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WO2025128893A1 - Composés de quinone fusionnés - Google Patents

Composés de quinone fusionnés Download PDF

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Publication number
WO2025128893A1
WO2025128893A1 PCT/US2024/059885 US2024059885W WO2025128893A1 WO 2025128893 A1 WO2025128893 A1 WO 2025128893A1 US 2024059885 W US2024059885 W US 2024059885W WO 2025128893 A1 WO2025128893 A1 WO 2025128893A1
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alkyl
compound
pharmaceutically acceptable
acceptable salt
haloalkyl
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Andrei W. Konradi
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Acurex Biosciences Corp
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Acurex Biosciences Corp
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole

Definitions

  • ferroptosis inhibitors includes radical-trapping antioxidants, which can trap chain-carrying radicals and thereby block propagation of the radical chain reactions during lipid peroxidation.
  • radical-trapping antioxidants can trap chain-carrying radicals and thereby block propagation of the radical chain reactions during lipid peroxidation.
  • ⁇ -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.
  • 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.
  • a compound of the present disclosure is a compound of Formula J: J), or a pharmaceutically acceptab wherein each R1 and R2 is independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1- 6 hydroxyalkyl, C 1-6 aminoalkyl, (C 0-6 alkyl)(C 3-8 cycloalkyl), (C 0-6 alkyl)(heterocyclyl), (C 0-6 alkyl)(C 6-10 aryl), (C 0-6 alkyl)(heteroaryl), halogen, OR a , SR a , NR a R b , NO 2 , or CN, wherein the alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0,
  • a pharmaceutical composition comprises a compound of the present disclosure or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • 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.
  • 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 DESCRIPTION I.
  • 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.
  • 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.
  • 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.
  • 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.
  • the compounds of the present disclosure are believed to exhibit superior neuroprotective properties compared to literature LRRK2 kinase inhibitors.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), 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(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl
  • 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.
  • 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., C 1 -C 3 alkoxy).
  • 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., C 1 -C 12 aminoalkyl), 1 to 8 carbon atoms (i.e., C 1 -C 8 aminoalkyl), 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.
  • haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CFH2, -CH2CF3, fluorochloromethyl, difluorochloromethyl, 1,1,1-trifluoroethyl and pentafluoroethyl.
  • 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.
  • 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.
  • alkyl-cycloalkyl groups include, but are not limited to, methyl-cyclopropyl, methyl-cyclobutyl, methyl-cyclopentyl and methyl- cyclohexyl.
  • “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).
  • 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.
  • 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- aza
  • 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, C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 .
  • the alkyl component can be absent.
  • the heterocycloalkyl component is as defined above.
  • “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.
  • an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms.
  • aryl groups include, but are not limited to, radicals derived from benzene (e.g., phenyl), naphthalene, anthracene, biphenyl, and the like.
  • 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 C 0-6 , C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3- 6, C4-5, C4-6 and C5-6.
  • 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.
  • Heteroaryl 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.
  • 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.
  • heteroaryls to form for example 1,8-naphthyridinyl
  • heterocycles to form for example 1,2,3,4-tetrahydro-1,8-naphth
  • 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 of the multiple condensed ring system may be connected in any order relative to one another.
  • 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).
  • a heteroatom e.g., a nitrogen
  • the atom range is for the total ring atoms of the heteroaryl and includes carbon atoms and heteroatoms.
  • a 5-membered heteroaryl would include a thiazolyl and a 10- membered heteroaryl would include a quinolinyl.
  • 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.
  • 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 C 0-6 , C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 2-3 , 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.
  • 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.
  • a compound of the present disclosure is a compound of Formula J: , or a pharmaceutically wherein 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), (C 0-6 alkyl)(C 6-10 aryl), (C 0-6 alkyl)(heteroaryl), halogen, OR a , SR a , NR a R b , NO 2 , or CN, wherein the alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0, 1, 2, 3, or 4 R 1a ; or R 1
  • the compound of the present disclosure is a compound of Formula I: , or a pharmaceutically wherein 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), (C0-6 alkyl)(C6-10 aryl), (C0-6 alkyl)(heteroaryl), halogen, OR a , SR a , NR a R b , NO2, or CN, wherein the alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0, 1, 2, or 3 R 1a ; or R 1 and R 2 taken together with
  • each R 1 is independently C1-6 alkyl, F, Cl, Br, I, OR a , SR a , NR a R b , or CN.
  • each R 2 is independently C1-6 alkyl, F, Cl, Br, I, OR a , SR a , NR a R b , or CN.
  • 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.
  • each R1 and R2 is independently C1-6 alkyl.
  • each R1 and R2 is methyl.
  • each R 1a is independently OR a , NR a R b , oxo, or CN.
  • each R 1b is independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1- 6 haloalkyl, halogen, or CN.
  • each R a is independently H or C 1-3 alkyl.
  • each R b is independently H or C1-3 alkyl.
  • each R 3a , R 3b , R 6a , and R 6b is H.
  • the compound of Formula J and/or I, or a pharmaceutically acceptable salt thereof has the structure of Formula Ia: .
  • the compound of Formula Ib has the structure of Formula Ib: O R 4a , wherein n is 0, 1, 2, or 3.
  • each R 4a and R 4b is independently H or C1-6 alkyl.
  • R 4a and R 4b are H, and the other is methyl. In some embodiments, R 4a and R 4b are each H. In some embodiments, R 4a and R 4b are each methyl. [0049] In some embodiments of the compound of Formula J, I, Ia, and/or Ib, or a pharmaceutically acceptable salt thereof, R 4a and R 4b taken together with the carbon to which they are attached form C 3-8 cycloalkyl or a heterocyclyl. In some embodiments, R 4a and R 4b taken together with the carbon to which they are attached form cyclohexyl. In some embodiments, R 4a and R 4b taken together with the carbon to which they are attached form tetrahydropyranyl.
  • each R 5a and R 5b is independently H or C 1-6 alkyl. In some embodiments, one of R 5a and R 5b is H, and the other is methyl. In some embodiments, R 5a and R 5b are each H. In some embodiments, R 5a and R 5b are each methyl. [0051] In some embodiments of the compound of the present disclosure or a pharmaceutically acceptable salt thereof, each R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , and R 6b is H.
  • each R 1b is independently halogen or OR a .
  • each R 1b is independently halogen.
  • each R 1b is Br.
  • each R 1b is independently OR a .
  • each R 1b is OMe.
  • each R 7a1 and R 7a2 is independently H, C 1-6 alkyl, C 2-6 alkoxyalkyl, C 1- 6 haloalkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, (C2-6 alkyl)-N(R 7c )C(O)-(R 7d ), (C2- 6 alkyl)-N(R 7c )C(O)(OR 7d ), (C2-6 alkyl)-N(R 7c )S(O)2R 7d , (C0-6 alkyl)(C3-8 cycloalkyl), (C0- 6 alkyl)(heterocyclyl), (C 0-6 alkyl)(C 6-10 aryl), (C 0-6 alkyl)(heteroaryl), (C 0-6 alkyl)-C(O)-R 7c , (C 0- 6 alkyl
  • each R 7a1 and R 7a2 is independently H, C1-6 alkyl, C2-6 alkoxyalkyl, C1- 6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, (C 2-6 alkyl)-N(R 7c )C(O)-(R 7d ), (C 2- 6 alkyl)-N(R 7c )C(O)(OR 7d ), (C2-6 alkyl)-N(R 7c )S(O)2R 7d , (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)-R 7c , (C0- 6 alkyl)-
  • each R 7a1 and R 7a2 is independently H, C1-3 alkyl, C2-3 alkoxyalkyl, C1- 3 haloalkyl, C 1-3 hydroxyalkyl, C 1-3 aminoalkyl, (C 2-3 alkyl)-N(R 7c )C(O)-(R 7d ), (C 2- 3 alkyl)-N(R 7c )C(O)(OR 7d ), (C2-3 alkyl)-N(R 7c )S(O)2R 7d , (C0-3 alkyl)(C3-8 cycloalkyl), (C0- 3 alkyl)(heterocyclyl), (C0-3 alkyl)(C6 aryl), (C0-3 alkyl)(heteroaryl), (C0-3 alkyl)-C(O)-R 7c , (C0- 3 alkyl)-C(O)O-R 7c , (C 0-3 alkyl)-
  • each R 7a1 and R 7a2 is independently H, C1-3 alkyl, C2-3 alkoxyalkyl, C1- 3 haloalkyl, C1-3 hydroxyalkyl, C1-3 aminoalkyl, (C2-3 alkyl)-N(R 7c )C(O)-(R 7d ), (C2- 3 alkyl)-N(R 7c )C(O)(OR 7d ), (C 2-3 alkyl)-N(R 7c )S(O) 2 R 7d , C 3-8 cycloalkyl, heterocyclyl, phenyl, heteroaryl, -C(O)-R 7c , -C(O)O-R 7c , -C(O)-N(R 7c )(R 7d ), -S(O)R 7c , -S(O)(NH)R 7c , -S(O)2R 7c , -S(O)2N(R
  • each R 7e is independently C 1-6 alkyl, C 2-6 alkoxyalkyl, C 1-6 haloalkyl, C 1- 6 hydroxyalkyl, C1-6 aminoalkyl, C3-8 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, (C0-3 alkyl)- C(O)-R 9a , (C0-3 alkyl)-C(O)O-R 9a , (C0-3 alkyl)-C(O)-N(R 9a )(R 9b ), (C0-3 alkyl)-S(O)R 9a , - S(O)(NH)R 9a , -S(O) 2 R 9a , -S(O) 2 N(R 9a )(R 9b ), or -S(O)(NR 9a )R 9b .
  • R 8 is H, C1-6 alkyl, C2- 6 alkoxyalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, (C 2-6 alkyl)-N(R 8a )C(O)-(R 8b ), (C2-6 alkyl)-N(R 8a )C(O)(OR 8b ), (C2-6 alkyl)-N(R 8a )S(O)2R 8b , (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)-C(O)
  • each R 8c is independently C 1-6 alkyl, C 2-6 alkoxyalkyl, C 1-6 haloalkyl, C 1- 6 hydroxyalkyl, C1-6 aminoalkyl, C3-8 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, (C0-6 alkyl)- C(O)-R 9a , (C0-6 alkyl)-C(O)O-R 9a , (C0-6 alkyl)-C(O)-N(R 9a )(R 9b ), (C0-6 alkyl)-S(O)R 9a , - S(O)(NH)R 9a , -S(O) 2 R 9a , -S(O) 2 N(R 9a )(R 9b ), or -S(O)(NR 9a )R 9b .
  • R 8 is H, C1- 6 alkyl, C 2-6 alkoxyalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, (C 2- 6 alkyl)-N(R 8a )C(O)-(R 8b ), (C 2-6 alkyl)-N(R 8a )C(O)(OR 8b ), (C 2-6 alkyl)-N(R 8a )S(O) 2 R 8b , (C 0- 6 alkyl)(C3-8 cycloalkyl), (C0-6 alkyl)(heterocyclyl), (C0-6 alkyl)(C6-10 aryl), (C0- 6 alkyl)(heteroaryl), (C0-6 alkyl)(heteroaryl), (C0-6 alkyl)(heteroaryl), (C0-6 alkyl)(heteroaryl), (C0-6 alkyl)(heteroary
  • R 8 is H, C1- 3 alkyl, C2-3 alkoxyalkyl, C1-3 haloalkyl, C1-3 hydroxyalkyl, C1-3 aminoalkyl, (C2- 3 alkyl)-N(R 8a )C(O)-(R 8b ), (C 2-3 alkyl)-N(R 8a )C(O)(OR 8b ), (C 2-3 alkyl)-N(R 8a )S(O) 2 R 8b , (C 0- 3 alkyl)(C 3-6 cycloalkyl), (C 0-3 alkyl)(heterocyclyl), (C 0-3 alkyl)(C 6 aryl), (C 0-3 alkyl)(heteroaryl), (C0-3 alkyl)-C(O)-R 8a , (C0-3 alkyl)-C(O)O-R 8a , (C0-3 alkyl)-C(O)-N(R 8
  • R 8 is H, C 1-3 alkyl, C 2-3 alkoxyalkyl, C 1-3 haloalkyl, C 1- 3 hydroxyalkyl, C1-3 aminoalkyl, (C2-3 alkyl)-N(R 8a )C(O)-(R 8b ), (C2-3 alkyl)-N(R 8a )C(O)(OR 8b ), (C2-3 alkyl)-N(R 8a )S(O)2R 8b , C3-6 cycloalkyl, heterocyclyl, phenyl, heteroaryl, -C(O)-R 8a , -C(O)O- R 8a , -C(O)-N(R 8a )(R 8b ), -S(O)R 8a , -S(O)(NH)R 8a , -S(O) 2 R 8a , -S(O) 2 N(R 8a )(R 8b ),
  • each R 7c , R 7d , R 8a , R 8b , R 9a , and R 9b is independently H, C 1-6 alkyl, C 2- 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 Z 1 .
  • each R 7c , R 7d , R 8a , R 8b , R 9a , and R 9b is 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- 6 alkyl)(C 6-10 aryl), or (C 0-6 alkyl)(heteroaryl).
  • each R 7c , R 7d , R 8a , R 8b , R 9a , and R 9b is independently H, C1-3 alkyl, C2-3 alkoxyalkyl, C1-3 haloalkyl, C1-3 hydroxyalkyl, C1- 3 aminoalkyl, (C 0-3 alkyl)(C 3-6 cycloalkyl), (C 0-3 alkyl)(heterocyclyl), (C 0-3 alkyl)(C 6 aryl), or (C 0- 3 alkyl)(heteroaryl).
  • the heteroaryl has 1, 2, or 3 atoms selected from N, O, and S.
  • 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.
  • 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).
  • the present invention also includes tautomers of compounds of the disclosure, e.g., a compound of Formula J.
  • 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.
  • salts may be derived from inorganic or organic acids or bases.
  • 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.
  • 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,
  • n is the number of hydrogen atoms in the molecule.
  • 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.
  • isotopes that can be incorporated into the disclosed compounds also include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I, respectively.
  • isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I, respectively.
  • Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron E
  • 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.
  • 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.
  • a compound of Formula J, or a pharmaceutically acceptable salt thereof has a solubility of greater than about 5 ⁇ M, such as greater than about 10 ⁇ M, greater than about 20 ⁇ M, greater than about 30 ⁇ M, greater than about 40 ⁇ M, greater than about 50 ⁇ M, greater than about 100 ⁇ M, greater than about 200 ⁇ M, or greater than about 300 ⁇ M.
  • a compound of Formula J, or a pharmaceutically acceptable salt thereof has a solubility of from about 5 ⁇ M to about 300 ⁇ M, such as from about 10 ⁇ M to about 200 ⁇ M or from about 20 ⁇ M to about 200 ⁇ M.
  • 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.
  • permeability assays known in the art, e.g., with Caco-2, MDR1-MDCK, MDCKII-MDR1, or MDCKII-BCRP cells, can assess compound permeability.
  • 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.
  • 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.
  • a compound of Formula J, or a pharmaceutically acceptable salt thereof has a permeability of from about 1 x 10- 6 cm/sec to about 100 x 10 -6 cm/sec, such as from about from about 1 x 10 -6 cm/sec to about 10 x 10 -6 cm/sec or from about from about 10 x 10 -6 cm/sec to about 100 x 10 -6 cm/sec.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 per day, 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.
  • the term “about” when referring to a value includes the stated value +/- 10% of the stated value.
  • about 50% can include a range of from 45% to 55%
  • about 20 molar equivalents can include a range of from 18 to 22 molar equivalents.
  • “about” refers to each of the stated values +/- 10% of the stated value of each end of the range.
  • a ratio of from about 1 to about 3 (weight/weight) can include a range of from 0.9 to 3.3.
  • 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").
  • the carrier is a finely divided solid, which is in a mixture with the finely divided active component.
  • 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.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions.
  • liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
  • 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.
  • 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.
  • preservatives such as ethyl or n-propyl p-hydroxybenzoate
  • coloring agents such as ethyl or n-propyl p-hydroxybenzoate
  • flavoring agents such as sucrose, aspartame or saccharin.
  • sweetening agents such as sucrose, aspartame or saccharin.
  • Formulations can be adjusted for osmolality.
  • 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 sweeten
  • 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.
  • 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.
  • compositions of the present invention can also be delivered as microspheres for slow release in the body.
  • 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).
  • 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.
  • acceptable vehicles and solvents that can be employed are water and Ringer's solution, an isotonic sodium chloride.
  • sterile fixed oils can conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • ligands specific for target cells or are otherwise preferentially directed to a specific organ.
  • 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).
  • 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®.
  • 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.
  • 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, at least about 6 months, or at least about 12 months or longer.
  • the compound is administered on a daily or intermittent schedule for the duration of the individual’s life.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the various components can be formulated separately.
  • 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 also include 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 USES A.
  • Ferroptosis is an iron-dependent form of cell death that occurs as a consequence of lipid reactive oxygen species (ROS) production.
  • ROS lipid reactive oxygen species
  • 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 by inhibitors, and by measuring lipid peroxides.
  • Dysregulation of mitochondrial metabolism is considered 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.
  • 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.
  • the method comprises administering the compound of the present disclosure or pharmaceutically acceptable salt thereof in vitro, ex vivo, or in vivo.
  • the compounds or compositions of the present disclosure are believed to be useful for inhibiting ferroptosis in the treatment of mitochondrial diseases.
  • 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.
  • a ferroptosis inhibitor of the present disclosure may also be useful for inhibiting Miro1 and/or Miro2.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the cell is a skin cell.
  • the cell is a muscle cell.
  • the muscle cell can be a cardiac cell, that is, a cardiomyocyte.
  • the cell is a renal cell.
  • the cell is a liver cell.
  • the cell is a neuronal cell.
  • the method can be performed in a cell in vitro, ex vivo, or in vivo.
  • the reducing Miro1 and/or Miro2 level is in vitro or ex vivo.
  • the reducing Miro1 and/or Miro2 level is in vivo.
  • any suitable biological sample described herein including urine, tissue, cerebrospinal fluid (CSF), or blood, can be used in the methods.
  • the biological sample and the control biological sample comprise fibroblasts.
  • skin fibroblasts can be directly obtained from the subject.
  • the biological sample and the control biological sample comprise iPSCs or cells differentiated from iPSCs.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a Miro1 and/or Miro2 normal range can be the range observed between untreated or na ⁇ ve 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).
  • DA dopaminergic
  • 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.
  • mitochondrial depolarizing agents such as carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP) and carbonyl cyanide 3- chlorophenylhydr
  • 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).
  • 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.
  • 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.
  • 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 of Miro1 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the concentration of Compound of Formula J or pharmaceutically acceptable salt thereof in the cell can be from about 1 nM to about 100 ⁇ M, such as from about 1 nM to about 10 ⁇ M, from about 1 nM to about 1 ⁇ M, from about 10 nM to about 100 ⁇ M, from about 10 nM to about 10 ⁇ M, from about 10 nM to about 1 ⁇ M, from about 100 nM to about 100 ⁇ M, from about 100 nM to about 10 ⁇ M, from about 100 nM to about 1 ⁇ M, from about 1 ⁇ M to about 100 ⁇ M, or from about 1 ⁇ M to about 10 ⁇ M.
  • 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.
  • a compound of Formula J or pharmaceutically acceptable salt thereof reduces the level or biological activity of Miro1 by about 20% relative to an untreated control not contacted with the compound of Formula J or pharmaceutically acceptable salt thereof.
  • 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.
  • 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.
  • 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.
  • 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 some embodiments, 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.
  • 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 or biological 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.
  • 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
  • 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.
  • treatment refers to an approach for obtaining beneficial or desired results.
  • 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.
  • 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.
  • 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
  • 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
  • relieving the disease or condition e.g., causing the
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Mitochondrial myopathy, encephalopathy, lactacidosis, and stroke (MELAS) can manifest itself in infants, children, or young adults.
  • 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.
  • ALS amyotrophic lateral sclerosis
  • 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.
  • the method of aiding in the treatment comprises administering a pharmaceutical composition of the compound of Formula I as described herein.
  • 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.
  • the use comprises a pharmaceutical composition of the compound of Formula I as described herein.
  • 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.
  • the compound for use comprises a pharmaceutical composition of the compound of Formula I as described herein.
  • 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.
  • the use comprises a pharmaceutical composition of the compound of Formula I as described herein.
  • 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.
  • additional therapeutic agents e.g., one, two, three, four, one or two, or one to three, or one to four
  • 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.
  • any suitable stationary phase can be used, including normal and reversed phases as well as ionic resins.
  • disclosed compounds can be purified via silica gel chromatography. See, e.g., Introduction to Modern Liquid Chromatography, 3 rd ed., 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 ( 1 H-NMR) and mass spectrum (MS). 1 H-NMR was measured at 400 MHz, unless otherwise specified.
  • 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 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.
  • 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.
  • LCMS method E LC/MS (The column used for chromatography was a Xtimate C18 2.1*30mm, 5 ⁇ m. 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
  • Example 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 ⁇ L, 5 eq), AcOH (41.90 mg, 697.71 ⁇ mol, 39.94 ⁇ L, 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.
  • Example 5 3-(pentan-3-yl)-2,3,4,5-tetrahydro-1H-naphtho[2,3-d]azepine- 6,11-dione 5 was prepared according to the general procedures described in other Examples in the application. Example 6.
  • Example 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 ⁇ L, 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).
  • Example 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 ⁇ mol, 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 ⁇ L, 3 eq) in one portion at 25°C under N 2 . The mixture was stirred at 60°C for 12 hours under N2.
  • Example 11 3-(pyrimidin-2-yl)-2,3,4,5-tetrahydro-1H-naphtho[2,3- d]azepine-6,11-dione [0185]
  • TEA 259.00 mg, 2.56 mmol, 356.26 ⁇ L, 3 eq
  • the mixture was stirred at 60°C for 12 hours under N 2 .
  • Example 12 6,7,9,10-tetrahydro-5H-cyclohepta[b]naphthalene-5,8,11- trione a g, acid (2.20 g, 12.65 mmol, 1 eq) in acetonitrile (200 mL) and H 2 O (100 mL) was added AgNO 3 (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.
  • Example 13 8-(isopropylamino)-7,8,9,10-tetrahydro-5H- cyclohepta[b]naphthalene-5,11(6H)-dione NH 2 O (3 eq) O [0187] To a mixture of Compound 12 (60 mg, 224.76 ⁇ mol, 1 eq, purity 90%) and propan-2- amine (39.86 mg, 674.29 ⁇ mol, 57.93 ⁇ L, 3 eq) in dichloromethane (1 mL) was added AcOH (13.50 mg, 224.76 ⁇ mol, 12.87 ⁇ L, 1 eq) dropwise at 25°C.
  • Example 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 of ammonium chloride (100 mL) and extracted with ethyl acetate (3 x 30 mL).
  • Example 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 ⁇ mol, 1 eq, HCl) in HFIP (4 mL) was added 4-chloro-2-(pyrrolidin-1-yl)pyrimidine (164.92 mg, 853.18 ⁇ mol, 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.
  • Example 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 ⁇ mol, 1 eq, HCl) in HFIP (5 mL) was added 2-chloro-4-(pyrrolidin-1-yl)pyrimidine (164.92 mg, 853.18 ⁇ mol, 1.5 eq) in one portion at 25°C under N 2 . The mixture was stirred at 50°C for 72 hours under N 2 . Then the mixture was concentrated under reduced pressure to remove the solvent.
  • 2-chloro-4-(pyrrolidin-1-yl)pyrimidine 164.92 mg, 853.18 ⁇ mol, 1.5 eq
  • Example 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 ⁇ mol, 1 eq, purity 90%) and 1- isopropylpiperazine (115.27 mg, 899.05 ⁇ mol, 128.65 ⁇ L, 3 eq) in dichloromethane (1 mL) was added AcOH (18.00 mg, 299.68 ⁇ mol, 17.16 ⁇ L, 1 eq) dropwise at 25°C. Then the reaction was stirred at 25°C for 30 minutes.
  • Example 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 ⁇ mol, 1 eq, HCl) in DCM (3 mL) was added methoxysulfinyl methyl sulfite (29.72 mg, 170.64 ⁇ mol, 1.5 eq) and TEA (23.02 mg, 227.51 ⁇ mol, 31.67 ⁇ L, 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 25 o C for 10 min and then filtered.
  • Example 20 8-(phenethylamino)-7,8,9,10-tetrahydro-5H- cyclohepta[b]naphthalene-5,11(6H)-dione NH 2 O O [0194] To a mixture of Compound 12 (60 mg, 224.76 ⁇ mol, 1 eq, purity 90%) and 2- phenylethanamine (81.71 mg, 674.29 ⁇ mol, 84.67 ⁇ L, 3 eq) in dichloromethane (2 mL) was added AcOH (13.50 mg, 224.76 ⁇ mol, 12.87 ⁇ L, 1 eq) dropwise at 25°C. Then the reaction was stirred at 25°C for 30 minutes.
  • 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 ⁇ mol, 1 eq, purity 90%) and 3,3,3- trifluoropropan-1-amine (134.45 mg, 899.05 ⁇ mol, 3 eq, HCl) in dichloromethane (1 mL) was added AcOH (18.00 mg, 299.68 ⁇ mol, 17.16 ⁇ L, 1 eq) dropwise at 25°C.
  • Example 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 ⁇ mol, 1 eq, purity 95%) and 4- (trifluoromethyl)aniline (66.90 mg, 415.19 ⁇ mol, 51.62 ⁇ L, 3 eq) in dichloromethane (1 mL) was added AcOH (8.31 mg, 138.40 ⁇ mol, 7.92 ⁇ L, 1 eq) dropwise at 25°C and stirred at 25°C for 30 minutes.
  • 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
  • Example 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 ⁇ mol, 1 eq, HCl) in DCM (3 mL) was added TEA (115.11 mg, 1.14 mmol, 158.34 ⁇ L, 3 eq) and acetyl chloride (59.53 mg, 758.38 ⁇ mol, 53.92 ⁇ L, 2 eq) in portions at 25°C under N2. The mixture was stirred at 25°C under N2 for 2 hours.
  • TEA 115.11 mg, 1.14 mmol, 158.34 ⁇ L, 3 eq
  • acetyl chloride 59.53 mg, 758.38 ⁇ mol, 53.92 ⁇ L, 2 eq
  • NaBH 3 CN (10.55 mg, 167.94 ⁇ mol, 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.
  • Example 28 8-amino-7,8,9,10-tetrahydro-5H-cyclohepta[b]naphthalene- 5,11(6H)-dione [0202]
  • NH 4 Cl 80.15 mg, 1.50 mmol, 1.2 eq
  • HOAc 74.98 mg, 1.25 mmol, 71.48 ⁇ L, 1 eq
  • NaBH(OAc)3 661.61 mg, 3.12 mmol, 2.5 eq
  • Example 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 ⁇ mol, 1 eq, purity 95%) and N- ethylethanamine (578.39 mg, 7.91 mmol, 814.63 ⁇ L, 10 eq) in dichloromethane (4 mL) was added AcOH (47.49 mg, 790.83 ⁇ mol, 45.27 ⁇ L, 1 eq) dropwise at 25°C.
  • Example 30 Compound 30: 3-methyl-2,3,4,5-tetrahydro-1H-naphtho[2,3-d]azepine-6,11- dione 1.
  • MeOH MeOH
  • AcOH 34.16 mg, 568.79 ⁇ mol, 32.56 ⁇ L, 1 eq
  • NaOAc 139.97 mg, 1.71 mmol, 3 eq
  • Example 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 ⁇ mol, 1 eq, HCl) in DMF (3 mL) was added TEA (115.11 mg, 1.14 mmol, 158.34 ⁇ L, 3 eq) and iodoethane (295.70 mg, 758.38 ⁇ mol, 151.64 ⁇ L, 2 eq) in portions at 25°C under N2. The mixture was stirred at 25°C under N2 for 2 hours.
  • Example 33 Compound 33: 3-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-naphtho[2,3- d]azepine-6,11-dione a mg, eq, was added TEA (172.67 mg, 1.71 mmol, 237.50 ⁇ L, 3 eq) and 2-iodoethanol (195.62 mg, 1.14 mmol, 88.92 ⁇ L, 2 eq) in portions at 25°C under N 2 . The mixture was stirred at 25°C under N 2 for 12 hours. One additional vial in 10 mg scale was set up as described above and these two reactions were combined.
  • Example 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 ⁇ mol, 1 eq, HCl) in DMF (3 mL) was added TEA (172.67 mg, 1.71 mmol, 237.50 ⁇ L, 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.
  • Example 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 ⁇ mol, 1 eq, purity 95%) and morpholine (103.35 mg, 1.19 mmol, 104.39 ⁇ L, 3 eq) in dichloromethane (2 mL) was added AcOH (23.75 mg, 395.42 ⁇ mol, 22.64 ⁇ L, 1 eq) dropwise at 25°C. The reaction mixture was stirred at 25°C for 30 minutes.
  • Example 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 ⁇ mol, 1 eq) and 2- methoxyethanamine (89.10 mg, 1.19 mmol, 103.12 ⁇ L, 3 eq) in DCM (2 mL) was added AcOH (23.74 mg, 395.42 ⁇ mol, 22.64 ⁇ L, 1 eq) in one portion at 25°C under N 2 . The reaction mixture was stirred at 25°C for 30 minutes.
  • Example 37 Compound 37: 8-((2-hydroxyethyl)amino)-7,8,9,10-tetrahydro-5H- cyclohepta[b]naphthalene-5,11(6H)-dione aminoethan-1-ol (72.46 mg, 1.19 mmol, 71.60 ⁇ L, 3 eq) in dichloromethane (1 mL) was added AcOH (23.75 mg, 395.42 ⁇ mol, 22.64 ⁇ L, 1 eq) dropwise at 25°C. The reaction mixture was stirred at 25°C for 30 minutes.
  • 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 ⁇ mol, 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 ⁇ mol, 22.64 ⁇ L, 1 eq) dropwise at 25°C. The reaction mixture was stirred at 25°C for 1 hour.
  • sodium triacetoxyboranuide (209.51 mg, 988.54 ⁇ mol, 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 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.
  • 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 ⁇ mol, 1 eq, HCl) in DMF (2 mL) was added TEA (40.66 mg, 401.81 ⁇ mol, 55.93 ⁇ L, 3 eq) and acetyl chloride (21.03 mg, 267.87 ⁇ mol, 19.05 ⁇ L, 2 eq) in portions at 0°C under N 2 . The mixture was stirred at 0°C under N 2 for 2 hours.
  • Example 40 Compound 40: N-(5,11-dioxo-6,7,8,9,10,11-hexahydro-5H- cyclohepta[b]naphthalen-8-yl)methanesulfonamide prepared in a similar manner as Compound 39.
  • 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.
  • Example 67 Compound 67: 8-(2-(diethylamino)ethyl)-7,8,9,10-tetrahydro-5H- cyclohepta[b]naphthalene-5,11(6H)-dione prepared in a similar manner as Compound 64.
  • Example 69 Compound 69: 8-((diethylamino)methyl)-7,8,9,10-tetrahydro-5H- cyclohepta[b]naphthalene-5,11(6H)-dione was added TEA (83.23 mg, 822.56 ⁇ mol, 114.49 ⁇ L, 3 eq) and iodoethane (427.64 mg, 2.74 mmol, 219.30 ⁇ L, 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.
  • reaction mixture was filtered and the filtrate was purified by prep-HPLC (NH 4 HCO 3 condition).
  • 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 ⁇ mol, 13.31% yield, 96.4% purity, HCl salt) as yellow solid.
  • Example 75 Compound 75: 8-(morpholinomethyl)-7,8,9,10-tetrahydro-5H- cyclohepta[b]naphthalene-5,11(6H)-dione prepared i 1 n a similar manner as Compound 74.
  • 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 Intermediate 79 as starting material.
  • 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.
  • 1 H NMR (400 MHz, DMSO-d6) ⁇ 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).
  • 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 ⁇ mol, 1 eq, HCl salt) in MeOH (1 mL) was added pentan-3-one (48.11 mg, 558.51 ⁇ mol, 59.18 ⁇ L, 3 eq), ZnCl 2 (25.38 mg, 186.17 ⁇ mol, 8.73 ⁇ L, 1 eq) and NaBH 3 CN (35.10 mg, 558.51 ⁇ mol, 3 eq) in portions at 25°C under N 2 .
  • 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 MnO 2 (30.20 g, 347.41 mmol) portion-wise at 20°C.
  • 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 ⁇ mol, 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.
  • 1,1,1-trifluoro-3-iodo-propane (625.43 mg, 2.79 mmol, 327.28 ⁇ L, 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.
  • 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 ⁇ mol, 1 eq, HCl) in DMF (10 mL) was added 4-(trifluoromethyl)benzoic acid (141.58 mg, 744.68 ⁇ mol, 1.5 eq), NMI (122.28 mg, 1.49 mmol, 118.72 ⁇ L, 3 eq) and 1-chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (TCFH, 278.59 mg, 992.91 ⁇ mol, 2 eq) at 25°C in order.
  • 4-(trifluoromethyl)benzoic acid 141.58 mg, 744.68 ⁇ mol, 1.5
  • 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 ⁇ mol, 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 ⁇ L, 3 eq) in one portion at 25°C under N 2 . The mixture was stirred at 60°C for 12 hours under N 2 .
  • 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.
  • 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 ⁇ mol, 1 eq, purity 90%, prepared according to the general procedure for Compound 12) and propan-2-amine (21.94 mg, 371.14 ⁇ mol, 31.89 ⁇ L, 3 eq) in dichloromethane (1 mL) was added AcOH (7.43 mg, 123.71 ⁇ mol, 7.08 ⁇ L, 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 ⁇ mol, 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 (NH 4 HCO 3 condition; 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.
  • 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 N 2 . One additional vial in 0.3 g scale was set up as described above and these two reactions were combined.
  • 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 ⁇ mol, 1 eq, HCl) in HFIP (5 mL) was added Intermediate 214-1 (179.94 mg, 930.85 ⁇ mol, 1.5 eq) in one portion at 25°C under N 2 . The mixture was stirred at 50°C for 72 hours under N 2 . Then the mixture was concentrated under reduced pressure to remove the solvent.
  • 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 ⁇ L, 1 eq) in order at 25°C.
  • 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 ⁇ mol, 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.
  • 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 ⁇ mol, 1 eq) in MeOH (1 mL) was added NaOAc (40.07 mg, 488.47 ⁇ mol, 3 eq), (HCHO)n (15.65 mg, 488.47 ⁇ mol, 3 eq) and AcOH (9.78 mg, 162.82 ⁇ mol, 9.32 ⁇ L, 1 eq) in order at 25°C.
  • Compound 219: 3-(2-(dimethylamino)ethyl)-7,8-dimethyl-2,3,4,5-tetrahydro- 1H-benzo[d]azepine-6,9-dione was prepared according to the general procedures described in other Examples in the application.
  • 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-carboxylate prepared in a similar manner as Compound 53.
  • 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).
  • IHC immunohistochemistry
  • 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).
  • 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 6210 represent tota number o tyros ne ydroxy ase-pos t ve dopam nerg c neurons rom an individual animal (N 3).
  • PD Parkinson's disease
  • iPSC patient induced pluripotent stem cell
  • Neurons were treated for 24 hours with RSL3 to induce lipid peroxidation-mediated neurodegeneration and co-treated with a dose-response of Compound 2.
  • 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.
  • the literature LRRK2 kinase inhibitor MLi-2 (CAS # 1627091-47-7) tested up to a concentration of 100 nM was unable to rescue neurite integrity from RSL3 challenge.
  • Example 131 The literature LRRK2 kinase inhibitor MLi-2 (CAS # 1627091-47-7) tested up to a concentration of 100 nM was unable to rescue neurite integrity from RSL3 challenge.
  • 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).
  • IKE Imidazole Ketone Erastin
  • 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 IKE Table 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 IC 50 between 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).

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Abstract

La présente divulgation concerne des composés de quinone fusionnés, ainsi que des compositions et des procédés associés. De tels composés peuvent être utiles dans le traitement de maladies mitochondriales chez un sujet, tel qu'un être humain.
PCT/US2024/059885 2023-12-13 2024-12-12 Composés de quinone fusionnés Pending WO2025128893A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020120148A1 (en) * 1998-04-06 2002-08-29 Fujisawa Pharmaceutical Co. Ltd. Propanolamine derivatives
US20050153957A1 (en) * 1999-06-04 2005-07-14 Bernard Cuenoud Beta2-adrenoceptor agonists
WO2014016314A1 (fr) * 2012-07-24 2014-01-30 Centro Atlantico Del Medicamento S.A (Ceamed, S.A) Composés quinoniques fusionnés
US8741898B2 (en) * 2006-12-29 2014-06-03 Rigel Pharmaceuticals, Inc. Polycyclic heteroaryl substituted triazoles useful as Axl inhibitors

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020120148A1 (en) * 1998-04-06 2002-08-29 Fujisawa Pharmaceutical Co. Ltd. Propanolamine derivatives
US20050153957A1 (en) * 1999-06-04 2005-07-14 Bernard Cuenoud Beta2-adrenoceptor agonists
US8741898B2 (en) * 2006-12-29 2014-06-03 Rigel Pharmaceuticals, Inc. Polycyclic heteroaryl substituted triazoles useful as Axl inhibitors
WO2014016314A1 (fr) * 2012-07-24 2014-01-30 Centro Atlantico Del Medicamento S.A (Ceamed, S.A) Composés quinoniques fusionnés

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE Compound 13 June 2012 (2012-06-13), .: "6,7,8,9-tetrahydro-5H-benzo[7]annulene-1,4-dione | C11H12O2 | CID 57046124 ", XP093328582, Database accession no. 57046124 *
DATABASE Compound 5 December 2007 (2007-12-05), "11-Ethyl-13-oxatetracyclo[8.5.0.03,8.012,14]pentadeca-1(10),3,5,7-tetraene-2,9-dione | C16H14O3 | CID 21263460 ", XP093328585, Database accession no. 21263460 *

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