WO2025230871A1

WO2025230871A1 - Compounds, compositions, methods of use, and methods for preparing compounds

Info

Publication number: WO2025230871A1
Application number: PCT/US2025/026600
Authority: WO
Inventors: Brian P. CERESA; John O. Trent; Joseph A. Burlison; Srinivasrao GANIPISETTI
Original assignee: University of Louisville Research Foundation ULRF
Current assignee: University of Louisville Research Foundation ULRF
Priority date: 2024-04-29
Filing date: 2025-04-28
Publication date: 2025-11-06
Anticipated expiration: 2026-10-29

Abstract

Some embodiments of the invention include inventive compounds (e.g., compounds of Formula (I)). Other embodiments include compositions (e.g., pharmaceutical compositions) comprising the inventive compound. Still other embodiments of the invention include compositions (e.g., pharmaceutical compositions) for treating, for example, certain conditions using the inventive compounds. Some embodiments include methods of using the inventive compound (e.g., in compositions or in pharmaceutical compositions) for administering and treating (e.g., wounds such as corneal wounds). Further embodiments include methods for making the inventive compounds. Additional embodiments of the invention are also discussed herein.

Description

COMPOUNDS, COMPOSITIONS, METHODS OF USE, AND METHODS FOR PREPARING COMPOUNDS CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application No.63/639,750, filed April 29, 2024, entitled “COMPOUNDS, COMPOSITIONS, METHODS OF USE, AND METHODS OF MAKING” which is herein incorporated by reference in its entirety. GOVERNMENT RIGHTS [0002] This invention was made with government support under (a) EY028911 awarded by the NIH/NEI and (b) EY027032 awarded by the NIH/NEI. The government has certain rights in the invention. REFERENCE TO A SEQUENCE LISTING [0003] The instant application contains a Sequence Listing that has been submitted in XML format via PatentCenter and is hereby incorporated by reference in its entirety. Said XML copy, created on April 25, 2025, is named 2025_04_seq_listing_35783_04268.xml and is 2,407 Bytes in size. BACKGROUND [0004] Growth Factor Receptor signaling can be helpful to tissue growth, homeostasis, and wound healing. However, receptor desensitization can sometimes limit the use of exogenous growth factors as a restorative agent therapeutically. An example of this is the Epidermal Growth Factor Receptor (EGFR) in the corneal epithelium. Despite promising experimental data, the clinical administration of EGF to damaged corneal epithelium has limited impact due to the attenuated signaling that occurs following sustained growth factor administration. [0005] If an epithelial tissue is damaged by trauma (physical, thermal, chemical, etc.) or disease, stimulating growth-promoting receptors with exogenous ligands can accelerate tissue regeneration. However, tissue restoration can be limited when treating with exogenous ligands due to intrinsic, negative regulatory mechanisms of signaling such as receptor desensitization. [0006] Certain embodiments of the invention address one or more of the deficiencies described above. For example, in some embodiments of the invention, inventive compounds such as Formula (I) are disclosed. In some embodiments, c-Cbl inhibitors are disclosed. Some embodiments of the invention include inventive compounds (e.g., compounds of Formula (I)). Other embodiments include compositions (e.g., pharmaceutical compositions) comprising the inventive compound. Still other embodiments of the invention include compositions (e.g., pharmaceutical compositions) for treating, for example, certain conditions using the inventive compounds. Some embodiments include methods of using the inventive compound (e.g., in compositions or in pharmaceutical compositions) for administering and treating (e.g., wounds such as corneal wounds). Further embodiments include methods for making the inventive compounds. Additional embodiments of the invention are also discussed herein. SUMMARY [0007] Some embodiments of the present invention include a compound selected from Formula (I), salts of Formula (I), optical isomers of Formula (I), geometric isomers of Formula (I), salts of optical isomers of Formula (I), salts of geometric isomers of Formula (I), and derivatives thereof (e.g., ethers, esters, or amides),

embodiments, R^1a, R^1b , R^1c, and R^1d can be the same or different and are H, halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), methanoyl (-COH), nitro (-NO₂), -NH₂, -N(CH₃)₂, cyano (-CN), sulfo (-SO₃H), -C(O)NH₂, -C(O)N(CH₃)₂, -C(O)(CH₃), -C(O)(C₂H₅), -C(O)(C₃H₇), C₁-C₃ perfluoronated alkyl, -CF₃, -OCF₃, C1-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁-C₉ alkoxy, phenyl, aryl, indolyl, or hetroaryl which methanoyl (-COH), -NH₂, -N(CH₃)₂, -C(O)NH₂, - C(O)N(CH₃)₂, -C(O)(CH₃), -C(O)(C₂H₅), -C(O)(C₃H₇), C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁-C₉ alkoxy, phenyl, aryl, indolyl, or hetroaryl can optionally be substituted with one or more of halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), methanoyl (-COH), carboxy (-CO₂H), nitro (-NO₂), -NH₂, -N(CH₃)₂, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), morpholinyl, -CO-morpholin-4-yl, -C(O)NH₂, -C(O)N(CH₃)₂, C₁-C₃ alkyl, C₁-C₃ perfluoronated alkyl, -CF₃, -OCF₃, C₁-C₃ alkoxy, aryl, aryl substituted with R^1x, phenyl, phenyl substituted with one or more R^1x, heteroaryl, heteroaryl substituted with one or more R^1x, indolyl, or indolyl substituted with one or more R^1x. In yet other embodiments, R^1x can be the same or different (e.,g., can be the same or different on the same ring or can be the same or different on different rings) and are halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), methanoyl (-COH), carboxy (- CO2H), nitro (-NO₂), -NH₂, -N(CH₃)₂, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), morpholinyl, -CO-morpholin-4-yl, -C(O)NH₂, -C(O)N(CH₃)₂, C₁-C₃ alkyl, C₁-C₃ perfluoronated alkyl, -CF₃, -OCF₃, or C1-C4 alkoxy (e.g., methoxy or ethoxy). In still other embodiments, R^1a and R^1b can optionally be joined to form a C₃-C₉ cycloalkyl, optionally substituted with halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), -NO₂, -CN, C₁-C₃ alkoxy, aryl, aryl substituted with one or more halogen (e.g., F, Cl, Br, or I), phenyl, phenyl substituted with one or more halogen (e.g., F, Cl, Br, or I), heteroaryl, heteroaryl substituted with one or more halogen (e.g., F, Cl, Br, or I), indolyl, or indolyl substituted with one or more halogen (e.g., F, Cl, Br, or I). In certain embodiments, R^1c and R^1d can optionally be joined to form a C₃-C₉ cycloalkyl optionally substituted with halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), -NO₂, -CN, C₁-C₃ alkoxy, aryl, aryl substituted with one or more halogen (e.g., F, Cl, Br, or I), phenyl, phenyl substituted with one or more halogen (e.g., F, Cl, Br, or I), heteroaryl, heteroaryl substituted with one or more halogen (e.g., F, Cl, Br, or I), indolyl, or indolyl substituted with one or more halogen (e.g., F, Cl, Br, or I). In some embodiments, n is 0, 1, 2, 3, 4, 5, or 6. In other embodiments, R² is H, halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), methanoyl (-COH), nitro (-NO₂), -NH₂, -N(CH₃)₂, cyano (-CN), sulfo (-SO3H), -C(O)NH₂, -C(O)N(CH₃)₂, -C(O)(CH₃), -C(O)(C2H5), -C(O)(C₃H₇), C₁-C₃ perfluoronated alkyl, -CF₃, -OCF₃, C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₁-C₆ alkoxy, aryl, hetroaryl, cycloalkyl, or heterocyclyl, which C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₁-C₆ alkoxy, aryl, hetroaryl, cycloalkyl, and heterocyclyl are optionally substituted with one or more of halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), methanoyl (-COH), nitro (-NO₂), -NH₂, -N(CH₃)₂, cyano (-CN), sulfo (-SO3H), -C(O)NH₂, -C(O)N(CH₃)₂, -C(O)(CH₃), - C(O)(C₂H₅), -C(O)(C₃H₇), C₁-C₃ perfluoronated alkyl, -CF₃, -OCF₃, or C₁-C₃ alkoxy. In still other embodiments, R³, R⁴, R⁵, and R⁶ can be the same or different and are H, halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), methanoyl (-COH), nitro (-NO₂), -NH₂, -N(CH₃)₂, cyano (-CN), sulfo (-SO₃H), -C(O)NH₂, -C(O)N(CH₃)₂, -C(O)(CH₃), -C(O)(C₂H₅), -C(O)(C₃H₇), C₁-C₃ perfluoronated alkyl, -CF₃, -OCF₃, C1-C6 alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, or C₁-C₅ alkoxy. In some embodiments, R^1a, R^1b , R^1c, and R^1d can be the same or different and are H, halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), methanoyl (-COH), nitro (-NO₂), -NH₂, -N(CH₃)₂, cyano (- CN), sulfo (-SO3H), -C(O)NH₂, -C(O)N(CH₃)₂, -C(O)(CH₃), -C(O)(C2H5), -C(O)(C₃H₇), C₁-C₃ perfluoronated alkyl, -CF₃, -OCF₃, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁-C₉ alkoxy, phenyl, aryl, indolyl, or hetroaryl which methanoyl (-COH), -NH₂, -N(CH₃)₂, -C(O)NH₂, - C(O)N(CH₃)₂, -C(O)(CH₃), -C(O)(C₂H₅), -C(O)(C₃H₇), C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁-C₉ alkoxy, phenyl, aryl, indolyl, or hetroaryl can optionally be substituted with one or more of halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), methanoyl (-COH), carboxy (-CO2H), nitro (-NO₂), -NH₂, -N(CH₃)₂, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO₃H), morpholinyl, -CO-morpholin-4-yl, -C(O)NH₂, -C(O)N(CH₃)₂, C₁-C₃ alkyl, C₁-C₃ perfluoronated alkyl, -CF₃, -OCF₃, C₁-C₃ alkoxy, aryl, aryl substituted with one or more halogens, aryl substituted with one or more C₁-C₃ alkoxy, phenyl, phenyl substituted with one or more halogens, phenyl substituted with one or more C₁-C₃ alkoxy, heteroaryl, heteroaryl substituted with one or more halogens, heteroaryl substituted with one or more C₁-C₃ alkoxy, indolyl, indolyl substituted with one or more halogens, or indolyl substituted with one or more C₁-C₃ alkoxy. In other embodiments, R^1a, R^1b , R^1c, and R^1d can be the same or different and are H, halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), methanoyl (-COH), nitro (-NO₂), -NH₂, -N(CH₃)₂, cyano (-CN), sulfo (-SO3H), -C(O)NH₂, -C(O)N(CH₃)₂, -C(O)(CH₃), -C(O)(C2H5), -C(O)(C₃H₇), C₁-C₃ perfluoronated alkyl, -CF₃, -OCF₃, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁-C₉ alkoxy, phenyl, aryl, indolyl, or hetroaryl which methanoyl (-COH), -NH₂, -N(CH₃)₂, -C(O)NH₂, -C(O)N(CH₃)₂, -C(O)(CH₃), -C(O)(C2H5), -C(O)(C₃H₇), C1-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁-C₉ alkoxy, phenyl, aryl, indolyl, or hetroaryl can optionally be substituted with one or more of halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), methanoyl (-COH), carboxy (-CO2H), nitro (-NO₂), -NH₂, -N(CH₃)₂, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO₃H), morpholinyl, -CO-morpholin-4-yl, -C(O)NH₂, -C(O)N(CH₃)₂, C₁-C₃ alkyl, C₁-C₃ perfluoronated alkyl, -CF₃, -OCF₃, C₁-C₃ alkoxy, aryl, aryl substituted with one or more halogens, phenyl, phenyl substituted with one or more halogens, heteroaryl, heteroaryl substituted with one or more halogens, indolyl, or indolyl substituted with one or more halogens. In still other embodiments, R^1a, R^1b , R^1c, and R^1d can be the same or different and are (a) C₁-C₅ alkyl (e.g., C₂ alkyl, C3 alkyl or C4 alkyl) substituted with phenyl, which phenyl is substituted with one or more halogen (e.g., F, Cl, Br, or I) or -OCH₃, (b) C₁-C₅ alkyl substituted with phenyl, (c) phenyl substituted with one or more halogen (e.g., F, Cl, Br, or I) or -OCH₃, (d) phenyl, or (e) C₁-C₅ alkyl. In yet other embodiments, (a) R^1a and R^1b are joined to form a C₅-C₇ monocyclic cycloalkyl or (b) R^1c and R^1d are joined to form a C₅-C₇ monocyclic cycloalkyl. In certain embodiments, (a) R^1a is methyl or (b) R^1c is methyl. In some embodiments, n is 1, 2, 3, or 4 (e.g., 2 or 3). In other embodiments, R² is H, methyl, ethyl, propyl, or phenyl. In yet other embodiments, R³ is H, -CH₃, -OCH₃, F, Cl, -CN, or -NO₂. In still other embodiments, R⁴ is H, - CH₃, -OCH₃, F, Cl, -CN, or -NO₂. In yet other embodiments, R⁴ is H or -OCH₃. In some embodiments, R⁵ is H, -CH₃, -OCH₃, F, Cl, -CN, or -NO₂ (e.g., H or -OCH₃). In certain embodiments, R⁶ is H, -CH₃, -OCH₃, F, Cl, -CN, or -NO₂. In other embodiments, R³, R⁵, and R⁶ are the same and are H. In still other embodiments, la (Ia),

some embodiments, the compound is any compound disclosed in this application (e.g., in the Examples of this application). [0008] In some embodiments, the compound increases EGFR phosphorylation. In other embodiments, the compound inhibits c-Cbl activity. In certain embodiments, the compound inhibits c-Cbl activity and the compound has a Kd to c-Cbl of less than or equal to 750 µM, less than or equal to 100 µM, less than or equal to 10 µM, less than or equal to 5 µM, less than or equal to 1 µM, or less than or equal to 0.75 µM. In other embodiments, the compound is I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I- 22, I-23, I-24, I-25, I-26, I-27, I-28, I-29, I-30, I-31, I-32, I-33, I-34, I-35, I-36, I-37, I-38, I-39, I- 40, I-41, I-42, I-43, I-44, I-45, I-46, I-47, I-48, I-49, I-50, I-51, I-52, I-53, I-54, I-55, I-56, I-57, I- 58, I-59, I-60, I-61, I-62, I-63, I-64, I-65, I-66, I-67, I-68, I-69, I-70, I-71, I-72, I-73, I-74, I-75, I- 76, I-77, I-78, I-79, I-80, I-81, I-82, I-83, I-84, I-85, I-86, I-87, I-88, I-89, I-90, I-91, or I-92. In yet other embodiments, the compound is I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-22, I-23, I-24, I-25, I-26, I-27, I-28, I-29, I-30, I-31, I-32, I-33, I-34, I-35, I-36, I-37, I-38, I-39, I-40, I-41, I-42, I-43, I-44, I-45, I-46, I-47, I-48, I-49, I-50, I-51, I-52, I-53, I-54, I-55, I-56, I-57, I-58, I-59, I-60, I-61, I-62, I-63, I-64, I-65, I-66, I-67, I-68, I-69, I-70, I-71, I-72, I-73, I-74, I-75, I-76, I-77, I-78, I-79, I-80, I-81, I-82, I-83, I-84, I-85, I-86, I-87, I-88, I-89, I-90, I-91, or I-92. In still other embodiments, the compound is I-1, I-36, I- 40, I-41, I-42, I-48, I-50, I-57, I-68, I-69, I-70, I-73, I-75, I-79, I-80, I-81, or I-82. In yet other embodiments, the compound is I-36, I-40, I-41, I-42, I-48, I-50, I-57, I-68, I-69, I-70, I-73, I-75, I-79, I-80, I-81, or I-82. In certain embodiments, the compound is I-40, I-41, I-42, I-48, I-50, I- 57, I-68, I-69, I-70, I-73, I-75, I-79, I-80, I-81, or I-82. In yet other embodiments, the compound is I-41 or I-79. In some embodiments, compound I-1 is excluded. [0009] Some embodiments of the invention include a composition comprising any compound as disclosed herein. In certain embodiments, the compound in the composition is in an amount of from about 0.0001% to about 99%. Other embodiments of the invention include a pharmaceutical composition comprising (a) any compound disclosed herein and (b) optionally a formulary ingredient (e.g., pharmaceutically acceptable carrier, other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, and excipients). In certain embodiments, the compound in the pharmaceutical composition is in an amount of from about 0.0001% to about 50%. [0010] Some embodiments, of the invention include a method for providing a cell with a compound (e.g., animal cell, mammalian cell, or human cell) comprising one or more administrations to (e.g., contacting or injecting) the cell of one or more compositions comprising (a) any compound as disclosed herein, (b) any composition as disclosed herein, or (c) any pharmaceutical composition as disclosed herein, wherein the compositions may be the same or different if there is more than one administration, and optionally administering EGF (e.g., immediately after the one or more administrations step or waiting 10 seconds, 30 seconds, 1 min., 5 mins., 10 mins., 15 mins., 20 mins., 30 mins., 45 mins., 60 mins., 90 mins., 120 mins., 150 mins., 180 mins., 240 mins., or 300 mins. after the one or more administrations step). In certain embodiments, the administering of EGF occurs. In other embodiments, the administering of EGF occurs and the EGF is at a concentration of from about 0.1 to 30 ng/mL. In still other embodiments, the cell is in vivo, ex vivo, or in vitro. [0011] Some embodiments of the invention include a method for providing an animal with a compound comprising one or more administrations to the animal of one or more compositions comprising (a) any compound as disclosed herein, (b) any composition as disclosed herein, or (c) any pharmaceutical composition as disclosed herein, wherein the compositions may be the same or different if there is more than one administration. In certain embodiments, at least one of the one or more compositions further comprises a formulary ingredient (e.g., pharmaceutically acceptable carrier, other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, and excipients). In other embodiments, at least one of the one or more compositions comprises any composition as disclosed herein or any pharmaceutical composition as disclosed herein. In still other embodiments, at least one of the one or more administrations comprises parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, inhalation administration, intrathecal administration, or intramuscular administration. In yet other embodiments, if there is more than one administration at least one composition used for at least one administration is different from the composition of at least one other administration. In certain embodiments, the compound of at least one of the one or more compositions is administered to the animal (a) in an amount of from about 0.01 mg/kg animal body weight to about 15 mg/kg animal body weight (e.g., 3.6 mg/kg), (b) with a volume of 1 µL to 150 µL (e.g., 15 µL) of a from 1 mM to 100 mM solution (e.g., 10 mM solution), (c) in a mole concentration amount of from 1.5 µmoles to 150 µmoles (e.g., 15 µmoles), and/or (d) in a mole amount per surface area of from 1.0 µmoles/cm² to 200 µmoles/cm² (e.g., 12.5 µmoles/cm²), where the amount per surface area (in µmoles/cm²) indicates the number of moles of the compound applied to a specified surface area of the animal (e.g., wound area, scar area, acne area, radiated skin area, dermatitis area, or hair loss area). In certain embodiments, the compound of at least one of the one or more compositions is administered to the animal (a) in an amount of from about 0.01 mg/kg animal body weight to about 15 mg/kg animal body weight (e.g., 3.6 mg/kg), (b) with a volume of from 1 µL to 150 µL (e.g., 20 µL) of a from 1 µM to 100 µM solution (e.g., 10 µM solution), (c) in a mole concentration amount of from 0.02 nmoles to 2.0 nmoles (e.g., 0.20 nmoles), and/or (d) in a mole amount per surface area of from 0.01 nmoles/mm² to 2.0 nmoles/mm² (e.g., 0.20 nmoles/mm²), where the amount per surface area (in nmoles/mm²) indicates the number of moles of the compound applied to a specified surface area of the animal (e.g., wound area, scar area, acne area, radiated skin area, dermatitis area, or hair loss area). In some embodiments, the animal is a human, a rodent, or a primate. In still other embodiments, the method further comprises administering EGF (e.g., immediately after the one or more administrations step or waiting 10 seconds, 30 seconds, 1 min., 5 mins., 10 mins., 15 mins., 20 mins., 30 mins., 45 mins., 60 mins., 90 mins., 120 mins., 150 mins., 180 mins., 240 mins., or 300 mins. after the one or more administrations step). In other embodiments, the method further comprises administering of EGF and the EGF is at a concentration of from about 0.1 to 30 ng/mL. [0012] Some embodiments of the invention include a method for treating an animal for a condition, comprising one or more administrations of one or more compositions comprising (a) any compound disclosed herein, (b) any composition disclosed herein, or (c) any pharmaceutical composition disclosed herein, wherein the compositions may be the same or different if there is more than one administration. In certain embodiments, at least one of the one or more compositions further comprises a formulary ingredient. In yet other embodiments, at least one of the one or more compositions comprises any composition disclosed herein or any pharmaceutical composition disclosed herein. In other embodiments, at least one of the one or more administrations comprises parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, inhalation administration, intrathecal administration, or intramuscular administration. In still other embodiments, if there is more than one administration at least one composition used for at least one administration is different from the composition of at least one other administration. In certain embodiments, the compound of at least one of the one or more compositions is administered to the animal (a) in an amount of from about 0.01 mg/kg animal body weight to about 15 mg/kg animal body weight (e.g., 3.6 mg/kg), (b) with a volume of from 1 µL to 150 µL (e.g., 15 µL) of a from 1 mM to 100 mM solution (e.g., 10 mM solution), (c) in a mole concentration amount of from 1.5 µmoles to 150 µmoles (e.g., 15 µmoles), and/or (d) in a mole amount per surface area of from 1.0 µmoles/cm² to 200 µmoles/cm² (e.g., 12.5 µmoles/cm²), where the amount per surface area (in µmoles/cm²) indicates the number of moles of the compound applied to a specified surface area of the animal (e.g., wound area, scar area, acne area, radiated skin area, dermatitis area, or hair loss area). In certain embodiments, the compound of at least one of the one or more compositions is administered to the animal (a) in an amount of from about 0.01 mg/kg animal body weight to about 15 mg/kg animal body weight (e.g., 3.6 mg/kg), (b) with a volume of from 1 µL to 150 µL (e.g., 20 µL) of a from 1 µM to 100 µM solution (e.g., 10 µM solution), (c) in a mole concentration amount of from 0.02 nmoles to 2.0 nmoles (e.g., 0.20 nmoles), and/or (d) in a mole amount per surface area of from 0.01 nmoles/mm² to 2.0 nmoles/mm² (e.g., 0.20 nmoles/mm²), indicates the number of moles of the compound applied to a specified surface area of the animal (e.g., wound area, scar area, acne area, radiated skin area, dermatitis area, or hair loss area). In some embodiments, the animal is a human, a rodent, or a primate. In still other embodiments, the animal is in need of the treatment. In certain embodiments, the method is for treating conditions where re-epithelialization (e.g., of the cornea or skin) would be beneficial, conditions where an increase in re-epithelialization (e.g., of the cornea or skin) would be beneficial, conditions where an acceleration in re- epithelialization (e.g., of the cornea or skin) would be beneficial, wounds, corneal wounds, wounds related to disease, wounds related to diabetes, wounds resulting from trauma (e.g., physical, thermal, chemical, radiological, etc.), dermal wounds, corneal scars, dermal scars, acne scars, dermatitis, radiation-related skin wounds/reactions (e.g., decreasing the effects of radiation-related skin wounds/reactions), hair loss (e.g., increasing hair growth), or wounds related to battlefield injuries. In yet other embodiments, the method is for treating (a) wounds (e.g., a corneal wound), (b) scars, (c) radiation-related skin wounds/reactions, (d) acne, (e) dermatitis, or (f) hair loss. In still other embodiments, the method is for treating a wound, such as treating one or more corneal wounds. In certain embodiments, the treating results in a decrease in the area of the wound or scar (e.g., a decrease of from 1% to 99%, from 5% to 95%, from 10% to 75%, 1%, 5%, 10% 25%, 50%, 75%, 95%, 99%, or 100% (based on the size of the original area)). In some embodiments, the method further comprises administering EGF (e.g., immediately after the one or more administrations step or waiting 10 secs., 30 secs., 1 min., 5 mins., 10 mins., 15 mins., 20 mins., 30 mins., 45 mins., 60 mins., 90 mins., 120 mins., 150 mins., 180 mins., 240 mins., or 300 mins. after the one or more administrations step). In other embodiments, the method further comprises administering of EGF and the EGF is at a concentration of from about 0.1 to 30 ng/mL. [0013] Some embodiments of the invention include a method for preparing compound as disclosed herein comprising, (a) reacting a compound of Formula (VIII) with a compound of Formula (IX) to result in a mixture comprising a compound of Formula (Ia); (b) optionally reacting a compound of Formula (Ia) to result in a mixture comprising a compound of Formula (Ib); and (c) recovering Formula (Ia), Formula (Ib), or both, wherein Formula (VIII) is and _{Formula (IX) is} _{. In certain embodiments, prior to step (a), the} method further comprises one or more of Scheme 1, Scheme 2, Scheme 3, Scheme 4, or Scheme 5. In other embodiments, step (b) occurs. In certain embodiments, step (b) occurs and step (c) recovers Formula (Ib). In some embodiments, step (b) does not occur and step (c) recovers Formula (Ia). [0014] Other embodiments of the invention are also discussed herein. BRIEF DESCRIPTION OF THE DRAWINGS [0015] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the description of specific embodiments presented herein. [0016] Figure 1. Knockout of c-Cbl and Cbl-b in corneal epithelial cells increases the magnitude and duration of EGFR phosphorylation. FIG.1A: Lysates were prepared from hTCEpi Cas9 (CAS9), hTCEpi c-Cbl knockout (c-Cbl KO), hTCEpi Cbl-b knockout (Cbl-B KO), and hTCEpi -c-Cbl/-Cbl-b knockout (DKO) cells. Lysates (30 µg) were resolved by SDS- PAGE, transferred to nitrocellulose, and immunoblotted using antibodies against c-Cbl, Cbl-b, and α-tubulin as a loading control. Shown are representative blots from an experiment repeated three times. FIG. 1B: Serum-starved CAS9 and DKO cells were treated with 50 ng/ml EGF for 0, 2, or 10 minutes and cell lysates were prepared as described in the Examples (e.g., Example Set B). EGFRs were immunoprecipitated using an anti-EGFR antibody (mAB-1, Merck Millipore). Immunoprecipitates divided into thirds, resolved by SDS-PAGE, transferred to nitrocellulose, and immunoblotted using antibodies against ubiquitin, phosphorylated EGFR (pY1068), and total EGFR. Shown is a representative blot repeated three times. FIG.1C: Immunoblots from FIG.1B were quantified using NIH Image J and the relative Ubiquitylation (Ubiquitin/phosphorylated EGFR) was plotted as the average ± S.D. (n=3). Symbols represent individual replicates. FIG. 1D: Serum-starved CAS9 and DKO cells were treated with 10 ng/ml EGF for 0-2 hours and cell lysates were prepared as described in the Examples (e.g., Example Set B). Lysates (30 µg) were resolved by SDS-PAGE, transferred to nitrocellulose, and immunoblotted using antibodies against phosphorylated EGFR (pY1068), total EGFR, and α- tubulin as a loading control. FIG.1E: Immunoblots from FIG 1D were quantified using NIH Image J and the relative EGFR phosphorylation (pY1068/α-tubulin) was plotted as the average ± S.D. (n=3). FIG.1F: From each of the three replicate time courses in FIG. E, the Area Under the Curve (AUC) was calculated. Plotted are the average ± S.D. (n=3). Symbols represent individual replicates. Data were analyzed by a paired t-test. * = p < 0.05; ** = p <0.01; *** = p < 0.001. [0017] Figure 2. Screen of in silico compounds. FIG.2A, FIG.2B, and FIG. 2C show Differential Scanning Fluorimetry used to measure c-Cbl (FIG. 2A and FIG. 2C) and Cbl-b (FIG. 2B) protein stability. Recombinant protein and Sypro Orange were combined with increasing concentrations of (FIG. 2A and FIG. 2B) phosphoEGFR peptide (DSFLQRpYSSDPTG (SEQ ID NO:1)) or (FIG.2C) 50 mM of candidate compound (AA, AF). Compound AA is N- (cyclohexylmethyl)-N-methyl-1-[1-(pyridin-3-ylmethyl)piperidin-4-yl]piperidine-3-carboxamide (PubChem CID 70723778); compound AF is the same as compound 1-119. FIG.2D: Serum- starved hTCEpi cells were pretreated with serum-free media containing either 0.2% DMSO or 200 µM AF for 30 minutes, followed by treatment with 50 ng/ml EGF for the indicated amounts of time. Cell lysates were prepared and immunoblotted for phosphorylated EGFR (pY1068) and α-tubulin. FIG. 2E: Serum-starved hTCEpi cells were pretreated with serum-free media containing either 0.1% DMSO, 100 µM AF, or 50 µM AF for 30 minutes. Cells were treated without or with 50 ng/ml EGF for 10 minutes. Cell lysates were prepared and immunoprecipitated with an anti-EGFR antibody. Immunoprecipitates were divided into thirds, resolved by 7.5% SDS-PAGE, and immunoblotted for ubiquitin (Ub), tyrosine phosphorylation (PY), or EGFR. [0018] Figure 3. Testing of Compounds. FIG.3A: Compounds were assessed for binding to c-Cbl using Microscale Thermophoresis (MST) as described in the Examples (e.g., Example Set B). Shown is a graph of those K_d (in µM) on the y-axis and the compounds on the x-axis. FIG.3B: Compounds that had the highest affinity. FIG. 3C: Cytotoxicity of compound 3-120 was tested in immortalized corneal epithelial (hTCEpi) cells by treating cells with varying concentrations of 3-120 (0-10 µM) for 24 hours and measuring cell viability using AlamarBlue® assay. Plotted are the average percentage ± S.D. (n=4). [0019] Figure 4. Compound 3-120 inhibits EGFR ubiquitylation. FIG.4A: Serum- starved hTCEpi cells were treated with the indicated concentrations of compound 3-120 for 30 minutes followed by treatment with or without EGF (50 ng/ml) as indicated. Cell lysates were prepared and immunoprecipitated for the EGFR using an anti-EGFR antibody (mAB-1, Merck Millipore). Immunoprecipitates divided into thirds, resolved by SDS-PAGE, transferred to nitrocellulose, and immunoblotted using antibodies against ubiquitin, phosphorylated EGFR (pY1045), and total EGFR. Shown is a representative blot repeated five times. FIG. 4B: Immunoblots from (A) were quantified using NIH Image J and the relative Ubiquitylation (Ubiquitin/phosphorylated EGFR) was plotted as the average ± S.D. (n=3). Symbols represent individual replicates. P values were determined using an ANOVA comparing the indicated data points. [0020] Figure 5. Compound 3-120 sustains EGFR phosphorylation. Serum-starved hTCEpi (FIG.5A) and primary human corneal epithelial cells (FIG.5F) were treated with compound 3-120 (50 µM) for 30 minutes followed by treatment with EGF (10 ng/ml) for the times indicated. Cell lysates were prepared, and equal amounts (30 µg) were resolved by SDS- PAGE, transferred to nitrocellulose, and immunoblotted using antibodies against phosphorylated EGFR (pY1068 and pY1045), and α-tubulin as a loading control. FIG. 5B, FIG.5C, and FIG. 5G show quantified immunoblots from (FIG.5A) and (FIG.5F); quantification was conducted using NIH Image J and the relative EGFR phosphorylation was plotted as the average ± S.D. (n=3). FIG. 5D, FIG.5E, and FIG.5H show calculation of the Area Under the Curve (AUC) for each of the three replicate time courses in (FIG.5B, FIG.5C, and FIG. 5G). Shown are the average ± S.D. (n=3) for each phosphorylation site. Symbols represent individual replicates. P values were determined using a Student’s t-test. Compound 5-6 sustains EGFR phosphorylation. FIG.5I: Serum-starved hTCEpi were treated with compound 5-6 (50 µM) for 30 minutes followed by treatment with EGF (10 ng/ml) for the times indicated. Cell lysates were prepared, and equal amounts (30 µg) were resolved by SDS-PAGE, transferred to nitrocellulose, and immunoblotted using antibodies against phosphorylated EGFR (pY1045), and α-tubulin as a loading control. FIG. 5J: Immunoblots from FIG. 5I were quantified using NIH Image J and the relative EGFR phosphorylation was plotted as the average ± S.D. (n=4). FIG.5K: From each of the three replicate time courses in FIG.5J the Area Under the Curve (AUC) was calculated. Shown are the average ± S.D. (n=4) for each phosphorylation site. Symbols represent individual replicates. P values were determined using a Student’s t-test. * = p < 0.05; ** = p <0.01. [0021] Figure 6. Compound 3-120 enhances EGF-mediated in vitro wound healing. FIG.6A: hTCEpi cells were plated in tissue culture dish with 2 mm silicone plugs attached to the bottom of the dish. When cells reached confluency, the cells were serum starved, pretreated with vehicle (0.05% DMSO) or 3 µM compound 3-120 for 30 minutes, followed by addition of 3 ng/ml of EGF (final) to the dish. The size of the 2 mm acellular area was imaged every 15 min for 24 hours. FIG.6B: wound closure was calculated as the percentage of the original wound that remained at each time point. Data were plotted as the percentage healed for each time point using Prism Software. Shown are the average +/- SD from 3-4 experiments. [0022] Figure 7. Compounds 3-120 and 5-6 enhance EGF-mediated in vivo wound healing. FIG.7A: A 1.5 mm debridement wound was made in the central cornea of an 8-week- old female mouse. After staining with fluorescein and imaging, mouse eyes were treated with either PBS, 10 ng/ml EGF with vehicle (0.01% DMSO), or 10 ng/ml EGF with 10 µM compound 3-120 or 10 µM compound 5-6. After 16 hours, the cornea was re-stained with fluorescein and imaged. Shown are representative images using compound 3-120 of an experiment repeated 4-6 times. FIG. 7B: For compound 3-120, the remaining debrided area was measured after 16 and 24 hours using Image J software. Plotted are the average percentage of wound healed ± S.D. Individual data points are indicated with in the bar graph. FIG.7C: For compound 5-6, the remaining debrided area was measured after 16 hours using Image J software. Plotted are the average percentage of wound healed ± S.D. Individual data points are indicated with in the bar graph. [0023] Figure 8. Various measurements of compounds. FIG.9: The following measurements were made with the listed compounds, as indicated: Thermoshift, pY1068, phoscCbl, phosMAPk, dose response, toxicity, and MST. Methods for conducting these measurements are described in the Examples (e.g., Example Set C). Dose response as provided in the figure is typically meant to show the qualitative nature of the dose response. DETAILED DESCRIPTION [0024] While embodiments encompassing the general inventive concepts may take diverse forms, various embodiments will be described herein, with the understanding that the present disclosure is to be considered merely exemplary, and the general inventive concepts are not intended to be limited to the disclosed embodiments. [0025] Some embodiments of the invention include inventive compounds (e.g., compounds of Formula (I)). Other embodiments include compositions (e.g., pharmaceutical compositions) comprising the inventive compound. Still other embodiments of the invention include compositions (e.g., pharmaceutical compositions) for treating, for example, certain conditions using the inventive compounds. Some embodiments include methods of using the inventive compound (e.g., in compositions or in pharmaceutical compositions) for administering and treating (e.g., wounds such as corneal wounds). Further embodiments include methods for making the inventive compounds. Additional embodiments of the invention are also discussed herein. [0026] As used herein (unless otherwise specified), the term “alkyl” means a monovalent, straight or branched hydrocarbon chain. For example, the terms “C₁-C₇ alkyl” or “C1-C4 alkyl” refer to straight- or branched-chain saturated hydrocarbon groups having from 1 to 7 (e.g., 1, 2, 3, 4, 5, 6, or 7), or 1 to 4 (e.g., 1, 2, 3, or 4), carbon atoms, respectively. Examples of C₁-C₇ alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s- butyl, t-butyl, n-pentyl, s-pentyl, n-hexyl, and n-septyl. Examples of C1-C4 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, and t-butyl. [0027] As used herein (unless otherwise specified), the term “alkenyl” means a monovalent, straight or branched hydrocarbon chain that includes one or more (e.g., 1, 2, 3, or 4) double bonds. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1- propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4- pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, and 5-hexenyl. [0028] As used herein (unless otherwise specified), the term “alkoxy” means any of the above alkyl groups which is attached to the remainder of the molecule by an oxygen atom (alkyl- O-). Examples of alkoxy groups include, but are not limited to, methoxy (sometimes shown as MeO-), ethoxy, isopropoxy, propoxy, and butyloxy. [0029] As used herein (unless otherwise specified), the term “alkynyl” means a monovalent, straight or branched hydrocarbon chain that includes one or more (e.g., 1, 2, 3, or 4) triple bonds and that also may optionally include one or more (e.g.1, 2, 3, or 4) double bonds in the chain. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2- propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1- hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl. [0030] As used herein (unless otherwise specified), the term “aryl” means a monovalent, monocyclic or bicyclic, 5, 6, 7, 8, 9, 10, 11, or 12 membered aromatic hydrocarbon group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tolyl, and xylyl. For a bicyclic aryl that is designated as substituted, one or both rings can be substituted. [0031] As used herein (unless otherwise specified), the term “cycloalkyl” means a monovalent, monocyclic or bicyclic, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 membered hydrocarbon group. The rings can be saturated or partially unsaturated. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and bicycloalkyls (e.g., bicyclooctanes such as [2.2.2]bicyclooctane or [3.3.0]bicyclooctane, bicyclononanes such as [4.3.0]bicyclononane, and bicyclodecanes such as [4.4.0]bicyclodecane (decalin), or spiro compounds). For a monocyclic cycloalkyl, the ring is not aromatic. For a bicyclic cycloalkyl, if one ring is aromatic, then the other is not aromatic. For a bicyclic cycloalkyl that is designated as substituted, one or both rings can be substituted. [0032] As used herein (unless otherwise specified), the term “halogen” means monovalent Cl, F, Br, or I. [0033] As used herein (unless otherwise specified), the term “heteroaryl” means a monovalent, monocyclic or bicyclic, 5, 6, 7, 8, 9, 10, 11, or 12 membered, hydrocarbon group, where 1, 2, 3, 4, 5, or 6 carbon atoms are replaced by a hetero atom independently selected from nitrogen, oxygen, or sulfur atom, and the monocyclic or bicyclic ring system is aromatic. Examples of heteroaryl groups include, but are not limited to, thienyl (or thiophenyl), furyl, indolyl, pyrrolyl, pyridinyl, pyrazinyl, oxazolyl, thiaxolyl, quinolinyl, pyrimidinyl, imidazolyl, triazolyl, tetrazolyl, 1H-pyrazol-4-yl, 1-Me-pyrazol-4-yl, pyridin-3-yl, pyridin-4-yl, 3,5- dimethylisoxazolyl, 1H-pyrrol-3-yl, 3,5-di-Me-pyrazolyl, and 1H-pyrazol-4-yl. For a bicyclic heteroaryl, if one ring is aryl, then the other is heteroaryl. For a bicyclic heteroaryl, one or both rings can have one or more hetero atoms. For a bicyclic heteroaryl that is designated as substituted, one or both rings can be substituted. [0034] As used herein (unless otherwise specified), the term “heterocyclyl” means a monovalent, monocyclic or bicyclic, 5, 6, 7, 8, 9, 10, 11, or 12 membered, hydrocarbon, where 1, 2, 3, 4, 5, or 6 carbon atoms are replaced by a hetero atom independently selected from nitrogen atom, oxygen atom, or sulfur atom, and the monocyclic or bicyclic ring system is not aromatic. Examples of heterocyclyl groups include, but are not limited to, tetrahydropyran, pyrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, or pyrrolidin-4-yl), piperazinyl (e.g., piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, or piperazin-4-yl), piperidinyl (e.g., piperadin-1-yl, piperadin-2-yl, piperadin-3-yl, or piperadin-4-yl), and morpholinyl (e.g., morpholin-1-yl, morpholin-2-yl, morpholin-3-yl, or morpholin-4-yl,). For a bicyclic heterocyclyl, if one ring is aromatic (e.g., monocyclic aryl or heteroaryl), then the other ring is not aromatic. For a bicyclic heterocyclyl, one or both rings can have one or more hetero atoms. For a bicyclic heterocyclyl that is designated as substituted, one or both rings can be substituted. [0035] As used herein (unless otherwise specified), the term “hetero atom” means an atom selected from nitrogen atom, oxygen atom, or sulfur atom. [0036] As used herein (unless otherwise specified), the terms “hydroxy” or “hydroxyl” indicates the presence of a monovalent -OH group. [0037] As used herein (unless otherwise specified), the term “substituted” (e.g., as in substituted alkyl) means that one or more hydrogen atoms of a chemical group (with one or more hydrogen atoms) can be replaced by one or more non-hydrogen substituents selected from the specified options. The replacement can occur at one or more positions. The term “optionally substituted” means that one or more hydrogen atoms of a chemical group (with one or more hydrogen atoms) can be, but is not required to be, substituted. [0038] Some compounds of the invention can have one or more chiral centers and can exist in and be isolated in optically active and racemic forms, for any of the one or more chiral centers. Some compounds can exhibit polymorphism. The compounds of the present invention (e.g., Formula I) encompass any optically active, racemate, stereoisomer form, polymorphism, or mixtures thereof. If a chiral center does not provide an indication of its configuration (i.e., R or S) in a chemical structure, it should be considered to represent R, S or a racemate. [0039] Compounds and Compositions including Pharmaceutical Compositions [0040] Some embodiments of the invention include compounds selected from Formula (I), salts of Formula (I), optical isomers of Formula (I), geometric isomers of Formula (I), salts of optical isomers of Formula (I), salts of geometric isomers of Formula (I), and derivatives thereof (e.g., ethers, esters, or amides),

[0042] In certain embodiments, . In other embodiments, Formula (I) is Formula (

[0043] In yet other embodiments, R¹ is where all R groups are the same, including R^1a is the same as R^1c and R^1b is the same as R^1d) in some in vivo environments, some in vitro environments, some ex vivo environments, or some in situ environments. [0045] In some embodiments, a compound with R¹ of R^1c and R^1b is the same as R^1d) in some in vivo environments, some in vitro environments, some ex vivo environments, or some in situ environments. [0046] In other embodiments, R^1a, R^1b , R^1c, and R^1d can be the same or different and are H, halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), methanoyl (-COH), nitro (-NO₂), -NH₂, - N(CH₃)₂, cyano (-CN), sulfo (-SO3H), -C(O)NH₂, -C(O)N(CH₃)₂, -C(O)(CH₃), -C(O)(C2H5), - C(O)(C₃H₇), C₁-C₃ perfluoronated alkyl, -CF₃, -OCF₃, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁-C₉ alkoxy, phenyl, aryl, indolyl, or hetroaryl which methanoyl (-COH), -NH₂, - N(CH₃)₂, -C(O)NH₂, -C(O)N(CH₃)₂, -C(O)(CH₃), -C(O)(C2H5), -C(O)(C₃H₇), C1-C₁₀ alkyl, C2- C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁-C₉ alkoxy, phenyl, aryl, indolyl, or hetroaryl can optionally be substituted with one or more of halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), methanoyl (- COH), carboxy (-CO2H), nitro (-NO₂), -NH₂, -N(CH₃)₂, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO₃H), morpholinyl, -CO-morpholin-4-yl, -C(O)NH₂, -C(O)N(CH₃)₂, C₁-C₃ alkyl, C₁-C₃ perfluoronated alkyl, -CF₃, -OCF₃, C₁-C₃ alkoxy, aryl, aryl substituted with one or more R^1x, phenyl, phenyl substituted with one or more R^1x, heteroaryl, heteroaryl substituted with one or more R^1x, indolyl, or indolyl substituted with one or more R^1x. [0047] In certain embodiments, R^1x can be the same or different (e.,g., can be the same or different on the same ring or can be the same or different on different rings) and are halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), methanoyl (-COH), carboxy (-CO2H), nitro (-NO₂), -NH₂, - N(CH₃)₂, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), morpholinyl, -CO-morpholin- 4-yl, -C(O)NH₂, -C(O)N(CH₃)₂, C₁-C₃ alkyl, C₁-C₃ perfluoronated alkyl, -CF₃, -OCF₃, or C₁-C₄ alkoxy (e.g., methoxy or ethoxy). [0048] In other embodiments, R^1a and R^1b can optionally be joined to form a C₃-C₉ cycloalkyl, optionally substituted with halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), -NO₂, -CN, C₁-C₃ alkoxy, aryl, aryl substituted with one or more halogen (e.g., F, Cl, Br, or I), phenyl, phenyl substituted with one or more halogen (e.g., F, Cl, Br, or I), heteroaryl, heteroaryl substituted with one or more halogen (e.g., F, Cl, Br, or I), indolyl, or indolyl substituted with one or more halogen (e.g., F, Cl, Br, or I); [0049] In some embodiments, R^1c and R^1d can optionally be joined to form a C3-C9 cycloalkyl optionally substituted with halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), -NO₂, -CN, C₁-C₃ alkoxy, aryl, aryl substituted with one or more halogen (e.g., F, Cl, Br, or I), phenyl, phenyl substituted with one or more halogen (e.g., F, Cl, Br, or I), heteroaryl, heteroaryl substituted with one or more halogen (e.g., F, Cl, Br, or I), indolyl, or indolyl substituted with one or more halogen (e.g., F, Cl, Br, or I). [0050] In other embodiments, R^1a R^1b , R^1c, and R^1d can be the same or different and are H, halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), methanoyl (-COH), nitro (-NO₂), -NH₂, - N(CH₃)₂, cyano (-CN), sulfo (-SO3H), -C(O)NH₂, -C(O)N(CH₃)₂, -C(O)(CH₃), -C(O)(C2H5), - C(O)(C₃H₇), C₁-C₃ perfluoronated alkyl, -CF₃, -OCF₃, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁-C₉ alkoxy, phenyl, aryl, indolyl, or hetroaryl which methanoyl (-COH), -NH₂, - N(CH₃)₂, -C(O)NH₂, -C(O)N(CH₃)₂, -C(O)(CH₃), -C(O)(C₂H₅), -C(O)(C₃H₇), C₁-C₁₀ alkyl, C₂- C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁-C₉ alkoxy, phenyl, aryl, indolyl, or hetroaryl can optionally be substituted with one or more of halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), methanoyl (- COH), carboxy (-CO₂H), nitro (-NO₂), -NH₂, -N(CH₃)₂, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), morpholinyl, -CO-morpholin-4-yl, -C(O)NH₂, -C(O)N(CH₃)₂, C₁-C₃ alkyl, C₁-C₃ perfluoronated alkyl, -CF₃, -OCF₃, C₁-C₃ alkoxy, aryl, aryl substituted with one or more halogens, aryl substituted with one or more C₁-C₃ alkoxy, phenyl, phenyl substituted with one or more halogens, phenyl substituted with one or more C₁-C₃ alkoxy, heteroaryl, heteroaryl substituted with one or more halogens, heteroaryl substituted with one or more C₁-C₃ alkoxy, indolyl, indolyl substituted with one or more halogens, or indolyl substituted with one or more C₁-C₃ alkoxy. [0051] In some embodiments, R^1a R^1b , R^1c, and R^1d can be the same or different and are H, halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), methanoyl (-COH), nitro (-NO₂), -NH₂, - N(CH₃)₂, cyano (-CN), sulfo (-SO₃H), -C(O)NH₂, -C(O)N(CH₃)₂, -C(O)(CH₃), -C(O)(C₂H₅), - C(O)(C₃H₇), C₁-C₃ perfluoronated alkyl, -CF₃, -OCF₃, C1-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁-C₉ alkoxy, phenyl, aryl, indolyl, or hetroaryl which methanoyl (-COH), -NH₂, - N(CH₃)₂, -C(O)NH₂, -C(O)N(CH₃)₂, -C(O)(CH₃), -C(O)(C₂H₅), -C(O)(C₃H₇), C₁-C₁₀ alkyl, C₂- C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁-C₉ alkoxy, phenyl, aryl, indolyl, or hetroaryl can optionally be substituted with one or more of halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), methanoyl (- COH), carboxy (-CO2H), nitro (-NO₂), -NH₂, -N(CH₃)₂, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), morpholinyl, -CO-morpholin-4-yl, -C(O)NH₂, -C(O)N(CH₃)₂, C₁-C₃ alkyl, C₁-C₃ perfluoronated alkyl, -CF₃, -OCF₃, C₁-C₃ alkoxy, aryl, aryl substituted with one or more halogens, phenyl, phenyl substituted with one or more halogens, heteroaryl, heteroaryl substituted with one or more halogens, indolyl, or indolyl substituted with one or more halogens. [0052] In certain embodiments, R^1a, R^1b , R^1c, and R^1d can be the same or different and are (a) C₁-C₅ alkyl (e.g., C2 alkyl, C3 alkyl or C4 alkyl) substituted with phenyl, which phenyl is substituted with one or more halogen (e.g., F, Cl, Br, or I) or -OCH₃, (b) C₁-C₅ alkyl substituted with phenyl, (c) phenyl substituted with one or more halogen (e.g., F, Cl, Br, or I) or -OCH₃, (d) phenyl, or (e) C₁-C₅ alkyl. [0053] In other embodiments, (a) R^1a and R^1b are joined to form a C₅-C₇ monocyclic cycloalkyl or (b) R^1c and R^1d are joined to form a C₅-C₇ monocyclic cycloalkyl. [0054] In yet other embodiments, (a) R^1a is methyl or (b) R^1c is methyl. [0055] In certain embodiments, n is 0, 1, 2, 3, 4, 5, or 6. [0056] In some embodiments, n is 1, 2, 3, or 4 (e.g., 2 or 3). [0057] In yet other embodiments, R² is H, halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), methanoyl (-COH), nitro (-NO₂), -NH₂, -N(CH₃)₂, cyano (-CN), sulfo (-SO3H), -C(O)NH₂, - C(O)N(CH₃)₂, -C(O)(CH₃), -C(O)(C₂H₅), -C(O)(C₃H₇), C₁-C₃ perfluoronated alkyl, -CF₃, -OCF₃, C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C1-C6 alkoxy, aryl, hetroaryl, cycloalkyl, or heterocyclyl, which C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₁-C₆ alkoxy, aryl, hetroaryl, cycloalkyl, and heterocyclyl are optionally substituted with one or more of halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), methanoyl (-COH), nitro (-NO₂), -NH₂, -N(CH₃)₂, cyano (-CN), sulfo (-SO₃H), -C(O)NH₂, -C(O)N(CH₃)₂, -C(O)(CH₃), -C(O)(C₂H₅), -C(O)(C₃H₇), C₁-C₃ perfluoronated alkyl, -CF₃, -OCF₃, or C₁-C₃ alkoxy. [0058] In certain embodiments, R² is H, methyl, ethyl, propyl, or phenyl, which methyl, ethyl, propyl, and phenyl are optionally substituted with one or more of halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), methanoyl (-COH), nitro (-NO₂), -NH₂, -N(CH₃)₂, cyano (-CN), sulfo (- SO₃H), -C(O)NH₂, -C(O)N(CH₃)₂, -C(O)(CH₃), -C(O)(C₂H₅), -C(O)(C₃H₇), C₁-C₃ perfluoronated alkyl, -CF₃, -OCF₃, or C₁-C₃ alkoxy. [0059] In certain embodiments, R² is H, methyl, ethyl, propyl, or phenyl. [0060] In still other embodiments, R³, R⁴, R⁵, and R⁶ can be the same or different and are H, halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), methanoyl (-COH), nitro (-NO₂), -NH₂, - N(CH₃)₂, cyano (-CN), sulfo (-SO₃H), -C(O)NH₂, -C(O)N(CH₃)₂, -C(O)(CH₃), -C(O)(C₂H₅), - C(O)(C₃H₇), C₁-C₃ perfluoronated alkyl, -CF₃, -OCF₃, C1-C6 alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, or C₁-C₅ alkoxy. [0061] In some embodiments, R³ is H, -CH₃, -OCH₃, F, Cl, -CN, or -NO₂. [0062] In certain embodiments, R⁴ is H, -CH₃, -OCH₃, F, Cl, -CN, or -NO₂. [0063] In other embodiments, R⁴ is H or -OCH₃. [0064] In yet other embodiments, R⁵ is H, -CH₃, -OCH₃, F, Cl, -CN, or -NO₂, preferably H or -OCH₃ [0065] In certain embodiments, R⁶ is H, -CH₃, -OCH₃, F, Cl, -CN, or -NO₂. [0066] In other embodiments, R³, R⁵, and R⁶ are the same and are H. [0067] In some embodiments, the compounds of Formula (I) can be selected from those specified in Table 1. In some instances, the disclosure herein (e.g., the Examples and Figures) the other identifier includes a “GSR-“ before the number (e.g., 2-12 is the same as GSR-2-12) Table 1 [0068] In some embodiments, one or more of compounds I-1, I-2, I-3, I-4, I-5, I-6, I-7, I- 8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-22, I-23, I-24, I-25, I- 26, I-27, I-28, I-29, I-30, I-31, I-32, I-33, I-34, I-35, I-36, I-37, I-38, I-39, I-40, I-41, I-42, I-43, I- 44, I-45, I-46, I-47, I-48, I-49, I-50, I-51, I-52, I-53, I-54, I-55, I-56, I-57, I-58, I-59, I-60, I-61, I- 62, I-63, I-64, I-65, I-66, I-67, I-68, I-69, I-70, I-71, I-72, I-73, I-74, I-75, I-76, I-77, I-78, I-79, I- 80, I-81, I-82, I-83, I-84, I-85, I-86, I-87, I-88, I-89, I-90, I-91, or I-92 are excluded from the compounds of the invention (e.g., Formula (I)). In certain embodiments, compound I-1 is excluded from the compounds of the invention (e.g., Formula (I)). [0069] In some embodiments, the compounds of the invention include one or more of I- 1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I- 21, I-22, I-23, I-24, I-25, I-26, I-27, I-28, I-29, I-30, I-31, I-32, I-33, I-34, I-35, I-36, I-37, I-38, I- 39, I-40, I-41, I-42, I-43, I-44, I-45, I-46, I-47, I-48, I-49, I-50, I-51, I-52, I-53, I-54, I-55, I-56, I- 57, I-58, I-59, I-60, I-61, I-62, I-63, I-64, I-65, I-66, I-67, I-68, I-69, I-70, I-71, I-72, I-73, I-74, I- 75, I-76, I-77, I-78, I-79, I-80, I-81, I-82, I-83, I-84, I-85, I-86, I-87, I-88, I-89, I-90, I-91, or I- 92. In some embodiments, the compounds of the invention include one or more of I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-22, I-23, I-24, I-25, I-26, I-27, I-28, I-29, I-30, I-31, I-32, I-33, I-34, I-35, I-36, I-37, I-38, I-39, I-40, I-41, I-42, I-43, I-44, I-45, I-46, I-47, I-48, I-49, I-50, I-51, I-52, I-53, I-54, I-55, I-56, I-57, I-58, I-59, I-60, I-61, I-62, I-63, I-64, I-65, I-66, I-67, I-68, I-69, I-70, I-71, I-72, I-73, I-74, I-75, I-76, I-77, I-78, I-79, I-80, I-81, I-82, I-83, I-84, I-85, I-86, I-87, I-88, I-89, I-90, I-91, or I-92. In some embodiments, the compounds of the invention include I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-22, I-23, I-24, I-25, I-26, I-27, I-28, I-29, I-30, I-31, I-32, I-33, I-34, I-35, I-36, I-37, I-38, I-39, I-40, I-41, I-42, I-43, I-44, I-45, I-46, I-47, I-48, I-49, I-50, I-51, I-52, I-53, I-54, I-55, I-56, I-57, I-58, I-59, I-60, I-61, I-62, I-63, I-64, I-65, I-66, I-67, I-68, I-69, I-70, I-71, I-72, I-73, I-74, I-75, I-76, I-77, I-78, I-79, I-80, I-81, I-82, I-83, I-84, I-85, I-86, I-87, I-88, I-89, I-90, I-91, or I-92. In some embodiments, the compounds of the invention include I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I- 17, I-18, I-19, I-20, I-21, I-22, I-23, I-24, I-25, I-26, I-27, I-28, I-29, I-30, I-31, I-32, I-33, I-34, I- 35, I-36, I-37, I-38, I-39, I-40, I-41, I-42, I-43, I-44, I-45, I-46, I-47, I-48, I-49, I-50, I-51, I-52, I- 53, I-54, I-55, I-56, I-57, I-58, I-59, I-60, I-61, I-62, I-63, I-64, I-65, I-66, I-67, I-68, I-69, I-70, I- 71, I-72, I-73, I-74, I-75, I-76, I-77, I-78, I-79, I-80, I-81, I-82, I-83, I-84, I-85, I-86, I-87, I-88, I- 89, I-90, I-91, or I-92. [0070] In some embodiments, the compounds of the invention include one or more of I- 1, I-6, I-15, I-16, I-19, I-22, I-24, I-26, I-27, I-28, I-29, I-30, I-35, I-36, I-37, I-39, I-40, I-41, I- 42, I-46, I-48, I-50, I-54, I-55, I-56, I-57, I-58, I-59, I-61, I-64, I-68, I-69, I-70, I-71, I-72, I-73, I- 74, I-75, I-77, I-78, I-79, I-80, I-81, or I-82. In some embodiments, the compounds of the invention include one or more of I-6, I-15, I-16, I-19, I-22, I-24, I-26, I-27, I-28, I-29, I-30, I-35, I-36, I-37, I-39, I-40, I-41, I-42, I-46, I-48, I-50, I-54, I-55, I-56, I-57, I-58, I-59, I-61, I-64, I-68, I-69, I-70, I-71, I-72, I-73, I-74, I-75, I-77, I-78, I-79, I-80, I-81, or I-82. In some embodiments, the compounds of the invention include one or more of I-1, I-36, I-40, I-41, I-42, I-48, I-50, I-57, I-68, I-69, I-70, I-73, I-75, I-79, I-80, I-81, or I-82. In some embodiments, the compounds of the invention include one or more of I-36, I-40, I-41, I-42, I-48, I-50, I-57, I-68, I-69, I-70, I-73, I- 75, I-79, I-80, I-81, or I-82. In some embodiments, the compounds of the invention include one or more of I-1, I-40, I-41, I-42, I-50, I-57, I-68, I-69, I-70, I-73, I-75, I-79, I-80, I-81, or I-82. In some embodiments, the compounds of the invention include one or more of I-40, I-41, I-42, I-50, I-57, I-68, I-69, I-70, I-73, I-75, I-79, I-80, I-81, or I-82. In some embodiments, the compounds of the invention include I-1, I-40, I-41, I-42, I-50, I-57, I-68, I-69, I-70, I-73, I-75, I-79, I-80, I- 81, and I-82. In some embodiments, the compounds of the invention include I-40, I-41, I-42, I- 50, I-57, I-68, I-69, I-70, I-73, I-75, I-79, I-80, I-81, and I-82. In some embodiments, the compounds of the invention include I-41, I-79, or both. In some embodiments, the compounds of the invention include I-41. [0071] In some embodiments, the compounds of Formula (I) can be in the form of salts, optical isomers, geometric isomers, salts of optical isomers, and salts of geometric isomers. In other embodiments, the compounds can be in various forms, such as uncharged molecules, components of molecular complexes, or non-irritating pharmacologically acceptable salts, including but not limited to hydrochloride, hydrobromide, sulphate, phosphate, nitrate, borate, acetate, maleate, tartrate, and salicylate. In some instances, for acidic compounds, salts can include metals, amines, or organic cations (e.g. quaternary ammonium). In yet other embodiments, simple derivatives of the compounds (e.g., ethers, esters, or amides); these simple derivatives can sometimes have desirable retention and release characteristics and can sometimes be easily hydrolyzed by body pH, enzymes, or other suitable means. [0072] In some embodiments, the compounds of the invention having a chiral center and can exist in and be isolated in optically active and racemic forms. In other embodiments, compounds may exhibit polymorphism. Some embodiments of the present invention encompass any racemic, optically active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound described herein. The preparation of optically active forms can be accomplished by any suitable method, including but not limited to, resolution of the racemic form by recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. [0073] In some embodiments, the compounds of the invention (e.g., Formula (I), I-41, or I-79) can inhibit the activity of one or more members of the Cbl (Casitas B-lineage lymphoma) family (e.g., c-Cbl, Cbl-b, or Cbl-3/c) or a combination thereof. In certain embodiments, the compounds of the invention (e.g., Formula (I), I-41, or I-79) can disrupt the interaction between EGFR (Epidermal Growth Factor Receptor) and Cbl (e.g., c-Cbl or Cbl-b). In other embodiments, the compounds of the invention (e.g., Formula (I), I-41, or I-79) can increase EGFR phosphorylation (e.g., pY1045, pY1068, or both). In other embodiments, the compounds of the invention (e.g., Formula (I), I-41, or I-79) can sustain EGFR phosphorylation (e.g., pY1045, pY1068, or both). In some embodiments, the compounds of the invention (e.g., Formula (I), I-41, or I-79) can decrease EGFR ubiquitylation (e.g., ligand mediated EGFR ubiquitylation). In other embodiments, the compounds of the invention (e.g., Formula (I), I-41, or I-79) can increase EGFR signaling. In other embodiments, the compounds of the invention (e.g., Formula (I), I-41, or I-79) can sustain EGFR signaling. In certain embodiments, the compounds of the invention (e.g., Formula (I), I-41, or I-79) can decrease (e.g., disrupt) the interaction between EGFR and c-Cbl. In some embodiments, the compounds of the invention (e.g., Formula (I), I-41, or I-79) can increase cell (e.g., epithelial cell) proliferation. In certain embodiments, the compounds of the invention (e.g., Formula (I), I-41, or I-79) can increase cell (e.g., epithelial cell) migration. In other embodiments, the compounds of the invention (e.g., Formula (I), I-41, or I-79) can increase cell (e.g., epithelial cell) differentiation. In yet other embodiments, the compounds of the invention (e.g., Formula (I), I-41, or I-79) can enhance and/or sustain epithelial regeneration. In still other embodiments, the compounds of the invention (e.g., Formula (I), I-41, or I-79) can enhance and/or sustain corneal epithelial regeneration. In yet other embodiments, the compounds of the invention (e.g., Formula (I), I-41, or I-79) can enhance and/or sustain wound healing. [0074] In some embodiments, the compounds of the invention (e.g., Formula (I), I-41, or I-79) inhibit the activity of c-Cbl. In other embodiments, the compound (e.g., Formula (I), I-41, or I-79) has a Kd (i.e., the dissociation constant of the compound to c-Cbl) of from 0.075 µM to 1000 µM, from 0.075 µM to 750 µM, from 0.075 µM to 100 µM, from 0.075 µM to 10 µM, from 0.1 µM to 100 µM, from 0.1 µM to 10 µM, from 0.5 µM to 100 µM, from 0.5 µM to 10 µM, less than or equal to 1000 µM, less than or equal to 750 µM, less than or equal to 100 µM, less than or equal to 10 µM, less than or equal to 5 µM, less than or equal to 1 µM, less than or equal to 0.75 µM, or less than or equal to 0.075 µM. [0075] Compositions including Pharmaceutical Compositions [0076] In certain embodiments, one or more compounds of the invention (e.g., Formula (I), I-41, or I-79) can be part of a composition and can be in an amount (by weight of the total composition) of at least about 0.0001%, at least about 0.001%, at least about 0.10%, at least about 0.15%, at least about 0.20%, at least about 0.25%, at least about 0.50%, at least about 0.75%, at least about 1%, at least about 10%, at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, at least about 99%, at least about 99.99%, no more than about 75%, no more than about 90%, no more than about 95%, no more than about 99%, or no more than about 99.99%, from about 0.0001% to about 99%, from about 0.0001% to about 50%, from about 0.01% to about 95%, from about 1% to about 95%, from about 10% to about 90%, or from about 25% to about 75%. [0077] In other embodiments, one or more compounds of the invention (e.g., Formula (I), I-41, or I-79) can be part of a composition and can be in a concentration of at least about 0.1 µM, at least about 1 µM, at least about 10 µM, at least about 100 µM, at least about 1 mM, at least about 10 mM, at least about 100 mM, no more than about 1 M, no more than about 500 mM, no more than about 100 mM, no more than about 10 mM, or no more than about 1 mM, from about 0.1 µM to about 1 M, from about 0.1 µM to about 100 mM, from about 1 µM to about 100 mM, from about 1 µM to about 10 mM, from about 3 µM to about 1 mM, or from about 5 µM to about 500 µM. [0078] In some embodiments, one or more compounds of the invention (e.g., Formula (I), I-41, or I-79) can be purified or isolated in an amount (by weight of the total composition) of at least about 0.0001%, at least about 0.001%, at least about 0.10%, at least about 0.15%, at least about 0.20%, at least about 0.25%, at least about 0.50%, at least about 0.75%, at least about 1%, at least about 10%, at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, at least about 99%, at least about 99.99%, no more than about 75%, no more than about 90%, no more than about 95%, no more than about 99%, no more than about 99.99%, from about 0.0001% to about 99%, from about 0.0001% to about 50%, from about 0.01% to about 95%, from about 1% to about 95%, from about 10% to about 90%, or from about 25% to about 75%. [0079] Some embodiments of the present invention include compositions comprising one or more compounds of the invention (e.g., Formula (I), I-41, or I-79). In certain embodiments, the composition is a pharmaceutical composition, such as compositions that are suitable for administration to animals (e.g., mammals, primates, monkeys, humans, canine, feline, porcine, mice, rabbits, or rats). In some instances, the pharmaceutical composition is non-toxic, does not cause side effects, or both. In some embodiments, there may be inherent side effects (e.g., it may harm the patient or may be toxic or harmful to some degree in some patients). [0080] “Therapeutically effective amount” means an amount effective to achieve a desired and/or beneficial effect. An effective amount can be administered in one or more administrations. For some purposes of this invention, a therapeutically effective amount is an amount appropriate to treat an indication. By treating an indication is meant achieving any desirable effect, such as one or more of palliate, ameliorate, stabilize, reverse, slow, or delay disease progression, increase the quality of life, or to prolong life. Such achievement can be measured by any suitable method, such as measurement of wound size. [0081] In some embodiments, one or more compounds of the invention (e.g., Formula (I), I-41, or I-79) can be part of a pharmaceutical composition and can be in an amount of at least about 0.0001%, at least about 0.001%, at least about 0.10%, at least about 0.15%, at least about 0.20%, at least about 0.25%, at least about 0.50%, at least about 0.75%, at least about 1%, at least about 10%, at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, at least about 99%, at least about 99.99%, no more than about 75%, no more than about 90%, no more than about 95%, no more than about 99%, no more than about 99.99%, from about 0.001% to about 99%, from about 0.001% to about 50%, from about 0.1% to about 99%, from about 1% to about 95%, from about 10% to about 90%, or from about 25% to about 75%. In other embodiments, one or more compounds of the invention (e.g., Formula (I), I- 41, or I-79) can be part of a pharmaceutical composition and can be in a concentration of at least about 0.1 µM, at least about 1 µM, at least about 10 µM, at least about 100 µM, at least about 1 mM, at least about 10 mM, at least about 100 mM, no more than about 1 M, no more than about 500 mM, no more than about 100 mM, no more than about 10 mM, or no more than about 1 mM, from about 0.1 µM to about 1 M, from about 0.1 µM to about 100 mM, from about 1 µM to about 100 mM, from about 1 µM to about 10 mM, from about 3 µM to about 1 mM, or from about 5 µM to about 500 µM. In some embodiments, the pharmaceutical composition can be presented in a dosage form which is suitable for the topical, subcutaneous, intrathecal, intraperitoneal, oral, parenteral, rectal, cutaneous, nasal, vaginal, or ocular administration route. In other embodiments, the pharmaceutical composition can be presented in a dosage form which is suitable for parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, inhalation administration, or intramuscular administration. The pharmaceutical composition can be in the form of, for example, tablets, capsules, pills, powders granulates, suspensions, emulsions, solutions, gels (including hydrogels), pastes, ointments, creams, plasters, drenches, delivery devices, suppositories, enemas, injectables, implants, sprays, aerosols or other suitable forms. [0082] In some embodiments, the pharmaceutical composition can include one or more formulary ingredients. A “formulary ingredient” can be any suitable ingredient (e.g., suitable for the drug(s), for the dosage of the drug(s), for the timing of release of the drugs(s), for the condition/disease, for the condition/disease state, or for the delivery route) including, but not limited to, pharmaceutically acceptable carriers, other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, excipients, water (e.g., boiled water, distilled water, filtered water, pyrogen-free water, or water with chloroform), sugar (e.g., sucrose, glucose, mannitol, sorbitol, xylitol, or syrups made therefrom), ethanol, glycerol, glycols (e.g., propylene glycol), acetone, ethers, DMSO, surfactants (e.g., anionic surfactants, cationic surfactants, zwitterionic surfactants, or nonionic surfactants (e.g., polysorbates)), oils (e.g., animal oils, plant oils (e.g., coconut oil or arachis oil), or mineral oils), oil derivatives (e.g., ethyl oleate, glyceryl monostearate, or hydrogenated glycerides), excipients, preservatives (e.g., cysteine, methionine, antioxidants (e.g., vitamins (e.g., A, E, or C), selenium, retinyl palmitate, sodium citrate, citric acid, chloroform, or parabens, (e.g., methyl paraben or propyl paraben)), or combinations thereof. [0083] In certain embodiments, pharmaceutical compositions can be formulated to release the active ingredient (e.g., one or more compounds of the invention such as Formula (I), I-41, or I-79) substantially immediately upon the administration or any substantially predetermined time or time after administration. Such formulations can include, for example, controlled release formulations such as various controlled release compositions and coatings. [0084] Other formulations (e.g., formulations of a pharmaceutical composition) can, in certain embodiments, include those incorporating the drug (or control release formulation) into food, food stuffs, feed, or drink. [0085] Other embodiments of the invention can include methods of administering or treating an organism, which can involve treatment with an amount of at least one compound of the invention (e.g., Formula (I), I-41, or I-79) that is effective to treat the disease, condition, or disorder that the organism has, or is suspected of having, or is susceptible to, or to bring about a desired physiological effect. In some embodiments, the composition or pharmaceutical composition comprises at least one compound of the invention (e.g., Formula (I), I-41, or I-79) which can be administered to an animal (e.g., mammals, primates, monkeys, or humans) in an amount of about 0.005 to about 50 mg/kg body weight, about 0.01 to about 15 mg/kg body weight, about 0.1 to about 10 mg/kg body weight, about 0.5 to about 7 mg/kg body weight, about 0.005 mg/kg, about 0.01 mg/kg, about 0.05 mg/kg, about 0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 3 mg/kg, about 5 mg/kg, about 5.5 mg/kg, about 6 mg/kg, about 6.5 mg/kg, about 7 mg/kg, about 7.5 mg/kg, about 8 mg/kg, about 10 mg/kg, about 12 mg/kg, or about 15 mg/kg. In regard to some conditions, the dosage can be about 0.5 mg/kg human body weight or about 6.5 mg/kg human body weight. In some embodiments, the composition or pharmaceutical composition comprises at least one compound of the invention (e.g., Formula (I), I-41, or I-79) which can be administered to an animal (e.g., mammals, primates, monkeys, or humans) in a concentration of at least about 0.1 µM, at least about 1 µM, at least about 10 µM, at least about 100 µM, at least about 1 mM, at least about 10 mM, at least about 100 mM, no more than about 1 M, no more than about 500 mM, no more than about 100 mM, no more than about 10 mM, or no more than about 1 mM, from about 0.1 µM to about 1 M, from about 0.1 µM to about 100 mM, from about 1 µM to about 100 mM, from about 1 µM to about 10 mM, from about 3 µM to about 1 mM, or from about 5 µM to about 500 µM. In regard to some conditions, the dosage can be about 0.5 mg/kg human body weight or about 6.5 mg/kg human body weight. In some instances, some animals (e.g., mammals, mice, rabbits, feline, porcine, or canine) can be administered a dosage of about 0.005 to about 50 mg/kg body weight, about 0.01 to about 15 mg/kg body weight, about 0.1 to about 10 mg/kg body weight, about 0.5 to about 7 mg/kg body weight, about 0.005 mg/kg, about 0.01 mg/kg, about 0.05 mg/kg, about 0.1 mg/kg, about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 20 mg/kg, about 30 mg/kg, about 40 mg/kg, about 50 mg/kg, about 80 mg/kg, about 100 mg/kg, or about 150 mg/kg. In some instances, some animals (e.g., mammals, mice, rabbits, feline, porcine, or canine) can be administered a dosage in a concentration of at least about 0.1 µM, at least about 1 µM, at least about 10 µM, at least about 100 µM, at least about 1 mM, at least about 10 mM, at least about 100 mM, no more than about 1 M, no more than about 500 mM, no more than about 100 mM, no more than about 10 mM, or no more than about 1 mM, from about 0.1 µM to about 1 M, from about 0.1 µM to about 100 mM, from about 1 µM to about 100 mM, from about 1 µM to about 10 mM, from about 3 µM to about 1 mM, or from about 5 µM to about 500 µM. Of course, those skilled in the art will appreciate that it is possible to employ many concentrations in the methods of the present invention, and using, in part, the guidance provided herein, will be able to adjust and test any number of concentrations in order to find one that achieves the desired result in a given circumstance. In other embodiments, the compounds of the invention (e.g., Formula (I), I-41, or I-79) can be administered in combination with one or more other therapeutic agents for a given disease, condition, or disorder. [0086] In some embodiments, the compositions can include a unit dose of one or more compounds of the invention (e.g., Formula (I), I-41, or I-79) in combination with a pharmaceutically acceptable carrier and, in addition, can include other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, and excipients. In certain embodiments, the carrier, vehicle or excipient can facilitate administration, delivery and/or improve preservation of the composition. In other embodiments, the one or more carriers, include but are not limited to, saline solutions such as normal saline, Ringer's solution, PBS (phosphate-buffered saline), and generally mixtures of various salts including potassium and phosphate salts with or without sugar additives such as glucose. Carriers can include aqueous and non-aqueous sterile injection solutions that can contain antioxidants, buffers, bacteriostats, bactericidal antibiotics, and solutes that render the formulation isotonic with the bodily fluids of the intended recipient; and aqueous and non-aqueous sterile suspensions, which can include suspending agents and thickening agents. In other embodiments, the one or more excipients can include, but are not limited to water, saline, dextrose, glycerol, ethanol, or the like, and combinations thereof. Nontoxic auxiliary substances, such as wetting agents, buffers, or emulsifiers may also be added to the composition. Oral formulations can include such normally employed excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, and magnesium carbonate. [0087] Administration and Treatments of Disease [0088] The compounds of the invention (e.g., Formula (I), I-41, or I-79) can be administered to cell(s). The cell(s) can be any suitable cell(s), such as but not limited to an animal cell, a mammalian cell, a human cell, or an epithelial cell. The cell(s) can be in vivo, ex vivo, or in vitro. The administration can include one or more administrations and can use any suitable administration procedure, such as but not limited to contacting or injecting. The compositions may be the same or different if there is more than one administration. In some embodiments, administered amount of at least one compound of the invention (e.g., Formula (I) such as but not limited to compounds I-41 or I-79) can be in a concentration of at least about 0.1 µM, at least about 1 µM, at least about 10 µM, at least about 100 µM, at least about 1 mM, at least about 10 mM, at least about 100 mM, no more than about 1 M, no more than about 500 mM, no more than about 100 mM, no more than about 10 mM, no more than about 1 mM, from about 0.1 µM to about 1 M, from about 0.1 µM to about 100 mM, from about 1 µM to about 100 mM, from about 1 µM to about 10 mM, from about 3 µM to about 1 mM, or from about 5 µM to about 500 µM. [0089] In certain embodiments, administration to the cell(s) (e.g., with or without EGF) can result in an increase in Epidermal Growth Factor Receptor (EGFR) phosphorylation (e.g., of Y1068, of Y1045 or of other amino acids capable of being phosphorylated) by more than 1%, more than 5%, more than 10%, from 1% to 200%, from 1% to 150%, from 1% to 100%, from 5% to 100%, 1%, 5%, 10%, 25%, 50%, 75%, 100%, 150%, or 200%. [0090] In other embodiments, the administration to the cell(s) can include administering Epidermal Growth Factor (EGF). The administration can occur at any suitable time with respect to the administration of the at least one compound of the invention (e.g., Formula (I) such as but not limited to compounds I-41 or I-79), such as simultaneously with, immediately after, or waiting 1 second to 300 minutes, 1 second, 10 seconds, 30 seconds, 1 mins., 5 mins., 10 mins., 15 mins., 20 mins., 30 mins., 45 mins., 60 mins., 90 mins., 120 mins., 150 mins., 180 mins., 240 mins., or 300 mins. EGF can be provided from any suitable source, including endogenous, recombinant, or other source. The concentration of EGF can be any suitable concentration, such as 0.1 to 30 ng/mL, 0.1 ng/mL, 0.5 ng/mL, 1 ng/mL, 2 ng/mL, 3 ng/mL, 4 ng/mL, 5 ng/mL, 10 ng/mL, 15 ng/mL, 20 ng/mL, 25 ng/mL, or 30 ng/mL. [0091] In certain embodiments, the compounds of the invention (e.g., Formula (I), I-41, or I-79) can have a cytotoxicity to cell(s) of less than 90%, less, than 75%, less than 50%, less than 25%, less than 10%, less than 5%, or less than 1% (where the % indicates the percentage of nonviable cells measured). Cytotoxicity can be measured using any suitable method using any suitable cell. For example, cytotoxicity can be determined by measuring hTCEpi cell viability following a 24-hour incubation with varying concentrations of a candidate compound (e.g., from 0 µM to 1 µM, from 0 µM to 10 µM, or from 0 µM to 100 µM); following compound incubation, alamarBlueTM (ThermoFisher Scientific, Waltham, MA) can be added and the number of viable cells measured. [0092] The compounds of the invention (e.g., Formula (I), I-41, or I-79) can be administered to animals by any number of suitable administration routes or formulations. The compounds of the invention (e.g., Formula (I), I-41, or I-79) can also be used to treat animals for a variety of diseases. Animals include but are not limited to mammals, primates, monkeys (e.g., macaque, rhesus macaque, or pig tail macaque), humans, canine, feline, bovine, porcine, avian (e.g., chicken), mice, rabbits, and rats. As used herein, the term “subject” refers to both human and animal subjects. [0093] The route of administration of the compounds of the invention (e.g., Formula (I), I-41, or I-79) can be of any suitable route. Administration routes can be, but are not limited to the oral route, the parenteral route, the cutaneous route, the nasal route, the rectal route, the vaginal route, and the ocular route. In other embodiments, administration routes can be parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, inhalation administration, or intramuscular administration. The choice of administration route can depend on the compound identity (e.g., the physical and chemical properties of the compound) as well as the age and weight of the animal, the particular disease (e.g., wound type or scar type), and the severity of the disease (e.g., stage or severity of the wound or scar). Of course, combinations of administration routes can be administered, as desired. [0094] In certain embodiments, administration (e.g., with or without EGF) can result in an increase in Epidermal Growth Factor Receptor (EGFR) phosphorylation (e.g., of Y1068, of Y1045 or of other amino acids capable of being phosphorylated) by more than 1%, more than 5%, more than 10%, from 1% to 200%, from 1% to 150%, from 1% to 100%, from 5% to 100%, 1%, 5%, 10%, 25%, 50%, 75%, 100%, 150%, or 200%. [0095] Some embodiments of the invention include a method for providing a subject with a composition comprising one or more compounds of the invention (e.g., Formula (I), I-41, or I- 79) described herein (e.g., a pharmaceutical composition) which comprises one or more administrations of one or more such compositions; the compositions may be the same or different if there is more than one administration. [0096] Diseases that can be treated in an animal (e.g., mammals, porcine, canine, avian (e.g., chicken), bovine, feline, primates, rodents, monkeys, rabbits, mice, rats, and humans) using a compound of the invention (e.g., Formula (I), I-41, or I-79) include, but are not limited to wounds (e.g., corneal wounds) or scars. [0097] In some embodiments, conditions (e.g., wounds) that can be treated in an animal (e.g., mammals, porcine, canine, avian (e.g., chicken), bovine, feline, primates, rodents, monkeys, rabbits, mice, rats, and humans) using a compound of the invention (e.g., Formula (I), I-41, or I-79) include, but are not limited to treating (e.g., wound healing) that is (a) enhanced by increased and/or sustained EGFR phosphorylation and/or (b) enhanced by inhibition of c-Cbl. In some embodiments, conditions that can be treated include, but are not limited to conditions where re-epithelialization (e.g., of the cornea or skin) would be beneficial (e.g., to decrease patient discomfort, to decrease the likelihood of infection, to decrease the potential for blindness), conditions where an increase in re-epithelialization (e.g., of the cornea or skin) would be beneficial (e.g., to decrease patient discomfort, to decrease the likelihood of infection, to decrease the potential for blindness), conditions where acceleration of re-epithelialization (e.g., of the cornea or skin) (e.g., to decrease patient discomfort, to decrease the likelihood of infection, to decrease the potential for blindness) would be beneficial, wounds, corneal wounds, wounds related to disease, wounds related to diabetes, wounds resulting from trauma (e.g., physical, thermal, chemical, radiological, etc.), dermal wounds, corneal scars, dermal scars, acne scars, dermatitis, radiation-related skin wounds/reactions (e.g., decreasing the effects of radiation- related skin wounds/reactions), hair loss (e.g., increasing hair growth), wounds related to battlefield injuries, wounds treated in trauma centers (e.g., level I trauma centers, level II trauma centers, level III trauma centers, level IV trauma centers, or level V trauma centers), or wounds treated where full medical care (e.g., medically trained personnel and/or medical facilities) is not available, partial medical care is not available or where no medical care is available. In some embodiments, conditions that can be treated include, but are not limited to, conditions where re- epithelialization (e.g., of the cornea or skin) would be beneficial (e.g., to decrease patient discomfort, to decrease the likelihood of infection, to decrease the potential for blindness), conditions where an increase or an acceleration of re-epithelialization (e.g., of the cornea or skin) would be beneficial (e.g., to decrease patient discomfort, to decrease the likelihood of infection, to decrease the potential for blindness), wounds, corneal wounds, wounds related to diabetes, dermal wounds, dermatitis, radiation-related skin wounds/reactions, corneal scars, dermal scars, or acne scars. Animals that can be treated include but are not limited to mammals, rodents, primates, monkeys (e.g., macaque, rhesus macaque, pig tail macaque), humans, canine, feline, porcine, avian (e.g., chicken), bovine, mice, rabbits, and rats. As used herein, the term “subject” refers to both human and animal subjects. In some instances, the animal is in need of the treatment (e.g., by showing signs of a condition, such as a wound, corneal wound, or scar). [0098] In some embodiments, conditions (e.g., wounds, corneal wounds, or scars) that can be treated in an animal (e.g., mammals, porcine, canine, avian (e.g., chicken), bovine, feline, primates, rodents, monkeys, rabbits, mice, rats, and humans) using a compound of the invention (e.g., Formula (I), I-41, or I-79) include, but are not limited to conditions (e.g., wounds, corneal wounds, or scars) that can be treated by increased and/or sustained EGFR phosphorylation. [0099] As used herein, the term “treating” (and its variations, such as “treatment”) is to be considered in its broadest context. In particular, the term “treating” does not necessarily imply that an animal is treated until total recovery. Accordingly, “treating” includes amelioration of the symptoms, relief from the symptoms or effects associated with a condition, decrease in severity of a condition, or preventing, preventively ameliorating symptoms, or otherwise reducing the risk of developing a particular condition. As used herein, reference to “treating” an animal includes but is not limited to prophylactic treatment and therapeutic treatment. Any of the compositions (e.g., pharmaceutical compositions) described herein can be used to treat an animal. [00100] As related to treating conditions (e.g., wounds, corneal wounds, or acne scars), treating can include but is not limited to prophylactic treatment and therapeutic treatment. As such, treatment can include, but is not limited to: preventing conditions (e.g., wounds, corneal wounds, or acne scars); reducing the risk of conditions (e.g., wounds, corneal wounds, or acne scars); ameliorating or relieving symptoms of conditions (e.g., wounds, corneal wounds, or acne scars); eliciting a bodily response against conditions (e.g., wounds, corneal wounds, or acne scars); inhibiting the development or progression of conditions (e.g., wounds, corneal wounds, or acne scars); inhibiting or preventing the onset of symptoms associated with conditions (e.g., wounds, corneal wounds, or acne scars); reducing the severity of conditions (e.g., wounds, corneal wounds, or acne scars); causing a regression of conditions (e.g., wounds, corneal wounds, or acne scars) or one or more of the symptoms associated with conditions (e.g., wounds, corneal wounds, or acne scars) (e.g., a decrease in the wound or scar size); or preventing infection or other problems associated with conditions (e.g., wounds, corneal wounds, or acne scars). In some embodiments, treating does not include prophylactic treatment of conditions (e.g., wounds, corneal wounds, or acne scars). [00101] In certain embodiments, the treatment (e.g., with or without EGF, as disclosed herein) can result in a decrease in the area of the wound or scar. In some instances, the decrease in the area of the wound or scar can be from 1% to 99%, from 5% to 95%, from 10% to 75%, 1%, 5%, 10% 25%, 50%, 75%, 95%, 99%, or 100% (based on the size of the original area). In other embodiments, the amount of time of the treatment resulting in the decrease in the area of the wound or scar can be any suitable time, such as from 1 to 144 hours, from 1 to 72 hours from 4 to 48 hours, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, 20 hours, 24 hours, 36 hours, 48 hours, 72 hours, or 144 hours. [00102] Treatment of an animal can occur using any suitable administration method (such as those disclosed herein) and using any suitable amount of a compound of the invention (e.g., Formula (I), I-41, or I-79). In some embodiments, methods of treatment comprise treating an animal for conditions (e.g., wounds, corneal wounds, or acne scars). Some embodiments of the invention include a method for treating a subject (e.g., an animal such as a human or primate) with a composition comprising a compound of the invention (e.g., Formula (I), I-41, or I-79) (e.g., a pharmaceutical composition) which comprises one or more administrations of one or more such compositions; the compositions may be the same or different if there is more than one administration. [00103] In some embodiments, the method of treatment includes administering an effective amount of a composition comprising a compound of the invention (e.g., Formula (I), I- 41, or I-79). As used herein, the term “effective amount” refers to a dosage or a series of dosages sufficient to affect treatment (e.g., to treat conditions (e.g., wounds, corneal wounds, or acne scars)) in an animal. In some embodiments, an effective amount can encompass a therapeutically effective amount, as disclosed herein. In certain embodiments, an effective amount can vary depending on the subject and the particular treatment being affected. The exact amount that is required can, for example, vary from subject to subject, depending on the age and general condition of the subject, the particular adjuvant being used (if applicable), administration protocol, and the like. As such, the effective amount can, for example, vary based on the particular circumstances, and an appropriate effective amount can be determined in a particular case. An effective amount can, for example, include any dosage or composition amount disclosed herein. In some embodiments, an effective amount of at least one compound of the invention (e.g., Formula (I) such as but not limited to compounds I-41 or I-79) (which can be administered to an animal such as mammals, primates, monkeys or humans) can be an amount of about 0.005 to about 50 mg/kg body weight, about 0.01 to about 15 mg/kg body weight, about 0.1 to about 10 mg/kg body weight, about 0.5 to about 7 mg/kg body weight, about 0.005 mg/kg, about 0.01 mg/kg, about 0.05 mg/kg, about 0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 3 mg/kg, about 5 mg/kg, about 5.5 mg/kg, about 6 mg/kg, about 6.5 mg/kg, about 7 mg/kg, about 7.5 mg/kg, about 8 mg/kg, about 10 mg/kg, about 12 mg/kg, or about 15 mg/kg body weight. In regard to some embodiments, the dosage can be about 3.6 mg/kg human body weight. In some embodiments, an effective amount of at least one compound of the invention (e.g., Formula (I) such as but not limited to compounds I-41 or I-79) (which can be administered to an animal such as mammals, primates, monkeys or humans) can be in a concentration of at least about 0.1 µM, at least about 1 µM, at least about 10 µM, at least about 100 µM, at least about 1 mM, at least about 10 mM, at least about 100 mM, no more than about 1 M, no more than about 500 mM, no more than about 100 mM, no more than about 10 mM, or no more than about 1 mM, from about 0.1 µM to about 1 M, from about 0.1 µM to about 100 mM, from about 1 µM to about 100 mM, from about 1 µM to about 10 mM, from about 3 µM to about 1 mM, or from about 5 µM to about 500 µM. In some instances, an effective amount of at least one compound of the invention (e.g., Formula (I) such as but not limited to compounds I-41 or I-79) (which can be administered to an animal such as mammals, rodents, mice, rabbits, feline, porcine, or canine) can be an amount of about 0.005 to about 50 mg/kg body weight, about 0.01 to about 15 mg/kg body weight, about 0.1 to about 10 mg/kg body weight, about 0.5 to about 7 mg/kg body weight, about 0.005 mg/kg, about 0.01 mg/kg, about 0.05 mg/kg, about 0.1 mg/kg, about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 20 mg/kg, about 30 mg/kg, about 40 mg/kg, about 50 mg/kg, about 80 mg/kg, about 100 mg/kg, or about 150 mg/kg body weight. In some instances, an effective amount of at least one compound of the invention (e.g., Formula (I) such as but not limited to compounds I-41 or I-79) (which can be administered to an animal such as mammals, rodents, mice, rabbits, feline, porcine, or canine) can be in a concentration of at least about 0.1 µM, at least about 1 µM, at least about 10 µM, at least about 100 µM, at least about 1 mM, at least about 10 mM, at least about 100 mM, no more than about 1 M, no more than about 500 mM, no more than about 100 mM, no more than about 10 mM, or no more than about 1 mM, from about 0.1 µM to about 1 M, from about 0.1 µM to about 100 mM, from about 1 µM to about 100 mM, from about 1 µM to about 10 mM, from about 3 µM to about 1 mM, or from about 5 µM to about 500 µM. [00104] In some embodiments, an effective amount of at least one compound of the invention (e.g., Formula (I) such as but not limited to compounds I-41 or I-79) (which can be administered to an animal such as mammals, primates, monkeys or humans) can be in an amount of from about 0.01 mg/kg animal body weight to about 15 mg/kg animal body weight, such as 0.01 mg/kg, 0.05 mg/kg, 0.1 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 7 mg/kg, 10 mg/kg, or 15 mg/kg (e.g., 3.6 mg/kg) body weight. [00105] In some embodiments, an effective amount of at least one compound of the invention (e.g., Formula (I) such as but not limited to compounds I-41 or I-79) (which can be administered to an animal such as mammals, primates, monkeys or humans) can be with a volume of from 1 µL to 150 µL (e.g., 15 µL) of a from 1 mM to 100 mM solution (e.g., 10 mM solution), such as 1 µL, 2 µL, 5 µL, 10 µL, 25 µL, 50 µL, 75 µL, 100 µL, 125 µL, or 150 µL, of a from 1 mM to 100 mM solution (e.g., 1 mM, 5 mM, 10 mM, 20 mM, 40, mM, 50 mM, 60 mM, 70 mM, 80 mM, 90 mM, or 100 mM solution). [00106] In other embodiments, an effective amount of at least one compound of the invention (e.g., Formula (I) such as but not limited to compounds I-41 or I-79) (which can be administered to an animal such as mammals, primates, monkeys or humans) can be with a volume of from 1 µL to 150 µL (e.g., 15 µL or 20 µL) of a from 1 µM to 100 µM solution (e.g., 10 µM solution), such as 1 µL, 2 µL, 5 µL, 10 µL, 15 µL, 20 µL, 25 µL, 50 µL, 75 µL, 100 µL, 125 µL, or 150 µL, of a from 1 µM to 100 µM solution (e.g., 1 µM, 5 µM, 10 µM, 20 µM, 40, µM, 50 µM, 60 µM, 70 µM, 80 µM, 90 µM, or 100 µM solution). [00107] In some embodiments, an effective amount of at least one compound of the invention (e.g., Formula (I) such as but not limited to compounds I-41 or I-79) (which can be administered to an animal such as mammals, primates, monkeys or humans) can be in a mole concentration amount of from 1.5 µmoles to 150 µmoles (e.g., 15 µmoles), such as 1.5 µmoles, 2 µmoles, 5 µmoles, 10 µmoles, 15 µmoles, 20 µmoles, 50 µmoles, 75 µmoles, 100 µmoles, 125 µmoles, or 150 µmoles. [00108] In other embodiments, an effective amount of at least one compound of the invention (e.g., Formula (I) such as but not limited to compounds I-41 or I-79) (which can be administered to an animal such as mammals, primates, monkeys or humans) can be in a mole concentration amount of from 0.02 nmoles to 2.0 nmoles (e.g., 0.15 nmoles or 0.20 nmoles), such as 0.02 nmoles, 0.05 nmoles, 0.10 nmoles, 0.15 nmoles, 0.20 nmoles, 0.30 nmoles, 0.50 nmoles, 0.75 nmoles, 1.00 nmoles, 1.25 nmoles, 1.50 nmoles, or 2.0 nmoles. [00109] In some embodiments, an effective amount of at least one compound of the invention (e.g., Formula (I) such as but not limited to compounds I-41 or I-79) (which can be administered to an animal such as mammals, primates, monkeys or humans) can be in a mole amount per surface area of from 1 µmoles/cm² to 200 µmoles/cm² (e.g., 12.5 µmoles/cm²), such as 1 µmoles/cm², 2 µmoles/cm², 4 µmoles/cm², 5 µmoles/cm², 10 µmoles/cm², 12.5 µmoles/cm², 15 µmoles/cm², 25 µmoles/cm², 50 µmoles/cm², 100 µmoles/cm², 150 µmoles/cm², or 200 µmoles/cm², where the amount per surface area (in µmoles/cm²) indicates the number of moles of the compound applied to a specified surface area of the animal (e.g., wound area, scar area, acne area, radiated skin area, dermatitis area, or hair loss area). [00110] In other embodiments, an effective amount of at least one compound of the invention (e.g., Formula (I) such as but not limited to compounds I-41 or I-79) (which can be administered to an animal such as mammals, primates, monkeys or humans) can be in a mole amount per surface area of from 0.01 nmoles/mm² to 2.0 nmoles/mm² (e.g., 0.125 nmoles/mm² or 0.15 nmoles/mm² or 0.20 nmoles/mm²), such as 0.01 nmoles/mm², 0.02 nmoles/mm², 0.04 nmoles/mm², 0.05 nmoles/mm², 0.10 nmoles/mm², 0.125 nmoles/mm², 0.15 nmoles/mm², 0.20 nmoles/mm², 0.25 nmoles/mm², 0.50 nmoles/mm², 1.00 nmoles/mm², 1.50 nmoles/mm², or 2.0 nmoles/mm², where the amount per surface area (in nmoles/mm²) indicates the number of moles of the compound applied to a specified surface area of the animal (e.g., wound area, scar area, acne area, radiated skin area, dermatitis area, or hair loss area). [00111] In certain embodiments, administration or treatment (e.g., with or without EGF) can result in an increase in Epidermal Growth Factor Receptor (EGFR) phosphorylation (e.g., of Y1068, of Y1045 or of other amino acids capable of being phosphorylated) by more than 1%, more than 5%, more than 10%, from 1% to 200%, from 1% to 150%, from 1% to 100%, from 5% to 100%, 1%, 5%, 10%, 25%, 50%, 75%, 100%, 150%, or 200%. [00112] “Therapeutically effective amount” means an amount effective to achieve a desired and/or beneficial effect (e.g., decreasing wound size). A therapeutically effective amount can be administered in one or more administrations. For some purposes of this invention, a therapeutically effective amount is an amount appropriate to treat an indication (e.g., to treat conditions (e.g., wounds, corneal wounds, or acne scars)). By treating an indication is meant achieving any desirable effect, such as one or more of palliate, ameliorate, stabilize, reverse, slow, or delay disease (e.g., conditions (e.g., wounds, corneal wounds, or acne scars)) progression, increase the quality of life, or to prolong life. Such achievement can be measured by any suitable method, such as but not limited to measurement of wound size. [00113] In other embodiments, the treatments can include administering Epidermal Growth Factor (EGF). The administration can occur at any suitable time with respect to the administration of the at least one compound of the invention (e.g., Formula (I) such as but not limited to compounds I-41 or I-79), such as simultaneously with, immediately after, or waiting 1 second to 300 mins., 1 second, 10 seconds, 30 seconds, 1 min., 5 mins., 10 mins., 15 mins., 20 mins., 30 mins., 45 mins., 60 mins., 90 mins., 120 mins., 150 mins., 180 mins., 240 mins., or 300 mins. EGF can be provided from any suitable source, including endogenous, recombinant, or other source. The concentration of EGF can be any suitable concentration, such as 0.1 to 30 ng/mL, 0.1 ng/mL, 0.5 ng/mL, 1 ng/mL, 2 ng/mL, 3 ng/mL, 4 ng/mL, 5 ng/mL, 10 ng/mL, 15 ng/mL, 20 ng/mL, 25 ng/mL, or 30 ng/mL. [00114] In some embodiments, the treatments can also include one or more of surgical intervention, hormone therapies, immunotherapy, or treatment of infections. [00115] In some embodiments, the treatments disclosed herein can include use of other drugs (e.g., antibiotics) or therapies for treating conditions (e.g., wounds, corneal wounds, or acne scars). For example, antibiotics can be used to treat infections and can be combined with a compound of the invention to treat disease (e.g., infections associated with conditions (e.g., wounds, corneal wounds, or acne scars)). [00116] Methods for Preparing Compounds of Formula (I) [00117] The compounds of Formula (I) can be prepared using any suitable method or they can be purchased, if available. Some embodiments of the present invention include methods for the preparation of compounds of Formula (I). In the synthetic schemes discussed below, R^1e is the same as R^1a or R^1c; R^1a and R^1c are the same as that defined in Formula (I). In the synthetic schemes discussed below, R^1f is the same as R^1b or R^1d; R^1b and R^1d are the same as that defined in Formula (I). [00118] In some embodiments, the preparation of Formula (I) (e.g., Formula (Ia) or Formula (Ib)) using the synthesis method provided in Scheme (i) and/or in Scheme (ii). In Scheme (i) and in Scheme (ii), R^1e is the same as R^1a or R^1c; R^1a and R^1c are the same as that defined in Formula (I). In Scheme (i) and in Scheme (ii), R^1f is the same as R^1b or R^1d; R^1b and R^1d are the same as that defined in Formula (I). Certain steps in Scheme (i) and Scheme (ii) are discussed in more detail herein. [00119] Scheme (i) [00120] Scheme (ii) [00121] In certain embodiments, a compound of Formula (I) can be prepared comprising the step of reacting a compound of Formula (II) with a compound of Formula (III) to result in Formula (IV), which is later made into Formula (I) (e.g., using one or more synthetic steps, such as those disclosed herein). [00122] Scheme 1 [00123] Formula (II) can be prepared using any suitable method (e.g., such as those disclosed herein) or can be purchased where available. Formula (III) can be prepared using any suitable method or can be purchased where available. In some embodiments, R²¹ can be any suitable leaving group, such as a halogen (e.g., F, Cl, Br, or I). In other embodiments, R²¹ can be Br or Cl. NaH is indicated in the reaction as the base used in the reaction, but any suitable base(s) can be used, such as those disclosed herein. DMF is indicated as the solvent used in the reaction, but any suitable solvent(s) or solvent mixture can be used, such as those disclosed herein. Any suitable conditions (e.g., temperature, pH, reaction time, pressure, or under nitrogen atmosphere) can be used for the reaction, such as those disclosed herein. Formula (IV) can be used in a later reaction (e.g., in a partially purified, fully purified, or crude form) and/or can be partially purified or fully purified. [00124] In certain embodiments, a compound of Formula (I) can be prepared comprising the step of reacting a compound of Formula (IV) to result in Formula (V), which is later made into Formula (I) (e.g., using one or more synthetic steps, such as those disclosed herein). [00125] Scheme 2 [00126] Formula (IV) can be prepared using any suitable method (e.g., such as those disclosed herein) or can be purchased where available. KOH/EtOH is indicated in the reaction as the base mixture used in the reaction, but any suitable base or base mixture can be used, such as those disclosed herein. Any suitable conditions (e.g., temperature, pH, reaction time, pressure, or under nitrogen atmosphere) can be used for the reaction, such as those disclosed herein. Formula (V) can be used in a later reaction (e.g., in a partially purified, fully purified, or crude form) and/or can be partially purified or fully purified. [00127] In certain embodiments, a compound of Formula (I) can be prepared comprising the step of reacting a compound of Formula (V) to result in Formula (VI), which is later made into Formula (I) (e.g., using one or more synthetic steps, such as those disclosed herein). [00128] Scheme 3 [00129] Formula (V) can be prepared using any suitable method (e.g., such as those disclosed herein) or can be purchased where available. Cl-CO-OCH2CH₃ is indicated in the reaction as the reactant used in the reaction to provide what will be a leaving group in a later reaction; any suitable reactant that provides a leaving group can be used instead of Cl-CO- OCH2CH₃, and the Cl (used as a leaving group in this reaction) can be replaced by any suitable leaving group for this reaction (e.g., Br, or I), such as those disclosed herein. Triethylamine (TEA) and tetrahydrofuran (THF) are indicated as the solvent mixture used in the reaction, but any suitable solvent(s) or solvent mixture can be used, such as those disclosed herein. Any suitable conditions (e.g., temperature, pH, reaction time, pressure, or under nitrogen atmosphere) can be used for the reaction, such as those disclosed herein. Formula (VI) can be used in a later reaction (e.g., in a partially purified, fully purified, or crude form) and/or can be partially purified or fully purified. [00130] In certain embodiments, a compound of Formula (I) can be prepared comprising the step of reacting a compound of Formula (VI) to result in Formula (VII), which is later made into Formula (I) (e.g., using one or more synthetic steps, such as those disclosed herein). [00131] Scheme 4 [00132] Formula (VI) can be prepared using any suitable method (e.g., such as those disclosed herein) or can be purchased where available. Water is indicated as the solvent used in the reaction, but any suitable solvent or solvent mixture can be used, such as other aqueous or aqueous-based solvents. Any suitable conditions (e.g., temperature, pH, reaction time, pressure, or under nitrogen atmosphere) can be used for the reaction, such as those disclosed herein. Formula (VII) can be used in a later reaction (e.g., in a partially purified, fully purified, or crude form) and/or can be partially purified or fully purified. [00133] In certain embodiments, a compound of Formula (I) can be prepared comprising the step of reacting a compound of Formula (VII) to result in Formula (VIII), which is later made into Formula (I) (e.g., using one or more synthetic steps, such as those disclosed herein). [00134] Scheme 5 [00135] Formula (VII) can be prepared using any suitable method (e.g., such as those disclosed herein) or can be purchased where available. Toluene is indicated as the solvent mixture used in the reaction, but any suitable solvent(s) or solvent mixture can be used. The temperature of 100°C and the time of 2 hours are indicated as the temperature and time used for this reaction. However, any suitable combination of temperature and time can be used, such as those disclosed herein. Any suitable conditions (e.g., temperature, pH, reaction time, pressure, or under nitrogen atmosphere) can be used for the reaction, such as those disclosed herein. Formula (VIII) can be used in a later reaction (e.g., in a partially purified, fully purified, or crude form) and/or can be partially purified or fully purified. [00136] In certain embodiments, a compound of Formula (Ia) can be prepared comprising the step of reacting a compound of Formula (VIII) with Formula (IX) to result in Formula (Ia). In Scheme A, R², R³, R⁴, R⁵, and R⁶ are the same as that defined in Formula (I) as disclosed herein. In Scheme A, R^1e is identical to R^1c; R^1c is the same as that defined in Formula (I) as disclosed herein. In Scheme A, R^1f is identical to R^1d; R^1d is the same as that defined in Formula (I) as disclosed herein. [00137] Scheme A [00138] Formula (VIII) can be prepared using any suitable method (e.g., such as those disclosed herein) or can be purchased where available. Formula (IX) can be prepared using any suitable method (e.g., such as those disclosed herein) or can be purchased where available. In certain embodiments, one or more of Schemes 1, 2, 3, 4, or 5 can be used prior to Scheme A. Ethanol is indicated as the solvent used in the reaction, but any suitable solvent or solvent mixture can be used. In certain embodiments, the reaction mixture of Formula (VIII) and Formula (IX) can mixed (e.g., stirred or any suitable manner to mix) for any suitable period of time (e.g., 0.1 hours, 0.2 hours, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, or 10 hours) at any suitable temperature (e.g., 0°C or room temperature such as 20-30°C, 20-25°C, or 25°C). In some embodiments, reaction progress (e.g., such as reaction completion) can be determined by TLC. Any suitable conditions (e.g., temperature, pH, reaction time, pressure, or under nitrogen atmosphere) can be used for the reaction, such as those disclosed herein. The resulting Formula (Ia) can be used in a later reaction (e.g., in a partially purified, fully purified, or crude form) and/or can be partially purified or fully purified. Purification (partial or full purification) can be accomplished using any suitable method(s), such as those disclosed herein. For example, purification can include one or more of the following: (a) the solvent phase can be removed using any suitable method (e.g., under reduced pressure and/or using Na2SO4), (b) the residue from the reaction or after solvent removal can be concentrated (e.g., in vacuo), or (c) extraction (e.g., of the residue after the reaction, after solvent removal, and/or after being concentrated) can occur using any suitable extraction method (e.g., taken up in a saturated NH4Cl solution and extracted three times with ethyl acetate). In some embodiments, purification can include the product or residue of a prior concentration/extraction/purification being chromatographed using any suitable method (e.g., over silica gel (Combiflash, 4 g column, 0 → 50%, hexanes–ethyl acetate, 12 minutes)) to provide Formula (Ia). [00139] In certain embodiments, a compound of Formula (Ib) can be prepared comprising the step of reacting Formula (Ia) to result in Formula (Ib). In Scheme B, R², R³, R⁴, R⁵, and R⁶ are the same as that defined in Formula (I) as disclosed herein. In Scheme B, R^1c is identical to R^1a; R^1a and R^1c are the same as that defined in Formula (I) as disclosed herein. In Scheme B, R^1d is identical to R^1b; R^1b and R^1d are the same as that defined in Formula (I) as disclosed herein. [00140] Scheme B [00141] Formula (Ia) can be prepared using any suitable method (e.g., such as those disclosed herein) or can be purchased where available. In certain embodiments, one or more of Schemes 1, 2, 3, 4, 5, or A can be used prior to Scheme B. Sodium ethoxide (NaOEt) is used as a base in this reaction, but any suitable base or mixture of bases can be used (e.g., such as those disclosed herein). Ethanol is indicated as the solvent used in the reaction, but any suitable solvent or solvent mixture can be used (e.g., such as those disclosed herein). Any suitable conditions (e.g., temperature, pH, reaction time, pressure, or under nitrogen atmosphere) can be used for the reaction, such as those disclosed herein. The resulting Formula (Ib) can be partially purified, fully purified, or used in crude form. Purification (partial or full purification) can be accomplished using any suitable method(s), such as those disclosed herein. For example, purification can include one or more of the following: (a) the solvent phase can be removed using any suitable method (e.g., under reduced pressure and/or using Na2SO4), (b) the residue from the reaction or after solvent removal can be concentrated (e.g., in vacuo), or (c) extraction (e.g., of the residue after the reaction, after solvent removal, and/or after being concentrated) can occur using any suitable extraction method (e.g., taken up in a saturated NH4Cl solution and extracted three times with ethyl acetate). In some embodiments, purification can include the product or residue of a prior concentration/extraction/purification being chromatographed using any suitable method (e.g., over silica gel (Combiflash, 4 g column, 0 → 50%, hexanes–ethyl acetate, 12 minutes)) to provide Formula (Ib). [00142] In general, in certain embodiments, purification (partial or full purification) can be accomplished using any suitable method(s), such as those disclosed herein. For example, purification can include one or more of the following: (a) the solvent phase can be removed using any suitable method (e.g., under reduced pressure and/or using Na₂SO₄), (b) the residue from the reaction or after solvent removal can be concentrated (e.g., in vacuo), or (c) extraction (e.g., of the residue after the reaction, after solvent removal, and/or after being concentrated) can occur using any suitable extraction method (e.g., taken up in a saturated NH4Cl solution and extracted three times with ethyl acetate). In some embodiments, purification can include the product or residue of a prior concentration/extraction/purification being chromatographed using any suitable method (e.g., over silica gel (Combiflash, 4 g column, 0 → 50%, hexanes–ethyl acetate, 12 minutes)). [00143] In some embodiments, Formula (I) (or any other formula recited above, such as Formula (Ia) or Formula (Ib)) can be recovered. Recovery can occur using any suitable method (e.g., such as those disclosed herein) including but not limited to solvent removal (e.g., as disclosed herein), residue concentration (e.g., as disclosed herein), extraction (e.g., as disclosed herein), purification (e.g., as disclosed herein), chromatography (e.g., as disclosed herein, such as over silica gel (Combiflash, 4 g column, 0 → 50%, hexanes–ethyl acetate, 12 minutes)), HPLC (e.g., reverse phase), LC, precipitation, centrifugation, column chromatography (e.g., size exclusion chromatography or ion exchange chromatography), use of silica gel, or combinations thereof. [00144] In some embodiments, a method for the preparation of a compound of Formula (I) (e.g., Formula (Ia) or Formula (Ib)) can comprise one or more of the above-mentioned steps. In certain embodiments, a method for preparing a compound of Formula (I) comprises (a) reacting a compound of Formula (VIII) with a compound of Formula (IX) to result in a mixture comprising a compound of Formula (Ia); (b) optionally reacting a compound of Formula (Ia) to result in a mixture comprising a compound of Formula (Ib); and; (c) recovering Formula (Ia), Formula (Ib), or both. [00145] The presently-disclosed subject matter is further illustrated by the following specific but non-limiting examples. The following examples may include compilations of data that are representative of data gathered at various times during the course of development and experimentation related to the present invention. EXAMPLES Example Set A [00146] All commercially chemicals and solvents were purchased from VWR or MilliporeSigma and were used without further purification. All reactions were conducted under a nitrogen atmosphere in flame dried glassware. Reactions were monitored by thin-layer chromatography (TLC) on 0.25 mm silica gel plates (Analtech, Uniplates) and were visualized with UV light (254 nm and 360 nm) or potassium permanganate stain. Microwave reactions were conducted in a Biotage Initiator Eight reactor. Isolated compounds were purified via flash chromatography by Teledyne Isco Combiflash 200Rf with prepacked silica gel columns. All NMR spectra were recorded either on an Agilent 400 MR spectrometer equipped with a OneProbe at 400 MHz for ¹H, 100.5 MHz for ¹³C or 376.4 MHz for ¹⁹F, or a Bruker 600 MHz for ¹H. Chemical shifts were recorded as δ values in parts per million (ppm) at 25^oC and either tetramethylsilane (TMS) or residue solvent was used as an internal standard. Coupling constants are reported in hertz (Hz) and splitting patterns are designated as s, singlet; d, doublet; t, triplet; q, quartet; qu, quintet; m, multiplet; br, broad. Analytical purity was determined by reverse- phase high-performance liquid chromatography (RP-HPLC) on an Agilent 1260 infinity equipped with a diode array (160 – 400 nm). The instrument was equipped with an Agilent Zobrax Extend C18 column (1.8 μm, 2.1 × 50 mm) with mobile phase consisting of mass spectrophotometry grade water (with 0.1% formic acid and 0.1% methanol) and acetonitrile (with 0.1% formic acid and 0.1% water). The RP-HPLC method employed a linear gradient from 5% - 100% acetonitrile at 0.3 mL/min over 15 mins with 4 mL injection volume. High- resolution MS were recorded on an Agilent 6224 time-of-flight detector connected to the HPLC system that utilized positive electrospray ionization. All final compounds are at least 95% pure as determined by HPLC. I. Synthesis of hydrazide intermediates. [00147] 3-(1H-indol-3-yl)propanehydrazide (2) was prepared by literature methods (Rapolu et al. (2013) “Synthesis and biological screening of 5-(alkyl(1H-indol-3-yl))-2- (substituted)-1,3,4-oxadiazoles as antiproliferative and anti-inflammatory agents.” Eur. J. Med. Chem., Vol.66, pp.91–100). 3-(2-(4-phenyl)-1H-indol-3-yl)propanehydrazide (6)² was prepared by literature methods (Purohit et al. (2013) “Synthesis and antimicrobial activity of new series of 2-phenyl-3-[2-(5-substituted-1,3,4-oxadiazol-2-yl)ethyl]-1H-indoles.” Indian J. Heterocyclic Chem., Vol.23, pp.177–182). [00148] 4-(1H-Indol-3-yl)butanehydrazide (4). Compound was prepared by a modified literature method (Rapolu et al. (2013) “Synthesis and biological screening of 5-(alkyl(1H-indol- 3-yl))-2-(substituted)-1,3,4-oxadiazoles as antiproliferative and anti-inflammatory agents.” Eur. J. Med. Chem., Vol.66, pp.91–100.), as follows. To a solution of 1.0 g (4.92 mmol) of commercially available 3-(1H-indol-3-yl)butanoic acid in 10 mL of anhydrous methanol was added dropwise at 0^oC a catalytic amount of H₂SO₄. The resulting mixture was stirred at reflux for 2 h and then cooled to room temperature. The solvent was removed in vacuo and the residue was treated with saturated Na2CO3(aq) solution. The aqueous solution was extracted three times with 50–mL portions of ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified over silica gel (4 g column, Combiflash, 0 → 10% hexanes-ethyl acetate, over 12 mins) to afford 0.93 g (87%) of methyl 4-(1H-Indol-3-yl)butanoate (3) as a white solid. To a solution of 0.93 g (4.28 mmol) of ester 3 in 10 mL of ethanol was added dropwise 0.64 g (12.8 mmol) of hydrazine hydrate. The resulting solution was stirred under reflux for 4 h. The reaction mixture was cooled to room temperature and then poured into ice-cold water. After sitting for 5 mins, the precipitant was collected by vacuum filtration, washed with cold water and dried under vacuum. The crude product was recrystallized from diethyl ether and hexane to afford 0.78 g (84%) of 4 as a yellow solid: ESI-HRMS m/z: calcd for C12H16N3O [M+H]⁺ 218.1293, found 218.1294. [00149] Ethyl (E)-3-(5-methoxy-2-methyl-1H-indol-3-yl)acrylate (8). To a stirred solution of 0.20 g (1.06 mmol) of 5-methoxy-2-methyl-1H-indole-3-carbaldehyde (7, prepared in one step, as described in Giraud, F. (2009) “Design, synthesis and evaluation of 3-(imidazol-1- ylmethyl)indoles as antileishmanial agents. Part II.” J. Enzyme Inhib. Med. Chem., Vol. 24, pp. 1067–1075) in 10 mL of toluene was added 0.74 g (2.12 mmol) of commercially available (carbethoxymethylene)triphenylphosphorane. The reaction was stirred under reflux for 4 h and then cooled to room temperature. The volatiles were removed in vacuo and the resulting product was purified by flash column chromatography (4 g silica gel column, Combiflash, 0 → 10% hexanes-ethyl acetate, over 12 mins) to afford 1.14 g (83%) of 8 as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 8.14 (s, br, 1H), 7.94 (d, J = 15.6 Hz, 1H), 7.30 (d, J = 2.0 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 6.85 (dd, J = 8.8, 2.4 Hz, 1H), 6.33 (d, J = 16.0 Hz, 1H), 4.28 (q, J = 7.2 Hz, 2H), 3.89 (s, 3H), 2.55 (s, 3H), 1.36 (d, J = 7.2 Hz, 3H); ESI-HRMS m/z: calcd for C15H18NO3 [M+H]⁺ 260.1287, found 260.1292. [00150] 3-(5-Methoxy-2-methyl-1H-indol-3-yl)propanehydrazide (9). A suspension of 1.0 g (3.85 mmol) of acrylate 8 and a catalytic amount of 10% Pd/C (100 mg) in 15 mL of MeOH was stirred under an atmosphere of hydrogen gas (balloon) for 6 h. The suspension was filtered and the filtrate was concentrated in vacuo to afford 0.95 g (94%) of ethyl 3-(5-methoxy- 2-methyl-1H-indol-3-yl)propanoate and was used in the next step without further purification: ESI-HRMS m/z: calcd [00151] for C₁₅H₂₀NO₃ [M+H]⁺ 262.1443, found 262.1448. To a solution of 500 mg (1.91 mmol) of ethyl 3-(5-methoxy-2-methyl-1H-indol-3-yl)propanoate in 10 mL of absolute ethanol was added 290 mg (5.74 mmol) hydrazine hydrate. The resulting solution was stirred under reflux for 4 h. The reaction mixture was cooled to room temperature and then poured into ice- cold water. After sitting for 5 mins, the precipitant was collected by vacuum filtration, washed with cold water and dried under vacuum. The crude product was recrystallized from diethyl ether and hexane to afford 430 mg (92%) of 9 as a yellow solid: ¹H NMR (400 MHz, CDCl3) δ 10.46 (s, br, 1H), 8.93 (s, br, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 2.4 Hz, 1H), 6.60 (dd, J = 8.8, 2.4 Hz, 1H), 4.12 (s, br, 2H), 3.74 (s, 3H), 2.81 (t, J = 8.0 Hz, 2H), 2.27 (s, 3H), 2.24 (t, J = 8.0 Hz, 2H); ESI-HRMS m/z: calcd for C13H18N3O2 [M+H]⁺ 248.1399, found 248.1396. [00152] Synthesis of hydrazide 12. [00153] 5-Fluoro-1H-indole-3-carbaldehyde (10). To a 0^oC solution of 2.86 mL (37.0 mmol) of DMF was added dropwise 1.73 mL (18.5 mmol) of phosphorus oxychloride and the resulting solution was stirred at 0°C for 40 min. A solution of 1.0 g (7.4 mmol) of 5-fluoro-1H- indole in 10 mL of DMF was slowly added and the temperature was maintained below 5°C during the addition. The solution was stirred at 0°C for 40 min, then warmed to room temperature and stirred for additional 40 min. Crushed ice was then added that was followed by dropwise addition of 19.2 mL of 3.85 M aqueous potassium hydroxide via dropping funnel with vigorous stirring. The solution was stirred at 100°C for 30 min. After cooling to room temperature, the resultant pale-yellow precipitate was isolated via vacuum filtration, washed with water and air dried. The product was further purified by recrystallization from diethyl ether and hexane to afford 1.04 g (84%) of 10 as a pale-yellow solid: ESI-HRMS m/z: calcd for C₉H₇FNO [M+H]⁺ 164.0512, found 164.0510. [00154] Ethyl (E)-3-(5-fluoro-1H-indol-3-yl)acrylate (11). To a stirred solution of 0.50 g (3.1 mmol) of aldehyde 10 in 40 mL of toluene was added 1.60 g (4.60 mmol) (carbethoxymethylene)triphenylphosphorane and then stirred under reflux for 4 h. After cooling to room temperature, the volatiles were removed in vacuo and the crude product was purified by flash column chromatography (4 g silica gel column, Combiflash, 0 → 10% hexanes-ethyl acetate, over 12 mins) to afford 1.17 g (82%) of 11 as a white solid. [00155] 3-(5-Fluoro-1H-indol-3-yl)propanehydrazide (12). To a solution of 1.0 g (4.29 mmol) of acrylate 11 in 15 mL of methanol was added a catalytic amount (100 mg) of 10% Pd/C. The suspension was stirred for 6 h at room temperature under an atmosphere (balloon) of hydrogen gas. The suspension was filtered over Celite (rinsed with 1:1 ethyl acetate-methanol) and concentrated in vacuo to afford 0.94 g (93%) of saturated ethyl ester. To a solution of 0.5 g (2.12 mmol) of saturated ethyl ester ethyl in 10 mL of ethanol was added 0.32 g (6.37 mmol) of hydrazine hydrate. The reaction mixture was then stirred under reflux for 2 h. After cooling to room temperature, the mixture was poured into ice-cold water. The precipitant was collected by vacuum filtration, washed with water, and air dried. The crude was further purified by recrystallization from diethyl ether and hexane to afford 0.42 g (90%) of 12 as a yellow solid: ESI-HRMS m/z: calcd for C11H13FN3O [M+H]⁺ 222.1043, found 222.1049. [00156] Synthesis of hydrazide 15. [00157] 5-Chloro-1H-indole-3-carbaldehyde (13). To a 0^oC solution of 5.1 mL of DMF was added dropwise 3.1 mL (5.1 g, 33 mmol) of phosphorus oxychloride and the resulting solution was stirred at 0°C for 40 min. A solution of 2.0 g (13.2 mmol) of 5-chloro-1H-indole in 20 mL of DMF was slowly added and the temperature was maintained below 5°C during the addition. The solution was stirred at 0°C for 40 min, then warmed to room temperature and stirred for an additional 40 min. Crushed ice was then added that was followed by dropwise addition of 39 mL of 3.5 M aqueous sodium hydroxide via dropping funnel with vigorous stirring. The solution was stirred at 100°C for 30 min. After cooling to room temperature, the resultant pale-yellow precipitate was isolated via vacuum filtration, washed with water and air dried. The product was further purified by recrystallization from diethyl ether and hexane to afford 1.34 g (57%) of 13 as a pale-yellow solid: ESI-HRMS m/z: calcd for C9H7ClNO [M+H]⁺ 180.0216, found 180.0213. [00158] Ethyl (E)-3-(5-chloro-1H-indol-3-yl)acrylate (14). To a stirred solution of 200 mg (1.11 mmol) of aldehyde 13 in 10 mL of toluene was added 778 mg (2.23 mmol) (carbethoxymethylene)triphenylphosphorane and then stirred under reflux for 4 h. After cooling to room temperature, the volatiles were removed in vacuo and the crude product was purified by flash column chromatography (4 g silica gel column, Combiflash, 0 → 10% hexanes-ethyl acetate, over 12 mins) to afford 246 mg (89%) of 14 as a white solid: ESI-HRMS m/z: calcd for C13H13ClNO₂ [M+H]⁺ 250.0635, found 250.0633. [00159] 3-(5-Chloro-1H-indol-3-yl)propanehydrazide (15). To a solution of 236 mg (0.945 mmol) of acrylate 14 in 10 mL of ethanol was added a catalytic amount (25 mg) of 10% Pd/C. The suspension was stirred for 6 h at room temperature under an atmosphere (balloon) of hydrogen gas. The suspension was filtered over Celite (rinsed with 1:1 ethyl acetate-methanol) and concentrated in vacuo to afford 76 mg (32%) of saturated ethyl ester. To a solution of 76 mg (0.30 mmol) of saturated ethyl ester ethyl in 5 mL of ethanol was added 45 mg (0.91 mmol) of hydrazine hydrate. The reaction mixture was then stirred under reflux for 2 h. After cooling to room temperature, the mixture was poured into ice-cold water. The precipitant was collected by vacuum filtration, washed with water, and air dried. The crude was further purified by recrystallization from diethyl ether and hexane to afford 87 mg (82%) of 15 as a yellow solid: ESI-HRMS m/z: calcd for C11H13ClN3O [M+H]⁺ 238.0747, found 238.0749. II. Synthesis of c-Cbl inhibitors. [00160] Synthesis of AF and GSR-2-180. [00161] 2-(Ethoxycarbonyl)-2-methyl-4-phenylbutanoic acid (17). Compound was prepared from a modified literature procedure (Leogane et al. (2009) “One-pot Curtius rearrangement processes from carboxylic acids.” Synthesis 2009, No.11, pp.1935–1940). A solution of 5.0 g (28.7 mmol) of diethyl methylmalonate in 50 mL of DMF was cooled to 0^oC and then was added portionwise to a suspension of 1.26 g (31.6 mmol) of NaH (60% dispersion in mineral oil) in 10 mL of DMF at 0°C. After hydrogen gas evolution ceased, (2- bromoethyl)benzene (4.30 mL, 31.6 mmol) was added dropwise and the reaction mixture was stirred for 5 h at room temperature. The mixture was quenched by slowly adding saturated NH₄Cl_(aq). After stirring for 5 mins, the aqueous solution was extracted three times with 100–mL portions of ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (24 g silica gel column, Combiflash, 0 → 10% hexanes-ethyl acetate, over 25 mins) to afford 6.94 g (87%) of diethyl 2-methyl-2-phenethylmalonate (16) as a colorless oil that was used without further purification. [00162] To a solution of 5.0 g (17.9 mmol) of malonate 16 in 20 mL of ethanol was added a solution of 1.0 g (17.9 mmol) of potassium hydroxide dissolved in 10 mL ethanol. The resulting mixture was stirred overnight at room temperature. The ethanol was removed in vacuo, and the remaining aqueous solution was extracted twice with 50–mL portions of diethyl ether. The washed aqueous layer was acidified to pH 2 by dropwise addition of 1 M hydrochloric acid and then extracted three times with 100–mL portions of ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. The crude product was purified by flash column chromatography (12 g silica gel column, Combiflash, 0 → 25% hexanes-ethyl acetate, over 15 mins) to afford 3.60 g (80%) of 17 as a colorless oil: ESI-HRMS m/z: calcd for C₁₄H₁₉O₄ [M+H]⁺ 251.1278, found 251.1281. [00163] 2-(Ethoxycarbonyl)-2-methyl-4-phenylbutanoic (ethyl carbonic) anhydride (18). To a stirred solution of 100 mg (0.40 mmol) of acid 17 in 5 mL of THF was cooled to 0^oC and then was added sequentially 0.17 mL (1.2 mmol) of triethylamine and 65 mg (0.60 mmol) of ethyl chloroformate. A white solid precipitated during the addition as triethylammonium chloride. After stirring for 30 mins, the suspension was filtered through a medium-porosity glass frit to afford a THF solution of 18 that was immediately used in the proceeding step without further purification. [00164] Ethyl 2-(azidocarbonyl)-2-methyl-4-phenylbutanoate (19). To a 0^oC solution of about 120 mg (0.37 mmol) of 18 in THF was added dropwise a solution of 78 mg (1.2 mmol) of sodium azide in 1 mL of water. After stirring at 0^oC for 1 h, the solution was diluted with water and extracted three times with 10–mL portions of ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (4 g silica gel column, Combiflash, 0 → 10% hexanes-ethyl acetate, over 12 mins) to afford 95 mg (94%) of 19 as a colorless oil: ESI-HRMS m/z: calcd for C₁₄H₁₈N₃O₃ [M+H]⁺ 276.1343, found 276.1346. [00165] Ethyl 2-isocyanato-2-methyl-4-phenylbutanoate (20). A solution of 95 mg (0.34 mmol) of azide 19 in 5 mL of toluene was stirred at 100°C for 2 h. After cooling to room temperature, the solvent was removed in vacuo to afford 63 mg (74%) of 20 as a pale yellow oil that was used immediately without further purification. [00166] Ethyl 2-(2-(3-(1H-indol-3-yl)propanoyl)hydrazine-1-carboxamido)-2-methyl- 4-phenylbutanoate (GSR-1-77). To a suspension of 99 mg (0.40 mmol) of isocyanate 20 in 5 mL of ethanol was added 81 mg (0.40 mmol) of hydrazide 2. The solution was stirred for 2 h and was completed as determined by TLC. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (4 g silica gel column, Combiflash, 0 → 50% hexanes-ethyl acetate, over 12 mins) to afford 131 mg (89%) of GSR-1-77 as a white solid: ¹H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 1.8 Hz, 1H), 7.82 (s, br, 1H), 7.54 (d, J = 5.2 Hz, 1H), 7.26 (d, J = 5.6 Hz, 1H), 7.19 (t, J = 4.8 Hz, 2H), 7.17 – 7.05 (m, 4H), 6.94 (d, J = 5.2 Hz, 1H), 6.21 (s, 1H), 4.15 – 4.06 (m, 2H), 3.07 (t, J = 7.2 Hz, 2H), 2.55 (t, J = 7.2 Hz, 2H), 2.44 – 2.36 (m, 2H), 2.12 – 2.05 (m, 1H), 1.85 – 1.73 (m, br, 1H), 1.53 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H); ESI-HRMS m/z: calcd for C₂₅H₃₁N₄O₄ [M+H]⁺ 451.2340, found 451.2353. [00167] 3-(1H-indol-3-yl)-N-(4-methyl-2,5-dioxo-4-phenethylimidazolidin-1- yl)propen-amide (AF, GSR-1-78). To a solution of 50 mg (0.11 mmol) of ester GSR-1-77 in 5 mL of EtOH at 0^oC was added 9 mg (0.13 mmol) of sodium ethoxide. The reaction mixture was stirred at room temperature for 2 h and then was concentrated in vacuo. The residue was taken up in 20 mL of saturated NH4Cl solution and was extracted three times with 20–mL portion of ethyl acetate. The combined ethyl acetate layers were dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by flash column chromatography (4 g silica gel column, Combiflash, 0 → 50% hexanes-ethyl acetate, over 12 mins) to afford 41 mg (92%) of AF as a colorless oil: ¹H NMR (400 MHz, CDCl3) δ 8.06 (s, br, 1H), 7.66 (s, br, 1H), 7.45 (d, J = 5.2 Hz, 1H), 7.22 (d, J = 5.6 Hz, 1H), 7.16 (t, J = 4.8 Hz, 2H), 7.09 (t, J = 4.8 Hz, 2H), 7.03 (d, J = 5.2 Hz, 2H), 7.01 (t, J = 4.8 Hz, 1H), 6.91 (s, 1H), 3.01 (t, J = 4.8 Hz, 2H), 2.57 (t, J = 4.8 Hz, 2H), 2.65 – 2.45 (m, 2H), 2.10 – 2.05 (m, 1H), 1.86 – 1.81 (m, 1H), 1.37 (s, 3H); ESI-HRMS m/z: calcd for C₂₃H₂₅N₄O₃ [M+H]⁺ 405.1921, found 405.1929. [00168] Synthesis of GSR-2-180. [00169] Ethyl 2-(2-(3-(5-chloro-1H-indol-3-yl)propanoyl)hydrazine-1-carboxamido)- 2-methyl-4-phenylbutanoate (GSR-2-177). To a suspension of 50 mg (0.20 mmol) of isocyanate 20 in 5 mL of ethanol was added 48 mg (0.20 mmol) of hydrazide 15. The solution was stirred for 2 h and was completed as determined by TLC. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (4 g silica gel column, Combiflash, 0 → 50% hexanes-ethyl acetate, over 12 mins) to afford 67 mg (69%) of GSR-2-177 as a white solid: ESI-HRMS m/z: calcd for C25H30ClN4O4 [M+H]⁺ 485.1950, found 485.1959. [00170] 3-(5-Chloro-1H-indol-3-yl)-N-(4-methyl-2,5-dioxo-4-phenethylimidazolidin- 1-yl)propenamide (GSR-2-180). To a solution of 50 mg (0.10 mmol) of ester GSR-2-177 in 5 mL of EtOH at 0^oC was added 14 mg (0.20 mmol) of sodium ethoxide. The reaction mixture was stirred at room temperature for 2 h and then was concentrated in vacuo. The residue was taken up in 20 mL of saturated NH4Cl solution and was extracted three times with 20–mL portion of ethyl acetate. The combined ethyl acetate layers were dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by flash column chromatography (4 g silica gel column, Combiflash, 0 → 50% hexanes-ethyl acetate, over 12 mins) to afford 36 mg (82%) of GSR-2- 180 as a colorless oil: ¹H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 10.48 (s, br, 1H), 8.57 (s, 1H), 7.60 (s, 1H), 7.36 (d, J = 5.2 Hz, 1H), 7.32 – 7.26 (m, 3H), 7.23 – 7.15 (m, 3H), 7.08 (dd, J = 8.0, 5.2 Hz, 1H), 2.96 (t, J = 7.2 Hz, 2H), 2.74 – 2.57 (m, br, 2H), 2.60 (t, J = 7.2 Hz, 2H), 2.01 – 1.93 (m, 1H), 1.93 – 1.85 (m, 1H), 1.39 (s, 3H); ESI-HRMS m/z: calcd for C23H24ClN4O3 [M+H]⁺ 439.1531, found 439.1535. [00171] Synthesis of GSR-2-12, 3-96, 3-119 and 3-120. [00172] Diethyl 2-(4-chlorophenethyl)-2-methylmalonate (22). A solution of 1.44 g (8.28 mmol) of diethyl methylmalonate in 20 mL of DMF was cooled to 0^oC and then was added portionwise to a suspension of 0.50 g (12.4 mmol) of sodium hydride (60% dispersion in mineral oil) in 10 mL of DMF at 0°C. After hydrogen gas evolution ceased, 1-(2-bromoethyl)-4- chlorobenzene (1.32 mL, 9.10 mmol) was added dropwise and the reaction mixture was stirred for 5 h at room temperature. The mixture was quenched by slowly adding saturated NH₄Cl_(aq). After stirring for 5 mins, the aqueous solution was extracted three times with 100–mL portions of ethyl acetate. The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography (24 g silica gel column, Combiflash, 0 → 10% hexanes-ethyl acetate, over 25 mins) to afford 2.94 g (82%) of 22 as a colorless oil: ESI-HRMS m/z: calcd for C₁₆H₂₂ClO₄ [M+H]⁺ 313.1201, found 313.1208. [00173] 4-(4-Chlorophenyl)-2-(ethoxycarbonyl)-2-methylbutanoic acid (23). To a solution of 2.0 g (6.39 mmol) of malonate 22 in 20 mL of ethanol was added a solution of 0.35 g (3.39 mmol) of potassium hydroxide dissolved in 10 mL ethanol. The resulting mixture was stirred overnight at room temperature. The ethanol was removed in vacuo, and the remaining aqueous solution was extracted twice with 50–mL portions of diethyl ether. The washed aqueous layer was acidified to pH 2 by dropwise addition of 1 M hydrochloric acid and then extracted three times with 100–mL portions of ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (12 g silica gel column, Combiflash, 0 → 25% hexanes-ethyl acetate, over 15 mins) to afford 1.27 g (70%) of 23 as a colorless oil: ESI- HRMS m/z: calcd for C₁₄H₁₈ClO₄ [M+H]⁺ 285.0888, found 285.0891. [00174] 4-(4-Chlorophenyl)-2-(ethoxycarbonyl)-2-methylbutanoic (ethyl carbonic) anhydride (24). To a stirred solution of 200 mg (0.70 mmol) of acid 23 in 5 mL of THF was cooled to 0^oC and then was added sequentially 0.14 mL (1.40 mmol) of triethylamine and 38 mg (0.35 mmol) of ethyl chloroformate. A white solid precipitated during the addition as triethylammonium chloride. After stirring for 30 mins, the suspension was filtered through a medium-porosity glass frit to afford a THF solution of 24 that was immediately used in the proceeding step without further purification. [00175] Ethyl 2-(azidocarbonyl)-4-(4-chlorophenyl)-2-methylbutanoate (25). To a 0^oC solution of about 220 mg (0.64 mmol) of 24 in THF was added dropwise a solution of 130 mg (1.92 mmol) of sodium azide in 1 mL of water. After stirring at 0^oC for 1 h, the solution was diluted with water and extracted three times with 10–mL portions of ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (4 g silica gel column, Combiflash, 0 → 10% hexanes-ethyl acetate, over 12 mins) to afford 170 mg (87%) of 25 as a colorless oil: ESI-HRMS m/z: calcd for C14H17ClN3O3 [M+H]⁺ 310.0953, found 310.0959. [00176] Ethyl 4-(4-chlorophenyl)-2-isocyanato-2-methylbutanoate (26). A solution of 170 mg (0.56 mmol) of azide 25 in 5 mL of toluene was stirred at 100°C for 2 h. After cooling to room temperature, the solvent was removed in vacuo to afford 130 mg (85%) of 26 as a colorless oil that was used immediately without further purification. [00177] Ethyl 2-(2-(3-(1H-indol-3-yl)propanoyl)hydrazine-1-carboxamido)-4-(4- chlorophenyl)-2-methylbutanoate (GSR-2-7). To a suspension of 100 mg (0.35 mmol) of isocyanate 26 in 5 mL of ethanol was added 71 mg (0.35 mmol) of hydrazide 2. The solution was stirred for 2 h and was completed as determined by TLC. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (4 g silica gel column, Combiflash, 0 → 50% hexanes-ethyl acetate, over 12 mins) to afford 140 mg (84%) of GSR-2-7 as a white solid. [00178] N-(4-(4-Chlorophenethyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-3-(1H-indol- 3-yl)propenamide (GSR-2-12). To a solution of 100 mg (0.21 mmol) of ester GSR-2-7 in 5 mL of EtOH at 0^oC was added 27 mg (0.42 mmol) of sodium ethoxide. The reaction mixture was stirred at room temperature for 2 h and then was concentrated in vacuo. The residue was taken up in 20 mL of saturated NH4Cl solution and was extracted three times with 20–mL portion of ethyl acetate. The combined ethyl acetate layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (4 g silica gel column, Combiflash, 0 → 50% hexanes-ethyl acetate, over 12 mins) to afford 74 mg (82%) of GSR-2-12 as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 8.17 (s, br, 1H), 7.85 (s, 1H), 7.54 (d, J = 5.2 Hz, 1H), 7.32 (d, J = 5.2 Hz, 1H), 7.21 – 7.17 (m, 3H), 7.11 (t, J = 5.2 Hz, 1H), 7.03 (d, J = 5.2 Hz, 1H), 7.00 (d, J = 1.6 Hz, 1H), 6.12 (s, 1H), 3.10 (t, J = 4.8 Hz, 1H), 2.66 (t, J = 4.8 Hz, 1H), 2.62 – 2.50 (m, 2H), 2.14 – 2.09 (m, 1H), 1.90 – 1.84 (m, 1H), 1.45 (s, 3H); ESI-HRMS m/z: calcd for C23H24ClN4O3 [M+H]⁺ 439.1531, found 439.2038. [00179] Synthesis of GSR-3-96. [00180] Ethyl 4-(4-chlorophenyl)-2-(2-(3-(5-fluoro-1H-indol-3- yl)propanoyl)hydrazine-1-carboxamido)-2-methylbutanoate (GSR-3-95). To a suspension of 100 mg (0.35 mmol) of isocyanate 26 in 10 mL of ethanol was added 79 mg (0.35 mmol) of hydrazide 12. The solution was stirred for 2 h and was completed as determined by TLC. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (4 g silica gel column, Combiflash, 0 → 50% hexanes-ethyl acetate, over 12 mins) to afford 87 mg (49%) of GSR-3-95 as a white solid: ESI-HRMS m/z: calcd for C25H29ClFN4O4 [M+H]⁺ 503.1856, found 503.1869. [00181] N-(4-(4-Chlorophenethyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-3-(5-fluoro- 1H-indol-3-yl)propenamide (GSR-3-96). To a solution of 50 mg (0.10 mmol) of ester GSR-3- 95 in 10 mL of EtOH at 0^oC was added 6.8 mg (0.10 mmol) of sodium ethoxide. The reaction mixture was stirred at room temperature for 2 h and then was concentrated in vacuo. The residue was taken up in 20 mL of saturated NH4Cl solution and was extracted three times with 20–mL portion of ethyl acetate. The combined ethyl acetate layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (4 g silica gel column, Combiflash, 0 → 50% hexanes-ethyl acetate, over 12 mins) to afford 32 mg (70%) of GSR-3-96 as a white solid: (400 MHz, DMSO-d₆) δ 10.94 (s, 1H), 10.49 (s, 1H), 8.54 (s, br, 1H), 7.37 – 7.29 (m, 4H), 7.27 (s, 1H), 7.21 (d, J = 8.0 Hz, 2H), 6.92 – 6.87 (m, 1H), 2.94 (t, J = 7.2 Hz, 2H), 2.69 – 2.56 (m, 2H), 2.60 (t, J = 7.2 Hz, 2H), 1.99 – 1.92 (m, 1H), 1.92 – 1.83 (m, 1H), 1.38 (s, 3H); ESI-HRMS m/z: calcd for C₂₃H₂₃ClFN₄O₃ [M+H]⁺ 457.1437, found 457.1445. [00182] Synthesis of GSR-3-119. [00183] Ethyl 2-(2-(4-(1H-indol-3-yl)butanoyl)hydrazine-1-carboxamido)-4-(4- chlorophenyl)-2-methylbutanoate (GSR-3-117). To a suspension of 50 mg (0.18 mmol) of isocyanate 26 in 5 mL of ethanol was added 39 mg (0.18 mmol) of hydrazide 4. The solution was stirred for 2 h and was completed as determined by TLC. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (4 g silica gel column, Combiflash, 0 → 50% hexanes-ethyl acetate, over 12 mins) to afford 71 mg (79%) of GSR-3-117 as a white solid: ESI-HRMS m/z: calcd for C₂₆H₃₂ClN₄O₄ [M+H]⁺ 499.2107, found 499.2118. [00184] N-(4-(4-Chlorophenethyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-4-(1H-indol- 3-yl)butanamide (GSR-3-119). To a solution of 50 mg (0.10 mmol) of ester GSR-3-117 in 5 mL of EtOH at 0^oC was added 6.8 mg (0.15 mmol) of sodium ethoxide. The reaction mixture was stirred at room temperature for 2 h and then was concentrated in vacuo. The residue was taken up in 20 mL of saturated NH4Cl solution and was extracted three times with 20–mL portion of ethyl acetate. The combined ethyl acetate layers were dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by flash column chromatography (4 g silica gel column, Combiflash, 0 → 50% hexanes-ethyl acetate, over 12 mins) to afford 24 mg (53%) of GSR-3-119 as a white solid: ¹H NMR (400 MHz, CDCl3) δ 8.02 (s, br, 1H), 7.63 (s, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 2H), 7.19 – 7.14 (m, 1H), 7.11 – 7.06 (m, 1H), 7.04 (d, J = 8.4 Hz, 2H), 6.98 (s, br, 1H), 2.84 (t, J = 7.2 Hz, 2H), 2.71 – 2.50 (m, 2H), 2.33 (t, J = 7.2 Hz, 2H), 2.19 – 2.02 (m, 3H), 1.94 – 1.82 (m ,1H), 1.47 (s, 3H); ESI-HRMS m/z: calcd for C₂₄H₂₆ClN₄O₃ [M+H]⁺ 453.1688, found 453.1699. [00185] Synthesis of GSR-3-120. [00186] Ethyl 4-(4-chlorophenyl)-2-(2-(3-(5-methoxy-2-methyl-1H-indol-3- yl)propanoyl)hydrazine-1-carboxamido)-2-methylbutanoate (GSR-3-118). To a suspension of 50 mg (0.18 mmol) of isocyanate 26 in 5 mL of ethanol was added 44 mg (0.18 mmol) of hydrazide 9. The solution was stirred for 2 h and was completed as determined by TLC. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (4 g silica gel column, Combiflash, 0 → 50% hexanes-ethyl acetate, over 12 mins) to afford 66 mg (69%) of GSR-3-118 as a white solid: ¹H NMR (400 MHz, CDCl3) δ 8.01 (s, br, 1H), 7.99 (s, 1H), 7.48 (s, br, 1H), 7.14 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.8 Hz, 1H), 7.00 (d, J = 8.4 Hz, 2H), 6.94 (s, 1H), 6.73 (dd, J = 8.8, 2.0 Hz, 1H), 6.30 (s, br, 1H), 4.18 – 4.03 (m, 2H), 3.80 (s, 3H), 2.97 (t, J = 7.2 Hz, 2H), 2.55 – 2.27 (m, 3H), 2.43 (t, J = 7.2 Hz, 2H), 2.23 (s, 3H), 2.09 – 2.00 (m, 1H), 1.51 (s, 3H), 1.22 (t, J = 7.2 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl3) δ 174.57, 172.51, 156.67, 153.71, 139.70, 132.83, 131.49, 130.42, 129.74 (2C), 128.56, 128.29 (2C), 111.02, 110.08, 109.48, 100.60, 61.71, 59.49, 55.98, 38.54, 34.62, 29.70, 23.50, 19.95, 14.05, 11.48; ESI-HRMS m/z: calcd for C₂₇H₃₄ClN₄O₅ [M+H]⁺ 529.2212, found 529.2210. [00187] N-(4-(4-Chlorophenethyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-3-(5- methoxy-2-methyl-1H-indol-3-yl)propanamide (GSR-3-120). To a solution of 50 mg (0.090 mmol) of ester GSR-3-118 in 5 mL of EtOH at 0^oC was added 9.6 mg (0.14 mmol) of sodium ethoxide. The reaction mixture was stirred at room temperature for 2 h and then was concentrated in vacuo. The residue was taken up in 20 mL of saturated NH4Cl solution and was extracted three times with 20–mL portion of ethyl acetate. The combined ethyl acetate layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (4 g silica gel column, Combiflash, 0 → 50% hexanes-ethyl acetate, over 12 mins) to afford 17 mg (40%) of GSR-3-120 as a white solid: ¹H NMR (400 MHz, CDCl3) δ 7.71 (s, br, 1H), 7.60 (s, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.8 Hz, 1H), 7.07 (d, J = 8.0 Hz, 2H), 6.94 (d, J = 2.0 Hz, 1H), 6.76 (dd, J = 8.0, 2.0 Hz, 1H), 5.69 (s, br, 1H), 3.84 (s, 3H), 3.07 (t, J = 7.6 Hz, 2H), 2.66 (t, J = 7.6 Hz, 2H), 2.34 (s, 3H), 2.24 – 2.11 (m, 2H), 1.97 – 1.84 (m, 2H), 1.50 (s, 3H); ESI-HRMS m/z: calcd for C25H28ClN4O4 [M+H]⁺ 483.1794, found 483.1800. [00188] Synthesis of GSR-4-138, 4-139, 4-140 and 4-141. [00189] Diethyl 2-(4-fluorophenethyl)-2-methylmalonate (27). A solution of 1.00 g (5.74 mmol) of diethyl methylmalonate in 10 mL of DMF was cooled to 0^oC and then was added portionwise to a suspension of 380 mg (9.46 mmol) of sodium hydride (60% dispersion in mineral oil) in 5 mL of DMF at 0 °C. After hydrogen gas evolution ceased, 1-(2-bromoethyl)-4- fluorobenzene (1.32 mL, 9.10 mmol) was added dropwise and the reaction mixture was stirred for 5 h at room temperature. The mixture was quenched by slowly adding saturated NH4Cl(aq). After stirring for 5 mins, the aqueous solution was extracted three times with 100–mL portions of ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (12 g silica gel column, Combiflash, 0 → 10% hexanes-ethyl acetate, over 25 mins) to afford 1.35 g (79%) of 27 as a colorless oil. [00190] 2-(Ethoxycarbonyl)-4-(4-fluorophenyl)-2-methylbutanoic acid (28). To a solution of 1.0 g (3.37 mmol) of malonate 27 in 10 mL of ethanol was added a solution of 135 mg (3.37 mmol) of sodium hydroxide dissolved in 5 mL ethanol. The resulting mixture was stirred overnight at room temperature. The ethanol was removed in vacuo, and the remaining aqueous solution was extracted twice with 25–mL portions of diethyl ether. The washed aqueous layer was acidified to pH 2 by dropwise addition of 1 M hydrochloric acid and then extracted three times with 50–mL portions of ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (4 g silica gel column, Combiflash, 0 → 25% hexanes-ethyl acetate, over 10 mins) to afford 647 mg (72%) of 28 as a colorless oil: ESI- HRMS m/z: calcd for C₁₄H₁₈FO₄ [M+H]⁺ 269.1184, found 269.1713. [00191] 2-(Ethoxycarbonyl)-4-(4-fluorophenyl)-2-methylbutanoic (ethyl carbonic) anhydride (29). To a stirred solution of 500 mg (1.86 mmol) of acid 28 in 10 mL of THF was cooled to 0^oC and then was added sequentially 377 mg (3.73 mmol) of triethylamine and 242 mg (2.23 mmol) of ethyl chloroformate. A white solid precipitated during the addition as triethylammonium chloride. After stirring for 30 mins, the suspension was filtered through a medium-porosity glass frit to afford a THF solution of 29 that was immediately used in the proceeding step without further purification. [00192] Ethyl 2-(azidocarbonyl)-4-(4-fluorophenyl)-2-methylbutanoate (30). To a 0^oC solution of about 633 mg (1.86 mmol) of 29 in THF was added dropwise a solution of 604 mg (9.30 mmol) of sodium azide in 3 mL of water. After stirring at 0^oC for 1 h, the solution was diluted with water and extracted three times with 10–mL portions of ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (4 g silica gel column, Combiflash, 0 → 10% hexanes-ethyl acetate, over 12 mins) to afford 365 mg (67%) of 30 as a colorless oil. [00193] Ethyl 4-(4-fluorophenyl)-2-isocyanato-2-methylbutanoate (31). A solution of 789 mg (2.69 mmol) of azide 30 in 15 mL of toluene was stirred at 100°C for 2 h. After cooling to room temperature, the solvent was removed in vacuo to afford 378 mg (53%) of 31 as a colorless oil that was immediately used without further purification. [00194] Ethyl 2-(2-(4-(1H-indol-3-yl)butanoyl)hydrazine-1-carboxamido)-4-(4- fluorophenyl)-2-methylbutanoate (GSR-4-138). To a suspension of 100 mg (0.38 mmol) of isocyanate 31 in 5 mL of ethanol was added 82 mg (0.38 mmol) of hydrazide 4. The solution was stirred for 2 h and was completed as determined by TLC. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (4 g silica gel column, Combiflash, 0 → 50% hexanes-ethyl acetate, over 12 mins) to afford 106 mg (58%) of GSR-4-138 as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 8.16 (s, br, 1H), 7.95 (s, br, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.15 (td, J = 7.2, 1.2 Hz, 1H), 7.10 – 6.99 (m, 3H), 6.91 (s, 1H), 6.86 (t, J = 8.8 Hz, 2H), 6.37 (s, br, 1H), 4.18 – 4.03 (m, 2H), 2.76 (t, J = 7.2 Hz, 2H), 2.55 (td, J = 7.6, 4.8 Hz, 1H), 2.50 – 2.39 (m, 1H), 2.33 (td, J = 7.6, 4.8 Hz, 1H), 2.22 (t, J = 7.2 Hz, 2H), 2.13 – 1.97 (m, 3H), 1.55 (s, 3H), 1.22 (t, J = 7.2 Hz, 3H); ESI-HRMS m/z: calcd for C₂₆H₃₂FN₄O₄ [M+H]⁺ 483.2402, found 483.2416. [00195] N-(4-(4-Fluorophenethyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-4-(1H-indol- 3-yl)butanamide (GSR-4-139). To a solution of 100 mg (0.21 mmol) of ester GSR-4-138 in 5 mL of EtOH at 0^oC was added 14 mg (0.21 mmol) of sodium ethoxide. The reaction mixture was stirred at room temperature for 2 h and then was concentrated in vacuo. The residue was taken up in 20 mL of saturated NH₄Cl solution and was extracted three times with 20–mL portion of ethyl acetate. The combined ethyl acetate layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (4 g silica gel column, Combiflash, 0 → 50% hexanes-ethyl acetate, over 12 mins) to afford 58 mg (63%) of GSR-4- 139 as a white solid: ¹H NMR (400 MHz, CDCl3) δ 8.01 (s, br, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.53 (s, br, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 7.13 – 7.04 (m, 3H), 7.00 (s, 1H), 6.93 (t, J = 8.8 Hz, 2H), 5.82 (s, br, 1H), 2.85 (t, J = 7.2 Hz, 2H), 2.69 (td, J = 7.6, 5.2 Hz, 1H), 2.60 (s, br, 1H), 2.35 (t, J = 7.6 Hz, 2H), 2.22 – 2.11 (m, 1H), 2.10 (t, J = 7.6 Hz, 2H), 1.96 – 1.85 (m, 1H), 1.55 (s, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 173.79, 171.65, 161.42 (d, J = 242.0 Hz, 1C), 154.01, 136.35, 129.71 (d, J = 7.8 Hz, 2C), 127.40, 121.96, 121.95 (d, J = 3.0 Hz, 1C), 119.25, 118.91, 115.30 (d, J = 21.1 Hz, 2C), 115.05, 111.15, 61.36, 39.58, 32.80, 29.08, 25.09, 24.36, 23.99; ESI-HRMS m/z: calcd for C24H26FN4O3 [M+H]⁺ 437.1983, found 437.1991. [00196] Synthesis of GSR-4-140 and 4-141. [00197] Ethyl 4-(4-fluorophenyl)-2-(2-(3-(5-methoxy-2-methyl-1H-indol-3- yl)propanoyl)hydrazine-1-carboxamido)-2-methylbutanoate (GSR-4-140). To a suspension of 100 mg (0.38 mmol) of isocyanate 31 in 5 mL of ethanol was added 94 mg (0.38 mmol) of hydrazide 9. The solution was stirred for 2 h and was completed as determined by TLC. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (4 g silica gel column, Combiflash, 0 → 50% hexanes-ethyl acetate, over 12 mins) to afford 110 mg (56%) of GSR-4-140 as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 7.84 (s, br, 1H), 7.74 (s, br, 1H), 7.24 (s, br, 1H), 7.10 (d, J = 8.8 Hz, 1H), 7.04 (dd, J = 8.8, 5.6 Hz, 1H), 6.94 (d, J = 2.0 Hz, 1H), 6.88 (t, J = 8.8 Hz, 2H), 6.75 (dd, J = 8.8, 2.4 Hz, 1H), 6.22 (s, br, 1H), 4.17 – 4.06 (m, 2H), 3.82 (s, 3H), 3.00 (t, J = 7.6 Hz, 2H), 2.61 – 2.48 (m, 1H), 2.47 (t, J = 7.6 Hz, 2H), 2.44 – 2.29 (m, 2H), 2.28 (s, 3H), 2.05 (td, J = 8.4, 4.4 Hz, 1H), 1.53 (s, 3H), 1.23 (t, J = 6.8 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 174.63, 172.69, 161.22 (d, J = 243.4 Hz, 1C), 156.65, 153.83, 136.85 (d, J = 3.2 Hz, 1C), 132.79, 130.42, 129.78 (d, J = 7.7 Hz, 2C), 128.55, 114.97 (d, J = 21.1 Hz, 2C), 111.02, 110.28, 109.52, 100.57, 61.80, 59.69, 56.02, 38.63, 34.68, 29.64, 23.59, 20.00, 14.08, 11.56; ESI-HRMS m/z: calcd for C27H34FN4O5 [M+H]⁺ 513.2508, found 513.2523. [00198] N-(4-(4-Fluorophenethyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-3-(5- methoxy-2-methyl-1H-indol-3-yl)propanamide (GSR-4-141). To a solution of 100 mg (0.20 mmol) of ester GSR-4-140 in 5 mL of EtOH at 0^oC was added 13 mg (0.20 mmol) of sodium ethoxide. The reaction mixture was stirred at room temperature for 2 h and then was concentrated in vacuo. The residue was taken up in 20 mL of saturated NH4Cl solution and was extracted three times with 20–mL portion of ethyl acetate. The combined ethyl acetate layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (4 g silica gel column, Combiflash, 0 → 50% hexanes-ethyl acetate, over 12 mins) to afford 63 mg (69%) of GSR-4-141 as a white solid: ¹H NMR (400 MHz, CDCl3) δ 7.88 (s, br, 1H), 7.72 (s, br, 1H), 7.13 (d, J = 8.8 Hz, 1H), 7.10 – 7.02 (m, 2H), 6.96 – 6.89 (m, 3H), 6.75 (dd, J = 8.4, 2.4 Hz, 1H), 5.92 (s, br, 1H), 3.82 (s, 3H), 3.05 (t, J = 7.6 Hz, 2H), 2.72 – 2.48 (m, 2H), 2.64 (t, J = 7.6 Hz, 2H), 2.32 (s, 3H), 2.21 – 2.09 (m, 1H), 1.95 – 1.83 (m, 1H), 1.48 (s, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 173.70, 171.79, 161.40 (d, J = 244.0 Hz, 1C), 154.11, 153.73, 133.15, 130.55, 129.68 (d, J = 7.8 Hz, 2C), 128.54, 115.27 (d, J = 21.1 Hz, 2C), 110.98, 110.13, 109.28, 100.80, 61.32, 56.18, 39.56, 34.39, 29.04, 24.33, 19.87, 11.67; ESI-HRMS m/z: calcd for C₂₅H₂₈FN₄O₄ [M+H]⁺ 467.2089, found 467.2103. [00199] Synthesis of GSR-4-169 and 4-171. [00200] Diethyl 2-(3-chlorophenethyl)-2-methylmalonate (32). A solution of 3.30 g (19.0 mmol) of diethyl methylmalonate in 10 mL of DMF was cooled to 0^oC and then was added portionwise to a suspension of 1.52 g (38.0 mmol) of sodium hydride (60% dispersion in mineral oil) in 10 mL of DMF at 0 °C. After hydrogen gas evolution ceased, 1-(2-bromoethyl)-3- chlorobenzene (5.00 g, 22.8 mmol) was added dropwise and the reaction mixture was stirred for 5 h at room temperature. The mixture was quenched by slowly adding saturated NH4Cl(aq). After stirring for 5 mins, the aqueous solution was extracted three times with 100–mL portions of ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (40 g silica gel column, Combiflash, 0 → 10% hexanes-ethyl acetate, over 35 mins) to afford 3.27 g (55%) of 32 as a colorless oil: ESI-HRMS m/z: calcd for C16H22ClO4 [M+H]⁺ 313.1201, found 313.1205. [00201] 4-(3-Chlorophenyl)-2-(ethoxycarbonyl)-2-methylbutanoic acid (33). To a solution of 1.50 g (4.80 mmol) of malonate 32 in 10 mL of ethanol was added a solution of 192 mg (4.80 mmol) of sodium hydroxide dissolved in 5 mL ethanol. The resulting mixture was stirred overnight at room temperature. The ethanol was removed in vacuo, and the remaining aqueous solution was extracted twice with 25–mL portions of diethyl ether. The washed aqueous layer was acidified to pH 2 by dropwise addition of 1 M hydrochloric acid and then extracted three times with 50–mL portions of ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. The crude product was purified by flash column chromatography (12 g silica gel column, Combiflash, 0 → 25% hexanes-ethyl acetate, over 10 mins) to afford 647 mg (47%) of 33 as a colorless oil: ESI- HRMS m/z: calcd for C14H18ClO4 [M+H]⁺ 285.0888, found 285.0894. [00202] 4-(3-Chlorophenyl)-2-(ethoxycarbonyl)-2-methylbutanoic (ethyl carbonic) anhydride (34). To a stirred solution of 500 mg (1.76 mmol) of acid 33 in 5 mL of THF was cooled to 0^oC and then was added sequentially 0.50 mL (3.5 mmol) of triethylamine and 0.20 mg (2.1 mmol) of ethyl chloroformate. After stirring for 30 mins, the suspension was filtered through a medium-porosity glass frit to afford a THF solution of 34 that was immediately used in the proceeding step without further purification. [00203] Ethyl 2-(azidocarbonyl)-4-(3-chlorophenyl)-2-methylbutanoate (35). To a 0^oC solution of about 628 mg (1.76 mmol) of 34 in THF was added dropwise a solution of 343 mg (5.28 mmol) of sodium azide in 2 mL of water. After stirring at 0^oC for 1 h, the solution was diluted with water and extracted three times with 10–mL portions of ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was used without further purification to afford 545 mg (100%) of 35 as a colorless oil: [00204] Ethyl 4-(3-chlorophenyl)-2-isocyanato-2-methylbutanoate (36). A solution of 545 mg (1.76 mmol) of azide 35 in 5 mL of toluene was stirred at 100°C for 2 h. After cooling to room temperature, the solvent was removed in vacuo to afford 339 mg (68%) of 36 as a colorless oil that was immediately used without further purification. [00205] Ethyl 2-(2-(4-(1H-indol-3-yl)butanoyl)hydrazine-1-carboxamido)-4-(3- chlorophenyl)-2-methylbutanoate (GSR-4-169). To a suspension of 100 mg (0.35 mmol) of isocyanate 36 in 5 mL of ethanol was added 76 mg (0.35 mmol) of hydrazide 4. The solution was stirred for 2 h and was completed as determined by TLC. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (4 g silica gel column, Combiflash, 0 → 50% hexanes-ethyl acetate, over 12 mins) to afford 91 mg (52%) of GSR-4-169 as a white solid: ¹H NMR (400 MHz, CDCl3) δ 8.12 (s, br, 1H), 7.83 (s, br, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.13 – 7.08 (m, 2H), 7.07 (t, J = 7.6 Hz, 1H), 7.02 – 6.95 (m, 1H), 6.94 (s, 1H), 6.38 (s, br, 1H), 4.19 – 4.02 (m, 2H), 2.78 (t, J = 7.2 Hz, 2H), 2.64 – 2.45 (m, 2H), 2.40 – 2.29 (m, 1H), 2.25 (t, J = 7.2 Hz, 2H), 2.16 – 2.04 (m, 1H), 2.05 (qu, J = 7.2 Hz, 2H), 1.56 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl3) δ 174.72, 173.76, 156.82, 143.31, 136.33, 133.92, 129.56, 128.55, 127.36, 126.79, 126.06, 121.94, 121.86, 119.13, 118.77, 114.95, 111.17, 61.97, 59.82, 38.10, 33.31, 30.22, 25.34, 24.28, 23.74, 14.09; ESI-HRMS m/z: calcd for C26H32ClN4O4 [M+H]⁺ 499.2107, found 499.2122. [00206] N-(4-(3-Chlorophenethyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)-4-(1H-indol- 3-yl)butanamide (GSR-4-171). To a solution of 50 mg (0.10 mmol) of ester GSR-4-169 in 10 mL of EtOH at 0^oC was added 8.2 mg (0.12 mmol) of sodium ethoxide. The reaction mixture was stirred at room temperature for 2 h and then was concentrated in vacuo. The residue was taken up in 20 mL of saturated citric acid solution and was extracted three times with 20–mL portion of ethyl acetate. The combined ethyl acetate layers were dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by flash column chromatography (4 g silica gel column, Combiflash, 0 → 50% hexanes-ethyl acetate, over 12 mins) to afford 33 mg (73%) of GSR-4-171 as a white solid: ¹H NMR (400 MHz, CDCl3) δ 8.01 (s, br, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.58 (s, br, 1H), 7.20 – 7.12 (m, 4H), 7.09 (ddd, J = 8.0, 6.8, 0.8 Hz, 1H), 7.03 – 6.98 (m, 1H), 7.00 (s, 1H), 5.92 (s, 1H), 2.85 (t, J = 7.6 Hz, 2H), 2.73 – 2.52 (m, 2H), 2.35 (t, J = 7.6 Hz, 2H), 2.22 – 2.11 (m, 1H), 2.10 (qu, J = 7.6 Hz, 2H), 1.96 – 1.85 (m, 1H), 1.49 (s, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 173.73, 171.68, 154.08, 142.43, 136.34, 134.20, 129.81, 128.42, 127.40, 126.61, 126.47, 121.95, 121.86, 119.24, 118.91, 115.03, 111.16, 61.32, 39.22, 32.80, 29.55, 25.09, 24.35, 23.98; ESI-HRMS m/z: calcd for C24H26ClN4O3 [M+H]⁺ 453.1688, found 453.1696.

[00207] Synthesis of GSR-5-8 (or 4-121), 5-9 and 5-11. [00208] 2-(Ethoxycarbonyl)-2-methyl-5-phenylpentanoic (ethyl carbonic) anhydride (37). To a stirred solution of 1.00 g (3.8 mmol) of 2-(ethoxycarbonyl)-2-methyl-5- phenylpentanoic acid (prepared in two steps according to Chottard et al. (1969) “Radical cyclization. XII. Decarboxylative cyclization of ethyl 2-carboxy-5-phenylvalerates.” Tetrahedron, Vol.25, pp. 4967–4983.) in 10 mL of THF was cooled to 0^oC and then was added sequentially 1.6 mL (11.0 mmol) of triethylamine and 0.44 mL (4.6 mmol) of ethyl chloroformate. After stirring for 30 mins, the suspension was filtered through a medium-porosity glass frit to afford a THF solution of 37 that was immediately used in the proceeding step without further purification. [00209] Ethyl 2-(azidocarbonyl)-2-methyl-5-phenylpentanoate (38). To a 0^oC solution of about 1.28 mg (3.8 mmol) of 37 in THF was added dropwise a solution of 1.29 g (19.0 mmol) of sodium azide in 5 mL of water. After stirring at 0^oC for 1 h, the solution was diluted with water and extracted three times with 20–mL portions of ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. The crude product was used without further purification to afford 737 mg (67%) of 38 as a colorless oil. [00210] Ethyl 2-isocyanato-2-methyl-5-phenylpentanoate (39). A solution of 720 mg (2.49 mmol) of azide 38 in 10 mL of toluene was stirred at 100°C for 2 h. After cooling to room temperature, the solvent was removed in vacuo to afford 475 mg (73%) of 39 as a colorless oil that was used without further purification. [00211] Ethyl 2-(2-(3-(5-methoxy-2-methyl-1H-indol-3-yl)propanoyl)hydrazine-1- carboxamido)-2-methyl-5-phenylpentanoate (GSR-5-8). To a suspension of 100 mg (0.38 mmol) of isocyanate 39 in 5 mL of ethanol was added 94 mg (0.38 mmol) of hydrazide 9. The solution was stirred for 2 h and was completed as determined by TLC. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (4 g silica gel column, Combiflash, 0 → 10% dichloromethane-methanol, over 12 mins) to afford 165 mg (85%) of GSR-5-8 as a white solid: (400 MHz, DMSO-d₆) δ 10.49 (s, 1H), 9.53 (d, J = 2.8 Hz, 1H), 7.77 (d, J = 2.8 Hz, 1H), 7.30 – 7.23 (m, 2H), 7.21 – 7.13 (m, 3H), 7.10 (d, J = 8.8 Hz, 1H), 6.91 (d, J = 2.4 Hz, 1H), 6.61 (dd, J = 8.8, 2.4 Hz, 1H), 6.41 (s, br, 1H), 4.02 (q, J = 6.8 Hz, 2H), 3.75 (s, 3H), 2.82 (t, J = 7.6 Hz, 2H), 2.54 (t, J = 8.0 Hz, 2H), 2.32 (t, J = 7.6 Hz, 2H), 2.27 (s, 3H), 1.84 – 1.64 (m, 2H), 1.55 – 1.41 (m, 2H), 1.36 (s, 3H), 1.12 (t, J = 7.2 Hz, 3H); ¹³C NMR (100.5 Hz, DMSO-d₆) δ 173.93, 171.40, 156.65, 152.87, 141.77, 132.41, 130.23, 128.32, 128.24 (2C), 128.22 (2C), 125.72, 110.85, 109.33, 109.00, 99.89, 60.37, 58.18, 55.36, 36.80, 35.06, 34.45, 25.12, 22.92, 19.90, 13.99, 11.30; ESI-HRMS m/z: calcd for C28H37N4O5 [M+H]⁺ 509.2758, found 509.2771. [00212] 3-(5-Methoxy-2-methyl-1H-indol-3-yl)-N-(4-methyl-2,5-dioxo-4-(3- phenylpropyl)imidazolidin-1-yl)propanamide (GSR-5-9). To a solution of 50 mg (0.098 mmol) of ester GSR-5-8 in 5 mL of EtOH at 0^oC was added 13 mg (0.20 mmol) of sodium ethoxide. The reaction mixture was stirred at room temperature for 2 h and then was concentrated in vacuo. The residue was taken up in 20 mL of saturated citric acid solution and was extracted three times with 20–mL portion of ethyl acetate. The combined ethyl acetate layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (4 g silica gel column, Combiflash, 0 → 50% hexanes-ethyl acetate, over 12 mins) to afford 38 mg (64%) of GSR-5-9 as a white solid: ¹H NMR (400 MHz, DMSO- d₆) δ 10.52 (s, 1H), 10.35 (d, J = 12.8 Hz, 1H), 8.44 (s, 1H), 7.33 – 7.23 (m, 2H), 7.23 – 7.13 (m, 3H), 7.11 (d, J = 8.4 Hz, 1H), 6.91 (s, 1H), 6.62 (dd, J = 8.8, 2.4 Hz, 1H), 3.75 (s, 3H), 2.86 (t, J = 7.6 Hz, 2H), 2.63 – 2.52 (m, br, 2H), 2.47 – 2.39 (m, br, 2H), 2.28 (s, 3H), 1.75 – 1.53 (m, br, 4H), 1.31 (d, J = 4.8 Hz, 3H); ¹³C NMR (100.5 Hz, DMSO-d₆) δ 174.39, 170.95, 153.37 (br), 152.94, 141.57, 132.61, 130.23, 128.29 (4C), 128.22, 125.80, 110.91, 109.44, 108.61, 99.72, 59.91, 55.37, 36.85 (br), 34.86 (br), 34.22, 25.32 (br), 23.95, 19.65, 11.28; ESI-HRMS m/z: calcd for C26H31N4O4 [M+H]⁺ 463.2340, found 463.2354. [00213] Synthesis of GSR-5-11. [00214] Ethyl 2-methyl-5-phenyl-2-(2-(3-(2-phenyl-1H-indol-3- yl)propanoyl)hydrazine-1-carboxamido)pentanoate (GSR-5-11). To a suspension of 100 mg (0.38 mmol) of isocyanate 39 in 5 mL of ethanol was added 94 mg (0.38 mmol) of hydrazide 6. The solution was stirred for 2 h and was completed as determined by TLC. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (4 g silica gel column, Combiflash, 0 → 10% dichloromethane-methanol, over 12 mins) to afford 152 mg (74%) of GSR-5-11 as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 7.67 – 7.61 (m, 3H), 7.47 (t, J = 8.0 Hz, 2H), 7.39 – 7.31 (m, 2H), 7.26 – 7.20 (m, 2H), 7.17 – 7.08 (m, 4H), 7.04 (ddd, J = 8.0, 7.0, 1.2 Hz, 1H), 4.12 (q, J = 7.2 Hz, 2H), 3.28 – 3.20 (m, 2H), 2.68 – 2.52 (m, 4H), 1.90 – 1.73 (m, 2H), 1.67 – 1.51 (m, 2H), 1.46 (s, 3H), 1.20 (t, J = 7.2 Hz, 3H); ¹³C NMR (100.5 Hz, CD3OD) δ 176.00, 175.46, 159.28, 143.25, 137.83, 134.73, 130.02, 129.81 (2C), 129.42 (2C), 129.38, 129.32 (2C), 129.11 (2C), 128.37, 126.82, 122.79, 120.01, 119.63, 112.02, 111.67, 62.44, 60.47, 38.03, 36.70, 36.17, 26.87, 23.61, 21.88, 14.43; ESI- HRMS m/z: calcd for C32H37N4O4 [M+H]⁺ 541.2809, found 541.2841. [00215] Synthesis of GSR-3-132, 5-6 and 5-10. [00216] 2-(Ethoxycarbonyl)-2-propylpentanoic acid (41). Compound prepared by a modified literature procedure (Wang et al. (2015) “Synthesis and pharmacological evaluation of novel benzenesulfonamide derivatives as potential anticonvulsant agents.” Molecules, Vol.20, pp.17585–17600). To a solution of 1.00 g (4.10 mmol) of diethyl 2,2-dipropylmalonate (40) in 10 mL of ethanol was added a solution of 230 mg (4.10 mmol) of potassium hydroxide dissolved in 5 mL ethanol. The resulting mixture was stirred overnight at room temperature. The ethanol was removed in vacuo, and the remaining aqueous solution was extracted twice with 25–mL portions of diethyl ether. The washed aqueous layer was acidified to pH 2 by dropwise addition of 1 M hydrochloric acid and then extracted three times with 50–mL portions of ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. The crude product was purified by flash column chromatography (12 g silica gel column, Combiflash, 0 → 25% hexanes-ethyl acetate, over 10 mins) to afford 399 mg (45%) of 41 as a colorless oil: NMR (400 MHz, CDCl₃) δ 4.28 (q, J = 7.2 Hz, 2H), 2.02 – 1.91 (m, 2H), 1.88 – 1.77 (m, 2H), 1.31 (t, J = 7.2 Hz, 3H), 1.32 – 1.21 (m, 2H), 1.21 – 1.08 (m, 2H), 0.90 (t, J = 7.2 Hz, 6H); ESI-HRMS m/z: calcd for C₁₁H₂₁O₄ [M+H]⁺ 271.1434, found 217.1435. [00217] 2-(Ethoxycarbonyl)-2-propylpentanoic (ethyl carbonic) anhydride (42). To a stirred solution of 100 mg (0.46 mmol) of acid 41 in 5 mL of THF was cooled to 0^oC and then was added sequentially 70 mg (0.69 mmol) of 4-methylmorpholine and 60 mg (0.55 mmol) of ethyl chloroformate. After stirring for 30 mins, the suspension was filtered through a medium- porosity glass frit to afford a THF solution of 42 that was immediately used in the proceeding step without further purification. [00218] Ethyl 2-(azidocarbonyl)-2-propylpentanoate (43). To a 0^oC solution of about 100 mg (0.35 mmol) of 42 in THF was added dropwise a solution of 68 mg (1.05 mmol) of sodium azide in 1 mL of water. After stirring at 0^oC for 1 h, the solution was diluted with water and extracted three times with 10–mL portions of ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. The crude product was used without further purification to afford 72 mg (86%) of 43 as a colorless oil. [00219] Ethyl 2-isocyanato-2-propylpentanoate (44). A solution of 100 mg (0.41 mmol) of azide 43 in 5 mL of toluene was stirred at 100°C for 2 h. After cooling to room temperature, the solvent was removed in vacuo to afford 77 mg (89%) of 44 as a colorless oil that was immediately used without further purification. [00220] Ethyl 2-(2-(3-(2-phenyl-1H-indol-3-yl)propanoyl)hydrazine-1-carboxamido)- 2-propylpentanoate (GSR-3-128). To a suspension of 50 mg (0.23 mmol) of isocyanate 44 in 5 mL of ethanol was added 65 mg (0.23 mmol) of hydrazide 6. The solution was stirred for 2 h and was completed as determined by TLC. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (4 g silica gel column, Combiflash, 0 → 50% hexanes-ethyl acetate, over 12 mins) to afford 86 mg (76%) of GSR-3-128 as a white solid: ESI-HRMS m/z: calcd for C₂₈H₃₇N₄O₄ [M+H]⁺ 493.2809, found 493.2817. [00221] N-(2,5-Dioxo-4,4-dipropylimidazolidin-1-yl)-3-(2-phenyl-1H-indol-3- yl)propenamide (3-132). To a solution of 50 mg (0.10 mmol) of ester GSR-3-128 in 5 mL of EtOH at 0^oC was added 10 mg (0.15 mmol) of sodium ethoxide. The reaction mixture was stirred at room temperature for 2 h and then was concentrated in vacuo. The residue was taken up in 20 mL of saturated citric acid solution and was extracted three times with 20–mL portion of ethyl acetate. The combined ethyl acetate layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (4 g silica gel column, Combiflash, 0 → 50% hexanes-ethyl acetate, over 12 mins) to afford 39 mg (87%) of GSR-3- 132 as a white solid: ¹H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 7.6 Hz, 2H), 7.46 (t, J = 7.6 Hz, 2H), 7.40 – 7.33 (m, 2H), 7.30 (s, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 5.48 (s, 1H), 3.35 – 3.24 (m, 2H), 2.74 – 2.64 (m, 2H), 1.88 – 1.76 (m, 2H), 1.68 – 1.57 (m, 2H), 1.49 – 1.36 (m, 2H), 1.36 – 1.21 (m, 2H), 0.92 (t, J = 7.6 Hz, 6H); ¹³C NMR (100.5 MHz, CDCl₃) δ 173.41, 170.84, 154.10, 135.86, 134.91, 132.72, 129.02 (2C), 128.55, 128.04 (2C), 127.93, 122.45, 119.84, 118.89, 110.97, 110.87, 65.07, 39.35 (2C), 34.36, 19.87, 16.60 (2C) 13.98 (2C); ESI-HRMS m/z: calcd for C₂₆H₃₁N₄O₃ [M+H]⁺ 447.2391, found 447.2397. [00222] Synthesis of GSR-5-6 and GSR-5-10. [00223] Ethyl 2-(2-(3-(5-methoxy-2-methyl-1H-indol-3-yl)propanoyl)hydrazine-1- carboxamido)-2-propylpentanoate (GSR-5-6). To a suspension of 100 mg (0.47 mmol) of isocyanate 44 in 5 mL of ethanol was added 116 mg (0.47 mmol) of hydrazide 9. The solution was stirred for 2 h and was completed as determined by TLC. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (4 g silica gel column, Combiflash, 0 → 50% hexanes-ethyl acetate, over 12 mins) to afford 185 mg (86%) of GSR-5-6 as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 10.48 (s, 1H), 9.55 (s, br, 1H), 7.98 (s, br, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 2.0 Hz, 1H), 6.61 (dd, J = 8.4, 2.4 Hz, 1H), 6.30 (s, br, 1H), 4.12 (q, J = 7.2 Hz, 2H), 3.75 (s, 3H), 2.83 (t, J = 8.0 Hz, 2H), 2.32 (t, J = 8.0 Hz, 2H), 2.28 (s, 3H), 2.13 – 2.01 (m, 2H), 1.71 – 1.58 (m, 2H), 1.29 – 1.14 (m, 2H), 1.18 (t, J = 7.2 Hz, 3H), 1.08 – 0.92 (m, 2H), 0.83 (t, J = 7.6 Hz, 6H); ¹³C NMR (100.5 MHz, DMSO-d6) δ 173.71, 171.52, 156.20, 152.88, 132.42, 130.23, 128.31, 110.84, 109.34, 108.96, 99.85, 62.54, 60.79, 55.35, 37.30 (2C), 34.48, 19.95, 16.65 (2C), 14.03 (3C), 11.28; ESI-HRMS m/z: calcd for C24H37N4O5 [M+H]⁺ 461.2758, found 461.2769. [00224] N-(2,5-Dioxo-4,4-dipropylimidazolidin-1-yl)-3-(5-methoxy-2-methyl-1H- indol-3-yl)propenamide (GSR-5-10). To a solution of 50 mg (0.11 mmol) of ester GSR-5-6 in 5 mL of EtOH at 0^oC was added 15 mg (0.22 mmol) of sodium ethoxide. The reaction mixture was stirred at room temperature for 2 h and then was concentrated in vacuo. The residue was taken up in 20 mL of saturated citric acid solution and was extracted three times with 20–mL portion of ethyl acetate. The combined ethyl acetate layers were dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by flash column chromatography (4 g silica gel column, Combiflash, 0 → 50% hexanes-ethyl acetate, over 12 mins) to afford 29 mg (63%) of GSR-5-10 as a white solid: ESI-HRMS m/z: calcd for C₂₂H₃₁N₄O₄ [M+H]⁺ 415.2340, found 415.2364. [00225] Synthesis of GSR-3-157 and 3-159. [00226] 2-Butyl-2-(ethoxycarbonyl)hexanoic acid (46). Compound prepared by a modified literature procedure (Cason et al. (1953) “Some aspects of the reaction of silver carboxylates with bromine.” J. Org. Chem., Vol.18, pp.1670–1673). To a solution of 1.0 g (3.68 mmol) of diethyl 2,2-dibutylmalonate (45) in 10 mL of ethanol was added a solution of 210 mg (3.68 mmol) of potassium hydroxide dissolved in 5 mL ethanol. The resulting mixture was stirred overnight at room temperature. The ethanol was removed in vacuo, and the remaining aqueous solution was extracted twice with 25–mL portions of diethyl ether. The washed aqueous layer was acidified to pH 2 by dropwise addition of 1 M hydrochloric acid and then extracted three times with 50–mL portions of ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. The crude product was purified by flash column chromatography (12 g silica gel column, Combiflash, 0 → 25% hexanes-ethyl acetate, over 10 mins) to afford 379 mg (38%) of 46 as a colorless oil: ESI- HRMS m/z: calcd for C13H25O4 [M+H]⁺ 245.1747, found 245.1749. [00227] 2-Butyl-2-(ethoxycarbonyl)hexanoic (ethyl carbonic) anhydride (47). To a stirred solution of 100 mg (0.41 mmol) of acid 46 in 5 mL of THF was cooled to 0^oC and then was added sequentially 62 mg (0.61 mmol) of 4-methylmorpholine and 53 mg (0.49 mmol) of ethyl chloroformate. After stirring for 30 mins, the suspension was filtered through a medium- porosity glass frit to afford a THF solution of 47 that was immediately used in the proceeding step without further purification. [00228] Ethyl 2-(azidocarbonyl)-2-butylhexanoate (48). To a 0^oC solution of about 100 mg (0.32 mmol) of 47 in THF was added dropwise a solution of 62 mg (0.96 mmol) of sodium azide in 1 mL of water. After stirring at 0^oC for 1 h, the solution was diluted with water and extracted three times with 10–mL portions of ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was used without further purification to afford 86 mg (100%) of 48 as a colorless oil. [00229] Ethyl 2-butyl-2-isocyanatohexanoate (49). A solution of 100 mg (0.37 mmol) of azide 48 in 5 mL of toluene was stirred at 100°C for 2 h. After cooling to room temperature, the solvent was removed in vacuo to afford 57 mg (64%) of 49 as a colorless oil that was immediately used without further purification. [00230] Ethyl 2-(2-(4-(1H-indol-3-yl)butanoyl)hydrazine-1-carboxamido)-2- butylhexanoate (GSR-3-154). To a suspension of 50 mg (0.21 mmol) of isocyanate 49 in 5 mL of ethanol was added 46 mg (0.21 mmol) of hydrazide 4. The solution was stirred for 2 h and was completed as determined by TLC. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (4 g silica gel column, Combiflash, 0 → 50% hexanes-ethyl acetate, over 12 mins) to afford 98 mg (56%) of GSR-3-154 as a white solid. [00231] N-(4,4-dibutyl-2,5-dioxoimidazolidin-1-yl)-4-(1H-indol-3-yl)butanamide (GSR-3-157). To a solution of 50 mg (0.11 mmol) of ester GSR-3-154 in 5 mL of EtOH at 0^oC was added 11 mg (0.16 mmol) of sodium ethoxide. The reaction mixture was stirred at room temperature for 2 h and then was concentrated in vacuo. The residue was taken up in 20 mL of saturated citric acid solution and was extracted three times with 20–mL portion of ethyl acetate. The combined ethyl acetate layers were dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by flash column chromatography (4 g silica gel column, Combiflash, 0 → 50% hexanes-ethyl acetate, over 12 mins) to afford 32 mg (71%) of GSR-3-157 as a white solid: ¹H NMR (400 MHz, DMSO-d6) δ 10.77 (s, br, 1H), 10.29 (s, 1H), 8.31 (s, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.13 (d, J = 2.4 Hz, 1H), 7.05 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H), 6.96 (ddd, J = 8.0, 7.2, 1.2 Hz, 1H), 2.72 (t, J = 7.6 Hz, 2H), 2.26 (t, J = 7.2 Hz, 2H), 1.90 (qu, J = 7.6 Hz, 2H), 1.70 – 1.51 (m, 4H), 1.36 – 1.18 (m, 8H), 0.85 (t, J = 6.0 Hz, 6H); ¹³C NMR (100.5 MHz, DMSO-d₆) δ 173.81, 171.10, 153.84, 136.28, 127.11, 122.34, 120.81, 118.31, 118.08, 113.82, 111.29, 63.49, 36.36, 32.62, 25.60, 25.03 (br), 24.67 (br), 22.14 (br, 2C), 22.05 (br, 2C), 13.83 (2C); ESI-HRMS m/z: calcd for C23H33N4O3 [M+H]⁺ 413.2547, found 413.2558. [00232] Synthesis of GSR-3-159. [00233] Ethyl 2-butyl-2-(2-(3-(2-phenyl-1H-indol-3-yl)propanoyl)hydrazine-1- carboxamido)hexanoate (GSR-3-153). To a suspension of 50 mg (0.21 mmol) of isocyanate 49 in 5 mL of ethanol was added 58 mg (0.21 mmol) of hydrazide 6. The solution was stirred for 2 h and was completed as determined by TLC. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (4 g silica gel column, Combiflash, 0 → 50% hexanes-ethyl acetate, over 12 mins) to afford 82 mg (75%) of GSR-3- 153 as a white solid: ESI-HRMS m/z: calcd for C₃₀H₄₁N₄O₄ [M+H]⁺ 521.3122, found 521.3132. [00234] N-(4,4-dibutyl-2,5-dioxoimidazolidin-1-yl)-3-(2-phenyl-1H-indol-3- yl)propenamide (GSR-3-159). To a solution of 50 mg (0.096 mmol) of ester GSR-3-153 in 5 mL of EtOH at 0^oC was added 9.8 mg (0.14 mmol) of sodium ethoxide. The reaction mixture was stirred at room temperature for 2 h and then was concentrated in vacuo. The residue was taken up in 20 mL of saturated citric acid solution and was extracted three times with 20–mL portion of ethyl acetate. The combined ethyl acetate layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (4 g silica gel column, Combiflash, 0 → 50% hexanes-ethyl acetate, over 12 mins) to afford 27 mg (59%) of GSR-3-159 as a white solid: ¹H NMR (400 MHz, DMSO-d6) δ 11.20 (s, br, 1H), 10.44 (s, 1H), 8.34 (s, 1H), 7.66 – 7.59 (m, 3H), 7.52 (t, J = 8.0 Hz, 2H), 7.43 – 7.34 (m, 2H), 7.12 (ddd, J = 7.6, 6.8, 1.2 Hz, 1H), 6.96 (ddd, J = 8.0, 7.2, 0.8 Hz, 1H), 3.14 – 3.05 (m, 2H), 2.62 – 2.54 (m, 2H), 1.71 – 1.52 (m, 4H), 1.37 – 1.16 (m, 8H), 0.92 – 0.79 (m, 6H); ¹³C NMR (100.5 MHz, DMSO-d₆) δ 173.74, 170.66, 153.78, 136.00, 134.26, 132.73, 128.76 (2C), 128.19, 127.90 (2C), 127.42, 121.59, 118.79, 118.49, 111.23, 110.16, 63.54, 36.39, 34.27, 25.06 (br), 24.68 (br), 22.09 (br, 2C), 20.09 (2C) 13.84 (2C); ESI-HRMS m/z: calcd for C₂₈H₃₅N₄O₃ [M+H]⁺ 475.2704, found 475.2716. [00235] Some compounds included in the experimental:

Example Set B [00236] Growth Factor Receptor signaling can be helpful to tissue growth, homeostasis, and wound healing. However, receptor desensitization can sometimes limit the use of exogenous growth factors as a restorative agent therapeutically. An example of this is the Epidermal Growth Factor Receptor (EGFR) in the corneal epithelium. Despite promising experimental data, the clinical administration of EGF to damaged corneal epithelium has limited impact due to the attenuated signaling that occurs following sustained growth factor administration. Without wishing to be bound by theory, we hypothesize that inhibition of receptor desensitization would prolong receptor activity and enhance tissue homeostasis. Having previously identified the E3 ubiquitin ligand, c-Cbl, as a negative regulator of EGFR signaling, we have developed a class of small molecule inhibitors of EGFR:Cbl binding. We have identified several potentially useful compounds, including compound 3-120. These compounds can sometimes compete with phosphotyrosine 1045 of the EGFR for binding to c-Cbl. For example, compound 3-120 binds to c-Cbl with an ~10-fold higher affinity than phosphoEGFR, reduces EGFR ubiquitylation by 40%, and increases the magnitude of ligand-stimulated EGFR phosphorylation by 30-40%. In general, these compounds can enhance the restoration of corneal epithelial debridement wounds. Thus, these compounds (e.g., compound 3-120) appear to represent a potentially first-in-class antagonist that specifically disrupts EGFR ubiquitylation to sustain receptor signaling. [00237] The proper magnitude and duration of cell surface receptor signaling can be helpful for maintaining tissue homeostasis. Enhanced ligand and receptor expression can lead to an increase in cell surface receptor activation and pro-growth signals. Conversely, signaling is attenuated by receptor dephosphorylation, endocytosis, and degradation, which can prevent tissue hyperplasia. These counter-regulatory mechanisms can be helpful for balancing tissue growth with tissue hyperplasia. [00238] If an epithelial tissue is damaged by trauma (physical, thermal, chemical, etc.) or disease, stimulating growth-promoting receptors with exogenous ligands can accelerate tissue regeneration. However, tissue restoration can be limited when treating with exogenous ligands due to intrinsic, negative regulatory mechanisms of signaling such as receptor desensitization. Without wishing to be bound by theory, we propose that the complementary strategies of exogenous ligand and antagonizing receptor desensitization will be a useful tool for prolonged receptor signaling and accelerated tissue regeneration. [00239] The endocytic pathway is a targetable molecular mechanism that negatively regulates receptor signaling. It is a mechanism for attenuating cell surface receptor signaling, particularly among receptor tyrosine kinases. Following ligand binding, the ligand:receptor complex enters the endocytic pathway and traffics through the early and late endosomes until it enters the lysosome for degradation. For some receptor tyrosine kinases, the post-translational modification ubiquitylation directs the internalization and lysosomal degradation of the active ligand:receptor complex. Inhibition of receptor ubiquitylation can prevent receptor degradation by diverting it from lysosomal degradation. [00240] This model has been validated in the corneal epithelium using the restorative signaling by the Epidermal Growth Factor Receptor (EGFR). EGFR activity is sufficient to promote the re-epithelialization of mechanically debrided corneas in laboratory studies. However, the clinical use of EGF is limited by its lack of reliable sustained signaling. We have demonstrated that in corneal epithelial cells, that one E3 ubiquitin ligase, c-Cbl, ubiquitylates the EGFR in a ligand-dependent manner. Using RNAi and CRISPR/CAS9 to attenuate expression of c-Cbl, we observed a partial decrease in EGFR ubiquitylation and an increase in the magnitude and duration of EGFR phosphorylation. Based on these findings, without wishing to be bound by theory, we hypothesize that pharmacologic inhibition of ubiquitylation would be a potential strategy for EGFR signaling with potential applications in enhancing wound healing. [00241] To develop small molecule inhibitor compounds of c-Cbl, we performed an in silico screen of the Zinc15 library. Compounds from the screen with the highest predicted affinity were biochemically tested for their ability to bind c-Cbl, inhibit ligand-mediated EGFR ubiquitylation, and sustain EGFR phosphorylation. The top biochemically tested compound was structurally modified to provide other compounds which were designed to enhance binding and increase c-Cbl antagonism. Here, we describe compounds (e.g., compound 3-120) that target EGFR:c-Cbl binding and antagonize ligand-mediated EGFR ubiquitylation. These compounds (e.g., compound 3-120) provide a treatment that increases the magnitude and duration of EGFR phosphorylation sufficiently to enhance EGFR-mediated corneal re-epithelialization. [00242] Materials and Methods [00243] Cell Culture - Telomerase reverse transcriptase-immortalized human corneal epithelial (hTCEpi, Robertson, D. M., Li, L., Fisher, S., Pearce, V. P., Shay, J. W., Wright, W. E. et al. (2005) Characterization of growth and differentiation in a telomerase-immortalized human corneal epithelial cell line Invest Ophthalmol Vis Sci 46, 470-478) cells were obtained from Evercyte (Vienna, Austria). All cells were grown in Keratinocyte Basal Medium (KBM-2) (#CC- 3103, Lonza, MD) with growth supplements (hydrocortisone, transferrin, epinephrine, BPE, hEGF, and insulin, #CC-4152, Lonza) and Pen Strep (#15140-122, Thermo-Fisher, MA) at 37°C with 5% CO2. Cells were propagated 2 times per week to maintain normal growth and never allowed to grow more than 90% confluent to prevent differentiation and quiescence of cells. [00244] c-Cbl, Cbl-b, and c-Cbl/Cbl-b (DKO) double knockout cells were generated as described in Tarvestad, K., and Ceresa, B. P. (2023) c-Met signaling is negatively regulated by c- Cbl/Cbl-b in human corneal epithelial cells Invest Ophth Vis Sci 64, 3112. [00245] Protein purification – GST-c-Cbl was a kind gift of Dr. Stan Lipkowitz (NIH). GST-Cbl-b was obtained from the Medical Research Council Protein Phosphorylation and Ubiquitylation Unit (University of Dundee, Scotland). Full length GST-c-Cbl and GST-Cbl-b were purified used glutathione agarose beads according to manufacturer’s instructions (GE Healthcare, Chicago, IL). [00246] Compound Screen - Initial compounds were identified using an in silico screen of compounds. Briefly, compounds from the ZINC15 library were screened for their predicted ability to disrupt the binding of the phosphorylated EGFR peptide (amino acids 1063-1078 with the tyrosine phosphorylated) (Monsen RC, Maguire JM, DeLeeuw LW, Chaires JB, Trent JO (2022) Drug discovery of small molecules targeting the higher-order hTERT promoter G- quadruplex. PLOS ONE 17(6): e0270165). The ~100 compounds with the lowest ΔG for binding at the pEGFR peptide binding site on c-Cbl were purchased and tested for binding to c-Cbl experimentally, using differential scanning fluorimetry. Of the six compounds that bound c-Cbl, two compounds were found to sustain EGFR signaling and inhibit ligand-mediated EGFR ubiquitination. [00247] Differential Scanning Fluorimetry (DSF) assays – DSF assays were performed using an Applied Biosystems StepOne Plus real-time PCR system. To create a 2x stock of fluorescently labeled protein, the c-Cbl and Cbl-b proteins were first exchanged into 1x PBS using 7k MWCO Zeba spin desalting devices (Thermo Scientific) prior to mixing with Sypro Orange dye to achieve a final concentration of 20 uM protein and 10x dye (diluted from 5,000x stock solution in DMSO). The 2x protein and dye solutions were then mixed 1:1 (10 µL to 10 µL) with their respective ligand or matched control solutions in a 96-well Applied Biosystems real-time PCR plate and briefly spun down at 1,350 rpm in an Eppendorf 5430 hanging bucket centrifuge for 2 minutes to remove bubbles. Melting curves were then obtained in the StepOne Plus by ramping the temperature from 20 to 99°C in 0.2°C increments using the step and hold option (not continuous mode) and monitoring the change in fluorescence as a function of temperature. An in-house script was used to normalize the raw data and identify the transition midpoint (T_m) using the first derivative of each curve. [00248] Microscale Thermophoresis (MST) – MST experiments were performed on a Monolith Nanotemper instrument (Nanotemper, München, Germany) using its MO.Control v2.0.4 software. The purified protein was dialyzed extensively against PBS buffer prior to labeling with the Nanotemper RED-NHS 2^nd generation lysine red kit protocol. In all cases, labeling efficiency was greater than 50%. Titration solutions consisted of 40 nM Lysine Red- labeled cCbl protein mixed in 12- or 16-point serial dilution series of compounds. The concentration series ranged from 100 μM to 0.31 nM of ligand or peptide with a matched background of 8% DMSO. Dilution reactions were made in 384 well plates at a volume of 20 μL and incubated in the dark for at least 10 minutes before loading into Nanotemper premium capillaries and measuring thermophoresis. Measurements were performed at 25°C. Data analysis was performed in the program PALMIST using the T-jump mode and fitting to a 1-site binding model (Scheuermann, T. H., Padrick, S. B., Gardner, K. H., and Brautigam, C. A. (2016) On the acquisition and analysis of microscale thermophoresis data Analytical Biochemistry 496, 79-93). [00249] Cell Viability assays – Cytotoxicity of candidate compounds was tested by measuring hTCEpi cell viability following a 24-hour incubation with varying concentrations of candidate compounds. Following compound incubation, alamarBlue^TM (ThermoFisher Scientific, Waltham, MA) was added and the number of viable cells were measured in accordance with manufacturer’s recommendation. [00250] In situ ubiquitylation assay - Epidermal growth factor receptor ubiquitylation was monitored using a modification of a protocol by Visser Smit, G. D., Place, T. L., Cole, S. L., Clausen, K. A., Vemuganti, S., Zhang, G. et al. (2009) Cbl controls EGFR fate by regulating early endosome fusion Sci Signal 2(102), ra86. Serum starved cells were pretreated the indicated concentrations of compound 3-120 for 30 minutes followed by stimulation with 50 ng/mL EGF in Keratinocyte Serum Free Media (K-SFM) with no additions for the indicated times, and harvested in 4°C EGFR-UB lysis buffer (0.5% Triton x-100/50 mM Tris pH 7.5/150 mM NaCl/1 mM EDTA/1 mM sodium orthovanadate/10 mM sodium fluoride) supplemented with 2 mM PMSF (Calbiochem, Billerica, MA, USA)/16 mM G5 Ubiquitin isopeptidase inhibitor I (Santa Cruz Biotechnology). Cell lysates were prepared and immunoprecipitated with 1 mg EGFR antibody (mouse monoclonal, clone 528), (Ab-1, EMD Millipore, Burlington, MA), incubated at 4°C overnight followed by another 2-hour incubation at 4°C with protein A/G Agarose (Santa Cruz Biotechnology). Immunoprecipitates were washed thrice in chilled EGFR-UB lysis buffer. Proteins were eluted with 6XSDS sample buffer and separated by 7.5% SDS-PAGE and immunoblotted for EGFR, Ub, or pY1068 EGFR as indicated. Immunoblots were quantified using NIH ImageJ software, taking care to make sure the exposures were in the linear range. [00251] EGF time courses – Prior to experimentation, cells were serum starved with two PBS washes and 2 hours in K-SFM. Cells were treated with either vehicle (0.05% DMSO in K- SFM) or compound 3-120 at the indicated concentrations for 30 minutes. After that time, cells were treated with the indicated concentrations of ligand (EGF) and harvested at 0, 15, 60, or 120 minutes. Cell lysates were prepared as described previously (Crotchett, B. L. M., and Ceresa, B. P. (2021) Knockout of c-Cbl slows EGFR endocytic trafficking and enhances EGFR signaling despite incompletely blocking receptor ubiquitylation Pharmacol Res Perspect 9, e00756) and the protein concentration was assessed by BCA assay (ThermoFisher, Waltham, MA) [00252] Cell lysate preparation and Immunoblotting – Equivalent amounts of protein were resolved by 7.5% SDS-PAGE, transferred to nitrocellulose and the upper portion of the nitrocellulose (>75 kDa) was immunoblotted with antibodies against total EGFR (Cell Signaling, #4267), phosphorylated EGFR (pY1068 Cell Signaling, #2234 or pY1045 Cell Signaling, #2237), or α-tubulin (Sigma, T6199). Immunoblots were exposed in the linear range and quantified using NIH Image J (NIH, Bethesda, MD). Data are plotted as the average (+/- SD) fold change in immunoreactivity (n=3). [00253] Statistical analysis – Statistical analysis was performed using GraphPad Prism (La Jolla, CA). Statistical tests are indicated in the Brief Description of the Drawings. [00254] In vitro wound healing – Silicone elastomer base (Sylgard 184 Elastomer; Dow Corning) was made per manufacturer’s instructions and cured for 96 h. Four 2 mm diameter silicone punch outs were placed directly on the bottom of a 6-well plate and spaced at least 2 mm apart. Cells were seeded around the plugs and incubated for 48 h with a media change at 24 h to achieve 95% confluency. The silicone plugs were removed following serum starvation, and the cells were rinsed with PBS to remove debris, creating a 2 mm uniform acellular area on the plate. Cells were kept in SFM or treated with vehicle alone (0.01% DMSO), vehicle with 3 ng/ml of EGF, 5 mM compound 3-120, or 5 mM compound 3-120 with 3 ng/ml EGF and imaged using a BZ-X800 Keyence All-in-One fluorescent microscope at 4× objective. “Wounds” were visualized for 24 h by taking brightfield images every 15 min. The Keyence software was used to create videos of the wound healing over 24 h. All wounds were analyzed by finding the area (μm²) every 2 to 4 h, graphing, and finding the AUC. The time it took to reach 50% confluency was found by analysis of images. GraphPad/Prism was used for statistical analysis and generating graphs (Rush J.S., Boeving M.A., Berry W.L., Ceresa B.P. Antagonizing c-Cbl enhances EGFR-dependent corneal epithelial homeostasis. Invest. Ophthalmol. Vis. Sci. 2014;55:4691–4699; Peterson J.L., Phelps E.D., Doll M.A., Schaal S., Ceresa B.P. The role of endogenous epidermal growth factor receptor ligands in mediating corneal epithelial homeostasis. Invest. Ophthalmol. Vis. Sci.2014;55:2870–2880). [00255] In vivo wound healing - Mechanical debridement of corneas is a well-established model for monitoring re-epithelialization of the cornea (Rush J.S., Boeving M.A., Berry W.L., Ceresa B.P. Antagonizing c-Cbl enhances EGFR-dependent corneal epithelial homeostasis. Invest. Ophthalmol. Vis. Sci. 2014;55:4691–4699; Peterson J.L., Phelps E.D., Doll M.A., Schaal S., Ceresa B.P. The role of endogenous epidermal growth factor receptor ligands in mediating corneal epithelial homeostasis. Invest. Ophthalmol. Vis. Sci.2014;55:2870–2880; Rush, J. S., Bingaman, D. P., Chaney, P. G., Wax, M. B., and Ceresa, B. P. (2016) Administration of Menadione, Vitamin K3, Ameliorates Off-Target Effects on Corneal Epithelial Wound Healing Due to Receptor Tyrosine Kinase Inhibition Invest Ophthalmol Vis Sci 57, 5864-5871). The epithelial layer from 1.5 mm circular wound is removed using an Algerbrush II from the right eye of an anesthetized C57Bl/6 mouse (Jackson Laboratory). The size of the initial wound was measured by fluorescein staining and imaged with a fluorescent microscope (Nikon SMZ1000 stereomicroscope). After imaging (t=0), the mouse was treated as indicated. [PBS, vehicle (0.01 DMSO) + 10 ng/ml EGF, or 10 mM 3-120+ 10ng/ml EGF). After 16 or 24 hours, the mouse was anesthetized and wounded eyes were fluorescein stained and re-imaged. [00256] Results [00257] c-Cbl and Cbl-b are EGFR E3 ubiquitin ligases in immortalized corneal epithelial cells [00258] In immortalized corneal epithelial cells, ubiquitylation of the EGFR is a negative regulator of EGFR signaling. Knockdown or knockout of c-Cbl results in an incomplete inhibition of ligand-mediated EGFR ubiquitylation indicating a role for additional E3 ligases. The structurally related E3 ligases Cbl-b emerged as a candidate. It is expressed in the corneal epithelium and has been reported to ubiquitylate the EGFR. [00259] Immortalized human corneal epithelial (hTCEpi) cells were bioengineered to knockout c-Cbl and Cbl-b (referred to as “Double knockout” or “DKO cells”; Tarvestad-Laise, K. E., and Ceresa, B. P. (2023) Knockout of c-Cbl/Cbl-b slows c-Met trafficking resulting in enhanced signaling in corneal epithelial cells J Biol Chem 299,(10), 105233) using CRISPR/CAS9 (Figure 1A). The double knockout cells were treated with EGF for 0-10 minutes, cell lysates were prepared, and the EGFR was immunoprecipitated. Immunoprecipitates were resolved by SDS-PAGE and immunoblotted for the presence of ubiquitin, phosphorylated EGFR, and total EGFR (Figure 1B). In the absence of both E3 ligases, there was a decrease in EGFR ubiquitylation. Quantification of multiple experiments reveals that there is a ~85% decrease in the EGFR ubiquitylation in DKO cells (Figure 1C). [00260] Loss of EGFR ubiquitylation results in enhanced and sustained EGFR phosphorylation [00261] To assess the consequence of decreased EGFR ubiquitylation, DKO cells were treated with EGF for 0-2 hours. At various points of this time course, cells were assayed by immunoblot for their EGFR phosphorylation (Figure 1D). In the absence of c-Cbl and Cbl-b (DKO cells), there was an increase in EGFR phosphorylation after 15 minutes of treatment that was sustained for 2 hours as compared to the parental (CAS9) cells (Figure 1E). An analysis of total phosphorylation as measured by the area under the curve indicates there is more than a 2.5- fold increase in receptor phosphorylation in DKO cells (Figure 1F). [00262] Scheme for identifying novel c-Cbl antagonist [00263] Based on these findings, we hypothesized that antagonizing c-Cbl and Cbl-b would be a feasible pharmacological approach for enhancing the EGFR signaling. Previous work by Ng et al. used X-ray crystallography to identify the site of interaction between c-Cbl and the EGFR (Ng, C., Jackson, R. A., Buschdorf, J. P., Sun, Q., Guy, G. R., and Sivaraman, J. (2008) Structural basis for a novel intrapeptidyl H-bond and reverse binding of c-Cbl-TKB domain substrates The EMBO journal 27, 804-816). Cbl-b has a closely related crystal structure to c-Cbl (Ohno, A., Ochi, A., Maita, N., Ueji, T., Bando, A., Nakao, R. et al. (2016) Structural analysis of the TKB domain of ubiquitin ligase Cbl-b complexed with its small inhibitory peptide, Cblin Arch Biochem Biophys 594, 1-7). There is a 100% identity between c-Cbl and Cbl-b in the amino acids that bind the phospho-EGFR peptide (Ng, C., Jackson, R. A., Buschdorf, J. P., Sun, Q., Guy, G. R., and Sivaraman, J. (2008) Structural basis for a novel intrapeptidyl H-bond and reverse binding of c-Cbl-TKB domain substrates The EMBO journal 27, 804-816). Thus, we predicted that compounds that displace phospho-EGFR peptide binding from c-Cbl, would also be able to displace phospho-EGFR peptide binding from Cbl-b. [00264] Using the (2.5 Å) crystal structure of this interaction, we performed an in silico screen of 25,000,000 compounds from the NIH Zinc15 library (Monsen RC, Maguire JM, DeLeeuw LW, Chaires JB, Trent JO (2022) Drug discovery of small molecules targeting the higher-order hTERT promoter G-quadruplex. PLOS ONE 17(6): e0270165). Compounds were ranked based on the lowest ΔG when modeled to bind to the EGFR-binding site on c-Cbl. [00265] The top 100 compounds from that list were obtained from commercial sources, screened for binding to purified, full-length c-Cbl, sustained EGFR phosphorylation, and inhibition of ligand-mediated EGFR ubiquitylation. [00266] Screen of top candidate compounds derived from in silico screen [00267] Compounds that bound to c-Cbl in silico were assessed using differential scanning fluorimetry (DSF), a high-throughput assay that measures protein unfolding as a function of increasing temperatures. Molecules that stably bind to the protein of interest, keep the protein in its folded stated at higher temperatures. Recombinant c-Cbl and Cbl-b were used in these assays. A phosphoEGFR peptide that binds to c-Cbl (DSFLQRpYSSDPTG (SEQ ID NO:1)) corresponding EGFR amino acids 1063-1078, published in Ng, C., Jackson, R. A., Buschdorf, J. P., Sun, Q., Guy, G. R., and Sivaraman, J. (2008) Structural basis for a novel intrapeptidyl H-bond and reverse binding of c-Cbl-TKB domain substrates The EMBO journal 27, 804-816), was used as a control. There is a dose-dependent stabilization in c-Cbl (Figure 2A) and Cbl-b (Figure 2B) in the presence of increasing concentrations of phosphoEGFR peptide. [00268] When the top-ranked compounds were tested, some compounds had no effect on the melting temperature of c-Cbl (Figure 2C – compare c-Cbl alone and c-Cbl with representative compound AA). Compound AA is N-(cyclohexylmethyl)-N-methyl-1-[1-(pyridin- 3-ylmethyl)piperidin-4-yl]piperidine-3-carboxamide (PubChem CID 70723778). However, six (6) compounds were identified that enhance c-Cbl stability (e.g., see Figure 2C which shows compound AA versus compound AF). [00269] These six compounds were subjected to functional analysis. Specifically, they were tested for the ability to sustain EGFR phosphorylation (pY1068) over the course of two hours (Figure 2D shows AF) and inhibit ligand-dependent EGFR ubiquitylation (Figure 2E shows AF). Shown in Figures 2D and 2E is a compound that was able to mimic the effects of c- Cbl/Cbl-b knockout cells in both assays. This compound, AF (also known as 1-119 or I-1), was used as the backbone for optimization. [00270] Identification of compounds that are c-Cbl antagonists [00271] The affinity for compound AF to bind to c-Cbl was optimized by systematically deleting and adding functional groups to the parent compound. Over 100 derivative compounds were synthesized that were subject to two levels of compound screening. Initial screens were functional in nature and tested whether each compound could sustain EGFR phosphorylation. The first assay examined whether pretreatment with compound (100 - 200 mM) could sustain ligand-stimulated EGFR phosphorylation. Of the ~40 compounds that sustained EGFR phosphorylation, their binding affinity to c-Cbl was measured using Microscale Thermophoresis (MST) titrations (Figures 3A and 3B). MST is a medium-throughput, immobilization-free assay that measures the diffusion of fluorescence molecules in a thermal gradient as a function of ligand concentration. The thermogram data is then transformed and plotted to be fit with a one- site binding model that yields the dissociation constant (K_d). As a control, we used MST to calculate the Kd of the phosphorylated EGFR peptide (pEGFR) binding to c-Cbl. Using MST, the Kd was ~10 fold lower affinity than what was published using isothermal calorimetry (Ng, C., Jackson, R. A., Buschdorf, J. P., Sun, Q., Guy, G. R., and Sivaraman, J. (2008) Structural basis for a novel intrapeptidyl H-bond and reverse binding of c-Cbl-TKB domain substrates The EMBO journal 27, 804-816). [00272] The top compounds were measured for cytotoxicity by treating immortalized corneal epithelial cells with increasing concentrations for 24 hours. Compound 3-120 had less than 10% cytotoxicity after 24 hours at 3 µM (Figure 3C) and was pursued for additional functional testing. [00273] Compound 3-120 decreases ligand-mediated EGFR ubiquitylation. [00274] To determine if compound 3-120 could antagonize the E3 activity, we measured ligand-dependent EGFR ubiquitylation in hTCEpi cells in the presence of increasing concentrations of 3-120. Serum starved cells were pre-incubated with 0-100 µM for 30 minutes to allow the compound to passively diffuse into the cell. Next, cells were incubated without (-) or with (+) EGF for 10 minutes. Cell lysates were prepared, and the EGFR was immunoprecipitated. Immunoprecipitates were resolved SDS-PAGE and immunoblotted for Ubiquitin (Ub), tyrosine phosphorylated EGFR (pY1045), and total EGFR. Treatment with EGF caused an increase in EGFR phosphorylation and ubiquitylation. In cells pre-treated with 3-120 for 30 minutes before the addition of EGF, we observe a 40% reduction in EGFR ubiquitylation (Figure 4A and Figure 4B). [00275] Treatment with 3-120 enhances EGFR signaling [00276] We wanted to assess whether these decreases in receptor ubiquitylation were sufficient to enhance EGFR signaling in magnitude and duration. hTCEpi cells (Figures 5A-5E) and primary human corneal epithelial cells (Figures 5F-5H) were pretreated with 50 µM 3-120 for 30 minutes, followed by EGF treatment (10 ng/ml) for 0-120 minutes. At the indicated time points, cell lysates were prepared and immunoblotted for phosphorylated EGFR at two different tyrosines (pY1068 and pY1045) EGFR to measure receptor activity (Figures 5A and 5F). Densitometric analysis of multiple immunoblot indicated both immortalized and primary corneal epithelial cells exhibited an increase in EGFR phosphorylation at all time points with 3-120 treatment (Figures 5B, 5C, and 5G). Both cell lines had a greater than 30% increase in the Area Under the Curve (Figures 5D, 5E, and 5H). Similar findings were observed with compound 5-6 using similar methods (Figures 5I, 5J, and 5K). [00277] To examine the consequence of 3-120 on cell function, we performed an in vitro wound healing assay. Cell movement into a 2 mm acellular area was monitored with time-lapse imaging in the presence of EGF (3 ng/ml) with vehicle or 5 µM 3-120. Images were collected every 15 min for 24 h (Figure 6A). The percent wound closure was quantified every 4 h and plotted as a function of time (Figure 6B). From these data, we observed a decrease in the time it took for the wound to close and the amount of time it took to achieve 50% wound closure. [00278] Finally, we wanted to determine if 3-120 could accelerate corneal re- epithelialization in a murine model. Briefly, a 1.5 mm circular debridement wound was made in a female wild type C57Bl/6 mouse (Figure 7A). After the initial wound stained with fluorescein and visualized with a fluorescent microscope, the mice were treated with either PBS alone, 10 ng/ml EGF + vehicle (0.01% DMSO), or 10 ng/ml EGF + 10 µM 3-120. Quantification of the wounds shows 3-120 significantly enhanced the EGF mediated increase at 16 hours, but not after 24 hours (Figure 7B). The experiments using the same methods were conducted using compound 5-6; quantification of the wounds shows compound 5-6 enhanced the EGF mediated increase at 16 hours (Figure 7C). [00279] Discussion: [00280] One strategy for enhancing receptor-mediated biology has been to add more ligand to increase the magnitude of response. However, this can result in ligand concentrations that saturate the receptor and cause desensitization, causing a net decrease in signaling. This is observed when exogenous EGF is added to accelerate the healing of damaged corneal epithelium. High levels of endogenous EGF coupled with the exogenous growth factor leads to EGFR desensitization. Without being bound by theory, we propose an alternative approach of inhibiting EGFR desensitization to sustain the duration of receptor signaling. [00281] In this study, we identify that c-Cbl and Cbl-b are E3 ligases that regulate the ubiquitylation of EGFR in the corneal epithelium. Knockout of these proteins results in an 85% decrease in ligand-mediated ubiquitylation and a 2-fold increase in receptor phosphorylation. Having identified a viable pharmacological target, we used molecular modeling to identify lead compounds that could bind and antagonize the E3 ligases. Additional structural modification led to the generation of increased affinity compounds (e.g., compound 3-120). The addition of the compound 3-120 decreases ligand-mediated EGFR ubiquitylation and sustains EGFR phosphorylation in both primary and immortalized corneal epithelial cells. Although the efficacy of compound 3-120 is less than what is observed with knockout of the target proteins, it is able to accelerate in vitro wound healing as well as in vivo corneal re-epithelialization. Other compounds disclosed herein also enhance EGFR phosphorylation and accelerate corneal re- epithelialization. Compounds disclosed herein (e.g., compound 3-120) represent first-in-class compounds and validate our model for enhancing EGFR signaling. [00282] Despite complete homology between the predicted binding site on c-Cbl and Cbl- b that interface with the phosphoEGFR, our compounds appear to be selective for c-Cbl, as illustrated by the Table below. There is 56% amino acid identity between c-Cbl and Cbl-b and they are encoded by distinct genes. Table A [00283] The use of small molecule inhibitors that prevent receptor downregulation has historically been overlooked as a therapeutic strategy. We see potential for the compounds disclosed herein, as accelerating epithelial tissue regeneration, such as the cornea. As the most anterior portion of the eye, it is exposed to physical, chemical, or thermal insults that can damage the epithelial layer. Not only is damage to this highly innervated tissue painful, but if left unhealed, it may lead to infection and possibly blindness. Despite the loss of quality of life, there are no FDA approved drugs available to promote corneal epithelial homeostasis and wound healing. [00284] Topical administration of the antagonist as an eye drop could be used with a volume of 20 µl and could be administered at a concentration of 10 µM (e.g., 10X the estimated K_d) [00285] Combining in silico, biochemical, and cell biological screens, we were able identify compounds that bind c-Cbl, inhibit ligand-mediated EGFR ubiquitylation, and sustain EGFR phosphorylation. Further structure/function analysis was performed to enhance its affinity. After synthesizing over 100 new compounds, we have identified compounds that: 1) bind c-Cbl (e.g., with 70 nM affinity), 2) decrease EGFR ubiquitylation, and/or 3) sustain the EGFR in corneal epithelial cells. As first-in-class compounds, they are a new therapeutic to promote corneal re-epithelialization and homeostasis, either alone or when co-administered with EGF (e.g., exogenous EGF, recombinant EGF (with or without full glycosylation made from various cell types), or EGF from other sources). Example Set C [00286] Figure 8 provides the results of various measurements for numerous compounds. The following measurements were made with the listed compounds, as indicated: Thermoshift, pY1068, phoscCbl, phosMAPk, dose response, toxicity, and MST. Methods are described below. Dose response as provided in Figure 8 is typically meant to show the qualitative nature of the dose response. [00287] Thermoshift – Differential Scanning Fluorimetry (DSF) assays – DSF assays were performed using an Applied Biosystems StepOne Plus real-time PCR system. To create a 2x stock of fluorescently labeled protein, the c-Cbl and Cbl-b proteins were first exchanged into 1x PBS using 7k MWCO Zeba spin desalting devices (Thermo Scientific) prior to mixing with Sypro Orange dye to achieve a final concentration of 20 uM protein and 10x dye (diluted from 5,000x stock solution in DMSO). The 2x protein and dye solutions were then mixed 1:1 (10 µL to 10 µL) with their respective ligand or matched control solutions in a 96-well Applied Biosystems real-time PCR plate and briefly spun down at 1,350 rpm in an Eppendorf 5430 hanging bucket centrifuge for 2 minutes to remove bubbles. Melting curves were then obtained in the StepOne Plus by ramping the temperature from 20 to 99°C in 0.2°C increments using the step and hold option (not continuous mode) and monitoring the change in fluorescence as a function of temperature. An in-house script was used to normalize the raw data and identify the transition midpoint (T_m) using the first derivative of each curve. [00288] pY1068, phospho-c-Cbl, phosMAPk, and dose response (using pY1068). These are immunoblots that use the same basic protocol described below. The first three were time course experiments with the same concentration of the compound, but varied the incubation time. The pY1068 measurement was repeated for the dose response curve using the same incubation time, but varied the concentration of compound. [00289] EGF time courses – Prior to experimentation, cells were serum starved with two PBS washes and 2 hours in K-SFM. Cells were treated with either vehicle (0.05% DMSO in K- SFM) or compound 3-120 at various concentrations for 30 minutes. After that time, cells were treated with the varying concentrations of ligand (EGF) and harvested at 0, 15, 60, or 120 minutes. Cell lysates were prepared as described previously (Crotchett, B. L. M., and Ceresa, B. P. (2021) Knockout of c-Cbl slows EGFR endocytic trafficking and enhances EGFR signaling despite incompletely blocking receptor ubiquitylation Pharmacol Res Perspect 9, e00756) and the protein concentration was assessed by BCA assay (ThermoFisher, Waltham, MA) [00290] Dose response curves - Prior to experimentation, cells were serum starved with two PBS washes and 2 hours in K-SFM. Cells were treated with either vehicle (0.05% DMSO in K-SFM) or compound 3-120 at various concentrations for 30 minutes. After that time, cells were treated with the varying concentrations of ligand (EGF) and harvested at 15 minutes. Cell lysates were prepared as described previously (Crotchett, B. L. M., and Ceresa, B. P. (2021) Knockout of c-Cbl slows EGFR endocytic trafficking and enhances EGFR signaling despite incompletely blocking receptor ubiquitylation Pharmacol Res Perspect 9, e00756) and the protein concentration was assessed by BCA assay (ThermoFisher, Waltham, MA) [00291] Cell lysate preparation and Immunoblotting – Equivalent amounts of protein were resolved by 7.5% SDS-PAGE, transferred to nitrocellulose and the upper portion of the nitrocellulose (>75 kDa) was immunoblotted with antibodies against total EGFR (Cell Signaling, #4267), phosphorylated EGFR (pY1068 Cell Signaling, #2234 or pY1045 Cell Signaling, #2237), phospho c-Cbl (Cell Signaling #8869, phospho MAPK (Cell Signaling #4370) or α- tubulin (Sigma, T6199). Immunoblots were exposed in the linear range and quantified using NIH Image J (NIH, Bethesda, MD). Data are plotted as the average (+/- SD) fold change in immunoreactivity (n=3). [00292] Toxicity - Cell Viability assays – Cytotoxicity of candidate compounds was tested by measuring hTCEpi cell viability following a 24-hour incubation with varying concentrations of candidate compounds. Following compound incubation, alamarBlue^TM (ThermoFisher Scientific, Waltham, MA) was added and the number of viable cells were measured in accordance with manufacturer’s recommendation. [00293] Microscale Thermophoresis (MST) – MST experiments were performed on a Monolith Nanotemper instrument (Nanotemper, München, Germany) using its MO.Control v2.0.4 software. The purified protein was dialyzed extensively against PBS buffer prior to labeling with the Nanotemper RED-NHS 2^nd generation lysine red kit protocol. In all cases, labeling efficiency was greater than 50%. Titration solutions consisted of 40 nM Lysine Red- labeled cCbl protein mixed in 12- or 16-point serial dilution series of compounds. The concentration series ranged from 100 μM to 0.31 nM of ligand or peptide with a matched background of 8% DMSO. Dilution reactions were made in 384 well plates at a volume of 20 μL and incubated in the dark for at least 10 minutes before loading into Nanotemper premium capillaries and measuring thermophoresis. Measurements were performed at 25°C. Data analysis was performed in the program PALMIST using the T-jump mode and fitting to a 1-site binding model (Scheuermann, T. H., Padrick, S. B., Gardner, K. H., and Brautigam, C. A. (2016) On the acquisition and analysis of microscale thermophoresis data Analytical Biochemistry 496, 79- 93). Example Set D [00294] 1. A compound selected from Formula (I), salts of Formula (I), optical isomers of Formula (I), geometric isomers of Formula (I), salts of optical isomers of Formula (I), salts of geometric isomers of Formula (I), and derivatives thereof (e.g., ethers, esters, or amides),

[00295] - R^1a R^1b , R^1c, and R^1d can be the same or different and are H, halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), methanoyl (-COH), nitro (-NO₂), -NH₂, -N(CH₃)₂, cyano (-CN), sulfo (-SO₃H), -C(O)NH₂, -C(O)N(CH₃)₂, -C(O)(CH₃), -C(O)(C₂H₅), -C(O)(C₃H₇), C₁-C₃ perfluoronated alkyl, -CF₃, -OCF₃, C1-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁-C₉ alkoxy, phenyl, aryl, indole, or hetroaryl which methanoyl (-COH), -NH₂, -N(CH₃)₂, -C(O)NH₂, -C(O)N(CH₃)₂, -C(O)(CH₃), -C(O)(C₂H₅), -C(O)(C₃H₇), C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁-C₉ alkoxy, phenyl, aryl, indolyl, or hetroaryl can optionally be substituted with one or more of halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), methanoyl (-COH), carboxy (-CO₂H), nitro (-NO₂), -NH₂, -N(CH₃)₂, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), morpholinyl, -CO-morpholin-4-yl, -C(O)NH₂, -C(O)N(CH₃)₂, C₁-C₃ alkyl, C₁-C₃ perfluoronated alkyl, -CF₃, -OCF₃, C₁-C₃ alkoxy, aryl, aryl substituted with one or more halogens, phenyl, phenyl substituted with one or more halogens, heteroaryl, heteroaryl substituted with one or more halogens, indolyl, or indolyl substituted with one or more halogens; (see claim 2 for additional R^1a, R^1b , R^1c, and R^1d) [00296] - R^1a and R^1b can optionally be joined to form a C3-C9 cycloalkyl, optionally substituted with halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), -NO₂, -CN, C₁-C₃ alkoxy, aryl, aryl substituted with one or more halogen (e.g., F, Cl, Br, or I), phenyl, phenyl substituted with one or more halogen (e.g., F, Cl, Br, or I), heteroaryl, heteroaryl substituted with one or more halogen (e.g., F, Cl, Br, or I), indolyl, or indolyl substituted with one or more halogen (e.g., F, Cl, Br, or I); [00297] - R^1c and R^1d can optionally be joined to form a C₃-C₉ cycloalkyl optionally substituted with halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), -NO₂, -CN, C₁-C₃ alkoxy, aryl, aryl substituted with one or more halogen (e.g., F, Cl, Br, or I), phenyl, phenyl substituted with one or more halogen (e.g., F, Cl, Br, or I), heteroaryl, heteroaryl substituted with one or more halogen (e.g., F, Cl, Br, or I), indolyl, or indolyl substituted with one or more halogen (e.g., F, Cl, Br, or I); [00298] - n is 0, 1, 2, 3, 4, 5, or 6; [00299] - R² is H, halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), methanoyl (-COH), nitro (-NO₂), -NH₂, -N(CH₃)₂, cyano (-CN), sulfo (-SO3H), -C(O)NH₂, - C(O)N(CH₃)₂, -C(O)(CH₃), -C(O)(C₂H₅), -C(O)(C₃H₇), C₁-C₃ perfluoronated alkyl, -CF₃, -OCF₃, C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C1-C6 alkoxy, aryl, hetroaryl, cycloalkyl, or heterocyclyl, which C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C1-C6 alkoxy, aryl, hetroaryl, cycloalkyl, and heterocyclyl are optionally substituted with one or more of halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), methanoyl (-COH), nitro (-NO₂), -NH₂, -N(CH₃)₂, cyano (-CN), sulfo (-SO₃H), -C(O)NH₂, -C(O)N(CH₃)₂, -C(O)(CH₃), -C(O)(C₂H₅), -C(O)(C₃H₇), C₁-C₃ perfluoronated alkyl, -CF₃, -OCF₃, or C₁-C₃ alkoxy; and [00300] - R³, R⁴, R⁵, and R⁶ can be the same or different and are H, halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), methanoyl (-COH), nitro (-NO₂), -NH₂, -N(CH₃)₂, cyano (-CN), sulfo (-SO3H), -C(O)NH₂, -C(O)N(CH₃)₂, -C(O)(CH₃), -C(O)(C2H5), -C(O)(C₃H₇), C₁-C₃ perfluoronated alkyl, -CF₃, -OCF₃, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, or C₁-C₅ alkoxy. [00301] 2. The compound of embodiment 1, wherein R^1a, R^1b , R^1c, and R^1d can be the same or different and are (a) C₁-C₅ alkyl substituted with phenyl, which phenyl is substituted with one or more halogen (e.g., F, Cl, Br, or I) or -OCH₃, (b) C₁-C₅ alkyl substituted with phenyl, (c) phenyl substituted with one or more halogen (e.g., F, Cl, Br, or I) or -OCH₃, (d) phenyl, or (e) C₁-C₅ alkyl. [00302] 3. The compound of embodiment 1 or embodiment 2, wherein (a) R^1a and R^1b are joined to form a C₅-C₇ monocyclic cycloalkyl or (b) R^1c and R^1d are joined to form a C₅-C₇ monocyclic cycloalkyl. [00303] 4. The compound of any of embodiments 1-3, wherein (a) R^1a is methyl or (b) R^1c is methyl. [00304] 5. The compound of any of embodiments 1-4, wherein n is 2, 3, or 4. [00305] 6. The compound of any of embodiments 1-5, wherein R² is H, methyl, ethyl, propyl, or phenyl. [00306] 7. The compound of any of embodiments 1-6, wherein R³ is H, -CH₃, -OCH₃, F, Cl, -CN, or -NO₂. [00307] 8. The compound of any of embodiments 1-7, wherein R⁴ is H, -CH₃, -OCH₃, F, Cl, -CN, or -NO₂. [00308] 9. The compound of any of embodiments 1-8, wherein R⁴ is H or -OCH₃. [00309] 10. The compound of any of embodiments 1-9, wherein R⁵ is H, -CH₃, -OCH₃, F, Cl, -CN, or -NO₂, preferably H or -OCH₃ [00310] 11. The compound of any of embodiments 1-10, wherein R⁶ is H, -CH₃, -OCH₃, F, Cl, -CN, or -NO₂. [00311] 12. The compound of any of embodiments 1-11, wherein R³, R⁵, and R⁶ are the same and are H.

[00312] 13. The compound of any of embodiments 1-12, wherein R¹ is . [00314] 15. A compound disclosed in this provisional application. [00315] 16. The compound of any of embodiments 1-15, wherein the compound inhibits c-Cbl. [00316] 17. The compound of any of embodiments 1-16, wherein the compound inhibits c-Cbl and the compound has a Kd of less than or equal to 750 µM, less than or equal to 100 µM, less than or equal to 10 µM, less than or equal to 5 µM, less than or equal to 1 µM, or less than or equal to 0.75 µM. [00317] 18. A composition comprising the compound of any of embodiments 1-17. [00318] 19. A pharmaceutical composition comprising (a) the compound of any of embodiments 1-17 and (b) optionally a formulary ingredient (e.g., pharmaceutically acceptable carrier, other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, and excipients). [00319] 20. A method for providing a cell (e.g., animal cell, mammalian cell, or human cell) comprising [00320] - one or more administrations to (e.g., contacting or injecting) the cell of one or more compositions comprising the compound any of embodiments 1-17, wherein the compositions may be the same or different if there is more than one administration and [00321] - optionally administering EGF (e.g., immediately after the one or more administrations step or waiting 10 second, 30 second, 1 min., 5 min., 10 min. 15 min., 20 min. 30 min., 45 min. 60 min., 90 min. 120 min., 150 min., 180 min., 240 min., or 300 min. after the one or more administrations step). [00322] 21. The method of embodiment 20, wherein the administering of EGF is not optional. [00323] 22. A method of embodiment 20 or embodiment 21, wherein the cell is in vivo, ex vivo, or in vitro. [00324] 23. A method for providing an animal with a compound comprising one or more administrations to the animal of one or more compositions comprising the compound of any of embodiments 1-17, wherein the compositions may be the same or different if there is more than one administration. [00325] 24. The method of embodiment 23, wherein at least one of the one or more compositions further comprises a formulary ingredient (e.g., pharmaceutically acceptable carrier, other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, and excipients). [00326] 25. The method of embodiment 23 or embodiment 24, wherein at least one of the one or more compositions comprises the composition of embodiment 18 or the pharmaceutical composition of embodiment 19. [00327] 26. The method of any of embodiments 23-25, wherein at least one of the one or more administrations comprises parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, intrathecal administration, or intramuscular administration. [00328] 27. The method of any of embodiments 23-26, wherein if there is more than one administration at least one composition used for at least one administration is different from the composition of at least one other administration. [00329] 28. The method of any of embodiments 23-27, wherein the compound of at least one of the one or more compositions is administered to the animal (a) in an amount of from about 0.01 mg/kg animal body weight to about 15 mg/kg animal body weight (e.g., 3.6 mg/kg), (b) with a volume of 1 µL to 150 µL (e.g., 15 µL) of a 1 mM-100 mM solution (e.g., 10 mM solution), (c) in a mole concentration amount of 1.5 µmoles to 150 µmoles (e.g., 15 µmoles), (d) in a mole amount per surface area of 1.0 µmoles/cm² to 200 µmoles/cm² (e.g., 12.5 µmoles/cm²), where the amount per surface area (in µmoles/cm²) indicates the number of moles of the compound applied to a specified surface area of the animal (e.g., wound area, scar area, acne area, radiated skin area, dermatitis area, or hair loss area). [00330] 29. The method of any of embodiments 23-28, wherein the animal is a human, a rodent, or a primate. [00331] 30. The method of any of embodiments 23-29, wherein the method further comprises administering EGF (e.g., immediately after the one or more administrations step or waiting 10 second, 30 second, 1 min., 5 min., 10 min. 15 min., 20 min. 30 min., 45 min. 60 min., 90 min. 120 min., 150 min., 180 min., 240 min., or 300 min. after the one or more administrations step). [00332] 31. A method for treating an animal for a disease or a disorder, comprising one or more administrations of one or more compositions comprising the compound of any of embodiments 1-17, wherein the compositions may be the same or different if there is more than one administration. [00333] 32. The method of embodiment 31, wherein at least one of the one or more compositions further comprises a formulary ingredient. [00334] 33. The method of embodiment 31 or embodiment 32, wherein at least one of the one or more compositions comprises the composition of embodiment 18 or the pharmaceutical composition of embodiment 19. [00335] 34. The method of any of embodiments 31-33, wherein at least one of the one or more administrations comprises parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, intrathecal administration, or intramuscular administration. [00336] 35. The method of any of embodiments 31-34, wherein if there is more than one administration at least one composition used for at least one administration is different from the composition of at least one other administration. [00337] 36. The method of any of embodiments 31-35, wherein the compound of at least one of the one or more compositions is administered to the animal (a) in an amount of from about 0.01 mg/kg animal body weight to about 15 mg/kg animal body weight (e.g., 3.6 mg/kg), (b) with a volume of 1 µL to 150 µL (e.g., 15 µL) of a 1 mM-100 mM solution (e.g., 10 mM solution), (c) in a mole concentration amount of 1.5 µmoles to 150 µmoles (e.g., 15 µmoles), (d) in a mole amount per surface area of 1.0 µmoles/cm² to 200 µmoles/cm² (e.g., 12.5 µmoles/cm²), where the amount per surface area (in µmoles/cm²) indicates the number of moles of the compound applied to a specified surface area of the animal (e.g., wound area, scar area, acne area, radiated skin area, dermatitis area, or hair loss area). [00338] 37. The method of any of embodiments 31-36, wherein the animal is a human, a rodent, or a primate. [00339] 38. The method of any of embodiments 31-37, wherein the animal is in need of the treatment. [00340] 39. The method of any of embodiments 31-38, wherein the method is for treating (a) wounds (e.g., a cornea wound), (b) scars (e.g., prevention of scars), (c) radiation-related skin reactions (e.g., decreasing the effects of radiation-related skin reactions), (d) acne, (e) dermatitis, and (f) hair loss. [00341] 40. The method of any of embodiments 31-39, wherein the method is for treating a wound, such as treating one or more cornea wounds. [00342] 41. The method of any of embodiments 31-40, wherein the method further comprises administering EGF (e.g., immediately after the one or more administrations step or waiting 10 second, 30 second, 1 min., 5 min., 10 min. 15 min., 20 min. 30 min., 45 min. 60 min., 90 min. 120 min., 150 min., 180 min., 240 min., or 300 min. after the one or more administrations step). [00343] 42. A method for preparing the compound of any of embodiments 1-17 using any suitable method, such as those disclosed herein. [00344] The headings used in the disclosure are not meant to suggest that all disclosure relating to the heading is found within the section that starts with that heading. Disclosure for any subject may be found throughout the specification. [00345] It is noted that terms like “preferably,” “commonly,” and “typically” are not used herein to limit the scope of the claimed invention or to imply that certain features are critical, essential, or even important to the structure or function of the claimed invention. Rather, these terms are merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment of the present invention. [00346] As used in the disclosure, “a” or “an” means one or more than one, unless otherwise specified. As used in the claims, when used in conjunction with the word “comprising” the words “a” or “an” means one or more than one, unless otherwise specified. As used in the disclosure or claims, “another” means at least a second or more, unless otherwise specified. As used in the disclosure, the phrases “such as”, “for example”, and “e.g.” mean “for example, but not limited to” in that the list following the term (“such as”, “for example”, or “e.g.”) provides some examples but the list is not necessarily a fully inclusive list. The word “comprising” means that the items following the word “comprising” may include additional unrecited elements or steps; that is, “comprising” does not exclude additional unrecited steps or elements. [00347] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about”. Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and claims are approximations that can vary depending upon the desired properties sought to be obtained by the presently-disclosed subject matter. [00348] As used herein, the term “about,” when referring to a value or to an amount of mass, weight, time, volume, concentration or percentage is meant to encompass variations of in some embodiments ±20%, in some embodiments ±10%, in some embodiments ±5%, in some embodiments ±1%, in some embodiments ±0.5%, and in some embodiments ±0.1% from the specified amount, as such variations are appropriate to perform the disclosed method. [00349] Detailed descriptions of one or more embodiments are provided herein. It is to be understood, however, that the present invention may be embodied in various forms. Therefore, specific details disclosed herein (even if designated as preferred or advantageous) are not to be interpreted as limiting, but rather are to be used as an illustrative basis for the claims and as a representative basis for teaching one skilled in the art to employ the present invention in any appropriate manner. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and the accompanying figures. Such modifications are intended to fall within the scope of the appended claims. [00350] What is claimed is:

Claims

CLAIMS 1. A compound selected from Formula (I), salts of Formula (I), optical isomers of Formula (I), geometric isomers of Formula (I), salts of optical isomers of Formula (I), salts of geometric isomers of Formula (I), and derivatives thereof (e.g., ethers, esters, or amides), (I); wherein - R^1a, R^1b , R^1c, and R^1d can be the same or different and are H, halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), methanoyl (-COH), nitro (-NO₂), -NH₂, -N(CH₃)₂, cyano (-CN), sulfo (- SO₃H), -C(O)NH₂, -C(O)N(CH₃)₂, -C(O)(CH₃), -C(O)(C₂H₅), -C(O)(C₃H₇), C₁-C₃ perfluoronated alkyl, -CF₃, -OCF₃, C1-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁-C₉ alkoxy, phenyl, aryl, indolyl, or hetroaryl which methanoyl (-COH), -NH₂, -N(CH₃)₂, -C(O)NH₂, - C(O)N(CH₃)₂, -C(O)(CH₃), -C(O)(C₂H₅), -C(O)(C₃H₇), C1-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁-C₉ alkoxy, phenyl, aryl, indolyl, or hetroaryl can optionally be substituted with one or more of halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), methanoyl (-COH), carboxy (-CO2H), nitro (-NO₂), -NH₂, -N(CH₃)₂, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), morpholinyl, -CO-morpholin-4-yl, -C(O)NH₂, -C(O)N(CH₃)₂, C₁-C₃ alkyl, C₁-C₃ perfluoronated alkyl, -CF₃, -OCF₃, C₁-C₃ alkoxy, aryl, aryl substituted with R^1x, phenyl, phenyl substituted with one or more R^1x, heteroaryl, heteroaryl substituted with one or more R^1x, indolyl, or indolyl substituted with one or more R^1x; - R^1x can be the same or different (e.,g., can be the same or different on the same ring or can be the same or different on different rings) and are halogen (e.g., F, Cl, Br, or I), hydroxy (- OH), methanoyl (-COH), carboxy (-CO2H), nitro (-NO₂), -NH₂, -N(CH₃)₂, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO₃H), morpholinyl, -CO-morpholin-4-yl, -C(O)NH₂, -C(O)N(CH₃)₂, C₁-C₃ alkyl, C₁-C₃ perfluoronated alkyl, -CF₃, -OCF₃, or C₁-C₄ alkoxy (e.g., methoxy or ethoxy); - R^1a and R^1b can optionally be joined to form a C3-C9 cycloalkyl, optionally substituted with halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), -NO₂, -CN, C₁-C₃ alkoxy, aryl, aryl substituted with one or more halogen (e.g., F, Cl, Br, or I), phenyl, phenyl substituted with one or more halogen (e.g., F, Cl, Br, or I), heteroaryl, heteroaryl substituted with one or more halogen (e.g., F, Cl, Br, or I), indolyl, or indolyl substituted with one or more halogen (e.g., F, Cl, Br, or I); - R^1c and R^1d can optionally be joined to form a C₃-C₉ cycloalkyl optionally substituted with halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), -NO₂, -CN, C₁-C₃ alkoxy, aryl, aryl substituted with one or more halogen (e.g., F, Cl, Br, or I), phenyl, phenyl substituted with one or more halogen (e.g., F, Cl, Br, or I), heteroaryl, heteroaryl substituted with one or more halogen (e.g., F, Cl, Br, or I), indolyl, or indolyl substituted with one or more halogen (e.g., F, Cl, Br, or I); - n is 0, 1, 2, 3, 4, 5, or 6; - R² is H, halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), methanoyl (-COH), nitro (-NO₂), -NH₂, -N(CH₃)₂, cyano (-CN), sulfo (-SO₃H), -C(O)NH₂, -C(O)N(CH₃)₂, -C(O)(CH₃), - C(O)(C2H5), -C(O)(C₃H₇), C₁-C₃ perfluoronated alkyl, -CF₃, -OCF₃, C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₁-C₆ alkoxy, aryl, hetroaryl, cycloalkyl, or heterocyclyl, which C₁-C₇ alkyl, C₂- C₇ alkenyl, C₂-C₇ alkynyl, C₁-C₆ alkoxy, aryl, hetroaryl, cycloalkyl, and heterocyclyl are optionally substituted with one or more of halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), methanoyl (-COH), nitro (-NO₂), -NH₂, -N(CH₃)₂, cyano (-CN), sulfo (-SO₃H), -C(O)NH₂, - C(O)N(CH₃)₂, -C(O)(CH₃), -C(O)(C₂H₅), -C(O)(C₃H₇), C₁-C₃ perfluoronated alkyl, -CF₃, -OCF₃, or C₁-C₃ alkoxy; and - R³, R⁴, R⁵, and R⁶ can be the same or different and are H, halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), methanoyl (-COH), nitro (-NO₂), -NH₂, -N(CH₃)₂, cyano (-CN), sulfo (-SO3H), - C(O)NH₂, -C(O)N(CH₃)₂, -C(O)(CH₃), -C(O)(C₂H₅), -C(O)(C₃H₇), C₁-C₃ perfluoronated alkyl, -CF₃, -OCF₃, C1-C6 alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, or C₁-C₅ alkoxy.

2. The compound of claim 1, wherein R^1a, R^1b , R^1c, and R^1d can be the same or different and are H, halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), methanoyl (-COH), nitro (-NO₂), -NH₂, - N(CH₃)₂, cyano (-CN), sulfo (-SO₃H), -C(O)NH₂, -C(O)N(CH₃)₂, -C(O)(CH₃), -C(O)(C₂H₅), - C(O)(C₃H₇), C₁-C₃ perfluoronated alkyl, -CF₃, -OCF₃, C1-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁-C₉ alkoxy, phenyl, aryl, indolyl, or hetroaryl which methanoyl (-COH), -NH₂, - N(CH₃)₂, -C(O)NH₂, -C(O)N(CH₃)₂, -C(O)(CH₃), -C(O)(C₂H₅), -C(O)(C₃H₇), C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁-C₉ alkoxy, phenyl, aryl, indolyl, or hetroaryl can optionally be substituted with one or more of halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), methanoyl (- COH), carboxy (-CO2H), nitro (-NO₂), -NH₂, -N(CH₃)₂, cyano (-CN), ethynyl (-CCH), propynyl, sulfo (-SO3H), morpholinyl, -CO-morpholin-4-yl, -C(O)NH₂, -C(O)N(CH₃)₂, C₁-C₃ alkyl, C₁-C₃ perfluoronated alkyl, -CF₃, -OCF₃, C₁-C₃ alkoxy, aryl, aryl substituted with one or more halogens, aryl substituted with one or more C₁-C₃ alkoxy, phenyl, phenyl substituted with one or more halogens, phenyl substituted with one or more C₁-C₃ alkoxy, heteroaryl, heteroaryl substituted with one or more halogens, heteroaryl substituted with one or more C₁-C₃ alkoxy, indolyl, indolyl substituted with one or more halogens, or indolyl substituted with one or more C₁-C₃ alkoxy.

3. The compound of claim 1 or claim 2, wherein R^1a, R^1b , R^1c, and R^1d can be the same or different and are H, halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), methanoyl (-COH), nitro (-NO₂), -NH₂, -N(CH₃)₂, cyano (-CN), sulfo (-SO3H), -C(O)NH₂, -C(O)N(CH₃)₂, -C(O)(CH₃), - C(O)(C₂H₅), -C(O)(C₃H₇), C₁-C₃ perfluoronated alkyl, -CF₃, -OCF₃, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁-C₉ alkoxy, phenyl, aryl, indolyl, or hetroaryl which methanoyl (- COH), -NH₂, -N(CH₃)₂, -C(O)NH₂, -C(O)N(CH₃)₂, -C(O)(CH₃), -C(O)(C₂H₅), -C(O)(C₃H₇), C₁- C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁-C₉ alkoxy, phenyl, aryl, indolyl, or hetroaryl can optionally be substituted with one or more of halogen (e.g., F, Cl, Br, or I), hydroxy (-OH), methanoyl (-COH), carboxy (-CO₂H), nitro (-NO₂), -NH₂, -N(CH₃)₂, cyano (-CN), ethynyl (- CCH), propynyl, sulfo (-SO3H), morpholinyl, -CO-morpholin-4-yl, -C(O)NH₂, -C(O)N(CH₃)₂, C₁-C₃ alkyl, C₁-C₃ perfluoronated alkyl, -CF₃, -OCF₃, C₁-C₃ alkoxy, aryl, aryl substituted with one or more halogens, phenyl, phenyl substituted with one or more halogens, heteroaryl, heteroaryl substituted with one or more halogens, indolyl, or indolyl substituted with one or more halogens.

4. The compound of any of claims 1-3, wherein R^1a, R^1b , R^1c, and R^1d can be the same or different and are (a) C₁-C₅ alkyl (e.g., C₂ alkyl, C₃ alkyl or C₄ alkyl) substituted with phenyl, which phenyl is substituted with one or more halogen (e.g., F, Cl, Br, or I) or -OCH₃, (b) C₁-C₅ alkyl substituted with phenyl, (c) phenyl substituted with one or more halogen (e.g., F, Cl, Br, or I) or -OCH₃, (d) phenyl, or (e) C₁-C₅ alkyl.

5. The compound of any of claims 1-4, wherein (a) R^1a and R^1b are joined to form a C₅-C₇ monocyclic cycloalkyl or (b) R^1c and R^1d are joined to form a C₅-C₇ monocyclic cycloalkyl.

6. The compound of any of claims 1-5, wherein (a) R^1a is methyl or (b) R^1c is methyl.

7. The compound of any of claims 1-6, wherein n is 1, 2, 3, or 4 (e.g., 2 or 3).

8. The compound of any of claims 1-7, wherein R² is H, methyl, ethyl, propyl, or phenyl.

9. The compound of any of claims 1-8, wherein R³ is H, -CH₃, -OCH₃, F, Cl, -CN, or -NO₂.

10. The compound of any of claims 1-9, wherein R⁴ is H, -CH₃, -OCH₃, F, Cl, -CN, or -NO₂.

11. The compound of any of claims 1-10, wherein R⁴ is H or -OCH₃.

12. The compound of any of claims 1-11, wherein R⁵ is H, -CH₃, -OCH₃, F, Cl, -CN, or -NO₂ (e.g., H or -OCH₃).

13. The compound of any of claims 1-12, wherein R⁶ is H, -CH₃, -OCH₃, F, Cl, -CN, or -NO₂.

14. The compound of any of claims 1-13, wherein R³, R⁵, and R⁶ are the same and are H.

15. The compound of any of claims 1-14, wherein such that Formula (I) is Formula (

16. The compound of any of claims 1-15, wherein R¹ is

17. A compound disclosed in this application (e.g., in the Examples of this application).

18. The compound of any of claims 1-17, wherein the compound increases EGFR phosphorylation.

19. The compound of any of claims 1-18, wherein the compound inhibits c-Cbl activity.

20. The compound of any of claims 1-19, wherein the compound inhibits c-Cbl activity and the compound has a Kd to c-Cbl of less than or equal to 750 µM, less than or equal to 100 µM, less than or equal to 10 µM, less than or equal to 5 µM, less than or equal to 1 µM, or less than or equal to 0.75 µM.

21. The compound of any of claims 1-20, wherein the compound is I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-22, I-23, I-24, I-25, I- 26, I-27, I-28, I-29, I-30, I-31, I-32, I-33, I-34, I-35, I-36, I-37, I-38, I-39, I-40, I-41, I-42, I-43, I- 44, I-45, I-46, I-47, I-48, I-49, I-50, I-51, I-52, I-53, I-54, I-55, I-56, I-57, I-58, I-59, I-60, I-61, I- 62, I-63, I-64, I-65, I-66, I-67, I-68, I-69, I-70, I-71, I-72, I-73, I-74, I-75, I-76, I-77, I-78, I-79, I- 80, I-81, I-82, I-83, I-84, I-85, I-86, I-87, I-88, I-89, I-90, I-91, or I-92.

22. The compound of any of claims 1-21, wherein the compound is I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19, I-20, I-21, I-22, I-23, I-24, I-25, I-26, I-27, I-28, I-29, I-30, I-31, I-32, I-33, I-34, I-35, I-36, I-37, I-38, I-39, I-40, I-41, I-42, I-43, I-44, I-45, I-46, I-47, I-48, I-49, I-50, I-51, I-52, I-53, I-54, I-55, I-56, I-57, I-58, I-59, I-60, I-61, I-62, I-63, I-64, I-65, I-66, I-67, I-68, I-69, I-70, I-71, I-72, I-73, I-74, I-75, I-76, I-77, I-78, I-79, I-80, I-81, I-82, I-83, I-84, I-85, I-86, I-87, I-88, I-89, I-90, I-91, or I-92.

23. The compound of any of claims 1-22, wherein the compound is I-1, I-36, I-40, I-41, I-42, I- 48, I-50, I-57, I-68, I-69, I-70, I-73, I-75, I-79, I-80, I-81, or I-82.

24. The compound of any of claims 1-23, wherein the compound is I-36, I-40, I-41, I-42, I-48, I- 50, I-57, I-68, I-69, I-70, I-73, I-75, I-79, I-80, I-81, or I-82.

25. The compound of any of claims 1-24, wherein the compound is I-40, I-41, I-42, I-48, I-50, I- 57, I-68, I-69, I-70, I-73, I-75, I-79, I-80, I-81, or I-82.

26. The compound of any of claims 1-25, wherein the compound is I-41 or I-79.

27. The compound of any of claims 1-26, wherein compound I-1 is excluded.

28. A composition comprising the compound of any of claims 1-27.

29. The composition of claim 28, wherein the compound is in an amount of from about 0.0001% to about 99%.

30. A pharmaceutical composition comprising (a) the compound of any of claims 1-27 and (b) optionally a formulary ingredient (e.g., pharmaceutically acceptable carrier, other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, and excipients).

31. The pharmaceutical composition of claim 30, wherein the compound is in an amount of from about 0.0001% to about 50%.

32. A method for providing a cell (e.g., animal cell, mammalian cell, or human cell) with a compound comprising - one or more administrations to (e.g., contacting or injecting) the cell of one or more compositions comprising (a) the compound of any of claims 1-27, (b) the composition of any of claims 28-29, or (c) the pharmaceutical composition of any of claims 30-31, wherein the compositions may be the same or different if there is more than one administration and - optionally administering EGF (e.g., immediately after the one or more administrations step or waiting 10 secs., 30 secs., 1 min., 5 mins., 10 mins., 15 mins., 20 mins., 30 mins., 45 mins., 60 mins., 90 mins., 120 mins., 150 mins., 180 mins., 240 mins., or 300 mins. after the one or more administrations step).

33. The method of claim 32, wherein the administering of EGF occurs.

34. The method of claim 32 or claim 33, wherein the administering of EGF occurs and the EGF is at a concentration of from 0.1 to 30 ng/mL.

35. A method of any of claims 32-34, wherein the cell is in vivo, ex vivo, or in vitro.

36. A method for providing an animal with a compound comprising one or more administrations to the animal of one or more compositions comprising (a) the compound of any of claims 1-27, (b) the composition of any of claims 28-29, or (c) the pharmaceutical composition of any of claims 30-31, wherein the compositions may be the same or different if there is more than one administration.

37. The method of claim 36, wherein at least one of the one or more compositions further comprises a formulary ingredient (e.g., pharmaceutically acceptable carrier, other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, and excipients).

38. The method of claim 36 or claim 37, wherein at least one of the one or more compositions comprises the composition of any of claims 28-29 or the pharmaceutical composition of any of claims 30-31.

39. The method of any of claims 36-38, wherein at least one of the one or more administrations comprises parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, inhalation administration, intrathecal administration, or intramuscular administration.

40. The method of any of claims 36-39, wherein if there is more than one administration at least one composition used for at least one administration is different from the composition of at least one other administration.

41. The method of any of claims 36-40, wherein the compound of at least one of the one or more compositions is administered to the animal (a) in an amount of from 0.01 mg/kg animal body weight to 15 mg/kg animal body weight (e.g., 3.6 mg/kg), (b) with a volume of from 1 µL to 150 µL (e.g., 20 µL) of a from 1 µM to 100 µM solution (e.g., 10 µM solution), (c) in a mole concentration amount of from 0.02 nmoles to 2.0 nmoles (e.g., 0.20 nmoles), and/or (d) in a mole amount per surface area of from 0.01 nmoles/mm² to 2.0 nmoles/mm² (e.g., 0.20 nmoles/mm²), where the amount per surface area (in nmoles/mm²) indicates the number of moles of the compound applied to a specified surface area of the animal (e.g., wound area, scar area, acne area, radiated skin area, dermatitis area, or hair loss area).

42. The method of any of claims 36-41, wherein the animal is a human, a rodent, or a primate.

43. The method of any of claims 36-42, wherein the method further comprises administering EGF (e.g., immediately after the one or more administrations step or waiting 10 secs., 30 secs., 1 min., 5 mins., 10 mins., 15 mins., 20 mins., 30 mins., 45 mins., 60 mins., 90 mins., 120 mins., 150 mins., 180 mins., 240 mins., or 300 mins. after the one or more administrations step).

44. The method of any of claims 36-43, wherein the method further comprises administering of EGF and the EGF is at a concentration of from 0.1 to 30 ng/mL.

45. A method for treating an animal for a condition, comprising one or more administrations of one or more compositions comprising (a) the compound of any of claims 1-27, (b) the composition of any of claims 28-29, or (c) the pharmaceutical composition of any of claims 30- 31, wherein the compositions may be the same or different if there is more than one administration.

46. The method of claim 45, wherein at least one of the one or more compositions further comprises a formulary ingredient.

47. The method of claim 45 or claim 46, wherein at least one of the one or more compositions comprises the composition of any of claims 28-29 or the pharmaceutical composition of any of claims 30-31.

48. The method of any of claims 45-47, wherein at least one of the one or more administrations comprises parenteral administration, a mucosal administration, intravenous administration, subcutaneous administration, topical administration, intradermal administration, oral administration, sublingual administration, intranasal administration, inhalation administration, intrathecal administration, or intramuscular administration.

49. The method of any of claims 45-48, wherein if there is more than one administration at least one composition used for at least one administration is different from the composition of at least one other administration.

50. The method of any of claims 45-49, wherein the compound of at least one of the one or more compositions is administered to the animal (a) in an amount of from 0.01 mg/kg animal body weight to 15 mg/kg animal body weight (e.g., 3.6 mg/kg), (b) with a volume of from 1 µL to 150 µL (e.g., 20 µL) of a from 1 µM to 100 µM solution (e.g., 10 µM solution), (c) in a mole concentration amount of from 0.02 nmoles to 2.0 nmoles (e.g., 0.20 nmoles), and/or (d) in a mole amount per surface area of from 0.01 nmoles/mm² to 2.0 nmoles/mm² (e.g., 0.20 nmoles/mm²), where the amount per surface area (in nmoles/mm²) indicates the number of moles of the compound applied to a specified surface area of the animal (e.g., wound area, scar area, acne area, radiated skin area, dermatitis area, or hair loss area).

51. The method of any of claims 45-50, wherein the animal is a human, a rodent, or a primate.

52. The method of any of claims 45-51, wherein the animal is in need of the treatment.

53. The method of any of claims 45-52, wherein the method is for treating conditions where re- epithelialization (e.g., of the cornea or skin) would be beneficial, conditions where an increase in re-epithelialization (e.g., of the cornea or skin) would be beneficial, conditions where an acceleration in re-epithelialization (e.g., of the cornea or skin) would be beneficial, wounds, corneal wounds, wounds related to disease, wounds related to diabetes, wounds resulting from trauma (e.g., physical, thermal, chemical, radiological, etc.), dermal wounds, corneal scars, dermal scars, acne scars, dermatitis, radiation-related skin wounds/reactions (e.g., decreasing the effects of radiation-related skin wounds/reactions), hair loss (e.g., increasing hair growth), or wounds related to battlefield injuries.

54. The method of any of claims 45-53, wherein the method is for treating (a) wounds (e.g., a corneal wound), (b) scars, (c) radiation-related skin wounds/reactions, (d) acne, (e) dermatitis, or (f) hair loss.

55. The method of any of claims 45-54, wherein the method is for treating a wound, such as treating one or more corneal wounds.

56. The method of any of claims 45-55, wherein the treating results in a decrease in the area of the wound or scar (e.g., a decrease of from 1% to 99%, from 5% to 95%, from 10% to 75%, 1%, 5%, 10% 25%, 50%, 75%, 95%, 99%, or 100% (based on the size of the original area)).

57. The method of any of claims 45-56, wherein the method further comprises administering EGF (e.g., immediately after the one or more administrations step or waiting 10 secs., 30 secs., 1 min., 5 mins., 10 mins., 15 mins., 20 mins., 30 mins., 45 mins., 60 mins., 90 mins., 120 mins., 150 mins., 180 mins., 240 mins., or 300 mins. after the one or more administrations step).

58. The method of any of claims 45-57, wherein the method further comprises administering of EGF and the EGF is at a concentration of from 0.1 to 30 ng/mL.

59. A method for preparing the compound of any of claims 1-27 comprising, (a) reacting a compound of Formula (VIII) with a compound of Formula (IX) to result in a mixture comprising a compound of Formula (Ia); (b) optionally reacting a compound of Formula (Ia) to result in a mixture comprising a compound of Formula (Ib); and (c) recovering Formula (Ia), Formula (Ib), or both, wherein Formula (VIII) is and

_{Formula (IX) is} _. 60. The method of claim 59, wherein, prior to step (a), the method further comprises one or more of Scheme 1, Scheme 2, Scheme 3, Scheme 4, or Scheme 5. 61. The method of claim 59 or claim 60, wherein step (b) occurs. 62. The method of any of claims 59-61, wherein step (b) occurs and step (c) recovers Formula (Ib). 63. The method of claim 59 or claim 60, wherein step (b) does not occur and step (c) recovers Formula (Ia).