[go: up one dir, main page]

WO2024173761A1 - Combinaisons comprenant des inhibiteurs de mek pour une utilisation dans le traitement du cancer - Google Patents

Combinaisons comprenant des inhibiteurs de mek pour une utilisation dans le traitement du cancer Download PDF

Info

Publication number
WO2024173761A1
WO2024173761A1 PCT/US2024/016100 US2024016100W WO2024173761A1 WO 2024173761 A1 WO2024173761 A1 WO 2024173761A1 US 2024016100 W US2024016100 W US 2024016100W WO 2024173761 A1 WO2024173761 A1 WO 2024173761A1
Authority
WO
WIPO (PCT)
Prior art keywords
optionally substituted
inhibitor
cancer
aliphatic
membered
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2024/016100
Other languages
English (en)
Inventor
Alfredo C. Castro
Sabine K. RUPPEL
Eric HAINES
Michael J. Burke
Thomas A. Wynn
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
ImageneBio Inc
Original Assignee
Ikena Oncology Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ikena Oncology Inc filed Critical Ikena Oncology Inc
Publication of WO2024173761A1 publication Critical patent/WO2024173761A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • 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
    • 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
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the present disclosure relates to compounds useful for inhibiting mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) in combination with other anti-cancer agents, such as a KRAS G12C inhibitor, for treatment of cancer.
  • mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) in combination with other anti-cancer agents, such as a KRAS G12C inhibitor, for treatment of cancer.
  • Activation of the p42/44 MAPK signaling pathway comprising mitogen-activated protein kinase/extracellular signal -regulated kinase (ERK) kinase (MEK)-ERK has been implicated in the pathogenesis and progression of various cancers.
  • the MEK-ERK pathway is often activated by mutation of upstream factors, BRAF or Ras, or by the signals of constitutively activated cell-surface receptors. Inhibition of MEK can be a promising strategy for controlling the growth of tumors, for example, the tumors associated with MEK pathway signaling.
  • the present disclosure provides a method for treating cancer in a patient comprising administering to the patient a therapeutically effective amount of a MEK inhibitor and a KRAS G12C inhibitor.
  • the present disclosure provides a method for treating cancer in a patient comprising administering to the patient a therapeutically effective amount of a MEK inhibitor and a RAS inhibitor.
  • the present disclosure provides a method for treating cancer in a patient comprising administering to the patient a therapeutically effective amount of a MEK inhibitor and an EGFR inhibitor.
  • the present disclosure provides a method for treating cancer in a patient comprising administering to the patient a therapeutically effective amount of a MEK inhibitor and a TEAD inhibitor.
  • the present disclosure provides a method for treating cancer in a patient comprising administering to the patient a therapeutically effective amount of a MEK inhibitor and an anti-HER2 agent.
  • the present disclosure provides a method for treating cancer in a patient comprising administering to the patient a therapeutically effective amount of a MEK inhibitor and a chemotherapeutic agent.
  • exemplary inhibitors showing synergistic effects for use in combination with the MEK inhibitors described herein include mTOR inhibitors, PI3Ka inhibitors, SOS1 inhibitors, and SHP2 inhibitors.
  • a MEK inhibitor is selected from those as described herein.
  • a RAS inhibitor is selected from those as described herein.
  • a KRAS G12C inhibitor is selected from those as described herein.
  • an EGFR inhibitor is selected from those as described herein.
  • a TEAD inhibitor is selected from those as described herein.
  • an anti-HER2 agent is selected from those as described herein.
  • a chemotherapeutic agent is selected from those as described herein.
  • a cancer is selected from those as described herein.
  • FIG. 1 illustrates synergy between compound III-2 and AMG510 in vitro in KRAS G12C mutant lung and pancreatic cancer cell lines.
  • FIG. 2 illustrates synergy between compound III-2 and MRTX849 in vitro in KRASG12C mutant lung and pancreatic cancer cell lines.
  • FIG. 3 illustrates in vitro combination of AMG510 with compound III-2 is superior to combinations with trametinib or VS-6766 (avutometinib) in a KRASG12C mutant lung cell line.
  • FIG. 4 illustrates synergy between compound III-2 and the S0S1 inhibitor BI-3406 in vitro in KRAS mutant lung and pancreatic cancer cell lines.
  • FIG. 5 illustrates synergy between compound III-2 and the SHP2 inhibitor RMC-4550 in vitro in KRAS mutant lung and pancreatic cancer cell lines.
  • FIG. 6 illustrates synergy between compound III-2 and the PI3Kalpha inhibitor inavolisib in vitro in KRAS mutant lung and pancreatic cancer cell lines.
  • FIG. 7 illustrates synergy between compound III-2 and the mTOR inhibitor everolimus in vitro in KRAS mutant lung and pancreatic cancer cell lines.
  • FIG. 8 illustrates synergy between compound III-2 and the EGFR monoclonal antibody cetuximab in vitro in KRAS wild-type and KRAS and BRAF Colorectal cancer cell lines.
  • FIG. 9 illustrates synergy between compound III-2 and a TEAD inhibitor T-l in vitro in mutant colorectal cancer and NRAS mutant melanoma cell lines.
  • FIG. 10 illustrates that MEK inhibitor III-2 inhibits MEK phosphorylation (A) and ERK1/2 phosphorylation (B) for a longer duration compared to trametinib and VS-6766 (avutometinib) following compound washout.
  • FIG. 11 illustrates synergy between compound III-2 and the EGFR/HER2 inhibitor, lapatinib, in vitro in KRAS mutant colorectal cancer cell lines.
  • FIG. 12 illustrates synergy between compound III-2 and the HER2 inhibitor, tucatinib, in vitro in KRAS mutant colorectal cancer cell lines.
  • FIG. 13 illustrates synergy between compound III-2 and the HER2 monoclonal antibody, trastuzumab, in vitro in KRAS mutant pancreatic and lung cancer cell lines, an NRAS mutant melanoma cell line, and a BRAF Class III mutant lung cancer cell line.
  • FIG. 14 illustrates synergy between compound III-2 and the HER2 antibody drug conjugate (ADC), trastuzumab-deruxtecan, in vitro in KRAS mutant pancreatic and lung cancer cell lines, an NRAS mutant melanoma cell line, and a BRAF Class III mutant lung cancer cell line.
  • FIG. 15 illustrates synergy between compound III-2 and the anti-metabolite chemotherapy, gemcitabine, in vitro in KRAS mutant pancreatic cancer cell lines.
  • FIG. 16 illustrates synergy between compound III-2 and the plant alkaloid chemotherapy, paclitaxel, in vitro in KRAS mutant pancreatic cancer cell lines.
  • FIG. 17 illustrates that compound III-2 enhances chemotherapy-induced apoptosis, in vitro in KRAS mutant pancreatic cancer cell lines.
  • FIG. 18 illustrates that compound III-2 enhances chemotherapy-induced apoptosis, in vitro in KRAS mutant colorectal cancer cell lines.
  • a combination of a MEK inhibitor and a KRAS G12C inhibitor demonstrated unexpected synergistic effects in treating cancer.
  • a combination of a MEK inhibitor compound III-2 and exemplary KRAS G12C inhibitors, such as sotorasib and adagrasib showed significant synergy across a variety of cells lines, as determined by Loewe sum of synergy scores, and as described in Example 9.
  • methods and uses for treating cancer comprising administering a MEK inhibitor and a KRAS G12C inhibitor to patients in need thereof.
  • methods and uses for treating cancer comprising administering a MEK inhibitor and a RAS inhibitor to patients in need thereof.
  • a combination of a MEK inhibitor and an EGFR inhibitor also demonstrated unexpected synergistic effects in treating cancer.
  • a combination of a MEK inhibitor compound III-2 and exemplary EGFR inhibitors, such as cetuximab showed significant synergy across a variety of cells lines, as determined by Loewe sum of synergy scores, and as described in Example 10. Accordingly, provided herein are methods and uses for treating cancer comprising administering a MEK inhibitor and an EGFR inhibitor to patients in need thereof.
  • a combination of a MEK inhibitor and a TEAD inhibitor also demonstrated unexpected synergistic effects in treating cancer.
  • a combination of a MEK inhibitor and a TEAD inhibitor also demonstrated unexpected synergistic effects in treating cancer.
  • a combination of a MEK inhibitor and a TEAD inhibitor also demonstrated unexpected synergistic effects in treating cancer.
  • MEK inhibitor compound III-2 and a TEAD inhibitor significant synergy across a variety of cells lines, as determined by Loewe sum of synergy scores, and as described in Example 11. Accordingly, provided herein are methods and uses for treating cancer comprising administering a MEK inhibitor and a TEAD inhibitor, such as the TEAD inhibitor pharmaceutically acceptable salt thereof, to patients in need thereof.
  • a combination of a MEK inhibitor and an HER2 inhibitor also demonstrated unexpected synergistic effects in treating cancer.
  • a combination of a MEK inhibitor compound ITI-2 and exemplary HER2 inhibitors, such as lapatinib (an EGFR/HER2 inhibitor) and tucatinib showed significant synergy across a variety of cells lines, as determined by Loewe sum of synergy scores, and as described in Example 13. Accordingly, provided herein are methods and uses for treating cancer comprising administering a MEK inhibitor and an HER2 inhibitor to patients in need thereof.
  • a combination of a MEK inhibitor and an HER2 monoclonal antibody also demonstrated unexpected synergistic effects in treating cancer.
  • a combination of a MEK inhibitor compound III-2 and an exemplary HER2 monoclonal antibody, such as trastuzumab showed significant synergy across a variety of cells lines, as determined by Loewe sum of synergy scores, and as described in Example 14. Accordingly, provided herein are methods and uses for treating cancer comprising administering a MEK inhibitor and an HER2 monoclonal antibody to patients in need thereof.
  • a combination of a MEK inhibitor and an HER2 antibody drug conjugate also demonstrated unexpected synergistic effects in treating cancer.
  • a combination of a MEK inhibitor compound III-2 and an exemplary HER2 antibody drug conjugate, such as trastuzumab-deruxtecan showed significant synergy across a variety of cells lines, as determined by Loewe sum of synergy scores, and as described in Example 15. Accordingly, provided herein are methods and uses for treating cancer comprising administering a MEK inhibitor and an HER2 antibody drug conjugate to patients in need thereof.
  • a combination of a MEK inhibitor and a chemotherapeutic agent also demonstrated unexpected synergistic effects in treating cancer.
  • a combination of a MEK inhibitor compound III-2 and an anti-metabolite chemotherapeutic agent, such as gemcitabine, or a plant alkaloid chemotherapeutic agent, such as paclitaxel showed significant synergy across a variety of cells lines, as determined by Loewe sum of synergy scores, and as described in Examples 16 and 17, respectively.
  • a combination of a MEK inhibitor compound III-2 and anti-metabolite chemotherapeutic agents such as gemcitabine and 5-FU, or a plant alkaloid chemotherapeutic agent, such as paclitaxel, showed increased apoptosis in PSN-1 cells, as described in Example 18.
  • a combination of a MEK inhibitor compound III-2 and an anti-metabolite chemotherapeutic agent, such as 5-FU, or a topoisomerase inhibitor, such as irinotecan showed increased apoptosis in HCT-116 cells, as described in Example 19. Accordingly, provided herein are methods and uses for treating cancer comprising administering a MEK inhibitor and a chemotherapeutic agent to patients in need thereof.
  • a combination of a MEK inhibitor and other inhibitors such as mTOR inhibitors, PI3Koc inhibitors, S0S1 inhibitors, and SHP2 inhibitors, demonstrated unexpected and significant synergy across a variety of cells lines, as determined by Loewe sum of synergy scores, and as described in Example 9.
  • an MEK inhibitor is selected from those as described herein.
  • a KRAS G12C inhibitor is selected from those as described herein.
  • a RAS inhibitor is selected from those as described herein.
  • an EGFR inhibitor is selected from those as described herein.
  • a TEAD inhibitor is selected from those as described herein.
  • an HER2 inhibitor is selected from those as described herein.
  • an HER2 monoclonal antibody is selected from those as described herein.
  • an HER2 antibody drug conjugate is selected from those as described herein.
  • a chemotherapeutic agent is selected from those as described herein.
  • a cancer is selected from those as described herein.
  • aliphatic or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle,” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule.
  • aliphatic groups contain 1-6 aliphatic carbon atoms.
  • aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms.
  • “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
  • a carbocyclic ring may be a 5-12 membered bicyclic, bridged bicyclic, or spirocyclic ring.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2/f-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).
  • Ci-8 saturated or unsaturated, straight or branched, hydrocarbon chain
  • bivalent Ci-8 (or Ci-e) saturated or unsaturated, straight or branched, hydrocarbon chain refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.
  • alkylene refers to a bivalent alkyl group.
  • An “alkylene chain” is a polymethylene group, /. ⁇ ?., -(CH2) n - wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
  • a substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • alkenylene refers to a bivalent alkenyl group.
  • a substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • cyclopropylenyl refers to a bivalent cyclopropyl group of the following structure:
  • halogen means F, Cl, Br, or I.
  • aryl used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or
  • aryloxyalkyl refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • aryl may be used interchangeably with the term “aryl ring.”
  • aryl refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
  • aryl is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
  • heteroaryl and “heteroar-,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 % electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
  • heteroaryl and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring.
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4/7-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one.
  • heteroaryl group may be mono- or bicyclic.
  • heteroaryl may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted.
  • heteroarylkyl refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.
  • heterocycle As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen may be N (as in 3,4-dihydro- 2/7 pyrrol yl), NH (as in pyrrolidinyl), or + NR (as in N substituted pyrrolidinyl).
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.
  • heterocycle used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 377-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl.
  • a heterocyclic ring may be a 5-12 membered bicyclic, bridged bicyclic, or spirocyclic ring.
  • heterocyclylalkyl refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
  • partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
  • partially unsaturated is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
  • compounds of the disclosure may contain “optionally substituted” moieties.
  • substituted whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • each R° may be substituted as defined below and is independently hydrogen, Ci- 6 aliphatic, -CH 2 Ph, -0(CH 2 )O iPh, -CH 2 -(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of
  • Suitable monovalent substituents on R° are independently halogen, -(CH 2 )o 2 R*, -(haloR*), -(CH 2 )O 2 OH, -(CH 2 )O - 2 OR*, -(CH 2 )O 2 CH(OR’) 2 ; O(haloR’), -CN, -N 3 , -(CH 2 ) 0 2 C(O)R’, -(CH 2 ) O 2 C(O)OH, -(CH 2 ) O 2 C(O)OR*, -(CH 2 )O - 2 SR’, -(CH 2 ) O 2 SH, -(CH 2 )O 2 NH 2 , - (CH 2 )o- 2 NHR*, -(CH 2 ) O 2 NR* 2 , -NO 2 , -SiR%,
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR* 2 ) 2 3 O- wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R* include halogen, -R*, (haloR*), OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH 2 , -NHR*, -NR* 2 , or -NO 2 , wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Ci 4 aliphatic, -CH 2 Ph, -0(CH 2 )o iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -R ⁇ -NR ⁇ -C(O)R f , -C(O)OR t , -C(O)C(O)R t , -C(O)CH 2 C(O)R t , S(O) 2 R f , S(O) 2 NR f 2 , -C(S)NR t 2 , -CCNHjNR ⁇ , or -N(R t )S(O) 2 R t ; wherein each R ⁇ is independently hydrogen, C1-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5- 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ⁇ taken together with their intervening atom(s
  • Suitable substituents on the aliphatic group of R are independently halogen, -R*, (haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH 2 , -NHR*, -NR* 2 , or NO 2 , wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, -CH 2 Ph, -0(CH 2 )o iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al.et al.et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pec
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (Ci ⁇ 4alkyl)4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this disclosure.
  • Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present disclosure.
  • the term “provided compound” refers to any MEK inhibitor genus, subgenus, and/or species set forth herein.
  • the terms “inhibitor” or “MEK inhibitor” or “MEK antagonist” are defined as a compound that binds to and/or inhibits MEK with measurable affinity. In some embodiments, inhibition in the presence of a MEK inhibitor or a MEK antagonist is observed in a dose-dependent manner.
  • the measured signal (e.g., signaling activity or biological activity) is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% lower than the signal measured with a negative control under comparable conditions.
  • an inhibitor has an IC50 and/or binding constant of less than about 100 pM, less than about 50 pM, less than about 1 pM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.
  • measurable affinity and “measurably inhibit,” as used herein, means a measurable change or inhibition in MEK activity between a sample comprising a compound of the present disclosure, or composition thereof, and MEK, and an equivalent sample comprising MEK, in the absence of said compound, or composition thereof.
  • a “RAS inhibitor” refers to any inhibitor or blocker or antagonist that binds to and/or inhibits signaling through RAS.
  • a RAS inhibitor is a KRAS G12C on-state inhibitor.
  • KRAS G12C on-state inhibitors include RMC-6291 and RMC-4998.
  • a RAS inhibitor is a pan-RAS inhibitor.
  • pan-RAS inhibitors include RMC-6236 and RMC-7977.
  • a RAS inhibitor is a pan-KRAS inhibitor.
  • Non-limiting examples of pan-KRAS inhibitors include BI-2493, BI-3406, and BI-2865.
  • a “KRAS G12C inhibitor” refers to any inhibitor or blocker or antagonist that binds to and/or inhibits signaling through KRAS.
  • a KRAS G12C inhibitor is selected from adagrasib (KRAZATI®, Mirati Therapeutics), sotorasib (LUMAKRAS® and I..UMYKRAS®, Amgen), or a pharmaceutically acceptable salt and/or solvate of any of the foregoing.
  • KRAS G12C inhibtiors for use in the methods and uses described herein include, but are not limited to, JDQ-443 (Novartis AG), D-1553 (Inventisbio Shanghai), GF-105 (GenFleet Therapeutics), GH-35 (Suzhou GenHouse Bio Co.), JAB-21822 (Jacobio Pharmaceuticals), JMKX-001899 (Shanghi Jiyu Pharmaceuticals), TAS-119 (Taiho Pharmaceuticals), XNW-14010 (Suzhou Sinovent Pharmaceuticals), YL-15293 (Shanghai Yingli Pharmaceuticals), ZG-19018 (Suzhou Zelgen Biopharma), BEBT-607 (Guangzhou Bibet Pharmaceuticals), BI-1701963 (Forma Therapeutics Holdings), BI-1823911 (Boehringer Ingelheim Gmbh), BPI-421286 (Betta Pharmaceuticals), D3S-001 (D3 Bio), ERAS-3490 (Reg
  • an U EGFR inhibitor refers to any inhibitor or blocker or antagonist that binds to and/or inhibits epidermal growth factor receptor (EGFR).
  • an EGFR inhibitor is selected from those as described in Ayati “"A review on progression of epidermal growth factor receptor (EGFR) inhibitors as an efficient approach in cancer targeted therapy,” Bioorganic Chemistry 2020, 99: 10381 1 , the contents of which are incorporated herein by reference in their entirety.
  • an EGFR inhibitor is selected from cetuximab, necitumumab, panitumumab, zalutumumab, nimotuzumab, and matuzumab.
  • an EGFR inhibitor is cetuximab.
  • an EGFR inhibitor is necitumumab.
  • an EGFR inhibitor is panitumumab.
  • an EGFR inhibitor is zalutumumab.
  • an EGFR inhibitor is nimotuzumab.
  • an EGFR inhibitor is matuzumab.
  • an EGFR inhibitor is selected from osimertinib, gefitinib, erlotinib, lapatinib, neratinib, vandetanib, afatinib, brigatinib, dacomitinib, and icotinib.
  • an EGFR inhibitor is osimertinib.
  • an EGFR inhibitor is gefitinib.
  • an EGFR inhibitor is erlotinib.
  • an EGFR inhibitor is lapatinib.
  • an EGFR inhibitor is neratinib.
  • an EGFR inhibitor is vandetanib. In some embodiments, an EGFR inhibitor is afatinib. In some embodiments, an EGFR inhibitor is brigatinib. In some embodiments, an EGFR inhibitor is dacomitinib. In some embodiments, an EGFR inhibitor is icotinib. [0071] In some embodiments, an EGFR inhibitor is a “1 st generation EGFR tyrosine kinase inhibitor” (“1st generation TKI”).
  • a 1 st generation TKI refers to reversible EGFR inhibitors, such as gefitinib and erlotinib, which are effective in first-line treatment of, for example, NSCLC harboring EGFR activating mutations, such as deletions in exon 19 and exon 21 L858R mutation.
  • an EGFR inhibitor is a “2nd generation EGFR tyrosine kinase inhibitor” (“2nd generation TKI”).
  • a 2 nd generation TKI refers to covalent irreversible EGFR inhibitors, such as afatinib and dacomitib, which are effective in first-line treatment of NSCLC harboring EGFR activating mutations, such as deletions in exon 19 and exon 21 L858R mutation.
  • an EGFR inhibitor is a “3rd generation EGFR tyrosine kinase inhibitor” (“3rd generation TKI”).
  • a 3rd generation TKI refers to covalent irreversible EGFR inhibitors, such as osimertinib and lazertinib, which are selective to the EGFR activating mutations, such as deletions in exon 19 and exon 21 L858R, alone or in combination with T790M mutation, and have lower inhibitory activity against wild-type EGFR.
  • TEAD inhibitor or “TEAD antagonist” are defined as a compound that binds to and/or inhibits TEAD with measurable affinity. In some embodiments, inhibition in the presence of a TEAD inhibitor or a TEAD antagonist is observed in a dosedependent manner.
  • the measured signal (e.g., signaling activity or biological activity) is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% lower than the signal measured with a negative control under comparable conditions.
  • an inhibitor has an IC50 and/or binding constant of less than about 100 pM, less than about 50 pM, less than about 1 pM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.
  • an “anti-HER2 agent” refers to any inhibitor or blocker or antagonist that binds to and/or inhibits the HER2 (Human epidermal growth factor receptor) pathway.
  • an anti-HER2 agent is an HER2 inhibitor.
  • Non-limiting examples of HER2 inhibitors include lapatinib, tucatinib, and neratinib.
  • an anti-HER2 agent is an HER2 monoclonal antibody.
  • Non-limiting examples of HER2 monoclonal antibodies include trastuzumab, pertuzumab, and margetuzumab.
  • an anti-HER2 agent is a HER2 antibody drug conjugate.
  • Non-limiting examples of HER2 antibody drug conjugates include trastuzumab-deruxtecan and trastuzumab-emtansine.
  • chemotherapeutic agent is a subset of the term “cytotoxic agent” and means specifically chemical agents that exert anti -neoplastic effects, preferably directly on the tumor cell, and less indirectly through mechanisms such as biological response modification as well as to increase apoptosis.
  • a chemotherapeutic agent is an alkylating agent
  • alkylating agents include nitrogen mustards, such as cyclophosphamide, melphalan, and chlorambucil; nitrosoureas, such as carmustine, lomustine, and streptozocin; alkyl sulfonates, such as busulfan; and platinums, such as cisplatin, oxaliplatin, and carboplatin.
  • a chemotherapeutic agent is an anti-metabolite.
  • Non-limiting examples of anti -metabolites include purine antagonists, such as azathioprine, cladribine, and fludarabine; purine antagonists, such as gemcitabine, fluorouracil, azacitidine, cytarabine, capecitabine; and purine antagonists, such as methotrexate and pemetrexed.
  • a chemotherapeutic agent is a plant alkaloid.
  • plant alkaloids include vinca alkaloids, such as vincristine, vinblastine, vinorelbine, and eribulin; and taxanes, such as abraxane, docetaxel, and paclitaxel.
  • a chemotherapeutic agent is a topoisomerase inhibitor.
  • topoisomerase inhibitors include irinotecan, topotecan, camptothecin, etoposide, doxorubicin, and epirubicin.
  • a chemotherapeutic agent is an anti -turn or antibiotic.
  • anti-tumor antibiotics include bleomycin, mitomycin C, and dactinomycin.
  • the terms “about” or “approximately” have the meaning of within 20% of a given value or range. In some embodiments, the term “about” refers to within 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of a given value.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease, or one or more symptoms thereof, as described herein.
  • treatment can be administered after one or more symptoms have developed.
  • treatment can be administered in the absence of symptoms.
  • treatment can be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment can also be continued after symptoms have resolved, for example to prevent, or delay their recurrence.
  • a patient or subject "in need of prevention,” “in need of treatment,” or “in need thereof,” refers to one, who by the judgment of an appropriate medical practitioner (e.g., a doctor, a nurse, or a nurse practitioner in the case of humans; a veterinarian in the case of nonhuman mammals), would reasonably benefit from a given treatment or therapy.
  • an appropriate medical practitioner e.g., a doctor, a nurse, or a nurse practitioner in the case of humans; a veterinarian in the case of nonhuman mammals
  • a “therapeutically effective amount” or “therapeutically effective dosage” of a drug or therapeutic agent is any amount of the drug that, when used alone or in combination with another therapeutic agent, protects a patient or subj ect against the onset of a disease, such as cancer, or promotes disease regression evidenced by a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction.
  • a therapeutic agent such as a MEK inhibitor or a KRAS G12C inhibitor
  • a therapeutic agent such as a MEK inhibitor or a KRAS G12C inhibitor
  • the present disclosure provides a method for treating cancer in a patient comprising administering to the patient a therapeutically effective amount of a MEK inhibitor and a RAS inhibitor.
  • the present disclosure provides a method for treating cancer in a patient comprising administering to the patient a therapeutically effective amount of a MEK inhibitor and a KRAS G12C inhibitor.
  • the present disclosure provides a method for treating cancer in a patient comprising administering to the patient a therapeutically effective amount of a MEK inhibitor and an EGFR inhibitor. [0084] In some aspects and embodiments, the present disclosure provides a method for treating cancer in a patient comprising administering to the patient a therapeutically effective amount of a MEK inhibitor and a TEAD inhibitor.
  • the present disclosure provides a method for treating cancer in a patient comprising administering to the patient a therapeutically effective amount of a MEK inhibitor and an anti-HER2 agent.
  • the present disclosure provides a method for treating cancer in a patient comprising administering to the patient a therapeutically effective amount of a MEK inhibitor and a chemotherapeutic agent.
  • the present disclosure provides a method of treating a KRAS mutant colorectal, KRAS mutant pancreatic, or KRAS mutant lung cancer comprising administering a MEK inhibitor and a KRAS G12C inhibitor.
  • the present disclosure provides a method of treating KRAS G12C inhibitor-resistant KRAS mutant pancreatic or KRAS G12C inhibitor-resistant KRAS mutant lung cancer comprising administering a MEK inhibitor and a KRAS G12C inhibitor.
  • the present disclosure provides a method of treating RAS/RAF wild-type colorectal cancer comprising administering a MEK inhibitor and an anti- EGER monoclonal antibody.
  • the present disclosure provides a method of treating chemotherapy -refractive colorectal cancer comprising administering a MEK inhibitor and an anti- EGFR monoclonal antibody.
  • the present disclosure provides a method of treating a KRAS mutant colorectal or KRAS mutant pancreatic cancer comprising administering a MEK inhibitor and an anti-HER2 monoclonal antibody.
  • the present disclosure provides a method of treating a KRAS mutant colorectal or KRAS mutant pancreatic cancer comprising administering a MEK inhibitor and an anti-HER2 antibody drug conjugate.
  • the present disclosure provides a method of treating a KRAS mutant colorectal cancer comprising administering a MEK inhibitor and a chemotherapeutic agent elected from 5-fluorouracil, irinotecan, and oxaliplatin.
  • the present disclosure provides a method of treating a KRAS mutant pancreatic cancer comprising administering a MEK inhibitor and a chemotherapeutic agent selected from gemcitabine, 5-fluorouracil, paclitaxel, abraxane, oxaliplatin.
  • the present disclosure provides a use of a MEK inhibitor for the treatment of cancer in combination with a RAS inhibitor.
  • the present disclosure provides a use of a MEK inhibitor in the manufacture of a medicament for the treatment of cancer, wherein the medicament is for use in combination with a RAS inhibitor.
  • the present disclosure provides a use of a MEK inhibitor for the treatment of cancer in combination with a KRAS G12C inhibitor. In some embodiments, the present disclosure provides a use of a MEK inhibitor in the manufacture of a medicament for the treatment of cancer, wherein the medicament is for use in combination with a KRAS G12C inhibitor. In some aspects and embodiments, the present disclosure provides a use of a MEK inhibitor for the treatment of cancer in combination with an EGFR inhibitor. In some embodiments, the present disclosure provides a use of a MEK inhibitor in the manufacture of a medicament for the treatment of cancer, wherein the medicament is for use in combination with an EGFR inhibitor.
  • the present disclosure provides a use of a MEK inhibitor for the treatment of cancer in combination with a TEAD inhibitor. In some embodiments, the present disclosure provides a use of a MEK inhibitor in the manufacture of a medicament for the treatment of cancer, wherein the medicament is for use in combination with a TEAD inhibitor. [0099] In some aspects and embodiments, the present disclosure provides a use of a MEK inhibitor for the treatment of cancer in combination with an anti-HER2 agent. In some embodiments, the present disclosure provides a use of a MEK inhibitor in the manufacture of a medicament for the treatment of cancer, wherein the medicament is for use in combination with an anti-HER2 agent.
  • the present disclosure provides a use of a MEK inhibitor for the treatment of cancer in combination with a chemotherapeutic agent.
  • the present disclosure provides a use of a MEK inhibitor in the manufacture of a medicament for the treatment of cancer, wherein the medicament is for use in combination with a chemotherapeutic agent.
  • the present disclosure provides a use of a MEK inhibitor for the treatment of KRAS mutant colorectal, KRAS mutant pancreatic, or KRAS mutant lung cancer in combination with a KRAS G12C inhibitor.
  • the present disclosure provides a use of a MEK inhibitor in the manufacture of a medicament for the treatment of a KRAS mutant colorectal, KRAS mutant pancreatic, or KRAS mutant lung cancer, wherein the medicament is for use in combination with a KRAS G12C inhibitor.
  • the present disclosure provides a use of a MEK inhibitor for the treatment of KRAS G12C inhibitor-resistant KRAS mutant pancreatic or KRAS mutant lung cancer in combination with a KRAS G12C inhibitor.
  • the present disclosure provides a use of a MEK inhibitor in the manufacture of a medicament for the treatment of KRAS G12C inhibitor-resistant KRAS mutant pancreatic or KRAS G12C inhibitorresistant KRAS mutant lung cancer, wherein the medicament is for use in combination with a KRAS G12C inhibitor.
  • the present disclosure provides a use of a MEK inhibitor for the treatment of RAS/RAF wild-type colorectal cancer in combination with an anti- EGER monoclonal antibody.
  • the present disclosure provides a use of a MEK inhibitor in the manufacture of a medicament for the treatment of RAS/RAF wild-type colorectal cancer, wherein the medicament is for use in combination with an anti-EGER monoclonal antibody.
  • the present disclosure provides a use of a MEK inhibitor for the treatment of chemotherapy-refractive colorectal cancer in combination with an anti-EGER monoclonal antibody.
  • the present disclosure provides a use of a MEK inhibitor in the manufacture of a medicament for the treatment of chemotherapy-refractive colorectal cancer, wherein the medicament is for use in combination with an anti-EGER monoclonal antibody.
  • the present disclosure provides a use of a MEK inhibitor for the treatment of KRAS mutant colorectal or KRAS mutant pancreatic cancer in combination with an anti-HER2 monoclonal antibody.
  • the present disclosure provides a use of a MEK inhibitor in the manufacture of a medicament for the treatment of KRAS mutant colorectal or KRAS mutant pancreatic cancer, wherein the medicament is for use in combination with an anti-HER2 monoclonal antibody.
  • the present disclosure provides a use of a MEK inhibitor for the treatment of KRAS mutant colorectal and pancreatic cancer in combination with an anti-HER2 antibody drug conjugate.
  • the present disclosure provides a use of a MEK inhibitor in the manufacture of a medicament for the treatment of KRAS mutant colorectal or KRAS mutant pancreatic cancer, wherein the medicament is for use in combination with an anti-HER2 antibody drug conjugate.
  • the present disclosure provides a use of a MEK inhibitor for the treatment of KRAS mutant colorectal cancer in combination with a chemotherapeutic agent selected from 5-fluorouracil, irinotecan, and oxaliplatin.
  • a chemotherapeutic agent selected from 5-fluorouracil, irinotecan, and oxaliplatin selected from 5-fluorouracil, irinotecan, and oxaliplatin.
  • the present disclosure provides a use of a MEK inhibitor for the treatment of KRAS mutant pancreatic cancer in combination with a chemotherapeutic agent selected from gemcitabine, 5-fluorouracil, paclitaxel, abraxane, oxaliplatin.
  • a chemotherapeutic agent selected from gemcitabine, 5-fluorouracil, paclitaxel, abraxane, oxaliplatin in the manufacture of a medicament for the treatment of KRAS mutant pancreatic cancer, wherein the medicament is for use in combination with a chemotherapeutic agent selected from gemcitabine, 5-fluorouracil, paclitaxel, abraxane, oxaliplatin.
  • a medicament comprises a MEK inhibitor, or a pharmaceutical composition thereof.
  • a pharmaceutical composition comprising a MEK inhibitor is as described herein.
  • a MEK inhibitor is a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:
  • R 1 and R 2 are independently H, optionally substituted C 1 -C 6 aliphatic, optionally substituted 3-8 membered carbocyclyl, or optionally substituted 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, O, or S, or R 1 and R 2 , taken together with the atom to which they attach, form optionally substituted 3-8 membered heterocyclyl having 0, 1, or 2 heteroatoms independently selected from N, O, or S in addition to the N atom to which R 1 and R 2 attach;
  • X 1 is C(R 21 ) or N;
  • X 2 is C(R 22 ) or N;
  • X 3 is C(R 23 ) or N;
  • L 1 is -C(R 5 )(R 6 )-; each of R 5 and R 6 is independently halogen, R, -OR, or -N(R) 2 ; or R 5 and R 6 , together with the atom to which they attach, form an optionally substituted 3-8 membered carbocyclic ring or an optionally substituted 3-8 membered heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S;
  • Ring A is an optionally substituted ring selected from a phenyl ring, a 5-6 membered heteroaromatic ring having 1-4 heteroatoms independently selected from N, O, or S, or a 8-11 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from N, O, or S; and each R is independently H, optionally substituted C 1 -C 6 aliphatic, optionally substituted 3- 8 membered carbocyclyl, or optionally substituted 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, O, or S.
  • R 1 and R 2 are independently H, optionally substituted Ci- Cg aliphatic, optionally substituted 3-8 membered carbocyclyl, or optionally substituted 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, O, or S, or R 1 and R 2 , taken together with the N atom to which they attach, form optionally substituted 3-8 membered heterocyclyl having 0, 1, or 2 heteroatoms independently selected from N, O, or S in addition to the N atom to which R 1 and R 2 attach.
  • R 1 and R 2 are independently H, optionally substituted Ci-6 aliphatic, or R 1 and R 2 , taken together with the N atom to which they attach, form optionally substituted 3-8 membered heterocyclyl having 0, 1, or 2 heteroatoms independently selected from N, O, or S in addition to the N atom to which R 1 and R 2 attach.
  • R 1 and R 2 are independently hydrogen or optionally substituted Ci-Cg alkyl. In some embodiments, R 1 and R 2 are independently hydrogen or Ci-Cg alkyl. In some embodiments, R 1 and R 2 are independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, R 1 and R 2 are methyl.
  • R 1 and R 2 taken together with the N atom to which they attach, form optionally substituted 3-8 membered heterocyclyl having 0, 1, or 2 heteroatoms independently selected from N, O, or S in addition to the N atom to which R 1 and R 2 attach.
  • R 1 and R 2 taken together with the N atom to which they attach form optionally substituted 3, 4, 5, 6, 7, or 8 membered heterocyclyl having 0, 1, or 2 heteroatoms independently selected from N, O, or S in addition to the N atom to which R 1 and R 2 attach.
  • R 1 and R 2 taken together with the N atom to which they attach, form optionally substituted 3, 4, 5, 6, 7, or 8 membered heterocyclyl having 1, 2, or 3 N atoms. In some embodiments, R 1 and R 2 , taken together with the N atom to which they attach, form an optionally substituted azetidine ring.
  • X 1 is C(R 21 ) or N. In some embodiments, X 1 is C(R 21 ). In some embodiments, X 1 is N. In some embodiments, X 1 is C(H).
  • X 2 is C(R 22 ) orN. In some embodiments, X 2 is C(R 22 ). In some embodiments, X 2 is N. In some embodiments, X 2 is C(H). In some embodiments, X 2 is C(R 22 ), wherein R 22 is halogen.
  • X 3 is C(R 23 ) or N. In some embodiments, X 3 is C(R 23 ). In some embodiments, X 3 is N. In some embodiments, X 3 is C(H). In some embodiments, X 3 is C(R 23 ), wherein R 23 is halogen.
  • each of R 21 , R 22 , and R 23 is independently halogen, R, - OR, -N(R) 2 , -N(R)-C(O)-R, or -C(O)-N(R) 2 .
  • R 21 is halogen. In some embodiments, R 21 is R. In some embodiments, R 21 is H. In some embodiments, R 21 is optionally substituted C 1 -C 6 aliphatic. In some embodiments, R 21 is optionally substituted C 1 -C 6 alkyl. In some embodiments, R 21 is -OR. In some embodiments, R 21 is optionally substituted C 1 -C 6 alkoxy. In some embodiments, R 21 is - N(R) 2 . In some embodiments, R 21 is -N(R)-C(O)-R. In some embodiments, R 21 is -C(O)-N(R) 2 .
  • R 22 is halogen. In some embodiments, R 22 is -Cl. In some embodiments, R 22 is -F. In some embodiments, R 22 is R. In some embodiments, R 22 is H. In some embodiments, R 22 is optionally substituted C 1 -C 6 aliphatic. In some embodiments, R 22 is optionally substituted C 1 -C 6 alkyl. In some embodiments, R 22 is -OR. In some embodiments, R 22 is optionally substituted Ci-Cs alkoxy. In some embodiments, R 22 is -N(R) 2 . In some embodiments, R 22 is - N(R)-C(O)-R. In some embodiments, R 22 is -C(O)-N(R) 2 .
  • R 23 is halogen. In some embodiments, R 23 is -Cl. In some embodiments, R 23 is -F. In some embodiments, R 23 is R. In some embodiments, R 23 is H. In some embodiments, R 23 is optionally substituted C 1 -C 6 aliphatic. In some embodiments, R 23 is optionally substituted Ci-Cg alkyl. In some embodiments, R 23 is -OR. In some embodiments, R 23 is optionally substituted C 1 -C 6 alkoxy. In some embodiments, R 23 is -N(R) 2 . In some embodiments, R 23 is - N(R)-C(O)-R. In some embodiments, R 23 is -C(O)-N(R) 2 .
  • R 4 is unsubstituted C 1 -C 6 alkoxy, or optionally substituted C 1 -C 6 alkoxy.
  • R 5 and R 4 are independently hydrogen, -CH 3 , -CH 2 N(CH 3 )2, or -(C3H5).
  • R 5 and R 4 are independently R; and each R is independently H, optionally substituted Ci-6 aliphatic, or optionally substituted 3-8 membered carbocyclyl. In some embodiments, R 5 and R 4 are independently R; and each R is independently H, methyl, or cyclopropyl. In some embodiments, R 5 and R 4 are independently hydrogen, -CH3, or -CH 2 N(CH3) 2 . In some embodiments, R 5 and R 4 are independently R; and each R is independently C 1 -C 6 aliphatic. In some embodiments, R 5 and R 4 are independently hydrogen or CH3.
  • R 5 is -T-N(R) 2 , wherein T is a bivalent Ci-Cs saturated or unsaturated, straight or branched, hydrocarbon chain wherein one, two or three methylene units of the chain are optionally and independently replaced by -Cy-, -C(R) 2 -, -S-, -N(R)-, -O-, -C(O)- , -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O) 2 - or -N(R)CH 2 C(O)-; and -Cy- is an optionally substituted 3-8 membered bivalent carbocyclic ring, or an optionally substituted 3-8 membered bivalent heterocyclic ring having 1, 2, or 3 heteroatoms independently selected from N, O, or S.
  • T is a bivalent Ci-Cs saturated or
  • R 4 is -T-N(R) 2 , wherein T is a bivalent Ci-Cs saturated or unsaturated, straight or branched, hydrocarbon chain wherein one, two or three methylene units of the chain are optionally and independently replaced by -Cy-, -C(R) 2 -, -S-, -N(R)-, -O-, -C(O)- , -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O) 2 - or -N(R)CH 2 C(O)-; and -Cy- is an optionally substituted 3-8 membered bivalent carbocyclic ring, or an optionally substituted 3-8 membered bivalent heterocyclic ring having 1, 2, or 3 heteroatoms independently selected from N, O, or S.
  • T is a bivalent Ci-Cs saturated or
  • L 1 is -C(R 5 )(R 6 )-, wherein each of R and R 6 is independently halogen, R, -OR, or -N(R)2; or R 5 and R 6 , together with the atom to which they attach, form an optionally substituted 3-8 membered carbocyclic ring or an optionally substituted 3-8 membered heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S.
  • R 5 is hydrogen
  • R 6 is R.
  • R 6 is hydrogen.
  • R 5 and R 6 are independently optionally substituted C 1 -C 6 aliphatic.
  • R 5 is unsubstituted C 1 -C 6 alkoxy, or optionally substituted C 1 -C 6 alkoxy.
  • R 6 is unsubstituted C 1 -C 6 alkoxy, or optionally substituted C 1 -C 6 alkoxy.
  • R ? and R 6 are independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, or hexyl.
  • R 5 is hydrogen, and R 6 is methyl.
  • R 5 and R 6 are independently halogen or R.
  • R 5 and R 6 are independently hydrogen, halogen, or C 1 -C 6 aliphatic.
  • L 1 is -CH2-. In some embodiments, L 1 is -C(H)(CH3)-.
  • Ring A is an optionally substituted ring selected from a phenyl ring, a 5-6 membered heteroaromatic ring having 1-4 heteroatoms independently selected from N, O, or S, or a 8-11 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from N, O, or S.
  • Ring A is an optionally substituted ring selected from a phenyl ring, a 5 or 6 membered heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S, or a 8, 9, 10, or 11 membered bicyclic heteroaromatic ring having 1, 2, 3, 4, or 5 heteroatoms independently selected from N, O, or S.
  • Ring A is an optionally substituted ring selected from a phenyl ring or a 6 membered heteroaromatic ring having 1-4 heteroatoms independently selected from N. In some embodiments, Ring A is an optionally substituted ring selected from a phenyl ring or a 6 membered heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from N. In some embodiments, Ring A is an optionally substituted ring selected form a phenyl ring or a 5 or 6 membered heteroaromatic having 1, 2, 3, or 4 heteroatoms independent selected from N. In some embodiments, Ring A is pyridinyl, pyrimidinyl, pyrazinyl, or pyrazolyl. [00129] In some embodiments, Ring is independently halogen, R, -OR, or -N(R)2; and R 8 is halogen, R, -OR, -N(R)2,
  • each of R 10 and R 11 is independently H, optionally substituted Ci-6 aliphatic, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, O, or S, optionally substituted phenyl, or optionally substituted 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from N, O, or S, or R 10 and R 11 taken together with the N atom to which they attach, form optionally substituted 3-8 membered heterocyclyl having 0, 1, or 2 heteroatoms independently selected from N, O, or S in addition to the N atom to which R 10 and R 11 attach; and R 12 is H, optionally substituted C 1 -C 6 aliphatic, optionally substituted 3-8 membered carbocyclyl, or optionally substituted 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, O, or S.
  • each R 7 is independently halogen, R, or -OR. In some embodiments, R 7 is independently H, or optionally substituted C 1 -C 6 aliphatic. In some embodiments, R 7 is independently H, halogen, or C 1 -C 6 aliphatic. In some embodiments, R 7 is unsubstituted C 1 -C 6 alkoxy, or optionally substituted C 1 -C 6 alkoxy. In some embodiments, each R 7 is independently halogen. In some embodiments, R 7 is independently H or fluoro. In some embodiments, R 7 is fluoro. In some embodiments, R 7 is H.
  • R 8 is each of R 10 and R 11 is independently H, Ci-Cg aliphatic, or 3-8 membered heterocyclyl having 1, 2, or 3 N atoms; and R 12 is H, optionally substituted C 1 -C 6 aliphatic, or optionally substituted 3-8 membered carbocyclyl. In some embodiments, R 8 is unsubstituted C 1 -C 6 alkoxy, or optionally substituted C 1 -C 6 alkoxy.
  • each of R 10 and R 11 is independently hydrogen or C 1 -C 6 alkyl.
  • R 12 is hydrogen or C 1 -C 6 alkyl. In some embodiments, R 12 is C 1 -C 6 alkyl. In some embodiments, R 12 is hydrogen, methyl, ethyl, propyl, butyl, pentyl, or hexyl. [00135] As defined generally above, each R is independently H, optionally substituted C 1 -C 6 aliphatic, optionally substituted 3-8 membered carbocyclyl, or optionally substituted 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, O, or S. In some embodiments, R is H.
  • R is unsubstituted, or optionally substituted C1-C6 aliphatic. In some embodiments, R is unsubstituted, or optionally substituted C 1 -C 6 alkyl. In some embodiments, R is unsubstituted, or optionally substituted 3-8 membered carbocyclyl. In some embodiments, R is unsubstituted, or optionally substituted 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, O, or S.
  • a MEK inhibitor is a compound of Formula (I- A): or a pharmaceutically acceptable salt thereof, wherein each variable is as defined above and described in embodiments herein, both singly and in combination.
  • a MEK inhibitor is a compound of Formula (I-A), or a pharmaceutically acceptable salt thereof, wherein:
  • R 1 and R 2 are independently H or optionally substituted C 1 -C 6 aliphatic, or R 1 and R 2 , taken together with the atom to which they attach, form optionally substituted 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, O, or S;
  • X 1 is C(R 21 ) or N;
  • X 2 is C(R 22 ) or N;
  • X 3 is C(R 23 ) or N;
  • each of R 21 , R 22 , and R 23 is independently halogen, R, -N(R) 2 , -OR, -N(R)-C(O)-R, or - C(O)-N(R) 2 ;
  • L 1 is -C(R 5 )(R 6 )-; each of R 5 and R 6 is independently H, halogen, R, or -OR; each R 7 is independently halogen, R, or -OR;
  • R 8 is halogen, each of R 10 and R 11 is independently H, optionally substituted Ci-6 aliphatic, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, O, or S, optionally substituted phenyl, or optionally substituted 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from N, O, or S, or R 10 and R 11 taken together with the N atom to which they attach, form optionally substituted 3-8 membered heterocyclyl having 0, 1, or 2 heteroatoms independently selected from N, O, or S in addition to the N atom to which R 10 and R 11 attach;
  • R 12 is H, optionally substituted Ci-6 aliphatic, optionally substituted 3-8 membered carbocyclyl, or optionally substituted 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, O, or S; and each R is independently H, optionally substituted Ci-6 aliphatic, optionally substituted 3-8 membered carbocyclyl, or optionally substituted 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, O, or S.
  • a MEK inhibitor is a compound of Formula (I-B):
  • a MEK inhibitor is a compound of Formula (I-B), or a pharmaceutically acceptable salt thereof wherein:
  • R 1 and R 2 are independently H, optionally substituted Ci-6 aliphatic, or R 1 and R 2 , taken together with the atom to which they attach, form optionally substituted 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, O, or S;
  • X 1 is C(R 21 ) or N;
  • X 2 is C(R 22 ) or N;
  • X 3 is C(R 23 ) or N;
  • each of R 21 , R 22 , and R 23 is independently halogen, R, -OR, -N(R)2, -N(R)-C(O)-R, or - C(O)-N(R) 2 ;
  • L 1 is -C(R 5 )(R 6 )-; each of R 5 and R 6 is independently H, halogen, R, or -OR;
  • R 7 is independently halogen, R, or -OR
  • R 8 is halogen, each of R 10 and R 11 is independently H, optionally substituted C 1 -C 6 aliphatic, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, O, or S, optionally substituted phenyl, or optionally substituted 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from N, O, or S, orR 10 and R 11 taken together with the N atom to which they attach, form optionally substituted 3-8 membered heterocyclyl having 0, 1, or 2 heteroatoms independently selected from N, O, or S in addition to the N atom to which R 10 and R 11 attach;
  • R 12 is H, optionally substituted Ci-6 aliphatic, optionally substituted 3-8 membered carbocyclyl, or optionally substituted 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, O, or S; and each R is independently H, optionally substituted C 1 -C 6 aliphatic, optionally substituted 3- 8 membered carbocyclyl, or optionally substituted 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, O, or S.
  • a MEK inhibitor is a compound set forth in Table 1 above, or a pharmaceutically acceptable salt thereof.
  • a MEK inhibitor is a compound of Formula (II): or a pharmaceutically acceptable salt thereof, wherein:
  • Ring A and Ring B are independently an optionally substituted ring selected from a phenyl ring, a 5-6 membered heteroaromatic ring having 1-4 heteroatoms independently selected from N, O, or S, or a 8-11 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from N, O, or S;
  • X 1 is C(R 21 ) or N;
  • X 2 is C(R 22 ) or N;
  • X 3 is C(R 23 ) or N;
  • L 1 is -C(R 5 )(R 6 )- or -NR-; each of R 5 and R 6 is independently halogen, R, -OR, or -N(R)2; or R 5 and R 6 , together with the atom to which they attach, form an optionally substituted 3-8 membered carbocyclic ring or an optionally substituted 3-8 membered heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S; and each R is independently H, optionally substituted C 1 -C 6 aliphatic, optionally substituted 3-8 membered carbocyclyl, or optionally substituted 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, O, or S.
  • Ring A is an optionally substituted ring selected from a phenyl ring, a 5-6 membered heteroaromatic ring having 1-4 heteroatoms independently selected from N, O, or S, or a 8-11 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from N, O, or S.
  • Ring A is an optionally substituted ring selected from a phenyl ring, a 5 or 6 membered heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S, or a 8, 9, 10, or 11 membered bicyclic heteroaromatic ring having 1, 2, 3, 4, or 5 heteroatoms independently selected from N, O, or S.
  • Ring A is an optionally substituted ring selected from a phenyl ring or a 6 membered heteroaromatic ring having 1-4 heteroatoms independently selected from N. In some embodiments, Ring A is an optionally substituted ring selected from a phenyl ring or a 6 membered heteroaromatic ring having 1, 2, 3, or 4 heteroatoms independently selected from N. In some embodiments, Ring A is an optionally substituted ring selected form a phenyl ring or a 5 or 6 membered heteroaromatic having 1, 2, 3, or 4 heteroatoms independent selected from N. In some embodiments, Ring A is pyridinyl, pyrimidinyl, pyrazinyl, or pyrazolyl. [00143] In some embodiments, Ring
  • R 10 and R 11 are independently H, optionally substituted Ci-6 aliphatic, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, O, or S, optionally substituted phenyl, or optionally substituted 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from N, O, or S, or R 10 and R 11 taken together with the N atom to which they attach, form optionally substituted 3-8 membered heterocyclyl having 0, 1, or 2 heteroatoms independently selected from N, O, or S in addition to the N atom to which R 10 and R 11 attach; and R 12 is H, optionally substituted C 1 -C 6 aliphatic, optionally substituted 3-8 membered carbocyclyl
  • each R 7 is independently halogen, R, or -OR. In some embodiments, R 7 is independently H, or optionally substituted C 1 -C 6 aliphatic. In some embodiments, R 7 is independently H, halogen, or C 1 -C 6 aliphatic. In some embodiments, R 7 is unsubstituted C 1 -C 6 alkoxy, or optionally substituted C 1 -C 6 alkoxy. In some embodiments, each R 7 is independently halogen. In some embodiments, R 7 is independently H or fluoro. In some embodiments, R 7 is fluoro. In some embodiments, R 7 is H.
  • each of R 10 and R 11 is independently H, Ci-Cg aliphatic, or 3-8 membered heterocyclyl having 1, 2, or 3 N atoms; and R 12 is H, optionally substituted C 1 -C 6 aliphatic, or optionally substituted 3-8 membered carbocyclyl.
  • R 8 is unsubstituted C 1 -C 6 alkoxy, or optionally substituted C 1 -C 6 alkoxy.
  • each of R 10 and R 11 is independently hydrogen or C 1 -C 6 alkyl.
  • R 12 is hydrogen or C 1 -C 6 alkyl. In some embodiments, R 12 is C 1 -C 6 alkyl. In some embodiments, R 12 is hydrogen, methyl, ethyl, propyl, butyl, pentyl, or hexyl.
  • Ring B is an optionally substituted ring selected from a phenyl ring, a 5-6 membered heteroaromatic ring having 1-4 heteroatoms independently selected from N, O, or S, or a 8-11 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from N, O, or S.
  • Ring B is an optionally substituted ring selected from a phenyl ring or a 6 membered heteroaromatic ring having 1-4 N atoms. In some embodiments, Ring B is optionally substituted pyridinyl or optionally substituted pyrimidinyl. In some embodiments, Ring
  • R is hydrogen or halogen. In some embodiments, R 1 is fluoro. In some embodiments, R 1 is R. In some embodiments, R 1 is unsubstituted, or optionally substituted C 1 -C 6 alkyl. In some embodiments, R 1 is unsubstituted C 1 -C 6 alkoxy, or optionally substituted C 1 -C 6 alkoxy.
  • X 1 is C(R 21 ) or N. In some embodiments, X 1 is C(R 21 ). In some embodiments, X 1 is N. In some embodiments, X 1 is C(H).
  • X 2 is C(R 22 ) or N. In some embodiments, X 2 is C(R 22 ). In some embodiments, X 2 is N. In some embodiments, X 2 is C(H). In some embodiments, X 2 is C(R 22 ), wherein R 22 is halogen.
  • X 3 is C(R 23 ) or N. In some embodiments, X 3 is C(R 23 ). In some embodiments, X 3 is N. In some embodiments, X 3 is C(H). In some embodiments, X 3 is C(R 23 ), wherein R 23 is halogen.
  • R 21 is halogen. In some embodiments, R 21 is R. In some embodiments, R 21 is H. In some embodiments, R 21 is optionally substituted C 1 -C 6 aliphatic. In some embodiments, R 21 is optionally substituted C 1 -C 6 alkyl. In some embodiments, R 21 is -OR. In some embodiments, R 21 is optionally substituted C 1 -C 6 alkoxy. In some embodiments, R 21 is - N(R) 2 . In some embodiments, R 21 is -N(R)-C(O)-R. In some embodiments, R 21 is -C(O)-N(R)2.
  • R 22 is halogen. In some embodiments, R 22 is R. In some embodiments, R 22 is H. In some embodiments, R 22 is optionally substituted C 1 -C 6 aliphatic. In some embodiments, R 22 is optionally substituted C 1 -C 6 alkyl. In some embodiments, R 22 is -OR. In some embodiments, R 22 is optionally substituted C 1 -C 6 alkoxy. In some embodiments, R 22 is - N(R) 2 . In some embodiments, R 22 is -N(R)-C(O)-R. In some embodiments, R 22 is -C(O)-N(R) 2 .
  • R 23 is halogen. In some embodiments, R 23 is R. In some embodiments, R 23 is H. In some embodiments, R 23 is optionally substituted Ci-Cg aliphatic. In some embodiments, R 23 is optionally substituted C 1 -C 6 alkyl. In some embodiments, R 23 is -OR. In some embodiments, R 23 is optionally substituted C 1 -C 6 alkoxy. In some embodiments, R 23 is - N(R) 2 . In some embodiments, R 23 is -N(R)-C(O)-R. In some embodiments, R 23 is -C(O)-N(R) 2 .
  • R 4 is unsubstituted Ci-Cg alkoxy, or optionally substituted C 1 -C 6 alkoxy.
  • R 5 and R 4 are independently hydrogen, -CH3, -CH 2 N(CH 3 ) 2 , or -(C3H5).
  • R 5 and R 4 are independently R; and each R is independently H, optionally substituted Ci-6 aliphatic, or optionally substituted 3-8 membered carbocyclyl. In some embodiments, R 5 and R 4 are independently R; and each R is independently H, methyl, or cyclopropyl. In some embodiments, R 5 and R 4 are independently hydrogen, -CH3, or -CH2N(CH3)2. In some embodiments, R 5 and R 4 are independently R; and each R is independently C 1 -C 6 aliphatic. In some embodiments, R 5 and R 4 are independently hydrogen or CH3.
  • R 5 is -T-N(R)2, wherein T is a bivalent C1-8 saturated or unsaturated, straight or branched, hydrocarbon chain wherein one, two or three methylene units of the chain are optionally and independently replaced by -Cy-, -C(R)2-, -S-, -N(R)-, -O-, -C(O)- , -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O) 2 - or -N(R)CH 2 C(O)-; and -Cy- is an optionally substituted 3-8 membered bivalent carbocyclic ring, or an optionally substituted 3-8 membered bivalent heterocyclic ring having 1, 2, or 3 heteroatoms independently selected from N, O, or S.
  • T is a bivalent C1-8 saturated or unsaturated, straight or
  • R 4 is -T-N(R)2, wherein T is a bivalent C1-8 saturated or unsaturated, straight or branched, hydrocarbon chain wherein one, two or three methylene units of the chain are optionally and independently replaced by -Cy-, -C(R)2-, -S-, -N(R)-, -O-, -C(O)- , -OC(O)-, -C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -S(O)-, -S(O) 2 - or -N(R)CH 2 C(O)-; and -Cy- is an optionally substituted 3-8 membered bivalent carbocyclic ring, or an optionally substituted 3-8 membered bivalent heterocyclic ring having 1, 2, or 3 heteroatoms independently selected from N, O, or S.
  • T is a bivalent C1-8 saturated or unsaturated, straight or
  • L 1 is -C(R 5 )(R 6 )-, wherein each of R 5 and R 6 is independently halogen, R, -OR, or -N(R)2; or R ? and R 6 , together with the atom to which they attach, form an optionally substituted 3-8 membered carbocyclic ring or an optionally substituted 3-8 membered heterocyclic ring having 1-3 heteroatoms independently selected from N, O, or S.
  • R is hydrogen
  • R 6 is R.
  • R 6 is hydrogen.
  • R ? and R 6 are independently optionally substituted C 1 -C 6 aliphatic.
  • R 5 and R 6 are independently methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, R 5 is hydrogen, and R 6 is methyl. In some embodiments, R 5 and R 6 are independently halogen or R. In some embodiments, R 5 and R 6 are independently hydrogen, halogen, or C 1 -C 6 aliphatic.
  • L 1 is -CH2-. In some embodiments, L 1 is -C(H)(CH3)-.
  • L 1 is -NR-, wherein R is as defined and described in embodiments herein. In some embodiments, L 1 is -NH-. In some embodiments, L 1 is -N(CH3)-.
  • each R is independently H, optionally substituted C 1 -C 6 aliphatic, optionally substituted 3-8 membered carbocyclyl, or optionally substituted 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, O, or S.
  • R is H.
  • R is unsubstituted, or optionally substituted C 1 -C 6 aliphatic.
  • R is unsubstituted, or optionally substituted C 1 -C 6 alkyl.
  • R is unsubstituted, or optionally substituted 3-8 membered carbocyclyl.
  • R is unsubstituted, or optionally substituted 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, O, or S.
  • a MEK inhibitor is a compound of Formula (II-A):
  • a MEK inhibitor is a compound of Formula (II-A), or a pharmaceutically acceptable salt thereof, wherein:
  • X 2 is C(R 22 ) or N;
  • X 3 is C(R 23 ) or N;
  • each of R 21 , R 22 , and R 23 is independently halogen, R, -OR, -N(R) 2 , -N(R)-C(O)-R, or - C(O)-N(R) 2 ;
  • L 1 is -C(R 5 )(R 6 )-; each of R 5 and R 6 is independently H, halogen, R, or -OR; and each R is independently H, optionally substituted C 1 -C 6 aliphatic, optionally substituted 3- 8 membered carbocyclyl, or optionally substituted 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, O, or S;
  • R 7 is independently halogen, R, or -OR
  • R 8 is halogen, each of R 10 and R 11 is independently H, optionally substituted C 1 -C 6 aliphatic, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, O, or S, optionally substituted phenyl, or optionally substituted 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from N, O, or S, or R 10 and R 11 taken together with the N atom to which they attach, form optionally substituted 3-8 membered heterocyclyl having 0, 1, or 2 heteroatoms independently selected from N, O, or S in addition to the N atom to which R 10 and R 11 attach; and
  • R 12 is H, optionally substituted C 1 -C 6 aliphatic, optionally substituted 3-8 membered carbocyclyl, or optionally substituted 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, O, or S.
  • a MEK inhibitor is a compound of Formula (II-B):
  • a MEK inhibitor is a compound of Formula (II-B), or a pharmaceutically acceptable salt thereof, wherein:
  • X 1 is C(R 21 ) orN;
  • X 2 is C(R 22 ) or N;
  • X 3 is C(R 23 ) or N;
  • each of R 21 , R 22 , and R 23 is independently halogen, R, -OR, -N(R)2, -N(R)-C(O)-R, or - C(O)-N(R) 2 ;
  • L 1 is -C(R 5 )(R 6 )-; each of R 5 and R 6 is independently H, halogen, R, or -OR; each R is independently H, optionally substituted C 1 -C 6 aliphatic, optionally substituted 3- 8 membered carbocyclyl, or optionally substituted 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, O, or S;
  • R 7 is independently halogen, R, or -OR
  • R 8 is halogen, each of R 10 and R 11 is independently H, optionally substituted C 1 -C 6 aliphatic, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, O, or S, optionally substituted phenyl, or optionally substituted 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from N, O, or S, or R 10 and R 11 taken together with the N atom to which they attach, form optionally substituted 3-8 membered heterocyclyl having 0, 1, or 2 heteroatoms independently selected from N, O, or S in addition to the N atom to which R 10 and R 11 attach; and
  • R 12 is H, optionally substituted C 1 -C 6 aliphatic, optionally substituted 3-8 membered carbocyclyl, or optionally substituted 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, O, or S.
  • a MEK inhibitor is a compound of Formula (II-C):
  • L 1 is -C(R 5 )(R 6 )-; each of R 5 and R 6 is independently H, halogen, R, or -OR; each R is independently H, optionally substituted C 1 -C 6 aliphatic, optionally substituted 3- 8 membered carbocyclyl, or optionally substituted 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, O, or S;
  • R 7 is independently halogen, R, or -OR
  • R 8 is halogen, each of R 10 and R 11 is independently H, optionally substituted C 1 -C 6 aliphatic, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, O, or S, optionally substituted phenyl, or optionally substituted 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from N, O, or S, orR 10 and R 11 taken together with the N atom to which they attach, form optionally substituted 3-8 membered heterocyclyl having 0, 1, or 2 heteroatoms independently selected from N, O, or S in addition to the N atom to which R 10 and R 11 attach; and
  • R 12 is H, optionally substituted C 1 -C 6 aliphatic, optionally substituted 3-8 membered carbocyclyl, or optionally substituted 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, O, or S.
  • a MEK inhibitor is a compound of Formula (II-D):
  • a MEK inhibitor is a compound of Formula (II-D), or a pharmaceutically acceptable salt thereof, wherein:
  • X 2 is C(R 22 ) or N;
  • X 3 is C(R 23 ) or N;
  • each of R 21 , R 22 , and R 23 is independently halogen, R, -OR, -N(R)2, -N(R)-C(O)-R, or - C(O)-N(R) 2 ;
  • L 1 is -C(R 5 )(R 6 )-; each of R 5 and R 6 is independently H, halogen, R, or -OR;
  • R 1 is H or halogen; each R is independently H, optionally substituted C 1 -C 6 aliphatic, optionally substituted 3- 8 membered carbocyclyl, or optionally substituted 3-8 membered heterocyclyl having 1 , 2, or 3 heteroatoms independently selected from N, O, or S; R 7 is independently halogen, R, -OR, or -N(R)2;
  • R 8 is halogen, each of R 10 and R 11 is independently H, optionally substituted C 1 -C 6 aliphatic, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, O, or S, optionally substituted phenyl, or optionally substituted 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from N, O, or S, or R 10 and R 11 taken together with the N atom to which they attach, form optionally substituted 3-8 membered heterocyclyl having 0, 1, or 2 heteroatoms independently selected from N, O, or S in addition to the N atom to which R 10 and R 11 attach; and
  • R 12 is H, optionally substituted C 1 -C 6 aliphatic, optionally substituted 3-8 membered carbocyclyl, or optionally substituted 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, O, or S.
  • a MEK inhibitor is a compound of Formulae (II-C-1), (II-C-2), (II-C-3), (II-C-4), or (II-C-5): (IT-C-3)
  • a MEK inhibitor is a compound of Formula (II-C-1), or a pharmaceutically acceptable salt thereof, wherein:
  • R 1 is H or halogen; each of R 5 and R 4 is independently H or optionally substituted C 1 -C 6 aliphatic;
  • R 22 is H or halogen
  • R 7 is H or halogen; each of R 10 and R 11 is independently H or optionally substituted C 1 -C 6 aliphatic; and
  • R 12 is H or optionally substituted C 1 -C 6 aliphatic.
  • a MEK inhibitor is a compound of Formula (II-C-2), or a pharmaceutically acceptable salt thereof, wherein:
  • R 1 is H or halogen
  • R 5 is H or optionally substituted C 1 -C 6 alkyl
  • R 22 is H or halogen
  • R 7 is halogen; and each of R 10 and R 11 is independently H or optionally substituted C 1 -C 6 alkyl.
  • a MEK inhibitor is a compound of Formula (II-C-3), or a pharmaceutically acceptable salt thereof, wherein: R 5 is H or optionally substituted C 1 -C 6 alkyl; R 22 is H or halogen; and each of R 10 and R 11 is independently H or optionally substituted C 1 -C 6 alkyl.
  • a MEK inhibitor is a compound of Formula (II-C-4), or a pharmaceutically acceptable salt thereof, wherein: each of R 5 and R 4 is independently H or optionally substituted C 1 -C 6 aliphatic;
  • R 22 is H or halogen; and each of R 10 and R 11 is independently H or optionally substituted C 1 -C 6 aliphatic; and
  • R 12 is H or optionally substituted C 1 -C 6 aliphatic.
  • a MEK inhibitor is a compound of Formula (II-C-5), or a pharmaceutically acceptable salt thereof, wherein:
  • R 1 is H or halogen; each of R 5 and R 4 is independently H or optionally substituted C 1 -C 6 aliphatic;
  • R 22 is H or halogen
  • R 7 is H or halogen.
  • a MEK inhibitor is a compound of Formula (II-E):
  • a MEK inhibitor is a compound of Formula (II-E), or a pharmaceutically acceptable salt thereof, wherein:
  • X 2 is C(R 22 ) or N;
  • X 3 is C(R 23 ) or N;
  • each of R 21 , R 22 , and R 23 is independently halogen, R, -OR, -N(R) 2 , -N(R)-C(O)-R, or - C(O)-N(R) 2 ;
  • L 1 is -C(R 5 )(R 6 )-; each of Rf and R 6 is independently H, halogen, R, or -OR;
  • R 1 is H, halogen, optionally substituted C 1 -C 6 aliphatic; each R is independently H, optionally substituted C 1 -C 6 aliphatic, optionally substituted 3- 8 membered carbocyclyl, or optionally substituted 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, O, or S;
  • R 7 is independently halogen, R, -OR, or -N(R)2;
  • R 8 is halogen, each of R 10 and R 11 is independently H, optionally substituted C 1 -C 6 aliphatic, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, O, or S, optionally substituted phenyl, or optionally substituted 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from N, O, or S, or R 10 and R 11 taken together with the N atom to which they attach, form optionally substituted 3-8 membered heterocyclyl having 0, 1, or 2 heteroatoms independently selected from N, O, or S in addition to the N atom to which R 10 and R 11 attach; and
  • R 12 is H, optionally substituted C 1 -C 6 aliphatic, optionally substituted 3-8 membered carbocyclyl, or optionally substituted 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, O, or S.
  • a MEK inhibitor is a compound of Formula (II-F):
  • a MEK inhibitor is a compound of Formula (II-F), or a pharmaceutically acceptable salt thereof, wherein:
  • X 1 is C(R 21 ) orN;
  • X 2 is C(R 22 ) or N;
  • X 3 is C(R 23 ) or N;
  • each of R 21 , R 22 , and R 23 is independently halogen, R, -OR, -N(R)2, -N(R)-C(O)-R, or - C(O)-N(R) 2 ;
  • L 1 is -C(R 5 )(R 6 )-; each of R 5 and R 6 is independently H, halogen, R, or -OR;
  • R 1 is H, halogen, or optionally substituted C 1 -C 6 aliphatic; each R is independently H, optionally substituted C 1 -C 6 aliphatic, optionally substituted 3- 8 membered carbocyclyl, or optionally substituted 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, O, or S;
  • R 7 is independently halogen, R, -OR, or -N(R) 2 ;
  • R 8 is halogen, each of R 10 and R 11 is independently H, optionally substituted C 1 -C 6 aliphatic, optionally substituted 3-8 membered carbocyclyl, optionally substituted 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from N, O, or S, optionally substituted phenyl, or optionally substituted 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from N, O, or S, orR 10 and R 11 taken together with the N atom to which they attach, form optionally substituted 3-8 membered heterocyclyl having 0, 1, or 2 heteroatoms independently selected from N, O, or S in addition to the N atom to which R 10 and R 11 attach; and
  • a MEK inhibitor is a compound of Formula (II-G): or a pharmaceutically acceptable salt thereof, wherein W is S or S(O)2, and each of X 1 , X 2 , X 3 , R 5 , R 4 , L 1 , Ring A and Ring B is as defined above and described in embodiments herein, both singly and in combination.
  • the present disclosure provides a compound set forth in Table 2 above, or a pharmaceutically acceptable salt thereof.
  • a MEK inhibitor is a compound of Formula (III-A): (III-A), or a pharmaceutically acceptable salt thereof, wherein: each is independently a single or double bond; each A is independently optionally substituted 5-6 membered heteroaryl;
  • X 1 , X 2 , X 3 , and X 5 are independently CR 1 or N;
  • X 6 is C(O), O orNH
  • X 7 is CH or N
  • X 8 is N or O; each R 1 is independently hydrogen, deuterium, halo, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 1 -C 6 alkoxy, optionally substituted C3-C10 cycloalkyl, optionally substituted C 6 -C 10 heterocycloalkyl, or optionally substituted C 6 -C 10 aryl;
  • R 2 , R 5 , R 4 , and R 5 are independently hydrogen, C( 2 D)s, OC( 2 D)s, optionally substituted Ci- Ce aliphatic, optionally substituted C 1 -C 6 alkoxy, optionally substituted C3-C10 cycloalkyl, optionally substituted C 6 -C 10 heterocycloalkyl, or optionally substituted C 6 -C 10 aryl; each R 6 is independently hydrogen, deuterium, C( 2 D)s, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 1 -C 6 alkoxy, optionally substituted C3-C10 cycloalkyl, optionally substituted C 6 -C 10 heterocycloalkyl, optionally substituted C 6 -C 10 aryl, or both R 6 taken together with the atom to which they attach form an optionally substituted 3-7 membered hetercycloalkyl ring, or
  • R ? and R 6 taken together with the atoms to which they attach form a 5-6 membered heterocycloalkyl ring; or
  • R 5 and X 5 or X 3 taken together with the atoms to which they attach form a 5-6 membered fused heterocycloalkyl ring;
  • R 7 is O or optionally substituted C1-C6 aliphatic
  • R 8 is absent, hydrogen, deuterium, or optionally substituted C 1 -C 6 aliphatic.
  • X 1 , X 2 , X 3 , and X 5 are independently CR 1 or N. In some embodiments, X 1 , X 2 , X 3 , and X 5 are CR 1 . In some embodiments, X 1 , X 3 , and X 5 are CR 1 and X 2 is N.
  • R 1 is independently hydrogen, halo, optionally substituted Ci- Cg aliphatic, optionally substituted Ci-Cg alkoxy, optionally substituted C3-C10 cycloalkyl, optionally substituted Cg-Cio heterocycloalkyl, and optionally substituted C 6 -C 10 aryl.
  • R 1 is hydrogen, halo, or optionally substituted C 1 -C 6 alkoxy.
  • R 1 is hydrogen, chloro, fluoro, methoxy, ethoxy, propoxy, ethoxy, or hexyloxy.
  • R 1 is hydrogen, fluoro, chloro, or methoxy.
  • each is independently a single or double bond.
  • each A is independently R 8 or optionally substituted 5-6 membered heteroaryl. In some embodiments, each A is independently R 8 .
  • X 8 is N or O. In some embodiments, X 8 is N. In some embodiments, X 8 is O. In some embodiments, X 8 is N; and R 5 and R 8 , taken together with the N atom to which they attach, form an optionally substituted 3-7 membered hetercycloalkyl ring.
  • R 8 is hydrogen, halo, or optionally substituted C 1 -C 6 aliphatic. In some embodiments, R 8 is hydrogen or methyl.
  • each A is independently optionally substituted 5-6 membered heteroaryl. In some embodiments, each A is independently optionally substituted 5- or 6- membered heteroaryl. In some embodiments, each A is independently optionally substituted 5- membered heteroaryl. In some embodiments, each A is optionally substituted imidazole. In some embodiments, each
  • X 6 is O or NH. In some embodiments, X 6 is O. In some embodiments, X 6 is NH. In some embodiments, X 6 is C(O).
  • each R 1 is independently hydrogen, deuterium, halo, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 1 -C 6 alkoxy, optionally substituted C3-C10 cycloalkyl, optionally substituted C 6 -C 10 heterocycloalkyl, and optionally substituted Ce- C10 aryl. In some embodiments, R 1 is halo.
  • R 1 is fluoro, chloro, iodo, - OCF3, cyclopropyl, -CF3, or ethyne. In some embodiments, R 1 is fluoro or iodo. In some embodiments, R 1 is -CN.
  • R 2 is hydrogen, C( 2 D)a, OC( 2 D)3, halo, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 1 -C 6 alkoxy, optionally substituted C3-C10 cycloalkyl, optionally substituted C 6 -C 10 heterocycloalkyl, or optionally substituted C 6 -C 10 aryl.
  • R 2 is optionally substituted C 1 -C 6 aliphatic.
  • R 2 is methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, R 2 is methyl.
  • R 5 is hydrogen, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 1 -C 6 alkoxy, optionally substituted C3-C10 cycloalkyl, optionally substituted C 6 -C 10 heterocycloalkyl, and optionally substituted C 6 -C 10 aryl.
  • R 5 is optionally substituted C3-C10 cycloalkyl.
  • R 5 is optionally substituted C3-C8 cycloalkyl.
  • R 5 is optionally substituted C3-C6 cycloalkyl.
  • R 5 is cyclopropyl, cyclopentyl, cyclobutyl, or cyclohexyl. In some embodiments, R 5 is cyclopropyl or optionally substituted cyclopropyl. In some embodiments, R 5 is cyclopropyl. In some embodiments, R 5 is -(C3Hs)F2.
  • R 4 is hydrogen, C( 2 D)3, OC( 2 D)3, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 1 -C 6 alkoxy, optionally substituted C3-C10 cycloalkyl, optionally substituted C 6 -C 10 heterocycloalkyl, and optionally substituted C 6 -C 10 aryl.
  • R 4 is optionally substituted C 1 -C 6 aliphatic.
  • R 4 is methyl, ethyl, propyl, butyl, pentyl, or hexyl.
  • R 4 is methyl.
  • R 4 is CF 3 .
  • R 5 is hydrogen, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 1 -C 6 alkoxy, optionally substituted C3-C10 cycloalkyl, optionally substituted C 6 -C 10 heterocycloalkyl, and optionally substituted C 6 -C 10 aryl.
  • R 5 is hydrogen, optionally substituted C 1 -C 6 aliphatic, or optionally substituted C 1 -C 6 alkoxy.
  • R 5 is hydrogen.
  • R 5 is absent when X 7 is N forming a double bond with the sulfur atom.
  • each R 6 is independently hydrogen, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 1 -C 6 alkoxy, optionally substituted C3-C10 cycloalkyl, optionally substituted C 6 -C 10 heterocycloalkyl, optionally substituted C 6 -C 10 aryl, or both R 6 taken together with the atom to which they attach form a 3-7 membered hetercycloalkyl ring, or R 5 and R 6 taken together with the atoms to which they attach form a 5-6 membered heterocycloalkyl ring.
  • each R 6 is independently hydrogen or optionally substituted Ci- Ce aliphatic.
  • each R 6 is independently hydrogen, methyl, or - (CH2) 2 N(CH 3 )2.
  • both R 6 taken together with the atom to which they attach form a 3-7 membered hetercycloalkyl ring. In some embodiments, both R 6 taken together with the atom to which they attach form a 3-, 4-, 5-, 6-, or 7-membered hetercycloalkyl ring.
  • R 5 and R 6 taken together with the atoms to which they attach form a 5-6 membered heterocycloalkyl ring. In some embodiments, R 5 and R 6 taken together with the atoms to which they attach form a 5- or 6-membered heterocycloalkyl ring. In some embodiments, R 5 and R 6 taken together with the atoms to which they attach form a 5-membered heterocycloalkyl ring.
  • R 5 and X 5 or X 3 taken together with the atoms to which they attach form a 5-6 membered fused heterocycloalkyl ring.
  • R 5 and X 5 or X 3 taken together with the atoms to which they attach form a 5-6 membered fused heteroaromatic ring.
  • R 6 and X 5 or X 3 taken together with the atoms to which they attach form a 5-6 membered fused heterocycloalkyl ring.
  • R 7 is O or optionally substituted C 1 -C 6 aliphatic. In some embodiments, R 7 is O. In some embodiments, R 7 is optionally substituted C 1 -C 6 aliphatic. In some embodiments, R 7 is methyl.
  • R 8 is absent, hydrogen, deuterium, or optionally substituted C 1 -C 6 aliphatic. In some embodiments, R 8 is hydrogen or methyl.
  • a MEK inhibitor is a compound of Formula (III-B): or a pharmaceutically acceptable salt thereof, wherein: each is independently a single or double bond;
  • X 1 , X 2 , X 3 , and X 5 are independently CR 1 or N;
  • X 6 is C(O), O, or NH
  • X 7 is CH or N
  • X 8 is N or O; each R 1 is independently hydrogen, deuterium, halo, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 1 -C 6 alkoxy, optionally substituted C3-C10 cycloalkyl, optionally substituted C 6 -C 10 heterocycloalkyl, or optionally substituted C 6 -C 10 aryl;
  • R 2 , R 5 , R 4 , and R ? are independently hydrogen, halo, C( 2 D)s, OC( 2 D)3, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 1 -C 6 alkoxy, optionally substituted C3-C10 cycloalkyl, optionally substituted C 6 -C 10 heterocycloalkyl, or optionally substituted C 6 -C 10 aryl; and each R 6 is independently hydrogen, deuterium, C( 2 D)s, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 1 -C 6 alkoxy, optionally substituted C3-C10 cycloalkyl, optionally substituted C 6 -C 10 heterocycloalkyl, optionally substituted C 6 -C 10 aryl, or both R 6 taken together with the atom to which they attach form an optionally substituted 3-7 membered hetercycloalkyl ring, or
  • R 5 and R 6 taken together with the atoms to which they attach form a 5-6 membered heterocycloalkyl ring; or R 5 and X 5 or X 3 taken together with the atoms to which they attach form a 5-6 membered fused heterocycloalkyl ring;
  • R 6 and X 5 or X 3 taken together with the atoms to which they attach form a 5-6 membered fused heterocycloalkyl ring;
  • R 7 is O or optionally substituted C 1 -C 6 aliphatic
  • R 8 is absent, hydrogen, deuterium, or optionally substituted C 1 -C 6 aliphatic.
  • X 1 , X 2 , X 3 , and X 3 are independently CR 1 or N.
  • X 1 , X 2 , X 3 , and X 5 are CR 1 .
  • X 1 , X 3 , and X 5 are CR 1 and X 2 is N.
  • R 1 is independently hydrogen, halo, optionally substituted Ci- Ce aliphatic, optionally substituted C 1 -C 6 alkoxy, optionally substituted C3-C10 cycloalkyl, optionally substituted C 6 -C 10 heterocycloalkyl, and optionally substituted C 6 -C 10 aryl.
  • R 1 is hydrogen, halo, or optionally substituted C 1 -C 6 alkoxy. In some embodiments, R 1 is hydrogen, chloro, fluoro, methoxy, ethoxy, propoxy, ethoxy, or hexyloxy. In some embodiments, R 1 is hydrogen, fluoro, chloro, or methoxy.
  • each is independently a single or double bond.
  • X 6 is O or NH. In some embodiments, X 6 is O. In some embodiments, X 6 is NH. In some embodiments, X 6 is C(O).
  • X 7 is CH or N. In some embodiments, X 7 is CH. In some embodiments, X 7 is N.
  • X 8 is N or O. In some embodiments, X 8 is N. In some embodiments, X 8 is O. In some embodiments, X 8 is N; and R 5 and R 8 , taken together with the N atom to which they attach, form an optionally substituted 3-7 membered hetercycloalkyl ring.
  • each R 1 is independently hydrogen, deuterium, halo, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 1 -C 6 alkoxy, optionally substituted C3-C10 cycloalkyl, optionally substituted C 6 -C 10 heterocycloalkyl, and optionally substituted Ce- C10 aryl.
  • R 1 is halo.
  • R 1 is fluoro, chloro, iodo, - OCF3, cyclopropyl, -CF3, or ethyne.
  • R 1 is fluoro or iodo.
  • R 1 is -CN.
  • R 2 is hydrogen, halo, C( 2 D)3, OC( 2 D)3, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 1 -C 6 alkoxy, optionally substituted C3-C10 cycloalkyl, optionally substituted C 6 -C 10 heterocycloalkyl, or optionally substituted C 6 -C 10 aryl.
  • R 2 is optionally substituted C 1 -C 6 aliphatic.
  • R 2 is methyl, ethyl, propyl, pentyl, butyl, or hexyl. In some embodiments, R 2 is methyl.
  • R 5 is hydrogen, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 1 -C 6 alkoxy, optionally substituted C3-C10 cycloalkyl, optionally substituted C 6 -C 10 heterocycloalkyl, and optionally substituted C 6 -C 10 aryl.
  • R 5 is optionally substituted C3-C10 cycloalkyl.
  • R 5 is optionally substituted C3-C8 cycloalkyl.
  • R 5 is optionally substituted C3-C6 cycloalkyl.
  • R 5 is cyclopropyl, cyclopentyl, cyclobutyl, or cyclohexyl. In some embodiments, R 5 is cyclopropyl or optionally substituted cyclopropyl. In some embodiments, R 5 is cyclopropyl. In some embodiments, R 5 is -(C3H3)F2.
  • R 4 is hydrogen, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 1 -C 6 alkoxy, optionally substituted C3-C10 cycloalkyl, optionally substituted C 6 -C 10 heterocycloalkyl, and optionally substituted C 6 -C 10 aryl. In some embodiments, R 4 is optionally substituted C 1 -C 6 aliphatic. In some embodiments, R 4 is methyl, ethyl, propyl, pentyl, butyl, or hexyl. In some embodiments, R 4 is methyl. In some embodiments, R 4 is CF3.
  • R 4 is hydrogen, C( 2 D)3, OC( 2 D)s, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 1 -C 6 alkoxy, optionally substituted C3-C10 cycloalkyl, optionally substituted C 6 -C 10 heterocycloalkyl, and optionally substituted C 6 -C 10 aryl.
  • R 4 is optionally substituted C 1 -C 6 aliphatic.
  • R 4 is methyl, ethyl, propyl, pentyl, butyl, or hexyl.
  • R 4 is methyl.
  • R 4 is CF3.
  • R 5 is hydrogen, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 1 -C 6 alkoxy, optionally substituted C3-C10 cycloalkyl, optionally substituted C 6 -C 10 heterocycloalkyl, and optionally substituted C 6 -C 10 aryl.
  • R 5 is hydrogen, optionally substituted C 1 -C 6 aliphatic, or optionally substituted C 1 -C 6 alkoxy.
  • R 5 is hydrogen.
  • R 5 is absent when X 7 is N forming a double bond with the sulfur atom.
  • each R 6 is independently hydrogen, deuterium, C( 2 D)3, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 1 -C 6 alkoxy, optionally substituted C3-C10 cycloalkyl, optionally substituted C 6 -C 10 heterocycloalkyl, optionally substituted C 6 -C 10 aryl, or both R 6 taken together with the atom to which they attach form a 3-7 membered hetercycloalkyl ring, or R 5 and R 6 taken together with the atoms to which they attach form a 5-6 membered heterocycloalkyl ring.
  • each R 6 is independently hydrogen or optionally substituted Ci- Cg aliphatic. In some embodiments, each R 6 is independently hydrogen, methyl, or - (CH2) 2 N(CH 3 )2.
  • both R 6 taken together with the atom to which they attach form a 3-7 membered hetercycloalkyl ring. In some embodiments, both R 6 taken together with the atom to which they attach form a 3-, 4-, 5-, 6-, or 7-membered hetercycloalkyl ring.
  • R 5 and R 6 taken together with the atoms to which they attach form a 5-6 membered heterocycloalkyl ring. In some embodiments, R 5 and R 6 taken together with the atoms to which they attach form a 5- or 6-membered heterocycloalkyl ring. In some embodiments, R 5 and R 6 taken together with the atoms to which they attach form a 5-membered heterocycloalkyl ring.
  • R 5 and X 5 or X 3 taken together with the atoms to which they attach form a 5-6 membered fused heterocycloalkyl ring.
  • R 5 and X 5 or X 3 taken together with the atoms to which they attach form a 5-6 membered fused heteroaromatic ring.
  • R 6 and X 5 or X 3 taken together with the atoms to which they attach form a 5-6 membered fused heterocycloalkyl ring.
  • R 7 is O or optionally substituted Ci-Cg aliphatic. In some embodiments, R 7 is O. In some embodiments, R 7 is optionally substituted Ci-Cg aliphatic. In some embodiments, R 7 is methyl.
  • R 8 is absent, hydrogen, deuterium, or optionally substituted Ci-Cg aliphatic. In some embodiments, R 8 is hydrogen or methyl.
  • a MEK inhibitor is a compound of Formulae (III-C) to (III-F):
  • a MEK inhibitor is a compound set forth in Table 3 above, or a pharmaceutically acceptable salt thereof.
  • a MEK inhibitor is a compound of Formula (III-G):
  • X 1 , X 2 , X 4 , and X 5 are independently CR 1 or N;
  • X 6 is O or NH
  • X 7 is CH or N
  • X 8 is N or O; each R 1 is independently hydrogen, deuterium, halo, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 1 -C 6 alkoxy, optionally substituted C3-C10 cycloalkyl, optionally substituted C 6 -C 10 heterocycloalkyl, or optionally substituted C 6 -C 10 aryl;
  • R 2 , R 5 , R 4 , and R ? are independently hydrogen, deuterium, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 1 -C 6 alkoxy, optionally substituted C3-C10 cycloalkyl, optionally substituted C 6 -C 10 heterocycloalkyl, or optionally substituted C 6 -C 10 aryl; and each R 6 is independently hydrogen, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 1 -C 6 alkoxy, optionally substituted C3-C10 cycloalkyl, optionally substituted C 6 -C 10 heterocycloalkyl, optionally substituted C 6 -C 10 aryl, or both R 6 taken together with the atom to which they attach form a 3-7 membered hetercycloalkyl ring, or
  • R ? and R 6 taken together with the atoms to which they attach form a 5-6 membered heterocycloalkyl ring; or
  • R 5 and X 2 or X 4 taken together with the atoms to which they attach form a 5-6 membered fused heterocycloalkyl ring;
  • R 6 and X 2 or X 4 taken together with the atoms to which they attach form a 5-6 membered fused heterocycloalkyl ring;
  • R 7 is O or optionally substituted C 1 -C 6 aliphatic
  • R 8 is absent, hydrogen, deuterium, or optionally substituted C 1 -C 6 aliphatic.
  • X 1 , X 2 , X 4 , and X 5 are independently CR 1 or N. In some embodiments, X 1 , X 2 , X 4 , and X 3 are CR 1 .
  • R 1 is independently hydrogen, halo, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 1 -C 6 alkoxy, optionally substituted C3-C10 cycloalkyl, optionally substituted C 6 -C 10 heterocycloalkyl, and optionally substituted C 6 -C 10 aryl. In some embodiments, R 1 is hydrogen, halo, or optionally substituted C 1 -C 6 alkoxy.
  • R 1 is hydrogen, chloro, fluoro, methoxy, ethoxy, propoxy, ethoxy, or hexyloxy. In some embodiments, R 1 is hydrogen, fluoro, chloro, or methoxy.
  • each is independently a single or double bond.
  • each A is independently R 8 or optionally substituted 5-6 membered heteroaryl. In some embodiments, each A is independently R 8 .
  • X 8 is N or O. In some embodiments, X 8 is N. In some embodiments, X 8 is O. In some embodiments, X 8 is N, and R 5 and R 8 , taken together with the N atom to which they attach form an optionally substituted 3-7 membered hetercycloalkyl ring.
  • each A is independently optionally substituted 5-6 membered heteroaryl. In some embodiments, each A is independently optionally substituted 5- or 6- membered heteroaryl. In some embodiments, each A is independently optionally substituted 5- membered heteroaryl. In some embodiments, each A is optionally substituted imidazole. In some embodiments, each
  • X 6 is O or NH. In some embodiments, X 6 is O. In some embodiments, X 6 is NH. In some embodiments, X 6 is C(O).
  • X 7 is CH or N. In some embodiments, X 7 is CH. In some embodiments, X 7 is N.
  • each R 1 is independently hydrogen, deuterium, halo, optionally substituted Ci-G, aliphatic, optionally substituted C 1 -C 6 alkoxy, optionally substituted C3-C10 cycloalkyl, optionally substituted C 6 -C 10 heterocycloalkyl, and optionally substituted Ce- C10 aryl.
  • R 1 is halo.
  • R 1 is fluoro, chloro, iodo, - OCF3, cyclopropyl, -CF3, or ethyne.
  • R 1 is fluoro or iodo.
  • R 1 is -CN.
  • R 2 is hydrogen, halo, C( 2 D)s, OC( 2 D)s, optionally substituted C1-C6 aliphatic, optionally substituted C1-C6 alkoxy, optionally substituted C3-C10 cycloalkyl, optionally substituted C 6 -C 10 heterocycloalkyl, or optionally substituted C 6 -C 10 aryl.
  • R 2 is optionally substituted C 1 -C 6 aliphatic.
  • R 2 is methyl, ethyl, propyl, pentyl, butyl, or hexyl. In some embodiments, R 2 is methyl.
  • R 5 is hydrogen, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 1 -C 6 alkoxy, optionally substituted C3-C10 cycloalkyl, optionally substituted C 6 -C 10 heterocycloalkyl, and optionally substituted C 6 -C 10 aryl.
  • R 5 is optionally substituted C3-C10 cycloalkyl.
  • R 5 is optionally substituted C3-C8 cycloalkyl.
  • R 5 is optionally substituted C3-C6 cycloalkyl.
  • R 5 is cyclopropyl, cyclopentyl, cyclobutyl, or cyclohexyl. In some embodiments, R 5 is cyclopropyl or optionally substituted cyclopropyl. In some embodiments, R 5 is cyclopropyl. In some embodiments, R 5 is -(C3HOF2.
  • R 4 is hydrogen, C( 2 D)s, OC( 2 D)s, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 1 -C 6 alkoxy, optionally substituted C3-C10 cycloalkyl, optionally substituted C 6 -C 10 heterocycloalkyl, and optionally substituted C 6 -C 10 aryl.
  • R 4 is optionally substituted C 1 -C 6 aliphatic.
  • R 4 is methyl, ethyl, propyl, pentyl, butyl, or hexyl.
  • R 4 is methyl.
  • R 4 is CF 3 .
  • R 5 is hydrogen, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 1 -C 6 alkoxy, optionally substituted C3-C10 cycloalkyl, optionally substituted C 6 -C 10 heterocycloalkyl, and optionally substituted C 6 -C 10 aryl.
  • R 5 is hydrogen, optionally substituted C 1 -C 6 aliphatic, or optionally substituted C 1 -C 6 alkoxy.
  • R 5 is hydrogen.
  • R 5 is absent when X 7 is N forming a double bond with the sulfur atom.
  • each R 6 is independently hydrogen, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 1 -C 6 alkoxy, optionally substituted C3-C10 cycloalkyl, optionally substituted C 6 -C 10 heterocycloalkyl, optionally substituted C 6 -C 10 aryl, or both R 6 taken together with the atom to which they attach form a 3-7 membered hetercycloalkyl ring, or R 5 and R 6 taken together with the atoms to which they attach form a 5-6 membered heterocycloalkyl ring.
  • each R 6 is independently hydrogen or optionally substituted Ci- Ce aliphatic.
  • each R 6 is independently hydrogen, methyl, or - (CH2) 2 N(CH 3 )2.
  • both R 6 taken together with the atom to which they attach form a 3-7 membered hetercycloalkyl ring. In some embodiments, both R 6 taken together with the atom to which they attach form a 3-, 4-, 5-, 6-, or 7-membered hetercycloalkyl ring.
  • R 5 and R 6 taken together with the atoms to which they attach form a 5-6 membered heterocycloalkyl ring. In some embodiments, R 5 and R 6 taken together with the atoms to which they attach form a 5- or 6-membered heterocycloalkyl ring. In some embodiments, R 5 and R 6 taken together with the atoms to which they attach form a 5-membered heterocycloalkyl ring.
  • R 5 and X 2 or X 4 taken together with the atoms to which they attach form a 5-6 membered fused heterocycloalkyl ring.
  • R 5 and X 2 or X 4 taken together with the atoms to which they attach form a 5-6 membered fused heteroaromatic ring.
  • R 6 and X 2 or X 4 taken together with the atoms to which they attach form a 5-6 membered fused heterocycloalkyl ring.
  • R 7 is O or optionally substituted C 1 -C 6 aliphatic. In some embodiments, R 7 is O. In some embodiments, R 7 is optionally substituted C 1 -C 6 aliphatic. In some embodiments, R 7 is methyl.
  • R 8 is absent, hydrogen, deuterium, or optionally substituted C 1 -C 6 aliphatic. In some embodiments, R 8 is hydrogen or methyl.
  • a MEK inhibitor is a compound of Formula (III-H): or a pharmaceutically acceptable salt thereof, wherein: each is independently a single or double bond;
  • X 1 , X 2 , X 4 , and X 5 are independently CR 1 or N;
  • X 6 is O or NH
  • X 7 is CH or N
  • X 8 is N or O; each R 1 is independently hydrogen, deuterium, halo, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 1 -C 6 alkoxy, optionally substituted C3-C10 cycloalkyl, optionally substituted C 6 -C 10 heterocycloalkyl, or optionally substituted C 6 -C 10 aryl;
  • R 2 , R 5 , R 4 , and R ? are independently hydrogen, C( 2 D)a, OC( 2 D)s, optionally substituted Ci- Ce aliphatic, optionally substituted C 1 -C 6 alkoxy, optionally substituted C3-C10 cycloalkyl, optionally substituted C 6 -C 10 heterocycloalkyl, or optionally substituted C 6 -C 10 aryl; and each R 6 is independently hydrogen, deuterium, C( 2 D)s, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 1 -C 6 alkoxy, optionally substituted C3-C10 cycloalkyl, optionally substituted C 6 -C 10 heterocycloalkyl, optionally substituted C 6 -C 10 aryl, or both R 6 taken together with the atom to which they attach form a 3-7 membered hetercycloalkyl ring, or
  • R 5 and R 6 taken together with the atoms to which they attach form a 5-6 membered heterocycloalkyl ring;
  • R 5 and X 2 or X 4 taken together with the atoms to which they attach form a 5-6 membered fused heterocycloalkyl ring;
  • R 6 and X 2 or X 4 taken together with the atoms to which they attach form a 5-6 membered fused heterocycloalkyl ring;
  • R 7 is O or optionally substituted C 1 -C 6 aliphatic
  • R 8 is absent, hydrogen, deuterium, or optionally substituted C 1 -C 6 aliphatic.
  • X 1 , X 2 , X 4 , and X 5 are independently CR 1 or N. In some embodiments, X 1 , X 2 , X 4 , and X 5 are CR 1 .
  • R 1 is independently hydrogen, halo, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 1 -C 6 alkoxy, optionally substituted C3-C10 cycloalkyl, optionally substituted C6-C10 heterocycloalkyl, and optionally substituted C 6 -C 10 aryl. In some embodiments, R 1 is hydrogen, halo, or optionally substituted C 1 -C 6 alkoxy.
  • R 1 is hydrogen, chloro, fluoro, methoxy, ethoxy, propoxy, ethoxy, or hexyloxy. In some embodiments, R 1 is hydrogen, fluoro, chloro, or methoxy.
  • each is independently a single or double bond.
  • each A is independently R 8 or optionally j?
  • each A is independently R 8 .
  • X 8 is N or O.
  • X 8 is N.
  • X 8 is O.
  • X 8 is N; and R 5 and R 8 , taken together with the N atom to which they attach, form an optionally substituted 3-7 membered hetercycloalkyl ring.
  • each A is independently optionally substituted 5-6 membered heteroaryl.
  • each A is independently optionally substituted 5- or 6- membered heteroaryl.
  • each A is independently optionally substituted 5- membered heteroaryl.
  • each A is optionally substituted imidazole.
  • X 6 is O or NH. In some embodiments, X 6 is O. In some embodiments, X 6 is NH. In some embodiments, X 6 is C(O).
  • X 7 is CH or N. In some embodiments, X 7 is CH. In some embodiments, X 7 is N.
  • each R 1 is independently hydrogen, deuterium, halo, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 1 -C 6 alkoxy, optionally substituted C3-C10 cycloalkyl, optionally substituted C 6 -C 10 heterocycloalkyl, and optionally substituted Ce- C10 aryl.
  • R 1 is halo.
  • R 1 is fluoro, chloro, iodo, - OCF3, cyclopropyl, -CF3, or ethyne.
  • R 1 is fluoro or iodo.
  • R 1 is -CN.
  • R 2 is hydrogen, C( 2 D)3, OC( 2 D)3, halo, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 1 -C 6 alkoxy, optionally substituted C3-C10 cycloalkyl, optionally substituted C 6 -C 10 heterocycloalkyl, or optionally substituted C 6 -C 10 aryl.
  • R 2 is optionally substituted C 1 -C 6 aliphatic.
  • R 2 is methyl, ethyl, propyl, pentyl, butyl, or hexyl. In some embodiments, R 2 is methyl.
  • R 5 is hydrogen, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 1 -C 6 alkoxy, optionally substituted C3-C10 cycloalkyl, optionally substituted C 6 -C 10 heterocycloalkyl, and optionally substituted C 6 -C 10 aryl.
  • R 5 is optionally substituted C3-C10 cycloalkyl.
  • R 5 is optionally substituted C3-C8 cycloalkyl.
  • R 5 is optionally substituted C3-C6 cycloalkyl.
  • R 5 is cyclopropyl, cyclopentyl, cyclobutyl, or cyclohexyl. In some embodiments, R 5 is cyclopropyl or optionally substituted cyclopropyl. In some embodiments, R 5 is cyclopropyl. In some embodiments, R 5 is -(C3HOF2.
  • R 4 is hydrogen, C( 2 D)3, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 1 -C 6 alkoxy, optionally substituted C3-C10 cycloalkyl, optionally substituted C 6 -C 10 heterocycloalkyl, and optionally substituted C 6 -C 10 aryl. In some embodiments, R 4 is optionally substituted C 1 -C 6 aliphatic. In some embodiments, R 4 is methyl, ethyl, propyl, pentyl, butyl, or hexyl. In some embodiments, R 4 is methyl. In some embodiments, R 4 is CF 3 .
  • R 5 is hydrogen, optionally substituted C 1 -C 6 aliphatic, optionally substituted C 1 -C 6 alkoxy, optionally substituted C3-C10 cycloalkyl, optionally substituted C 6 -C 10 heterocycloalkyl, and optionally substituted C 6 -C 10 aryl.
  • R 5 is hydrogen, optionally substituted C 1 -C 6 aliphatic, or optionally substituted C 1 -C 6 alkoxy.
  • R 5 is hydrogen.
  • R 5 is absent when X 7 is N forming a double bond with the sulfur atom.
  • each R 6 is independently hydrogen, deuterium, C( 2 D) 3 , optionally substituted Ci-Cs aliphatic, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 3 -Cio cycloalkyl, optionally substituted C 6 -C 10 heterocycloalkyl, optionally substituted C 6 -C 10 aryl, or both R 6 taken together with the atom to which they attach form a 3-7 membered hetercycloalkyl ring, or R? and R 6 taken together with the atoms to which they attach form a 5-6 membered heterocycloalkyl ring.
  • each R 6 is independently hydrogen or optionally substituted Ci- Ce aliphatic. In some embodiments, each R 6 is independently hydrogen, methyl, or - (CH 2 )2N(CH 3 ) 2 .
  • both R 6 taken together with the atom to which they attach form a 3-7 membered hetercycloalkyl ring. In some embodiments, both R 6 taken together with the atom to which they attach form a 3-, 4-, 5-, 6-, or 7-membered hetercycloalkyl ring.
  • R 5 and R 6 taken together with the atoms to which they attach form a 5-6 membered heterocycloalkyl ring. In some embodiments, R 5 and R 6 taken together with the atoms to which they attach form a 5- or 6-membered heterocycloalkyl ring. In some embodiments, R 5 and R 6 taken together with the atoms to which they attach form a 5-membered heterocycloalkyl ring.
  • R 5 and X 2 or X 4 taken together with the atoms to which they attach form a 5-6 membered fused heterocycloalkyl ring.
  • R 5 and X 2 or X 4 taken together with the atoms to which they attach form a 5-6 membered fused heteroaromatic ring.
  • R 7 is O or optionally substituted C 1 -C 6 aliphatic. In some embodiments, R 7 is O. In some embodiments, R 7 is optionally substituted C 1 -C 6 aliphatic. In some embodiments, R 7 is methyl.
  • R 8 is absent, hydrogen, deuterium, or optionally substituted C 1 -C 6 aliphatic. In some embodiments, R 8 is hydrogen or methyl.
  • a MEK inhibitor is a compound set forth in Table 4 above, or a pharmaceutically acceptable salt thereof.
  • a MEK inhibitor is a compound of Formula (III-I):
  • Ring B is an optionally substituted ring selected from C3-C10 cycloalkyl, C3-C10 heterocycloalkyl having 1-4 heteroatoms N, S, or O, phenyl, 5-6 membered heteroaryl having 1-4 heteroatoms N, S, or O, or 6-10 membered bicyclic heteroaryl having 1-4 heteroatoms is H or optionally substituted C 1 -C 6 aliphatic; and each of R 1 , R 2 , R 5 , R 4 , R 5 , R 6 , R 7 , R 8 , X 6 , and X 7 is independently as described above and described in embodiments herein.
  • a MEK inhibitor is a compound of Formulae (III-J), (III-K), or (III-
  • Ring B is an optionally substituted ring selected from C3-C10 cycloalkyl, C3-C10 heterocycloalkyl having 1-4 heteroatoms N, S, or O, phenyl, 5-6 membered heteroaryl having 1-4 heteroatoms N, S, or O, or 6-10 membered bicyclic heteroaryl having 1-4 heteroatoms N, S, or O;
  • R 12 is H or optionally substituted C 1 -C 6 aliphatic; and each of R 1 , R 2 , R 5 , R 4 , R 5 , R 6 , R 7 , R 8 , X 6 , and X 7 is independently as described above and described in embodiments herein.
  • Ring B is optionally substituted C3-C10 cycloalkyl. In some embodiments, Ring B is optionally substituted C3-C10 heterocycloalkyl having 1-4 heteroatoms N, S, or O. In some embodiments, Ring B is optionally substituted phenyl. In some embodiments, Ring B is optionally substituted 5-6 membered heteroaryl having 1 -4 heteroatoms N, S, or O. In some embodiments, Ring B is optionally substituted 6-10 membered bicyclic heteroaryl having 1- 4 heteroatoms N, S, or O.
  • Ring B is optionally substituted . In some embodiments,
  • Ring B is optionally substituted In some embodiments, Ring B is optionally substituted
  • R 12 is H or optionally substituted C 1 -C 6 aliphatic. In some embodiments, R 12 is H. In some embodiments, R 12 is optionally substituted C 1 -C 6 aliphatic. In some embodiments, R 12 is optionally substituted C 1 -C 6 alkyl. In some embodiments, R 12 is unsubstituted C 1 -C 6 alkyl. In some embodiments, R 12 is methyl.
  • a MEK inhibitor is a compound set forth in Table 5 above, or a pharmaceutically acceptable salt thereof.
  • a KRAS G12C inhibitor is selected from adagrasib and sotorasib. In some embodiments, a KRAS G12C inhibitor is adagrasib. In some embodiments, a KRAS G12C inhibitor is sotorasib.
  • an EGFR inhibitor is selected from cetuximab, necitumumab, panitumumab, zalutumumab, nimotuzumab, and matuzumab.
  • an EGFR inhibitor is cetuximab.
  • an EGFR inhibitor is necitumumab.
  • an EGFR inhibitor is panitumumab.
  • an EGFR inhibitor is zalutumumab.
  • an EGFR inhibitor is nimotuzumab.
  • an EGFR inhibitor is matuzumab.
  • an EGFR inhibitor is selected from osimertinib, gefitinib, erlotinib, lapatinib, neratinib, vandetanib, afatinib, brigatinib, dacomitinib, and icotinib.
  • an EGFR inhibitor is Osimertinib.
  • an EGFR inhibitor is gefitinib.
  • an EGFR inhibitor is erlotinib.
  • an EGFR inhibitor is lapatinib.
  • an EGFR inhibitor is neratinib.
  • an EGFR inhibitor is vandetanib. In some embodiments, an EGFR inhibitor is afatinib. In some embodiments, an EGFR inhibitor is brigatinib. In some embodiments, an EGFR inhibitor is dacomitinib. In some embodiments, an EGFR inhibitor is icotinib.
  • an EGFR inhibitor is a “1st generation EGFR tyrosine kinase inhibitor” (1st generation TKI).
  • a 1 st generation TKI refers to reversible EGFR inhibitors, such as gefitinib and erlotinib, which are effective in first-line treatment of NSCLC harboring EGFR activating mutations such as deletions in exon 19 and exon 21 L858R mutation.
  • an EGFR inhibitor is a “2nd generation EGFR tyrosine kinase inhibitor” (2nd generation TKI).
  • 2nd generation TKI refers to covalent irreversible EGFR inhibitors, such as afatinib and dacomitib, which are effective in first-line treatment of NSCLC harboring EGFR activating mutations such as deletions in exon 19 and exon 21 L858R mutation.
  • an EGFR inhibitor is a “3rd generation EGFR tyrosine kinase inhibitor” (3rd generation TKI).
  • a 3rd generation TKI refers to covalent irreversible EGFR inhibitors, such as osimertinib and lazertinib, which are selective to the EGFR activating mutations, such as deletions in exon 19 and exon 21 L858R, alone or in combination with T790M mutation, and have lower inhibitory activity against wild-type EGFR.
  • a TEAD (Transcriptional Enhanced Associate Domain) inhibitor is a compound capable of binding to one or more of TEAD1, TEAD2, TEAD3, or TEAD4.
  • a TEAD inhibitor is selected from the TEAD inhibitors as described in WO 2020/243415, the contents of which are herein incorporated by reference in their entirety. In some embodiments, a TEAD inhibitor is selected from the TEAD inhibitors described in U.S. Patent 11,274,082, the contents of which are herein incorporated by reference in their entirety. In some embodiments, a TEAD inhibitor pharmaceutically acceptable salt thereof.
  • a TEAD inhibitor is selected from the TEAD inhibitors as described in WO 2020/243423, the contents of which are herein incorporated by reference in their entirety. In some embodiments, a TEAD inhibitor is selected from the TEAD inhibitors described in U.S. Patent 11,458,149, the contents of which are herein incorporated by reference in their entirety.
  • a TEAD inhibitor is selected from the TEAD inhibitors as described in WO 2022/120353, the contents of which are herein incorporated by reference in their entirety.
  • a TEAD inhibitor is selected from the TEAD inhibitors as described in WO 2022/120354, the conten ts of which are herein incorporated by reference in their entirety.
  • a TEAD inhibitor is selected from the TEAD inhibitors as described in WO 2022/120355, the contents of which are herein incorporated by reference in their entirety.
  • a TEAD inhibitor is selected from the TEAD inhibitors as described in Pobbati et al., “Targeting the Central Pocket in Human Transcription Factor TEAD as a Potential Cancer Therapeutic Strategy,” Structure 2015, 23, 2076-2086; Gibault et al., “Targeting Transcriptional Enhanced Associate Domains (TEADs),” J. Med. Chem. 2018, 61, 5057-5072; Bum-Erdene et al., “Small -Molecule Covalent Modification of conserveed Cysteine Leads to Allosteric Inhibition of the TEAD’Yap Protein-Protein Interaction,” Cell Chemical Biology 2019, 26, 1-12; Holden et.
  • exemplary inhibitors showing synergistic effects for use in combination with the MEK inhibitors described herein include mTOR inhibitors, PI3Ka inhibitors, S0S1 inhibitors, and SHP2 inhibitors.
  • Non-limiting examples of mTOR inhibitors for use in combination with the MEK inhibitors described herein include everolimus, sirolimus, and temsirolimus.
  • Non-limiting examples of PI3Ka inhibitors for use in combination with the MEK inhibitors described herein include inavolisib, copanlisib, idelalisib, umbralisib, duvelisib, and alpelisib.
  • Non-limiting examples of S0S1 inhibitors for use in combination with the MEK inhibitors described herein include BI-3406 and BAY-293.
  • Non-limiting examples of SHP2 inhibitors for use in combination with the MEK inhibitors described herein include RMC-4550, RMC-4630, IACS-15414, TNO155, JAB-3068, JAB-3312, BBP-398, ERAS-601, and Rl-5C.
  • RAS inhibitors such as KRAS G12C onstate inhibitors, pan-RAS inhibitors, and pan-KRAS inhibitors.
  • KRAS G12C on-state inhibitors for use in combination with the MEK inhibitors described herein include RMC-6291 and RMC-4998.
  • a KRAS G12C onstate inhibitor is RMC-6291.
  • a KRAS G12C onstate inhibitor is RMC-4998.
  • pan-RAS inhibitors for use in combination with the MEK inhibitors described herein include RMC-6236 and RMC-7977.
  • a pan-RAS inhibitor is RMC-6236.
  • a pan-RAS inhibitor is RMC-7977.
  • pan-KRAS inhibitors for use in combination with the MEK inhibitors described herein include BI-2493, BI-3406, and BI-2865.
  • a pan- KRAS inhibitor is BI-2493.
  • a pan-KRAS inhibitor is BI-3406.
  • a pan-KHER2 inhibitors are examples of pan-KRAS inhibitors.
  • Non-limiting examples of HER2 inhibitors for use in combination with the MEK inhibitors described herein include lapatinib (an EGFR/HER2 inhibitor), tucatinib, and neratinib.
  • an HER2 inhibitor is lapatinib.
  • an HER2 inhibitor is tucatinib.
  • an HER2 inhibitor is neratinib.
  • anti-HER2 agents showing synergistic effects for use in combination with the MEK inhibitors described herein include anti-HER2 monoclonal antibodies.
  • Non-limiting examples of anti-HER2 monoclonal antibodies for use in combination with the MEK inhibitors described herein include trastuzumab, pertuzumab, and margetuzumab.
  • an anti-HER2 monoclonal antibody is trastuzumab.
  • an anti-HER2 monoclonal antibody is pertuzumab.
  • an anti-HER2 monoclonal antibody is margetuzumab.
  • ADCs anti-HER2 antibody-drug-conjugates
  • Non-limiting examples of anti-HER2 antibody-drug-conjugates for use in combination with the MEK inhibitors described herein include trastuzumab-deruxtecan and trastuzumab- emtansine.
  • an anti-HER2 ADC is trastuzumab-deruxtecan.
  • an anti-HER2 monoclonal antibody is trastuzumab-emtansine.
  • chemotherapeutic agents for use in combination with the MEK inhibitors described herein include alkylating agents, such as nitrogen mustards, nitrosoureas, alkyl sulfonates, and platinums; anti-metabolites, such as purine antagonists, pyrimidine antagonists, and folic acid antagonists; topoisomerase inhibitors, such as Type I and Type II topoisomerase inhibitors; plant alkaloids, such as vinca alkaloids and taxanes; and antitumor antibiotics.
  • Non-limiting examples of alkylating agents for use in combination with the MEK inhibitors described herein include nitrogen mustards, such as cyclophosphamide, melphalan, and chlorambucil; nitrosoureas, such as carmustine, lomustine, and streptozocin; alkyl sulfonates, such as busulfan; and platinums, such as cisplatin, oxaliplatin, and carboplatin.
  • an alkylating agent is cyclophosphamide.
  • an alkylating agent is melphalan.
  • an alkylating agent is chlorambucil.
  • an alkylating agent is carmustine. In some embodiments, an alkylating agent is lomustine. In some embodiments, an alkylating agent is streptozocin. In some embodiments, an alkylating agent is busulfan. In some embodiments, an alkylating agent is cisplatin. In some embodiments, an alkylating agent is oxaliplatin. In some embodiments, an alkylating agent is carboplatin.
  • Non-limiting examples of anti-metabolites for use in combination with the MEK inhibitors described herein include purine antagonists, such as azathioprine, cladribine, and fludarabine; pyrimidine antagonists, such as gemcitabine, fluorouracil, azacitidine, cytarabine, and capecitabine; folic acid antagonists, such as methotrexate and pemetrexed.
  • an anti-metabolite is azathioprine.
  • an anti-metabolite is cladribine.
  • an anti-metabolite is fludarabine.
  • an anti-metabolite is gemcitabine.
  • an anti-metabolite is fluorouracil. In some embodiments, an anti-metabolite is azacitidine. In some embodiments, an anti-metabolite is cytarabine. In some embodiments, an anti -metabolite is capecitabine. In some embodiments, an anti-metabolite is methotrexate. In some embodiments, an anti-metabolite is pemetrexed.
  • Non-limiting examples of topoisomerase inhibitors for use in combination with the MEK inhibitors described herein include Type I topoisomerase inhibitors, such as irinotecan, topotecan, and camptothecin; and Type II topoisomerase inhibitors such as etoposide, doxorubicin, and epirubicin.
  • a topoisomerase inhibitor is irinotecan.
  • a topoisomerase inhibitor is topotecan.
  • a topoisomerase inhibitor is camptothecin.
  • a topoisomerase inhibitor is etoposide.
  • a topoisomerase inhibitor is doxorubicin.
  • a topoisomerase inhibitor is epirubicin.
  • Non-limiting examples of plant alkaloids for use in combination with the MEK inhibitors described herein include vinca alkaloids, such as vincristine, vinblastine, vinorelbine, and eribulin; and taxanes, such as abraxane, docetaxel, and paclitaxel.
  • a plant alkaloid is vincristine.
  • a plant alkaloid is vinblastine.
  • a plant alkaloid is vinorelbine.
  • a plant alkaloid is eribulin.
  • a plant alkaloid is abraxane.
  • a plant alkaloid is docetaxel.
  • a plant alkaloid is paclitaxel.
  • Non-limiting examples of anti-tumor antibiotics for use in combination with the MEK inhibitors described herein include bleomycin, mitomycin C, and dactinomycin.
  • an anti-tumor antibiotic is bleomycin.
  • an anti-tumor antibiotic is mitomycin C.
  • an anti-tumor antibiotic is dactinomycin.
  • the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of this disclosure or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the amount of compound in compositions of this disclosure is such that is effective to measurably inhibit MEK in a biological sample or in a patient.
  • the amount of compound in compositions of this disclosure is such that is effective to measurably inhibit MEK thereof, in a biological sample or in a patient.
  • composition of this disclosure is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this disclosure is formulated for oral administration to a patient.
  • the terms “subject” and “patient” are used interchangeably and refer to organisms to be treated by the methods of the present disclosure. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and, most preferably, includes humans.
  • mammals e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like
  • humans most preferably, includes humans.
  • compositions of this disclosure refers to a nontoxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
  • Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropy
  • a “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this disclosure that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this disclosure or an active metabolite or residue thereof.
  • active metabolite or residue thereof means that a metabolite or residue thereof also inhibits MEK, or a variant or mutant thereof.
  • compositions of the present disclosure can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions of this disclosure may be aqueous or oleaginous suspension. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3 -butanediol.
  • a non-toxic parenterally acceptable diluent or solvent for example as a solution in 1,3 -butanediol.
  • acceptable vehicles and solvents that can be employed are water, Ringer’s solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • compositions of this disclosure can be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include lactose and com starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents can also be added.
  • compositions of this disclosure can be administered in the form of suppositories for rectal administration.
  • suppositories can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, beeswax and polyethylene glycols.
  • compositions of this disclosure can also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches can also be used.
  • compositions can be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2octyldodecanol, benzyl alcohol and water.
  • compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
  • the pharmaceutically acceptable compositions can be formulated in an ointment such as petrolatum.
  • compositions of this disclosure can also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • compositions of this disclosure are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this disclosure are administered without food. In other embodiments, pharmaceutically acceptable compositions of this disclosure are administered with food.
  • the pharmaceutical compositions of this disclosure are brainpenetrant or CNS-penetrant or provide brain exposure.
  • the terms “brain-penetrant, “CNS-penetrant, “ or “brain exposure” refers that the compounds and pharmaceutical compositions of this disclosure are capable of crossing the blood brain barrier (BBB), and thus are useful for treating a brain or CNS disease, condition, injury or disorder.
  • a brain or CNS disease, condition, injury or disorder is a neurodegenerative diseases, neuronal injury, stroke, genetic disorders, psychiatric disorders, developmental disorders, inflammation, infection or damage, and brain cancers, spinal cord injury (SCI) and traumatic brain injury (TBI).
  • a brain disorder is selected from epilepsy, meningitis, encephalitis including HIV Encephalitis, progressive multifocal leukoencephalopathy, neuromyelitis optica, multiple sclerosis, late-stage neurological trypanosomiasis, amyotrophic lateral sclerosis (ALS), progressive bulbar palsy (PBP), primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), Alzheimer's disease, Parkinson's disease, Huntington's disease, De Vivo disease, and any type of tumor, cancer or hyperproliferative disease in the brain or CNS.
  • epilepsy meningitis
  • encephalitis including HIV Encephalitis
  • progressive multifocal leukoencephalopathy progressive multifocal leukoencephalopathy
  • neuromyelitis optica multiple sclerosis
  • late-stage neurological trypanosomiasis amyotrophic lateral sclerosis (ALS), progressive bulbar palsy (PBP), primary lateral sclerosis (PLS), progressive muscular atrophy (
  • a brain or CNS disease, condition, injury or disorder is a neurological disorder which affects the CNS and/or which has an etiology in the CNS, which includes, but is not limited to, neuropathy, amyloidosis, cancer, an ocular disease or disorder, viral or microbial infection, inflammation, ischemia, neurodegenerative disease, seizure, behavioral disorders, and a lysosomal storage disease.
  • the CNS will be understood to include the eye, which is normally sequestered from the rest of the body by the blood-retina barrier.
  • central nervous system or “CNS” refers to the complex of nerve tissues that control bodily function, and includes the brain and spinal cord.
  • the therapeutic agents can act synergistically. Therefore, the amount of each therapeutic agents in such compositions may be less than that required in a monotherapy utilizing only that therapeutic agent. In some embodiments, the amount of each therapeutic agent in the compositions comprising multiple therapeutic agents ranges from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent. In some embodiments, a MEK inhibitor is administered at a dosage of about 50%, about 55%>, about 60%, about 65%, about 70%, about 75%>, about 80%, about 85%>, about 90%, or about 95% of the amount normally administered for that agent.
  • a KRAS G12C inhibitor is administered at a dosage of about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% of the amount normally administered for that agent.
  • the phrase “normally administered” means the amount an FDA approved therapeutic agent is approved for dosing per the FDA label insert.
  • a specific dosage and treatment regimen for any particular patient depends upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • the amount of a compound of the present disclosure in the composition also depends upon the particular compound in the composition.
  • the present disclosure provides a method of using a compound as described herein for treating a disease or disorder associated with MEK.
  • a disease or disorder associated with MEK is a proliferative disorder.
  • a disease or disorder associated with MEK is a cancer.
  • a disease or disorder associated with MEK is a cancer as described herein.
  • provided herein are methods of treating, reducing the severity of, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, of a disease or disorder characterized by or associated with increased MEK expression and/or increased MEK activity, comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound of the present disclosure, or pharmaceutically acceptable composition thereof.
  • provided herein are methods of treating, reducing the severity of, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof of a disease or disorder in which inhibition or antagonizing of MEK activity is beneficial, comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound of the present disclosure, or pharmaceutically acceptable composition thereof.
  • a compound as described herein is an “ATP non-competitive MEK inhibitor” that stabilizes or “glues” the complex formed between MEK and KSR, and/or BRAF/CRAF.
  • a compound as described herein allosterically binds an “inhibitor pocket” formed at an interaction interface between human MEK (MEK1 or MEK2) and human Kinase Suppressor of Ras (KSR1 or KSR2 or the KSR homolog BRAF or CRAF) adjacent to ATP in a physiological complex between MEK and KSR (or BRAF or CRAF), forming an inhibitor-inhibitor pocket complex.
  • a compound as described herein is an ATP non-competitive kinase inhibitor.
  • a compound as described herein has a structure such that when bound to the inhibitor-inhibitor pocket complex, the complex comprises the structural elements: (a) at least one moiety of the inhibitor engaging A825 of hKSRl, or P878 of hKSR2, or R662 of BRAF, or R554 of CRAF (b) at least one moiety engaging R234 of hMEKl or R238 of hMEK2, wherein R234 is within about 5 A to about 8 A from any atoms of hKSRl or hKSR2 or BRAF or CRAF.
  • a compound as described herein does not engage one or more of 1216 in hMEKl or 1220 of hMEK2 and A825 in KSR1 or P878 in KSR2.
  • a compound as described herein comprises a structural element according to (a) as described in the above paragraph, which is an H-bond acceptor, inter alia, an oxygen or nitrogen atom, or a fluorine atom attached to an aromatic ring, or an H bond donor.
  • a compound as described herein comprises a structural element according to (a) as described in the above paragraph, which is a moiety of a linker engaging the backbone of A825 of hKSRl, or P878 of hKSR2, or R662 of hBRAF, or R554 of CRAF, directly or through a water-mediated contact.
  • a compound as described herein comprising one or more of the following:
  • At least one moiety is a H-bond acceptor or donor engaging the backbone carbonyl of N823 of hKSRl, or T876 of hKSR2 through a water-mediated contact or backbone amino group of R662 of hBRAF or R554 of hCRAF directly;
  • At least one moiety is a heteroaryl group engaging Ml 43 of hMEKl or Ml 47 of hMEK2;
  • At least one moiety is a heteroaryl group engaging F209 of hMEKl or F213 of hMEK2;
  • At least one moiety (inter alia, a H-bond acceptor) is engaging the backbone amino group of S212 of hMEKl or S216 of hMEK2;
  • (l) at least one moiety engaging M219 of hMEKl or M223 of hMEK2 where hMEKl residues 215-219 adopt a helical conformation.
  • a moiety corresponding to (c) as described above is selected from substituted or unsubstituted alkyl or cycloalkyl.
  • a backbone CO residue of a compound as described herein engages with T876 of hKSR2 or N823 of hKSRl.
  • a compound as described herein engages with a binding pocket, which is lined by the hMEKl residues R234 and M230, or hMEK2 residues R238 and M234, and P877 of KSR2 or A825 of KSR1 or R662 ofBRAF or R554 of CRAF.
  • a compound as described herein engages a binding pocket via multiple hydrogen bond contacts, including through a water mediated H-bond to Argl89 and Arg234 in hMEKl or ARG193 and A238 of hMEK2, as well as a direct H-bond to the backbone of the pre-helix aG loop -NH- of Arg662 ofBRAF or ARG 554 of CRAF.
  • a compound as described herein engage A825 of hKSRl or P878 of hKSR2 or R662 of BRAF or R554 of CRAF. In some embodiments, a compound as described herein has a distance of less than or equal to about 5 A to about 8 A from at least one moiety selected from A825 of hKSRl, P878 of hKSR2, and R662 ofBRAF and R554 of CRAF.
  • the present disclosure provides a method for treating one or more disorders, diseases, and/or conditions wherein the disorder, disease, or condition includes, but is not limited to, a cellular proliferative disorder, comprising administering to a patient in need thereof, a MEK inhibitor compound as described herein, or a pharmaceutical salt or composition thereof.
  • the cellular proliferative disorder is cancer.
  • the canceris characterized by increased MEK expression and/or increased MEK activity, i.e., “increased activated MEK.”
  • an increase can be by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 2-fold, about 3-fold, about 4- fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20- fold, about 25-fold, about 50-fold, about 100-fold, or higher, relative to a control or baseline amount of a function, or activity, or concentration.
  • the terms “increased expression” and/or “increased activity” of a substance, such as MEK, in a sample or cancer or patient refers to an increase in the amount of the substance, such as MEK, of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 25-fold, about 50- fold, about 100-fold, or higher, relative to the amount of the substance, such as MEK, in a control sample or control samples, such as an individual or group of individuals who are not suffering from the disease or disorder (e.g.
  • a subject can also be determined to have an "increased expression” or “increased activity” of MEK if the expression and/or activity of MEK is increased by one standard deviation, two standard deviations, three standard deviations, four standard deviations, five standard deviations, or more, relative to the mean (average) or median amount of MEK in a control group of samples or a baseline group of samples or a retrospective analysis of patient samples.
  • control or baseline expression levels can be previously determined, or measured prior to the measurement in the sample or cancer or subject, or can be obtained from a database of such control samples.
  • the present disclosure provides a method for treating or preventing or reducing the risk of a cancer in patient comprising administering to the patient a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • a "cancer,” as used herein, refers a broad group of various diseases characterized by the uncontrolled growth of abnormal cells in the body. Unregulated cell division and growth divide and grow results in the formation of malignant tumors that invade neighboring tissues and can also metastasize to distant parts of the body through the lymphatic system or bloodstream.
  • the cancer or proliferative disorder or tumor to be treated using the compounds and methods and uses described herein include, but are not limited to, a hematological cancer, a lymphoma, a myeloma, a leukemia, a neurological cancer, skin cancer, breast cancer, a prostate cancer, a colorectal cancer, lung cancer, head and neck cancer, a gastrointestinal cancer, a liver cancer, a pancreatic cancer, a genitourinary cancer, a bone cancer, renal cancer, and a vascular cancer.
  • the cancer is a K-Ras mutant cancer.
  • the K-Ras mutant cancer is an activated mutant K-Ras cancer.
  • the K-Ras mutant cancer is a cancer having a mutant or variant K-Ras G12.
  • the mutant or variant K-Ras G12 is K-Ras G12D, K-Ras G12V, K-Ras G12C, K-Ras G12R, K-Ras G12A, or any combination thereof.
  • the mutant or variant K-Ras G12 is K-Ras G12D.
  • the mutant or variant K-Ras G12 is K-Ras G12V. In some embodiments, the mutant or variant K-Ras G12 is K-Ras G12C. In some embodiments, the mutant or variant K- Ras G12 is K-Ras G12R. In some embodiments, the mutant or variant K-Ras G12 is K-Ras G12A. In some embodiments, the K-Ras mutant cancer is a cancer having a mutant or variant K-Ras G13. In some embodiments, the mutant or variant K-Ras G13 is K-Ras G13D, K-Ras G13C, or any combination thereof.
  • the K-Ras mutant cancer is a cancer having a mutant or variant K-Ras Q61.
  • the mutant or variant K-Ras Q61 is K-Ras Q61H, K-Ras Q61R, or any combination thereof.
  • the K-Ras mutant cancer is a cancer having a mutant or variant K-Ras A146.
  • the mutant or variant K- Ras A146 is K-Ras A146T.
  • the K-Ras mutant cancer is a cancer having a mutant or variant K-Ras G12D, K-Ras G12V, K-Ras G12C, K-Ras G12R, K-Ras G12A, K-Ras G13D, K-Ras G13C, K-Ras Q61H, K-Ras Q61R, K-Ras A146T, or any combination thereof.
  • the cancer is a mutant B-Raf cancer.
  • the mutant B-Raf cancer comprises a B-Raf amplification.
  • a “B-Raf amplification” refers to a cancer or cancer cell comprising at least three B-Raf copies, at least four B-Raf copies, at least five B-Raf copies, at least six B-Raf copies, at least seven B-Raf copies, at least eight B- Raf copies, at least nine B-Raf copies, at least ten B-Raf copies, or more.
  • the mutant B-Raf cancer is a cancer having a mutant or variant B-Raf V600, also referred to as a “Class I B-Raf mutation.”
  • the mutant or variant B-Raf V600 is B-Raf V600E, V600K, V600D, V600R, or any combination thereof.
  • the mutant B-Raf cancer is a cancer having a mutant or variant B-Raf K601, B-Raf P367, B-Raf G464, B-Raf L485, B-Raf E586, B-Raf T588, B-Raf T599, B-Raf L597, B-Raf G469, or any combination thereof, which are also collectively referred to as “Class II B-Raf mutations.”
  • the mutant B-Raf K601 is B-Raf K601E, K601N, K601T, or any combination thereof.
  • the mutant B-Raf P367 is B-Raf P367L, P367S, or any combination thereof.
  • the mutant B-Raf G464 is B-Raf G464V, G464E, or any combination thereof.
  • the mutant B-Raf L485 is L485W.
  • the mutant B-Raf E586 is E586K.
  • the mutant B-Raf T599 is T588TT, T588TS, T599I, T599K, or any combination thereof.
  • the mutant B-Raf L597 is B-Raf L597Q, L597R, L597S, L597V, or any combination thereof.
  • the mutant B-Raf G469 is B-Raf G469A, G469V, G469R, or any combination thereof.
  • the mutant B-Raf cancer is a cancer having a mutant or variant B- RafD287, B-RafV459, B-Raf G466, B-Raf S467, B-Raf G469, B-RafN581, B-Raf D595, B-Raf F595, B-Raf G596, or any combination thereof, which are also collectively referred to as “Class III B-Raf mutations.”
  • the mutant B-Raf D287 is B-Raf D287N.
  • the mutant B-Raf V459 is B-Raf B459L.
  • the mutant B-Raf G466 is B-Raf G466A, B-Raf G466E, B-Raf G466V, or any combination thereof.
  • the mutant B-Raf S467 is B-Raf S467L.
  • the mutant B-Raf G469 is B-Raf-G469E.
  • the mutant B-Raf N581 is B-Raf N581I, B-Raf N581S, B-RafN581T, or any combination thereof.
  • the mutant B-Raf D595 is B-Raf D595A, B-Raf D595G, B-Raf D595H, B-Raf D595N, or any combination thereof.
  • the mutant B-Raf F595 is B-Raf F595L.
  • the mutant B- Raf G596 is B-Raf G596D, B-Raf G596R, or any combination thereof.
  • the mutant B-Raf cancer comprises a B-Raf amplification and at least one B-Raf mutant or variant B- Raf Class I, Class II, or Class III mutation.
  • the cancer is an N-Ras mutant cancer.
  • the N-Ras mutant cancer is an activated mutant N-Ras cancer.
  • the N-Ras mutant cancer is a cancer having a mutant or variant N-Ras G12.
  • the mutant or variant N-Ras G12 is N-Ras G12D, N-Ras G12V, N-Ras G12C, N-Ras G12A, N-Ras G12R, N-Ras G12S, or any combination thereof.
  • the mutant or variant N-Ras G12 is N-Ras G12D.
  • the mutant or variant N-Ras G12 is N-Ras is N-Ras G12V. In some embodiments, the mutant or variant N-Ras G12 is N-Ras G12C. In some embodiments, the mutant or variant N-Ras G12 is N-Ras G12R. In some embodiments, the mutant or variant N- Ras G12 is N-Ras is N-Ras G12A. In some embodiments, the mutant or variant N-Ras G12 is N- Ras G12S. In some embodiments, the N-Ras mutant cancer is a cancer having a mutant or variant N-Ras Q61.
  • the N-Ras mutant cancer is a cancer having a mutant or variant N-Ras G12D, N-Ras G12V, N-Ras G12C, N-Ras G12R, N-Ras G12A, N-Ras G12S, N-Ras Q61, or any combination thereof.
  • the cancer is a C-Raf mutant cancer.
  • the mutant C-Raf cancer comprises a C-Raf amplification.
  • a “C-Raf amplification” refers to a cancer cell comprising at least three C-Raf copies, at least four C-Raf copies, at least five C-Raf copies, at least six C-Raf copies, at least seven C-Raf copies, at least eight C-Raf copies, at least nine C-Raf copies, at least ten C-Raf copies, or more.
  • the mutant C-Raf cancer is a cancer having a mutant or variant C-Raf S427.
  • the mutant or variant C-Raf S427 is C-Raf S427G.
  • the mutant C-Raf cancer is a cancer having a mutant or variant C-Raf 1448.
  • the mutant C-Raf 1448 is C-Raf I448V.
  • the mutant C-Raf cancer comprises a C-Raf amplification and/or at least one C-Raf mutant or variant C-Raf.
  • the cancer is an NF 1 and/or NF2 mutant cancer.
  • an “NF1 mutant cancer” refers to a cancer having a mutant or variant gene encoding the neurofibromin protein, and includes deletion mutations, loss-of-function mutations, microdeletion mutations, missense mutations, copy number loss mutations, and substitution mutations.
  • an “NF2 mutant cancer” refers to a cancer having a mutant or variant gene encoding the Merlin protein (also known as schwannomin protein), and includes deletion mutations, loss-of- function mutations, microdeletion mutations, missense mutations, copy number loss mutations, and substitution mutations.
  • a cancer is mediated by activation of transcriptional coactivator with PDZ binding motif/Yes-associated protein transcription coactivator (TAZ/YAP).
  • a cancer is mediated by modulation of the interaction of YAP/TAZ with TEAD (e.g.,TEADl, TEAD2, TEAD3, and/or TEAD4).
  • the cancer is characterized by or associated with increased TEAD (e.g.,TEADl, TEAD2, TEAD3, and/or TEAD4) expression and/or increased TEAD (c.g.,TEADl, TEAD2, TEAD3, and/or TEAD4) activity.
  • the cancer is a cancer in which YAP is localized in the nucleus of the cancer cells.
  • the cancer is characterized or associated with a genetic alteration in one or more Hippo pathway genes.
  • genetic alteration in one or more Hippo pathway genes refers to that certain percentage of cells in a sample, such as a tumor sample, having a detectable amount of genetic alteration in one or more Hippo pathway genes.
  • a genetic alteration in a gene can refer, for example, to a loss-of-function mutation in the gene (including, for example, frameshifts, nonsense mutations and splicing mutations), a change in gene copy number (including, for example, copy gain, amplification, copy loss, or deletion), or a fusion of the gene with another gene, such as, for example, a TAZ-CAMTA1 fusion or YAP1-TFE3 fusion.
  • genetic alteration in Hippo pathway genes refers to that about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or 100% of cells, such as tumor cells, in a sample have at least about three copies of genetically altered Hippo pathway genes, at least about four copies of genetically altered Hippo pathway genes, at least about five copies of genetically altered Hippo pathway genes, at least about six copies of genetically altered Hippo pathway genes, at least about seven copies of genetically altered Hippo pathway genes, at least about eight copies of genetically altered Hippo pathway genes, at least about nine copies of genetically altered Hippo pathway genes, at least about ten copies of genetically altered Hippo pathway genes, at least about eleven copies of genetically altered Hippo pathway genes, at least about twelve copies of genetically altered Hippo pathway genes,
  • genetic alteration in Hippo pathway genes refers to that about 10% tumor cells in a sample have at least about 15 copies of genetically altered Hippo pathway genes. In some embodiments, genetic alteration in Hippo pathway genes refers to that about 40% tumor cells in a sample have at least about 4 copies of genetically altered Hippo pathway genes. In some embodiments, genetic alteration in Hippo pathway genes refers to that about 10% tumor cells in a sample have at least about four copies of genetically altered Hippo pathway genes.
  • a Hippo pathway gene is NF2.
  • the genetic alteration in the one or more Hippo pathway genes is NF2 deficiency.
  • NF2 deficiency refers to NF2 loss of function mutations.
  • NF2 deficiency refers to NF2 copy losses or deletions.
  • NF2 deficiency refers to absent or very low NF2 mRNA expression.
  • a Hippo pathway gene is YAP1.
  • the genetic alteration in the one or more Hippo pathway genes is YAP1 amplification.
  • the genetic alteration in the one or more Hippo pathway genes is a YAP1 fusion, such as a YAP1-TFE3 fusion.
  • a Hippo pathway gene is TAZ.
  • the genetic alteration in the one or more Hippo pathway genes is TAZ amplification.
  • the genetic alteration in the one or more Hippo pathway genes is a TAZ fusion, such as a TAZ-CAMTA1 fusion.
  • a Hippo pathway gene is LATS 1/2.
  • the genetic alteration in the one or more Hippo pathway genes is LATS 1/2 copy number loss or deletion.
  • a Hippo pathway gene is MST1/2.
  • a Hippo pathway gene is BAP1.
  • a cancer is characterized by a mutant Ga-protein.
  • a mutant Ga-protein is selected from G12, G13, Gq, Gi l, Gi, Go, and Gs.
  • a mutant Ga-protein is G12.
  • a mutant Ga-protein is G13.
  • a mutant Ga-protein is Gq.
  • a mutant Ga-protein is Gl 1 .
  • a mutant Ga-protein is Gi.
  • a mutant Ga-protein is Go.
  • a mutant Ga-protein is Gs.
  • the cancer is selected from non-small cell lung cancer (NSCLC), pancreatic cancer, colorectal cancer (CRC), uterine carcinoma, endometrial carcinoma, bladder cancer, head and neck cancer, thyroid cancer, melanoma, multiple myeloma, acute myeloid leukemia (AML), low-grade serous ovarian cancer, neurofibroma, and glioma.
  • NSCLC non-small cell lung cancer
  • CRC colorectal cancer
  • uterine carcinoma endometrial carcinoma
  • bladder cancer bladder cancer
  • head and neck cancer thyroid cancer
  • melanoma multiple myeloma
  • AML acute myeloid leukemia
  • neurofibroma neurofibroma
  • glioma glioma
  • the cancer is a K-Ras mutant non-small cell lung cancer (NSCLC).
  • NSCLC non-small cell lung cancer
  • the cancer is a K-Ras mutant pancreatic cancer.
  • the cancer is a K-Ras mutant colorectal cancer.
  • the cancer is a K-Ras mutant uterine carcinoma.
  • the cancer is a K-Ras mutant endometrial carcinoma.
  • the cancer is a K-Ras mutant bladder cancer.
  • the cancer is a K-Ras mutant head and neck cancer. In some embodiments of the methods and uses described herein, the cancer is a K-Ras mutant thyroid cancer. In some embodiments of the methods and uses described herein, the cancer is a K-Ras mutant low-grade serous ovarian cancer. In some embodiments of the methods and uses described herein, the cancer is an N-Ras mutant melanoma. In some embodiments of the methods and uses described herein, the cancer is an N-Ras mutant multiple myeloma. In some embodiments of the methods and uses described herein, the cancer is an N-Ras mutant acute myeloid leukemia (AML).
  • AML acute myeloid leukemia
  • the cancer is an N-Ras mutant Bladder cancer. In some embodiments of the methods and uses described herein, the cancer is a K-Ras mutant low-grade serous ovarian cancer. In some embodiments of the methods and uses described herein, the cancer is a B-Raf mutant non-small cell lung cancer (NSCLC). In some embodiments of the methods and uses described herein, the cancer is a C-Raf mutant bladder cancer. In some embodiments of the methods and uses described herein, the cancer is an NF1 mutant glioma. In some embodiments of the methods and uses described herein, the cancer is an NF1 mutant nonsmall cell lung cancer (NSCLC). In some embodiments of the methods and uses described herein, the cancer is an NF2 mutant neurofibroma.
  • NSCLC non-small cell lung cancer
  • the cancer is lung cancer, thyroid cancer, ovarian cancer, colorectal cancer, prostate cancer, cancer of the pancreas, cancer of the esophagus, liver cancer, breast cancer, skin cancer, or mesothelioma.
  • the cancer is mesothelioma, such as malignant mesothelioma.
  • a cancer includes, without limitation, leukemias (e.g., acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin’s disease or non-Hodgkin’s disease), Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angios
  • leukemias e
  • a cancer is glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.
  • GBM glioblastoma multiforme
  • medulloblastoma craniopharyngioma
  • ependymoma pinealoma
  • hemangioblastoma acoustic neuroma
  • oligodendroglioma oligodendroglioma
  • schwannoma oligodendroglioma
  • Grade I Pilocytic Astrocytoma, Grade II - Low-grade Astrocytoma, Grade III - Anaplastic Astrocytoma, or Grade IV - Glioblastoma (GBM)), chordoma, CNS lymphoma, craniopharyngioma, brain stem glioma, ependymoma, mixed glioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumors, primitive neuroectodermal (PNET) tumor, or schwannoma.
  • GBM Glioblastoma
  • the cancer is a type found more commonly in children than adults, such as brain stem glioma, craniopharyngioma, ependymomajuvenile pilocytic astrocytoma (JPA), medulloblastoma, optic nerve glioma, pineal tumor, primitive neuroectodermal tumors (PNET), or rhabdoid tumor.
  • the patient is an adult human. In some embodiments, the patient is a child or pediatric patient.
  • Cancer includes, in another embodiment, without limitation, mesothelioma, hepatobilliary (hepatic and billiary duct), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin’s Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia,
  • a cancer is a solid tumor, such as a sarcoma, carcinoma, or lymphoma.
  • Solid tumors generally comprise an abnormal mass of tissue that typically does not include cysts or liquid areas.
  • the cancer is selected from renal cell carcinoma, or kidney cancer; hepatocellular carcinoma (HCC) or hepatoblastoma, or liver cancer; melanoma; breast cancer; colorectal carcinoma, or colorectal cancer; colon cancer; rectal cancer; anal cancer; lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC); ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomy
  • a cancer is hepatocellular carcinoma (HCC).
  • the cancer is hepatoblastoma.
  • the cancer is colon cancer.
  • the cancer is rectal cancer.
  • the cancer is ovarian cancer, or ovarian carcinoma.
  • the cancer is ovarian epithelial cancer.
  • the cancer is fallopian tube cancer.
  • the cancer is papillary serous cystadenocarcinoma.
  • the cancer is uterine papillary serous carcinoma (UPSC).
  • the cancer is hepatocholangiocarcinoma.
  • the cancer is soft tissue and bone synovial sarcoma. In some embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is osteosarcoma. In some embodiments, the cancer is anaplastic thyroid cancer. In some embodiments, the cancer is adrenocortical carcinoma. In some embodiments, the cancer is pancreatic cancer, or pancreatic ductal carcinoma. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is glioma. In some embodiments, the cancer is malignant peripheral nerve sheath tumors (MPNST). In some embodiments, the cancer is neurofibromatosis- 1 associated MPNST. In some embodiments, the cancer is Waldenstrom’s macroglobulinemia. In some embodiments, the cancer is medulloblastoma.
  • MPNST peripheral nerve sheath tumors
  • the cancer is neurofibromatosis- 1 associated MPNST.
  • the cancer is Waldenstrom
  • a cancer is a viral-associated cancer, including human immunodeficiency virus (HIV) associated solid tumors, human papillomavirus (HPV)-16 positive incurable solid tumors, and adult T-cell leukemia, which is caused by human T-cell leukemia virus type I (HTLV-I) and is a highly aggressive form of CD4+ T-cell leukemia characterized by clonal integration of HTLV-I in leukemic cells (See https://clinicaltrials.gov/ct2/show/study/ NCT02631746); as well as virus-associated tumors in gastric cancer, nasopharyngeal carcinoma, cervical cancer, vaginal cancer, vulvar cancer, squamous cell carcinoma of the head and neck, and Merkel cell carcinoma.
  • HCV human immunodeficiency virus
  • HPV human papillomavirus
  • the methods or uses described herein inhibit or reduce or arrest or ameliorate the growth or spread of a cancer or tumor.
  • the tumor is treated by arresting, reducing, or inhibiting further growth of the cancer or tumor.
  • the methods or uses described herein increase or potentiate or activate one or more immune responses to inhibit or reduce or arrest or ameliorate the growth or spread of a cancer or tumor.
  • the cancer or tumor is treated by reducing the size (e.g., volume or mass) of the cancer or tumor by at least 5%, at least 10%, at least 25%, at least 50%, at least 75%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% relative to the size of the cancer or tumor prior to treatment.
  • cancers or tumors are treated by reducing the quantity of the cancers or tumors in the patient by at least 5%, at least 10%, at least 25%, at least 50%, at least 75%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% relative to the quantity of cancers or tumors prior to treatment.
  • a patient treated using the methods or uses described herein exhibits progression-free survival of at least about one month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about one year, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years after the treatment is initiated.
  • a patient treated using the methods or uses described herein exhibits an overall survival of at least about one month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about one year, at least about 14 months, at least about 16 months, at least about 18 months, at least about 20 months, at least about 22 months, at least about two years, at least about three years, at least about four years, or at least about five years after the treatment is initiated.
  • a patient treated using the methods or uses described herein exhibits an objective response rate (ORR) of at least about 15%, at least about 20%, at least about 25%, at least about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.
  • ORR objective response rate
  • the compounds and compositions, according to the method of the present disclosure may be administered using any amount and any route of administration effective for inhibiting MEK and treating or lessening the severity of a disease, for example, as those described herein.
  • the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease or condition, the particular agent, its mode of administration, and the like.
  • Compounds of the disclosure are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
  • dosage unit form refers to a physically discrete unit of agent appropriate for the patient to be treated.
  • the specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.
  • patient means an animal, preferably a mammal, and most preferably a human.
  • a RAS inhibitor can be administered separately from a MEK inhibitor, as part of a multiple dosage regimen.
  • a RAS inhibitor may be part of a single dosage form, mixed together with a MEK inhibitor in a single composition.
  • a RAS inhibitor and a MEK inhibitor can be administered simultaneously, sequentially or within a period of time from one another, for example within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours from one another.
  • a RAS inhibitor and a MEK inhibitor are administered as a multiple dosage regimen with greater than 24 hours apart.
  • a KRAS G12C inhibitor can be administered separately from aMEK inhibitor, as part of a multiple dosage regimen.
  • a KRAS G12C inhibitor may be part of a single dosage form, mixed together with a MEK inhibitor in a single composition.
  • a KRAS G12C inhibitor and a MEK inhibitor can be administered simultaneously, sequentially or within a period of time from one another, for example within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours from one another.
  • a KRAS G12C inhibitor and a MEK inhibitor are administered as a multiple dosage regimen with greater than 24 hours apart.
  • An EGFR inhibitor can be administered separately from a MEK inhibitor, as part of a multiple dosage regimen.
  • an EGFR inhibitor may be part of a single dosage form, mixed together with an MEK inhibitor in a single composition.
  • an EGFR inhibitor and a MEK inhibitor can be administered simultaneously, sequentially or within a period of time from one another, for example within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours from one another.
  • an EGFR inhibitor and a MEK inhibitor are administered as a multiple dosage regimen with greater than 24 hours apart.
  • a TEAD inhibitor can be administered separately from a MEK inhibitor, as part of a multiple dosage regimen.
  • a TEAD inhibitor may be part of a single dosage form, mixed together with an MEK inhibitor in a single composition.
  • a TEAD inhibitor and a MEK inhibitor can be administered simultaneously, sequentially or within a period of time from one another, for example within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours from one another.
  • a TEAD inhibitor and a MEK inhibitor are administered as a multiple dosage regimen with greater than 24 hours apart.
  • An anti-HER2 agent can be administered separately from a MEK inhibitor, as part of a multiple dosage regimen.
  • an anti-HER2 agent may be part of a single dosage form, mixed together with an MEK inhibitor in a single composition.
  • an anti-HER2 agent and a MEK inhibitor can be administered simultaneously, sequentially or within a period of time from one another, for example within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours from one another.
  • an anti-HER2 agent and a MEK inhibitor are administered as a multiple dosage regimen with greater than 24 hours apart.
  • a chemotherapeutic agent can be administered separately from a MEK inhibitor, as part of a multiple dosage regimen.
  • a chemotherapeutic agent may be part of a single dosage form, mixed together with an MEK inhibitor in a single composition.
  • a chemotherapeutic agent and a MEK inhibitor can be administered simultaneously, sequentially or within a period of time from one another, for example within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours from one another.
  • a chemotherapeutic agent and a MEK inhibitor are administered as a multiple dosage regimen with greater than 24 hours apart.
  • the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this disclosure.
  • a MEK inhibitor can be administered with a KRAS G12C inhibitor simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.
  • the present disclosure provides a single unit dosage form comprising a MEK inhibitor, a KRAS G12C inhibitor, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the present disclosure also provides a single unit dosage form comprising a MEK inhibitor, a RAS inhibitor, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the present disclosure also provides a single unit dosage form comprising a MEK inhibitor, an EGFR inhibitor, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the present disclosure also provides a single unit dosage form comprising a MEK inhibitor, a TEAD inhibitor, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the present disclosure also provides a single unit dosage form comprising a MEK inhibitor, an anti-HER2 agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the present disclosure also provides a single unit dosage form comprising a MEK inhibitor, a chemotherapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • a MEK inhibitor can also be administered with a KRAS G12C inhibitor simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present disclosure provides a single unit dosage form comprising a MEK inhibitor and a KRAS G12C inhibitor, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. [00379] A MEK inhibitor can also be administered with a RAS inhibitor simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present disclosure provides a single unit dosage form comprising a MEK inhibitor and a RAS inhibitor, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • a MEK inhibitor can also be administered with an anti-HER2 agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present disclosure provides a single unit dosage form comprising a MEK inhibitor and an anti- HER2 agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • a MEK inhibitor can also be administered with a chemotherapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present disclosure provides a single unit dosage form comprising a MEK inhibitor and a chemotherapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • compositions of this disclosure can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the disease or disorder being treated.
  • the compounds of the disclosure may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents,
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol.
  • Suitable vehicles and solvents that may be employed are water, Ringer’s solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • Injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle.
  • injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide- polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this disclosure with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay
  • Solid compositions of a similar type may also be employed as fdlers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
  • Solid compositions of a similar type may also be employed as fdlers in soft and hard-fdled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g, tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • buffering agents include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this disclosure.
  • the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
  • Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • pellets were resuspended in NP-40 buffer (50 mM Tris pH 7.8, 100 mM NaCl, 0.5% (v/v) NP-40, 10% (v/v) glycerol, 1 mM EDTA) supplemented with protease and phosphatase inhibitor cocktail (Thermo Fisher, 78440) and incubated on ice for 30 min. Lysates were centrifuged for 20 min at 2,100g, and supernatants are collected. Cleared lysates were quantified using BCA reagent (Pierce, 23225), with BSA as a standard.
  • AsPCl cells KRAS G12D pancreatic tumor cells
  • AsPCl cells were seeded at 20,000 cells/well overnight in 96-well plates, then treated with a 12-point dose response of compounds (Starting dose of 3000 nM and 3-fold dilution) for 4 hours.
  • Phosphorylation of ERK1/2 on residues Thr202 and Tyr204 were detected using a Homogenous Time-Resolved Fluorescence (HTRF) assay (Cisbio Cat# 64ERKPEG). Briefly, ERK phosphorylation was detected using a sandwich assay format using two phospho-ERK specific antibodies, one labelled with Eu 3+ - Cryptate (donor) and the second with d2 (acceptor).
  • HTRF Homogenous Time-Resolved Fluorescence
  • FRET Fluorescence Resonance Energy Transfer
  • AsPCl cells KRAS G12D pancreatic tumor cells
  • AsPCl cells were seeded at 10,000 cells/ well overnight in 96-well plates, then treated with a 12-point dose response of compounds (Starting dose of 1000 nM and 3-fold dilution) for 4 hours.
  • Phosphorylation of MEK1/2 on residues Ser217 and Ser221 were detected using a MesoScale Discovery (MSD) assay (MSD Cat# K15129D-2).
  • MSD MesoScale Discovery
  • MEK1/2 phosphorylation levels were normalized to total MEK1/2 protein detected in each well on the same MSD plate.
  • IC50 values were determined by fitting a variable slope, four parameters curve to the compound concentration to normalized Phospho-MEKl/2 relationship.
  • EXAMPLE 4 Biological Assay for Inhibiting Mouse Xenograft Tumor Growth
  • a second anti-cancer agent such as a EGFR inhibitor, a KRAS G12C inhibitor, and/or a Pan-RAF inhibitor for ability to inhibit tumor growth in patient-derived mouse xenograft models of cancers, such as pancreatic cancer and lung cancer. Assay procedures are described below.
  • mice (6-8 weeks old) are inoculated subcutaneously in the right flank with a primary human tumor xenograft model tumor fragment (2-3 mm 3 in diameter) for tumor development.
  • mice are inoculated with a human lung adenocarcinoma tumor model (MSCLC, ADC model LU6424) that harbors a BRAF mutation (LU6424);
  • mice are inoculated with a human pancreatic tumor model (adenosquamous carcinoma model PA6258) with a K-Ras G12D mutation (PA6258).
  • mean tumor volume reaches approximately 150- 200 mm 3 , animals are randomly allocated to appropriate treatment groups.
  • Mice are treated with one of the following: (1) Vehicle control, (2) Exemplary MEK inhibitor alone, (3) Second anticancer agent alone, or (4) Combination of MEK inhibitor and second anti-cancer agent. Tumors are measured twice per week using calipers.
  • Pharmacokinetics studies are conducted using cassette dosing protocols, with test compounds administered per mouse.
  • Treatment groups are 3 mice ( ⁇ 6-8 week old, ⁇ 20-30g balb/c male mice) per route of administration.
  • Compounds are formulated in 5% DMSO and 95% PEG400 with final concentrations of 0.5 mg/mL for IV and PO dosing.
  • Compounds are dosed at 2 mg/kg for IV dosing and 5 mg/kg for PO dosing.
  • Blood samples are withdrawn at 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 hours following IV dosing, and 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 hours following PO dosing.
  • Plasma samples are centrifuged at 4,000 g for 5 minutes at 4 °C to obtain plasma samples.
  • Plasma samples are diluted with acetonitrile containing internal standard, vortexed for 30 seconds, then centrifuged at 4,000 rpm for 15 minutes at 4 °C.
  • the supernatant is diluted with water, and compound concentration is determined by HPLC/MS/MS compared to calibration standards of 0.5-1,000 ng/mL.
  • the antitumor activity of MEKi was evaluated in vivo using a human cell line derived xenografts grown from MIA PaCa-2 cell line in immunodeficient mice.
  • the tumor cell lines are maintained in vitro as monolayer culture in medium at 37°C in an atmosphere of 5% CO2 in air.
  • the tumor cells are routinely sub-cultured before confluence by trypsin-EDTA treatment, not to exceed 4-5 passages.
  • the cells growing in an exponential growth phase are harvested for tumor inoculation.
  • MIA PaCa-2 tumor cells (1 x 10 6 cells) were implanted into Nu/Nu nude mice subcutaneously on the right flank with tumor cells in a 1 : 1 mixture with matrigel.
  • Tumors are allowed to grow to approximately 250 mm 3 .
  • Compounds were administrated to the tumor-bearing mice via QD oral gavage at a dose of 1 mg/kg. After 10 days of dosing, when tumors in the vehicle control mice reached the ethical endpoint (mean tumor volume > 1500 mm 3 ).
  • Plasma samples were centrifuged at 4,000 g for 5 minutes at 4 °C to obtain plasma samples.
  • Plasma samples were diluted with acetonitrile containing internal standard, vortexed for 30 seconds, then centrifuged at 4,000 rpm for 15 minutes at 4 °C. The supernatant was diluted with water, and compound concentration was determined by HPLC/MS/MS compared to calibration standards of 0.5-1,000 ng/mL.
  • EXAMPLE 8 In vivo efficacy studies using human MIA PaCa-2 xenografts in mice
  • the antitumor activity of MEK inhibitor compounds was evaluated in vivo using a human cell line derived xenografts grown from MIA PaCa-2 cell line in immunodeficient mice.
  • the tumor cell lines are maintained in vitro as monolayer culture in medium at 37°C in an atmosphere of 5% CO2 in air.
  • the tumor cells are routinely sub-cultured before confluence by trypsin-EDTA treatment, not to exceed 4-5 passages.
  • the cells growing in an exponential growth phase are harvested for tumor inoculation.
  • MIA PaCa-2 tumor cells (1 x 10 6 cells) are implanted into Nu/Nu nude mice subcutaneously on the right flank with tumor cells in a 1 : 1 mixture with matrigel.
  • Tumors are allowed to grow to approximately 250 mm 3 .
  • Compounds are administrated to the tumor-bearing mice via QD oral gavage at a dose of 1 mg/kg. After 10 days of dosing, when tumors in the vehicle control mice reached the ethical endpoint (mean tumor volume > 1500 mm 3 ).
  • NCI-H358, NCI-H2122, NCI- 141373, and MiaPACA2 cells were plated in 384-well plates and treated with increasing doses of compound III-2 (Max dose 100 nM, 10-fold dilution) and MRTX849 (Adagrasib) (Max dose 1000 nM, 3-fold dilution) for 5 days.
  • Cell viability was determined by Cell Titer Gio assay. Loewe sum of synergy scores for the combination were determined using the ComBenefit software (Di Veroli GY et al. Combenefit: an interactive platform for the analysis and visualization of drug combinations. Bioinformatics 2016).
  • AsPC-1, HPAF, MiaPACA2, PANC0327, NCI-H2122, and NCLH1373 cells were plated in 384-well plates and treated with increasing doses of compound III-2 (Max dose 100 nM, 10-fold dilution) and RMC-4550 (Max dose 1000 nM, 3-fold dilution) for 5 days.
  • Cell viability was determined by Cell Titer Gio assay. Loewe sum of synergy scores for the combination were determined using the ComBenefit software (Di Veroli GY et al. Combenefit: an interactive platform for the analysis and visualization of drug combinations. Bioinformatics 2016). As shown herein in FIG.
  • compound III-2 synergizes with the PI3Kalpha inhibitor inavolisib in vitro in KRAS mutant lung and pancreatic cancer cell lines.
  • AsPC-1, HPAF, MiaPACA2, PANC0327, NCLH2122, and NCI-H1373 cells were plated in 384- well plates and treated with increasing doses of compound III-2 (Max dose 100 nM, 10-fold dilution) and inavolisib (Max dose 1000 nM, 3-fold dilution) for 5 days.
  • Cell viability was determined by Cell Titer Gio assay. Loewe sum of synergy scores for the combination were determined using the ComBenefit software (Di Veroli GY et al.
  • Combenefit an interactive platform for the analysis and visualization of drug combinations. Bioinformatics 2016).
  • compound III-2 synergizes with the mTOR inhibitor everolimus in vitro in KRAS mutant lung and pancreatic cancer cell lines.
  • AsPC-1, HPAF, MiaPACA2, PANC0327, NCI- H2122, and NCI-H1373 cells were plated in 384-well plates and treated with increasing doses of compound III-2 (Max dose 100 nM, 10-fold dilution) and everolimus (Max dose 1000 nM, 3 -fold dilution) for 5 days.
  • Cell viability was determined by Cell Titer Gio assay. Loewe sum of synergy scores for the combination were determined using the ComBenefit software (Di Veroli GY et al. Combenefit: an interactive platform for the analysis and visualization of drug combinations. Bioinformatics 2016).
  • EXAMPLE 10 In vitro synergy data between MEK inhibitors and an EGFR monoclonal antibody
  • MEK inhibitor III-2 inhibits MEK and ERK1/2 phosphorylation for a longer duration compared to trametinib and VS-6766 following compound washout.
  • HCT-116 cells were plated in 6-well plates and treated with DMSO, VS-6766 (30 nM), Trametinib (10 nM), or III-2 (3 nM) for 1 hour. Cells were then washed 6 times with PBS and incubated for up to 24 hours.
  • MEK and ERK1/2 phosphorylation was evaluated by Western blot analysis.
  • HCT-116, LS180, and SKCO-1 cells were plated in 384-well plates and treated with increasing doses of MEK inhibitor compound III-2 (Max dose 100 nM, 10-fold dilution) and lapatinib or tucatinib (Max dose 1000 nM, 3-fold dilution) for 5 days.
  • Cell viability was determined by Cell Titer Gio assay. Loewe sum of synergy scores for the combination were determined using the ComBenefit software.
  • AsPC-1, NCL H2122, NCI-H1666, and SKMEL-2 cells were plated in 384-well plates and treated with MEK inhibitor compound III-2 at doses of 1 and 3 nM and trastuzumab (Max dose 1000 nM, 3 -fold dilution) for 5 days.
  • Cell viability was determined by Cell Titer Gio assay. Loewe sum of synergy scores for the combination were determined using the ComBenefit software.
  • EXAMPLE 15 In vitro synergy data between MEK inhibitors and HER2 Antibody Drug Conjugate (ADC)
  • AsPC-1, NCI-H2122, NCI-H1666, and SKMEL-2 cells were plated in 384-well plates and treated with MEK inhibitor compound III-2 at doses of 1 and 3 nM and trastuzumab-deruxtecan (Max dose 1000 nM, 3-fold dilution) for 5 days.
  • Cell viability was determined by Cell Titer Gio assay. Loewe sum of synergy scores for the combination were determined using the ComBenefit software.
  • MEK inhibitor compound III-2 synergizes with the plant alkaloid chemotherapeutic, paclitaxel, in vitro in KRAS mutant pancreatic cancer cell lines.
  • AsPC-1, DANG, HP AC, HPAF- II, HUPT-3, KP-2, PANC 03 27, PSN-1, and QGP-1 cells were plated in 384-well plates and treated with MEK inhibitor compound III-2 at doses of 1 and 3 nM and paclitaxel (Max dose 10000 nM, 3-fold dilution) for 3 days.
  • Cell viability was determined by Cell Titer Gio assay. Loewe sum of synergy scores for the combination were determined using the ComBenefit software.
  • PSN-1 cells were treated with MEK inhibitor compound III-2 (10 nM) alone, gemicitabine (10000 nM), paclitaxel (10000 nM), or 5-FU (10000 nM) alone, or MEK inhibitor compound III-2 in combination with gemcitabine, paclitaxel, or 5-FU for 24 hours.
  • Apoptosis was quantified by flow cytometry following staining with Annexin V.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Immunology (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Engineering & Computer Science (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des combinaisons comprenant des inhibiteurs de MEK dotés d'un second agent sélectionné parmi l'inhibiteur FRASG12C, l'inhibiteur EFGR, l'inhibiteur TEAD, l'inhibiteur RAS, l'inhibiteur anti-HER2 et un agent chimio thérapeutique aux fins d'utilisation dans le traitement du cancer, de préférence le cancer pancréatique mutant KRAS, colorectal pulmonaire.
PCT/US2024/016100 2023-02-17 2024-02-16 Combinaisons comprenant des inhibiteurs de mek pour une utilisation dans le traitement du cancer Ceased WO2024173761A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US202363446628P 2023-02-17 2023-02-17
US63/446,628 2023-02-17
US202363488816P 2023-03-07 2023-03-07
US63/488,816 2023-03-07
US202363584994P 2023-09-25 2023-09-25
US63/584,994 2023-09-25

Publications (1)

Publication Number Publication Date
WO2024173761A1 true WO2024173761A1 (fr) 2024-08-22

Family

ID=90361737

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2024/016100 Ceased WO2024173761A1 (fr) 2023-02-17 2024-02-16 Combinaisons comprenant des inhibiteurs de mek pour une utilisation dans le traitement du cancer

Country Status (1)

Country Link
WO (1) WO2024173761A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025167655A1 (fr) * 2024-02-07 2025-08-14 成都赜灵生物医药科技有限公司 Composé lactame à six chaînons et son utilisation
US12458647B2 (en) 2022-09-29 2025-11-04 Guangzhou Joyo Pharmatech Co., Ltd. Macrocyclic derivative and use thereof

Citations (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017053706A1 (fr) 2015-09-23 2017-03-30 The General Hospital Corporation Inhibiteurs de l'autopalmitoylation du facteur de transcription tead
WO2017111076A1 (fr) 2015-12-24 2017-06-29 協和発酵キリン株式会社 COMPOSÉ AMIDE α, β INSATURÉ
WO2018204532A1 (fr) 2017-05-03 2018-11-08 Vivace Therapeutics, Inc. Composés tricycliques non fusionnés
WO2018235926A1 (fr) 2017-06-23 2018-12-27 協和発酵キリン株式会社 COMPOSÉ AMIDE α, β-INSATURÉ
WO2019040380A1 (fr) 2017-08-21 2019-02-28 Vivace Therapeutics, Inc. Composés de benzosulfonyle
WO2019113236A1 (fr) 2017-12-06 2019-06-13 Vivace Therapeutics, Inc. Composés benzocarbonyle
WO2019222431A1 (fr) 2018-05-16 2019-11-21 Vivace Therapeutics, Inc. Composés d'oxadiazole
WO2019232216A1 (fr) 2018-05-31 2019-12-05 Genentech, Inc. Composés thérapeutiques
WO2020051099A1 (fr) 2018-09-03 2020-03-12 Genentech, Inc. Dérivés de carboxamide et de sulfonamide utiles en tant que modulateurs de tead
WO2020081572A1 (fr) 2018-10-15 2020-04-23 Dana-Farber Cancer Institute, Inc. Inhibiteurs du facteur de transcription à domaine associé transcriptionnel amélioré (tead) et leurs utilisations
WO2020097389A1 (fr) 2018-11-09 2020-05-14 Vivace Therapeutics, Inc. Composés bicycliques
WO2020156162A1 (fr) * 2019-01-29 2020-08-06 贝达药业股份有限公司 Inhibiteur de mek et son utilisation pharmaceutique
WO2020190774A1 (fr) 2019-03-15 2020-09-24 The General Hospital Corporation Nouveaux inhibiteurs à petites molécules de facteurs de transcription tead
WO2020214734A1 (fr) 2019-04-16 2020-10-22 Vivace Therapeutics, Inc. Composés bicycliques
WO2020243423A1 (fr) 2019-05-31 2020-12-03 Ikena Oncology, Inc. Inhibiteurs de tead et leurs utilisations
WO2020243415A2 (fr) 2019-05-31 2020-12-03 Ikena Oncology, Inc. Inhibiteurs de tead et leurs utilisations
WO2021047573A1 (fr) * 2019-09-11 2021-03-18 江苏恒瑞医药股份有限公司 Utilisation d'un inhibiteur de mek en combinaison avec un inhibiteur de cdk4/6 dans la préparation de médicaments pour le traitement de tumeurs
WO2021091982A1 (fr) * 2019-11-04 2021-05-14 Revolution Medicines, Inc. Inhibiteurs de ras
WO2021120890A1 (fr) 2019-12-20 2021-06-24 Novartis Ag Dérivés pyrazolyle utiles en tant qu'agents anticancéreux
WO2021142345A1 (fr) 2020-01-08 2021-07-15 Icahn School Of Medicine At Mount Sinai Modulateurs à petites molécules de mek liant ksr
CN113979995A (zh) * 2020-07-27 2022-01-28 贝达药业股份有限公司 Mek抑制剂及其在医药上的应用
WO2022120354A1 (fr) 2020-12-02 2022-06-09 Ikena Oncology, Inc. Inhibiteurs de tead et utilisations associées
WO2022120353A1 (fr) 2020-12-02 2022-06-09 Ikena Oncology, Inc. Inhibiteurs de tead et leurs utilisations
WO2022120355A1 (fr) 2020-12-02 2022-06-09 Ikena Oncology, Inc. Agents de dégradation de tead et leurs utilisations
WO2022159986A1 (fr) * 2021-01-25 2022-07-28 Ikena Oncology, Inc. Combinaison d'un inhibiteur de tead de 3-(imidazol-4-yl)-4-(amino)-benzène sulfonamide avec un inhibiteur de l'egfr et/ou un inhibiteur de mek pour une utilisation dans le traitement du cancer du poumon
WO2022165142A1 (fr) * 2021-01-29 2022-08-04 Mirati Therapeutics, Inc. Polythérapies
CN114853754A (zh) * 2022-05-23 2022-08-05 云白药征武科技(上海)有限公司 一种硫代酰胺衍生物及其制备方法和应用
WO2022214594A1 (fr) * 2021-04-09 2022-10-13 Boehringer Ingelheim International Gmbh Thérapie anticancéreuse
WO2022269525A1 (fr) * 2021-06-23 2022-12-29 Novartis Ag Associations pharmaceutiques comprenant un inhibiteur de kras g12c et leurs utilisations pour le traitement de cancers
WO2023009572A1 (fr) * 2021-07-27 2023-02-02 Verastem, Inc. Polythérapie pour le traitement d'une croissance cellulaire anormale
WO2023230205A1 (fr) * 2022-05-25 2023-11-30 Ikena Oncology, Inc. Inhibiteurs de mek et leurs utilisations

Patent Citations (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017053706A1 (fr) 2015-09-23 2017-03-30 The General Hospital Corporation Inhibiteurs de l'autopalmitoylation du facteur de transcription tead
WO2017111076A1 (fr) 2015-12-24 2017-06-29 協和発酵キリン株式会社 COMPOSÉ AMIDE α, β INSATURÉ
US20190010136A1 (en) 2015-12-24 2019-01-10 Kyowa Hakko Kirin Co., Ltd. Alpha,beta-unsaturated amide compound
WO2018204532A1 (fr) 2017-05-03 2018-11-08 Vivace Therapeutics, Inc. Composés tricycliques non fusionnés
WO2018235926A1 (fr) 2017-06-23 2018-12-27 協和発酵キリン株式会社 COMPOSÉ AMIDE α, β-INSATURÉ
WO2019040380A1 (fr) 2017-08-21 2019-02-28 Vivace Therapeutics, Inc. Composés de benzosulfonyle
WO2019113236A1 (fr) 2017-12-06 2019-06-13 Vivace Therapeutics, Inc. Composés benzocarbonyle
WO2019222431A1 (fr) 2018-05-16 2019-11-21 Vivace Therapeutics, Inc. Composés d'oxadiazole
WO2019232216A1 (fr) 2018-05-31 2019-12-05 Genentech, Inc. Composés thérapeutiques
WO2020051099A1 (fr) 2018-09-03 2020-03-12 Genentech, Inc. Dérivés de carboxamide et de sulfonamide utiles en tant que modulateurs de tead
WO2020081572A1 (fr) 2018-10-15 2020-04-23 Dana-Farber Cancer Institute, Inc. Inhibiteurs du facteur de transcription à domaine associé transcriptionnel amélioré (tead) et leurs utilisations
WO2020097389A1 (fr) 2018-11-09 2020-05-14 Vivace Therapeutics, Inc. Composés bicycliques
WO2020156162A1 (fr) * 2019-01-29 2020-08-06 贝达药业股份有限公司 Inhibiteur de mek et son utilisation pharmaceutique
WO2020190774A1 (fr) 2019-03-15 2020-09-24 The General Hospital Corporation Nouveaux inhibiteurs à petites molécules de facteurs de transcription tead
WO2020214734A1 (fr) 2019-04-16 2020-10-22 Vivace Therapeutics, Inc. Composés bicycliques
WO2020243415A2 (fr) 2019-05-31 2020-12-03 Ikena Oncology, Inc. Inhibiteurs de tead et leurs utilisations
WO2020243423A1 (fr) 2019-05-31 2020-12-03 Ikena Oncology, Inc. Inhibiteurs de tead et leurs utilisations
US11274082B2 (en) 2019-05-31 2022-03-15 Ikena Oncology, Inc. Tead inhibitors and uses thereof
US11458149B1 (en) 2019-05-31 2022-10-04 Ikena Oncology, Inc. TEAD inhibitors and uses thereof
WO2021047573A1 (fr) * 2019-09-11 2021-03-18 江苏恒瑞医药股份有限公司 Utilisation d'un inhibiteur de mek en combinaison avec un inhibiteur de cdk4/6 dans la préparation de médicaments pour le traitement de tumeurs
WO2021091982A1 (fr) * 2019-11-04 2021-05-14 Revolution Medicines, Inc. Inhibiteurs de ras
WO2021120890A1 (fr) 2019-12-20 2021-06-24 Novartis Ag Dérivés pyrazolyle utiles en tant qu'agents anticancéreux
WO2021142345A1 (fr) 2020-01-08 2021-07-15 Icahn School Of Medicine At Mount Sinai Modulateurs à petites molécules de mek liant ksr
CN113979995A (zh) * 2020-07-27 2022-01-28 贝达药业股份有限公司 Mek抑制剂及其在医药上的应用
WO2022120353A1 (fr) 2020-12-02 2022-06-09 Ikena Oncology, Inc. Inhibiteurs de tead et leurs utilisations
WO2022120355A1 (fr) 2020-12-02 2022-06-09 Ikena Oncology, Inc. Agents de dégradation de tead et leurs utilisations
WO2022120354A1 (fr) 2020-12-02 2022-06-09 Ikena Oncology, Inc. Inhibiteurs de tead et utilisations associées
WO2022159986A1 (fr) * 2021-01-25 2022-07-28 Ikena Oncology, Inc. Combinaison d'un inhibiteur de tead de 3-(imidazol-4-yl)-4-(amino)-benzène sulfonamide avec un inhibiteur de l'egfr et/ou un inhibiteur de mek pour une utilisation dans le traitement du cancer du poumon
WO2022165142A1 (fr) * 2021-01-29 2022-08-04 Mirati Therapeutics, Inc. Polythérapies
WO2022214594A1 (fr) * 2021-04-09 2022-10-13 Boehringer Ingelheim International Gmbh Thérapie anticancéreuse
WO2022269525A1 (fr) * 2021-06-23 2022-12-29 Novartis Ag Associations pharmaceutiques comprenant un inhibiteur de kras g12c et leurs utilisations pour le traitement de cancers
WO2023009572A1 (fr) * 2021-07-27 2023-02-02 Verastem, Inc. Polythérapie pour le traitement d'une croissance cellulaire anormale
CN114853754A (zh) * 2022-05-23 2022-08-05 云白药征武科技(上海)有限公司 一种硫代酰胺衍生物及其制备方法和应用
WO2023230205A1 (fr) * 2022-05-25 2023-11-30 Ikena Oncology, Inc. Inhibiteurs de mek et leurs utilisations

Non-Patent Citations (13)

* Cited by examiner, † Cited by third party
Title
"March's Advanced Organic Chemistry", 2001, JOHN WILEY & SONS
"Uniprot", Database accession no. P04049
AYATI ET AL.: "A review on progression of epidermal growth factor receptor (EGFR) inhibitors as an efficient approach in cancer targeted therapy", BIOORGANIC CHEMISTRY, vol. 99, 2020, pages 103811
BUM-ERDENE ET AL.: "Small-Molecule Covalent Modification of Conserved Cysteine Leads to Allosteric Inhibition of the TEAD·Yap Protein-Protein Interaction", CELL CHEMICAL BIOLOGY, vol. 26, 2019, pages 1 - 12
DI VEROLI GY ET AL.: "Combenefit: an interactive platform for the analysis and visualization of drug combinations", BIOINFORMATICS, 2016
GIBAULT: "Targeting Transcriptional Enhanced Associate Domains (TEADs", J. MED. CHEM., vol. 61, 2018, pages 5057 - 5072
HOLDEN: "Small Molecule Dysregulation of TEAD Lipidation Induces a Dominant-Negative Inhibition of HippoPathway Signaling", CELL REPORTS, vol. 31, 2020, pages 107809
JEANSON ARNAUD ET AL: "Therapeutic potential of trametinib to inhibit the mutagenesis by inactivating the protein kinase pathway in non-small cell lung cancer", EXPERT REVIEW OF ANTICANCER THERAPY, FUTURE DRUGS LTD, UK, vol. 19, no. 1, 1 January 2019 (2019-01-01), pages 11 - 17, XP009553963, ISSN: 1744-8328, DOI: 10.1080/14737140.2019.1554440 *
JUDE CANON ET AL: "The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity", NATURE, vol. 575, no. 7781, 30 October 2019 (2019-10-30), pages 217 - 223, XP055770919, DOI: 10.1038/s41586-019-1694-1 *
POBBATI ET AL.: "Targeting the Central Pocket in Human Transcription Factor TEAD as a Potential Cancer Therapeutic Strategy", STRUCTURE, vol. 23, 2015, pages 2076 - 2086, XP055570312, DOI: 10.1016/j.str.2015.09.009
S. M. BERGE ET AL., J. PHARMACEUTICAL SCIENCES, vol. 66, 1977, pages 1 - 19
SHUAI LI: "Assessing Therapeutic Efficacy of MEK Inhibition in a KRASG12C-Driven Mouse Model of Lung Cancer", CLINICAL CANCER RESEARCH, vol. 24, no. 19, 1 October 2018 (2018-10-01), US, pages 4854 - 4864, XP093159199, ISSN: 1078-0432, Retrieved from the Internet <URL:https://aacrjournals.org/clincancerres/article-pdf/24/19/4854/2047310/4854.pdf> DOI: 10.1158/1078-0432.CCR-17-3438 *
T. W. GREENEP. G. M. WUTS: "Protecting Groups in Organic synthesis", 1999, UNIVERSITY SCIENCE BOOKS

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12458647B2 (en) 2022-09-29 2025-11-04 Guangzhou Joyo Pharmatech Co., Ltd. Macrocyclic derivative and use thereof
WO2025167655A1 (fr) * 2024-02-07 2025-08-14 成都赜灵生物医药科技有限公司 Composé lactame à six chaînons et son utilisation

Similar Documents

Publication Publication Date Title
EP3600270B1 (fr) Composés et compositions pour le traitement de troubles hématologiques
TWI726363B (zh) Fak/alk/ros1抑制劑與egfr抑制劑的組合治療癌症的方法
WO2022159986A1 (fr) Combinaison d&#39;un inhibiteur de tead de 3-(imidazol-4-yl)-4-(amino)-benzène sulfonamide avec un inhibiteur de l&#39;egfr et/ou un inhibiteur de mek pour une utilisation dans le traitement du cancer du poumon
DK2947086T3 (en) UNKNOWN CONDENSED PYRIMIDINE COMPOUND OR SALT THEREOF
TWI726362B (zh) Bcl-2抑制劑與利妥昔單抗和/或苯達莫司汀或Bcl-2抑制劑與CHOP聯合用藥的協同抗腫瘤作用
WO2016201354A1 (fr) Méthodes et compositions pour le traitement du cancer
US20100273778A1 (en) Treatment of osteoarthritis pain
WO2024173761A1 (fr) Combinaisons comprenant des inhibiteurs de mek pour une utilisation dans le traitement du cancer
US20170226100A1 (en) Aminothiazole compounds
TW201836606A (zh) 一種ｍｏｒ激動劑與ｋｏｒ激動劑聯合在製備緩解和／或治療疼痛的藥物中的用途
TW202208375A (zh) ４－胺基－５－（６－（４－甲基哌－１－基）－１ｈ－苯并［ｄ］咪唑－２－基）噻吩并［２，３－ｂ］吡啶－６（７ｈ）－酮之鹽及晶形
WO2019039525A1 (fr) Produit pharmaceutique destiné au traitement du cancer comprenant un inhibiteur d&#39;axl en tant que principe actif
JP2008543756A (ja) チエノピリミジンおよびチエノピリジンキナーゼモジュレーターを用いるｆｌｔ３キナーゼの相乗的モジュレーター
JP2025519119A (ja) Ｍｅｋ阻害剤及びその使用
CN113543784A (zh) 用于治疗或预防癌症的喹啉衍生物
CN116261455B (zh) 一种药物组合物及其在治疗癌症中的用途
TWI649082B (zh) 使用奧諾拉（ａｕｒｏｒａ）激酶抑制劑治療癌症的方法
WO2024092116A1 (fr) Association d&#39;inhibiteurs de tead et d&#39;inhibiteurs d&#39;egfr et utilisations associées
WO2023059582A1 (fr) Composés hétérobifonctionnels et leur utilisation dans le traitement de maladies
WO2019049891A1 (fr) MÉTHODE DE TRAITEMENT DU CANCER À L&#39;AIDE D&#39;UNE COMBINAISON D&#39;INHIBITEUR DE Trk ET D&#39;INHIBITEUR DE KINASES
CN117957018A (zh) 一种药物组合及其用途
CN117715893A (zh) 包含mat2a抑制剂和ii型prmt抑制剂的组合疗法
CN117321050A (zh) 修饰的膜铁转运蛋白抑制剂
US20250042918A1 (en) Compounds
EA045568B1 (ru) Солевые и кристаллические формы 4-амино-5-(6-(4-метилпиперазин-1-ил)-1н-бензо[d]имидазол-2-ил)тиено[2,3-в]пиридин-6(7н)-она

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24710002

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE