WO2019099457A1 - Composés de benzodioxinone - Google Patents

Composés de benzodioxinone Download PDF

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Publication number
WO2019099457A1
WO2019099457A1 PCT/US2018/060937 US2018060937W WO2019099457A1 WO 2019099457 A1 WO2019099457 A1 WO 2019099457A1 US 2018060937 W US2018060937 W US 2018060937W WO 2019099457 A1 WO2019099457 A1 WO 2019099457A1
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Prior art keywords
optionally substituted
compound
pharmaceutically acceptable
alkyl
acceptable salt
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PCT/US2018/060937
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English (en)
Inventor
Yusheng Xiong
Hong-Ping GUAN
Wenjun Huang
Zenghong ZHANG
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Quixgen, Inc.
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Publication of WO2019099457A1 publication Critical patent/WO2019099457A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention is generally related to a novel class of benzodioxinone compounds, salts thereof, pharmaceutical compositions comprising the same, synthetic methods therefor, and uses thereof.
  • Fatty acids are essential components for normal function of living cells including
  • Acetyl-CoA carboxylase is a cytoplasmic enzyme catalyzing the conversion of acetyl-CoA to malonyl-CoA, the rate-limiting step for fatty acid metabolism in cells. Cytoplasmic malonyl-CoA controls two downstream pathways of lipid metabolism, de novo fatty acid synthesis and fatty acid b-oxidation. Malonyl-CoA is the building block for long chain fatty acids synthesis and elongation.
  • Malonyl-CoA can also allosterically inhibit the fatty acid transporter on mitochondrial membrane, carnitine palmitoyltransferase- 1, and block the entry of fatty acyl-CoA into mitochondria.
  • By inhibiting ACC cellular long chain fatty acid synthesis can be blocked and b-oxidation can be stimulated in the mitochondria. As a result, cellular lipid contents are reduced.
  • ACC has two isoforms, ACC1 and ACC2, localized in cytosol and mitochondrial
  • ACC protein is composed of three domains, in which biotin carboxylase domain catalyzes the carboxylation of biotin that is covalently linked to the biotin carboxyl carrier protein domain, and the carboxyltransferase domain catalyzes the transfer of the carboxyl group from carboxyl biotin to acetyl-CoA (Zhang et al, Science 299:2064-2067 (2003)).
  • biotin carboxylase domain catalyzes the carboxylation of biotin that is covalently linked to the biotin carboxyl carrier protein domain
  • carboxyltransferase domain catalyzes the transfer of the carboxyl group from carboxyl biotin to acetyl-CoA (Zhang et al, Science 299:2064-2067 (2003)).
  • Molecular masses of ACC1 and ACC2 are about 265 and about 280 kDa respectively.
  • ACC1 is mainly expressed in lipogenic tissues such as liver, adipose, and lactating mammary gland, and ACC2 is predominantly expressed in muscle tissues and heart.
  • ACC1 is mainly responsible for de novo fatty acid synthesis and ACC2 for fatty acid beta-oxidation (Abu- Elheiga et al, The Journal of biological chemistry 272: 10669-10677 (1997); Abu-Elheiga et al, Proceedings of the National Academy of Sciences of the United States of America 92:4011-4015(1995)).
  • ACC2 isoforms are also abundantly expressed in adipose tissue and liver and capable of de novo lipogenesis in these tissues (Castle et al, PloS one 4: e4369(2009)). Genetic studies show that ACC1 is essential for development and ACC1 deficiency causes embryonic lethality (Abu-Elheiga et al., Proceedings of the National Academy of Sciences of the United States of America 97: 1444-1449(2000)).
  • ACC2 mutant mice live and breed normally although they are leaner due to increased fatty acid oxidation, and resistant to high-fat high-carbohydrate diets in terms of body weight gain and insulin resistance (Abu-Elheiga et al, Science 297:2613-2616(2001); Abu-Elheiga et al, Proceedings of the National Academy of Sciences of the United States of America
  • the present disclosure provides a benzodioxinone compound that can be an inhibitor of ACC1 and/or ACC2, or a pharmaceutically acceptable salt thereof.
  • the present disclosure also provides pharmaceutical compositions comprising the benzodioxinone compound or pharmaceutically acceptable salt thereof.
  • the present disclosure also provides methods of using the
  • benzodioxinone compound or pharmaceutically acceptable salt thereof for treating a disease or disorder associated with aberrant ACC1 and/or ACC2 activities, for example, non alcoholic steatohepatitis (NASH), acne, obesity, diabetes, and cancer (e.g., non-small cell lung cancer).
  • NASH non alcoholic steatohepatitis
  • acne e.g., acne, obesity, diabetes, and cancer (e.g., non-small cell lung cancer).
  • cancer e.g., non-small cell lung cancer
  • the compound of Formula I is a compound of Formula 1-1, Formula la, Formula lb, Formula II-1 to II-4, Formula III-1 to III- 10 or Formula IV- 1 to Formula IV- 10 as defined herein.
  • the benzodioxinone compound can be r-(4,8-dimethoxy quinoline-2 - carbonyl)-6-isopropyl-4H-spiro[benzo[d][l,3]dioxine-2,4'-piperidin]-4-one, l'-(4,8- dimethoxy-2-naphthoyl)-6-isopropyl-4H-spiro[benzo[d][l,3]dioxine-2,4'-piperidin]-4-one, 6- isopropyl-r-(2-methyl-lH-benzo[d]imidazole-6-carbonyl)-4H-spiro[benzo[d][l,3]dioxine- 2,4'-piperidin]-4-one, l'-(lH-indazole-5-carbonyl)-6-isopropyl-4H- spiro[benzo[d][l
  • composition comprising a benzodioxinone compound of Formula I (e.g., a compound of Formula 1-1, Formula la, Formula lb, Formula II-1 to II -4, Formula III-1 to III-10 or Formula IV-l to Formula IV-10, or Examples 2-15) as defined herein, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition further comprises one or more additional active agents.
  • the pharmaceutical composition described herein can be formulated for different routes of administration.
  • the pharmaceutical composition can be formulated for intravenous injection or infusion, oral administration, inhalation, or topical administration.
  • the pharmaceutical composition can be formulated in the form of a topical solution, lotion, shampoo, transdermal spray, topical film, foam, powder, paste, sponge, transdermal patch, tincture, tape, cream, gel, or ointment.
  • Certain embodiments of the present disclosure are directed to a method of inhibiting
  • the method comprises contacting the cell with a benzodioxinone compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.
  • the present disclosure also provides a method of inhibiting
  • a cell e.g., a sebocyte, an adipocyte, or a hepatocyte
  • proliferation of cells e.g., sebocytes, keratinocytes, adipocytes, melanocytes, squamous cells, Merkel cells, Langerhans cells, or skin stem cells, e.g., in epidermis, dermis, and/or hypodermis
  • differentiation of fibroblast to adipocytes, sebum production, or a combination thereof, in a subject in need thereof e.g., a sebocyte, an adipocyte, or a hepatocyte
  • proliferation of cells e.g., sebocytes, keratinocytes, adipocytes, melanocytes, squamous cells, Merkel cells, Langerhans cells, or skin stem cells, e.g., in epidermis, dermis, and/or hypodermis
  • the subject is characterized as having a disease or disorder chosen from acne, seborrhea, sebaceous hyperplasia, seborrheic keratosis, sebaceous adenoma, sebaceous cyst, actinic keratosis, sebaceous carcinoma, squamous cell carcinoma, melanoma, phymatous rosacea,
  • the method comprises administering to the subject an effective amount of a benzodioxinone compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.
  • Certain embodiments of the present disclosure are directed to a method of treating a
  • the method comprises administering to the subject in need thereof a therapeutically effective amount of a benzodioxinone compound described herein (e.g., a compound of Formula I, Formula 1-1, Formula la, Formula lb, Formula II-1 to II-4, Formula III-1 to III- 10 or IV-l to IV- 10, or Examples 2-15), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.
  • the method further comprises treating the subject in need thereof with one or more additional therapies for the respective disease or disorder (e.g., as described herein).
  • Non-limiting diseases or disorders suitable to be treated with the methods described herein include a skin disease, such as a disease or disorder associated with aberrant sebocyte and/or keratinocyte activities (e.g., acne), a non-alcoholic fatty liver disease (such as nonalcoholic steatohepatitis (NASH)), a metabolic disease or disorder (e.g., obesity or diabetes), and cancer (e.g., non small cell lung cancer).
  • a skin disease such as a disease or disorder associated with aberrant sebocyte and/or keratinocyte activities (e.g., acne), a non-alcoholic fatty liver disease (such as nonalcoholic steatohepatitis (NASH)), a metabolic disease or disorder (e.g., obesity or diabetes), and cancer (e.g., non small cell lung cancer).
  • a skin disease such as a disease or disorder associated with aberrant sebocyte and/or keratinocyte activities (e.g., acne)
  • NASH nonalcoholic steatohepatit
  • the present disclosure also provides a method of delivering
  • the method comprises administering (e.g., topically) to the subject a benzodioxinone compound of the present disclosure (e.g., a compound of Formula I, Formula 1-1, Formula la, Formula lb, Formula II-1 to II-4, Formula III-1 to III-10 or IV-l to IV-10, or Examples 2-15), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.
  • a benzodioxinone compound of the present disclosure e.g., a compound of Formula I, Formula 1-1, Formula la, Formula lb, Formula II-1 to II-4, Formula III-1 to III-10 or IV-l to IV-10, or Examples 2-15
  • R 1 and R 2 in Formula I of the benzodioxinone compound herein are both hydrogen, and the administering can deliver salicyclic acid to the subject, for example, in an anti-inflammatory amount.
  • the present disclosure also provides a method of treating
  • the method comprises administering to the subject a benzodioxinone compound of the present disclosure (e.g., a compound of Formula I, Formula 1-1, Formula la, Formula lb, Formula II-1 to II-4, Formula III-1 to III- 10 or IV-l to IV- 10, or Examples 2-15), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.
  • R 1 and R 2 in Formula I of the benzodioxinone compound herein are both hydrogen, and the administering can deliver salicyclic acid to the subject, for example, in an anti-inflammatory amount.
  • the inflammation is associated with a skin disease, e.g., as described herein.
  • FIG. 1 shows images of Immunohistochemical (IHC) staining of human normal skin structure including layers of epidermis, dermis, and hypodermis.
  • the top rows show images with lOx magnification, and the bottom rows show images with 40 x magnification of the sebaceous gland appearing in the images on top.
  • Images on the left column show IHC staining by using control rabbit IgG; whereas images on the right column show IHC staining by using rabbit anti-ACC antibody.
  • ACC proteins are abundantly and specifically expressed in sebaceous gland, see e.g., where Arrow 1 points to.
  • the figure also shows nuclei stained by hematoxylin (see e.g., where Arrow 2 points to) and cytosol stained by eosin (see e.g., where Arrow 3 points to).
  • FIG. 2 shows images of Immunohistochemical (IHC) staining of human normal skin.
  • the left column shows images with lOx magnification
  • the right column shows images with 40x magnification of the epidermis part shown on the left images.
  • Images on the top row show IHC staining by using control rabbit IgG; whereas images on the bottom row show IHC staining by using rabbit anti-ACC antibody.
  • the figure also shows nuclei stained by hematoxylin (see e.g., where Arrow 2 points to) and cytosol stained by eosin (see e.g., where Arrow 3 points to).
  • FIG. 3 shows images of Immunohistochemical (IHC) staining of human in situ squamous cell carcinoma (indicated by arrows) with adjacent skin tissue including sebaceous gland.
  • the left column shows images with lOx magnification
  • the right column shows images with 40x magnification of the epidermis part shown on the left images.
  • Images on the top row show IHC staining by using control rabbit IgG; whereas images on the botom row show IHC staining by using rabbit anti-ACC antibody.
  • the figure also shows nuclei stained by hematoxylin (see e.g., where Arrow 2 points to) and cytosol stained by eosin (see e.g., where Arrow 3 points to). Tumor cells in the squamous cell carcinoma, sebaceous gland and epidermal squamous cells are stained with comparable density of dark color (see e.g., where Arrow 1 points to), indicating abundant expression of ACC proteins.
  • FIG. 4 shows images of Immunohistochemical (IHC) staining of human seborrheic
  • the left column shows images with lOx magnification
  • the right column shows images with 40x magnification of the epidermis part shown on the left images.
  • Images on the top row show IHC staining by using control rabbit IgG; whereas images on the bottom row show IHC staining by using rabbit anti-ACC antibody.
  • the figure also shows nuclei stained by hematoxylin (see e.g., where Arrow 2 points to) and cytosol stained by eosin (see e.g., where Arrow 3 points to). Keratin layer is apparent in this disease and keratinocytes next to the keratin layer are stained with dark color (see e.g., where Arrow 1 points to), indicating abundant expression of ACC proteins in keratinocytes in skin disease of keratosis.
  • the present disclosure is generally related to a novel class of benzodioxinone compounds that can be used as an ACC inhibitor (ACC1 and/or ACC2 inhibitor).
  • ACC1 and/or ACC2 inhibitor a novel class of benzodioxinone compounds that can be used as an ACC inhibitor
  • the present disclosure provides compounds, pharmaceutical compositions, methods, and uses related to the novel benzodioxinone compounds described herein.
  • Certain embodiments of the present disclosure are directed to novel benzodioxinone compounds.
  • the present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt thereof,
  • R 1 and R 2 are each independently hydrogen, halogen, cyano, an optionally substituted alkyl (e.g., an optionally substituted Ci- 6 alkyl), an optionally substituted cycloalkyl (e.g., an optionally substituted C3-6 cycloalkyl), an optionally substituted alkenyl (e.g., an optionally substituted C2-6 alkenyl), an optionally substituted alkynyl (e.g., an optionally substituted C2-6 alkynyl), an optionally substituted aryl (e.g., an optionally substituted C 6- 10 aryl), an optionally substituted heteroaryl (e.g., an optionally substituted 5-10 membered heteroaryl), an optionally substituted heterocyclyl (e.g., an optionally substituted 4-6 membered heterocyclyl), -NR 10 R n , -COOR 12 , -CONR 13 R 14 , -CN, -S(0) n R 15
  • R 10 and R 11 are each independently hydrogen, an optionally substituted alkyl (e.g., an optionally substituted Ci- 6 alkyl), an optionally substituted cycloalkyl (e.g., an optionally substituted C3-6 cycloalkyl), an optionally substituted alkanoyl (e.g., an optionally substituted Ci-6 alkanoyl), an optionally substituted cycloalkanoyl (e.g., an optionally substituted C3-6 cycloalkanoyl), an optionally substituted aryl (e.g., an optionally substituted C6-10 aryl), an optionally substituted heteroaryl (e.g., an optionally substituted 5-10 membered heteroaryl), an optionally substituted heterocyclyl (e.g., an optionally substituted 4-6 membered heterocyclyl), -COOR 12 , or -CONR 13 R 14 ;
  • an optionally substituted alkyl e.g., an optionally substituted Ci
  • R 12 , R 13 and R 14 are each independently hydrogen or an optionally substituted alkyl (e.g., an optionally substituted Ci- 6 alkyl);
  • n 0, 1, or 2;
  • R 15 is an optionally substituted alkyl (e.g., an optionally substituted Ci- 6 alkyl), an optionally substituted cycloalkyl (e.g., an optionally substituted C3-6 cycloalkyl), or -NR !O R 11 ;
  • R 16 is hydrogen, an optionally substituted alkyl (e.g., an optionally substituted Ci- 6 alkyl), an optionally substituted cycloalkyl (e.g., an optionally substituted C3-6 cycloalkyl), an optionally substituted alkanoyl (e.g., an optionally substituted Ci- 6 alkanoyl), an optionally substituted cycloalkanoyl (e.g., an optionally substituted C3-6 cycloalkanoyl), an optionally substituted aryl (e.g., an optionally substituted C6-10 aryl), an optionally substituted heteroaryl (e.g., an optionally substituted 5-10 membered heteroaryl), an optionally substituted heterocyclyl (e.g., an optionally substituted 4-6 membered heterocyclyl) or -CONR 13 R 14 ; and
  • R 3 is an optionally substituted aryl (e.g., an optionally substituted C 6 -io aryl) or an optionally substituted heteroaryl (e.g., an optionally substituted 5-10 membered heteroaryl).
  • aryl e.g., an optionally substituted C 6 -io aryl
  • heteroaryl e.g., an optionally substituted 5-10 membered heteroaryl
  • both R 1 and R 2 are hydrogen. In some embodiments, only one of R 1 and R 2 is hydrogen. In some embodiments, neither of R 1 and R 2 is hydrogen.
  • the compound of Formula I is a compound of Formula I- 1 :
  • R 1 , R 2 and R 3 are as defined herein.
  • R 1 is not hydrogen.
  • R 1 is hydrogen.
  • R 2 can be hydrogen.
  • the compound of Formula I is a compound of Formula la.
  • R 1 and R 3 are as defined herein.
  • R 1 is not hydrogen.
  • R 1 is hydrogen.
  • the compound of Formula la can be hydrolyzed into salicyclic acid, in vitro or in vivo.
  • such compounds can serve at least a dual function, an ACC inhibitor and a precursor to salicyclic acid, and therefore can have anti-inflammatory effects independent of ACC inhibition.
  • R 1 is a halogen, such as F, Cl, Br, or I.
  • R 1 is -CN.
  • the compound of Formula I e.g., a compound of Formula la
  • R 1 can also serve as a synthetic intermediate for the synthesis of other compounds, such as compounds of Formula I wherein R 1 is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, -NR 10 R n , -COOR 12 , -CONR 13 R 14 , -CN,
  • the aryl halide can be first converted into an aryl boronic acid or ester derivative, which can then couple with various groups such as an amine, to form a compound of Formula I.
  • the aryl halide can be first converted into a pinacol arylboronate, which can then be converted into the corresponding aryl boronic acid for use in the coupling reactions (e.g., a palladium mediated or copper mediated coupling reaction).
  • R 1 is an optionally substituted alkyl. In some embodiments, R 1 is an optionally substituted Ci- 6 alkyl. In some preferred embodiments, R 1 is an optionally substituted CM alkyl.
  • R 1 can be a CM alkyl (e.g., methyl, ethyl, isopropyl, sec-butyl, tert-butyl).
  • R 1 can be a CM alkyl optionally substituted with one or more (e.g., 1-3) substituents independently chosen from halogen (e.g., F) and CM alkyl.
  • R 1 can be a CM alkyl optionally substituted with 1-3 fluorines, such as CF 3 , CF 3 CH 2 , etc.
  • R 1 is an optionally substituted alkoxy. In some embodiments, R 1 is an optionally substituted C1-6 alkoxy. In some preferred embodiments, R 1 is an optionally substituted CM alkoxy.
  • R 1 can be a CM alkoxy (e.g., methoxy, ethoxy, isopropoxy, sec-butoxy, tert-butoxy).
  • R 1 can be a CM alkoxy optionally substituted with one or more (e.g., 1-3) substituents independently chosen from halogen (e.g., F) and CM alkyl.
  • R 1 can be a CM alkoxy optionally substituted with 1-3 fluorines, such as CF 3 O, CF 3 CH 2 O, etc.
  • R 1 is an optionally substituted cycloalkyl. In some embodiments, R 1 is an optionally substituted C 3-6 cycloalkyl. In some embodiments, R 1 is a C 3-6 cycloalkyl. In some embodiments, R 1 is a C 3-6 cycloalkyl, optionally substituted with one or more (e.g., 1-3) substituents independently chosen from halogen (e.g., F) and C M alkyl. For example, in some embodiments, R 1 is cyclopropyl or cyclobutyl. In some embodiments, R 1 is cyclopropyl or cyclobutyl, optionally substituted with 1-3 fluorines.
  • R 1 is an optionally substituted cycloalkoxy. In some embodiments, R 1 is an optionally substituted C3-6 cycloalkoxy. In some embodiments, R 1 is a C3-6 cycloalkoxy. In some embodiments, R 1 is a C3-6 cycloalkoxy, optionally substituted with one or more (e.g., 1-3) substituents independently chosen from halogen (e.g., F) and C 14 alkyl. For example, in some embodiments, R 1 is cyclopropoxy or cyclobutoxy. In some embodiments, R 1 is cyclopropoxy or cyclobutoxy, optionally substituted with 1-3 fluorines.
  • R 1 is halogen, an optionally substituted Ci- 6 alkyl, an optionally substituted Ci- 6 alkoxy, an optionally substituted C3-6 cycloalkyl, or an optionally substituted C3-6 cycloalkoxy.
  • R 1 is C1-4 alkyl, C14 alkoxy, C3-6 cycloalkyl, or C3-6 cycloalkoxy, each optionally substituted with one or more (e.g., 1-3) substituents independently chosen from halogen and C14 alkyl.
  • R 1 is C14 alkyl or C14 alkoxy, each optionally substituted with 1-3 fluorines.
  • R 1 is an optionally substituted aryl, such as optionally substituted C6-12 aryl (e.g., phenyl).
  • R 1 is a C 6- i2 aryl (e.g., phenyl) optionally substituted with one or more (e.g., 1 or 2) substituents independently chosen from halogen, hydroxyl, cyano, optionally substituted C 14 alkyl, optionally substituted C 14 alkoxy, optionally substituted C3-6 cycloalkyl, and optionally substituted C3-6 cycloalkoxy.
  • R 1 is a C 6- i2 aryl (e.g., phenyl) optionally substituted with one or more (e.g., 1 or 2) substituents independently chosen from halogen (e.g., F, Cl), cyano, C 14 alkyl, C 14 alkoxy, C3-6 cycloalkyl, and C3-6 cycloalkoxy, wherein each of the alkyl, alkoxy, cycloalkyl, and cycloalkoxy is optionally substituted with one or more (e.g., 1-3) substituents independently chosen from halogen (e.g., F) and C 14 alkyl.
  • halogen e.g., F, Cl
  • R 1 is an optionally substituted heteroaryl.
  • R 1 is a 5-10 membered heteroaryl (e.g., a 5 or 6 membered heteroaryl as described herein) optionally substituted with one or more (e.g., 1 or 2) substituents independently chosen from halogen, hydroxyl, cyano, optionally substituted C 14 alkyl, optionally substituted C 14 alkoxy, optionally substituted C3-6 cycloalkyl, and optionally substituted C3-6 cycloalkoxy.
  • R 1 is a 5-10 membered heteroaryl (e.g., a 5 or 6 membered heteroaryl as described herein) optionally substituted with one or more (e.g., 1 or 2) substituents independently chosen from halogen (e.g., F, Cl), hydroxyl, cyano, C 1-4 alkyl, C 14 alkoxy, C3-6 cycloalkyl, and C3-6 cycloalkoxy, wherein each of the alkyl, alkoxy, cycloalkyl, and cycloalkoxy is optionally substituted with one or more (e.g., 1-3) substituents independently chosen from halogen (e.g., F) and CM alkyl.
  • halogen e.g., F, Cl
  • R 1 can also be an optionally substituted heterocyclyl.
  • R 1 is a 4-6 membered heterocyclyl (e.g., piperidinyl, piperazinyl, morpholinyl, etc.) optionally substituted with one or more (e.g., 1 or 2) substituents independently chosen from halogen, oxo, optionally substituted C1-4 alkyl, optionally substituted CM alkoxy, optionally substituted C 3-6 cycloalkyl, and optionally substituted C 3-6 cycloalkoxy.
  • one or more e.g., 1 or 2
  • substituents independently chosen from halogen, oxo, optionally substituted C1-4 alkyl, optionally substituted CM alkoxy, optionally substituted C 3-6 cycloalkyl, and optionally substituted C 3-6 cycloalkoxy.
  • R 1 is a 4-6 membered heterocyclyl (e.g., piperidinyl, piperazinyl, morpholinyl, etc.) optionally substituted with one or more (e.g., 1 or 2) substituents independently chosen from halogen (e.g., F, Cl), C alkyl, CM alkoxy, C 3-6 cycloalkyl, and C 3-6 cycloalkoxy, wherein each of the alkyl, alkoxy, cycloalkyl, and cycloalkoxy is optionally substituted with one or more (e.g., 1-3) substituents independently chosen from halogen (e.g., F) and C M alkyl.
  • halogen e.g., F, Cl
  • R 1 is -NR 10 R n .
  • the compound of Formula la is a compound of Formula lb:
  • R 10 , R 11 and R 3 are as defined herein.
  • one of R 10 and R 11 is an optionally substituted phenyl or optionally substituted 5 or 6 membered heteroaryl (e.g., as described herein).
  • one of R 10 and R 11 is a 5-membered heteroaryl (e.g., those having 2-4 nitrogen atoms as described herein) optionally substituted with one or more (e.g., 1 or 2) substituents independently chosen from halogen, hydroxyl, cyano and C M alkyl.
  • one of R 10 and R 11 is a pyrazolyl, triazolyl or tetrazolyl.
  • one of R 10 and R 11 is pyrazolyl, triazolyl or tetrazolyl, each optionally substituted with 1 or 2 independently chosen C M alkyl (e.g., methyl or ethyl).
  • the other of R 10 and R 11 can be hydrogen or an optionally substituted alkyl (e.g., a C M alkyl such as methyl or ethyl).
  • R 1 can be a carboxylic acid derivative such as -COOR 12 or - CONR 13 R 14 , wherein R 12 , R 13 and R 14 are defined herein.
  • R 12 , R 13 and R 14 are defined herein.
  • R 1 is -COOR 12 , and R 12 can be hydrogen or an optionally substituted alkyl.
  • R 12 can be hydrogen or an optionally substituted Ci- 6 alkyl, such as a C M alkyl optionally substituted with one or more (e.g., 1-3) substituents independently chosen from halogen and C1-4 alkyl.
  • R 1 is -CONR 13 R 14 , and R 13 and R 14 are each independently hydrogen or an optionally substituted alkyl.
  • R 13 and R 14 are each independently hydrogen or an optionally substituted Ci- 6 alkyl, such as a C M alkyl optionally substituted with one or more (e.g., 1-3) substituents independently chosen from halogen and C1-4 alkyl.
  • R 1 can be -S(0) n R 15 , wherein n and R 15 are defined herein. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, R 15 is an optionally substituted alkyl. In some embodiments, R 15 is an optionally substituted Ci- 6 alkyl, such as a C14 alkyl optionally substituted with one or more (e.g., 1-3) substituents independently chosen from halogen and Ci4 alkyl. In some embodiments, R 15 is an optionally substituted cycloalkyl.
  • R 15 is an optionally substituted C3-6 cycloalkyl, such as a C3-6 cycloalkyl optionally substituted with one or more (e.g., 1-3) substituents independently chosen from halogen and C 14 alkyl.
  • R 15 is -NR 10 R n , suitable groups for R 10 and R 11 are described herein.
  • R 1 can be -OR 16 , wherein R 16 is defined herein.
  • R 16 is H.
  • R 16 is an optionally substituted alkyl (e.g., an optionally substituted Ci- 6 alkyl) or an optionally substituted cycloalkyl (e.g., an optionally substituted C3-6 cycloalkyl), thus R 1 is an optionally substituted alkoxy or cycloalkoxy as described herein.
  • R 16 is described herein.
  • R 3 is an optionally substituted aryl, for example, an optionally substituted C 6 -ioaryl.
  • R 3 is a C 6 -ioaryl optionally substituted with one or more (e.g., 1-3) substituents independently chosen from halogen, hydroxyl, cyano, optionally substituted C 14 alkyl, optionally substituted C1-4 alkoxy, optionally substituted C3-6 cycloalkyl, and optionally substituted C3-6 cycloalkoxy.
  • R 3 can be an optionally substituted phenyl.
  • R 3 can be an optionally substituted bicyclic aryl.
  • R 3 is an optionally substituted naphthyl.
  • R 3 is a naphthyl optionally substituted with one or more (e.g., 1-3) substituents independently chosen from halogen, hydroxyl, cyano, CM alkyl, C 1-4 alkoxy, C3-6 cycloalkyl, and C3-6 cycloalkoxy, wherein each of the alkyl, alkoxy, cycloalkyl, and cycloalkoxy is optionally substituted with one or more (e.g., 1-3) substituents independently chosen from halogen (e.g., F) and C 1-4 alkyl.
  • halogen e.g., F
  • R 3 is a naphthyl optionally substituted with one or more (e.g., 1-3) substituents independently chosen from halogen, hydroxyl, cyano, C 14 alkyl optionally substituted with 1- 3 halogens, C 14 alkoxy optionally substituted with 1-3 halogens, C3-6 cycloalkyl optionally substituted with 1-3 halogens, and C3-6 cycloalkoxy optionally substituted with 1-3 halogens.
  • R 3 is a naphthyl optionally substituted with one or more (e.g., 1-3) substituents independently chosen from fluoro, chloro, hydroxyl, methyl, ethyl,
  • R 3 can also be an optionally substituted heteroaryl.
  • R 3 is an optionally substituted 8-10 membered bicyclic heteroaryl.
  • R 3 is a 8-10 membered bicyclic heteroaryl optionally substituted with one or more (e.g., 1-3) substituents independently chosen from halogen, hydroxyl, cyano, optionally substituted C 14 alkyl, optionally substituted C1-4 alkoxy, optionally substituted C3-6 cycloalkyl, and optionally substituted C3-6 cycloalkoxy.
  • R 3 is an optionally substituted benzimidazolyl, pyrrolopyridinyl, pyrazolopyridinyl, indazolyl, indolyl, quinolinyl or isoquinolinyl.
  • R 3 is benzimidazolyl, pyrrolopyridinyl, pyrazolopyridinyl, indazolyl, indolyl, quinolinyl or isoquinolinyl, each optionally substituted with one or more (e.g., 1-3) substituents independently chosen from halogen, cyano, hydroxyl, C 1-4 alkyl, C 14 alkoxy, C3-6 cycloalkyl, and C3-6 cycloalkoxy, wherein each of the alkyl, alkoxy, cycloalkyl, and cycloalkoxy is optionally substituted with one or more (e.g., 1-3) substituents independently chosen from halogen (e.g., F) and C 14 alkyl.
  • halogen e.g., F
  • R 3 is benzimidazolyl, pyrrolopyridinyl, pyrazolopyridinyl, indazolyl, indolyl, quinolinyl or isoquinolinyl, each optionally substituted with one or more (e.g., 1-3) substituents independently chosen from halogen, cyano, hydroxyl, C 14 alkyl optionally substituted with 1-3 halogens, C 1-4 alkoxy optionally substituted with 1-3 halogens, C3-6 cycloalkyl optionally substituted with 1-3 halogens, and C3-6 cycloalkoxy optionally substituted with 1-3 halogens.
  • substituents independently chosen from halogen, cyano, hydroxyl, C 14 alkyl optionally substituted with 1-3 halogens, C 1-4 alkoxy optionally substituted with 1-3 halogens, C3-6 cycloalkyl optionally substituted with 1-3 halogens, and C3-6 cycloalkoxy optional
  • R 3 is benzimidazolyl, pyrrolopyridinyl, pyrazolopyridinyl, indazolyl, indolyl, quinolinyl or isoquinolinyl, each optionally substituted with one or more (e.g., 1-3) substituents independently chosen from fluoro, chloro, hydroxyl, methyl, ethyl, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, and cyclopropyl.
  • substituents independently chosen from fluoro, chloro, hydroxyl, methyl, ethyl, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, and cyclopropyl.
  • substitutions of the heteroaryls herein do not result in a halogen, cyano, or oxygen atom (from a hydroxyl, alkoxy or cycloalkoxy group) directly attach to a ring heteroatom, such as a ring nitrogen atom, of the heteroaryls.
  • a ring heteroatom such as a ring nitrogen atom
  • those skilled in the art would understand that when a compound has a hydroxyl group attached to a carbon next to a nitrogen ring atom, the compound may exist predominantly in one or more tautomeric forms.
  • a 2-hydroxyl substituted 1 -methyl-benzimidazole may exist predominantly in Form B as shown below
  • a heteroaryl substituted with a hydroxyl group should be understood as encompassing all tautomeric forms when possible, e.g., Forms A and B above.
  • Suitable R 3 can be used to attach to the benzodioxinone core, for example, a position that is not immediately adjacent to the distal ring.
  • a position that is not immediately adjacent to the distal ring for example, both 1- and 2-naphthyl are suitable R 3 groups.
  • R 3 is preferably 2-naphthyl.
  • quinolinyl can have seven different
  • R 3 is preferably 2-
  • R 3 is 4-, 5-, or 8-quinolinyl.
  • R 3 can be optionally substituted naphthyl, quinolinyl, benzimidazolyl, pyrrolopyridinyl, or indazolyl:
  • the naphthyl, quinolinyl, benzimidazolyl, pyrrolopyridinyl, or indazolyl is optionally substituted with one or more (e.g., 1-3) substituents independently chosen from halogen, cyano, hydroxyl, C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, and C3-6 cycloalkoxy, wherein each of the alkyl, alkoxy, cycloalkyl, and cycloalkoxy is optionally substituted with one or more (e.g., 1-3) substituents independently chosen from halogen (e.g., F) and C14 alkyl.
  • halogen e.g., F
  • the naphthyl, quinolinyl, benzimidazolyl, pyrrolopyridinyl, or indazolyl is optionally substituted with one or more (e.g., 1-3) substituents independently chosen from halogen, cyano, hydroxyl, C14 alkyl optionally substituted with 1-3 halogens, C1-4 alkoxy optionally substituted with 1-3 halogens, C3-6 cycloalkyl optionally substituted with 1-3 halogens, and C3-6 cycloalkoxy optionally substituted with 1-3 halogens.
  • benzimidazolyl, pyrrolopyridinyl, or indazolyl is optionally substituted with one or more (e.g., 1-3) substituents independently chosen from fluoro, chloro, hydroxyl, methyl, trifluoromethyl, ethyl, methoxy, trifluoromethoxy, ethoxy, and cyclopropyl.
  • substituents independently chosen from fluoro, chloro, hydroxyl, methyl, trifluoromethyl, ethyl, methoxy, trifluoromethoxy, ethoxy, and cyclopropyl.
  • substitutions of the benzimidazolyl, pyrrolopyridinyl, or indazolyl herein do not result in a halogen, cyano, or oxygen atom (from a hydroxyl, alkoxy or cycloalkoxy group) directly attach to a ring nitrogen atom.
  • R 3 can be an optionally substituted benzo[b]thienyl (abbreviated benzothienyl).
  • the benzo[b]thienyl can be connected to the remainder of the molecule via various attaching points, for example, through the 2- or 3- position.
  • various attaching points for example, through the 2- or 3- position.
  • R 3 can be
  • R 30 and R 31 are each independently hydrogen, an optionally substituted alkyl (e.g., an optionally substituted C 1-6 alkyl), an optionally substituted cycloalkyl (e.g., an optionally substituted C3-6 cycloalkyl), an optionally substituted alkanoyl (e.g., an optionally substituted C1-6 alkanoyl), an optionally substituted cycloalkanoyl (e.g., an optionally substituted C3-6 cycloalkanoyl), an optionally substituted
  • thienyl can be substituted with -NR 30 R 31 , and optionally substituted with other suitable substituents described herein.
  • the substituent -NR 30 R 31 can be selected from - NH 2 , -NHCOOR 32 or -NHCONR 33 R 34 , wherein R 32 is a C 1-6 alkyl, R 33 and R 34 are each independently hydrogen or a C alkyl optionally substituted with 1-3 fluorines.
  • one of R 33 and R 34 is hydrogen and the other of R 33 and R 34 is hydrogen or a C 1-6 alkyl optionally substituted with 1-3 fluorines, for example, a C 14 alkyl (e.g., methyl, ethyl, etc.).
  • R 3 can be any of the embodiments described herein.
  • R 3 can be any of the embodiments described herein.
  • the present disclosure provides a compound of Formula II-1 to Formula II -4, or a pharmaceutically acceptable salt thereof:
  • R la is H or CM alkyl optionally substituted with 1-3 fluorines (e.g., CF3, ethyl, isopropyl, tert-butyl);
  • R lb is C1-4 alkoxyl optionally substituted with 1-3 fluorines (e.g., methoxy, trifluoromethoxy, ethoxy or isopropoxy);
  • R lc is F, Cl, Br, -CN, or -C0 2 (Ci 4 alkyl) (e.g., -CC Me);
  • R 3 can be any of those defined herein.
  • R 3 is an optionally substituted naphthyl, benzimidazolyl, pyrrolopyridinyl, pyrazolopyridinyl, indazolyl, indolyl, quinolinyl or isoquinolinyl.
  • R 3 is naphthyl, benzimidazolyl, pyrrolopyridinyl, pyrazolopyridinyl, indazolyl, indolyl, quinolinyl or isoquinolinyl, each optionally substituted with 1-3 substituents independently chosen from halogen, cyano, hydroxyl, C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, and C3-6 cycloalkoxy, wherein each of the alkyl, alkoxy, cycloalkyl, and cycloalkoxy is optionally substituted with one to three substituents independently chosen from halogen (e.g., F) and Ci- 4 alkyl.
  • R 3 is naphthyl, benzimidazolyl, pyrrolopyridinyl,
  • pyrazolopyridinyl indazolyl, indolyl, quinolinyl or isoquinolinyl, each optionally substituted with 1-3 substituents independently chosen from halogen, cyano, hydroxyl, C14 alkyl optionally substituted with 1-3 halogens, C1-4 alkoxy optionally substituted with 1-3 halogens, C3-6 cycloalkyl optionally substituted with 1-3 halogens, and C3-6 cycloalkoxy optionally substituted with 1-3 halogens.
  • R 3 is naphthyl, benzimidazolyl, pyrrolopyridinyl, pyrazolopyridinyl, indazolyl, indolyl, quinolinyl or isoquinolinyl, each optionally substituted with 1-3 substituents independently chosen from fluoro, chloro, hydroxyl, methyl, ethyl, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, and
  • pyrazolopyridinyl, indazolyl, indolyl, quinolinyl or isoquinolinyl herein do not result in halogen, cyano, or oxygen atom (from a hydroxyl, alkoxy or cycloalkoxy group) directly attach to a ring nitrogen atom.
  • R 3 in Formula II-1 to Formula II-4 can be optionally substituted naphthyl, quinolinyl, benzimidazolyl, pyrrolopyridinyl, or indazolyl:
  • each of the naphthyl, quinolinyl, benzimidazolyl, pyrrolopyridinyl, or indazolyl can be optionally substituted with 1-3 substituents independently chosen from fluoro, chloro, hydroxyl, methyl, trifluoromethyl, ethyl, methoxy, trifluoromethoxy, ethoxy, and cyclopropyl.
  • R 3 in Formula II-1 to Formula II-4 can be optionally substituted benzothienyl
  • the benzothienyl can be substituted with -NR 30 R 31 , and optionally substituted with other suitable substituents described herein.
  • the substituent - NR 30 R 31 can be selected from -NFh, -NHCOOR 32 or -NHCONR 33 R 34 , wherein R 32 is a C 1-6 alkyl, R 33 and R 34 are each independently hydrogen or a C 1-6 alkyl optionally substituted with 1-3 fluorines.
  • one of R 33 and R 34 is hydrogen and the other of R 33 and R 34 is hydrogen or a C 1-6 alkyl optionally substituted with 1-3 fluorines, for example, a C 14 alkyl (e.g., methyl, ethyl, etc.).
  • the present disclosure provides a compound of Formula III-1 to Formula III- 10, or a pharmaceutically acceptable salt thereof:
  • R 1 and R 2 can be any of those defined herein, and R 30 and R 31 , as applicable, can be any of those defined herein.
  • R 2 in Formula III-1 to Formula III-10 is hydrogen.
  • both R 30 and R 31 are hydrogen.
  • the substituent -NR 30 R 31 can be -NH 2 , -NH-C(0)-0-(CI-4 alkyl) (e.g., NHBoc) or -NH-C(O)- NH-(C i alkyl) (e.g., -NHCONHEt).
  • the present disclosure provides a compound of Formula IV-l to Formula IV- 10, or a pharmaceutically acceptable salt thereof:
  • R 1 and R 2 , and R 30 and R 31 can be any of those defined herein.
  • R 2 in Formula IV-l to Formula IV-10 is hydrogen.
  • both R 30 and R 31 are hydrogen.
  • the substituent - NR 30 R 31 can be -NH 2 , -NH-C(0)-0-(Ci4 alkyl) (e.g., NHBoc) or -NH-C(0)-NH-(Ci4 alkyl) (e g., -NHCONHEt).
  • R 1 in any of Formula III-1 to III- 10 and IV-l to IV- 10 can be hydrogen or an optionally substituted C M alkyl, for example, methyl, ethyl, isopropyl, or tert- butyl.
  • R 1 in any of Formula III-1 to III-10 and IV-l to IV-10 can be an optionally substituted C M alkoxy, for example, methoxy, trifluoromethoxy, ethoxy or isopropoxy.
  • R 1 in any of Formula III-1 to III-10 and IV-l to IV-10 can be -NR 10 R n .
  • one of R 10 and R 11 is an optionally substituted 5 or 6 membered heteroaryl.
  • one of R 10 and R 11 is a 5-membered heteroaryl having 2-4 ring nitrogen atoms (e.g., pyrazolyl, triazolyl or tetrazolyl), which is optionally substituted with 1 or 2 substituents independently chosen from halogen, hydroxyl, cyano and Ci- 4 alkyl.
  • one of R 10 and R 11 is a pyrazolyl, triazolyl or tetrazolyl, each optionally substituted with a CM alkyl.
  • the other of R 10 and R 11 can be hydrogen or C M alkyl (e.g., methyl).
  • C M alkyl e.g., methyl
  • R 10 and R 11 is , and the other of R 10 and R 11 is hydrogen or methyl.
  • R 2 in any of Formula III-1 to III-10 and IV-l to IV-10 can be hydrogen.
  • Other suitable R 1 and R 2 are described herein.
  • the present disclosure also provides the following compounds:
  • Certain embodiments of the present disclosure are directed to methods of synthesizing the benzodioxinone compounds described herein.
  • the present disclosure provides a method of synthesizing a
  • the method comprises reacting a compound of Formula S-l, or a salt thereof, with an acid of Formula S-2, or an activated form thereof (e.g., acyl chloride, anhydride, etc.) to form a compound of Formula I,
  • R 1 , R 2 , and R 3 are as defined herein.
  • Suitable reagents and conditions for this transformation are known in the art and exemplified in the Examples section, e.g., using HATU ((l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate)) and diisopropyl amine.
  • the method comprises reacting a compound of Formula S-3 with R'G 2 to form a compound of Formula I,
  • G 1 is halo (preferably Br or I), or B(OH) 2 (or a corresponding boronic ester, such as a pinacol boronate), and R 1 , R 2 , and R 3 are as defined herein, wherein R'G 2 is a reagent capable of reacting with Formula S-3 to form Formula I under suitable conditions.
  • R'G 2 is an amino compound with G 2 being H
  • G 1 is B(OH) 2 (or a corresponding boronic ester)
  • R'G 2 can react with the compound of Formula S-3, for example, under copper catalyzed (such as in the presence of Cu(OAc) 2 ) coupling reaction conditions to form the compound of Formula I.
  • R 2 is H.
  • the compound of Formula S-3 is Formula S-3a, wherein G 1 is B(OH) 2 (or a corresponding boronic ester), which can couple with R'G 2 to form a compound of Formula la:
  • Suitable coupling reaction conditions are known in the art and are exemplified in the Examples section.
  • the method comprises reacting a compound of Formula S-3b with R'G 2 to form a compound of Formula S-4, which can be deprotected to form a compound of Formula S-l,
  • G 1 is halo (preferably Br or I) or B(OH) 2 (or a corresponding boronic ester such as pinacol boronate), Pg 1 is a nitrogen protecting group, such as Boc, benzyl, etc., and R 1 , R 2 , and R 3 are as defined herein, wherein R'G 2 is a reagent capable of reacting with Formula S- 3b to form Formula S-4 under suitable conditions.
  • R'G 2 is an amino compound with G 2 being H, and G 1 is B(OH) 2 (or a corresponding boronic ester), and R'G 2 can react with the compound of Formula S-3b, for example, under copper catalyzed coupling reaction conditions to form the compound of Formula S-4.
  • R 2 is H.
  • the compound of Formula S-3b is a compound of Formula S-3c, wherein G 1 is B(OH) 2 (or a corresponding boronic ester), which can couple with R'G 2 to form a compound of Formula S-4a, which upon deprotection can form a compound of Formula S-l a.
  • Suitable coupling reaction conditions are known in the art and are exemplified in the Examples section.
  • Suitable nitrogen protecting groups and deprotection conditions are known in the art, for example, as described in “Protective Groups in Organic Synthesis”, 4 th ed. P. G. M. Wuts; T. W. Greene, John Wiley, 2007, and references cited therein.
  • Compounds of Formula S-3, S-3a, S-3b, and S-3c can be prepared by following the methods described herein.
  • the benzodioxinone compound of Formula S-3c, wherein G 1 is B(OH) 2 can be prepared from the corresponding bromide by following the following scheme:
  • the halogenated compound e.g., compound of Formula S-3 or S-3b, wherein G 1 is Br
  • Suitable oxidation conditions are known in the art, for example, by using KMn0 4 , which is also exemplified in the Examples section.
  • R 1 is -COOR 12 and the method comprises reacting a compound of Formula S-3 or S-3b under palladium catalyzed coupling condition in the presence of carbon monoxide and R 12 OH (e.g., MeOH).
  • R 12 OH e.g., MeOH
  • the compound of Formula S-5 can, for example, react with the compound of Formula S-6 under ketal forming condition to form a spirocyclic compound of Formula S-7.
  • the spirocyclic compound of Formula S-7 can then be oxidized (e.g., by KMnCri) to form a compound of Formula S-8, which can then be deprotected to form the compound of Formula S-l.
  • Suitable nitrogen protecting groups and deprotection conditions are known in the art, for example, as described in“Protective Groups in Organic Synthesis”, 4 th ed. P. G. M. Wuts; T. W. Greene, John Wiley, 2007, and references cited therein.
  • certain compounds of Formula S-l (such as Formula S-13 below) can also be prepared through an ester intermediate Formula S-9 by following Scheme 2 below:
  • R 12 and Pg 2 are as defined herein, G 3 and G 4 are independently an optionally substituted alkyl (e.g., a C M alkyl).
  • the bromide of Formula S-7a can be converted into a compound of Formula S-9 under palladium catalyzed coupling condition in the presence of carbon monoxide and R 12 OH (e.g., MeOH).
  • the ester of Formula S-9 can then be functionalized, e.g., through reaction with Grignard reagent (e.g., MeMgCl) to form an alcohol of Formula S-10.
  • Grignard reagent e.g., MeMgCl
  • a selective reaction with the ester of Formula S-9 can be carried out first to form a ketone intermediate, which can then be further converted into the compound of Formula S-10.
  • the ketone intermediate can be obtained from the bromide of Formula S-7a through appropriate coupling reactions.
  • both G 3 and G 4 groups are methyl.
  • the ketal of Formula S-10 can then be oxidized (e.g., by KMnCri) to form a benzodioxinone compound of Formula S-l l.
  • the alcohol function of Formula S-l 1 can then be reduced, e.g., through hydrogenation in the presence of Pd/C to form a compound of Formula S-12, which can then be deprotected to form an amine of Formula S-l 3.
  • protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in“Protective Groups in Organic Synthesis”, 4 th ed. P. G. M. Wuts; T. W. Greene, John Wiley, 2007, and references cited therein.
  • the reagents for the reactions described herein are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the reagents are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Sigma (St. Louis, Missouri, USA).
  • Certain embodiments are directed to a pharmaceutical composition comprising one or more of the benzodioxinone compounds of the present disclosure.
  • the pharmaceutical composition can optionally contain a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises a
  • compositions are known in the art.
  • suitable excipients include, for example, encapsulating materials or additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof. See also Remington's The Science and Practice of Pharmacy, 2lst Edition, A. R.
  • the pharmaceutical composition can include any one or more of the benzodioxinone compounds of the present disclosure.
  • the benzodioxinone compounds of the present disclosure can include any one or more of the benzodioxinone compounds of the present disclosure.
  • the benzodioxinone compounds of the present disclosure can include any one or more of the benzodioxinone compounds of the present disclosure.
  • composition comprises a compound of any of Formula I, Formula 1-1, Formula la, Formula lb, Formula II- 1 to II-4, Formula III-1 to III- 10 and IV- 1 to IV- 10, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition comprises a compound of
  • the pharmaceutical composition can also be formulated for delivery via different routes, such as oral, parenteral, inhalation, topical, etc.
  • the pharmaceutical composition is formulated for oral
  • the oral formulations can be presented in discrete units, such as capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or a suspension in an aqueous or non- aqueous liquid; or as an oil-in-water or water-in-oil emulsion.
  • Excipients for the preparation of compositions for oral administration are known in the art.
  • Non-limiting suitable excipients include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1, 3-butylene glycol, carbomers, castor oil, cellulose, cellulose acetate, cocoa butter, com starch, com oil, cottonseed oil, cross-povidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropylmethyl cellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate salts, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carb
  • the pharmaceutical composition is formulated for parenteral
  • parenteral formulations can be, for example, an aqueous solution, a suspension, or an emulsion.
  • Excipients for the preparation of parenteral formulations are known in the art.
  • suitable excipients include, for example, l,3-butanediol, castor oil, com oil, Lacseed oil, dextrose, germ oil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, U.S.P. or isotonic sodium chloride solution, water and mixtures thereof.
  • the pharmaceutical composition is formulated for inhalation.
  • the inhalable formulations can be, for example, formulated as a nasal spray, dry powder, or an aerosol administrable through a metered-dose inhaler.
  • Excipients for preparing formulations for inhalation are known in the art. Non-limiting suitable excipients include, for example, lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, and mixtures of these substances.
  • Sprays can additionally contain propellants, such as
  • chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.
  • the pharmaceutical composition is formulated for topical
  • the topical formulations can be, for example, in the form of a topical solution, lotion, shampoo, transdermal spray, topical film, foam, powder, paste, sponge, transdermal patch, tincture, tape, cream, gel, or ointment.
  • Excipients for preparing topical formulations are known in the art.
  • suitable excipients include, for example, animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, and mixtures thereof.
  • the topical formulations described herein can have one or more“lipophilic solvent(s)” that acts as a carrier into the pilosebaceous unit.
  • a lipophilic solvent useful in the invention can be miscible with water and/or lower chain (e.g., Ci- 6 ) alcohols.
  • the lipophilic solvent can be a glycol, e.g., propylene glycol.
  • the lipophilic solvent can be a polyethylene glycol, e.g., with average molecular weight (e.g., M n or M w ) ranging from 200 to 20000 Dalton.
  • the lipophilic solvent is a glycol ether, e.g., diethylene glycol monoethyl ether (transcutol).
  • the topical formulations described herein can also have one or more“filler(s)”.
  • Non limiting useful fillers include water and lower (e.g., Ci- 6 ) alcohols, including ethanol, 2- propanol and n-propanol. In some embodiments, the filler is water, ethanol and/or 2- propanol.
  • the topical formulations described herein can also have one or more“humectant(s)” used to provide a moistening effect.
  • Non-limiting useful humectants include glycerin, polyhydric alcohols and silicone oils.
  • the topic formulation comprises one or more humectants chosen from glycerin, propylene glycol and cyclomethicone.
  • the topical formulations described herein can also have a gelling agent that increases the viscosity of the final formulation.
  • the gelling agent can also act as an emulsifying agent.
  • Non-limiting useful gelling agents include classes of celluloses, acrylate polymers and acrylate copolymers, for example, hydroxypropyl cellulose, hydroxymethyl cellulose, Pluronic PF127 polymer, carbomer 980, carbomer 1342 and carbomer 940.
  • the topic formulation comprises one or more gelling agents chosen from hydroxypropyl cellulose (Klucel® EF, GF and/or HF), Pluronic PF127, carbomer 980 and carbomer 1342 (Pemulen® TR-l, TR-2 and/or Carbopol® ETD 2020).
  • Gelling agents chosen from hydroxypropyl cellulose (Klucel® EF, GF and/or HF), Pluronic PF127, carbomer 980 and carbomer 1342 (Pemulen® TR-l, TR-2 and/or Carbopol® ETD 2020).
  • topical formulations described herein can also have one or more anti-oxidants,
  • Non-limiting useful examples include butylatedhydroxytoluene, butylatedhydroxyanisole, ascorbyl palmitate, citric acid, vitamin E, vitamin E acetate, vitamin E-TPGS, ascorbic acid, tocophersolan and propyl gallate.
  • the topical formulations described herein can also have one or more preservatives that exhibit anti-bacterial and/or anti-fungal properties.
  • Non-limiting useful examples include diazolidinyl urea, methylparaben, propylparaben, tetrasodium EDTA, and ethylparaben.
  • topical formulations described herein can also have one or more chelating agents.
  • Non-limiting examples for use herein include EDTA, disodium edeate, dipotassium edeate, cyclodextrin, trisodium edetate, tetrasodium edetate, citric acid, sodium citrate, gluconic acid and potassium gluconate.
  • the pharmaceutical composition can include various amounts of the benzodioxinone compounds of the present disclosure, depending on various factors such as the intended use and potency of the compound.
  • the pharmaceutical composition can comprise a benzodioxinone compound of the present disclosure in an amount effective for inhibiting ACC1 and/or ACC2 activities in a cell, which is in vitro, in vivo, or ex vivo.
  • the amount is effective to achieve about 10%, about 20%, about 50%, about 70%, about 90%, about 99% inhibition of the ACC1 and/or ACC2 activities, compared to a control, or any ranges between the recited values.
  • the pharmaceutical composition can comprise the benzodioxinone compound of the present disclosure in an amount, when administered to a subject (e.g., a human) in need thereof, effective to inhibit one or more activities in the subject.
  • the one or more activities are chosen from acetyl-CoA carboxylases ACC1 and/or ACC2 activities, lipogenesis, proliferation of cells (e.g., adipocytes, melanocytes, keratinocytes, squamous cells, Merkel cells, Langerhans cells, or skin stem cells) in epidermis, dermis, and/or hypodermis, proliferation of human sebocytes, proliferation of human keratinocytes, differentiation of fibroblast to adipocytes in cutaneous and/or subcutaneous layers, sebum production, inflammation, and combinations thereof.
  • adipocytes melanocytes, keratinocytes, squamous cells, Merkel cells, Langerhans cells, or skin stem cells
  • proliferation of human sebocytes
  • the pharmaceutical composition can comprise the benzodioxinone compound of the present disclosure in an amount, when administered to a subject (e.g., a human) in need thereof, (a) effective to inhibit acetyl-CoA carboxylases ACC1 and/or ACC2 activities in a cell (e.g., a sebocyte, adipocyte) of the subject; (b) effective to inhibit lipogenesis (e.g., lipogenesis of sebocytes, lipogenesis of adipocytes, etc.) in the subject; (c) effective to inhibit proliferation of cells, such as adipocytes, melanocytes, keratinocytes, squamous cells, Merkel cells, Langerhans cells, or skin stem cells, in epidermis, dermis, and/or hypodermis in the subject; (d) effective to inhibit proliferation of human sebocytes in the subject; (e) effective to inhibit proliferation of human keratinocytes in the subject; (f) effective to inhibit
  • the subject is characterized as having a disease or disorder chosen from acne, seborrhea, sebaceous hyperplasia, seborrheic keratosis, sebaceous adenoma, sebaceous cyst, actinic keratosis, sebaceous carcinoma, squamous cell carcinoma, melanoma, phymatous rosacea,
  • the pharmaceutical composition comprises a therapeutically
  • the pharmaceutical composition comprises a therapeutically effective amount of the benzodioxinone compound of the present disclosure and a pharmaceutically acceptable excipient.
  • a therapeutically effective amount of a benzodioxinone compound of the present disclosure is an amount effective to treat a disease or disorder as described herein, which can depend on the recipient of the treatment, the disease or disorder being treated and the severity thereof, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the compound potency, its rate of clearance and whether or not another drug is co-administered.
  • the pharmaceutical composition can be used for treating various diseases or disorders.
  • Non-limiting diseases or disorders suitable for such treatment include skin diseases (such as diseases or disorders associated with aberrant sebocyte and/or keratinocyte activity), non alcoholic fatty liver diseases or disorders, metabolic diseases or disorders, and proliferative diseases such as cancer (e.g., non-small cell lung cancer).
  • Non-limiting suitable diseases or disorders associated with aberrant sebocyte and/or keratinocyte activity include, for example, acne, seborrhea, sebaceous hyperplasia, seborrheic keratosis, sebaceous adenoma, sebaceous cyst, actinic keratosis, sebaceous carcinoma, squamous cell carcinoma, melanoma, phymatous rosacea, fibrofolliculomas in Birt-Hogg-Dube syndrome, and a combination thereof.
  • Non-limiting suitable non-alcoholic fatty liver diseases or disorders include, for example, non-alcoholic steatohepatitis (NASH).
  • Non-limiting suitable metabolic diseases or disorders include, for example, obesity and/or diabetes.
  • the pharmaceutical composition can also include one or more active agents in addition to the benzodioxinone compounds of the present disclosure.
  • the benzodioxinone compound of the present disclosure and the one or more active agents can be present in a single dosage form (e.g., in a single pill, tablet, capsule, topic ointment, gel, paste, cream, etc.) or in separate dosage forms.
  • the benzodioxinone compound of the present disclosure can be in an oral or topical formulation, whereas the one or more active agents can be in the same formulation or a different oral or topical formulation.
  • the benzodioxinone compound of the present disclosure and one or more active agents can be included in a kit.
  • the one or more active agents are suitable for treating diseases or disorders associated with aberrant sebocyte and/or keratinocyte activity, such as acne.
  • diseases or disorders associated with aberrant sebocyte and/or keratinocyte activity such as acne.
  • Non-limiting useful examples include antibiotics (e.g., clindamycin, erythromycin, metronidazole, sulfacetamide, or tetracyclines such as doxy cy cline and minocycline), retinoids (e.g., adapalene, isotretinoin, retinol, tazarotene, or tretinoin), and combinations thereof.
  • the one or more active agents are present in an amount effective for treating a disease or disorder associated with aberrant sebocyte and/or keratinocyte activity such as acne.
  • the one or more active agents are suitable for treating metabolic diseases or non-alcoholic fatty liver diseases.
  • Non-limiting useful examples of such agents include angiotensin II receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, caspase inhibitors, cathepsin B inhibitors, CCR2 chemokine antagonists, CCR5 chemokine antagonists, chloride channel stimulators, cholesterol solubilizers, diacyl glycerol O- acyltransferase 1 or 2 (DGAT1 or DGAT2) inhibitors, dipeptidyl peptidase IV (DPPIV) inhibitors, famesoid X receptor (FXR) agonists, galectin-3 inhibitors, glucagon-like peptide 1 (GLP1) agonists, glutathione precursors, hepatitis C virus NS3 protease inhibitors, HMG CoA reductase inhibitors, 11 b-hydroxysteroid dehydrogenase ( 1 1 1
  • PLC phospholipase C
  • PPAR-alpha agonists PPAR-gamma agonists
  • PPAR-delta agonists Rho associated protein kinase 2 (ROCK2) inhibitors
  • SGLT2 sodium glucose transporter-2
  • stearoyl CoA desaturase-l inhibitors thyroid hormone receptor b agonists
  • TNF-alpha tumor necrosis factor alpha
  • the one or more active agents can be chosen from acetylsalicylic acid, alipogene tiparvovec, aramchol, atorvastatin, BLX-1002, cenicriviroc, cobiprostone, colesevelam, emricasan, enalapril, GFT-505, GR-MD-02, hydrochlorothiazide, icosapent ethyl ester (ethyl eicosapentaenoic acid), IMM-124E, KD-025, linagliptin, liraglutide, mercaptamine, MGL-3196, obeti cholic acid, olesoxime, peg-ilodecakin, pioglitazone, PX- 102, remogliflozin etabonate, SHP-626, solithromycin, tipelukast, TRX-318, ursode
  • the one or more active agents are present in a therapeutically effective amount for treating a non-alcoholic fatty liver disease (e.g., NASH). In some embodiments, the one or more active agents are present in a therapeutically effective amount for treating a metabolic disease (e.g., obesity and/or diabetes).
  • the benzodioxinone compounds of the present disclosure are useful for inhibiting ACC1 and/or ACC2 activities in a cell and for treating diseases or disorders associated with ACC1 and/or ACC2 activities (e.g., a metabolic disease, a disease associated with aberrant sebum production, or a non-alcoholic fatty liver disease).
  • diseases or disorders associated with ACC1 and/or ACC2 activities e.g., a metabolic disease, a disease associated with aberrant sebum production, or a non-alcoholic fatty liver disease.
  • the present disclosure provides a method of inhibiting ACC1 and/or ACC2 activities in a cell.
  • the method comprises contacting the cell with an effective amount of a benzodioxinone compound of the present disclosure or a pharmaceutical composition described herein.
  • the cell can be in vitro (e.g., a human cell line), in vivo (e.g., a human cell in a human subject), or ex vivo (a human cell from a human subject).
  • inhibition of ACC1 and/or ACC2 activities can also lead to
  • malonyl-CoA production in a cell lipogenesis, proliferation of cells, differentiation of fibroblast to adipocytes, sebum production, and/or inflammation, which is implicated in diseases or disorders such as diseases or disorders associated with aberrant sebocyte and/or keratinocyte activity (e.g., acne, and others as described herein), metabolic diseases (e.g., obesity, diabetes, and others as described herein), non-alcohol fatty liver disease (e.g., NASH), and cancer (e.g., non-small cell lung cancer).
  • diseases or disorders such as diseases or disorders associated with aberrant sebocyte and/or keratinocyte activity (e.g., acne, and others as described herein), metabolic diseases (e.g., obesity, diabetes, and others as described herein), non-alcohol fatty liver disease (e.g., NASH), and cancer (e.g., non-small cell lung cancer).
  • the present disclosure provides a method of inhibiting
  • the method comprises contacting the cell (e.g., a human cell) with an effective amount of a benzodioxinone compound of the present disclosure or a pharmaceutical composition described herein.
  • the cell is a sebocyte, adipocyte, or a hepatocyte.
  • the present disclosure provides a method of inhibiting proliferation of cells.
  • the method comprises contacting the cells (e.g., human cells) with an effective amount of a benzodioxinone compound of the present disclosure or a pharmaceutical composition described herein.
  • the cells are adipocytes, melanocytes, keratinocytes, squamous cells, Merkel cells, Langerhans cells, and/or skin stem cells.
  • the cells are adipocytes, melanocytes, keratinocytes, squamous cells, Merkel cells, Langerhans cells, and/or skin stem cells in epidermis, dermis, and/or hypodermis.
  • the cells are human sebocytes.
  • the cells are human keratinocytes.
  • the method comprises contacting the fibroblast with an effective amount of a benzodioxinone compound of the present disclosure or a pharmaceutical composition described herein. In some embodiments, the method inhibits the differentiation of fibroblast to adipocytes in cutaneous and/or subcutaneous layers.
  • the present disclosure provides a method of inhibiting sebum production.
  • the method comprises contacting a sebocyte (e.g., a human sebocyte) with an effective amount of a benzodioxinone compound of the present disclosure or a pharmaceutical composition described herein.
  • a sebocyte e.g., a human sebocyte
  • the present disclosure also provides a method of inhibiting ACC1 and/or ACC2 activities and one or more (e.g., 1, 2, 3, 4, 5, 6, or all) activities in a subject (e.g., a human subject) in need thereof, wherein the one or more activities are chosen from (a) lipogenesis (e.g., lipogenesis of sebocytes, lipogenesis of adipocytes, lipogenesis of hepaocytes, etc.) in the subject; (b) proliferation of cells, such as adipocytes, melanocytes, keratinocytes, squamous cells, Merkel cells, Langerhans cells, or skin stem cells, in epidermis, dermis, and/or hypodermis in the subject; (c) proliferation of human sebocytes in the subject; (d) proliferation of human keratinocytes in the subject; (e) differentiation of fibroblast to adipocytes in cutaneous and/or subcutaneous layers in the subject; (f
  • the subject is characterized as having a disease or disorder chosen from acne, seborrhea, sebaceous hyperplasia, seborrheic keratosis, sebaceous adenoma, sebaceous cyst, actinic keratosis, sebaceous carcinoma, squamous cell carcinoma, melanoma, phymatous rosacea, fibrofolliculomas in Birt-Hogg-Dube syndrome, and combinations thereof.
  • a disease or disorder chosen from acne, seborrhea, sebaceous hyperplasia, seborrheic keratosis, sebaceous adenoma, sebaceous cyst, actinic keratosis, sebaceous carcinoma, squamous cell carcinoma, melanoma, phymatous rosacea, fibrofolliculomas in Birt-Hogg-Dube syndrome, and combinations thereof.
  • the present disclosure also provides a method of treating a disease or disorder associated with ACC1 and/or ACC2 in a subject in need thereof.
  • the method comprises administering to the subject a therapeutically effective amount of a benzodioxinone compound of the present disclosure or a pharmaceutical composition described herein.
  • Various diseases or disorders are associated with undesired or aberrant (e.g., hyperactive) ACC1 and/or ACC2 activities and can be treated by the methods described herein.
  • Skin is the largest organ of human body that provides the interface between the external environment and the host. Lipids play an essential role in the formation and maintenance of both the permeability and antimicrobial barriers of skin. The normal function of skin is maintained by the hydrophobic extracellular lipid matrix in the stratum comeum composed primarily of ceramides, cholesterol, and free fatty acids, which prevents loss of water and electrolytes in the body. Sebaceous gland is the organ producing and secreting sebum into the follicular duct, which reaches the skin’s surface to maintain the normal function of the skin as barriers.
  • Acne vulgaris is a common dermatological condition affecting many people.
  • Acne is a chronic inflammatory dermatosis notable for open or closed comedones (blackheads and whiteheads) and inflammatory lesions, including papules, pustules, or nodules (also known as cysts).
  • Key pathogenic factors that play an important role in the development of acne are follicular
  • Acne can have different severities, such as mild, moderate, and severe.
  • the severity of the condition is affected by multiple factors including seasonal and psychological influences.
  • antibiotics oral or topical
  • TMP/SMX trimethoprim/sulfamethoxazole
  • trimethoprim trimethoprim
  • erythromycin clindamycin
  • azelaic acid dapsone
  • azithromycin amoxicillin
  • cephalexin hormonal agents, such as combined oral contraceptives with an estrogen and a progestin, for example, ethinyl estradiol/norgestimate, ethinyl estradiol/norethindrone acetate/ferrous fumarate, ethinyl estradiol/drospirenone, and ethinyl estradiol/drospirenone/levomefo
  • Dermatological therapies are not fully effective against acne such as mild to moderate acne and many of the agents employed in these therapies produce skin irritation or have other side effects. See e.g., Zaenglein, A. et al., J.
  • Sebaceous gland is filled with mature sebocytes, which is mainly occupied by lipid
  • sebocytes droplets in cytosol and undergoes holocrine secretion.
  • mature sebocytes is constantly regenerated from epidermal stem cells.
  • Overactivity of sebocytes, including proliferation, differentiation, and production of sebum can cause different skin diseases including acne, seborrhea, sebaceous hyperplasia, seborrheic keratosis, sebaceous adenoma, sebaceous cyst, actinic keratosis, sebaceous carcinoma, squamous cell carcinoma, melanoma, phymatous rosacea, and fibrofolliculomas in Birt- Hogg-Dube syndrome, etc.
  • the benzodioxinone compounds of the present disclosure can also be used for treating diseases or disorders associated with aberrant sebocyte and/or keratinocyte activities, e.g., through topical administration.
  • exemplary representative benzodioxinone compounds of the present disclosure are inhibitors of ACC1 and/or ACC2.
  • exemplary representative benzodioxinone compounds of the present disclosure were shown to inhibit sebocytes activities such as cellular levels of malonyl-CoA of sebocytes.
  • the present disclosure provides a method of treating a disease or disorder associated with aberrant sebocyte and/or keratinocyte activity in a subject in need thereof.
  • the method comprises administering to the subject in need thereof a therapeutically effective amount of a benzodioxinone compound of the present disclosure or a pharmaceutical composition described herein.
  • Non-limiting suitable diseases or disorders associated with aberrant sebocyte and/or keratinocyte activity include, for example, acne, seborrhea, sebaceous hyperplasia, seborrheic keratosis, sebaceous adenoma, sebaceous cyst, actinic keratosis, sebaceous carcinoma, squamous cell carcinoma, melanoma, phymatous rosacea, fibrofolliculomas in Birt-Hogg-Dube syndrome, and a combination thereof.
  • Various routes of administration are suitable, for example, orally or topically.
  • the method can use the benzodioxinone compound of the present disclosure as the active agent or use it in combination with another therapy.
  • the benzodioxinone compound of the present disclosure is the only active agent administered to the subject for treating the disease or disorder associated with aberrant sebocyte and/or keratinocyte activity.
  • the method is a combination therapy and further comprises treating the subject with one or more additional therapies effective for the treatment of the disease or disorder associated with aberrant sebocyte and/or keratinocyte activity.
  • the benzodioxinone compound of the present disclosure can be administered to the subject concurrently with, prior to, or subsequent to the one or more additional therapies.
  • the benzodioxinone compound of the present disclosure and the one or more additional therapies can be administered to the subject through the same or different routes.
  • the benzodioxinone compound of the present disclosure can be administered topically, whereas the one or more additional therapies (e.g., additional active agents) can be administered orally.
  • the present disclosure provides a method of treating acne in a subject in need thereof.
  • the method comprises administering (e.g., topically) to the subject in need thereof a therapeutically effective amount of a benzodioxinone compounds of the present disclosure or a pharmaceutical composition described herein.
  • the method is a combination therapy and further comprises treating the subject with an additional therapy for acne. Any of the known therapies for treating acne can be part of the combination therapy, some of which are exemplified herein.
  • the method further comprises administering to the subject an antibiotic, either topically or systemically, a retinoid, either topically or systemically, or a combination thereof.
  • the antibiotic is clindamycin, erythromycin, metronidazole, sulfacetamide, a tetracycline such as doxycycline and minocycline, or a combination thereof.
  • the retinoid is adapalene, isotretinoin, retinol, tazarotene, tretinoin, or a combination thereof.
  • Other suitable antibiotics and retinoids are known in the art and exemplified herein.
  • Inhibitions of ACC1 and/or ACC2 activities have also been found to be associated with and/or useful for treating various metabolic diseases, non-alcoholic fatty liver diseases, and/or cancer (e.g.,. non-small cell lung cancer).
  • cancer e.g.,. non-small cell lung cancer.
  • U.S. Pat. No. 8,288,405 and Griffith et al Journal of medicinal chemistry 57: 10512-10526(2014) (obesity, diabetes); Harriman et al, Proceedings of the National Academy of Sciences of the United States of America 773:El796-l 805(2016) (nonalcoholic steatohepatitis (NASH), and Svensson et al, Nature medicine 22, 1108-1119(2016) ( non-small cell lung cancer).
  • certain embodiments of the present disclosure are directed to the use of the benzodioxinone compounds of the present disclosure or pharmaceutical composition described herein, for the treatment of metabolic diseases, non-alcoholic fatty liver diseases, and/or cancer (e.g., non-small cell lung cancer).
  • Various routes of administration are suitable, for example, orally or topically.
  • the method can use the benzodioxinone compound of the present disclosure as the active agent or use it in combination with another therapy.
  • the benzodioxinone compound of the present disclosure is the only active agent administered to the subject for treating the metabolic diseases, non-alcoholic fatty liver diseases, and/or cancer (e.g., non-small cell lung cancer).
  • the method is a combination therapy and further comprises treating the subject with one or more additional therapies effective for the treatment of the metabolic diseases, non-alcoholic fatty liver diseases, and/or cancer (e.g., non-small cell lung cancer).
  • additional therapies effective for the treatment of the metabolic diseases, non-alcoholic fatty liver diseases, and/or cancer (e.g., non-small cell lung cancer).
  • the benzodioxinone compound of the present disclosure can be administered to the subject concurrently with, prior to, or subsequent to the one or more additional therapies.
  • the benzodioxinone compound of the present disclosure and the one or more additional therapies can be administered to the subject through the same or different routes.
  • the present disclosure provides a method of treating
  • obesity and/or obesity-related disorders e.g., overweight, weight gain, or weight
  • BMI body mass index
  • Overweight is typically defined as a BMI of 25-29.9 kg/m 2
  • obesity is typically defined as a BMI of 30 kg/m 2 .
  • the method comprises administering (e.g., orally) to the subject in need thereof a therapeutically effective amount of a benzodioxinone compounds of the present disclosure or a pharmaceutical composition described herein.
  • the present disclosure also provides a method of treating diabetes and/or diabetes-related disorders in a subject (e.g., human subject) in need thereof, such as Type 1 (insulin-dependent diabetes mellitus, also referred to as“IDDM”) and Type 2 (noninsulin-dependent diabetes mellitus, also referred to as“NIDDM”) diabetes etc.
  • the method comprises administering (e.g., orally) to the subject in need thereof a therapeutically effective amount of a benzodioxinone compounds of the present disclosure or a pharmaceutical composition described herein.
  • the present disclosure also provides a method of treating a non alcoholic fatty liver disease in a subject (e.g., human subject) in need thereof, for example, NASH.
  • the method comprises administering (e.g., orally) to the subject in need thereof a therapeutically effective amount of a benzodioxinone compounds of the present disclosure or a pharmaceutical composition described herein.
  • the methods of treating obesity, obesity-related disorders, diabetes, diabetes-related disorders, and/or non-alcoholic fatty liver diseases can be a combination therapy.
  • the methods can include administering to the subject one or more additional active agents in a therapeutically effective amount for treating the respective disease or disorder.
  • Non-limiting useful agents for the combination therapy include angiotensin II receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, caspase inhibitors, cathepsin B inhibitors, CCR2 chemokine antagonists, CCR5 chemokine antagonists, chloride channel stimulators, cholesterol solubilizers, diacyl glycerol O- acyltransferase 1 or 2 (DGAT1 or DGAT2) inhibitors, dipeptidyl peptidase IV (DPPIV) inhibitors, famesoid X receptor (FXR) agonists, galectin-3 inhibitors, glucagon-like peptide 1 (GLP1) agonists, glutathione precursors, hepatitis C virus NS3 protease inhibitors, HMG CoA reductase inhibitors, 11 b-hydroxysteroid dehydrogenase ( 1 1 b-HSDl) inhibitors, IL-Ib antagonists, IL-6 antagonists, IL-10
  • PLC phospholipase C
  • PPAR-alpha agonists PPAR-gamma agonists
  • PPAR-delta agonists Rho associated protein kinase 2 (ROCK2) inhibitors
  • SGLT2 sodium glucose transporter-2
  • stearoyl CoA desaturase-l inhibitors thyroid hormone receptor b agonists
  • TNF-alpha tumor necrosis factor alpha
  • the one or more additional agents can be chosen from acetylsalicylic acid, alipogene tiparvovec, aramchol, atorvastatin, BLX-1002, cenicriviroc, cobiprostone, colesevelam, emricasan, enalapril, GFT-505, GR-MD-02, hydrochlorothiazide, icosapent ethyl ester (ethyl eicosapentaenoic acid), IMM-124E, KD-025, linagliptin, liraglutide, mercaptamine, MGL-3196, obeti cholic acid, olesoxime, peg-ilodecakin, pioglitazone, PX- 102, remogliflozin etabonate, SHP-626, solithromycin, tipelukast, TRX-318, urs
  • the present disclosure also provides a method of treating cancer (e.g., non-small cell lung cancer), which comprises administering (e.g., orally) to a subject in need thereof a therapeutically effective amount of a benzodioxinone compound of the present disclosure or a pharmaceutical composition described herein.
  • cancer e.g., non-small cell lung cancer
  • the present disclosure also provides a method of delivering
  • salicyclic acid or a derivative thereof to a subject in need thereof comprising administering to the subject a benzodioxinone compound of the present disclosure or a pharmaceutical composition described herein.
  • administering the benzodioxinone compound can deliver salicyclic acid to the subject.
  • the administering delivers an anti-inflammatory amount of salicyclic acid to the subject.
  • the benzodioxinone compounds administered are hydrolyzed into salicyclic acid slowly in vivo, and thus the administering provides an extended release of salicyclic acid.
  • both the benzodioxione compounds and salicyclic acid can be present over a period of time after administration.
  • the benzodioxinone compounds can have at least a dual function in vivo : inhibiting ACC activity and providing salicyclic acid, which can for example reduce inflammation.
  • a few benzodioxinone compounds with both R 1 and R 2 as hydrogens were prepared and tested, see Examples 12-15. These compounds showed inhibition of ACC with an IC50 less than 10 uM and can be converted into salicyclic acid through hydrolysis.
  • the benzodioxinone compounds are administered to deliver salicyclic acid either locally and/or systemically.
  • the benzodioxinone compounds are administered topically.
  • the subject is characterized as having inflammation associated with a skin disease, e.g., as described herein.
  • the present disclosure also provides a method of treating
  • the method comprising administering to the subject a benzodioxinone compound of the present disclosure or a pharmaceutical composition described herein.
  • the compounds herein can be hydrolyzed into salicyclic acid or derivative, and can have anti-inflammatory effect independent of the inhibition of ACC.
  • benzodioxinone compound are both hydrogen, administering the benzodioxinone compound can deliver salicyclic acid to the subject. In some embodiments, the administering delivers an anti-inflammatory amount of salicyclic acid to the subject. In some embodiments, the administering provides an extended release of salicyclic acid. In some embodiments, the benzodioxinone compounds are administered to deliver salicyclic acid either locally and/or systemically. In some embodiments, the benzodioxinone compounds are administered topically. In some embodiments, the inflammation is associated with a skin disease, e.g., as described herein.
  • variable moiety herein may be the same or different as another specific embodiment having the same identifier.
  • Suitable groups for R 1 , R 2 , and R 3 in compounds of Formula I are independently selected.
  • the described embodiments of the present invention may be combined. Such combination is contemplated and within the scope of the present invention.
  • embodiments for any of R 1 , R 2 , and R 3 can be combined with embodiments defined for any other of R 1 , R 2 , and R 3 .
  • the term“benzodioxinone compound(s) of the present disclosure” refers to any of the compounds described herein according to Formula I (e.g., Formula la, Formula lb, Formula II- 1 to Formula II-4, Formula III-1 to Formula III- 10 or Formula IV- 1 to Formula IV-10, Examples 2-15), isotopically labeled compound(s) thereof (e.g., deuterated analogs thereof), possible stereoisomers thereof (including diastereoisomers, enantiomers, and racemic mixtures), tautomers thereof, conformational isomers thereof, and/or
  • Formula I e.g., Formula la, Formula lb, Formula II- 1 to Formula II-4, Formula III-1 to Formula III- 10 or Formula IV- 1 to Formula IV-10, Examples 2-15
  • isotopically labeled compound(s) thereof e.g., deuterated analogs thereof
  • possible stereoisomers thereof including diastereoisomers, enantiomers, and racemic mixtures
  • compositions of the present disclosure wherein the compound(s) is in association with water or solvent, respectively.
  • the phrase“administration” of a compound,“administering” a compound, or other variants thereof means providing the compound or a prodrug of the compound to the individual in need of treatment.
  • alkyl refers to a straight- or branched-chain aliphatic hydrocarbon containing one to twelve carbon atoms (i.e., C M 2 alkyl) or the number of carbon atoms designated (i.e., a Ci alkyl such as methyl, a C 2 alkyl such as ethyl, a C3 alkyl such as propyl or isopropyl, etc.).
  • the alkyl group is a straight chain Ci-io alkyl group.
  • the alkyl group is a branched chain C3-10 alkyl group.
  • the alkyl group is a straight chain C1-6 alkyl group. In another embodiment, the alkyl group is a branched chain C3-6 alkyl group. In another embodiment, the alkyl group is a straight chain C14 alkyl group. In another embodiment, the alkyl group is a branched chain C34 alkyl group. In another embodiment, the alkyl group is a straight or branched chain C34 alkyl group.
  • Non-limiting exemplary Ci-io alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, iso-butyl, 3- pentyl, hexyl, heptyl, octyl, nonyl, decyl, and the like.
  • Non-limiting exemplary C14 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, and iso-butyl.
  • the optionally substituted alkyl is substituted with three substituents, e.g., three fluorines. In one embodiment, the optionally substituted alkyl is substituted with one substituent. In one embodiment, the optionally substituted alkyl is substituted with two substituents.
  • each of R a , R d and R e at each occurrence is independently selected from hydrogen, C i-io alkyl, C i-io haloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, 3-14 membered heterocyclyl, C 6- i4 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R 8 groups.
  • At least one of R b and R c is chosen from hydrogen, Ci 10 alkyl, C i-10 haloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R 8 groups.
  • both R b and R c are independently chosen from hydrogen, C i-10 alkyl, C i-10 haloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, 3-14 membered heterocyclyl, C 6-i4 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R 8 groups.
  • halo e.g., F
  • nitro, cyano e.g., F
  • each of R 33 , R bb , R cc , R dd , R ee , R ff and R 1 * at each occurrence is
  • R bb and R cc independently selected from hydrogen, Ci-6 alkyl, C i r, haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 4-6 membered heterocyclyl, C 6-i o aryl, and 5-10 membered heteroaryl, or R bb and R cc , R ff and R 1 *, R ff and one of R bb and R cc , or R 1 * and one of R bb and R cc , are j oined to form a 4-6 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R 88 groups.
  • R 88 at each occurrence is independently selected from halo (e.g., F), nitro, cyano, hydroxy, -NH2, -N(H)(CI-6 alkyl), -N(CI-6 alkyl)( C1-6 alkyl), -N(H)(C3-6 cycloalkyl), -N(CI_6 alkyl)(C 3- 6 cycloalkyl), -N(C 3- 6 cycloalkyl)( C3-6 cycloalkyl), -O-C1-6 alkyl, C1-6 alkyl, C 1-6 haloalkyl, -O-C 1-6 haloalkyl, C 3-6 cycloalkyl optionally substituted with 1-5 substituents independently selected from halogen, C1-4 alkyl, and C3-6 cycloalkyl, -O-C3-6 cycloalkyl optionally substituted with 1-5 substituents independently selected from halogen, C1-4 alkyl, and C3-6 cycloalkyl
  • cycloalkyl refers to saturated and partially unsaturated (containing one or two double bonds) cyclic aliphatic hydrocarbons containing one to three rings having from three to twelve carbon atoms (i.e., C3-12 cycloalkyl) or the number of carbons designated.
  • the cycloalkyl group has two rings.
  • the cycloalkyl group has one ring.
  • the cycloalkyl group is a C3-8 cycloalkyl group.
  • the cycloalkyl group is a C3-6 cycloalkyl group.
  • Non-limiting exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbomyl, decalin, adamantyl, cyclopentenyl, and cyclohexenyl.
  • the optionally substituted cycloalkyl is substituted with three substituents. In one embodiment, the optionally substituted cycloalkyl is substituted with two substituents. In another embodiment, the optionally substituted cycloalkyl is substituted with one substituent.
  • alkenyl as used by itself or as part of another group refers to an alkyl group as defined above containing one, two or three carbon-to-carbon double bonds.
  • the alkenyl group is a C2-6 alkenyl group.
  • the alkenyl group is a C2-4 alkenyl group.
  • Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.
  • alkenyl as used herein by itself or as part of another group means the alkenyl as defined above is either unsubstituted or substituted with one or more (e.g., one, two, or three) substituents each independently chosen from, e.g., halo (e.g., F), oxo, nitro, cyano, -OR a , -C0 2 R a , -0C0 2 R a , -0S0 2 NR b R c , -S0 3 R a ,
  • halo e.g., F
  • alkynyl refers to an alkyl group as defined above containing one to three carbon-to-carbon triple bonds. In one embodiment, the alkynyl has one carbon-carbon triple bond. In one embodiment, the alkynyl group is a C2-6 alkynyl group. In another embodiment, the alkynyl group is a C24 alkynyl group.
  • Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2- butynyl, pentynyl, and hexynyl groups.
  • alkynyl as used herein by itself or as part of another group means the alkynyl as defined above is either unsubstituted or substituted with one or more (e.g., one, two, or three) substituents each independently chosen from, e.g., halo (e.g., F), oxo, nitro, cyano, -OR a , -C0 2 R a , -0C0 2 R a , -0S0 2 NR b R c , -S0 3 R a ,
  • halo e.g., F
  • haloalkyl refers to an alkyl substituted with one or more fluorine, chlorine, bromine and/or iodine atoms.
  • the haloalkyl is an alkyl group substituted with one, two, or three fluorine atoms.
  • the haloalkyl group is a Ci-io haloalkyl group.
  • the haloalkyl group is a Ci- 6 haloalkyl group.
  • the haloalkyl group is a C i4 haloalkyl group.
  • alkoxy as used by itself or as part of another group refers to a radical of the formula -OR al , wherein R al is an alkyl.
  • optionally substituted alkoxy refers to a radical of the formula -OR al , wherein R al is an optionally substituted alkyl.
  • cycloalkoxy as used by itself or as part of another group refers to a radical of the formula -OR al , wherein R al is a cycloalkyl.
  • optionally substituted cycloalkoxy refers to a radical of the formula -OR al , wherein R al is an optionally substituted cycloalkyl.
  • aryl as used by itself or as part of another group refers to a monocyclic, bicyclic or tricyclic aromatic ring system having from six to fourteen carbon atoms (i.e., C 6-i 4 aryl). In one embodiment, the aryl group is a C 6-i 2 aryl. In one
  • the aryl group is chosen from phenyl and naphthyl. In one embodiment, the aryl group is naphthyl.
  • heteroaryl refers to monocyclic, bicyclic or tricyclic aromatic ring systems having 5 to 14 ring atoms (i.e., a 5- to l4-membered heteroaryl) and 1, 2, 3, or 4 heteroatoms independently chosen from oxygen, nitrogen and sulfur.
  • the heteroaryl has three heteroatoms, e.g., three nitrogen atoms.
  • the heteroaryl has two heteroatoms, e.g., two nitrogen atoms, one nitrogen and one oxygen, or one nitrogen and one sulfur.
  • the heteroaryl has one heteroatom, e.g., one nitrogen.
  • the heteroaryl has 5 ring atoms, e.g., pyrazolyl.
  • the heteroaryl has 6 ring atoms, e.g., pyridyl.
  • Non-limiting exemplary heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofuranyl,
  • the heteroaryl is chosen from thienyl (e.g., thien-2-yl and thien-3-yl), furyl (e.g., 2-furyl and 3-furyl), pyrrolyl (e.g., lH-pyrrol-2-yl and lH-pyrrol-3-yl), imidazolyl (e.g., 2H-imidazol-2-yl and 2H-imidazol-4-yl), pyrazolyl (e.g., lH-pyrazol-3-yl, 1H- pyrazol- 4-yl, and lH-pyrazol-5-yl), pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, and pyridin- 4-yl), pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, and pyrimidin-5-yl), thiazo
  • the heteroaryl is a bicyclic heteroaryl having 8 to 10 ring atoms, e.g., a bicyclic heteroaryl having 1, 2, or 3 nitrogen ring atoms, such as quinolyl.
  • heteroaryl is also meant to include possible N-oxides.
  • heterocycle or “heterocyclyl” as used by itself or as part of another group refers to saturated and partially unsaturated (e.g., containing one or two double bonds) cyclic groups containing one, two, or three rings having from three to fourteen ring members (i.e., a 3- to l4-membered heterocycle) and at least one heteroatom.
  • Each heteroatom is independently selected from the group consisting of oxygen, sulfur, including sulfoxide and sulfone, and/or nitrogen atoms, which can be quatemized.
  • heterocyclyl is meant to include cyclic ureido groups such as imidazolidinyl-2-one, cyclic amide groups such as b-lactam, g-lactam, d-lactam and e-lactam, and cyclic carbamate groups such as oxazolidinyl-2-one.
  • the heterocyclyl group is a 4-, 5-, 6-, 7- or 8- membered cyclic group containing one ring and one or two oxygen and/or nitrogen atoms.
  • the heterocyclyl group is a 5- or 6-membered cyclic group containing one ring and one or two nitrogen atoms.
  • the heterocyclyl group is an 8-, 9-, 10-, 11-, or l2-membered cyclic group containing two rings and one or two nitrogen atoms.
  • the heterocyclyl can be optionally linked to the rest of the molecule through a carbon or nitrogen atom.
  • salt includes both internal salt and external salt.
  • the salt is an internal salt, i.e., a zwitterion structure.
  • the salt is an external salt.
  • the external salt is a pharmaceutically acceptable salt having a suitable counter ion. Suitable counterions for pharmaceutical use are known in the art.
  • the terms “treat,” “treating,” “treatment,” and the like refer to eliminating, reducing, or ameliorating a disease or condition, and/or symptoms associated therewith. Although not precluded, treating a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated.
  • the terms “treat,” “treating,” “treatment,” and the like may include “prophylactic treatment,” which refers to reducing the probability of redeveloping a disease or condition, or of a recurrence of a previously-controlled disease or condition, in a subject who does not have, but is at risk of or is susceptible to, redeveloping a disease or condition or a recurrence of the disease or condition.
  • the term “treat” and synonyms contemplate administering a therapeutically effective amount of a compound described herein to a subject in need of such treatment.
  • subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
  • embodiments can be isolated and purified where appropriate using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography. Characterization of these compounds can be performed using conventional methods such as by melting point, mass spectrum, nuclear magnetic resonance, and various other
  • Step 1 To a solution of 5-bromo-2-hydroxybenzyl alcohol (102 g, 0.5mol) and N-Boc-4- piperidone (140 g, 0.7mmol) in chloroform (700 mL) was added p-toluenesulphonic acid (10 g). The mixture was heated at reflux for 18 h, during which time condensate (5x 50 mL) was removed and replaced with equal volume of fresh dry chloroform. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (500 mL) and washed with a 2M sodium hydroxide solution (100 mL) and brine (300 mL).
  • Step 2 tert-butyl 6-bromo-rH,4H-spiro[l,3-benzodioxine-2,4'-piperidine]-r- carboxylate(38.4g, 0.1 mol) was mixed with MeOH(l50ml), Triethylamine(l5g, 0. l5mol) and Pd(PPh 3 ) 4 (l.0g) in an autoclave(lL), the autoclave was purged with CO three times, then filled with CO under lOOPsi and heated at 100 °C for 5h.
  • Step 3 To a solution of MeMgCl(l00ml, 3M)in THF at 0 °C was added dropwise a
  • Step 5 Og of the crude material A6 from step 4 was dissolved in MeOH(lOOml), 0.5g of Pd/C(5%) was added, and the mixture was charged with Hydrogen at 30Psi at room temperature. The reaction was done after 6 hr, as indicated by HPLC. After removal of the catalyst by filtration, the solution was evaporated under vacuum to give the desired product A7 (l5.0g as crude).
  • Step 6 Og of the crude material A7 from step 5 was dissolved in EtOAc(50ml) and then treated with 7N of a HCl-solution in EtOAc (50ml) at 0 °C. After stirring for 6 hr, the resulting suspension was filtered to collect the white solid as pure product A8 (10.5g as HC1 salt).
  • Step 7 Compound A8 can be treated with 1 eq. of R 3 COOH in the presence of DIEA (2.5 eq.) and HATU (1.1 eq.) in DMF (0.5 mL for 0.1 mmol of A8) at room temperature for 4 hr.
  • the reaction mixture was diluted with ethyl acetate and washed with 1N HC1, saturated NaHC03, and brine.
  • the crude product was purified by preparative TLC eluting with appropriate solvent to give the desired product A9.
  • Example 2
  • Example 2 was prepared according to the general procedure described in Example 1 using ethyl acetate as solvent in prepTLC.
  • 'HNMR (CDCb) d: 7.85 (br s, 1H); 7.80 (d, 1H); 7.51 (d, 1H); 7.46 (m, 1H); 7.22 (s, 1H); 7.11 (d, 1H); 6.98 (d, 1H); 4.12 (s, 3H); 4.05 (s, 3H); 3.9 (m, 4H); 2.94 (pent, 1H); 2.3 (br, 4H); 1.27 (d, 6H).
  • LC-MS 477.10 (M+H).
  • Example 3 was prepared according to the general procedure described in Example 1 using 1:20 ethyl acetate/dichloromethane as solvent in prepTLC. ⁇ NMR (CDCb) d: 7.91 (s,
  • Example 4 was prepared according to the general procedure described in Example 1 using 1: 10 methanol/ethyl acetate as solvent in prepTLC.
  • LC-MS 420.2 (M+H).
  • Example 5 was prepared according to the general procedure described in Example 1 using 1: 1 ethyl acetate/dichloromethane as solvent in prepTLC. LC-MS: 406.2 (M+H)
  • Example 6 was prepared according to the general procedure described in Example 1 using l;l ethyl acetate/dichloromethane as solvent in prepTLC.
  • Example 7 was prepared according to the general procedure described in Example 1 using 1: 1 ethyl acetate/dichloromethane as solvent in prepTLC.
  • 1 HNMR (CDCb) d: 9.58 (br s, 1H); 8.58 (m, 1H); 7.88 (s, 1H); 7.80 (d, 1H); 7.52 (d, 1H); 7.27 (m, 1H); 7.0 (m, 2H); 4.2- 4.0 (br, 4H); 2.98 (pent, 1H); 2.28 (br, 4H); 1.3 (d, 6H).
  • LC-MS 406.2 (M+H).
  • Example 8 was prepared according to the general procedure described in Example 1 using ethyl acetate as solvent in prepTLC.
  • Example 9 was prepared according to the general procedure described in Example 1 using 1:20 methanol/ethyl acetate as solvent in prepTLC.
  • 1 HNMR (CDCb) d: 7.84 (s, 1H); 7.7.63 (s, 1H); 7.55-7.45 (m, 3H); 7.28 (m, 2H); 6.98 (d, 1H); 3.8 (br, 4H); 2.98 (q, 2H); 2.997 (pent, 1H); 2.2 (br, 4H); 1.43 (t, 3H); 1.27 (d, 6H).
  • LC-MS 434 (M+H).
  • Example 10 was prepared according to the general procedure described in Example 1 using 1:20 methanol/ethyl acetate as solvent in prepTLC. 'HNMR (CDCT) d: 9.36 (s, 1H); 7.83 (s, 1H); 7.46 (d, 1H); 7.18-7.08 (m, 3H); 6.96 (d, 1H); 3.9-3.75 (br, 4H); 3.46 (s, 3H); 2.96 (pent, 1H); 2.2 (br, 4H); 1.28 (d, 6H). LC-MS: 436 (M+H).
  • Step 2 Starting material B1 (4.0g, lOmmol) was mixed with KOAc(6g), 0.2g of
  • Step 4 The boronic acid B3 (2.9 g, 7 mmole) was mixed with 5-amino-l-methyl-lH- pyrazole (l.2g), Cu(OAc) 2 (2.0g) and Triethylamine(4ml) in DCM(20ml) at room temperature and was stirred for 4h. Water was then added and the resulting mixture was extracted with EtOAc(2x30ml), the combined EtOAc solution was washed by 1N HCl(50ml) and dried over MgS0 4 . After evaporation of the solvent, the residue was purified through flash column chromatography to give the title compound B5 (0. lOg as solid).
  • 1 HNMR (CDC13) d: 7.48 (d, 1H); 7.28 (d, 1H); 6.96 (dd, 1H); 6.90 (d, 1H); 6.02 (d, 1H); 5.40 (s,
  • Step 4 Starting material B5 (obtained from step 4) was dissolved in EtOAc and then treated with 7N of HC1 solution in EtOAc at 0 °C. After 6h with stirring, the suspension was filtered to collect the white solid as HC1 salt B6.
  • Example 12 was prepared according to the general amide coupling procedure described in Example 1. Starting material 4H-spiro[benzo[d][l,3]dioxine-2,4'-piperidin]-4-one hydrochloride was prepared according to literature published procedure. Preparatory TLC using 1:20 MeOEPDCM as solvent provided r-(4,8-dimethoxyquinoline-2-carbonyl)-4H- spiro[benzo[d][l,3]dioxine-2,4'-piperidin]-4-one as a white powder. 1 HNMR (CDCb) d:
  • Example 13 was prepared in the same method as Example 12. Preparatory TLC using 1:3 ethyl acetate: hexane as solvent provide Example 3 (tert-butyl (3-(4-oxo-4H- spiro[benzo[d][l,3]dioxine-2,4'-piperidin]-r-ylcarbonyl)benzo[b]thiophen-2-yl)carbamate) as a white powder after lyophilization. 1 ElNMR.
  • Step 2 A solution of l'-(2-aminobenzo[b]thiophene-3-carbonyl)-4H- spiro[benzo[d][l,3]dioxine-2,4'-piperidin]-4-one hydrochloride (32 mg), DIEA (13 uL) in DCM (300 uL) was added to a solution of triphosgen (8 mg), DIEA (28 uL) in DCM (150 uL). After 30 min stirring at room temperature, a solution of EtNH2 HC1 (6 mg), DIEA (15 uL) in DCM (50 uL) and acetonitrile (60 uL) was added to the reaction mixture.
  • Human ACC enzymatic activity assays were performed by using purified human ACC1 and ACC2 proteins (BPS Bioscience). ACC1 and ACC2 proteins were diluted in 24.5 pL reaction buffer (50 mM HEPES pH 7.5, 10 mM MgCh, 2.0 mM DTT, 4.0 mM ATP, 15 mM 1 3 C-NaHC0 3 , 0.75 mg/mL BSA, 0.5 mM sodium citrate), and final concentrations of ACC1 and ACC2 were 0.4 pg/mL and 0.48 pg/mL.
  • reaction buffer 50 mM HEPES pH 7.5, 10 mM MgCh, 2.0 mM DTT, 4.0 mM ATP, 15 mM 1 3 C-NaHC0 3 , 0.75 mg/mL BSA, 0.5 mM sodium citrate
  • Examples 12-15 showed IC50 in the range of 0.1-10 uM in this assay.
  • Malonyl-CoA and malonyl- 13 C-CoA were monitored in positive ion mode following MRM transitions at 854.2/347.1 and 855.1/246.1, respectively.
  • the product and internal standard were coeluted to the mass spectrometer in 3 s with 50% LLO, 25% MeCN, 25% acetone, and 5 mM ammonium acetate.
  • Ion chromatograms were integrated using the Analyst 1.5.2 software. Peak area ratios were compared against a standard curve and final cellular concentration of malonyl-CoA or production rate of malonyl- 13 C-CoA was calculated as pmoles/mg protein per minute.
  • glucose 0.584 g/L L-glutamine (Sigma), 100 units/mL of penicillin and 100 pg/mL of streptomycin (Gibco), 10% fetal bovine serum (Gibco)) at 37°C in a humidified water jacketed incubator (Forma Scientific) supplemented with 5% CO2 till 100% confluency.
  • Examples 2 to 11 showed IC50 in the range of 0.01- 1 uM in this assay.
  • VectaMount (Vector Laboratories). Pictures were taken by using Zeiss Primo Star and Nikon D800.
  • ACC proteins are abundantly and specifically expressed in sebaceous glands. This represents the first report on the localization of ACC proteins in human skin structure and it suggests that delivering ACC inhibitors to sebocytes, such as by topical administration of ACC inhibitors, will specifically inhibit ACCs in sebaceous gland, thus provides a powerful method of suppressing lipid accumulation and progression of diseases related to overproduction of lipids in sebocytes.
  • ACC proteins are not abundantly expressed in keratinocytes of human normal skin.
  • FIG. 3 shows images of Immunohistochemical (IHC) staining of human in situ squamous cell carcinoma (indicated by arrows) with adjacent skin tissue including sebaceous gland.
  • IHC Immunohistochemical
  • FIG. 4 shows images of Immunohistochemical (IHC) staining of human seborrheic
  • keratosis and actinic keratosis As can be seen, keratin layer is apparent in this disease and keratinocytes next to the keratin layer are stained with dark color (indicated by arrows), indicating abundant expression of ACC proteins in keratinocytes in skin disease of keratosis.

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Abstract

La présente invention concerne des composés de benzodioxinone de formule I qui sont utiles en tant qu'inhibiteurs de ACC1 et/ou ACC2. Les composés de benzodioxinone selon la présente invention peuvent être utilisés pour traiter une maladie ou un trouble associé à des activités aberrantes de ACC1 et/ou ACC2, par exemple, la stéatohépatite non alcoolique (NASH), l'acné, l'obésité, le diabète et le cancer. L'invention concerne également des compositions pharmaceutiques qui comprennent le composé de benzodioxinone de formule I, ou un sel pharmaceutiquement acceptable de celui-ci.
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US11542256B2 (en) 2017-09-03 2023-01-03 Angion Biomedica Corp. Vinylheterocycles as Rho-associated coiled-coil kinase (ROCK) inhibitors

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