EP4185584A1 - Srebp inhibitors comprising a thiophene central ring - Google Patents

Srebp inhibitors comprising a thiophene central ring

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Publication number
EP4185584A1
EP4185584A1 EP21847228.0A EP21847228A EP4185584A1 EP 4185584 A1 EP4185584 A1 EP 4185584A1 EP 21847228 A EP21847228 A EP 21847228A EP 4185584 A1 EP4185584 A1 EP 4185584A1
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EP
European Patent Office
Prior art keywords
compound
pharmaceutically acceptable
solvate
isotope
isomer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP21847228.0A
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German (de)
French (fr)
Inventor
Michael John Green
Barry Patrick Hart
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Capulus Therapeutics LLC
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Capulus Therapeutics LLC
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Publication of EP4185584A1 publication Critical patent/EP4185584A1/en
Withdrawn legal-status Critical Current

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    • 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
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present disclosure relates to compounds comprising a three-ring core, their use for inhibiting components of the sterol regulatory element binding protein (SREBP) pathway, such as SREBP or SREBP cleavage activating protein (SCAP), and their use in therapeutic methods of treating conditions and disorders.
  • SREBP sterol regulatory element binding protein
  • SCAP SREBP cleavage activating protein
  • SREBPs are membrane-bound transcription factors that regulate cholesterol, fatty acid, and triglyceride biosynthesis, and lipid uptake.
  • Fatty acids and lipids are a source of energy and important components of many biological structures, such as lipid membranes of cells.
  • Cholesterol is an important component of biological processes and structures.
  • SREBP-la controls a broad range of target genes that are involved in the production of fatty acids, triglycerides, phospholipids, and cholesterol.
  • SREBP-lc primarily activates genes which control fatty acid and triglyceride synthesis.
  • SREBP-2 activates genes involved in the synthesis of regulators of cholesterol metabolism, which has been demonstrated in mouse, human, and Drosophila studies.
  • the activity of SREBPs is regulated by SREBP cleavage activating protein (SCAP), which transports SREBP(s) from the endoplasmic reticulum to the Golgi apparatus where the SREBP(s) are proteolytically cleaved, releasing the transcription factor domain.
  • SCAP SREBP cleavage activating protein
  • NASH nonalcoholic steatohepatitis
  • SREBP- lc is the major transcriptional regulator of the biosynthesis of fatty acids, and expression of this transcription factor can be stimulated by androgens and epidermal growth factor in prostate cancer cells. Overexpression of SREBP- lc may drive tumorgenicity and invasion of prostate cancer cells.
  • SREBP-2 itself is also regulated by androgens in a direct feedback circuit of androgen production.
  • prostate cancer cells have dysfunctional cholesterol homeostasis, resulting in accumulation of cholesterol and increased proliferation. This increase in cholesterol levels has been shown to be driven by regulated by increased SREBP-2 activity. SREBP-2 expression increases during disease progression, and is significantly higher after castration compared to prior.
  • Regulating components of the SREBP pathway is an important therapeutic approach for treating disorders, such as metabolic diseases and cancer.
  • disorders such as metabolic diseases and cancer.
  • compounds that can inhibit components of the SREBP pathway such as SREBPs and SCAP.
  • R 4 is hydrogen, unsubstituted alkyl, or unsubstituted cycloalkyl
  • Y is CH and Z is S, or Y is S and Z is CH;
  • R 1 is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, heterocycloalkyl, heterocycloalkyl-alkyl, or alkyl-heterocycloalkyl; wherein each alkyl, cycloalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, heterocycloalkyl, heterocycloalkyl-alkyl, or alkyl-heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -OH and fluoro;
  • R 2 is hydrogen, halo, or alkyl, wherein each alkyl is unsubstituted or substituted with fluorine;
  • R 3 is -NR 5 S(0) 2 R 6 , -NR 5 S(0) 2 NR 6 R 7 , -NR 5 C(0)0R 6 , or -C(0)NR 6 R 7 ;
  • R 5 , R 6 and R 7 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl, wherein each alkyl or cycloalkyl is unsubstituted or substituted with one with one or more substituents selected from the group consisting of -OH and fluorine; or R 6 and R 7 , together with the nitrogen atom to which they are attached, form a heterocycloalkyl, which is unsubstituted or substituted with one or more substituents selected from the group consisting of -OH and fluorine.
  • the compound of Formula (I) is a compound of Formula (I-A): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound of Formula (I) is a compound of Formula (I-A-i): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound of Formula (I) is a compound Formula (I-A-ii): -ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound of Formula (I) is a compound of Formula (I-A): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound of Formula (I) is a compound of Formula (I-B-i): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound of Formula (I) is a compound of Formula (I-B- ii): -ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound of Formula (I) is a compound of Formula (II): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound of Formula (I) is a compound of Formula (P-A): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound of Formula (I) is a compound of Formula (II-A- i): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound of Formula (I) is a compound of Formula (II-A- ii): -ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound of Formula (I) is a compound of Formula (P-B): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound of Formula (I) is a compound of Formula (II-B- i): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound of Formula (I) is a compound of Formula (II-B- ii): -ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient.
  • the compound of Formula (I) is a compound of Formula (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II- A), II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient.
  • a method of inhibiting a sterol regulatory element-binding protein comprising contacting the SREBP or contacting an SREBP cleavage activating-protein (SCAP) with the compound of Formula (I- A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • SREBP sterol regulatory element-binding protein
  • a method of inhibiting the proteolytic activation of a sterol regulatory element-binding protein comprising contacting an SREBP cleavage activating-protein (SCAP) with the compound of Formula (I-A), (I-A-i), (I-A- ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • SCAP SREBP cleavage activating-protein
  • SREBP sterol regulatory element-binding protein
  • a method of treating a disorder in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), II-A-i), (II-A-ii), (II-B), (II-B- i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • SREBP sterol regulatory element-binding protein
  • SREBP sterol regulatory element-binding protein
  • SREBP sterol regulatory element-binding protein
  • SREBP sterol regulatory element-binding protein
  • SREBP sterol regulatory element-binding protein
  • SREBP sterol regulatory element-binding protein
  • provided herein is the use of the compound of a compound of Formula (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), II-A-i), (II-A-ii), (II-B), (II-B- i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition thereof, for treating a disorder in a subject in need thereof.
  • NASH non-alcoholic steatohepatitis
  • a method of treating non-alcoholic steatohepatitis (NASH) in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition thereof,
  • NASH non-alcoholic steatohepatitis
  • NASH non-alcoholic steatohepatitis
  • NASH non alcoholic steatohepatitis
  • a method of treating a hyperproliferative disorder in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), II-A-i), (II- A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition thereof.
  • the present disclosure provides a compound of Formula (I): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein:
  • X is N or CR 4 ;
  • R 4 is hydrogen, unsubstituted alkyl, or unsubstituted cycloalkyl
  • Y is CH and Z is S, or Y is S and Z is CH;
  • R 1 is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, heterocycloalkyl, heterocycloalkyl-alkyl, or alkyl-heterocycloalkyl; wherein each alkyl, cycloalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, heterocycloalkyl, heterocycloalkyl-alkyl, or alkyl-heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -OH and fluoro;
  • R 2 is hydrogen, halo, or alkyl, wherein each alkyl is unsubstituted or substituted with one or more fluorine;
  • R 3 is -NR 5 S(0) 2 R 6 , -NR 5 S(0) 2 NR 6 R 7 , -NR 5 C(0)0R 6 , or -C(0)NR 6 R 7 ;
  • R 5 , R 6 and R 7 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl, wherein each alkyl or cycloalkyl is unsubstituted or substituted with one with one or more substituents selected from the group consisting of -OH and fluorine; or R 6 and R 7 , together with the nitrogen atom to which they are attached, form a heterocycloalkyl, which is unsubstituted or substituted with one or more substituents selected from the group consisting of -OH and fluorine.
  • the compound of Formula (I) is a compound of Formula (I-A): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound of Formula (I) or (I-A) is a compound of Formula (I-A-i): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound of Formula (I) or (I-A) is a compound of Formula (I-A-ii): -ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound of Formula (I) is a compound of Formula (I-B): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound of Formula (I) or Formula (I-B) is a compound of Formula (I-B-i): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound of Formula (I) or Formula (I-B) is a compound of Formula (I-B-ii): -ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound of Formula (I) is a compound of Formula (II): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound of Formula (I), (I-A), or (II) is a compound of Formula (II- A): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound of Formula (I), (I-A), (I-A-i), or (II) is a compound of Formula (II-A-i): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound of Formula (I), (I-A), (I-A-ii), or (II) is a compound of Formula (II-A-ii): -ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound of Formula (I), (I-A), or (II) is a compound of Formula (P-B): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound of Formula (I), (I-A), (I-B-i) or (II) is a compound of Formula (II-B-i): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound of Formula (I), (I-A), (I-B-ii), or (II) is a compound of Formula (II-B-ii): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof
  • Alkyl refers to an unbranched or branched saturated hydrocarbon chain. Alkyl can be used alone, or as part of another radical, such as cycloalkyl-alkyl. In some embodiments, alkyl as used herein has 1 to 50 carbon atoms ((Ci-5o)alkyl), 1 to 20 carbon atoms ((Ci-2o)alkyl), 1 to 12 carbon atoms ((Ci-i2)alkyl), 1 to 10 carbon atoms ((Ci-io)alkyl), 1 to 8 carbon atoms ((Ci-8)alkyl), 1 to 6 carbon atoms ((Ci- 6 )alkyl), 1 to 4 carbon atoms ((Ci-4)alkyl), or 1 to 3 carbon atoms ((Ci-3)alkyl).
  • alkyl as used herein has 2 to 6 carbon atoms ((C2-6)alkyl).
  • alkyl groups include methyl, ethyl, propyl, isopropyl, n- butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3- methyl pentyl.
  • alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons may be encompassed.
  • butyl can include n-butyl, sec-butyl, isobutyl and t-butyl
  • propyl can include n-propyl and isopropyl.
  • Cycloalkyl refers to a monocyclic or polycyclic saturated hydrocarbon.
  • cycloalkyl has 3 to 50 carbon atoms ((C3-5o)cycloalkyl), 3 to 20 carbon atoms ((C 3 -2o)cycloalkyl), 3 to 12 carbon atoms ((C 3 -i2)cycloalkyl), 3 to 10 carbon atoms ((C 3 -io)cycloalkyl), 3 to 8 carbon atoms ((C 3 -8)cycloalkyl), 3 to 6 carbon atoms ((C3- 6 )cycloalkyl), or 3 to 5 carbon atoms ((C3-4)cycloalkyl).
  • Cycloalkyl includes monocyclic and polycyclic groups, such as fused bicycles, bridged rings, and spirocycles.
  • Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, octahydropentalenyl, octahydro- l//-indene, decahydronaphthalene, cubane, bicyclo[3.1.0]hexane, and bicyclo[l.l.l]pentane.
  • Cycloalkyl-alkyl refers to a cycloalkyl group (as defined above) connected to an alkyl group (as defined above), wherein the alkyl group is attached to another moiety (such as the core structure of the molecule). Substituted cycloalkyl-alkyl can include one or more additional attachments to substituents at any point of the cycloalkyl or alkyl, as valency permits.
  • the cycloalkyl-alkyl may comprise any combination of cycloalkyl and alkyl groups.
  • the cycloalkyl has 3 to 50 carbon atoms ((C35o)cycloalkyl-alkyl), 3 to 20 carbon atoms ((C 3 -2o)cycloalkyl-alkyl), 3 to 12 carbon atoms ((C 3 -i2)cycloalkyl-alkyl), 3 to 10 carbon atoms ((C 3 -io)cycloalkyl-alkyl), 3 to 8 carbon atoms ((C 3 -8)cycloalkyl-alkyl), 3 to 6 carbon atoms ((C 3 - 6 )cycloalkyl-alkyl), or 3 to 5 carbon atoms ((C 3 -4)cycloalkyl-alkyl).
  • the alkyl has 1 to 50 carbon atoms (cycloalkyl-(Ci-5o)alkyl), 1 to 20 carbon atoms (cycloalkyl-(Ci-2o)alkyl), 1 to 12 carbon atoms (cycloalkyl-(Ci-i2)alkyl), 1 to 10 carbon atoms (cycloalkyl-(Ci-io)alkyl), 1 to 8 carbon atoms (cycloalkyl-(Ci-8)alkyl), 1 to 6 carbon atoms (cycloalkyl-(Ci- 6 )alkyl), or 1 to 4 carbon atoms (cycloalkyl-(Ci-4)alkyl).
  • the cycloalkyl-alkyl is a (C 3 -2o)cycloalkyl(Cl-2o)alkyl, (C 3 -i2)cycloalkyl(Ci- i2)alkyl, (C 3 -io)cycloalkyl(Ci-io)alkyl, (C 3 -io)cycloalkyl(Ci-8)alkyl, (C 3 -io)cycloalkyl(Ci- 6 )alkyl, (C 3 - 6 )cycloalkyl(Ci-8)alkyl, (C 3 - 6 )cycloalkyl(Ci- 6 )alkyl, or (C 3 - 6 )cycloalkyl(Ci-4)alkyl.
  • Alkyl-cycloalkyl refers to an alkyl group (as defined above) connected to a cycloalkyl group (as defind above), wherein the cycloalkyl group is attached to another moiety (such as the core structure of the molecule). Substituted alkyl-cycloalkyl can include one or more additional attachments to substituents at any point of the alkyl or cycloalkyl, as valency permite.
  • the alkyl-cycloalkyl may comprise any combination of alkyl and cycloalkyl groups.
  • the cycloalkyl has 3 to 50 carbon atoms ((C 3 -C5o)alkyl-cycloalkyl), 3 to 20 carbon atoms ((C3-C20) alkyl-cycloalkyl), 3 to 12 carbon atoms ((C3-C12) alkyl-cycloalkyl), 3 to 10 carbon atoms ((C3-C10) alkyl-cycloalkyl), 3 to 8 carbon atoms ((C3-C8) alkyl-cycloalkyl), 3 to
  • the alkyl has 1 to 50 carbon atoms ((Ci-C5o)alkyl-cycloalkyl), 1 to 20 carbon atoms ((Ci-C2o)alkyl-cycloalkyl), 1 to 12 carbon atoms ((Ci-Ci2)alkyl cycloalkyl), 1 to 10 carbon atoms ((Ci-Cio)alkyl cycloalkyl), 1 to 8 carbon atoms ((Ci-C8)alkyl-cycloalkyl), 1 to 6 carbon atoms ((Ci-C6)alkyl-cycloalkyl), or 1 to 4 carbon atoms ((Ci-C4)alkyl-cycloalkyl).
  • the cycloalkyl-alkyl is a (Cl-C2o)alkyl(C3-C2o)cycloalkyl, (Ci- Ci2)alkyl(C3-i2)cycloalkyl, (Ci-Cio)alkyl(C3-Cio)cycloalkyl, (Ci-C8)alkyl(C3-Cio)cycloalkyl, (Ci-C6)alkyl(C3-Cio)cycloalkyl, (Ci-C8)alkyl(C3-C6)cycloalkyl, (Ci-C6)alkyl(C3-C6)cycloalkyl, or (Ci-C4)alkyl(C3-C6)cycloalkyl.
  • Heterocycloalkyl refers to a saturated monocyclic or polycyclic ring containing carbon and at least one heteroatom selected from the group consisting of O, N, and S.
  • the heterocycloalkyl group may comprise 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more ring atoms ( e.g ., be a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9- membered, 10-membered, 11-membered, or 12-membered heterocycloalkyl).
  • Heterocycloalkyl may include groups comprising 1 to 5 ring heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 or 2 ring heteroatoms, or 1 ring heteroatom, wherein each heteroatom is independently selected from the group consisting of N, O, and S.
  • Each ring S atom where present, may independently be unoxidized sulfur (e.g., -S-) or a sulfur oxide, such as -S(O)-, or - S(0)2-.
  • a heterocycloalkyl has 2 to 8 ring carbon atoms and with 1 to 3 ring heteroatoms independently selected from N, O, and S.
  • heterocycloalkyl is connected through an annular carbon atom, wherein the point of attachment of the heterocycloalkyl to another group is a ring carbon atom of the heterocycloalkyl.
  • Heterocycloalkyl includes polycyclic systems, such as bridged, fused, and spirocycles comprising at least one heteroatom in at least one of the rings.
  • heterocycloalkyl include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S- oxide, thiomorpholinyl S-di oxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, and tropanyl.
  • Heterocycloalkyl-alkyl refers to a heterocycloalkyl group (as defined above) connected to an alkyl group (as defined above), wherein the alkyl group is attached to another moiety (such as the core structure of the molecule).
  • the alkyl group may be attached to the heterocycloalkyl through an annular carbon atom of the heterocycloalkyl, or through an annular heteroatom of the heterocycloalkyl (such as through a ring N atom).
  • Substituted heterocycloalkyl-alkyl can include one or more additional attachments to substituents at any point of the heterocycloalkyl or alkyl, as valency permits.
  • the heterocycloalkyl-alkyl may comprise any combination of heterocycloalkyl and alkyl groups.
  • the heterocycloalkyl comprises 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more ring atoms.
  • the heterocycloalkyl may include groups comprising 1 to 5 ring heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 or 2 ring heteroatoms, or 1 ring heteroatom, wherein each heteroatom is independently selected from the group consisting of N, O, and S.
  • the alkyl has 1 to 50 carbon atoms (heterocycloalkyl-(Ci-5o)alkyl), 1 to 20 carbon atoms (heterocycloalkyl-(Ci-2o)alkyl), 1 to 12 carbon atoms (heterocycloalkyl-(Ci-i2)alkyl), 1 to 10 carbon atoms (heterocycloalkyl-(Ci-io)alkyl), 1 to 8 carbon atoms (heterocycloalkyl-(Ci-8)alkyl), 1 to 6 carbon atoms (heterocycloalkyl-(Ci- 6 )alkyl), or 1 to 4 carbon atoms (heterocycloalkyl-(Ci- 4)alkyl).
  • the heterocycloalkyl-alkyl is a (3-20 membered)heterocycloalkyl(Ci-2o)alkyl, (3-12 membered)heterocycloalkyl(Ci-i2)alkyl, (3-12 membered)heterocycloalkyl(Ci-io)alkyl, (3-10 membered)heterocycloalkyl(Ci-8)alkyl, (3-10 membered)heterocycloalkyl(Ci- 6 )alkyl, (3-6 membered)heterocycloalkyl(Ci-8)alkyl, (3-6 membered)heterocycloalkyl(Ci- 6 )alkyl, or (3-6 membered)heterocycloalkyl(Ci-4)alkyl.
  • Alkyl-heterocycloalkyl refers to an alkyl group (as defined above) connected to a heterocycloalkyl group (as defind above), wherein the heterocycloalkyl group is attached to another moiety (such as the core structure of the molecule). Substituted alkyl-heterocycloalkyl can include one or more additional attachments to substituents at any point of the alkyl or heterocycloalkyl, as valency permite.
  • the alkyl-heterocycloalkyl may comprise any combination of alkyl and heterocycloalkyl groups.
  • the heterocycloalkyl has 3 to 50 carbon atoms ((C3-C5o)alkyl-heterocycloalkyl), 3 to 20 carbon atoms ((C3-C20) alkyl- heterocycloalkyl), 3 to 12 carbon atoms ((C3-C12) alkyl-heterocycloalkyl), 3 to 10 carbon atoms ((C3-C10) alkyl-heterocycloalkyl), 3 to 8 carbon atoms ((C3-C8) alkyl-heterocycloalkyl), 3 to 6 carbon atoms ((C3-C6) alkyl-heterocycloalkyl), or 3 to 5 carbon atoms ((C3-C4) alkyl- heterocycloalkyl).
  • the alkyl has 1 to 50 carbon atoms ((Ci-C5o)alkyl- heterocycloalkyl), 1 to 20 carbon atoms ((Ci-C2o)alkyl-heterocycloalkyl), 1 to 12 carbon atoms ((Ci-Ci2)alkyl heterocycloalkyl), 1 to 10 carbon atoms ((Ci-Cio)alkyl heterocycloalkyl), 1 to 8 carbon atoms ((Ci-C8)alkyl-heterocycloalkyl), 1 to 6 carbon atoms ((Ci-Ce)alkyl- heterocycloalkyl), or 1 to 4 carbon atoms ((Ci-C4)alkyl-heterocycloalkyl).
  • the heterocycloalkyl-alkyl is a (Cl-C2o)alkyl(C3-C2o)heterocycloalkyl, (Ci- Ci2)alkyl(C 3 -i2)heterocycloalkyl, (Ci-Cio)alkyl(C 3 -Cio)heterocycloalkyl, (Ci-C8)alkyl(C 3 - Cio)heterocycloalkyl, (Ci-C 6 )alkyl(C 3 -Cio)heterocycloalkyl, (Ci-C8)alkyl(C 3 - C 6 )heterocycloalkyl, (Ci-C 6 )alkyl(C 3 -C 6 )heterocycloalkyl, or (Ci-C4)alkyl(C 3 - C 6 )heterocycloalkyl.
  • (Ci- 6 )alkyl (which may also be referred to as C1-C6 alkyl, C1-C 6 alkyl, or Cl -6 alkyl) is intended to encompass Ci, C2, C 3 , C4, C5, Ce, C l -6, C l -5, C l -4, C l -3, C l -2, C2- 6 , C2-5, C2-4, C2-3, C 3 - 6 , C3-5, C3-4, C4- 6 , C4-5, and C5- 6 alkyl.
  • Halo refers to fluoro, chloro, bromo, or iodo radicals.
  • the disclosure includes isomers, also referred to as, stereoisomers, of the compounds described herein.
  • isomers refers to a set of compounds that have the same number and type of atoms, and the same bond connectivity between those atoms, but different three- dimensional structures.
  • the term “isomer” may refer to any member of this set of compounds.
  • isomers may be mirror images that are related by a reflection operation (enantiomers) or non-mirror images that are not related through a reflection operation (diastereomers).
  • the compounds of the present disclosure may occur as mixtures of enantiomers, mixtures of diastereomers, or as individual enantiomers or diastereomers. Mixtures of enantiomers may be racemic mixtures that contain different enantiomers in equal amounts.
  • the solvate is a hydrate.
  • “Pharmaceutically acceptable” includes that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and not biologically or otherwise undesirable, and includes that which is acceptable for veterinary use as well as human pharmaceutical use.
  • a pharmaceutical composition comprising a compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), II-A-i), (II- A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient.
  • “Pharmaceutically acceptable salt” includes a salt which is generally safe, non-toxic and not biologically or otherwise undesirable, and includes that which is acceptable for veterinary use as well as human pharmaceutical use. Such salts may include acid addition salts and base addition salts.
  • Acid addition salts may be formed with inorganic acid such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or an organic acid such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4- acetamidobenzoic acid, camphoric acid, camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluc
  • Salts derived from inorganic bases may include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts.
  • Salts derived from organic bases may include, but are not limited to, salts of primary, secondary, or tertiary amines; substituted amines including naturally occurring substituted amines; cyclic amines; ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine,
  • structures depicted herein such as compounds of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-ii), (II-B), (II-B-i), or (II- B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, or isomer thereof, are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • the compounds herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compound is isotopically-labeled, such as an isotopically-labeled compound of Formula (I), (I-A), (I-A-i), (I- A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, or isomer thereof, where a fraction of one or more atoms are replaced by an isotope of the same element.
  • Exemplary isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine, such as 2 H, 3 H, U C, 13 C, 14 C 13 N, 15 0, 17 0, 35 S, 18 F, 36 C1.
  • Certain isotope labeled compounds e.g. 3 H and 14 C
  • Incorporation of heavier isotopes such as deuterium ( 2 H) may, in some embodiments, afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, or reduced dosage requirements.
  • the compounds disclosed herein such as compounds of Formula (I), (I-A), (I-A-i), (I- A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, or isotope thereof, may contain one or more asymmetric centers and thus may give rise to one or more isomers.
  • the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or isotope thereof, wherein:
  • X is N or CR 4 ;
  • R 4 is hydrogen, unsubstituted alkyl, or unsubstituted cycloalkyl
  • Y is CH and Z is S, or Y is S and Z is CH;
  • R 1 is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, heterocycloalkyl, heterocycloalkyl-alkyl, or alkyl-heterocycloalkyl; wherein each alkyl, cycloalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, heterocycloalkyl, heterocycloalkyl-alkyl, or alkyl-heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -OH and fluoro;
  • R 2 is hydrogen, halo, or alkyl, wherein each alkyl is unsubstituted or substituted with fluorine;
  • R 3 is -NR 5 S(0) 2 R 6 , -NR 5 S(0) 2 NR 6 R 7 , -NR 5 C(0)0R 6 , or -C(0)NR 6 R 7 ;
  • R 5 , R 6 and R 7 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl, wherein each alkyl or cycloalkyl is unsubstituted or substituted with one with one or more substituents selected from the group consisting of -OH and fluorine; or R 6 and R 7 , together with the nitrogen atom to which they are attached, form a heterocycloalkyl, which is unsubstituted or substituted with one or more substituents selected from the group consisting of -OH and fluorine.
  • the present disclosure provides a compound of Formula (I), (I- A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, or isotope thereof, wherein:
  • X is N or CR 4 ;
  • R 4 is hydrogen, unsubstituted alkyl, or unsubstituted cycloalkyl
  • Y is CH and Z is S, or Y is S and Z is CH;
  • R 1 is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, heterocycloalkyl, heterocycloalkyl-alkyl, or alkyl-heterocycloalkyl; wherein each alkyl, cycloalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, heterocycloalkyl, heterocycloalkyl-alkyl, or alkyl-heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -OH and fluoro;
  • R 2 is hydrogen, halo, or alkyl, wherein each alkyl is unsubstituted or substituted with fluorine;
  • R 3 is -NR 5 S(0) 2 R 6 , -NR 5 S(0) 2 NR 6 R 7 , -NR 5 C(0)0R 6 , or -C(0)NR 6 R 7 ;
  • R 5 , R 6 and R 7 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl, wherein each alkyl or cycloalkyl is unsubstituted or substituted with one with one or more substituents selected from the group consisting of -OH and fluorine; or R 6 and R 7 , together with the nitrogen atom to which they are attached, form a heterocycloalkyl, which is unsubstituted or substituted with one or more substituents selected from the group consisting of -OH and fluorine.
  • R 1 is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, heterocycloalkyl, heterocycloalkyl-alkyl, or alkyl- heterocycloalkyl.
  • R 1 is hydrogen. In certain embodiments, R 1 is alkyl. In certain embodiments, R 1 is cycloalkyl. In certain embodiments, R 1 is cycloalkyl-alkyl. In certain embodiments, R 1 is alkyl-cycloalkyl. In certain embodiments, R 1 is heterocycloalkyl. In certain embodiments, R 1 is heterocycloalkyl-alkyl. In certain embodiments, R 1 is alkyl- heterocycloalkyl.
  • R 1 is unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted cycloalkyl-alkyl, unsubstituted alkyl-cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted heterocycloalkyl-alkyl, or unsubstituted alkyl-heterocycloalkyl.
  • each alkyl, cycloalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, heterocycloalkyl, heterocycloalkyl-alkyl, or alkyl-heterocycloalkyl of R 1 is substituted with one or more substituents independently selected from the group consisting of -OH and fluoro.
  • each alkyl, cycloalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, heterocycloalkyl, heterocycloalkyl-alkyl, or alkyl-heterocycloalkyl of R 1 is substituted with one or more -OH.
  • each alkyl, cycloalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, heterocycloalkyl, heterocycloalkyl-alkyl, or alkyl-heterocycloalkyl of R 1 is substituted with one or more -fluoro.
  • each alkyl, cycloalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, heterocycloalkyl, heterocycloalkyl-alkyl, or alkyl-heterocycloalkyl of R 1 is substituted with one or more -OH and one or more fluoro.
  • R 1 is (Ci-C5)alkyl. In certain embodiments, R 1 is methyl. In certain embodiments, R 1 is ethyl. In certain embodiments, R 1 is propyl.
  • R 1 is butyl. In some embodiments, R 1 is (C3-C6)cycloalkyl. In certain embodiments, R 1 is cyclopropyl. In certain embodiments, R 1 is cyclobutyl. In some embodiments, R 1 is (C3-C6)heterocycloalkyl. In some embodiments, R 1 is (C5)heterocycloalkyl. In some embodiments, R 1 is a (Ci-Cs)alkyl substituted with one or more -OH. In certain embodiments, R 1 is a (Ci-C5)alkyl substituted with one -OH. In certain embodiments, R 1 is a (Ci-C5)alkyl substituted with two -OH. In some embodiments, R 1 is (C4-C7)alkyl-cycloalkyl.
  • R 1 is (C4-C7)alkyl-cycloalkyl substituted with one or more -OH.
  • R 1 is (C4-C7)alkyl-cycloalkyl substituted with one -OH.
  • R 1 is:
  • R 2 is hydrogen, halo, or alkyl. In certain embodiments, R 2 is hydrogen. In certain embodiments, R 2 is halo. In certain embodiments, R 2 is alkyl. In some embodiments, R 2 is chloro.
  • the alkyl of R 2 is unsubstituted or substituted with fluorine. In certain embodiments, the alkyl of R 2 is unsubstituted. In some embodiments, the alkyl of R 2 is unsubstituted or substituted with 1-3 fluorine. In some embodiments, the alkyl of R 2 is unsubstituted or substituted with 1 fluorine. In some embodiments, the alkyl of R 2 is unsubstituted or substituted with 2 fluorines. In some embodiments, the alkyl of R 2 is unsubstituted or substituted with 3 fluorines.
  • R 3 is -NR 5 S(0)2R 6 , - NR 5 S(0) 2 NR 6 R 7 , -NR 5 C(0)0R 6 , or -C(0)NR 6 R 7 . In some embodiments, R 3 is -NR 5 S(0) 2 R 6 .
  • R 3 -NR 5 S(0) 2 NR 6 R 7 . In some embodiments, R 3 is -NR 5 C(0)0R 6 . In some embodiments, R 3 is -C(0)NR 6 R 7 .
  • R 5 , R 6 and R 7 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl.
  • R 3 is -NR 5 S(0) 2 R 6 , R 5 is hydrogen, and R 6 is alkyl.
  • R 3 is -NR 5 S(0) 2 R 6 , R 5 is hydrogen, and R 6 is methyl.
  • R 3 is — NR 5 S(0) 2 NR 6 R 7 , R 5 is hydrogen, R 6 is hydrogen, and R 7 is alkyl.
  • R 3 is — NR 5 S(0) 2 NR 6 R 7 , R 5 is hydrogen, R 6 is hydrogen, and R 7 is (C3)alkyl.
  • R 3 is — NR 5 S(0) 2 NR 6 R 7 , R 5 is hydrogen, R 6 is hydrogen, and R 7 is isopropyl.
  • R 3 is -NR 5 C(0)0R 6 , R 5 is hydrogen, and R 6 is cycloalkyl.
  • R 3 is -NR 5 C(0)0R 6 , R 5 is hydrogen, and R 6 is cyclopropyl.
  • the alkyl or cycloalkyl of R 5 , R 6 , or R 7 is unsubstituted.
  • the alkyl or cycloalkyl of R 5 , R 6 , or R 7 is substituted with one or more substituents selected from the group consisting of -OH and fluorine. In certain embodiments, the alkyl or cycloalkyl of R 5 , R 6 , or R 7 is substituted with one or more -OH. In certain embodiments, the alkyl or cycloalkyl of R 5 , R 6 , or R 7 is substituted with one or more fluorine. In certain embodiments, the alkyl or cycloalkyl of R 5 , R 6 , or R 7 is substituted with one or more -OH and one or more fluorine.
  • R 6 and R 7 together with the nitrogen atom to which they are attached, form a heterocycloalkyl.
  • R 6 and R 7 together with the nitrogen atom to which they are attached, form a (C 6 )heterocycloalkyl.
  • the heterocycloalkyl formed by R 6 and R 7 together with the nitrogen atom to which they are attached, is unsubstituted.
  • the heterocycloalkyl formed by R 6 and R 7 , together with the nitrogen atom to which they are attached is substituted with one or more substituents selected from the group consisting of -OH and fluorine.
  • the heterocycloalkyl formed by R 6 and R 7 , together with the nitrogen atom to which they are attached, is substituted with one or more -OH. In certain embodiments, the heterocycloalkyl formed by R 6 and R 7 , together with the nitrogen atom to which they are attached, is substituted with one or more fluorine. In certain embodiments, the heterocycloalkyl formed by R 6 and R 7 , together with the nitrogen atom to which they are attached is substituted with one or more -OH and one or more fluorine.
  • R 3 is -C(0)NR 6 R 7 , and R 6 and R 7 , together with the nitrogen atom to which they are attached, form a heterocycloalkyl.
  • R 3 is - C(0)NR 6 R 7 , and R 6 and R 7 , together with the nitrogen atom to which they are attached, form an unsubstituted heterocycloalkyl.
  • R 3 is -C(0)NR 6 R 7 , and R 6 and R 7 , together with the nitrogen atom to which they are attached, form a heterocycloalkyl substituted with with one or more substituents selected from the group consisting of -OH and fluorine.
  • R 3 is
  • R 3 is -C(0)NR 6 R 7 , and R 6 and R 7 , together with the nitrogen atom to which they are attached, form a heterocycloalkyl substituted with with one or more -OH.
  • R 3 is -C(0)NR 6 R 7 , and R 6 and R 7 , together with the nitrogen atom to which they are attached, form a heterocycloalkyl substituted with with one or more fluorine.
  • R 3 is -C(0)NR 6 R 7 , and R 6 and R 7 , together with the nitrogen atom to which they are attached, form a heterocycloalkyl substituted with with one or more -OH and one or more fluorine.
  • R 3 is -C(0)NR 6 R 7 , and R 6 and R 7 , together with the nitrogen atom to which they are attached, form a (C6)heterocycloalkyl. In some emodiments, R 3 is -C(0)NR 6 R 7 , and R 6 and R 7 , together with the nitrogen atom to which they are attached, form a (C6)heterocycloalkyl. In some emodiments, R 3 is -C(0)NR 6 R 7 , and R 6 and R 7 , together with the nitrogen atom to which they are attached, form a (C6)heterocycloalkyl substituted with -OH.
  • R 3 is:
  • X is N.
  • X is N.
  • X is CR 4 .
  • X is CR 4 .
  • X is CR 4 .
  • R 4 is hydrogen, unsubstituted alkyl, or unsubstituted cycloalkyl. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is unsubstituted alkyl. In some embodiments, R 4 is unsubstituted cycloalkyl.
  • R 4 is unsubstituted (Ci- C4)alkyl. In certain embodiments, R 4 is propyl. [0090] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, Y is CH and Z is S. In some embodiments of the compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (II), (II-A), (II-A-i), (II-A- ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, Y is CH and Z is S.
  • Y is S and Z is CH.
  • Y is S and Z is CH.
  • B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii) is: acceptable salt, solvate, tautomer, isotope, or isomer of any of the foregoing.
  • compositions comprising any of the compounds disclosed herein, such as a compound of (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient.
  • the compounds disclosed herein such as a compound of (I), (I-A), (I-A-i), (I-A-ii), (I- B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, may be prepared, for example, through the reaction route depticted in General Reaction Scheme I.
  • General Reaction Scheme I provides two routes to compound 1-5, which can be a compound of Formula (I), or an intermediate to compounds of Formula (I), (I-A), (I-A-i), (I-A- ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-B), (II-B-i), or (II-B-ii).
  • a compound 1-1 can be coupled to a compound 1-2, or a compound 1-3 can be coupled to a compound 1-4, using palladium catalysis.
  • Suitable palladium catalysts may include, for example, tetrakis(triphenylphosphine)palladium(0).
  • Suitable bases may include, for example, aqueous sodium carbonate or potassium carbonate.
  • the steps depicted in General Reaction Scheme I may further include a solvent, for example, dioxane, tetrahydrofuran, or dimethoxyethane. In some embodiments, the reactions are carried out between about 25°C to 120°C, for between about 8 h to 24 h.
  • the reactants, solvents, coupling agents, catalysts, and other compounds used to prepare compounds of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, by following General Reaction Scheme I, or by another route, may be commercially available or may be prepared following organic chemical techniques.
  • kits for using the compounds disclosed herein such as compounds of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II- A-ii), (P-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient.
  • these include methods of inhibiting a component of the SREBP pathway, such as an SREBP or SCAP; and methods of treating a disorder in a subject in need thereof.
  • the disorder is mediated by an SREBP or SCAP.
  • treat refers to any indicia of success in the amelioration of a disorder (such as injury, disease pathology, or condition), including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the disorder more tolerable to the subject; slowing or stopping the rate of degeneration, decline, or development; slowing the progression of disorder; making the final point of degeneration less debilitating; improving a subject’s physical or mental well-being; or relieving or causing regression of the disorder.
  • a disorder such as injury, disease pathology, or condition
  • any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the disorder more tolerable to the subject; slowing or stopping the rate of degeneration, decline, or development; slowing the progression of disorder; making the final point of degeneration less debilitating; improving a subject’s physical or mental well-being; or relieving or causing regression of the disorder.
  • the treatment of symptoms can be based on objective or subjective parameters, which may include the results of a physical examination, a neuropsychiatric exam, and/or a psychiatric evaluation.
  • Certain methods and uses disclosed herein may treat cancer by, for example, decreasing the incidence of cancer, causing remission of cancer, slowing the rate of growth of cancer cells, slowing the rate of spread of cancer cells, reducing metastasis, or reducing the growth of metastatic tumors, reducing the size of one or more tumors, reducing the number of one or more tumors, or any combinations thereof.
  • a component of the SREBP pathway such as an SREBP or SCAP.
  • a combination of an SREBP and SCAP is inhibited.
  • Such methods may include contacting an SREBP with a compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition comprising any of the forgoing and a pharmaceutically acceptable excipient.
  • Such uses and methods may also include contacting SCAP with a compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II- A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition comprising any of the forgoing and a pharmaceutically acceptable excipient.
  • a compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B- i), (I-B-ii), (II), (II-A), (II-A-i), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof is administered to a subject in need thereof to inhibit a component of the SREBP pathway.
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, is administered to the subject in need thereof.
  • the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof is administered as a pharmaceutical composition, as described herein.
  • the component of the SREBP pathway that is inhibited by the methods and uses described herein may be an SREBP or SCAP. In some embodiments, an SREBP is inhibited.
  • the SREBP may be, for example, an SREBP-1 (such as SREBP-la or SREBP-lc) or SREBP-2. In certain variations, two or three of SREBP-la, SREBP-lc, and SREBP-2 are inhibited.
  • the component is an SREBP-1. In other embodiments, the SREBP is SREBP-la. In certain embodiments, the component is SREBP-lc. In still other embodiments, the SREBP is SREBP-2. In other embodiments, the component of the SREBP pathway is SCAP. In some embodiments, both an SREBP and SCAP are inhibited. In certain embodiments, two or three of SREBP-la, SREBP-lc, and SREBP-2 are inhibited, and SCAP is inhibited.
  • Inhibition of a component of the SREBP pathway may include partial inhibition or full inhibition. Partial inhibition may include reducing the activity of a component of the SREBP pathway to a level that is still detectable. Full inhibition may include stopping all activity of a component of the SREBP pathway (such as stopping the activity of an SREBP or SCAP), or reducing the activity of a component of the SREBP pathway to a level below detection. Inhibition of a component of the SREBP pathway may be measured directly or indirectly, using any methods known in the art.
  • inhibition of a component of the SREBP pathway is measured directly, for example by measuring the product of a reaction catalyzed by an SREBP pathway component.
  • Inhibition of SREBP activation may in some embodiments be demonstrated by western blotting and quantitatively assessing the levels of full- length and cleaved SREBP-1 and/or SREBP-2 proteins from a cell line (such as a hepatic cell lines) or primary cells (such as primary hepatocytes of mouse, rat or human origin).
  • inhibition of a component of the SREBP pathway is measured indirectly, for example by measuring the level of expression of one or more genes that are regulated by SREBP.
  • the inhibition of a component of the SREBP pathway such as an SREBP or SCAP, may reduce the expression of one or more genes that are regulated by an SREBP, for example an SREBP-1 (such as SREBP-la or SREBP-lc) or SREBP-2.
  • SCAP plays a role in activating SREBPs, thus inhibiting the activity of SCAP may reduce the expression of one or more genes that are regulated by an SREBP.
  • SREBP pathway inhibition may also be determined by assessing gene transcription levels of one or more target genes of SREBP-1 and/or SREBP-2, such as one or more of ACSS2, ALDOC, CYP51A1, DHCR7, ELOVL6, FASN, FDFT1, FDPS, HMGCS1, HSD17B7, IDI1, INSIG1, LDLR, LSS, ME1, PCSK9, PMVK, RDHll, SC5DL, SQLE, STARD4, TM7SF2, PNPLA3, SREBFl, SREBF2, HMGCR, MVD, MVK, ACLY, MSMOl, ACACA, or ACACB.
  • the transcription levels may be assessed, for example, by transcriptomic analysis, including but not limited to q-PCR.
  • a reduction in one, two, three, four, five, or more of these genes may indicate inhibition of SREBP activation.
  • This evaluation of endogenous SREBP gene expression may be assessed in cell lines (such as hepatic cell lines) or primary cells (such as primary hepatocytes of mouse, rat, or human origin).
  • the gene transcription levels of PCSK9 or PNPLA3, or a combination thereof are evaluated.
  • the expression of PCSK9 is reduced. In other embodiments, the expression of PNPLA3 is reduced. In still further embodiments, both the expression of PCSK9 and PNPLA3 are reduced.
  • one or more SREBP is contacted, for example an SREBP-1 (such as SREBP- la or SREBP- lc) or SREBP-2, or any combinations thereof.
  • SCAP is contacted. In still further embodiments, one or more of SREBP-la, SREBP-lc, SREBP-2, and SCAP is contacted. In certain embodiments, inhibition of a component of the SREBP pathway may treat a disorder mediated by an SREBP, such as the disorders as described herein. Thus, in certain embodiments, expression of one or more genes as described above is reduced in a subject in need thereof.
  • Another method of indirectly detecting SREBP pathway inhibition may include:
  • the cells may then be treated with a compound, such as a compound of Formula (I), (I- A), (I-A-i), (I-A-ii), (I-B), (I- B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • a reduction of luciferase activity reflects inhibition of SREBP activation, and non-cytotoxicity of the compound can be assessed by LDH release.
  • a disorder in a subject in need thereof comprising administering to the subject in need thereof a compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • provided herein are uses and methods of treating a disorder in a subject in need thereof, comprising administering to the subject in need thereof a pharmaceutical composition comprising a compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I- B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising a compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I- B), (I-B-i), (I-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically
  • the compound is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound is a compound of Formula (I-A), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound is a compound of Formula (I-A-i), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound is a compound of Formula (I-A-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound is a compound of Formula (I-B), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound is a compound of Formula (I-B-i), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound is a compound of Formula (I-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound is a compound of Formula (P-A), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound is a compound of Formula (II-A-i), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound is a compound of Formula (II-A-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound is a compound of Formula (P-B), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the compound is a compound of Formula (II-B-i), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In some embodiments, the compound is a compound of Formula (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • the uses and methods of treatment describe herein may use a compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising a compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I- B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof;
  • the disorder is a metabolic disorder, such as a disorder that affects lipid metabolism, cholesterol metabolism, or insulin metabolism.
  • the disorder is related to lipid metabolism, cholesterol metabolism, or insulin metabolism, for example, liver disease as a result of the buildup of fat in the liver, or cardiovascular disease.
  • the disorder is a liver disease, such as chronic liver disease.
  • the liver disease is mediated by a component of the SREBP pathway, such as an SREBP or SCAP.
  • the liver disease is mediated by an SREBP.
  • the liver disease is mediated by a downstream gene target of an SREBP, such as PNPLA-3.
  • the liver disease is mediated by SCAP.
  • a liver disease in a subject in need thereof comprising administering to the subject in need thereof a compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient.
  • the chronic liver disease may be, for example, primary alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), or nonalcoholic steatohepatitis (NASH).
  • the liver disease is liver fat, liver inflammation, or liver fibrosis, or a combination thereof.
  • the liver disease is non-alcoholic fatty liver disease (NAFLD).
  • NAFLD is a group of conditions that are related to fat buildup in the liver.
  • NASH Non-alcoholic steatohepatitis
  • the liver inflammation may lead to liver damage and scarring, which can be irreversible, and it can also progress to cirrhosis and liver failure.
  • NAFLD and NASH are associated with metabolic disorders such as obesity, dyslipidemia, insulin resistance, and type 2 diabetes. Other disorders associated with NAFLD and NASH include increased abdominal fat and high blood pressure.
  • NASH is mediated by a component of the SREBP pathway, such as an SREBP or SCAP.
  • Treatment of NASH may include reduction in average liver fat content, which may be evaluated, for example, by magnetic resonance imaging (MRI), magnetic resonance elastography (MRE), ultrasound, or computerized tomography (CT); reduction of the liver enzyme alanine aminotransferase (ALT); reduction of the liver enzyme aspartate aminotransferase (ALT); reduction of liver inflammation as evaluated through histological scoring of liver biopsy; reduction of liver fibrosis as evaluated through histological scoring of liver biopsy; reduction of liver fat content as evaluated through histological scoring of liver biopsy; or any combinations thereof.
  • Treatment of NASH may be evaluated using the NAFLD activity score (NAS); or steatosis, activity, and fibrosis score (SAF); or other NASH diagnostic and/or scoring metrics (such as FIB4 or ELF).
  • NAS NAFLD activity score
  • SAF steatosis, activity, and fibrosis score
  • FIB4 or ELF NASH diagnostic and/or scoring metrics
  • a disorder in a subject in need thereof wherein the disorder is liver fibrosis associated with NASH, comprising administering to the subject in need thereof a compound of(I), (I- A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii),
  • liver fibrosis is mediated by SREBP.
  • Treatment of liver fibrosis may be evaluated, for example, by magnetic resonance imaging (MRI), magnetic resonance elastography (MRE), ultrasound, or computerized tomography (CT); reduction of the liver enzyme alanine aminotransferase (ALT); reduction of the liver enzyme aspartate aminotransferase (ALT); reduction of liver inflammation and/or fibrosis as evaluated through histological scoring of liver biopsy; or any combinations thereof
  • MRI magnetic resonance imaging
  • MRE magnetic resonance elastography
  • CT computerized tomography
  • ALT liver enzyme aspartate aminotransferase
  • ALT aspartate aminotransferase
  • a disorder in a subject in need thereof wherein the disorder is fatty liver disease
  • administering comprising administering to the subject in need thereof a compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II- A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient.
  • the fatty liver disease is mediated by SREBP.
  • a subject may have fatty liver disease when the fat content of the subject’s liver is 5% or greater.
  • a subject with fatty liver disease has NASH, or liver fibrosis associated with NASH.
  • a subject with fatty liver disease has not been diagnosed with NASH or liver fibrosis associated with NASH.
  • Treatment of fatty liver disease may be evaluated, for example, by magnetic resonance imaging (MRI), magnetic resonance elastography (MRE), ultrasound, or computerized tomography (CT); reduction of the liver enzyme alanine aminotransferase (ALT); reduction of the liver enzyme aspartate aminotransferase (ALT); reduction of liver inflammation as evaluated through histological scoring of liver biopsy; reduction of liver fibrosis as evaluated through histological scoring of liver biopsy; reduction of liver fat content as evaluated through histological scoring of liver biopsy; or any combinations thereof.
  • MRI magnetic resonance imaging
  • MRE magnetic resonance elastography
  • CT computerized tomography
  • the subject is administered between about 0.01 mg/kg to about 100 mg/kg of compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, relative to the body mass of the subject.
  • about 0.7 mg to about 7 g daily, or about 7 mg to about 350 mg daily, or about 350 mg to about 1.75 g daily, or about 1.75 to about 7 g daily of the compound of (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof is administered to the subject in need thereof.
  • the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof is administered as a pharmaceutical composition, as described herein.
  • Other metabolic disorders which may be treated with the compounds or pharmaceutical compositions described herein may include, for example, insulin resistance, hyperglycemia, diabetes mellitus, dyslipidemia, adiposopathy, obesity, and Metabolic Syndrome.
  • the metabolic disorder is mediated by a genetic factor.
  • the metabolic disorder is mediated by one or more environmental factors, such as a diet rich in fat, or a diet rich in sugar, or a combination thereof.
  • the metabolic disorder is mediated by SREBP.
  • the diabetes mellitus is type I diabetes. In certain embodiments, the diabetes mellitus is type II diabetes.
  • Diabetes also known as diabetes mellitus refers to a disease or condition that is generally characterized by metabolic defects in production and utilization of glucose, which result in the failure to maintain appropriate blood sugar levels in the body.
  • the diabetes is type II diabetes, which is characterized by insulin resistance, in which insulin loses its ability to exert its biological effects across a broad range of concentrations.
  • the diabetes is mediated by a component of the SREBP pathway, such as an SREBP or SCAP.
  • a compound of Formula ((I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient.
  • Insulin resistance has been hypothesized to unify the clustering of hypertension, glucose intolerance, hyperinsulinemia, increased levels of triglyceride, decreased HDL cholesterol, and central and overall obesity.
  • “Metabolic Syndrome” refers to a similar clustering of conditions, which may include abdominal obesity, hypertension, high blood sugar, high serum triglycerides (such as elevated fasting serum triglycerides), and low HDL levels, and is associated with a risk of developing cardiovascular disease and/or type II diabetes.
  • Metabolic Syndrome in a subject in need thereof, comprising administering to the subject in need thereof a compound of Formula (I), (I- A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-ii), (II-B), (II-B-i), or (II-B- ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient.
  • the Metabolic Syndrome or insulin resistance is mediated by a component of the SREBP pathway, such as an SREBP or SCAP.
  • the subject is administered between about 0.01 mg/kg to about 100 mg/kg of compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, relative to the body mass of the subject.
  • about 0.7 mg to about 7 g daily, or about 7 mg to about 350 mg daily, or about 350 mg to about 1.75 g daily, or about 1.75 to about 7 g daily of the compound of Formula (I), (I- A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II- A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof is administered to the subject in need thereof.
  • the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof is administered as a pharmaceutical composition, as described herein.
  • the metabolic disorder is dyslipidemia.
  • uses and methods of treating dyslipidemia in a subject in need thereof comprising administering to the subject in need thereof a compound of Formula(I), (I- A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-ii), (II-B), (II-B-i), or (II-B- ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient.
  • Dyslipidemia refers to abnormal blood plasma levels of one or more lipids or one or more lipoproteins, or any combinations thereof.
  • Dyslipidemia may include depressed levels or elevated levels of one or more lipids and/or one or more lipoproteins, or a combination of depressed and elevated levels (for example, elevated levels of one type of lipid and depressed levels of another type of lipid and/or lipoprotein).
  • Dyslipidemia may include, but is not limited to, elevated low density lipoprotein cholesterol (LDL), elevated apolipoprotein B, elevated triglycerides (TGs), elevated lipoprotein(a), elevated apolipoprotein A, reduced high density lipoprotein cholesterol (HDL), or reduced apolipoprotein Al, or any combinations thereof.
  • LDL low density lipoprotein cholesterol
  • TGs elevated triglycerides
  • HDL reduced high density lipoprotein cholesterol
  • Dyslipidemia such as abnormal cholesterol or abnormal TG levels, is associated with an increased risk for vascular disease (such as heart attack or stroke), atherosclerosis, and coronary artery disease.
  • the dyslipidemia is hyperlipidemia.
  • Hyperlipidemia refers to the presence of an abnormally elevated level of lipids in the blood, and may include (1) hypercholesterolemia (an elevated cholesterol level); (2) hypertriglyceridemia, (an elevated triglyceride level); and (3) combined hyperlipidemia, (a combination of hypercholesterolemia and hypertriglyceridemia).
  • Dyslipidemia may arise from a combination of genetic predisposition and diet, and may be associated with being overweight, diabetes, or Metabolic Syndrome.
  • Lipid disorders may also arise as the result of certain medications (such as those used for anti -rejection regimens in people who have had organ or tissue transplants).
  • the dyslipidemia such as hyperlipidemia
  • the SREBP pathway such as an SREBP or SCAP.
  • provided herein are uses and methods of reducing cholesterol levels, modulating cholesterol metabolism, modulating cholesterol catabolism, modulating the absorption of dietary cholesterol, reversing cholesterol transport, or lowering triglycerides in a subject in need thereof, comprising administering to the subject in need thereof a compound of Formula (I), (I-A), (I-A- i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient.
  • the subject is administered between about 0.01 mg/kg to about 100 mg/kg of compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, relative to the body mass of the subject.
  • about 0.7 mg to about 7 g daily, or about 7 mg to about 350 mg daily, or about 350 mg to about 1.75 g daily, or about 1.75 to about 7 g daily of the compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof is administered to the subject in need thereof.
  • the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof is administered as a pharmaceutical composition, as described herein.
  • adiposopathy in a subject in need thereof, comprising administering to the subject in need thereof a compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II- A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient.
  • the adiposopathy is associated with Metabolic Syndrome.
  • the adiposopathy is mediated by a component of the SREBP pathway, such as an SREBP or SCAP.
  • Gallstones may be associated with gallbladder inflammation, pancreas inflammation, or liver inflammation.
  • the gallstones are cholesterol gallstones, which may form when bile contains a high concentration of cholesterol and not enough bile salts.
  • the gallstones, which may include cholesterol gallstone disease is mediated by a component of the SREBP pathway, such as an SREBP or SCAP.
  • the disorder is pancreatitis.
  • the disorder is endotoxic shock, systemic inflammation, or xanthoma.
  • the disorder is atherosclerosis, coronary artery disease, angina pectoris, carotid artery disease, stroke, or cerebral arteriosclerosis.
  • any of the foregoing disorders are mediated by a component of the SREBP pathway, such as an SREBP or SCAP.
  • the subject is administered between about 0.01 mg/kg to about 100 mg/kg of compound of (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, relative to the body mass of the subject.
  • about 0.7 mg to about 7 g daily, or about 7 mg to about 350 mg daily, or about 350 mg to about 1.75 g daily, or about 1.75 to about 7 g daily of the compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof is administered to the subject in need thereof.
  • the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof is administered as a pharmaceutical composition, as described herein.
  • the subject is overweight, obese, has insulin resistance, is pre-diabetic or has type II diabetes. In certain embodiments of any of the preceding embodiments, the subject has NASH.
  • the disorder is a hyperproliferative disorder.
  • uses and methods of treating a hyperproliferative disorder in a subject in need thereof comprising administering to the subject in need thereof a compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient.
  • the metabolism of fatty acids, cholesterol, and triglycerides may play a role in hyperproliferative disorders, such as cancer.
  • hyperproliferative disorders such as cancer.
  • cell metabolism shifts from catabolic to anabolic processes.
  • the tumor cells may synthesize up to 95% of the saturated and mono-unsaturated fatty acids.
  • Some cancers exhibit increased synthesis of fatty acids and other lipids (such as cholesterol), and steroids (such as androgens).
  • Elevated fatty acid synthase (FAS) expression may induce progression to S phase in cancer cells, and inhibition of FAS expression may reduce cell growth and may induce apoptosis.
  • components of the SREBP pathway may play a role in hyperproliferative disorders.
  • Hyperproliferative disorders which are disorders associated with some degree of abnormal cell proliferation, may be benign or malignant. Benign hyperproliferative disorders may include pre-cancerous disorders.
  • the disorder is a benign hyperproliferative disorder.
  • the benign hyperproliferative disorder is mediated by a component of the SREBP pathway, such as an SREBP or SCAP.
  • the disorder is a malignant hyperproliferative disorder.
  • the malignant hyperproliferative disorder is mediated by a component of the SREBP pathway, such as an SREBP or SCAP.
  • the hyperproliferative disorder is breast cancer, liver cancer, ovarian cancer, pancreatic cancer, prostate cancer, soft tissue sarcoma, bladder cancer, endometrial cancer, skin cancer, colon cancer, hematologic cancer, placenta cancer, brain cancer, kidney cancer, lung cancer, or bone cancer.
  • Sarcoma can include cancers that begin in the bones and in the soft tissues.
  • Sarcoma includes, for example, connective tissue cancers, such as muscle cancers.
  • a hyperproliferative disorder in a subject in need thereof between about 0.01 mg/kg to about 100 mg/kg. In some embodiments, about 0.7 mg to about 7 g daily, or about 7 mg to about 350 mg daily, or about 350 mg to about 1.75 g daily, or about 1.75 to about 7 g daily of the compound of Formula
  • a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, administered to a subject in need thereof according to any of the disclosed methods may vary with the particular compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; the method of administration; the particular disorder being treated; and the characteristics of the subject (such as weight, sex, and/or age).
  • the amount of the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof is a therapeutically effective amount.
  • the effective amount of the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, relative to the subject’s body mass may in some embodiments be between about 0.01 mg/kg to about 100 mg/kg.
  • about 0.7 mg to about 7 g daily, or about 7 mg to about 350 mg daily, or about 350 mg to about 1.75 g daily, or about 1.75 to about 7 g daily of the compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I- B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof is administered to a subject in need thereof.
  • the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof is administered as a pharmaceutical composition, as described herein.
  • Any of the uses and methods provided herein may comprise administering to a subject in need therein a pharmaceutical composition that comprises an effective amount of a compound provided herein, such as a compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B- ii), (II), (P-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a corresponding amount of a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient.
  • a compound provided herein such as a compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), or (II-B-ii), or a corresponding amount of a pharmaceutically
  • the compounds of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II- A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof as provided herein, or a pharmaceutical composition comprising any of these and a pharmaceutically acceptable excipient as provided herein, may be administered to a subject via any suitable route, including, for example, intravenous, intramuscular, subcutaneous, oral, or transdermal routes.
  • the present disclosure provides a method of treating a disorder in subject in need thereof by parenterally administering to the subject in need thereof an effective amount of a compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii),
  • the disorder is a hyperproliferative disorder.
  • the hyperproliferative disorder is cancer.
  • the disorder is fatty liver disease.
  • the disorder is NASH.
  • the route of administration is intravenous, intra-arterial, intramuscular, or subcutaneous. In some embodiments, the route of administration is transdermal.
  • compositions comprising a compound of Formula(I), (I- A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II- A), (II-A-i), (II- A-ii), (P-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient, for the use in treating a disorder as described herein.
  • the disorder is prevented, or the onset delayed, or the development delayed.
  • the disorder is a hyperproliferative disorder.
  • the hyperproliferative disorder is cancer.
  • the disorder is fatty liver disease.
  • the disorder is NASH.
  • the composition comprises a pharmaceutical formulation, which is present in a one or more unit dosage forms, for example one, two, three, four, or more unit dosage forms.
  • articles of manufacture comprising a compound of Formula (I), (I- A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-B), (II-B-i), or (II-B- ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or pharmaceutical compositions comprising any of the foregoing, or unit dosages comprising any of these, as described herein in suitable packaging for use in the methods described herein.
  • suitable packaging may include, for example, vials, vessels, ampules, bottles, jars, flexible packaging, and the like.
  • An article of manufacture may further be sterilized and/or be sealed kits.
  • kits comprising a compound of Formula (I), (I-A), (I-A-i),
  • kits may be used in any of the uses and methods described herein. In some embodiments, the kit further comprises instructions.
  • kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for the treatment of a hyperproliferative disorder (such as cancer), fatty liver disease, or NASH.
  • the kits may comprise one or more containers. Each component (if there is more than one component) may be packaged in separate containers or some components may be combined in one container where cross-reactivity and shelf life permit.
  • kits may be in unit dosage forms, bulk packages (e.g ., multi-dose packages) or subunit doses.
  • kits may be provided that contain sufficient dosages of a compound of Formula (I), (I- A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II- A), (II-A-i), (II-A-ii), (II- B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient, as disclosed herein and/or a second pharmaceutically active compound useful for a disorder detailed herein to provide effective treatment of a subject for an extended period, such as one week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months,
  • Kits may also include multiple unit doses of a compound of Formula (I), (I- A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (P-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient, and instructions for use, and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies or compounding pharmacies).
  • pharmacies e.g., hospital pharmacies or compounding pharmacies.
  • kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g, magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component s) of the uses and methods as described herein.
  • the instructions included with the kit may include information as to the components and their administration to an individual.
  • Embodiment I- 1 A compound of Formula (I): or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, wherein:
  • X is N or CR 4 ;
  • R 4 is hydrogen, unsubstituted alkyl, or unsubstituted cycloalkyl
  • Y is CH and Z is S, or Y is S and Z is CH;
  • R 1 is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, heterocycloalkyl, heterocycloalkyl-alkyl, or alkyl-heterocycloalkyl; wherein each alkyl, cycloalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, heterocycloalkyl, heterocycloalkyl-alkyl, or alkyl-heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -OH and fluoro;
  • R 2 is hydrogen, halo, or alkyl, wherein each alkyl is unsubstituted or substituted with fluorine;
  • R 3 is -NR 5 S(0) 2 R 6 , -NR 5 S(0) 2 NR 6 R 7 , -NR 5 C(0)0R 6 , or -C(0)NR 6 R 7 ;
  • R 5 , R 6 and R 7 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl, wherein each alkyl or cycloalkyl is unsubstituted or substituted with one with one or more substituents selected from the group consisting of -OH and fluorine; or R 6 and R 7 , together with the nitrogen atom to which they are attached, form a heterocycloalkyl, which is unsubstituted or substituted with one or more substituents selected from the group consisting of -OH and fluorine.
  • Embodiment 1-2 The compound of embodiment 1-1, wherein the compound is of Formula (I- A): or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
  • Embodiment 1-3 The compound of embodiment 1-1 or 1-2, wherein the compound is of Formula (I-A-i): or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
  • Embodiment 1-4 The compound of embodiment 1-1 or 1-2, wherein the compound is of Formula (I-A-ii): -ii), or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
  • Embodiment 1-5 The compound of embodiment 1-1, wherein the compound is of Formula (I- A): or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
  • Embodiment 1-6 The compound of embodiment 1-1 or 1-5, wherein the compound is of Formula (I-B-i): or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
  • Embodiment 1-7 The compound of embodiment 1-1 or 1-5, wherein the compound is of Formula (I-B-ii): or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
  • Embodiment 1-8 The compound of embodiment 1-1, wherein the compound is of Formula (II): or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
  • Embodiment 1-9 The compound of any one of embodiments 1-1, 1-2, or 1-8, wherein the compound is of Formula (II- A): or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
  • Embodiment 1-10 The compound of any one of embodiments 1-1 to 1-3 or 1-8, wherein the compound is of Formula (II-A-i): or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
  • Embodiment 1-11 The compound of any one of embodiments 1-1 to 1-2, 1-4, or 1-8, wherein the compound is of Formula (II-A-ii): or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
  • Embodiment 1-12 The compound of any one of embodiments 1-1, 1-5 or 1-8, wherein the compound is of Formula (P-B): or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
  • Embodiment 1-13 The compound of any one of embodiments 1-1, 1-5 to 1-6, or 1-8, wherein the compound is of Formula (II-B-i): or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
  • Embodiment 1-14 The compound of any one of embodiments 1-1, 1-5, or 1-7 to 1-8, wherein the compound is of Formula (II-B-ii): or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
  • Embodiment 1-15 The compound of any one of embodiments 1-1 to 1-13, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, wherein R 1 is alkyl, unsubstituted or substituted with one or more substituents independently selected from the group consisting of -OH and fluoro.
  • Embodiment 1-16 The compound of any one of embodiments 1-1 to 1-14, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, wherein R 1 is hydrogen.
  • Embodiment 1-17 The compound of any one of embodiments 1-1 to 1-15, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, wherein R 1 is cycloalkyl, unsubstituted or substituted with one or more substituents independently selected from the group consisting of -OH and fluoro.
  • Embodiment 1-18 The compound of any one of embodiments 1-1 to 1-16, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, wherein R 1 is heterocycloalkyl, unsubstituted or substituted with one or more substituents independently selected from the group consisting of -OH and fluoro.
  • Embodiment 1-19 The compound of any one of embodiments 1-1 to 1-17, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, wherein R 1 is alkyl- cycloalkyl, unsubstituted or substituted with one or more substituents independently selected from the group consisting of -OH and fluoro.
  • Embodiment 1-20 The compound of any one of embodiments 1-1 to 1-19, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, wherein R 1 is substituted with one or more -OH.
  • Embodiment 1-21 The compound of any one of embodiments 1-1 to 1-20, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, wherein R 2 is halo.
  • Embodiment 1-22 The compound of any one of embodiments 1-1 to 1-21, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, wherein R 2 is chloro.
  • Embodiment 1-2 The compound of any one of embodiments 1-1 to 1-20, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, wherein R 2 is alkyl, wherein each alkyl is unsubstituted or substituted with fluorine.
  • Embodiment 1-24 The compound of any one of embodiments 1-1 to 1-23, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, wherein R 3 is - NR 5 S(0) 2 R 6 .
  • Embodiment 1-25 The compound of any one of embodiments 1-1 to 1-23, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, wherein R 3 is -NR 5 S(0) 2 NR 6 R 7 , -NR 5 C(0)0R 6 , or -C(0)NR 6 R 7 .
  • Embodiment 1-26 The compound of any one of embodiments 1-1 to 1-3, 1-5 to 1-6, 1-8 to 1-10, or 1-12 to 1-13, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, wherein R 4 is unsubstituted alkyl.
  • Embodiment 1-27 The compound of any one of embodiments 1-1 to 1-26, selected from the group consisting of: acceptable salt, solvate, isotope, or isomer of any of the foregoing.
  • Embodiment 1-28 A pharmaceutical composition, comprising the compound of any one of embodiments 1-1 to 1-27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, and a pharmaceutically acceptable excipient.
  • Embodiment 1-29. A method of inhibiting a sterol regulatory element-binding protein (SREBP), comprising contacting the SREBP or contacting an SREBP cleavage activating- protein (SCAP) with the compound of any one of embodiments 1-1 to 1-27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-28.
  • SREBP sterol regulatory element-binding protein
  • SCAP SREBP cleavage activating- protein
  • Embodiment 1-30 A method of inhibiting the proteolytic activation of a sterol regulatory element-binding protein (SREBP), comprising contacting an SREBP cleavage activating-protein (SCAP) with the compound of any one of embodiments 1-1 to 1-27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-28.
  • SREBP sterol regulatory element-binding protein
  • SCAP SREBP cleavage activating-protein
  • Embodiment 1-3 A method of treating a disorder in a subject in need thereof, wherein the disorder is mediated by a sterol regulatory element-binding protein (SREBP), comprising administering to the subject an effective amount of the compound of any one of embodiments 1-1 to 1-27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-28.
  • SREBP sterol regulatory element-binding protein
  • Embodiment 1-32 A method of treating a disorder in a subject in need thereof, comprising administering to the subject an effective amount of the compound of any one of embodiments 1-1 to 1-27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-28.
  • Embodiment 1-33 The method of any one of embodiments 1-29 to 1-31, wherein the SREBP is an SREBP-1.
  • Embodiment 1-34 The method of embodiment 1-33, wherein the SREBP-1 is SREBP- l a.
  • Embodiment 1-35 The method of embodiment 1-33, wherein the SREBP-1 is SREBP- lc.
  • Embodiment 1-36 The method of any one of embodiments 1-29 to 1-31, wherein the SREBP is SREBP-2.
  • Embodiment 1-37 The method of any one of embodiments 1-29 to 1-36, wherein SREBP is inhibited in a subject in need thereof.
  • Embodiment 1-38 The method of any one of embodiments 1-29 to 1-37, wherein SCAP is inhibited in a subject in need thereof.
  • Embodiment 1-39 The method of any one of embodiments 1-29 to 1-38, comprising contacting SREBP or SCAP with the compound, or pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition, wherein the expression of one or more genes selected from the group consisting of ACSS2, ALDOC, CYP51A1, DHCR7, ELOVL6, FASN, FDFT1, FDPS, HMGCS1, HSD17B7, IDI1, INSIG1, LDLR, LSS, ME1, PCSK9, PMVK, RDH11, SC5DL, SQLE, STARD4, TM7SF2, PNPLA3, SREBF1, SREBF2, HMGCR, MVD, MVK, ACLY, MSMOl, AC AC A, and ACACB is reduced after contacting the SREBP or SCAP with the compound, or pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition.
  • ACSS2 ACSS2
  • Embodiment 1-40 The method of embodiment 1-31 or 1-32, wherein the disorder is Metabolic Syndrome, type 2 diabetes, obesity, liver disease, insulin resistance, adiposopathy, or dyslipidemia.
  • Embodiment 1-4 The method of embodiment 1-40, wherein the dyslipidemia is hypertriglyceridemia or elevated cholesterol levels.
  • Embodiment 1-42 The method of embodiment 1-40, wherein the liver disease is nonalcoholic steatohepatitis, liver fibrosis, or liver inflammation, or a combination thereof.
  • Embodiment 1-43 The method of embodiment 1-31 or 1-32, wherein the disorder is a hyperproliferative disorder.
  • Embodiment 1-44 The method of embodiment 1-43, wherein the hyperproliferative disorder is cancer.
  • Embodiment 1-45 The method of embodiment 1-44, wherein the cancer is breast cancer, liver cancer, ovarian cancer, pancreatic cancer, prostate cancer, soft tissue sarcoma, bladder cancer, endometrial cancer, skin cancer, colon cancer, hematologic cancer, placenta cancer, brain cancer, kidney cancer, lung cancer, or bone cancer.
  • Embodiment 1-46 The method of embodiment 1-31 or 1-32, wherein the disorder is endotoxic shock, systemic inflammation, or atherosclerosis.
  • Embodiment 1-47 Else of the compound of any one of embodiments 1-1 to 1-27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, in the manufacture of a medicament for inhibiting a sterol regulatory element-binding protein (SREBP) in a subject in need thereof.
  • SREBP sterol regulatory element-binding protein
  • Embodiment 1-48 The use of embodiment 1-47, wherein the inhibiting comprises contacting the SREBP or contacting an SREBP cleavage activating-protein (SCAP) with the compound or pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
  • SCAP SREBP cleavage activating-protein
  • Embodiment 1-49 Else of the compound of any one of embodiments 1-1 to 1-27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, in the manufacture of a medicament for inhibiting the proteolytic activation of a sterol regulatory element-binding protein (SREBP) in a subject in need thereof.
  • SREBP sterol regulatory element-binding protein
  • Embodiment 1-50 The use of embodiment 1-49, wherein the inhibiting comprises contacting an SREBP cleavage activating-protein (SCAP) with the compound or pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
  • SCAP SREBP cleavage activating-protein
  • Embodiment 1-51 Use of the compound of any one of embodiments 1-1 to 1-27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, in the manufacture of a medicament for treating a disorder in a subject in need thereof, wherein the disorder is mediated by a sterol regulatory element-binding protein (SREBP).
  • SREBP sterol regulatory element-binding protein
  • Embodiment 1-52 Use of the compound of any one of embodiments 1-1 to 1-27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, in the manufacture of a medicament for treating a disorder in a subject in need thereof.
  • Embodiment 1-53 The use of any one of embodiments 1-47 to 1-51, wherein the SREBP is an SREBP-1.
  • Embodiment 1-54 The use of embodiment 1-53, wherein the SREBP-1 is SREBP-la.
  • Embodiment 1-55 The use of embodiment 1-53, wherein the SREBP-1 is SREBP-lc.
  • Embodiment 1-56 The use of any one of embodiments 1-47 to 1-51, wherein the SREBP is SREBP-2.
  • Embodiment 1-57 The use of any one of embodiments 1-47 to 1-56, wherein SREBP is inhibited in a subject in need thereof.
  • Embodiment 1-58 The use of any one of embodiments 1-47 to 1-57, wherein SCAP is inhibited in a subject in need thereof.
  • Embodiment 1-59 The use of any one of embodiments 1-47 to 1-58, wherein an SREBP or SCAP is contacted with the compound, or pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, and the expression of one or more genes selected from the group consisting of ACSS2, ALDOC, CYP51A1, DHCR7, ELOVL6, FASN, FDFT1, FDPS, HMGCS1, HSD17B7, IDI1, INSIG1, LDLR, LSS, ME1, PCSK9, PMVK, RDH11, SC5DL, SQLE, STARD4, TM7SF2, PNPLA3, SREBF1, SREBF2, HMGCR, MVD, MVK, ACLY, MSMOl, AC AC A, and ACACB is reduced after contacting the SREBP or SCAP with the compound, or pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
  • ACSS2 ACSS2
  • ALDOC CYP51A1, DH
  • Embodiment 1-60 The use of embodiment 1-51 or 1-52, wherein the disorder is Metabolic Syndrome, type 2 diabetes, obesity, liver disease, insulin resistance, adiposopathy, or dyslipidemia.
  • Embodiment 1-61 The use of embodiment 1-60, wherein the dyslipidemia is hypertriglyceridemia or elevated cholesterol levels.
  • Embodiment 1-62 The use of embodiment 1-60, wherein the liver disease is nonalcoholic steatohepatitis, liver fibrosis, or liver inflammation, or a combination thereof.
  • Embodiment 1-63 The use of embodiment 1-51 or 1-52, wherein the disorder is a hyperproliferative disorder.
  • Embodiment 1-64 The use of embodiment 1-63, wherein the hyperproliferative disorder is cancer.
  • Embodiment 1-65 The use of embodiment 1-64, wherein the cancer is breast cancer, liver cancer, ovarian cancer, pancreatic cancer, prostate cancer, soft tissue sarcoma, bladder cancer, endometrial cancer, skin cancer, colon cancer, hematologic cancer, placenta cancer, brain cancer, kidney cancer, lung cancer, or bone cancer.
  • Embodiment 1-66 The use of embodiment 1-51 or 1-52, wherein the disorder is endotoxic shock, systemic inflammation, or atherosclerosis.
  • Embodiment 1-67 Use of the compound of any one of embodiments 1-1 to 1-27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-28, for inhibiting a sterol regulatory element-binding protein (SREBP).
  • SREBP sterol regulatory element-binding protein
  • Embodiment 1-68 The use of embodiment 1-67, wherein the inhibiting comprises contacting the SREBP or contacting an SREBP cleavage activating-protein (SCAP) with the compound or pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
  • SCAP SREBP cleavage activating-protein
  • Embodiment 1-68 Use of the compound of any one of embodiments 1-1 to 1-27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-28, for inhibiting the proteolytic activation of a sterol regulatory element-binding protein (SREBP).
  • SREBP sterol regulatory element-binding protein
  • Embodiment 1-70 The use of embodiment 1-69, wherein the inhibiting comprises contacting an SREBP cleavage activating-protein (SCAP) with the compound or pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
  • SCAP SREBP cleavage activating-protein
  • Embodiment 1-71 Use of the compound of any one of ⁇ embodiments 1-1 to 1-27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-28, for treating a disorder in a subject in need thereof, wherein the disorder is mediated by a sterol regulatory element-binding protein (SREBP).
  • SREBP sterol regulatory element-binding protein
  • Embodiment 1-72 Use of the compound of any one of embodiments 1-1 to 1-27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-26, for treating a disorder in a subject in need thereof.
  • Embodiment 1-73 The use of any one of embodiments 1-67 to 1-71, wherein the SREBP is an SREBP-1.
  • Embodiment 1-74 The use of embodiment 1-73, wherein the SREBP-1 is SREBP-la.
  • Embodiment 1-75 The use of embodiment 1-73, wherein the SREBP-1 is SREBP-lc.
  • Embodiment 1-76 The use of any one of embodiments 1-67 to 1-71, wherein the SREBP is SREBP-2.
  • Embodiment 1-77 The use of any one of embodiments 1-67 to 1-76, wherein SREBP is inhibited in a subject in need thereof.
  • Embodiment 1-78 The use of any one of embodiments 1-67 to 1-77, wherein SCAP is inhibited in a subject in need thereof.
  • Embodiment 1-79 The use of any one of embodiments 1-67 to 1-78, wherein an SREBP or SCAP is contacted with the compound, or pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition, and the expression of one or more genes selected from the group consisting of ACSS2, ALDOC, CYP51A1, DHCR7, ELOVL6, FASN, FDFT1, FDPS, HMGCS1, HSD17B7, IDI1, INSIG1, LDLR, LSS, ME1, PCSK9,
  • Embodiment 1-80 The use of embodiment 1-71 or 1-72, wherein the disorder is Metabolic Syndrome, type 2 diabetes, obesity, liver disease, insulin resistance, adiposopathy, or dyslipidemia.
  • Embodiment 1-81 The use of embodiment 1-80, wherein the dyslipidemia is hypertriglyceridemia or elevated cholesterol levels.
  • Embodiment 1-82 The use of embodiment 1-81, wherein the liver disease is nonalcoholic steatohepatitis, liver fibrosis, or liver inflammation, or a combination thereof.
  • Embodiment 1-83 The use of embodiment 1-71 or 1-72, wherein the disorder is a hyperproliferative disorder.
  • Embodiment 1-84 The use of embodiment 1-83, wherein the hyperproliferative disorder is cancer.
  • Embodiment 1-85 The use of embodiment 1-84, wherein the cancer is breast cancer, liver cancer, ovarian cancer, pancreatic cancer, prostate cancer, soft tissue sarcoma, bladder, cancer, endometrial cancer, skin cancer, colon cancer, hematologic cancer, placenta cancer, brain cancer, kidney cancer, lung cancer, or bone cancer.
  • the cancer is breast cancer, liver cancer, ovarian cancer, pancreatic cancer, prostate cancer, soft tissue sarcoma, bladder, cancer, endometrial cancer, skin cancer, colon cancer, hematologic cancer, placenta cancer, brain cancer, kidney cancer, lung cancer, or bone cancer.
  • Embodiment 1-86 The use of embodiment 1-71 or 1-72, wherein the disorder is endotoxic shock, systemic inflammation, or atherosclerosis.
  • Embodiment 1-87 A method of treating non-alcoholic steatohepatitis (NASH) in a subject in need thereof, comprising administering to the subject an effective amount of the compound of any one of embodiments 1-1 to 1-27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-28.
  • NASH non-alcoholic steatohepatitis
  • Embodiment 1-88 Use of the compound of any one of embodiments 1-1 to 1-27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-28, for treating non-alcoholic steatohepatitis (NASH) in a subject in need thereof.
  • Embodiment 1-89 Use of the compound of any one of embodiments 1-1 to 1-27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-28, in the manufacture of a medicament for treating non-alcoholic steatohepatitis (NASH) in a subject in need thereof.
  • Embodiment 1-90 A method of treating a hyperproliferative disorder in a subject in need thereof, comprising administering to the subject an effective amount of the compound of any one of embodiments 1-1 to 1-27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-28.
  • Embodiment 1-91 Use of the compound of any one of embodiments 1-1 to 1-27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-28, for treating a hyperproliferative disorder in a subject in need thereof.
  • Embodiment 1-92 Use of the compound of any one of embodiments 1-1 to 1-27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-28, in the manufacture of a medicament for treating a hyperproliferative disorder in a subject in need thereof.
  • Step 1 Synthesis of 3-chloro-4-( 4, 4, 5, 5-tetramethyl-l , 3, 2 -dioxaborolan-2-yl) aniline.
  • PdCk (dppf)-DCM adduct (791.87 mg, 0.969 mmol) was added to a stirred solution of 4-bromo- 3-chloroaniline (2 g, 9.69 mmol), bispinacolatodiboron (4.9 g, 19.38 mmol), and potassium acetate (2.8 g, 29.07 mmol) in 1,4-dioxane (20 mL).
  • the reaction mixture was purged with nitrogen for 20 minutes and then heated to 80 °C for 16 h.
  • Step 2 Synthesis of 4-(4-hromothiophen-2-yl)-3-chloroaniline.
  • Palladium tetrakis (273.85 mg, 0.237 mmol) was added and the reaction mixture again with purged with nitrogen for 30 minutes.
  • Step 3 Synthesis ofN-(4-(4-bromothiophen-2-yl)-3-chlorophenyl)methanesulfonamide.
  • Methanesulfonyl chloride (437.55 mg, 3.819 mmol) was added drop wise to a solution of the product of Step 2 (550 mg, 1.909 mmol) in pyridine (10 mL) at 0-5°C and stirred at rt for 4 h. The reaction mixture was quenched with water and the product extracted into DCM. The organic layer was washed with water, dried and concentrated under reduced pressure to a crude product which was purified over silica gel to give product N-(4-(4-bromothiophen-2-yl)-3- chlorophenyl)methanesulfonamide (450 mg) as a light yellow solid.
  • Step 4 Synthesis of N-(3-chloro-4-( 4-( 4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl)thiophen-2-yl)phenyl)methanesulfonamide.
  • the reaction mixture was heated to 80 °C for 16 hr, cooled to RT, filtered through a bed of celite and washed with ethyl acetate (30 mL). The combined organic layers were concentrated under reduced pressure to afford a crude product which was dissolved in 5% ethyl acetate in pet ether, filtered and evaporated under reduced pressure to give the desired boronate (0.4g) as a gum which was used for the preparation of other compounds without further purification.
  • Step 1 Synthesis of l-cyclopropyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2(lH)-one.
  • Step 2 Synthesis of 5-(5-(4-amino-2-chlorophenyl)thiophen-3-yl)-l- cyclopropylpyridin-2( lH)-one.
  • Step 1 Synthesis of 4-(4-bromothiophen-2-yl)-3-chlorobenzoic acid.
  • Step 2 Synthesis of (4-(4-bromothiophen-2-yl)-3-chlorophenyl)(4-hydroxypiperidin-l- yl)methanone.
  • 4-(4-bromothiophen-2-yl)-3-chlorobenzoic acid (0.450 g, 1.428 m. moles)
  • DMF 1.8 mL, 20 v
  • DIPEA 0.90 mL 4.284 m. moles
  • HATU 0.15g, 2.142 m. moles
  • reaction mixture was diluted with ethyl acetate and washed with cold water (4 x 5ml).
  • the organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude material which was purified by column chromatography (silica gel: #230-400) using 20-60% EtOAc in hexane as eluent to afford (4-(4-bromothiophen-2-yl)-3-chlorophenyl)(4-hydroxypiperidin-l- yl)methanone (0.270 g, 50.0%) as a pale yellow semi-solid.
  • Step 1 Synthesis of 5-bromo-l-propylpyridin-2(lH)-one.
  • DMF dimethyl methyl-N-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-aminoethyl)-one
  • 1-iodopropane (1.17 g, 6.93 mmol) & K2CO3 (2.39 g, 17.34 mmol.
  • the reaction mixture was heated to 80 °C while stirring for 16 h and then quenched with water.
  • the product was extracted into ethyl acetate and the organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure.
  • the crude was purified by column chromatography over silica by using 4% of MeOH/DCM as eluent
  • Step 2 Synthesis of N-(3-chloro-4-(4-(6-oxo-l -propyl-1, 6-dihydropyridin-3- yl)thiophen-2-yl)phenyl)methanesulfonamide.
  • Step 1 Synthesis of 3-allyl-5-bromopyridin-2-yl 4-methylbenzenesulfonate.
  • a solution of i-PrMgCl LiCl (1.55 M in THF, 12.84 mmol) was added slowly at -30 °C to a solution of 3,5-dibromopyridin-2-yl 4-methylbenzenesulfonate (2.6 g, 6.42 mmol) in dry THF (35 mL) and stirred at this temperature for 2 h.
  • Step 2 Synthesis of 5-bromo-3-propyIpyridin-2-yI 4-methylbenzenesulfonate.
  • EtOAc a stirred solution of the product of Step 1 (1.45 g, 3.95 mmol) in EtOAc (20 mL) was added platinum oxide (0.44 g, 1.97 mmol) under hydrogen atmosphere.
  • the reaction mixture was stirred at rt for 4 h, filtered over a celite bed and evaporated to dryness to give a crude product which was purified by reverse phase column chromatography to give 5-bromo-3-propylpyridin- 2-yl 4-methylbenzenesulfonate (lg; 69%) as a viscous liquid.
  • Step 3 Synthesis of 5-bromo-3-propylpyridin-2(lH)-one.
  • THF tetrahydrofuran
  • KOH 0.05 g, 5.42 mmol
  • the reaction was quenched with ice cold water and the product extracted into ethyl acetate.
  • the organic layer was dried and concentrated to give a crude product that was purified by silica gel column chromatography to give 5-bromo-3-propylpyridin-2(lH)-one (0.5g; 86%) as brown solid.
  • Step 4 Synthesis of N-(3-chloro-4-( 4-( 6-oxo-5-propyl-l , 6-dihydropyridin-3- yl)thiophen-2-yl)phenyl)methanesulfonamide.
  • Step 1 Synthesis of 5-bromo-l-methyl-3-propylpyridin-2(lH)-one.
  • DMF dimethyl sulfoxide
  • Step 2 Synthesis of N-( 3-chloro-4-( 4-( 1 -methyl-6-oxo-5-propyl-l , 6-dihydropyridin-3- yl)thiophen-2-yl)phenyl)methanesulfonamide.
  • Step 1 Synthesis of 5-bromo-l-propylpyrimidin-2(lH)-one.
  • l-iodopropane((0.33 mL, 3.46 mmol) was added dropwise to a stirred solution of 5-bromopyrimidin-2(lH)-one (0.5 g, 2.89 mmol) and potassium carbonate (1.19 g, 8.67 mmol) in DMF (10 mL).
  • the reaction mixture was heated for 16 h at 80 °C, quenched with ice cold water and the product extracted with ethyl acetate.
  • Step 2 Synthesis of N-(3-chloro-4-(4-(2-oxo-l -propyl-1, 2-dihydropyrimidin-5- yl)thiophen-2-yl)phenyl)methanesulfonamide.
  • Stepl Synthesis of 5-bromo-l-(2-hydroxy-2-methylpropyl)pyridin-2(lH)-one.
  • DMF dimethylethyl-N-(2-hydroxy-2-methylpropyl)pyridin-2(lH)-one.
  • 2,2-dimethyloxirane 0.62 g, 8.62 mmol
  • K2CO3 1.18 g, 8.62 mmol
  • Step 2 Synthesis of N-(3-chloro-4-(4-(l-(2-hydroxy-2-methylpropyl)-6-oxo-l ,6- dihydropyridin-3-yl)thiophen-2-yl)phenyl)methanesulfinamide.
  • Step 1 The product of Step 1 was reacted with N-(3-chloro-4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophen-2- yl)phenyl)methanesulfonamide as described in Example 1 to give N-(3-chloro-4-(4-(l-(2- hydroxy-2-methylpropyl)-6-oxo-l,6-dihydropyridin-3-yl)thiophen-2- yl)phenyl)methanesulfmamide as a white solid.
  • Step 1 Synthesis of 5-bromo-l-(tetrahydrofuran-3-yl)pyridin-2(lH)-one.
  • 5- bromopyridin-2(lH)-one (1 g, 3.93 mmol) in DMF (10 mL)
  • 3- bromotetrahydrofuran (0.72 g, 3.54 mmol)
  • K2CO3 (1.62 g, 11.79 mmol) at rt for 16 h.
  • 5-bromo-l-(tetrahydrofuran-3- yl)pyridin-2(lH)-one was isolated as a brown solid (0.1 g, 11%).
  • Step 2 Synthesis of N-(3-chloro-4-(4-(6-oxo-l-(tetrahydrofuran-3-yl)-l ,6- dihydropyridin-3-yl)thiophen-2-yl)phenyl)methanesulfonamide.
  • Step 1 The product of Step 1 was reacted withN-(3-chloro-4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophen-2- yl)phenyl)methanesulfonamide as described in Example 1 to give N-(3-chloro-4-(4-(6-oxo-l- (tetrahydrofuran-3-yl)-l,6-dihydropyridin-3-yl)thiophen-2-yl)phenyl)methanesulfonamide as a white solid.
  • Step 1 Synthesis of Methyl l-(5-bromo-2-oxopyridin- 1 (2H)-yl)cyclopropane- 1- carboxylate.
  • a suspension of 5-bromopyridin-2(lH)-one (3 g, 17.24 mmol), methyl 2,4- dibromobutanoate (6.72 g, 25.86 mmol) and K2CO3 (9.53 g, 68.97 mmol) in DMF (25 ml) was stirred at rt for 24h. The reaction mixture was evaporated under vacuum and the residue was partitioned between water and ethyl acetate.
  • Step 2 Synthesis of 5-bromo-l-( l-(hydroxymethyl)cyclopropyl)pyridin-2( lH)-one.
  • Step 3 Synthesis of N-( -chloro-4-( 4-( l-(l -(hydroxymethyl)cyclopropyl)-6-oxo-l, 6- dihydropyridin-3-yl)thiophen-2-yl)phenyl)methanesulfonamide.
  • Step 2 The product of Step 2 was reacted with N-(3-chloro-4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophen-2- yl)phenyl)methanesulfonamide as described in Example 1 to give N-(3-chloro-4-(4-(l-(l- (hydroxymethyl)cyclopropyl)-6-oxo-l,6-dihydropyridin-3-yl)thiophen-2- yl)phenyl)methanesulfonamide as an off white solid.
  • Step 1 Synthesis of 5-bromo-l-((2-methyloxiran-2-yl)methyl)pyridin-2(lH)-one.
  • a solution of 5-bromopyridin-2(lH)-one (5 g, 28.74 mmol) in DMF (50 mL), 2-(chloromethyl)-2- methyloxirane (9.13 g, 86.2 mmol) and CS2CO3 (11.89 g, 86.2 mmol) was stirred at 80 ° C in sealed tube for 8h.
  • Step 2 Synthesis of 5-hromo- 1 -( 2,3-dihydroxy-2-methyIpropyI)pyridin-2( l H)-one.
  • the product of Step 1 in dioxane (3 mL) and 2M H2SO4 (5 mL) was stirred at rt for overnight and, after aqueous work up, was purified by column chromatography to give 5-bromo-l-(2,3- dihydroxy-2-methylpropyl)pyridin-2(lH)-one (0.38 g, 78%) as a yellow oil.
  • Step 3 N-(3-chloro-4-(4-(l-(2,3-dihydroxy-2-methylpropyl)-6-oxo-l,6-dihydropyridin- 3-yl)thiophen-2-yl)phenyl)methanesulfonamide.
  • Step 2 The product of Step 2 was reacted with N-(3- chloro-4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophen-2- yl)phenyl)methanesulfonamide as described in Example 1 to give N-(3-chloro-4-(4-(l-(2,3- dihydroxy-2-methylpropyl)-6-oxo-l,6-dihydropyridin-3-yl)thiophen-2- yl)phenyl)methanesulfonamide as an off white solid.
  • Racemic N-(3-chloro-4-(4-(l-(2,3-dihydroxy-2-methylpropyl)-6-oxo-l,6- dihydropyridin-3-yl)thiophen-2-yl)phenyl)methanesulfonamide (0.25g) was separated into two enantiomers using supercritical fluid chromatography (SFC) (Chiralpak AD-3; CO260%, 40% (0.5% DEA in MeOH)), which gave a first eluting isomer 1-9306 (0.03g) and a second eluting isomer 1-9307 (0.05g).
  • SFC supercritical fluid chromatography
  • Step 1 Synthesis of 5-(4-bromothiophen-2-yl)-l-cyclopropylpyridin-2(lH)-one.
  • Pd(PPh 3 )4 (0.16 g, 0.14 mmol
  • Step 2 Synthesis of N-(3-chloro-4-(5-(l-cyclopropyl-6-oxo-l ,6-dihydropyridin-3- yl)thiophen-3-yl)phenyl)methanesulfonamide.
  • Reporter Screening Assay This assay was used to evaluate the effect on transcriptional activity SREBP of selected compounds using an SRE-luciferase reporter construct. On day 1, 10,000 cells were seeded in a 96 well (white) plate as per the plate map in standard growth media without antibiotics. Cells were incubated at 37°C for 8 hours. After 8 hours, cells were washed with 100 pL sterile PBS and replaced with 100 pL of low-serum media without antibiotics. The cells were then incubated at 37°C for 24 hours. 10 pL of 10X compound was added to reach the desired treatment concentration (10 mM to 0.51 nM). The cells were once again incubated for 24 hours before being removed. A Luciferase assay was performed.
  • Reagents for performing Luciferase assay were stored at -20°C.
  • To a tube of lyophilized assay substrate was added 1 mL Substrate Solvent and mixed well.
  • the Substrate tube after reconstitution was covered with aluminum foil so as to keep it protected from light.
  • the assay buffer was thawed to room temperature.
  • To 20 mL Assay Buffer was added 200 pL of reconstituted lOOx Substrate and mixed well.
  • the reconstituted substrate as well as the assay solution (buffer + substrate) was protected from light throughout the procedure by keeping it covered with aluminum foil.
  • Reporter Assay Materials SREBPvl Reporter cell line: HepG2 - #32251. Growth Medium: MEM (Coming 10-010), 10% FBS, 1% GlutaMax (Invitrogen Catalog # 35050061), pg/ml Puromycin (Invitrogen Catalog # Ai 113803) and 1% Penicillin-Streptomycin (Pen- Strep). Treatment Media: Phenol-free MEM (Invitrogen Catalog # 51200-038) and 1% GlutaMax (Invitrogen Catalog # 35050061). Luciferase Assay: LightSwitch Luciferase Assay Kit (Catalog # 32032). LDH assay: Pierce LDH Cytotoxicity Assay Kit (Catalog# SD249616).
  • Half-life Human Microsomes Compounds were evaluated for stability in human liver microsomes. A 10 mM stock solution of the compound being evaluated was prepared in DMSO and diluted with water: acetonitrile (1 : 1) to a concentration of 1 mM. A working concentration of 100 mM was prepared by further dilution with water: acetonitrile (1 : 1). To make the preincubation mixture, 2.5 pL of the diluted compound was combined with 75 pL of human liver microsomes at 3.33 mg/mL, and 85 pL of 100 mM potassium phosphate buffer, and this mixture was pre-incubated for 10 min at 37°C.
  • sample mixture 25 pL incubation mixture was combined with 200 pL of acetonitrile containing internal standard and vortexed for 5 min at 1200 rpm, then centrifuged for 10 min at 4000 rpm. The supernatant was diluted 2 fold with water and injected on LC-MS/MS. The sample mixture was evaluated by LC-MS/MS using 10 mM ammonium acetate with 0.1% FA as the aqueous mobile phase, and methanol as the organic mobile phase.
  • NIH 3T3-L1 cell differentiation Cells are thawed into Pre-Adipocyte Media (ZenBio) and grown to 80-85% confluence. Cells are seeded 50,000 cells/well into 96-wp in Pre- Adipocyte Media (ZenBio) and allowed to reach confluence for 48-72 hours. They are grown an additional 48 hours after reaching confluence, then the media is changed to Differentiation Media (Zen Bio) and incubated for 72 hours. The media is changed to Adipocyte Differentiation Media (ZenBio) using 150 microliters/well in 96-wp for 72 hours, then media is removed and replaced with 150 microliters of Adipocyte Maintenance Media for an additional 8-14 days, feeding cells every 2-3 days. The compound being evaluated is added to the cells for day 3-6 during differentiation, or day 7-14 during maturation. Cells are then stained with oil red-0 as described below.
  • Oil Red-0 staining After maturation, the cells are washed, then fixed in 10% Formalin for 30-60 minutes. The formalin is removed, the cells are washed in water twice, and then the cells are incubated in 60% isopropanol for 5 minutes. The isopropanol is removed and Oil Red- O solution added for 20 minutes with gentle rotation of plate. The stain is removed, the cells washed twice with water, and Hematoxylin added for 1 minute. The cells are washed twice with water and air dried, then images are acquired.
  • the Log D of selected compounds is evaluated by octanol/aqueous buffer partitioning.
  • 500 pL of organic phase (1-octanol) is added to each well of a 2 mL deep well plate, followed by 500 pL of buffer and 15 pL of test compound in DMSO (0.15 mM).
  • the plate is vortexed for 10 seconds and incubated at room temperature for 1 hr on a plate shaker at 200 rpm. After incubation, the samples are allowed to equilibrate for 20 min and then centrifuged at 4000 rpm for 30 min for complete phase separation.
  • the distribution of test compound in buffer and octanol phase was analyzed by HPLC-UV.
  • Log D Log (Area of Octanol/Area of Buffer).
  • the in vivo effect of selected compounds may be assessed using the ob/ob mouse model.
  • the ob/ob mouse is a well characterized model of obesity, fatty liver, and diabetes, which are exhibited due to a mutation in the ob gene, which encodes for leptin.
  • Compounds are administered by the oral route once or twice daily for 4 weeks in male ob/ob mice. Body weight and food and water intake are assessed daily, and improvements in glucose control are assessed by plasma glucose and insulin measurement. Upon completion of the test period, terminal blood samples are taken and analyzed for triglyceride, cholesterol (total, HDL-C and LDL-C), blood urea nitrogen (BUN), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels. Liver and fat pad weights are determined and liver tissue is processed for histological determination of NASH activity scores (NAS: ballooning, inflammation, steatosis and fibrosis). Liver levels of triglycerides, cholesterol, and non-esterified fatty acids (NEFA) are also determined.
  • NAS ballooning, inflammation, steatosis and fibrosis
  • Animals are housed in cages with clean bedding. Certified rodent diet is provided. Water was available ad libitum. Environmental controls for the animal room are set to maintain a temperature of 22°C to 25°C, humidity of 40-70% RH, and a 12-hour light /12-hour dark cycle. Normal healthy animals certified by the attending veterinarian are selected and acclimatized for minimum three days prior to initiation of study.
  • Rats are anaesthetized with a single dose of ketamine 50 mg/kg i.p. + xylazine 6 mg/kg i.p.
  • the right jugular vein is exposed, a loose ligature is placed caudally, and the cranial end of vein is ligated.
  • a small incision is made between the ligatures into which the catheter (polyethylene 50 tubing of internal diameter 0.58 mm and outer diameter 0.96 mm) is inserted.
  • the catheter is secured in place by tying the loose ligature around the catheterized vessel.
  • a small incision is made in the scapular region to serve as the exit site of the catheter.
  • the catheter is subcutaneously tunneled and exteriorized through scapular incision.
  • a stay suture is placed in the scapular area. Patency is tested, and catheter is filled with a locking solution (heparinized saline) and sealed with a stainless steel plug.
  • the incision is then sutured with sterile suturing material. Anti-septic solution is applied to the sutured site and animal is placed back in the home cage.
  • mice Male Sprague Dawley rats or mice (C5B1/6J) are administered 10 mg compound/kg animal weight by mouth.
  • the concentration of compound in the plasma of the animals is evaluated at 0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 hr by taking blood samples from the cannulated jugular vein (rats) or through a capillary, guided in retro-orbital plexus (mice).
  • mice The pharmacodynamic properties of selected compounds are evaluated in mice.
  • the animals are housed in cages with clean bedding, and maintained and monitored for good health in accordance with Test Facility SOPs and at the discretion of the laboratory animal veterinarian.
  • Certified rodent diet is provided. Food and water is available ad libitum.
  • Environmental controls for the animal room are set to maintain a temperature of 22°C to 25°C, humidity of 40-70% RH, and a 12-hour light/12-hour dark cycle.
  • Normal healthy animals certified by the attending veterinarian are selected and acclimatized for minimum three days prior to initiation of study. Animals are identified with body markings.
  • mice are anesthetized using gaseous anesthesia. Blood samples are collected through a capillary, guided in retro-orbital plexus, at 6 h or at 24 h. Approximately 100 uL of blood is collected from each mouse, in pre-labeled tubes. The collected blood is stored on ice prior to centrifugation. Blood samples are then centrifuged within 1 hour of collection to separate plasma. Centrifugation was conducted at 2500 x g for 15 minutes at 4°C. The plasma is separated and transferred to pre-labeled micro-centrifuge tubes and promptly frozen at -80 ⁇ 10°C until bioanalysis.
  • liver tissue is collected without perfusion. Animals are euthanized using carbon dioxide gas in a CO2 chamber. The whole blood is drained by cutting the both side jugular vein and abdominal aorta. The liver is separated out. All the liver samples are divided in two parts. The first part (200 mg approx.) is snap frozen using liquid nitrogen as soon as possible. These samples are immediately transferred to -80°C for storage. The remaining part was weighed and used for bioanalysis.
  • RNA Processing and Gene Expression Analysis Liver Tissue RNA is harvested with the RNEasy kit and 20-100 ng used to synthesize cDNA with random primers following the manufacturer’s protocol. Quantitative PCR is performed on 1 pg to 100 ng cDNA for the following genes: ACACA, ACLY, FASN, LSS, PNPLA3. Gene expression levels are determined using DDOT method comparing treated to vehicle treated samples as a baseline, and fold change calculated. The average value for all 5 genes above is averaged and termed to Total Fold Change.
  • Reporter Screening Assay An assay was performed to evaluate the effect on transcriptional activity SREBP of the thiophene- and pyridine-containing compounds using an SRE-luciferase reporter construct. The assays were performed in accordance with the methods and materials of Biological Example 1. The results are presented in Table 2, below.
  • Half-life Human Microsomes The compounds were evaluated for stability in human liver microsomes using a method in accordance with the procedure described in Biological Example 1. The results are presented in Table 2, below.
  • Half-life Mouse Microsomes The compounds were evaluated for stability in mouse liver microsomes using a method in accordance with the procedure described in Biological Example 1. The results are presented in Table 2, below.

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Abstract

Provided herein are compounds comprising a three-ring core and pharmaceutically acceptable salts, solvates, tautomers, isotopes, or isomers thereof. Also provided herein are methods of inhibiting a component of the sterol regulatory element binding protein (SREBP) pathway, such as an SREBP or SREBP cleavage activating protein (SCAP), using these compounds, or pharmaceutically acceptable salts, solvates, tautomers, isotopes, or isomers thereof. Further provided are methods of treating a disorder in a subject in need thereof, such as liver disease, non-alcoholic steatohepatitis, insulin resistance, or cancer.

Description

SREBP INHIBITORS COMPRISING A THIOPHENE CENTRAL RING
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Application No. 63/056,413, filed July 24, 2020, the content of which is hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present disclosure relates to compounds comprising a three-ring core, their use for inhibiting components of the sterol regulatory element binding protein (SREBP) pathway, such as SREBP or SREBP cleavage activating protein (SCAP), and their use in therapeutic methods of treating conditions and disorders.
BACKGROUND
[0003] SREBPs are membrane-bound transcription factors that regulate cholesterol, fatty acid, and triglyceride biosynthesis, and lipid uptake. Fatty acids and lipids are a source of energy and important components of many biological structures, such as lipid membranes of cells. Cholesterol is an important component of biological processes and structures. In mammals, there are three known SREBP isoforms: SREBP-la, SREBP-lc, and SREBP-2. SREBP-la controls a broad range of target genes that are involved in the production of fatty acids, triglycerides, phospholipids, and cholesterol. SREBP-lc primarily activates genes which control fatty acid and triglyceride synthesis. SREBP-2 activates genes involved in the synthesis of regulators of cholesterol metabolism, which has been demonstrated in mouse, human, and Drosophila studies. The activity of SREBPs is regulated by SREBP cleavage activating protein (SCAP), which transports SREBP(s) from the endoplasmic reticulum to the Golgi apparatus where the SREBP(s) are proteolytically cleaved, releasing the transcription factor domain.
[0004] The pathways regulated by SREBPs and SCAP have been implicated in disorders of metabolism, such as hypertension, dyslipidemia, obesity, type 2 diabetes, insulin resistance, fatty liver, and nonalcoholic steatohepatitis (NASH). NASH, for example, is liver inflammation and hepatocyte ballooning as a result of fat building up in the liver, which can lead to liver damage, such as cirrhosis. NASH can also be associated with other metabolism disorders, such as insulin resistance and metabolic syndrome.
[0005] The metabolism of fatty acids, cholesterol, and triglycerides may also be linked to hyperproliferative disorders, such as cancer. One characteristic of the oncogenic transformation of cancer cells is the shift of metabolism from catabolic to anabolic processes. Many cancers require synthesis of fatty acids and other lipids (such as cholesterol), and steroids (such as androgens). Thus, components of the SREBP pathway may play a role in hyperproliferative disorders, such as prostate cancer. SREBP- lc is the major transcriptional regulator of the biosynthesis of fatty acids, and expression of this transcription factor can be stimulated by androgens and epidermal growth factor in prostate cancer cells. Overexpression of SREBP- lc may drive tumorgenicity and invasion of prostate cancer cells. In addition to regulating androgen synthesis, SREBP-2 itself is also regulated by androgens in a direct feedback circuit of androgen production. However, prostate cancer cells have dysfunctional cholesterol homeostasis, resulting in accumulation of cholesterol and increased proliferation. This increase in cholesterol levels has been shown to be driven by regulated by increased SREBP-2 activity. SREBP-2 expression increases during disease progression, and is significantly higher after castration compared to prior.
[0006] Regulating components of the SREBP pathway, such as SCAP or SREBPs, is an important therapeutic approach for treating disorders, such as metabolic diseases and cancer. Thus, there is a need for compounds that can inhibit components of the SREBP pathway, such as SREBPs and SCAP.
BRIEF SUMMARY
[0007] In some embodiments, provided herein is a compound of Formula (I): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein: X is N or CR4;
R4 is hydrogen, unsubstituted alkyl, or unsubstituted cycloalkyl;
Y is CH and Z is S, or Y is S and Z is CH;
R1 is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, heterocycloalkyl, heterocycloalkyl-alkyl, or alkyl-heterocycloalkyl; wherein each alkyl, cycloalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, heterocycloalkyl, heterocycloalkyl-alkyl, or alkyl-heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -OH and fluoro;
R2 is hydrogen, halo, or alkyl, wherein each alkyl is unsubstituted or substituted with fluorine;
R3 is -NR5S(0)2R6, -NR5S(0)2NR6R7, -NR5C(0)0R6, or -C(0)NR6R7;
R5, R6 and R7 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl, wherein each alkyl or cycloalkyl is unsubstituted or substituted with one with one or more substituents selected from the group consisting of -OH and fluorine; or R6 and R7, together with the nitrogen atom to which they are attached, form a heterocycloalkyl, which is unsubstituted or substituted with one or more substituents selected from the group consisting of -OH and fluorine.
[0008] In some embodiments, the compound of Formula (I) is a compound of Formula (I-A): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
[0009] In some embodiments, the compound of Formula (I) is a compound of Formula (I-A-i): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
[0010] In some embodiments, the compound of Formula (I) is a compound Formula (I-A-ii): -ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
[0011] In some embodiments, the compound of Formula (I) is a compound of Formula (I-A): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
[0012] In some embodiments, the compound of Formula (I) is a compound of Formula (I-B-i): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. [0013] In some embodiments, the compound of Formula (I) is a compound of Formula (I-B- ii): -ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
[0014] In some embodiments, the compound of Formula (I) is a compound of Formula (II): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
[0015] In some embodiments, the compound of Formula (I) is a compound of Formula (P-A): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
[0016] In some embodiments, the compound of Formula (I) is a compound of Formula (II-A- i): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
[0017] In some embodiments, the compound of Formula (I) is a compound of Formula (II-A- ii): -ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
[0018] In some embodiments, the compound of Formula (I) is a compound of Formula (P-B): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
[0019] In some embodiments, the compound of Formula (I) is a compound of Formula (II-B- i): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
[0020] In some embodiments, the compound of Formula (I) is a compound of Formula (II-B- ii): -ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
[0021] In some embodiments, provided herein is a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient. In some variations, the compound of Formula (I) is a compound of Formula (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II- A), II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient.
[0022] In some embodiments, provided herein is a method of inhibiting a sterol regulatory element-binding protein (SREBP), comprising contacting the SREBP or contacting an SREBP cleavage activating-protein (SCAP) with the compound of Formula (I- A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
[0023] In some embodiments, provided herein is a method of inhibiting the proteolytic activation of a sterol regulatory element-binding protein (SREBP), comprising contacting an SREBP cleavage activating-protein (SCAP) with the compound of Formula (I-A), (I-A-i), (I-A- ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
[0024] In some embodiments, provided herein is a method of treating a disorder in a subject in need thereof, wherein the disorder is mediated by a sterol regulatory element-binding protein (SREBP), comprising administering to the subject an effective amount of a compound of Formula (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), II-A-i), (II-A-ii), (II-B), (II-B- i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. [0025] In some embodiments, provided herein is a method of treating a disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), II-A-i), (II-A-ii), (II-B), (II-B- i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
[0026] In some embodiments, provided herein is the use of a compound of Formula (I-A), (I- A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, in the manufacture of a medicament for inhibiting a sterol regulatory element-binding protein (SREBP) in a subject in need thereof.
[0027] In some embodiments, provided herein is the use of a compound of Formula (I-A), (I- A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, in the manufacture of a medicament for inhibiting the proteolytic activation of a sterol regulatory element-binding protein (SREBP) in a subject in need thereof.
[0028] In some embodiments, provided herein is the use of a compound of Formula (I-A), (I- A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, in the manufacture of a medicament for treating a disorder in a subject in need thereof, wherein the disorder is mediated by a sterol regulatory element-binding protein (SREBP).
[0029] In some embodiments, provided herein is the use of a compound of Formula (I-A), (I- A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, in the manufacture of a medicament for treating a disorder in a subject in need thereof.
[0030] In some embodiments, provided herein is the use of a compound of Formula (I-A), (I- A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition thereof, for inhibiting a sterol regulatory element-binding protein (SREBP).
[0031] In some embodiments, provided herein is the use of a compound of Formula (I-A), (I- A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition thereof, for inhibiting the proteolytic activation of a sterol regulatory element-binding protein (SREBP).
[0032] In some embodiments, provided herein is the use of a compound of Formula (I-A), (I- A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition thereof, wherein the disorder is mediated by a sterol regulatory element-binding protein (SREBP).
[0033] In some embodiments, provided herein is the use of the compound of a compound of Formula (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), II-A-i), (II-A-ii), (II-B), (II-B- i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition thereof, for treating a disorder in a subject in need thereof.
[0034] In some embodiments, provided herein is a method of treating non-alcoholic steatohepatitis (NASH) in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition thereof,
[0035] In some embodiments, provided herein is the use of a compound of Formula (I-A), (I- A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition thereof, for treating non-alcoholic steatohepatitis (NASH) in a subject in need thereof. [0036] In some embodiments, provided herein is the use of a compound of Formula (I-A), (I- A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating non alcoholic steatohepatitis (NASH) in a subject in need thereof.
[0037] In some embodiments, provided herein is a method of treating a hyperproliferative disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), II-A-i), (II- A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition thereof.
[0038] In some embodiments, provided herein is the use of a compound of Formula (I-A), (I- A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition thereof, for treating a hyperproliferative disorder in a subject in need thereof.
[0039] In some embodiments, provided herein is the use of a compound of Formula (I-A), (I- A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating a hyperproliferative disorder in a subject in need thereof.
DETAILED DESCRIPTION
[0040] The following description sets forth numerous exemplary configurations, methods, parameters, and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure, but is instead provided as a description of exemplary embodiments.
I. Compounds
[0041] The present disclosure provides a compound of Formula (I): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein:
X is N or CR4;
R4 is hydrogen, unsubstituted alkyl, or unsubstituted cycloalkyl;
Y is CH and Z is S, or Y is S and Z is CH;
R1 is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, heterocycloalkyl, heterocycloalkyl-alkyl, or alkyl-heterocycloalkyl; wherein each alkyl, cycloalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, heterocycloalkyl, heterocycloalkyl-alkyl, or alkyl-heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -OH and fluoro;
R2 is hydrogen, halo, or alkyl, wherein each alkyl is unsubstituted or substituted with one or more fluorine;
R3 is -NR5S(0)2R6, -NR5S(0)2NR6R7, -NR5C(0)0R6, or -C(0)NR6R7;
R5, R6 and R7 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl, wherein each alkyl or cycloalkyl is unsubstituted or substituted with one with one or more substituents selected from the group consisting of -OH and fluorine; or R6 and R7, together with the nitrogen atom to which they are attached, form a heterocycloalkyl, which is unsubstituted or substituted with one or more substituents selected from the group consisting of -OH and fluorine.
[0042] In some embodiments, the compound of Formula (I) is a compound of Formula (I-A): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
[0043] In some embodiments, the compound of Formula (I) or (I-A) is a compound of Formula (I-A-i): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
[0044] In some embodiments, the compound of Formula (I) or (I-A) is a compound of Formula (I-A-ii): -ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
[0045] In some embodiments, the compound of Formula (I) is a compound of Formula (I-B): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
[0046] In some embodiments, the compound of Formula (I) or Formula (I-B) is a compound of Formula (I-B-i): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
[0047] In some embodiments, the compound of Formula (I) or Formula (I-B) is a compound of Formula (I-B-ii): -ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
[0048] In some embodiments, the compound of Formula (I) is a compound of Formula (II): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
[0049] In some embodiments, the compound of Formula (I), (I-A), or (II) is a compound of Formula (II- A): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. [0050] In some embodiments, the compound of Formula (I), (I-A), (I-A-i), or (II) is a compound of Formula (II-A-i): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
[0051] In some embodiments, the compound of Formula (I), (I-A), (I-A-ii), or (II)is a compound of Formula (II-A-ii): -ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
[0052] In some embodiments, the compound of Formula (I), (I-A), or (II) is a compound of Formula (P-B): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
[0053] In some embodiments, the compound of Formula (I), (I-A), (I-B-i) or (II) is a compound of Formula (II-B-i): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
[0054] In some embodiments, the compound of Formula (I), (I-A), (I-B-ii), or (II) is a compound of Formula (II-B-ii): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof
[0055] “Alkyl”, as used herein, refers to an unbranched or branched saturated hydrocarbon chain. Alkyl can be used alone, or as part of another radical, such as cycloalkyl-alkyl. In some embodiments, alkyl as used herein has 1 to 50 carbon atoms ((Ci-5o)alkyl), 1 to 20 carbon atoms ((Ci-2o)alkyl), 1 to 12 carbon atoms ((Ci-i2)alkyl), 1 to 10 carbon atoms ((Ci-io)alkyl), 1 to 8 carbon atoms ((Ci-8)alkyl), 1 to 6 carbon atoms ((Ci-6)alkyl), 1 to 4 carbon atoms ((Ci-4)alkyl), or 1 to 3 carbon atoms ((Ci-3)alkyl). In other embodiments, alkyl as used herein has 2 to 6 carbon atoms ((C2-6)alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n- butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3- methyl pentyl. When an alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons may be encompassed. Thus, for example, "butyl" can include n-butyl, sec-butyl, isobutyl and t-butyl, and "propyl" can include n-propyl and isopropyl.
[0056] “Cycloalkyl”, as used herein, refers to a monocyclic or polycyclic saturated hydrocarbon. In some embodiments, cycloalkyl has 3 to 50 carbon atoms ((C3-5o)cycloalkyl), 3 to 20 carbon atoms ((C3-2o)cycloalkyl), 3 to 12 carbon atoms ((C3-i2)cycloalkyl), 3 to 10 carbon atoms ((C3-io)cycloalkyl), 3 to 8 carbon atoms ((C3-8)cycloalkyl), 3 to 6 carbon atoms ((C3- 6)cycloalkyl), or 3 to 5 carbon atoms ((C3-4)cycloalkyl). Cycloalkyl includes monocyclic and polycyclic groups, such as fused bicycles, bridged rings, and spirocycles. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, octahydropentalenyl, octahydro- l//-indene, decahydronaphthalene, cubane, bicyclo[3.1.0]hexane, and bicyclo[l.l.l]pentane.
[0057] “Cycloalkyl-alkyl” refers to a cycloalkyl group (as defined above) connected to an alkyl group (as defined above), wherein the alkyl group is attached to another moiety (such as the core structure of the molecule). Substituted cycloalkyl-alkyl can include one or more additional attachments to substituents at any point of the cycloalkyl or alkyl, as valency permits. The cycloalkyl-alkyl may comprise any combination of cycloalkyl and alkyl groups. In some embodiments, the cycloalkyl has 3 to 50 carbon atoms ((C35o)cycloalkyl-alkyl), 3 to 20 carbon atoms ((C3-2o)cycloalkyl-alkyl), 3 to 12 carbon atoms ((C3-i2)cycloalkyl-alkyl), 3 to 10 carbon atoms ((C3-io)cycloalkyl-alkyl), 3 to 8 carbon atoms ((C3-8)cycloalkyl-alkyl), 3 to 6 carbon atoms ((C3-6)cycloalkyl-alkyl), or 3 to 5 carbon atoms ((C3-4)cycloalkyl-alkyl). In some embodiments, the alkyl has 1 to 50 carbon atoms (cycloalkyl-(Ci-5o)alkyl), 1 to 20 carbon atoms (cycloalkyl-(Ci-2o)alkyl), 1 to 12 carbon atoms (cycloalkyl-(Ci-i2)alkyl), 1 to 10 carbon atoms (cycloalkyl-(Ci-io)alkyl), 1 to 8 carbon atoms (cycloalkyl-(Ci-8)alkyl), 1 to 6 carbon atoms (cycloalkyl-(Ci-6)alkyl), or 1 to 4 carbon atoms (cycloalkyl-(Ci-4)alkyl). In certain embodiments, the cycloalkyl-alkyl is a (C3-2o)cycloalkyl(Cl-2o)alkyl, (C3-i2)cycloalkyl(Ci- i2)alkyl, (C3-io)cycloalkyl(Ci-io)alkyl, (C3-io)cycloalkyl(Ci-8)alkyl, (C3-io)cycloalkyl(Ci-6)alkyl, (C3-6)cycloalkyl(Ci-8)alkyl, (C3-6)cycloalkyl(Ci-6)alkyl, or (C3-6)cycloalkyl(Ci-4)alkyl.
[0058] “Alkyl-cycloalkyl” refers to an alkyl group (as defined above) connected to a cycloalkyl group (as defind above), wherein the cycloalkyl group is attached to another moiety (such as the core structure of the molecule). Substituted alkyl-cycloalkyl can include one or more additional attachments to substituents at any point of the alkyl or cycloalkyl, as valency permite. The alkyl-cycloalkyl may comprise any combination of alkyl and cycloalkyl groups. In some embodiments, the cycloalkyl has 3 to 50 carbon atoms ((C3-C5o)alkyl-cycloalkyl), 3 to 20 carbon atoms ((C3-C20) alkyl-cycloalkyl), 3 to 12 carbon atoms ((C3-C12) alkyl-cycloalkyl), 3 to 10 carbon atoms ((C3-C10) alkyl-cycloalkyl), 3 to 8 carbon atoms ((C3-C8) alkyl-cycloalkyl), 3 to
6 carbon atoms ((C3-C6) alkyl-cycloalkyl), or 3 to 5 carbon atoms ((C3-C4) alkyl-cycloalkyl). In some embodiments, the alkyl has 1 to 50 carbon atoms ((Ci-C5o)alkyl-cycloalkyl), 1 to 20 carbon atoms ((Ci-C2o)alkyl-cycloalkyl), 1 to 12 carbon atoms ((Ci-Ci2)alkyl cycloalkyl), 1 to 10 carbon atoms ((Ci-Cio)alkyl cycloalkyl), 1 to 8 carbon atoms ((Ci-C8)alkyl-cycloalkyl), 1 to 6 carbon atoms ((Ci-C6)alkyl-cycloalkyl), or 1 to 4 carbon atoms ((Ci-C4)alkyl-cycloalkyl). In certain embodiments, the cycloalkyl-alkyl is a (Cl-C2o)alkyl(C3-C2o)cycloalkyl, (Ci- Ci2)alkyl(C3-i2)cycloalkyl, (Ci-Cio)alkyl(C3-Cio)cycloalkyl, (Ci-C8)alkyl(C3-Cio)cycloalkyl, (Ci-C6)alkyl(C3-Cio)cycloalkyl, (Ci-C8)alkyl(C3-C6)cycloalkyl, (Ci-C6)alkyl(C3-C6)cycloalkyl, or (Ci-C4)alkyl(C3-C6)cycloalkyl.
[0059] “Heterocycloalkyl”, as used herein, refers to a saturated monocyclic or polycyclic ring containing carbon and at least one heteroatom selected from the group consisting of O, N, and S. The heterocycloalkyl group may comprise 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more ring atoms ( e.g ., be a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9- membered, 10-membered, 11-membered, or 12-membered heterocycloalkyl). Heterocycloalkyl may include groups comprising 1 to 5 ring heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 or 2 ring heteroatoms, or 1 ring heteroatom, wherein each heteroatom is independently selected from the group consisting of N, O, and S. Each ring S atom, where present, may independently be unoxidized sulfur (e.g., -S-) or a sulfur oxide, such as -S(O)-, or - S(0)2-. In certain examples, a heterocycloalkyl has 2 to 8 ring carbon atoms and with 1 to 3 ring heteroatoms independently selected from N, O, and S. In some embodiments, heterocycloalkyl is connected through an annular carbon atom, wherein the point of attachment of the heterocycloalkyl to another group is a ring carbon atom of the heterocycloalkyl.
Heterocycloalkyl includes polycyclic systems, such as bridged, fused, and spirocycles comprising at least one heteroatom in at least one of the rings. Examples of heterocycloalkyl include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S- oxide, thiomorpholinyl S-di oxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, and tropanyl.
[0060] “Heterocycloalkyl-alkyl” refers to a heterocycloalkyl group (as defined above) connected to an alkyl group (as defined above), wherein the alkyl group is attached to another moiety (such as the core structure of the molecule). The alkyl group may be attached to the heterocycloalkyl through an annular carbon atom of the heterocycloalkyl, or through an annular heteroatom of the heterocycloalkyl (such as through a ring N atom). Substituted heterocycloalkyl-alkyl can include one or more additional attachments to substituents at any point of the heterocycloalkyl or alkyl, as valency permits. The heterocycloalkyl-alkyl may comprise any combination of heterocycloalkyl and alkyl groups. In some embodiments, the heterocycloalkyl comprises 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more ring atoms. The heterocycloalkyl may include groups comprising 1 to 5 ring heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 or 2 ring heteroatoms, or 1 ring heteroatom, wherein each heteroatom is independently selected from the group consisting of N, O, and S. In some embodiments, the alkyl has 1 to 50 carbon atoms (heterocycloalkyl-(Ci-5o)alkyl), 1 to 20 carbon atoms (heterocycloalkyl-(Ci-2o)alkyl), 1 to 12 carbon atoms (heterocycloalkyl-(Ci-i2)alkyl), 1 to 10 carbon atoms (heterocycloalkyl-(Ci-io)alkyl), 1 to 8 carbon atoms (heterocycloalkyl-(Ci-8)alkyl), 1 to 6 carbon atoms (heterocycloalkyl-(Ci-6)alkyl), or 1 to 4 carbon atoms (heterocycloalkyl-(Ci- 4)alkyl). In certain embodiments, the heterocycloalkyl-alkyl is a (3-20 membered)heterocycloalkyl(Ci-2o)alkyl, (3-12 membered)heterocycloalkyl(Ci-i2)alkyl, (3-12 membered)heterocycloalkyl(Ci-io)alkyl, (3-10 membered)heterocycloalkyl(Ci-8)alkyl, (3-10 membered)heterocycloalkyl(Ci-6)alkyl, (3-6 membered)heterocycloalkyl(Ci-8)alkyl, (3-6 membered)heterocycloalkyl(Ci-6)alkyl, or (3-6 membered)heterocycloalkyl(Ci-4)alkyl.
[0061] “Alkyl-heterocycloalkyl” refers to an alkyl group (as defined above) connected to a heterocycloalkyl group (as defind above), wherein the heterocycloalkyl group is attached to another moiety (such as the core structure of the molecule). Substituted alkyl-heterocycloalkyl can include one or more additional attachments to substituents at any point of the alkyl or heterocycloalkyl, as valency permite. The alkyl-heterocycloalkyl may comprise any combination of alkyl and heterocycloalkyl groups. In some embodiments, the heterocycloalkyl has 3 to 50 carbon atoms ((C3-C5o)alkyl-heterocycloalkyl), 3 to 20 carbon atoms ((C3-C20) alkyl- heterocycloalkyl), 3 to 12 carbon atoms ((C3-C12) alkyl-heterocycloalkyl), 3 to 10 carbon atoms ((C3-C10) alkyl-heterocycloalkyl), 3 to 8 carbon atoms ((C3-C8) alkyl-heterocycloalkyl), 3 to 6 carbon atoms ((C3-C6) alkyl-heterocycloalkyl), or 3 to 5 carbon atoms ((C3-C4) alkyl- heterocycloalkyl). In some embodiments, the alkyl has 1 to 50 carbon atoms ((Ci-C5o)alkyl- heterocycloalkyl), 1 to 20 carbon atoms ((Ci-C2o)alkyl-heterocycloalkyl), 1 to 12 carbon atoms ((Ci-Ci2)alkyl heterocycloalkyl), 1 to 10 carbon atoms ((Ci-Cio)alkyl heterocycloalkyl), 1 to 8 carbon atoms ((Ci-C8)alkyl-heterocycloalkyl), 1 to 6 carbon atoms ((Ci-Ce)alkyl- heterocycloalkyl), or 1 to 4 carbon atoms ((Ci-C4)alkyl-heterocycloalkyl). In certain embodiments, the heterocycloalkyl-alkyl is a (Cl-C2o)alkyl(C3-C2o)heterocycloalkyl, (Ci- Ci2)alkyl(C3-i2)heterocycloalkyl, (Ci-Cio)alkyl(C3-Cio)heterocycloalkyl, (Ci-C8)alkyl(C3- Cio)heterocycloalkyl, (Ci-C6)alkyl(C3-Cio)heterocycloalkyl, (Ci-C8)alkyl(C3- C6)heterocycloalkyl, (Ci-C6)alkyl(C3-C6)heterocycloalkyl, or (Ci-C4)alkyl(C3- C6)heterocycloalkyl.
[0062] It should be understood that when a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “(Ci-6)alkyl” (which may also be referred to as C1-C6 alkyl, C1-C6 alkyl, or Cl -6 alkyl) is intended to encompass Ci, C2, C3, C4, C5, Ce, Cl-6, Cl-5, Cl-4, Cl-3, Cl-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.
[0063] “Halo”, as used herein, refers to fluoro, chloro, bromo, or iodo radicals.
[0064] The disclosure includes isomers, also referred to as, stereoisomers, of the compounds described herein. The term “isomers” refers to a set of compounds that have the same number and type of atoms, and the same bond connectivity between those atoms, but different three- dimensional structures. The term “isomer” may refer to any member of this set of compounds. For instance, isomers may be mirror images that are related by a reflection operation (enantiomers) or non-mirror images that are not related through a reflection operation (diastereomers). The compounds of the present disclosure may occur as mixtures of enantiomers, mixtures of diastereomers, or as individual enantiomers or diastereomers. Mixtures of enantiomers may be racemic mixtures that contain different enantiomers in equal amounts.
[0065] “Optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
[0066] In some embodiments of the compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I- B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), the compound is a solvate. In some embodiments of the compound of Formula (I), (I- A), (I-A-i), (I-A-ii), (I-B), (I- B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), the solvate is a hydrate.
[0067] In some embodiments, provided is a pharmaceutically acceptable salt of a compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii).
[0068] “Pharmaceutically acceptable” includes that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and not biologically or otherwise undesirable, and includes that which is acceptable for veterinary use as well as human pharmaceutical use. For example, provided herein is a pharmaceutical composition comprising a compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), II-A-i), (II- A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient.
[0069] “Pharmaceutically acceptable salt” includes a salt which is generally safe, non-toxic and not biologically or otherwise undesirable, and includes that which is acceptable for veterinary use as well as human pharmaceutical use. Such salts may include acid addition salts and base addition salts. Acid addition salts may be formed with inorganic acid such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or an organic acid such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4- acetamidobenzoic acid, camphoric acid, camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene- 1,5-disulfonic acid, naphthalene-2-sulfonic acid, l-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, or undecylenic acid. Salts derived from inorganic bases may include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from organic bases may include, but are not limited to, salts of primary, secondary, or tertiary amines; substituted amines including naturally occurring substituted amines; cyclic amines; ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, or N-ethylpiperidine.
[0070] In some embodiments, provided is an isotope of a compound of Formula (I), (I- A), (I- A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii).
[0071] Unless otherwise stated, structures depicted herein, such as compounds of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II- B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, or isomer thereof, are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. The compounds herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. In some embodiments, the compound is isotopically-labeled, such as an isotopically-labeled compound of Formula (I), (I-A), (I-A-i), (I- A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, or isomer thereof, where a fraction of one or more atoms are replaced by an isotope of the same element. Exemplary isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine, such as 2H, 3H, UC, 13C, 14C 13N, 150, 170, 35S, 18F, 36C1. Certain isotope labeled compounds (e.g. 3H and 14C) may be useful in compound or substrate tissue distribution study. Incorporation of heavier isotopes such as deuterium (2H) may, in some embodiments, afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, or reduced dosage requirements. [0072] The compounds disclosed herein, such as compounds of Formula (I), (I-A), (I-A-i), (I- A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, or isotope thereof, may contain one or more asymmetric centers and thus may give rise to one or more isomers.
[0073] In some embodiments, provided is a tautomer of a compound of Formula (I), (I-A), (I- A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii).
[0074] As described above, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or isotope thereof, wherein:
X is N or CR4;
R4 is hydrogen, unsubstituted alkyl, or unsubstituted cycloalkyl;
Y is CH and Z is S, or Y is S and Z is CH;
R1 is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, heterocycloalkyl, heterocycloalkyl-alkyl, or alkyl-heterocycloalkyl; wherein each alkyl, cycloalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, heterocycloalkyl, heterocycloalkyl-alkyl, or alkyl-heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -OH and fluoro;
R2 is hydrogen, halo, or alkyl, wherein each alkyl is unsubstituted or substituted with fluorine;
R3 is -NR5S(0)2R6, -NR5S(0)2NR6R7, -NR5C(0)0R6, or -C(0)NR6R7;
R5, R6 and R7 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl, wherein each alkyl or cycloalkyl is unsubstituted or substituted with one with one or more substituents selected from the group consisting of -OH and fluorine; or R6 and R7, together with the nitrogen atom to which they are attached, form a heterocycloalkyl, which is unsubstituted or substituted with one or more substituents selected from the group consisting of -OH and fluorine. [0075] As described above, the present disclosure provides a compound of Formula (I), (I- A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, or isotope thereof, wherein:
X is N or CR4;
R4 is hydrogen, unsubstituted alkyl, or unsubstituted cycloalkyl;
Y is CH and Z is S, or Y is S and Z is CH;
R1 is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, heterocycloalkyl, heterocycloalkyl-alkyl, or alkyl-heterocycloalkyl; wherein each alkyl, cycloalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, heterocycloalkyl, heterocycloalkyl-alkyl, or alkyl-heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -OH and fluoro;
R2 is hydrogen, halo, or alkyl, wherein each alkyl is unsubstituted or substituted with fluorine;
R3 is -NR5S(0)2R6, -NR5S(0)2NR6R7, -NR5C(0)0R6, or -C(0)NR6R7;
R5, R6 and R7 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl, wherein each alkyl or cycloalkyl is unsubstituted or substituted with one with one or more substituents selected from the group consisting of -OH and fluorine; or R6 and R7, together with the nitrogen atom to which they are attached, form a heterocycloalkyl, which is unsubstituted or substituted with one or more substituents selected from the group consisting of -OH and fluorine.
[0076] In some embodiments of the compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I- B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, R1 is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, heterocycloalkyl, heterocycloalkyl-alkyl, or alkyl- heterocycloalkyl. In certain embodiments, R1 is hydrogen. In certain embodiments, R1 is alkyl. In certain embodiments, R1 is cycloalkyl. In certain embodiments, R1 is cycloalkyl-alkyl. In certain embodiments, R1 is alkyl-cycloalkyl. In certain embodiments, R1 is heterocycloalkyl. In certain embodiments, R1 is heterocycloalkyl-alkyl. In certain embodiments, R1 is alkyl- heterocycloalkyl. In some embodiments, R1 is unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted cycloalkyl-alkyl, unsubstituted alkyl-cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted heterocycloalkyl-alkyl, or unsubstituted alkyl-heterocycloalkyl.
[0077] In some embodiments, each alkyl, cycloalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, heterocycloalkyl, heterocycloalkyl-alkyl, or alkyl-heterocycloalkyl of R1 is substituted with one or more substituents independently selected from the group consisting of -OH and fluoro. In some embodiments, each alkyl, cycloalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, heterocycloalkyl, heterocycloalkyl-alkyl, or alkyl-heterocycloalkyl of R1 is substituted with one or more -OH. In some embodiments, each alkyl, cycloalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, heterocycloalkyl, heterocycloalkyl-alkyl, or alkyl-heterocycloalkyl of R1 is substituted with one or more -fluoro.
In some embodiments, each alkyl, cycloalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, heterocycloalkyl, heterocycloalkyl-alkyl, or alkyl-heterocycloalkyl of R1 is substituted with one or more -OH and one or more fluoro.
[0078] In some embodiments of the compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I- B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, R1 is (Ci-C5)alkyl. In certain embodiments, R1 is methyl. In certain embodiments, R1 is ethyl. In certain embodiments, R1 is propyl. In certain embodiments, R1 is butyl. In some embodiments, R1 is (C3-C6)cycloalkyl. In certain embodiments, R1 is cyclopropyl. In certain embodiments, R1 is cyclobutyl. In some embodiments, R1 is (C3-C6)heterocycloalkyl. In some embodiments, R1 is (C5)heterocycloalkyl. In some embodiments, R1 is a (Ci-Cs)alkyl substituted with one or more -OH. In certain embodiments, R1 is a (Ci-C5)alkyl substituted with one -OH. In certain embodiments, R1 is a (Ci-C5)alkyl substituted with two -OH. In some embodiments, R1 is (C4-C7)alkyl-cycloalkyl.
In some embodiments, R1 is (C4-C7)alkyl-cycloalkyl substituted with one or more -OH. R1 is (C4-C7)alkyl-cycloalkyl substituted with one -OH.
[0079] In some embodiments of the compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I- B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically H acceptable salt, solvate, tautomer, isotope, or isomer thereof, R1 is:
[0080] In some embodiments of the compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I- B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, R2 is hydrogen, halo, or alkyl. In certain embodiments, R2 is hydrogen. In certain embodiments, R2 is halo. In certain embodiments, R2 is alkyl. In some embodiments, R2 is chloro.
[0081] In some embodiments, the alkyl of R2 is unsubstituted or substituted with fluorine. In certain embodiments, the alkyl of R2 is unsubstituted. In some embodiments, the alkyl of R2 is unsubstituted or substituted with 1-3 fluorine. In some embodiments, the alkyl of R2 is unsubstituted or substituted with 1 fluorine. In some embodiments, the alkyl of R2 is unsubstituted or substituted with 2 fluorines. In some embodiments, the alkyl of R2 is unsubstituted or substituted with 3 fluorines.
[0082] In some embodiments of the compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I- B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, R3 is -NR5S(0)2R6, - NR5S(0)2NR6R7, -NR5C(0)0R6, or -C(0)NR6R7. In some embodiments, R3 is -NR5S(0)2R6.
In some embodiments, R3 -NR5S(0)2NR6R7. In some embodiments, R3 is -NR5C(0)0R6. In some embodiments, R3 is -C(0)NR6R7.
[0083] In some embodiments, R5, R6 and R7 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl. In some embodiments, R3 is -NR5S(0)2R6, R5 is hydrogen, and R6 is alkyl. In certain embodiments, R3 is -NR5S(0)2R6, R5 is hydrogen, and R6 is methyl. In some embodiments, R3 is — NR5S(0)2NR6R7, R5 is hydrogen, R6 is hydrogen, and R7 is alkyl. In certain embodiments, R3 is — NR5S(0)2NR6R7, R5 is hydrogen, R6 is hydrogen, and R7 is (C3)alkyl. In certain embodiments, R3 is — NR5S(0)2NR6R7, R5 is hydrogen, R6 is hydrogen, and R7 is isopropyl. In some embodiments, R3 is -NR5C(0)0R6, R5 is hydrogen, and R6 is cycloalkyl. In some embodiments, R3 is -NR5C(0)0R6, R5 is hydrogen, and R6 is cyclopropyl. In some embodiments, the alkyl or cycloalkyl of R5, R6, or R7 is unsubstituted.
[0084] In certain embodiments, the alkyl or cycloalkyl of R5, R6, or R7 is substituted with one or more substituents selected from the group consisting of -OH and fluorine. In certain embodiments, the alkyl or cycloalkyl of R5, R6, or R7 is substituted with one or more -OH. In certain embodiments, the alkyl or cycloalkyl of R5, R6, or R7 is substituted with one or more fluorine. In certain embodiments, the alkyl or cycloalkyl of R5, R6, or R7 is substituted with one or more -OH and one or more fluorine.
[0085] In some embodiments, R6 and R7, together with the nitrogen atom to which they are attached, form a heterocycloalkyl. In certain embodiments, R6 and R7, together with the nitrogen atom to which they are attached, form a (C6)heterocycloalkyl. In some embodiments, the heterocycloalkyl formed by R6 and R7, together with the nitrogen atom to which they are attached, is unsubstituted. In some embodiments, the heterocycloalkyl formed by R6 and R7, together with the nitrogen atom to which they are attached, is substituted with one or more substituents selected from the group consisting of -OH and fluorine. In certain embodiments, the heterocycloalkyl formed by R6 and R7, together with the nitrogen atom to which they are attached, is substituted with one or more -OH. In certain embodiments, the heterocycloalkyl formed by R6 and R7, together with the nitrogen atom to which they are attached, is substituted with one or more fluorine. In certain embodiments, the heterocycloalkyl formed by R6 and R7, together with the nitrogen atom to which they are attached is substituted with one or more -OH and one or more fluorine.
[0086] In some emodiments, R3 is -C(0)NR6R7, and R6 and R7, together with the nitrogen atom to which they are attached, form a heterocycloalkyl. In certain emodiments, R3 is - C(0)NR6R7, and R6 and R7, together with the nitrogen atom to which they are attached, form an unsubstituted heterocycloalkyl. In certain emodiments, R3 is -C(0)NR6R7, and R6 and R7, together with the nitrogen atom to which they are attached, form a heterocycloalkyl substituted with with one or more substituents selected from the group consisting of -OH and fluorine. In certain emodiments, R3 is
-C(0)NR6R7, and R6 and R7, together with the nitrogen atom to which they are attached, form a heterocycloalkyl substituted with with one or more -OH. In certain emodiments, R3 is -C(0)NR6R7, and R6 and R7, together with the nitrogen atom to which they are attached, form a heterocycloalkyl substituted with with one or more fluorine. In certain emodiments, R3 is -C(0)NR6R7, and R6 and R7, together with the nitrogen atom to which they are attached, form a heterocycloalkyl substituted with with one or more -OH and one or more fluorine. In some emodiments, R3 is -C(0)NR6R7, and R6 and R7, together with the nitrogen atom to which they are attached, form a (C6)heterocycloalkyl. In some emodiments, R3 is -C(0)NR6R7, and R6 and R7, together with the nitrogen atom to which they are attached, form a (C6)heterocycloalkyl. In some emodiments, R3 is -C(0)NR6R7, and R6 and R7, together with the nitrogen atom to which they are attached, form a (C6)heterocycloalkyl substituted with -OH.
[0087] In some embodiments of the compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I- B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, R3 is:
[0088] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, X is N. In some embodiments of the compound of Formula (I), (I-A), (I-A-ii), (I-B), (I-B-ii), (II), (II-A), (II-A-ii), (II-B), or (II-B- ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, X is N.
In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, X is CR4. In some embodiments of the compound of Formula (I), (I- A), (I-A-i), (I-B), (I-B-i), (II), (II- A), (II-A-i), (II-B), or (II-B-i), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, X is CR4.
[0089] In some embodiments of the compound of Formula (I), (I-A), (I-A-i), (I-B), (I-B-i), (II), (P-A), (II-A-i), (II-B), or (II-B-i), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, R4 is hydrogen, unsubstituted alkyl, or unsubstituted cycloalkyl. In some embodiments, R4 is hydrogen. In some embodiments, R4 is unsubstituted alkyl. In some embodiments, R4 is unsubstituted cycloalkyl. In certain embodiments, R4 is unsubstituted (Ci- C4)alkyl. In certain embodiments, R4 is propyl. [0090] In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, Y is CH and Z is S. In some embodiments of the compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (II), (II-A), (II-A-i), (II-A- ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, Y is CH and Z is S. In some embodiments of the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, Y is S and Z is CH. In some embodiments of the compound of Formula (I), (I-B), (I-B-i), (I-B-ii), (II), (II-B), (II-B-i), or (II- B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, Y is S and Z is CH.
[0091] In some embodiments, the compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-
B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii) is: acceptable salt, solvate, tautomer, isotope, or isomer of any of the foregoing. [0092] Further provided are pharmaceutical compositions comprising any of the compounds disclosed herein, such as a compound of (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient.
[0093] The compounds disclosed herein, such as a compound of (I), (I-A), (I-A-i), (I-A-ii), (I- B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, may be prepared, for example, through the reaction route depticted in General Reaction Scheme I.
General Reaction Scheme I
[0094] General Reaction Scheme I provides two routes to compound 1-5, which can be a compound of Formula (I), or an intermediate to compounds of Formula (I), (I-A), (I-A-i), (I-A- ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii). A compound 1-1 can be coupled to a compound 1-2, or a compound 1-3 can be coupled to a compound 1-4, using palladium catalysis. Suitable palladium catalysts may include, for example, tetrakis(triphenylphosphine)palladium(0). Suitable bases may include, for example, aqueous sodium carbonate or potassium carbonate. The steps depicted in General Reaction Scheme I may further include a solvent, for example, dioxane, tetrahydrofuran, or dimethoxyethane. In some embodiments, the reactions are carried out between about 25°C to 120°C, for between about 8 h to 24 h.
[0095] The variables R1, R2, R3, X, Y, and Z in the compounds of General Reaction Scheme I are as described for Formula (I) herein. While General Reaction Scheme I depicts the preparation of compounds of Formula (I) or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, compounds of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, may also in some embodiments be prepared following analogous reaction schemes, with for example, addition or removal of protecting groups or the modification of substituents R1, R2, or R3 using standard organic chemical techniques. The reactants, solvents, coupling agents, catalysts, and other compounds used to prepare compounds of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, by following General Reaction Scheme I, or by another route, may be commercially available or may be prepared following organic chemical techniques.
II. Methods of Using Compounds of Formula (I) and Pharmaceutical Compositions Comprising Compounds of Formula (I)
[0096] Provided herein are methods of using the compounds disclosed herein, such as compounds of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II- A-ii), (P-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient. These include methods of inhibiting a component of the SREBP pathway, such as an SREBP or SCAP; and methods of treating a disorder in a subject in need thereof. In some embodiments, the disorder is mediated by an SREBP or SCAP.
[0097] The terms “treat,” "treating,” or "treatment" refers to any indicia of success in the amelioration of a disorder (such as injury, disease pathology, or condition), including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the disorder more tolerable to the subject; slowing or stopping the rate of degeneration, decline, or development; slowing the progression of disorder; making the final point of degeneration less debilitating; improving a subject’s physical or mental well-being; or relieving or causing regression of the disorder. The treatment of symptoms, including the amelioration of symptoms, can be based on objective or subjective parameters, which may include the results of a physical examination, a neuropsychiatric exam, and/or a psychiatric evaluation. Certain methods and uses disclosed herein may treat cancer by, for example, decreasing the incidence of cancer, causing remission of cancer, slowing the rate of growth of cancer cells, slowing the rate of spread of cancer cells, reducing metastasis, or reducing the growth of metastatic tumors, reducing the size of one or more tumors, reducing the number of one or more tumors, or any combinations thereof.
[0098] The embodiments described herein for methods of treatment should also be considered to apply to the use of compounds of Formula (I), (I- A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (P-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition comprising any of the forgoing, for the treatment of disorders; and the use of compounds of Formula (I), (I-A), (I- A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition comprising any of the forgoing, for inhibiting an SREBP or inhibiting the proteolytic activation of an SREBP; and other uses of compounds of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II- B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition comprising any of the forgoing, as described herein; and the use of compounds of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II- A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, in the manufacture of medicaments. A. Inhibiting SREBP or SCAP
[0099] Provided herein are uses and methods of inhibiting a component of the SREBP pathway, such as an SREBP or SCAP. In some embodiments, a combination of an SREBP and SCAP is inhibited. Such methods may include contacting an SREBP with a compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition comprising any of the forgoing and a pharmaceutically acceptable excipient. Such uses and methods may also include contacting SCAP with a compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II- A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition comprising any of the forgoing and a pharmaceutically acceptable excipient.
[00100] In certain embodiments, a compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B- i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof is administered to a subject in need thereof to inhibit a component of the SREBP pathway. In other embodiments, a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, is administered to the subject in need thereof. In certain embodiments, the amount of the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, relative to the subject’s body mass, is between about 0.01 mg/kg to about 100 mg/kg. In some embodiments, about 0.7 mg to about 7 g daily, or about 7 mg to about 350 mg daily, or about 350 mg to about 1.75 g daily, or about 1.75 to about 7 g daily of the compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II- B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof is administered to a subject in need thereof to inhibit a component of the SREBP pathway. In certain embodiments, the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, is administered as a pharmaceutical composition, as described herein. [00101] The component of the SREBP pathway that is inhibited by the methods and uses described herein may be an SREBP or SCAP. In some embodiments, an SREBP is inhibited.
The SREBP may be, for example, an SREBP-1 (such as SREBP-la or SREBP-lc) or SREBP-2. In certain variations, two or three of SREBP-la, SREBP-lc, and SREBP-2 are inhibited. In some embodiments, the component is an SREBP-1. In other embodiments, the SREBP is SREBP-la. In certain embodiments, the component is SREBP-lc. In still other embodiments, the SREBP is SREBP-2. In other embodiments, the component of the SREBP pathway is SCAP. In some embodiments, both an SREBP and SCAP are inhibited. In certain embodiments, two or three of SREBP-la, SREBP-lc, and SREBP-2 are inhibited, and SCAP is inhibited.
[00102] Inhibition of a component of the SREBP pathway, such as an SREBP or SCAP, may include partial inhibition or full inhibition. Partial inhibition may include reducing the activity of a component of the SREBP pathway to a level that is still detectable. Full inhibition may include stopping all activity of a component of the SREBP pathway (such as stopping the activity of an SREBP or SCAP), or reducing the activity of a component of the SREBP pathway to a level below detection. Inhibition of a component of the SREBP pathway may be measured directly or indirectly, using any methods known in the art.
[00103] In some embodiments, inhibition of a component of the SREBP pathway is measured directly, for example by measuring the product of a reaction catalyzed by an SREBP pathway component. Inhibition of SREBP activation (for example, by inhibiting SCAP) may in some embodiments be demonstrated by western blotting and quantitatively assessing the levels of full- length and cleaved SREBP-1 and/or SREBP-2 proteins from a cell line (such as a hepatic cell lines) or primary cells (such as primary hepatocytes of mouse, rat or human origin).
[00104] In some embodiments, inhibition of a component of the SREBP pathway is measured indirectly, for example by measuring the level of expression of one or more genes that are regulated by SREBP. The inhibition of a component of the SREBP pathway, such as an SREBP or SCAP, may reduce the expression of one or more genes that are regulated by an SREBP, for example an SREBP-1 (such as SREBP-la or SREBP-lc) or SREBP-2. SCAP plays a role in activating SREBPs, thus inhibiting the activity of SCAP may reduce the expression of one or more genes that are regulated by an SREBP. SREBP pathway inhibition may also be determined by assessing gene transcription levels of one or more target genes of SREBP-1 and/or SREBP-2, such as one or more of ACSS2, ALDOC, CYP51A1, DHCR7, ELOVL6, FASN, FDFT1, FDPS, HMGCS1, HSD17B7, IDI1, INSIG1, LDLR, LSS, ME1, PCSK9, PMVK, RDHll, SC5DL, SQLE, STARD4, TM7SF2, PNPLA3, SREBFl, SREBF2, HMGCR, MVD, MVK, ACLY, MSMOl, ACACA, or ACACB. The transcription levels may be assessed, for example, by transcriptomic analysis, including but not limited to q-PCR. A reduction in one, two, three, four, five, or more of these genes may indicate inhibition of SREBP activation. This evaluation of endogenous SREBP gene expression may be assessed in cell lines (such as hepatic cell lines) or primary cells (such as primary hepatocytes of mouse, rat, or human origin). In some embodiments, the gene transcription levels of PCSK9 or PNPLA3, or a combination thereof, are evaluated.
[00105] Therefore, provided herein are uses and methods of reducing the expression of one or more genes selected from the group consisting of ACSS2, ALDOC, CYP51A1, DHCR7, ELOVL6, FASN, FDFT1, FDPS, HMGCS1, HSD17B7, IDI1, INSIG1, LDLR, LSS, ME1, PCSK9, PMVK, RDHll, SC5DL, SQLE, STARD4, TM7SF2, PNPLA3, SREBFl, SREBF2, HMGCR, MVD, MVK, ACLY, MSMOl, ACACA, and ACACB, comprising contacting an SREBP or SCAP with a compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (P-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In some embodiments, the expression of PCSK9 is reduced. In other embodiments, the expression of PNPLA3 is reduced. In still further embodiments, both the expression of PCSK9 and PNPLA3 are reduced. In certain embodiments, one or more SREBP is contacted, for example an SREBP-1 (such as SREBP- la or SREBP- lc) or SREBP-2, or any combinations thereof. In other embodiments, SCAP is contacted. In still further embodiments, one or more of SREBP-la, SREBP-lc, SREBP-2, and SCAP is contacted. In certain embodiments, inhibition of a component of the SREBP pathway may treat a disorder mediated by an SREBP, such as the disorders as described herein. Thus, in certain embodiments, expression of one or more genes as described above is reduced in a subject in need thereof.
[00106] Another method of indirectly detecting SREBP pathway inhibition may include:
Serum-starving a hepatic cell line (HepG2) expressing luciferase under the control of the LSS- promoter to induce SREBP activation and increased luciferase expression. The cells may then be treated with a compound, such as a compound of Formula (I), (I- A), (I-A-i), (I-A-ii), (I-B), (I- B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. Following treatment, a reduction of luciferase activity reflects inhibition of SREBP activation, and non-cytotoxicity of the compound can be assessed by LDH release.
B. Treating a disorder
[00107] In other embodiments, provided herein are uses and methods of treating a disorder in a subject in need thereof, comprising administering to the subject in need thereof a compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In certain embodiments, provided herein are uses and methods of treating a disorder in a subject in need thereof, comprising administering to the subject in need thereof a pharmaceutical composition comprising a compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I- B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the compound is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In some embodiments, the compound is a compound of Formula (I-A), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In some embodiments, the compound is a compound of Formula (I-A-i), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In some embodiments, the compound is a compound of Formula (I-A-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In some embodiments, the compound is a compound of Formula (I-B), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In some embodiments, the compound is a compound of Formula (I-B-i), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In some embodiments, the compound is a compound of Formula (I-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In some embodiments, the compound is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In some embodiments, the compound is a compound of Formula (P-A), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In some embodiments, the compound is a compound of Formula (II-A-i), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In some embodiments, the compound is a compound of Formula (II-A-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In some embodiments, the compound is a compound of Formula (P-B), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In some embodiments, the compound is a compound of Formula (II-B-i), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof. In some embodiments, the compound is a compound of Formula (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
[00108] The uses and methods of treatment describe herein may use a compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising a compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I- B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient.
1. Metabolic Disorders
[00109] In some embodiments, the disorder is a metabolic disorder, such as a disorder that affects lipid metabolism, cholesterol metabolism, or insulin metabolism. In certain embodiments, the disorder is related to lipid metabolism, cholesterol metabolism, or insulin metabolism, for example, liver disease as a result of the buildup of fat in the liver, or cardiovascular disease.
[00110] In some embodiments, the disorder is a liver disease, such as chronic liver disease. In some embodiments, the liver disease is mediated by a component of the SREBP pathway, such as an SREBP or SCAP. In some embodiments, the liver disease is mediated by an SREBP. In certain embodiments, the liver disease is mediated by a downstream gene target of an SREBP, such as PNPLA-3. In other embodiments, the liver disease is mediated by SCAP. Thus, in some embodiments, provided herein are uses and methods of treating a liver disease in a subject in need thereof, comprising administering to the subject in need thereof a compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient. The chronic liver disease may be, for example, primary alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), or nonalcoholic steatohepatitis (NASH). In some embodiments, the liver disease is liver fat, liver inflammation, or liver fibrosis, or a combination thereof.
[00111] In certain embodiments, the liver disease is non-alcoholic fatty liver disease (NAFLD). NAFLD is a group of conditions that are related to fat buildup in the liver. Non-alcoholic steatohepatitis (NASH) is a form of NAFLD which includes liver inflammation. In NASH, the liver inflammation may lead to liver damage and scarring, which can be irreversible, and it can also progress to cirrhosis and liver failure. NAFLD and NASH are associated with metabolic disorders such as obesity, dyslipidemia, insulin resistance, and type 2 diabetes. Other disorders associated with NAFLD and NASH include increased abdominal fat and high blood pressure.
In some embodiments, NASH is mediated by a component of the SREBP pathway, such as an SREBP or SCAP.
[00112] In other embodiments, provided herein are uses and methods of treating NASH in a subject in need thereof, comprising administering to the subject in need thereof a compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient. Treatment of NASH may include reduction in average liver fat content, which may be evaluated, for example, by magnetic resonance imaging (MRI), magnetic resonance elastography (MRE), ultrasound, or computerized tomography (CT); reduction of the liver enzyme alanine aminotransferase (ALT); reduction of the liver enzyme aspartate aminotransferase (ALT); reduction of liver inflammation as evaluated through histological scoring of liver biopsy; reduction of liver fibrosis as evaluated through histological scoring of liver biopsy; reduction of liver fat content as evaluated through histological scoring of liver biopsy; or any combinations thereof. Treatment of NASH may be evaluated using the NAFLD activity score (NAS); or steatosis, activity, and fibrosis score (SAF); or other NASH diagnostic and/or scoring metrics (such as FIB4 or ELF).
[00113] Further provided herein are uses and methods of treating a disorder in a subject in need thereof, wherein the disorder is liver fibrosis associated with NASH, comprising administering to the subject in need thereof a compound of(I), (I- A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii),
(II), (P-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient. In some embodiments, the liver fibrosis is mediated by SREBP. Treatment of liver fibrosis may be evaluated, for example, by magnetic resonance imaging (MRI), magnetic resonance elastography (MRE), ultrasound, or computerized tomography (CT); reduction of the liver enzyme alanine aminotransferase (ALT); reduction of the liver enzyme aspartate aminotransferase (ALT); reduction of liver inflammation and/or fibrosis as evaluated through histological scoring of liver biopsy; or any combinations thereof
[00114] Further provided herein are uses and methods of treating a disorder in a subject in need thereof, wherein the disorder is fatty liver disease, comprising administering to the subject in need thereof a compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II- A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient. In some embodiments, the fatty liver disease is mediated by SREBP. In certain embodiments, a subject may have fatty liver disease when the fat content of the subject’s liver is 5% or greater. In some embodiments, a subject with fatty liver disease has NASH, or liver fibrosis associated with NASH. In certain embodiments, a subject with fatty liver disease has not been diagnosed with NASH or liver fibrosis associated with NASH. Treatment of fatty liver disease may be evaluated, for example, by magnetic resonance imaging (MRI), magnetic resonance elastography (MRE), ultrasound, or computerized tomography (CT); reduction of the liver enzyme alanine aminotransferase (ALT); reduction of the liver enzyme aspartate aminotransferase (ALT); reduction of liver inflammation as evaluated through histological scoring of liver biopsy; reduction of liver fibrosis as evaluated through histological scoring of liver biopsy; reduction of liver fat content as evaluated through histological scoring of liver biopsy; or any combinations thereof.
[00115] In some embodiments of the uses and methods of treating liver disease provided herein, such as methods of treating liver fibrosis, fatty liver disease, or NASH, the subject is administered between about 0.01 mg/kg to about 100 mg/kg of compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, relative to the body mass of the subject. In some embodiments, about 0.7 mg to about 7 g daily, or about 7 mg to about 350 mg daily, or about 350 mg to about 1.75 g daily, or about 1.75 to about 7 g daily of the compound of (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof is administered to the subject in need thereof. In certain embodiments, the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, is administered as a pharmaceutical composition, as described herein.
[00116] Other metabolic disorders which may be treated with the compounds or pharmaceutical compositions described herein may include, for example, insulin resistance, hyperglycemia, diabetes mellitus, dyslipidemia, adiposopathy, obesity, and Metabolic Syndrome. In some embodiments, the metabolic disorder is mediated by a genetic factor. In other embodiments, the metabolic disorder is mediated by one or more environmental factors, such as a diet rich in fat, or a diet rich in sugar, or a combination thereof. In some embodiments, the metabolic disorder is mediated by SREBP. In some embodiments, the diabetes mellitus is type I diabetes. In certain embodiments, the diabetes mellitus is type II diabetes.
[00117] Provided herein are uses and methods of treating diabetes in a subject in need thereof, comprising administering to the subject in need thereof a compound of Formula (I), (I-A), (I-A- i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient. Diabetes (also known as diabetes mellitus) refers to a disease or condition that is generally characterized by metabolic defects in production and utilization of glucose, which result in the failure to maintain appropriate blood sugar levels in the body. In some embodiments, the diabetes is type II diabetes, which is characterized by insulin resistance, in which insulin loses its ability to exert its biological effects across a broad range of concentrations. In some embodiments, the diabetes is mediated by a component of the SREBP pathway, such as an SREBP or SCAP.
[00118] Further provided herein are uses and methods of treating insulin resistance in a subject in need thereof, comprising administering to the subject in need thereof a compound of Formula ((I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient. Insulin resistance has been hypothesized to unify the clustering of hypertension, glucose intolerance, hyperinsulinemia, increased levels of triglyceride, decreased HDL cholesterol, and central and overall obesity. “Metabolic Syndrome” refers to a similar clustering of conditions, which may include abdominal obesity, hypertension, high blood sugar, high serum triglycerides (such as elevated fasting serum triglycerides), and low HDL levels, and is associated with a risk of developing cardiovascular disease and/or type II diabetes. Further provided herein are uses and methods of treating Metabolic Syndrome in a subject in need thereof, comprising administering to the subject in need thereof a compound of Formula (I), (I- A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B- ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient. In some embodiments, the Metabolic Syndrome or insulin resistance is mediated by a component of the SREBP pathway, such as an SREBP or SCAP.
[00119] In some embodiments of the uses and methods of treating insulin resistance, hyperglycemia, diabetes mellitus, obesity, or Metabolic Syndrome provided herein, the subject is administered between about 0.01 mg/kg to about 100 mg/kg of compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, relative to the body mass of the subject. In some embodiments, about 0.7 mg to about 7 g daily, or about 7 mg to about 350 mg daily, or about 350 mg to about 1.75 g daily, or about 1.75 to about 7 g daily of the compound of Formula (I), (I- A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II- A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof is administered to the subject in need thereof. In certain embodiments, the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, is administered as a pharmaceutical composition, as described herein.
[00120] In other embodiments, the metabolic disorder is dyslipidemia. Thus, in other embodiments, provided herein are uses and methods of treating dyslipidemia in a subject in need thereof, comprising administering to the subject in need thereof a compound of Formula(I), (I- A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B- ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient. Dyslipidemia refers to abnormal blood plasma levels of one or more lipids or one or more lipoproteins, or any combinations thereof. Dyslipidemia may include depressed levels or elevated levels of one or more lipids and/or one or more lipoproteins, or a combination of depressed and elevated levels (for example, elevated levels of one type of lipid and depressed levels of another type of lipid and/or lipoprotein). Dyslipidemia may include, but is not limited to, elevated low density lipoprotein cholesterol (LDL), elevated apolipoprotein B, elevated triglycerides (TGs), elevated lipoprotein(a), elevated apolipoprotein A, reduced high density lipoprotein cholesterol (HDL), or reduced apolipoprotein Al, or any combinations thereof. Dyslipidemia, such as abnormal cholesterol or abnormal TG levels, is associated with an increased risk for vascular disease (such as heart attack or stroke), atherosclerosis, and coronary artery disease. In some embodiments of the uses and methods provided herein, the dyslipidemia is hyperlipidemia. Hyperlipidemia refers to the presence of an abnormally elevated level of lipids in the blood, and may include (1) hypercholesterolemia (an elevated cholesterol level); (2) hypertriglyceridemia, (an elevated triglyceride level); and (3) combined hyperlipidemia, (a combination of hypercholesterolemia and hypertriglyceridemia). Dyslipidemia may arise from a combination of genetic predisposition and diet, and may be associated with being overweight, diabetes, or Metabolic Syndrome. Lipid disorders may also arise as the result of certain medications (such as those used for anti -rejection regimens in people who have had organ or tissue transplants). In some embodiments, the dyslipidemia, such as hyperlipidemia, is mediated by a component of the SREBP pathway, such as an SREBP or SCAP. Thus, in some embodiments, provided herein are uses and methods of reducing cholesterol levels, modulating cholesterol metabolism, modulating cholesterol catabolism, modulating the absorption of dietary cholesterol, reversing cholesterol transport, or lowering triglycerides in a subject in need thereof, comprising administering to the subject in need thereof a compound of Formula (I), (I-A), (I-A- i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient.
[00121] In some embodiments of the uses and methods of treating dyslipidemia provided herein, such as reducing cholesterol levels, modulating cholesterol metabolism, modulating cholesterol catabolism, modulating the absorption of dietary cholesterol, reversing cholesterol transport, or lowering triglycerides in a subject in need thereof as provided herein, the subject is administered between about 0.01 mg/kg to about 100 mg/kg of compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, relative to the body mass of the subject. In some embodiments, about 0.7 mg to about 7 g daily, or about 7 mg to about 350 mg daily, or about 350 mg to about 1.75 g daily, or about 1.75 to about 7 g daily of the compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof is administered to the subject in need thereof. In certain embodiments, the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, is administered as a pharmaceutical composition, as described herein.
[00122] In still other embodiments, provided herein are uses and methods of treating adiposopathy in a subject in need thereof, comprising administering to the subject in need thereof a compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II- A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient. In some embodiments, the adiposopathy is associated with Metabolic Syndrome. In some embodiments, the adiposopathy is mediated by a component of the SREBP pathway, such as an SREBP or SCAP.
[00123] In certain embodiments, provided herein are uses and methods of treating gallstones in a subject in need thereof, comprising administering to the subject in need thereof a compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient. Gallstones may be associated with gallbladder inflammation, pancreas inflammation, or liver inflammation. In certain embodiments, the gallstones are cholesterol gallstones, which may form when bile contains a high concentration of cholesterol and not enough bile salts. In some embodiments, the gallstones, which may include cholesterol gallstone disease, is mediated by a component of the SREBP pathway, such as an SREBP or SCAP.
[00124] In other embodiments, the disorder is pancreatitis. In yet other embodiments, the disorder is endotoxic shock, systemic inflammation, or xanthoma. In still further embodiments, the disorder is atherosclerosis, coronary artery disease, angina pectoris, carotid artery disease, stroke, or cerebral arteriosclerosis. In certain embodiments, any of the foregoing disorders are mediated by a component of the SREBP pathway, such as an SREBP or SCAP.
[00125] In some embodiments of the uses and methods of treating gall stones, pancreatitis, endotoxic shock, systemic inflammation, xanthoma, atherosclerosis, coronary artery disease, angina pectoris, carotid artery disease, stroke, or cerebral arteriosclerosis provided herein, the subject is administered between about 0.01 mg/kg to about 100 mg/kg of compound of (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, relative to the body mass of the subject. In some embodiments, about 0.7 mg to about 7 g daily, or about 7 mg to about 350 mg daily, or about 350 mg to about 1.75 g daily, or about 1.75 to about 7 g daily of the compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof is administered to the subject in need thereof. In certain embodiments, the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, is administered as a pharmaceutical composition, as described herein.
[00126] In some embodiments of any of the above embodiments, the subject is overweight, obese, has insulin resistance, is pre-diabetic or has type II diabetes. In certain embodiments of any of the preceding embodiments, the subject has NASH.
2. Hyperproliferative Disorders
[00127] In another embodiment, the disorder is a hyperproliferative disorder. Thus, in some embodiments, provided herein are uses and methods of treating a hyperproliferative disorder in a subject in need thereof, comprising administering to the subject in need thereof a compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient.
[00128] As described above, the metabolism of fatty acids, cholesterol, and triglycerides may play a role in hyperproliferative disorders, such as cancer. Often, during transformation of non- cancerous cells to cancerous cell, cell metabolism shifts from catabolic to anabolic processes. Depending on the type of tumor, the tumor cells may synthesize up to 95% of the saturated and mono-unsaturated fatty acids. Some cancers exhibit increased synthesis of fatty acids and other lipids (such as cholesterol), and steroids (such as androgens). Elevated fatty acid synthase (FAS) expression may induce progression to S phase in cancer cells, and inhibition of FAS expression may reduce cell growth and may induce apoptosis. Thus, components of the SREBP pathway may play a role in hyperproliferative disorders.
[00129] Hyperproliferative disorders, which are disorders associated with some degree of abnormal cell proliferation, may be benign or malignant. Benign hyperproliferative disorders may include pre-cancerous disorders.
[00130] In some embodiments of the uses and methods provided herein, the disorder is a benign hyperproliferative disorder. In some embodiments, the benign hyperproliferative disorder is mediated by a component of the SREBP pathway, such as an SREBP or SCAP. In other embodiments, the disorder is a malignant hyperproliferative disorder. In some embodiments, the malignant hyperproliferative disorder is mediated by a component of the SREBP pathway, such as an SREBP or SCAP.
[00131] In some embodiments, the hyperproliferative disorder is breast cancer, liver cancer, ovarian cancer, pancreatic cancer, prostate cancer, soft tissue sarcoma, bladder cancer, endometrial cancer, skin cancer, colon cancer, hematologic cancer, placenta cancer, brain cancer, kidney cancer, lung cancer, or bone cancer. Sarcoma can include cancers that begin in the bones and in the soft tissues. Sarcoma includes, for example, connective tissue cancers, such as muscle cancers.
[00132] In some embodiments of the uses and methods of treating a hyperproliferative disorder in a subject in need thereof, as described herein, between about 0.01 mg/kg to about 100 mg/kg. In some embodiments, about 0.7 mg to about 7 g daily, or about 7 mg to about 350 mg daily, or about 350 mg to about 1.75 g daily, or about 1.75 to about 7 g daily of the compound of Formula
(I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, relative to the body mass of the subject, is administered to the subject in need thereof. In certain embodiments, the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, is administered as a pharmaceutical composition, as described herein.
III. Dosing and Methods of Administration
[00133] The dose of a compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii),
(II), (P-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, administered to a subject in need thereof according to any of the disclosed methods may vary with the particular compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; the method of administration; the particular disorder being treated; and the characteristics of the subject (such as weight, sex, and/or age). In some embodiments, the amount of the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof is a therapeutically effective amount. [00134] The effective amount of the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, relative to the subject’s body mass, may in some embodiments be between about 0.01 mg/kg to about 100 mg/kg. In some embodiments, about 0.7 mg to about 7 g daily, or about 7 mg to about 350 mg daily, or about 350 mg to about 1.75 g daily, or about 1.75 to about 7 g daily of the compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I- B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof is administered to a subject in need thereof. In certain embodiments, the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, is administered as a pharmaceutical composition, as described herein.
[00135] Any of the uses and methods provided herein may comprise administering to a subject in need therein a pharmaceutical composition that comprises an effective amount of a compound provided herein, such as a compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B- ii), (II), (P-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a corresponding amount of a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient.
[00136] The compounds of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II- A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof as provided herein, or a pharmaceutical composition comprising any of these and a pharmaceutically acceptable excipient as provided herein, may be administered to a subject via any suitable route, including, for example, intravenous, intramuscular, subcutaneous, oral, or transdermal routes.
[00137] In certain embodiments, the present disclosure provides a method of treating a disorder in subject in need thereof by parenterally administering to the subject in need thereof an effective amount of a compound of Formula (I), (I-A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii),
(II), (P-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof as provided herein, or a pharmaceutical composition comprising an effective amount of any of the foregoing and a pharmaceutically acceptable excipient as provided herein. In some embodiments, the disorder is a hyperproliferative disorder. In certain embodiments, the hyperproliferative disorder is cancer. In other embodiments, the disorder is fatty liver disease. In certain embodiments, the disorder is NASH. In some embodiments, the route of administration is intravenous, intra-arterial, intramuscular, or subcutaneous. In some embodiments, the route of administration is transdermal.
[00138] In some embodiments, provided herein are pharmaceutical compositions comprising a compound of Formula(I), (I- A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II- A), (II-A-i), (II- A-ii), (P-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient, for the use in treating a disorder as described herein. In some embodiments, the disorder is prevented, or the onset delayed, or the development delayed. In some embodiments, the disorder is a hyperproliferative disorder. In certain embodiments, the hyperproliferative disorder is cancer. In some embodiments, the disorder is fatty liver disease. In certain embodiments, the disorder is NASH. In certain embodiments, the composition comprises a pharmaceutical formulation, which is present in a one or more unit dosage forms, for example one, two, three, four, or more unit dosage forms.
IV. Kits
[00139] Also provided are articles of manufacture comprising a compound of Formula (I), (I- A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B- ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or pharmaceutical compositions comprising any of the foregoing, or unit dosages comprising any of these, as described herein in suitable packaging for use in the methods described herein. Suitable packaging may include, for example, vials, vessels, ampules, bottles, jars, flexible packaging, and the like. An article of manufacture may further be sterilized and/or be sealed kits.
[00140] Further provided herein are kits comprising a compound of Formula (I), (I-A), (I-A-i),
(I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient. The kits may be used in any of the uses and methods described herein. In some embodiments, the kit further comprises instructions. The kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for the treatment of a hyperproliferative disorder (such as cancer), fatty liver disease, or NASH. The kits may comprise one or more containers. Each component (if there is more than one component) may be packaged in separate containers or some components may be combined in one container where cross-reactivity and shelf life permit.
[00141] The kits may be in unit dosage forms, bulk packages ( e.g ., multi-dose packages) or subunit doses. For example, kits may be provided that contain sufficient dosages of a compound of Formula (I), (I- A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (II- A), (II-A-i), (II-A-ii), (II- B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient, as disclosed herein and/or a second pharmaceutically active compound useful for a disorder detailed herein to provide effective treatment of a subject for an extended period, such as one week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. Kits may also include multiple unit doses of a compound of Formula (I), (I- A), (I-A-i), (I-A-ii), (I-B), (I-B-i), (I-B-ii), (II), (P-A), (II-A-i), (II-A-ii), (II-B), (II-B-i), or (II-B-ii), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition comprising any of the foregoing and a pharmaceutically acceptable excipient, and instructions for use, and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies or compounding pharmacies).
[00142] The kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g, magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component s) of the uses and methods as described herein. The instructions included with the kit may include information as to the components and their administration to an individual.
Enumerated Embodiments
[00143] Embodiment I- 1. A compound of Formula (I): or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, wherein:
X is N or CR4;
R4 is hydrogen, unsubstituted alkyl, or unsubstituted cycloalkyl;
Y is CH and Z is S, or Y is S and Z is CH;
R1 is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, heterocycloalkyl, heterocycloalkyl-alkyl, or alkyl-heterocycloalkyl; wherein each alkyl, cycloalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, heterocycloalkyl, heterocycloalkyl-alkyl, or alkyl-heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -OH and fluoro;
R2 is hydrogen, halo, or alkyl, wherein each alkyl is unsubstituted or substituted with fluorine;
R3 is -NR5S(0)2R6, -NR5S(0)2NR6R7, -NR5C(0)0R6, or -C(0)NR6R7;
R5, R6 and R7 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl, wherein each alkyl or cycloalkyl is unsubstituted or substituted with one with one or more substituents selected from the group consisting of -OH and fluorine; or R6 and R7, together with the nitrogen atom to which they are attached, form a heterocycloalkyl, which is unsubstituted or substituted with one or more substituents selected from the group consisting of -OH and fluorine. [00144] Embodiment 1-2. The compound of embodiment 1-1, wherein the compound is of Formula (I- A): or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
[00145] Embodiment 1-3. The compound of embodiment 1-1 or 1-2, wherein the compound is of Formula (I-A-i): or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
[00146] Embodiment 1-4. The compound of embodiment 1-1 or 1-2, wherein the compound is of Formula (I-A-ii): -ii), or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
[00147] Embodiment 1-5. The compound of embodiment 1-1, wherein the compound is of Formula (I- A): or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
[00148] Embodiment 1-6. The compound of embodiment 1-1 or 1-5, wherein the compound is of Formula (I-B-i): or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
[00149] Embodiment 1-7. The compound of embodiment 1-1 or 1-5, wherein the compound is of Formula (I-B-ii): or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
[00150] Embodiment 1-8. The compound of embodiment 1-1, wherein the compound is of Formula (II): or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
[00151] Embodiment 1-9. The compound of any one of embodiments 1-1, 1-2, or 1-8, wherein the compound is of Formula (II- A): or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
[00152] Embodiment 1-10. The compound of any one of embodiments 1-1 to 1-3 or 1-8, wherein the compound is of Formula (II-A-i): or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
[00153] Embodiment 1-11. The compound of any one of embodiments 1-1 to 1-2, 1-4, or 1-8, wherein the compound is of Formula (II-A-ii): or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
[00154] Embodiment 1-12. The compound of any one of embodiments 1-1, 1-5 or 1-8, wherein the compound is of Formula (P-B): or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
[00155] Embodiment 1-13. The compound of any one of embodiments 1-1, 1-5 to 1-6, or 1-8, wherein the compound is of Formula (II-B-i): or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
[00156] Embodiment 1-14. The compound of any one of embodiments 1-1, 1-5, or 1-7 to 1-8, wherein the compound is of Formula (II-B-ii): or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
[00157] Embodiment 1-15. The compound of any one of embodiments 1-1 to 1-13, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, wherein R1 is alkyl, unsubstituted or substituted with one or more substituents independently selected from the group consisting of -OH and fluoro.
[00158] Embodiment 1-16. The compound of any one of embodiments 1-1 to 1-14, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, wherein R1 is hydrogen. [00159] Embodiment 1-17. The compound of any one of embodiments 1-1 to 1-15, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, wherein R1 is cycloalkyl, unsubstituted or substituted with one or more substituents independently selected from the group consisting of -OH and fluoro.
[00160] Embodiment 1-18. The compound of any one of embodiments 1-1 to 1-16, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, wherein R1 is heterocycloalkyl, unsubstituted or substituted with one or more substituents independently selected from the group consisting of -OH and fluoro.
[00161] Embodiment 1-19. The compound of any one of embodiments 1-1 to 1-17, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, wherein R1 is alkyl- cycloalkyl, unsubstituted or substituted with one or more substituents independently selected from the group consisting of -OH and fluoro.
[00162] Embodiment 1-20. The compound of any one of embodiments 1-1 to 1-19, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, wherein R1 is substituted with one or more -OH.
[00163] Embodiment 1-21. The compound of any one of embodiments 1-1 to 1-20, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, wherein R2 is halo.
[00164] Embodiment 1-22. The compound of any one of embodiments 1-1 to 1-21, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, wherein R2 is chloro.
[00165] Embodiment 1-23. The compound of any one of embodiments 1-1 to 1-20, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, wherein R2 is alkyl, wherein each alkyl is unsubstituted or substituted with fluorine.
[00166] Embodiment 1-24. The compound of any one of embodiments 1-1 to 1-23, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, wherein R3 is - NR5S(0)2R6. [00167] Embodiment 1-25. The compound of any one of embodiments 1-1 to 1-23, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, wherein R3 is -NR5S(0)2NR6R7, -NR5C(0)0R6, or -C(0)NR6R7.
[00168] Embodiment 1-26. The compound of any one of embodiments 1-1 to 1-3, 1-5 to 1-6, 1-8 to 1-10, or 1-12 to 1-13, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, wherein R4 is unsubstituted alkyl.
[00169] Embodiment 1-27. The compound of any one of embodiments 1-1 to 1-26, selected from the group consisting of: acceptable salt, solvate, isotope, or isomer of any of the foregoing.
[00170] Embodiment 1-28. A pharmaceutical composition, comprising the compound of any one of embodiments 1-1 to 1-27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, and a pharmaceutically acceptable excipient. [00171] Embodiment 1-29. A method of inhibiting a sterol regulatory element-binding protein (SREBP), comprising contacting the SREBP or contacting an SREBP cleavage activating- protein (SCAP) with the compound of any one of embodiments 1-1 to 1-27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-28.
[00172] Embodiment 1-30. A method of inhibiting the proteolytic activation of a sterol regulatory element-binding protein (SREBP), comprising contacting an SREBP cleavage activating-protein (SCAP) with the compound of any one of embodiments 1-1 to 1-27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-28.
[00173] Embodiment 1-31. A method of treating a disorder in a subject in need thereof, wherein the disorder is mediated by a sterol regulatory element-binding protein (SREBP), comprising administering to the subject an effective amount of the compound of any one of embodiments 1-1 to 1-27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-28.
[00174] Embodiment 1-32. A method of treating a disorder in a subject in need thereof, comprising administering to the subject an effective amount of the compound of any one of embodiments 1-1 to 1-27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-28.
[00175] Embodiment 1-33. The method of any one of embodiments 1-29 to 1-31, wherein the SREBP is an SREBP-1.
[00176] Embodiment 1-34. The method of embodiment 1-33, wherein the SREBP-1 is SREBP- l a.
[00177] Embodiment 1-35. The method of embodiment 1-33, wherein the SREBP-1 is SREBP- lc.
[00178] Embodiment 1-36. The method of any one of embodiments 1-29 to 1-31, wherein the SREBP is SREBP-2. [00179] Embodiment 1-37. The method of any one of embodiments 1-29 to 1-36, wherein SREBP is inhibited in a subject in need thereof.
[00180] Embodiment 1-38. The method of any one of embodiments 1-29 to 1-37, wherein SCAP is inhibited in a subject in need thereof.
[00181] Embodiment 1-39. The method of any one of embodiments 1-29 to 1-38, comprising contacting SREBP or SCAP with the compound, or pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition, wherein the expression of one or more genes selected from the group consisting of ACSS2, ALDOC, CYP51A1, DHCR7, ELOVL6, FASN, FDFT1, FDPS, HMGCS1, HSD17B7, IDI1, INSIG1, LDLR, LSS, ME1, PCSK9, PMVK, RDH11, SC5DL, SQLE, STARD4, TM7SF2, PNPLA3, SREBF1, SREBF2, HMGCR, MVD, MVK, ACLY, MSMOl, AC AC A, and ACACB is reduced after contacting the SREBP or SCAP with the compound, or pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition.
[00182] Embodiment 1-40. The method of embodiment 1-31 or 1-32, wherein the disorder is Metabolic Syndrome, type 2 diabetes, obesity, liver disease, insulin resistance, adiposopathy, or dyslipidemia.
[00183] Embodiment 1-41. The method of embodiment 1-40, wherein the dyslipidemia is hypertriglyceridemia or elevated cholesterol levels.
[00184] Embodiment 1-42. The method of embodiment 1-40, wherein the liver disease is nonalcoholic steatohepatitis, liver fibrosis, or liver inflammation, or a combination thereof.
[00185] Embodiment 1-43. The method of embodiment 1-31 or 1-32, wherein the disorder is a hyperproliferative disorder.
[00186] Embodiment 1-44. The method of embodiment 1-43, wherein the hyperproliferative disorder is cancer.
[00187] Embodiment 1-45. The method of embodiment 1-44, wherein the cancer is breast cancer, liver cancer, ovarian cancer, pancreatic cancer, prostate cancer, soft tissue sarcoma, bladder cancer, endometrial cancer, skin cancer, colon cancer, hematologic cancer, placenta cancer, brain cancer, kidney cancer, lung cancer, or bone cancer.
[00188] Embodiment 1-46. The method of embodiment 1-31 or 1-32, wherein the disorder is endotoxic shock, systemic inflammation, or atherosclerosis.
[00189] Embodiment 1-47. Else of the compound of any one of embodiments 1-1 to 1-27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, in the manufacture of a medicament for inhibiting a sterol regulatory element-binding protein (SREBP) in a subject in need thereof.
[00190] Embodiment 1-48. The use of embodiment 1-47, wherein the inhibiting comprises contacting the SREBP or contacting an SREBP cleavage activating-protein (SCAP) with the compound or pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
[00191] Embodiment 1-49. Else of the compound of any one of embodiments 1-1 to 1-27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, in the manufacture of a medicament for inhibiting the proteolytic activation of a sterol regulatory element-binding protein (SREBP) in a subject in need thereof.
[00192] Embodiment 1-50. The use of embodiment 1-49, wherein the inhibiting comprises contacting an SREBP cleavage activating-protein (SCAP) with the compound or pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
[00193] Embodiment 1-51. Use of the compound of any one of embodiments 1-1 to 1-27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, in the manufacture of a medicament for treating a disorder in a subject in need thereof, wherein the disorder is mediated by a sterol regulatory element-binding protein (SREBP).
[00194] Embodiment 1-52. Use of the compound of any one of embodiments 1-1 to 1-27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, in the manufacture of a medicament for treating a disorder in a subject in need thereof. [00195] Embodiment 1-53. The use of any one of embodiments 1-47 to 1-51, wherein the SREBP is an SREBP-1.
[00196] Embodiment 1-54. The use of embodiment 1-53, wherein the SREBP-1 is SREBP-la.
[00197] Embodiment 1-55. The use of embodiment 1-53, wherein the SREBP-1 is SREBP-lc.
[00198] Embodiment 1-56. The use of any one of embodiments 1-47 to 1-51, wherein the SREBP is SREBP-2.
[00199] Embodiment 1-57. The use of any one of embodiments 1-47 to 1-56, wherein SREBP is inhibited in a subject in need thereof.
[00200] Embodiment 1-58. The use of any one of embodiments 1-47 to 1-57, wherein SCAP is inhibited in a subject in need thereof.
[00201] Embodiment 1-59. The use of any one of embodiments 1-47 to 1-58, wherein an SREBP or SCAP is contacted with the compound, or pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, and the expression of one or more genes selected from the group consisting of ACSS2, ALDOC, CYP51A1, DHCR7, ELOVL6, FASN, FDFT1, FDPS, HMGCS1, HSD17B7, IDI1, INSIG1, LDLR, LSS, ME1, PCSK9, PMVK, RDH11, SC5DL, SQLE, STARD4, TM7SF2, PNPLA3, SREBF1, SREBF2, HMGCR, MVD, MVK, ACLY, MSMOl, AC AC A, and ACACB is reduced after contacting the SREBP or SCAP with the compound, or pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
[00202] Embodiment 1-60. The use of embodiment 1-51 or 1-52, wherein the disorder is Metabolic Syndrome, type 2 diabetes, obesity, liver disease, insulin resistance, adiposopathy, or dyslipidemia.
[00203] Embodiment 1-61. The use of embodiment 1-60, wherein the dyslipidemia is hypertriglyceridemia or elevated cholesterol levels.
[00204] Embodiment 1-62. The use of embodiment 1-60, wherein the liver disease is nonalcoholic steatohepatitis, liver fibrosis, or liver inflammation, or a combination thereof. [00205] Embodiment 1-63. The use of embodiment 1-51 or 1-52, wherein the disorder is a hyperproliferative disorder.
[00206] Embodiment 1-64. The use of embodiment 1-63, wherein the hyperproliferative disorder is cancer.
[00207] Embodiment 1-65. The use of embodiment 1-64, wherein the cancer is breast cancer, liver cancer, ovarian cancer, pancreatic cancer, prostate cancer, soft tissue sarcoma, bladder cancer, endometrial cancer, skin cancer, colon cancer, hematologic cancer, placenta cancer, brain cancer, kidney cancer, lung cancer, or bone cancer.
[00208] Embodiment 1-66. The use of embodiment 1-51 or 1-52, wherein the disorder is endotoxic shock, systemic inflammation, or atherosclerosis.
[00209] Embodiment 1-67. Use of the compound of any one of embodiments 1-1 to 1-27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-28, for inhibiting a sterol regulatory element-binding protein (SREBP).
[00210] Embodiment 1-68. The use of embodiment 1-67, wherein the inhibiting comprises contacting the SREBP or contacting an SREBP cleavage activating-protein (SCAP) with the compound or pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
[00211] Embodiment 1-68. Use of the compound of any one of embodiments 1-1 to 1-27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-28, for inhibiting the proteolytic activation of a sterol regulatory element-binding protein (SREBP).
[00212] Embodiment 1-70. The use of embodiment 1-69, wherein the inhibiting comprises contacting an SREBP cleavage activating-protein (SCAP) with the compound or pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
[00213] Embodiment 1-71. Use of the compound of any one of \embodiments 1-1 to 1-27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-28, for treating a disorder in a subject in need thereof, wherein the disorder is mediated by a sterol regulatory element-binding protein (SREBP).
[00214] Embodiment 1-72. Use of the compound of any one of embodiments 1-1 to 1-27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-26, for treating a disorder in a subject in need thereof.
[00215] Embodiment 1-73. The use of any one of embodiments 1-67 to 1-71, wherein the SREBP is an SREBP-1.
[00216] Embodiment 1-74. The use of embodiment 1-73, wherein the SREBP-1 is SREBP-la.
[00217] Embodiment 1-75. The use of embodiment 1-73, wherein the SREBP-1 is SREBP-lc.
[00218] Embodiment 1-76. The use of any one of embodiments 1-67 to 1-71, wherein the SREBP is SREBP-2.
[00219] Embodiment 1-77. The use of any one of embodiments 1-67 to 1-76, wherein SREBP is inhibited in a subject in need thereof.
[00220] Embodiment 1-78. The use of any one of embodiments 1-67 to 1-77, wherein SCAP is inhibited in a subject in need thereof.
[00221] Embodiment 1-79. The use of any one of embodiments 1-67 to 1-78, wherein an SREBP or SCAP is contacted with the compound, or pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition, and the expression of one or more genes selected from the group consisting of ACSS2, ALDOC, CYP51A1, DHCR7, ELOVL6, FASN, FDFT1, FDPS, HMGCS1, HSD17B7, IDI1, INSIG1, LDLR, LSS, ME1, PCSK9,
PMVK, RDH11, SC5DL, SQLE, STARD4, TM7SF2, PNPLA3, SREBF1, SREBF2, HMGCR, MVD, MVK, ACLY, MSMOl, AC AC A, and ACACB is reduced after contacting the SREBP or SCAP with the compound, or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition. [00222] Embodiment 1-80. The use of embodiment 1-71 or 1-72, wherein the disorder is Metabolic Syndrome, type 2 diabetes, obesity, liver disease, insulin resistance, adiposopathy, or dyslipidemia.
[00223] Embodiment 1-81. The use of embodiment 1-80, wherein the dyslipidemia is hypertriglyceridemia or elevated cholesterol levels.
[00224] Embodiment 1-82. The use of embodiment 1-81, wherein the liver disease is nonalcoholic steatohepatitis, liver fibrosis, or liver inflammation, or a combination thereof.
[00225] Embodiment 1-83. The use of embodiment 1-71 or 1-72, wherein the disorder is a hyperproliferative disorder.
[00226] Embodiment 1-84. The use of embodiment 1-83, wherein the hyperproliferative disorder is cancer.
[00227] Embodiment 1-85. The use of embodiment 1-84, wherein the cancer is breast cancer, liver cancer, ovarian cancer, pancreatic cancer, prostate cancer, soft tissue sarcoma, bladder, cancer, endometrial cancer, skin cancer, colon cancer, hematologic cancer, placenta cancer, brain cancer, kidney cancer, lung cancer, or bone cancer.
[00228] Embodiment 1-86. The use of embodiment 1-71 or 1-72, wherein the disorder is endotoxic shock, systemic inflammation, or atherosclerosis.
[00229] Embodiment 1-87. A method of treating non-alcoholic steatohepatitis (NASH) in a subject in need thereof, comprising administering to the subject an effective amount of the compound of any one of embodiments 1-1 to 1-27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-28.
[00230] Embodiment 1-88. Use of the compound of any one of embodiments 1-1 to 1-27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-28, for treating non-alcoholic steatohepatitis (NASH) in a subject in need thereof. [00231] Embodiment 1-89. Use of the compound of any one of embodiments 1-1 to 1-27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-28, in the manufacture of a medicament for treating non-alcoholic steatohepatitis (NASH) in a subject in need thereof.
[00232] Embodiment 1-90. A method of treating a hyperproliferative disorder in a subject in need thereof, comprising administering to the subject an effective amount of the compound of any one of embodiments 1-1 to 1-27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-28.
[00233] Embodiment 1-91. Use of the compound of any one of embodiments 1-1 to 1-27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-28, for treating a hyperproliferative disorder in a subject in need thereof.
[00234] Embodiment 1-92. Use of the compound of any one of embodiments 1-1 to 1-27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-28, in the manufacture of a medicament for treating a hyperproliferative disorder in a subject in need thereof.
EXAMPLES
[00235] The following Examples are merely illustrative and are not meant to limit any aspects of the present disclosure in any way.
Synthesis Example 1: N-(3-chloro-4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)thiophen-2-yl)phenyl)methanesulfonamide
Step 2
[00236] Step 1 : Synthesis of 3-chloro-4-( 4, 4, 5, 5-tetramethyl-l , 3, 2 -dioxaborolan-2-yl) aniline. PdCk (dppf)-DCM adduct (791.87 mg, 0.969 mmol) was added to a stirred solution of 4-bromo- 3-chloroaniline (2 g, 9.69 mmol), bispinacolatodiboron (4.9 g, 19.38 mmol), and potassium acetate (2.8 g, 29.07 mmol) in 1,4-dioxane (20 mL). The reaction mixture was purged with nitrogen for 20 minutes and then heated to 80 °C for 16 h. The cooled mixture was filtered over celite bed and washed with ethyl acetate (80 mL). The combined organic layers were concentrated under reduced pressure to afford crude material which was dissolved in 5% ethyl acetate in pet ether, filtered and evaporated under reduced pressure to give the desired boronate ( 1.3 g) as an off white solid which was used for the next step without further purification.
[00237] Step 2: Synthesis of 4-(4-hromothiophen-2-yl)-3-chloroaniline. A stirred solution of the product of Step 1 (600 mg, 2.371 mmol), 2,4-dibromothiophene (573.74 mg, 2.371 mmol), potassium carbonate (981.30 mg, 7.113 mmol) in water (1.8 mL) and 1, 4-dioxane (6.0 mL) was purged with nitrogen for 5 min. Palladium tetrakis (273.85 mg, 0.237 mmol) was added and the reaction mixture again with purged with nitrogen for 30 minutes. After to 80 °C for 16 h, the reaction mixture was cooled, filtered through a bed of celite and washed with ethyl acetate (40 mL). The combined organic layers were concentrated under reduced pressure to afford crude (800 mg which was purified over silica gel to afford 4-(4-bromothiophen-2-yl)-3-chloroaniline (550 mg) as a light yellow gummy solid. [00238] Step 3: Synthesis ofN-(4-(4-bromothiophen-2-yl)-3-chlorophenyl)methanesulfonamide. Methanesulfonyl chloride (437.55 mg, 3.819 mmol) was added drop wise to a solution of the product of Step 2 (550 mg, 1.909 mmol) in pyridine (10 mL) at 0-5°C and stirred at rt for 4 h. The reaction mixture was quenched with water and the product extracted into DCM. The organic layer was washed with water, dried and concentrated under reduced pressure to a crude product which was purified over silica gel to give product N-(4-(4-bromothiophen-2-yl)-3- chlorophenyl)methanesulfonamide (450 mg) as a light yellow solid.
[00239] Step 4: Synthesis of N-(3-chloro-4-( 4-( 4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl)thiophen-2-yl)phenyl)methanesulfonamide. A mixture of the product of Step 3 (300 mg, 0.819 mmol), bispinacolato diboron (312.23 mg, 1.469 mmol) and potassium acetate (241.15 mg, 2.9367) in 1, 4-dioxane (30 mL) was purged with nitrogen, PdCh(dppf)-DCM adduct (66.93 mg, 0.082 mmol) was added and the mixture was again purged with nitrogen. The reaction mixture was heated to 80 °C for 16 hr, cooled to RT, filtered through a bed of celite and washed with ethyl acetate (30 mL). The combined organic layers were concentrated under reduced pressure to afford a crude product which was dissolved in 5% ethyl acetate in pet ether, filtered and evaporated under reduced pressure to give the desired boronate (0.4g) as a gum which was used for the preparation of other compounds without further purification.
Synthesis Example 2: 5-(5-(4-amino-2-chlorophenyl)thiophen-3-yl)-l-cyclopropylpyridin- 2(lH)-one
Step 2
[00240] Step 1: Synthesis of l-cyclopropyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2(lH)-one. A stirred solution of 5-bromo-l-cyclopropylpyridin-2(lH)-one (0.45 g, 2.11 mmol), bispinacolatodiboron (0.80 g, 3.16 mmol) and potassium acetate (0.62 g, 6.33 mmol) in 1, 4-dioxane (10 mL) in a 100 ml glass tube, was purged with nitrogen for 20 minutes.
PdCh (dppf) (0.15 g, 0.21 mmol) as added and the reaction mixture was again purged with nitrogen and then stirred to 80 °C for 16 h. The reaction mixture was then cooled, filtered through a bed of celite and evaporated under reduced pressure.
[00241] Step 2: Synthesis of 5-(5-(4-amino-2-chlorophenyl)thiophen-3-yl)-l- cyclopropylpyridin-2( lH)-one. A suspension of 4-(4-bromothiophen-2-yl)-3-chloroaniline (0.4 g, 1.39 mmol), the product of Step 1 (0.54 g, 2.08 mmol) and K2CO3 (0.57 g, 4.17 mmol) in 1, 4-dioxane and water (10 mL) was reacted with Pd(PPh3)4 (0.16 g, 0.13 mmol) under the same conditions as Step 1. After 16hr the reaction mixture was cooled, filtered over a bed of celite, concentrated the filtrate under reduced pressure and purified by reverse phase column chromatography to give 5-(5-(4-amino-2-chlorophenyl)thiophen-3-yl)-l-cyclopropylpyridin- 2(lH)-one as yellow oil (0.19g, 40%).
Synthesis Example 3: (4-(4-bromothiophen-2-yl)-3-chlorophenyl)(4-hydroxypiperidin-l- yl)methanone
[00242] Step 1: Synthesis of 4-(4-bromothiophen-2-yl)-3-chlorobenzoic acid. A mixture of 2,4- dibromothiophene (0.500 g, 2.066 m.mol), 4-borono-3-chlorobenzoic acid (0.518 g, 2.583) and Na2CCb (0.559 g, 5.371 m.mol) in DMF and water in a glass seal tube was purged with nitrogen gas for 10 minutes. After adding palladium tetrakis (0.239 g, 0.206 m.mol) the mixture was again purged with nitrogen gas for 10 minutes, sealed and then stirred at 100°C for 16 h. The reaction mixture was then cooled to RT and evaporated under reduced pressure and 10ml water was added. The precipitated solid was filtered, washed with cold water (5x2mL) and finally dried under reduced pressure to give 4-(4-bromothiophen-2-yl)-3-chlorobenzoic acid (0.460 g, (70.76%) as an off white solid.
[00243] Step 2: Synthesis of (4-(4-bromothiophen-2-yl)-3-chlorophenyl)(4-hydroxypiperidin-l- yl)methanone. To a solution of 4-(4-bromothiophen-2-yl)-3-chlorobenzoic acid (0.450 g, 1.428 m. moles), in DMF (1.8 mL, 20 v), was added DIPEA (0.790 mL 4.284 m. moles) and HATU (0.815g, 2.142 m. moles). After stirring for 30min atRT, 4-hydroxy piperidine (0.173 g, 1.714 m. moles) was added and stirred was continued for another 16h. The reaction mixture was diluted with ethyl acetate and washed with cold water (4 x 5ml). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude material which was purified by column chromatography (silica gel: #230-400) using 20-60% EtOAc in hexane as eluent to afford (4-(4-bromothiophen-2-yl)-3-chlorophenyl)(4-hydroxypiperidin-l- yl)methanone (0.270 g, 50.0%) as a pale yellow semi-solid. *H NMR (400 MHz, DMSO d6): d (ppm): 7.87 (1H, 7=1.6 Hz, d), 7.72-7.70 (1H, 7 = 8Hz, d), 7.60-7.59 (1H, 7=1.6 Hz, d), 7.52- 7.51 (1H, 7=1.6 Hz, d), 7.42-7.40 (1H, 7=1.6 Hz, d), 4.80-4.79 (1H, 7=1.6 Hz, d), 4.03-3.98 (1H, m), 3.77-3.71 (1H, m), 3.48 (1H, m), 3.29-3.25 (2H, m), 2.73 (1H, m), 1.98-1.90 (2H, m), 1.78- 1.72 (2H, m); MS (m/z = 399.06) [M+H]).
Synthesis Example 4: N-(3-chloro-4-(4-(6-oxo-l-propyl-l,6-dihydropyridin-3-yl)thiophen- 2-yl)phenyl)methanesulfonamide (1-9102)
[00244] Step 1: Synthesis of 5-bromo-l-propylpyridin-2(lH)-one. To a stirred solution of 5- bromopyridin-2(lH)-one (1.0 g, 5.78 mmol) in DMF (15 mL) was added 1-iodopropane (1.17 g, 6.93 mmol) & K2CO3 (2.39 g, 17.34 mmol). The reaction mixture was heated to 80 °C while stirring for 16 h and then quenched with water. The product was extracted into ethyl acetate and the organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The crude was purified by column chromatography over silica by using 4% of MeOH/DCM as eluent to give 5-bromo-l-propylpyridin-2(lH)-one as a yellow liquid (0.7g;
56% yield). Ή NMR 400 MHz, CDCb: d 7.38 (d, J = 2.4 Hz, 1H), 7.33 (dd, J = 2.40, 9.60 Hz, 1H), 6.49 (d, J = 9.60 Hz, 1H), 3.87-3.84 (m, 2H), 1.80-1.74 (m, 2H), 0.96 (t, J = 7.20, 3H); LCMS 93.58% ((M+H) 216.08) [00245] Step 2: Synthesis of N-(3-chloro-4-(4-(6-oxo-l -propyl-1, 6-dihydropyridin-3- yl)thiophen-2-yl)phenyl)methanesulfonamide. To a stirred solution of the product of step 1 (200 mg, 0.93 mmol) in 1, 4-dioxane: H2O (10 mL) was added (5-(2-chloro-4- (methylsulfonamido)phenyl)thiophen-3-yl)boronic acid (461.7 mg, 1.39 mmol) & K2CO3 (385.02 mg, 2.79 mmol). The reaction mixture was purged with N2, Pd(PPh3)4 (103.9 mg, 2.79 mmol) was added then heated to 80°C while stirring for 16 h. The reaction mixture was cooled 25°C, filtered through a celite bed, which was then washed with ethyl acetate (30 mL). The combined organic layers were dried and then concentrated under reduced pressure to give a crude product which was purified by prep-HPLC, to give N-(3 -chi oro-4-(4-(6-oxo-l -propyl- 1,6- dihydropyridin-3-yl)thiophen-2-yl)phenyl)methanesulfonamide (28mg) as an off-white solid. 'H NMR 401 MHz, DMSO: d 10.17 (s, 1H), 8.20 (d, J= 2.4 Hz, 1H), 7.88 (dd, 7=2.4, 5.2 Hz, 1H), 7.78 (d, J= 1.2 Hz, 1H), 7.72 (d, J= 1.2 Hz, 1H), 7.68 (d, J= 8.4 Hz, 1H), 7.37 (d, J= 2.0 Hz, 1H), 7.26 (dd, 7=2.0, 8.4 Hz, 1H), 6.47 (d, 7= 9.2 Hz, 1H), 3.89 (t, 7= 7.2 Hz, 2H), 3.10 (s, 3H), 1.74-1.65 (m, 2H), 0.89 (t, 7= 7.2 Hz, 3H); LCMS: 99.80% ((M+H) 423.21).
Synthesis Example 5: N-(3-chloro-4-(4-(l-cyclopropyl-6-oxo-l,6-dihydropyridin-3- yl)thiophen-2-yl)phenyl)methanesulfonamide (1-9156)
[00246] To a stirred solution of 5-bromopyridin-2(lH)-one (1.5 g, 8.67 mmol) in toluene: water (20 mL) was added potassium cyclopropyltriflouroborate (3.84 g, 26.01 mmol), K2CO3 (2.39 g, 17.34 mmol) 1,10-phenanthroline (3.12 g, 17.34 mmol) and copper acetate (1.57 g, 8.67 mmol). The reaction mixture was purged with nitrogen for 10 min and heated to 80°C while stirring for 16 h. It was then cooled to RT, water added and the product extracted into EtOAc (3x20 mL). The extracts were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product which was purified by column chromatography to afford 5-bromo-l-cyclopropylpyridin-2(lH)-one (0.35g, 22%) as a light yellow liquid. Reaction of this product with (5-(2-chloro-4-(methylsulfonamido)phenyl)thiophen-3-yl)boronic acid as described in Example 1 gave N-(3-chloro-4-(4-(l-cyclopropyl-6-oxo-l,6-dihydropyridin-3- yl)thiophen-2-yl)phenyl)methanesulfonamide (42 mg; 7%) as a light brown solid. 'H NMR 400 MHz, DMSO-de: d 10.16 (s, 1H), 7.86-7.80 (m, 3H), 7.75 (d, J = 1.20 Hz, 1H), 7.69 (d, J = 8.40 Hz, 1H), 7.36 (d, J = 2.00 Hz, 1H), 7.24 (dd, J = 2.00, 8.60 Hz, 1H), 6.46 (d, J = 9.20 Hz, 1H), 3.40-3.35 (m, 1H), 3.09 (s, 3H), 0.97-0.99 (m, 4H); LCMS: 99.04 % (421.09 [M+H] +).
Synthesis Example 6: N-(3-chloro-4-(4-(6-oxo-5-propyl-l,6-dihydropyridin-3-yl)thiophen- 2-yl)phenyl)methanesulfonamide (1-9169)
[00247] Step 1: Synthesis of 3-allyl-5-bromopyridin-2-yl 4-methylbenzenesulfonate. A solution of i-PrMgCl LiCl (1.55 M in THF, 12.84 mmol) was added slowly at -30 °C to a solution of 3,5-dibromopyridin-2-yl 4-methylbenzenesulfonate (2.6 g, 6.42 mmol) in dry THF (35 mL) and stirred at this temperature for 2 h. Allylbromide (0.69 g, 5.77 mmol in 5 mL of THF) and CuCN-2LiCl (2 mol %, 10 pL, 1.0 M in THF) were added and the reaction mixture was warmed to 25 °C. The reaction mixture was quenched with saturated aqueous NH4CI and the product extracted into diethyl ether. The extract was washed with brine, dried (NaiSCri) and concentrated in vacuum to give a crude product which was purified by column chromatography to give as 3- allyl-5-bromopyridin-2-yl 4-methylbenzenesulfonate (1.45g; 63%) as an oil.
[00248] Step 2: Synthesis of 5-bromo-3-propyIpyridin-2-yI 4-methylbenzenesulfonate. To a stirred solution of the product of Step 1 (1.45 g, 3.95 mmol) in EtOAc (20 mL) was added platinum oxide (0.44 g, 1.97 mmol) under hydrogen atmosphere. The reaction mixture was stirred at rt for 4 h, filtered over a celite bed and evaporated to dryness to give a crude product which was purified by reverse phase column chromatography to give 5-bromo-3-propylpyridin- 2-yl 4-methylbenzenesulfonate (lg; 69%) as a viscous liquid.
[00249] Step 3: Synthesis of 5-bromo-3-propylpyridin-2(lH)-one. To a stirred solution of the product of Step 2 (1.0 g, 1.89 mmol) in THF (15 mL) was added KOH (0.30 g, 5.42 mmol) at 0 °C and the mixture was subjected to microwave irradiation at 100 °C for lh. The reaction was quenched with ice cold water and the product extracted into ethyl acetate. The organic layer was dried and concentrated to give a crude product that was purified by silica gel column chromatography to give 5-bromo-3-propylpyridin-2(lH)-one (0.5g; 86%) as brown solid.
[00250] Step 4: Synthesis of N-(3-chloro-4-( 4-( 6-oxo-5-propyl-l , 6-dihydropyridin-3- yl)thiophen-2-yl)phenyl)methanesulfonamide. Reaction of the product of Step 3 with (5-(2- chloro-4-(methylsulfonamido)phenyl)thiophen-3-yl)boronic acid as described in Example 1 gave N-(3-chloro-4-(4-(6-oxo-5-propyl-l,6-dihydropyridin-3-yl)thiophen-2- yl)phenyl)methanesulfonamide (14mg; 6%) as a light brown solid. 1HNMR 400 MHz, DMSO- d6: d 11.67 (br s, 1H), 10.22 (br s, 1H), 7.72 (m, 2H), 7.66 (m, 2H), 7.60 (d, J = 7.20 Hz, 1H), 7.27 (m, 1H), 7.12 (d, J = 7.60 Hz, 1H), 2.98 (s, 3H), 2.43 (t, J = 7.60 Hz, 2H), 1.60-1.52 (m, 2H), 0.92 (t, J = 7.60 Hz, 3H); LCMS: 99.18 % (m/z = 423.11 [M+H]).
Synthesis Example 7: N-(3-chloro-4-(4-(l-methyl-6-oxo-5-propyl-l,6-dihydropyridin-3- yl)thiophen-2-yl)phenyl)methanesulfonamide (1-9184)
Step 2
[00251] Step 1: Synthesis of 5-bromo-l-methyl-3-propylpyridin-2(lH)-one. To a stirred solution of 5-bromo-3-propylpyridin-2(lH)-one (0.6 g, 2.79 mmol) in DMF (10 mL) was added NaH (60%, 0.26 g, 11.16 mmol) at 0°C. After 15 minutes methyl iodide (0.86 mL, 13.95 mmol) was added and the reaction mixture was stirred for 4 h at room temperature. The reaction was quenched with ice cold water and the product was extracted into ethyl acetate. The organic extract was dried over sodium sulfate, evaporated to dryness and the residue was purified by reverse phase column chromatography (0.01%Ammoniumbicarbonate in MeOH as eluent to give 5-bromo-l-methyl-3-propylpyridin-2(lH)-one (0.45g; 54%) as a yellow liquid.
[00252] Step 2: Synthesis of N-( 3-chloro-4-( 4-( 1 -methyl-6-oxo-5-propyl-l , 6-dihydropyridin-3- yl)thiophen-2-yl)phenyl)methanesulfonamide. Reaction of the product of Step 3 with (5-(2- chloro-4-(methylsulfonamido)phenyl)thiophen-3-yl)boronic acid as described in Example 1 gave N-(3-chloro-4-(4-(l-methyl-6-oxo-5-propyl-l,6-dihydropyridin-3-yl)thiophen-2- yl)phenyl)methanesulfonamide (21mg; 2%) as a white solid. 1HNMR400 MHz, DMSO-d6: d 10.17 (s, 1H), 8.09 (d, J = 2.40 Hz, 1H), 7.76 (d, J = 1.60 Hz, 1H), 7.73-7.66 (m, 3H), 7.37 (d, J = 2.40 Hz, 1H), 7.25 (dd, J = 2.40, 8.40 Hz, 1H), 3.49 (s, 3H), 3.09 (s, 3H), 2.45 (t, J = 7.20 Hz, 2H), 1.60-1.55 (m, 2H), 0.91 (t, J = 7.20 Hz, 3H); LCMS: 99.94 % (m/z = 437.35 [M+H]+).
Synthesis Example 8: N-(3-chloro-4-(4-(2-oxo-l-propyl-l,2-dihydropyrimidin-5- yl)thiophen-2-yl)phenyl)methanesulfonamide (1-9150)
[00253] Step 1: Synthesis of 5-bromo-l-propylpyrimidin-2(lH)-one. l-iodopropane((0.33 mL, 3.46 mmol) was added dropwise to a stirred solution of 5-bromopyrimidin-2(lH)-one (0.5 g, 2.89 mmol) and potassium carbonate (1.19 g, 8.67 mmol) in DMF (10 mL). The reaction mixture was heated for 16 h at 80 °C, quenched with ice cold water and the product extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure to afford a crude product which was purified by column chromatography by using silica to get 5- bromo-l-propylpyrimidin-2(lH)-one (0.45g; 82%) as a brown solid. [00254] Step 2: Synthesis of N-(3-chloro-4-(4-(2-oxo-l -propyl-1, 2-dihydropyrimidin-5- yl)thiophen-2-yl)phenyl)methanesulfonamide. Reaction of the product of Step 2 with (5-(2- chloro-4-(methylsulfonamido)phenyl)thiophen-3-yl)boronic acid as described in Example 1 gave N-(3-chloro-4-(4-(2-oxo-l-propyl-l,2-dihydropyrimidin-5-yl)thiophen-2- yl)phenyl)methanesulfonamide (29mg; 5%) as a white solid. 1HNMR 400 MHz, DMSO-d6: d 10.21 (s, 1H), 9.05 (d, J = 3.20 Hz, 1H), 8.67 (d, J = 3.20 Hz, 1H), 7.91 (d, J = 1.20 Hz, 1H),
7.75 (d, J = 1.60 Hz, 1H), 7.66 (d, J = 8.80 Hz, 1H), 7.37 (d, J = 2.40 Hz, 1H), 7.25 (dd, J = 2.40, 8.60 Hz, 1H), 3.86 (t, J = 7.20 Hz, 2H), 3.09 (s, 3H), 1.77.-1.71 (m, 2H), 0.90 (t, J = 7.20 Hz, 3H); LCMS: 96.21 % (424.37 [M+H] +).
Synthesis Example 9: N-(3-chloro-4-(4-(l-(2-hydroxy-2-methylpropyl)-6-oxo-l,6- dihydropyridin-3-yl)thiophen-2-yl)phenyl)methanesulfinamide (1-9217)
Step 2
[00255] Stepl: Synthesis of 5-bromo-l-(2-hydroxy-2-methylpropyl)pyridin-2(lH)-one. To a stirred solution of 5-bromopyridin-2(lH)-one (0.5 g, 2.87 mmol) in DMF (5 mL), was added 2,2-dimethyloxirane (0.62 g, 8.62 mmol) and K2CO3 (1.18 g, 8.62 mmol). The reaction mixture was stirred at 130°C in microwave for 30 min then diluted with ice water and product extracted into EtOAc. The organic solvents were dried over anhydrous sodium sulfate and evaporated under reduced pressure to give a crude product which was purified by column chromatography to give 5-bromo-l-(2-hydroxy-2-methylpropyl)pyridin-2(lH)-one (0.22 g, 29%) as a yellow oil. ¾NMR (400 MHz, DMSO-d6): d 7.81 (d, J= 2.80 Hz, 1H), 7.52 (dd, J= 2.80 Hz and 9.60 Hz, 1H), 6.39 (d, J= 9.60 Hz, 1H), 4.77 (s, 1H), 3.87 (s, 2H), 1.06 (s, 6H).
[00256] Step 2: Synthesis of N-(3-chloro-4-(4-(l-(2-hydroxy-2-methylpropyl)-6-oxo-l ,6- dihydropyridin-3-yl)thiophen-2-yl)phenyl)methanesulfinamide. The product of Step 1 was reacted with N-(3-chloro-4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophen-2- yl)phenyl)methanesulfonamide as described in Example 1 to give N-(3-chloro-4-(4-(l-(2- hydroxy-2-methylpropyl)-6-oxo-l,6-dihydropyridin-3-yl)thiophen-2- yl)phenyl)methanesulfmamide as a white solid. 1HNMR (400 MHz, DMSO-d6): d 10.20 (br s, 1H), 8.07 (d, J= 2.40 Hz, 1H), 7.89-7.86 (dd, J= 2.40 Hz and 9.40 Hz, 1H), 7.71 (s, 1H), 7.58 (m, 2H), 7.31 (d, J= 2.00 Hz, 1H), 7.18-7.15 (dd, J= 2.00 Hz and 8.80 Hz, 1H), 6.49 (dd, J = 9.20 Hz, 1H), 4.83 (s, 1H), 3.97 (s, 2H), 3.02 (s, 3H), 1.10 (s, 6H); MS (m/z = 453.19 [M+H]).
Synthesis Example 10: N-(3-chloro-4-(4-(6-oxo-l-(tetrahydrofuran-3-yl)-l,6- dihydropyridin-3-yl)thiophen-2-yl)phenyl)methanesulfonamide (1-9218)
Step 1 ,
Step 2
[00257] Step 1: Synthesis of 5-bromo-l-(tetrahydrofuran-3-yl)pyridin-2(lH)-one. 5- bromopyridin-2(lH)-one (1 g, 3.93 mmol) in DMF (10 mL), was reacted with 3- bromotetrahydrofuran (0.72 g, 3.54 mmol) and K2CO3 (1.62 g, 11.79 mmol) at rt for 16 h. After aqueous work up and purification by column chromatography, 5-bromo-l-(tetrahydrofuran-3- yl)pyridin-2(lH)-one was isolated as a brown solid (0.1 g, 11%). 1HNMR (400 MHz, DMSO- d6): d 7.69 (d, J= 2.40 Hz, 1H), 7.52 (dd, J= 2.40, 9.80 Hz, 1H), 6.39 (d, J= 10.00 Hz, 1H), 5.29-5.25 (m, 1H), 4.04-4.03 (m, 1H), 3.87-3.86 (m, 1H), 3.77-3.74 (m, 1H), 3.70-3.68 (m, 1H), 2.42-2.41 (m, 1H), 1.99-1.98 (m, 1H).
[00258] Step 2: Synthesis of N-(3-chloro-4-(4-(6-oxo-l-(tetrahydrofuran-3-yl)-l ,6- dihydropyridin-3-yl)thiophen-2-yl)phenyl)methanesulfonamide. The product of Step 1 was reacted withN-(3-chloro-4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophen-2- yl)phenyl)methanesulfonamide as described in Example 1 to give N-(3-chloro-4-(4-(6-oxo-l- (tetrahydrofuran-3-yl)-l,6-dihydropyridin-3-yl)thiophen-2-yl)phenyl)methanesulfonamide as a white solid. 1H NMR (400 MHz, DMSO): d 10.19 (s, 1H), 7.86-7.83 (m, 2H), 7.79 (d, J= 1.4 Hz, 1H), 7.67-7.64 (m, 2H), 7.34 (d, J= 2.4 Hz, 1H), 7.23-7.20 (dd, J= 2.0 Hz and 8.8 Hz, 1H), 6.50 (d, J= 6.8 Hz, 1H), 5.45-5.37 (m 1H), 4.14-4.08 (m, 1H), 3.95-3.85 (m 2H), 3.77 (q, J =
8.4 Hz, 1H), 3.06 (s, 3H), 2.48-2.40 (m, 1H), 2.16-2.06 (m, 1H); MS (m/z = 451.18 [M+H]).
[00259] The following compounds were prepared in a similar fashion:
Synthesis Example 11: N-(3-chloro-4-(4-(l-(l-(hydroxymethyl)cyclopropyl)-6-oxo-l,6- dihydropyridin-3-yl)thiophen-2-yl)phenyl)methanesulfonamide (1-9223) Step 1 Step-2 80 “C, 16 h
Step-3
[00260] Step 1: Synthesis of Methyl l-(5-bromo-2-oxopyridin- 1 (2H)-yl)cyclopropane- 1- carboxylate. A suspension of 5-bromopyridin-2(lH)-one (3 g, 17.24 mmol), methyl 2,4- dibromobutanoate (6.72 g, 25.86 mmol) and K2CO3 (9.53 g, 68.97 mmol) in DMF (25 ml) was stirred at rt for 24h. The reaction mixture was evaporated under vacuum and the residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated to afford the crude compound was purified by column chromatography to give methyl l-(5-bromo-2-oxopyridin-l(2H)-yl)cyclopropane-l-carboxylate as a pale brown solid (1.3g, 24%). [00261] Step 2: Synthesis of 5-bromo-l-( l-(hydroxymethyl)cyclopropyl)pyridin-2( lH)-one. A suspension of methyl l-(5-bromo-2-oxopyridin-l(2H)-yl)cyclopropane-l-carboxylate (250 mg, 0.92 mmol) in THF/ethanol (20 ml) was cooled to 0 °C and NaBFF (174 mg, 4.59 mmol) was added slowly over 10 minutes at the same temperature. The reaction mixture was warmed to RT and stirred for 6h. The solvent was evaporated under vacuum and the residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated to afford the crude compound which was purified by column chromatography to give 5-bromo-l-(l-(hydroxymethyl)cyclopropyl)pyridin-2(lH)-one as a pale brown solid.
[00262] Step 3: Synthesis of N-( -chloro-4-( 4-( l-(l -(hydroxymethyl)cyclopropyl)-6-oxo-l, 6- dihydropyridin-3-yl)thiophen-2-yl)phenyl)methanesulfonamide. The product of Step 2 was reacted with N-(3-chloro-4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophen-2- yl)phenyl)methanesulfonamide as described in Example 1 to give N-(3-chloro-4-(4-(l-(l- (hydroxymethyl)cyclopropyl)-6-oxo-l,6-dihydropyridin-3-yl)thiophen-2- yl)phenyl)methanesulfonamide as an off white solid. 1HNMR (400 MHz, DMSO-dr,): d 10.19 (br s, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.84-7.81 (dd, J = 2.4 Hz and 9.6 Hz, 1H), 7.74 (d, J = 0.8 Hz, 1H), 7.65 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 2.0 Hz, 1H), 7.19-7.16 (dd, J = 2.0 Hz and 8.8 Hz, 1H), 6.42 (d, J = 9.2 Hz, 1H), 4.90 (t, J = 5.6 Hz, 1H), 3.56 (s, 2H), 3.02 (s, 3H), 1.04 (s, 4H); MS (451.18 [M+H] +).
Synthesis Example 12: N-(3-chloro-4-(4-(l-(2,3-dihydroxy-2-methylpropyl)-6-oxo-l,6- dihydropyridin-3-yl)thiophen-2-yl)phenyl)methanesulfonamide (1-9224)
[00263] Step 1: Synthesis of 5-bromo-l-((2-methyloxiran-2-yl)methyl)pyridin-2(lH)-one. A solution of 5-bromopyridin-2(lH)-one (5 g, 28.74 mmol) in DMF (50 mL), 2-(chloromethyl)-2- methyloxirane (9.13 g, 86.2 mmol) and CS2CO3 (11.89 g, 86.2 mmol) was stirred at 80°C in sealed tube for 8h. After aqueous work up and purification by column chromatography 5-bromo- l-((2-methyloxiran-2-yl)methyl)pyridin-2(lH)-one (0.45 g, 6%) was isolated as a as a yellow oil.
[00264] Step 2: Synthesis of 5-hromo- 1 -( 2,3-dihydroxy-2-methyIpropyI)pyridin-2( l H)-one. The product of Step 1 in dioxane (3 mL) and 2M H2SO4 (5 mL) was stirred at rt for overnight and, after aqueous work up, was purified by column chromatography to give 5-bromo-l-(2,3- dihydroxy-2-methylpropyl)pyridin-2(lH)-one (0.38 g, 78%) as a yellow oil.
[00265] Step 3: N-(3-chloro-4-(4-(l-(2,3-dihydroxy-2-methylpropyl)-6-oxo-l,6-dihydropyridin- 3-yl)thiophen-2-yl)phenyl)methanesulfonamide. The product of Step 2 was reacted with N-(3- chloro-4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophen-2- yl)phenyl)methanesulfonamide as described in Example 1 to give N-(3-chloro-4-(4-(l-(2,3- dihydroxy-2-methylpropyl)-6-oxo-l,6-dihydropyridin-3-yl)thiophen-2- yl)phenyl)methanesulfonamide as an off white solid. *H NMR (400 MHz, DMSO-de): d 10.17 (s, 1H), 8.09 (d, J = 2.40 Hz, 1H), 7.94-7.91 (dd, J = 9.60 Hz and 2.80 Hz, 1H), 7.76 (d, J = 1.20 Hz, 1H), 7.66-7.63 (m, 2H), 7.37 (d, J = 2.4 Hz, 1H), 7.26-7.23 (dd, J = 8.4 Hz and 2.00 Hz,
1H), 6.54 (d, J = 9.20 Hz, 1H), 4.92 (t, J = 6.40 Hz, 1H), 4.86 (s, 1H), 4.09 (d, J = 13.20 Hz,
1H), 3.96 (d, J = 13.60 Hz, 1H), 3.16 (d, J = 6.40 Hz, 2H), 3.09 (s, 3H), 1.04 (s, 3H); MS (m/z = 469.18 [M+H]).
Synthesis Example 12A: Isolated enantiomers of N-(3-chloro-4-(4-(l-(2,3-dihydroxy-2- methylpropyl)-6-oxo-l,6-dihydropyridin-3-yl)thiophen-2-yl)phenyl)methanesulfonamide (1-9306 and 1-9307)
[00266] Racemic N-(3-chloro-4-(4-(l-(2,3-dihydroxy-2-methylpropyl)-6-oxo-l,6- dihydropyridin-3-yl)thiophen-2-yl)phenyl)methanesulfonamide (0.25g) was separated into two enantiomers using supercritical fluid chromatography (SFC) (Chiralpak AD-3; CO260%, 40% (0.5% DEA in MeOH)), which gave a first eluting isomer 1-9306 (0.03g) and a second eluting isomer 1-9307 (0.05g). The isomers have specific optical rotations of [o 25 = -14.5° (1-9306) and [OC]D25 = -16.1° (1-9307) (c 0.1% MeOH) and chiral purities of 99.8% (1-9306) and 99.9% (I- 9307). ¾ NMR (400 MHz, DMSO-de): d 10.17 (s, 1H), 8.09 (d, J = 2.40 Hz, 1H), 7.94-7.91 (dd, J = 9.60 Hz and 2.80 Hz, 1H), 7.76 (d, J = 1.20 Hz, 1H), 7.66-7.63 (m, 2H), 7.37 (d, J = 2.4 Hz, 1H), 7.26-7.23 (dd, J = 8.4 Hz and 2.00 Hz, 1H), 6.54 (d, J = 9.20 Hz, 1H), 4.92 (t, J = 6.40 Hz, 1H), 4.86 (s, 1H), 4.09 (d, J = 13.20 Hz, 1H), 3.96 (d, J = 13.60 Hz, 1H), 3.16 (d, J = 6.40 Hz, 2H), 3.09 (s, 3H), 1.04 (s, 3H).
Synthesis Example 13: N-(3-chloro-4-(5-(l-cyclopropyl-6-oxo-l,6-dihydropyridin-3- yl)thiophen-3-yl)phenyl)methanesulfonamide (1-9214)
Step-2
[00267] Step 1: Synthesis of 5-(4-bromothiophen-2-yl)-l-cyclopropylpyridin-2(lH)-one. A suspension of 5-bromo-l-cyclopropylpyridin-2(lH)-one (0.3 g, 1.40 mmol), (4-bromothiophen- 2-yl)boronic acid (0.28 g, 1.40 mmol) and K2CO3 (0.57 g, 4.2 mmol) in 1, 4-dioxane and water (10 mL) as purged with nitrogen gas for 2 minutes. After adding Pd(PPh3)4 (0.16 g, 0.14 mmol) the reaction mass was heated at 80 °C under nitrogen. After 16hr the reaction mixture was cooled, filtered through a bed of celite and evaporated under reduced pressure. The crude product was purified by column chromatography to give 5-(4-bromothiophen-2-yl)-l- cyclopropylpyridin-2(lH)-one (0.15g, 22%) as a light yellow liquid.
[00268] Step 2: Synthesis of N-(3-chloro-4-(5-(l-cyclopropyl-6-oxo-l ,6-dihydropyridin-3- yl)thiophen-3-yl)phenyl)methanesulfonamide. Reaction of the product of Step 1 with N-(3- chloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (0.19g, 0.6mmole), Pd (PPh3P)4 (0.057 g, 0.05 mmol) and K2CO3 (0.20 g, 1.5 mmol) in 1, 4-Dioxane & water (5 mL) in the same manner as in Step 1 gave N-(3-chloro-4-(5-(l-cyclopropyl-6-oxo-l,6- dihydropyridin-3-yl)thiophen-3-yl)phenyl)methanesulfonamide (0.33g, 16%) as a white solid. !HNMR 400 MHz, DMSO-de: d 10.09 (br s, 1H), 7.81 (d, J = 2.80 Hz, 1H), 7.72 (dd, J = 2.80, 9.20 Hz, 1H), 7.55 (dd, J = 1.20, 10.80 Hz, 2H), 7.50 (d, J = 8.40 Hz, 1H), 7.32 (d, J = 2.00 Hz, 1H), 7.20 (dd, J = 2.00, 8.40 Hz, 1H), 6.47 (d, J = 9.60 Hz, 1H), 3.37-3.33 (m, 1H), 3.04 (s, 3H), 1.02-0.94 (m, 4H); MS (421.13 [M+H] +.
Synthesis Example 14: N-(3-chloro-4-(4-(l-cyclopropyl-6-oxo-l,6-dihydropyridin-3- yl)thiophen-2-yl)phenyl)-N'-isopropylsulfamide (1-9211)
[00269] Isopropyl sulfamoyl chloride (157.6 mg, 3.818 mmol) was added drop wise to a solution of 5-(5-(4-amino-2-chlorophenyl)thiophen-3-yl)-l-cyclopropylpyridin-2(lH)-one (100 mg, 1.909 mmol) in pyridine (3 mL) at 0°C. The reaction was then allowed to come to RT and stirred for 4hr. After aqueous work up the product was purified by prep-HPLC to give 1-9211 as a white solid (28mg, 19%). ΉNMI OO MHz, DMSO-de: d 10.07 (s, 1H), 7.86-7.83 (m, 2H), 7.78 (d, J = 1.20 Hz, 1H), 7.73 (d, J = 1.20 Hz, 1H), 7.66 (br s, 1H), 7.62 (d, J = 8.40 Hz, 2H), 7.32 (d, J = 2.00 Hz, 1H), 7.14 (dd, J = 2.00, 8.80 Hz, 1H), 6.45 (d, J = 9.20 Hz, 1H), 3.39-3.34 (m, 2H), 1.03-0.97 (m, 10H); MS (464.23 [M+H] +).
Synthesis Example 15: Cyclopropyl (3-chloro-4-(4-(l-cyclopropyl-6-oxo-l,6- dihydropyridin-3-yl)thiophen-2-yl)phenyl)carbamate (1-9212)
[00270] A solution of phosgene in toluene (20%, 130.1 mg, 1.31 mmol) was added dropwise to a stirred solution of 5-(5-(4-amino-2-chlorophenyl)thiophen-3-yl)-l-cyclopropylpyridin-2(lH)- one (90 mg 0.263 mmol), triethylamine (174 mg, 0.263 mmol) and cyclopropanol (45.7 mg, 0.789 mmol) in dichloromethane (3mL) at 0°C. The reaction mixture was allowed to come to RT and stirred at RT for 4hr. After aqueous work up the product was purified by prep-HPLC to give cyclopropyl (3-chloro-4-(4-(l-cyclopropyl-6-oxo-l,6-dihydropyridin-3-yl)thiophen-2- yl)phenyl)carbamate as a white solid (28mg, 25%). 1HNMR 400 MHz, DMSO-d6: d 10.07 (s, 1H), 7.86-7.83 (m, 2H), 7.79 (d, J = 1.60 Hz, 1H), 7.74-7.72 (m, 2H), 7.65 (d, J = 8.40 Hz, 1H), 7.47 (dd, J = 2.00, 8.40 Hz, 1H), 6.45 (d, J = 9.20 Hz, 1H), 4.11-4.07 (m, 1H), 3.40-3.36 (m,
1H), 1.03-0.94 (m, 4H), 0.75-0.65 (m, 4H); MS (427.06 [M+H] +).
Synthesis Example 16: 5-(5-(2-chloro-4-(4-hydroxypiperidine-l-carbonyl)phenyl)thiophen- 3-yl)-l-cyclopropylpyridin-2(lH)-one (1-9213)
[00271] A suspension of (4-(4-bromothiophen-2-yl)-3-chlorophenyl)(4-hydroxypiperidin-l- yl)methanone (0.3 g, 0.75 mmol), l-cyclopropyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2(lH)-one (0.29 g, 1.12 mmol) and K2CO3 (0.41 g, 2.25 mmol) in 1, 4-dioxane and water (10 mL) was purged with nitrogen gas for 2 minutes. After adding Pd(PPh3)4 (0.086 g, 00.075 mmol) the reaction mixture was again purged with nitrogen and heated at 80 °C. After 16 h the reaction was cooled, filtered through a bed of celite, evaporated and purified by prep- HPLC to give 5-(5-(2-chloro-4-(4-hydroxypiperidine-l-carbonyl)phenyl)thiophen-3-yl)-l- cyclopropylpyridin-2(lH)-one as a white solid (70mg, 20%). *H NMR 400 MHz, DMSO-d6: d 7.91-7.85 (m, 4H), 7.81 (d, J = 8.00 Hz, 1H), 7.59 (d, J = 1.60 Hz, 1H), 7.43 (dd, J = 1.60, 8.00 Hz, 1H), 6.47 (d, J = 9.20 Hz, 1H), 4.80 (d, J = 3.60 Hz, 1H), 4.00 (br s, 1H), 3.80-3.70 (m, 1H), 3.51 (br s, 1H), 3.45-3.35 (m, 1H), 3.27-3.10 (m, 2H), 1.85-1.65 (m, 2H), 1.45-1.30 (br s, 2H), 1.05-0.96 (m, 4H); MS (455.26 [M+H] +).
Synthesis Example 17: N-(3-chloro-4-(6'-oxo-l'-propyl-l',6'-dihydro-[3,3'-bipyridin]-5- yl)phenyl)methanesulfonamide (1-9103)
[00272] To a stirred solution of 5-bromo-l-propylpyridin-2(lH)-one (200 mg, 0.925 mmol) in 1, 4-dioxane and H2O (7 mL) was added N-(3-chloro-4-(5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-3-yl)phenyl)methanesulfonamide (571 mg, 1.38 mmol) and K2CCb (383 mg, 2.77 mmol). The reaction mixture was purged with nitrogen gas. After adding Pd(PPh3)4 (64 mg, 0.055 mmol), the reaction mixture was purged again with nitrogen gas and then heated to 80°C. After stirring for 16 h, the reaction mixture was cooled and filtered through a bed of celite. The resulting filtrate was concentrated under reduced pressure to obtain a crude product which was purified by reverse phase column chromatography to give N-(3-chloro-4-(6'- oxo-r-propyl-r,6'-dihydro-[3,3'-bipyridin]-5-yl)phenyl)methanesulfonamide as a whilte solid (19 mg; 7%). ¾ NMR (401 MHz, DMSO-de) d 10.18 (s, 1H), 8.85 (d, J= 2.4 Hz, 1H), 8.54 (d, J= 2.0 Hz, 1H), 8.30 (d, J= 2.8 Hz, 1H), 8.06 (t, J= 2.4 Hz, 1H), 7.95 (dd, J= 2.8, 9.2 Hz, 1H), 7.54 (d, J= 8.4 Hz, 1H), 7.41 (d, J= 2.0 Hz, 1H), 7.31 (dd, J= 2.4, 8.4 Hz, 1H), 6.51 (d, J= 9.2 Hz, 1H), 3.92 (t, J= 7.2 Hz, 2H), 3.11 (s, 3H), 1.75-1.66 (m, 2H), 0.89 (t, J= 7.2 Hz, 3H); LCMS: 99.62 % (418.12 [M+H]+).
Biological Example 1: Reporter Assay and Liver Microsomes
[00273] Reporter Screening Assay: This assay was used to evaluate the effect on transcriptional activity SREBP of selected compounds using an SRE-luciferase reporter construct. On day 1, 10,000 cells were seeded in a 96 well (white) plate as per the plate map in standard growth media without antibiotics. Cells were incubated at 37°C for 8 hours. After 8 hours, cells were washed with 100 pL sterile PBS and replaced with 100 pL of low-serum media without antibiotics. The cells were then incubated at 37°C for 24 hours. 10 pL of 10X compound was added to reach the desired treatment concentration (10 mM to 0.51 nM). The cells were once again incubated for 24 hours before being removed. A Luciferase assay was performed.
[00274] Reagents for performing Luciferase assay were stored at -20°C. To a tube of lyophilized assay substrate was added 1 mL Substrate Solvent and mixed well. The Substrate tube after reconstitution was covered with aluminum foil so as to keep it protected from light. The assay buffer was thawed to room temperature. To 20 mL Assay Buffer was added 200 pL of reconstituted lOOx Substrate and mixed well. The reconstituted substrate as well as the assay solution (buffer + substrate) was protected from light throughout the procedure by keeping it covered with aluminum foil. Using a multi-channel pipette, 100 pL Assay Solution (buffer + substrate) was added directly to each sample well in Plate 1, which was incubated for 30 min (plate was covered with aluminum foil). After 30 min incubation, the plate was read for total luminescence. Each well was read for 2 seconds in a plate luminometer. (Microplate reader Envision Microplate reader from Perkin Elmer). Precaution was taken to incubate plate exactly for 30 min prior to reading on the plate reader. Results are presented in Table 1 below.
[00275] Reporter Assay Materials: SREBPvl Reporter cell line: HepG2 - #32251. Growth Medium: MEM (Coming 10-010), 10% FBS, 1% GlutaMax (Invitrogen Catalog # 35050061), pg/ml Puromycin (Invitrogen Catalog # Ai 113803) and 1% Penicillin-Streptomycin (Pen- Strep). Treatment Media: Phenol-free MEM (Invitrogen Catalog # 51200-038) and 1% GlutaMax (Invitrogen Catalog # 35050061). Luciferase Assay: LightSwitch Luciferase Assay Kit (Catalog # 32032). LDH assay: Pierce LDH Cytotoxicity Assay Kit (Catalog# SD249616).
[00276] Half-life Human Microsomes: Compounds were evaluated for stability in human liver microsomes. A 10 mM stock solution of the compound being evaluated was prepared in DMSO and diluted with water: acetonitrile (1 : 1) to a concentration of 1 mM. A working concentration of 100 mM was prepared by further dilution with water: acetonitrile (1 : 1). To make the preincubation mixture, 2.5 pL of the diluted compound was combined with 75 pL of human liver microsomes at 3.33 mg/mL, and 85 pL of 100 mM potassium phosphate buffer, and this mixture was pre-incubated for 10 min at 37°C. To make the 60 minute mixture without cofactor, 32.5 pL of the preincubation mixture was combined with 17.5 pL of 100 mM potassium phosphate buffer and incubated for 60 min at 37°C. To make the 0 min sample with cofactor (NADPH), 16.25 pL of the preincubation mixture was combined with 200 pL of acetonitrile containing internal standard and 8.75 pL of cofactor (NADPH). To make the incubation mixture, 62 pL of cofactor (2.85 mM) was combined with the remaining incubation mixture, and incubated for 60 min at 37°C. To prepare the sample mixture to be evaluated, 25 pL incubation mixture was combined with 200 pL of acetonitrile containing internal standard and vortexed for 5 min at 1200 rpm, then centrifuged for 10 min at 4000 rpm. The supernatant was diluted 2 fold with water and injected on LC-MS/MS. The sample mixture was evaluated by LC-MS/MS using 10 mM ammonium acetate with 0.1% FA as the aqueous mobile phase, and methanol as the organic mobile phase.
[00277] Half-life Mouse Microsomes: Compounds were evaluated in mouse liver microsomes following a similar procedure as described above for human liver microsomes. A similar procedure could be used to evaluate compounds in rat liver microsomes. Results are presented in Table 1 below.
Table 1. Data for selected compounds. Entries A and B are the half-life of liver microsomes (percent rem @ 60 min; A is human, B is mouse), where 0-30 = +; 30.1-60 = ++; > 60.1 = +++. Entry C is for the Reporter Screening Assay (Ave EC50 (nM)), where 0-249 = +++, 250-500 = ++, and > 500 = +.
Biological Example 2: Kinetic Solubility
[00278] Kinetic Solubility Procedure: A 10 mM stock solution of a compound is prepared in DMSO, then 4 pL of the stock is added to a deep well plate containing 396 pL of pH 7.4 buffer. The sample plate is vortexed at 800 rpm for 24 h on thermomixer at room temperature. The plate is sealed well during the incubation process. The dimethylsulfoxide (DMSO) content in the sample is 1.0%. The concentration of the evaluated compound in the final incubation is 100 mM. At the end of the incubation period, the sample plate is centrifuged at 4000 rpm for 10 min and analyzed in LC-UV against a calibration curve (CC).
Biological Example 3: Western Blotting of SREBP Processing
[00279] The effect of selected compounds on SREBP processing and activation is evaluated in HepG2 cells via Western blotting. Cells are seeded at a density of 8e6 in 150mm plate in DMEM (Dulbecco’s modified Eagle’s medium) supplemented with 10% (V/V) heat-inactivated FBS (fetal bovine serum), penicillin G (100 units/ml) and gentamycin (0.2 mg/ml). After overnight incubation, they are washed twice in PBS, and then DMEM media with 0% FBS with 500nM of compound is added to the plate. Cells are incubated at 37°C. After 48 hours, the cells are washed and lysed to obtain cytoplasmic and nuclear extracts for Western blotting to measure SREBP expression along with topoisomerase I as loading control.
Biological Example 4: Adipocyte differentiation and Oil Red-O Staining
[00280] The effect of selected compounds on adipocyte differentiation in human pre-adipocyte and 3T3-L1 cells is evaluated.
[00281] Human Pre-Adipocyte differentiation: Cells are thawed and seeded at 40,625 cells/cm2 in pre-adipocyte media (ZenBio) as per manufacturer’s direction. The cells are allowed to reach confluence for 48 hours, and media switched to Adipocyte Differentiation Media (ZenBio) for 7 days. The media is then switched to Adipocyte Maintenance Media (ZenBio) for additional 7 days. The compound being evaluated is added to the cells for day 1-7 during differentiation, or day 7-14 during maturation. Cells are then stained with oil red-0 as described below.
[00282] NIH 3T3-L1 cell differentiation: Cells are thawed into Pre-Adipocyte Media (ZenBio) and grown to 80-85% confluence. Cells are seeded 50,000 cells/well into 96-wp in Pre- Adipocyte Media (ZenBio) and allowed to reach confluence for 48-72 hours. They are grown an additional 48 hours after reaching confluence, then the media is changed to Differentiation Media (Zen Bio) and incubated for 72 hours. The media is changed to Adipocyte Differentiation Media (ZenBio) using 150 microliters/well in 96-wp for 72 hours, then media is removed and replaced with 150 microliters of Adipocyte Maintenance Media for an additional 8-14 days, feeding cells every 2-3 days. The compound being evaluated is added to the cells for day 3-6 during differentiation, or day 7-14 during maturation. Cells are then stained with oil red-0 as described below.
[00283] Oil Red-0 staining: After maturation, the cells are washed, then fixed in 10% Formalin for 30-60 minutes. The formalin is removed, the cells are washed in water twice, and then the cells are incubated in 60% isopropanol for 5 minutes. The isopropanol is removed and Oil Red- O solution added for 20 minutes with gentle rotation of plate. The stain is removed, the cells washed twice with water, and Hematoxylin added for 1 minute. The cells are washed twice with water and air dried, then images are acquired.
Biological Example 5: Log D of Compounds
[00284] The Log D of selected compounds is evaluated by octanol/aqueous buffer partitioning. 500 pL of organic phase (1-octanol) is added to each well of a 2 mL deep well plate, followed by 500 pL of buffer and 15 pL of test compound in DMSO (0.15 mM). The plate is vortexed for 10 seconds and incubated at room temperature for 1 hr on a plate shaker at 200 rpm. After incubation, the samples are allowed to equilibrate for 20 min and then centrifuged at 4000 rpm for 30 min for complete phase separation. The distribution of test compound in buffer and octanol phase was analyzed by HPLC-UV. Log D = Log (Area of Octanol/Area of Buffer).
Biological Example 6: In vivo Activity Assay
[00285] The in vivo effect of selected compounds may be assessed using the ob/ob mouse model. The ob/ob mouse is a well characterized model of obesity, fatty liver, and diabetes, which are exhibited due to a mutation in the ob gene, which encodes for leptin.
[00286] Compounds are administered by the oral route once or twice daily for 4 weeks in male ob/ob mice. Body weight and food and water intake are assessed daily, and improvements in glucose control are assessed by plasma glucose and insulin measurement. Upon completion of the test period, terminal blood samples are taken and analyzed for triglyceride, cholesterol (total, HDL-C and LDL-C), blood urea nitrogen (BUN), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels. Liver and fat pad weights are determined and liver tissue is processed for histological determination of NASH activity scores (NAS: ballooning, inflammation, steatosis and fibrosis). Liver levels of triglycerides, cholesterol, and non-esterified fatty acids (NEFA) are also determined.
Biological Example 7: Evaluation of in vivo pharmacokinetic properties of compounds
[00287] The in vivo pharmacokinetic properties of compounds by both intravenous and oral administration is evaluated in male Sprague Dawley rats or C57BL/6J mice.
[00288] Animals are housed in cages with clean bedding. Certified rodent diet is provided. Water was available ad libitum. Environmental controls for the animal room are set to maintain a temperature of 22°C to 25°C, humidity of 40-70% RH, and a 12-hour light /12-hour dark cycle. Normal healthy animals certified by the attending veterinarian are selected and acclimatized for minimum three days prior to initiation of study.
[00289] Surgical Procedure for Jugular Vein Cannulation of Rats: Rats are anaesthetized with a single dose of ketamine 50 mg/kg i.p. + xylazine 6 mg/kg i.p. The right jugular vein is exposed, a loose ligature is placed caudally, and the cranial end of vein is ligated. A small incision is made between the ligatures into which the catheter (polyethylene 50 tubing of internal diameter 0.58 mm and outer diameter 0.96 mm) is inserted. The catheter is secured in place by tying the loose ligature around the catheterized vessel. A small incision is made in the scapular region to serve as the exit site of the catheter. The catheter is subcutaneously tunneled and exteriorized through scapular incision. A stay suture is placed in the scapular area. Patency is tested, and catheter is filled with a locking solution (heparinized saline) and sealed with a stainless steel plug. The incision is then sutured with sterile suturing material. Anti-septic solution is applied to the sutured site and animal is placed back in the home cage.
[00290] To evaluate pharmacokinetic properties of intravenous delivery, male Sprague Dawley rats are administered 2.00 mg compound/kg animal weight through the tail vein. The concentration of the compound in the plasma of the animals is evaluated at 0.083, 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hr by taking blood samples from the cannulated jugular vein.
[00291] To evaluate pharmacokinetic properties of oral delivery, rats (male Sprague Dawley rats) or mice (C5B1/6J) are administered 10 mg compound/kg animal weight by mouth. The concentration of compound in the plasma of the animals is evaluated at 0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 hr by taking blood samples from the cannulated jugular vein (rats) or through a capillary, guided in retro-orbital plexus (mice).
Biological Example 8: Evaluation of compounds on liver gene expression in mice
[00292] The pharmacodynamic properties of selected compounds are evaluated in mice. The animals are housed in cages with clean bedding, and maintained and monitored for good health in accordance with Test Facility SOPs and at the discretion of the laboratory animal veterinarian. Certified rodent diet is provided. Food and water is available ad libitum. Environmental controls for the animal room are set to maintain a temperature of 22°C to 25°C, humidity of 40-70% RH, and a 12-hour light/12-hour dark cycle. Normal healthy animals certified by the attending veterinarian are selected and acclimatized for minimum three days prior to initiation of study. Animals are identified with body markings.
[00293] Aliquots of the compounds being evaluated are weighed and triturated with 0.5% methylcellulose (with the addition of 5% N-methyl pyrrolidone when required to remove clumping) to an appropriate dose concentration. Vials are labeled with the information about study number, test item, concentration and date of preparation. A description of appearance of formulation is recorded (e.g., color, turbidity, etc.). The composition of formulation vehicle is recorded. An aliquot of each dose solution was taken before the dosing began and after dosing is finished, and stored at approximately -20°C or below for subsequent analysis. The animals are dosed orally through oral gavage needle, and time of dosing is recorded.
[00294] After dosing, the mice are anesthetized using gaseous anesthesia. Blood samples are collected through a capillary, guided in retro-orbital plexus, at 6 h or at 24 h. Approximately 100 uL of blood is collected from each mouse, in pre-labeled tubes. The collected blood is stored on ice prior to centrifugation. Blood samples are then centrifuged within 1 hour of collection to separate plasma. Centrifugation was conducted at 2500 x g for 15 minutes at 4°C. The plasma is separated and transferred to pre-labeled micro-centrifuge tubes and promptly frozen at -80±10°C until bioanalysis.
[00295] Liver Collection at 6 h or 24 h: Immediately after blood withdrawal for pharmacokinetic evaluation (at 6 or at 24 h), liver tissue is collected without perfusion. Animals are euthanized using carbon dioxide gas in a CO2 chamber. The whole blood is drained by cutting the both side jugular vein and abdominal aorta. The liver is separated out. All the liver samples are divided in two parts. The first part (200 mg approx.) is snap frozen using liquid nitrogen as soon as possible. These samples are immediately transferred to -80°C for storage. The remaining part was weighed and used for bioanalysis.
[00296] RNA Processing and Gene Expression Analysis : Liver Tissue RNA is harvested with the RNEasy kit and 20-100 ng used to synthesize cDNA with random primers following the manufacturer’s protocol. Quantitative PCR is performed on 1 pg to 100 ng cDNA for the following genes: ACACA, ACLY, FASN, LSS, PNPLA3. Gene expression levels are determined using DDOT method comparing treated to vehicle treated samples as a baseline, and fold change calculated. The average value for all 5 genes above is averaged and termed to Total Fold Change.
Biological Example 9: Comparative Reporter Assay and Liver Microsomes
[00297] The properties of a thiophene-containing compound (1-9102) and its pyridine- containing analogue (1-9103) are compared below.
[00298] Reporter Screening Assay: An assay was performed to evaluate the effect on transcriptional activity SREBP of the thiophene- and pyridine-containing compounds using an SRE-luciferase reporter construct. The assays were performed in accordance with the methods and materials of Biological Example 1. The results are presented in Table 2, below.
[00299] Half-life Human Microsomes: The compounds were evaluated for stability in human liver microsomes using a method in accordance with the procedure described in Biological Example 1. The results are presented in Table 2, below. [00300] Half-life Mouse Microsomes: The compounds were evaluated for stability in mouse liver microsomes using a method in accordance with the procedure described in Biological Example 1. The results are presented in Table 2, below.
Table 2. Data for selected compounds. Entries A and B are the half-life of liver microsomes (percent rem @ 60 min; A is human, B is mouse), where 0-30 = +; 30.1-60 = ++; > 60.1 = +++. Entry C is for the Reporter Screening Assay (Ave EC50 (nM)), where 0-249 = +++, 250-500 = ++, and > 500 = +.

Claims

CLAIMS What is claimed is:
Claim 1. A compound of Formula (I): or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, wherein:
X is N or CR4;
R4 is hydrogen, unsubstituted alkyl, or unsubstituted cycloalkyl;
Y is CH and Z is S, or Y is S and Z is CH;
R1 is hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, heterocycloalkyl, heterocycloalkyl-alkyl, or alkyl-heterocycloalkyl; wherein each alkyl, cycloalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, heterocycloalkyl, heterocycloalkyl-alkyl, or alkyl-heterocycloalkyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -OH and fluoro;
R2 is hydrogen, halo, or alkyl, wherein each alkyl is unsubstituted or substituted with one or more fluorine;
R3 is -NR5S(0)2R6, -NR5S(0)2NR6R7, -NR5C(0)0R6, or -C(0)NR6R7;
R5, R6 and R7 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl, wherein each alkyl or cycloalkyl is unsubstituted or substituted with one with one or more substituents selected from the group consisting of -OH and fluorine; or R6 and R7, together with the nitrogen atom to which they are attached, form a heterocycloalkyl, which is unsubstituted or substituted with one or more substituents selected from the group consisting of -OH and fluorine.
Claim 2. The compound of claim 1, wherein the compound is of Formula (I- A): or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
Claim 3. The compound of claim 1 or 2, wherein the compound is of Formula (I-A-i): or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
Claim 4. The compound of claim 1 or 2, wherein the compound is of Formula (I-A-ii): -ii), or a pharmaceutically acceptable salt, solvate, isotope, or stereoisomer thereof.
Claim 5. The compound of claim 1, wherein the compound is of Formula (I-A): or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
Claim 6. The compound of claim 1 or 5, wherein the compound is of Formula (I-B-i): or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
Claim 7. The compound of claim 1 or 5, wherein the compound is of Formula (I-B-ii): -ii), or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
Claim 8. The compound of claim 1, wherein the compound is of Formula (II): or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
Claim 9. The compound of any one of claims 1, 2, or 8, wherein the compound is of Formula (II- A): or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
Claim 10. The compound of any one of claims 1-3 or 8, wherein the compound is of Formula (II-A-i): or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
Claim 11. The compound of any one of claims 1-2, 4, or 8, wherein the compound is of Formula (II-A-ii): -ii), or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
Claim 12. The compound of any one of claims 1, 5 or 8, wherein the compound is of Formula
(P-B): or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
Claim 13. The compound of any one of claims 1, 5-6, or 8, wherein the compound is of Formula (II-B-i): or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
Claim 14. The compound of any one of claims 1, 5, or 7-8, wherein the compound is of Formula (II-B-ii): or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof.
Claim 15. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, wherein R1 is alkyl, unsubstituted or substituted with one or more substituents independently selected from the group consisting of -OH and fluoro.
Claim 16. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, wherein R1 is hydrogen.
Claim 17. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, wherein R1 is cycloalkyl, unsubstituted or substituted with one or more substituents independently selected from the group consisting of -OH and fluoro.
Claim 18. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, wherein R1 is heterocycloalkyl, unsubstituted or substituted with one or more substituents independently selected from the group consisting of -OH and fluoro.
Claim 19. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, wherein R1 is alkyl-cycloalkyl, unsubstituted or substituted with one or more substituents independently selected from the group consisting of -OH and fluoro.
Claim 20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, wherein R1 is substituted with one or more -OH.
Claim 21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, wherein R2 is halo.
Claim 22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, wherein R2 is chloro.
Claim 23. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, wherein R2 is alkyl, wherein each alkyl is unsubstituted or substituted with one or more fluorine.
Claim 24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, wherein R3 is -NR5S(0)2R6.
Claim 25. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, wherein R3 is -NR5S(0)2NR6R7, -NR5C(0)0R6, or - C(0)NR6R7.
Claim 26. The compound of any one of claims 1-3, 5-6, 8-10, or 12-13, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, wherein R4 is unsubstituted alkyl.
Claim 27. The compound of any one of claims 1 to 26, selected from the group consisting of:
Claim 28. A pharmaceutical composition, comprising the compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, and a pharmaceutically acceptable excipient.
Claim 29. A method of inhibiting a sterol regulatory element-binding protein (SREBP), comprising contacting the SREBP or contacting an SREBP cleavage activating-protein (SCAP) with the compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of claim 28.
Claim 30. A method of inhibiting the proteolytic activation of a sterol regulatory element binding protein (SREBP), comprising contacting an SREBP cleavage activating-protein (SCAP) with the compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of claim 28.
Claim 31. A method of treating a disorder in a subject in need thereof, wherein the disorder is mediated by a sterol regulatory element-binding protein (SREBP), comprising administering to the subject an effective amount of the compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of claim 28.
Claim 32. A method of treating a disorder in a subject in need thereof, comprising administering to the subject an effective amount of the compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of claim 28.
Claim 33. Use of the compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, in the manufacture of a medicament for inhibiting a sterol regulatory element-binding protein (SREBP) in a subject in need thereof.
Claim 34. Use of the compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, in the manufacture of a medicament for inhibiting the proteolytic activation of a sterol regulatory element-binding protein (SREBP) in a subject in need thereof.
Claim 35. Use of the compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, in the manufacture of a medicament for treating a disorder in a subject in need thereof, wherein the disorder is mediated by a sterol regulatory element-binding protein (SREBP).
Claim 36. Use of the compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, in the manufacture of a medicament for treating a disorder in a subject in need thereof.
Claim 37. Use of the compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of claim 28, for inhibiting a sterol regulatory element-binding protein (SREBP).
Claim 38. Use of the compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of claim 28, for inhibiting the proteolytic activation of a sterol regulatory element-binding protein (SREBP).
Claim 39. Use of the compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of claim 28, for treating a disorder in a subject in need thereof, wherein the disorder is mediated by a sterol regulatory element-binding protein (SREBP).
Claim 40. Use of the compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of claim 26, for treating a disorder in a subject in need thereof.
Claim 41. A method of treating non-alcoholic steatohepatitis (NASH) in a subject in need thereof, comprising administering to the subject an effective amount of the compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of claim 28.
Claim 42. Use of the compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of claim 28, for treating non-alcoholic steatohepatitis (NASH) in a subject in need thereof.
Claim 43. Use of the compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of claim 28, in the manufacture of a medicament for treating non-alcoholic steatohepatitis (NASH) in a subject in need thereof.
Claim 44. A method of treating a hyperproliferative disorder in a subject in need thereof, comprising administering to the subject an effective amount of the compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of claim 28.
Claim 45. Use of the compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of claim 28, for treating a hyperproliferative disorder in a subject in need thereof.
Claim 46. Use of the compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt, solvate, isotope, or isomer thereof, or the pharmaceutical composition of claim 28, in the manufacture of a medicament for treating a hyperproliferative disorder in a subject in need thereof.
EP21847228.0A 2020-07-24 2021-07-23 Srebp inhibitors comprising a thiophene central ring Withdrawn EP4185584A1 (en)

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EP3265457A1 (en) * 2015-03-04 2018-01-10 Medivation Technologies LLC Sterol regulatory element-binding proteins (srebps) inhibitors
CA2978627A1 (en) * 2015-03-04 2016-09-09 Medivation Technologies, Inc. Srebp blockers for use in treating liver fibrosis, elevated cholesterol and insulin resistance
KR20200128531A (en) * 2018-01-29 2020-11-13 카풀루스 테라퓨틱스, 엘엘씨 SREBP inhibitors containing a six-membered central ring
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