WO2021154735A1 - Inhibiteurs de srebp comprenant un noyau central de thiophène - Google Patents

Inhibiteurs de srebp comprenant un noyau central de thiophène Download PDF

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WO2021154735A1
WO2021154735A1 PCT/US2021/015101 US2021015101W WO2021154735A1 WO 2021154735 A1 WO2021154735 A1 WO 2021154735A1 US 2021015101 W US2021015101 W US 2021015101W WO 2021154735 A1 WO2021154735 A1 WO 2021154735A1
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alkyl
cycloalkyl
compound
pharmaceutically acceptable
heterocycloalkyl
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PCT/US2021/015101
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English (en)
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Michael John Green
Barry Patrick Hart
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Capulus Therapeutics, Llc
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Priority to EP21748420.3A priority Critical patent/EP4096659A4/fr
Publication of WO2021154735A1 publication Critical patent/WO2021154735A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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

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.
  • the present disclosure provides a compound of Formula (III): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein:
  • X is H, halo, alkyl, or cycloalkyl, wherein the alkyl or cycloalkyl is unsubstituted or substituted with one or more fluoro;
  • R 1 is alkyl, cycloalkyl, alkyl-cycloalkyl, or cycloalkyl-alkyl, which is unsubstituted or substituted with one or more fluoro;
  • R 4 is H or alkyl
  • R 2 is (Ci-C8)alkyl, cycloalkyl, alkyl-cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl, -O-alkyl, -O-cycloalkyl, -O-alkyl-cycloalkyl, -O-cycloalkyl-alkyl, -O-heterocycloalkyl, -O-alkyl-heterocycloalkyl, or -O-heterocycloalkyl- alkyl, and R 3 is hydrogen; wherein the (Ci-C8)alkyl, cycloalkyl, alkyl-cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl, -O-alkyl, -
  • the present disclosure provides a compound of Formula (II): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein:
  • X is H, halo, alkyl, or cycloalkyl, wherein the alkyl or cycloalkyl is unsubstituted or substituted with one or more fluoro;
  • R 1 is alkyl, cycloalkyl, alkyl-cycloalkyl, or cycloalkyl-alkyl, which is unsubstituted or substituted with one or more fluoro;
  • R 4 is H or alkyl
  • R 2 is (Ci-C8)alkyl, cycloalkyl, alkyl-cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl, -O-alkyl, -O-cycloalkyl, -O-alkyl-cycloalkyl, - O-cycloalkyl-alkyl, -O-heterocycloalkyl, -O-alkyl-heterocycloalkyl, or -O-heterocycloalkyl- alkyl, and R 3 is hydrogen; wherein the (Ci-C8)alkyl, cycloalkyl, alkyl-cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl, -O-alkyl, -
  • the present disclosure provides a compound of Formula (I): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein:
  • X is H, halo, alkyl, or cycloalkyl, wherein the alkyl or cycloalkyl is unsubstituted or substituted with one or more fluoro;
  • R 1 is alkyl, cycloalkyl, alkyl-cycloalkyl, or cycloalkyl-alkyl, which is unsubstituted or substituted with one or more fluoro;
  • R 4 is H or alkyl
  • R 2 is (Ci-C8)alkyl, cycloalkyl, alkyl-cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl, -O-alkyl, -O-cycloalkyl, -O-alkyl-cycloalkyl, - O-cycloalkyl-alkyl, -O-heterocycloalkyl, -O-alkyl-heterocycloalkyl, or -O-heterocycloalkyl- alkyl, and R 3 is hydrogen; wherein the (Ci-C8)alkyl, cycloalkyl, alkyl-cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl, -O-alkyl, -
  • R 2 is substituted with one or more substituents independently selected from the group consisting of fluoro, -OH and - 0C(0)R 5 ; wherein eachR 5 is independently -R 6 N(R 7 )2 or -(CH2CH2-0-)niCH3; wherein each R 6 is (C2-C6)alkylene; each R 7 is independently H or -CH3; and each nl is independently an integer from 2 to 8; or R 2 and R 3 , together with the atoms to which they are attached, form a heterocyclyl.
  • the compound is of Formula (I-A): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein: X is halo;
  • R 1 is alkyl, which is unsubstituted or substituted with one or more fluoro;
  • R 2 is (Ci-C8)alkyl and R 3 is hydrogen; wherein the (Ci-C8)alkyl is substituted with one or more substituents independently selected from the group consisting of -OH and -OC(0)R 5 ; wherein eachR 5 is independently -R 6 N(R 7 )2 or -(CH2CH2-0-)niCH3; wherein each R 6 is (C2-C 6 )alkylene; each R 7 is independently H or -CH3; and each nl is independently an integer from 2 to 8; or R 2 and R 3 , together with the atoms to which they are attached, form a heterocyclyl.
  • a pharmaceutical composition comprising a compound as described herein, 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 an effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition as described herein.
  • SREBP sterol regulatory element-binding protein
  • a compound as described herein, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof for use in inhibiting a sterol regulatory element-binding protein (SREBP).
  • a compound as described herein, 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).
  • SREBP sterol regulatory element-binding protein
  • a method of inhibiting the proteolytic activation of a sterol regulatory element-binding protein (SREBP) comprising contacting an SREBP cleavage activating-protein (SCAP) with an effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition described herein.
  • a compound as described herein, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof for use in inhibiting the proteolytic activation of a sterol regulatory element binding protein (SREBP).
  • SREBP sterol regulatory element binding protein
  • provided herein is a method of treating a disorder in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of a compound as described herein, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or a pharmaceutical composition described herein.
  • a compound as described herein, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof for use in treating a disorder in a subject in need thereof.
  • provided herein is the use of a compound as described herein, 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.
  • SREBP sterol regulatory element-binding protein
  • a compound as described herein, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof for use in treating a disorder in a subject in need thereof.
  • the disorder is Metabolic Syndrome, type 2 diabetes, obesity, liver disease, insulin resistance, adiposopathy, or dyslipidemia.
  • the liver disease is nonalcoholic steatohepatitis, liver fibrosis, or liver inflammation, or a combination thereof.
  • the disorder is a hyperproliferative disorder, such as cancer, for example, 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.
  • a hyperproliferative disorder such as cancer, for example, 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 present disclosure provides a compound of Formula (III): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein:
  • X is H, halo, alkyl, or cycloalkyl, wherein the alkyl or cycloalkyl is unsubstituted or substituted with one or more fluoro;
  • R 1 is alkyl, cycloalkyl, alkyl-cycloalkyl, or cycloalkyl-alkyl, which is unsubstituted or substituted with one or more fluoro;
  • R 4 is H or alkyl
  • R 2 is (Ci-C8)alkyl, cycloalkyl, alkyl-cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl, -O-alkyl, -O-cycloalkyl, -O-alkyl-cycloalkyl, - O-cycloalkyl-alkyl, -O-heterocycloalkyl, -O-alkyl-heterocycloalkyl, or -O-heterocycloalkyl- alkyl, and R 3 is hydrogen; wherein the (Ci-C8)alkyl, cycloalkyl, alkyl-cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl, -O-alkyl, -
  • the present disclosure provides a compound of Formula (II): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein:
  • X is H, halo, alkyl, or cycloalkyl, wherein the alkyl or cycloalkyl is unsubstituted or substituted with one or more fluoro;
  • R 1 is alkyl, cycloalkyl, alkyl-cycloalkyl, or cycloalkyl-alkyl, which is unsubstituted or substituted with one or more fluoro;
  • R 4 is H or alkyl
  • R 2 is (Ci-C8)alkyl, cycloalkyl, alkyl-cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl, -O-alkyl, -O-cycloalkyl, -O-alkyl-cycloalkyl, - O-cycloalkyl-alkyl, -O-heterocycloalkyl, -O-alkyl-heterocycloalkyl, or -O-heterocycloalkyl- alkyl, and R 3 is hydrogen; wherein the (Ci-C8)alkyl, cycloalkyl, alkyl-cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl, -O-alkyl, -
  • the present disclosure provides a compound of Formula (I): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein:
  • X is H, halo, alkyl, or cycloalkyl, wherein the alkyl or cycloalkyl is unsubstituted or substituted with one or more fluoro;
  • R 1 is alkyl, cycloalkyl, alkyl-cycloalkyl, or cycloalkyl-alkyl, which is unsubstituted or substituted with one or more fluoro;
  • R 4 is H or alkyl
  • R 2 is (Ci-C8)alkyl, cycloalkyl, alkyl-cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl, -O-alkyl, -O-cycloalkyl, -O-alkyl-cycloalkyl, - O-cycloalkyl-alkyl, -O-heterocycloalkyl, -O-alkyl-heterocycloalkyl, or -O-heterocycloalkyl- alkyl, and R 3 is hydrogen; wherein the (Ci-C8)alkyl, cycloalkyl, alkyl-cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl, -O-alkyl, -
  • R 2 is substituted with one or more substituents independently selected from the group consisting of fluoro, -OH and - 0C(0)R 5 ; wherein eachR 5 is independently -R 6 N(R 7 )2 or -(CH2CH2-0-)niCH3; wherein each R 6 is (C2-C 6 )alkylene; each R 7 is independently H or -CH3; and each nl is independently an integer from 2 to 8; or R 2 and R 3 , together with the atoms to which they are attached, form a heterocyclyl.
  • substituents independently selected from the group consisting of fluoro, -OH and - 0C(0)R 5 ; wherein eachR 5 is independently -R 6 N(R 7 )2 or -(CH2CH2-0-)niCH3; wherein each R 6 is (C2-C 6 )alkylene; each R 7 is independently H or -CH3; and each nl is independently an integer from 2 to 8; or R 2 and R
  • the compound of Formula (I) is a compound of Formula (I-A): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein: X is halo;
  • R 1 is alkyl, which is unsubstituted or substituted with one or more fluoro;
  • R 2 is (Ci-C8)alkyl and R 3 is hydrogen; wherein the (Ci-C8)alkyl is substituted with one or more substituents independently selected from the group consisting of -OH and -0C(0)R 5 ; wherein eachR 5 is independently -R 6 N(R 7 )2 or -(CH2CH2-0-)niCH3; wherein each R 6 is (C2-C 6 )alkylene; each R 7 is independently H or -CH3; and each nl is independently an integer from 2 to 8; or R 2 and R 3 , together with the atoms to which they are attached, form a heterocyclyl.
  • 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), or 1 to 4 carbon atoms ((Ci- 4)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.
  • alkylene refers to a divalent radical derived from a branched or unbranched alkyl, as exemplified, but not limited, by -CH2CH2CH2CH2-.
  • alkylene as used herein, has 1 to 50 carbon atoms ((Ci-5o)alkylene), 1 to 20 carbon atoms ((Ci- 2o)alkylene), 1 to 12 carbon atoms ((Ci-i2)alkylene), 1 to 10 carbon atoms ((Ci-io)alkylene), 1 to 8 carbon atoms ((Ci-8)alkylene), 1 to 6 carbon atoms ((Ci-6)alkylene), or 1 to 4 carbon atoms ((Ci-4)alkylene).
  • Cycloalkyl refers to a monocyclic or polycyclic saturated hydrocarbon.
  • 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-liT-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 ((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).
  • 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 (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.
  • 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 ((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).
  • 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.
  • Heterocycloalkenyl refers to a non-aromatic monocyclic or polycyclic ring containing carbon, at least one heteroatom selected from the group consisting of O, N, and S, and at least one double bond.
  • Each ring S atom where present, may independently be a sulfur oxide, such as -S(O)-, or -S(0)2-.
  • the heterocycloalkenyl group may comprise 3, 4,
  • Heterocycloalkenyl 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.
  • a heterocycloalkenyl has 2 to 8 ring carbon atoms and with 1 to 3 ring heteroatoms independently selected from N, O, and S.
  • heterocycloalkenyl is connected through an annular carbon atom, wherein the point of attachment of the heterocycloalkenyl to another group is a ring carbon atom of the heterocycloalkenyl.
  • Heterocycloalkenyl may have one, two, three, four, five, or more double bonds, as valency permits, and each double bond independently may be between two ring carbon atoms, two ring heteroatoms, or one ring carbon atom and one ring heteroatom, as valency permits.
  • Heterocyclyl refers to a saturated or unsaturated monocyclic or polycyclic ring containing carbon and at least one heteroatom selected from the group consisting of O, N, and S. Each ring S atom, where present, may independently be a sulfur oxide, such as -S(O)-, or -S(0)2-. Heterocyclyl includes heterocycloalkyl, heteroaryl, and non-aromatic unsaturated heterocyclic groups such as heterocycloalkenyl.
  • the heterocyclyl 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 heterocyclyl), and 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.
  • heterocyclyl is connected through an annular carbon atom, wherein the point of attachment of the heterocyclyl to another group is a ring carbon atom of the heterocyclyl.
  • 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-Cso)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(C 3 -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-C6 alkyl, or Cl -6 alkyl) is intended to encompass Ci, C2, C3, 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 , C3-6, C 3 -5, C 3 -4, C4-6, C4-5, and C5-6 alkyl.
  • Halo refers to fluoro, chloro, bromo, or iodo radicals.
  • the compound is a solvate.
  • 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 (III), (II), (I), or (I-A), 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 (III), (II), (I), or (I-A), 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 (III), (II), (I), or (I-A), 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.
  • 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,
  • 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 (III), (II), (I), or (I- A), 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 (III), or a pharmaceutically acceptable salt, solvate, tautomer, or isotope thereof, wherein:
  • X is H, halo, alkyl, or cycloalkyl, wherein the alkyl or cycloalkyl is unsubstituted or substituted with one or more fluoro;
  • R 1 is alkyl, cycloalkyl, alkyl-cycloalkyl, or cycloalkyl-alkyl, which is unsubstituted or substituted with one or more fluoro;
  • R 4 is H or alkyl
  • R 2 is (Ci-C8)alkyl, cycloalkyl, alkyl-cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl, -O-alkyl, -O-cycloalkyl, -O-alkyl-cycloalkyl, - O-cycloalkyl-alkyl, -O-heterocycloalkyl, -O-alkyl-heterocycloalkyl, or -O-heterocycloalkyl- alkyl, and R 3 is hydrogen; wherein the (Ci-C8)alkyl, cycloalkyl, alkyl-cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl, -O-alkyl, -
  • the present disclosure provides a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, tautomer, or isotope thereof, wherein:
  • X is H, halo, alkyl, or cycloalkyl, wherein the alkyl or cycloalkyl is unsubstituted or substituted with one or more fluoro;
  • R 1 is alkyl, cycloalkyl, alkyl-cycloalkyl, or cycloalkyl-alkyl, which is unsubstituted or substituted with one or more fluoro;
  • R 4 is H or alkyl
  • R 2 is (Ci-C8)alkyl, cycloalkyl, alkyl-cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl, -O-alkyl, -O-cycloalkyl, -O-alkyl-cycloalkyl, - O-cycloalkyl-alkyl, -O-heterocycloalkyl, -O-alkyl-heterocycloalkyl, or -O-heterocycloalkyl- alkyl, and R 3 is hydrogen; wherein the (Ci-C8)alkyl, cycloalkyl, alkyl-cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl, -O-alkyl, -
  • the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, tautomer, or isotope thereof, wherein:
  • X is H, halo, alkyl, or cycloalkyl, wherein the alkyl or cycloalkyl is unsubstituted or substituted with one or more fluoro;
  • R 1 is alkyl, cycloalkyl, alkyl-cycloalkyl, or cycloalkyl-alkyl, which is unsubstituted or substituted with one or more fluoro;
  • R 4 is H or alkyl
  • R 2 is (Ci-C8)alkyl, cycloalkyl, alkyl-cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl, -O-alkyl, -O-cycloalkyl, -O-alkyl-cycloalkyl, - O-cycloalkyl-alkyl, -O-heterocycloalkyl, -O-alkyl-heterocycloalkyl, or -O-heterocycloalkyl- alkyl, and R 3 is hydrogen; wherein the (Ci-C8)alkyl, cycloalkyl, alkyl-cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl, -O-alkyl, -
  • X is halo
  • R 1 is alkyl, which is unsubstituted or substituted with one or more fluoro;
  • R 2 is (Ci-C8)alkyl and R 3 is hydrogen; wherein the (Ci-C8)alkyl is substituted with one or more substituents independently selected from the group consisting of -OH and -0C(0)R 5 ; wherein eachR 5 is independently -R 6 N(R 7 )2 or -(CH2CH2-0-)niCH3; wherein each R 6 is (C2-C6)alkyl; each R 7 is independently H or -CH3; and each nl is independently an integer from 2 to 8; or R 2 and R 3 , together with the atoms to which they are attached, form a heterocyclyl.
  • R 1 is alkyl. In certain embodiments, R 1 is an unsubstituted alkyl. In certain embodiments, R 1 is methyl. In certain embodiments, R 1 is an unsubstituted methyl. In certain embodiments, R 1 is a substituted alkyl. In certain embodiments, R 1 is a substituted methyl. In still further embodiments, R 1 is - CF3.
  • R 2 is (Ci-C8)alkyl and R 3 is hydrogen.
  • R 2 is (Ci)alkyl and R 3 is hydrogen.
  • R 2 is (C2)alkyl and R 3 is hydrogen.
  • R 2 is (C3)alkyl and R 3 is hydrogen.
  • R 2 is (C4)alkyl and R 3 is hydrogen.
  • R 2 is (Cs)alkyl and R 3 is hydrogen.
  • R 2 is (Ce)alkyl and R 3 is hydrogen. In certain embodiments, R 2 is (Cv)alkyl and R 3 is hydrogen. In certain embodiments, R 2 is (Cs)alkyl and R 3 is hydrogen. In certain embodiments, R 2 is a branched (Ci- C8)alkyl. In certain embodiments, R 2 is a substituted (Ci-C8)alkyl. In certain embodiments, R 2 is a branched, substituted (Ci-C8)alkyl. In certain embodiments, R 2 is a (Ci-C8)alkyl substituted with more than one -OH. In certain embodiments, R 2 is a (Ci-C8)alkyl substituted with one - OH.
  • R 2 is a (C3)alkyl substituted with one -OH. In still further embodiments, R 2 is a (C4)alkyl substituted with one -OH. [0051] In some embodiments of the compound of Formula (III), (II), (I), or (I-A), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, R 2 is is a (C4)alkyl substituted with one -OH. In some embodiments, R 2 is is a (C4)alkyl substituted with more than one -OH. In some embodiments, R 2 is is a (C4)alkyl substituted with two -OH.
  • R 2 is (Ci-C8)alkyl and R 3 is hydrogen.
  • R 2 is (Ci)alkyl and R 3 is hydrogen.
  • R 2 is (C2)alkyl and R 3 is hydrogen.
  • R 2 is (C3)alkyl and R 3 is hydrogen.
  • R 2 is (C4)alkyl and R 3 is hydrogen.
  • R 2 is (Cs)alkyl and R 3 is hydrogen.
  • R 2 is (Ce)alkyl and R 3 is hydrogen.
  • R 2 is (Cv)alkyl and R 3 is hydrogen. In certain embodiments, R 2 is (Cx)alkyl and R 3 is hydrogen. In certain embodiments, R 2 is a branched (Ci-C8)alkyl. In certain embodiments, R 2 is a substituted (Ci-C8)alkyl. In certain embodiments, R 2 is a branched, substituted (Ci-C8)alkyl. In certain embodiments, R 2 is a (Ci-C8)alkyl substituted with more than one -OH. In certain embodiments, R 2 is a (Ci-C8)alkyl substituted with one or more -OH and one or more -O-alkyl.
  • R 2 is a (Ci-C8)alkyl substituted with one -OH and one -O-alkyl. In certain embodiments, R 2 is a (Ci-C8)alkyl substituted with one or more -OH and one or more - O-methyl. In certain embodiments, R 2 is a (Ci-C8)alkyl substituted with one -OH and one -O- methyl. In some embodiments, R 2 is a (C4)alkyl substituted with one -OH and one -O-alkyl. In some embodiments, R 2 is a (C4)alkyl substituted with one -OH and one -O-methyl.
  • R 2 is: [0054] In some embodiments of the compound of Formula (III), (II), (I), or (I- A), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, R 2 is: [0055] In some embodiments of the compound of Formula (III), (II), (I), or (I- A), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, R 2 is:
  • R 2 is:
  • R 2 and R 3 together with the atoms to which they are attached, form a heterocyclyl.
  • R 2 and R 3 together with the atoms to which they are attached, form a heterocyclyl containing 1 nitrogen.
  • R 2 and R 3 together with the atoms to which they are attached, form a heterocyclyl containing 2 nitrogens.
  • R 2 and R 3 together with the atoms to which they are attached, form a heterocyclyl containing 1 oxygen. In certain embodiments, R 2 and R 3 , together with the atoms to which they are attached, form a heterocyclyl containing 2 oxygens. In certain embodiments, R 2 and R 3 , together with the atoms to which they are attached, form a heterocyclyl containing 1 nitrogen and 1 oxygen. In certain embodiments, R 2 and R 3 , together with the atoms to which they are attached, form:
  • R 2 and R 3 together with the atoms to which they are attached, form a heterocyclyl.
  • R 2 and R 3 together with the atoms to which they are attached, form a heterocyclyl; wherein the heterocyclyl is unsubstituted or substituted with (Cl-C3)alkyl.
  • the (Cl-C3)alkyl is methyl.
  • the (Cl-C3)alkyl is ethyl.
  • the (Cl-C3)alkyl is propyl.
  • R 2 and R 3 together with the atoms to which they are attached, form a heterocyclyl; wherein the heterocyclyl is unsubstituted or substituted with (Cl-C3)alkyl; wherein the (Cl-C3)alkyl is substituted with one or more -OH.
  • the (Cl-C3)alkyl is substituted with one -OH.
  • the (Cl-C3)alkyl is substituted with two -OH.
  • R 2 and R 3 together with the atoms to which they are attached, form:
  • R 4 is hydrogen or alkyl. In certain embodiments, R 4 is hydrogen. In certain embodiments, R 4 is alkyl.
  • X is halo. In certain embodiments, X is fluoro. In certain embodiments, X is chloro. In certain embodiments, X is bromo. In certain embodiments, X is iodo.
  • the compound of Formula (III), (II), (I), or Formula (I- A) is: pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of the foregoing.
  • the compound of Formula (III), (II), (I), or Formula (I-A) is: pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of the foregoing.
  • the compound of Formula (III), (II), (I), or Formula (I-A) is: pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of the foregoing
  • the compound of Formula (III) or (II) is: pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of the foregoing.
  • the compound of Formula (III) is: , or a pharmaceutically acceptable salt, solvated, tautomer, isotope, or isomer of any of the foregoing.
  • compositions comprising any of the compounds disclosed herein, such as a compound of Formula (III), Formula (II), Formula (I), or Formula (I- A), 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 Formula (III), Formula (II), Formula (I), or Formula (I-A), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof may be prepared, for example, through the reaction routes depicted in General Schemes I and II.
  • R H1 and R H2 are independently Br, Cl, or I
  • General Reaction Scheme I provides a route to compound 1-4, which is an intermediate in the synthesis of a compound of Formula (I-A).
  • a metal halogen exchange of compound 1-1 is effected using a Grignard or organolithium reagent, and treatment with an organoborate furnishes 1-2.
  • 1-2 is coupled to 1-3 in the presence of a palladium catalyst and base to produce compound 1-4.
  • Suitable Grignard or organolithium reagents for the first step may include, for example, (Me)2HCMgCl.
  • Suitable organoborates for the first step may include, for example, B(OCH3)3.
  • Suitable palladium catalysts for the second step of the route may include, for example, tetrakis(triphenylphosphine)palladium(0).
  • Suitable bases for the second step may include, for example, aqueous sodium carbonate or potassium carbonate.
  • Any of 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.
  • General Reaction Scheme II provides a route to compound II-4, which is a compound of Formula (I-A).
  • compound II-l is treated with a sulfonyl chloride compound II-2 in the presence of a base to produce compound II-3.
  • compound II-3 is coupled to 1-4 in the presence of a palladium catalyst and base to produce compound II-4.
  • Suitable bases for the first step may include, for example, pyridine.
  • Suitable palladium catalysts for the second step of the route may include, for example, tetrakis(triphenylphosphine)palladium(0).
  • Suitable bases for the second step may include, for example, aqueous sodium carbonate or potassium carbonate.
  • any of the steps depicted in General Reaction Scheme II may further include a solvent, for example, dioxane, dichloromethane, tetrahydrofuran, or dimethoxyethane.
  • 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 Formulae (III), (II), (I) or (I-A), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, by following General Reaction Schemes I or II, 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 (III), (II), (I), or (I-A), 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 (III), (II), (I), or (I-A), 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 (III), (II), (I), or (I-A), 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 (III), (II), (I), or (I-A), 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 (III), (II), (I), or (I-A), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, is administered to the subject in need thereof.
  • 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 (III), (II), (I), or (I-A), 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.
  • 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,
  • 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.
  • 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 (III), (II), (I), or (I- A), 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.
  • 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 (III), (II), (I), or (I-A), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • a pharmaceutical composition comprising a compound of Formula (III), (II), (I), or (I-A), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient.
  • the compound is a compound of Formula (III), 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 (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 uses and methods of treatment describe herein may use a compound of Formula (III), (II), (I), or (I-A), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof; or a pharmaceutical composition comprising a compound of Formula (III), (II), (I), or (I-A), or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient.
  • 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 (III), (II), (I), or (I- A), 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.
  • a component of the SREBP pathway such as an SREBP or SCAP.
  • uses and methods of treating NASH in a subject in need thereof comprising administering to the subject in need thereof a compound of Formula (III), (II), (I), or (I-A), 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).
  • NAS NAFLD activity score
  • SAF steatosis, activity, and fibrosis score
  • FIB4 or ELF NASH diagnostic and/or scoring metrics
  • liver fibrosis associated with NASH
  • 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 Formula (III), (II), (I), or (I-A), 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 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
  • the disorder is fatty liver disease
  • administering to the subject in need thereof a compound of Formula (III), (II), (I), or (I-A), 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. 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.
  • MRI magnetic resonance imaging
  • MRE magnetic resonance elastography
  • CT computerized tomography
  • ALT liver enzyme aspartate aminotransferase
  • ALT aspartate aminotransferase
  • the subject is administered between about 0.01 mg/kg to about 100 mg/kg of compound of Formula (III), (II), (I), or (I-A), 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 (III), (II), (I), or (I-A), 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
  • 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.
  • 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.
  • 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 (III), (II), (I), or (I-A), 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 (III), (II),
  • 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 (III), (II), (I), or (I-A), 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.
  • 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.
  • 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, is mediated by a component of 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 (III), (II), (I), or (I- A), 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 (III), (II), (I), or (I-A), 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 (III), (II), (I), or (I-A), 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 (III), (II), (I), or (I-A), 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 Formula (III), (II), (I), or (I-A), 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 (III), (II), (I), or (I-A), 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 (III), (II), (I), or (I-A), 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.
  • 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 (III), (II), (I), or (I-A) 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.
  • the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof is administered as a pharmaceutical composition, as described herein.
  • the dose of a compound of Formula (III), (II), (I), or (I-A), 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).
  • 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. 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 (III), (II), (I), or (I-A), 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 (III), (II), (I), or (I- A), 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 (III), (II), (I), or (I- A)
  • the compounds of Formula (III), (II), (I), or (I-A), 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 (III), (II), (I), or (I-A), 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.
  • 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 (III), (II), (I), or (I-A), 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.
  • 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 (III), (II), (I), or (I-A),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.
  • 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.
  • 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 (III), (II), (I), or (I- A), 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 (III), (II), (I), or (I-A),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, tautomer, isotope, or isomer thereof, wherein:
  • X is H, halo, alkyl, or cycloalkyl, wherein the alkyl or cycloalkyl is unsubstituted or substituted with one or more fluoro;
  • R 1 is alkyl, cycloalkyl, alkyl-cycloalkyl, or cycloalkyl-alkyl, which is unsubstituted or substituted with one or more fluoro;
  • R 4 is H or alkyl
  • R 2 is (Ci-C8)alkyl, cycloalkyl, alkyl-cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl, -O-alkyl, -O-cycloalkyl, -O-alkyl-cycloalkyl, - O-cycloalkyl-alkyl, -O-heterocycloalkyl, -O-alkyl-heterocycloalkyl, or -O-heterocycloalkyl- alkyl, and R 3 is hydrogen; wherein the (Ci-C8)alkyl, cycloalkyl, alkyl-cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl, -O-alkyl, -
  • R 2 is substituted with one or more substituents independently selected from the group consisting of fluoro, -OH and - 0C(0)R 5 ; wherein eachR 5 is independently -R 6 N(R 7 )2 or -(CH2CH2-0-)niCH3; wherein each R 6 is (C2-C6)alkylene; each R 7 is independently H or -CH3; and each nl is independently an integer from 2 to 8; or R 2 and R 3 , together with the atoms to which they are attached, form a heterocyclyl.
  • Embodiment 1-2 A compound of Formula (I- A): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein: X is halo;
  • R 1 is alkyl, which is unsubstituted or substituted with one or more fluoro;
  • R 2 is (Ci-C8)alkyl and R 3 is hydrogen; wherein the (Ci-C8)alkyl is substituted with one or more substituents independently selected from the group consisting of -OH and -0C(0)R 5 ; wherein eachR 5 is independently -R 6 N(R 7 )2 or -(CH2CH2-0-)niCH3; wherein each R 6 is (C2-C6)alkyl; each R 7 is independently H or -CH3; and each nl is independently an integer from 2 to 8; or R 2 and R 3 , together with the atoms to which they are attached, form a heterocyclyl.
  • Embodiment 1-3 The compound of embodiment 1-1 or 1-2, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R 2 is (Ci-C8)alkyl and R 3 is hydrogen; wherein the (Ci-C8)alkyl is substituted with -OH; or R 2 and R 3 , together with the atoms to which they are attached, form a heterocyclyl.
  • Embodiment 1-4 The compound of embodiment 1-1 or 1-2, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R 2 and R 3 , together with the atoms to which they are attached, form a heterocyclyl.
  • Embodiment 1-5 The compound of embodiment 1-1 or 1-2, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R 2 is (Ci-C8)alkyl and R 3 is hydrogen; wherein the (Ci-C8)alkyl is substituted with -OH.
  • Embodiment 1-6 The compound of embodiment 1-1 or 1-2, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R 2 is (Ci-C8)alkyl substituted with -OC(0)R 5 .
  • Embodiment 1-7 The compound of embodiments 1-1 to 1-4, wherein R 2 and R 3 , together with the atoms to which they are attached, form a heterocyclyl with the structure:
  • Embodiment 1-8 The compound of any one of embodiments 1-1 to 1-7, selected from the group consisting of:
  • Embodiment 1-9 A pharmaceutical composition, comprising the compound of any one of embodiments 1-1 to 1-8, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient.
  • Embodiment I- 10 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 1-8, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-9.
  • SREBP sterol regulatory element-binding protein
  • SCAP SREBP cleavage activating- protein
  • Embodiment 1-11 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 1-8, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-9.
  • SREBP sterol regulatory element-binding protein
  • SCAP SREBP cleavage activating-protein
  • Embodiment 1-12 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 1-8, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-9.
  • 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 the compound of any one of embodiments 1-1 to 1-8, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-9.
  • Embodiment 1-14 The method of any one of embodiments 1-10 to 1-12, wherein the SREBP is an SREBP-1.
  • Embodiment 1-15 The method of embodiment 1-14, wherein the SREBP-1 is SREBP- l a.
  • Embodiment 1-16 The method of embodiment 1-14, wherein the SREBP-1 is SREBP- lc.
  • Embodiment 1-17 The method of any one of embodiments 1-10 to 1-12, wherein the SREBP is SREBP-2.
  • Embodiment 1-18 The method of any one of embodiments 1-10 to 1-17, wherein SREBP is inhibited in a subject in need thereof.
  • Embodiment 1-19 The method of any one of embodiments 1-10 to 1-18, wherein SCAP is inhibited in a subject in need thereof.
  • Embodiment 1-20 The method of any one of embodiments 1-10 to 1-19, comprising contacting SREBP or SCAP with the compound, or pharmaceutically acceptable salt, solvate, tautomer, 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, tautomer, isotope, or isomer thereof, or the pharmaceutical composition, where
  • Embodiment 1-22 The method of embodiment 1-21, wherein the dyslipidemia is hypertriglyceridemia or elevated cholesterol levels.
  • Embodiment 1-2 The method of embodiment 1-21, wherein the liver disease is nonalcoholic steatohepatitis, liver fibrosis, or liver inflammation, or a combination thereof.
  • Embodiment 1-24 The method of embodiment 1-12 or 1-13, wherein the disorder is a hyperproliferative disorder.
  • Embodiment 1-25 The method of embodiment 1-24, wherein the hyperproliferative disorder is cancer.
  • Embodiment 1-26 The method of embodiment 1-25, 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 1-27 The method of embodiment 1-12 or 1-13, wherein the disorder is endotoxic shock, systemic inflammation, or atherosclerosis.
  • Embodiment 1-28 Use of the compound of any one of embodiments 1-1 to 1-8, 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.
  • SREBP sterol regulatory element-binding protein
  • Embodiment 1-2 The use of embodiment 1-28, wherein the inhibiting comprises contacting the SREBP or contacting an SREBP cleavage activating-protein (SCAP) with the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • SCAP SREBP cleavage activating-protein
  • Embodiment 1-30 Use of the compound of any one of embodiments 1-1 to 1-8, 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.
  • SREBP sterol regulatory element-binding protein
  • Embodiment 1-3 The use of embodiment 1-30, wherein the inhibiting comprises contacting an SREBP cleavage activating-protein (SCAP) with the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • SCAP SREBP cleavage activating-protein
  • Embodiment 1-3 Else of the compound of any one of embodiments 1-1 to 1-8, 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).
  • SREBP sterol regulatory element-binding protein
  • Embodiment 1-3 Else of the compound of any one of embodiments 1-1 to 1-8, 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.
  • Embodiment 1-34 The use of any one of embodiments 1-28 to 1-32, wherein the SREBP is an SREBP-1.
  • Embodiment 1-35 The use of embodiment 1-34, wherein the SREBP-1 is SREBP- la.
  • Embodiment 1-36 The use of embodiment 1-34, wherein the SREBP-1 is SREBP-lc.
  • Embodiment 1-37 The use of any one of embodiments 1-28 to 1-32, wherein the SREBP is SREBP-2.
  • Embodiment 1-38 The use of any one of embodiments 1-28 to 1-37, wherein SREBP is inhibited in a subject in need thereof.
  • Embodiment 1-39 The use of any one of embodiments 1-28 to 1-38, wherein SCAP is inhibited in a subject in need thereof.
  • Embodiment 1-40 The use of any one of embodiments 1-28 to 1-39, wherein an SREBP or SCAP is contacted with the compound, or pharmaceutically acceptable salt, solvate, tautomer, 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, RDHll, SC5DL, SQLE, STARD4, TM7SF2, PNPLA3, SREBFl, 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.
  • Embodiment 1-4 The use of embodiment 1-32 or 1-33, wherein the disorder is Metabolic Syndrome, type 2 diabetes, obesity, liver disease, insulin resistance, adiposopathy, or dyslipidemia.
  • Embodiment 1-42 The use of embodiment 1-41, wherein the dyslipidemia is hypertriglyceridemia or elevated cholesterol levels.
  • Embodiment 1-43 The use of embodiment 1-41, wherein the liver disease is nonalcoholic steatohepatitis, liver fibrosis, or liver inflammation, or a combination thereof.
  • Embodiment 1-44 The use of embodiment 1-32 or 1-33, wherein the disorder is a hyperproliferative disorder.
  • Embodiment 1-45 The use of embodiment 1-44, wherein the hyperproliferative disorder is cancer.
  • Embodiment 1-46 The use of embodiment 1-45, 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 1-47 The use of embodiment 1-32 or 1-33, wherein the disorder is endotoxic shock, systemic inflammation, or atherosclerosis.
  • Embodiment 1-48 Use of the compound of any one of embodiments 1-1 to 1-8, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-9, for inhibiting a sterol regulatory element binding protein (SREBP).
  • SREBP sterol regulatory element binding protein
  • Embodiment 1-49 The use of embodiment 1-48, wherein the inhibiting comprises contacting the SREBP or contacting an SREBP cleavage activating-protein (SCAP) with the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • SCAP SREBP cleavage activating-protein
  • Embodiment 1-50 Use of the compound of any one of embodiments 1-1 to 1-8, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-9, for inhibiting the proteolytic activation of a sterol regulatory element-binding protein (SREBP).
  • SREBP sterol regulatory element-binding protein
  • Embodiment 1-51 The use of embodiment 1-50, wherein the inhibiting comprises contacting an SREBP cleavage activating-protein (SCAP) with the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • SCAP SREBP cleavage activating-protein
  • Embodiment 1-52 Use of the compound of any one of embodiments 1-1 to 1-8, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-9, 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 1-53 Use of the compound of any one of embodiments 1-1 to 1-8, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-9, for treating a disorder in a subject in need thereof.
  • Embodiment 1-54 The use of any one of embodiments 1-48 to 1-52, wherein the SREBP is an SREBP-E
  • Emb odiment 1-55 The use of embodiment 1-54, wherein the SREBP- 1 is SREBP- la.
  • Emb odiment 1-56 The use of embodiment 1-54, wherein the SREBP- 1 is SREBP- lc.
  • Embodiment 1-57 The use of any one of embodiments 1-48 to 1-52, wherein the SREBP is SREBP-2.
  • Embodiment 1-58 The use of any one of embodiments 1-48 to 1-57, wherein SREBP is inhibited in a subject in need thereof.
  • Embodiment 1-59 The use of any one of embodiments 1-48 to 1-58, wherein SCAP is inhibited in a subject in need thereof.
  • Embodiment 1-60 The use of any one of embodiments 1-48 to 1-59, wherein an SREBP or SCAP is contacted with the compound, or pharmaceutically acceptable salt, solvate, tautomer, 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,
  • Embodiment 1-61 The use of embodiment 1-52 or 1-53, wherein the disorder is Metabolic Syndrome, type 2 diabetes, obesity, liver disease, insulin resistance, adiposopathy, or dyslipidemia.
  • Embodiment 1-62 The use of embodiment 1-61, wherein the dyslipidemia is hypertriglyceridemia or elevated cholesterol levels.
  • Embodiment 1-63 The use of embodiment 1-62, wherein the liver disease is nonalcoholic steatohepatitis, liver fibrosis, or liver inflammation, or a combination thereof.
  • Embodiment 1-64 The use of embodiment 1-52 or 1-53, wherein the disorder is a hyperproliferative disorder.
  • Embodiment 1-65 The use of embodiment 1-64, wherein the hyperproliferative disorder is cancer.
  • Embodiment 1-66 The use of embodiment 1-65, 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 1-67 The use of embodiment 1-52 or 1-53, wherein the disorder is endotoxic shock, systemic inflammation, or atherosclerosis.
  • Embodiment 1-68 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 1-8, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-9.
  • NASH non-alcoholic steatohepatitis
  • Embodiment 1-69 Else of the compound of any one of embodiments 1-1 to 1-8, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-9, for treating non-alcoholic steatohepatitis (NASH) in a subject in need thereof.
  • NASH non-alcoholic steatohepatitis
  • Embodiment 1-70 Else of the compound of any one of embodiments 1-1 to 1-8, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-9, in the manufacture of a medicament for treating non-alcoholic steatohepatitis (NASH) in a subject in need thereof.
  • NASH non-alcoholic steatohepatitis
  • Embodiment 1-71 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 1-8, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-9.
  • Embodiment 1-72 Use of the compound of any one of embodiments 1-1 to 1-8, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-9, for treating a hyperproliferative disorder in a subject in need thereof.
  • Embodiment 1-73 Use of the compound of any one of embodiments 1-1 to 1-8, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 1-9, in the manufacture of a medicament for treating a hyperproliferative disorder in a subject in need thereof.
  • Embodiment II- 1 A compound of Formula (II): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein:
  • X is H, halo, alkyl, or cycloalkyl, wherein the alkyl or cycloalkyl is unsubstituted or substituted with one or more fluoro;
  • R 1 is alkyl, cycloalkyl, alkyl-cycloalkyl, or cycloalkyl-alkyl, which is unsubstituted or substituted with one or more fluoro;
  • R 4 is H or alkyl
  • R 2 is (Ci-C8)alkyl, cycloalkyl, alkyl-cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl, -O-alkyl, -O-cycloalkyl, -O-alkyl-cycloalkyl, - O-cycloalkyl-alkyl, -O-heterocycloalkyl, -O-alkyl-heterocycloalkyl, or -O-heterocycloalkyl- alkyl, and R 3 is hydrogen; wherein the (Ci-C8)alkyl, cycloalkyl, alkyl-cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl, -O-alkyl, -
  • -O-heterocycloalkyl-alkyl of R 2 is substituted with one or more substituents independently selected from the group consisting of fluoro, -OH, -0C(0)R 5 , and -O- alkyl; wherein eachR 5 is independently -R 6 N(R 7 )2 or -(CH2CH2-0-)niCH3; wherein each R 6 is (C2-C6)alkylene; each R 7 is independently H or -CH3; and each nl is independently an integer from 2 to 8; or R 2 and R 3 , together with the atoms to which they are attached, form a heterocyclyl.
  • X is H, halo, alkyl, or cycloalkyl, wherein the alkyl or cycloalkyl is unsubstituted or substituted with one or more fluoro;
  • R 1 is alkyl, cycloalkyl, alkyl-cycloalkyl, or cycloalkyl-alkyl, which is unsubstituted or substituted with one or more fluoro;
  • R 4 is H or alkyl
  • R 2 is (Ci-C8)alkyl, cycloalkyl, alkyl-cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl, -O-alkyl, -O-cycloalkyl, -O-alkyl-cycloalkyl, - O-cycloalkyl-alkyl, -O-heterocycloalkyl, -O-alkyl-heterocycloalkyl, or -O-heterocycloalkyl- alkyl, and R 3 is hydrogen; wherein the (Ci-C8)alkyl, cycloalkyl, alkyl-cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl, -O-alkyl, -
  • X is halo
  • R 1 is alkyl, which is unsubstituted or substituted with one or more fluoro;
  • R 2 is (Ci-C8)alkyl and R 3 is hydrogen; wherein the (Ci-C8)alkyl is substituted with one or more substituents independently selected from the group consisting of -OH and -0C(0)R 5 ; wherein eachR 5 is independently -R 6 N(R 7 )2 or -(CH2CH2-0-)niCH3; wherein each R 6 is (C2-C6)alkyl; each R 7 is independently H or -CH3; and each nl is independently an integer from 2 to 8; or R 2 and R 3 , together with the atoms to which they are attached, form a heterocyclyl.
  • Embodiment II-4 The compound of embodiments II- 1, II-2, or II-3, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R 2 is (Ci-C8)alkyl and R 3 is hydrogen; wherein the (Ci-C8)alkyl is substituted with -OH; or R 2 and R 3 , together with the atoms to which they are attached, form a heterocyclyl.
  • Embodiment II-5 The compound of embodiments II- 1, II-2, or II-3, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R 2 and R 3 , together with the atoms to which they are attached, form a heterocyclyl.
  • Embodiment II-6 The compound of embodiments II- 1, II-2, or II-3, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R 2 is (Ci-C8)alkyl and R 3 is hydrogen; wherein the (Ci-C8)alkyl is substituted with -OH.
  • Embodiment II-7 The compound of embodiments II- 1, II-2, or II-3, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R 2 is (Ci-Cs)alkyl substituted with -OC(0)R 5 .
  • Embodiment II-8 The compound of any one of embodiments II- 1 to II-5, wherein R 2 and R 3 , together with the atoms to which they are attached, form a heterocyclyl with the structure:
  • Embodiment II-9 The compound of any one of embodiments II- 1 to II-8, selected from the group consisting of: isotope, or isomer of any of the foregoing.
  • Embodiment II- 10 The compound of any one of embodiments II- 1 to II-3, II-4 to II-6, or II-8 , selected from the group consisting of: pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of the foregoing.
  • Embodiment II- 11 A pharmaceutical composition, comprising the compound of any one of embodiments II- 1 to II- 10, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient.
  • Embodiment 11-12 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 II- 1 to II- 10, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment II- 11.
  • SREBP sterol regulatory element-binding protein
  • SCAP SREBP cleavage activating- protein
  • Embodiment 11-13 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 II- 1 to II- 10, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment II- 11.
  • SREBP sterol regulatory element-binding protein
  • SCAP SREBP cleavage activating-protein
  • Embodiment 11-14 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 II-l to II- 10, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment II- 11.
  • SREBP sterol regulatory element-binding protein
  • Embodiment 11-15 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 II-l to II- 10, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment II-l 1.
  • Embodiment 11-16 The method of any one of embodiments 11-12 to 11-14, wherein the SREBP is an SREBP-1.
  • Embodiment 11-17 The method of embodiment 11-16, wherein the SREBP-1 is SREBP- la.
  • Embodiment 11-18. The method of embodiment 11-16, wherein the SREBP-1 is SREBP-lc.
  • Embodiment 11-19 The method of any one of embodiments 11-12 to 11-14, wherein the SREBP is SREBP-2.
  • Embodiment 11-20 The method of any one of embodiments 11-12 to 11-19, wherein SREBP is inhibited in a subject in need thereof.
  • Embodiment 11-21 The method of any one of embodiments 11-12 to 11-20, wherein SCAP is inhibited in a subject in need thereof.
  • Embodiment 11-22 The method of any one of embodiments 11-12 to 11-21, comprising contacting SREBP or SCAP with the compound, or pharmaceutically acceptable salt, solvate, tautomer, 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, tautomer, isotope, or isomer thereof, or the pharmaceutical composition, where
  • Embodiment 11-23 The method of embodiment 11-14 or 11-15, wherein the disorder is Metabolic Syndrome, type 2 diabetes, obesity, liver disease, insulin resistance, adiposopathy, or dyslipidemia.
  • Embodiment 11-24 The method of embodiment 11-23, wherein the dyslipidemia is hypertriglyceridemia or elevated cholesterol levels.
  • Embodiment 11-25 The method of embodiment 11-23, wherein the liver disease is nonalcoholic steatohepatitis, liver fibrosis, or liver inflammation, or a combination thereof.
  • Embodiment 11-26 The method of embodiment 11-14 or 11-15, wherein the disorder is a hyperproliferative disorder.
  • Embodiment 11-27 The method of embodiment 11-26, wherein the hyperproliferative disorder is cancer.
  • Embodiment 11-28 The method of embodiment 11-27, 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 11-29 The method of embodiment 11-14 or 11-15, wherein the disorder is endotoxic shock, systemic inflammation, or atherosclerosis.
  • Embodiment 11-30 Use of the compound of any one of embodiments II-l to II- 10, 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.
  • SREBP sterol regulatory element-binding protein
  • Embodiment II-31 The use of embodiment 11-30, wherein the inhibiting comprises contacting the SREBP or contacting an SREBP cleavage activating-protein (SCAP) with the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • SCAP SREBP cleavage activating-protein
  • Embodiment 11-32 Use of the compound of any one of embodiments II-l to II- 10, 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.
  • SREBP sterol regulatory element-binding protein
  • Embodiment 11-33 The use of embodiment 11-32, wherein the inhibiting comprises contacting an SREBP cleavage activating-protein (SCAP) with the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • SCAP SREBP cleavage activating-protein
  • Embodiment 11-34 Use of the compound of any one of embodiments II-l to II- 10, 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).
  • SREBP sterol regulatory element-binding protein
  • Embodiment 11-35 Use of the compound of any one of embodiments II-l to II- 10, 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.
  • Embodiment 11-36 The use of any one of embodiments 11-30 to 11-34, wherein the SREBP is an SREBP-1.
  • Embodiment 11-37 The use of embodiment 11-36, wherein the SREBP-1 is SREBP-la.
  • Embodiment 11-38 The use of embodiment 11-36, wherein the SREBP-1 is SREBP-lc.
  • Embodiment 11-39 The use of any one of embodiments 11-30 to 11-34, wherein the SREBP is SREBP-2.
  • Embodiment 11-40 The use of any one of embodiments 11-30 to 11-39, wherein SREBP is inhibited in a subject in need thereof.
  • Embodiment 11-41 The use of any one of embodiments 11-30 to 11-40, wherein SCAP is inhibited in a subject in need thereof.
  • Embodiment 11-42 The use of any one of embodiments 11-30 to 11-41, wherein an SREBP or SCAP is contacted with the compound, or pharmaceutically acceptable salt, solvate, tautomer, 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, RDHl l, 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.
  • Embodiment 11-43 The use of embodiment 11-34 or 11-35, wherein the disorder is Metabolic Syndrome, type 2 diabetes, obesity, liver disease, insulin resistance, adiposopathy, or dyslipidemia.
  • Embodiment 11-44 The use of embodiment 11-43, wherein the dyslipidemia is hypertriglyceridemia or elevated cholesterol levels.
  • Embodiment 11-45 The use of embodiment 11-43, wherein the liver disease is nonalcoholic steatohepatitis, liver fibrosis, or liver inflammation, or a combination thereof.
  • Embodiment 11-46 The use of embodiment 11-34 or 11-35, wherein the disorder is a hyperproliferative disorder.
  • Embodiment 11-47 The use of embodiment 11-46, wherein the hyperproliferative disorder is cancer.
  • Embodiment 11-48 The use of embodiment 11-47, 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 11-49 The use of embodiment 11-34 or 11-35, wherein the disorder is endotoxic shock, systemic inflammation, or atherosclerosis.
  • Embodiment 11-50 Else of the compound of any one of embodiments II-l to II- 10, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment II- 11 , for inhibiting a sterol regulatory element binding protein (SREBP).
  • SREBP sterol regulatory element binding protein
  • Embodiment II-51 The use of embodiment 11-50, wherein the inhibiting comprises contacting the SREBP or contacting an SREBP cleavage activating-protein (SCAP) with the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • SCAP SREBP cleavage activating-protein
  • Embodiment 11-52 Use of the compound of any one of embodiments II-l to II- 10, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment II-l 1, for inhibiting the proteolytic activation of a sterol regulatory element-binding protein (SREBP).
  • SREBP sterol regulatory element-binding protein
  • Embodiment 11-53 The use of embodiment 11-52, wherein the inhibiting comprises contacting an SREBP cleavage activating-protein (SCAP) with the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • SCAP SREBP cleavage activating-protein
  • Embodiment 11-54 Use of the compound of any one of embodiments II-l to II- 10, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment II- 11 , 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 11-55 Use of the compound of any one of embodiments II-l to II- 10, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment II-l 1, for treating a disorder in a subject in need thereof.
  • Embodiment 11-56 The use of any one of embodiments 11-50 to 11-54, wherein the SREBP is an SREBP-1.
  • Embodiment 11-57 The use of embodiment 11-56, wherein the SREBP-1 is SREBP- la.
  • Embodiment 11-58 The use of embodiment 11-56, wherein the SREBP-1 is SREBP-lc.
  • Embodiment 11-59 The use of any one of embodiments 11-50 to 11-54, wherein the SREBP is SREBP-2.
  • Embodiment 11-60 The use of any one of embodiments 11-50 to 11-59, wherein SREBP is inhibited in a subject in need thereof.
  • Embodiment 11-61 The use of any one of embodiments 11-50 to 11-60, wherein SCAP is inhibited in a subject in need thereof.
  • Embodiment 11-62 The use of any one of embodiments 11-50 to 11-61, wherein an SREBP or SCAP is contacted with the compound, or pharmaceutically acceptable salt, solvate, tautomer, 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
  • Embodiment 11-63 The use of embodiment 11-54 or 11-55, wherein the disorder is Metabolic Syndrome, type 2 diabetes, obesity, liver disease, insulin resistance, adiposopathy, or dyslipidemia.
  • Embodiment 11-64 The use of embodiment 11-63, wherein the dyslipidemia is hypertriglyceridemia or elevated cholesterol levels.
  • Embodiment 11-65 The use of embodiment 11-64, wherein the liver disease is nonalcoholic steatohepatitis, liver fibrosis, or liver inflammation, or a combination thereof.
  • Embodiment 11-66 The use of embodiment 11-54 or 11-55, wherein the disorder is a hyperproliferative disorder.
  • Embodiment 11-67 The use of embodiment 11-66, wherein the hyperproliferative disorder is cancer.
  • Embodiment 11-68 The use of embodiment 11-67, 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 11-69 The use of embodiment 11-54 or 11-55, wherein the disorder is endotoxic shock, systemic inflammation, or atherosclerosis.
  • Embodiment 11-70 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 II- 1 to II- 10, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment 11 11
  • Embodiment 11-71 Use of the compound of any one of embodiments II-l to II- 10, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment II-l 1, for treating non-alcoholic steatohepatitis (NASH) in a subject in need thereof.
  • NASH non-alcoholic steatohepatitis
  • Embodiment 11-72 Use of the compound of any one of embodiments II-l to II- 10, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment II-l 1, in the manufacture of a medicament for treating non-alcoholic steatohepatitis (NASH) in a subject in need thereof.
  • NASH non-alcoholic steatohepatitis
  • Embodiment 11-73 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 II-l to II- 10, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment II-l 1.
  • Embodiment 11-74 Use of the compound of any one of embodiments II-l to II- 10, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment II-l 1, for treating a hyperproliferative disorder in a subject in need thereof.
  • Embodiment 11-75 Use of the compound of any one of embodiments II-l to II- 10, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment II-l 1, in the manufacture of a medicament for treating a hyperproliferative disorder in a subject in need thereof.
  • Embodiment III- 1 A compound of Formula (III): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein: X is H, halo, alkyl, or cycloalkyl, wherein the alkyl or cycloalkyl is unsubstituted or substituted with one or more fluoro; R 1 is alkyl, cycloalkyl, alkyl-cycloalkyl, or cycloalkyl-alkyl, which is unsubstituted or substituted with one or more fluoro;
  • R 4 is H or alkyl
  • R 2 is (Ci-C8)alkyl, cycloalkyl, alkyl-cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl, -O-alkyl, -O-cycloalkyl, -O- alkyl-cycloalkyl, -O-cycloalkyl-alkyl, -O-heterocycloalkyl, -O-alkyl- heterocycloalkyl, or -O-heterocycloalkyl-alkyl, and R 3 is hydrogen; wherein the (Ci-C8)alkyl, cycloalkyl, alkyl-cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl, -O-alkyl, -O-
  • Embodiment III-2 A compound of Formula (II): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein: X is H, halo, alkyl, or cycloalkyl, wherein the alkyl or cycloalkyl is unsubstituted or substituted with one or more fluoro;
  • R 1 is alkyl, cycloalkyl, alkyl-cycloalkyl, or cycloalkyl-alkyl, which is unsubstituted or substituted with one or more fluoro;
  • R 4 is H or alkyl
  • R 2 is (Ci-C8)alkyl, cycloalkyl, alkyl-cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl, -O-alkyl, -O-cycloalkyl, -O- alkyl-cycloalkyl, -O-cycloalkyl-alkyl, -O-heterocycloalkyl, -O-alkyl- heterocycloalkyl, or -O-heterocycloalkyl-alkyl, and R 3 is hydrogen; wherein the (Ci-C8)alkyl, cycloalkyl, alkyl-cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl, -O-alkyl, -O-
  • Embodiment III-3 A compound of Formula (I): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein: X is H, halo, alkyl, or cycloalkyl, wherein the alkyl or cycloalkyl is unsubstituted or substituted with one or more fluoro; R 1 is alkyl, cycloalkyl, alkyl-cycloalkyl, or cycloalkyl-alkyl, which is unsubstituted or substituted with one or more fluoro;
  • R 4 is H or alkyl
  • R 2 is (Ci-C8)alkyl, cycloalkyl, alkyl-cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl, -O-alkyl, -O-cycloalkyl, -O- alkyl-cycloalkyl, -O-cycloalkyl-alkyl, -O-heterocycloalkyl, -O-alkyl- heterocycloalkyl, or -O-heterocycloalkyl-alkyl, and R 3 is hydrogen; wherein the (Ci-C8)alkyl, cycloalkyl, alkyl-cycloalkyl, cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl, -O-alkyl, -O-
  • Embodiment III-4 A compound of Formula (I- A): or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein: X is halo;
  • R 1 is alkyl, which is unsubstituted or substituted with one or more fluoro;
  • R 2 is (Ci-C8)alkyl and R 3 is hydrogen; wherein the (Ci-C8)alkyl is substituted with one or more substituents independently selected from the group consisting of -OH and -0C(0)R 5 ; wherein eachR 5 is independently -R 6 N(R 7 )2 or -(CH2CH2-0-)niCH3; wherein each R 6 is (C2-C6)alkyl; ' each R 7 is independently H or -CH3; and each nl is independently an integer from 2 to 8; or R 2 and R 3 , together with the atoms to which they are attached, form a heterocyclyl.
  • Embodiment III-5 The compound of any one of embodiments III- 1 to III-4, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R 2 is (Ci-C8)alkyl and R 3 is hydrogen; wherein the (Ci-C8)alkyl is substituted with -OH; or R 2 and R 3 , together with the atoms to which they are attached, form a heterocyclyl.
  • Embodiment III-6 The compound of any one of embodiments III- 1 to III-4, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R 2 and R 3 , together with the atoms to which they are attached, form a heterocyclyl.
  • Embodiment III-7 The compound of any one of embodiments III- 1 to III-4, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R 2 is (Ci-C8)alkyl and R 3 is hydrogen; wherein the (Ci-C8)alkyl is substituted with -OH.
  • Embodiment III-8 The compound of any one of embodiments III- 1 to III-4, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, wherein R 2 is (Ci-C8)alkyl substituted with -OC(0)R 5 .
  • Embodiment III-9 The compound of any one of embodiments III- 1 to III-6, wherein R 2 and R 3 , together with the atoms to which they are attached, form a heterocyclyl with the structure:
  • Embodiment III-10 The compound of embodiment III- 1 , wherein R 2 and R 3 , together with the atoms to which they are attached, form a heterocyclyl with the structure:
  • Embodiment III- 11 The compound of any one of embodiments III- 1 to III-8, selected from the group consisting of: isotope, or isomer of any of the foregoing.
  • Embodiment III-12 The compound of any one of embodiments III- 1 -5 or III-7 to III-8 , selected from the group consisting of: pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of the foregoing.
  • Embodiment III- 13 The compound of any one of embodiments III-1-5 or III-7 to III- 8, selected from the group consisting of: pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer of any of the foregoing.
  • Embodiment III- 14 The compound of embodiment III- 1 : , or a pharmaceutically acceptable salt, solvated, tautomer, isotope, or isomer of any of the foregoing.
  • Embodiment III-l A pharmaceutical composition, comprising the compound of any one of embodiments III-l to III- 14, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, and a pharmaceutically acceptable excipient.
  • Embodiment III- 16 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 III-l to III- 14, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment III- 15.
  • SREBP sterol regulatory element-binding protein
  • SCAP SREBP cleavage activating-protein
  • Embodiment III-17 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 III-l to III- 14, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment III- 15.
  • SREBP sterol regulatory element-binding protein
  • SCAP SREBP cleavage activating-protein
  • Embodiment III- 18 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 III-l to III-14, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment III- 15.
  • SREBP sterol regulatory element-binding protein
  • Embodiment III-19 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 III-l to III-14, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment III-l 5.
  • Embodiment III-20 The method of any one of embodiments III- 16 to III-18, wherein the SREBP is an SREBP-1.
  • Embodiment III-2E The method of embodiment III-20, wherein the SREBP-1 is SREBP- la.
  • Embodiment III-22 The method of embodiment III-20, wherein the SREBP-1 is SREBP- lc.
  • Embodiment III-23 The method of any one of embodiments III- 16 to III- 18, wherein the SREBP is SREBP-2.
  • Embodiment III-24 The method of any one of embodiments III- 16 to III-23, wherein SREBP is inhibited in a subject in need thereof.
  • Embodiment III-25 The method of any one of embodiments III- 16 to III-24, wherein SCAP is inhibited in a subject in need thereof.
  • Embodiment III-26 The method of any one of embodiments III- 16 to III-25, comprising contacting SREBP or SCAP with the compound, or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment III- 15, 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, RDHll, SC5DL, SQLE, STARD4, TM7SF2, PNPLA3, SREBFl, SREBF2, HMGCR, MVD, MVK, ACLY, MSMOl, ACACA, and ACACB is reduced after contacting the SREBP or SCAP with the compound, or pharmaceutically acceptable salt, solvate, tautomer, isotope, or is
  • Embodiment III-27 The method of embodiment III- 18 or III- 19, wherein the disorder is Metabolic Syndrome, type 2 diabetes, obesity, liver disease, insulin resistance, adiposopathy, or dyslipidemia.
  • Embodiment III-28 The method of embodiment III-27, wherein the dyslipidemia is hypertriglyceridemia or elevated cholesterol levels.
  • Embodiment III-29 The method of embodiment III-27, wherein the liver disease is nonalcoholic steatohepatitis, liver fibrosis, or liver inflammation, or a combination thereof.
  • Embodiment III-30 The method of embodiment III- 18 or III- 19, wherein the disorder is a hyperproliferative disorder.
  • Embodiment III-31 The method of embodiment III-30, wherein the hyperproliferative disorder is cancer.
  • Embodiment III-32 The method of embodiment III-31, 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 III-33 The method of embodiment III- 18 or III- 19, wherein the disorder is endotoxic shock, systemic inflammation, or atherosclerosis.
  • Embodiment III-34 Use of the compound of any one of embodiments III- 1 to III- 14, 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.
  • SREBP sterol regulatory element-binding protein
  • Embodiment III-35 The use of embodiment III-34, wherein the inhibiting comprises contacting the SREBP or contacting an SREBP cleavage activating-protein (SCAP) with the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • SCAP SREBP cleavage activating-protein
  • Embodiment III-36 Else of the compound of any one of embodiments III- 1 to III- 14, 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.
  • SREBP sterol regulatory element-binding protein
  • Embodiment III-37 The use of embodiment III-36, wherein the inhibiting comprises contacting an SREBP cleavage activating-protein (SCAP) with the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • SCAP SREBP cleavage activating-protein
  • Embodiment III-38 Use of the compound of any one of embodiments III- 1 to III- 14, 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).
  • SREBP sterol regulatory element-binding protein
  • Embodiment III-39 Use of the compound of any one of embodiments III- 1 to III- 14, 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.
  • Embodiment III-40 The use of any one of embodiments III-34 to III-38, wherein the SREBP is an SREBP-1.
  • Embodiment III-41 The use of embodiment III-40, wherein the SREBP-1 is SREBP- l a.
  • Embodiment III-42 The use of embodiment III-40, wherein the SREBP-1 is SREBP- lc.
  • Embodiment III-43 The use of any one of embodiments III-34 to III-38, wherein the SREBP is SREBP-2.
  • Embodiment III-44 The use of any one of embodiments III-34 to III-38, wherein SREBP is inhibited in a subject in need thereof.
  • Embodiment III-45 The use of any one of embodiments III-34 to III-44, wherein SCAP is inhibited in a subject in need thereof.
  • Embodiment III-46 The use of any one of embodiments III-34 to III-45, wherein an SREBP or SCAP is contacted with the compound, or pharmaceutically acceptable salt, solvate, tautomer, 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, tautomer, isotope, or isomer thereof.
  • Embodiment III-47 The use of embodiment III-38 or III-39, wherein the disorder is Metabolic Syndrome, type 2 diabetes, obesity, liver disease, insulin resistance, adiposopathy, or dyslipidemia.
  • Embodiment III-48 The use of embodiment III-47, wherein the dyslipidemia is hypertriglyceridemia or elevated cholesterol levels.
  • Embodiment III-49 The use of embodiment III-47, wherein the liver disease is nonalcoholic steatohepatitis, liver fibrosis, or liver inflammation, or a combination thereof.
  • Embodiment III-50 The use of embodiment III-37 or III-39, wherein the disorder is a hyperproliferative disorder.
  • Embodiment III-51 The use of embodiment III-50, wherein the hyperproliferative disorder is cancer.
  • Embodiment III-53 The use of embodiment III-38 or III-39, wherein the disorder is endotoxic shock, systemic inflammation, or atherosclerosis.
  • Embodiment III-54 Else of the compound of any one of embodiments III- 1 to III- 14, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment III- 15, for inhibiting a sterol regulatory element binding protein (SREBP).
  • SREBP sterol regulatory element binding protein
  • Embodiment III-55 The use of embodiment III-54, wherein the inhibiting comprises contacting the SREBP or contacting an SREBP cleavage activating-protein (SCAP) with the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • SCAP SREBP cleavage activating-protein
  • Embodiment III-56 Use of the compound of any one of embodiments III- 1 to III- 14, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment III- 15, for inhibiting the proteolytic activation of a sterol regulatory element-binding protein (SREBP).
  • SREBP sterol regulatory element-binding protein
  • Embodiment III-57 The use of embodiment III-56, wherein the inhibiting comprises contacting an SREBP cleavage activating-protein (SCAP) with the compound or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof.
  • SCAP SREBP cleavage activating-protein
  • Embodiment III-58 Use of the compound of any one of embodiments III- 1 to III- 14, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment III- 15 , 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 III-59 Use of the compound of any one of embodiments III- 1 to III- 14, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment III- 15 , for treating a disorder in a subject in need thereof.
  • Embodiment III-60 The use of any one of embodiments III-54 to III-59, wherein the SREBP is an SREBP-E
  • Embodiment III-61 The use of embodiment III-60, wherein the SREBP-1 is SREBP- l a.
  • Embodiment III-62 The use of embodiment III-60, wherein the SREBP-1 is SREBP- lc.
  • Embodiment III-63 The use of any one of embodiments III-54 to III-58, wherein the SREBP is SREBP-2.
  • Embodiment III-64 The use of any one of embodiments III-54 to III-63, wherein SREBP is inhibited in a subject in need thereof.
  • Embodiment III-65 The use of any one of embodiments III-54 to III-64, wherein SCAP is inhibited in a subject in need thereof.
  • Embodiment III-66 The use of any one of embodiments III-54 to III-65, wherein an SREBP or SCAP is contacted with the compound, or pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment III- 15, 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,
  • Embodiment III-67 The use of embodiment III-58 or III-59, wherein the disorder is Metabolic Syndrome, type 2 diabetes, obesity, liver disease, insulin resistance, adiposopathy, or dyslipidemia.
  • Embodiment III-68 The use of embodiment III-67, wherein the dyslipidemia is hypertriglyceridemia or elevated cholesterol levels.
  • Embodiment III-69 The use of embodiment III-68, wherein the liver disease is nonalcoholic steatohepatitis, liver fibrosis, or liver inflammation, or a combination thereof.
  • Embodiment III-70 The use of embodiment III-58 or III-59, wherein the disorder is a hyperproliferative disorder.
  • Embodiment III-71 The use of embodiment III-70, wherein the hyperproliferative disorder is cancer.
  • Embodiment III-72 The use of embodiment III-71, 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 III-73 The use of embodiment III-58 or III-59, wherein the disorder is endotoxic shock, systemic inflammation, or atherosclerosis.
  • Embodiment III-74 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 III-l to III- 14, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment III- 15.
  • NASH non-alcoholic steatohepatitis
  • Embodiment III-75 Use of the compound of any one of embodiments III- 1 to III- 14, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment III- 15, for treating non-alcoholic steatohepatitis (NASH) in a subject in need thereof.
  • NASH non-alcoholic steatohepatitis
  • Embodiment III-76 Use of the compound of any one of embodiments III- 1 to III- 14, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment III- 15, in the manufacture of a medicament for treating non-alcoholic steatohepatitis (NASH) in a subject in need thereof.
  • NASH non-alcoholic steatohepatitis
  • Embodiment III-77 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 III-l to III- 14, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment III- 15.
  • Embodiment III-78 Use of the compound of any one of embodiments III- 1 to III- 14, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment III- 15, for treating a hyperproliferative disorder in a subject in need thereof.
  • Embodiment III-79 Use of the compound of any one of embodiments III- 1 to III- 14, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment III- 15, in the manufacture of a medicament for treating a hyperproliferative disorder in a subject in need thereof.
  • Embodiment III-80 The compound of any one of embodiments III- 1 to III- 14, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, or the pharmaceutical composition of embodiment III- 15, for inhibiting a sterol regulatory element binding protein (SREBP).
  • SREBP sterol regulatory element binding protein
  • Embodiment III-81 The compound of any one of embodiments III- 1 to III- 14, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, for inhibiting the proteolytic activation of a sterol regulatory element-binding protein (SREBP).
  • SREBP sterol regulatory element-binding protein
  • Embodiment III-82 The compound of any one of embodiments III- 1 to III- 14, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, for treating a disorder in a subject in need thereof, wherein the disorder is mediated by a sterol regulatory element-binding protein (SREBP).
  • Embodiment III-83 The compound of any one of embodiments III- 1 to III- 14, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, for treating a disorder in a subject in need thereof.
  • Embodiment III-84 The compound of any one of embodiments III- 1 to III- 14, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, for treating non alcoholic steatohepatitis (NASH) in a subject in need thereof.
  • NASH non alcoholic steatohepatitis
  • Embodiment III-85 The compound of any one of embodiments III- 1 to III- 14, or a pharmaceutically acceptable salt, solvate, tautomer, isotope, or isomer thereof, for treating a hyperproliferative disorder in a subject in need thereof.
  • Step 1 Synthesis of (4-hromothiophen-2-yl)horonic acid.
  • 2,4- dibromothiphene (2 g, 8.29 mmol) in dry THF (20 mL) at -10°C under argon, was added isopropyl magnesium chloride (2.0 M in THF, 3.72 mL, 7.46 mmol) dropwise by syringe over
  • Step 2 Synthesis of 8-(4-hromothiophen-2-yl)-2, 3-dihydro-[ 1, 4 ]dioxino[2, 3- bjpyridine.
  • 8-bromo-2,3-dihydro-[l,4]dioxino[2,3-b]pyridine 0.3 g, 1.38 mmol
  • 1, 4-dioxane, H2O (7 mL) was added the product of Step 1 (0.284 g, 1.38 mmol) and K2CO3 (0.575 g, 4.16 mmol).
  • Step 3 Synthesis ofN-(3-chloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)methanesulfonamide .
  • Methane sulfonyl chloride (1.35 g, 11.85 mmol) was added dropwise to a solution of 3-chloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (2 g, 7.90 mmol) in pyridine at 0-5 °C. After stirring for 16 h at RT (room temperature) the reaction was quenched with water and the product extracted into DCM (dichloromethane).
  • Step 4 Synthesis of N-(3-chloro-4-(5-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-8- yl)thiophen-3-yl)phenyl)methanesulfonamide.
  • Step 1 l-(4-bromopyridin-2-yl)-3-methoxy-2-methylpropan-2-ol.
  • a solution of LDA (8.77 mL, 5.84 mmol) 1.0M in THF was added dropwise to 4-bromo-2-methylpyridine (l.Og, 5.84 mmol) in THF (15 mL) at -78 °C.
  • the reaction mixture was then warmed to -15 to -25°C for lhr and then cooled to -50 °C and a solution of l-methoxypropan-2-one (0.514 g, 5.84 mmol) in THF (5 mL) was added drop wise.
  • Step 2 l-(4-(4-bromothiophen-2-yl)pyridin-2-yl)-3-methoxy-2-methylpropan-2-ol.
  • Step 3 Synthesis o/N-(3-chloro-4-(5-(2-(2-hydroxy-3-methoxy-2- methylpropyl)pyridin-4-yl)thiophen-3-yl)phenyl)methanesulfonamide.
  • a stirred solution of the product of Step 2 (0.250 g, 0.733 mmol), N-(3-chloro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)phenyl)methanesulfonamide (0.218 g, 0.659 mmol) and potassium carbonate (0.303 g,
  • Step 1 3-((benzyloxy)methyl)-8-(4-bromothiophen-2-yl)-2,3-dihydro-[l,4]dioxino[2,3- b]pyridine.
  • 3-((benzyloxy)methyl)-8-bromo-2,3-dihydro- [l,4]dioxino[2,3-b]pyridine 0.5 g, 1.49 mmol
  • 1,4-dioxane H2O (10 mL) was added (4- bromothiophen-2-yl)boronic acid (0.3 g, 1.49 mmol) & K2CO3 (0.61 g, 4.47 mmol).
  • Step 2 N-(4-(5-(3-((benzyloxy)methyl)-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-8- yl)thiophen-3-yl)-3-chlorophenyl)methanesulfonamide.
  • Step 3 N-(3-chloro-4-(5-(3-(hydroxymethyl)-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin- 8-yl)thiophen-3-yl)phenyl)methanesulfonamide.
  • the product of Step 2 (80 mg, 0.14 mmol) was dissolved in 47% aqueous hydrobromic acid solution (5 mL) for 16h at RT. The reaction, mixture was then quenched with water and adjusted to pH 8-9 with aqueous NaHCCh.
  • HepG2 cells The effect of selected compounds on the gene expression of HepG2 cells was evaluated.
  • HepG2 cells (P2) were seeded in 24 well plate (80,000 cells/well) for RNA extraction and in a 96 well plate (10,000 cells/well) for Cell Titer Glow (CTG).
  • the media used was DMEM and contained 10% FBS. Each compound was evaluated at 500 Mm for 48 hours.
  • Two biological replicates per experimental group were evaluated for RNA.
  • RNA was harvested with RNEasy kit and 20-100 ng used to synthesize cDNA with random primers. Quantitative PCR was performed on 1 pg to 100 ng cDNA for the following genes: ACACA, ACLY, FASN, LSS, PNPLA3.
  • 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 Growth media without antibiotics. Cells were incubated at 37°C for 8 hours. After 8 hours, cells were washed with DPBS for complete removal of FBS. DPBS was completely removed and Growth media was replaced with phenol free treatment medium (90 m ⁇ ) with different FBS concentrations. The cells were then incubated at 37°C for 24 hours with varying doses (0.01 uM to 10 uM) of compounds. Then a Luciferase assay was performed.
  • 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.
  • 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.
  • 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 # A1113803) 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 pM 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.
  • Entries A-F are effect of compounds on gene expression of HepG2 cells.
  • Assay results marked with an asterisk (*) were obtained using the modified Reporter Screening Assay above.
  • Human Pre-Adipocyte differentiation Cells are thawed and seeded at 40,625 cells/cm 2 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.
  • 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.
  • triglyceride 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.
  • BUN blood urea nitrogen
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • 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.
  • 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.
  • 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 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 was 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.

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Abstract

L'invention concerne des composés comprenant un noyau tricyclique et des sels, solvates, tautomères, isotopes ou isomères pharmaceutiquement acceptables de ceux-ci. L'invention concerne également des procédés d'inhibition d'un composant de la voie de la protéine de liaison à l'élément régulateur de stérol (SREBP), telle qu'une SREBP ou une protéine d'activation de clivage de SREBP (SCAP), à l'aide de ces composés ou de sels, solvates, tautomères, isotopes ou isomères pharmaceutiquement acceptables de ceux-ci. L'invention concerne en outre des méthodes de traitement d'un trouble chez un sujet en ayant besoin, par exemple, une maladie du foie, la stéatohépatite non alcoolique, l'insulinorésistance ou le cancer.
PCT/US2021/015101 2020-01-27 2021-01-26 Inhibiteurs de srebp comprenant un noyau central de thiophène WO2021154735A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024089216A1 (fr) 2022-10-27 2024-05-02 Syngenta Crop Protection Ag Nouveaux composés hétéroaryl-carboxamides contenant du soufre

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Publication number Priority date Publication date Assignee Title
US8207196B2 (en) * 2007-02-02 2012-06-26 Baylor College Of Medicine Compositions and methods for the treatment of metabolic disorders
WO2015031650A1 (fr) * 2013-08-28 2015-03-05 Sarvajit Chakravarty Composés hétérocycliques et leurs méthodes d'utilisation
WO2016141258A1 (fr) * 2015-03-04 2016-09-09 Medivation Technologies, Inc. Inhibiteurs des protéines de liaison à l'elément de régulation des stérols (srebp)
US20180028518A1 (en) * 2015-03-04 2018-02-01 Medivation Technologies, Inc. Heterocyclic Compounds and Methods of Use

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Publication number Priority date Publication date Assignee Title
CA2922703A1 (fr) * 2013-08-29 2015-03-05 Baylor College Of Medicine Compositions et procedes de traitement de troubles metaboliques et troubles associes au poids corporel
MX2018013221A (es) * 2016-04-29 2019-06-24 Fgh Biotech Inc Compuestos de pirazol disustituidos para el tratamiento de enfermedades.
WO2018049080A1 (fr) * 2016-09-07 2018-03-15 Fgh Biotech, Inc. Composés de pyrazole di-substitués pour le traitement de maladies

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8207196B2 (en) * 2007-02-02 2012-06-26 Baylor College Of Medicine Compositions and methods for the treatment of metabolic disorders
WO2015031650A1 (fr) * 2013-08-28 2015-03-05 Sarvajit Chakravarty Composés hétérocycliques et leurs méthodes d'utilisation
WO2016141258A1 (fr) * 2015-03-04 2016-09-09 Medivation Technologies, Inc. Inhibiteurs des protéines de liaison à l'elément de régulation des stérols (srebp)
US20180028518A1 (en) * 2015-03-04 2018-02-01 Medivation Technologies, Inc. Heterocyclic Compounds and Methods of Use

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024089216A1 (fr) 2022-10-27 2024-05-02 Syngenta Crop Protection Ag Nouveaux composés hétéroaryl-carboxamides contenant du soufre

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