WO2022266384A1 - Methods for treating cancer - Google Patents

Methods for treating cancer Download PDF

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Publication number
WO2022266384A1
WO2022266384A1 PCT/US2022/033878 US2022033878W WO2022266384A1 WO 2022266384 A1 WO2022266384 A1 WO 2022266384A1 US 2022033878 W US2022033878 W US 2022033878W WO 2022266384 A1 WO2022266384 A1 WO 2022266384A1
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Prior art keywords
compound
cancer
alkyl
optionally substituted
pharmaceutically acceptable
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PCT/US2022/033878
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French (fr)
Inventor
Martijn Fenaux
Weidong Zhong
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Terns Pharmaceuticals, Inc.
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Publication of WO2022266384A1 publication Critical patent/WO2022266384A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof

Definitions

  • 5-FU is intracellularly metabolized to 5-fluorouridine-5’-triphosphate (5-FUTP) and 5-fluoro-2’-deoxyuridine-5’- triphosphate (5-FdUTP), pharmacodynamically active metabolites that can be incorporated into RNA and DNA, respectively, resulting in cell death. Additionally, 5-FU is metabolized to 5-fluoro-2’-deoxyuridine-5’-monophosphate (5-FdUMP), which is believed to inhibit the activity of thymidylate synthase (TS), interrupting the production of DNA, and eventually inducing cell death (Malet-Martino et al., (2002) Oncologist, 7:288-323; see FIG. 1).
  • TS thymidylate synthase
  • 5-FU is catabolized by the enzyme dihydropyrimidine dehydrogenase (DPD) to pharmacodynamically inactive metabolites, which contributes to the neurotoxicity and cardiotoxicity of a 5-FU-based treatment regimen.
  • DPD dihydropyrimidine dehydrogenase
  • This catabolization contributes to the low half-life (5-20 min) of 5-FU and limited availability in vivo, which constitutes a major drawback of its use as a chemotherapeutic agent.
  • the activity level of DPD in patients can vary widely, thus making the bioavailability of 5-FU unpredictable, and can result in severe and even fatal 5-FU toxicity.
  • 5-FU is typically administered by either bolus injections or continuous infusion.
  • Prodrugs of 5-FU such as capecitabine, ftorafur plus uracil (UFT), and ftorafur plus 5-chloro-2,4-dihydroxypyridine plus potassium oxonate (S-1), have been developed to permit oral administration and to attempt to address the many drawbacks associated with 5- FU discussed above.
  • S-1 and capecitabine can be administered orally, switching 5-FU for either S-1 or capecitabine does not result in any significant changes in either efficacy or adverse events.
  • ftorafur-based treatment regimens can lead to certain gastrointestinal-related side effects.
  • the disclosure provides methods of treating liver cancer, colon cancer, small intestine cancer, or gastric cancer in a subject in need thereof, comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein X, R 1 , R 2 , R 3 , and R 4 are defined herein.
  • the compound of formula (I) is a compound selected from the group consisting of: ,
  • the compound of formula (I) distributes primarily to the liver, stomach and upper gastrointestinal tract following administration to a subject and distributes to a negligible extent in other tissues, including the bone marrow and skin.
  • the compound of formula (I) (e.g., Compound 1), or a pharmaceutically acceptable salt thereof, can be administered to subjects with liver cancer, gastric cancer, small intestine cancer, and colon cancer at efficacious doses without concurrent side effects often associated with administration of 5-FU or prodrugs of 5- FU (e.g., capecitabine, UFT, or S-1).
  • 5-FU e.g., capecitabine, UFT, or S-1).
  • methods of treating liver cancer, gastric cancer, small intestine cancer, or colon cancer in a subject in need thereof comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein said compound selectively accumulates in the liver and/or gastrointestinal tract.
  • the methods comprise administering to the subject a compound of formula (I) (e.g., Compound 1) or a pharmaceutically acceptable salt thereof, via oral administration.
  • liver metastases secondary liver cancer
  • methods of treating liver metastases comprising administering to the subject a compound of formula (I) (e.g., Compound 1), or a pharmaceutically acceptable salt thereof.
  • the liver metastases originate from a primary cancer including, but not limited to, colon cancer, rectal cancer, breast cancer, small intestine cancer, gastric cancer, pancreatic cancer, lung cancer, kidney cancer, skin cancer, ovarian cancer or lung cancer.
  • the compound of formula (I) is administered conjointly with a multikinase inhibitor such as sorafenib.
  • kits for treating a primary liver cancer in a subject in need thereof comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • the primary liver cancer is hepatocellular carcinoma (HCC).
  • HCC hepatocellular carcinoma
  • the subject with HCC also suffers from a chronic liver disease such as cirrhosis.
  • methods of treating gastric cancer in a subject in need thereof comprising administering to the subject a compound of formula (I) (e.g., Compound 1), or a pharmaceutically acceptable salt thereof.
  • the gastric cancer has metastasized to other tissue.
  • the gastric cancer has metastasized to the liver.
  • methods of treating small intestine cancer in a subject in need thereof comprising administering to the subject a compound of formula (I) (e.g., Compound 1), or a pharmaceutically acceptable salt thereof.
  • the small intestine cancer has metastasized to other tissue.
  • the small intestine cancer has metastasized to the liver.
  • methods of treating colon cancer in a subject in need thereof comprising administering to the subject a compound of formula (I) (e.g., Compound 1), or a pharmaceutically acceptable salt thereof.
  • the colon cancer has metastasized to other tissue.
  • the colon cancer has metastasized to the liver.
  • the colon cancer has metastasized to the small intestine or the stomach.
  • the method of treating cancer with a compound of formula (I), or a pharmaceutically acceptable salt thereof is effective for treating a subject who was unresponsive or has become refractory to a prior therapy.
  • the subject discontinued a prior therapy.
  • the subject discontinued a prior therapy due to the incidence of dermatological toxicity, myelotoxicity, or leukopenia during said prior therapy.
  • the administering reduces the occurrence or severity of dermatological toxicity or myelotoxicity relative to a prior therapy.
  • the dermatological toxicity is palmar-plantar erythrodysesthesia (hand-foot syndrome), dermatitis, or stomatitis.
  • said prior therapy comprises treatment with a 5-FU prodrug such as capecitabine, UFT, or S-1.
  • said prior therapy comprises treatment with capecitabine.
  • the prior therapy comprises treatment with a multikinase inhibitor. In some such embodiments, the multikinase inhibitor is sorafenib.
  • the compound of formula (I) is Compound 1
  • the compound can be administered orally to a subject at a dose that does not result in accumulation of the compound in the skin or the bone of a patient.
  • Compound 1 can be administered orally twice daily to a subject at a dose of from about 2 mg/kg to about 50 mg/kg.
  • Compound 1, or a pharmaceutically acceptable salt thereof can be administered orally twice daily to a subject at a dose of from about 5 mg/kg to about 50 mg/kg.
  • Compound 1, or a pharmaceutically salt thereof can be administered orally twice daily to a subject at a dose of from about 10 mg/kg to about 50 mg/kg.
  • Compound 1, or a pharmaceutically salt thereof can be administered orally twice daily to a subject at a dose of from about 20 mg/kg to about 40 mg/kg. In some embodiments, Compound 1, or a pharmaceutically salt thereof, can be administered orally twice daily to a subject at a dose of from about 30 mg/kg to about 40 mg/kg. In some embodiments, Compound 1, or a pharmaceutically salt thereof, can be administered orally twice daily to a subject at a dose of from about 30 mg/kg to about 50 mg/kg. In some embodiments, Compound 1, or a pharmaceutically salt thereof, can be administered orally twice daily to a subject at a dose of from about 40 mg/kg to about 50 mg/kg.
  • the method further comprises administering one or more additional pharmaceutical agents.
  • the one or more additional pharmaceutical agents is selected from the group consisting of cabozantinib S-malate, pembrolizumab, lenvatinib mesylate, sorafenib tosylate, nivolumab, and regorafenib.
  • the one or more additional pharmaceutical agents is leucovorin.
  • FIG. 2 shows tumor weight in an orthotopic hepatocellular carcinoma model in mice after 17 days of treatment with vehicle (IP, QD), sorafenib (30 mg/kg PO, QD), or Compound 1 (90 mg/kg IP, QD for all 17 days; 60 mg/kg IP, QD for all 17 days; or 30 mg/kg IP, BID for the first 7 days, then 20 mg/kg BID for the last 10 days).
  • FIG. 3 shows tumor weight in a metastatic gastric cancer model in mice after 21 days of treatment with vehicle (IP, BID), Xeloda (400 mg/kg PO, QD), or Compound 1 (20 mg/kg IP, BID).
  • FIG. 1 shows tumor weight in an orthotopic hepatocellular carcinoma model in mice after 17 days of treatment with vehicle (IP, QD), sorafenib (30 mg/kg PO, QD), or Compound 1 (90 mg/kg IP, QD for all 17 days; 60 mg/kg IP, QD for all 17 days; or 30 mg/
  • compositions consisting essentially of the elements as defined herein would not exclude other elements that do not materially affect the basic and novel characteristic(s) of the claimed invention.
  • Consisting of shall mean excluding more than trace amount of, e.g., other ingredients and substantial method steps recited. Embodiments defined by each of these transition terms are within the scope of this invention. Thus, it is understood that aspects and embodiments described herein as “comprising” include “consisting of” and “consisting essentially of” embodiments. [0024] “Effective amount” or dose of a compound or a composition, refers to that amount of the compound, or a pharmaceutically acceptable salt thereof, or the composition that results in an intended result as desired based on the disclosure herein.
  • Effective amounts can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., and without limitation, by determining the LD 50 (the dose lethal to 50 % of the population) and the ED 50 (the dose therapeutically effective in 50 % of the population). In some variations, the desired result or outcome is due to one or more metabolites of an administered compound.
  • excipient as used herein means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound of the invention as an active ingredient.
  • excipient including without limitation any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending/gelling agent, or wet granulation agent.
  • Subject refers to mammals and includes humans and non-human mammals. Examples of patients include, but are not limited to mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cows, and humans. In some embodiments, patient refers to a human.
  • “Pharmaceutically acceptable” refers to safe and non-toxic, preferably for in vivo, more preferably, for human administration.
  • “Pharmaceutically acceptable salt” refers to a salt that is pharmaceutically acceptable. A compound described herein may be administered as a pharmaceutically acceptable salt.
  • Prodrug refers to a compound that, after administration, is metabolized or otherwise converted to a biologically active or more active compound (or drug) with respect to at least one property.
  • a prodrug, relative to the drug is modified chemically in a manner that renders it, relative to the drug, less active or inactive, but the chemical modification is such that the corresponding drug is generated by metabolic or other biological processes after the prodrug is administered.
  • a prodrug may have, relative to the active drug, altered metabolic stability or transport characteristics, fewer side effects or lower toxicity, or improved flavor (for example, see the reference Nogrady, 1985, Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392, incorporated herein by reference).
  • a prodrug may be synthesized using reactants other than employing the corresponding drug.
  • prodrugs include, carboxy esters, linear and cyclic phosphate esters and phosphoramides and phosphoramidates, carbamates, preferably phenolic carbamates (i.e., carbamates where the hydroxy group is part of an aryl or heteroaryl moiety, where the aryl and heteroaryl may be optionally substituted), and the like.
  • Salt refers to an ionic compound formed between an acid and a base. When the compound provided herein contains an acidic functionality, such salts include, without limitation, alkali metal, alkaline earth metal, and ammonium salts.
  • ammonium salts include, salts containing protonated nitrogen bases and alkylated nitrogen bases.
  • Exemplary and non-limiting cations useful in pharmaceutically acceptable salts include Na, K, Rb, Cs, NH 4 , Ca, Ba, imidazolium, and ammonium cations based on naturally occurring amino acids.
  • such salts include, without limitation, salts of organic acids, such as carboxylic acids and sulfonic acids, and mineral acids, such as hydrogen halides, sulfuric acid, phosphoric acid, and the like.
  • anions useful in pharmaceutically acceptable salts include oxalate, maleate, acetate, propionate, succinate, tartrate, chloride, sulfate, bisulfate, mono-, di-, and tribasic phosphate, mesylate, tosylate, and the like.
  • “Therapeutically effective amount” or dose of a compound or a composition refers to that amount of the compound or the composition that results in reduction or inhibition of symptoms or a prolongation of survival in a patient. The results may require multiple doses of the compound or the composition. In some variations, the desired therapeutic outcome is due to one or more metabolites of an administered compound.
  • beneficial or desired results include, but are not limited to, one or more of the following: decreasing one more symptoms resulting from the disease or disorder, diminishing the extent of the disease or disorder, stabilizing the disease or disorder (e.g., preventing or delaying the worsening of the disease or disorder), delaying the occurrence or recurrence of the disease or disorder, delay or slowing the progression of the disease or disorder, ameliorating the disease or disorder state, providing a remission (whether partial or total) of the disease or disorder, decreasing the dose of one or more other medications required to treat the disease or disorder, enhancing the effect of another medication used to treat the disease or disorder, delaying the progression of the disease or disorder, increasing the quality of life, and/or prolonging survival of a patient.
  • treatment is a reduction of pathological consequence of the disease or disorder.
  • the methods of the invention contemplate any one or more of these aspects of treatment.
  • “upper gastrointestinal tract” or “upper GI” refers to the stomach and small intestine.
  • R 1 is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 6 -C 10 aryl, or optionally substituted 5- to 10-membered heteroaryl; or R 1 and one R 5 group are taken together with the atoms to which they are attached to form an optionally substituted 5- to 7-membered heterocyclyl;
  • R 2 is H, optionally substituted C 1 -C 6 alkyl, -OR 5 , or -N(R 5 ) 2 ; or R 1 and R 2 are taken together with the carbon atom to which they are attached to form an optionally substituted 4- to 7-membered heterocyclyl or an optionally substituted C 3 -
  • X is O, C(R 6 ) 2 , or a bond. In some embodiments, X is O. In some embodiments, X is a bond. In some embodiments, X is C(R 6 ) 2 .
  • each R 6 is independently H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 3 -C 6 cycloalkyl; or two R 6 groups are taken together with the carbon atom to which they are attached to form an optionally substituted C 3 -C 6 cycloalkyl or an optionally substituted 3- to 7-membered heterocyclyl.
  • each R 6 is independently H; C 1 -C 6 alkyl optionally substituted with halogen, -OH, -CN, or -NH 2 ; or C 3 - C 6 cycloalkyl optionally substituted with halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or two R 6 groups are taken together with the carbon atom to which they are attached to form a C 3 -C 6 cycloalkyl or a 3- to 7-membered heterocyclyl, each of which is optionally substituted with halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R 6 is independently H or unsubstituted C 1 -C 3 alkyl. In some embodiments, each R 6 is independently H or -CH 3 . [0038] In some embodiments, each R 6 is independently H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C3-C6 cycloalkyl.
  • each R 6 is independently H; C 1 -C 6 alkyl optionally substituted with halogen, -OH, -CN, or -NH 2 ; or C 3 - C 6 cycloalkyl optionally substituted with halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • two R 6 groups are taken together with the carbon atom to which they are attached to form a C 3 -C 6 cycloalkyl or a 3- to 7-membered heterocyclyl, each of which is optionally substituted with halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R 6 is independently H or unsubstituted C 1 -C 3 alkyl.
  • each R 6 is independently H or -CH 3 .
  • each R 6 is independently optionally substituted C 1 -C 6 alkyl.
  • each R 6 is independently C 1 -C 6 alkyl substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, and -NH 2 . In some embodiments, each R 6 is independently unsubstituted C 1 -C 6 alkyl. In some embodiments, each R 6 is independently C 1 -C 3 alkyl optionally substituted with halogen, -OH, -CN, or -NH 2 .
  • each R 6 is independently C 1 -C 3 alkyl, such as methyl, ethyl, n-propyl, or isopropyl, which is optionally substituted with halogen, -OH, -CN, or -NH 2 .
  • each R 6 is independently C 1 -C 3 alkyl, such as methyl, ethyl, n-propyl, or isopropyl, which is substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, and -NH 2 .
  • each R 6 is independently unsubstituted C 1 -C 3 alkyl, such as methyl, ethyl, n-propyl, or isopropyl. In some embodiments, both R 6 groups are -CH 3 . [0040] In some embodiments, each R 6 is independently optionally substituted C 3 -C 6 cycloalkyl. In some embodiments, each R 6 is independently C 3 -C 6 cycloalkyl optionally substituted with halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R 6 is independently C 3 -C 6 cycloalkyl substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, and C 1 - C 6 haloalkyl. In some embodiments, each R 6 is independently unsubstituted C 3 -C 6 cycloalkyl. [0041] In some embodiments, the two R 6 groups are the same. In some embodiments, both R 6 groups are H.
  • both R 6 groups are C 1 -C 6 alkyl substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, and -NH 2 . In some embodiments, both R 6 groups are C 1 -C 3 alkyl substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, and -NH2. In some embodiments, both R 6 groups are unsubstituted C 1 -C 3 alkyl. In some embodiments, both R 6 groups are -CH 3 . [0042] In some embodiments, the two R 6 groups are not the same.
  • At least one R 6 group is C 1 -C 6 alkyl optionally substituted with halogen, -OH, -CN, or -NH 2 . In some embodiments, at least one R 6 group is C 1 -C 3 alkyl optionally substituted with halogen, -OH, -CN, or -NH 2 . In some embodiments, at least one R 6 group is unsubstituted C 1 - C 3 alkyl, such as methyl, ethyl, n-propyl, or isopropyl.
  • At least one R 6 group is C 3 -C 6 cycloalkyl optionally substituted with halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments, at least one R 6 group is unsubstituted C 3 -C 6 cycloalkyl. In some embodiments, one R 6 is H and the other R 6 is optionally substituted C 1 - C 6 alkyl or optionally substituted C 3 -C 6 cycloalkyl.
  • X is CH(C 1 -C 6 alkyl), wherein the C 1 -C 6 alkyl is optionally substituted with halogen, -OH, -CN, or -NH 2 .
  • the C 1 -C 6 alkyl is substituted with one, two, or three groups selected from the group consisting of halogen, - OH, -CN, and -NH 2 .
  • X is CH(unsubstituted C 1 -C 6 alkyl).
  • X is CH(C 1 -C 3 alkyl), wherein the C 1 -C 3 alkyl is optionally substituted with halogen, -OH, -CN, or -NH 2 .
  • X is CH(C 1 -C 3 alkyl), wherein the C 1 -C 3 alkyl is substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, and -NH 2 .
  • X is CH(methyl), CH(ethyl), CH(n- propyl), or CH(isopropyl), wherein the methyl, ethyl, n-propyl, and isopropyl are optionally substituted with halogen, -OH, -CN, or -NH 2 .
  • X is CH(methyl), CH(ethyl), CH(n-propyl), or CH(isopropyl), wherein the methyl, ethyl, n-propyl, and isopropyl are substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, and -NH 2 .
  • X is CH(methyl), CH(ethyl), CH(n- propyl), or CH(isopropyl). In some embodiments, X is CH(CH 3 ). [0044] In some embodiments, X is CH(C 3 -C 6 cycloalkyl), wherein the C 3 -C 6 cycloalkyl is optionally substituted with halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • the C 3 -C 6 cycloalkyl is substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl. In some embodiments, the C 3 -C 6 cycloalkyl is unsubstituted. In some embodiments, X is CH(cyclopropyl), CH(cyclobutyl), CH(cyclopentyl), or CH(cyclohexyl).
  • two R 6 groups are taken together with the carbon atom to which they are attached to form a C 3 -C 6 cycloalkyl optionally substituted with halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • the C 3 -C 6 cycloalkyl is substituted with one, two, or three groups selected from the group consisting of halogen, - OH, -CN, -NH 2 , C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl.
  • the C 3 -C 6 cycloalkyl is unsubstituted.
  • two R 6 groups are taken together with the carbon atom to which they are attached to form a 3- to 7-membered heterocyclyl optionally substituted with halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • the 3- to 7- membered heterocyclyl is aziridinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, thianyl, azepanyl, oxepanyl, thiepanyl, pyrazolidinyl, imidazolidinyl, dioxolanyl, oxazolidinyl, isoxazolidinyl, morpholinyl, or thiomorpholinyl, each of which is optionally substituted with halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • the 3- to 7-membered heterocyclyl is substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, and C 1 - C 6 haloalkyl.
  • the 3- to 7-membered heterocyclyl is unsubstituted.
  • the 3- to 7-membered heterocyclyl contains one or two nitrogen atoms.
  • the 3- to 7-membered heterocyclyl contains one nitrogen atom.
  • the 3- to 7-membered heterocyclyl contains one or two oxygen atoms.
  • the 3- to 7-membered heterocyclyl contains one oxygen atom.
  • the 3- to 7-membered heterocyclyl contains one or two sulfur atoms. In some embodiments, the 3- to 7-membered heterocyclyl contains one sulfur atom. In some embodiments, the 3- to 7-membered heterocyclyl contains one nitrogen atom and two oxygen atoms. In some embodiments, the 3- to 7-membered heterocyclyl contains two nitrogen atoms and one oxygen atom. In some embodiments, the 3- to 7-membered heterocyclyl contains one nitrogen atom and one oxygen atom. In some embodiments, the 3- to 7-membered heterocyclyl contains one nitrogen atom and two sulfur atoms.
  • the 3- to 7-membered heterocyclyl contains two nitrogen atoms and one sulfur atom. In some embodiments, the 3- to 7-membered heterocyclyl contains one nitrogen atom and one sulfur atom. In some embodiments, the 3- to 7-membered heterocyclyl contains one oxygen atom and two sulfur atoms. In some embodiments, the 3- to 7-membered heterocyclyl contains two oxygen atoms and one sulfur atom. In some embodiments, the 3- to 7-membered heterocyclyl contains one oxygen atom and one sulfur atom.
  • R 1 is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 6 -C 10 aryl, or optionally substituted 5- to 10-membered heteroaryl.
  • R 1 and one R 5 group are taken together with the atoms to which they are attached to form an optionally substituted 5- to 7-membered heterocyclyl.
  • R 1 and R 2 are taken together with the carbon atom to which they are attached to form an optionally substituted 4- to 7-membered heterocyclyl or an optionally substituted C 3 -C 6 cycloalkyl.
  • R 1 is H; C 1 -C 6 alkyl optionally substituted with halogen, -OH, -CN, or -NH 2 ; or C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with halogen, -OH, - CN, -NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 1 is H or unsubstituted C 1 -C 3 alkyl.
  • R 1 is H or -CH 3 .
  • R 1 and one R 5 group are taken together with the atoms to which they are attached to form a 5- to 7- membered heterocyclyl optionally substituted with halogen, -OH, -NH 2 , C 1 -C 6 alkyl, or C 1 - C 6 haloalkyl.
  • R 1 and one R 5 group are taken together with the atoms to which they are attached to form an unsubstituted 5- to 6-membered heterocyclyl.
  • R1 and one R 5 group are taken together with the atoms to which they are attached to form an unsubstituted 5-membered heterocyclyl.
  • R 1 and R 2 are taken together with the carbon atom to which they are attached to form a 4- to 7- membered heterocyclyl or C 3 -C 6 cycloalkyl, each of which is optionally substituted with halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 1 and R 2 are taken together with the carbon atom to which they are attached to form an unsubstituted 5- to 6-membered heterocyclyl.
  • R 1 and R 2 are taken together with the carbon atom to which they are attached to form an unsubstituted pyrrolidinyl.
  • R 1 is H. [0049] In some embodiments, R 1 is optionally substituted C 1 -C 6 alkyl. In some embodiments, R 1 is C 1 -C 6 alkyl optionally substituted with halogen, -OH, -CN, or -NH 2 . In some embodiments, R 1 is C 1 -C 6 alkyl substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, and -NH 2 . In some embodiments, R 1 is unsubstituted C1-C6 alkyl.
  • R 1 is C1-C3 alkyl, such as methyl, ethyl, n- propyl, or isopropyl, which is optionally substituted with halogen, -OH, -CN, or -NH 2 .
  • R 1 is C 1 -C 3 alkyl, such as methyl, ethyl, n-propyl, or isopropyl, which is substituted with one, two, or three groups selected from the group consisting of halogen, - OH, -CN, and -NH 2 .
  • R 1 is unsubstituted C 1 -C 3 alkyl, such as methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 1 is -CH 3 . [0050] In some embodiments, R 1 optionally substituted C 3 -C 6 cycloalkyl. In some embodiments, R 1 is C 3 -C 6 cycloalkyl optionally substituted with halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 1 is C 3 -C 6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, which is optionally substituted with halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 1 is C cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, which is substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, - NH 2 , C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl.
  • R 1 is unsubstituted C 3 -C 6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 1 is optionally substituted C 6 -C 10 aryl.
  • R 1 is C 6 -C 10 aryl optionally substituted with halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 1 is C 6 -C 10 aryl, such as phenyl or naphthyl, which is optionally substituted with halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, or C 1 - C 6 haloalkyl.
  • R 1 is C 6 -C 10 aryl, such as phenyl or naphthyl, which is substituted with one, two, or three groups selected from the group consisting of halogen, - OH, -CN, -NH 2 , C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl.
  • R 1 is unsubstituted C 6 -C 10 aryl, such as phenyl or naphthyl.
  • R 1 is phenyl substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, -NH 2 , C 1 - C 6 alkyl, and C 1 -C 6 haloalkyl. In some embodiments, R 1 is unsubstituted phenyl. [0052] In some embodiments, R 1 is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, the 5- to 10-membered heteroaryl is optionally substituted with halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • the 5- to 10-membered heteroaryl such as a 5- to 6- membered heteroaryl, contains one or two nitrogen atoms. In some embodiments, the 5- to 10-membered heteroaryl contains one nitrogen atom. In some embodiments, the 5- to 10- membered heteroaryl contains one or two oxygen atoms. In some embodiments, the 5- to 10- membered heteroaryl contains one oxygen atom. In some embodiments, the 5- to 10- membered heteroaryl contains one or two sulfur atoms. In some embodiments, the 5- to 10- membered heteroaryl contains one sulfur atom. In some embodiments, the 5- to 10-membered heteroaryl contains one nitrogen atom and two oxygen atoms.
  • the 5- to 10-membered heteroaryl contains two nitrogen atoms and one oxygen atom. In some embodiments, the 5- to 10-membered heteroaryl contains one nitrogen atom and one oxygen atom. In some embodiments, the 5- to 10-membered heteroaryl contains one nitrogen atom and two sulfur atoms. In some embodiments, the 5- to 10-membered heteroaryl contains two nitrogen atoms and one sulfur atom. In some embodiments, the 5- to 10-membered heteroaryl contains one nitrogen atom and one sulfur atom. In some embodiments, the 5- to 10- membered heteroaryl contains one oxygen atom and two sulfur atoms. In some embodiments, the 5- to 10-membered heteroaryl contains two oxygen atoms and one sulfur atom.
  • the 5- to 10-membered heteroaryl contains one oxygen atom and one sulfur atom.
  • the 5- to 10-membered heteroaryl such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, thiophenyl, oxazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, or naphthyridinyl, is optionally substituted with halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • the 5- to 10-membered heteroaryl is substituted with one, two, or three groups selected from the group consisting of halogen, - OH, -CN, -NH 2 , C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl.
  • the 5- to 10- membered heteroaryl including any variation detailed herein, is unsubstituted.
  • R 1 and one R 5 group are taken together with the atoms to which they are attached to form an optionally substituted 5- to 7-membered heterocyclyl.
  • the 5- to 7-membered heterocyclyl is optionally substituted with halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • the 5- to 7- membered heterocyclyl is substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl.
  • the 5- to 7-membered heterocyclyl is unsubstituted.
  • the additional heteroatoms are two nitrogen atoms.
  • the additional heteroatom is one nitrogen atom.
  • the additional heteroatoms are two oxygen atoms.
  • the additional heteroatom is one oxygen atom.
  • the additional heteroatoms are two sulfur atoms.
  • the additional heteroatom is one sulfur atom.
  • the additional heteroatoms are one nitrogen atom and one oxygen atom. In some embodiments, the additional heteroatoms are one nitrogen atom and one sulfur atom. In some embodiments, the additional heteroatoms are one oxygen atom and one sulfur atom. In some embodiments, the 5- to 7-membered substituted with halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • the 5- to 7-membered heterocyclyl is substituted with one, two, or three groups selected from the group consisting of halogen, - OH, -CN, -NH 2 , C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl.
  • the 5- to 7- membered heterocyclyl is unsubstituted.
  • the 5- to 7-membered heterocyclyl is a 5- to 6-membered heterocyclyl optionally substituted with halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • the 5- to 7-membered heterocyclyl is unsubstituted 5- to 6-membered heterocyclyl.
  • the 5- to 7-membered heterocyclyl is a 5-membered heterocyclyl optionally substituted with halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • the 5- to 7-membered heterocyclyl is unsubstituted 5- membered heterocyclyl.
  • the 5- to 7-membered heterocyclyl is pyrrolidin-2-yl optionally substituted with halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • the 5- to 7-membered heterocyclyl is unsubstituted pyrrolidin-2-yl.
  • R 1 and R 2 are taken together with the carbon atom to which they are attached to form an optionally substituted 4- to 7-membered heterocyclyl.
  • the 4- to 7-membered heterocyclyl is optionally substituted with halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • the 4- to 7- membered heterocyclyl is substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl.
  • the 4- to 7-membered heterocyclyl is unsubstituted.
  • the 4- to 7-membered heterocyclyl contains one or two nitrogen atoms.
  • the 4- to 7- membered heterocyclyl contains one nitrogen atom.
  • the 4- to 7- membered heterocyclyl contains one or two oxygen atoms.
  • the 4- to 7- membered heterocyclyl contains one oxygen atom. In some embodiments, the 4- to 7- membered heterocyclyl contains one or two sulfur atoms. In some embodiments, the 4- to 7- membered heterocyclyl contains one sulfur atom. In some embodiments, the 4- to 7- membered heterocyclyl contains one nitrogen atom and two oxygen atoms. In some embodiments, the 4- to 7-membered heterocyclyl contains two nitrogen atoms and one oxygen atom. In some embodiments, the 4- to 7-membered heterocyclyl contains one nitrogen atom and one oxygen atom. In some embodiments, the 4- to 7-membered heterocyclyl contains one nitrogen atom and two sulfur atoms.
  • the 4- to 7-membered heterocyclyl contains two nitrogen atoms and one sulfur atom. In some embodiments, the 4- to 7-membered heterocyclyl contains one nitrogen atom and one sulfur atom. In some embodiments, the 4- to 7-membered heterocyclyl contains one oxygen atom and two sulfur atoms. In some embodiments, the 4- to 7-membered heterocyclyl contains two oxygen atoms and one sulfur atom. In some embodiments, the 4- to 7-membered heterocyclyl contains one oxygen atom and one sulfur atom.
  • the 4- to 7-membered heterocyclyl such as , , , , , , , , , is optionally substituted with halogen, -OH, -CN, -NH 2, C1-C6 alkyl, or C 1 -C 6 haloalkyl.
  • the 4- to 7-membered heterocyclyl including any variation detailed herein, is substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl.
  • the 4- to 7-membered heterocyclyl is unsubstituted.
  • the 4- to 7-membered heterocyclyl is a 5- to 6-membered heterocyclyl optionally substituted with halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • the 4- to 7-membered heterocyclyl is unsubstituted 5- to 6-membered heterocyclyl.
  • the 4- to 7-membered heterocyclyl is a 5-membered heterocyclyl optionally substituted with halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments, the 4- to 7-membered heterocyclyl is unsubstituted 5-membered heterocyclyl. In some embodiments, the 4- to 7-membered heterocyclyl is pyrrolidinyl optionally substituted with halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, or C 1-C6 haloalkyl.
  • the 4- to 7-membered heterocyclyl is unsubstituted pyrrolidinyl.
  • R 1 and R 2 are taken together with the carbon atom to which they are attached to form an optionally substituted cycloalkyl.
  • the C 3 -C 6 cycloalkyl is optionally substituted with halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • the C 3 -C 6 cycloalkyl is substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, - NH 2 , C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl.
  • the C 3 -C 6 cycloalkyl is unsubstituted.
  • R 1 and R 2 are taken together with the carbon atom to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 2 is H, optionally substituted C 1 -C 6 alkyl, -OR 5 , or - or R 1 and R 2 are taken together with the carbon atom to which they are attached to form an optionally substituted 4- to 7-membered heterocyclyl or an optionally substituted C 3 - C6 cycloalkyl.
  • R 2 is H; C1-C6 alkyl optionally substituted with halogen, -OH, -CN, or -NH 2 ; -OR 5 ; or -N(R 5 ) 2 .
  • R 2 is H, unsubstituted C 1 -C 3 alkyl, -O(unsubstituted C 1 -C 6 alkyl), -OH, -NH 2 , or -NH(unsubstituted C 1 -C 6 alkyl).
  • R 2 is H, -CH 3 , -OCH 3 , -OH, -NH 2 , or -N(H)CH 3 .
  • R 2 is H.
  • R 2 is optionally substituted C 1 -C 6 alkyl.
  • R 2 is C 1 -C 6 alkyl optionally substituted with halogen, -OH, -CN, or -NH 2 . In some embodiments, R 2 is C 1 -C 6 alkyl substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, and -NH 2 . In some embodiments, R 2 is unsubstituted C 1 -C 6 alkyl. In some embodiments, R 2 is C 1 -C 3 alkyl, such as methyl, ethyl, n- propyl, or isopropyl, which is optionally substituted with halogen, -OH, -CN, or -NH 2 .
  • R 2 is C 1 -C 3 alkyl, such as methyl, ethyl, n-propyl, or isopropyl, which is substituted with one, two, or three groups selected from the group consisting of halogen, - OH, -CN, and -NH 2 .
  • R 2 is unsubstituted C 1 -C 3 alkyl, such as methyl, ethyl, n-propyl, or isopropyl.
  • R 2 is -CH 3 .
  • R 2 is -OR 5 .
  • R 2 is –OH, – O(optionally substituted C 1 -C 6 alkyl), or –O(optionally substituted C 3 -C 6 cycloalkyl). In some embodiments, R 2 is –OH. In some embodiments, R 2 is –O(C 1 -C 6 alkyl) optionally substituted with halogen, -OH, -CN, or -NH 2 . In some embodiments, R 2 is –O(C 1 -C 6 alkyl) substituted with one, two, or three groups selected from the group consisting of halogen, - OH, -CN, and -NH 2 .
  • R 2 is–O(unsubstituted C 1 -C 6 alkyl). In some embodiments, R 2 is –O(C 1 -C 3 alkyl) optionally substituted with halogen, -OH, -CN, or -NH 2 . In some embodiments, R 2 is –O(C 1 -C 3 alkyl), such as –O(methyl), –O(ethyl), –O(n-propyl), or –O(isopropyl), which is optionally substituted with halogen, -OH, -CN, or -NH 2 .
  • R 2 is –O(C 1 -C 3 alkyl), such as –O(methyl), –O(ethyl), –O(n-propyl), or – O(isopropyl), which is substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, and -NH 2 .
  • R 2 is–O(unsubstituted C 1 - C 3 alkyl), such as –O(methyl), –O(ethyl), –O(n-propyl), or –O(isopropyl).
  • R 2 is –OCH 3 .
  • R 2 is –O(C 3 -C 6 cycloalkyl) optionally substituted with halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 2 is –O(C 3 -C 6 cycloalkyl), such as –O(cyclopropyl), –O(cyclobutyl), – O(cyclopentyl), or –O(cyclohexyl), which is optionally substituted with halogen, -OH, -CN, - NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 2 is –O(C 3 -C 6 cycloalkyl), such as –O(cyclopropyl), –O(cyclobutyl), –O(cyclopentyl), or –O(cyclohexyl), which is substituted with one, two, or three groups selected from the group consisting of halogen, - OH, -CN, -NH 2 , C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl.
  • R 2 is – O(unsubstituted C 3 -C 6 cycloalkyl), such as –O(cyclopropyl), –O(cyclobutyl), – O(cyclopentyl), or –O(cyclohexyl).
  • R 2 is –N(R 5 ) 2 .
  • each R 5 is independently H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 3 -C 6 cycloalkyl.
  • each R 5 is independently C 1 -C 6 alkyl optionally substituted with halogen, -OH, -CN, or -NH 2 .
  • each R 5 is independently unsubstituted C 1 -C 6 alkyl. In some embodiments, each R 5 is independently C 1 - C 3 alkyl optionally substituted with halogen, -OH, -CN, or -NH 2 . In some embodiments, each R 5 is independently unsubstituted C 1 -C 3 alkyl. In some embodiments, both R 5 groups are - CH 3 . [0061] In some embodiments, R 2 is –N(R 5 ) 2 , and both R 5 groups are the same. In some embodiments, R 2 is –NH 2 . In some embodiments, R 2 is –N(CH 3 ) 2 .
  • R 2 is –N(R 5 ) 2 , and the two R 5 groups are not the same.
  • at least one R 5 is C 1 -C 6 alkyl optionally substituted with halogen, -OH, - CN, or -NH 2 .
  • at least one R 5 is C 1 -C 3 alkyl optionally substituted with halogen, -OH, -CN, or -NH 2 .
  • at least one R 5 is unsubstituted C 1 -C 3 alkyl, such as methyl, ethyl, n-propyl, or isopropyl.
  • At least one R 5 is C 3 -C 6 cycloalkyl optionally substituted with halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments, at least one R 5 is unsubstituted C 3 -C 6 cycloalkyl. In some embodiments, one R 5 is H and the other R 5 is optionally substituted C 1 -C 6 alkyl or optionally substituted C 3 -C 6 cycloalkyl.
  • R 2 is –NH(C 1 -C 6 alkyl), wherein the C 1 -C 6 alkyl is optionally substituted with halogen, -OH, -CN, or -NH 2 .
  • R 2 is – NH(C 1 -C 6 alkyl), wherein the C 1 -C 6 alkyl is substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, and -NH 2 .
  • R 2 is –NH(unsubstituted C 1 -C 6 alkyl).
  • R 2 is –NH(C 1 -C 3 alkyl), wherein the C 1 -C 3 alkyl is optionally substituted with halogen, -OH, -CN, or -NH 2 .
  • R 2 is –NH(C 1 -C 3 alkyl), wherein the C 1 -C 3 alkyl is substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, and -NH 2 .
  • R 2 is –NH(methyl), –NH(ethyl), –NH(n-propyl), or –NH(isopropyl), wherein the methyl, ethyl, n-propyl, and isopropyl are optionally substituted with halogen, -OH, -CN, or -NH 2 .
  • R 2 is –NH(methyl), –NH(ethyl), –NH(n-propyl), or – NH(isopropyl), wherein the methyl, ethyl, n-propyl, and isopropyl are substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, and -NH 2 .
  • R 2 is –NH(methyl), –NH(ethyl), –NH(n-propyl), or –NH(isopropyl).
  • R 2 is –NH(CH 3 ).
  • R 2 is –NH(C 3 -C 6 cycloalkyl), wherein the C 3 -C 6 cycloalkyl is optionally substituted with halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 2 is –NH(C 3 - 6 cycloalkyl), wherein the C 3 -C 6 cycloalkyl is substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, - NH 2 , C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl.
  • R 2 is —NH(unsubstituted C 3 -C 6 cycloalkyl). In some embodiments, R 2 is –NH(cyclopropyl), –NH(cyclobutyl), – NH(cyclopentyl), or –NH(cyclohexyl). [0065] In some embodiments, R 2 is –N(R 5 ) 2 and two R 5 groups are taken together with the nitrogen atom to which they are attached to form an optionally substituted 5- to 7- membered heterocyclyl.
  • the 5- to 7-membered heterocyclyl is optionally substituted with halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments, the 5- to 7-membered heterocyclyl is substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, and C 1 - C 6 haloalkyl. In some embodiments, the 5- to 7-membered heterocyclyl is unsubstituted.
  • the 5- to 7-membered heterocyclyl contains two additional ring heteroatoms which are the same as each other.
  • the 5- to 7-membered heterocyclyl contains two additional ring heteroatoms which are different from each other.
  • the additional heteroatoms are two nitrogen atoms.
  • the additional heteroatom is one nitrogen atom. In some embodiments, the additional heteroatoms are two oxygen atoms. In some embodiments, the additional heteroatom is one oxygen atom. In some embodiments, the additional heteroatoms are two sulfur atoms. In some embodiments, the additional heteroatom is one sulfur atom. In some embodiments, the additional ring heteroatoms are one nitrogen atom and one oxygen atom. In some embodiments, the additional ring heteroatoms one nitrogen atom and one sulfur atom. In some embodiments, the additional ring heteroatoms are one oxygen atom and one sulfur atom.
  • the 5- to 7-membered heterocyclyl such as optionally substituted with halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • the 5- to 7-membered heterocyclyl including any variation detailed herein, is substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl.
  • the 5- to 7-membered heterocyclyl including any variation detailed herein, is unsubstituted.
  • the 5- to 7-membered heterocyclyl is a 5- to 6-membered heterocyclyl optionally substituted with halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • the 5- to 7-membered heterocyclyl is an unsubstituted 5- to 6-membered heterocyclyl.
  • R 3 is H or optionally substituted C 1 -C 6 alkyl.
  • R 3 is H; or C 1 -C 6 alkyl optionally substituted with halogen, -OH, -CN, or - NH2.
  • R 3 is H or unsubstituted C1-C3 alkyl. In some embodiments, R 3 is H or -CH 3 . [0067] In some embodiments, R 3 is H. [0068] In some embodiments, R 3 is optionally substituted C 1 -C 6 alkyl. In some embodiments, R 3 is C 1 -C 6 alkyl optionally substituted with halogen, -OH, -CN, or -NH 2 . In some embodiments, R 3 is C 1 -C 6 alkyl substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, and -NH 2 .
  • R 3 is unsubstituted C 1 -C 6 alkyl.
  • R 3 is C 1 -C 3 alkyl, such as methyl, ethyl, n- propyl, or isopropyl, which is optionally substituted with halogen, -OH, -CN, or -NH 2 .
  • R 3 is C 1 -C 3 alkyl, such as methyl, ethyl, n-propyl, or isopropyl, which is substituted with one, two, or three groups selected from the group consisting of halogen, - OH, -CN, and -NH 2 .
  • R 3 is unsubstituted C 1 -C 3 alkyl, such as methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 3 is –CH 3 . [0069] In some embodiments, R 4 is H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 3 -C 6 cycloalkyl.
  • R 4 is H; C 1 -C 6 alkyl optionally substituted with halogen, -OH, -CN, or -NH 2 ; or C 3 -C 6 cycloalkyl optionally substituted with halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 4 is H or unsubstituted C 1 -C 3 alkyl.
  • R 4 is H or -CH 3 .
  • R 4 is H.
  • R 4 is optionally substituted C 1 -C 6 alkyl.
  • R 4 is C 1 -C 6 alkyl optionally substituted with halogen, -OH, -CN, or -NH 2 . In some embodiments, R 4 is C 1 -C 6 alkyl substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, and -NH 2 . In some embodiments, R 4 is unsubstituted C 1 -C 6 alkyl. In some embodiments, R 4 is C 1 -C 3 alkyl, such as methyl, ethyl, n- propyl, or isopropyl, which is optionally substituted with halogen, -OH, -CN, or -NH 2 .
  • R 4 is C 1 -C 3 alkyl, such as methyl, ethyl, n-propyl, or isopropyl, which is substituted with one, two, or three groups selected from the group consisting of halogen, - OH, -CN, and -NH 2 .
  • R 4 is unsubstituted C 1 -C 3 alkyl, such as methyl, ethyl, n-propyl, or isopropyl.
  • R 4 is –CH 3 .
  • R 4 is optionally substituted C 3 -C 6 cycloalkyl.
  • R 4 is C 3 -C 6 cycloalkyl optionally substituted with halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 4 is C 3 -C 6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, which is optionally substituted with halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 4 is C 3 -C 6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, which is substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, - NH 2 , C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl.
  • R 4 is unsubstituted C 3 -C 6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • each R 5 is independently H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 3 -C 6 cycloalkyl; or two R 5 groups are taken together with the nitrogen atom to which they are attached to form an optionally substituted 5- to 7-membered heterocyclyl;or R 1 and one R 5 group are taken together with the atoms to which they are attached to form an optionally substituted 5- to 7-membered heterocyclyl.
  • R 5 is H; C 1 -C 6 alkyl optionally substituted with halogen, -OH, -CN, or -NH 2 ; or C 3 -C 6 cycloalkyl optionally substituted with halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, or C 1 - C 6 haloalkyl.
  • at least one R 5 is H.
  • both R 5 groups are H.
  • R 2 is -OR 5
  • R 5 is H.
  • each R 5 is independently optionally substituted C 1 -C 6 alkyl. In some embodiments, each R 5 is independently C 1 -C 6 alkyl optionally substituted with halogen, -OH, -CN, or -NH 2 . In some embodiments, each R 5 is independently C 1 -C 6 alkyl substituted with one, two, or three groups selected from the group consisting of halogen, - OH, -CN, and -NH 2 . In some embodiments, each R 5 is independently unsubstituted C 1 -C 6 alkyl.
  • each R 5 is independently C 1 -C 3 alkyl, such as methyl, ethyl, n- propyl, or isopropyl, which is optionally substituted with halogen, -OH, -CN, or -NH 2 .
  • each R 5 is independently C 1 -C 3 alkyl, such as methyl, ethyl, n-propyl, or isopropyl, which is substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, and -NH 2 .
  • each R 5 is independently unsubstituted C 1 -C 3 alkyl, such as methyl, ethyl, n-propyl, or isopropyl. In some embodiments, at least one R 5 is –CH 3 . In some embodiments, both R 5 groups are –CH 3 . In some embodiments, R 2 is -OR 5 , and R 5 is –CH 3 . [0076] In some embodiments, R 5 is optionally substituted C 3 -C 6 cycloalkyl.
  • R 5 is C 3 -C 6 cycloalkyl optionally substituted with halogen, -OH, -CN, -NH 2 , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • R 5 is C 3 -C 6 cycloalkyl substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, - NH 2 , C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl.
  • R 5 is unsubstituted C 3 -C 6 cycloalkyl.
  • R 5 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • the compound provided is of formula (II): or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , and R 4 are as defined herein for any embodiment or variation of a compound of formula (I).
  • R 1 , R 2 , R 3 , and R 4 are independently H or optionally substituted C 1 -C 6 alkyl.
  • R 1 and R 2 are independently C 1 -C 6 alkyl optionally substituted with halogen, -OH, -CN, or -NH 2 .
  • R 1 and R 2 are independently unsubstituted C 1 -C 3 alkyl. In some embodiments, R 1 and R 2 are both – CH 3 . In some embodiments, R 3 is H. In some embodiments, R 4 is H. In some embodiments, R 4 is unsubstituted C 1 -C 3 alkyl. In some embodiments, R 4 is -CH 3 . [0078] In some embodiments, the compound provided is of formula (III): or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , and R 4 are as defined herein for any embodiment of a compound of formula (I).
  • R 1 is C 1 -C 6 alkyl optionally substituted with halogen, - OH, -CN, or -NH 2 . In some embodiments, R 1 is unsubstituted C 1 -C 3 alkyl. In some embodiments, R 1 is –CH 3 . In some embodiments, R 2 is –NH 2 or C 1 -C 6 alkyl optionally substituted with halogen, -OH, -CN, or -NH 2 . In some embodiments, R 2 is –NH 2 . In some embodiments, R 2 is unsubstituted C 1 -C 3 alkyl. In some embodiments, R 2 is –CH 3 .
  • R 3 is H or C 1 -C 6 alkyl optionally substituted with halogen, -OH, -CN, or -NH 2 . In some embodiments, R 3 is H. In some embodiments, R 3 is unsubstituted C 1 -C 3 alkyl. In some embodiments, R 3 is –CH 3 . In some embodiments, R 1 , R 2 , and R 3 are C 1 -C 6 alkyl optionally substituted with halogen, -OH, -CN, or -NH 2 . In some embodiments, R 1 , R 2 , and R 3 are unsubstituted C 1 -C 3 alkyl.
  • R 1 , R 2 , and R 3 are –CH 3 .
  • R 1 is C 1 -C 6 alkyl optionally substituted with halogen, -OH, -CN, or -NH 2 ;
  • R 2 is -NH 2 ; and
  • R 3 is H.
  • R 1 is -CH 3
  • R 2 is -NH 2
  • R 3 is H.
  • R 1 and R 2 are taken together with the carbon atom to which they are attached to form an optionally substituted 4- to 7-membered heterocyclyl.
  • R 1 and R 2 are taken together with the carbon atom to which they are attached to form an unsubstituted 5- to 6-membered heterocyclyl. In some embodiments, R 1 and R 2 are taken together with the carbon atom to which they are attached to form an unsubstituted pyrrolidinyl. In some embodiments, R 4 is H. [0079] In some embodiments, the compound provided is of formula (IV): or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , and R 6 are as defined herein for any embodiment of a compound of formula (I).
  • R 1 , R 2 , R 3 , R 4 , and R 6 are independently H or optionally substituted C 1 -C 6 . In some embodiments, R 1 , R 2 , R 3 , and R 4 are H. In some embodiments, each R 6 is independently C 1 -C 6 alkyl optionally substituted with halogen, -OH, -CN, or -NH 2 . In some embodiments, each R 6 is independently unsubstituted C 1 -C 3 alkyl. In some embodiments, both R 6 group are –CH 3 .
  • the compound provided is of formula (V): or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , and X are as defined herein for any embodiment of a compound of formula (I).
  • R 1 is C 1 -C 6 alkyl optionally substituted with halogen, - OH, -CN, or -NH 2 .
  • R 1 is unsubstituted C 1 -C 3 alkyl.
  • R 1 is –CH 3 .
  • R 1 is H.
  • R 2 is –NH 2 or C 1 -C 6 alkyl optionally substituted with halogen, -OH, -CN, or -NH 2 . In some embodiments, R 2 is –NH 2 . In some embodiments, R 2 is unsubstituted C 1 -C 3 alkyl. In some embodiments, R 2 is –CH 3 . In some embodiments, R 3 is H or C 1 -C 6 alkyl optionally substituted with halogen -OH -CN or -NH 2 In some embodiments R 3 is H In some embodiments, R 3 is unsubstituted C 1 -C 3 alkyl. In some embodiments, R 3 is –CH 3 .
  • R 1 , R 2 , and R 3 are H. In some embodiments, R 1 , R 2 , and R 3 are independently H or C 1 -C 6 alkyl optionally substituted with halogen, -OH, -CN, or -NH 2. In some embodiments, R 1 and R 2 are taken together with the carbon atom to which they are attached to form an optionally substituted 4- to 7-membered heterocyclyl. In some embodiments, R 1 and R 2 are taken together with the carbon atom to which they are attached to form an unsubstituted 5- to 6-membered heterocyclyl.
  • R 1 and R 2 are taken together with the carbon atom to which they are attached to form an unsubstituted pyrrolidinyl.
  • X is O.
  • X is a bond.
  • X is C(R 6 ) 2 , wherein R 6 is as defined herein for any embodiment of a compound of formula (I).
  • X is C(CH 3 ) 2 .
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof which has any one or more of the following structural features: (I) X is: (i) O; (ii) a bond; or (iii) C(C 1 -C 6 alkyl) 2 optionally substituted with halogen or -OH, (II) R 1 is: (iv) H; or (v) C 1 -C 6 alkyl optionally substituted with halogen or -OH; (III) R 2 is: (vi) H; (vii) C 1 -C 6 alkyl optionally substituted with halogen or -OH; or (viii) NH 2 ; (IV) R 1 and R 2 are taken together with the carbon atom to which they are attached to form a 4- to 7-membered heterocyclyl optionally substituted with halogen, -OH, or C 1 -C 6 alkyl; (V) R 2 is -N(R 5 ) 2 ,
  • (I) applies. In one variation, (II) applies. In one variation, (III) applies. In one variation, (IV) applies. In one variation, (V) applies. In one variation, (VI) applies. In one variation, (VII) applies. In one aspect of this variation, (I), (II), (III), (VI), and (VII) apply. In another aspect of this variation, (I), (IV), (VI), and (VII) apply. In one variation, (I), (V), (VI), and (VII) apply. In one variation, (i), (v), (vii), (ix), and (xi) apply. In one variation, (i), (v), (vii), (ix), and (xii) apply.
  • the present disclosure also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms of the compounds described.
  • a particular stereochemical form such as a specific enantiomeric form or diastereomeric form
  • tautomeric forms may be present for any of the compounds described herein, each and every tautomeric form is intended even though only one or some of the tautomeric forms may be explicitly depicted.
  • the tautomeric forms specifically depicted may or may not be the predominant forms in solution or when used according to the methods described herein.
  • Solvates of a compound provided herein or a salt thereof are also contemplated. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
  • compositions comprising a compound as detailed herein or a salt thereof are provided, such as compositions of substantially pure compounds.
  • a composition containing a compound as detailed herein or a salt thereof is in substantially pure form.
  • substantially pure intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound comprising the majority of the composition or a salt thereof.
  • a composition of substantially pure compound or a salt thereof wherein the composition contains no more than 25%, 20%, 15%, 10%, or 5% impurity. In some embodiments, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 3%, 2%, 1% or 0.5% impurity.
  • Articles of manufacture comprising a compound described herein, or a salt or solvate thereof, in a suitable container are provided.
  • the container may be a vial, jar, ampoule, preloaded syringe, i.v. bag, and the like.
  • the compounds detailed herein are orally bioavailable.
  • the compounds detailed herein are formulated for parenteral (e.g., intravenous) administration.
  • parenteral e.g., intravenous
  • One or several compounds described herein can be used in the preparation of a medicament by combining the compound or compounds disclosed herein with a pharmacologically acceptable carrier, which are known in the art. Depending on the therapeutic form of the medication, the carrier may be in various forms.
  • the manufacture of a medicament is for use in any of the methods disclosed herein, e.g., for the treatment of liver cancer, colon cancer, or gastric cancer.
  • Pharmaceutical Compositions and Formulations [0091] Any of the compounds described herein may be formulated as a pharmaceutically acceptable composition. [0092] Pharmaceutical compositions of any of the compounds detailed herein are embraced by this disclosure.
  • compositions comprising a compound as detailed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid.
  • Pharmaceutical compositions may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation.
  • a compound as detailed herein may in one aspect be in a purified form and compositions comprising a compound in purified forms are detailed herein.
  • Compositions comprising a compound as detailed herein or a salt thereof are provided, such as compositions of substantially pure compounds.
  • a composition containing a compound as detailed herein or a salt thereof is in substantially pure form.
  • the compounds herein are synthetic compounds prepared for administration to an individual.
  • compositions are provided containing a compound in substantially pure form.
  • the present disclosure embraces pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier.
  • methods of administering a compound are provided. The purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein.
  • a compound detailed herein, or a pharmaceutically acceptable salt thereof may be formulated for any available delivery route, including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery form.
  • oral, mucosal e.g., nasal, sublingual, vaginal, buccal or rectal
  • parenteral e.g., intramuscular, subcutaneous or intravenous
  • topical or transdermal delivery form e.g., topical or transdermal delivery form.
  • a compound or salt thereof may be formulated with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs.
  • suitable carriers include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultic
  • a compound detailed herein, or a pharmaceutically acceptable salt thereof can be used in the preparation of a formulation, such as a pharmaceutical formulation, by combining the compound or compounds, or a salt thereof, with a pharmaceutically acceptable carrier.
  • a pharmaceutical formulation such as a pharmaceutical formulation
  • the carrier may be in various forms.
  • pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.
  • Formulations comprising the compound may also contain other substances which have valuable therapeutic properties.
  • Pharmaceutical formulations may be prepared by known pharmaceutical methods.
  • a compound detailed herein, or a pharmaceutically acceptable salt thereof may be administered to individuals in a form of generally accepted oral compositions, such as tablets, coated tablets, and gel capsules in a hard or in soft shell, emulsions or suspensions.
  • carriers which may be used for the preparation of such compositions, are lactose, corn starch or its derivatives, talc, stearate or its salts, etc.
  • Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid poly-ols, and so on.
  • pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.
  • Compositions comprising a compound provided herein are also described.
  • the composition comprises a compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • a composition of substantially pure compound is provided.
  • the composition is for use as a human or veterinary medicament.
  • compositions formulated for co-administration of a compound provided herein and one or more additional pharmaceutical agents are also described. The co-administration can be simultaneous or sequential in any order.
  • a compound provided herein may be formulated for co-administration with the one or more additional pharmaceutical agents in the same dosage form (e.g., single tablet or single i.v.) or separate dosage forms (e.g., two separate tablets, two separate i.v., or one tablet and one i.v.).
  • co-administration can be, for example, 1) concurrent delivery, through the same route of delivery (e.g., tablet or i.v.), 2) sequential delivery on the same day, through the same route or different routes of delivery, or 3) delivery on different days, through the same route or different routes of delivery.
  • a compound provided herein is metabolized to release a therapeutically effective amount of 5-FU and/or one or more 5-FU metabolites, such as 5- FdUMP.
  • the therapeutically effective amount of 5-FU and/or one or more 5-FU metabolites, such as 5-FdUMP is effective in treating cancer.
  • the amount of 5-FU and/or one or more 5-FU metabolites, such as 5-FdUMP, in the bloodstream is effective in treating cancer.
  • a compound provided herein is metabolized to release one or more metabolites in an amount effective in treating cancer.
  • a prodrug is a pharmacologically inactive compound that is metabolized to a therapeutically active agent by one or more metabolic biotransformations. These metabolic biotransformations can occur when the prodrug is administered to a subject or cell. Metabolic processes include acid- or base-catalyzed chemical reaction(s) and enzyme-catalyzed chemical reaction(s).
  • Embodiments are described herein wherein the therapeutically active compound is 5-FU, a metabolite of 5-FU (such as 5-FdUMP), and/or additional metabolites of the prodrugs described herein.
  • the therapeutically active compound is 5-FU, a metabolite of 5-FU (such as 5-FdUMP), and/or additional metabolites of the prodrugs described herein.
  • Provided herein are methods of treating liver cancer, gastric cancer, small intestine, or colon cancer in a subject in need thereof, comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof), wherein said compound selectively accumulates in the liver and/or upper gastrointestinal tract.
  • said compound selectively accumulates in the liver, esophagus, or stomach.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof selectively accumulates in the liver, wherein the method does not result in the occurrence of dermatological toxicity, myelotoxicity, and/or leukopenia.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof selectively accumulates in the upper gastrointestinal tract, wherein the method does not result in the occurrence of dermatological toxicity, myelotoxicity, and/or leukopenia.
  • a pharmaceutically acceptable salt thereof e.g., Compound 1 or a pharmaceutically acceptable salt thereof
  • the method substantially minimizes the occurrence or severity of dermatological toxicity, myelotoxicity, and/or leukopenia.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof selectively accumulates in the liver, wherein the method substantially minimizes the occurrence or severity of dermatological toxicity, myelotoxicity, and/or leukopenia.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof selectively accumulates in the upper gastrointestinal tract, wherein the method substantially minimizes the occurrence or severity of dermatological toxicity, myelotoxicity, and/or leukopenia.
  • liver metastases in a subject in need thereof, comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof).
  • the liver metastases originate from a primary cancer including, but not limited to, colon cancer, rectal cancer, small intestine, breast cancer, esophageal cancer, gastric cancer, pancreatic cancer, lung cancer, kidney cancer, skin cancer, ovarian cancer or lung cancer.
  • the liver metastases originate from a primary cancer wherein the primary cancer is colon cancer, gastric cancer, or rectal cancer.
  • the liver metastases originate from a primary cancer wherein the primary cancer is colon cancer or gastric cancer.
  • the compound of formula (I) is coadministered with a multikinase inhibitor such as sorafenib.
  • a multikinase inhibitor such as sorafenib.
  • methods of treating a primary liver cancer in a subject in need thereof comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof).
  • the primary liver cancer is hepatocellular carcinoma (HCC).
  • HCC hepatocellular carcinoma
  • the subject with HCC also suffers from a chronic liver disease such as cirrhosis.
  • kits for treating small intestine cancer in a subject in need thereof comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof).
  • the small intestine cancer is a primary cancer.
  • the small intestine cancer has metastasized to other tissue.
  • the small intestine cancer has metastasized to the liver.
  • kits for treating gastric cancer in a subject in need thereof comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof).
  • the gastric cancer is primary gastric cancer.
  • the gastric cancer has metastasized to other tissue.
  • the gastric cancer has metastasized to the liver.
  • methods of treating colon cancer in a subject in need thereof comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof).
  • the colon cancer has metastasized to other tissue. In particular, embodiments, the colon cancer has metastasized to the liver.
  • methods of treating small intestine cancer in a subject in need thereof comprising administering to the subject a compound of formula (I) (e.g., Compound 1), or a pharmaceutically acceptable salt thereof.
  • the small intestine cancer has metastasized to other tissue. In particular, embodiments, the small intestine cancer has metastasized to the liver.
  • the small intestine cancer is an adenocarcinoma, a sarcoma, a carcinoid tumor, a gastrointestinal stromal tumor (GIST) or an intestinal lymphoma.
  • the method of treating cancer with a compound of formula (I), or a pharmaceutically acceptable salt thereof is effective for treating a subject was unresponsive or had become refractory to a prior therapy.
  • the subject discontinued a prior therapy.
  • the subject discontinued a prior therapy due to the incidence of dermatological toxicity, myelotoxicity, or leukopenia during said prior therapy.
  • the administering reduces the occurrence of dermatological toxicity or myelotoxicity relative to a prior therapy.
  • the dermatological toxicity is palmar-plantar erythrodysesthesia (hand-foot syndrome), dermatitis, or stomatitis.
  • said prior therapy comprises treatment with a 5-FU prodrug such as capecitabine, UFT, or S-1.
  • said prior therapy comprises treatment with capecitabine.
  • the prior therapy comprises treatment with a multikinase inhibitor. In some such embodiments, the multikinase inhibitor is sorafenib.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof)
  • said compound selectively accumulates in the liver, esophagus, or stomach.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof e.g., Compound 1 or a pharmaceutically acceptable salt thereof
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof selectively accumulates in the liver, wherein the method does not result in the occurrence of dermatological toxicity, myelotoxicity, and/or leukopenia.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof selectively accumulates in the upper gastrointestinal tract, wherein the method does not result in the occurrence of dermatological toxicity, myelotoxicity, and/or leukopenia.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof e.g., Compound 1 or a pharmaceutically acceptable salt thereof
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof selectively accumulates in the liver, wherein the method substantially minimizes the occurrence or severity of dermatological toxicity, myelotoxicity, and/or leukopenia.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof selectively accumulates in the upper gastrointestinal tract, wherein the method substantially minimizes the occurrence or severity of dermatological toxicity, myelotoxicity, and/or leukopenia.
  • liver metastases originate from a primary cancer including, but not limited to, colon cancer, rectal cancer, breast cancer, esophageal cancer, small intestine, gastric cancer, pancreatic cancer, lung cancer, kidney cancer, skin cancer, ovarian cancer or lung cancer.
  • the liver metastases originate from a primary cancer wherein the primary cancer is colon cancer, gastric cancer, or rectal cancer.
  • the liver metastases originate from a primary cancer wherein the primary cancer is colon cancer or gastric cancer.
  • the compound of formula (I) is co-administered with a multikinase inhibitor such as sorafenib.
  • a multikinase inhibitor such as sorafenib.
  • methods of delaying the onset and/or development of a primary liver cancer in a subject in need thereof comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof).
  • the primary liver cancer is hepatocellular carcinoma (HCC).
  • the subject with HCC also suffers from a chronic liver disease such as cirrhosis.
  • a chronic liver disease such as cirrhosis.
  • methods of delaying the onset and/or development of small intestine in a subject in need thereof comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • the small intestine cancer has metastasized to other tissue.
  • the small intestine cancer has metastasized to the liver.
  • methods of delaying the onset and/or development of gastric cancer in a subject in need thereof comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • the gastric cancer is primary gastric cancer. In other such embodiments, the gastric cancer has metastasized to other tissue. In particular embodiments, the gastric cancer has metastasized to the liver. [0119] In another aspect, provided herein are methods of delaying the onset and/or development of colon cancer in a subject in need thereof, comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt thereof. In some such embodiments, the colon cancer has metastasized to other tissue. In particular, embodiments, the colon cancer has metastasized to the liver.
  • the compound of formula (I) (e.g., Compound 1) can be administered to a subject at a dose that does not result in accumulation of the compound in the skin or the bone of a patient.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof can be administered orally twice daily to a subject at a dose of from about 2 mg/kg to about 50 mg/kg.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof can be administered orally twice daily to a subject at a dose of from about 5 mg/kg to about 50 mg/kg.
  • the compound of formula (I), or a pharmaceutically salt thereof can be administered orally twice daily to a subject at a dose of from about 10 mg/kg to about 50 mg/kg. In some embodiments, the compound of formula (I), or a pharmaceutically salt thereof, can be administered orally twice daily to a subject at a dose of from about 20 mg/kg to about 40 mg/kg. In some embodiments, the compound of formula (I), or a pharmaceutically salt thereof, can be administered orally twice daily to a subject at a dose of from about 30 mg/kg to about 40 mg/kg.
  • the compound of formula (I), or a pharmaceutically salt thereof can be administered orally twice daily to a subject at a dose of from about 30 mg/kg to about 50 mg/kg. In some embodiments, the compound of formula (I), or a pharmaceutically salt thereof, can be administered orally twice daily to a subject at a dose of from about 40 mg/kg to about 50 mg/kg. [0121] In particular embodiments wherein the compound of formula (I) is Compound 1, the compound can be administered to a subject at a dose that does not result in accumulation of the compound in the skin or the bone of a patient.
  • Compound 1, or a pharmaceutically acceptable salt thereof can be administered orally twice daily to a subject at a dose of from about 100 mg to about 4 g. In some embodiments, Compound 1, or a pharmaceutically salt thereof, can be administered orally twice daily to a subject at a dose of from about 100 mg to about 1 g. In some embodiments, Compound 1, or a pharmaceutically salt thereof, can be administered orally twice daily to a subject at a dose of from about 100 mg to about 500 mg. In some embodiments, Compound 1, or a pharmaceutically salt thereof, can be administered orally twice daily to a subject at a dose of from about 200 mg to about 600 mg.
  • Compound 1, or a pharmaceutically salt thereof can be administered orally twice daily to a subject at a dose of from about 400 mg to about 4 g. In some embodiments, Compound 1, or a pharmaceutically salt thereof, can be administered orally twice daily to a subject at a dose of from about 1 g to about 4 g. In some embodiments, Compound 1, or a pharmaceutically salt thereof, can be administered orally twice daily to a subject at a dose of from about 2 g to about 4 g. [0122] In some embodiments, the method further comprises administering the compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof), and one or more additional pharmaceutical agents.
  • a pharmaceutically acceptable salt thereof e.g., Compound 1 or a pharmaceutically acceptable salt thereof
  • the one or more additional pharmaceutical agents is selected from the group consisting of cabozantinib S-malate, pembrolizumab, lenvatinib mesylate, sorafenib tosylate, nivolumab, and regorafenib.
  • the one or more additional pharmaceutical agents is leucovorin.
  • the method comprises simultaneously administering the compound of formula (I), or a pharmaceutically acceptable salt thereof, and the one or more additional pharmaceutical agents.
  • the method comprises sequentially administering the compound of formula (I), or a pharmaceutically acceptable salt thereof, and the one or more additional pharmaceutical agents.
  • the method comprises administering the compound of formula (I) or a pharmaceutically acceptable salt thereof and the one or more additional pharmaceutical agents on the same dosing schedule. In other embodiments, the method comprises administering the compound of formula (I) or a pharmaceutically acceptable salt thereof and the one or more additional pharmaceutical agents on a different dosing schedule.
  • a method of inhibiting the activity of thymidylate synthase in a cell or in an individual or patient in need thereof comprising administering an effective amount of a compound of formula (I) to the cell, individual, or patient.
  • a method for treating a condition mediated by thymidylate synthase activity comprising administering to a mammal in need of treatment an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • the condition is cancer originating from the liver or upper gastrointestinal tract, or a cancer that has spread to one or more of the liver or upper gastrointestinal tract.
  • thymidylate synthase is inhibited by a metabolite of the compound.
  • thymidylate synthase is inhibited by 5- FdUMP.
  • a method of treating liver cancer, gastric cancer, small intestine cancer or colon cancer wherein modulation of thymidylate synthase activity prevents, inhibits, or ameliorates the pathology and/or symptomology of the cancer, in a patient, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof).
  • a method of treating liver cancer, gastric cancer, small intestine cancer or colon cancer, wherein modulation of thymidylate synthase activity prevents the pathology and/or symptomology of the cancer, in a patient comprising administering to the patient a therapeutically effective amount of compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof).
  • a therapeutically effective amount of compound of formula (I), or a pharmaceutically acceptable salt thereof e.g., Compound 1 or a pharmaceutically acceptable salt thereof.
  • a method of treating liver cancer, gastric cancer, small intestine cancer or colon cancer, wherein modulation of thymidylate synthase activity inhibits the pathology and/or symptomology of the cancer, in a patient comprising administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof).
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof).
  • a method of treating liver cancer, gastric cancer, small intestine cancer or colon cancer wherein modulation of thymidylate synthase activity ameliorates the pathology and/or symptomology of the cancer, in a patient, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof).
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof
  • thymidylate synthase is inhibited by a metabolite of the compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof).
  • thymidylate synthase is inhibited by 5-FdUMP.
  • a method of delaying the onset and/or development of a cancer that is mediated by thymidylate synthase activity in a patient such as a human who is at risk for developing liver cancer, gastric cancer, small intestine cancer or colon cancer. It will be appreciated that delayed development may encompass prevention in the event the individual or patient does not develop the cancer.
  • thymidylate synthase is inhibited by a metabolite of the compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof).
  • thymidylate synthase is inhibited by 5-FdUMP.
  • compounds of formula (I), or salts thereof for use in the methods as described herein.
  • a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof for use in therapy.
  • a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof or pharmaceutical composition comprising such compound or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.
  • the medicament is for the treatment of liver cancer. In some embodiments, the medicament is for the treatment of a cancer which originates from the liver or spreads to the liver.
  • the cancer is sensitive to treatment by 5-FU. In some embodiments, the cancer is resistant to treatment by 5-FU.
  • the individual was previously treated with 5-FU or a 5-FU prodrug. In some embodiments, the previously administered 5-FU prodrug is capecitabine.
  • the individual or patient is a mammal. In some embodiments, the patient is a primate, dog, cat, rabbit, or rodent. In some embodiments, the patient is a primate. In some embodiments, the patient is a human.
  • the human is at least about or is about any of 18, 21, 30, 50, 60, 65, 70, 75, 80, or 85 years old. In some embodiments, the human is a child. In some embodiments, the human is less than about or about any of 21, 18, 15, 10, 5, 4, 3, 2, or 1 years old. [0131] In some embodiments, the method further comprises administering one or more additional pharmaceutical agents. In some embodiments, the method further comprises administering radiation. In some embodiments, the method further comprises administering one or more additional pharmaceutical agents and radiation. [0132] In some embodiments, the method further comprises administering an additional thymidylate synthase inhibitor.
  • the method further comprises administering an agent which enhances the potency of the prodrug of formula (I) or any variation or aspect described herein, or a pharmaceutically acceptable salt thereof, or a metabolite thereof. In some embodiments, the method further comprises administering leucovorin. [0133] In some embodiments, the method further comprises administering a platinum- based agent. In some embodiments, the method further comprises administering oxaliplatin or cisplatin. In some embodiments, the method further comprises administering leucovorin and oxaliplatin. [0134] In some embodiments, the method further comprises administering a topoisomerase I inhibitor. In some embodiments, the method further comprises administering irinotecan.
  • the method further comprises administering leucovorin and irinotecan. [0135] In some embodiments, the method further comprises administering mitomycin and/or methotrexate. In some embodiments, the method further comprises administering mitomycin. In some embodiments, the method further comprises administering methotrexate. [0136] In some embodiments, the method further comprises administering a taxane. In some embodiments, the method further comprises administering a taxane and a platinum- based agent. In some embodiments, the method further comprises administering docetaxel or paclitaxel. [0137] In some embodiments, the method further comprises administering one or more additional pharmaceutical agents which are useful for treating liver cancer (Vallanueva, A. (2019) N.
  • the method further comprises administering one or more additional pharmaceutical agents which are cabozantinib S-malate, pembrolizumab, lenvatinib mesylate, sorafenib tosylate, nivolumab, regorafenib, or combinations thereof.
  • the method further comprises administering cabozantinib S-malate.
  • the method further comprises administering pembrolizumab.
  • the method further comprises administering lenvatinib mesylate.
  • the method further comprises administering sorafenib tosylate.
  • the method further comprises administering nivolumab. In some embodiments, the method further comprises administering regorafenib. In some embodiments, the method further comprises administering ramucirumab.
  • Dosing and Method of Administration The dose of a compound described herein, or a stereoisomer, tautomer, solvate, or salt thereof, administered to an individual (such as a human) may vary with the particular compound or salt thereof, the method of administration, and the particular cancer, such as type and stage of cancer, being treated. In some embodiments, the amount of the compound, or a stereoisomer, tautomer, solvate, or salt thereof, is a therapeutically effective amount.
  • the compounds provided herein or a salt thereof may be administered to a patient via various routes, including, e.g., intravenous, intramuscular, subcutaneous, oral, and transdermal. In some embodiments, the compounds provided herein are orally administered. [0140] Any of the methods provided herein may in one aspect comprise administering to an individual a pharmaceutical composition that contains an effective amount of a compound provided herein, or a stereoisomer, tautomer, solvate, or salt thereof, and a pharmaceutically acceptable excipient.
  • the methods as described herein may comprise administration to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer, which in some variations may be for the duration of the individual’s life.
  • the methods comprise administering on a daily or intermittent schedule.
  • the methods may comprise continuous administration (for example, at least once daily) over a period of time.
  • the dosing frequency can be more than once daily, e.g., twice or three times daily.
  • the dosing frequency can also be intermittent, including a ‘drug holiday’ (e.g., once daily dosing for 7 days followed by no doses for 7 days, repeated for any 14 day time period, such as about 2 months, about 4 months, about 6 months or more). Any of the dosing frequencies can employ any of the compounds described herein together with any of the dosages described herein.
  • Articles of Manufacture and Kits [0142] The present disclosure further provides articles of manufacture comprising a compound described herein or a salt thereof, a composition described herein, or one or more unit dosages described herein in suitable packaging, for use in any of the methods described herein.
  • kits for carrying out the methods of the present disclosure which comprises one or more compounds described herein or a composition comprising a compound described herein.
  • the kits may employ any of the compounds disclosed herein.
  • the kit employs a compound described herein or pharmaceutically acceptable salt thereof.
  • kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for the treatment of any disease or described herein, for example for the treatment of cancer, including liver, colorectal, anal, breast, gastrointestinal, skin, stomach, esophageal, and pancreatic cancer.
  • the cancer originated from the liver or spread to the liver.
  • the kits optionally further comprise a container comprising one or more additional pharmaceutical agents and which kits further comprise instructions on or in the package insert for treating the subject with an effective amount of the one or more additional pharmaceutical agents.
  • kits generally comprise suitable packaging.
  • the kits may comprise one or more containers comprising any compound described herein.
  • Each component if there is more than one component
  • the kits may be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelf life permit.
  • the kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses.
  • kits may be provided that contain sufficient dosages of a compound as disclosed herein and/or an additional pharmaceutically active compound useful for a disease detailed herein to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more.
  • Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).
  • kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present disclosure.
  • the instructions included with the kit generally include information as to the components and their administration to an individual.
  • EXAMPLES [0148] The compounds disclosed herein are prepared as disclosed in PCT/US2020/031132, the contents of which are hereby incorporated by reference in their entirety. [0149] It is understood that the present disclosure has been made only by way of example, and that numerous changes in the combination and arrangement of parts can be resorted to by those skilled in the art without departing from the spirit and scope of present disclosure. Example 1.
  • Biodistribution Study Male hamsters, 7-9 weeks old, were used for 5-FdUMP biodistribution analysis. Compound 1 was weighed and mixed with 0.5% sodium carboxymethyl cellulose and administered as a single intraperitoneal dose (30 mg/kg) to 3 animals. Blood collection (about 200 ⁇ L per time point) was performed by jugular puncture of each animal into polypropylene tubes containing EDTA-K2 as anti-coagulant at 4 hours after dosing. Tubes were centrifuged for 15 minutes at 4°C and 3000 g for plasma collection. 150 milligram tissue samples from stomach, liver, upper gastrointestinal tract, pancreas, lung, bone marrow, and skin from the paw were collected at termination (4 hours post dosing).
  • Tissue homogenates were prepared by homogenizing with 9 volumes (w:v) of homogenizing solution (MeOH/15 mM PBS (1:2, v:v)). Protein was precipitated from 40 ⁇ L of plasma and tissue homogenates by the addition of 200 ⁇ L ACN and then the mixture was vortex-mixed for 10 min at 800 rpm and centrifuged for 15 min at 3220 g and 4 °C. 64 ⁇ L of the supernatant was transferred to a 96- well plate and centrifuged for 5 min at 3220 g (4 °C) and 10 ⁇ L of the supernatant was directly injected for LC-MS/MS analysis.
  • Chromatographic separation was performed using an Xbridge C183.5 ⁇ m (2.1 ⁇ 30 mm) column.
  • the mobile phases were 10% 2-Propanol and 0.1%NH 3.H2O in water (A) and 0.1% NH3.H2O in MeOH (B).
  • the flow rate was 0.4 mL/min, and the run time was 1.4 minutes per injection.
  • a Triple Quad 5500 mass spectrometer coupled with an electrospray ionization ion source was used to monitor the mass transitions. The system was operated in negative mode, and mass transitions were recorded.
  • Sorafenib was weighed and mixed with 20% (2-Hydroxypropyl)- ⁇ -cyclodextrin.
  • mice were treated with vehicle (IP; QD), sorafenib (PO; 30 mg/kg QD) or Compound 1 (IP; 90 mg/kg QD, 60 mg/kg QD, or 30 mg/kg BID x 7d then 20 mg/kg BID x 10d) for 17 days. Animals were sacrificed the following day, and primary tumors excised and weighed.
  • Median and quartile tumor weight values are displayed in FIG. 2 via dashed and dotted lines, respectively; *p ⁇ 0.05 vs Vehicle control; statistics determined by one-way ANOVA followed by Tukey.
  • Example 3 Liver Metastatic Gastric Tumor Growth Experiment [0154] Female BALB/c nude mice, 6-8 weeks old, were used for a liver metastatic gastric cancer model.
  • the bioluminescent MKN45-luc tumor cell line was maintained in vitro as monolayer culture in RPMI-1640 medium supplemented with 10% fetal bovine serum and 2 ug/mL Puromycin at 37°C in an atmosphere of 5% CO 2 in air.
  • the tumor cells were routinely sub-cultured weekly by trypsin-EDTA treatment, not exceeding 4-5 passages.
  • the cells growing in an exponential growth phase were harvested and counted for tumor inoculation. Animals were anesthetized by i.m.
  • mice were incised to expose the left liver lobe. 1 x 10 6 MKN45- luc cells suspended in 10 ⁇ L RPMI 1640/Matrigel mixture (1:1) were injected slowly into the left liver lobe, so that a transparent bleb of cells was seen through the liver capsule. The liver was returned into the peritoneal cavity, and the abdominal wall and skin was closed. The tumor growth was monitored by luciferase-mediated image analysis and tumor weight at termination. Mice were randomized into 3 groups (8 mice per group) for drug treatment.
  • mice The skin and peritoneum of anesthetized mice were incised to expose the left liver lobe.
  • 1 x 10 6 HT29-luc cells suspended in 10 ⁇ L RPMI 1640/Matrigel mixture (1:1) were injected slowly into the left liver lobe, so that a transparent bleb of cells was seen through the liver capsule.
  • the liver was returned into the peritoneal cavity, and the abdominal wall and skin was closed.
  • the tumor growth was monitored by luciferase-mediated image analysis and tumor weight at termination.
  • Mice were randomized into 3 groups (8 mice per group) for drug treatment.
  • Compound 1 and capecitabine (Xeloda) were weighed and mixed with 0.5% sodium carboxymethyl cellulose (vehicle).
  • mice were treated with vehicle (IP; BID), Xeloda (PO; 400 mg/kg QD) or Compound 1 (IP; 20 mg/kg BID) for 21 days. Animals were sacrificed the following day, and primary and metastatic (abdominal wall) tumors excised and weighed. [0157] Median and quartile tumor weight values are displayed in FIG. 4 via dashed and dotted lines, respectively; *p ⁇ 0.05 vs Vehicle control; statistics determined by one-way ANOVA followed by Tukey. Only statistically significant differences indicated.
  • Compound 1 showed selective distributions of 5-FdUMP, the active drug metabolite, to the liver, stomach, and upper gastrointestinal tissues when dosed by intraperitoneal injection in hamsters. Surprisingly, Compound 1 was undetectable in other tissues, including the pancreas, plasma, skin, and bone marrow in hamsters. This data suggests that Compound 1 has potential to minimize skin- and bone marrow-related side effects, such as dermatological toxicity and myelotoxicity, that occur when using existing 5- FU-related drugs due to systemic drug exposure.
  • the combination of improved potency and selective uptake of Compound 1 into liver and gastrointestinal tissues may result in a synergistic improvement in efficacy for the treatment of liver and/or gastrointestinal cancers relative to other 5-FU-related drugs.
  • Compound 1 90 mg/kg IP; or 60 mg/kg IP
  • Compound 1 demonstrated comparable efficacy to once daily treatment with a standard-of-care drug Sorafenib (30 mg/kg PO) relative to a vehicle- treated group, as determined by mean tumor weight after 17 days of treatment.
  • Compound 1 demonstrated an unexpected, statistically significant reduction in tumor growth relative to the other treatment groups when administered twice daily at a lower dose (30 mg/kg twice daily for seven days, followed by 20 mg/kg twice daily for ten days). This data suggests that a twice daily dosing schedule may be sufficient to maintain the concentration of Compound 1 within its therapeutic window, thereby enhancing the effect of Compound 1 on tumor growth.
  • twice daily treatment with Compound 1 (20 mg/kg IP) demonstrated comparable efficacy to once daily treatment with a standard-of-care drug Xeloda (capecitabine) (400 mg/kg PO).

Abstract

Provided herein are methods of treating liver, colon, small intestine, or gastric cancers in a subject in need thereof, comprising administering to the subject a prodrug of 5-fluorodeoxyuridine monophosphate compounds.

Description

METHODS FOR TREATING CANCER CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Patent Application No. 63/202,623, filed on June 17, 2021, which is incorporated herein by reference in its entirety. FIELD [0002] The present application relates generally to prodrugs of 5-fluorodeoxyuridine monophosphate compounds, compositions thereof, methods of their preparation, and their use in treating cancers. BACKGROUND [0003] 5-Fluorouracil (5-FU) is a chemotherapeutic agent extensively used in the treatment of various cancers. Classified as an antimetabolite, 5-FU is intracellularly metabolized to 5-fluorouridine-5’-triphosphate (5-FUTP) and 5-fluoro-2’-deoxyuridine-5’- triphosphate (5-FdUTP), pharmacodynamically active metabolites that can be incorporated into RNA and DNA, respectively, resulting in cell death. Additionally, 5-FU is metabolized to 5-fluoro-2’-deoxyuridine-5’-monophosphate (5-FdUMP), which is believed to inhibit the activity of thymidylate synthase (TS), interrupting the production of DNA, and eventually inducing cell death (Malet-Martino et al., (2002) Oncologist, 7:288-323; see FIG. 1). [0004] However, 80-85% of 5-FU is catabolized by the enzyme dihydropyrimidine dehydrogenase (DPD) to pharmacodynamically inactive metabolites, which contributes to the neurotoxicity and cardiotoxicity of a 5-FU-based treatment regimen. This catabolization contributes to the low half-life (5-20 min) of 5-FU and limited availability in vivo, which constitutes a major drawback of its use as a chemotherapeutic agent. Additionally, the activity level of DPD in patients can vary widely, thus making the bioavailability of 5-FU unpredictable, and can result in severe and even fatal 5-FU toxicity. 5-FU is typically administered by either bolus injections or continuous infusion. However, bolus injection is associated with myelotoxicity, whereas continuous infusion is associated with palmar-plantar erythrodysesthesia, stomatitis, neurotoxicity, and cardiotoxicity. Furthermore, both intravenous modes of administration have elevated risk of infection at the injection site, nausea, diarrhea, alopecia, and dermatitis (Malet-Martino et al., (2002) Oncologist, 7:288- 323). Oral administration of 5-FU has been investigated, but it is plagued by unpredictable absorption due the varying levels of DPD in the gastrointestinal tract (Cao et al., (1994) Cancer Res, 54:1507-1510). [0005] Prodrugs of 5-FU, such as capecitabine, ftorafur plus uracil (UFT), and ftorafur plus 5-chloro-2,4-dihydroxypyridine plus potassium oxonate (S-1), have been developed to permit oral administration and to attempt to address the many drawbacks associated with 5- FU discussed above. However, although S-1 and capecitabine can be administered orally, switching 5-FU for either S-1 or capecitabine does not result in any significant changes in either efficacy or adverse events. In addition, ftorafur-based treatment regimens can lead to certain gastrointestinal-related side effects. Accordingly, there is a need for improved methods to treat a variety of cancers with 5-FU derivatives or 5-FdUMP derivatives, while simultaneously minimizing systemic drug exposure to reduce off-target toxicity including dermatologic toxicity, myelotoxicity, and/or leukopenia. BRIEF SUMMARY [0006] The disclosure provides methods of treating liver cancer, colon cancer, small intestine cancer, or gastric cancer in a subject in need thereof, comprising administering to the subject a compound of formula (I)
Figure imgf000004_0001
or a pharmaceutically acceptable salt thereof, wherein X, R1, R2, R3, and R4 are defined herein. [0007] In particular embodiments, the compound of formula (I) is a compound selected from the group consisting of:
Figure imgf000004_0002
,
Figure imgf000005_0001
or a pharmaceutically acceptable salt thereof. In some such embodiments, the compound of formula
Figure imgf000005_0002
, referred to herein as “Compound 1.” [0008] It has been surprisingly discovered that the compound of formula (I) (e.g., Compound 1) distributes primarily to the liver, stomach and upper gastrointestinal tract following administration to a subject and distributes to a negligible extent in other tissues, including the bone marrow and skin. Accordingly, the compound of formula (I) (e.g., Compound 1), or a pharmaceutically acceptable salt thereof, can be administered to subjects with liver cancer, gastric cancer, small intestine cancer, and colon cancer at efficacious doses without concurrent side effects often associated with administration of 5-FU or prodrugs of 5- FU (e.g., capecitabine, UFT, or S-1). [0009] Accordingly, provided herein are methods of treating liver cancer, gastric cancer, small intestine cancer, or colon cancer in a subject in need thereof, comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein said compound selectively accumulates in the liver and/or gastrointestinal tract. Also provided herein are methods of treating liver cancer, gastric cancer, small intestine cancer, or colon cancer in a subject in need thereof, comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof wherein the method does not result in or substantially minimizes the occurrence or severity of dermatological toxicity, myelotoxicity, and/or leukopenia. In some embodiments, the methods comprise administering to the subject a compound of formula (I) (e.g., Compound 1) or a pharmaceutically acceptable salt thereof, via oral administration. [0010] In one aspect, provided herein are methods of treating liver metastases (secondary liver cancer) in a subject in need thereof, comprising administering to the subject a compound of formula (I) (e.g., Compound 1), or a pharmaceutically acceptable salt thereof. In some embodiments, the liver metastases originate from a primary cancer including, but not limited to, colon cancer, rectal cancer, breast cancer, small intestine cancer, gastric cancer, pancreatic cancer, lung cancer, kidney cancer, skin cancer, ovarian cancer or lung cancer. In some embodiments, the compound of formula (I) is administered conjointly with a multikinase inhibitor such as sorafenib. [0011] In another aspect, provided herein are methods of treating a primary liver cancer in a subject in need thereof, comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the primary liver cancer is hepatocellular carcinoma (HCC). In some such embodiments, the subject with HCC also suffers from a chronic liver disease such as cirrhosis. [0012] In another aspect, provided herein are methods of treating gastric cancer in a subject in need thereof, comprising administering to the subject a compound of formula (I) (e.g., Compound 1), or a pharmaceutically acceptable salt thereof. In some such embodiments, the gastric cancer has metastasized to other tissue. In particular, embodiments, the gastric cancer has metastasized to the liver. [0013] In another aspect, provided herein are methods of treating small intestine cancer in a subject in need thereof, comprising administering to the subject a compound of formula (I) (e.g., Compound 1), or a pharmaceutically acceptable salt thereof. In some such embodiments, the small intestine cancer has metastasized to other tissue. In particular, embodiments, the small intestine cancer has metastasized to the liver. [0014] In another aspect, provided herein are methods of treating colon cancer in a subject in need thereof, comprising administering to the subject a compound of formula (I) (e.g., Compound 1), or a pharmaceutically acceptable salt thereof. In some such embodiments, the colon cancer has metastasized to other tissue. In particular embodiments, the colon cancer has metastasized to the liver. In other particular embodiments, the colon cancer has metastasized to the small intestine or the stomach. [0015] In some embodiments, the method of treating cancer with a compound of formula (I), or a pharmaceutically acceptable salt thereof, is effective for treating a subject who was unresponsive or has become refractory to a prior therapy. In some embodiments, the subject discontinued a prior therapy. In some embodiments, the subject discontinued a prior therapy due to the incidence of dermatological toxicity, myelotoxicity, or leukopenia during said prior therapy. In some embodiments, the administering reduces the occurrence or severity of dermatological toxicity or myelotoxicity relative to a prior therapy. In some embodiments, the dermatological toxicity is palmar-plantar erythrodysesthesia (hand-foot syndrome), dermatitis, or stomatitis. In some embodiments, said prior therapy comprises treatment with a 5-FU prodrug such as capecitabine, UFT, or S-1. In particular embodiments, said prior therapy comprises treatment with capecitabine. In other embodiments, the prior therapy comprises treatment with a multikinase inhibitor. In some such embodiments, the multikinase inhibitor is sorafenib. [0016] In particular embodiments wherein the compound of formula (I) is Compound 1, the compound can be administered orally to a subject at a dose that does not result in accumulation of the compound in the skin or the bone of a patient. For instance, in some embodiments, Compound 1 can be administered orally twice daily to a subject at a dose of from about 2 mg/kg to about 50 mg/kg. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, can be administered orally twice daily to a subject at a dose of from about 5 mg/kg to about 50 mg/kg. In some embodiments, Compound 1, or a pharmaceutically salt thereof, can be administered orally twice daily to a subject at a dose of from about 10 mg/kg to about 50 mg/kg. In some embodiments, Compound 1, or a pharmaceutically salt thereof, can be administered orally twice daily to a subject at a dose of from about 20 mg/kg to about 40 mg/kg. In some embodiments, Compound 1, or a pharmaceutically salt thereof, can be administered orally twice daily to a subject at a dose of from about 30 mg/kg to about 40 mg/kg. In some embodiments, Compound 1, or a pharmaceutically salt thereof, can be administered orally twice daily to a subject at a dose of from about 30 mg/kg to about 50 mg/kg. In some embodiments, Compound 1, or a pharmaceutically salt thereof, can be administered orally twice daily to a subject at a dose of from about 40 mg/kg to about 50 mg/kg. [0017] In some embodiments, the method further comprises administering one or more additional pharmaceutical agents. In some embodiments, the one or more additional pharmaceutical agents is selected from the group consisting of cabozantinib S-malate, pembrolizumab, lenvatinib mesylate, sorafenib tosylate, nivolumab, and regorafenib. In some embodiments, the one or more additional pharmaceutical agents is leucovorin. BRIEF DESCRIPTION OF THE DRAWINGS [0018] FIG. 1 shows the biodistribution of 5-FdUMP in hamsters after one dose of Compound 1 (30 mg/kg, intraperitoneal injection). Upper GI indicates stomach and small intestine. [0019] FIG. 2 shows tumor weight in an orthotopic hepatocellular carcinoma model in mice after 17 days of treatment with vehicle (IP, QD), sorafenib (30 mg/kg PO, QD), or Compound 1 (90 mg/kg IP, QD for all 17 days; 60 mg/kg IP, QD for all 17 days; or 30 mg/kg IP, BID for the first 7 days, then 20 mg/kg BID for the last 10 days). [0020] FIG. 3 shows tumor weight in a metastatic gastric cancer model in mice after 21 days of treatment with vehicle (IP, BID), Xeloda (400 mg/kg PO, QD), or Compound 1 (20 mg/kg IP, BID). [0021] FIG. 4 shows tumor weight in a metastatic colon cancer model in mice after 21 days of treatment with vehicle (IP, BID), Xeloda (400 mg/kg PO, QD), or Compound 1 (20 mg/kg IP, BID). DETAILED DESCRIPTION Definitions [0022] As used herein, the following definitions shall apply unless otherwise indicated. Further, if any term or symbol used herein is not defined as set forth below, it shall have its ordinary meaning in the art. [0023] “Comprising” is intended to mean that the compositions and methods include the recited elements, but not excluding others. “Consisting essentially of” when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination. For example, a composition consisting essentially of the elements as defined herein would not exclude other elements that do not materially affect the basic and novel characteristic(s) of the claimed invention. “Consisting of” shall mean excluding more than trace amount of, e.g., other ingredients and substantial method steps recited. Embodiments defined by each of these transition terms are within the scope of this invention. Thus, it is understood that aspects and embodiments described herein as “comprising” include “consisting of” and “consisting essentially of” embodiments. [0024] “Effective amount” or dose of a compound or a composition, refers to that amount of the compound, or a pharmaceutically acceptable salt thereof, or the composition that results in an intended result as desired based on the disclosure herein. Effective amounts can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., and without limitation, by determining the LD50 (the dose lethal to 50 % of the population) and the ED50 (the dose therapeutically effective in 50 % of the population). In some variations, the desired result or outcome is due to one or more metabolites of an administered compound. [0025] The term “excipient” as used herein means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound of the invention as an active ingredient. Various substances may be embraced by the term excipient, including without limitation any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending/gelling agent, or wet granulation agent. Binders include, e.g., carbomers, povidone, xanthan gum, etc.; coatings include, e.g., cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrin, enteric coatings, etc.; compression/encapsulation aids include, e.g., calcium carbonate, dextrose, fructose dc (dc = “directly compressible”), honey dc, lactose (anhydrate or monohydrate; optionally in combination with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.; disintegrants include, e.g., croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, e.g., maltodextrin, carrageenans, etc.; lubricants include, e.g., magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; materials for chewable tablets include, e.g., dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; suspending/gelling agents include, e.g., carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulation agents include, e.g., calcium carbonate, maltodextrin, microcrystalline cellulose, etc. [0026] “Subject” refers to mammals and includes humans and non-human mammals. Examples of patients include, but are not limited to mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cows, and humans. In some embodiments, patient refers to a human. [0027] “Pharmaceutically acceptable” refers to safe and non-toxic, preferably for in vivo, more preferably, for human administration. [0028] “Pharmaceutically acceptable salt” refers to a salt that is pharmaceutically acceptable. A compound described herein may be administered as a pharmaceutically acceptable salt. [0029] “Prodrug” refers to a compound that, after administration, is metabolized or otherwise converted to a biologically active or more active compound (or drug) with respect to at least one property. A prodrug, relative to the drug, is modified chemically in a manner that renders it, relative to the drug, less active or inactive, but the chemical modification is such that the corresponding drug is generated by metabolic or other biological processes after the prodrug is administered. A prodrug may have, relative to the active drug, altered metabolic stability or transport characteristics, fewer side effects or lower toxicity, or improved flavor (for example, see the reference Nogrady, 1985, Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392, incorporated herein by reference). A prodrug may be synthesized using reactants other than employing the corresponding drug. For illustration and without limitation, prodrugs include, carboxy esters, linear and cyclic phosphate esters and phosphoramides and phosphoramidates, carbamates, preferably phenolic carbamates (i.e., carbamates where the hydroxy group is part of an aryl or heteroaryl moiety, where the aryl and heteroaryl may be optionally substituted), and the like. [0030] “Salt” refers to an ionic compound formed between an acid and a base. When the compound provided herein contains an acidic functionality, such salts include, without limitation, alkali metal, alkaline earth metal, and ammonium salts. As used herein, ammonium salts include, salts containing protonated nitrogen bases and alkylated nitrogen bases. Exemplary and non-limiting cations useful in pharmaceutically acceptable salts include Na, K, Rb, Cs, NH4, Ca, Ba, imidazolium, and ammonium cations based on naturally occurring amino acids. When the compounds utilized herein contain basic functionality, such salts include, without limitation, salts of organic acids, such as carboxylic acids and sulfonic acids, and mineral acids, such as hydrogen halides, sulfuric acid, phosphoric acid, and the like. Exemplary and non-limiting anions useful in pharmaceutically acceptable salts include oxalate, maleate, acetate, propionate, succinate, tartrate, chloride, sulfate, bisulfate, mono-, di-, and tribasic phosphate, mesylate, tosylate, and the like. [0031] “Therapeutically effective amount” or dose of a compound or a composition refers to that amount of the compound or the composition that results in reduction or inhibition of symptoms or a prolongation of survival in a patient. The results may require multiple doses of the compound or the composition. In some variations, the desired therapeutic outcome is due to one or more metabolites of an administered compound. [0032] As used herein, “treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. For purposes of this invention, beneficial or desired results include, but are not limited to, one or more of the following: decreasing one more symptoms resulting from the disease or disorder, diminishing the extent of the disease or disorder, stabilizing the disease or disorder (e.g., preventing or delaying the worsening of the disease or disorder), delaying the occurrence or recurrence of the disease or disorder, delay or slowing the progression of the disease or disorder, ameliorating the disease or disorder state, providing a remission (whether partial or total) of the disease or disorder, decreasing the dose of one or more other medications required to treat the disease or disorder, enhancing the effect of another medication used to treat the disease or disorder, delaying the progression of the disease or disorder, increasing the quality of life, and/or prolonging survival of a patient. Also encompassed by “treatment” is a reduction of pathological consequence of the disease or disorder. The methods of the invention contemplate any one or more of these aspects of treatment. [0033] As used herein, “upper gastrointestinal tract” or “upper GI” refers to the stomach and small intestine. [0034] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of the embodiments pertaining to the chemical groups represented by the variables are specifically embraced by the present invention and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). In addition, all subcombinations of the chemical groups listed in the embodiments describing such variables are also specifically embraced by the present invention and are disclosed herein just as if each and every such sub-combination of chemical groups was individually and explicitly disclosed herein. Compounds [0035] In one aspect, provided are methods of treating liver cancer, colon cancer, small intestine cancer or gastric cancer in a subject in need thereof, comprising administering to the subject a compound of formula (I)
Figure imgf000012_0001
or a pharmaceutically acceptable salt thereof, wherein: R1 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C6-C10 aryl, or optionally substituted 5- to 10-membered heteroaryl; or R1 and one R5 group are taken together with the atoms to which they are attached to form an optionally substituted 5- to 7-membered heterocyclyl; R2 is H, optionally substituted C1-C6 alkyl, -OR5, or -N(R5)2; or R1 and R2 are taken together with the carbon atom to which they are attached to form an optionally substituted 4- to 7-membered heterocyclyl or an optionally substituted C3-C6 cycloalkyl; R3 is H or optionally substituted C1-C6 alkyl; R4 is H optionally substituted C1-C6 alkyl or optionally substituted C3-C6 cycloalkyl; X is O, C(R6)2, or a bond; each R5 is independently H, optionally substituted C1-C6 alkyl, or optionally substituted C3- C6 cycloalkyl; or two R5 groups are taken together with the nitrogen atom to which they are attached to form an optionally substituted 5- to 7-membered heterocyclyl; and each R6 is independently H, optionally substituted C1-C6 alkyl, or optionally substituted C3- C6 cycloalkyl; or two R6 groups are taken together with the carbon atom to which they are attached to form an optionally substituted C3-C6 cycloalkyl or an optionally substituted 3- to 7-membered heterocyclyl. [0036] In some embodiments, X is O, C(R6)2, or a bond. In some embodiments, X is O. In some embodiments, X is a bond. In some embodiments, X is C(R6)2. [0037] In some embodiments, each R6 is independently H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl; or two R6 groups are taken together with the carbon atom to which they are attached to form an optionally substituted C3-C6 cycloalkyl or an optionally substituted 3- to 7-membered heterocyclyl. In some embodiments, each R6 is independently H; C1-C6 alkyl optionally substituted with halogen, -OH, -CN, or -NH2; or C3- C6 cycloalkyl optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl; or two R6 groups are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl or a 3- to 7-membered heterocyclyl, each of which is optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, each R6 is independently H or unsubstituted C1-C3 alkyl. In some embodiments, each R6 is independently H or -CH3. [0038] In some embodiments, each R6 is independently H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl. In some embodiments, each R6 is independently H; C1-C6 alkyl optionally substituted with halogen, -OH, -CN, or -NH2; or C3- C6 cycloalkyl optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, two R6 groups are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl or a 3- to 7-membered heterocyclyl, each of which is optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, each R6 is independently H or unsubstituted C1-C3 alkyl. In some embodiments, each R6 is independently H or -CH3. [0039] In some embodiments, each R6 is independently optionally substituted C1-C6 alkyl. In some embodiments, each R6 is independently C1-C6 alkyl substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, and -NH2. In some embodiments, each R6 is independently unsubstituted C1-C6 alkyl. In some embodiments, each R6 is independently C1-C3 alkyl optionally substituted with halogen, -OH, -CN, or -NH2. In some embodiments, each R6 is independently C1-C3 alkyl, such as methyl, ethyl, n-propyl, or isopropyl, which is optionally substituted with halogen, -OH, -CN, or -NH2. In some embodiments, each R6 is independently C1-C3 alkyl, such as methyl, ethyl, n-propyl, or isopropyl, which is substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, and -NH2. In some embodiments, each R6 is independently unsubstituted C1-C3 alkyl, such as methyl, ethyl, n-propyl, or isopropyl. In some embodiments, both R6 groups are -CH3. [0040] In some embodiments, each R6 is independently optionally substituted C3-C6 cycloalkyl. In some embodiments, each R6 is independently C3-C6 cycloalkyl optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, each R6 is independently C3-C6 cycloalkyl substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, -NH2, C1-C6 alkyl, and C1- C6 haloalkyl. In some embodiments, each R6 is independently unsubstituted C3-C6 cycloalkyl. [0041] In some embodiments, the two R6 groups are the same. In some embodiments, both R6 groups are H. In some embodiments, both R6 groups are C1-C6 alkyl substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, and -NH2. In some embodiments, both R6 groups are C1-C3 alkyl substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, and -NH2. In some embodiments, both R6 groups are unsubstituted C1-C3 alkyl. In some embodiments, both R6 groups are -CH3. [0042] In some embodiments, the two R6 groups are not the same. In some embodiments, at least one R6 group is C1-C6 alkyl optionally substituted with halogen, -OH, -CN, or -NH2. In some embodiments, at least one R6 group is C1-C3 alkyl optionally substituted with halogen, -OH, -CN, or -NH2. In some embodiments, at least one R6 group is unsubstituted C1- C3 alkyl, such as methyl, ethyl, n-propyl, or isopropyl. In some embodiments, at least one R6 group is C3-C6 cycloalkyl optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, at least one R6 group is unsubstituted C3-C6 cycloalkyl. In some embodiments, one R6 is H and the other R6 is optionally substituted C1- C6 alkyl or optionally substituted C3-C6 cycloalkyl. [0043] In some embodiments, X is CH(C1-C6 alkyl), wherein the C1-C6 alkyl is optionally substituted with halogen, -OH, -CN, or -NH2. In some embodiments, the C1-C6 alkyl is substituted with one, two, or three groups selected from the group consisting of halogen, - OH, -CN, and -NH2. In some embodiments, X is CH(unsubstituted C1-C6 alkyl). In some embodiments, X is CH(C1-C3 alkyl), wherein the C1-C3 alkyl is optionally substituted with halogen, -OH, -CN, or -NH2. In some embodiments, X is CH(C1-C3 alkyl), wherein the C1-C3 alkyl is substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, and -NH2. In some embodiments, X is CH(methyl), CH(ethyl), CH(n- propyl), or CH(isopropyl), wherein the methyl, ethyl, n-propyl, and isopropyl are optionally substituted with halogen, -OH, -CN, or -NH2. In some embodiments, X is CH(methyl), CH(ethyl), CH(n-propyl), or CH(isopropyl), wherein the methyl, ethyl, n-propyl, and isopropyl are substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, and -NH2. In some embodiments, X is CH(methyl), CH(ethyl), CH(n- propyl), or CH(isopropyl). In some embodiments, X is CH(CH3). [0044] In some embodiments, X is CH(C3-C6 cycloalkyl), wherein the C3-C6 cycloalkyl is optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, the C3-C6 cycloalkyl is substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, -NH2, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, the C3-C6 cycloalkyl is unsubstituted. In some embodiments, X is CH(cyclopropyl), CH(cyclobutyl), CH(cyclopentyl), or CH(cyclohexyl). [0045] In some embodiments, two R6 groups are taken together with the carbon atom to which they are attached to form a C3-C6 cycloalkyl optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, the C3-C6 cycloalkyl is substituted with one, two, or three groups selected from the group consisting of halogen, - OH, -CN, -NH2, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, the C3-C6 cycloalkyl is unsubstituted. [0046] In some embodiments, two R6 groups are taken together with the carbon atom to which they are attached to form a 3- to 7-membered heterocyclyl optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, the 3- to 7- membered heterocyclyl is aziridinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, thianyl, azepanyl, oxepanyl, thiepanyl, pyrazolidinyl, imidazolidinyl, dioxolanyl, oxazolidinyl, isoxazolidinyl, morpholinyl, or thiomorpholinyl, each of which is optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, the 3- to 7-membered heterocyclyl, including any variation detailed herein, is substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, -NH2, C1-C6 alkyl, and C1- C6 haloalkyl. In some embodiments, the 3- to 7-membered heterocyclyl, including any variation detailed herein, is unsubstituted. In some embodiments, the 3- to 7-membered heterocyclyl contains one, two, or three heteroatoms selected from nitrogen, oxygen, sulfur, S(=O), and S(=O) 2 and is optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, the 3- to 7-membered heterocyclyl contains one or two nitrogen atoms. In some embodiments, the 3- to 7-membered heterocyclyl contains one nitrogen atom. In some embodiments, the 3- to 7-membered heterocyclyl contains one or two oxygen atoms. In some embodiments, the 3- to 7-membered heterocyclyl contains one oxygen atom. In some embodiments, the 3- to 7-membered heterocyclyl contains one or two sulfur atoms. In some embodiments, the 3- to 7-membered heterocyclyl contains one sulfur atom. In some embodiments, the 3- to 7-membered heterocyclyl contains one nitrogen atom and two oxygen atoms. In some embodiments, the 3- to 7-membered heterocyclyl contains two nitrogen atoms and one oxygen atom. In some embodiments, the 3- to 7-membered heterocyclyl contains one nitrogen atom and one oxygen atom. In some embodiments, the 3- to 7-membered heterocyclyl contains one nitrogen atom and two sulfur atoms. In some embodiments, the 3- to 7-membered heterocyclyl contains two nitrogen atoms and one sulfur atom. In some embodiments, the 3- to 7-membered heterocyclyl contains one nitrogen atom and one sulfur atom. In some embodiments, the 3- to 7-membered heterocyclyl contains one oxygen atom and two sulfur atoms. In some embodiments, the 3- to 7-membered heterocyclyl contains two oxygen atoms and one sulfur atom. In some embodiments, the 3- to 7-membered heterocyclyl contains one oxygen atom and one sulfur atom. [0047] In some embodiments, R1 is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C6-C10 aryl, or optionally substituted 5- to 10-membered heteroaryl. In some embodiments, R1 and one R5 group are taken together with the atoms to which they are attached to form an optionally substituted 5- to 7-membered heterocyclyl. In some embodiments, R1 and R2 are taken together with the carbon atom to which they are attached to form an optionally substituted 4- to 7-membered heterocyclyl or an optionally substituted C3-C6 cycloalkyl. In some embodiments, R1 is H; C1-C6 alkyl optionally substituted with halogen, -OH, -CN, or -NH2; or C3-C6 cycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, each of which is optionally substituted with halogen, -OH, - CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R1 is H or unsubstituted C1-C3 alkyl. In some embodiments, R1 is H or -CH3. In some embodiments, R1 and one R5 group are taken together with the atoms to which they are attached to form a 5- to 7- membered heterocyclyl optionally substituted with halogen, -OH, -NH2, C1-C6 alkyl, or C1- C6 haloalkyl. In some embodiments, R1 and one R5 group are taken together with the atoms to which they are attached to form an unsubstituted 5- to 6-membered heterocyclyl. In some embodiments, R1 and one R 5 group are taken together with the atoms to which they are attached to form an unsubstituted 5-membered heterocyclyl. In some embodiments, R1 and R2 are taken together with the carbon atom to which they are attached to form a 4- to 7- membered heterocyclyl or C3-C6 cycloalkyl, each of which is optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R1 and R2 are taken together with the carbon atom to which they are attached to form an unsubstituted 5- to 6-membered heterocyclyl. In some embodiments, R1 and R2 are taken together with the carbon atom to which they are attached to form an unsubstituted pyrrolidinyl. [0048] In some embodiments, R1 is H. [0049] In some embodiments, R1 is optionally substituted C1-C6 alkyl. In some embodiments, R1 is C1-C6 alkyl optionally substituted with halogen, -OH, -CN, or -NH2. In some embodiments, R1 is C1-C6 alkyl substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, and -NH2. In some embodiments, R1 is unsubstituted C1-C6 alkyl. In some embodiments, R1 is C1-C3 alkyl, such as methyl, ethyl, n- propyl, or isopropyl, which is optionally substituted with halogen, -OH, -CN, or -NH2. In some embodiments, R1 is C1-C3 alkyl, such as methyl, ethyl, n-propyl, or isopropyl, which is substituted with one, two, or three groups selected from the group consisting of halogen, - OH, -CN, and -NH2. In some embodiments, R1 is unsubstituted C1-C3 alkyl, such as methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R1 is -CH3. [0050] In some embodiments, R1 optionally substituted C3-C6 cycloalkyl. In some embodiments, R1 is C3-C6 cycloalkyl optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R1 is C3-C6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, which is optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R1 is C
Figure imgf000018_0001
cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, which is substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, - NH2, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, R1 is unsubstituted C3-C6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. [0051] In some embodiments, R1 is optionally substituted C6-C10 aryl. In some embodiments, R1 is C6-C10 aryl optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R1 is C6-C10 aryl, such as phenyl or naphthyl, which is optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1- C6 haloalkyl. In some embodiments, R1 is C6-C10 aryl, such as phenyl or naphthyl, which is substituted with one, two, or three groups selected from the group consisting of halogen, - OH, -CN, -NH2, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, R1 is unsubstituted C6-C10 aryl, such as phenyl or naphthyl. In some embodiments, R1 is phenyl substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, -NH2, C1- C6 alkyl, and C1-C6 haloalkyl. In some embodiments, R1 is unsubstituted phenyl. [0052] In some embodiments, R1 is optionally substituted 5- to 10-membered heteroaryl. In some embodiments, the 5- to 10-membered heteroaryl is optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, the 5- to 10-membered heteroaryl contains one, two or three heteroatoms selected from nitrogen, oxygen, sulfur, S(=O), and S(=O)2 and is optionally substituted with halogen, -OH, -CN, - NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R1 is a 5- to 6-membered heteroaryl containing one, two or three heteroatoms selected from nitrogen, oxygen, sulfur, S(=O), and S(=O)2 and optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, the 5- to 10-membered heteroaryl, such as a 5- to 6- membered heteroaryl, contains one or two nitrogen atoms. In some embodiments, the 5- to 10-membered heteroaryl contains one nitrogen atom. In some embodiments, the 5- to 10- membered heteroaryl contains one or two oxygen atoms. In some embodiments, the 5- to 10- membered heteroaryl contains one oxygen atom. In some embodiments, the 5- to 10- membered heteroaryl contains one or two sulfur atoms. In some embodiments, the 5- to 10- membered heteroaryl contains one sulfur atom. In some embodiments, the 5- to 10-membered heteroaryl contains one nitrogen atom and two oxygen atoms. In some embodiments, the 5- to 10-membered heteroaryl contains two nitrogen atoms and one oxygen atom. In some embodiments, the 5- to 10-membered heteroaryl contains one nitrogen atom and one oxygen atom. In some embodiments, the 5- to 10-membered heteroaryl contains one nitrogen atom and two sulfur atoms. In some embodiments, the 5- to 10-membered heteroaryl contains two nitrogen atoms and one sulfur atom. In some embodiments, the 5- to 10-membered heteroaryl contains one nitrogen atom and one sulfur atom. In some embodiments, the 5- to 10- membered heteroaryl contains one oxygen atom and two sulfur atoms. In some embodiments, the 5- to 10-membered heteroaryl contains two oxygen atoms and one sulfur atom. In some embodiments, the 5- to 10-membered heteroaryl contains one oxygen atom and one sulfur atom. In some embodiments, the 5- to 10-membered heteroaryl, such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furanyl, thiophenyl, oxazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, or naphthyridinyl, is optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, the 5- to 10-membered heteroaryl, including any variation detailed herein, is substituted with one, two, or three groups selected from the group consisting of halogen, - OH, -CN, -NH2, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, the 5- to 10- membered heteroaryl, including any variation detailed herein, is unsubstituted. [0053] In some embodiments, R1 and one R5 group are taken together with the atoms to which they are attached to form an optionally substituted 5- to 7-membered heterocyclyl. In some embodiments, the 5- to 7-membered heterocyclyl is optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, the 5- to 7- membered heterocyclyl is substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, -NH2, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, the 5- to 7-membered heterocyclyl is unsubstituted. In some embodiments, the 5- to 7-membered heterocyclyl contains one or two additional heteroatoms selected from nitrogen, oxygen, sulfur, S(=O), and S(=O)2 and is optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, the additional heteroatoms are two nitrogen atoms. In some embodiments, the additional heteroatom is one nitrogen atom. In some embodiments, the additional heteroatoms are two oxygen atoms. In some embodiments, the additional heteroatom is one oxygen atom. In some embodiments, the additional heteroatoms are two sulfur atoms. In some embodiments, the additional heteroatom is one sulfur atom. In some embodiments, the additional heteroatoms are one nitrogen atom and one oxygen atom. In some embodiments, the additional heteroatoms are one nitrogen atom and one sulfur atom. In some embodiments, the additional heteroatoms are one oxygen atom and one sulfur atom. In some embodiments, the 5- to 7-membered
Figure imgf000020_0001
substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, the 5- to 7-membered heterocyclyl, including any variation detailed herein, is substituted with one, two, or three groups selected from the group consisting of halogen, - OH, -CN, -NH2, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, the 5- to 7- membered heterocyclyl, including any variation detailed herein, is unsubstituted. In some embodiments, the 5- to 7-membered heterocyclyl is a 5- to 6-membered heterocyclyl optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, the 5- to 7-membered heterocyclyl is unsubstituted 5- to 6-membered heterocyclyl. In some embodiments, the 5- to 7-membered heterocyclyl is a 5-membered heterocyclyl optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, the 5- to 7-membered heterocyclyl is unsubstituted 5- membered heterocyclyl. In some embodiments, the 5- to 7-membered heterocyclyl is pyrrolidin-2-yl optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, the 5- to 7-membered heterocyclyl is unsubstituted pyrrolidin-2-yl. [0054] In some embodiments, R1 and R2 are taken together with the carbon atom to which they are attached to form an optionally substituted 4- to 7-membered heterocyclyl. In some embodiments, the 4- to 7-membered heterocyclyl is optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, the 4- to 7- membered heterocyclyl is substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, -NH2, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, the 4- to 7-membered heterocyclyl is unsubstituted. In some embodiments, the 4- to 7-membered heterocyclyl contains one, two, or three heteroatoms selected from nitrogen, oxygen, sulfur, S(=O), and S(=O)2 and is optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, the 4- to 7-membered heterocyclyl contains one or two nitrogen atoms. In some embodiments, the 4- to 7- membered heterocyclyl contains one nitrogen atom. In some embodiments, the 4- to 7- membered heterocyclyl contains one or two oxygen atoms. In some embodiments, the 4- to 7- membered heterocyclyl contains one oxygen atom. In some embodiments, the 4- to 7- membered heterocyclyl contains one or two sulfur atoms. In some embodiments, the 4- to 7- membered heterocyclyl contains one sulfur atom. In some embodiments, the 4- to 7- membered heterocyclyl contains one nitrogen atom and two oxygen atoms. In some embodiments, the 4- to 7-membered heterocyclyl contains two nitrogen atoms and one oxygen atom. In some embodiments, the 4- to 7-membered heterocyclyl contains one nitrogen atom and one oxygen atom. In some embodiments, the 4- to 7-membered heterocyclyl contains one nitrogen atom and two sulfur atoms. In some embodiments, the 4- to 7-membered heterocyclyl contains two nitrogen atoms and one sulfur atom. In some embodiments, the 4- to 7-membered heterocyclyl contains one nitrogen atom and one sulfur atom. In some embodiments, the 4- to 7-membered heterocyclyl contains one oxygen atom and two sulfur atoms. In some embodiments, the 4- to 7-membered heterocyclyl contains two oxygen atoms and one sulfur atom. In some embodiments, the 4- to 7-membered heterocyclyl contains one oxygen atom and one sulfur atom. In some embodiments, the 4- to 7-membered heterocyclyl, such as ,
Figure imgf000021_0001
, , , , , , , , ,
Figure imgf000021_0002
, is optionally substituted with halogen, -OH, -CN, -NH 2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, the 4- to 7-membered heterocyclyl, including any variation detailed herein, is substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, -NH2, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, the 4- to 7-membered heterocyclyl, including any variation detailed herein, is unsubstituted. In some embodiments, the 4- to 7-membered heterocyclyl is a 5- to 6-membered heterocyclyl optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, the 4- to 7-membered heterocyclyl is unsubstituted 5- to 6-membered heterocyclyl. In some embodiments, the 4- to 7-membered heterocyclyl is a 5-membered heterocyclyl optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, the 4- to 7-membered heterocyclyl is unsubstituted 5-membered heterocyclyl. In some embodiments, the 4- to 7-membered heterocyclyl is pyrrolidinyl optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C 1-C6 haloalkyl. In some embodiments, the 4- to 7-membered heterocyclyl is unsubstituted pyrrolidinyl. [0055] In some embodiments, R1 and R2 are taken together with the carbon atom to which they are attached to form an optionally substituted
Figure imgf000022_0001
cycloalkyl. In some embodiments, the C3-C6 cycloalkyl is optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, the C3-C6 cycloalkyl is substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, - NH2, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, the C3-C6 cycloalkyl is unsubstituted. In some embodiments, R1 and R2 are taken together with the carbon atom to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. [0056] In some embodiments, R2 is H, optionally substituted C1-C6 alkyl, -OR5, or - or R1 and R2 are taken together with the carbon atom to which they are attached to form an optionally substituted 4- to 7-membered heterocyclyl or an optionally substituted C3- C6 cycloalkyl. In some embodiments, R2 is H; C1-C6 alkyl optionally substituted with halogen, -OH, -CN, or -NH2; -OR5; or -N(R5)2. In some embodiments, R2 is H, unsubstituted C1-C3 alkyl, -O(unsubstituted C1-C6 alkyl), -OH, -NH2, or -NH(unsubstituted C1-C6 alkyl). In some embodiments, R2 is H, -CH3, -OCH3, -OH, -NH2, or -N(H)CH3. [0057] In some embodiments, R2 is H. [0058] In some embodiments, R2 is optionally substituted C1-C6 alkyl. In some embodiments, R2 is C1-C6 alkyl optionally substituted with halogen, -OH, -CN, or -NH2. In some embodiments, R2 is C1-C6 alkyl substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, and -NH2. In some embodiments, R2 is unsubstituted C1-C6 alkyl. In some embodiments, R2 is C1-C3 alkyl, such as methyl, ethyl, n- propyl, or isopropyl, which is optionally substituted with halogen, -OH, -CN, or -NH2. In some embodiments, R2 is C1-C3 alkyl, such as methyl, ethyl, n-propyl, or isopropyl, which is substituted with one, two, or three groups selected from the group consisting of halogen, - OH, -CN, and -NH2. In some embodiments, R2 is unsubstituted C1-C3 alkyl, such as methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R2 is -CH3. [0059] In some embodiments, R2 is -OR5. In some embodiments, R2 is –OH, – O(optionally substituted C1-C6 alkyl), or –O(optionally substituted C3-C6 cycloalkyl). In some embodiments, R2 is –OH. In some embodiments, R2 is –O(C1-C6 alkyl) optionally substituted with halogen, -OH, -CN, or -NH2. In some embodiments, R2 is –O(C1-C6 alkyl) substituted with one, two, or three groups selected from the group consisting of halogen, - OH, -CN, and -NH2. In some embodiments, R2 is–O(unsubstituted C1-C6 alkyl). In some embodiments, R2 is –O(C1-C3 alkyl) optionally substituted with halogen, -OH, -CN, or -NH2. In some embodiments, R2 is –O(C1-C3 alkyl), such as –O(methyl), –O(ethyl), –O(n-propyl), or –O(isopropyl), which is optionally substituted with halogen, -OH, -CN, or -NH2. In some embodiments, R2 is –O(C1-C3 alkyl), such as –O(methyl), –O(ethyl), –O(n-propyl), or – O(isopropyl), which is substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, and -NH2. In some embodiments, R2 is–O(unsubstituted C1- C3 alkyl), such as –O(methyl), –O(ethyl), –O(n-propyl), or –O(isopropyl). In some embodiments, R2 is –OCH3. In some embodiments, R2 is –O(C3-C6 cycloalkyl) optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R2 is –O(C3-C6 cycloalkyl), such as –O(cyclopropyl), –O(cyclobutyl), – O(cyclopentyl), or –O(cyclohexyl), which is optionally substituted with halogen, -OH, -CN, - NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R2 is –O(C3-C6 cycloalkyl), such as –O(cyclopropyl), –O(cyclobutyl), –O(cyclopentyl), or –O(cyclohexyl), which is substituted with one, two, or three groups selected from the group consisting of halogen, - OH, -CN, -NH2, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, R2 is – O(unsubstituted C3-C6 cycloalkyl), such as –O(cyclopropyl), –O(cyclobutyl), – O(cyclopentyl), or –O(cyclohexyl). [0060] In some embodiments, R2 is –N(R5)2. In some embodiments, each R5 is independently H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl. In some embodiments, each R5 is independently C1-C6 alkyl optionally substituted with halogen, -OH, -CN, or -NH2. In some embodiments, each R5 is independently unsubstituted C1-C6 alkyl. In some embodiments, each R5 is independently C1- C3 alkyl optionally substituted with halogen, -OH, -CN, or -NH2. In some embodiments, each R5 is independently unsubstituted C1-C3 alkyl. In some embodiments, both R5 groups are - CH3. [0061] In some embodiments, R2 is –N(R5)2, and both R5 groups are the same. In some embodiments, R2 is –NH2. In some embodiments, R2 is –N(CH3)2. [0062] In some embodiments, R2 is –N(R5)2, and the two R5 groups are not the same. In some embodiments, at least one R5 is C1-C6 alkyl optionally substituted with halogen, -OH, - CN, or -NH2. In some embodiments, at least one R5 is C1-C3 alkyl optionally substituted with halogen, -OH, -CN, or -NH2. In some embodiments, at least one R5 is unsubstituted C1-C3 alkyl, such as methyl, ethyl, n-propyl, or isopropyl. In some embodiments, at least one R5 is C3-C6 cycloalkyl optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, at least one R5 is unsubstituted C3-C6 cycloalkyl. In some embodiments, one R5 is H and the other R5 is optionally substituted C1-C6 alkyl or optionally substituted C3-C6 cycloalkyl. [0063] In some embodiments, R2 is –NH(C1-C6 alkyl), wherein the C1-C6 alkyl is optionally substituted with halogen, -OH, -CN, or -NH2. In some embodiments, R2 is – NH(C1-C6 alkyl), wherein the C1-C6 alkyl is substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, and -NH2. In some embodiments, R2 is –NH(unsubstituted C1-C6 alkyl). In some embodiments, R2 is –NH(C1-C3 alkyl), wherein the C1-C3 alkyl is optionally substituted with halogen, -OH, -CN, or -NH2. In some embodiments, R2 is –NH(C1-C3 alkyl), wherein the C1-C3 alkyl is substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, and -NH2. In some embodiments, R2 is –NH(methyl), –NH(ethyl), –NH(n-propyl), or –NH(isopropyl), wherein the methyl, ethyl, n-propyl, and isopropyl are optionally substituted with halogen, -OH, -CN, or -NH2. In some embodiments, R2 is –NH(methyl), –NH(ethyl), –NH(n-propyl), or – NH(isopropyl), wherein the methyl, ethyl, n-propyl, and isopropyl are substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, and -NH2. In some embodiments, R2 is –NH(methyl), –NH(ethyl), –NH(n-propyl), or –NH(isopropyl). In some embodiments, R2 is –NH(CH3). [0064] In some embodiments, R2 is –NH(C3-C6 cycloalkyl), wherein the C3-C6 cycloalkyl is optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R2 is –NH(C3-
Figure imgf000025_0001
6 cycloalkyl), wherein the C3-C6 cycloalkyl is substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, - NH2, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, R2 is –NH(unsubstituted C3-C6 cycloalkyl). In some embodiments, R2 is –NH(cyclopropyl), –NH(cyclobutyl), – NH(cyclopentyl), or –NH(cyclohexyl). [0065] In some embodiments, R2 is –N(R5)2 and two R5 groups are taken together with the nitrogen atom to which they are attached to form an optionally substituted 5- to 7- membered heterocyclyl. In some embodiments, the 5- to 7-membered heterocyclyl is optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, the 5- to 7-membered heterocyclyl is substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, -NH2, C1-C6 alkyl, and C1- C6 haloalkyl. In some embodiments, the 5- to 7-membered heterocyclyl is unsubstituted. In some embodiments, the 5- to 7-membered heterocyclyl optionally contains one or two additional ring heteroatoms selected from the group consisting of nitrogen, oxygen, sulfur, S(=O), and S(=O)2, and is optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, the 5- to 7-membered heterocyclyl contains two additional ring heteroatoms which are the same as each other. In some embodiments, the 5- to 7-membered heterocyclyl contains two additional ring heteroatoms which are different from each other. In some embodiments, the additional heteroatoms are two nitrogen atoms. In some embodiments, the additional heteroatom is one nitrogen atom. In some embodiments, the additional heteroatoms are two oxygen atoms. In some embodiments, the additional heteroatom is one oxygen atom. In some embodiments, the additional heteroatoms are two sulfur atoms. In some embodiments, the additional heteroatom is one sulfur atom. In some embodiments, the additional ring heteroatoms are one nitrogen atom and one oxygen atom. In some embodiments, the additional ring heteroatoms one nitrogen atom and one sulfur atom. In some embodiments, the additional ring heteroatoms are one oxygen atom and one sulfur atom. In some embodiments, the 5- to 7-membered heterocyclyl, such as
Figure imgf000026_0001
optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments,the 5- to 7-membered heterocyclyl, including any variation detailed herein, is substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, -NH2, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, the 5- to 7-membered heterocyclyl, including any variation detailed herein, is unsubstituted. In some embodiments,the 5- to 7-membered heterocyclyl is a 5- to 6-membered heterocyclyl optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, the 5- to 7-membered heterocyclyl is an unsubstituted 5- to 6-membered heterocyclyl. [0066] In some embodiments, R3 is H or optionally substituted C1-C6 alkyl. In some embodiments, R3 is H; or C1-C6 alkyl optionally substituted with halogen, -OH, -CN, or - NH2. In some embodiments, R3 is H or unsubstituted C1-C3 alkyl. In some embodiments, R3 is H or -CH3. [0067] In some embodiments, R3 is H. [0068] In some embodiments, R3 is optionally substituted C1-C6 alkyl. In some embodiments, R3 is C1-C6 alkyl optionally substituted with halogen, -OH, -CN, or -NH2. In some embodiments, R3 is C1-C6 alkyl substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, and -NH2. In some embodiments, R3 is unsubstituted C1-C6 alkyl. In some embodiments, R3 is C1-C3 alkyl, such as methyl, ethyl, n- propyl, or isopropyl, which is optionally substituted with halogen, -OH, -CN, or -NH2. In some embodiments, R3 is C1-C3 alkyl, such as methyl, ethyl, n-propyl, or isopropyl, which is substituted with one, two, or three groups selected from the group consisting of halogen, - OH, -CN, and -NH2. In some embodiments, R3 is unsubstituted C1-C3 alkyl, such as methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R3 is –CH3. [0069] In some embodiments, R4 is H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl. In some embodiments, R4 is H; C1-C6 alkyl optionally substituted with halogen, -OH, -CN, or -NH2; or C3-C6 cycloalkyl optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R4 is H or unsubstituted C1-C3 alkyl. In some embodiments, R4 is H or -CH3. [0070] In some embodiments, R4 is H. [0071] In some embodiments, R4 is optionally substituted C1-C6 alkyl. In some embodiments, R4 is C1-C6 alkyl optionally substituted with halogen, -OH, -CN, or -NH2. In some embodiments, R4 is C1-C6 alkyl substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, and -NH2. In some embodiments, R4 is unsubstituted C1-C6 alkyl. In some embodiments, R4 is C1-C3 alkyl, such as methyl, ethyl, n- propyl, or isopropyl, which is optionally substituted with halogen, -OH, -CN, or -NH2. In some embodiments, R4 is C1-C3 alkyl, such as methyl, ethyl, n-propyl, or isopropyl, which is substituted with one, two, or three groups selected from the group consisting of halogen, - OH, -CN, and -NH2. In some embodiments, R4 is unsubstituted C1-C3 alkyl, such as methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R4 is –CH3. [0072] In some embodiments, R4 is optionally substituted C3-C6 cycloalkyl. In some embodiments, R4 is C3-C6 cycloalkyl optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R4 is C3-C6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, which is optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R4 is C3-C6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, which is substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, - NH2, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, R4 is unsubstituted C3-C6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. [0073] In some embodiments, each R5 is independently H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl; or two R5 groups are taken together with the nitrogen atom to which they are attached to form an optionally substituted 5- to 7-membered heterocyclyl;or R1 and one R5 group are taken together with the atoms to which they are attached to form an optionally substituted 5- to 7-membered heterocyclyl. In some embodiments, R5 is H; C1-C6 alkyl optionally substituted with halogen, -OH, -CN, or -NH2; or C3-C6 cycloalkyl optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1- C6 haloalkyl. In some embodiments, two R5 groups are taken together with the nitrogen atom to which they are attached to form a 5- to 7-membered heterocyclyl optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl, wherein the 5- to 7- membered heterocyclyl optionally contains 1-2 additional ring heteroatoms selected from the group consisting of O, N, S, S(=O), and S(=O)2. [0074] In some embodiments, at least one R5 is H. In some embodiments, both R5 groups are H. In some embodiments, R2 is -OR5, and R5 is H. [0075] In some embodiments, each R5 is independently optionally substituted C1-C6 alkyl. In some embodiments, each R5 is independently C1-C6 alkyl optionally substituted with halogen, -OH, -CN, or -NH2. In some embodiments, each R5 is independently C1-C6 alkyl substituted with one, two, or three groups selected from the group consisting of halogen, - OH, -CN, and -NH2. In some embodiments, each R5 is independently unsubstituted C1-C6 alkyl. In some embodiments, each R5 is independently C1-C3 alkyl, such as methyl, ethyl, n- propyl, or isopropyl, which is optionally substituted with halogen, -OH, -CN, or -NH2. In some embodiments, each R5 is independently C1-C3 alkyl, such as methyl, ethyl, n-propyl, or isopropyl, which is substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, and -NH2. In some embodiments, each R5 is independently unsubstituted C1-C3 alkyl, such as methyl, ethyl, n-propyl, or isopropyl. In some embodiments, at least one R5 is –CH3. In some embodiments, both R5 groups are –CH3. In some embodiments, R2 is -OR5, and R5 is –CH3. [0076] In some embodiments, R5 is optionally substituted C3-C6 cycloalkyl. In some embodiments, R5 is C3-C6 cycloalkyl optionally substituted with halogen, -OH, -CN, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R5 is C3-C6 cycloalkyl substituted with one, two, or three groups selected from the group consisting of halogen, -OH, -CN, - NH2, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, R5 is unsubstituted C3-C6 cycloalkyl. In some embodiments, R5 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. [0077] In some embodiments, the compound provided is of formula (II):
Figure imgf000028_0001
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and R4 are as defined herein for any embodiment or variation of a compound of formula (I). In some embodiments, R1, R2, R3, and R4 are independently H or optionally substituted C1-C6 alkyl. In some embodiments, R1 and R2 are independently C1-C6 alkyl optionally substituted with halogen, -OH, -CN, or -NH2. In some embodiments, R1 and R2 are independently unsubstituted C1-C3 alkyl. In some embodiments, R1 and R2 are both – CH3. In some embodiments, R3 is H. In some embodiments, R4 is H. In some embodiments, R4 is unsubstituted C1-C3 alkyl. In some embodiments, R4 is -CH3. [0078] In some embodiments, the compound provided is of formula (III):
Figure imgf000029_0001
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and R4 are as defined herein for any embodiment of a compound of formula (I). In some embodiments, R1 is C1-C6 alkyl optionally substituted with halogen, - OH, -CN, or -NH2. In some embodiments, R1 is unsubstituted C1-C3 alkyl. In some embodiments, R1 is –CH3. In some embodiments, R2 is –NH2 or C1-C6 alkyl optionally substituted with halogen, -OH, -CN, or -NH2. In some embodiments, R2 is –NH2. In some embodiments, R2 is unsubstituted C1-C3 alkyl. In some embodiments, R2 is –CH3. In some embodiments, R3 is H or C1-C6 alkyl optionally substituted with halogen, -OH, -CN, or -NH2. In some embodiments, R3 is H. In some embodiments, R3 is unsubstituted C1-C3 alkyl. In some embodiments, R3 is –CH3. In some embodiments, R1, R2, and R3 are C1-C6 alkyl optionally substituted with halogen, -OH, -CN, or -NH2. In some embodiments, R1, R2, and R3 are unsubstituted C1-C3 alkyl. In some embodiments, R1, R2, and R3 are –CH3. In some embodiments, R1 is C1-C6 alkyl optionally substituted with halogen, -OH, -CN, or -NH2; R2 is -NH2; and R3 is H. In some embodiments, R1 is -CH3, R2 is -NH2, and R3 is H. In some embodiments, R1 and R2 are taken together with the carbon atom to which they are attached to form an optionally substituted 4- to 7-membered heterocyclyl. In some embodiments, R1 and R2 are taken together with the carbon atom to which they are attached to form an unsubstituted 5- to 6-membered heterocyclyl. In some embodiments, R1 and R2 are taken together with the carbon atom to which they are attached to form an unsubstituted pyrrolidinyl. In some embodiments, R4 is H. [0079] In some embodiments, the compound provided is of formula (IV):
Figure imgf000030_0001
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, and R6 are as defined herein for any embodiment of a compound of formula (I). In some embodiments, R1, R2, R3, R4, and R6 are independently H or optionally substituted C1-C6. In some embodiments, R1, R2, R3, and R4 are H. In some embodiments, each R6 is independently C1-C6 alkyl optionally substituted with halogen, -OH, -CN, or -NH2. In some embodiments, each R6 is independently unsubstituted C1-C3 alkyl. In some embodiments, both R6 group are –CH3. [0080] In some embodiments, the compound provided is of formula (V):
Figure imgf000030_0002
or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and X are as defined herein for any embodiment of a compound of formula (I). In some embodiments, R1 is C1-C6 alkyl optionally substituted with halogen, - OH, -CN, or -NH2. In some embodiments, R1 is unsubstituted C1-C3 alkyl. In some embodiments, R1 is –CH3. In some embodiments, R1 is H. In some embodiments, R2 is –NH2 or C1-C6 alkyl optionally substituted with halogen, -OH, -CN, or -NH2. In some embodiments, R2 is –NH2. In some embodiments, R2 is unsubstituted C1-C3 alkyl. In some embodiments, R2 is –CH3. In some embodiments, R3 is H or C1-C6 alkyl optionally substituted with halogen -OH -CN or -NH2 In some embodiments R3 is H In some embodiments, R3 is unsubstituted C1-C3 alkyl. In some embodiments, R3 is –CH3. In some embodiments, R1, R2, and R3 are H. In some embodiments, R1, R2, and R3 are independently H or C1-C6 alkyl optionally substituted with halogen, -OH, -CN, or -NH2. In some embodiments, R1 and R2 are taken together with the carbon atom to which they are attached to form an optionally substituted 4- to 7-membered heterocyclyl. In some embodiments, R1 and R2 are taken together with the carbon atom to which they are attached to form an unsubstituted 5- to 6-membered heterocyclyl. In some embodiments, R1 and R2 are taken together with the carbon atom to which they are attached to form an unsubstituted pyrrolidinyl. In some embodiment, X is O. In some embodiments, X is a bond. In some embodiments, X is C(R6)2, wherein R6 is as defined herein for any embodiment of a compound of formula (I). In some embodiments, X is C(CH3)2. [0081] In one aspect, provided is a compound of formula (I), or a pharmaceutically acceptable salt thereof, which has any one or more of the following structural features: (I) X is: (i) O; (ii) a bond; or (iii) C(C1-C6 alkyl)2 optionally substituted with halogen or -OH, (II) R1 is: (iv) H; or (v) C1-C6 alkyl optionally substituted with halogen or -OH; (III) R2 is: (vi) H; (vii) C1-C6 alkyl optionally substituted with halogen or -OH; or (viii) NH2; (IV) R1 and R2 are taken together with the carbon atom to which they are attached to form a 4- to 7-membered heterocyclyl optionally substituted with halogen, -OH, or C1-C6 alkyl; (V) R2 is -N(R5)2, wherein one R5 group and R1 are taken together with the atoms to which they are attached to form a 5- to 7-membered heterocyclyl optionally substituted with halogen, -OH, or C1-C6 alkyl, and the other R5 group is H or C1-C6 alkyl optionally substituted with halogen or -OH; (VI) R3 is: (ix) H; or (x) C1-C6 alkyl optionally substituted with halogen or -OH; is: (xi) H; or (xii) C1-C6 alkyl optionally substituted with halogen or -OH. In one variation, (I) applies. In one variation, (II) applies. In one variation, (III) applies. In one variation, (IV) applies. In one variation, (V) applies. In one variation, (VI) applies. In one variation, (VII) applies. In one aspect of this variation, (I), (II), (III), (VI), and (VII) apply. In another aspect of this variation, (I), (IV), (VI), and (VII) apply. In one variation, (I), (V), (VI), and (VII) apply. In one variation, (i), (v), (vii), (ix), and (xi) apply. In one variation, (i), (v), (vii), (ix), and (xii) apply. In one variation, (iii), (iv), (vi), (ix), and (xi) apply. In one variation, (ii), (v), (viii), (ix), and (xi) apply. In one variation, (ii), (v), (ix), and (xi) apply. [0082] In the descriptions herein, it is understood that every description, variation, embodiment or aspect of a moiety may be combined with every description, variation, embodiment or aspect of other moieties the same as if each and every combination of descriptions is specifically and individually listed. For example, every description, variation, embodiment or aspect provided herein with respect to R4 of formula (I) may be combined with every description, variation, embodiment or aspect of R1, R2, R3, R5, R6, and X the same as if each and every combination were specifically and individually listed. It is also understood that all descriptions, variations, embodiments or aspects of formula (I), where applicable, apply equally to other formulae detailed herein, and are equally described, the same as if each and every description, variation, embodiment or aspect were separately and individually listed for all formulae. For example, all descriptions, variations, embodiments or aspects of formula (I), where applicable, apply equally to any of formulae as detailed herein, such as formulae (II), (III), (IV), and (V), and are equally described, the same as if each and every description, variation, embodiment or aspect were separately and individually listed for all formulae. [0083] In some embodiments, provided are methods of treating liver cancer, colon cancer, small intestine, or gastric cancer in a subject in need thereof, comprising administering to the subject a compound selected from the compounds in Table 1, or pharmaceutically acceptable salt thereof. Although certain compounds described in Table 1 are presented as specific stereoisomers and/or in a non-stereochemical form, it is understood that any or all stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms of any of the compounds of Table 1 are herein described. [0084] In some embodiments, provided are methods of treating liver cancer, colon cancer, small intestine, or gastric cancer in a subject in need thereof, comprising administering to the subject Compound (I), or a pharmaceutically acceptable salt thereof, or a stereochemical form thereof or a tautomer thereof. Table 1.
Figure imgf000033_0001
Figure imgf000034_0001
[0085] Also provided are methods of treating liver cancer, colon cancer, small intestine or gastric cancer in a subject in need thereof, comprising administering salts of compounds referred to herein, such as pharmaceutically acceptable salts. The present disclosure also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms of the compounds described. Thus, if a particular stereochemical form, such as a specific enantiomeric form or diastereomeric form, is depicted for a given compound, then it is understood that any or all stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms of any of that same compound are herein described. Where tautomeric forms may be present for any of the compounds described herein, each and every tautomeric form is intended even though only one or some of the tautomeric forms may be explicitly depicted. The tautomeric forms specifically depicted may or may not be the predominant forms in solution or when used according to the methods described herein. [0086] Solvates of a compound provided herein or a salt thereof are also contemplated. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. [0087] Methods as detailed herein may in one aspect comprise administering compounds in a purified form and compositions comprising a compound in purified forms are detailed herein. Compositions comprising a compound as detailed herein or a salt thereof are provided, such as compositions of substantially pure compounds. In some embodiments, a composition containing a compound as detailed herein or a salt thereof is in substantially pure form. Unless otherwise stated, “substantially pure” intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound comprising the majority of the composition or a salt thereof. In some embodiments, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains no more than 25%, 20%, 15%, 10%, or 5% impurity. In some embodiments, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 3%, 2%, 1% or 0.5% impurity. [0088] Articles of manufacture comprising a compound described herein, or a salt or solvate thereof, in a suitable container are provided. The container may be a vial, jar, ampoule, preloaded syringe, i.v. bag, and the like. [0089] In some embodiments, the compounds detailed herein are orally bioavailable. In some embodiments, the compounds detailed herein are formulated for parenteral (e.g., intravenous) administration. [0090] One or several compounds described herein can be used in the preparation of a medicament by combining the compound or compounds disclosed herein with a pharmacologically acceptable carrier, which are known in the art. Depending on the therapeutic form of the medication, the carrier may be in various forms. In one variation, the manufacture of a medicament is for use in any of the methods disclosed herein, e.g., for the treatment of liver cancer, colon cancer, or gastric cancer. Pharmaceutical Compositions and Formulations [0091] Any of the compounds described herein may be formulated as a pharmaceutically acceptable composition. [0092] Pharmaceutical compositions of any of the compounds detailed herein are embraced by this disclosure. Thus, the present disclosure includes pharmaceutical compositions comprising a compound as detailed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. In one aspect, the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid. Pharmaceutical compositions may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation. [0093] A compound as detailed herein may in one aspect be in a purified form and compositions comprising a compound in purified forms are detailed herein. Compositions comprising a compound as detailed herein or a salt thereof are provided, such as compositions of substantially pure compounds. In some embodiments, a composition containing a compound as detailed herein or a salt thereof is in substantially pure form. [0094] In one variation, the compounds herein are synthetic compounds prepared for administration to an individual. In another variation, compositions are provided containing a compound in substantially pure form. In another variation, the present disclosure embraces pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier. In another variation, methods of administering a compound are provided. The purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein. [0095] A compound detailed herein, or a pharmaceutically acceptable salt thereof, may be formulated for any available delivery route, including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery form. A compound or salt thereof may be formulated with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs. [0096] A compound detailed herein, or a pharmaceutically acceptable salt thereof, can be used in the preparation of a formulation, such as a pharmaceutical formulation, by combining the compound or compounds, or a salt thereof, with a pharmaceutically acceptable carrier. Depending on the therapeutic form of the system (e.g., transdermal patch vs. oral tablet), the carrier may be in various forms. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants. Formulations comprising the compound may also contain other substances which have valuable therapeutic properties. Pharmaceutical formulations may be prepared by known pharmaceutical methods. Suitable formulations can be found, e.g., in Remington’s Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 20th ed. (2000), which is incorporated herein by reference. [0097] A compound detailed herein, or a pharmaceutically acceptable salt thereof, may be administered to individuals in a form of generally accepted oral compositions, such as tablets, coated tablets, and gel capsules in a hard or in soft shell, emulsions or suspensions. Examples of carriers, which may be used for the preparation of such compositions, are lactose, corn starch or its derivatives, talc, stearate or its salts, etc. Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid poly-ols, and so on. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants. [0098] Compositions comprising a compound provided herein are also described. In one variation, the composition comprises a compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. In another variation, a composition of substantially pure compound is provided. In some embodiments, the composition is for use as a human or veterinary medicament. In some embodiments, the composition is for use in a method described herein. In some embodiments, the composition is for use in the treatment of a disease or disorder described herein. [0099] Compositions formulated for co-administration of a compound provided herein and one or more additional pharmaceutical agents are also described. The co-administration can be simultaneous or sequential in any order. A compound provided herein may be formulated for co-administration with the one or more additional pharmaceutical agents in the same dosage form (e.g., single tablet or single i.v.) or separate dosage forms (e.g., two separate tablets, two separate i.v., or one tablet and one i.v.). Furthermore, co-administration can be, for example, 1) concurrent delivery, through the same route of delivery (e.g., tablet or i.v.), 2) sequential delivery on the same day, through the same route or different routes of delivery, or 3) delivery on different days, through the same route or different routes of delivery. [0100] In one variation, a compound provided herein is metabolized to release a therapeutically effective amount of 5-FU and/or one or more 5-FU metabolites, such as 5- FdUMP. In some embodiments, the therapeutically effective amount of 5-FU and/or one or more 5-FU metabolites, such as 5-FdUMP, is effective in treating cancer. In some embodiments, the amount of 5-FU and/or one or more 5-FU metabolites, such as 5-FdUMP, in the bloodstream is effective in treating cancer. In one variation, a compound provided herein is metabolized to release one or more metabolites in an amount effective in treating cancer. Methods of Use [0101] A prodrug is a pharmacologically inactive compound that is metabolized to a therapeutically active agent by one or more metabolic biotransformations. These metabolic biotransformations can occur when the prodrug is administered to a subject or cell. Metabolic processes include acid- or base-catalyzed chemical reaction(s) and enzyme-catalyzed chemical reaction(s). Embodiments are described herein wherein the therapeutically active compound is 5-FU, a metabolite of 5-FU (such as 5-FdUMP), and/or additional metabolites of the prodrugs described herein. [0102] Provided herein are methods of treating liver cancer, gastric cancer, small intestine, or colon cancer in a subject in need thereof, comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof), wherein said compound selectively accumulates in the liver and/or upper gastrointestinal tract. In some embodiments, said compound selectively accumulates in the liver, esophagus, or stomach. [0103] Also provided herein are methods of treating liver cancer, gastric cancer, small intestine, or colon cancer in a subject in need thereof, comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof), wherein the method does not result in the occurrence of dermatological toxicity, myelotoxicity, and/or leukopenia. In some embodiments the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof), selectively accumulates in the liver, wherein the method does not result in the occurrence of dermatological toxicity, myelotoxicity, and/or leukopenia. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof), selectively accumulates in the upper gastrointestinal tract, wherein the method does not result in the occurrence of dermatological toxicity, myelotoxicity, and/or leukopenia. [0104] Also provided herein are methods of treating liver cancer, gastric cancer, small intestine, or colon cancer in a subject in need thereof, comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof), wherein the method substantially minimizes the occurrence or severity of dermatological toxicity, myelotoxicity, and/or leukopenia. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof), selectively accumulates in the liver, wherein the method substantially minimizes the occurrence or severity of dermatological toxicity, myelotoxicity, and/or leukopenia. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof), selectively accumulates in the upper gastrointestinal tract, wherein the method substantially minimizes the occurrence or severity of dermatological toxicity, myelotoxicity, and/or leukopenia. [0105] In one aspect, provided herein are methods of treating liver metastases in a subject in need thereof, comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof). In some embodiments, the liver metastases originate from a primary cancer including, but not limited to, colon cancer, rectal cancer, small intestine, breast cancer, esophageal cancer, gastric cancer, pancreatic cancer, lung cancer, kidney cancer, skin cancer, ovarian cancer or lung cancer. In some embodiments, the liver metastases originate from a primary cancer wherein the primary cancer is colon cancer, gastric cancer, or rectal cancer. In some embodiments, the liver metastases originate from a primary cancer wherein the primary cancer is colon cancer or gastric cancer. In some embodiments, the compound of formula (I) is coadministered with a multikinase inhibitor such as sorafenib. [0106] In another aspect, provided herein are methods of treating a primary liver cancer in a subject in need thereof, comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof). In some embodiments, the primary liver cancer is hepatocellular carcinoma (HCC). In some such embodiments, the subject with HCC also suffers from a chronic liver disease such as cirrhosis. [0107] In another aspect, provided herein are methods of treating small intestine cancer in a subject in need thereof, comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof). In some such embodiments, the small intestine cancer is a primary cancer. In other such embodiments, the small intestine cancer has metastasized to other tissue. In particular embodiments, the small intestine cancer has metastasized to the liver. [0108] In another aspect, provided herein are methods of treating gastric cancer in a subject in need thereof, comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof). In some such embodiments, the gastric cancer is primary gastric cancer. In other such embodiments, the gastric cancer has metastasized to other tissue. In particular embodiments, the gastric cancer has metastasized to the liver. [0109] In another aspect, provided herein are methods of treating colon cancer in a subject in need thereof, comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof). In some such embodiments, the colon cancer has metastasized to other tissue. In particular, embodiments, the colon cancer has metastasized to the liver. [0110] In another aspect, provided herein are methods of treating small intestine cancer in a subject in need thereof, comprising administering to the subject a compound of formula (I) (e.g., Compound 1), or a pharmaceutically acceptable salt thereof. In some such embodiments, the small intestine cancer has metastasized to other tissue. In particular, embodiments, the small intestine cancer has metastasized to the liver. In some embodiments, the small intestine cancer is an adenocarcinoma, a sarcoma, a carcinoid tumor, a gastrointestinal stromal tumor (GIST) or an intestinal lymphoma. [0111] In some embodiments, the method of treating cancer with a compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof), is effective for treating a subject was unresponsive or had become refractory to a prior therapy. In some embodiments, the subject discontinued a prior therapy. In some embodiments, the subject discontinued a prior therapy due to the incidence of dermatological toxicity, myelotoxicity, or leukopenia during said prior therapy. In some embodiments, the administering reduces the occurrence of dermatological toxicity or myelotoxicity relative to a prior therapy. In some embodiments, the dermatological toxicity is palmar-plantar erythrodysesthesia (hand-foot syndrome), dermatitis, or stomatitis. In some embodiments, said prior therapy comprises treatment with a 5-FU prodrug such as capecitabine, UFT, or S-1. In particular embodiments, said prior therapy comprises treatment with capecitabine. In other embodiments, the prior therapy comprises treatment with a multikinase inhibitor. In some such embodiments, the multikinase inhibitor is sorafenib. [0112] Also provided herein are methods of delaying the onset and/or development of liver cancer, gastric cancer, small intestine, or colon cancer in a subject in need thereof, comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof), wherein said compound selectively accumulates in the liver and/or upper gastrointestinal tract. In some embodiments, said compound selectively accumulates in the liver, esophagus, or stomach. [0113] Also provided herein are methods of delaying the onset and/or development of liver cancer, gastric cancer, small intestine, or colon cancer in a subject in need thereof, comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof), wherein the method does not result in the occurrence of dermatological toxicity, myelotoxicity, and/or leukopenia. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof), selectively accumulates in the liver, wherein the method does not result in the occurrence of dermatological toxicity, myelotoxicity, and/or leukopenia. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof), selectively accumulates in the upper gastrointestinal tract, wherein the method does not result in the occurrence of dermatological toxicity, myelotoxicity, and/or leukopenia. [0114] Also provided herein are methods of delaying the onset and/or development of liver cancer, gastric cancer, small intestine, or colon cancer in a subject in need thereof, comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof), wherein the method substantially minimizes the occurrence or severity occurrence of dermatological toxicity, myelotoxicity, and/or leukopenia. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof), selectively accumulates in the liver, wherein the method substantially minimizes the occurrence or severity of dermatological toxicity, myelotoxicity, and/or leukopenia. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof), selectively accumulates in the upper gastrointestinal tract, wherein the method substantially minimizes the occurrence or severity of dermatological toxicity, myelotoxicity, and/or leukopenia. [0115] In one aspect, provided herein are methods of delaying the onset and/or development of liver metastases in a subject in need thereof, comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof). In some embodiments, the liver metastases originate from a primary cancer including, but not limited to, colon cancer, rectal cancer, breast cancer, esophageal cancer, small intestine, gastric cancer, pancreatic cancer, lung cancer, kidney cancer, skin cancer, ovarian cancer or lung cancer. In some embodiments, the liver metastases originate from a primary cancer wherein the primary cancer is colon cancer, gastric cancer, or rectal cancer. In some embodiments, the liver metastases originate from a primary cancer wherein the primary cancer is colon cancer or gastric cancer. In some embodiments, the compound of formula (I) is co-administered with a multikinase inhibitor such as sorafenib. [0116] In another aspect, provided herein are methods of delaying the onset and/or development of a primary liver cancer in a subject in need thereof, comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof). In some embodiments, the primary liver cancer is hepatocellular carcinoma (HCC). In some such embodiments, the subject with HCC also suffers from a chronic liver disease such as cirrhosis. [0117] In another aspect, provided herein are methods of delaying the onset and/or development of small intestine in a subject in need thereof, comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt thereof. In some such embodiments, the small intestine cancer has metastasized to other tissue. In particular embodiments, the small intestine cancer has metastasized to the liver. [0118] In another aspect, provided herein are methods of delaying the onset and/or development of gastric cancer in a subject in need thereof, comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt thereof. In some such embodiments, the gastric cancer is primary gastric cancer. In other such embodiments, the gastric cancer has metastasized to other tissue. In particular embodiments, the gastric cancer has metastasized to the liver. [0119] In another aspect, provided herein are methods of delaying the onset and/or development of colon cancer in a subject in need thereof, comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt thereof. In some such embodiments, the colon cancer has metastasized to other tissue. In particular, embodiments, the colon cancer has metastasized to the liver. [0120] In particular embodiments the compound of formula (I) (e.g., Compound 1) can be administered to a subject at a dose that does not result in accumulation of the compound in the skin or the bone of a patient. For instance, in some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, can be administered orally twice daily to a subject at a dose of from about 2 mg/kg to about 50 mg/kg. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, can be administered orally twice daily to a subject at a dose of from about 5 mg/kg to about 50 mg/kg. In some embodiments, the compound of formula (I), or a pharmaceutically salt thereof, can be administered orally twice daily to a subject at a dose of from about 10 mg/kg to about 50 mg/kg. In some embodiments, the compound of formula (I), or a pharmaceutically salt thereof, can be administered orally twice daily to a subject at a dose of from about 20 mg/kg to about 40 mg/kg. In some embodiments, the compound of formula (I), or a pharmaceutically salt thereof, can be administered orally twice daily to a subject at a dose of from about 30 mg/kg to about 40 mg/kg. In some embodiments, the compound of formula (I), or a pharmaceutically salt thereof, can be administered orally twice daily to a subject at a dose of from about 30 mg/kg to about 50 mg/kg. In some embodiments, the compound of formula (I), or a pharmaceutically salt thereof, can be administered orally twice daily to a subject at a dose of from about 40 mg/kg to about 50 mg/kg. [0121] In particular embodiments wherein the compound of formula (I) is Compound 1, the compound can be administered to a subject at a dose that does not result in accumulation of the compound in the skin or the bone of a patient. For instance, in some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, can be administered orally twice daily to a subject at a dose of from about 100 mg to about 4 g. In some embodiments, Compound 1, or a pharmaceutically salt thereof, can be administered orally twice daily to a subject at a dose of from about 100 mg to about 1 g. In some embodiments, Compound 1, or a pharmaceutically salt thereof, can be administered orally twice daily to a subject at a dose of from about 100 mg to about 500 mg. In some embodiments, Compound 1, or a pharmaceutically salt thereof, can be administered orally twice daily to a subject at a dose of from about 200 mg to about 600 mg. In some embodiments, Compound 1, or a pharmaceutically salt thereof, can be administered orally twice daily to a subject at a dose of from about 400 mg to about 4 g. In some embodiments, Compound 1, or a pharmaceutically salt thereof, can be administered orally twice daily to a subject at a dose of from about 1 g to about 4 g. In some embodiments, Compound 1, or a pharmaceutically salt thereof, can be administered orally twice daily to a subject at a dose of from about 2 g to about 4 g. [0122] In some embodiments, the method further comprises administering the compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof), and one or more additional pharmaceutical agents. In some embodiments, the one or more additional pharmaceutical agents is selected from the group consisting of cabozantinib S-malate, pembrolizumab, lenvatinib mesylate, sorafenib tosylate, nivolumab, and regorafenib. In some embodiments, the one or more additional pharmaceutical agents is leucovorin. In some embodiments, the method comprises simultaneously administering the compound of formula (I), or a pharmaceutically acceptable salt thereof, and the one or more additional pharmaceutical agents. In some embodiments, the method comprises sequentially administering the compound of formula (I), or a pharmaceutically acceptable salt thereof, and the one or more additional pharmaceutical agents. In some embodiments, the method comprises administering the compound of formula (I) or a pharmaceutically acceptable salt thereof and the one or more additional pharmaceutical agents on the same dosing schedule. In other embodiments, the method comprises administering the compound of formula (I) or a pharmaceutically acceptable salt thereof and the one or more additional pharmaceutical agents on a different dosing schedule. [0123] Also provided herein is a method of inhibiting the activity of thymidylate synthase in a cell or in an individual or patient in need thereof, comprising administering an effective amount of a compound of formula (I) to the cell, individual, or patient. [0124] In some embodiments, provided herein is a method for treating a condition mediated by thymidylate synthase activity comprising administering to a mammal in need of treatment an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the condition is cancer originating from the liver or upper gastrointestinal tract, or a cancer that has spread to one or more of the liver or upper gastrointestinal tract. In some embodiments, thymidylate synthase is inhibited by a metabolite of the compound. In some embodiments, thymidylate synthase is inhibited by 5- FdUMP. [0125] In one aspect, provided herein is a method of treating liver cancer, gastric cancer, small intestine cancer or colon cancer, wherein modulation of thymidylate synthase activity prevents, inhibits, or ameliorates the pathology and/or symptomology of the cancer, in a patient, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof). In one embodiment, provided herein is a method of treating liver cancer, gastric cancer, small intestine cancer or colon cancer, wherein modulation of thymidylate synthase activity prevents the pathology and/or symptomology of the cancer, in a patient, comprising administering to the patient a therapeutically effective amount of compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof). In one embodiment, provided herein is a method of treating liver cancer, gastric cancer, small intestine cancer or colon cancer, wherein modulation of thymidylate synthase activity inhibits the pathology and/or symptomology of the cancer, in a patient, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof). In one embodiment, provided herein is a method of treating liver cancer, gastric cancer, small intestine cancer or colon cancer, wherein modulation of thymidylate synthase activity ameliorates the pathology and/or symptomology of the cancer, in a patient, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof). In some embodiments, thymidylate synthase is inhibited by a metabolite of the compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof). In some embodiments, thymidylate synthase is inhibited by 5-FdUMP. [0126] In another aspect, provided herein is a method of delaying the onset and/or development of a cancer that is mediated by thymidylate synthase activity in a patient (such as a human) who is at risk for developing liver cancer, gastric cancer, small intestine cancer or colon cancer. It will be appreciated that delayed development may encompass prevention in the event the individual or patient does not develop the cancer. In some embodiments, thymidylate synthase is inhibited by a metabolite of the compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g., Compound 1 or a pharmaceutically acceptable salt thereof). In some embodiments, thymidylate synthase is inhibited by 5-FdUMP. [0127] Also provided herein are compounds of formula (I), or salts thereof, for use in the methods as described herein. In one aspect, provided herein is a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof, for use in therapy. In some embodiments, provided herein is a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof or pharmaceutical composition comprising such compound or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer. In some embodiments, provided is a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such compound or a pharmaceutically acceptable salt thereof, for use in the treatment of liver cancer. In some embodiments, provided is a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such compound or a pharmaceutically acceptable salt thereof, for use in the treatment of a cancer which originates from the liver or spreads to the liver. [0128] In another embodiment, provided herein is a compound of formula (I) or any variation thereof, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of liver cancer, colon cancer, small intestine, or gastric cancer as described herein. In some embodiments, the medicament is for the treatment of liver cancer. In some embodiments, the medicament is for the treatment of a cancer which originates from the liver or spreads to the liver. [0129] In some embodiments, the cancer is sensitive to treatment by 5-FU. In some embodiments, the cancer is resistant to treatment by 5-FU. In some embodiments, the individual was previously treated with 5-FU or a 5-FU prodrug. In some embodiments, the previously administered 5-FU prodrug is capecitabine. [0130] In some embodiments, the individual or patient is a mammal. In some embodiments, the patient is a primate, dog, cat, rabbit, or rodent. In some embodiments, the patient is a primate. In some embodiments, the patient is a human. In some embodiments, the human is at least about or is about any of 18, 21, 30, 50, 60, 65, 70, 75, 80, or 85 years old. In some embodiments, the human is a child. In some embodiments, the human is less than about or about any of 21, 18, 15, 10, 5, 4, 3, 2, or 1 years old. [0131] In some embodiments, the method further comprises administering one or more additional pharmaceutical agents. In some embodiments, the method further comprises administering radiation. In some embodiments, the method further comprises administering one or more additional pharmaceutical agents and radiation. [0132] In some embodiments, the method further comprises administering an additional thymidylate synthase inhibitor. In some embodiments, the method further comprises administering an agent which enhances the potency of the prodrug of formula (I) or any variation or aspect described herein, or a pharmaceutically acceptable salt thereof, or a metabolite thereof. In some embodiments, the method further comprises administering leucovorin. [0133] In some embodiments, the method further comprises administering a platinum- based agent. In some embodiments, the method further comprises administering oxaliplatin or cisplatin. In some embodiments, the method further comprises administering leucovorin and oxaliplatin. [0134] In some embodiments, the method further comprises administering a topoisomerase I inhibitor. In some embodiments, the method further comprises administering irinotecan. In some embodiments, the method further comprises administering leucovorin and irinotecan. [0135] In some embodiments, the method further comprises administering mitomycin and/or methotrexate. In some embodiments, the method further comprises administering mitomycin. In some embodiments, the method further comprises administering methotrexate. [0136] In some embodiments, the method further comprises administering a taxane. In some embodiments, the method further comprises administering a taxane and a platinum- based agent. In some embodiments, the method further comprises administering docetaxel or paclitaxel. [0137] In some embodiments, the method further comprises administering one or more additional pharmaceutical agents which are useful for treating liver cancer (Vallanueva, A. (2019) N. Engl. J. Med., 380:1450-62). In some embodiments, the method further comprises administering one or more additional pharmaceutical agents which are cabozantinib S-malate, pembrolizumab, lenvatinib mesylate, sorafenib tosylate, nivolumab, regorafenib, or combinations thereof. In some embodiments, the method further comprises administering cabozantinib S-malate. In some embodiments, the method further comprises administering pembrolizumab. In some embodiments, the method further comprises administering lenvatinib mesylate. In some embodiments, the method further comprises administering sorafenib tosylate. In some embodiments, the method further comprises administering nivolumab. In some embodiments, the method further comprises administering regorafenib. In some embodiments, the method further comprises administering ramucirumab. Dosing and Method of Administration [0138] The dose of a compound described herein, or a stereoisomer, tautomer, solvate, or salt thereof, administered to an individual (such as a human) may vary with the particular compound or salt thereof, the method of administration, and the particular cancer, such as type and stage of cancer, being treated. In some embodiments, the amount of the compound, or a stereoisomer, tautomer, solvate, or salt thereof, is a therapeutically effective amount. [0139] The compounds provided herein or a salt thereof may be administered to a patient via various routes, including, e.g., intravenous, intramuscular, subcutaneous, oral, and transdermal. In some embodiments, the compounds provided herein are orally administered. [0140] Any of the methods provided herein may in one aspect comprise administering to an individual a pharmaceutical composition that contains an effective amount of a compound provided herein, or a stereoisomer, tautomer, solvate, or salt thereof, and a pharmaceutically acceptable excipient. [0141] The methods as described herein may comprise administration to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer, which in some variations may be for the duration of the individual’s life. In one variation, the methods comprise administering on a daily or intermittent schedule. The methods may comprise continuous administration (for example, at least once daily) over a period of time. The dosing frequency can be more than once daily, e.g., twice or three times daily. The dosing frequency can also be intermittent, including a ‘drug holiday’ (e.g., once daily dosing for 7 days followed by no doses for 7 days, repeated for any 14 day time period, such as about 2 months, about 4 months, about 6 months or more). Any of the dosing frequencies can employ any of the compounds described herein together with any of the dosages described herein. Articles of Manufacture and Kits [0142] The present disclosure further provides articles of manufacture comprising a compound described herein or a salt thereof, a composition described herein, or one or more unit dosages described herein in suitable packaging, for use in any of the methods described herein. Suitable packaging is known in the art and includes, for example, vials, vessels, ampules, bottles, jars, flexible packaging and the like. An article of manufacture may further be sterilized and/or sealed. [0143] The present disclosure further provides kits for carrying out the methods of the present disclosure, which comprises one or more compounds described herein or a composition comprising a compound described herein. The kits may employ any of the compounds disclosed herein. In one variation, the kit employs a compound described herein or pharmaceutically acceptable salt thereof. The kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for the treatment of any disease or described herein, for example for the treatment of cancer, including liver, colorectal, anal, breast, gastrointestinal, skin, stomach, esophageal, and pancreatic cancer. In some embodiments, the cancer originated from the liver or spread to the liver. [0144] The kits optionally further comprise a container comprising one or more additional pharmaceutical agents and which kits further comprise instructions on or in the package insert for treating the subject with an effective amount of the one or more additional pharmaceutical agents. The one or more additional pharmaceutical agents may be leucovorin, cabozantinib S-malate, pembrolizumab, lenvatinib mesylate, sorafenib tosylate, nivolumab, or regorafenib. [0145] Kits generally comprise suitable packaging. The kits may comprise one or more containers comprising any compound described herein. Each component (if there is more than one component) can be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelf life permit. [0146] The kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses. For example, kits may be provided that contain sufficient dosages of a compound as disclosed herein and/or an additional pharmaceutically active compound useful for a disease detailed herein to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies). [0147] The kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present disclosure. The instructions included with the kit generally include information as to the components and their administration to an individual. EXAMPLES [0148] The compounds disclosed herein are prepared as disclosed in PCT/US2020/031132, the contents of which are hereby incorporated by reference in their entirety. [0149] It is understood that the present disclosure has been made only by way of example, and that numerous changes in the combination and arrangement of parts can be resorted to by those skilled in the art without departing from the spirit and scope of present disclosure. Example 1. Biodistribution Study [0150] Male hamsters, 7-9 weeks old, were used for 5-FdUMP biodistribution analysis. Compound 1 was weighed and mixed with 0.5% sodium carboxymethyl cellulose and administered as a single intraperitoneal dose (30 mg/kg) to 3 animals. Blood collection (about 200 μL per time point) was performed by jugular puncture of each animal into polypropylene tubes containing EDTA-K2 as anti-coagulant at 4 hours after dosing. Tubes were centrifuged for 15 minutes at 4°C and 3000 g for plasma collection. 150 milligram tissue samples from stomach, liver, upper gastrointestinal tract, pancreas, lung, bone marrow, and skin from the paw were collected at termination (4 hours post dosing). Tissue homogenates were prepared by homogenizing with 9 volumes (w:v) of homogenizing solution (MeOH/15 mM PBS (1:2, v:v)). Protein was precipitated from 40 μL of plasma and tissue homogenates by the addition of 200 μL ACN and then the mixture was vortex-mixed for 10 min at 800 rpm and centrifuged for 15 min at 3220 g and 4 °C. 64 μL of the supernatant was transferred to a 96- well plate and centrifuged for 5 min at 3220 g (4 °C) and 10 μL of the supernatant was directly injected for LC-MS/MS analysis. Chromatographic separation was performed using an Xbridge C183.5μm (2.1×30 mm) column. The mobile phases were 10% 2-Propanol and 0.1%NH 3.H2O in water (A) and 0.1% NH3.H2O in MeOH (B). The flow rate was 0.4 mL/min, and the run time was 1.4 minutes per injection. A Triple Quad 5500 mass spectrometer coupled with an electrospray ionization ion source was used to monitor the mass transitions. The system was operated in negative mode, and mass transitions were recorded. [0151] The ng 5- FdUMP per gram tissue is shown in FIG. 1 on the Y-axis (Mean +/- SD, n=3). Tissue samples with FdUMP levels below the lower limit of quantitation (LLOQ) are indicated. Example 2. Orthotopic HCC Tumor Growth Experiment [0152] Female BALB/c nude mice, 6-8 weeks old, were used for an orthotopic hepatocellular carcinoma tumor model. The bioluminescent HuH-7-luc tumor cell line was maintained in vitro as monolayer culture in DMEM medium supplemented with 10% heat inactivated fetal calf serum at 37°C in an atmosphere of 5% CO2 in air. The tumor cells were routinely sub-cultured twice weekly by trypsin-EDTA treatment, not exceeding 4-5 passages. The cells growing in an exponential growth phase were harvested and counted for tumor inoculation. Animals were anesthetized by i.m. injection of ZoletilTM 50 (Virbac S.A). The skin and peritoneum of anesthetized mice were incised to expose the left liver lobe. 1 x 106 HuH-7-luc cells suspended in 10 μL DMEM/Matrigel mixture (1:1) were injected slowly into the left liver lobe, so that a transparent bleb of cells was seen through the liver capsule. The liver was returned into the peritoneal cavity, and the abdominal wall and skin was closed. The tumor growth was monitored by luciferase-mediated image analysis and tumor weight at termination. Mice were randomized into 5 groups (8 mice per group) for drug treatment. Compound 1 was weighed and mixed with 0.5% sodium carboxymethyl cellulose (vehicle). Sorafenib was weighed and mixed with 20% (2-Hydroxypropyl)-β-cyclodextrin. Ten days after tumor implantation, mice were treated with vehicle (IP; QD), sorafenib (PO; 30 mg/kg QD) or Compound 1 (IP; 90 mg/kg QD, 60 mg/kg QD, or 30 mg/kg BID x 7d then 20 mg/kg BID x 10d) for 17 days. Animals were sacrificed the following day, and primary tumors excised and weighed. [0153] Median and quartile tumor weight values are displayed in FIG. 2 via dashed and dotted lines, respectively; *p  ^ 0.05 vs Vehicle control; statistics determined by one-way ANOVA followed by Tukey. Only statistically significant differences indicated. Example 3. Liver Metastatic Gastric Tumor Growth Experiment [0154] Female BALB/c nude mice, 6-8 weeks old, were used for a liver metastatic gastric cancer model. The bioluminescent MKN45-luc tumor cell line was maintained in vitro as monolayer culture in RPMI-1640 medium supplemented with 10% fetal bovine serum and 2 ug/mL Puromycin at 37°C in an atmosphere of 5% CO2 in air. The tumor cells were routinely sub-cultured weekly by trypsin-EDTA treatment, not exceeding 4-5 passages. The cells growing in an exponential growth phase were harvested and counted for tumor inoculation. Animals were anesthetized by i.m. injection of ZoletilTM 50 (Virbac S.A). The skin and peritoneum of anesthetized mice were incised to expose the left liver lobe. 1 x 106 MKN45- luc cells suspended in 10 μL RPMI 1640/Matrigel mixture (1:1) were injected slowly into the left liver lobe, so that a transparent bleb of cells was seen through the liver capsule. The liver was returned into the peritoneal cavity, and the abdominal wall and skin was closed. The tumor growth was monitored by luciferase-mediated image analysis and tumor weight at termination. Mice were randomized into 3 groups (8 mice per group) for drug treatment. Compound 1 and capecitabine (Xeloda) were weighed and mixed with 0.5% sodium carboxymethyl cellulose (vehicle). Ten days after tumor implantation, mice were treated with vehicle (IP; BID), Xeloda (PO; 400 mg/kg QD) or Compound 1 (IP; 20 mg/kg BID) for 21 days. Animals were sacrificed the following day, and primary and metastatic (abdominal wall) tumors excised and weighed. [0155] Median and quartile tumor weight values are displayed in FIG. 3 via dashed and dotted lines, respectively; *p  ^ 0.05, **p  ^ 0.01 vs Vehicle control; statistics determined by one-way ANOVA followed by Tukey. Only statistically significant differences indicated. Example 4. Liver Metastatic Colon Cancer Growth Experiment [0156] Female BALB/c nude mice, 6-8 weeks old, were used for a liver metastatic colon cancer model. The bioluminescent HT29-luc tumor cell line was maintained in vitro as monolayer culture in McCoy's 5a Medium Modified medium supplemented with 10% fetal bovine serum and 2 ug/mL Puromycin at 37°C in an atmosphere of 5% CO2 in air. The tumor cells were routinely sub-cultured weekly by trypsin-EDTA treatment, not exceeding 4-5 passages. The cells growing in an exponential growth phase were harvested and counted for tumor inoculation. Animals were anesthetized by i.m. injection of ZoletilTM 50 (Virbac S.A). The skin and peritoneum of anesthetized mice were incised to expose the left liver lobe. 1 x 106 HT29-luc cells suspended in 10 μL RPMI 1640/Matrigel mixture (1:1) were injected slowly into the left liver lobe, so that a transparent bleb of cells was seen through the liver capsule. The liver was returned into the peritoneal cavity, and the abdominal wall and skin was closed. The tumor growth was monitored by luciferase-mediated image analysis and tumor weight at termination. Mice were randomized into 3 groups (8 mice per group) for drug treatment. Compound 1 and capecitabine (Xeloda) were weighed and mixed with 0.5% sodium carboxymethyl cellulose (vehicle). Ten days after tumor implantation, mice were treated with vehicle (IP; BID), Xeloda (PO; 400 mg/kg QD) or Compound 1 (IP; 20 mg/kg BID) for 21 days. Animals were sacrificed the following day, and primary and metastatic (abdominal wall) tumors excised and weighed. [0157] Median and quartile tumor weight values are displayed in FIG. 4 via dashed and dotted lines, respectively; *p  ^ 0.05 vs Vehicle control; statistics determined by one-way ANOVA followed by Tukey. Only statistically significant differences indicated. Results and Conclusions [0158] Compound 1 showed selective distributions of 5-FdUMP, the active drug metabolite, to the liver, stomach, and upper gastrointestinal tissues when dosed by intraperitoneal injection in hamsters. Surprisingly, Compound 1 was undetectable in other tissues, including the pancreas, plasma, skin, and bone marrow in hamsters. This data suggests that Compound 1 has potential to minimize skin- and bone marrow-related side effects, such as dermatological toxicity and myelotoxicity, that occur when using existing 5- FU-related drugs due to systemic drug exposure. In addition, the combination of improved potency and selective uptake of Compound 1 into liver and gastrointestinal tissues may result in a synergistic improvement in efficacy for the treatment of liver and/or gastrointestinal cancers relative to other 5-FU-related drugs. [0159] In a murine orthotopic model of hepatocellular carcinoma, once daily treatment with Compound 1 (90 mg/kg IP; or 60 mg/kg IP) demonstrated comparable efficacy to once daily treatment with a standard-of-care drug Sorafenib (30 mg/kg PO) relative to a vehicle- treated group, as determined by mean tumor weight after 17 days of treatment. Surprisingly, Compound 1 demonstrated an unexpected, statistically significant reduction in tumor growth relative to the other treatment groups when administered twice daily at a lower dose (30 mg/kg twice daily for seven days, followed by 20 mg/kg twice daily for ten days). This data suggests that a twice daily dosing schedule may be sufficient to maintain the concentration of Compound 1 within its therapeutic window, thereby enhancing the effect of Compound 1 on tumor growth. [0160] In a murine heterotopic metastatic model of gastric cancer in the liver, twice daily treatment with Compound 1 (20 mg/kg IP) demonstrated comparable efficacy to once daily treatment with a standard-of-care drug Xeloda (capecitabine) (400 mg/kg PO). In a murine heterotopic metastatic model of colon cancer in the liver, twice daily treatment with Compound 1 (20 mg/kg IP) demonstrated a statistically significant reduction in tumor mass relative to once daily treatment with a standard-of-care drug Xeloda (capecitabine) (400 mg/kg PO). Importantly, treatment with capecitabine is associated with negative side effects and off-target toxicity, including in the skin (stomatitis, palmar-plantar erythrodysesthesia, skin inflammation). Therefore, this data in combination with the biodistribution data suggests that a twice daily dosing schedule of Compound 1 may provide equivalent or improved efficacy relative to capecitabine, while reducing or avoiding systemic side effects. [0161] All publications, including patents, patent applications, and scientific articles, mentioned in this specification are herein incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, including patent, patent application, or scientific article, were specifically and individually indicated to be incorporated by reference. [0162] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is apparent to those skilled in the art that certain minor changes and modifications will be practiced in light of the above teaching. Therefore, the description and examples should not be construed as limiting the scope of the invention.

Claims

CLAIMS 1. A method of treating liver metastases in a subject in need thereof, comprising administering to the subject a compound having the structure
Figure imgf000056_0001
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1, wherein the liver metastases are from a primary cancer in the upper gastrointestinal tract.
3. The method of claim 1, wherein the liver metastases are from a gastric cancer.
4. The method of claim 1, wherein the liver metastases are from a colon cancer.
5. The method of claim 1, wherein the liver metastases are from a cancer of the small intestine.
6. The method of any one of claims 1 to 5, wherein the compound depicted in claim 1, or a pharmaceutically acceptable salt thereof, is administered twice daily.
7. The method of claim 6, wherein each dose of the compound depicted in claim 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of from about 2 mg/kg to about 50 mg/kg.
8. The method of claim 6, wherein each dose of the compound depicted in claim 1, or a pharmaceutically acceptable salt thereof, is administered at a dose of from about 20 mg/kg to about 40 mg/kg.
9. The method of any one of claims 1 to 8, wherein the subject was previously administered capecitabine.
10. The method of claim 9, wherein the subject had a cancer that was refractory to treatment with capecitabine
11. The method of any one of claims 1 to 10, wherein the subject was previously administered sorafenib.
12. The method of claim 11, wherein the subject had a cancer that was refractory to treatment with sorafenib.
13. The method of any one of claims 1 to 12, further comprising administering a multikinase inhibitor to the subject.
14. The method of claim 13, wherein the multikinase inhibitor is sorafenib.
15. A method of treating a cancer selected from liver cancer, small intestine cancer, colon cancer, or gastric cancer in a subject in need thereof, comprising administering to the subject the compound having the structure
Figure imgf000057_0001
or a pharmaceutically acceptable salt thereof, wherein the compound is administered at a dose that does not result in the occurrence of dermatological toxicity, myelotoxicity, and/or leukopenia.
16. The method of claim 15, wherein the cancer is liver cancer.
17. The method of claim 16, wherein the liver cancer is hepatocellular carcinoma (HCC).
18. The method of claim 16 or claim 17, wherein the liver cancer has metastasized.
19. The method of claim 15, wherein the cancer is gastric cancer.
20. The method of claim 19, wherein the gastric cancer has metastasized to the liver.
21. The method of claim 15, wherein the cancer is colon cancer.
22. The method of claim 21, wherein the colon cancer has metastasized to the liver.
23. The method of claim 15, wherein the cancer is small intestine cancer.
24. The method of claim 23, wherein the small intestine cancer has metastasized to the liver.
25. The method of any one of claims 15-24, wherein the compound depicted in claim 15, or a pharmaceutically acceptable salt thereof, is administered twice daily.
26. The method of claim 25, wherein each dose of the compound depicted in claim 15, or a pharmaceutically acceptable salt thereof, is administered at a dose of from about 2 mg/kg to about 50 mg/kg.
27. The method of claim 25, wherein each dose of the compound depicted in claim 15, or a pharmaceutically acceptable salt thereof, is administered at a dose of from about 20 mg/kg to about 40 mg/kg.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9370569B2 (en) * 2014-02-06 2016-06-21 Riboscience Llc 4′-difluoromethyl substituted nucleoside derivatives as inhibitors of influenza RNA replication
WO2019143860A1 (en) * 2018-01-19 2019-07-25 Nucorion Pharmaceuticals, Inc. 5-fluorouracil compounds
WO2020227132A1 (en) * 2019-05-03 2020-11-12 Terns, Inc. Compounds for treating cancer
US20200399227A1 (en) * 2018-01-19 2020-12-24 Nucorion Pharmaceuticals, Inc. 5-fluorouracil compounds

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9370569B2 (en) * 2014-02-06 2016-06-21 Riboscience Llc 4′-difluoromethyl substituted nucleoside derivatives as inhibitors of influenza RNA replication
WO2019143860A1 (en) * 2018-01-19 2019-07-25 Nucorion Pharmaceuticals, Inc. 5-fluorouracil compounds
US20200399227A1 (en) * 2018-01-19 2020-12-24 Nucorion Pharmaceuticals, Inc. 5-fluorouracil compounds
WO2020227132A1 (en) * 2019-05-03 2020-11-12 Terns, Inc. Compounds for treating cancer

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CARRILLO ESMERALDA, NAVARRO SAÚL ABENHAMAR, RAMÍREZ ALBERTO, GARCÍA MARÍA ÁNGEL, GRIÑÁN-LISÓN CARMEN, PERÁN MACARENA, MARCHAL JUAN: "5-Fluorouracil derivatives: a patent review (2012 – 2014)", EXPERT OPINION ON THERAPEUTIC PATENTS, TAYLOR & FRANCIS, GB, vol. 25, no. 10, 3 October 2015 (2015-10-03), GB , pages 1131 - 1144, XP093017059, ISSN: 1354-3776, DOI: 10.1517/13543776.2015.1056736 *
DATABASE Pubchem Compound 19 December 2020 (2020-12-19), "COMPOUND SUMMARY [3-[(4aR,6R,7aS)-2-hydroxy-2-oxo-4a,6,7,7a-tetrahydro-4H-furo[3,2-d][1,3,2]dioxaphosphinin-6-yl]-5-fluoro-2,6-dioxopyrimidin-1-yl]methyl propan-2-yl carbonate", XP093017061, retrieved from ncbi Database accession no. CID 155271757 *

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