WO2024086194A1 - Polythérapie pour traiter le cancer - Google Patents

Polythérapie pour traiter le cancer Download PDF

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WO2024086194A1
WO2024086194A1 PCT/US2023/035367 US2023035367W WO2024086194A1 WO 2024086194 A1 WO2024086194 A1 WO 2024086194A1 US 2023035367 W US2023035367 W US 2023035367W WO 2024086194 A1 WO2024086194 A1 WO 2024086194A1
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substituted
unsubstituted
nhnr
heterocycloalkyl
heteroaryl
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PCT/US2023/035367
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Jude Robert CANON
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Suvalent Therapeutics, Inc.
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Publication of WO2024086194A1 publication Critical patent/WO2024086194A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • SUMOylation is a reversible post-translational modification by small ubiquitin-like modifier (SUMO). SUMOylation controls many cellular functions and plays a critical role in the regulation of genome integrity, cell cycle progression, and the immune response.
  • SUMO E1 or SAE1/UBA2 small ubiquitin-like modifier
  • UBC9 ubiquitin-conjugating enzyme 9
  • the process of SUMOylation starts when SUMO E1 activates SUMO through ATP hydrolysis and forms a thioester conjugate with SUMO. Next, SUMO is transferred and forms a new thioester conjugate with E2. Finally, SUMO is attached to target proteins, a step catalyzed by an E3 ligase.
  • E3 ligase Specific small molecule inhibitors of the SUMO E1 enzyme have recently been developed that allow for the exploration of pharmacological SUMOylation inhibitors as novel anticancer therapeutics. Inhibition of SUMOylation by small molecules impairs cancer cell proliferation and triggers antitumor immune responses by stimulating the interferon (IFN) response.
  • IFN interferon
  • SUMMARY Provided herein is a method of treating cancer in a subject in need thereof, the method comprising: (i) administering to the subject a therapeutically-effective amount of a compound that blocks SUMOylation in the subject; and (ii) administering to the subject a therapeutically-effective amount of an anti-cancer agent that functions through a pathway other than SUMOylation.
  • a compound of the disclosure comprises a substituted 4,5,6,7-tetrahydrothieno[2,3-c]pyridine group, wherein the compound blocks SUMOylation.
  • the compound binds to Uba2.
  • the compound has an inhibitory effect on activating enzymes (E1) of SUMO.
  • Group 1 [small circle] Vehicle control p.o, (BIWx2weeks)
  • Group 2 [square] Compound A 50 mg/kg, p.o. (BIWx2weeks)
  • Group 3 [triangle] rituximab 20 mg/kg, i.p. (BIWx2weeks)
  • Group 4 [diamond] Compound A, 50 mg/kg, p.o.+ Rituximab, 20 mg/kg,i.p.
  • Group 1 [small circle] Vehicle control p.o, (BIWx2weeks)
  • Group 2 [square] Compound A 50 mg/kg, p.o.
  • FIG.3 Effect upon combination treatment with Compound A and decitabine in AML cell lines.
  • GDM-1 and MV4-11 cells were treated with indicated doses of Compound A and decitabine for 72-hrs, and cell viability was measured to generate dose response curves.
  • IC50 values were calculated from treatment with Compound A alone, and in combination with decitabine, and these values were used to measure ZIP scores, see Table 4.
  • Dose response graphs and IC50 calculations were generated using GraphPad Prism 9 (ver.9.4.0). ZIP scores were calculated using SynergyFinder 3.0 (https://synergyfinder.fim m.fi/synergy/20220701215205193938/).
  • FIG.4 Combination of Compound A with anti-PD-1 therapy Inhibits TumorGrowth in a CT26 model of syngeneic colon cancer in BALB/c mice. Data points represent tumor volume curves for four treatment groups.
  • Group 1 [small circle] Vehicle control.
  • Group 2 [triangle] Compound A 50 mg/kg
  • Group 3 [square] antiPD-12.5 mg/kg
  • Group 4 [triangle] Compound A, 50 mg/kg, + antiPD-12.5 mg/kg
  • the y-axis reflects the tumor volumes in mm 2 for each group of animals per length of experiment - 15 days [x-axis].
  • FIG 5 Combination of Compound A with anti-PD-1 therapy Improves Survival in a CT26 model of syngeneic colon cancer in BALB/c mice. Data points represent survival for four treatment groups. Group 1: [small circle] Vehicle control. Group 2: [triangle] Compound A 50 mg/kg, Group 3: [square] antiPD-12.5 mg/kg, Group 4: [triangle] Compound A, 50 mg/kg, + antiPD-12.5 mg/kg The y-axis reflects the number of mice surviving as a percentage of the total in each group of animals per length of experiment - 80 days [x-axis]. [010] FIG 6. Compound A Induces CD8 + T Cell Infiltration in a CT26 model of syngeneic colon cancer in BALB/c mice.
  • the bar graph represents the percent of CD8+ as a percent of CD45/CD3 for the treatment groups -
  • Column 1 Vehicle control.
  • Column 2 Compound A at 50 mg/kg.
  • the present disclosure provides compounds and methods for blocking SUMOylation.
  • the combinations of the present disclosure include SUMO inhibitors and at least one other anti-cancer agent that functions through a pathway other than SUMOylation.
  • the SUMO inhibitors of the present disclosure bind to Uba2.
  • the SUMO inhibitors of the present disclosure have an inhibitory effect on activating enzymes (E1) of SUMO.
  • a method comprising: a) administering a therapeutically-effective amount of a compound to a subject in need thereof, wherein the compound blocks SUMOylation in the subject; and b) after the administering, observing that the administering increases an immune response in the subject against a cancer.
  • the method comprises after the administering, obtaining a population of an immune cell in a biological sample obtained from the subject.
  • the biological sample is obtained from a tumor.
  • the administering increases a population of tumor infiltrating lymphocytes.
  • the administering increases a population of CD8+ cells.
  • the population of the immune cell is determined using a multiplexed immunofluorescence. In some embodiments, the population of the immune cell is determined using flow cytometry. In some embodiments, the population of the immune cell is determined using fluorescence activated cell sorting [FACS]. In some embodiments, the population of the immune cell is determined using antibody staining. [013] The disclosure further provides methods of treatment of a cancerous lesion or a tumor harboring a SUMOylation. [014] Cancer is a collection of related diseases characterized by uncontrolled proliferation of cells with the potential to metastasize throughout the body.
  • Cancer can be classified into five broad categories including, for example: carcinomas, which can arise from cells that cover internal and external parts of the body such as the lung, breast, and colon; sarcomas, which can arise from cells that are located in bone, cartilage, fat, connective tissue, muscle, and other supportive tissues; lymphomas, which can arise in the lymph nodes and immune system tissues; leukemia, which can arise in the bone marrow and accumulate in the bloodstream; and adenomas, which can arise in the thyroid, the pituitary gland, the adrenal gland, and other glandular tissues. [015] Although different cancers can develop in virtually any of the body's tissues, and contain unique features, the basic processes that cause cancer can be similar in all forms of the disease.
  • SUMOylation is a reversible post-translational modification by small ubiquitin-like modifier (SUMO). SUMOylation controls many cellular functions and plays a critical role in the regulation of genome integrity, cell cycle progression, and the immune response (1).
  • SUMO E1 or SAE1/UBA2 small ubiquitin-like modifier
  • UBC9 ubiquitin-conjugating enzyme 9
  • the process of SUMOylation starts when SUMO E1 activates SUMO through ATP hydrolysis and forms a thioester conjugate with SUMO. Next, SUMO is transferred and forms a new thioester conjugate with E2. Finally, SUMO is attached to target proteins, a step catalyzed by an E3 ligase.
  • E3 ligase Specific small molecule inhibitors of the SUMO E1 enzyme have recently been developed that allow for the exploration of pharmacological SUMOylation inhibitors as novel anticancer therapeutics. Inhibition of SUMOylation by small molecules impairs cancer cell proliferation and triggers antitumor immune responses by stimulating the interferon (IFN) response (2).
  • One embodiment of the disclosure includes compounds that block SUMOylation when used in combination with other treatments for cancer. Mechanism of compounds disclosed herein.
  • assays can be employed to detect, for example, binding of a compound to Uba2, or an inhibitory effect on activating enzymes (E1) of SUMO. Such assays are described in PCT application PCT/US22/73985.
  • a compound of the disclosure can increase the inhibit SUMOylation by at least or up to about 0.1%, at least or up to about 0.2%, at least or up to about 0.3%, at least or up to about 0.4%, at least or up to about 0.5%, at least or up to about 0.6%, at least or up to about 0.7%, at least or up to about 0.8%, at least or up to about 0.9%, at least or up to about 1%, at least or up to about 2%, at least or up to about 3%, at least or up to about 4%, at least or up to about 5%, at least or up to about 6%, at least or up to about 7%, at least or up to about 8%, at least or up to about 9%, at least or up to about 10%, at least or up to about 11%, at least or up to about 12%, at least or up to about 13%, at least or up to about 14%, at least or up to about 15%, at least or up to about 16%, at least or up to about 17%, at least or up
  • a compound described herein can bind SUMO E1 enzyme that is, for example, by at least or up to about 0.1%, at least or up to about 0.2%, at least or up to about 0.3%, at least or up to about 0.4%, at least or up to about 0.5%, at least or up to about 0.6%, at least or up to about 0.7%, at least or up to about 0.8%, at least or up to about 0.9%, at least or up to about 1%, at least or up to about 2%, at least or up to about 3%, at least or up to about 4%, at least or up to about 5%, at least or up to about 6%, at least or up to about 7%, at least or up to about 8%, at least or up to about 9%, at least or up to about 10%, at least or up to about 11%, at least or up to about 12%, at least or up to about 13%, at least or up to about 14%, at least or up to about 15%, at least or up to about 16%, at least or up to about 1
  • a compound of the disclosure can be used, for example, to reduce cell proliferation or trigger antitumor immune response in a subject.
  • Compounds of the disclosure [022]
  • a compound of the disclosure comprises a substituted 4,5,6,7- tetrahydrothieno[2,3-c]pyridine group, wherein the compound blocks SUMOylation.
  • the compound binds to Uba2.
  • the compound has an inhibitory effect on activating enzymes (E1) of SUMO.
  • the 4,5,6,7-tetrahydrothieno[2,3-c]pyridine group has a nitrile substituent at a 2-position of the 4,5,6,7-tetrahydrothieno[2,3-c]pyridine group.
  • the nitrile substituent is alternatively described as a cyano group.
  • the compound has plasma protein binding of less than about 99.5% or less than that of an analogous compound that lacks the cyano substituent.
  • the 4,5,6,7-tetrahydrothieno[2,3-c]pyridine group has an electrophilic moiety at a 6-position of the 4,5,6,7-tetrahydrothieno[2,3-c]pyridine group.
  • the 4,5,6,7-tetrahydrothieno[2,3-c]pyridine group has an unsubstituted or substituted C2-6 alkenylcarbonyl or an unsubstituted or substituted C2-6 alkynylcarbonyl substituent at a 6-position of the 4,5,6,7- tetrahydrothieno[2,3-c]pyridine group.
  • the 4,5,6,7-tetrahydrothieno[2,3-c]pyridine group has an unsubstituted or substituted aminopropenylcarbonyl or an unsubstituted or substituted aminobutenylcarbonyl substituent at a 6-position of the 4,5,6,7-tetrahydrothieno[2,3-c]pyridine group.
  • the 4,5,6,7-tetrahydrothieno[2,3-c]pyridine group comprises a substituted phenyl substituent at a 4-position of the 4,5,6,7-tetrahydrothieno[2,3-c]pyridine group.
  • R 1 is selected from hydrogen, halogen, -C(X 1 )3, -CHX 1 2, -CH2X 1 , -OCX 1 3, -OCH2X 1 , -OCHX 1 2, -CN, -SOn1R 1A , -SOv1NR 1A R 1B , -NHC(O)NR 1A R 1B , -N(O)m1, -NR 1A R 1B , -NHNR 1A R 1B , -C(O)R 1A , -C(O)-OR 1A , -C(O)NR 1A R 1B , -C(O)NHNR 1A R 1B , -OR 1A , -NR 1A SO2R 1B , -NR 1A C(O)R 1B , -NR 1A C(O)OR 1B , -NR 1A OR 1B , -N3, substituted or unsubstituted alky
  • R 3 and R 3 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl;
  • R 5 is selected from hydrogen, halogen, -CX 5 3 , -CHX 5 2 , -CH 2 X 5 , -OCX 5 3 , -OCH 2 X 5 , -OCHX 5 2 , -CN, -SO n5 R 5A , -SO v5 NR 5A R 5B , -NHC(O)NR 5A R 5B , -N(O) m5 , -NR 5A R 5B , -NHNR 5A R 5B , -C(O)R 5A , -C(O)-OR 5A , -C(O)NR 5A R 5B , -C(O)NHNR 5A R 5B , -OR 5A , -NR 5A SO 2 R 5B ,
  • Z is N.
  • ring A is selected from 5-membered heteroaryl, wherein ring A is optionally substituted with one or more substituent groups.
  • R 2 is selected from substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • ring A is selected from thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, triazolyl and isothiazolyl, wherein ring A is optionally substituted with one or more substituent groups. [032] In some embodiments, ring A is selected from
  • R 2 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted 5- or 6-membered heteroaryl. [034] In some embodiments, R 2 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl and substituted or unsubstituted pyridyl.
  • M is CR 3 R 4 .
  • Y is CR 6 R 7 .
  • R 1 is selected from hydrogen, halogen, -CX 1 3, -CHX 1 2, -CH2X 1 , -OCX 1 3, -OCH2X 1 , -OCHX 1 2, -CN, -SOn1R 1A , -SOv1NR 1A R 1B , -NHC(O)NR 1A R 1B , -N(O)m1, -NR 1A R 1B , -NHNR 1A R 1B , -C(O)R 1A , -C(O)-OR 1A , -C(O)NR 1A R 1B , -C(O)NHNR 1A R 1B , -OR 1A , -NR 1A SO2R 1B , -NR 1A C(O)R 1B , -NR 1A C(O)OR 1B , -NR 1A OR 1B , -N3, substituted or unsubstituted alkyl, substituted or
  • ring B is selected from thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, triazolyl and isothiazolyl, wherein Ring B is optionally substituted with one or more substituents.
  • ring B is selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl, wherein ring B is optionally substituted with one or more substituent groups.
  • ring B is selected from [044]
  • W is S.
  • R 10 is selected from hydrogen, fluoro, chloro, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 heteroalkyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted 6-10 membered aryl, and substituted or unsubstituted 5-10 membered heteroaryl; and R 11 is selected from hydrogen, fluoro, chloro, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 heteroalkyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted 6-10 membered aryl, and substituted or unsubstituted 5-10 membered heteroaryl; and R 11 is selected
  • Non-limiting examples of compounds of the disclosure include compounds of the following formula wherein R 36 is H, halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl or C 3 -C 6 cycloalkyl; R 37 is substituted or unsubstituted C 2 -C 4 alkenyl or C 2 -C 4 alkynyl; and R 38 is selected from substituted or unsubstituted nitrogen containing 5-membered heteroaryl, substituted or unsubstituted nitrogen containing 5- or 6- membered partially unsaturated heterocyclyl and substituted or unsubstituted nitrogen containing 6-10 membered heteroaryl; provided R 38 is not 4-pyridyl; or an isomer or stereoisomer of any of the foregoing, or a mixture thereof.
  • R 38 is selected from substituted or unsubstituted nitrogen containing 5- membered heteroaryl selected from pyrazolyl, isoxazolyl, isothiazolyl, pyrrolyl, thiazolyl, triazolyl and imidazolyl; substituted or unsubstituted nitrogen containing 6- membered heteroaryl selected from pyridinyl, pyrimidinyl and pyrazinyl; substituted or unsubstituted nitrogen containing 5-membered partially unsaturated heterocyclyl selected from pyrrolinyl, and imidazolidinyl; and substituted or unsubstituted dihydropyridinyl.
  • R 36 is selected from chloro, methyl, ethyl, isopropyl, allylyl, and cyclopropyl;.
  • R 38 is selected from substituted 5-pyrazolyl, substituted 4-pyrazolyl, substituted 1-pyrazolyl, substituted or unsubstituted 4-isoxazolyl, substituted or unsubstituted 4- isothiazolyl, substituted or unsubstituted 3-pyrrolyl, substituted or unsubstituted 5-thiazolyl, substituted or unsubstituted 5-imidazolyl, substituted or unsubstituted 1-imidazolyl, substituted or unsubstituted [1,2,4]triazol-5-yl, substituted or unsubstituted 3-pyridyl, and substituted or unsubstituted 5-pyrimidinyl.
  • R 38 is selected from 3-trifluoromethyl-pyrazol-4-yl, 1-isopropyl-3- trifluoromethyl-pyrazol-4-yl, 1-ethyl-3-trifluoromethyl-pyrazol-4-yl, 1-methyl-3-difluoromethyl-pyrazol- 4-yl, 1-butyl-3-trifluoromethyl-pyrazol-4-yl, 1-methoxymethyl-3-trifluoromethyl-pyrazol-4-yl, 1-propyl- 3-trifluoromethyl-pyrazol-4-yl, 1,3-dimethyl-pyrazol-4-yl, 1,3,5-trimethyl-pyrazol-4-yl, 1-methyl-3- cyclopropyl-pyrazol-4-yl, 1-methyl-3-trifluoromethyl-pyrazol-4-yl, 1-ethyl-3-amino-pyrazol-4-yl, 1-ethyl- 3-methoxy-pyrazol-4-y
  • R 38 is selected from 5-pyrimidinyl, 2-methyl-5-pyrimidinyl, 4-methyl-5- pyrimidinyl, 4,6-dimethoxy-5-pyrimidinyl, 4,6-dimethyl-5-pyrimidinyl, 4-triflouromethyl-5-pyrimidinyl, 4-pyrimidinyl, 2-methyl-4-pyrimidinyl, 4-methyl-6-pyrimidinyl, 2,4-dimethyl-6-pyrimidinyl, 3-pyridinyl, 2-pyridinyl, 4-methyl-2-pyridinyl, 2-triflouromethyl-3-pyridinyl, 4-triflouromethyl-3-pyridinyl, 2-methyl- 3-pyridinyl, 2,5-dimethyl-3-pyridinyl, 2,6-dimethyl-3-pyridinyl, 2,4-dimethyl-3-pyridinyl, 2-ethyl-3- pyridinyl, 5-methyl-3-pyridinyl, 5-methyl-3-pyri
  • R 38 is selected from substituted or unsubstituted tetrahydroquinolinyl, substituted or unsubstituted 1-pyrrolin-3-yl, substituted or unsubstituted 1-imidazolidinyl, and substituted or unsubstituted dihydropyridin-3-yl.
  • R 38 is selected from 4-isoquinolinyl, 1-methoxy-4-isoquinolinyl, 1-chloro- 4-isoquinolinyl, 6-methyl-4-isoquinolinyl, 1-oxo-2-methyl-4-isoquinolinyl, 3-quinolinyl, 4-quinolinyl, 5- pyrrolopyridinyl, [1,3,3a]-triazainden-5-yl, 1-ethyl-3-pyrrolopyridinyl, and 1-methyl-5-pyrrolopyridinyl.
  • R 37 is selected from ethenyl, fluoroethenyl, propynyl, dialkylaminopropenyl, alkylaminopropenyl, aminopropenyl and nitrogen-containing heterocyclyl- propenyl.
  • Non-limiting examples of compounds of the disclosure include compounds of the following formula wherein R 36 is selected from H, halo, C1-C4 alkyl, C2-C4 alkenyl and C3-C6 cycloalkyl; R 37 is substituted or unsubstituted C2-C4 alkenyl, or C2-C4 alkynyl; and R 41 is selected from H, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxyalkyl, C1-6 alkylamino-C1-6 alkyl, C1-6 alkylaminocarbonyl-C1-6 alkyl, aminocarbonyl-C1-6 alkyl, C1-6 alkoxycarbonyl-C1-6 alkyl, carboxy- C1-6 alkyl, C1-6 alkylcarbonylamino-C1-6 alkyl, C1-6 cyanoalkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1- 6 alkyl, aryl-C1-6 alkyl, substituted
  • R 41 is selected from H, ethyl, isopropyl, butyl, propyl, methyl, D 3 -methyl, 1- hydroxyethyl, 2-hydroxymethylethyl, 1-hydroxy-2,2-dimethylethyl, 2-hydroxypropyl, 2-hydroxy-2- methylpropyl, methoxymethyl, methoxyethyl, dimethylaminoethyl, carboxymethyl, carboxyethyl, methoxycarbonylmethyl, dimethylaminocarbonylmethyl, dimethylaminocarbonylethyl, methylaminocarbonylethyl, methylaminocarbonylmethyl, aminocarbonylmethyl, aminocarbonylethyl, aminocarbonyl-1,1-dimethyl, methylcarbonylaminoethyl, 1-methylcarbonylamino-2.2- dimethylethyl, 2-cyano-2-methylethyl, cyanomethyl, cyanoethyl,
  • R 36 is H, chloro, methyl, ethyl, isopropyl, propenyl, trifluoromethyl, 2-furyl, 2-pyridinyl, or cyclopropyl.
  • R 37 is selected from ethenyl, fluoroethenyl, fluoropropenyl, propynyl, dialkylaminopropenyl, alkylaminopropenyl, aminopropenyl, substituted or unsubstituted 3-7 membered nitrogen-containing heterocyclyl-ethenyl and substituted or unsubstituted 3-7 membered nitrogen- containing heterocyclyl-propenyl.
  • R 37 is azetidin-1-ylpropenyl, 1-methylpyrrolidin-2-ylethenyl, dimethylaminopropenyl, methylaminopropenyl, piperidin-1-ylpropenyl, 4-hydroxy-piperidin-1-ylpropenyl, pyrrolidin-1-ylpropenyl, 3-hydroxypyrrolidin-1-ylpropenyl, morpholin-1-ylpropenyl, or aminopropenyl.
  • R 42 is selected from H, trifluoromethyl, difluoromethyl, methyl, ethyl, methoxy, amino, dimethylamino, carboxy.
  • R 43 is selected from H, trifluoromethyl, methyl, ethyl, carboxy, cyano and methylaminocarbonyl.
  • R 44 is one or more substituents selected from H, hydroxy, fluoro and methoxyl.
  • Non-limiting examples of compounds of the disclosure include compounds of any one of the following formulae wherein R 1 is substituted or unsubstituted C 2 -C 6 alkenyl, or substituted or unsubstituted C 2 -C 6 alkynyl; R 6 is selected from H, C 1-6 alkyl, C 2-4 alkynyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, C 1-6 alkylamino-C 1- 6 alkyl, C1-6 alkylaminocarbonyl-C1-6 alkyl, aminocarbonyl-C1-6 alkyl, C1-6 alkoxycarbonyl-C1-6 alkyl, carboxy-C1-6 alkyl, C1-6 alkylcarbonylamino-C1-6 alkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkylsulfonyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, aryl-
  • R 1 is selected from C2-C6 alkenyl, halo-substituted C2-C6 alkenyl; alkoxy substituted C2-C6 alkenyl; dialkylamino substituted C2-C6 alkenyl, alkylamino substituted C2-C6 alkenyl, amino substituted C2-C6 alkenyl, hydroxy substituted amino-C2-C6 alkenyl, phenyl substituted amino-C2- C6 alkenyl, amino substituted C2-C6 alkynyl, dialkylamino substituted C2-C6 alkynyl, alkylamino substituted C 2 -C 6 alkynyl, alkoxy substituted C 2 -C 6 alkynyl, substituted or unsubstituted 3-7 membered nitrogen-containing heterocyclyl- substituted C 2 -C 6 alkynyl, substituted or unsubstituted 3-7 membered cycloalkyl- substitute
  • R 1 is selected from ethenyl, fluoropropenyl, 3,3-difluoropropenyl, 3,3,3- trifluoropropenyl, 3,3,3-trifluoroprop-1-enyl, alkoxypropenyl, dialkylaminopropenyl, alkylaminopropenyl, aminopropenyl, 3-amino-4-hydroxy-butenyl, 3-amino-4-phenyl-butenyl, dialkylaminobutenyl, alkylaminobutenyl, aminobutenyl, dialkylaminopentenyl, alkylaminopentenyl, aminopentenyl, aminopropynyl, dialkylaminopropynyl, alkylaminopropynyl, methoxypropynyl, substituted or unsubstituted 3-7 membered nitrogen-containing heterocyclyl-propynyl, substituted or unsubstituted 3-7 membered nitrogen
  • R 1 is selected from ethenyl, fluoropropenyl, 3,3-difluoropropenyl, 3,3,3- trifluoropropenyl, 3,3,3-trifluoroprop-1-enyl, methoxypropenyl, ethoxypropenyl, aminopropenyl, 3- amino-butenyl, 3-methylamino-butenyl, 3-amino-4-hydroxy-butenyl, 3-methylamino-4-methoxy-butenyl, 3-amino-4-phenyl-butenyl, 3-amino-pentenyl, aminopropynyl, methoxypropynyl, dimethylaminopropenyl, di(d1,d2,d3-methyl)aminopropenyl, diethylaminopropenyl, 3-(N,N-dimethylamino)-3-phenyl-propenyl, 3- (N,N-dimethylamino)-3-pheny
  • R 6 is selected from H, ethyl, isopropyl, butyl, propyl, methyl, propynyl, 1- hydroxyethyl, 2-hydroxymethylethyl, 1-hydroxy-2,2-dimethylethyl, 2-hydroxypropyl, 2-hydroxy-2- methylpropyl, methoxymethyl, methoxyethyl, dimethylaminoethyl, carboxymethyl, carboxyethyl, carboxypropyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, ethoxycarbonylpropyl, dimethylaminocarbonylmethyl, dimethylaminocarbonyl-1-ethyl, methylaminocarbonyl-1-ethyl, methylaminocarbonylethyl, methylaminocarbonylmethyl, aminocarbonylmethyl, aminocarbonylethyl, 1-aminocarbonylethyl
  • R 7 is selected from H, trifluoromethyl, difluoromethyl, 1,1-difluoroethyl, methyl, ethyl, methoxy, amino, dimethylamino, carboxy. methylaminocarbonyl, dimethylaminocarbonyl, and cyclopropyl.
  • R 8 is selected from H, trifluoromethyl, methyl, ethyl, carboxy, cyano and methylaminocarbonyl.
  • R 9 is selected from H, fluoro, chloro, methyl, and cyano.
  • R 10 is selected from H, fluoro, methylcarbonylamino, chloro, amino, hydroxy, methyl, difluoromethyl, methylsulfonylamino, and methylaminocarbonylamino.
  • R 11 is H or fluoro.
  • R 6 is ethyl; R 7 is trifluoromethyl; and R 8 is H.
  • R 6 is methyl; R 7 is trifluoromethyl; and R 8 is H.
  • R 6 is H; R 7 is trifluoromethyl; and R 8 is H.
  • R 6 is 3,5-difluoropyridin-4-yl; R 7 is trifluoromethyl; and R 8 is H.
  • R 1 is substituted ethenyl.
  • R 1 is dimethylaminopropenyl.
  • R 1 is methylaminopropenyl.
  • R 1 is 3,3-difluoropropenyl.
  • R 1 is 2-(azetin-2-yl)ethenyl.
  • R 1 is 2-(2-methyl-pyrrolidiny-5-yl)ethenyl. [084] In some embodiments, R 1 is 3-(methylamino)butenyl. [085] In some embodiments, R 1 is ethylaminopropenyl. [086] In some embodiments, R 1 is 2-(3-methoxypyrrolidiny-5-yl)ethenyl. [087] In some embodiments, R 1 is 2-(3-fluoropyrrolidiny-5-yl)ethenyl. [088] In some embodiments, R 1 is 2-(pyrrolidiny-2-yl)ethenyl.
  • R 1 is aminopropenyl.
  • R 9 is fluoro;
  • R 10 is H; and
  • R 11 is H.
  • Non-limiting examples of compounds of the current disclosure include the following compounds identified in Table A: TABLE A F F F F N N N S N O NH
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di- and multivalent radicals, having the number of carbon atoms designated (i.e., C1-C10 means one to ten carbons).
  • Alkyl is an uncyclized chain.
  • Preferred alkyl substituents are C1-C6 alkyl.
  • saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • alkylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, -CH2CH2CH2CH2-.
  • An unsaturated alkyl group is one having one or more double bonds or triple bonds referred to as “alkenyl” or “alkynyl” groups, respectively.
  • Preferred alkenyl substituents are C2-C6 alkenyl and preferred alkynyl substituents are C2-C6 alkynyl.
  • alkenyl or alkynyl groups include, but are not limited to, ethenyl, vinyl, 2-propenyl, butenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4- pentadienyl), ethynyl, 1-propynyl, 3-propynyl, and 3-butynyl.
  • heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, S, B, As, or Si), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom(s) e.g., O, N, P, S, B, As, or Si
  • Heteroalkyl is an uncyclized chain.
  • Heteroalkyl also includes terms such as alkoxy, and alkylamino.
  • An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-O-).
  • Preferred alkoxy substituents include C1-4 alkoxy. Examples of alkoxy groups include, but are not limited to methoxy, ethoxy and propoxy.
  • Preferred alkylamino substituents include mono substituted C1-4 alkylamino and disubstituted alkylamino. Examples of alkylamino groups include, but are not limited to methylamino, dimethylamino and diethylamino.
  • heteroalkyl includes “alkoxyalkyl” where an alkyl group is substituted with an alkoxy group, as defined above.
  • Preferred alkoxyalkyl substituents include C 1-4 alkoxy- C 1-4 alkyl.
  • alkoxyalkyl groups include, but are not limited to methoxymethyl, ethoxymethyl and methoxyethyl.
  • heteroalkyl groups include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', -NR'R'', -OR', -SR', and/or -SO 2 R'.
  • cycloalkyl by itself or in combination with other terms, mean, unless otherwise stated, cyclic versions of “alkyl”. Cycloalkyl are not fully aromatic rings. Preferred cycloalkyl substituents include C 3 -C 6 cycloalkyl. A “cycloalkylene” alone or as part of another substituent, means a divalent radical derived from a cycloalkyl.
  • a cycloalkyl group having 3 to 8 ring members may be referred to as a (C 3 -C 8 )cycloalkyl
  • a cycloalkyl group having 3 to 7 ring members may be referred to as a (C 3 -C 7 )cycloalkyl
  • a cycloalkyl group having 4 to 7 ring members may be referred to as a (C 4 - C 7 )cycloalkyl.
  • the cycloalkyl group can be a (C 3 -C 10 )cycloalkyl, a (C 3 - C 8 )cycloalkyl, a (C 3 -C 7 )cycloalkyl, a (C 3 -C 6 )cycloalkyl, or a (C 4 -C 7 )cycloalkyl group and these may be referred to as C 3 -C 10 cycloalkyl, C 3 -C 8 cycloalkyl, C 3 -C 7 cycloalkyl, C 3 -C 6 cycloalkyl, or C 4 -C 7 cycloalkyl groups.
  • cycloalkenyl by itself or in combination with other terms, mean, unless otherwise stated, cyclic versions of “alkenyl”. Cycloalkenyl are not fully aromatic rings. Preferred cycloalkenyl substituents include C4-C6 cycloalkenyl.
  • a cycloalkenyl group having 4 to 8 ring members may be referred to as a (C4-C8)cycloalkenyl
  • a cycloalkenyl group having 3 to 7 ring members may be referred to as a (C3-C7)cycloalkenyl
  • a cycloalkenyl group having 4 to 6 ring members may be referred to as a (C4-C6)cycloalkenyl.
  • Heterocycloalkyl is also referred by the term heterocyclyl.
  • Preferred heterocyclyl substituents include C3-C7 oxygen or nitrogen containing rings, or both nitrogen and oxygen atms. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule.
  • a “heterocycloalkylene,” alone or as part of another substituent, means a divalent radical derived from heterocycloalkyl.
  • “Heterocyclyl” refers to a cyclic group that includes at least one saturated, partially unsaturated, but non-aromatic, cyclic ring. Heterocyclyl groups include at least one heteroatom as a ring member.
  • Typical heteroatoms include, O, S and N and are independently chosen.
  • Heterocyclyl groups include monocyclic ring systems and bicyclic ring systems.
  • Bicyclic heterocyclyl groups include at least one non-aromatic ring with at least one heteroatom ring member that may be fused to a cycloalkyl ring or may be fused to an aromatic ring where the aromatic ring may be carbocyclic or may include one or more heteroatoms.
  • the point of attachment of a bicyclic heterocyclyl group may be at the non-aromatic cyclic ring that includes at least one heteroatom or at another ring of the heterocyclyl group.
  • a heterocyclyl group derived by removal of a hydrogen atom from one of the 9 membered heterocyclic compounds shown below may be attached to the rest of the molecule at the 5-membered ring or at the 6- membered ring.
  • a heterocyclyl group includes 5 to 10 ring members of which 1, 2, 3 or 4 or 1, 2, or 3 are heteroatoms independently selected from O, S, or N.
  • a heterocyclyl group includes 3 to 7 ring members of which 1, 2, or 3 heteroatom are independently selected from O, S, or N.
  • a heterocyclyl group includes 3 or 4 ring members of which 1 is a heteroatom selected from O, S, or N. In other embodiments, a heterocyclyl group includes 5 to 7 ring members of which 1, 2, or 3 are heteroatoms independently selected from O, S, or N.
  • Typical heterocyclyl groups include, but are not limited to, groups derived from epoxides, aziridine, azetidine, imidazolidine, morpholine, piperazine, piperidine, hexahydropyrimidine, 1,4,5,6-tetrahydropyrimidine, pyrazolidine, pyrrolidine, quinuclidine, tetrahydrofuran, tetrahydropyran, benzimidazolone, pyridinone, and the like.
  • Heterocyclyl groups may be fully saturated, but may also include one or more double bonds.
  • heterocyclyl groups include, but are not limited to, 1,2,3,6-tetrahydropyridinyl, 3,6-dihydro-2H- pyranyl, 3,4-dihydro-2H-pyranyl, 2,5-dihydro-1H-pyrolyl, 2,3-dihydro-1H-pyrolyl, 1H-azirinyl, 1,2- dihydroazetenyl, and the like.
  • halo or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • haloalkyl is meant to include monohaloalkyl and polyhaloalkyl.
  • C1-C3 -haloalkyl includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2- trifluoroethyl, 3-bromopropyl, and the like.
  • acyl means, unless otherwise stated, -C(O)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • aryl means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently.
  • a fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring.
  • heteroaryl refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
  • heteroaryl includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring).
  • a heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom.
  • Heteroaryl refers to a monovalent heteroaromatic group derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system.
  • Heteroaryl groups typically include 5- to 14-membered, but more typically include 5- to 10-membered aromatic, monocyclic, bicyclic, and tricyclic rings containing one or more, for example, 1, 2, 3, or 4, or in certain embodiments, 1, 2, or 3, heteroatoms chosen from O, S, or N, with the remaining ring atoms being carbon.
  • monocyclic heteroaryl groups the single ring is aromatic and includes at least one heteroatom.
  • a monocyclic heteroaryl group may include 5 or 6 ring members and may include 1, 2, 3, or 4 heteroatoms, 1, 2, or 3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom where the heteroatom(s) are independently selected from O, S, or N.
  • both rings are aromatic.
  • bicyclic heteroaryl groups at least one of the rings must include a heteroatom, but it is not necessary that both rings include a heteroatom although it is permitted for them to do so.
  • heteroaryl includes a 5- to 7-membered heteroaromatic ring fused to a carbocyclic aromatic ring or fused to another heteroaromatic ring.
  • tricyclic aromatic rings all three of the rings are aromatic and at least one of the rings includes at least one heteroatom.
  • the point of attachment may be at the ring including at least one heteroatom or at a carbocyclic ring.
  • the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another.
  • the total number of S and O atoms in the heteroaryl group is not more than 2.
  • the total number of S and O atoms in the aromatic heterocycle is not more than 1.
  • Heteroaryl does not encompass or overlap with aryl as defined above.
  • heteroaryl groups include, but are not limited to, groups derived from acridine, carbazole, cinnoline, furan, imidazole, indazole, indole, indolizine, isobenzofuran, isochromene, isoindole, isoquinoline, isothiazole, 2H-benzo[d][1,2,3]triazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazo
  • the heteroaryl group can be between 5 to 20 membered heteroaryl, such as, for example, a 5 to 14 membered or 5 to 10 membered heteroaryl.
  • heteroaryl groups can be those derived from thiophene, pyrrole, benzothiophene, 2H-benzo[d][1,2,3]triazole benzofuran, indole, pyridine, quinoline, imidazole, benzimidazole, oxazole, tetrazole, and pyrazine.
  • cyano refers to the radical -CN.
  • amino referes to the radical -NH2.
  • aminocarbonyl refers to the radical -CO-NH2.
  • Aminocarbonyl radicals may be substituted with one or two alkyl groups to form “alkylaminocarbonyl” groups.
  • alkylcarbonyl refers to the radical alkyl-CO-.
  • hydroxyl and “hydroxy” refers to the radical -OH.
  • oxo means an oxygen that is double bonded to a carbon atom.
  • R, R', R'', R'', and R''' each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups.
  • aryl e.g., aryl substituted with 1-3 halogens
  • substituted or unsubstituted heteroaryl substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups.
  • each of the R groups is independently selected as are each R', R'', R''', and R''' group when more than one of these groups is present.
  • R' and R'' are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring.
  • -NR'R'' includes, but is not limited to, 1-pyrrolidinyl and 4- morpholinyl.
  • alkyl is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like).
  • haloalkyl e.g., -CF3 and -CH2CF3
  • acyl e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like.
  • Such substituted alkyl groups include hydroxyalkyl; carboxyalkyl, alkoxycarbonylalkyl, cyanoalkyl, aminocarbonylalkyl, alkylaminocarbonylalkyl, alkylaminoalkyl, alkylcarbonylaminoalkyl, cycloalkylalkyl, aralkyl, heteroarylalkyl and heterocyclylalkyl; wherein the heterocyclyl, heteroaryl, aryl, cycloalkyl, hydroxyl; carboxyl, alkoxy, cyano, aminocarbonyl, alkylaminocarbonyl, alkylamino, and alkylcarbonylamino groups are defined above.
  • alkenyl and alkynyl groups can be specifically substituted to form halo-substituted C2- C6 alkenyl; alkoxy substituted C2-C6 alkenyl; dialkylamino substituted C2-C6 alkenyl, alkylamino substituted C2-C6 alkenyl, amino substituted C2-C6 alkenyl, hydroxy substituted amino-C2-C6 alkenyl, phenyl substituted amino-C2-C6 alkenyl, amino substituted C2-C6 alkynyl, dialkylamino substituted C2-C6 alkynyl, alkylamino substituted C2-C6 alkynyl, alkoxy substituted C2-C6 alkynyl, heterocyclyl- substituted C2-C6 alkynyl, cycloalkyl- substituted C2-C6 alkenyl, oxygen-containing heterocyclyl- substituted C2-C6 alkenyl, oxygen-containing heterocyclyl
  • alkylsufonyl refers to the radical alkyl-SO 2 -; where alkyl is defined elseqhere.
  • Substituted amino groups include “alkylcarbonylamino,” “alkylsulfonylamino,” “alkylaminocarbonylamino” and “alkylsulfonylamino”; wherein the amino radical is substituted, preferably with one substituent selected from alkylcarbonyl, alkylsulfonyl, alkylaminocarbonyl, defined elsewhere.
  • each of the R groups is independently selected as are each R', R'', R'', and R''' groups when more than one of these groups is present.
  • Substituents for rings e.g. cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene
  • substituents on the ring may be depicted as substituents on the ring rather than on a specific atom of a ring (commonly referred to as a floating substituent).
  • the substituent may be attached to any of the ring atoms (obeying the rules of chemical valency) and in the case of fused rings or spirocyclic rings, a substituent depicted as associated with one member of the fused rings or spirocyclic rings (a floating substituent on a single ring), may be a substituent on any of the fused rings or spirocyclic rings (a floating substituent on multiple rings).
  • the multiple substituents may be on the same atom, same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may optionally be different.
  • a point of attachment of a ring to the remainder of a molecule is not limited to a single atom (a floating substituent)
  • the attachment point may be any atom of the ring and in the case of a fused ring or spirocyclic ring, any atom of any of the fused rings or spirocyclic rings while obeying the rules of chemical valency.
  • a ring, fused rings, or spirocyclic rings contain one or more ring heteroatoms and the ring, fused rings, or spirocyclic rings are shown with one more floating substituents (including, but not limited to, points of attachment to the remainder of the molecule), the floating substituents may be bonded to the heteroatoms.
  • the ring heteroatoms are shown bound to one or more hydrogens (e.g. a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen) in the structure or formula with the floating substituent, when the heteroatom is bonded to the floating substituent, the substituent will be understood to replace the hydrogen, while obeying the rules of chemical valency.
  • Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups.
  • Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure.
  • the ring-forming substituents are attached to adjacent members of the base structure.
  • two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure.
  • the ring-forming substituents are attached to a single member of the base structure.
  • two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure.
  • the ring-forming substituents are attached to non-adjacent members of the base structure.
  • heteroatom or “ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), Boron (B), and silicon (Si).
  • a “substituent group,” as used herein, means a group selected from the following moieties: (A) halogen, oxo, cyano, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -SO 4 H, -SO 2 NH 2 , -NHNH 2 , -ONH 2 , -NHOH, -NHC(O)NHNH 2 , -NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -OCCl 3 ,
  • a “size-limited substituent” or “ size-limited substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10 aryl, and each substituted or unsubstituted heteroaryl is a group selected
  • a “lower substituent” or “ lower substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 -C 7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 -C 10 aryl, and each substituted or unsubstituted heteroaryl is
  • each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene described in the compounds herein are substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group.
  • each substituted or unsubstituted alkyl may be a substituted or unsubstituted C1-C20 alkyl
  • each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl
  • each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl
  • each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl
  • each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10 aryl
  • each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5
  • each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C20 alkylene
  • each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered heteroalkylene
  • each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8 cycloalkylene
  • each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene
  • each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C10 arylene
  • each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene.
  • each substituted or unsubstituted alkyl is a substituted or unsubstituted C1- C8 alkyl
  • each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl
  • each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl
  • each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl
  • each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C10 aryl
  • each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl.
  • each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C8 alkylene
  • each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene
  • each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C 3 -C 7 cycloalkylene
  • each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene
  • each substituted or unsubstituted arylene is a substituted or unsubstituted C 6 -C 10 arylene
  • each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene.
  • the compound is a chemical species set forth in the Examples section, figures, or tables below.
  • a substituted or unsubstituted moiety e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and/or substituted or unsubstituted heteroarylene) is unsubstituted (e.g., is an unsubstituted alkyl, unsubstituted cycloalkyl, substituted
  • a substituted or unsubstituted moiety e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and/or substituted or unsubstituted heteroarylene) is substituted (e.g., is a substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alky
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
  • is substituted with at least one substituent group wherein if the substituted moiety is substituted with a plurality of substituent groups, each substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of substituent groups, each substituent group is different.
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
  • is substituted with at least one size-limited substituent group wherein if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group may optionally be different.
  • each size-limited substituent group is different.
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
  • each lower substituent group is different.
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
  • each substituent group, size-limited substituent group, and/or lower substituent group is different.
  • Certain compounds of the present invention possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present invention.
  • the compounds of the present invention do not include those that are known in art to be too unstable to synthesize and/or isolate.
  • the present invention is meant to include compounds in racemic and optically pure forms.
  • Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • R Optically active
  • S S
  • D dibenzyl- and (L)-isomers
  • the term “isomers” refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.
  • the term “tautomer,” as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another. [0140] It will be apparent to one skilled in the art that certain compounds of this invention may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the invention.
  • stereoisomer or “stereomerically pure” means one stereoisomer of a compound that is substantially free of other stereoisomers of that compound.
  • a stereomerically pure compound having one chiral center will be substantially free of the mirror image enantiomer of the compound.
  • a stereomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound.
  • a typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, more preferably greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, even more preferably greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, and most preferably greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound.
  • stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it.
  • a bond drawn with a wavy line indicates that both stereoisomers are encompassed. This is not to be confused with a wavy line drawn perpendicular to a bond which indicates the point of attachment of a group to the rest of the molecule.
  • this invention encompasses the use of stereomerically pure forms of such compounds, as well as the use of mixtures of those forms. For example, mixtures comprising equal or unequal amounts of the enantiomers of a particular compound of the invention may be used in methods and compositions of the invention.
  • isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley- Interscience, New York, 1981); Wilen, S. H., et al. (1997) Tetrahedron 33:2725; Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972).
  • structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium [D] or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of this is selected from invention.
  • D deuterium
  • carbon replacement of a carbon by 13 C- or 14 C-enriched carbon
  • a or “an,” as used in herein means one or more.
  • substituted with a[n] means the specified group may be substituted with one or more of any or all of the named substituents.
  • a group such as an alkyl or heteroaryl group
  • the group may contain one or more unsubstituted C 1 -C 20 alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls.
  • R-substituted where a moiety is substituted with an R substituent, the group may be referred to as “R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. Where a particular R group is present in the description of a chemical genus (such as Formula (XV)), a Roman alphabetic symbol may be used to distinguish each appearance of that particular R group. [0146] Any compound herein can be purified.
  • a compound herein can be least 1% pure, at least 2% pure, at least 3% pure, at least 4% pure, at least 5% pure, at least 6% pure, at least 7% pure, at least 8% pure, at least 9% pure, at least 10% pure, at least 11% pure, at least 12% pure, at least 13% pure, at least 14% pure, at least 15% pure, at least 16% pure, at least 17% pure, at least 18% pure, at least 19% pure, at least 20% pure, at least 21% pure, at least 22% pure, at least 23% pure, at least 24% pure, at least 25% pure, at least 26% pure, at least 27% pure, at least 28% pure, at least 29% pure, at least 30% pure, at least 31% pure, at least 32% pure, at least 33% pure, at least 34% pure, at least 35% pure, at least 36% pure, at least 37% pure, at least 38% pure, at least 39% pure, at least 40% pure, at least 41% pure, at least 42% pure, at least 4
  • compounds as disclosed herein can be used to treat cancer in a subject.
  • a compound as disclosed herein can, for example, slow the proliferation of cancer cell lines, or kill cancer cells.
  • cancer that can be treated by a compound as disclosed herein include: acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphoma, anal cancer, appendix cancer, astrocytomas, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancers, brain tumors, such as cerebellar astrocytoma, cerebral astrocytoma/malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors, visual pathway and hypothalamic glioma, breast cancer, bronchial adenomas, Burkitt lymphoma, carcinoma of unknown primary origin, central nervous system lympho
  • the compounds of the disclosure show non-lethal toxicity.
  • Pharmaceutically-acceptable salts include, for example, acid-addition salts and base- addition salts.
  • the acid that is added to the compound to form an acid-addition salt can be an organic acid or an inorganic acid.
  • a base that is added to the compound to form a base-addition salt can be an organic base or an inorganic base.
  • a pharmaceutically-acceptable salt is a metal salt.
  • a pharmaceutically-acceptable salt is an ammonium salt.
  • Metal salts can arise from the addition of an inorganic base to a compound of the invention.
  • the inorganic base consists of a metal cation paired with a basic counterion, such as, for example, hydroxide, carbonate, bicarbonate, or phosphate.
  • the metal can be an alkali metal, alkaline earth metal, transition metal, or main group metal.
  • the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc.
  • a metal salt is a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, or a zinc salt.
  • Ammonium salts can arise from the addition of ammonia or an organic amine to a compound of the invention.
  • the organic amine is triethyl amine, diisopropyl amine, ethanol amine, diethanol amine, triethanol amine, morpholine, N-methylmorpholine, piperidine, N- methylpiperidine, N-ethylpiperidine, dibenzylamine, piperazine, pyridine, pyrrazole, pipyrrazole, imidazole, pyrazine, or pipyrazine.
  • an ammonium salt is a triethyl amine salt, a diisopropyl amine salt, an ethanol amine salt, a diethanol amine salt, a triethanol amine salt, a morpholine salt, an N- methylmorpholine salt, a piperidine salt, an N-methylpiperidine salt, an N-ethylpiperidine salt, a dibenzylamine salt, a piperazine salt, a pyridine salt, a pyrrazole salt, a pipyrrazole salt, an imidazole salt, a pyrazine salt, or a pipyrazine salt.
  • Acid addition salts can arise from the addition of an acid to a compound of the invention.
  • the acid is organic.
  • the acid is inorganic.
  • the acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, a phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, gentisinic acid, gluconic acid, glucaronic acid, saccaric acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, propionic acid, butyric acid, fumaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, oxalic acid, or maleic acid.
  • the salt is a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a nitrate salt, a nitrite salt, a sulfate salt, a sulfite salt, a phosphate salt, isonicotinate salt, a lactate salt, a salicylate salt, a tartrate salt, an ascorbate salt, a gentisinate salt, a gluconate salt, a glucaronate salt, a saccarate salt, a formate salt, a benzoate salt, a glutamate salt, a pantothenate salt, an acetate salt, a propionate salt, a butyrate salt, a fumarate salt, a succinate salt, a methanesulfonate (mesylate) salt, an ethanesulfonate salt, a benzenesulfonate salt, a p-tolu
  • compositions of the disclosure can be used, for example, before, during, or after treatment of a subject with, for example, another pharmaceutical agent.
  • Subjects can be, for example, elderly adults, adults, adolescents, pre-adolescents, children, toddlers, infants, neonates, and non-human animals.
  • a subject is a patient.
  • a pharmaceutical composition of the disclosure can be a combination of any pharmaceutical compounds described herein with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients. The pharmaceutical composition facilitates administration of the compound to an organism.
  • compositions can be administered in therapeutically-effective amounts as pharmaceutical compositions by various forms and routes including, for example, intravenous, subcutaneous, intramuscular, oral, parenteral, ophthalmic, subcutaneous, transdermal, nasal, vaginal, and topical administration.
  • a pharmaceutical composition can be administered in a local manner, for example, via injection of the compound directly into an organ, optionally in a depot or sustained release formulation or implant.
  • Pharmaceutical compositions can be provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation.
  • a rapid release form can provide an immediate release.
  • An extended release formulation can provide a controlled release or a sustained delayed release.
  • compositions can be formulated by combining the active compounds with pharmaceutically-acceptable carriers or excipients.
  • Such carriers can be used to formulate liquids, gels, syrups, elixirs, slurries, or suspensions, for oral ingestion by a subject.
  • Non- limiting examples of solvents used in an oral dissolvable formulation can include water, ethanol, isopropanol, saline, physiological saline, DMSO, dimethylformamide, potassium phosphate buffer, phosphate buffer saline (PBS), sodium phosphate buffer, 4-2-hydroxyethyl-1-piperazineethanesulfonic acid buffer (HEPES), 3-(N-morpholino)propanesulfonic acid buffer (MOPS), piperazine-N,N′-bis(2- ethanesulfonic acid) buffer (PIPES), and saline sodium citrate buffer (SSC).
  • PBS phosphate buffer saline
  • MOPS 4-2-hydroxyethyl-1-piperazineethanesulfonic acid buffer
  • MOPS 3-(N-morpholino)propanesulfonic acid buffer
  • PES piperazine-N,N′-bis(2- ethanesulfonic acid) buffer
  • SSC saline sodium
  • Non-limiting examples of co- solvents used in an oral dissolvable formulation can include sucrose, urea, cremaphor, DMSO, and potassium phosphate buffer.
  • Pharmaceutical compositions can be formulated for intravenous administration.
  • the pharmaceutical compositions can be in a form suitable for parenteral injection as a sterile suspension, solution or emulsion in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Suspensions of the active compounds can be prepared as oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • the suspension can also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • the active compounds can be administered topically and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, and ointments.
  • Such pharmaceutical compositions can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • the compounds of the disclosure can be applied topically to the skin, or a body cavity, for example, oral, vaginal, bladder, cranial, spinal, thoracic, or pelvic cavity of a subject.
  • the compounds of the disclosure can be applied to an accessible body cavity.
  • the compounds can also be formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, and PEG.
  • rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas
  • conventional suppository bases such as cocoa butter or other glycerides
  • synthetic polymers such as polyvinylpyrrolidone, and PEG.
  • a low-melting wax such as a mixture of fatty acid glycerides, optionally in combination with cocoa butter, can be melted.
  • therapeutically-effective amounts of the compounds described herein are administered in pharmaceutical compositions to a subject having a disease or condition to be treated.
  • the subject is a mammal such as a human.
  • a therapeutically-effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compounds used, and other factors.
  • the compounds can be used singly or in combination with one or more therapeutic agents as components of mixtures.
  • Pharmaceutical compositions can be formulated using one or more physiologically-acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations that can be used pharmaceutically. Compositions can be modified depending upon the route of administration chosen.
  • compositions comprising a compound described herein can be manufactured, for example, by mixing, dissolving, emulsifying, encapsulating, entrapping, or compression processes.
  • the pharmaceutical compositions can include at least one pharmaceutically-acceptable carrier, diluent, or excipient and compounds described herein as free-base or pharmaceutically-acceptable salt form.
  • Pharmaceutical compositions can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • Methods for the preparation of compositions comprising the compounds described herein include formulating the compounds with one or more inert, pharmaceutically-acceptable excipients or carriers to form a solid, semi-solid, or liquid composition.
  • Solid compositions include, for example, powders, tablets, dispersible granules, capsules, and cachets.
  • Liquid compositions include, for example, solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein.
  • Semi-solid compositions include, for example, gels, suspensions and creams. The compositions can be in liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions can also contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additives.
  • Non-limiting examples of dosage forms suitable for use in the disclosure include liquid, powder, gel, nanosuspension, nanoparticle, microgel, aqueous or oily suspensions, emulsion, and any combination thereof.
  • Non-limiting examples of pharmaceutically-acceptable excipients suitable for use in the disclosure include binding agents, disintegrating agents, anti-adherents, anti-static agents, surfactants, anti-oxidants, coating agents, coloring agents, plasticizers, preservatives, suspending agents, emulsifying agents, anti-microbial agents, spheronization agents, and any combination thereof.
  • a composition of the disclosure can be, for example, an immediate release form or a controlled release composition.
  • An immediate release composition can be formulated to allow the compounds to act rapidly.
  • immediate release compositions include readily dissolvable formulations.
  • a controlled release compositions can be a pharmaceutical composition that has been adapted such that release rates and release profiles of the active agent can be matched to physiological and chronotherapeutic requirements or, alternatively, has been formulated to effect release of an active agent at a programmed rate.
  • Non-limiting examples of controlled release compositions include granules, delayed release granules, hydrogels (e.g., of synthetic or natural origin), other gelling agents (e.g., gel- forming dietary fibers), matrix-based compositions (e.g., compositions comprising a polymeric material having at least one active ingredient dispersed through), granules within a matrix, polymeric mixtures, and granular masses.
  • a controlled release composition is a delayed release form.
  • a delayed release form can be formulated to delay a compound’s action for an extended period of time.
  • a delayed release form can be formulated to delay the release of an effective dose of one or more compounds, for example, for about 4, about 8, about 12, about 16, or about 24 hours.
  • a controlled release composition can be a sustained release form.
  • a sustained release form can be formulated to sustain, for example, the compound’s action over an extended period of time.
  • a sustained release form can be formulated to provide an effective dose of any compound described herein (e.g., provide a physiologically-effective blood profile) over about 4, about 8, about 12, about 16 or about 24 hours.
  • Non-limiting examples of pharmaceutically-acceptable excipients can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A.
  • Multiple therapeutic agents can be administered in any order or simultaneously.
  • a compound of the disclosure is administered in combination with, before, or after treatment with another therapeutic agent.
  • the multiple therapeutic agents can be provided in a single, unified form, or in multiple forms, for example, as multiple separate pills.
  • the agents can be packed together or separately, in a single package or in a plurality of packages.
  • One or all of the therapeutic agents can be given in multiple doses.
  • compositions described herein can be administered before, during, or after the occurrence of a disease or condition, and the timing of administering the composition containing a therapeutic agent can vary.
  • the compositions can be used as a prophylactic and can be administered continuously to subjects with a propensity to conditions or diseases in order to lessen a likelihood of the occurrence of the disease or condition.
  • the compositions can be administered to a subject during or as soon as possible after the onset of the symptoms.
  • the administration of the therapeutic agents can be initiated within the first 48 hours of the onset of the symptoms, within the first 24 hours of the onset of the symptoms, within the first 6 hours of the onset of the symptoms, or within 3 hours of the onset of the symptoms.
  • the initial administration can be via any route practical, such as by any route described herein using any formulation described herein.
  • a compound can be administered as soon as is practical after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease, such as, for example, from about 1 month to about 3 months.
  • the length of time a compound can be administered can be about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 2 months, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 3 months, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 4 months, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 5 months, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months about 23 months, about 2 years, about 2.5 years, about 3 years, about 3.5 years, about 4 years, about 4.5 years, about
  • compositions described herein can be in unit dosage forms suitable for single administration of precise dosages.
  • the formulation is divided into unit doses containing appropriate quantities of one or more compounds.
  • the unit dosage can be in the form of a package containing discrete quantities of the formulation.
  • Non-limiting examples are packaged injectables, vials, or ampoules.
  • Aqueous suspension compositions can be packaged in single-dose non- reclosable containers. Multiple-dose reclosable containers can be used, for example, in combination with or without a preservative.
  • Formulations for injection can be presented in unit dosage form, for example, in ampoules, or in multi-dose containers with a preservative.
  • compositions provided herein can be administered in conjunction with other therapies, for example, chemotherapy, radiation, surgery, anti-inflammatory agents, and selected vitamins.
  • the other agents can be administered prior to, after, or concomitantly with the pharmaceutical compositions.
  • the pharmaceutical compositions can be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, lotions, creams, or gels, for example, in unit dosage form suitable for single administration of a precise dosage.
  • nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, and magnesium carbonate.
  • pharmaceutically active agents suitable for combination with compositions of the disclosure include anti-infectives, i.e., aminoglycosides, antiviral agents, antimicrobials, anticholinergics/antispasmotics, antidiabetic agents, antihypertensive agents, antineoplastics, cardiovascular agents, central nervous system agents, coagulation modifiers, hormones, immunologic agents, immunosuppressive agents, and ophthalmic preparations.
  • Liposomes are composed of natural phospholipids, and can contain mixed lipid chains with surfactant properties (e.g., egg phosphatidylethanolamine).
  • a liposome design can employ surface ligands for attaching to unhealthy tissue.
  • Non-limiting examples of liposomes include the multilamellar vesicle (MLV), the small unilamellar vesicle (SUV), and the large unilamellar vesicle (LUV).
  • Liposomal physicochemical properties can be modulated to optimize penetration through biological barriers and retention at the site of administration, and to reduce a likelihood of developing premature degradation and toxicity to non-target tissues.
  • Optimal liposomal properties depend on the administration route: large-sized liposomes show good retention upon local injection, small-sized liposomes are better suited to achieve passive targeting.
  • PEGylation reduces the uptake of the liposomes by the liver and spleen, and increases the circulation time, resulting in increased localization at the inflamed site due to the enhanced permeability and retention (EPR) effect.
  • liposomal surfaces can be modified to achieve selective delivery of the encapsulated drug to specific target cells.
  • Non-limiting examples of targeting ligands include monoclonal antibodies, vitamins, peptides, and polysaccharides specific for receptors concentrated on the surface of cells associated with the disease.
  • Non-limiting examples of dosage forms suitable for use in the disclosure include liquid, elixir, nanosuspension, aqueous or oily suspensions, drops, syrups, and any combination thereof.
  • compositions of the disclosure can be packaged as a kit.
  • a kit includes written instructions on the administration/use of the composition.
  • the written material can be, for example, a label.
  • the written material can suggest conditions methods of administration.
  • the instructions provide the subject and the supervising physician with the best guidance for achieving the optimal clinical outcome from the administration of the therapy.
  • the written material can be a label.
  • the label can be approved by a regulatory agency, for example the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or other regulatory agencies.
  • Dosing can be in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the composition is divided into unit doses containing appropriate quantities of one or more compounds. The unit dosage can be in the form of a package containing discrete quantities of the composition. Non-limiting examples are liquids in vials or ampoules. Aqueous suspension compositions can be packaged in single-dose non-reclosable containers.
  • compositions for parenteral injection can be presented in unit dosage form, for example, in ampoules, or in multi-dose containers with a preservative.
  • a compound described herein can be present in a composition in a range of from about 1 mg to about 2000 mg; from about 10 mg to about 1000 mg; from about 100 mg to about 750 mg; from about 250 mg to about 500 mg, from about 100 mg to about 500 mg, from about 200 mg to about 500 mg, from about 250 mg to about450 mg, from about 100 mg to about 200 mg, from about 1 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 150 mg, from about 150 mg to about 200 mg, from about 200 mg to about 250 mg, from about 250 mg to about 300 mg, from about 300 mg to about 350 mg, from about 350 mg to about 400 mg, from about 400 mg to about 450 mg, from about 450 mg to about 500 mg, from about 500 mg to about 550 mg
  • a compound described herein can be present in a composition in an amount of about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg.
  • a dose can be expressed in terms of an amount of the drug divided by the mass of the subject, for example, milligrams of drug per kilograms of subject body mass.
  • a compound is administered in an amount ranging from about 1 mg/kg to about 20 mg/kg, or about 5 mg/kg to about 10 mg/kg.
  • a compound is administered in an amount of about 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, about 7 mg/kg, 8 mg/kg, about 9 mg/kg, or about 10 mg/kg.
  • Combination Treatment with an anti-cancer agent can be used to treat a condition.
  • the combination therapy can produce a significantly better therapeutic result than the additive effects achieved by each individual constituent when administered alone at a therapeutic dose.
  • the dosage of the compound or anti-cancer agent described herein, in combination therapy can be reduced as compared to monotherapy with each agent, while still achieving an overall therapeutic effect.
  • a compound and an anti-cancer agent described herein can exhibit a synergistic effect.
  • the synergistic effect of a compound and anti-cancer agent described herein can be used to reduce the total amount drugs administered to a subject, which decrease side effects experienced by the subject.
  • the compounds of the disclosure can be used in combination with at least one anti-cancer agent described herein.
  • the at least one anti-cancer agent described herein can modulate the same or a different target as the compounds of the disclosure.
  • the at least one anti-cancer agent described herein can modulate the same target as the compounds of the disclosure, or other components of the same pathway, or overlapping sets of target enzymes.
  • the at least one anti-cancer agent described herein can modulate a different target from the compounds of the disclosure.
  • the present disclosure provides a method for treating cancer, the method comprising administering to a subject in need thereof (a) an effective amount of a compound of the disclosure and (b) an effective amount of at least one anti-cancer agent described herein, to provide a combination therapy.
  • the combination therapy may have an enhanced therapeutic effect compared to the effect of the compound and the at least one anti-cancer agent each administered alone.
  • the combination therapy has a synergistic therapeutic effect.
  • the combination therapy produces a significantly better therapeutic result (e.g., anti-cancer, cell growth arrest, apoptosis, induction of differentiation, cell death, etc.) than the additive effects achieved by each individual constituent when administered alone at a therapeutic dose.
  • Combination therapy includes but is not limited to the combination of compounds of the disclosure with anti-cancer agents such as chemotherapeutic agents, therapeutic antibodies, or radiation treatment, to provide a synergistic therapeutic effect.
  • the compounds of the disclosure are used in combination with one or more anti-cancer (antineoplastic or cytotoxic) chemotherapy drug.
  • Suitable chemotherapeutic agents for use in the combinations of the present disclosure include, but are not limited to, alkylating agents, antibiotic agents, antimetabolic agents, hormonal agents, plant-derived agents, anti-angiogenic agents, differentiation inducing agents, cell growth arrest inducing agents, apoptosis inducing agents, cytotoxic agents, agents affecting cell bioenergetics, biologic agents, e.g., monoclonal antibodies, kinase inhibitors and inhibitors of growth factors and their receptors, gene therapy agents, cell therapy, or any combination thereof.
  • a compound of the disclosure is used in combination with an estrogen receptor antagonist.
  • a compound of the disclosure is used in combination with toremifene (Fareston®), fulvestrant (Faslodex®), or tamoxifen citrate (Soltamox®).
  • Fulvestrant is a selective estrogen receptor degrader (SERD) and is indicated for the treatment of hormone receptor positive metastatic breast cancer in postmenopausal women with disease progression following anti-estrogen therapy.
  • Fulvestrant is a complete estrogen receptor antagonist with little to no agonist effects and accelerates the proteasomal degradation of the estrogen receptor. Fulvestrant has poor oral bioavailability and is administered via intramuscular injection.
  • Fulvestrant-induced expression of ErbB3 and ErbB4 receptors sensitizes estrogen receptor-positive breast cancer cells to heregulin beta1.
  • a compound of the disclosure is used in combination with fulvestrant.
  • a compound of the disclosure is used in combination with an aromatase inhibitor.
  • Aromatase inhibitors are used in the treatment of breast cancer in post-menopausal women and gynecomastia in men. Aromatase inhibitors can be used off-label to reduce estrogen conversion when using external testosterone. Aromatase inhibitors can also be used for chemoprevention in high-risk women.
  • a compound of the disclosure is used in combination with a non-selective aromatase inhibitor.
  • a compound of the disclosure is used in combination with a non-selective aromatase inhibitor, such as aminoglutethimide or testolactone (Teslac®).
  • a compound of the disclosure is used in combination with a selective aromatase inhibitor.
  • a compound of the disclosure is used in combination with a selective aromatase inhibitor, such as anastrozole (Arimidex®), letrozole (Femara®), exemestane (Aromasin®), vorozole (Rivizor®), formestane (Lentaron®), or fadrozole (Afema®).
  • a compound of the disclosure is used in combination with exemestane.
  • a compound of the disclosure is used in combination with an aromatase inhibitor such as 1,4,6-androstatrien-3,17-dione (ATD) or 4- androstene-3,6,17-trione.
  • a compound of the disclosure is used in combination with an mTOR inhibitor.
  • mTOR inhibitors are drugs that inhibit the mechanistic target of rapamycin (mTOR), which is a serine/threonine-specific protein kinase that belongs to the family of phosphatidylinositol-3 kinase (PI3K)-related kinases (PIKKs).
  • mTOR regulates cellular metabolism, growth, and proliferation by forming and signaling through the protein complexes mTORC1 and mTORC2.
  • a compound of the disclosure is used in combination with an mTOR inhibitor, such as rapamycin, temsirolimus (CCI-779), everolimus (RAD001), ridaforolimus (AP-23573).
  • an mTOR inhibitor such as rapamycin, temsirolimus (CCI-779), everolimus (RAD001), ridaforolimus (AP-23573).
  • a compound of the disclosure is used in combination with everolimus (Afinitor®).
  • Everolimus affects the mTORC1 protein complex and can lead to hyper-activation of the kinase AKT, which can lead to longer survival in some cell types.
  • Everolimus binds to FKBP12, a protein receptor which directly interacts with mTORC1 and inhibits downstream signaling.
  • a compound of the disclosure is used in combination with a mTOR inhibitor and an aromatase inhibitor.
  • a compound of the disclosure is used in combination with everolimus and exemestane.
  • Combination treatment with antimetabolites [0201] Antimetabolites are chemotherapy treatments that are similar to normal substances within the cell. When cells incorporate the antimetabolites into the cellular metabolism, the cells are unable to divide. Antimetabolites are cell-cycle specific and attack cells at specific phases in the cell cycle.
  • a compound of the disclosure is used in combination with one or more antimetabolites, such as a folic acid antagonist, pyrimidine antagonist, purine antagonist, or an adenosine deaminase inhibitor.
  • a compound of the disclosure is used in combination with an antimetabolite, such as methotrexate, 5-fluorouracil, foxuridine, cytarabine, capecitabine, gemcitabine, 6- mercaptopurine, 6-thioguanine, cladribine, fludarabine, nelarabine, or pentostatin.
  • a compound of the disclosure is used in combination with capecitabine (Xeloda®), gemcitabine (Gemzar®), or cytarabine (Cytosar-U®).
  • capecitabine Xeloda®
  • gemcitabine gemcitabine
  • Cytosar-U® cytarabine
  • a compound of the disclosure is used in combination with a plant alkaloid.
  • a plant alkaloid such as vinca alkaloids, taxanes, podophyllotoxins, or camptothecan analogues.
  • a compound of the disclosure is used in combination with plant alkaloids, such as vincristine, vinblastine, vinorelbine, paclitaxel, docetaxel, etoposide, tenisopide, irinotecan, or topotecan.
  • plant alkaloids such as vincristine, vinblastine, vinorelbine, paclitaxel, docetaxel, etoposide, tenisopide, irinotecan, or topotecan.
  • a compound of the disclosure is used in combination with a taxane, such as paclitaxel (Abraxane® or Taxol®) and docetaxel (Taxotere®).
  • paclitaxel Abraxane® or Taxol®
  • docetaxel such as paclitaxel (Abraxane® or Taxol®)
  • paclitaxel such as paclitaxel (Abraxane® or Taxol®) and docetaxel (
  • a compound of the disclosure is used in combination with therapeutic antibodies.
  • a compound of the disclosure is used in combination with monoclonal antibodies, such as alemtuzumab (Campath®) or trastuzumab (Herceptin®).
  • a compound of the disclosure is used in combination with conjugated monoclonal antibodies, such as radiolabeled antibodies or chemolabeled antibodies.
  • a compound of the disclosure is used in combination with conjugated monoclonal antibodies, such as ibritumomab tiuxetan (Zevalin®), brentuximab vedotin (Adcetris®), ado-trastuzumab emtansine (Kadcyla®), or denileukin diftitox (Ontak®).
  • conjugated monoclonal antibodies such as ibritumomab tiuxetan (Zevalin®), brentuximab vedotin (Adcetris®), ado-trastuzumab emtansine (Kadcyla®), or denileukin diftitox (Ontak®).
  • a compound of the disclosure is used in combination with bispecific monoclonal antibodies, such as blinatumomab (Blincyto®).
  • a compound of the disclosure is used in combination with an anti-CD20 antibody, such as rituximab (Mabthera®/ Rituxan®), obinutuzumab (Gazyva®), ibritumomab tiuxetan, tositumomab, ofatumumab (Genmab®), ocaratuzumab, ocrelizumab, TRU-015, or veltuzumab.
  • an anti-CD20 antibody such as rituximab (Mabthera®/ Rituxan®), obinutuzumab (Gazyva®), ibritumomab tiuxetan, tositumomab, ofatumumab (Genmab®), ocaratuzumab, ocrelizumab, TRU-015, or veltuzumab.
  • the PD-1 pathway comprises the immune cell co-receptor Programmed Death-1 (PD-1) and the PD-1 ligands PD-L1 and PD-L2.
  • the PD-1 pathway mediates local immunosuppression in the tumor microenvironment.
  • PD-1 and PD-L1 antagonists suppress the immune system.
  • a PD-1 or PD-L1 antagonist is a monoclonal antibody or antigen binding fragment thereof that specifically binds to, blocks, or downregulates PD-1 or PD-L1, respectively.
  • a PD-1 or PD-L1 antagonist is a compound or biological molecule that specifically binds to, blocks, or downregulates PD-1 or PD-L1, respectively.
  • the compounds of the disclosure are used in combination with a PD-1 or PD-L1 antagonist.
  • the compounds of the disclosure are used in combination with a PD-1/PD-L1 antagonist, for example, MK-3475, nivolumab (Opdivo®), pembrolizumab (Keytruda®), humanized antibodies (i.e., h409Al l, h409A16 and h409A17), AMP-514, BMS-936559, MEDI0680, MEDI4736, MPDL3280A, MSB0010718C, MDX-1105, MDX-1106, or pidilzumab.
  • a PD-1/PD-L1 antagonist for example, MK-3475, nivolumab (Opdivo®), pembrolizumab (Keytruda®), humanized antibodies (i.e., h409Al l, h409A16 and h409A17), AMP-514, BMS-936559, MEDI0680, MEDI4736, MPDL3280A,
  • the compounds of the disclosure are used in combination with a PD-1/PD-L1 antagonist that is an immunoadhesion molecule, such as AMP-224. In some embodiments, the compounds of the disclosure are used in combination with a PD-1/PD-L1 antagonist to treat cancer cells or a tumor that overexpresses PD-1 or PD-L1. In some embodiments, the compounds of the disclosure are used in combination with a PD-1/PD-L1 antagonist to treat cancer cells or a tumor that overexpresses miR-34. h. Combination treatment with anti-hormone therapy [0209] Anti-hormone therapy uses an agent to suppress selected hormones or the effects.
  • Anti-hormone therapy is achieved by antagonizing the function of hormones with a hormone antagonist and/or by preventing the production of hormones. In some embodiments, the suppression of hormones can be beneficial to subjects with certain cancers that grow in response to the presence of specific hormones.
  • a compound of the disclosure is used in combination with a hormone antagonist. [0210] In some embodiments, a compound of the disclosure is used in combination with anti-androgens, anti-estrogens, aromatase inhibitors, or luteinizing hormone-releasing hormone (LHRH) agonists.
  • a compound of the disclosure is used in combination with anti-androgens, such as bicalutamide (Casodex®), cyproterone (Androcur®), flutamide (Euflex®), or nilutamide (Anandron®).
  • anti-estrogens such as fulvestrant (Faslodex®), raloxifene (Evista®), or tamoxifen (Novaladex®, Tamofen®).
  • a compound of the disclosure is used in combination with LHRH agonists, such as buserelin (Suprefact®), goserelin (Zoladex®), or leuprolide (Lupron®, Lupron Depot®, Eligard®).
  • LHRH agonists such as buserelin (Suprefact®), goserelin (Zoladex®), or leuprolide (Lupron®, Lupron Depot®, Eligard®).
  • HMAs hypomethylating (demethylating) agents
  • Treatment of these and other types of cancer may be improved by examining combinations that increase anti-tumor activities and may allow for similar activity at reduced doses compared to single agent treatment, leading to improved patient outcomes, and limiting adverse events.
  • Hypomethylating (demethylating) agents inhibit DNA methylation, which affects cellular function through successive generations of cells without changing the underlying DNA sequence.
  • Hypomethylating agents can block the activity of DNA methyltransferase.
  • a compound of the disclosure is used in combination with hypomethylating agents, such as azacitidine (Vidaza®, Azadine®) or decitabine (Dacogen®).
  • azacitidine such as azacitidine (Vidaza®, Azadine®) or decitabine (Dacogen®).
  • a compound of the disclosure is used in combination with nonsteroidal anti-inflammatory drugs (NSAIDs), specific COX-2 inhibitors, or corticosteroids.
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • a compound of the disclosure is used in combination with NSAIDs, such as aspirin, ibuprofen, naproxen, celecoxib, ketorolac, or diclofenac.
  • NSAIDs such as aspirin, ibuprofen, naproxen, celecoxib, ketorolac, or diclofenac.
  • a compound of the disclosure is used in combination with specific COX-2 inhibitors, such as celecoxib (Celebrex®), rofecoxib, or etoricoxib.
  • a compound of the disclosure is used in combination with corticosteroids, such as dexamethasone or glucosteroids (e.g., hydrocortisone and prednisone). k.
  • Histone deacetylase (HDAC) inhibitors are chemical compounds that inhibit histone deacetylase. HDAC inhibitors can induce p21 expression, a regulator of p53 activity. In some embodiments, a compound of the disclosure is used in combination with an HDAC inhibitor.
  • a compound of the disclosure is used in combination with an HDAC inhibitor, such as vorinostat, romidepsin (Istodax®), chidamide, panobinostat (Farydak®), belinostat (PDX101), panobinostat (LBH589), valproic acid, mocetinostat (MGCD0103), abexinostat (PCI-24781), entinostat (MS-275), SB939, resminostat (4SC-201), givinostat (ITF2357), quisinostat (JNJ-26481585), HBI-8000, kevetrin, CUDC-101, AR-42, CHR-2845, CHR-3996, 4SC-202, CG200745, ACY-1215, ME-344, sulforaphane, or trichostatin A.
  • HDAC inhibitor such as vorinostat, romidepsin (Istodax®), chid
  • Platinum-based antineoplastic drugs are coordinated complex of platinum.
  • a compound of the disclosure is used in combination with a platinum-based antineoplastic drug, such as cisplatin, oxaliplatin, carboplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, or satraplatin.
  • a compound of the disclosure is used in combination with cisplatin or carboplatin.
  • a compound of the disclosure is used in combination with cisplatinum, platamin, neoplatin, cismaplat, cis-diamminedichloroplatinum(II), or CDDP; Platinol®) and carboplatin (also known as cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II); tradenames Paraplatin® and Paraplatin-AQ®).
  • Combination treatment with kinase inhibitors [0215] Abnormal activation of protein phosphorylation is frequently either a driver of direct consequence of cancer.
  • MEK inhibitors are drugs that inhibit the mitogen-activated protein kinase enzymes MEK1 and/or MEK2.
  • a compound of the disclosure is used in combination with a MEK1 inhibitor.
  • a compound of the disclosure is used in combination with a MEK2 inhibitor.
  • a compound of the disclosure is used in combination with an agent that can inhibit MEK1 and MEK2.
  • a compound of the disclosure is used in combination with a MEK1/MEK2 inhibitor, such as trametinib (Mekinist®), cobimetinib, binimetinib, selumetinib (AZD6244), pimasertibe (AS-703026), PD-325901, CI-1040, PD035901, or TAK-733.
  • a compound of the disclosure is used in combination with trametinib.
  • a compound of the disclosure is used in combination with cobimetinib.
  • BRAF inhibitors are drugs that inhibit the serine/threonine-protein kinase B- raf (BRAF) protein.
  • BRAF serine/threonine-protein kinase B- raf
  • a compound of the disclosure is used in combination with a BRAF inhibitor.
  • a compound of the disclosure is used in combination with a BRAF inhibitor that can inhibit wild type BRAF.
  • a compound of the disclosure is used in combination with a BRAF inhibitor that can inhibit mutated BRAF.
  • a compound of the disclosure is used in combination with a BRAF inhibitor that can inhibit V600E mutated BRAF.
  • a compound of the disclosure is used in combination with a BRAF inhibitor, such as vemurafenib (Zelboraf®), dabrafenib (Tafinlar®), C-1, NVP-LGX818, or sorafenib (Nexavar®).
  • KRAS inhibitors KRAS is a gene that acts as an on/off switch in cell signaling.
  • a compound of the disclosure is used in combination with a KRAS inhibitor.
  • a compound of the disclosure is used in combination with a wild type KRAS inhibitor.
  • a compound of the disclosure is used in combination with a mutated KRAS inhibitor (e.g., a G12C mutated KRAS).
  • the KRAS inhibitor is sotorasib (AMG-510), COTI-219, ARS-3248, WDB-178, BI-3406, BI-1701963, SML-8-73-1 (G12C), Compound 3144 (G12D), Kobe0065, Kobe/2602, (Ras GTP), RT11, or adagrasib (MRTX-849).
  • BTK inhibitors Bruton’s tyrosine kinase (BTK) is a non-receptor tyrosine kinase of the Tec kinase family that is involved in B-cell receptor signaling.
  • a compound of the disclosure is used in combination with a BTK inhibitor.
  • a compound of the disclosure is used in combination with a BTK inhibitor, such as ibrutinib or acalabrutinib.
  • CDK inhibitors: CDK4 and CDK6 are cyclin-dependent kinases that control the transition between the G1 and S phases of the cell cycle. CDK4/CDK6 activity is deregulated and overactive in cancer cells.
  • CDK4/CDK6 inhibitors can block cell-cycle progression in the mid-G1 phase of the cell cycle, causing arrest and preventing the proliferation of cancer cells.
  • a compound of the disclosure is used in combination with a CDK4/CDK6 inhibitor.
  • a compound of the disclosure is used in combination with a CDK4/CDK6 inhibitor, such as palbociclib (Ibrance®), ribociclib, trilaciclib, seliciclib, dinaciclib, milciclib, roniciclib, atuveciclib, briciclib, riviciclib, voruciclib, or abemaciclib.
  • a compound of the disclosure is used in combination with palbociclib.
  • a compound of the disclosure is used in combination with ribociclib. In some embodiments, a compound of the disclosure is used in combination with abemaciclib. [0221] In some examples, a compound of the disclosure is used in combination with an inhibitor of CDK4 and/or CDK6 and with an agent that reinforces the cytostatic activity of CDK4/6 inhibitors and/or with an agent that converts reversible cytostasis into irreversible growth arrest or cell death. Examples of cancer subtypes include NSCLC, melanoma, neuroblastoma, glioblastoma, liposarcoma, and mantle cell lymphoma.
  • a compound of the disclosure is used in combination with at least one additional pharmaceutically active agent that alleviates CDKN2A (cyclin-dependent kinase inhibitor 2A) deletion.
  • a compound of the disclosure is used in combination with at least one additional pharmaceutically active agent that alleviates CDK9 (cyclin-dependent kinase 9) abnormality.
  • a compound of the disclosure is used in combination with a CDK2, CDK7, and/or CDK9 inhibitor.
  • a compound of the disclosure is used in combination with a CDK2, CDK7, or CDK9 inhibitor, such as seliciclib, voruciclib, or milciclib.
  • a compound of the disclosure is used in combination with a CDK inhibitor, such as dinaciclib, roniciclib (Kisqali®), or briciclib.
  • a compound of the disclosure is used in combination with at least one additional pharmaceutically-active agent that alleviates CDKN2A (cyclin-dependent kinase inhibitor 2A) deletion.
  • CDKN2A cyclin-dependent kinase inhibitor 2A
  • ATM regulators A compound of the disclosure can be used in combination with one or more anti-cancer agent that regulates the ATM (upregulate or downregulate).
  • the compounds described herein can synergize with one or more ATM regulators.
  • one or more of the compounds described herein can synergize with all ATM regulators.
  • AKT inhibitors In some embodiments, a compound of the disclosure is used in combination with one or more anti-cancer agent that inhibits the AKT (protein kinase B (PKB)). In some embodiments the compounds described herein can synergize with one or more AKT inhibitors. n. Combination treatment with other anti-cancer agents [0225] In some examples, a compound of the disclosure is used in combination with at least one anti- cancer agent that alleviates PTEN (phosphatase and tensin homolog) deletion. In some examples, a compound of the disclosure is used in combination with at least one anti-cancer agent that alleviates Wip- 1Alpha over expression.
  • PTEN protein kinase B
  • a compound of the disclosure is used in combination with at least one anti-cancer agent that is a Nucleoside metabolic inhibitor.
  • nucleoside metabolic inhibitors include capecitabine, gemcitabine and cytarabine (Arac).
  • Arac cytarabine
  • a compound of the disclosure or a pharmaceutical composition comprising a compound of the disclosure and at least one anti-cancer agent as disclosed herein can be administered simultaneously (i.e., simultaneous administration) or sequentially (i.e., sequential administration).
  • a compound of the disclosure and the at least one anti-cancer agent described herein are administered simultaneously, either in the same composition or in separate compositions.
  • the compound and the at least one anti- cancer agent described herein may be contained in the same composition (e.g., a composition comprising both the compound and the at least one anti-cancer agent) or in separate compositions (e.g., the compound is contained in one composition and the at least one anti-cancer agent is contained in another composition).
  • the compound and the at least one anti-cancer agent are administered sequentially, i.e., the compound is administered either prior to or after the administration of the anti- cancer agent.
  • the compound is administered before the anti-cancer agent.
  • the anti-cancer agent described herein is administered before the compound.
  • the compound and the anti-cancer agent described herein are contained in separate compositions, which may be contained in the same or different packages.
  • the administration of the compound and the anti-cancer agent described herein are concurrent, i.e., the administration period of the compounds and that of the anti-cancer agent overlap with each other.
  • the administration of the compounds and the anti-cancer agent described herein are non-concurrent.
  • the administration of the compound is terminated before the anti-cancer agent described herein is administered.
  • the administration of the anti-cancer agent described herein is terminated before the compound is administered.
  • the time period between these two non-concurrent administrations can range from being hours apart to being days apart to being weeks apart.
  • the dosing frequency of the compound and the at least one anti-cancer agent described herein may be adjusted over the course of the treatment, based on the judgment of the administering physician.
  • the compound and the at least one anti-cancer agent described herein can be administered at different dosing frequency or intervals.
  • the compound can be administered weekly, while the at least one anti-cancer agent described herein can be administered more or less frequently.
  • the compound can be administered twice weekly, while the at least one anti-cancer agent described herein can be administered more or less frequently.
  • the compound and the at least one anti-cancer agent described herein can be administered using the same route of administration or using different routes of administration.
  • a therapeutically-effective amount of a compound and/or the anti-cancer agent described herein for use in therapy can vary with the nature of the condition being treated, the length of treatment time desired, the age and the condition of the patient, and can be determined by the attending physician.
  • the dosage of the compound when a compound of the disclosure is administered in combination with at least one anti-cancer agent described herein, can be given a lower dosage than when the compound is administered alone.
  • the dosage of a compound of the disclosure in combination therapy can be from about 1 mg/kg to about 20 mg/kg. In some embodiments, the dosage of a compound of the disclosure in combination therapy can be from about 5 mg/kg to about 10 mg/kg..
  • the dosage of a compound of the disclosure in combination therapy can be in an amount of about 0.5 mg/kg; about 1 mg/kg; about 2 mg/kg; about 3 mg/kg; about 4 mg/kg; about 5 mg/kg; about 6 mg/kg; about 7 mg/kg; about 8 mg/kg; about 9 mg/kg; or about 10 mg/kg.
  • the dosage of the compound of the disclosure in combination therapy with at least one additional therapeutic agent can be at least 5% less than the dose of the compound of the disclosure administered alone, or at least 10% less, at least 15% less, at least 20% less, at least 25% less, at least 30% less, at least 35% less, at least 40% less, at least 45% less, at least 50% less, at least 55% less, at least 60% less, at least 65% less, at least 70% less, or at least 75% less than the dose of the compound of the disclosure administered alone.
  • the dosage of the at least one additional anti-cancer agent can be given a lower dosage than when the anti-cancer agent is administered alone.
  • the dosage of the at least one anti-cancer agent in combination therapy can be from about 50 ⁇ g to about 100 ⁇ g; from about 100 ⁇ g to about 150 ⁇ g; from about 150 ⁇ g to about 200 ⁇ g; from about 200 ⁇ g to about 250 ⁇ g; from about 250 ⁇ g to about 300 ⁇ g; from about 300 ⁇ g to about 350 ⁇ g; from about 350 ⁇ g to about 400 ⁇ g; from about 400 ⁇ g to about 450 ⁇ g; from about 450 ⁇ g to about 500 ⁇ g; from about 500 ⁇ g to about 600 ⁇ g; from about 600 ⁇ g to about 700 ⁇ g; from about 700 ⁇ g to about 800 ⁇ g; from about 800 ⁇ g to about 900 ⁇ g; or from about 900 ⁇ g to about 1000 ⁇ g.
  • the dosage of the at least one anti-cancer agent in combination therapy can be from about 100 ⁇ g to about 150 ⁇ g. In some embodiments, the dosage of the at least one anti-cancer agent in combination therapy can be from about 150 ⁇ g to about 200 ⁇ g. In some embodiments, the dosage of the at least one additional anti-cancer agent in combination therapy can be from about 200 ⁇ g to about 250 ⁇ g.
  • the dosage of the at least one anti-cancer agent in combination therapy can be in an amount of about 50 ⁇ g; about 100 ⁇ g; about 150 ⁇ g; about 200 ⁇ g; about 250 ⁇ g; about 300 ⁇ g; about 350 ⁇ g; about 400 ⁇ g; about 450 ⁇ g; or about 500 ⁇ g. In some embodiments, the dosage of the at least one anti-cancer agent in combination therapy can be in an amount of about 200 ⁇ g.
  • the dosage of the at least one anti-cancer agent in combination therapy can be from about 1 mg/kg to about 5 mg/kg; from about 5 mg/kg to about 25 mg/kg; from about 25 mg/kg to about 50 mg/kg; from about 50 mg/kg to about 75 mg/kg; from about 75 mg/kg to about 100 mg/kg; from about 100 mg/kg to about 150 mg/kg; from about 150 mg/kg to about 200 mg/kg; from about 200 mg/kg to about 250 mg/kg; from about 250 mg/kg to about 300 mg/kg; from about 300 mg/kg to about 350 mg/kg; from about 350 mg/kg to about 400 mg/kg; from about 400 mg/kg to about 450 mg/kg; from about 450 mg/kg to about 500 mg/kg; from about 500 mg/kg to about 600 mg/kg; from about 600 mg/kg to about 700 mg/kg; from about 700 mg/kg to about 800 mg/kg; from about 800 mg/kg to about 900 mg/kg; or from about 900
  • the dosage of the at least one anti- cancer agent in combination therapy can be from about 1 mg/kg to about 5 mg/kg. In some embodiments, the dosage of the at least one anti-cancer agent in combination therapy can be from about 100 mg/kg to about 150 mg/kg. In some embodiments, the dosage of the at least one additional therapeutic agent in combination therapy can be from about 200 mg/kg to about 250 mg/kg.
  • the dosage of the at least one anti-cancer agent in combination therapy can be at least 5% less than the dose of the at least one anti-cancer agent administered alone, or at least 10% less, at least 15% less, at least 20% less, at least 25% less, at least 30% less, at least 35% less, at least 40% less, at least 45% less, at least 50% less, at least 55% less, at least 60% less, at least 65% less, at least 70% less, or at least 75% less than the dose of the at least one anti-cancer agent administered alone.
  • the dosage of the compound of the disclosure administered in combination therapy can be from about 1 mg/kg to about 20 mg/kg; and the dosage of the at least one anti-cancer agent in combination therapy can be from about 1 mg/kg to about 500 mg/kg. In some embodiments, the dosage of the compound of the disclosure administered in combination therapy can be from about 5 mg/kg to about 10 mg/kg; and the dosage of the at least one anti-cancer agent in combination therapy can be from about 1 mg/kg to about 250 mg/kg. [0241] In some embodiments, the dosage of the compound of the disclosure administered in combination therapy can be about 1 mg/kg; and the dosage of the at least one anti-cancer agent in combination therapy can about 5 mg/kg.
  • the dosage of the compound of the disclosure administered in combination therapy can be about 2 mg/kg; and the dosage of the at least one anti-cancer agent in combination therapy can about 5 mg/kg. In some embodiments, the dosage of the compound of the disclosure administered in combination therapy can be about 4 mg/kg; and the dosage of the at least one anti-cancer agent in combination therapy can about 5 mg/kg. In some embodiments, the dosage of the compound of the disclosure administered in combination therapy can be about 6 mg/kg; and the dosage of the at least one anti-cancer agent in combination therapy can about 5 mg/kg. In some embodiments, the dosage of the compound of the disclosure administered in combination therapy can be about 8 mg/kg; and the dosage of the at least one anti-cancer agent in combination therapy can about 5 mg/kg.
  • the dosage of the compound of the disclosure administered in combination therapy can be from about 1 mg/kg to about 20 mg/kg; and the dosage of the at least one anti-cancer agent in combination therapy can be from about 100 ⁇ g to about 500 ⁇ g. In some embodiments, the dosage of the compound of the disclosure administered in combination therapy can be from about 5 mg/kg to about 10 mg/kg; and the dosage of the at least one anti-cancer agent in combination therapy can be from about 100 ⁇ g to about 500 ⁇ g. [0243] In some embodiments, the dosage of the compound of the disclosure administered in combination therapy can be about 1 mg/kg; and the dosage of the at least one anti-cancer agent in combination therapy is about 200 ⁇ g.
  • the dosage of the compound of the disclosure administered in combination therapy is about 2 mg/kg; and the dosage of the at least one anti-cancer agent in combination therapy is about 200 ⁇ g. In some embodiments, the dosage of the compound of the disclosure administered in combination therapy is about 4 mg/kg; and the dosage of the at least one anti-cancer agent in combination therapy is about 200 ⁇ g. In some embodiments, the dosage of the compound of the disclosure administered in combination therapy is about 6 mg/kg; and the dosage of the at least one anti- cancer agent in combination therapy is about 200 ⁇ g. In some embodiments, the dosage of the compound of the disclosure administered in combination therapy is about 8 mg/kg; and the dosage of the at least one anti-cancer agent in combination therapy is about 200 ⁇ g.
  • the dosage of the compound of the disclosure administered in combination therapy can be from about 1 mg/kg to about 20 mg/kg; and the dosage of anti-PD-1 agent as an anti- cancer agent in combination therapy is about 200 ⁇ g. In some embodiments, the dosage of the compound of the disclosure administered in combination therapy can be from about 5 mg/kg to about 10 mg/kg; and the dosage of anti-PD-1 agent as an anti-cancer agent in combination therapy is about 200 ⁇ g. [0245] In some embodiments, the dosage of the compound of the disclosure administered in combination therapy is about 1 mg/kg or about 100 mg; and the dosage of anti-PD-1 agent as an anti-cancer agent in combination therapy is about 200 ⁇ g.
  • the dosage of the compound of the disclosure administered in combination therapy is about 2 mg/kg or about 150 mg; and the dosage of anti-PD-1 agent as an anti-cancer agent in combination therapy is about 200 ⁇ g. In some embodiments, the dosage of the compound of the disclosure administered in combination therapy is about 4 mg/kg or about 300 mg; and the dosage of anti-PD-1 agent as an anti-cancer agent in combination therapy is about 200 ⁇ g. In some embodiments, the dosage of the compound of the disclosure administered in combination therapy is about 6 mg/kg or about 400 mg; and the dosage of anti-PD-1 agent as an anti-cancer agent in combination therapy is about 200 ⁇ g..
  • the dosage of the compound of the disclosure administered in combination therapy is about 8 mg/kg or about 500 mg; and the dosage of anti-PD-1 agent as an anti-cancer agent in combination therapy is about 200 ⁇ g.
  • the dosage of the compound of the disclosure administered in combination therapy can be from about 1 mg/kg to about 20 mg/kg; and the dosage of anti-CD20 agent as an anti- cancer agent in combination therapy is about 200 ⁇ g.
  • the dosage of the compound of the disclosure administered in combination therapy can be from about 5 mg/kg to about 10 mg/kg; and the dosage of anti- CD20 agent as an anti-cancer agent in combination therapy is about 200 ⁇ g.
  • the dosage of the compound of the disclosure administered in combination therapy is about 1 mg/kg; and the dosage of anti- CD20 agent as an anti-cancer agent in combination therapy is about 200 ⁇ g. In some embodiments, the dosage of the compound of the disclosure administered in combination therapy is about 2 mg/kg; and the dosage of anti- CD20 agent as an anti- cancer agent in combination therapy is about 200 ⁇ g. In some embodiments, the dosage of the compound of the disclosure administered in combination therapy is about 4 mg/kg; and the dosage of anti- CD20 agent as an anti-cancer agent in combination therapy is about 200 ⁇ g.
  • the dosage of the compound of the disclosure administered in combination therapy is about 6 mg/kg; and the dosage of anti- CD20 agent as an anti-cancer agent in combination therapy is about 200 ⁇ g. In some embodiments, the dosage of the compound of the disclosure administered in combination therapy is about 8 mg/kg; and the dosage of anti- CD20 agent as an anti-cancer agent in combination therapy is about 200 ⁇ g [0248]
  • a pharmaceutically-acceptable amount of a compound of the disclosure can be administered to a subject 1, 2, 3, 4, or 5 times a day. In some embodiments, a pharmaceutically- acceptable amount of a compound of the disclosure can be administered to a subject once a day.
  • a pharmaceutically-acceptable amount of a compound of the disclosure can be administered to a subject twice a day. In some embodiments, a pharmaceutically-acceptable amount of a compound of the disclosure can be administered to a subject three times a day. [0249] In some embodiments, a pharmaceutically-acceptable amount of a compound of the disclosure can be administered to a subject 1, 2, 3, 4, or 5 times a day once every 1, 2, 3, 4, 5, 6, or 7 days. In some embodiments, a pharmaceutically-acceptable amount of a compound of the disclosure can be administered to a subject once a day once every 3 days. In some embodiments, a pharmaceutically-acceptable amount of a compound of the disclosure can be administered to a subject twice a day once every 3 days.
  • a pharmaceutically-acceptable amount of a compound of the disclosure can be administered to a subject 1, 2, 3, 4, or 5 times a day once every 7 days. In some embodiments, a pharmaceutically- acceptable amount of a compound of the disclosure can be administered to a subject once a day once every 7 days. In some embodiments, a pharmaceutically-acceptable amount of a compound of the disclosure can be administered to a subject twice a day once every 7 days. [0250] In some embodiments, a pharmaceutically-acceptable amount of a compound of the disclosure can be administered to a subject 1, 2, 3, 4, or 5 times a day once every 1, 2, 3, 4, 5, 6, or 7 days for 1 to 50 doses.
  • a pharmaceutically-acceptable amount of a compound of the disclosure can be administered to a subject 1, 2, 3, 4, or 5 times a day once every 1, 2, 3, 4, 5, 6, or 7 days for about 5 doses. In some embodiments, a pharmaceutically-acceptable amount of a compound of the disclosure can be administered to a subject 1, 2, 3, 4, or 5 times a day once every 1, 2, 3, 4, 5, 6, or 7 days for about 10 doses. In some embodiments, a pharmaceutically-acceptable amount of a compound of the disclosure can be administered to a subject 1, 2, 3, 4, or 5 times a day once every 1, 2, 3, 4, 5, 6, or 7 days for about 15 doses.
  • a pharmaceutically-acceptable amount of a compound of the disclosure can be administered to a subject 1, 2, 3, 4, or 5 times a day once every 1, 2, 3, 4, 5, 6, or 7 days for about 20 doses. In some embodiments, a pharmaceutically-acceptable amount of a compound of the disclosure can be administered to a subject 1, 2, 3, 4, or 5 times a day once every 1, 2, 3, 4, 5, 6, or 7 days for about 25 doses. In some embodiments, a pharmaceutically-acceptable amount of a compound of the disclosure can be administered to a subject 1, 2, 3, 4, or 5 times a day once every 1, 2, 3, 4, 5, 6, or 7 days for about 30 doses.
  • a pharmaceutically-acceptable amount of a compound of the disclosure can be administered to a subject 1, 2, 3, 4, or 5 times a day once every 1, 2, 3, 4, 5, 6, or 7 days for about 35 doses.
  • a pharmaceutically-acceptable amount of a compound of the disclosure can be administered to a subject once a day every 7 days for about 5 doses.
  • a pharmaceutically-acceptable amount of a compound of the disclosure can be administered to a subject once a day every 7 days for about 10 doses.
  • a pharmaceutically-acceptable amount of a compound of the disclosure can be administered to a subject twice a day every 7 days for about 15 doses.
  • a pharmaceutically-acceptable amount of a compound of the disclosure can be administered to a subject once a day every 3 days for about 20 doses. In some embodiments, a pharmaceutically-acceptable amount of a compound of the disclosure can be administered to a subject once a day every 3 days for about 35 doses. [0252] In some embodiments, a pharmaceutically-acceptable amount of a compound of the disclosure can be administered to a subject twice a day every 7 days for about 5 doses. In some embodiments, a pharmaceutically-acceptable amount of a compound of the disclosure can be administered to a subject twice a day every 7 days for about 15 doses.
  • compositions for combination treatment are administered within a single pharmaceutical composition.
  • the compounds of the disclosure and the anti-cancer agent described herein can be provided in a single unit dosage form for being taken together.
  • the pharmaceutical composition further comprises a pharmaceutically-acceptable diluent or carrier.
  • the compounds of the disclosure and the anti-cancer agent described herein are administered within different pharmaceutical compositions.
  • the compounds of the disclosure and the anti-cancer agent described herein can be provided in a single unit dosage as separate entities (e.g., in separate containers) to be administered simultaneously or with a certain time difference.
  • the compounds of the disclosure and the anti-cancer agent described herein can be administered via the same route of administration. In some embodiments, the compounds of the disclosure and the anti-cancer agent described herein can be administered via the different route of administration. In some embodiments, a compound of the disclosure and the anti-cancer agent are administered orally. In some embodiments, a compound of the disclosure is administered orally, and the anti-cancer agent is not administered orally. In some embodiments, a compound of the disclosure is not administered orally, and the anti-cancer agent is administered orally.
  • Treatment of a condition by administering a compound of the disclosure in combination with an anti-cancer agent can increase a median survival time of a subject compared to subjects who do not receive the combination therapy.
  • a median survival time of a first patient population receiving the combination therapy can be greater than a median survival time of a second patient population that does not receive any cancer therapy.
  • a median survival time of a first patient population receiving the combination therapy can be greater than a median survival time of a second patient population that receives therapy with a compound of the disclosure alone.
  • a median survival time of a first patient population receiving the combination therapy can be greater than a median survival time of a second patient population that receives therapy with the anti- cancer agent alone.
  • a median survival time of a first patient population receiving the combination therapy can be greater than a median survival time of a second patient population not receiving the combination therapy (e.g., no therapy, a compound of the disclosure alone, or the anti-cancer agent alone) by at least about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 110%, about 120%, about 130%, about 140%, about 150%, about 160%, about 170%, about 180%, about 190%, about 200%, about 210%, about 220%, about 230%, about 240%, about 250%, about 260%, about 270%, about 280%, about 290%, about 300%, about 310%, about 320%, about 330%, about 340%, about 350%, about 360%, about 370%, about 380%, about 390%, about 400%, about 410%, about 420%, about 430%, about 440%, about 450%, about 460%, about 470%, about 480%, about 490%, or about 500%.
  • a median survival time of a first patient population receiving the combination therapy can be greater than a median survival time of a second patient population not receiving the combination therapy by at least about 50%. In some embodiments, a median survival time of a first patient population receiving the combination therapy can be greater than a median survival time of a second patient population not receiving the combination therapy by at least about 100%. In some embodiments, a median survival time of a first patient population receiving the combination therapy can be greater than a median survival time of a second patient population not receiving the combination therapy by at least about 150%. In some embodiments, a median survival time of a first patient population receiving the combination therapy can be greater than a median survival time of a second patient population not receiving the combination therapy by at least about 200%.
  • Methods of treatment Provided herein is a method of treating cancer in a subject in need thereof, the method comprising: (i) administering to the subject a therapeutically-effective amount of a compound that blocks SUMOylation in the subject; and (ii) administering to the subject a therapeutically-effective amount of an anti-cancer agent that functions through a pathway other than SUMOylation.
  • a compound of the disclosure comprises a substituted 4,5,6,7-tetrahydrothieno[2,3-c]pyridine group, wherein the compound blocks SUMOylation.
  • the compound binds to Uba2.
  • the compound has an inhibitory effect on activating enzymes (E1) of SUMO.
  • the cancer is ovarian cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is AML. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is a lymphoma. In some embodiments, the subject is human. [0259] In some embodiments, the administering of the compound is oral. In some embodiments, the administering of the compound is subcutaneous. In some embodiments, the administering of the compound is topical. [0260] In some embodiments, the therapeutically-effective amount of the compound is from about 1 mg/kg to about 20 mg/kg. In some embodiments, the therapeutically-effective amount of the compound is from about 5 mg to about 10 mg..
  • the therapeutically-effective amount of the compound is about 50 mg, about 5100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg. In some embodiments, the therapeutically- effective amount of the compound is about 150 mg. In some embodiments, the therapeutically-effective amount of the compound is about 200 mg. In some embodiments, the therapeutically-effective amount of the compound is about 300 mg. In some embodiments, the therapeutically-effective amount of the compound is about 400 mg. [0261] In some embodiments, the anti-cancer agent is a small molecule. In some embodiments, the anti- cancer agent is an antibody. [0262] In some embodiments, the anti-cancer agent is an immune checkpoint inhibitor.
  • the immune checkpoint inhibitor is an anti-PD-1 agent.
  • the anti-PD- 1 agent is nivolumab.
  • the anti-PD-1 agent is pembrolizumab.
  • the anti-PD-1 agent is cemiplimab.
  • the immune checkpoint inhibitor is an anti-PD-L1 agent.
  • the anti-PD-L1 agent is atezolizumab.
  • the anti-PD-L1 agent is avelumab.
  • the anti-PD-L1 agent is durvalumab.
  • the administering of the anti-cancer agent is oral.
  • the administering of the anti-cancer agent is subcutaneous. In some embodiments, the administering of the anti-cancer agent is topical. In some embodiments, the therapeutically-effective amount of the anti-cancer agent is from about 5 mg/kg to about 500 mg/kg. In some embodiments, the therapeutically-effective amount of the anti-cancer agent is from about 10 ⁇ g to about 500 ⁇ g. In some embodiments, the therapeutically-effective amount of the anti-cancer agent is about 200 ⁇ g. [0263] In some embodiments, the anti-cancer agent is an anti-CD20 antibody.
  • anti-CD-20 antibodies include rituximab (Mabthera®/ Rituxan®), obinutuzumab (Gazyva®), ibritumomab tiuxetan, tositumomab, ofatumumab (Genmab®), ocaratuzumab, ocrelizumab, TRU-015, and veltuzumab.
  • the anti-cancer agent is rituximab.
  • the therapeutically-effective amount of the anti-CD20 antibody is from about 5 mg/kg to about 500 mg/kg.
  • the therapeutically-effective amount of the anti-CD20 antibody is from about 10 ⁇ g to about 500 ⁇ g.
  • the anti-cancer agent is a hypomethylating agent (HMA).
  • HMA hypomethylating agent
  • a compound of the disclosure is used in combination with a HMA, such as azacitidine (Vidaza®, Azadine®) or decitabine (Dacogen®).
  • the therapeutically-effective amount of the HMA is from about 5 mg/kg to about 500 mg/kg.
  • the therapeutically-effective amount of the HMA is from about 0.005 ⁇ M to about 0.500 ⁇ M.
  • Compound A is (S,E)-6-(4-(dimethylamino)but-2-enoyl)-4-(2-(1-ethyl-3-(trifluoromethyl)-1H- pyrazol-4-yl)-3-fluorophenyl)-3-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carbonitrile.
  • EXAMPLE 2 Combination of Compound A and anti-CD-20 agents [rituximab] in subcutaneous mouse lymphoma xenograft model [Raji human B cell] [0267]
  • the anti-tumor efficacy of Compound A in combination with rituximab was evaluated in the subcutaneous Raji human lymphoma xenograft model in female CB17 SCID mice.
  • the overall dosing regimen is included in Table 1.
  • the Raji tumor cells (ATCC, Cat# CCL-86) were maintained in vitro as a suspension culture in RPMI 1640 medium supplemented with 10% heat inactivated fetal bovine serum, 100 U/mL penicillin and 100 ⁇ g/mL streptomycin at 37oC in an atmosphere of 5% CO2 in air.
  • the tumor cells were routinely subcultured twice weekly. The cells growing to a confluency around 70% - 80% were harvested and counted for tumor inoculation.
  • 75 CB17 SCID mice [female, 6-8 weeks old, 18-20g weight] were inoculated subcutaneously at the right flanks with Raji cells for tumor development.
  • mice were kept in individual ventilation cages at constant temperature and humidity with 4 animals in each cage [temperature 20-26 C and 40-70% humidity].
  • 48 mice with tumor sizes ranging from 65-268 mm 3 (average tumor size 147.16 mm3) were selected and assigned into 6 groups using stratified randomization with 8 mice in each group based upon their tumor volumes.
  • mice were treated as follows: Group 1: Vehicle control, p.o., (BIW on D1/4/8/11/14); Group 2: Compound A, 50 mg/kg, p.o., (BIW on D1/4/8/11/14/17); Group 3: Rituximab, 20 mg/kg, i.p., (BIW on D1/4/8/11/14); Group 4: Compound A, 50 mg/kg, p.o.,+ Rituximab, 20 mg/kg, i.p., (BIW on D1/4/8/11/14/17); Group 5: Compound A, 50 mg/kg, p.o., (QD x 17 days); and Group 6: SUMO comparator, 15 mg/kg, i.v., (BIW on D1/4/8/11/14/17).
  • the tumor sizes were used for the calculations of both tumor growth inhibition (TGI) values.
  • TVTreatment_DayN is the average tumor volume of a treatment group on a given day
  • TVTreatment_Day0 is the average tumor volume of the treatment group on the first day of treatment
  • TVVehicle_DayN is the average tumor volume of the vehicle control group on a given day
  • TVVehicle_Day0 is the average tumor volume of the vehicle group on the first day of treatment.
  • Mean tumor volumes over time are shown in Table 2 and tumor growth curves are shown in Figure 1.
  • EXAMPLE 3 Combination of Compound A and a hypomethylating agent (HMA) in AML cell line model [GDM-1 cells and MV4-11]
  • HMA hypomethylating agent
  • Assay Principle This cellular assay measures the viability of leukemia cell lines upon treatment with a SUMO E1 inhibitor, Compound A, and a hypomethylating agent (HMA), decitabine, as single agents, as well as in combination. Cell viability was measured using the Promega CellTiter-Glo Luminescent Cell Viability Assay, which determines the number of viable cells based on the quantitation of ATP (as an indicator of metabolically active cells).
  • AML acute myeloid leukemia
  • GDM-1 Three acute myeloid leukemia (AML) cell lines, including GDM-1, and MV4-11, were first treated with Compound A or decitabine as single treatments to establish single agent IC50s to describe the quantity of compound needed to inhibit 50% of cell viability.
  • cells were treated with both Compound A and decitabine, with 4 to 5 decreasing doses of each compound, to generate a matrix of 25 combinations.
  • Dose response curves and IC50 values were generated, and Zero interaction potency (ZIP) synergy scores were calculated using SynergyFinder 3.0 (https://synergyfinder.fimm.fi/synergy/20220701215205193938/).
  • the ZIP model determines whether combination treatments result in synergistic or additive effects by comparing the potency at specific dose levels between single and combination treatments.
  • the ZIP model determines whether combination treatments result in synergistic or additive effects by comparing the potency at specific dose levels between single and combination treatments.
  • the cell viability of three different AML cells lines were evaluated during single and combination treatment with Compound A and decitabine to determine the efficacy of combination therapy.
  • GDM-1 and MV4-11 cells were plated overnight in white-walled 96-well plates (10,000 cells/well in 100ul total volume). The next day, compounds were diluted in cell culture media and cells were treated with 4 to 5 different doses of Compound A and decitabine (either as single treatment or in combination). Cells were then incubated for 72 hrs.
  • FIG. 1 shows cell viability dose response curves of Compound A alone, along with the combination of escalating doses with decitabine in GDM-1 and MV-411 cells. The IC50 values from each curve, along with the calculated ZIP score are found in Table 4.
  • mice Tumor-immune profiling of CT-26 and Colon 26 syngeneic mouse models reveals mechanism of anti-PD-1 response.
  • BALB/c mice are injected subcutaneously with 1 x 10 5 CT26 cells on Day 0. Beginning day 5, mice are treated with Compound A [50 mpk]. and 250 pg of anti-PD-1 (BioXcell, Clone RMP1-14) or isotype control (BioXcell, Clone 2A3). Subsequently, all mice were continued on study the assigned combination therapy on days 12, 15, and 19.
  • a method of treating a cancer in a subject in need thereof comprising: (i) administering to the subject a therapeutically-effective amount of a compound that blocks SUMOylation in the subject; and (ii) administering to the subject a therapeutically-effective amount of an anti-cancer agent that functions through a pathway other than SUMOylation.
  • Embodiment 2. The method of embodiment 1, wherein the compound binds to Uba2.
  • Embodiment 3 The method of embodiment 1, wherein the compound has an inhibitory effect on activating enzymes (E1) of SUMO.
  • the cancer is selected from acute myeloid leukemia, large B-cell lymphoma, lung squamous cell carcinoma, pancreatic adenocarcoma, esophegeal carcinoma, cervical squamous cell carcinoma, endocervical adenocarcoma, stomach adenocarcinomathymoma, renal cell carcinoma, head and neck squamous cell carcinoma, bladder carcinoma, ovarian cystadenocarcinoma, multiple myeloma, non-Hodgkin’s lymphoma (NHL), and mesothelioma.
  • Embodiment 5 Embodiment 5.
  • Embodiment 6 The method of embodiment 1, wherein the cancer is selected from head and neck squamous cell carcinoma (HNSCC), non-squamous non-small cell lung cancer (NSCLC), cervical cancer, colorectal cancer (CRC), cutaneous melanoma, squamous NSCLC, and small cell lung cancer.
  • HNSCC head and neck squamous cell carcinoma
  • NSCLC non-squamous non-small cell lung cancer
  • CRC colorectal cancer
  • cutaneous melanoma squamous NSCLC
  • small cell lung cancer small cell lung cancer.
  • Embodiment 6 The method of embodiment 1, wherein the cancer is B Cell Lymphoma.
  • Embodiment 7. The method of embodiment 1, wherein the cancer is acute myeloid leukemia.
  • Embodiment 8 The method of embodiment 1, wherein the cancer is colon cancer.
  • Embodiment 9. The method of embodiment 1, wherein the administering of the compound is oral.
  • Embodiment 11 The method of embodiment 1, wherein the subject is human [0289] Embodiment 11. The method of embodiment 1, wherein the therapeutically-effective amount of the compound is from about 100 mg to about 500 mg. [0290] Embodiment 12. The method of any one of embodiments 1-12, wherein the therapeutically- effective amount of the compound is from about 200 mg to about 400 mg. [0291] Embodiment 13. The method of any one of embodiments 1-13, wherein the therapeutically- effective amount of the compound is about 300 mg. [0292] Embodiment 14. The method of any one of embodiments 1-13, wherein the therapeutically- effective amount of the compound is about 200 mg. [0293] Embodiment 15.
  • Embodiment 18 The method of any one of embodiments 1-13, wherein the therapeutically- effective amount of the compound is about 400 mg.
  • Embodiment 18 The method of any one of embodiments 1-17, wherein the anti-cancer agent is a small molecule.
  • Embodiment 19 The method of any one of embodiments 1-17, wherein the anti-cancer agent is an antibody.
  • Embodiment 20 The method of any one of embodiments 1-17, wherein the anti-cancer agent is an immune checkpoint inhibitor.
  • Embodiment 21 The method of any one of embodiments 1-17 or 20, wherein the immune checkpoint inhibitor is an anti-PD-1 agent.
  • Embodiment 22 The method of any one of embodiments 1-13, wherein the therapeutically- effective amount of the compound is about 400 mg.
  • Embodiment 18 The method of any one of embodiments 1-17, wherein the anti-cancer agent is a small molecule.
  • Embodiment 19 The method of any one of embodiments 1-17, wherein the anti-cancer
  • Embodiment 23 The method of any one of embodiments 1-17, 20, or 21, wherein the anti-PD-1 agent is pembrolizumab.
  • Embodiment 24 The method of any one of embodiments 1-17, 20, or 21, wherein the anti-PD-1 agent is cemiplimab.
  • Embodiment 25 The method of any one of embodiments 1-17 or 20, wherein the immune checkpoint inhibitor is an anti-PD-L1 agent.
  • Embodiment 26 Embodiment 26.
  • Embodiment 27 The method of any one of embodiments 1-17, 20, or 25, wherein the anti-PD-L1 agent is atezolizumab.
  • Embodiment 28 The method of any one of embodiments 1-17, 20, or 25, wherein the anti-PD-L1 agent is avelumab.
  • Embodiment 28 The method of any one of embodiments 1-17, 20, or 25, wherein the anti-PD-L1 agent is durvalumab.
  • Embodiment 29 The method of any one of embodiments 1-28, wherein the administering of the anti-cancer agent is oral.
  • Embodiment 30 The method of any one of embodiments 1-28, wherein the administering of the anti-cancer agent is subcutaneous.
  • Embodiment 31 The method of any one of embodiments 1-28, wherein the administering of the anti-cancer agent is topical.
  • Embodiment 32 The method of any one of embodiments 1-31, wherein the therapeutically- effective amount of the anti-cancer agent is from about 1 mg/kg to about 20 mg/kg.
  • Embodiment 33 The method of any one of embodiments 1-31, wherein the therapeutically- effective amount of the anti-cancer agent is from about 10 ⁇ g to about 500 ⁇ g.
  • Embodiment 34 The method of any one of embodiments 1-31 or 33, wherein the therapeutically- effective amount of the anti-cancer agent is about 200 ⁇ g. [0311] Embodiment 35.
  • R 1 is selected from hydrogen, halogen, -C(X 1 )3, -CHX 1 2, -CH2X 1 , -OCX 1 3, -OCH2X 1 , -OCHX 1 2, -CN, -SOn1R 1A , -SOv1NR 1A R 1B , -NHC(O)NR 1A R 1B , -N(O)m1, -NR 1A R 1B , -NHNR 1A R 1B , -C(O)R 1A , -C(O)-OR 1A , -C(O)NR 1A R 1B , -C(O)NHNR 1A R 1B , -OR 1A , -NR 1A SO2R 1B , -NR 1A C(O)R 1B , -NR 1A C(O)OR 1B , -NR 1A OR 1B , -N3, substituted or unsubstituted alky
  • R 3 and R 3 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl or heterocycloalkyl;
  • R 5 is selected from hydrogen, halogen, -CX 5 3, -CHX 5 2, -CH2X 5 , -OCX 5 3, -OCH2X 5 , -OCHX 5 2, -CN, -SOn5R 5A , -SOv5NR 5A R 5B , -NHC(O)NR 5A R 5B , -N(O)m5, -NR 5A R 5B , -NHNR 5A R 5B , -C(O)R 5A , -C(O)-OR 5A , -C(O)NR 5A R 5B , -C(O)NHNR 5A R 5B , -OR 5A , -NR 5A SO2R 5B , -NR 5A C(O)R 5B , -NR
  • Embodiment 36 The method of embodiment 35 wherein l is 1; m is 0; and n is 1.
  • Embodiment 37 The method of embodiment 35 wherein Z is N.
  • Embodiment 38 The method of embodiment 35 wherein ring A is selected from 5-membered heteroaryl, wherein ring A is optionally substituted with one or more substituent groups.
  • Embodiment 39 The method of embodiment 35 R 2 is selected from substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • Embodiment 40 Embodiment 40.
  • ring A is selected from thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, triazolyl and isothiazolyl, wherein ring A is optionally substituted with one or more substituent groups [0317] Embodiment 41.
  • Embodiment 42 The method of embodiment 39 wherein R 2 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted 5- or 6- membered heteroaryl [0319]
  • Embodiment 43 The method of embodiment 42, wherein R 2 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl and substituted or unsubstituted pyridyl [0320]
  • Embodiment 44 Embodiment 44.
  • Embodiment 45 The method of embodiment 35 wherein M is CR 3 R 4 .
  • Embodiment 46 The method of embodiment 35 wherein , .
  • Embodiment 47 The method of embodiment 35 wherein Y is CR 6 R 7 .
  • Embodiment 48 Embodiment 48.
  • R 1 is selected from hydrogen, halogen, -CX 1 3, -CHX 1 2, -CH2X 1 , -OCX 1 3, -OCH2X 1 , -OCHX 1 2, -CN, -SOn1R 1A , -SOv1NR 1A R 1B , -NHC(O)NR 1A R 1B , -N(O)m1, -NR 1A R 1B , -NHNR 1A R 1B , -C(O)R 1A , -C(O)-OR 1A , -C(O)NR 1A R 1B , -C(O)NHNR 1A R 1B , -OR 1A , -NR 1A SO 2 R 1B , -NR 1A C(O)R 1B , -NR 1A C(O)OR 1B , -NR 1A OR 1B , -N3, substituted or unsubstituted alkyl, substituted or
  • Embodiment 49 The method of embodiment 48 wherein ring B is selected from thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, triazolyl and isothiazolyl, wherein Ring B is optionally substituted with one or more substituents.
  • Embodiment 50 The method of embodiment 48 wherein ring B is selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl, wherein ring B is optionally substituted with one or more substituent groups.
  • Embodiment 51 The method of embodiment 50 wherein ring B is selected from [0328] Embodiment 52.
  • Embodiment 53 The method of embodiment 48 wherein W is S.
  • R 10 is selected from hydrogen, fluoro, chloro, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted 6-10 membered aryl, and substituted or unsubstituted 5-10 membered heteroaryl; and R 11 is selected from hydrogen, fluoro, chloro, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C1-6 heteroalkyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted 6-10 membered aryl, and substituted or unsubstituted 5-10 membered heteroaryl.
  • Embodiment 55 The method of any one of embodiments 1-34, wherein the compound is of the formula: wherein R 36 is H, halo, C1-C4 alkyl, C2-C4 alkenyl or C3-C6 cycloalkyl; R 37 is substituted or unsubstituted C2-C4 alkenyl or C2-C4 alkynyl; and R 38 is selected from substituted or unsubstituted nitrogen containing 5-membered heteroaryl, substituted or unsubstituted nitrogen containing 5- or 6- membered partially unsaturated heterocyclyl and substituted or unsubstituted nitrogen containing 6-10 membered heteroaryl; provided R 38 is not 4-pyridyl; or an isomer or stereoisomer of any of the foregoing, or a mixture thereof.
  • Embodiment 56 The method of embodiment 55 wherein R 38 is selected from substituted or unsubstituted nitrogen containing 5-membered heteroaryl selected from pyrazolyl, isoxazolyl, isothiazolyl, pyrrolyl, thiazolyl, triazolyl and imidazolyl; substituted or unsubstituted nitrogen containing 6- membered heteroaryl selected from pyridinyl, pyrimidinyl and pyrazinyl; substituted or unsubstituted nitrogen containing 5-membered partially unsaturated heterocyclyl selected from pyrrolinyl, and imidazolidinyl; and substituted or unsubstituted dihydropyridinyl;.
  • Embodiment 57 The method of embodiment 55 wherein R 36 is selected from chloro, methyl, ethyl, isopropyl, allylyl, and cyclopropyl;.
  • Embodiment 58 Embodiment 58.
  • R 38 is selected from substituted 5- pyrazolyl, substituted 4-pyrazolyl, substituted 1-pyrazolyl, substituted or unsubstituted 4-isoxazolyl, substituted or unsubstituted 4-isothiazolyl, substituted or unsubstituted 3-pyrrolyl, substituted or unsubstituted 5-thiazolyl, substituted or unsubstituted 5-imidazolyl, substituted or unsubstituted 1- imidazolyl, substituted or unsubstituted [1,2,4]triazol-5-yl, substituted or unsubstituted 3-pyridyl, and substituted or unsubstituted 5-pyrimidinyl;.
  • Embodiment 59 The method of embodiment 58 wherein R 38 is selected from 3-trifluoromethyl- pyrazol-4-yl, 1-isopropyl-3-trifluoromethyl-pyrazol-4-yl, 1-ethyl-3-trifluoromethyl-pyrazol-4-yl, 1- methyl-3-difluoromethyl-pyrazol-4-yl, 1-butyl-3-trifluoromethyl-pyrazol-4-yl, 1-methoxymethyl-3- trifluoromethyl-pyrazol-4-yl, 1-propyl-3-trifluoromethyl-pyrazol-4-yl, 1,3-dimethyl-pyrazol-4-yl, 1,3,5- trimethyl-pyrazol-4-yl, 1-methyl-3-cyclopropyl-pyrazol-4-yl, 1-methyl-3-trifluoromethyl-pyrazol-4-yl, 1- ethyl-3-amino-pyrazol-4-yl, 1-ethyl
  • Embodiment 60 The method of embodiment 59 wherein R 38 is selected from 5-pyrimidinyl, 2- methyl-5-pyrimidinyl, 4-methyl-5-pyrimidinyl, 4,6-dimethoxy-5-pyrimidinyl, 4,6-dimethyl-5-pyrimidinyl, 4-triflouromethyl-5-pyrimidinyl, 4-pyrimidinyl, 2-methyl-4-pyrimidinyl, 4-methyl-6-pyrimidinyl, 2,4- dimethyl-6-pyrimidinyl, 3-pyridinyl, 2-pyridinyl, 4-methyl-2-pyridinyl, 2-triflouromethyl-3-pyridinyl, 4- triflouromethyl-3-pyridinyl, 2-methyl-3-pyridinyl, 2,5-dimethyl-3-pyridinyl, 2,6-dimethyl-3-pyridinyl, 2,4-dimethyl-3-pyridinyl, 2-ethyl-3-pyridinyl, 5-
  • Embodiment 61 The method of embodiment 55 wherein R 38 is selected from substituted or unsubstituted tetrahydroquinolinyl, substituted or unsubstituted 1-pyrrolin-3-yl, substituted or unsubstituted 1-imidazolidinyl, and substituted or unsubstituted dihydropyridin-3-yl;.
  • Embodiment 62 The method of embodiment 55 wherein R 38 is selected from substituted or unsubstituted tetrahydroquinolinyl, substituted or unsubstituted 1-pyrrolin-3-yl, substituted or unsubstituted 1-imidazolidinyl, and substituted or unsubstituted dihydropyridin-3-yl;.
  • R 38 is selected from 4-isoquinolinyl, 1- methoxy-4-isoquinolinyl, 1-chloro-4-isoquinolinyl, 6-methyl-4-isoquinolinyl, 1-oxo-2-methyl-4- isoquinolinyl, 3-quinolinyl, 4-quinolinyl, 5-pyrrolopyridinyl, [1,3,3a]-triazainden-5-yl, 1-ethyl-3- pyrrolopyridinyl, and 1-methyl-5-pyrrolopyridinyl; [0339] Embodiment 63.
  • R 37 is selected from ethenyl, fluoroethenyl, propynyl, dialkylaminopropenyl, alkylaminopropenyl, aminopropenyl and nitrogen- containing heterocyclyl-propenyl.
  • R 36 is selected from H, halo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl and C 3 -C 6 cycloalkyl
  • R 37 is substituted or unsubstituted C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl
  • R 41 is selected from H, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, C 1-6 alkylamino-C 1-6 alkyl, C1-6 alkylaminocarbonyl-C1-6 alkyl, aminocarbonyl-C1-6 alkyl, C1-6 alkoxycarbonyl- C1-6 alkyl, carboxy-C1-6 alkyl, C1-6 alkylcarbonylamino-C1-6 alkyl, C1-6 cyanoalkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl,
  • Embodiment 65 The method of embodiment 64, wherein R 41 is selected from H, ethyl, isopropyl, butyl, propyl, methyl, D3-methyl, 1-hydroxyethyl, 2-hydroxymethylethyl, 1-hydroxy-2,2-dimethylethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl, methoxymethyl, methoxyethyl, dimethylaminoethyl, carboxymethyl, carboxyethyl, methoxycarbonylmethyl, dimethylaminocarbonylmethyl, dimethylaminocarbonylethyl, methylaminocarbonylethyl, methylaminocarbonylmethyl, aminocarbonylmethyl, aminocarbonylethyl, aminocarbonyl-1,1-dimethyl, methylcarbonylaminoethyl, 1-methylcarbonylamino-2.2-dimethylethyl, 2-cyano-2-methylethyl, cyanomethyl,
  • Embodiment 66 The method of embodiment 64, wherein R 36 is H, chloro, methyl, ethyl, isopropyl, propenyl, trifluoromethyl, 2-furyl, 2-pyridinyl, or cyclopropyl; or an isomer or stereoisomer of any of the foregoing, or a mixture thereof or a pharmaceutically acceptable salt thereof.
  • Embodiment 67 Embodiment 67.
  • R 37 is selected from ethenyl, fluoroethenyl, fluoropropenyl, propynyl, dialkylaminopropenyl, alkylaminopropenyl, aminopropenyl, substituted or unsubstituted 3-7 membered nitrogen-containing heterocyclyl-ethenyl and substituted or unsubstituted 3-7 membered nitrogen-containing heterocyclyl-propenyl; or an isomer or stereoisomer of any of the foregoing, or a mixture thereof or a pharmaceutically acceptable salt thereof.
  • Embodiment 68 Embodiment 68.
  • R 37 is azetidin-1-ylpropenyl, 1- methylpyrrolidin-2-ylethenyl, dimethylaminopropenyl, methylaminopropenyl, piperidin-1-ylpropenyl, 4- hydroxy-piperidin-1-ylpropenyl, pyrrolidin-1-ylpropenyl, 3-hydroxypyrrolidin-1-ylpropenyl, morpholin- 1-ylpropenyl, or aminopropenyl; or an isomer or stereoisomer of any of the foregoing, or a mixture thereof or a pharmaceutically acceptable salt thereof.
  • Embodiment 69 Embodiment 69.
  • Embodiment 70 The method of embodiment 64, wherein R 43 is selected from H, trifluoromethyl, methyl, ethyl, carboxy, cyano and methylaminocarbonyl; or an isomer or a pharmaceutically acceptable salt thereof.
  • Embodiment 71 Embodiment 71.
  • Embodiment 72 The method of any one of embodiments 1-34 wherein the compound is of the formula: wherein R 1 is substituted or unsubstituted C2-C6 alkenyl, or substituted or unsubstituted C2-C6 alkynyl; R 6 is selected from H, C 1-6 alkyl, C 2-4 alkynyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, C 1-6 alkylamino-C 1- 6 alkyl, C 1-6 alkylaminocarbonyl-C 1-6 alkyl, aminocarbonyl-C 1-6 alkyl, C 1-6 alkoxycarbonyl-C 1-6 alkyl, carboxy-C 1-6 alkyl, C 1-6 alkylcarbonylamino-C 1-6 alkyl, C
  • Embodiment 73 The method of embodiment 72, wherein R 1 is selected from C2-C6 alkenyl, halo- substituted C2-C6 alkenyl; alkoxy substituted C2-C6 alkenyl; dialkylamino substituted C2-C6 alkenyl, alkylamino substituted C 2 -C 6 alkenyl, amino substituted C 2 -C 6 alkenyl, hydroxy substituted amino-C 2 -C 6 alkenyl, phenyl substituted amino-C2-C6 alkenyl, amino substituted C2-C6 alkynyl, dialkylamino substituted C2-C6 alkynyl, alkylamino substituted C2-C6 alkynyl, alkoxy substituted C2-C6 alkynyl, substituted or unsubstituted 3-7 membered nitrogen-containing heterocyclyl- substituted C2-C6 alkynyl, substituted or unsubstituted 3-7 membered
  • Embodiment 74 The method of embodiment 73, wherein R 1 is selected from ethenyl, fluoropropenyl, 3,3-difluoropropenyl, 3,3,3-trifluoropropenyl, 3,3,3-trifluoroprop-1-enyl, alkoxypropenyl, dialkylaminopropenyl, alkylaminopropenyl, aminopropenyl, 3-amino-4-hydroxy-butenyl, 3-amino-4- phenyl-butenyl, dialkylaminobutenyl, alkylaminobutenyl, aminobutenyl, dialkylaminopentenyl, alkylaminopentenyl, aminopentenyl, aminopropynyl, dialkylaminopropynyl, alkylaminopropynyl, methoxypropynyl, substituted or unsubstituted 3-7 membered nitrogen-containing heterocyclyl
  • R 1 is selected from ethenyl, fluoropropenyl, 3,3-difluoropropenyl, 3,3,3-trifluoropropenyl, 3,3,3-trifluoroprop-1-enyl, methoxypropenyl, ethoxypropenyl, aminopropenyl, 3-amino-butenyl, 3-methylamino-butenyl, 3-amino-4- hydroxy-butenyl, 3-methylamino-4-methoxy-butenyl, 3-amino-4-phenyl-butenyl, 3-amino-pentenyl, aminopropynyl, methoxypropynyl, dimethylaminopropenyl, di(d1,d2,d3-methyl)aminopropenyl, diethylaminopropenyl, 3-(N,N-dimethylamino)-3-phenyl-propenyl, 3-(N,N-
  • R 6 is selected from H, ethyl, isopropyl, butyl, propyl, methyl, propynyl, 1-hydroxyethyl, 2-hydroxymethylethyl, 1-hydroxy-2,2-dimethylethyl, 2- hydroxypropyl, 2-hydroxy-2-methylpropyl, methoxymethyl, methoxyethyl, dimethylaminoethyl, carboxymethyl, carboxyethyl, carboxypropyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, ethoxycarbonylpropyl, dimethylaminocarbonylmethyl, dimethylaminocarbonyl-1- ethyl, methylaminocarbonyl-1-ethyl, methylaminocarbonylethyl, methylaminocarbonylmethyl, aminocarbonylmethyl, aminocarbonylethyl, 1-aminocarbonylethyl,
  • Embodiment 80 The method of embodiment 72, wherein R 10 is selected from H, fluoro, methylcarbonylamino, chloro, amino, hydroxy, methyl, difluoromethyl, methylsulfonylamino, and methylaminocarbonylamino; [0357] Embodiment 81.
  • R 11 is H or fluoro;
  • Embodiment 82 The method of embodiment 72, wherein R 6 is ethyl; R 7 is trifluoromethyl; and R 8 is H; [0359] Embodiment 83.
  • Embodiment 72 wherein R 6 is methyl; R 7 is trifluoromethyl; and R 8 is H; [0360] Embodiment 84.
  • R 1 is substituted ethenyl;.
  • Embodiment 87 The method of embodiment 72, wherein R 1 is dimethylaminopropenyl;.
  • Embodiment 88 The method of embodiment 72, wherein R 1 is methylaminopropenyl; or an isomer or stereoisomer of any of the foregoing, or a mixture thereof or a pharmaceutically acceptable salt thereof.
  • Embodiment 89 The method of embodiment 72, wherein R 1 is 3,3-difluoropropenyl; or an isomer or stereoisomer of any of the foregoing, or a mixture thereof or a pharmaceutically acceptable salt thereof.
  • Embodiment 90 Embodiment 90.
  • Embodiment 91 The method of embodiment 72, wherein R 1 is 2-(2-methyl-pyrrolidiny-5- yl)ethenyl; or an isomer or stereoisomer of any of the foregoing, or a mixture thereof or a pharmaceutically acceptable salt thereof.
  • Embodiment 92 Embodiment 92.
  • Embodiment 93 The method of embodiment 72, wherein R 1 is ethylaminopropenyl; or an isomer or stereoisomer of any of the foregoing, or a mixture thereof or a pharmaceutically acceptable salt thereof.
  • Embodiment 94 Embodiment 94.
  • Embodiment 95 The method of embodiment 72, wherein R 1 is 2-(3-fluoropyrrolidiny-5- yl)ethenyl; or an isomer or stereoisomer of any of the foregoing, or a mixture thereof or a pharmaceutically acceptable salt thereof.
  • Embodiment 96 Embodiment 96.
  • Embodiment 97 The method of embodiment 72, wherein R 1 is aminopropenyl; or an isomer or stereoisomer of any of the foregoing, or a mixture thereof or a pharmaceutically acceptable salt thereof.
  • Embodiment 98 The method of embodiment 72, wherein R 9 is fluoro; R 10 is H; and R 11 is H; an isomer or stereoisomer of any of the foregoing, or a mixture thereof or a pharmaceutically acceptable salt thereof.
  • Embodiment 99 The method of any one of embodiments 1-34 wherein the compound is a compound of Table A.

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Abstract

La présente divulgation concerne des méthodes de traitement d'un sujet souffrant d'un cancer à l'aide d'une polythérapie comprenant (i) l'administration au sujet d'une quantité thérapeutiquement efficace d'un composé qui bloque la SUMOylation chez le sujet ; et (ii) l'administration au sujet d'une quantité thérapeutiquement efficace d'un agent anticancéreux qui fonctionne par l'intermédiaire d'une voie autre que la SUMOylation.
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Citations (3)

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WO2021150918A1 (fr) * 2020-01-22 2021-07-29 Oncovalent Therapeutics Inc. Inhibiteurs de 4,5,6,7-tétrahydrothiéno[2,3-c]pyridine sumo et leurs utilisations
US20220177488A1 (en) * 2019-03-19 2022-06-09 Suvalent Therapeutics, Inc. Sumo inhibitor compounds and uses thereof
US20220298171A1 (en) * 2018-07-31 2022-09-22 City Of Hope Sumo inhibitor compounds and uses thereof

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Publication number Priority date Publication date Assignee Title
US20220298171A1 (en) * 2018-07-31 2022-09-22 City Of Hope Sumo inhibitor compounds and uses thereof
US20220177488A1 (en) * 2019-03-19 2022-06-09 Suvalent Therapeutics, Inc. Sumo inhibitor compounds and uses thereof
WO2021150918A1 (fr) * 2020-01-22 2021-07-29 Oncovalent Therapeutics Inc. Inhibiteurs de 4,5,6,7-tétrahydrothiéno[2,3-c]pyridine sumo et leurs utilisations

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