphtho[2,3-d]azepine-6,11-dione- 7,8,9,10-d4

[0299] To a solution of HCl (12 M, 300 mL, 22.17 eq) added Intermediate 90-1 (20 g, 162.40 mmol, 19.61 mL, 1 eq) dropwise at 25°C. The mixture was stirred at 130°C for 15 hours. LCMS showed the reaction was complete. The mixture was concentrated under reduced pressure to give Intermediate 90-2 (40 g, 161.93 mmol, 99.71% yield, 80% purity, HCl salt) as a colorless oil which was used to next step directly. Method D LCMS (ESI+): rt = 0.095 min, m / z 162 (M+1). O O O O CbzCl, NaOHH2O (280 mL) and THF (140 mL) was added NaOH (47.65 g, 1.19 mol, 6 eq) at 0°C. The mixture was stirred at 25°C for 10 min. Then CbzCl (50.81 g, 297.85 mmol, 42.52 mL, 1.5 eq) was added to the mixture dropwise at 0°C. Then the resulting mixture was stirred at 25°C for 12 hrs. LCMS showed the reaction was complete. The mixture was extracted with EtOAc (2 x 150 mL) and the organic phase was discarded. The aqueous phase was adjusted to pH = 3 with HCl (6N) and extracted with EtOAc (3 x 300 mL). The combined organic layer was washed with brine (300mL), dried over Na2SO4, and concentrated under reduced pressure to give Intermediate 90-3 (48 g, 154.43 mmol, 77.77% yield, 95% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 2.43 - 2.49 (m, 4 H) 3.43 (br s, 4 H) 5.07 (s, 2 H) 7.26 - 7.42 (m, 5 H) 12.28 (br d, J=2.75 Hz, 2 H)1 eq) in MeCN (320 mL) and H2SO4(80 mL, 2 N) was added a solution of cerium ammonium sulfate (27.99 g, 110.12 mmol, 15 eq) in H2SO4 (400 mL, 2 N) dropwise at 25°C. The mixture was stirred at 25 °C for 3 days.3 batches were set up as above in parallel. The reaction mixtures were diluted with water (1000 mL), extracted with EtOAc (300 mL x 3) and combined. The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give crude Intermediate 90-5 (3.4 g, 17.60 mmol, 79.92% yield, 85% purity) as a light brown solid which was used directly in the next step. Method D LCMS (ESI+): rt = 0.399 min, m / z 165 (M+1).

[0302] To a solution of Intermediate 90-5 (2.5 g, 8.47 mmol, 1 eq) and Intermediate 90-3 (1.39 g, 8.47 mmol, 1 eq) in MeCN (100 mL) was added a solution of AgNO3(1.73 g, 10.16 mmol, 1.2 eq) and ammonium persulfate (6.18 g, 27.09 mmol, 5.89 mL, 3.2 eq) in H2O (150 mL) at 25°C in one portion. The above mixture was poured into a 500 mL three-necked, round- bottomed flask and heated in an oil bath to 85°C. The mixture was stirred at 85°C for 2 hours under N2. LCMS showed material was consumed completely and one peak with the desired masswas detected. The mixture was cooled to 0-10°C and quenched with saturated sodium sulfite solution (500 mL). The mixture was extracted with ethyl acetate (3 x 0.5 L). The organic layer was dried with Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=15%) to give Intermediate 90-6 (0.35 g, 862.03 μmol, 10.18% yield, 90% purity) as a light orange solid.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.07 (br s, 4 H) 3.69 (br s, 4 H) 5.18 (s, 2 H) 7.29 - 7.41 (m, 5 H).

[0303] To a solution of Intermediate 90-6 (150 mg, 369.44 μmol, 1 eq) in THF (10 mL) was added Pd / C (150.00 mg, 704.75 μmol, 50% purity) and Boc2O (241.89 mg, 1.11 mmol, 254.62 μL, 3 eq) at 25°C under N2 atmosphere. The suspension was degassed and purged with H2 3 times. The mixture was stirred under H2 (15 Psi) at 25 °C for 48 hr. LCMS showed the reaction was complete. The reaction mixture was filtered and concentrated under reduced pressure give a residue. The residue was combined with another 10 mg batch and purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=20 / 1 to 10 / 1) and additionally by by Prep_HPLC (HCl system, column: Phenomenex luna C18100*40mm*5 um; mobile phase: [H2O (0.04% HCl)-ACN]; gradient:40%-70% B over 8.0 min) and lyophilized to give Intermediate 90-7 (70 mg, 200.66 μmol, 50.90% yield, 95% purity) as a light orange solid. Method C LCMS (ESI+): rt = 1.895 min, m / z 232 (M-100).EtOAc (3 mL) was added HCl / EtOAc (4 M, 3.23 mL, 61.18 eq) at 25°C. The mixture was stirred at 25°C for 3 hr.LCMS showed the reaction was complete. The mixture was concentrated under reduced pressure. The crude material was triturated with a mixture of EtOAc:MTBE=1:1 (5 mL), and filtered. The cake was washed with MTBE (3 mL), then dried under reduced pressure to give Compound 90 (51 mg, 184.39 μmol, 87.29% yield, 96.8% purity, HCl salt) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 3.06 - 3.13 (m, 4 H) 3.19 - 3.26 (m, 4 H) 8.96 (br s, 2 H). Method C LCMS (ESI+): rt = 1.235 min, m / z 232 (M+1). Example 91. Compound 91: benzyl trans-7,10-dimethoxy-2,4-dimethyl-6,11-dioxo- 1,2,4,5,6,11-hexahydro-3H-naphtho[2,3-d]azepine-3-carboxylate O O in a similar manner as Comp1ound 54. H NMR (400 MHz, DMSO-d6) δ 1.16 (br d, J=6.88 Hz, 6H), 2.80-2.88 (m, 2H), 2.89-2.98 (m, 2H), 3.85 (s, 6H), 4.53 (br d, J=3.50 Hz, 2H), 5.04 (s, 2H), 7.21-7.31 (m, 5H), 7.54 (s, 2H). Method D LCMS (MS+): rt = 2.631 min, m / z 450 (M+1). Example 92. Compound 92: 7,10-dimethoxy-2,3,4,5-tetrahydro-1H-naphtho[2,3-d]azepine- 6,11-dione92 was prepared in a similar manner as Compound 2.1H NMR (400 MHz, DMSO-d6) δ ppm 2.93 - 3.03 (m, 4 H) 3.14 - 3.24 (m, 4 H) 3.85 (s, 6 H) 7.53 (s, 2 H) 8.87 (br s, 2 H). Method C LCMS (ESI+): rt = 1.369 min, m / z 288 (M+H). Example 93. Compound 93: 3-(2-hydroxyethyl)-7,10-dimethoxy-2,3,4,5-tetrahydro-1H- naphtho[2,3-d]azepine-6,11-dionewas prepared in a similar manner as Compound 7.1H NMR (400 MHz, DMSO-d6) δ ppm 2.89 (br dd, J=16.82, 9.57 Hz, 2 H) 3.11 - 3.26 (m, 6 H) 3.58 - 3.64 (m, 2 H) 3.72 - 3.79 (m, 2 H) 3.85 (s, 6 H) 5.38 (br s, 1 H) 7.54 (s, 2 H) 9.71 - 9.95 (m, 1 H). Method C LCMS (ESI+): rt = 1.359 min, m / z 332 (M+H). Example 94. Compound 201: 3-isopropyl-7,8-dimethyl-2,3,4,5-tetrahydro-1H- benzo[d]azepine-6,9-dione

[0308] To a mixture of Compound 205 (100 mg, 409.58 μmol, HCl), acetone (237.88 mg,4.10 mmol,), NaOAc (134.40 mg, 1.64 mmol), 4A molecular sieve (100 mg) in MeOH (5 mL) was stirred at 20°C for 0.2 hr. Then was added AcOH (24.60 mg, 409.58 μmol) at 20°C. The mixture was stirred at 40°C for 1 hr before NaBH3CN (51.48 mg, 819.15 μmol) was added into the reaction at 20°C. The resulting mixture was stirred at 40°C for 3 hrs. Additional two reactions were set up as described above. The reaction mixtures were combined and purified follows. The solution was poured into ice NaHCO3 (20 mL). The aqueous phase was extracted with EtOAc (10 mL × 3). The combined organic phase was washed with brine (10 mL × 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC to give Compound 201 (66.2 mg, 14.91% yield, 100% purity, TFA) as a yellow solid:1H NMR: 400 MHz, DEUTERIUM OXIDE δ = 3.70 - 3.61 (m, 1H), 3.57 (br dd, J = 6.8, 13.4 Hz, 2H), 3.37 (br dd, J = 6.5, 17.8 Hz, 2H), 3.12 (br t, J = 12.1 Hz, 2H), 2.79 - 2.64 (m, 2H), 1.97 (s, 6H), 1.30 (d, J = 6.6 Hz, 6H); Method A LCMS (ESI+):1.611 min, m / z 448.1. Example 95. Compound 202: 3-cyclopentyl-7,8-dimethyl-2,3,4,5-tetrahydro-1H- benzo[d]azepine-6,9-dione[HCl) and cyclopentanone (226.20 mg, 2.69 mmol, 238.10 μL, 5 eq) in MeOH (15 mL) wasadded NaOAc (132.36 mg, 1.61 mmol, 3 eq) and AcOH (32.30 mg, 537.83 μmol, 30.79 μL, 1 eq) at 25°C. The mixture was stirred for 1 hr at 40°C. Then NaBH3CN (101.39 mg, 1.61 mmol, 3 eq) was added to the mixture in portions at 25°C. The mixture was stirred for 2 hrs at 40°C. To the mixture was added saturated Na2CO3(aqueous) to pH = 8, extracted with ethyl acetate (3 x 15 mL). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Ethyl acetate in Petroleum ether = 0 to 100%) to give Compound 202 (56 mg, 201.57 μmol, 37.48% yield, 98.4% purity) as a light brown solid:1H NMR (400 MHz, METHANOL-d4) δ ppm 2.87 - 2.95 (m, 1 H), 2.80 - 2.87 (m, 4 H), 2.65 - 2.74 (m, 4 H), 2.00 (s, 6 H), 1.86 - 1.96 (m, 2 H), 1.66 - 1.76 (m, 2 H), 1.54 - 1.63 (m, 2 H), 1.39 - 1.51 (m, 2 H); Method A LCMS (ESI+): 1.750 min, m / z 274 (M+H). Example 96. Compound 203: 7,8-dimethyl-3-(pentan-3-yl)-2,3,4,5-tetrahydro-1H- benzo[d]azepine-6,9-dione

[0310] To a solution of Compound 205 (50 mg, 186.17 μmol, 1 eq, HCl salt) in MeOH (1 mL) was added pentan-3-one (48.11 mg, 558.51 μmol, 59.18 μL, 3 eq), ZnCl2(25.38 mg, 186.17μmol, 8.73 μL, 1 eq) and NaBH3CN (35.10 mg, 558.51 μmol, 3 eq) in portions at 25°C under N2. The mixture was stirred at 70°C under N2 for 6 hours with microwave. Additional vials at 10 mg and 40 mg scale were set up as described above and these three reactions were combined. The residue was diluted with H2O (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (HCl condition, column: Phenomenex luna C18100*40mm*5 um; mobile phase: [H2O(0.04% HCl)-ACN];gradient:1%-35% B over 8.0 min) and the desired eluent was lyophilized to give Compound 203 in two batches (17 mg, 51.79 μmol, 11.13% yield, 95% purity, HCl salt; 26 mg, 80.87 μmol, 17.38% yield, 97% purity, HCl salt) as light yellow solids:1H NMR (400 MHz, DMSO-d6) δ ppm 0.96 (t, J=7.44 Hz, 6 H) 1.50 - 1.67 (m, 2 H) 1.84 (dqd, J=14.39, 7.40, 7.40, 7.40, 4.19 Hz, 2 H) 1.98 (s, 6 H) 2.89 - 3.03 (m, 2 H) 3.06 - 3.24 (m, 5 H) 3.50 (br dd, J=12.63, 6.38 Hz, 2 H) 10.07 (br dd, J=3.94, 1.94 Hz, 1 H); Method A LCMS (ESI+): 1.882 min, m / z 276 (M+H). Example 97. Compound 204: tert-butyl 7,8-dimethyl-6,9-dioxo-1,2,4,5,6,9-hexahydro-3H- benzo[d]azepine-3-carboxylate Example 98. Compound 205: 7,8-dimethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine-6,9- dione

[0311] To a solution of 2,3-dimethylbenzene-1,4-diol (8 g, 57.90 mmol) in acetone (60 mL) was added MnO2(30.20 g, 347.41 mmol) portion-wise at 20°C. The mixture was stirred at 20°C for 4 hrs. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give Intermediate 204-1 (2,3-dimethylcyclohexa-2,5-diene-1,4-dione, 7 g, 79.92% yield, 90% purity) as a yellow solid:1H NMR (400 MHz, CHLOROFORM-d) δ 6.73 (s, 2H), 2.04 (s, 6H).O O O O O HO N OH Bocag, 29.75mmol) in H2O (300 mL) and ACN (400 mL) was added AgNO3 (4.04 g, 23.80 mmol) and Intermediate 204-1 (3 g, 19.83 mmol) at 20°C. The mixture was stirred at 100°C for 0.2hr. Then the mixture was cooled to 20°C, and to a reaction mixture was added the solution of (NH4)2S2O8 (14.48 g, 63.46 mmol) in H2O (300 mL) and ACN (400 mL) dropwise at 20°C. The mixture was stirred at 100°C for 3hrs. The mixture was cooled to 20°C. The solution was poured into water (400 mL). The aqueous phase was extracted with EtOAc (200 mL × 3). The combined organic phase was washed with brine (200mL × 3), dried with anhydrous Na2SO, filtered and concentrated in vacuum. The residue was purified by prep-HPLC to give Compound 204 (200 mg, 3.01% yield, 91% purity) and Compound 205 in two batches (1.2 g, 18.78% yield, 75% purity, HCl; 0.3 g, 1.23 mmol, 6.20% yield, 99% purity, HCl) as brown solids.

[0313] The crude product Compound 204 (200 mg, 3.01% yield, 91% purity) was re-purifiedby prep-HPLC to give the compound (130.6 mg, 77.4% yield, 96.4% purity) as brown solid: 1HNMR (400 MHz, CHLOROFORM-d) δ = 3.54 (br s, 4H), 2.93 - 2.82 (m, 4H), 2.04 (s, 6H), 1.48 (s, 9H).

[0314] The crude product Compound 205 was purified by prep-HPLC [Column: Phenomenex luna C18100*40mm*5 um;mobile phase: [H2O(0.04% HCl)-ACN];gradient:5%-30% B over 8.0 min] to give purified Compound 205 (35.2 mg, 7.15% yield, 97.37% purity, HCl) as brown solid:1H NMR: (400 MHz, DEUTERIUM OXIDE) δ = 3.37 - 3.27 (m, 4H), 3.08 - 3.00 (m, 4H), 1.99 (s, 6H); Method A LCMS (ESI+): rt = 1.474 min, m / z 206.1 (M+H)+. Example 99. Compound 206: 7,8-dimethyl-3-phenethyl-2,3,4,5-tetrahydro-1H- benzo[d]azepine-6,9-dione

[0315] To a solution of Compound 205 (200 mg, 744.68 μmol, 1 eq, HCl salt) and 2- phenylacetaldehyde (268.42 mg, 2.23 mmol, 174.30 μL, 3 eq) in MeOH (3 mL) was added AcOH (44.72 mg, 744.68 μmol, 42.63 μL, 1 eq) and NaOAc (183.26 mg, 2.23 mmol, 3 eq) in portions at 25°C under N2. The mixture was stirred at 40°C under N2for 1 hour. Then to the mixture was added NaBH3CN (140.39 mg, 2.23 mmol, 3 eq) in one portion at 25°C under N2. The mixture was stirred at 40°C under N2 for 12 hours. One additional vial in 15 mg scale was set up as described above and these two reactions were combined. The mixture was diluted with H2O (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (HCl condition; column: Phenomenex luna C18100*40mm*5 um;mobile phase: [H2O(0.04% HCl)- ACN];gradient:1%-40% B over 8.0 min) and the desired eluent was lyophilized to give Compound 206 (48 mg, 138.78 μmol, 17.34% yield, 100% purity, HCl salt) as a light yellow solid:1H NMR (400 MHz, DMSO-d6) δ ppm 1.99 (s, 6 H) 2.77 - 2.93 (m, 2 H) 2.98 - 3.07 (m, 2 H) 3.14 - 3.24 (m, 4 H) 3.36 - 3.43 (m, 2 H) 3.68 (ddd, J=9.57, 7.75, 2.06 Hz, 2 H) 7.21 - 7.42 (m, 5 H) 10.04 - 10.28 (m, 1 H); Method A LCMS (ESI+): 2.053 min, m / z 310 (M+H). Example 100. Compound 207: 7,8-dimethyl-3-(3,3,3-trifluoropropyl)-2,3,4,5-tetrahydro- 1H-benzo[d]azepine-6,9-dione

[0316] To a mixture of Compound 205 (250 mg, 930.85 μmol, 1 eq, HCl salt) in DMF (8 mL) was added K2CO3 (514.61 mg, 3.72 mmol, 4 eq) at 25°C. The mixture was stirred for 0.5 hr at 25°C. Then 1,1,1-trifluoro-3-iodo-propane (625.43 mg, 2.79 mmol, 327.28 μL, 3 eq) was added to the mixture at 25°C and stirred for 8 hrs at 50°C. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 8 mL). The combined organic phases were washed with brine (3 x 10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Two additional vial in 50 mg scale was set up as described above. The residue was combined and purified by prep-HPLC (neutral condition, column: Waters Xbridge Prep OBD C18150*40 mm*10 um; mobile phase: [H2O (10 mM NH4HCO3)-MeCN]; gradient: 45%- 75% B over 8.0 min) and lyophilization to give Compound 207 (29 mg, 94.03 μmol, 7.22% yield, 97.7% purity) as a gray solid:1H NMR (400 MHz, METHANOL-d4) δ ppm 2.80 - 2.88 (m, 4 H), 2.73 - 2.79 (m, 2 H), 2.58 - 2.63 (m, 4 H), 2.34 - 2.48 (m, 2 H), 2.01 (s, 6 H); Method A LCMS (ESI+): 1.699 min, m / z 302 (M+H). Example 101. Compound 208: 7,8-dimethyl-3-(4-(trifluoromethyl)benzoyl)-2,3,4,5- tetrahydro-1H-benzo[d]azepine-6,9-dione

[0317] To a solution of Compound 205 (120 mg, 496.46 μmol, 1 eq, HCl) in DMF (10 mL) was added 4-(trifluoromethyl)benzoic acid (141.58 mg, 744.68 μmol, 1.5 eq), NMI (122.28 mg, 1.49 mmol, 118.72 μL, 3 eq) and 1-chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (TCFH, 278.59 mg, 992.91 μmol, 2 eq) at 25°C in order. The mixture was stirred at 25°C for 12 hours. The mixture was diluted with ethyl acetate (10 mL) and water (10 mL). The mixture was extracted with ethyl acetate (3 x 10 mL). The organic layer was dried with Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=92%) andthen triturated with ethyl acetate (2 mL). The solid was dried in high vacuum to give Compound 208 (56 mg, 144.39 μmol, 29.08% yield, 97.3% purity) as yellow solid: 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 7.82 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 3.75 (br s, 2H), 3.40 (br s, 2H), 2.94 (br s, 2H), 2.77 (br s, 2H), 1.97 (br s, 6H); Method A LCMS (ESI+): 2.806 min, m / z 378 (M+H). Example 102. Compound 209: 7,8-dimethyl-1,2,4,5-tetrahydrobenzo[d]oxepine-6,9-dione

[0318] a mg, oxydipropionic acid (476.37 mg, 2.94 mmol, 1 eq) in MeCN (40 mL) and H2O (25 mL) was added AgNO3 (598.90 mg, 3.53 mmol, 1.2 eq) in portions at 25°C. Then the mixture was stirred for 30 min at 100°C. Then a solution of (NH4)2S2O8 (2.15 g, 9.40 mmol, 2.04 mL, 3.2 eq) in MeCN (40 mL) and H2O (25 mL) was added to the mixture dropwise at 25°C. The mixture was stirred for 3 hrs at 100°C. The mixture was extracted with EtOAc (3 x 50 mL). The combined organic phase was washed with saturated Na2S2O3 (aqueous, 50 mL), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (neutral condition, column: Waters Xbridge BEH C18 100*30 mm*10 um; mobile phase: [H2O (10 mM NH4HCO3)-MeCN]; gradient: 24%-56%, B over 8.0 min) and lyophilization of appropriate fractions to give Compound 209 (8.6 mg, 41.70 μmol, 1.42% yield) as a yellow solid:1H NMR (400 MHz, DMSO-d6) δ ppm 3.58 - 3.67 (m, 4 H), 2.78 - 2.86 (m, 4 H), 1.96 (s, 6 H); Method B LCMS (ESI-): 2.566 min; GCMS: m / z: 206. Example 103. Compound 210: 7,8-dimethyl-3-(pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H- benzo[d]azepine-6,9-dione

[0319] To a solution of Compound 205 (200 mg, 744.68 μmol, 1 eq, HCl) and 4- chloropyrimidine (170.58 mg, 1.49 mmol, 2 eq) in THF (4 mL) was added TEA (226.06 mg, 2.23 mmol, 310.95 μL, 3 eq) in one portion at 25°C under N2. The mixture was stirred at 60°C for 12 hours under N2. The mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (neutral condition, column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient: 25%-55% B over 8.0 min) and the desired eluent was lyophilized to give Compound 210 (42 mg, 148.24 μmol, 19.91% yield, 100% purity) as a light yellow solid:1H NMR (400 MHz, DMSO-d6) δ ppm 1.85 - 2.04 (m, 6 H) 2.07 (s, 1 H) 2.78 - 2.96 (m, 4 H) 3.81 (br s, 4 H) 6.80 (dd, J=6.25, 0.88 Hz, 1 H) 8.17 (d, J=6.25 Hz, 1 H) 8.49 (s, 1 H); Method A LCMS (ESI+): 1.828 min, m / z 284 (M+H). Example 104. Compound 211: 7,8-dimethyl-3-(pyrimidin-2-yl)-2,3,4,5-tetrahydro-1H- benzo[d]azepine-6,9-dione

[0320] To a solution of Compound 205 (200 mg, 744.68 μmol, 1 eq, HCl salt) and 2- chloropyrimidine (170.58 mg, 1.49 mmol, 2 eq) in THF (4 mL) was added TEA (226.06 mg, 2.23 mmol, 310.95 μL, 3 eq) in one portion at 25°C under N2. The mixture was stirred at 60°Cfor 12 hours under N2. One additional vial in 100 mg scale was set up as described above and these two reactions were combined. The mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (neutral condition,column: Waters Xbridge BEH C18 100*30mm*10um;mobile phase: [H2O (10mM NH4HCO3)-ACN];gradient:30%-60% B over 8.0 min) and the desired eluent was lyophilized to give Compound 211 (26 mg, 84.43 μmol, 7.56% yield, 92% purity) as a light green solid:1H NMR (400 MHz, DMSO-d6) δ ppm 1.95 (s, 6 H) 2.80 - 2.89 (m, 4 H) 3.84 - 3.95 (m, 4 H) 6.61 (t, J=4.75 Hz, 1 H) 8.37 (d, J=4.75 Hz, 2 H); Method A LCMS (ESI+): 2.311 min, m / z 284 (M+H). Example 105. Compound 212: 2,3-dimethyl-5,6,8,9-tetrahydro-1H-benzo[7]annulene-1,4,7- trione

[0321] To a solution of Intermediate 204-1 (1 g, 7.34 mmol, 1 eq) in ACN (100 mL) and H2O(50 mL) was added 4-oxoheptanedioic acid (1.92 g, 11.02 mmol, 1.5 eq) and AgNO3 (1.50 g,8.81 mmol, 1.2 eq) at 25°C. The mixture was stirred at 100°C for 45 mins. Then a mixture of ammonium persulfate (5.36 g, 23.50 mmol, 5.11 mL, 3.2 eq) in ACN (100 mL) and H2O (50 mL) was added to the solution dropwise at 25°C. The mixture was stirred at 100°C for 3 hours. TLC showed the reaction worked. The mixture was diluted with ethyl acetate (100 mL) and water (50 mL). The mixture was extracted with ethyl acetate (3 x 80 mL). The organic layer was washed with saturated sodium sulfite solution (100 mL), dried with Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=8%), and then purified by prep- HPLC (HCl system; column: Phenomenex luna C18100*40mm*5 um; mobile phase: [H2O (0.04% HCl)-ACN]; gradient: 25%-45% B over 8.0 min) and lyophilized to give Compound212 (39.4 mg, 180.53 μmol, 2.46% yield) as a yellow solid:1H NMR (METHANOL-d4, 400 MHz) δ (ppm) 2.88-2.94 (m, 4H), 2.59-2.65 (m, 4H), 2.05 (s, 6H); Method A LCMS (ESI+): 2.245 min, m / z 219 (M+1). Example 106. Compound 213: 7-(isopropylamino)-2,3-dimethyl-6,7,8,9-tetrahydro-1H- benzo[7]annulene-1,4(5H)-dione

[0322] To a mixture of Compound 212 (30 mg, 123.71 μmol, 1 eq, purity 90%, prepared according to the general procedure for Compound 12) and propan-2-amine (21.94 mg, 371.14 μmol, 31.89 μL, 3 eq) in dichloromethane (1 mL) was added AcOH (7.43 mg, 123.71 μmol, 7.08 μL, 1 eq) dropwise at 25°C. The reaction mixture was stirred at 25°C for 30 minutes. Then sodium triacetoxyboranuide (65.55 mg, 309.28 μmol, 2.5 eq) was added to the mixture at 25°C. The reaction mixture was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure to give the residue. The residue was purified by prep-HPLC (NH4HCO3condition; column: Waters Xbridge Prep OBD C18150*40mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:25%-65% B over 8.0 min) and the desired eluent was lyophilized to give the product. The product was purified again by prep-HPLC (NH4HCO3condition; column: Waters Xbridge BEH C18100*25mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:15%-45% B over 8.0 min) and the desired eluent was lyophilized to give Compound 213 (9.2 mg, 34.22 μmol, 21.27% yield, 97.2% purity) as yellow solid:1H NMR (400 MHz, DMSO-d6) δ 0.95 (d, J=6.25 Hz, 6H), 1.00-1.11 (m, 2H), 1.13-1.27 (m, 1H), 1.74-1.87 (m, 2H), 1.95 (br s, 6H), 2.24 (br t, J=12.07 Hz, 2H), 2.74-2.82 (m, 1H), 2.82-2.88 (m, 1H), 2.88-3.00 (m, 2H); Method A LCMS (ESI+): 2.238 min, m / z 262 (M+1).Example 107. Compound 214: 7,8-dimethyl-3-(2-(pyrrolidin-1-yl)pyrimidin-4-yl)-2,3,4,5- tetrahydro-1H-benzo[d]azepine-6,9-dione

[0323] To a solution of 2,4-dichloropyrimidine (5.7 g, 38.26 mmol, 1 eq) in THF (60 mL) was added pyrrolidine (5.44 g, 76.52 mmol, 6.39 mL, 2 eq) dropwise at 25°C. The mixture was stirred at 25°C for 2 hours under N2. One additional vial in 0.3 g scale was set up as described above and these two reactions were combined. Then the mixture was diluted with H2O (80 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic phases were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude. The crude was purified by reversed-phase HPLC (0.1% HCl condition). The desired eluent was concentrated under reduced pressure to remove the solvent and extracted with ethyl acetate (2 x 100 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. Intermediate 214-1 (3 g, 15.52 mmol, 38.63% yield, 95% purity) and Intermediate 214-2 (1 g, 5.17 mmol, 12.88% yield, 95% purity) were obtained as white solid: 214-1:1H NMR (400 MHz, DMSO-d6) δ ppm 1.80 - 2.03 (m, 4 H) 3.33 - 3.50 (m, 4 H) 6.48 (d, J=6.13 Hz, 1 H) 8.01 (d, J=6.00 Hz, 1 H); 214-2:1H NMR (400 MHz, DMSO-d6) δ ppm 1.85 - 1.99 (m, 4 H) 3.45

[0324] To a solution of Compound 205 (150 mg, 620.57 μmol, 1 eq, HCl) in HFIP (5 mL) was added Intermediate 214-2 (179.94 mg, 930.85 μmol, 1.5 eq) dropwise at 25°C under N2. The mixture was stirred at 50°C for 12 hours under N2. LCMS showed 30% of starting material remained and 40% of desired mass was detected. Then the mixture was concentrated under reduced pressure to remove the solvent. The crude was purified by prep-HPLC (neutral condition, column: Waters Xbridge Prep OBD C18150*40mm*10um; mobile phase: [H2O (10mM NH4HCO3)-ACN];gradient:40%-80% B over 8.0 min) and the desired eluent was lyophilized to give Compound 214 (22 mg, 56.57 μmol, 9.12% yield, HCl) as a yellow solid:1H NMR (400 MHz, DMSO-d6) δ ppm 1.84 - 1.91 (m, 4 H) 1.94 (s, 6 H) 2.81 - 2.90 (m, 4 H) 3.42 (br t, J=6.44 Hz, 4 H) 3.77 (br s, 4 H) 6.05 (d, J=6.13 Hz, 1 H) 7.82 (d, J=6.13 Hz, 1 H); Method A LCMS (ESI+): 2.188 min, m / z 353 (M+H). Example 108. Compound 215: 7,8-dimethyl-3-(4-(pyrrolidin-1-yl)pyrimidin-2-yl)-2,3,4,5- tetrahydro-1H-benzo[d]azepine-6,9-dione

[0325] To a solution of Compound 205 (150 mg, 620.57 μmol, 1 eq, HCl) in HFIP (5 mL) was added Intermediate 214-1 (179.94 mg, 930.85 μmol, 1.5 eq) in one portion at 25°C under N2. The mixture was stirred at 50°C for 72 hours under N2. Then the mixture was concentrated under reduced pressure to remove the solvent. The crude was purified by prep-HPLC (neutral condition, column: Waters Xbridge Prep OBD C18150*40mm*10um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient:15%-75% B over 8.0 min) and the desired eluent was lyophilized to give Compound 215 (30 mg, 83.42 μmol, 13.44% yield, 98% purity) as an orange solid:1H NMR (400 MHz, DMSO-d6) δ ppm 1.80 - 2.03 (m, 10 H) 2.81 (br s, 4 H) 3.32 - 3.55 (m, 4 H) 3.74 - 3.91 (m, 4 H) 5.73 (d, J=5.88 Hz, 1 H) 7.82 (d, J=5.88 Hz, 1 H); LCMS (ESI+): 2.205 min, m / z 353 (M+H).Example 109. Compound 216: tert-butyl (3-(7,8-dimethyl-6,9-dioxo-1,2,4,5,6,9-hexahydro- 3H-benzo[d]azepin-3-yl)propyl)(methyl)carbamate

[0326] To a solution of Compound 205 (300 mg, 1.24 mmol, 1 eq, HCl) and tert-butyl N- methyl-N-(3-oxopropyl)carbamate (697.16 mg, 3.72 mmol, 3 eq) in MeOH (4 mL) was added NaOAc (305.43 mg, 3.72 mmol, 3 eq) and AcOH (74.53 mg, 1.24 mmol, 71.05 μL, 1 eq) in order at 25°C. The mixture was stirred for 1 hr at 25°C. Then NaBH3CN (233.98 mg, 3.72 mmol, 3 eq) was added to the mixture and stirred for 12 hrs at 25°C. The mixture wasfiltered. The filtrate was purified by prep-HPLC (FA condition, column: Phenomenex luna C18100*40 mm*3 um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 5%-40% B over 8.0 min) and lyophilized to give Compound 216 (255 mg, crude) as a purple solid:1H NMR (400 MHz, DMSO-d6) δ ppm 3.14 - 3.19 (m, 2 H), 2.76 (br s, 3 H), 2.70 - 2.74 (m, 4 H), 2.51 - 2.53 (m, 2 H), 2.49 - 2.49 (m, 2 H), 2.39 (br t, J=7.00 Hz, 2 H), 1.95 (s, 6 H), 1.58 - 1.64 (m, 2 H), 1.39 (s, 9 H). Example 110. Compound 217: 7,8-dimethyl-3-(3-(methylamino)propyl)-2,3,4,5-tetrahydro- 1H-benzo[d]azepine-6,9-dione

[0327] A mixture of Compound 216 (35 mg, 84.76 μmol, 1 eq, HCl) in EtOAc (2 mL) and HCl / EtOAc (2 mL) was stirred for 2 hrs at 25°C. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (HCl condition, column: Phenomenex luna C18100*40 mm*5 um; mobile phase: [H2O (0.04% HCl)-ACN]; gradient: 1%-20% B over 8.0 min) and lyophilized to give Compound 217 (5.6 mg, 15.63 μmol, 18.44% yield, 97.5% purity, 2HCl) as a yellow solid:1H NMR (400 MHz, METHANOL-d4) δ ppm 3.74 (br dd, J=13.01, 7.13 Hz, 2 H), 3.32 - 3.44 (m, 4 H), 3.21 (br t, J=12.01 Hz, 2 H), 3.10 - 3.15 (m, 2 H), 2.95 (br dd, J=17.70, 10.69 Hz, 2 H), 2.75 (s, 3 H), 2.17 - 2.26 (m, 2 H), 2.04 (s, 6 H); Method A LCMS (ESI+): m / z 277.1 (M+H). Example 111. Compound 218: 3-(3-(dimethylamino)propyl)-7,8-dimethyl-2,3,4,5- tetrahydro-1H-benzo[d]azepine-6,9-dione

[0328] To a mixture of Compound 217 (45 mg, 162.82 μmol, 1 eq) in MeOH (1 mL) was added NaOAc (40.07 mg, 488.47 μmol, 3 eq), (HCHO)n (15.65 mg, 488.47 μmol, 3 eq) and AcOH (9.78 mg, 162.82 μmol, 9.32 μL, 1 eq) in order at 25°C. The mixture was stirred for 1 hr at 25°C. Then NaBH3CN (30.70 mg, 488.47 μmol, 3 eq) was added to the mixture in portions at 25°C. The mixture was stirred for 12 hrs at 25°C. One additional vial in 30 mg scale was set up as described above. The mixture was combined and filtered, and the filter cake was washed with 2 mL MeOH. The filtrate was purified by prep-HPLC (HCl condition, column: Phenomenex Luna C1875*30 mm*3 um; mobile phase: [H2O (0.04% HCl)- ACN]; gradient:1%-25% B over 8.0 min) and lyophilized to give Compound 218 (14.1 mg, 46.85 μmol, 21.78% yield, 96.5% purity) as a brick-red solid:1H NMR (400 MHz, DMSO-d6) δ ppm 3.56 - 3.66 (m, 2 H), 3.08 - 3.22 (m, 8 H), 2.84 - 2.92 (m, 2 H), 2.78 (s, 6 H), 2.07 - 2.18 (m, 2 H), 1.97 (s, 6 H); Method A LCMS (ESI+): m / z 293.1 (M+H).Example 112. Compound 219: 3-(2-(dimethylamino)ethyl)-7,8-dimethyl-2,3,4,5-tetrahydro- 1H-benzo[d]azepine-6,9-dionewas prepared according to the general procedures described in other Examples in the application. Example 113. Compound 2207,8-dimethyl-1,3,4,5-tetrahydrospiro[benzo[d]azepine-2,1'- cyclohexane]-6,9-dione

[0330] To a solution of Intermediate 204-1 (100 mg, 734.50 μmol, 1 eq) and Intermediate42-5 (433.74 mg, 954.85 μmol, 1.3 eq) in ACN (3 mL) and H2O (2 mL) was added AgNO3 (149.72 mg, 881.40 μmol, 1.2 eq) in one portion at 20°C. The mixture was stirred at 90°C for 0.5 hours. Then the mixture was cooled to 20°C, and to this was added a solution of ammonium persulfate (536.36 mg, 2.35 mmol, 510.82 μL, 3.2 eq) in H2O (2 mL) and ACN (3 mL) dropwise at 20°C. The mixture was stirred at 100°C for 3 hours. LCMS showed the starting material was consumed completely and 15% of desired mass was detected. The mixture was cooled to 20°C. The mixture was quenched with aqueous of saturated sodium sulfite (30 mL). The aqueous phase was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with brine (2 x 30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by prep-HPLC (neutral condition) and the desired eluent was lyophilized give the product Intermediate 220-2 (9.2 mg, 20.73 μmol, 2.82% yield, 91.8% purity) as a yellow solid:1H NMR (400 MHz, DMSO-d6) δ ppm 1.02 - 1.18 (m, 1 H) 1.33 - 1.53(m, 6 H) 1.57 (br d, J=12.01 Hz, 1 H) 1.95 (d, J=11.26 Hz, 6 H) 2.52 - 2.60 (m, 2 H) 2.63 - 2.73 (m, 2 H) 3.20 (s, 2 H) 3.88 (t, J=5.75 Hz, 2 H) 5.03 (s, 2 H) 7.24 - 7.45 (m, 5 H). Method C LCMS (ESI+): rt = 3.239 min, m / z 408 (M+H).

[0331] To a suspension of Pd / C (240.00 mg, 1.13 mmol, 50% purity, 8.51 eq) in MeOH (10 mL) was added Intermediate 220-2 (0.06 g, 132.52 μmol, 1 eq) and HCl (2 mL, 2 M) under N2atmosphere. The suspension was degassed and purged with H23 times. The mixture was stirred under H2 (267.68 μg, 132.52 μmol, 1 eq) (15 Psi) for 12 hours at 20°C. LCMS showed the starting material was consumed completely and two main peaks with the desired mass were detected. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give Compound 220 (30 mg, 96.83 μmol, 73.07% yield, HCl) and Intermediate 220-3 (30 mg, 96.20 μmol, 72.60% yield, HCl) as a yellow solid. Method C LCMS (ESI+): rt = 0.310min / 0.355min, m / z 276 / 274 (M+H). O OH O HCl HCl

[0332] To a solution of Compound 220 (30 mg, 96.83 μmol, 1 eq, HCl) and Intermediate 220-3 (30 mg, 96.20 μmol, 9.94e-1 eq, HCl) in acetone (1 mL) and MeOH (1 mL) was added MnO2(25.25 mg, 290.48 μmol, 3 eq) in one portion at 20°C. The mixture was stirred at 20°C for 4 hours. LCMS showed the starting material was consumed completely and one main peak with desired mass was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by prep-HPLC (HCl condition) and the desired eluent was lyophilized to give the Compound 220 (10.9 mg, 34.41 μmol, 35.53% yield,97.8% purity, HCl) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ ppm 1.08 - 1.24 (m, 1 H) 1.36 (q, J=10.13 Hz, 2 H) 1.46 - 1.64 (m, 5 H) 1.73 - 1.86 (m, 2 H) 1.98 (d, J=3.25 Hz, 6 H) 2.99 (br dd, J=6.25, 3.63 Hz, 2 H) 3.05 (s, 2 H) 3.15 (br s, 2 H) 9.32. Method C LCMS (ESI+): rt = 1.916 min, m / z 274 (M+H). Example 114. Compound 221: 7-(2-aminoethyl)-2,3-dimethyl-6,7,8,9-tetrahydro-1H- benzo[7]annulene-1,4(5H)-dionewas prepared in a similar manner as Compound 45.1H NMR (400 MHz, DMSO-d6) δ ppm 7.70 (br s, 3 H), 3.02 (br dd, J=14.45, 7.32 Hz, 2 H), 2.75 - 2.88 (m, 2 H), 2.23 (br dd, J=14.26, 11.88 Hz, 2 H), 1.95 (s, 6 H), 1.78 (br dd, J=12.76, 7.38 Hz, 2 H), 1.72(dt, J=6.88, 3.31 Hz, 1 H), 1.41 - 1.50 (m, 2 H), 0.87 - 1.00 (m, 2 H) Method A LCMS (ESI+): rt= 1.910 min, m / z 248 (M+H). Example 115. Compound 222: benzyl-cis-2,4,7,8-tetramethyl-6,9-dioxo-1,2,4,5,6,9- hexahydro-3H-benzo[d]azepine-3-carboxylateprepared in a similar manner as Compound 53.1H NMR (400 MHz, DMSO-d6) δ ppm 1.27 (br d, J=6.00 Hz, 6 H) 1.92 (s, 6 H) 2.71 - 3.00 (m, 4 H) 4.03 - 4.21 (m, 2 H) 4.83 - 5.10 (m, 2 H) 7.07 - 7.30 (m, 5 H). Method C LCMS (ESI+): rt = 2.934 min, m / z 368 (M+H). Example 116. Compound 223: cis-2,4,7,8-tetramethyl-2,3,4,5-tetrahydro-1H- benzo[d]azepine-6,9-dione

[0335] To a suspension of Pd / C (46.34 mg, 43.54 μmol, 10% purity, 0.1 eq) in THF (20 mL) was added a solution of Compound 222 (160 mg, 435.45 μmol, 1 eq) and HCl (1 M, 1.60 mL, 3.67 eq) in 1 mL THF at 20°C under Ar. The mixture was degassed and purged with H23 times. The mixture was stirred for 2 hours at 20°C under H2 (15 Psi). LCMS showed the starting material was consumed. The mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give a mixture of Intermediate 223-1 and Compound 223 (100 mg, crude, HCl salt) as an orange oil which was used for next step directly. Method D LCMS (ESI+): rt = 0.255 / 0.315 min, m / z 236 / 234 (M+H).

[0336] To a mixture of Intermediate 223-1 and Compound 223 (100 mg, 367.94 μmol, 1 eq, HCl) in acetone (3 mL) and MeOH (0.3 mL) was added MnO2(95.97 mg, 1.10 mmol, 3 eq) in portions at 20°C. The mixture was stirred for 2 hrs at 20°C. LCMS showed the reaction worked well. One additional reaction on 10 mg scale was set up as described above and combined. The mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition, column: Phenomenex luna C18100*40 mm*3 um; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 1%-25% B over 10.0 min) and lyophilized to give Compound 223 (57.2 mg, 204.78 μmol, 50.59% yield, FA salt) as a brown solid.1H NMR (400 MHz, DMSO-d6) δ ppm 8.33 (s, 1 H), 3.40 (br t, J=6.75Hz, 2 H), 2.81 - 2.92 (m, 2 H), 2.70 (br dd, J=15.95, 8.69 Hz, 2 H), 1.95 (s, 6 H), 1.11 (d, J=6.63 Hz, 6 H). Method A LCMS (ESI+): rt = 1.606 min, m / z 234 (M+H). Example 117. Compound 224: 7-(aminomethyl)-2,3-dimethyl-6,7,8,9-tetrahydro-1H- benzo[7]annulene-1,4(5H)-dione 224 was prepared in a similar manner as Compound 63.1H NMR (400MHz, DMSO-d6) δ 0.93-1.08 (m, 2H), 1.80-1.90 (m, 2H), 1.95 (s, 7H), 2.20-2.31 (m, 2H), 2.66 (br d, J=6.38 Hz, 2H), 3.01 (br dd, J=14.88, 7.50 Hz, 2H), 7.92 (br s, 3H). Method C LCMS (ESI+): rt = 1.684 min, m / z 234 (M+1). Example 118. Compound 225: 7-((isopropylamino)methyl)-2,3-dimethyl-6,7,8,9-tetrahydro- 1H-benzo[7]annulene-1,4(5H)-dionewas prepared in a similar manner as Compound 64.1H NMR (400 MHz, DMSO-d6) δ 0.97-1.11 (m, 2H), 1.22 (d, J=6.50 Hz, 6H), 1.88 (br dd, J=12.94, 7.94 Hz, 2H), 1.92-2.07 (m, 7H), 2.23-2.33 (m, 2H), 2.76 (br s, 2H), 3.03 (br dd, J=15.01, 7.38 Hz, 2H), 3.22-3.29 (m, 1H), 8.24 (br d, J=1.75 Hz, 2H). Method C LCMS (ESI+): rt = 1.902 min, m / z 276 (M+1). Example 119. Compound 226: 7-((dimethylamino)methyl)-2,3-dimethyl-6,7,8,9-tetrahydro- 1H-benzo[7]annulene-1,4(5H)-dione226 was prepared in a similar manner as Compound 64.1H NMR (400 MHz, DMSO-d6) δ 0.94-1.10 (m, 2H), 1.83-1.92 (m, 2H), 1.95 (s, 6H), 2.15 (ddd, J=13.73, 6.85, 3.69 Hz, 1H), 2.31 (br dd, J=14.70, 11.44 Hz, 2H), 2.75 (d, J=4.88 Hz, 6H), 2.92 (br t, J=6.32 Hz, 2H), 3.00 (br dd, J=15.13, 7.50 Hz, 2H), 9.70 (br d, J=3.13 Hz, 1H). Method C LCMS (ESI+): rt = 1.819 min, m / z 262 (M+1) Example 120. Compound 227: 7-(2-(dimethylamino)ethyl)-2,3-dimethyl-6,7,8,9-tetrahydro- 1H-benzo[7]annulene-1,4(5H)-dione was prepared in a simila1r manner as Compound 64. H NMR (400 MHz, DMSO-d6) δ ppm 9.90 - 10.22 (m, 1 H), 2.96 - 3.10 (m, 4 H), 2.71 (d, J=4.88 Hz, 6 H), 2.20 - 2.30 (m, 2 H), 1.95 (s, 6 H), 1.78 (br dd, J=12.44, 7.82 Hz, 2 H), 1.71 (br dd, J=6.19, 3.31 Hz, 1 H), 1.51 - 1.61 (m, 2 H), 0.91 - 1.04 (m, 2 H). Method A LCMS (ESI+): rt = 1.938 min, m / z 276 (M+H). Example 121. Compound 228: 7-(2-(diethylamino)ethyl)-2,3-dimethyl-6,7,8,9-tetrahydro- 1H-benzo[7]annulene-1,4(5H)-dionewas prepared in a similar manner as Compound 64.1H NMR (400 MHz, DMSO-d6) δ ppm 9.90 (br s, 1 H), 2.96 - 3.20 (m, 8 H), 2.24 (br dd, J=14.13, 11.76 Hz, 2 H), 1.95 (s, 6 H), 1.80 (br dd, J=12.63, 7.75 Hz, 2 H), 1.67 - 1.76 (m, 1 H), 1.50 - 1.63 (m, 2 H),1.18 (t, J=7.25 Hz, 6 H), 0.92 - 1.05 (m, 2 H). Method A LCMS (ESI+): rt = 2.046 min, m / z 304 (M+H). Example 122. Compound 229: 7-(2-(isopropylamino)ethyl)-2,3-dimethyl-6,7,8,9-tetrahydro- 1H-benzo[7]annulene-1,4(5H)-dione was prepared in a similar manner as Compound 64.1H NMR (400MHz, DMSO-d6) δ ppm 8.64 (br s, 2 H), 3.23 (dt, J=12.32, 6.10 Hz, 1 H), 3.01 (br dd, J=14.63, 7.13 Hz, 2 H), 2.78 - 2.93 (m, 2 H), 2.18 - 2.31 (m, 2 H), 1.95 (s, 5 H), 1.71 - 1.87 (m, 3 H), 1.48 - 1.63 (m, 2 H), 1.22 (d, J=6.50 Hz, 6 H), 0.87 - 1.04 (m, 2 H). Method A LCMS (ESI+): rt = 2.032 min, m / z 290 (M+H). Example 123. Compound 230: 2,3-dimethyl-7-(morpholinomethyl)-6,7,8,9-tetrahydro-1H- benzo[7]annulene-1,4(5H)-dione Owas prepared in a similar manner as Compound 74. 1H NMR (400MHz, DMSO-d6) δ 0.97-1.14 (m, 2H), 1.95 (s, 8H), 2.19-2.36 (m, 3H), 2.90-3.11 (m, 6H), 3.42 (br d, J=12.13 Hz, 2H), 3.81-3.99 (m, 4H), 10.36 (br s, 1H). Method C LCMS (ESI+): rt = 1.800 min, m / z 304 (M+1). Example 124. Compound 231: 2,3-dimethyl-7-(2-(pyrrolidin-1-yl)ethyl)-6,7,8,9-tetrahydro- 1H-benzo[7]annulene-1,4(5H)-dione

[0344] Compound 231 was prepared in a similar manner as Compound 74.1H NMR (400 MHz, DMSO-d6) δ ppm 10.12 - 10.44 (m, 1 H), 3.47 (br dd, J=10.44, 5.07 Hz, 2 H), 3.07 - 3.16 (m, 2 H), 3.01 (br dd, J=14.63, 7.25 Hz, 2 H), 2.87 - 2.96 (m, 2 H), 2.24 (br dd, J=14.20, 11.69 Hz, 2 H), 1.91 - 2.05 (m, 8 H), 1.67 - 1.90 (m, 5 H), 1.51 - 1.65 (m, 2 H), 0.87 - 1.04 (m, 2 H). Method A LCMS (ESI+): rt = 2.016 min, m / z 302 (M+H). Example 125. Compound 232: 2,3-dimethyl-7-(2-morpholinoethyl)-6,7,8,9-tetrahydro-1H- benzo[7]annulene-1,4(5H)-dione p1repared in a similar manner as Compound 74. H NMR (400 MHz, DMSO-d6) δ ppm 10.62 (br s, 1 H), 3.90 - 4.00 (m, 2 H), 3.74 (br t, J=11.44 Hz, 2 H), 3.39 (br d, J=12.26 Hz, 2 H), 3.10 (dt, J=10.79, 5.17 Hz, 2 H), 3.01 (br dd, J=14.38, 7.63 Hz, 4 H), 2.25 (br dd, J=14.07, 11.69 Hz, 2 H), 1.89 - 2.04 (m, 6 H), 1.67 - 1.84 (m, 3 H), 1.57 - 1.66 (m, 2 H), 0.88 - 1.10 (m, 2 H). Method A LCMS (ESI+): rt = 1.945 min, m / z 318 (M+H). Example 126. Compound 233: benzyl 7,8-dimethyl-6,9-dioxo-2',3',4,5,5',6,6',9- octahydrospiro[benzo[d]azepine-2,4'-pyran]-3(1H)-carboxylateprepared in a similar manner as Compound 78.1H NMR (400 MHz, DMSO-d6) δ ppm 1.32 (br d, J=13.13 Hz, 2 H) 1.94 (d, J=10.63 Hz, 6 H) 2.64 - 2.84 (m, 4 H) 3.26 - 3.31 (m, 2 H) 3.50 (br t, J=11.26 Hz, 2 H) 3.71 (br dd, J=11.44, 4.57 Hz, 2 H) 3.91 (t, J=5.82 Hz, 2 H) 5.04 (s, 2 H) 7.22 - 7.46 (m, 5 H). Method C LCMS (ESI+): rt = 2.818 min, m / z 410 (M+H).Example 127. Compound 234: 7,8-dimethyl-1,2',3,3',4,5,5',6'- octahydrospiro[benzo[d]azepine-2,4'-pyran]-6,9-dione 234 was prepared in a similar manner as Compound 223.1H NMR (400δ ppm 1.69 - 1.83 (m, 4 H) 1.98 (d, J=2.25 Hz, 6 H) 2.07 (s, 1 H) 2.95 - 3.05 (m, 2 H) 3.17 (br s, 4 H) 3.40 - 3.50 (m, 2 H) 3.78 (br d, J=11.88 Hz, 2 H) 9.47 (br s, 2 H). Method C LCMS (ESI+): rt = 1.626 min, m / z 276 (M+H). Example 128. Biological Data: In Vitro Cell

[0348] Compounds were tested in the following survival assay. Human fibroblasts were maintained and passaged with standard protocols used by the field. Fibroblasts are split and plated at 3K / well in 96-well culture plates. After 24 hours, cells were treated with either DMSO (vehicle), 75nM RSL3 (challenge), or 75nM RSL3 with 100nM, 33nM, or 5nM doses of each compound. Each condition was performed in quadruplicate wells. After 24 hours, images of the cells were captured using the Sartorius IncuCyte SX5 imaging system and cell confluency was calculated using the built-in confluency calculation software. To determine % Cell Viability Rescue, the DMSO (vehicle) cell confluency was first set to 100% and the 75nM RSL3 (challenge) cell confluency was set to 0%. The data shown in Table 4 and Table 5 below represent the cell confluency of each condition (the average of quadruplicate wells) normalized to that scale. Table 4. Cell Viability of Human Fibroblasts with Compound after RSL3 Challenge % Cell Viability Rescue from RSL3% Cell Viability Rescue from RSL3 Challenge% Cell Viability Rescue from RSL3 ChallengeTable 5. Cell Viability of Human Fibroblasts with Compound after RSL3 Challenge % Cell Viability Rescue from RSL3 Challenge% Cell Viability Rescue from RSL3 Challenge Compound 30 nM 3 nM 0.3 nM% Cell Viability Rescue from RSL3 Challenge Compound 30 nM 3 nM 0.3 nMExample 129. In Vivo Evaluation of Compound 2 in a Rat Parkinson’s Disease Model

[0349] Aged male Lewis rats were challenged with the mitochondrial Complex 1 inhibitor rotenone (2.8 mg / kg, once a day, I.P. route) as previously described (Rocha et al. Neurobiology of Disease 134 (2020), 104626). Rotenone challenged animals were concomitantly treated either with 0.5 mg / kg Compound 2, 1.5 mg / kg Compound 2, or 5.0 mg / kg Compound 2, or the corresponding vehicle (once a day, P.O. route). After 21 days of treatment, animals were euthanized and then immunohistochemistry (IHC) was performed on the substantia nigra (SN) brain region. Specifically, 15-lipoxygenase (15-LO) target engagement was confirmed by quantifying 4-hydroxynonenal (4-HNE) protein adduct levels by IHC, revealing a dose-dependent and ultimately complete prevention of rotenone-induced 4-HNE protein adduct levels (Table 6). Table 6.4-HNE Levels in Rat Substantia Nigra Compound 2 vehicle rotenone (m / k )represen average num er o - o jec s neuron - neurons rom an n v ua animal (N=3).

[0350] LRRK2 kinase activity has been reported to be pathologically elevated by 15-LO generated 4-HNE. LRRK2 kinase activity levels were also measured in the SN by IHC using a proximity ligation method to measure the levels of the LRRK2 S1292 auto-phosphorylation site (Keeney et al., BioRxiv 2024.06.12.598654).15-LO pathway engagement was confirmed by this method, as Compound 2 exhibited a dose-dependent prevention of rotenone-induced LRRK2 kinase hyperactivity (Table 7). Table 7. Phospho-S1292-LRRK2 Levels in Rat Substantia Nigra Compound 2 vehicle rotenonerepresent average number of 4-HNE objects / neuron (40-90 DA neurons) from an individual animal (N=3).

[0351] Rotenone challenge induced the death of tyrosine hydroxylase (TH)-positive dopaminergic neurons in the substantia nigra of rats in this model of PD. This was determined by performing TH immunohistochemistry to quantify TH-positive neurons (Rocha et al. Neurobiology of Disease 134 (2020), 104626). Co-treatment with Compound 2 at 1.5 mg / kg resulted in the robust protection of TH-positive dopaminergic neuron viability from rotenone challenge, providing evidence of in vivo efficacy (Table 8). Table 8. Dopaminergic Neuron Viability in Rat Substantia Nigra vehicle rotenone hi l 10100 12420 12540 490 950 6210represent tota number o tyros ne ydroxy ase-pos t ve dopam nerg c neurons rom an individual animal (N=3). Example 130. In Vitro Evaluation of Compound 2 in Parkinson’s Disease Patient Neurons

[0352] Human Parkinson's disease (PD) patient induced pluripotent stem cell (iPSC)-derived dopaminergic neurons carrying the pathogenic G2019S LRRK2 mutation were cultured in vitro according to standard culture protocols. Neurons were treated for 24 hours with RSL3 to induce lipid peroxidation-mediated neurodegeneration and co-treated with a dose-response of Compound 2. After 24 hours, neurons were fixed and immunocytochemistry for the neurite marker Beta III-Tubulin was performed to quantify total neurite integrity. Images were acquired and analyzed using the Yokogawa CQ1 confocal high content microscopy platform. Compound 2 dose-dependently rescued RSL3-induced neurite loss with an EC50 of approximately 5 nM. Incontrast, the literature LRRK2 kinase inhibitor MLi-2 (CAS # 1627091-47-7) tested up to aconcentration of 100 nM was unable to rescue neurite integrity from RSL3 challenge.Example 131. In Vitro Evaluation of Compound 2 in Parkinson’s Disease Patient Fibroblast

[0353] Human PD patient-derived fibroblasts carrying the pathogenic G2019S LRRK2 mutation were cultured in vitro according to standard culture protocols. Fibroblasts were first pre-loaded with the lipid membrane peroxidation sensing dye referred to as C11-BODIPY (also known as BODIPY 581 / 591 C11, ThermoFisher Scientific) according to standard protocols. Fibroblasts were then treated for 24 hours with Imidazole Ketone Erastin (IKE) to induce lipid peroxidation-mediated cell death, and cells were co-treated with either 100nM Compound 2, 100nM of the LRRK2 kinase inhibitor MLi-2 or 100nM of the LRRK2 kinase inhibitor PFE-360 (CAS # 1527475-61-1). After 24 hours, C11-BODIPY fluorescence intensity was quantified to assess lipid peroxidation levels and cell confluence was calculated to assess cell viability / cell death using the Sartorius IncuCyte SX5 longitudinal imaging system. IKE also induced robust lipid peroxidation that was completely rescued by Compound 2, while PFE-360 exhibited no rescue and MLi-2 only exhibited a modest rescue (Table 9). IKE-induced robust cell death that was completely rescued by Compound 2, while PFE-360 exhibited no rescue and MLi-2 only exhibited a modest rescue (Table 10). Table 9. IKE-Induced Lipid Peroxidation in PD Patient Fibroblasts Treatment % Rescue from IKETable 10. IKE-Induced Cell Death in PD Patient Fibroblasts Treatment % Rescue from IKE

[0354] To demonstrate that Compound 2 rescued in a dose-dependent manner, PD patient fibroblasts were challenged with RSL3 to induce lipid peroxidation-mediated cell death, and cells were co-treated with multiple doses of Compound 2. After 24 hours, Compound 2 exhibited an IC50between 50pM and 500pM for the rescue of lipid peroxidation (Table 11) and similarly an EC50 between 50pM and 500pM for the rescue of cell viability (Table 12).

[0355] To test whether interventional treatment with Compound 2 could rescue cells from pre- existing RSL3-induced lipid peroxidation and cell death, PD patient fibroblasts were first treated with RSL3 and then 1nM Compound 2 was added 10 hours later. At 10 hours (right before Compound 2 addition) and 24 hours (14 hours after Compound 2 addition) after RSL3 challenge, lipid peroxidation and cell viability were measured with the IncuCyte SX5. At 10 hours, RSL3 alone induced ~90% increase in lipid peroxidation above baseline. At 24 hours, RSL3 alone maintained a ~90% increase in lipid peroxidation above baseline, while the 1nM Compound 2 interventional treatment lowered lipid peroxidation to ~35% above baseline (Table 13), suggesting that it may be possible to therapeutically lower pre-existing lipid peroxidation stress. Also at 10 hours, RSL3 alone induced ~40% decrease in cell viability below baseline. At 24 hours, RSL3 alone maintained a ~40% decrease in cell viability below baseline, while the 1nM Compound 2 interventional treatment increased cell viability to ~15% below baseline (Table 14), suggesting that it may be possible to therapeutically rescue pre-existing lipid peroxidation stress-induced cell death. Table 11. Dose Dependent Rescue from RSL3-Induced Lipid Peroxidation in PD Patient Fibroblasts Compound 2 (nM) % Rescue from RSL3Table 12. Dose Dependent Rescue from RSL3-Induced Cell Death in PD Patient Fibroblasts Compound 2 (nM) % Rescue from RSL3 30 95Table 13. Lipid Oxidation Rescue After RSL3 Challenge in PD Patient Fibroblasts % Change from BaselineTable 14. Cell Death Rescue After RSL3 Challenge in PD Patient Fibroblasts % Change from Baseline

[0356] Although the foregoing invention has been described in some detail by way of illustration and Example for purposes of clarity of understanding, one of skill in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference. Where a conflict exists between the instant application and a reference provided herein, the instant application shall dominate.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula J: , or a pharmaceuticallywherein each R1 and R2 is independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl,C1-6 hydroxyalkyl, C1-6 aminoalkyl, (C0-6 alkyl)(C3-8 cycloalkyl), (C0- 6 alkyl)(heterocyclyl), (C0-6alkyl)(C6-10aryl), (C0-6alkyl)(heteroaryl), halogen, ORa, SRa, NRaRb, NO2, or CN, wherein the alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0, 1, 2, 3, or 4 R1a; or R1and R2taken together with the carbon atoms to which they are attached form a C5-10cycloalkyl, heterocyclyl, C6-10 aryl, or heteroaryl ring each substituted with 0, 1, 2, 3, or 4 R1b; each R1aand R1bis independently D, halogen, ORa, SRa, NRaRb, oxo, NO2, or CN; each Ra and Rb is independently H or C1-6 alkyl;each R3a, R3b, R4a, R4b, R5a, R5b, R6a, and R6bis independently H, C1-6 alkyl, C1-6 alkyl, C2- 6 alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6aminoalkyl; or two of R3a,R3b,R4a,R4b,R5a,R5b,R6a,and R6btaken together with the atoms to which they are attached form a C3-8 cycloalkyl or a heterocyclyl; X is –C(R7a)(R7b)-, -N(R8)-, -O-, or –S-; R7ais (C0-6alkyl)-N(R7a1)(R7a2), (C0-6alkyl)-OR7a1, or (C0-6alkyl)-SR7a1; R7bis H or C1-6 alkyl; or R7aand R7btaken together form an oxo;each R7a1and R7a2is independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C2-6 alkoxyalkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, (C2- 6 alkyl)-N(R7c)C(O)-(R7d), (C2-6 alkyl)-N(R7c)C(O)(OR7d), (C2- 6 alkyl)-N(R7c)S(O)2R7d, (C0-6alkyl)(C3-8cycloalkyl), (C0-6alkyl)(heterocyclyl), (C0-6 alkyl)(C6-10 aryl), (C0-6 alkyl)(heteroaryl), (C0-6 alkyl)-C(O)-R7c, (C0-6 alkyl)- C(O)O-R7c, (C0-6 alkyl)-C(O)-N(R7c)(R7d), (C0-6 alkyl)-S(O)R7c, (C0-6 alkyl)- S(O)(NH)R7c, (C0-6alkyl)-S(O)2R7c, (C0-6alkyl)-S(O)2N(R7c)(R7d), or (C0-6alkyl)- S(O)(NR7c)R7d, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0, 1, 2, or 3 R7e; or R7a1and R7a2taken together with the atoms to which they are attached form a heterocyclyl, which is substituted with 0, 1, 2, or 3 R7e; R8is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-6 alkoxyalkyl, C1-6 haloalkyl, C1- 6 hydroxyalkyl, C1-6 aminoalkyl, (C2-6 alkyl)-N(R8a)C(O)-(R8b), (C2- 6 alkyl)-N(R8a)C(O)(OR8b), (C2-6alkyl)-N(R8a)S(O)2R8b, (C0-6alkyl)(C3-8cycloalkyl), (C0-6 alkyl)(heterocyclyl), (C0-6 alkyl)(C6-10 aryl), (C0- 6 alkyl)(heteroaryl), (C0-6 alkyl)-C(O)-R8a, (C0-6 alkyl)-C(O)O-R8a, (C0- 6 alkyl)-C(O)-N(R8a)(R8b), (C0-6alkyl)-S(O)R8a, (C0-6alkyl)-S(O)(NH)R8a, (C0-6 alkyl)-S(O)2R8a, (C0-6 alkyl)-S(O)2N(R8a)(R8b), or (C0-6 alkyl)-S(O)(NR8a)R8b, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0, 1, 2, or 3 R8c; each R7eand R8cis independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C2-6alkoxyalkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, C3-8 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, (C0-6 alkyl)-C(O)-R9a, (C0-6 alkyl)-C(O)O-R9a, (C0- 6 alkyl)-C(O)-N(R9a)(R9b), (C0-6alkyl)-S(O)R9a, -S(O)(NH)R9a, - S(O)2R9a, -S(O)2N(R9a)(R9b), or -S(O)(NR9a)R9b; each R7c, R7d, R8a, R8b, R9a, and R9bis independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-6alkoxyalkyl, C1-6haloalkyl, C1-6hydroxyalkyl, C1-6aminoalkyl, (C0-6 alkyl)(C3-8 cycloalkyl), (C0-6 alkyl)(heterocyclyl), (C0-6 alkyl)(C6-10 aryl), or (C0- 6 alkyl)(heteroaryl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0 to 4 Z1;each Z1is independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C2-6alkoxyalkyl, C1-6haloalkyl, C3-8 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, halogen, oxo, - OH, -CN, -NO2, -NH2, -N3, -SH, -O(C1-6 alkyl), -O(C1-6 haloalkyl), -NH(C1-6 alkyl), -NH(C1-6haloalkyl), -N(C1-6alkyl)2, -N(C1-6haloalkyl)2, -N(C1-6alkyl)(C1-6 haloalkyl), -C(O)(C1-6 alkyl), -C(O)(C1-6 haloalkyl), -C(O)O(C1-6 alkyl), - C(O)O(C1-6 haloalkyl), -C(O)NH2, -C(O)NH(C1-6 alkyl), -C(O)NH(C1-6 haloalkyl), -C(O)N(C1-6alkyl)2, -C(O)N(C1-6haloalkyl)2, -NHC(O)(C1-6alkyl), -NHC(O)(C1-6 haloalkyl), -NHC(O)O(C1-6 alkyl), -NHC(O)O(C1-6 haloalkyl), -NHC(O)NH(C1-6 alkyl), -NHC(O)NH(C1-6 haloalkyl), -NHS(O)(C1-6 alkyl), -N(C1-6alkyl)(S(O)(C1-6alkyl), -S(C1-6alkyl), -S(C1-6haloalkyl), - S(O)N(C1-6alkyl)2, -S(O)(C1-6alkyl), -S(O)(C1-6haloalkyl), -S(O)2(C1-6alkyl), - S(O)2(C1-6 haloalkyl), -S(O)(NH)(C1-6 alkyl), -S(O)2NH(C1-6 alkyl), or -S(O)2N(C1-6 alkyl)2; each heterocyclyl is a 4- to 10-membered ring having 1, 2, 3, or 4 heteroatoms selected from N, O, and S; and each heteroaryl is a 5- to 10-membered ring having 1, 2, 3, or 4 heteroatoms selected from N, O, and S.

2. The compound of claim 1, or pharmaceutically acceptable salt thereof,wherein each R1 and R2 is independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl,wherein the alkyl, alkenyl, alkynyl, or haloalkyl is substituted with 0, 1, 2, or 3 R1a.

3. The compound of claim 1 or 2, or pharmaceutically acceptable salt thereof, wherein each R1ais independently ORa, NRaRb, oxo, or CN.

4. The compound of any one of claims 1 to 3, or pharmaceutically acceptablesalt thereof, wherein each R1 and R2 is independently C1-6 alkyl.

5. The compound of any one of claims 1 to 4, or pharmaceutically acceptablesalt thereof, wherein each R1 and R2 is methyl.

6. The compound of any one of claims 1 to 5, or pharmaceutically acceptable salt thereof, wherein each R1bis independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1- 6 haloalkyl, halogen, or CN.

7. The compound of any one of claims 1 to 6, or pharmaceutically acceptable salt thereof, wherein each R3a, R3b, R6a, and R6bis H.

8. The compound of any one of claims 1 to 7, or pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula Ib: O R4a, wherein n is 0, 1,9. The compound of any one of claims 1 to 7, or pharmaceutically acceptable salt thereof, wherein each R3a,R3b,R4a,R4b,R5a,R5b,R6a,and R6bis H.

10. The compound of any one of claims 1 to 9, or pharmaceutically acceptable salt thereof, having the structure of Formula II: .

11. The compound of any one of claims 1 to 9, or pharmaceutically acceptable salt thereof, wherein R1and R2taken together with the carbon atoms to which they are attached form C6-10aryl or heteroaryl ring substituted with 0, 1, 2, or 3 R1b.

12. The compound of any one of claims 1 to 11, or pharmaceutically acceptable salt thereof, having the structure of Formula III: , whereinn is 0, 1, 2, or 3.

13. The compound of any one of claims 1 to 12, or pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

14. The compound of any one of claims 1 to 13, or pharmaceutically acceptable salt thereof, wherein X is –C(R7a)(R7b)- or -N(R8)-.

15. The compound of any one of claims 1 to 14, or pharmaceutically acceptable salt thereof, wherein X is –C(R7a)(R7b)- .

16. The compound of any one of claims 1 to 14, or pharmaceutically acceptable salt thereof, wherein X is -N(R8)-.

17. The compound of any one of claims 1 to 15, or pharmaceutically acceptable salt thereof, wherein R7ais -N(R7a1)(R7a2); and R7bis H.

18. The compound of any one of claims 1 to 17, or pharmaceutically acceptable salt thereof, wherein each R7a1and R7a2is independently H, C1-6alkyl, C2-6alkoxyalkyl, C1-6haloalkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, (C2-6 alkyl)-N(R7c)C(O)-(R7d), (C2- 6 alkyl)-N(R7c)C(O)(OR7d), (C2-6alkyl)-N(R7c)S(O)2R7d, (C0-6alkyl)(C3-8cycloalkyl), (C0-6alkyl)(heterocyclyl), (C0-6alkyl)(C6-10aryl), (C0-6alkyl)(heteroaryl), (C0-6alkyl)-C(O)-R7c, (C0-6alkyl)-C(O)O-R7c, (C0-6 alkyl)-C(O)-N(R7c)(R7d), (C0-6 alkyl)-S(O)R7c, (C0-6 alkyl)-S(O)(NH)R7c, (C0- 6 alkyl)-S(O)2R7c, (C0-6 alkyl)-S(O)2N(R7c)(R7d), or (C0-6 alkyl)-S(O)(NR7c)R7d, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0, 1, or 2 R7e.

19. The compound of any one of claims 1 to 18, or pharmaceutically acceptable salt thereof, wherein R7a1and R7a2taken together with the atoms to which they are attached form a heterocyclyl, which is substituted with 0, 1, 2, or 3 R7e.

20. The compound of any one of claims 1 to 19, or pharmaceutically acceptable salt thereof, wherein each R7eis independently C1-6 alkyl, C2-6 alkoxyalkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, C3-8 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, (C0-3 alkyl)- C(O)-R9a, (C0-3alkyl)-C(O)O-R9a, (C0-3alkyl)-C(O)-N(R9a)(R9b), (C0-3 alkyl)-S(O)R9a, -S(O)(NH)R9a, -S(O)2R9a, -S(O)2N(R9a)(R9b), or -S(O)(NR9a)R9b.

21. The compound of any one of claims 1 to 20, or pharmaceutically acceptable salt thereof, wherein R8is H, C1-6 alkyl, C2-6 alkoxyalkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, (C2-6 alkyl)-N(R8a)C(O)-(R8b), (C2-6 alkyl)-N(R8a)C(O)(OR8b), (C2- 6 alkyl)-N(R8a)S(O)2R8b, (C0-6alkyl)(C3-8cycloalkyl), (C0-6alkyl)(heterocyclyl), (C0-6alkyl)(C6-10aryl), (C0-6alkyl)(heteroaryl), (C0-6alkyl)-C(O)-R8a, (C0-6alkyl)- C(O)O-R8a, (C0-6 alkyl)-C(O)-N(R8a)(R8b), (C0-6 alkyl)-S(O)R8a, (C0-6 alkyl)- S(O)(NH)R8a, (C0-6 alkyl)-S(O)2R8a, (C0-6 alkyl)-S(O)2N(R8a)(R8b), or (C0-6 alkyl)- S(O)(NR8a)R8b, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0, 1, or 2 R8c.

22. The compound of any one of claims 1 to 21, or pharmaceutically acceptable salt thereof, wherein each R8cis independently C1-6 alkyl, C2-6 alkoxyalkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, C3-8 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, (C0-6 alkyl)-C(O)-R9a, (C0-6alkyl)-C(O)O-R9a, (C0-6alkyl)-C(O)-N(R9a)(R9b), (C0-6 alkyl)-S(O)R9a, -S(O)(NH)R9a, -S(O)2R9a, -S(O)2N(R9a)(R9b), or -S(O)(NR9a)R9b.

23. The compound of any one of claims 1 to 22, or pharmaceutically acceptable salt thereof, wherein each R7c, R7d, R8a, R8b, R9a, and R9bis independently H, C1-6 alkyl, C2-6 alkoxyalkyl, C1- 6 haloalkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, (C0-6 alkyl)(C3-8 cycloalkyl), (C0- 6 alkyl)(heterocyclyl), (C0-6alkyl)(C6-10aryl), or (C0-6alkyl)(heteroaryl), wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0 to 4 Z1.

24. The compound of any one of claims 1 to 23, or pharmaceutically acceptable salt thereof, wherein R7ais NH2, N(CH2CH3)2, NHCH(CH3)2, NHCH2CH2OCH3, NHCH2CH2F, NHCH2CH2OH, NHCH2CH2CF3, NHCH2CH2Ph, ,25. The compound of any one of claims 1 to 24, or pharmaceutically acceptable salt thereof, wherein R8is H, CH3, CH2CH3, CH(CH3)2, CH(CH2CH3)2, CH2CH2OCH3, CH2CH2F, CH2CH2OH, CH2CH2CF3, CH2CH2N(CH3)2, CH2CH2CH2NHCH3, CH2CH2CH2N(CH3)2, CH2CH2CH2N(CH3)C(O)(C(CH3)3), cyclopentyl, CH2CH2Ph, ,,r 26. The compound of any one of claims 1 to 25, or pharmaceutically acceptable salt thereof, wherein the compound has a structure as shown in Table 1 or Table 2.

27. A pharmaceutical composition comprising a compound of any one of claims 1 to 26, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

28. A method of inhibiting ferroptosis in a cell, comprising administering to the cell an effective amount of a compound of any one of claims 1 to 26, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 27.

29. A method of treating a mitochondrial disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 26, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 27.

30. The method of claim 29, wherein the mitochondrial disease comprises a neurodegenerative disease.

31. The method of claim 30, wherein the neurodegenerative disease is traumatic brain injury (TBI); spinal cord injury (SCI); stroke; Parkinson's Disease (PD); Parkinson’s Disease with Dementia (PDD); Lewy Body Disease (LBD); Alzheimer's Disease (AD); Huntington’s Disease (HD); spinocerebellar ataxia (SCA); amyotrophic lateral sclerosis (ALS); multiple systems atrophy (MSA); multiple sclerosis, including primary progressive multple sclerosis (PPMS), secondary progressive multiple sclerosis (SPMS), and relapsing remitting multple sclerosis (RRMS); frontotemporal dementia (FTD); Leigh's syndrome (LS); progressive Supranuclear Palsy (PSP); Friedreich's Ataxia (FA); mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS); macular degeneration (MD), including wet-type and dry-type MD; Leber's Hereditary Optic Neuropathy (LHON); PLA2G6-associated neurodegeneration (PLAN); infantile neuroaxonal dystrophy (INAD); or neurodegeneration with brain iron accumulation (NBIA).

32. The method of claim 29, wherein the mitochondrial disease is Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, Friedreich's ataxia (FRDA), Leber's Hereditary Optic Neuropathy (LHON), mitochondrial myopathy, encephalopathy, lactacidosis, and stroke (MELAS), Myoclonus Epilepsy Associated with Ragged-Red Fibers (MERRF) syndrome, Maternally Inherited Diabetes and Deafness (MIDD), or a respiratory chain disorder.

33. Use of a compound of any one of claims 1 to 26, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 27, in the manufacture of a medicament for treating a mitochondrial disease in a subject in need thereof.

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