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WO2025090810A1 - Utilisation d'inhibiteurs de sos1 et d'amivantamab pour traiter le cancer - Google Patents

Utilisation d'inhibiteurs de sos1 et d'amivantamab pour traiter le cancer Download PDF

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WO2025090810A1
WO2025090810A1 PCT/US2024/052876 US2024052876W WO2025090810A1 WO 2025090810 A1 WO2025090810 A1 WO 2025090810A1 US 2024052876 W US2024052876 W US 2024052876W WO 2025090810 A1 WO2025090810 A1 WO 2025090810A1
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alkyl
carbocycle
membered heterocycle
optionally substituted
egfr
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Yi Liu
Matthew R. Janes
Rasmus Hansen
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Kumquat Biosciences Inc
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Kumquat Biosciences Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/504—Pyridazines; Hydrogenated pyridazines forming part of bridged ring systems
    • 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
    • A61K31/529—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim forming part of bridged ring systems
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • 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
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • 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
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • 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

Definitions

  • the ErbB family of receptor tyrosine kinases includes EGFR (HERl/ErbBl), EIER2 (ErbB2), EIER3 (ErbB3) and HER4 (ErbB4), each of which is a mediator of normal cell growth and development.
  • EGFR HERl/ErbBl
  • EIER2 ErbB2
  • EIER3 ErbB3
  • HER4 HER4
  • phosphorylation of EGFR activates downstream signaling pathways — including the PI3K/AKT/mTOR, STAT, and RAS/MAPK pathways — that involve cell proliferation, angiogenesis, apoptosis, and metastasis.
  • Overexpression of EGFR is frequently observed in a variety of tumors, including brain, breast, cervical, colorectal, esophageal, head and neck, kidney, lung, ovarian, and stomach cancers.
  • EGFR mutations have been detected in over 40% of non-small cell lung cancer (NSCLC) cases in Asia and over 10% of NSCLC cases in North America and Europe, making them the most prevalent genetic alterations in NSCLC.
  • the L858R point mutation and exon 19 deletions are often referred to as classical EGFR activating mutations and result in constitutive activation of EGFR and downstream signaling pathways, particularly in non- small cell lung cancer (NSCLC).
  • NSCLC non-small cell lung cancer
  • exon 20 mutations including T790M and exon 20 insertions, activate EGFR while affording the tumor resistance to first- and second-generation EGFR inhibitors targeting the classical EGFR mutations, such as gefitinib, erlotinib, and afatinib.
  • Lung cancer is the leading cause of cancer-related death worldwide, due in part to these resistance mechanisms.
  • an estimated 238,000 people will be diagnosed with lung and bronchus cancer and approximately 127,000 people will die from lung and bronchus cancer in the United States.
  • SOS1 Son of Sevenless 1
  • GEF guanine nucleotide exchange factor
  • SOS1 has been implicated in cancer via its ability to activate RAS-family protein signaling.
  • SOS1 interacts with the adaptor protein Grb2 and the resulting SOSl/Grb2 complex binds to activated/phosphorylated Receptor Tyrosine Kinases (e.g., EGFR, ErbB2, ErbB 3, ErbB4,TrkA, TrkB, TrkC, RET, c-MET, VEGFR 1 /2/3).
  • activated/phosphorylated Receptor Tyrosine Kinases e.g., EGFR, ErbB2, ErbB 3, ErbB4,TrkA, TrkB, TrkC, RET, c-MET, VEGFR 1 /2/3.
  • SOS1 is also recruited to other phosphorylated cell surface receptors such as the T cell Receptor (TCR), B cell Receptor (BCR) and monocyte colony-stimulating factor receptor.
  • TCR T cell Receptor
  • BCR B cell Receptor
  • monocyte colony-stimulating factor receptor monocyte colony-stimulating factor receptor
  • the present disclosure provides a method of treating an EGFR-mediated cancer in a subject, comprising administering to the subject (a) a SOS1 inhibitor and (b) amivantamab, wherein (a) is administered prior to, concurrently with, or subsequent to administering (b).
  • the cancer is lung cancer, such as non-small cell lung cancer.
  • cancer cells of the subject comprise an EGFR mutation.
  • the subject has previously been treated with a non-exon 20 insertion EGFR TKI, such as a non-exon 20 insertion EGFR TKI selected from gefitinib, erlotinib, afatinib, lazertinib, osimertinib, dacomitinib, neratinib, cetuximab, panitumumab, lapatinib, necitumumab, clawdetanib, BLU-945, and zorifertinib.
  • a non-exon 20 insertion EGFR TKI selected from gefitinib, erlotinib, afatinib, lazertinib, osimertinib, dacomitinib, neratinib, cetuximab, panitumumab, lapatinib, necitumumab, toartinib, vandetanib, BLU-945, and zori
  • the subject has previously been treated with an EGFR exon 20 insertion TKI, such as an EGFR exon 20 insertion TKI selected from poziotinib, mobocertinib, amivantamab, zipalertinib, sunvozertinib, BAY-2927088, BLU-451, and STX-721.
  • an EGFR exon 20 insertion TKI selected from poziotinib, mobocertinib, amivantamab, zipalertinib, sunvozertinib, BAY-2927088, BLU-451, and STX-721.
  • the subject exhibits resistance or intolerance to the TKI.
  • the subject exhibits resistance or intolerance to osimertinib.
  • resistance to the TKI is characterized by one or more changes selected from (1) progression of the cancer, (2) EGFR gene mutation, (3) loss of EGFR T790M mutation, (4) EGFR gene amplification, (5) MET amplification, (6) HER2 amplification, (7) RAS-MAPK pathway activation, (8) PI3K pathway activation, (9) cell-cycle gene alteration, (10) oncogenic fusion, (11) histologic transformation, and (12) phenotypic transformation.
  • the present disclosure provides a method of reducing proliferation of cancer cells comprising an epidermal growth factor receptor (EGFR) exon 20 insertion, the method comprising administering to the cells (a) a SOS1 inhibitor and (b) amivantamab, wherein (a) is administered prior to, concurrently with, or subsequent to administering (b).
  • the cancer cells are non-small cell lung cancer cells.
  • the synergistic value is at least 0.4, such as at least 1 or at least 5.
  • the present disclosure provides a method of downregulating EGFR signaling output in a plurality of non-small cell lung cancer cells, comprising: (i) assessing EGFR mutation status in a biological sample comprising nucleic acid from the subject; and (ii) administering an effective dose of (a) a SOS1 inhibitor and an effective dose of (b) amivantamab if an EGFR exon 20 insertion is detected in the sample, wherein (a) is administered prior to, concurrently with, or subsequent to administering (b).
  • the cancer cells may previously have been treated with chemotherapy, such as platinum-based chemotherapy.
  • chemotherapy such as platinum-based chemotherapy.
  • the cancer cells have previously been treated with a tyrosine kinase inhibitor (TKI) against EGFR other than amivantamab prior to administering (a).
  • TKI tyrosine kinase inhibitor
  • the subject has previously been treated with an EGFR exon 20 insertion TKI, such as an EGFR exon 20 insertion TKI selected from poziotinib, mobocertinib, zipalertinib, sunvozertinib, BAY-2927088, BLU-451, and STX-721.
  • an EGFR exon 20 insertion TKI selected from poziotinib, mobocertinib, zipalertinib, sunvozertinib, BAY-2927088, BLU-451, and STX-721.
  • the cancer cells exhibit resistance or intolerance to the TKI.
  • resistance to the TKI is characterized by one or more changes selected from (1) progression of the cancer, (2) EGFR gene mutation, (3) loss of EGFR T790M mutation, (4) EGFR gene amplification, ⁇ S') MET amplification, (6) HER2 amplification, (7) RAS-MAPK pathway activation, (8) PI3K pathway activation, (9) cellcycle gene alteration, (10) oncogenic fusion, (11) histologic transformation, and (12) phenotypic transformation.
  • a method described herein may further comprise administering (c) an additional agent or additional therapy.
  • the additional agent is selected from an EGFR TKI other than amivantamab, a MET inhibitor, an immunomodulatory agent, an anti-nausea agent, an antiemetic, a pain reliever, and a chemotherapeutic agent.
  • the additional agent is selected from an immunomodulatory agent, a cytokine blockade agent, and a checkpoint immune blockade agent.
  • the additional agent is selected from an anti-PD-Ll antibody, an anti-CTLA-4 antibody, an anti-PD-1 antibody, an anti-LAG3 antibody, an anti-TIM3 antibody, and combinations thereof.
  • the additional therapy is selected from surgery, cell therapy, chemotherapy, and radiation.
  • the administration of (a) and (b) may reduce incidence of one or more adverse event associated with amivantamab, such as an adverse event selected from rash, pruritus, dry skin, fatigue, edema, pyrexia, paronychia, pneumonia, musculoskeletal pain, dyspnea, cough, nausea, stomatitis, constipation, vomiting, diarrhea, abdominal pain, hemorrhage, decreased appetite, peripheral neuropathy, dizziness, and headache.
  • the adverse event is selected from diarrhea, rash, and nausea.
  • the administration of (a) and (b) exhibits a synergistic effect.
  • the synergistic effect is characterized by a synergistic value of at least 0.05 as ascertained by Bliss independence criterion.
  • one or both of (a) and (b) are administered at a sub-therapeutic dose but achieve a therapeutic effect at least comparable to administering (a) or (b) alone at its therapeutically effective amount.
  • amivantamab is administered at a dose less than about 25% the standard monotherapy dose.
  • (a) and (b) are administered in the same formulation.
  • (a) and (b) are administered in separate formulations.
  • the S0S1 inhibitor may be selected from BI-3406, MRTX0902, BAY 293, RMC-5845, and BI-1701963.
  • the S0S1 inhibitor is a compound of Formula (1-1):
  • L 1 is selected from a bond, Ci-6 alkylene, and Ci-6 haloalkylene:
  • L 2 is selected from C5.25 alkylene, C5.25 alkenylene, C5.25 alkynylene, 5- to 25-membered heteroalkylene, and 5- to 25-membered heteroalkenylene, each of which is optionally substituted with one or more R l lb , wherein L 2 is covalently bound to one of W 3 , W 4 , W 5 , W 6 , or W 7 ;
  • W 3 is selected from N(R 3b ), N, C(R 3 ), and C(O);
  • W 4 is selected from N(R 4b ), N, C(R 4 ), and C(O);
  • W 5 is selected from N(R 5b ), N, and C(R 5 );
  • W 6 is selected from C(R 6 ) and C(O);
  • W 7 is C(R 7 );
  • R 1 is C1.3 alkyl optionally substituted with one or more R llc ;
  • R 8 is selected from hydrogen, halogen, -CN, Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10- membered heterocycle, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), - N(R 14 )C(O)OR 15 , -N(R 14 )S(O) 2 R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), - N(R 14 )C(O)R 15 , -S(O) 2
  • R 3 , R 4 , R 5 , R 6 , and R 7 are each independently selected from a bond to L 2 , hydrogen, halogen, -CN, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), - C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O) 2 R 15 , -C(O)R 15 , -S(O)R 15 , - OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(
  • R 11 and R lla are each independently selected at each occurrence from halogen, -CN, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , - OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O) 2 R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , - C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15
  • R llb is independently selected at each occurrence from halogen, oxo, -CN, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , - OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O) 2 R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , - C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R
  • R llc is independently selected at each occurrence from halogen, -OR 12 , and -N(R 12 )(R 13 );
  • R 12 is independently selected at each occurrence from hydrogen, Ci-6 alkyl, Ci-e haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R 20 ;
  • R 13 is independently selected at each occurrence from hydrogen, Ci-6 alkyl, and Ci-6 haloalkyl; or R 12 and R 13 , together with the nitrogen atom to which they are attached, form a 3- to 10-membered heterocycle optionally substituted with one, two, or three R 20 ;
  • R 14 is independently selected at each occurrence from hydrogen, Ci-6 alkyl, and Ci-6 haloalkyl;
  • R 15 is independently selected at each occurrence from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R 20 ;
  • R 17 and R 17a are each independently selected at each occurrence from Ci-6 alkyl and C3.6 cycloalkyl, wherein Ci-6 alkyl and C3.6 cycloalkyl are optionally substituted with one, two or three R 20 ; or R 17 and R 17a , together with the phosphorous atom to which they are attached, form a 3- to 10-membered heterocycle;
  • R 21 is independently selected at each occurrence from H, Ci-6 alkyl, Ci-6 haloalkyl, C 2 .e alkenyl, C 2 .e alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and Ci-6 alkyl;
  • R 22 is independently selected at each occurrence from H, Ci-6 alkyl, Ci-6 haloalkyl, C 2 .e alkenyl, C 2 .e alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and Ci-6 alkyl;
  • R 23 is independently selected at each occurrence from H and Ci-e alkyl
  • R 24 is independently selected at each occurrence from H and Ci-e alkyl
  • R 25 is independently selected at each occurrence from Ci-6 alkyl, C 2 .e alkenyl, C 2 .e alkynyl, carbocycle, and 3- to 10-membered heterocycle, wherein Ci-6 alkyl, carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen, Ci-e alkyl, Ci-e haloalkyl, Ci-6 alkoxy, C3-10 carbocycle, and 3- to 10-membered heterocycle; and indicates a single or double bond such that all valences are satisfied.
  • the present disclosure provides a kit for use in reducing proliferation of cancer cells comprising an epidermal growth factor receptor (EGFR) exon 20 insertion, the kit comprising: (1) a composition comprising a SOS1 inhibitor of Formula (1-1); (2) a composition comprising amivantamab; and (3) instructions for using the composition(s) of (1) and (2).
  • the SOS1 inhibitor and the amivantamab are formulated in a same unit dosage form.
  • the SOS1 inhibitor and the amivantamab are formulated in different unit dosage forms.
  • FIG. 1 shows results of a study in which mice bearing Ba/F3-EGFR Exon 20 insertion (V769_D770insASV) allograft tumors were treated with (i) a SOS1 inhibitor of the present disclosure (e.g., Compound A) alone, (ii) amivantamab alone, or (iii) a combination of (i) and (ii).
  • SOS1 inhibitor of the present disclosure e.g., Compound A
  • amivantamab alone
  • iii a combination of (i) and (ii).
  • the results demonstrate that the SOS1 inhibitor disclosed herein synergistically inhibits tumor growth in combination with amivantamab.
  • FIG. 2 shows results of a study in which LU0858 mice (an NSCLC patient-derived xenograft (PDX) model exhibiting EGFR-L858R mutation with amplified MET) were treated with (i) a SOS1 inhibitor of the present disclosure (e.g., Compound A) alone, (ii) amivantamab alone, or (iii) a combination of (i) and (ii).
  • a SOS1 inhibitor of the present disclosure e.g., Compound A
  • amivantamab alone
  • the results demonstrate that the SOS1 inhibitor disclosed herein in combination with amivantamab synergistically reduces tumor volume in EGFR-mediated lung cancer, particularly MET amplified lung cancer.
  • FIG. 3 shows results of a study in which mice bearing a squamous NSCLC PDX model exhibiting an EGFR-Exon 20 D772_N773insDNP mutation were treated with (i) a SOS1 inhibitor of the present disclosure (e.g., Compound A) alone, (ii) amivantamab alone, or (iii) a combination of (i) and (ii).
  • a SOS1 inhibitor of the present disclosure e.g., Compound A
  • amivantamab alone
  • the results demonstrate that the SOS1 inhibitor disclosed herein synergistically reduces tumor volume in combination with amivantamab in the tumor model.
  • FIG. 4 shows results of a study in which mice bearing a colorectal cancer PDX model exhibiting a KRAS G12C mutation were treated with (i) a SOS1 inhibitor of the present disclosure (e.g., Compound A) alone, (ii) amivantamab alone, or (iii) a combination of (i) and (ii).
  • a SOS1 inhibitor of the present disclosure e.g., Compound A
  • amivantamab alone
  • iiii a combination of (i) and (ii).
  • the results demonstrate that the SOS1 inhibitor disclosed herein synergistically inhibits tumor growth in combination with amivantamab in a KRAS G12C mutant model.
  • FIG. 5 shows results of a study in which mice bearing H820 xenograft tumors (a papillary adenocarcinoma model exhibiting EGFR L858R/T790M mutations and MET amplification) were treated with (i) a SOS1 inhibitor of the present disclosure (e.g., Compound A) alone, (ii) amivantamab alone, or (iii) a combination of (i) and (ii).
  • a SOS1 inhibitor of the present disclosure e.g., Compound A
  • amivantamab alone
  • the results demonstrate that the SOS1 inhibitor disclosed herein synergistically reduces tumor volume in combination with amivantamab in the tumor model.
  • FIG. 6 shows results of a study in which mice bearing H820 xenograft tumors were treated with amivantamab alone for the first 22 days of the study, then amivantamab in combination with a S0S1 inhibitor of the present disclosure (e.g., Compound A) until dosing was stopped at day 53 of the study.
  • S0S1 inhibitor of the present disclosure e.g., Compound A
  • FIG. 7 shows results of a study in which mice bearing Ba/F3-EGFR-L858R+T790M+C797S allograft tumors were treated with (i) a SOS1 inhibitor of the present disclosure (e.g., Compound A) alone, (ii) amivantamab alone, or (iii) a combination of (i) and (ii).
  • a SOS1 inhibitor of the present disclosure e.g., Compound A
  • amivantamab alone
  • the results demonstrate that the SOS1 inhibitor disclosed herein synergistically reduces tumor volume in combination with amivantamab in the tumor model.
  • C x.y or “C x -C y ” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl, is meant to include groups that contain from x to y carbons in the chain.
  • C x.y alkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched- chain alkyl groups, that contain from x to y carbons in the chain.
  • Alkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including linear and branched alkyl groups.
  • An alkyl group may contain from one to twelve carbon atoms (e.g., Cm alkyl), such as one to eight carbon atoms (Cns alkyl) or one to six carbon atoms (Ci-6 alkyl).
  • alkyl groups include methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl, and decyl.
  • An alkyl group is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more substituents such as those substituents described herein.
  • Haloalkyl refers to an alkyl group that is substituted by one or more halogens.
  • exemplary haloalkyl groups include trifluoromethyl, difluoromethyl, tri chloromethyl, 2,2,2-trifluoroethyl, 1 ,2-difluoroethyl, 3-bromo-2- fluoropropyl, and 1 ,2-dibromoethyl.
  • alkenyl refers to substituted or unsubstituted hydrocarbon groups, including linear and branched alkenyl groups, containing at least one double bond.
  • An alkenyl group may contain from two to twelve carbon atoms (e.g., C2-12 alkenyl), such as two to eight carbon atoms (C2-8 alkenyl) or two to six carbon atoms (C2-6 alkenyl).
  • Exemplary alkenyl groups include ethenyl (i.e., vinyl), prop-l -enyl, but-l-enyl, pent-l-enyl, penta- 1,4-dienyl, and the like.
  • an alkenyl group is optionally substituted by one or more substituents such as those substituents described herein.
  • Alkynyl refers to substituted or unsubstituted hydrocarbon groups, including linear and branched alkynyl groups, containing at least one triple bond.
  • An alkynyl group may contain from two to twelve carbon atoms (e.g., C2- 12 alkynyl), such as two to eight carbon atoms (C2-8 alkynyl) or two to six carbon atoms (C2-6 alkynyl).
  • Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more substituents such as those substituents described herein.
  • Alkylene or “alkylene chain” refers to substituted or unsubstituted divalent saturated hydrocarbon groups, including linear alkylene and branched alkylene groups, that contain from one to twelve carbon atoms (e.g., CM2 alkylene), such as one to eight carbon atoms (Cns alkylene) or one to six carbon atoms (Ci-6 alkylene).
  • CM2 alkylene such as one to eight carbon atoms (Cns alkylene) or one to six carbon atoms (Ci-6 alkylene).
  • Exemplary alkylene groups include methylene, ethylene, propylene, and n-butylene.
  • alkenylene and alkynylene refer to alkylene groups, as defined above, which comprise one or more carbon-carbon double or triple bonds, respectively.
  • alkylene, alkenylene or alkynylene chain can be through one carbon or any two carbons of the chain.
  • an alkylene, alkenylene, or alkynylene group is optionally substituted by one or more substituents such as those substituents described herein.
  • Heteroalkyl refers to substituted or unsubstituted alkyl, alkenyl and alkynyl groups, respectively, in which one or more, such as 1, 2 or 3, of the carbon atoms are replaced with a heteroatom, such as O, N, P, Si, S, or combinations thereof. Any nitrogen, phosphorus, and sulfur heteroatoms present in the chain may optionally be oxidized, and any nitrogen heteroatoms may optionally be quatemized. If given, a numerical range refers to the chain length in total. For example, a 3- to 8-membered heteroalkyl group has a chain length of 3 to 8 atoms.
  • Connection to the rest of the molecule may be through either a heteroatom or a carbon in the heteroalkyl, heteroalkenyl, or heteroalkynyl chain.
  • a heteroalkyl, hetero alkenyl, or heteroalkynyl group is optionally substituted by one or more substituents such as those substituents described herein.
  • Hetero alkylene refers to substituted or unsubstituted alkylene, alkenylene and alkynylene groups, respectively, in which one or more, such as 1, 2 or 3, of the carbon atoms are replaced with a heteroatom, such as O, N, P, Si, S, or combinations thereof. Any nitrogen, phosphorus, and sulfur heteroatoms present in the chain may optionally be oxidized, and any nitrogen heteroatoms may optionally be quatemized. If given, a numerical range refers to the chain length in total. For example, a 3- to 8- membered hetero alkylene group has a chain length of 3 to 8 atoms.
  • the points of attachment of the heteroalkylene, hetero alkenylene or heteroalkynylene chain to the rest of the molecule can be through either one heteroatom or one carbon, or any two heteroatoms, any two carbons, or any one heteroatom and any one carbon in the heteroalkylene, hetero alkenylene or heteroalkynylene chain.
  • a heteroalkylene, heteroalkenylene, or heteroalkynylene group is optionally substituted by one or more substituents such as those substituents described herein.
  • Carbocycle refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is a carbon atom.
  • Carbocycle may include C3-10 monocyclic rings, Ce-i2 bicyclic rings, Ce-i2 spirocyclic rings, and Ce-i2 bridged rings.
  • Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings.
  • the carbocycle is a Ce-i2 aryl group, such as Ce-io aryl.
  • the carbocycle is a Ce-i2 cycloalkyl group.
  • the carbocycle is a Ce-i2 cycloalkenyl group.
  • an aromatic ring e.g., phenyl
  • a saturated or unsaturated ring e.g., cyclohexane, cyclopentane, or cyclohexene.
  • Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, are included in the definition of carbocycle.
  • Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantly, phenyl, indanyl, and naphthyl. Unless state otherwise specifically in the specification, a carbocycle is optionally substituted by one or more substituents such as those substituents described herein.
  • Heterocycle refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms, for example 1, 2 or 3 heteroatoms selected from O, S and N. Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, 6- to 12-membered spirocyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic heterocycle may be selected from saturated, unsaturated, and aromatic rings. The heterocycle may be attached to the rest of the molecule through any atom of the heterocycle, valence permitting, such as a carbon or nitrogen atom of the heterocycle.
  • the heterocycle is a 5- to 10-membered heteroaryl group, such as 5- or 6-membered heteroaryl.
  • the heterocycle is a 3- to 12-membered heterocycloalkyl group.
  • a heterocycle e.g., pyridyl
  • heterocycles include pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, oxazolyl, thiazolyl, morpholinyl, indazolyl, indolyl, and quinolinyl.
  • a heterocycle is optionally substituted by one or more substituents such as those substituents described herein.
  • Heteroaryl refers to a 5- to 12-membered aromatic ring that comprises at least one heteroatom, such as 1, 2 or 3 heteroatoms, selected from O, S and N.
  • the heteroaryl ring may be selected from monocyclic or bicyclic — including fused, spirocyclic and bridged ring systems — wherein at least one of the rings in the ring system is aromatic.
  • the heteroatom(s) in the heteroaryl may optionally be oxidized.
  • One or more nitrogen atoms, if present, are optionally quatemized.
  • the heteroaryl may be attached to the rest of the molecule through any atom of the heteroaryl, valence permitting, such as a carbon or nitrogen atom of the heteroaryl.
  • heteroaryl groups include, but are not limited to, azepinyl, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzofuranyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, furanyl, imidazolyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyridazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroquinolinyl, thiadiazolyl, thiazolyl, and thienyl groups. Unless stated otherwise,
  • a waved line drawn across a bond or a dashed bond are used interchangeably herein to denote where a bond disconnection or attachment occurs.
  • R 7 if R 7 is 1- cyclopropyl- 1 -carbonitrile as in , ”
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons or heteroatoms of the structure. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • heteroatoms such as nitrogen may have any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • “Optional” or “optionally” means that the subsequently described event or circumstances may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
  • an “optionally substituted” group may be either unsubstituted or substituted.
  • Compounds of the present disclosure also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, amorphous forms of the compounds, and mixtures thereof.
  • the compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.
  • hydrogen has three naturally occurring isotopes, denoted 1 H (protium), 2 H (deuterium), and 3 H (tritium). Protium is the most abundant isotope of hydrogen in nature.
  • Enriching for deuterium may afford certain therapeutic advantages, such as increased in vivo half-life and/or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism.
  • isotopes that may be incorporated into compounds of the present disclosure include, but are not limited to, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 36 Cl, and 18 F.
  • compound of Formula (I) enriched in tritium or carbon-14 which can be used, for example, in tissue distribution studies; compounds of the disclosure enriched in deuterium—especially at a site of metabolism—resulting, for example, in compounds having greater metabolic stability; and compounds of Formula (I) enriched in a positron emitting isotope, such as 11 C, 18 F, 15 O and 13 N, which can be used, for example, in Positron Emission Topography (PET) studies.
  • Isotopically-enriched compounds may be prepared by conventional techniques well known to those skilled in the art.
  • Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
  • the carbon atoms in order to optimize the therapeutic activity of the compounds of the disclosure, e.g., to treat cancer, it may be desirable that the carbon atoms have a particular configuration (e.g., (R,R), (S,S), (S,R), or (R,S)) or are enriched in a stereoisomeric form having such configuration.
  • the compounds of the disclosure may be provided as racemic mixtures.
  • the disclosure relates to racemic mixtures, pure stereoisomers (e.g., enantiomers and diastereomers), stereoisomer-enriched mixtures, and the like, unless otherwise indicated.
  • pure stereoisomers e.g., enantiomers and diastereomers
  • stereoisomers may be obtained by numerous methods that are known in the art, including preparation using chiral synthons or chiral reagents, resolution using chiral chromatography using a suitable chiral stationary phase or support, or by chemically converting them into diastereomers, separating the diastereoisomers by conventional means such as chromatography or recrystallization, then regenerating the original stereoisomer.
  • pharmaceutically acceptable refers to a material that is not biologically or otherwise unacceptable when used in the subject compositions and methods.
  • pharmaceutically acceptable carrier refers to a material — such as an adjuvant, excipient, glidant, sweetening agent, diluent, preservative, dye, colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifier — that can be incorporated into a composition and administered to a patient without causing unacceptable biological effects or interacting in an unacceptable manner with other components of the composition.
  • Such pharmaceutically acceptable materials typically have met the required standards of toxicological and manufacturing testing, and include those materials identified as suitable inactive ingredients by the U.S. Food and Drug Administration.
  • salts and “pharmaceutically acceptable salt” refer to a salt prepared from a base or an acid.
  • Pharmaceutically acceptable salts are suitable for administration to a patient, such as a mammal (for example, salts having acceptable mammalian safety for a given dosage regime). Salts can be formed from inorganic bases, organic bases, inorganic acids and organic acids.
  • a compound contains both a basic moiety, such as an amine, pyridine or imidazole, and an acidic moiety, such as a carboxylic acid or tetrazole, zwitterions may be formed and are included within the term “salt” as used herein.
  • Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like.
  • salts that are formed with organic acids such as aliphatic mono- and dicarboxy lie acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc., and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • organic acids such as aliphatic mono- and dicarboxy lie acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedio
  • Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like.
  • Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.
  • “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, poly amine resins and the like. See Berge et
  • treating refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition (such as cancer) in a subject, including but not limited to the following: (a) ameliorating the disease or medical condition, e.g., eliminating or causing regression of the disease or medical condition in a subject; (b) suppressing the disease or medical condition, e.g., slowing or arresting the development of the disease or medical condition in a subject; or (c) alleviating symptoms of the disease or medical condition in a subject.
  • “treating cancer” would include preventing cancer from reoccurring, ameliorating cancer, suppressing cancer, and alleviating the symptoms of cancer.
  • a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder.
  • a prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
  • administer refers to the methods that may be used to enable delivery of a composition to the desired site of biological action. These methods include, but are not limited to parenteral administration (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, intrathecal, intranasal, intravitreal, infusion and local injection), transmucosal injection, oral administration, administration as a suppository, and topical administration. Administration is by any route, including parenteral. Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial.
  • the term “effective amount” or “therapeutically effective amount” or “therapeutically effective dose” refers to the amount of an agent that is sufficient to effect beneficial or desired results.
  • the therapeutically effective amount may vary depending upon one or more of: the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • An effective amount of an active agent may be administered in a single dose or in multiple doses.
  • a component may be described herein as having at least an effective amount, or at least an amount effective, such as that associated with a particular goal or purpose, such as any described herein.
  • the term “effective amount” also applies to a dose that will provide an image for detection by an appropriate imaging method.
  • the specific dose may vary depending on one or more of: the particular agent chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to be imaged, and the physical delivery system in which it is carried.
  • sub-therapeutic amount refers to the amount of an agent that is less than the effective amount for that agent, but when combined with an effective or sub-therapeutic amount of a different agent can produce a desired result, due to, for example, synergy in the resulting efficacious effects and/or reduced side effects by the combination of (i) the sub- therapeutic amount of the agent and (ii) the different agent (e.g., one or more different agents).
  • an agent can be approved for clinical use for a specified indication at a defined dose or range thereof (e.g., 150 milligrams per day (mg/d)) over the course of one or more administrations, and a sub-therapeutic amount of such agent can be lower than the approved dose or range thereof by at least about 0.1-fold, 0.2-fold, 0.5-fold, 1-fold, 2- fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, 200-fold, 500-fold, 1,000-fold, 2,000-fold, 5,000-fold, 10,000-fold, 20,000-fold, 50,000-fold, 100,000-fold, or more.
  • a defined dose or range thereof e.g. 150 milligrams per day (mg/d)
  • a sub-therapeutic amount of such agent can be lower than the approved dose or range thereof by at least about 0.1-fold, 0.2-fold, 0.5-fold, 1-fold, 2- fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, 200-fold,
  • the sub-therapeutic amount of such agent can be lower than the approved dose or range thereof by at most about 100,000-fold, 50,000-fold, 20,000-fold, 10,000-fold, 5,000-fold, 2,000-fold, 1,000-fold, 500-fold, 200-fold, 100-fold, 50-fold, 20-fold, 10-fold, 5-fold, 2-fold, 1-fold, 0.5-fold, 0.2- fold, 0.1 -fold or less.
  • a sub -therapeutic amount of an agent can be achieved by reducing the amount of the agent per dosage and/or by reducing the number of administrations (or cycles) of the agent to the subject.
  • the synergistic effect can be at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 150%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1,000%, 5,000%, or more than (i) the effect of each therapeutic component alone and/or (ii) the sum of individual effects.
  • the effect can be any measurable effect including but not limited to an enhancement of a therapeutic effect of an individual component within the combination or a reduction in a side effect of an individual component within the combination.
  • the effect is a pharmacodynamic effect, such as phosphorylated ERK (p-ERK) and/or DUSP6 inhibition, optionally assessed in whole blood.
  • a pharmacodynamic effect such as phosphorylated ERK (p-ERK) and/or DUSP6 inhibition, optionally assessed in whole blood.
  • p-ERK phosphorylated ERK
  • DUSP6 inhibition optionally assessed in whole blood.
  • the two or more different therapeutic components of the combination treatment as disclosed herein can be administered concurrently or sequentially, as separate components or as a unit dosage.
  • a synergistic effect of a combination comprising a first agent and a second agent can yield a desired therapeutic outcome (e.g., in treating cancer) that is comparable (e.g., substantially the same) or better than (i) the therapeutic outcome of each therapeutic component alone at the therapeutically effective amount and/or (ii) the sum of individual effects, where either or both of the first and the second agent are administered in a respective sub-therapeutic amount.
  • a synergistic effect of a combination comprising a first agent and a second agent can yield a desired therapeutic outcome (e.g., reducing side effect of either one of the agent) that is comparable (e.g., substantially the same) or better than the therapeutic outcome of each therapeutic component alone.
  • IC50 refers to the half maximal inhibitory amount (e.g., concentration) of an inhibitor in inhibiting a biological or biochemical effect.
  • IC50 can be a quantitative measure that indicates how much of a particular inhibitor is needed to inhibit a given biological or biochemical effect (e.g., expression and/or activity level of a gene/protein of interest, growth, or growth rate of a cell, etc.) by substantially half (e.g., about 50%).
  • determination of IC50 can be made by determining and constructing a dose-response curve and examining the effect of different concentrations of an inhibitor on reducing cell growth (e.g., inhibiting proliferation of cancer cells), and determining the concentration of the inhibitor at which 50% inhibition of cell growth is observed.
  • the term “combination”, as applied to agents including inhibitors disclosed herein, refers to the use of two or more agents (e.g., a SOS1 inhibitor and at least another inhibitor against a different signaling molecule) in vitro, in vivo, or ex-vivo.
  • the two or more agents in combination can be formulated in one single formulation, or in separate formulation(s).
  • a combination treatment or therapy with two or more agents can be carried out conjunctively in any temporal order, administered simultaneously or separately.
  • the term “conjunction” refers to a temporal aspect of the use of two or more agents (e.g., a SOS1 inhibitor and at least another inhibitor against a different signaling molecule) in vitro, in vivo, or ex-vivo.
  • agents e.g., a SOS1 inhibitor and at least another inhibitor against a different signaling molecule
  • one agent of a set of agents of interest can be administered prior to, subsequent to, or concurrently with the administration of a second agent of the set.
  • Simultaneous administration can be effectuated by simultaneously administering multiple agents as separate agents, or as a unit dosage comprising the multiple agents.
  • antagonists are used interchangeably, and they refer to a compound having the ability to inhibit a biological function (e.g., activity, expression, binding, protein-protein interaction) of a target protein (e.g., SOS1). Accordingly, the terms “antagonist” and “inhibitor” are defined in the context of the biological role of the target protein. While preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit a biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included within this definition. [067] The term “selective inhibition” or “selectively inhibit” refers to the ability of a biologically active agent to preferentially reduce the target signaling activity as compared to off-target signaling activity, via direct or indirect interaction with the target.
  • the terms “subject”, “individual”, and “patient” are used interchangeably herein to refer to an animal, such as a mammal, for example a human.
  • the methods described herein can be useful in both human therapeutics and veterinary applications.
  • the subject is a mammal, such as a human.
  • “Mammal” includes humans and both domestic animals such as laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like. Tissues, cells, and their progeny of a biological entity obtained in vivo or cultured in vitro are also encompassed.
  • therapeutic agent refers to a molecule or compound that confers some beneficial effect upon administration to a subject.
  • the beneficial effect includes enablement of diagnostic determinations; amelioration of a disease, symptom, disorder, or pathological condition; reducing or preventing the onset of a disease, symptom, disorder or condition; and generally counteracting a disease, symptom, disorder or pathological condition.
  • polypeptide refers to polymers of amino acids of any length.
  • the polymer may be linear or branched, it may comprise modified amino acids, and it may be interrupted by non-amino acids.
  • the terms also encompass an amino acid polymer that has been modified; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation, such as conjugation with a labeling component.
  • amino acid refers to either natural and/or unnatural or synthetic amino acids, including glycine and both the D or L optical isomers, and amino acid analogs and peptidomimetics.
  • polynucleotide refers to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof. Polynucleotides may have any three-dimensional structure, and may perform any function, known or unknown.
  • polynucleotides coding or noncoding regions of a gene or gene fragment, loci (locus) defined from linkage analysis, exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, short interfering RNA (siRNA), short-hairpin RNA (shRNA), micro-RNA (miRNA), ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers.
  • loci locus defined from linkage analysis, exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, short interfering RNA (siRNA), short-hairpin RNA (shRNA), micro-RNA (miRNA), ribozymes, cDNA, recombinant polynucleotides, branched polyn
  • a polynucleotide may comprise one or more modified nucleotides, such as methylated nucleotides and nucleotide analogs, such as peptide nucleic acid (PNA), morpholino and locked nucleic acid (LNA), glycol nucleic acid (GNA), threose nucleic acid (TNA), 2 ’-fluoro, 2’-0Me, and phosphorothiolated DNA. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component or other conjugation target.
  • modified nucleotides such as methylated nucleotides and nucleotide analogs, such as peptide nucleic acid (PNA), morpholino and locked nucleic acid (LNA), glycol nucle
  • nucleic acid agent refers to an inhibitory agent capable of downregulating (e.g., reducing or inhibiting) expression and/or activity of a target moiety (e.g., a protein or a gene encoding thereof).
  • a nucleic acid agent may consist of a nucleic acid molecule.
  • a nucleic acid agent may comprise a nucleic acid molecule.
  • a nucleic acid agent may comprise a nucleic acid molecule and a non-nucleic acid molecule. The nucleic acid molecule and the non-nucleic acid molecule may be operatively coupled to each other to yield the inhibitory effect on the target moiety.
  • the nucleic acid molecule and the non-nucleic acid molecule may be coupled (e.g., covalently and/or non-covalently) to each other.
  • the nucleic acid molecule and the non-nucleic acid molecule can be linked to each other via a linker.
  • the nucleic acid molecule can be configured to bind to the non-nucleic acid molecule.
  • the non- nucleic acid molecule can be configured to bind to the nucleic acid molecule.
  • Non-limiting examples of the non- nucleic acid molecule include a small molecule, a polypeptide (e.g., an enzyme), etc.
  • the non-nucleic acid molecule is a nuclease, e.g., an endonuclease.
  • expression refers to the process by which a polynucleotide is transcribed from a DNA template (such as into and mRNA or other RNA transcript) and/or the process by which a transcribed mRNA is subsequently translated into peptides, polypeptides, or proteins.
  • Transcripts and encoded polypeptides may be collectively referred to as “gene product.” If the polynucleotide is derived from genomic DNA, expression may include splicing of the mRNA in a eukaryotic cell.
  • an “antigen” is a moiety or molecule that contains an epitope, and, as such, also specifically binds to an antibody.
  • An “antigen binding unit” may be whole or a fragment (or fragments) of a full-length antibody, a structural variant thereof, a functional variant thereof, or a combination thereof.
  • a full-length antibody may be, for example, a monoclonal, recombinant, chimeric, deimmunized, humanized and human antibody.
  • Examples of a fragment of a full-length antibody may include, but are not limited to, variable heavy (VH), variable light (VL), a heavy chain found in camelids, such as camels, llamas, and alpacas (VHH or VHH), a heavy chain found in sharks (V-NAR domain), a single domain antibody (sdAb, e.g., “nanobody”) that comprises a single antigen-binding domain, Fv, Fd, Fab, Fab', F(ab')2, and “r IgG“ (or half antibody).
  • VH variable heavy
  • VL variable light
  • VHH or VHH a heavy chain found in camelids
  • VHH or VHH a heavy chain found in sharks
  • V-NAR domain a single domain antibody
  • sdAb e.g., “nanobody” that comprises a single antigen-binding domain, Fv, Fd, Fab, Fab', F(ab')2, and “
  • modified fragments of antibodies may include, but are not limited to scFv, di-scFv or bi(s)-scFv, scFv-Fc, scFv-zipper, scFab, Fab2, Fab3, diabodies, single chain diabodies, tandem diabodies (Tandab's), tandem di-scFv, tandem tri-scFv, minibodies (e.g., (VH-VL- CH3)2, (scFv-CH3)2, ((scFv)2-CH3+CH3), ((scFv)2-CH3) or (scFv-CH3-scFv)2), and multibodies (e.g., tnabodies or tetrabodies).
  • minibodies e.g., (VH-VL- CH3)2, (scFv-CH3)2, ((scFv)2-CH3+CH3), ((scFv)2-CH3) or (scF
  • antibody encompass any antigen binding units, including without limitation: monoclonal antibodies, human antibodies, humanized antibodies, camelised antibodies, chimeric antibodies, and any other epitope -binding fragments.
  • Prodrug is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound described herein (e.g., a compound of Formula (I)).
  • a prodrug refers to a precursor of a biologically active compound that is pharmaceutically acceptable.
  • a prodrug is inactive when administered to a subject but is converted in vivo to an active compound, for example, by hydrolysis.
  • the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp.
  • prodrug is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of an active compound are typically prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound.
  • Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively.
  • Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of a hydroxy functional group, or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound, and the like.
  • in vivo refers to an event that takes place in a subject’s body.
  • ex vivo refers to an event that first takes place outside of the subject’s body for a subsequent in vivo application into a subject’s body.
  • an ex vivo preparation may involve preparation of cells outside of a subject’s body for the purpose of introduction of the prepared cells into the same or a different subject’s body.
  • in vitro refers to an event that takes place outside of a subject’s body.
  • an in vitro assay encompasses any assay run outside of a subject’s body.
  • In vitro assays encompass cell-based assays in which cells alive or dead are employed.
  • In vitro assays also encompass a cell-free assay in which no intact cells are employed.
  • the disclosure is also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the disclosure includes compounds produced by a process comprising administering a compound disclosed herein to a mammal for a period of time sufficient to yield a metabolic product thereof. Such products are typically identified by administering a radiolabeled compound of the disclosure in a detectable dose to an animal, such as rat, mouse, guinea pig, monkey, or to a human, allowing sufficient time for metabolism to occur, and isolating its conversion products from the urine, blood or other biological samples.
  • an animal such as rat, mouse, guinea pig, monkey, or to a human
  • Ras refers to a protein in the Rat sarcoma (Ras) superfamily of small GTPases, such as in the Ras subfamily.
  • the Ras superfamily includes, but is not limited to, the Ras subfamily, Rho subfamily, Rab subfamily, Rap subfamily, Arf subfamily, Ran subfamily, Rheb subfamily, RGK subfamily, Rit subfamily, Miro subfamily, and Unclassified subfamily.
  • a Ras protein is selected from the group consisting of KRAS (K-Ras or K-ras or Kras), ERAS (or H-Ras), NRAS (or N-Ras), MRAS (or M-Ras), ERAS (or E-Ras), RRAS2 (or R-Ras2), RALA (or RalA), RALB (or RalB), RIT1, and any combination thereof, such as from KRAS, HRAS, NRAS, RALA, RALB, and any combination thereof.
  • Amivantamab and “amivantamab-vmjw” are used interchangeably herein to refer to a low-fucose human immunoglobulin G1 -based bispecific antibody directed against the EGF and MET receptors that has a molecular weight of approximately 148 kDa.
  • Amivantamab may be produced by mammalian cell line (Chinese Hamster Ovary [CHO]) using recombinant DNA technology.
  • Amivantamab is sold under the brand name Rybrevant as an injection for intravenous infusion and is indicated for the treatment of adult patients with locally advanced or metastatic nonsmall cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.
  • NSCLC locally advanced or metastatic nonsmall cell lung cancer
  • EGFR epidermal growth factor receptor
  • Rybrevant injection is a sterile, preservative-free, colorless to pale yellow solution in single-dose vials having a pH of approximately 5.7.
  • Each Rybrevant vial contains 350 mg (50 mg/mL) amivantamab-vmjw, EDTA disodium salt dihydrate (0.14 mg), L-histidine (2.3 mg), L-histidine hydrochloride monohydrate (8.6 mg), L-methionine (7 mg), polysorbate 80 (4.2 mg), sucrose (595 mg), and water for injection, USP.
  • the recommended dosage of Rybrevant is based on baseline body weight and administered as an intravenous infusion after dilution. For patients weighing less than 80 kg, a dose of 1050 mg (3 vials) is recommended, and for patients weighing greater than or equal to 80 kg, a dose of 1400 mg (4 vials) is recommended.
  • the SOS1 inhibitors and the pharmaceutical compositions thereof, as disclosed herein, are particularly useful in treating epidermal growth factor receptor (EGFR)-mediated diseases and the symptoms associated therewith.
  • EGFR epidermal growth factor receptor
  • Common EGFR mutations including variable deletions of at least three amino acid residues in exon 19 (exon 19 deletion), L858R point mutation in exon 21, and exon 20 insertion mutations (ex20ins), are activating mutations that result in constitutive activation of EGFR and downstream signaling pathways, particularly in nonsmall cell lung cancer (NSCLC).
  • NSCLC nonsmall cell lung cancer
  • compositions and methods disclosed herein open a new avenue for remission or treatment free remission (TFR) for EGFR-mediated cancers, and in particular NSCLC in which an exon 19 deletion, L858R mutation, T790M mutation, C797S mutation, and/or exon 20 insertion is detected.
  • TFR treatment free remission
  • the present disclosure provides a method of reducing proliferation of cancer cells comprising an epidermal growth factor receptor (EGFR) exon 20 insertion, the method comprising administering to the cells (a) a SOS1 inhibitor and (b) amivantamab, wherein (a) is administered prior to, concurrently with, or subsequent to administering (b).
  • the cancer cells are non-small cell lung cancer cells.
  • the present disclosure provides a method of downregulating EGFR signaling output in a plurality of non-small cell lung cancer cells, comprising: (i) assessing EGFR mutation status in a biological sample comprising nucleic acid from the subject; and (ii) administering an effective dose of (a) a SOS1 inhibitor and an effective dose of (b) amivantamab if an EGFR exon 20 insertion is detected in the sample, wherein (a) is administered prior to, concurrently with, or subsequent to administering (b).
  • the present disclosure provides a method of treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy, the method comprising administering to the subject (a) a SOS1 inhibitor and (b) amivantamab.
  • NSCLC locally advanced or metastatic non-small cell lung cancer
  • EGFR epidermal growth factor receptor
  • the present disclosure provides a method of treating an EGFR-mediated disease or condition or ameliorating the symptoms thereof in a subject in need thereof.
  • the method may comprise administering to the subject (a) a SOS1 inhibitor and (b) amivantamab.
  • the disease or condition is a cancer comprising an EGFR mutation, including but not limited to an exon 19 deletion, an L858R mutation, a T790M mutation, a C797S mutation, and/or an exon 20 insertion.
  • the cancer comprises an exon 20 insertion.
  • the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject (a) a SOS1 inhibitor and (b) amivantamab, optionally wherein the cancer comprises an EGFR mutation, such as an exon 19 deletion, L858R, T790M, C797S, and/or an exon 20 insertion.
  • the cancer exhibits MET amplification.
  • the present disclosure provides a method of treating an EGFR-mediated cancer in a subject, comprising administering to the subject a pharmaceutical composition comprising (i) a SOS1 inhibitor of Formula (I- 1 ), or a pharmaceutically acceptable salt or solvate thereof, (ii) amivantamab, and (iii) a pharmaceutically acceptable excipient.
  • the present disclosure provides a method of treating an EGFR-mediated cancer in a subject, comprising administering to the subject (a) a SOS1 inhibitor and (b) amivantamab, wherein (a) is administered prior to, concurrently with, or subsequent to administering (b).
  • Any method described herein that comprises administering (a) a SOS1 inhibitor and (b) amivantamab may further comprise administering (c) an additional agent or additional therapy.
  • Suitable agents that can be administered in combination with (a) the SOS1 inhibitor and (b) amivantamab include other anti-cancer agents, anti-allergic agents, anti-nausea agents (or anti-emetics), pain relievers, cytoprotective agents, immunomodulatory agents, steroids, chemotherapeutic agents, and combinations thereof.
  • the additional therapy is selected from surgery, cell therapy, chemotherapy, and radiation.
  • the EGFR-mediated disease or condition may be any disease or condition in which the EGFR signaling pathway contributes to the progression of the disease or condition.
  • the disease or condition is characterized by aberrant activation of EGFR, optionally due to EGFR amplification, EGFR overexpression, overexpression of EGFR ligands, and/or occurrence of one or more EGFR mutation.
  • EGFR-mediated diseases or conditions include, but are not limited to: cancer, such as lung adenocarcinoma, squamous cell lung carcinoma, nonsmall cell lung cancer, anal cancer, ovarian cancer, breast cancer, colorectal cancer, bladder cancer, esophageal cancer, glioblastoma, and head and neck carcinomas; inflammatory disease, such as psoriasis, eczema, atopic dermatitis, and atherosclerosis; and renal disease, such as renal fibrosis, chronic kidney disease, acute kidney injury, obstructive nephropathy, diabetic nephropathy, hypertensive nephropathy, and glomerulonephritis.
  • cancer such as lung adenocarcinoma, squamous cell lung carcinoma, nonsmall cell lung cancer, anal cancer, ovarian cancer, breast cancer, colorectal cancer, bladder cancer, esophageal cancer, glioblastoma, and head and neck
  • the EGFR-mediated disease or condition is an EGFR-mediated cancer.
  • the cancer is lung cancer, such as non-small cell lung cancer.
  • the cancer is metastatic, such as metastatic NSCLC.
  • the cancer is locally advanced, such as locally advanced NSCLC.
  • the cancer comprises an EGFR mutation, such as a mutation selected from L858R, T790M, C797S, an exon 19 deletion, and an exon 20 insertion.
  • the cancer comprises an exon 20 insertion.
  • the cancer comprises a double or triple EGFR mutant, such as T790M/C797S, L858R/T790M, dell9/T790M/C797S, or L858R/T790M/C797S.
  • the cancer comprises aberrant MET expression, such as overexpression of MET or MET amplification.
  • Determining whether a tumor or cancer comprises an EGFR mutation can be undertaken by assessing the nucleotide sequence encoding the protein, by assessing the amino acid sequence of the protein, or by assessing the characteristics of a putative protein.
  • Exemplary nucleic acid assays include but are not limited to genotyping assays and sequencing methods. Sequencing methods can include next-generation sequencing, targeted sequencing, exome sequencing, whole genome sequencing, massively parallel sequencing, and the like. Several platforms for next generation sequencing are commercially available, including those marketed by Illumina and Pacific Biosciences.
  • Additional nucleic acid assays include but not limited to in situ hybridization (e.g., FISH), polymerase chain reaction (PCR), quantitative PCR (qPCR), quantitative real-time PCR (qRT-PCR), and ligase chain reaction (LCR), all of which are applicable for detecting a genetic aberration in EGFR.
  • FISH in situ hybridization
  • PCR polymerase chain reaction
  • qPCR quantitative PCR
  • qRT-PCR quantitative real-time PCR
  • LCR ligase chain reaction
  • one or more nucleic acids can be employed to detect a genetic aberration resulting in formation of EGFR gene including but not limited to translation, as well as genetic mutations within the EGFR gene via point mutation, insertion, deletion, or frameshift.
  • Additional methods for detecting a nucleotide sequence of a gene include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) assays, real-time PCR assays, PCR sequencing, mutant allele-specific PCR amplification (MASA) assays, direct sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high resolution melting assays, and microarray analyses.
  • PCR-RFLP polymerase chain reaction-restriction fragment length polymorphism
  • PCR-SSCP polymerase chain reaction-single strand conformation polymorphism
  • MSA mutant allele-specific PCR amplification
  • the EGFR mutation is identified using a direct sequencing method of specific regions in the gene. This technique can identify all possible mutations in the region sequenced. Methods for detecting a mutant EGFR protein include, but are not limited to, detection of a mutant protein using a binding agent (e.g., an antibody) specific for the mutant protein, protein electrophoresis and Western blotting, and direct peptide sequencing.
  • the EGFR mutation is identified using a PCR-based or next-generation sequencing (NGS)-based diagnostic.
  • NGS next-generation sequencing
  • the presence of an EGFR mutation is determined in a tumor or plasma specimen using an FDA-approved test, such as the cobas EGFR Mutation Test vl (Roche Molecular Systems, Inc.), cobas EGFR Mutation Test v2 (Roche Molecular Systems, Inc.), FoundationOne CDx (Foundation Medicine, Inc.), FoundationOne Liquid CDx (Foundation Medicine, Inc.), Guardant360 CDx (Guardant Health, Inc.), ONCO/Reveal Dx Lung & Colon Cancer Assay (O/RDx-LCCA, Pillar Biosciences, Inc.), Oncomine Dx Target Test (Life Technologies Corporation), or therascreen EGFR RGQ PCR Kit (Qiagen Manchester, Ltd.).
  • an FDA-approved test such as the cobas EGFR Mutation Test vl (Roche Molecular Systems, Inc.), cobas EGFR Mutation Test v2 (Roche Molecular Systems, Inc.), FoundationOne CDx (Foundation Medicine, Inc.), FoundationOne Li
  • the presence of an EGFR mutation is determined in a tumor or plasma specimen using an FDA- approved test, such as the therascreen EGFR RGQ PCR Kit (Qiagen Manchester, Ltd.).
  • EGFR protein expression is assessed in a tumor or plasma specimen using an FDA-approved test, such as the Dako EGFR pharmDx Kit (Dako North America, Inc.).
  • the presence of an EGFR mutation is determined in a tumor or plasma specimen using an FDA-approved test, such as the FoundationOne Liquid CDx (Foundation Medicine, Inc.), Guardant360 CDx (Guardant Health, Inc.), or Oncomine Dx Target Test (Life Technologies Corporation).
  • FDA-approved test such as the FoundationOne Liquid CDx (Foundation Medicine, Inc.), Guardant360 CDx (Guardant Health, Inc.), or Oncomine Dx Target Test (Life Technologies Corporation).
  • an EGFR-mediated disease or condition is one comprising a known EGFR activating mutation, such as an exon 19 deletion, L858R, T790M, or an exon 20 insertion.
  • Suitable protein assays include, without limitation, immunohistochemistry (IHC), ELISA (enzyme linked immunosorbent assays), “sandwich” immunoassays, immunoradiometric assays, in situ immunoassays, western blot analysis, immunoprecipitation assays, immunofluore scent assays, flow cytometry, confocal microscopy, enzymatic assays, surface plasmon resonance, and PAGE-SDS.
  • IHC immunohistochemistry
  • ELISA enzyme linked immunosorbent assays
  • “sandwich” immunoassays immunoradiometric assays
  • in situ immunoassays western blot analysis
  • immunoprecipitation assays immunofluore scent assays
  • flow cytometry confocal microscopy
  • enzymatic assays surface plasmon resonance
  • PAGE-SDS PAGE-SDS
  • One or more of these protein assays utilize antibodies or fragments thereof that exhibit specific binding to EGFR polypeptides.
  • a large number of anti-EGFR antibodies are available, including those provided by Thermofisher and Abeam. Commercially available antibodies can also be used in immunoassays to ascertain a decrease in EGFR TKI binding affinity to EGFR as a result of a genetic mutation in the EGFR gene.
  • Methods for determining whether a tumor or cancer comprises an EGFR mutation can use a variety of samples.
  • the sample is taken from a subject having a tumor or cancer.
  • the sample is a fresh tumor/cancer sample.
  • the sample is a frozen tumor/cancer sample.
  • the sample is a formalin-fixed paraffin-embedded sample.
  • the sample is processed to a cell lysate.
  • the sample is processed to DNA or RNA.
  • the sample is a plasma sample.
  • the sample comprises cell-free DNA (cfDNA).
  • the method utilizes circulating cfDNA from plasma of peripheral whole blood collected from the subject.
  • the presence of EGFR gene, mutations within the EGFR gene, or other genetic aberrations associated with resistance to an EGFR TKI can be determined using any biological sample comprising the target cells (e.g., cancer cells from a subject under investigation) or constituents thereof (e.g., constituents such as cfDNA from the tumor tissue or cancer cells).
  • the biological sample may be a liquid biological sample or a solid biological sample from the subject under investigation or treatment.
  • the biological sample may be a biopsy sample that is fixed, paraffin-embedded, fresh, or frozen.
  • the biological sample may be obtained by any suitable means, including but not limited to blood draw, needle aspiration, fine needle aspiration, core needle biopsy, vacuum assisted biopsy, large core biopsy, incisional biopsy, excisional biopsy, punch biopsy, shave biopsy, skin biopsy, surgical specimen, and venipuncture.
  • the biological sample can be obtained from, without limitation, blood or plasma, skin, heart, lung, kidney, bone marrow, breast, pancreas, liver, muscle, smooth muscle, bladder, gall bladder, colon, intestine, brain, prostate, esophagus, thyroid, serum, saliva, urine, gastric and digestive fluid, tears, stool, semen, vaginal fluid, interstitial fluids derived from tumorous tissue, ocular fluids, sweat, mucus, earwax, oil, glandular secretions, spinal fluid, hair, fingernails, plasma, nasal swab or nasopharyngeal wash, spinal fluid, cerebral spinal fluid, tissue, throat swab, biopsy, placental fluid, amniotic fluid, cord blood, emphatic fluids, cavity fluids, sputum, pus, microbiota, meconium, breast milk, and/or other excretions or body tissues of the subject.
  • blood or plasma skin, heart, lung, kidney, bone marrow, breast, pancre
  • a biological sample comprises cell-free DNA (cfDNA) derived from a whole blood or plasma of the subject.
  • a sample may be analyzed directly for its contents, or may be processed to purify one or more of its contents for analysis.
  • the purified component of the biological sample is protein (e.g. total protein, cytoplasmic protein, or membrane protein).
  • the purified component of the sample is a nucleic acid, such as DNA (e.g. genomic DNA, cDNA, ctDNA, or cfDNA) or RNA (e.g. total RNA, mRNA, or microRNA).
  • EGFR exon 20 insertions include in-frame insertions within exon 20 of EGFR.
  • an EGFR exon 20 insertion is found between residues E762 and C775.
  • an EGFR exon 20 insertion is found after E762, A763, Y764, V765, M766, A767, S768, V769, D770, N771, P772, H773, V774, or C775.
  • an EGFR exon 20 insertion is found after residue L747, A763, Y764, M766, A767 , V769, D770, P772, or H773.
  • an EGFR exon 20 insertion is found after residue V769 or D770.
  • an EGFR exon 20 insertion is selected from A763_Y764ins, Y764_V765ins, M766_A767ins, A767_V769dup, V769_D770ms, D770_N771ms, delD770ms, P772_H773ms, P772_V774ms, and H773_V774ins.
  • an EGFR exon 20 insertion is selected from D770_N771ins and V769_D770ins.
  • an EGFR exon 20 insertion is selected from delL747_P753insS, A763_Y764insFQEA, Y764_V765msHH, M766_A767insAI, M766_A767insASV, A767_V769dupASV, V769_D770insASV, D770_N771insGL, D770_N771insGT, D770_N771insNPG, D770_N771insSVD, delD770insGY, P772_H773insYNP, P772_V774insPHV, H773_V774insH, and H773_V774insNPH.
  • an EGFR exon 20 insertion is selected from D770_N771insSVD and V769_D770insASV.
  • an EGFR exon 20 insertion consists of one to four amino acid residues, such as one, two, three or four amino acid residues.
  • a cancer comprising an EGFR exon 20 insertion is insensitive to treatment with gefitinib or erlotinib.
  • the criterion can compare the observed combination response with the predicted combination response, which predicted combination response is obtained based on the assumption that there is no effect from drug-drug interactions.
  • the combination effect can be determined to be synergistic when the observed combination response is greater than the predicted combination response (e.g., greater by a threshold value).
  • the observed combined percent inhibition Y AB,O is compared with the predicted percentage growth inhibition Y AB,P in accordance with equation (1).
  • the comparison can determine whether the combination treatment promotes a synergistic effect, an additive effect, or an antagonistic effect, as summarized in equation (3).
  • YAB,O > YAB,P the combination treatment can be determined to be more efficacious than expected (e.g., a synergistic effect).
  • Y AB,O ⁇ Y AB,P the combination treatment can be determined to be worse than expected (e.g., an antagonistic effect).
  • the combination treatment can be determined to be substantially the same as a simple addition of two separate drugs (e.g., independent effects, or an additive effect).
  • > YAB,P Synergy Y AB,P ⁇ YAB,P Independent (3)
  • ⁇ YAB,P Antagonism [100]
  • the percent growth inhibition of the target cells can be provided based on a percentage scale (e.g., between about 0% to about 100%) or a fractional scale (e.g., between about 0 to 1). For example, a 75% growth inhibition of the target cells can be expressed as 0.75 for purposes of analysis in accordance with the Bliss independence criterion.
  • the difference between the observed combined percent inhibition Y AB,O and the predicted percent growth inhibition Y AB,P in accordance with equation (1) (e.g., based on one or more in vitro experiments), can be determined to be additive (or antagonistic) when the difference is less than or equal to zero.
  • Such difference can be determined to be synergistic when the difference is greater than zero.
  • the synergistic effect can be divided into a plurality of sub-ranges, e.g., a first synergistic sub-range having the difference between about 0.05 and about 0.1 (e.g., mild synergy), a second synergistic sub-range having the difference between about 0.1 and about 0.2 (e.g., moderate synergy), and a third synergistic sub-range having the difference greater than or equal to 0.2 (e.g., robust synergy).
  • a first synergistic sub-range having the difference between about 0.05 and about 0.1 e.g., mild synergy
  • a second synergistic sub-range having the difference between about 0.1 and about 0.2 e.g., moderate synergy
  • a third synergistic sub-range having the difference greater than or equal to 0.2 e.g., robust synergy
  • the combination treatment comprising a plurality of agents (e.g., a SOS1 inhibitor disclosed or exemplified herein and amivantamab), can be utilized to reduce growth or proliferation of target cells, such as NSCLC cells, in vitro or in vivo.
  • a SOS1 inhibitor disclosed or exemplified herein and amivantamab can be utilized to reduce growth or proliferation of target cells, such as NSCLC cells, in vitro or in vivo.
  • the therapeutic efficacy of the combination treatment can be characterized by a synergistic value of above 0. 1 as ascertained by the Bliss independence criterion.
  • the therapeutic efficacy of the combination treatment can be characterized by a synergistic value of at least about 0.1, 0.2, 0.3, 0.4, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 9, 10, 11, 12, 13, 14, 15, or above as ascertained by the Bliss independence criterion.
  • the therapeutic efficacy of the combination treatment can be characterized by a synergistic value of about 0.1 to about 1, about 1.0 to about 5, about 5 to about 10, or about 10 to about 15.
  • the synergistic value is at least 0.4, such as at least 1.
  • the synergistic value is at least 5.
  • the subject is a naive subject that has not been treated for the cancer.
  • the naive subject has not been treated with a TKI against EGFR prior to administering (a) and (b).
  • the subject has been treated with chemotherapy.
  • the subject has received surgery to treat the cancer.
  • the subject has not been treated with chemotherapy.
  • the subject has not received surgery.
  • the subject has been treated with a non- amivantamab TKI against EGFR prior to administering (a) and (b).
  • the subject has not been treated with amivantamab as a TKI prior to administering (a) and (b).
  • a subject suitable for a treatment method of the present disclosure has previously been treated with one or more tyrosine kinase inhibitor (TKI) against EGFR prior to administering (a) and (b).
  • TKI tyrosine kinase inhibitor
  • the subject has previously been treated with a first-generation EGFR TKI (e.g., gefitinib), a second generation EGFR TKI (e.g., afatinib), or a third generation EGFR TKI (e.g., osimertinib).
  • the subject has previously been treated with a non-exon 20 insertion EGFR TKI, such as gefitinib, erlotinib, afatinib, osimertinib, dacomitinib, neratinib, cetuximab, panitumumab, lapatinib, necitumumab, soloartinib, vandetanib, BLU-945, or zorifertinib.
  • the subject has previously been treated with gefitinib, erlotinib, or afatinib.
  • the subject has previously been treated with osimertinib.
  • the subject has previously been treated with an EGFR exon 20 insertion TKI, such as poziotinib, mobocertinib, amivantamab, zipalertinib, sunvozertinib, BAY-2927088, BLU-451, or STX-721.
  • TKI such as poziotinib, mobocertinib, amivantamab, zipalertinib, sunvozertinib, BAY-2927088, BLU-451, or STX-721.
  • the subject has previously been treated with amivantamab.
  • the subject has previously been treated with an EGFR TKI selected from gefitinib, erlotinib, afatinib, lazertinib, osimertinib, dacomitinib, neratinib, cetuximab, panitumumab, lapatinib, necitumumab, soloartinib, vandetanib, BLU-945, zorifertinib, poziotinib, mobocertinib, amivantamab, zipalertinib, sunvozertinib, BAY-2927088, BLU-451, and STX-721.
  • an EGFR TKI selected from gefitinib, erlotinib, afatinib, lazertinib, osimertinib, dacomitinib, neratinib, cetuximab, panitumumab, lapatinib
  • a subject suitable for a treatment method of the present disclosure has previously been treated with chemotherapy prior to administering (a) and (b). In some embodiments, the disease of the subject has progressed on or after chemotherapy. In some embodiments, a subject suitable for a treatment method of the present disclosure has previously been treated with platinum-based chemotherapy prior to administering (a) and (b). In some embodiments, the disease of the subject has progressed on or after platinum-based chemotherapy. In some embodiments, the subject has undergone tumor resection.
  • Resistance to an EGFR TKI may be characterized by one or more changes selected from (1) progression of the cancer, (2) EGFR gene mutation including point mutation, insertion, deletion, and translocation, (3) loss of EGFR T790M mutation, (4) EGFR gene amplification, ⁇ S') MET amplification, (6) HER2 amplification, (7) RAS-MAPK pathway activation, (8) PI3K pathway activation, (9) cell-cycle gene alteration, (10) oncogenic fusion, (11) histologic transformation, and (12) phenotypic transformation.
  • resistance to an EGFR TKI is characterized by an exon 20 insertion resulting in a decrease in TKI binding affinity to EGFR.
  • a subject resistant to an EGFR TKI comprises one or more mutation selected from L858R, T790M, C797S, an exon 19 deletion, and an exon 20 insertion.
  • a subject resistant to an EGFR TKI comprises a double or triple EGFR mutant, including but not limited to T790M/C797S, L858R/T790M, dell9/T790M/C797S, and L858R/T790M/C797S.
  • a subject suitable for a treatment method of the present disclosure exhibits intolerance to an EGFR TKI.
  • Amivantamab is known to cause a number of side effects, including back pain, bleeding gums, blistering, crusting, irritation, itching, or reddening of the skin, blood in the urine, bloody nose, burning, crawling, itching, numbness, painful, prickling, "pins and needles", or tingling feelings, chest pain or tightness, chills, cough, coughing or spitting up blood, cracked, dry, or scaly skin, dry, itching skin, fever, flushing, headache, loosening of the fingernails, muscle or bone pain, nausea and vomiting, nerve pain, rash with flat lesions or small raised lesions on the skin, redness or soreness around the fingernails, sneezing, swelling, trouble breathing, unsteadiness or awkwardness, and/or weakness in the arms, hands, legs, or feet.
  • the side effects of amivantamab include rash, pruritus, dry skin, fatigue, edema, pyrexia, paronychia, pneumonia, musculoskeletal pain, dyspnea, cough, nausea, stomatitis, constipation, vomiting, diarrhea, abdominal pain, hemorrhage, decreased appetite, peripheral neuropathy, dizziness, and/or headache, any or all of which may render the subject intolerant to EGFR TKI treatment.
  • a subject resistant to treatment with an EGFR TKI may exhibit progression of the disease or condition, such as cancer (e.g., NSCLC), despite treatment with the EGFR TKI.
  • An exemplary EGFR-mediated cancer is NSCLC, which typically manifests one or more symptoms which may include a cough, coughing up blood, chest pain or discomfort, trouble breathing, wheezing, hoarseness, loss of appetite, unexplained weight loss, fatigue, trouble swallowing, and swelling in the face and/or veins in the neck.
  • Progression of NSCLC may be observed using one or more imaging methods, such as CT, PET, or MRI scans or a bronchoscopy.
  • Progression may be established by a lack of reduction in any or some of the symptoms disclosed herein or known in the art that are associated with an EGFR-mediated cancer, such as NSCLC. In some embodiments, progression is established for a lack of reduction in one or more symptoms after, for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more months from the initial treatment of EGFR TKI.
  • a subject suitable for a treatment method of the present disclosure suffers from a relapse of an EGFR-mediated cancer, such as lung cancer.
  • the subject suffers from a relapse of NSCLC.
  • a relapse can be established by a renewed onset of any of the symptoms associated with the cancer with which the subject has previously been diagnosed, or by the detection of the cancer via a suitable method, such as a CT scan, a PET scan, an MRI, a bronchoscopy, or a lung biopsy.
  • a relapse may occur, e.g., 3, 5, 7, 8, 9, 10, 11, 12, 15, 18, 24, 25, 26, 27, 28, 29, 30, 36, or more months after the initial treatment with EGFR TKI.
  • administrating a S0S1 inhibitor or a pharmaceutical composition comprising an effective amount of a S0S1 inhibitor typically involves contacting a cell with a SOS1 inhibitor disclosed herein.
  • the SOS1 inhibitor can be a small molecule, a nucleic acid agent, or a polypeptide (e.g., an endonuclease).
  • the contacting, as disclosed herein, can occur in vitro, ex vivo, or in vivo.
  • the cell is contacted with (i) a SOS1 inhibitor disclosed herein and (ii) amivantamab.
  • Contacting with (i) and (ii) can take place conjunctively.
  • a SOS1 inhibitor can be administered prior to, subsequent to, or concurrently with the administration of amivantamab.
  • the SOS1 inhibitor and amivantamab can be in the same composition (e.g., as a formulation or as a unit dosage) or in different compositions (e.g., subjecting the cell to two different compositions at the same time).
  • the SOS1 inhibitor and amivantamab can be in the same composition (e.g., a single composition exhibiting different release profiles or in different compositions).
  • a first contacting of the cell e.g., with the SOS1 inhibitor or amivantamab
  • a second contacting of the cell e.g., with amivantamab or the SOS1 inhibitor
  • Suitable agents that can be administered in combination with a subject SOS1 inhibitor and amivantamab include but are not limited to EGFR TKIs disclosed herein, other anti-cancer agents, anti-allergic agents, anti-nausea agents (or anti-emetics), pain relievers, cytoprotective agents, immunomodulatory agents, steroids, chemotherapeutic agents, and combinations thereof.
  • a MET inhibitor is administered in combination with a subject SOS1 inhibitor and amivantamab.
  • immunomodulatory agents include but are not limited to immuno stimulatory agents, checkpoint immune blockade agents (e.g., blockade agents or inhibitors of immune checkpoint genes, such as, for example, PD- 1, PD-L1, CTLA-4, IDO, TIM3, LAG3, TIGIT, BTLA, VISTA, ICOS, KIRs and CD39), radiation therapy agents, chemotherapy agents, and combinations thereof.
  • the immunostimulatory agents are selected from the group consisting of IL- 12, an agonist costimulatory monoclonal antibody, and combinations thereof.
  • the immuno stimulatory agent is IL- 12.
  • the agonist costimulatory monoclonal antibody is selected from the group consisting of an anti -4- IBB antibody (e.g., urelumab, PF-05082566), an anti- 0X40 antibody (pogalizumab, tavolixizumab, PF-04518600), an anti-ICOS antibody (BMS986226, MEDI-570, GSK3359609, JTX-2011), and combinations thereof.
  • the agonist costimulatory monoclonal antibody is an anti-4- IBB antibody.
  • the checkpoint immune blockade agents are selected from the group consisting of anti-PD-Ll antibodies (atezolizumab, avelumab, durvalumab, BMS-936559), anti- CTLA-4 antibodies (e.g., tremelimumab, ipilimumab), anti-PD-1 antibodies (e.g., pembrolizumab, nivolumab), anti- LAG3 antibodies (e.g., C9B7W, 410C9), anti-B7-H3 antibodies (e.g., DS-5573a), anti-TIM3 antibodies (e.g., F38- 2E2), and combinations thereof.
  • the checkpoint immune blockade agent is an anti-PD-L 1 antibody.
  • chemotherapeutic agents include an anthracycline (e.g., doxorubicin (e.g., liposomal doxorubicin)), a vinca alkaloid (e.g., vinblastine, vincristine, vindesine, vinorelbine), an alkylating agent (e.g., cyclophosphamide, decarbazine, melphalan, ifosf amide, temozolomide), an immune cell antibody (e.g., alemtuzamab, gemtuzumab, rituximab, ofatumumab, tositumomab, brentuximab), an antimetabolite (including, e.g., folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors (e.g., fludarabine)), a TNFR glucocorticoid
  • chemotherapeutic agents contemplated for use in combination include busulfan (Myleran®), busulfan injection (Busulfex®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposome injection (DepoCyt®), daunorubicin hydrochloride (Cerubidine®), daunorubicin citrate liposome injection (DaunoXome®), dexamethasone, doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), hydroxyurea (Hydrea®), Idarubicin (Idamycin®), mitoxantrone (Novantrone®), Gemtuzumab Ozogamic
  • a method described herein that comprises administering (a) a SOS 1 inhibitor and (b) amivantamab further comprises administering (c) an additional agent selected from (1) a SHP2 inhibitor (e.g., 6-(4- amino-4-methylpiperidin-l-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine, RMC-4630, ERAS-601, TNO155, JAB- 3068, IACS-13909/BBP-398, SHP099, RMC-4550), (2) an inhibitor of wildtype or mutant RAS, such as wildtype KRAS, wildtype ERAS, wildtype NRAS, mutant KRAS, mutant ERAS, mutant NRAS, KRAS G12C, KRAS G12D, KRAS G12S, KRAS G12V, KRAS G13D, KRAS G13C, KRAS G13V, or KRAS Q61E (e.g., LY3537982, J
  • a MET inhibitor for use in the present disclosure can be any MET inhibitor that is known in the art, and can include any entity that, upon administration to a subject, results in downregulation of MET in the subject.
  • a suitable MET inhibitor can be selected from a variety of types of molecules.
  • the MET inhibitor can be a biological or chemical compound, such as a simple or complex organic or inorganic molecule, peptide, peptido mimetic, protein (e.g., antibody), liposome, or a polynucleotide (e.g., small interfering RNA, short hairpin RNA, microRNA, antisense, aptamer, ribozyme, triple helix).
  • a method disclosed herein utilizes a small molecule MET inhibitor.
  • MET inhibitors for use in such combinations include one or more of foretinib, AMG-458, tivantinib, crizotinib, cabozantinib, tepotinib, capmatinib, and glesatinib.
  • the MET inhibitor is selected from capmatinib, tepotinib, and cabozantinib.
  • any treatment methods disclosed herein may involve administering a SOS1 inhibitor and amivantamab in combination or in conjunction with an additional therapy.
  • Applicable therapies for treating EGFR- mediated diseases include surgery, radiotherapy, cell therapy, chemotherapy, bone marrow transplant, and radiation.
  • the subject combination therapy comprising a plurality of different therapeutic agents (e.g. a SOS1 inhibitor and amivantamab) can synergistically achieve one or more desired therapeutic actions or outcomes, including, but not limited to, reduced progression of NSCLC.
  • the reduced progression of EGFR-mediated cancer is evidenced by disease stabilization, disease regression, improved lung function, or improvement of one or more symptoms of the cancer, such as improvement in one or more symptoms selected from a cough, coughing up blood, chest pain or discomfort, trouble breathing, wheezing, hoarseness, loss of appetite, unexplained weight loss, fatigue, trouble swallowing, and swelling in the face and/or veins in the neck.
  • a subject treated according to a method of the present disclosure may exhibit one or more desired therapeutic outcomes described herein, any of which may persist for at least 1 month, such as at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least 24 months, at least 30 months, at least 36 months, or longer.
  • a subject treated according to a method of the present disclosure may exhibit one or more of (i) disease stabilization, (ii) disease regression, (iii) improved lung function, and (iv) improvement of one or more symptoms of the cancer, any one or more of which may persist for at least 1 month, such as at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least 24 months, at least 30 months, at least 36 months, or longer.
  • the subject combination treatment disclosed herein can achieve such desired actions or outcomes, while synergistically providing one or more superior advantages including, but not limited to, (i) decreased amount (e.g., dosage regimen, number of doses, etc.) of one, more, or all of the therapeutic agents utilized in the combination therapy; (ii) avoiding, limiting, or reducing one or more undesirable side-effects associated with the use of any one of the plurality of different therapeutic agents when used in the therapeutically effective amount or clinically approved amount; and (iii) allowing for the use of an EGFR TKI that would otherwise be intolerable to the subject.
  • decreased amount e.g., dosage regimen, number of doses, etc.
  • avoiding, limiting, or reducing one or more undesirable side-effects associated with the use of any one of the plurality of different therapeutic agents when used in the therapeutically effective amount or clinically approved amount allowing for the use of an EGFR TKI that would otherwise be intolerable to the subject.
  • any of a range of undesirable sideeffects associated with amivantamab may be reduced, including rash, pruritus, dry skin, fatigue, edema, pyrexia, paronychia, pneumonia, musculoskeletal pain, dyspnea, cough, nausea, stomatitis, constipation, vomiting, diarrhea, abdominal pain, hemorrhage, decreased appetite, peripheral neuropathy, dizziness, and headache.
  • diarrhea, rash, and/or nausea can be reduced.
  • the combination treatment with a SOS1 inhibitor disclosed herein may allow administration of amivantamab when it would otherwise not be tolerable to the subject.
  • the combination treatment with a subject SOS1 inhibitor may allow a more frequent dosage regimen of amivantamab that is otherwise too toxic or not tolerable to a subject in need of such treatment.
  • the combination treatment as disclosed herein can utilize amivantamab at a therapeutically sub-optimal dose when used alone, but in combination with a SOS1 inhibitor disclosed herein yields overall therapeutic efficacy (e.g., promoting one or more desired therapeutic outcomes and/or reducing undesirable side-effects).
  • the combination therapy utilizes a dose of amivantamab less than that approved or recommended for treating a human subject for a given indication (e.g., a sub-therapeutic dose).
  • the sub- therapeutic dose is less than 95% of the approved dose of amivantamab, such as less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, or less than 10% of the approved dose of amivantamab.
  • a sub-therapeutic dose of amivantamab is less than the recommended dose of 1050 mg for patients less than 80 kg or less than the recommended dose of 1400 mg for patients greater than or equal to 80 kg.
  • a sub-therapeutic dose of amivantamab may be less than 90% of the recommended dose of 1050 mg for patients less than 80 kg or less than 90% of the recommended dose of 1400 mg for patients greater than or equal to 80 kg, such as less than 945 mg for patients less than 80 kg or less than 1260 mg for patients greater than or equal to 80 kg.
  • amivantamab is administered at a dose of 1050 mg in combination with a SOS1 inhibitor disclosed herein.
  • amivantamab is administered at a dose of 1400 mg in combination with a SOS1 inhibitor disclosed herein.
  • amivantamab is administered at a dose of 10 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, or 1500 mg in combination with a SOS1 inhibitor disclosed herein.
  • the SOS1 inhibitor may be administered at a dose of at least 5 mg daily, such as 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg daily in combination with amivantamab.
  • the SOS1 inhibitor is administered at a dose of 5 to 1000 mg, such as about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, about 360 mg, about 380 mg, about 400 mg, about 420 mg, about 440 mg, about 460 mg, about 480 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg in combination with amivantamab, such as in combination with 1050 mg or 1400 mg amivantamab.
  • the SOS1 inhibitor is administered once daily in an oral dosage form.
  • the present disclosure provides a method of treating cancer in a subject in need thereof.
  • the method may comprise administering a pharmaceutical composition that comprises an effective amount of a small molecule SOS1 inhibitor to the subject, wherein said SOS1 inhibitor inhibits growth of a NSCLC cell line with an IC50 less than about 500 nM, 400 nM, 300 nM, 200 nM, 100 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 5 nM or even less, as ascertained in a growth inhibition assay utilizing the NSCLC cell line.
  • the SOS1 inhibitor inhibits an NSCLC cell line selected from the group consisting of Ba/F3-EGFR_Ex20_ASV insertion, Ba/F3-EGFR_L858R/T790M, PC9-EGFR Exl9 E746_A750 deletion, H1975-EGFR L858R/T790M, Ba/F3-EGFR-V769_D770insASV, Ba/F3-EGFR_D770_N771insNPH, H1993, LU0858, LU0387, LU3075, H3122, and H2228 with an IC50 less than about 500 nM, 400 nM, 300 nM, 200 nM, 100 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 5 nM or even less.
  • an NSCLC cell line selected from the group consisting of Ba/F3-EGFR_Ex20_ASV insertion, Ba/F3-EGFR
  • the S0S1 inhibitor inhibits growth of an NSCLC cell line with an IC50 at least 10, 50, or 100 times less than that of BI3406 or that of MRTX0902. In some embodiments, the SOS1 inhibitor synergistically inhibits growth of an NSCLC cell line in combination with amivantamab.
  • the SOS1 inhibitor is characterized in that it synergistically inhibits growth of NSCLC cells in combination with amivantamab to yield at least about 80% growth inhibition, when less than about 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, or 5 nM of the SOS1 inhibitor is applied in combination with amivantamab applied at its IC50 molarity, in an in vitro growth inhibition assay using NSCLC cells.
  • the SOS1 inhibitor is characterized in that it synergistically increases percent of cell growth inhibition from about 10% to at least about 50%, when less than about 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, or 5 nM of the SOS1 inhibitor is applied in combination with amivantamab applied at its IC10 molarity, as ascertained in an in vitro growth inhibition assay using NSCLC cells.
  • the SOS1 inhibitor is characterized in that it synergistically increases percent of cell growth inhibition from about 50% to at least about 80%, when less than about 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, or 5 nM of the SOS1 inhibitor is applied in combination with amivantamab applied at its IC50 molarity, in an in vitro growth inhibition assay using NSCLC cells.
  • the present disclosure provides a method of reducing proliferation of a cell comprising an EGFR mutation.
  • the method may comprise administering to the cell (a) a small molecule SOS1 inhibitor disclosed herein, and (b) amivantamab, wherein the administration of (a) and (b) synergistically inhibits growth of NSCLC cells as evidenced by achieving a comparable or higher degree of growth inhibition when either (1) less than 90% of the SOS1 inhibitor is administered as compared to the amount required for the SOS1 inhibitor when administered alone; or (2) less than 90% of amivantamab is administered as compared to the amount required for amivantamab when administered alone.
  • amivantamab is administered in less than about 80%, 70%, 60%, 50%, 40%, 30%, 25%, 20%, 15%, or 10% of the amount required to achieve a comparable or higher degree of growth inhibition.
  • less than 1400 mg such as less than 1350 mg, less than 1300 mg, less than 1250 mg, less than 1200 mg, less than 1150 mg, less than 1100 mg, less than 1050 mg, less than 1000 mg, less than 950 mg, less than 900 mg, less than 800 mg, less than 700 mg, less than 600 mg, less than 500 mg, less than 400 mg, or less than 350 mg of amivantamab is administered.
  • 1050 mg or 1400 mg amivantamab is administered.
  • a SOS1 inhibitor for use in the present disclosure can be any SOS1 inhibitor that is known in the art, and can include any entity that, upon administration to a subject, results in downregulation of SOS1 in the subject.
  • a suitable SOS1 inhibitor can be selected from a variety of types of molecules.
  • the SOS1 inhibitor can be a biological or chemical compound, such as a simple or complex organic or inorganic molecule, peptide, peptido mimetic, protein (e.g., antibody), liposome, or a polynucleotide (e.g., small interfering RNA, short hairpin RNA, microRNA, antisense, aptamer, ribozyme, triple helix).
  • a method disclosed herein utilizes a small molecule SOS1 inhibitor.
  • small molecule refers to a low molecular weight organic compound, such as a compound having a molecular weight of less than 1500 g/mol, less than 1250 g/mol, less than 1000 g/mol, or less than 750 g/mol.
  • Many compounds are known to inhibit SOS1 (e.g., compounds of WO 2005/097119, which is incorporated herein by reference in its entirety).
  • a subject S0S1 inhibitor disrupts the interaction between SOS1 and KRAS at an IC50 of less than about 20 nM, 10 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, 0.1 nM or even less, as ascertained utilizing the Ras-SOS interaction assay described in Example 3.
  • the SOS1 inhibitor is at least 5-times more potent than BI-3406, MRTX0902, BAY 293, RMC-5845, or BI-1701963, such as at least 10-times, 20-times, 30-times, 40-times, 50-times, 60-times, 70-times, 80-times, 90-times, or 100- times more potent, as ascertained utilizing the Ras-SOS interaction assay described in Example 3.
  • a subject SOS1 inhibitor inhibits growth of a cancer cell, such as an NSCLC cell line, with an IC50 less than about 500 nM, 400 nM, 300 nM, 200 nM, 100 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 5 nM or even less, as ascertained in a growth inhibition assay, optionally utilizing the NSCLC cell line.
  • the SOS1 inhibitor inhibits a NSCLC cell line selected from the group consisting of Ba/F3-EGFR_Ex20_ASV insertion, Ba/F3-EGFR_L858R/T790M, PC9-EGFR Exl9 E746_A750 deletion, H1975-EGFR L858R/T790M, Ba/F3-EGFR- V769_D770msASV, Ba/F3-EGFR_D770_N771insNPH, Hl 993, LU0858, LU0387, LU3075, H3122, and H2228 with an IC50 less than about 500 nM, 400 nM, 300 nM, 200 nM, 100 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 5 nM or even less.
  • a NSCLC cell line selected from the group consisting of Ba/F3-EGFR_Ex20_ASV insertion, Ba/F3
  • the SOS1 inhibitor inhibits growth of a NSCLC cell line with an IC50 at least 10, 50, 100, 200, 300, 500, or 1000 times less than that of RMC-5845, BI-1701963, some embodiments, the SOS1 inhibitor inhibits growth of a NSCLC cell line with an IC50 at least 10, 50, 100, 200, 300, 500, or 1000 times less than that of a SOS inhibitor described in
  • the SOS1 inhibitor synergistically inhibits growth of a cancer cell, such as an NSCLC cell line, in combination with amivantamab.
  • the SOS1 inhibitor is characterized in it synergistically inhibits growth of NSCLC cells in combination with amivantamab to yield at least about 80% growth inhibition when less than about 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, or 5 nM of the SOS1 inhibitor is applied in combination with amivantamab applied at its IC50 molarity, in an in vitro growth inhibition assay using NSCLC cells.
  • the SOS1 inhibitor is characterized in that it synergistically increases percent of cell growth inhibition from about 10% to at least about 50%, when less than about 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, or 5 nM of the SOS1 inhibitor is applied in combination with amivantamab applied at its IC10 molarity, as ascertained in an in vitro growth inhibition assay using NSCLC cells.
  • the SOS1 inhibitor is characterized in that it synergistically increases percent of cell growth inhibition from about 50% to at least about 80%, when less than about 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, or 5 nM of the SOS1 inhibitor is applied in combination with amivantamab applied at its IC50 molarity, in an in vitro growth inhibition assay using NSCLC cells.
  • the present disclosure provides a compound of Formula (I): or a pharmaceutically acceptable salt or solvate thereof, wherein: is selected from C5-7 carbocycle and 5- to 7-membered heterocycle, each of which is optionally substituted with one or more R 11 ; is absent or selected from C 3-8 carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more R 11a ; L 1 is selected from a bond, C1-6 alkylene, and C1-6 haloalkylene; L 2 is selected from C 5-25 alkylene, C 5-25 alkenylene, C 5-25 alkynylene, 5- to 25-membered heteroalkylene, and 5- to 25-membered heteroalkenylene, each of which is optionally substituted with one or more R 11b , wherein L 2 is covalently bound to one of W 3 , W 4 , W 5 , W 6 , or W 7 ; or L 2 is -L 3 -D-L 4
  • the present disclosure provides a compound of Formula (I): or a pharmaceutically acceptable salt or solvate thereof, wherein: is selected from C5-7 carbocycle and 5- to 7-membered heterocycle, each of which is optionally substituted with one or more R 11 ; is absent or selected from C 3-8 carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more R 11a ; L 1 is selected from a bond, C1-6 alkylene, and C1-6 haloalkylene; L 2 is selected from C 5-25 alkylene, C 5-25 alkenylene, C 5-25 alkynylene, 5- to 25-membered heteroalkylene, and 5- to 25-membered heteroalkenylene, each of which is optionally substituted with one or more R 11b , wherein L 2 is covalently bound to one of W 3 , W 4 , W 5 , W 6 , or W 7 ; W 2 is selected from N(R 2b ), N, C
  • the compound of Formula (I) is a compound of Formula (I-A): or a pharmaceutically acceptable salt or solvate thereof.
  • the compound of Formula (I-A) is a compound selected from: [133]
  • the compound of Formula (I) is a compound of Formula (I-B), such as a compound of Formula (I-B1) or (I-B2):
  • the compound of Formula (I-B) is a compound selected from: .
  • the compound of Formula (I) is a compound of Formula (I-C), such as a compound of Formula (I-C1), (I-C2), or (I-C3):
  • the compound of Formula (I-C) is a compound selected from: .
  • the compound of Formula (I) is a compound of Formula (I-D), such as a compound of Formula (I-D1) or (I-D2): or a pharmaceutically acceptable salt or solvate thereof.
  • the compound of Formula (I-D) is a compound selected from: [139]
  • the compound of Formula (I) is a compound of Formula (I-E), such as a compound of Formula (I-E1):
  • the compound of Formula (I-E) is a compound selected from: .
  • W2 is N.
  • W 3 is selected from N(R 3b ), N, C(R 3 ), and C(O), such as NCH3, N, CH, CCH3, and C(O).
  • W 3 is selected from C(R 3 ) and C(O), such as CH, CCH 3 and C(O).
  • W 3 is CH.
  • W 3 is CCH 3 .
  • W 4 is selected from N(R 4b ), N, C(R 4 ), and C(O), such as N(R 4b ), N, C(R 4 ), and C(O), wherein R 4b and R 4 are each independently a bond to L 2 .
  • W 4 is selected from N(R 4b ) and N, such as N(R 4b ), wherein R 4b is a bond to L 2 .
  • W 4 is N.
  • W 5 is selected from N(R 5b ), N, C(R 5 ), and C(O), such as N(R 5b ), NCH 3 , N, CH, C(R 5 ), and C(O), wherein R 5b and R 5 are each independently a bond to L 2 .
  • W 5 is selected from N(R 5b ), N, and C(R 5 ), such as N(R 5b ), NCH3, N, CH, and C(R 5 ), wherein R 5b and R 5 are each independently a bond to L 2 .
  • W 5 is selected from N(R 5b ) and C(R 5 ), such as N(R 5b ), NCH3, and CH, wherein R 5b is a bond to L 2 .
  • W 5 is N(R 5b ).
  • W 6 is selected from C(R 6 ) and C(O), such as COCH 3 , CH, C(R 6 ), and C(O), wherein R 6 is a bond to L 2 .
  • W 6 is C(O).
  • W 7 is C(R 7 ), such as W 7 is C(R 7 ) wherein R 7 is a bond to L 2 .
  • W 7 is C(R 7 ), wherein R 7 is not hydrogen, such as R 7 is selected from C3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and -OR 12 , wherein C3-10 cycloalkyl and 3- to 10-membered heterocycloalkyl are optionally substituted with one, two, or three R 20 .
  • W 8 is C(R 8 ), such as W 8 is CH.
  • W 9 is C.
  • W 10 is C.
  • W2 is N; W3 is N(R3b); W 4 is C(O); and W 9 and W 10 are each C, such as W 2 is N; W 3 is NCH3; W 4 is C(O); and W 9 and W 10 are each C.
  • W 2 is N; W 3 is C(O); W 4 is N(R 4b ); and W 9 and W 10 are each C, such as W 2 is N; W 3 is C(O); W 4 is N(R 4b ), wherein R 4b is a bond to L 2 ; and W 9 and W 10 are each C.
  • W 2 is N; W 3 is C(R 3 ); W 4 is N; and W 9 and W 10 are each C, such as W 2 is N; W 3 is CH or CCH3; W 4 is N; and W 9 and W 10 are each C.
  • W 5 is C(R 5 ); W 6 is C(R 6 ); W 7 is C(R 7 ); W 8 is C(R 8 ); and W 9 and W 10 are each C, such as W 5 is CH or C(R 5 ), wherein R 5 is a bond to L 2 ; W 6 is CH or C(R 6 ), wherein R 6 is a bond to L 2 ; W 7 is C(R 7 ); W 8 is CH; and W 9 and W 10 are each C.
  • W 5 is N(R 5b ); W 6 is C(O); W 7 is C(R 7 ); W 8 is C(R 8 ); and W 9 and W 10 are each C, such as W 5 is NCH 3 or N(R 5b ), wherein R 5b is a bond to L 2 ; W 6 is C(O); W 7 is C(R 7 ); W 8 is CH; and W 9 and W 10 are each C.
  • W 5 is N; W 6 is C(R 6 ); W 7 is C(R 7 ); W 8 is C(R 8 ); and W 9 and W 10 are each C, such as W 5 is N; W 6 is COCH3, CH, or C(R 6 ), wherein R 6 is a bond to L 2 ; W 7 is C(R 7 ); W 8 is CH; and W 9 and W 10 are each C.
  • W 2 is N; W 3 is selected from N(R 3b ), N, C(R 3 ), and C(O); W 4 is selected from N(R 4b ), N, C(R 4 ), and C(O); W 5 is selected from N(R 5b ), N, and C(R 5 ); W 6 is selected from C(R 6 ) and C(O); W 7 is C(R 7 ); W 8 is C(R 8 ); and W 9 and W 10 are each C, such as W 2 is N; W 3 is selected from NCH3, N, CH, CCH3, and C(O); W 4 is selected from N(R 4b ), N, C(R 4 ), and C(O), wherein R 4b and R 4 are each independently a bond to L 2 ; W 5 is selected from N(R 5b ), NCH 3 , N, CH, and C(O); W 5 is selected from N(R 5b ), NCH 3 , N, CH, and C(O); W 5 is selected from N(R 5b
  • W 2 is N; W 3 is selected from C(R 3 ) and C(O); W 4 is selected from N(R 4b ) and N; W 5 is selected from N(R 5b ) and C(R 5 ); W 6 is selected from C(R 6 ) and C(O); W 7 is C(R 7 ); W 8 is CH; and W 9 and W 10 are each C, such as W 2 is N; W 3 is selected from CH, CCH 3 , and C(O); W 4 is selected from N(R 4b ) and N, wherein R 4b is a bond to L 2 ; W 5 is selected from N(R 5b ), NCH3, CH, and C(R 5 ), wherein R 5b and R 5 are each independently a bond to L 2 ; W 6 is selected from COCH3, CH, C(R 6 ), and C(O), wherein R
  • R2, R2a, R3a, R4a, R 5a , R 6a , R 7a , R 8 , and R 8a are each independently selected from hydrogen, halogen, -CN, C1-3 alkyl, C1-3 haloalkyl, - OH, -NH 2 , -NHCH 3 , and -N(CH 3 ) 2 .
  • R 2 , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8 , and R 8a are each independently selected from hydrogen and -CH3, such as hydrogen.
  • R3, R4, R5, and R6 are each independently selected from a bond to L 2 , hydrogen, halogen, -CN, C1-6 alkyl, C3-6 carbocycle, 3- to 6- membered heterocycle, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), - N(R 14 )C(O)R 15
  • R 3 , R 4 , R 5 , and R 6 are each independently selected from a bond to L 2 , hydrogen, halogen, -CN, C 1-3 alkyl, C 1-3 haloalkyl, -OH, -OCH 3 , -NH 2 , -NHCH 3 , - N(CH3)2; and R 7 is selected from a bond to L 2 , C1-6 alkyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -OR 12 , - N(R 12 )(R 13 ), -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -S(O)2R 15 , and -SO2N(R 12 )(R 13 ), wherein C1-6 alkyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R 20 .
  • R 3 , R 4 , R 5 , and R 6 are each independently selected from a bond to L 2 , hydrogen, -CH 3 , and -OCH 3 ; and R 7 is selected from a bond to L 2 , C1-6 alkyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -OR 12 , -N(R 12 )(R 13 ), -C(O)R 15 , - C(O)N(R 12 )(R 13 ), -S(O)2R 15 , and -SO2N(R 12 )(R 13 ), wherein C1-6 alkyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R 20 .
  • R2b and R8b are each independently selected from hydrogen and C1-3 alkyl, such as hydrogen and -CH3.
  • R 3b , R 4b , R 5b , R 6b , and R 7b are each independently selected from a bond to L 2 , hydrogen, and C1-3 alkyl, such as a bond to L 2 , hydrogen, and -CH 3 .
  • R 3b , R 4b , R 5b , R 6b , and R 7b are each independently selected from a bond to L 2 and -CH 3 .
  • R 3b , R 4b , R 5b , R 6b , and R 7b are each independently selected from a bond to L 2 .
  • R 9 and R 10 are each hydrogen.
  • the selection of “a bond to L2” for one of R 3 , R 4 , R 5 , R 6 , R 7 , R 3b , R 4b , R 5b , R 6b , or R 7b inherently includes a bond to -L 3 -D-L 4 -, specifically to L 4 .
  • any recitation of R 3 , R 4 , R 5 , R 6 , R 7 , R 3b , R 4b , R 5b , R 6b , and/or R 7b that includes “a bond to L 2 ” also may be considered to include “a bond to L 4 ”.
  • R 1 is selected from C 1-3 alkyl and C 1-3 haloalkyl, such as -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 F, -CHF 2 , -CF 3 , CH 2 CH 2 F, -CH 2 CHF 2 , and -CH 2 CF 3 .
  • R 1 is selected from C1-3 alkyl, such as -CH3 and -CH2CH3. In some embodiments, R 1 is -CH3. In some embodiments, R 1 is (R)-CH3. In some embodiments, R 1 is (S)-CH3.
  • R 3 is selected from hydrogen, halogen, -CN, C 1-6 alkyl, C 3-6 carbocycle, 3- to 6-membered heterocycle, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , - S(O)2R 15 , and -S(O)2N(R 12 )(R 13 ), wherein each C1-6 alkyl, C3-6 carbocycle, and 3- to 6-membere
  • R 3 is selected from hydrogen, halogen, -CN, C 1-3 alkyl, C 1-3 haloalkyl, -OH, -OCH 3 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 .
  • R 3 is selected from hydrogen, halogen, -CN, -OR 12 , and C1-6 alkyl optionally substituted with one, two, or three R 20 .
  • R 3 is C1-6 alkyl optionally substituted with one, two, or three R 20 .
  • R 3 is hydrogen or -CH 3 .
  • R 3 is hydrogen.
  • R 3 is -CH 3 .
  • R3b is selected from hydrogen and C1-3 alkyl, such as hydrogen and -CH3. In some embodiments, R 3b is -CH3. In some embodiments, R 3b is hydrogen.
  • R 5 is selected from hydrogen, halogen, -CN, C 1-6 alkyl, C 3-6 carbocycle, 3- to 6-membered heterocycle, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O) 2 R 15 , and - S(O)2N(R 12 )(R 13 ), wherein each C1-6 alkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle is independently optionally substituted with one,
  • R 5 is selected from hydrogen, halogen, - CN, C 1-3 alkyl, C 1-3 haloalkyl, -OH, -OCH 3 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 .
  • R 5 is selected from hydrogen, -OR 12 , and C 1-6 alkyl optionally substituted with one, two, or three R 20 .
  • R 5 is hydrogen or -CH3.
  • R 5 is hydrogen.
  • R 5 is -CH3.
  • R5b is selected from hydrogen and C 1-3 alkyl, such as hydrogen and -CH 3 .
  • R 5b is selected from hydrogen and C 1-6 alkyl optionally substituted with one, two, or three R 20 .
  • R 5b is -CH 3 .
  • R 5b is hydrogen.
  • R 5b is a bond to L 2 .
  • R6 is selected from hydrogen, halogen, -CN, C 1-6 alkyl, C 3-6 carbocycle, 3- to 6-membered heterocycle, -OR 12 , -SR 12 , - N(R 12 )(R 13 ), -C(O)OR 12 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O) 2 R 15 , and - S(O)2N(R 12 )(R 13 ), wherein each C1-6 alkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle is independently optionally substituted with one,
  • R 6 is selected from hydrogen, halogen, - CN, C 1-3 alkyl, C 1-3 haloalkyl, -OH, -OCH 3 , -NH 2 , -NHCH 3 , and -N(CH 3 ) 2 .
  • R 6 is selected from hydrogen, -OR 12 , and C 1-6 alkyl optionally substituted with one, two, or three R 20 , and wherein R 12 is selected from C1-6 alkyl.
  • R 6 is selected from hydrogen and -OCH3.
  • R 6 is hydrogen.
  • R 6 is -OCH3.
  • R 7 is selected from C 1-6 alkyl, C 3-10 carbocycle, 3- to 10-membered heterocycle, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), - CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , -CH2S(O)2R 15 ,
  • R 7 is selected from C 1-6 alkyl, C 3-10 carbocycle, 3- to 10-membered heterocycle, -OR 12 , - N(R 12 )(R 13 ), -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -S(O)2R 15 , and -SO2N(R 12 )(R 13 ), wherein C1-6 alkyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R 20 .
  • R 7 is selected from C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and -N(R 12 )(R 13 ), wherein C 1-6 alkyl, C 3-10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one, two, or three R 20 .
  • R 7 is 3- to 10-membered heterocycloalkyl optionally substituted with one, two, or three R 20 , such as R 7 is 4- to 6-membered heterocycloalkyl optionally substituted with one, two, or three R 20 .
  • R 7 is 3- to 10-membered heterocycloalkyl optionally substituted with one, two, or three R 20 , wherein the heterocycloalkyl comprises at least one O, N, or S, such as one O atom, one or two N atoms, or one S atom.
  • R 7 is 3- to 6-membered heterocycloalkyl optionally substituted with one, two, or three R 20 , wherein the heterocycloalkyl comprises S(O)2.
  • R 7 is C3-10 cycloalkyl optionally substituted with one, two, or three R 20 , such as R 7 is C 3-6 cycloalkyl optionally substituted with one, two, or three R 20 .
  • R 7 is C 3-4 cycloalkyl optionally substituted with one R 20 , optionally wherein R 20 is -CN.
  • R 7 is C1-6 alkyl optionally substituted with one, two, or three R 20 , such as R 7 is C1-6 alkyl substituted with one or two R 20 .
  • R 7 is -N(R 12 )(R 13 ).
  • R 7 is -OR 12 , such as -O(3- to 6-membered heterocycloalkyl).
  • R 7 is substituted with at least one -CN. In some embodiments, R 7 is unsubstituted.
  • R 7 is C 3-4 cycloalkyl substituted with one, two, or three substituents selected from oxo, -CN, and C 1-3 alkyl.
  • R 7 is selected from C 1-6 alkyl, C 3-10 carbocycle, 3- to 10-membered heterocycle, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O) 2 R 15 , -S(O)(NR 12 )R 15 , -S(O) 2 R 15 , -S(O)(NR 12 )R 15 , -S(O) 2 R 15 , -S(O)(NR 12 )R 15 , -S(O) 2 R 15 , -S(O)(NR 12 )R 15 , -S(O) 2 R 15
  • R 7 is selected from C 1-6 alkyl, C 3-10 carbocycle, 3- to 10-membered heterocycle, -OR 12 , -N(R 12 )(R 13 ), -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -S(O) 2 R 15 , -S(O)(NR 12 )R 15 , and -SO 2 N(R 12 )(R 13 ), wherein C1-6 alkyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R 20 .
  • R 7 is 3- to 6-membered heterocycloalkyl optionally substituted with one, two, or three R 20 , wherein the heterocycloalkyl comprises S(O)(NR 12 ).
  • n1 is an integer from 1 to 3; n2 is an integer from 0 to 2; n3 is an integer from 0 to 2; n4 is 0 or 1; and X is selected from -O-, -S(O 2 )-, -P(O)-, -CH 2 -, -CH(OH)-, -CH(OR 12 )-, -CH(R 20 )-, -C(R 20 ) 2 -, -NR 12 -, - CH(N(R 12 )
  • R 7 may be selected from some embodiments, X is selected from -O-, -S(O) 2 -, - S(O)(NR 12 )-, -P(O)-, -CH2-, -CH(OH)-, -CH(OR 12 )-, -CH(R 20 )-, -C(R 20 )2-, -NR 12 -, -CH(N(R 12 )(R 13 ))-, - CH(C(O)N(R 12 )(R 13 ))-, and -CH(S(O) 2 N(R 12 )(R 13 ))-.
  • R 7 is selected from ' — f 0 , and . , In some embodiments, R 7 is In some embodiments, , In some embodiments, R 7 is ,P
  • R 7 is — f . In some embodiments, R 7 is ' In some embodiments, R 7 is . , In some embodiments, R 7 is
  • R 8 is selected from hydrogen, halogen, and Ci-6 alkyl optionally substituted with one, two, or three R 20 . In some embodiments, R 8 is hydrogen.
  • (I-D), (I-Dl), (I-D2), (I-E), or (I-El), is selected from C3-10 carbocycle and 3- to 10-membered heterocycle, such as C5.7 carbocycle and 5- to 7-membered heterocycle, each of which is optionally substituted with one or more R 11 .
  • R 11 is selected from phenyl, pyridyl, and thiophenyl, each of which is optionally substituted with one or more R 11 . In some embodiments, is selected from embodiments, R 11 , when present, is independently selected at each occurrence from fluorine and -CH3. In some
  • L 1 is selected from Ci-6 alkylene and Ci-6 haloalkylene, such as C1.3 alkylene and C1.3 haloalkylene. In some embodiments, L 1 is selected from a bond and C1.3 haloalkylene. In some embodiments, L 1 is C1.3 haloalkylene, such as -CF2-, -CF2CH2-, or -CF2CH2CH2-.
  • L 1 is C1.2 haloalkylene, such as -CF2- or -CF2CH2-. In some embodiments, L 1 is -CF2-. In some embodiments, L 1 is -CF2CH2-. In some embodiments, L 1 is -CF2CH2CH2-. In some embodiments, L 1 is a bond. In some embodiments, L 1 is selected from a bond, -O-, -NR 12 -, -S-, Ci-6 alkylene, Ci-6 haloalkylene, and 2- to 6-membered heteroalkylene, wherein Ci-6 alkylene, Ci-e haloalkylene, and 2- to 6-membered hetero alkylene are optionally substituted with one or more R llb .
  • L 1 is selected from -O-, -NR 12 -, -S-, and 2- to 6-membered heteroalkylene, wherein 2- to 6-membered heteroalkylene is optionally substituted with one or more R llb .
  • L 1 is Ci-6 alkylene optionally substituted with one or more R l lb , such as one, two, or three R llb .
  • L 1 is selected from a bond, -O-, -NR 12 -, -S-, C1.3 alkylene, C1.3 haloalkylene, and 2- to 3-membered heteroalkylene, wherein C1.3 alkylene, C1.3 haloalkylene, and 2- to 3-membered hetero alkylene are optionally substituted with one or more R llb .
  • L 1 is selected from -O-, -NR 12 -, -S-, and 2- to 3-membered heteroalkylene, wherein 2- to 3-membered heteroalkylene is optionally substituted with one or more R llb .
  • L 1 is C1.3 alkylene substituted with one or more R llb , such as one, two, or three R l lb .
  • (I-D), (I-Dl), (I-D2), (I-E), or (I-El), is absent or selected from C4.8 carbocycle and 4- to 8-membered heterocycle, each of which is optionally substituted with one or more R l la .
  • R lla In some embodiments, optionally substituted with one or more R l la . In some embodiments, is absent or selected from phenyl, azetidine, pyrrolidine, and piperidine, each of which is optionally substituted with one or more R l la . In some embodiments, is selected from phenyl, azetidine, pyrrolidine, and piperidine, each of which is optionally substituted with one or more R l la . In some embodiments, is selected from azetidine, pyrrolidine, and piperidine, each of which is optionally substituted with one or more -CH3. In some embodiments, phenyl, optionally substituted with one or more R l la .
  • R l la optionally substituted with one or more R l la .
  • azetidine optionally substituted with one or more R l la .
  • R l la optionally substituted with one or more R l la .
  • pyrrolidine optionally substituted with one or more R l la .
  • is piperidine optionally substituted with one or more R l la .
  • R lla optionally substituted with one or more R lla .
  • . is unsubstituted.
  • is substituted with one or more R l la such as one, two or three R l la .
  • R l la such as one, two or three R l la .
  • R lla is independently selected at each occurrence from halogen, -CN, Ci-6 alkyl, C3.6 carbocycle, 3- to 6-membered heterocycle, -OR 12 , -N(R 12 )(R 13 ), -N(R 14 )S(O) 2 R 15 , -C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O) 2 R 15 , and - S(O) 2 N(R 12 )(R 13 ), wherein Ci-6 alkyl, C3.6 carbocycle, and 3- to 6-membered heterocycle are optionally substituted with one, two, or three R 20 .
  • R l la is independently selected at each occurrence from halogen, Ci-6 alkyl, and Ci-e haloalkyl. In some embodiments, R l la is independently selected at each occurrence from Ci-6 alkyl. In some embodiments, R lla is -CH3.
  • L 2 is selected from Cs. 2 5 alkylene, Cs. 2 5 alkenylene, Cs. 2 5 alkynylene, 5- to 25-membered heteroalkylene, and 5- to 25-membered heteroalkenylene, each of which is optionally substituted with one or more R l lb . In some embodiments, L 2 is selected from Cs.
  • L 2 together with the atoms to which it is attached, forms a 16- to 36-membered macrocyclic ring, such as a 16- to 24-membered macrocyclic ring.
  • L 2 is selected from Ce-is alkylene, Ce-is alkenylene, Ce-is alkynylene, 6- to 15-membered heteroalkylene, and 6- to 15-membered heteroalkenylene, each of which is optionally substituted with one or more R l lb .
  • L 2 is selected from C5-10 alkylene, C5-10 alkenylene, 5- to 10-membered heteroalkylene, and 5- to 10-membered heteroalkenylene, each of which is optionally substituted with one or more R l lb .
  • an alkenylene or hetero alkenylene of L 2 comprises one carbon-carbon double bond.
  • a hetero alkylene or heteroalkenylene of L 2 comprises at least one oxygen or nitrogen atom. In some embodiments, a hetero alkylene or heteroalkenylene of L 2 comprises at least one basic nitrogen. In some embodiments, L 2 is selected from C5.9 alkylene, C5.9 alkenylene, and 5- to 9-membered heteroalkylene, each of which is optionally substituted with one or more R llb . In some embodiments, L 2 is selected from Ce-9 alkylene, Ce-9 alkenylene, and 6- to 9- membered heteroalkylene, each of which is optionally substituted with one or more R llb .
  • L 2 is selected from C5.8 alkylene, C5.8 alkenylene, and 5- to 8-membered heteroalkylene, each of which is optionally substituted with one or more R l lb .
  • L 2 is selected from Ce-s alkylene, Ce-s alkenylene, and 6- to 8-membered heteroalkylene, each of which is optionally substituted with one or more R l lb .
  • L 2 is selected from Ce-s alkylene and Ce-s alkenylene, each of which is optionally substituted with one or more R l lb .
  • L 2 is selected from Ce alkylene and Ce alkenylene, each of which is optionally substituted with one or more R llb . In some embodiments, L 2 is selected from C7 alkylene and C7 alkenylene, each of which is optionally substituted with one or more R l lb . In some embodiments, L 2 is selected from Cs alkylene and Cs alkenylene, each of which is optionally substituted with one or more R llb . In some embodiments, L 2 is - CH 2 CHCH(CH 2 )4-. In some embodiments, L 2 is 6- to 8-membered heteroalkylene, optionally substituted with one or more R llb .
  • L 2 is 6-membered hetero alkylene, optionally substituted with one or more R l lb . In some embodiments, L 2 is 7-membered heteroalkylene, optionally substituted with one or more R l lb . In some embodiments, L 2 is 8-membered hetero alkylene, optionally substituted with one or more R l lb . In some embodiments, L 2 is 8-membered hetero alkylene, wherein the heteroalkylene comprises one oxygen atom.
  • L 2 is -(CH2)2-sO(CH2)o-5-, such as L 2 is -(CH2)2-sO(CH2)2-5-- In some embodiments, L 2 is - (CH2)4O(CH2)3-.
  • R l lb is independently selected at each occurrence from halogen, oxo, Ci-e alkyl, Ci-e haloalkyl, (Ci-6 alkyl)-OH, and -OH.
  • R l lb is independently selected at each occurrence from -CH 3 , -CH2OH, -CH2F, -CHF2, and -CF 3 , or two R llb join to form C 3 .e cycloalkyl, such as cyclopropyl.
  • R llb is independently selected at each occurrence from -CH 3 , -F, -CN, and -OH.
  • L 2 comprises -C(O)N(R 14 )- or -N(R 14 )C(O)-.
  • L 2 comprises - 0-.
  • L 2 is substituted with at least one -CH 3 , -CH2OH, -CH2F, -CHF2, or -CF 3 , or two substituents join to form cyclopropyl. In some embodiments, L 2 is substituted with at least one -CH 3 , -F, -CN, or - OH. In some embodiments, L 2 is unsubstituted.
  • L 2 is -(C1.5 alkylene)-C(O)N(R 14 )-(Ci.
  • L 2 is -(C1.2 alkylene)-C(O)N(R 14 )-(C 3 .4 alkylene)-, such as -(C1.2 alkylene)-C(O)N(CH 3 )-(C 3 .4 alkylene)- or -(C1.2 alkylene)-C(O)NH-(C 3 .4 alkylene)-, wherein C1.2 alkylene and C 3 .4 alkylene are each independently optionally substituted with one or more R llb .
  • R l lb is independently selected at each occurrence from halogen, Ci-6 alkyl, Ci-6 haloalkyl, (Ci-6 alkyl)-OH, and -OH.
  • L 2 is selected from -C(R llb )(R l lb )-(C 3 .io alkylene)-C(R l lb )(R l lb )-, -CH(R l lb )-(C 3 .io alkylene)-C(R llb )(R l lb )-, -CH 2 -(C 3 -io alkylene)-C(R l lb )(R l lb )-, -CH(R llb )-(C 3 .io alkylene)-CH(R llb )-, -CH 2 -(C 3 -io alkylene)-CH(R llb )-, -C(R l lb )(R llb )-(C 3 .io alkenylene)-C(R llb )(R ll
  • L 2 is selected from -C(R llb )(R llb )- (C 3 .io alkylene)-C(R llb )(R l lb )-, -CH(R llb )-(C 3 .io alkylene)-C(R llb )(R l lb )-, -CH 2 -(C 3 .IO alkylene)-C(R llb )(R l lb )-, - CH(R llb )-(C 3 .io alkylene)-CH(R l lb )-, and -CH 2 -(C 3 .io alkylene)-CH(R llb )-.
  • L 2 is selected from -C(R llb )(R l lb )-(3- to 10-membered heteroalkylene)-C(R l lb )(R llb )-, -CH(R l lb )-( 3- to 10-membered heteroalky lene)-C(R l lb )(R l lb )-, -CH2-(3- to 10-membered heteroalkylene)-C(R llb )(R llb )-, - CH(R llb )-( 3- to 10-membered heteroalky lene)-CH(R l lb )-, and -CH2-(3- to 10-membered heteroalky lene)-CH(R l lb )-.
  • L 2 is selected from -C(R llb )(R l lb )-(3- to 10-membered heteroalkenylene)-C(R l lb )(R llb )-, - CH(R llb )-(3- to 10-membered heteroalkenylene)-C(R llb )(R l lb )-, -CH2-(3- to 10-membered heteroalkenylene)- C(R llb )(R llb )-, -CH(R l lb )-(3- to 10-membered heteroalkenylene)-CH(R llb )-, and -CH2-(3- to 10-membered heteroalkenylene)-CH(R llb )-.
  • R l lb is independently selected at each occurrence from halogen, oxo, Ci-6 alkyl, Ci-6 haloalky 1, (Ci-6 alkyl)-OH, and -OH.
  • R llb is independently selected at each occurrence from -F, -CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2OH, and -OH.
  • L 2 is -L 3 -D-L 4 -, wherein L 3 is selected from Cnio alkylene, C2-10 alkenylene, C2-10 alkynylene, 2- to 10-membered heteroalkylene, and 3- to 10-membered heteroalkenylene, each of which is optionally substituted with one or more R l lb ; D is absent or selected from C3-12 carbocycle and 3- to 12- membered heterocycle, each of which is optionally substituted with one or more R lld ; and L 4 is selected from Cnio alkylene, C2-10 alkenylene, C2-10 alkynylene, 2- to
  • alkenylene and alkynylene groups comprise one or more carbon-carbon double or triple bonds, respectively (i.e., comprising two or more carbon atoms, for example as in C2-10 alkenylene, C2-10 alkynylene, C2-8 alkenylene, C2-8 alkynylene, C5.25 alkenylene, C5.25 alkynylene, Ce-is alkenylene, Ce-is alkynylene, C5-10 alkenylene, and C5-10 alkynylene).
  • L 2 is -L 3 -D-L 4 -, wherein L 3 is selected from Ci-io alkylene, C2-10 alkenylene, C2-10 alkynylene, 2- to 10-membered heteroalkylene, and 3- to 10-membered heteroalkenylene, each of which is optionally substituted with one or more R l lb ; D is selected from C3-12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more R l ld ; and L 4 is absent.
  • L 2 is -L 3 -D-L 4 -, wherein L 3 is selected from Ci-8 alkylene, C2-8 alkenylene, 2- to 8-membered heteroalkylene, and 3- to 8-membered heteroalkenylene, each of which is optionally substituted with one or more R llb ; D is absent or selected from C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more R lld ; and L 4 is selected from Cns alkylene, C2-8 alkenylene, 2- to 8-membered heteroalkylene, and 3- to 8- membered heteroalkenylene, each of which is optionally substituted with one or more R llb .
  • L 2 is -L 3 -D-L 4 -, wherein L 3 is selected from Ci-8 alkylene, C2-8 alkenylene, 2- to 8-membered heteroalkylene, and 3- to 8-membered heteroalkenylene, each of which is optionally substituted with one or more R llb ; D is selected from C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more R lld ; and L 4 is selected from Ci-8 alkylene, C2-8 alkenylene, 2- to 8-membered hetero alkylene, and 3- to 8-membered heteroalkenylene, each of which is optionally substituted with one or more R l lb .
  • R l lb is independently selected at each occurrence from halogen, oxo, Ci-6 alkyl, Ci-e haloalkyl, (Ci-e alkyl)-OH, and -OH. In some embodiments, R l lb is independently selected at each occurrence from -F, -CH3, -CH2F, -CHF2, -CF3, - CH2CH2F, -CH2CHF2, -CH2OH, and -OH.
  • L 2 is covalently bound to one of W 3 , W 4 , W 5 , W 6 , or W 7 ; or L 2 is -L 3 -D-L 4 -, wherein L 4 is covalently bound to one of W 3 , W 4 , W 5 , W 6 , or W 7 .
  • L 2 may be covalently bound to W 3 — wherein R 3b or R 3 is a bond to L 2 — as depicted in Formula (I-A).
  • L 2 is covalently bound to W 4 — wherein R 4b or R 4 is a bond to L 2 — as depicted in Formula (I-B).
  • L 2 is covalently bound to W 5 — wherein R 5b or R 5 is a bond to L 2 — as depicted in Formula (I-C). In some embodiments, L 2 is covalently bound to W 6 — wherein R 6b or R 6 is a bond to L 2 — as depicted in Formula (I-D). In some embodiments, L 2 is covalently bound to W 7 — wherein R 7b or R 7 is a bond to L 2 — as depicted in Formula (I- E).
  • R 21 is independently selected at each occurrence from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and Ci-6 alkyl;
  • R 22 is independently selected at each occurrence from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and Ci-6 alkyl;
  • R 23 is independently selected at each occurrence from H and Ci-e alkyl
  • R 24 is independently selected at each occurrence from H and Ci-e alkyl
  • R 25 is independently selected at each occurrence from alkyl, alkenyl, alkynyl, carbocycle, and 3- to 10-membered heterocycle, wherein Ci-6 alkyl, carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen, Ci-e alkyl, Ci-e haloalkyl, Ci-6 alkoxy, C3-10 carbocycle, and 3- to 10-membered heterocycle.
  • R 5b is -CI E:
  • R 7 is selected from Ci-6 alkyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -N(R 12 )(R 13 ), -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -S(O) 2 R 15 , and - SO 2 N(R 12 )(R 13 ), wherein Ci. 6 alkyl, C 3 .10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R 20 ; and R 8 is hydrogen.
  • R 5 is hydrogen;
  • R 6 is selected from hydrogen and -OCH3;
  • R 7 is selected from Ci-6 alkyl, C3-10 carbocycle, 3- to 10- membered heterocycle, -N(R 12 )(R 13 ), -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -S(O) 2 R 15 , and -SO 2 N(R 12 )(R 13 ), wherein Ci. 6 alkyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R 20 ; and R 8 is hydrogen.
  • R 3 is hydrogen or -CH3;
  • R 7 is selected from Ci-6 alkyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -N(R 12 )(R 13 ), -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -S(O) 2 R 15 , and - SO 2 N(R 12 )(R 13 ), wherein Ci. 6 alkyl, C 3 .10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R 20 ; and R 8 is hydrogen.
  • R 3b is - CH3;
  • R 7 is selected from Ci-6 alkyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -N(R 12 )(R 13 ), -C(O)R 15 , - C(O)N(R 12 )(R 13 ), -S(O) 2 R 15 , and -SO 2 N(R 12 )(R 13 ), wherein Ci-6 alkyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R 20 ; and R 8 is hydrogen.
  • R 3 is hydrogen or -CH3;
  • R 6 is selected from hydrogen and -OCH3;
  • R 7 is selected from C1.6 alkyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -N(R 12 )(R 13 ), -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -S(O) 2 R 15 , and -SO 2 N(R 12 )(R 13 ), wherein Ci-6 alkyl, C3.10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R 20 ; and R 8 is hydrogen.
  • R 1 is -CH3; is selected from phenyl and 5- to 7-membered heteroaryl, each of which is optionally substituted with one or more R 11 ;
  • L 1 is selected from a bond and C1.3 haloalkylene; is selected from absent, phenyl, and 4- to 8-membered heterocycle, wherein the phenyl and 4- to 8-membered heterocycle are optionally substituted with one or more R lla ; and
  • L 2 is selected from C5-10 alkylene, C5-10 alkenylene, 5- to 10-membered heteroalkylene, and 5- to 10-membered heteroalkenylene, each of which is optionally substituted with one or more R l lb .
  • R 11 when present, is fluorine;
  • R l la when present, is -CH3;
  • R llb when present, is selected from halogen, oxo, Ci-e alkyl, Ci-e haloalkyl, (C1-6 alkyl)-OH, and -OH.
  • L 2 is selected from Ce-s alkylene and Ce-s alkenylene, each of which is optionally substituted with one or more R l lb .
  • R 1 is -CI E: L’ is C1-2 haloalkylene; ; and L 2 is Ce-s alkenylene, optionally substituted with one or more R llb .
  • R 1 is -CH3; is selected from L 1 is C1-2 haloalkylene; is , optionally substituted with one or more R l la ; and L 2 is -(C1-2 alkylene)-C(O)N(CH3)-(C3-4 alkylene)- or -
  • R 1 is -CH3; s selected from Ce-s alkylene and Ce-s alkenylene, each of which is optionally substituted with one or more R l lb .
  • L 2 is -(C1.2 alkylene)-C(O)N(CH3)-(C3-4 alkylene)- or -(C1.2 alkylene)-C(O)NH-(C3-4 alkylene)-, wherein C1.2 alkylene and C3.4 alkylene are each independently optionally substituted with one or more R llb .
  • R l lb when present, is selected from halogen, -CN, oxo, C1.3 alkyl, C1.3 haloalkyl, (C1.3 alkyl)-
  • a compound of Formula (I) is a compound of the formula: , wherein R 50 is hydrogen or R 11 and R 51 is hydrogen or halogen.
  • a compound of Formula (I) is a compound of the formula:
  • R 50 is hydrogen or fluoro
  • a compound of Formula (I-A) is a compound of the formula:
  • a compound of Formula (I-B) is a compound of the formula:
  • R 50 is hydrogen or fluoro
  • a compound of Formula (I-C) is a compound of the formula: , wherein R 50 is hydrogen or fluoro.
  • a compound of Formula (I-D) is a compound of the formula:
  • E) is a compound of the formula: , wherein R 50 is hydrogen or fluoro.
  • L 1 is C1.3 haloalkylene, such as Ci-2 haloalkylene or C1.2 fluoroalkylene.
  • L 2 is selected from Ce-s alkylene, Ce-s alkenylene, and 6- to 8-membered heteroalkylene, each of which is optionally substituted with one or more R llb .
  • L 2 is selected from Ce-s alkylene and Ce-s alkenylene, each of which is optionally substituted with one or more R llb .
  • L 2 is -(C1-2 alkylene)-C(O)N(CH3)-(C3-4 alkylene)- or -(C1-2 alkylene)-
  • R l lb when present, is selected from halogen, -CN, C1.3 alkyl, C1.3 haloalkyl, (C1.3 alkyl)-OH, and -OH.
  • R 50 is hydrogen. In some embodiments, R 50 is fluoro.
  • the present disclosure provides a compound of Formula (I-Cl): or a pharmaceutically acceptable salt or solvate thereof, wherein: is selected from azetidine, pyrrolidine, and piperidine, each of which is optionally substituted with one or more -CI I;,:
  • L 1 is C1.3 haloalkylene
  • L 2 is selected from C5-10 alkylene, C5-10 alkenylene, 5- to 10-membered heteroalkylene, and 5- to 10- membered heteroalkenylene, each of which is optionally substituted with one or more R llb ;
  • R 1 is -CH 3 ;
  • R 3 is hydrogen or -CH3
  • R 8 is hydrogen
  • R 11 is selected from fluorine and -CH3;
  • R llb is selected from halogen, oxo, Ci-6 alkyl, Ci-6 haloalkyl, (Ci-6 alkyl)-OH, and -OH.
  • the present disclosure provides a compound of Formula (I-Cl): or a pharmaceutically acceptable salt or solvate thereof, wherein: is selected from azetidine, pyrrolidine, and piperidine;
  • L 1 is selected from -CF 2 -, -CF 2 CH 2 -, and -CF 2 CH 2 CH 2 -;
  • L 2 is selected from C5-10 alkylene, C5-10 alkenylene, 5- to 10-membered heteroalkylene, and 5- to 10- membered heteroalkenylene;
  • R 1 is -CH 3 ;
  • R 8 is hydrogen
  • the present disclosure provides a compound of Formula (I-Cl):
  • azetidine pyrrolidine, and piperidine, each of which is optionally substituted with one or more -CI h:
  • L 1 is Ci-3 haloalkylene
  • L 2 is C 5 .io alkenylene optionally substituted with one or more R l lb ;
  • R 1 is -CH 3 ;
  • R 3 is -CH 3 ;
  • R 7 is selected from
  • R 8 is hydrogen
  • R 11 is selected from fluorine and -CH 3 ;
  • R llb is selected from halogen, oxo, Ci-6 alkyl, Ci-6 haloalkyl, (Ci-6 alkyl)-OH, and -OH.
  • the present disclosure provides a compound of Formula (I-Cl): or a pharmaceutically acceptable salt or solvate thereof, wherein: is selected from azetidine, pyrrolidine, and piperidine, each of which is optionally substituted with one or more -CI h:
  • R 1 is -CH 3 ;
  • R 3 is hydrogen or -
  • R 7 is selected from
  • R 8 is hydrogen
  • R 11 is selected from fluorine and -CH 3 ;
  • R llb is selected from halogen, oxo, Ci-6 alkyl, Ci-6 haloalkyl, (Ci-6 alkyl)-OH, and -OH.
  • the present disclosure provides a compound of Formula (I): or a pharmaceutically acceptable salt or solvate thereof, wherein: is selected from phenyl and 5- to 7-membered heteroaryl, each of which is optionally substituted with one or more R 11 ; is absent or selected from phenyl and 4- to 8-membered heterocycle, each of which is optionally substituted with one or more R l la ;
  • L 1 is selected from a bond and C1.3 haloalkylene
  • L 2 is selected from C5-10 alkylene, C5-10 alkenylene, 5- to 10-membered heteroalkylene, and 5- to 10- membered heteroalkenylene, each of which is optionally substituted with one or more R llb , wherein L 2 is covalently bound to one of W 3 , W 4 , W 5 , W 6 , or W 7 ; or L 2 is -L 3 -D-L 4 -, wherein L 4 is covalently bound to one of W 3 , W 4 , W 5 , W 6 , or W 7 ;
  • L 3 is selected from Ci-8 alkylene, C2-8 alkenylene, 2- to 8-membered heteroalkylene, and 3- to 8-membered heteroalkenylene, each of which is optionally substituted with one or more R l lb ;
  • D is selected from C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more R l ld ;
  • L 4 is selected from Ci-s alkylene, C2-8 alkenylene, 2- to 8-membered heteroalkylene, and 3- to 8-membered heteroalkenylene, each of which is optionally substituted with one or more R l lb
  • W 2 is N; W 3 is selected from N(R 3b ), N, C(R 3 ), and C(O);
  • W 4 is selected from N(R 4b ), N, C(R 4 ), and C(O);
  • W 5 is selected from N(R 5b ), N, and C(R 5 );
  • W 6 is selected from C(R 6 ) and C(O);
  • W 7 is C(R 7 );
  • W 8 is C(R 8 );
  • W 9 and W 10 are each C
  • R 1 is -CH 3 ;
  • R 2 , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8 , and R 8a are each independently selected from hydrogen and -CI I;,:
  • R 3 , R 4 , R 5 , and R 6 are each independently selected from a bond to L 2 , hydrogen, halogen, -CN, C1.3 alkyl, C1.3 haloalkyl, -OH, -OCH 3 , -NH 2 , -NHCH3, -N(CH 3 ) 2 ;
  • R 7 is selected from a bond to L 2 , Ci-e alkyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -OR 12 , - N(R 12 )(R 13 ), -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -S(O) 2 R 15 , and -SO 2 N(R 12 )(R 13 ), wherein Ci. 6 alkyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R 20 ;
  • R 3b , R 4b , and R 5b are each independently selected from a bond to L 2 , hydrogen, and C1.3 alkyl;
  • R 11 , R lla , and R lld are each independently selected at each occurrence from halogen, -CN, Ci-6 alkyl, C 2 .e alkenyl, C 2 .e alkynyl, carbocycle, 3- to 10-membered heterocycle, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , - OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O) 2 R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , - C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R
  • R llb is independently selected at each occurrence from halogen, oxo, -CN, Ci-6 alkyl, C 2 .e alkenyl, C 2 .e alkynyl, carbocycle, 3- to 10-membered heterocycle, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , - OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O) 2 R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , - C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)
  • R 12 is independently selected at each occurrence from hydrogen, Ci-6 alkyl, Ci-e haloalkyl, C 2 .e alkenyl, C 2 .e alkynyl, carbocycle, and 3- to 10-membered heterocycle, wherein Ci-6 alkyl, C 2 .e alkenyl, C 2 .e alkynyl, carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R 20 ;
  • R 13 is independently selected at each occurrence from hydrogen, Ci-6 alkyl, and Ci-6 haloalkyl; or R 12 and R 13 , together with the nitrogen atom to which they are attached, form a 3- to 10-membered heterocycle optionally substituted with one, two, or three R 20 ;
  • R 14 is independently selected at each occurrence from hydrogen, Ci-6 alkyl, and Ci-6 haloalkyl;
  • R 15 is independently selected at each occurrence from Ci-6 alkyl, C 2 .e alkenyl, C 2 .e alkynyl, carbocycle, and 3- to 10-membered heterocycle, wherein Ci-6 alkyl, C 2 .e alkenyl, C 2 .e alkynyl, carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R 20 ;
  • the present disclosure provides a compound of Formula (III): or a pharmaceutically acceptable salt or solvate thereof, wherein: B is selected from 3- to 8-membered heterocycle, optionally substituted with one or more R 11a ; L 1 is selected from a bond, C1-6 alkylene, and C1-6 haloalkylene; L 2 is selected from C5-25 alkylene, C5-25 alkenylene, C5-25 alkynylene, 5- to 25-membered heteroalkylene, and 5- to 25-membered heteroalkenylene, each of which is optionally substituted with one or more R 11b , wherein L 2 is covalently bound to one of W 3 , W 4 , W 5 , W 6 , or W 7 ; or L 2 is -L 3 -D-L 4 -, wherein L 4 is covalently bound to one of W 3 , W 4 , W 5 , W 6 , or W 7 ; L 3 is selected from C1-10 alkylene
  • L 1 is selected from a bond, C 1-6 alkylene, and C 1-6 haloalkylene
  • L 2 is selected from C 5-25 alkylene, C 5-25 alkenylene, C 5-25 alkynylene, 5- to 25-membered heteroalkylene, and 5- to 25-membered heteroalkenylene, each of which is optionally substituted with one or more R 11b , wherein L 2 is covalently bound to one of W 3 , W 4 , W 5 , W 6 , or W 7 ;
  • W 3 is selected from N(R 3b ) and N and W 4 is selected from C(R 4 ) and C(O); or W 3 is selected from C(R 3 ) and C(O), and W 4 is selected from N(R 4b ) and N;
  • W 5 is selected from N(R 5b ), N, and C(
  • a compound of Formula (III) is selected from azetidine, pyrrolidine, and piperidine, each of which is optionally substituted with one or more R 11a . In some embodiments, , each of which is optionally substituted with one or more R 11a . In some embodiments, optionally substituted with one or more R 11a . In some embodiments, L 1 is C 1-3 haloalkylene.
  • L 2 is selected from C 5-10 alkylene, C 5-10 alkenylene, 5- to 10-membered heteroalkylene, and 5- to 10-membered heteroalkenylene, each of which is optionally substituted with one or more R 11b , wherein L 2 is covalently bound to one of W 3 , W 4 , W 5 , W 6 , or W 7 ; or L 2 is -L 3 -D-L 4 -, wherein L 4 is covalently bound to one of W 3 , W 4 , W 5 , W 6 , or W 7 ;
  • L 3 is selected from C 1-8 alkylene, C 2-8 alkenylene, 2- to 8-membered heteroalkylene, and 3- to 8-membered heteroalkenylene, each of which is optionally substituted with one or more R 11b ;
  • D is selected from C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more R 11d ; and L 4 is selected from
  • the present disclosure provides a compound of the formula: , or a pharmaceutically acceptable salt or solvate thereof, wherein: L 2 is selected from C 5-10 alkylene, C 5-10 alkenylene, 5- to 10-membered heteroalkylene, and 5- to 10- membered heteroalkenylene, each of which is optionally substituted with one or more R 11b , wherein L 2 is covalently bound to one of W 3 , W 4 , W 5 , W 6 , or W 7 ; or L 2 is -L 3 -D-L 4 -, wherein L 4 is covalently bound to one of W 3 , W 4 , W 5 , W 6 , or W 7 ; L 3 is selected from C 1-8 alkylene, C 2-8 alkenylene, 2- to 8-membered heteroalkylene, and 3- to 8-membered heteroalkenylene, each of which is optionally substituted with one or more R 11b ; D is selected from C3-10 carbocycle and 3-
  • the present disclosure provides a compound of Formula (II-B) or (II-C): or a pharmaceutically acceptable salt or solvate thereof, wherein: is absent or 4- to 8-membered heterocycle optionally substituted with one or more R 11a ;
  • L 1 is C 1-3 haloalkylene;
  • L 2 is selected from C5-10 alkylene, C5-10 alkenylene, 5- to 10-membered heteroalkylene, and 5- to 10- membered heteroalkenylene, each of which is optionally substituted with one or more R 11b ; or L 2 is -L 3 -D-L 4 -;
  • L 3 is selected from C 1-8 alkylene, C 2-8 alkenylene, 2- to 8-membered heteroalkylene, and 3- to 8-membered heteroalkenylene, each of which is optionally substituted with one or more R 11b ;
  • D is selected from C3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted
  • the present disclosure provides a compound of Formula (II-B) or (II-C): or a pharmaceutically acceptable salt or solvate thereof, wherein: is absent or 4- to 8-membered heterocycle optionally substituted with one or more R 11a ;
  • L 1 is C1-3 haloalkylene;
  • L 2 is selected from C 5-10 alkylene, C 5-10 alkenylene, 5- to 10-membered heteroalkylene, and 5- to 10- membered heteroalkenylene, each of which is optionally substituted with one or more R 11b ;
  • R 3 , R 5b , and R 8 are each independently selected from hydrogen and -CH3;
  • R 7 is selected from C3-8 carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three R 20 ;
  • R 50 is selected from hydrogen and halogen;
  • R 11a is independently selected at each occurrence from halogen, C1-3 alkyl, and C1-3 haloalky
  • L 1 is C 1-3 haloalkylene
  • L 2 is selected from C5-10 alkylene, C5-10 alkenylene, 5- to 10-membered heteroalkylene, and 5- to 10- membered heteroalkenylene, each of which is optionally substituted with one or more R 11b
  • R 3 is hydrogen
  • R 8 is selected from hydrogen and -CH 3
  • R 7 is selected from R 50 is selected from hydrogen and halogen
  • R 11a is independently selected at each occurrence from halogen, C 1-3 alkyl, and C 1-3 haloalkyl
  • R 11b is independently selected at each occurrence from halogen, oxo, -CN, C1-3 alkyl, and -OH
  • R 20 is independently selected at each occurrence from halogen, oxo, -CN, and C1-6 alkyl.
  • the present disclosure provides a compound of Formula (II-C): or a pharmaceutically acceptable salt or solvate thereof, wherein: is 4- to 8-membered heterocycle optionally substituted with one or more R 11a ;
  • L 1 is C 1-3 haloalkylene;
  • L 2 is selected from C5-10 alkylene, C5-10 alkenylene, 5- to 10-membered heteroalkylene, and 5- to 10- membered heteroalkenylene, each of which is optionally substituted with one or more R 11b ;
  • R 3 is selected from hydrogen and -CH 3 ;
  • R 50 is selected from hydrogen and halogen;
  • R 11a is independently selected at each occurrence from halogen, C 1-3 alkyl, and C 1-3 haloalkyl; and
  • R 11b is independently selected at each occurrence from halogen, oxo, -CN, C 1-3 alkyl, and -OH.
  • L 1 is -CF 2 CH 2 -; L 2 is 5- to 10-membered heteroalkylene, wherein the heteroalkylene comprises one oxygen atom; R 3 is selected from hydrogen and -CH3; R 8 is hydrogen; R 50 is selected from hydrogen and halogen.
  • the present disclosure provides a compound of Formula (II-C): or a pharmaceutically acceptable salt or solvate thereof, wherein: L 1 is -CF2-; L 2 is selected from C 5-10 alkenylene; R 3 is selected from hydrogen and -CH 3 ; R 8 is hydrogen; R 50 is selected from hydrogen and halogen.
  • a compound of Formula (II-B) is a compound of the formula: hydrogen and fluoro.
  • R 5b is -CH3; R 8 is hydrogen; and R 50 is hydrogen.
  • R 5b is -CH 3 ; R 8 is hydrogen; and R 50 is fluoro.
  • R 7 is selected from , .
  • R 5b is -CH 3 ; R 8 is hydrogen; R 50 is hydrogen; and R 7 is selected from .
  • R 5b is -CH 3 ; R 8 is hydrogen; R 50 is fluoro; and R 7 is selected from .
  • R 5b is -CH3; R 8 is hydrogen; R 50 is selected from hydrogen and fluoro; and R 7 is .
  • R 5b is -CH3; R 8 is hydrogen; R 50 is selected from hydrogen and fluoro; and R 7 is .
  • R 5b is -CH3; R 8 is hydrogen; R 50 is selected from hydrogen and fluoro; and R 7 is .
  • a compound of Formula (II-C) is a compound of the formula:
  • R 3 is selected from hydrogen and - CH3; R 8 is hydrogen; and R 50 is hydrogen. In some embodiments, R 3 is selected from hydrogen and -CH3; R 8 is hydrogen; and R 50 is fluoro. In some embodiments, R 3 is hydrogen; R 8 is hydrogen; and R 50 is hydrogen. In some embodiments, R 3 is hydrogen; R 8 is hydrogen; and R 50 is fluoro. In some embodiments, R 3 is -CH 3 ; R 8 is hydrogen; and R 50 is hydrogen. In some embodiments, R 3 is -CH 3 ; R 8 is hydrogen; and R 50 is hydrogen. In some embodiments, R 3 is -CH 3 ; R 8 is hydrogen; and R 50 is fluoro. In some embodiments, R 7 is selected from .
  • R 3 is selected from hydrogen and - CH3; R 8 is hydrogen; R 50 is hydrogen; and R 7 is selected from , , .
  • R 3 is selected from hydrogen and -CH 3 ; R 8 is hydrogen; R 50 is fluoro; and R 7 is selected from , .
  • R 3 is hydrogen; R 8 is hydrogen; R 50 is selected from hydrogen and fluoro; and R 7 is selected from .
  • R 3 is hydrogen; R 8 is hydrogen; R 50 is hydrogen; and R 7 is selected from .
  • R 3 is hydrogen; R 8 is hydrogen; R 50 is fluoro; and R 7 is selected from , , and , d from In some embodiments, R 3 is selected from hydrogen and -CH 3 ; R 8 is hydrogen; R 50 is selected from hydrogen and fluoro; and R 7 is . In some embodiments, R 3 is selected from hydrogen and -CH 3 ; R 8 is hydrogen; R 50 is selected from hydrogen and fluoro; and R 7 is . In some embodiments, R 3 is selected from hydrogen and -CH3; R 8 is hydrogen; R 50 is selected from hydrogen and fluoro; and .
  • Embodiments disclosed herein that refer to a compound of Formula (I), (I-A), (I-B), (I-B1), (I-B2), (I-C), (I-C1), (I-C2), (I-C3), (I-D), (I-D1), (I-D2), (I-E), and/or (I-E1) are also intended to apply to a compound of Formula (I-1), (II-B), (II-C), and (III) unless the context of the embodiment clearly dictates otherwise (e.g., the embodiment refers solely to a variable not present in the compound of Formula (I-1), (II-B), (II-C), or (III), such as R 1 ).
  • a compound of Formula (I) is a compound of the formula: solvate thereof.
  • the present disclosure provides a compound of Formula (I-1):
  • A is selected from C 5-7 carbocycle and 5- to 7-membered heterocycle, each of which is optionally substituted with one or more R 11 ; is absent or selected from C3-8 carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more R 11a ;
  • L 1 is selected from a bond, C 1-6 alkylene, and C 1-6 haloalkylene;
  • L 2 is selected from C5-25 alkylene, C5-25 alkenylene, C5-25 alkynylene, 5- to 25-membered heteroalkylene, and 5- to 25-membered heteroalkenylene, each of which is optionally substituted with one or more R 11b , wherein L 2 is covalently bound to one of W 3 , W 4 , W 5 , W 6 , or W 7 ;
  • W 3 is selected from N(R 3b ), N, C(R 3 ), and C(O);
  • W 4 is selected from N
  • the compound of Formula (I-1) is a compound of Formula (I-B1) or (I-B2): [201] In some embodiments, the compound of Formula (I-1) is a compound of Formula (I-C1), (I-C2), or (I-C3): C3), or a pharmaceutically acceptable salt or solvate thereof. [202] In some embodiments, for a compound of Formula (I-1), (I-B1), (I-B2), (I-C1), (I-C2), or (I-C3), R1 is - CH 3 .
  • R 3 is selected from hydrogen, -CN, -OR 12 , and -CH 3 .
  • R 6 is selected from hydrogen, -OR 12 , and C1-6 alkyl optionally substituted with one, two, or three R 20 , and wherein R 12 is selected from C1-6 alkyl.
  • R 8 is hydrogen for a compound of Formula (I-1), (I-B1), (I-B2), (I-C1), (I-C2), or (I-C3).
  • R7 is selected from C1-6 alkyl, C3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and -N(R 12 )(R 13 ), wherein C1-6 alkyl, C3-10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one, two, or three R 20 .
  • R 7 is selected from , .
  • (I-B1), (I-B2), (I-C1), (I-C2), or (I-C3) is selected from phenyl and 5- to 7-membered heteroaryl, each of which is optionally substituted with one or more R 11 .
  • R 11 is independently selected from fluorine and -CH3.
  • L1 is C1-3 haloalkylene.
  • L 1 is selected from -CF 2 -, -CF 2 CH 2 -, and -CF 2 CH 2 CH 2 -.
  • (I-B1), (I-B2), (I-C1), (I-C2), or (I-C3) is selected from absent, phenyl, and 4- to 8-membered heterocycle, wherein the phenyl and 4- to 8-membered heterocycle are optionally substituted with one or more R 11a .
  • L2 is selected from C 6-15 alkylene, C 6-15 alkenylene, C 6-15 alkynylene, 6- to 15-membered heteroalkylene, and 6- to 15- membered heteroalkenylene, each of which is optionally substituted with one or more R 11b .
  • L 2 is selected from C5-10 alkylene, C5-10 alkenylene, 5- to 10-membered heteroalkylene, and 5- to 10-membered heteroalkenylene, each of which is optionally substituted with one or more R 11b .
  • the alkenylene and heteroalkenylene contain one carbon-carbon double bond.
  • the heteroalkylene and heteroalkenylene comprise at least one oxygen or nitrogen atom.
  • R5 is hydrogen;
  • R5b is -CH3;
  • R6 is selected from hydrogen and -OCH3;
  • R 7 is selected from C1-6 alkyl, C3-10 carbocycle, 3- to 10-membered heterocycle, -N(R 12 )(R 13 ), -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -S(O) 2 R 15 , and -SO 2 N(R 12 )(R 13 ), wherein C 1-6 alkyl, C 3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R 20 ; and R 8 is hydrogen.
  • R3 is hydrogen or -CH3;
  • R 3b is -CH 3 ;
  • R 6 is selected from hydrogen and -OCH 3 ;
  • R 7 is selected from C 1-6 alkyl, C 3-10 carbocycle, 3- to 10- membered heterocycle, -N(R 12 )(R 13 ), -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -S(O) 2 R 15 , and -SO 2 N(R 12 )(R 13 ), wherein C 1-6 alkyl, C3-10 carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R 20 ; and R 8 is hydrogen.
  • Exemplary small molecule SOS1 inhibitors include, but are not limited to, compounds selected from Table 1 (including Compound A), or a salt or solvate thereof.
  • a compound disclosed herein such as a compound of Formula (I), (I-A), (I-B), (I-1), (I-B1), (I-B2), (I-C), (I-C1), (I-C2), (I-C3), (I-D), (I-D1), (I-D2), (I-E), (I-E1), (II-B), (II-C), or (III), is provided as a substantially pure stereoisomer.
  • the stereoisomer is provided in at least 80% enantiomeric excess, such as at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.9% enantiomeric excess.
  • the compounds described herein exist as their pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
  • the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases or inorganic or organic acids to form a pharmaceutically acceptable salt.
  • such salts are prepared in situ during the final isolation and purification of the compounds described herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
  • the compounds described herein exist as solvates. In some embodiments are methods of treating diseases by administering such solvates. Further described herein are methods of treating diseases by administering such solvates as pharmaceutical compositions.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or MeOH. In addition, the compounds provided herein exist in unsolvated as well as solvated forms.
  • solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • the chemical entities described herein can be synthesized according to one or more illustrative schemes herein and/or techniques known in the art. Materials used herein are either commercially available or prepared by synthetic methods generally known in the art. These schemes are not limited to the compounds listed in the examples or by any particular substituents, which are employed for illustrative purposes. Although various steps are described and depicted in Schemes 1-8, the steps in some cases may be performed in a different order than the order shown in Schemes 1-8. Various modifications to these synthetic reaction schemes may be made and will be suggested to one skilled in the art having referred to the present disclosure.
  • heteroaryl amine 1b can be formed from chloride 1a via a nucleophilic aromatic substitution reaction. Substitution of the lactam can proceed under basic conditions to give diene 1c, which can undergo a cross metathesis reaction—such as Grubbs cross metathesis reaction—to form macrocycle 1d. Optionally, 1d may be subjected to one or more subsequent reactions, such as a hydrogenation reaction, to provide a compound of Formula 1e.
  • Scheme 2
  • a compound of Formula 2e may be prepared according to Scheme 2.
  • heteroaryl amine 2b can be formed from chloride 2a via a nucleophilic aromatic substitution reaction. Substitution of the lactam can proceed under basic conditions to give diene 2c, which can undergo a cross metathesis reaction—such as Grubbs cross metathesis reaction—to form macrocycle 2d. Optionally, 2d may be subjected to one or more subsequent reactions, such as a hydrogenation reaction, to provide a compound of Formula 2e.
  • Scheme 3 [221]
  • a compound of Formula 3e may be prepared according to Scheme 3.
  • heteroaryl amine 3b can be formed from chloride 3a via a substitution reaction.
  • a compound of Formula 4e may be prepared according to Scheme 4.
  • heteroaryl amine 4b can be formed from chloride 4a via a substitution reaction.
  • Substitution of the lactam can give protected amine 4c.
  • Hydrolysis of the ester can form carboxylic acid 4d, which can undergo deprotection and peptide coupling reactions to afford a macrocycle of Formula 4e.
  • Scheme 5 [223] In some embodiments, a compound of Formula 5g may be prepared according to Scheme 5.
  • heteroaryl amine 3c can be formed by coupling chloride 5a with amine 5b. Oxidation of the alcohol can give aldehyde 5d, which can be followed with substitution of the phenol to give 5e. Removal of the amine protecting group can afford 5f, which can undergo a reductive amination to form a macrocycle of Formula 5g.
  • Scheme 6 [224]
  • a compound of Formula 6f may be prepared according to Scheme 6.
  • heteroaryl amine 6c can be formed by coupling chloride 1a with amine 6b. Substitution of the phenol to olefin 6d can be followed by installation of a second olefin to give diene 6e.
  • a cross metathesis reaction such as Grubbs cross metathesis reaction—can be followed by hydrogenation of the resulting double bond to provide a macrocycle of Formula 6f.
  • a compound of Formula 8g may be prepared according to Scheme 8.
  • substitution of lactam 8a with a suitable bromo dioxolane (8b) can give acetal 8c.
  • Nucleophilic aromatic substitution with amine 8d can provide heteroaryl amine 8e, which can be treated with a suitable acid, such as HC1, to remove the Boc protecting group and reveal the aldehyde.
  • cyclization of 8f can proceed via reductive amination conditions to give a macrocycle of Formula 8g.
  • a SOS1 inhibitor of the present disclosure is a compound described in U.S. Pat. No.
  • a compound of the present disclosure for example, a compound of a formula given in Table 1, was synthesized according to one of the general routes outlined in Schemes 1-8 or by methods generally known in the art.
  • exemplary compounds may include, but are not limited to, a compound selected from Table 1, or a salt or solvate thereof. Table 1
  • the compounds of the present disclosure exhibit one or more functional characteristics described herein.
  • a subject compound is capable of reducing Ras signaling output.
  • a subject compound is capable of disrupting a Ras-SOS interaction, including disrupting interaction or binding between a mutant Kras (e.g., Kras G12C) and SOS1 , or between a wildtype Kras and SOS1, thereby reducing Ras signaling output.
  • a subject compound binds specifically to a SOS protein, including SOS1.
  • the IC50 of a subject compound (including those shown in Table 1) for a SOS protein is less than about 5 pM, less than about 1 pM, less than about 50 nM, less than about 10 nM, less than about 1 nM, less than about 0.5 nM, less than about 100 pM, or less than about 50 pM, as measured in an in vitro assay known in the art or exemplified herein.
  • a reduction in Ras signaling output can be evidenced by one or more members of the following: (i) an increase in steady state level of GDP -bound Ras protein; (ii) a reduction in steady state level of GTP-bound Ras protein; (iii) a reduction of phosphorylated AKTs473, (iv) a reduction of phosphorylated ERKT202/y204, (v) a reduction of phosphorylated S6S235/236, (vi) reduction (e.g., inhibition) of cell growth of Ras-driven tumor cells (e.g., those derived from a tumor cell line disclosed herein), and (vii) an interference or disruption of the interaction or binding between a SOS protein (e.g., SOS1) with a Ras protein such as a wildtype or a mutant Ras.
  • the reduction in Ras signaling output can be evidenced by two, three, four, five, six, or all of (i)-(vii) above.
  • kits for use in reducing proliferation of cancer cells comprising an EGFR mutation, such as an EGFR exon 20 insertion.
  • the kit comprises: (1) a composition comprising a SOS1 inhibitor of Formula (I), (I-A), (I-B), (1-1), (I-Bl), (I-B2), (I-C), (I-Cl), (I-C2), (I-C3), (I-D), (I- Dl), (I-D2), (I-E), (I-El), (II-B), (II-C), or (III); (2) a composition comprising amivantamab; and (3) instructions for using the composition(s) of (1) and (2).
  • a composition comprising a SOS1 inhibitor of Formula (I), (I-A), (I-B), (1-1), (I-Bl), (I-B2), (I-C), (I-Cl), (I-C2), (I-C3), (I-D), (I- Dl), (I-D2),
  • the small molecule SOS1 inhibitor is a compound described in Table 1, or a pharmaceutically acceptable salt or solvate thereof.
  • instructions for contacting the cells in vitro, ex vivo, or in vivo are provided.
  • the SOS1 inhibitor and amivantamab are formulated in the same unit dosage form.
  • the SOS1 inhibitor and amivantamab are formulated in different unit dosage forms.
  • the kit can comprise a multi -day supply, including instructions directing the multi-day administration.
  • compositions and methods of administration are provided.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.
  • a compound of Formula (I), (I-A), (I-B), (1-1), (I-Bl), (I-B2), (I-C), (I-Cl), (I-C2), (I-C3), (I-D), (I-Dl), (I- D2), (I-E), (I-El), (II-B), (II-C), or (III), or a pharmaceutically acceptable salt or solvate thereof, may be administered to a subject in a biologically compatible form suitable for administration to treat or prevent a disease, disorder or condition.
  • a compound described herein may be administered in any pharmacological form including a therapeutically effective amount of a compound of Formula (I), (I-A), (I-B), (1-1), (I-B 1), (I-B2), (I-C), (I-C 1), (I- C2), (I-C3), (I-D), (I-Dl), (I-D2), (I-E), (I-El), (II-B), (II-C), or (III), or a pharmaceutically acceptable salt or solvate thereof, alone or in combination with a pharmaceutically acceptable carrier.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I), (I-A), (I-B), (1-1), (I-Bl), (I-B2), (I-C), (I-Cl), (I-C2), (I-C3), (I-D), (I-Dl), (I-D2), (I-E), (I-El), (II-B), (II-C), or (III), or a pharmaceutically acceptable salt or solvate thereof.
  • a pharmaceutically acceptable excipient comprising a pharmaceutically acceptable excipient and a compound of Formula (I), (I-A), (I-B), (1-1), (I-Bl), (I-B2), (I-C), (I-Cl), (I-C2), (I-C3), (I-D), (I-Dl), (I-D2), (I-E), (I-El), (II-B), (II-C), or
  • a compound described herein is administered as a pure chemical.
  • a compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).
  • composition comprising at least one compound described herein, or a pharmaceutically acceptable salt, together with one or more pharmaceutically acceptable excipients.
  • excipient(s) or carrier(s)
  • carrier(s) is acceptable or suitable if the excipient is compatible with the other ingredients of the composition and not deleterious to the recipient of the composition.
  • the compounds described herein may be administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition.
  • Administration of the compounds and compositions described herein can be effected by any method that enables delivery of the compounds to the site of action.
  • enteral routes including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema
  • parenteral routes injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalational, transdermal, transmucosal, sublingual, buccal and topical (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most suitable route may depend upon, for example, the condition and disorder of the recipient.
  • a compound described herein can be administered locally to the area in need of treatment, by for example, local infusion during surgery, topical application such as creams or ointments, injection, catheter, or implant.
  • the administration can also be by direct injection at the site of a diseased tissue or organ.
  • a compound described herein is administered orally.
  • a pharmaceutical composition suitable for oral administration may be presented as a discrete unit such as a capsule, cachet or tablet, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient is presented as a bolus, electuary or paste.
  • compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free -flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets are coated or scored and are formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or Dragee coatings for identification or to characterize different combinations of active compound doses.
  • a pharmaceutical composition is formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen- free water, immediately prior to use.
  • sterile liquid carrier for example, saline or sterile pyrogen- free water
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • compositions for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • compositions may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • SOS purification A SOS construct or a variant thereof is His-tagged. E. coli cultures are induced in a fermenter, harvested, and lysed in lysis buffer, for example, in 25 mM Tris HC1 7.5, 500 mM NaCl, 20 mM Imidazol, Complete EDTA- free (Roche)).
  • the centrifuged lysate (50,000 x g, 45 min, 40) is incubated with 30 mL Ni-NTA (Macherey -Nagel; #745400.100) in a spinner flask (16 h, 40) and subsequently transferred to a chromatography column connected to a chromatography system, e.g., an Akta chromatography system.
  • a chromatography system e.g., an Akta chromatography system.
  • the column is rinsed with wash buffer, e.g., in 25 mM Tris HC1 7.5, 500 mM NaCl, 20 mM Imidazol and the bound protein is eluted with a linear gradient (0-100%) of elution buffer (25 mM Tris HC1 7.5, 500 mM NaCl, 300 mM Imidazol).
  • wash buffer e.g., in 25 mM Tris HC1 7.5, 500 mM NaCl, 20 mM Imidazol
  • the main fractions of the elution peak (monitored by OD280) containing homogenous HislO-hSOS is pooled.
  • any compound of the present disclosure to reduce a Ras protein signaling output by, e.g., interfering or disrupting interaction (or binding) between SOS1 and a Ras protein can be assessed in vitro.
  • the equilibrium interaction of human SOS1 (hSOSl) with human wildtype Kras or K-Ras mutant e.g., hK-Ras G12C mutant, or hK-Ras G12C
  • K-Ras mutant e.g., hK-Ras G12C mutant, or hK-Ras G12C
  • Detection of such interaction is achieved by measuring homogenous time-resolved fluorescence resonance energy transfer (HTRF) from (i) a fluorescence resonance energy transfer (FRET) donor (e.g., antiGST-Europium) that is bound to GST-tagged K-Ras G12C to (ii) a FRET acceptor (e.g., anti-6His-XL665) bound to a His-tagged hSOSl .
  • FRET fluorescence resonance energy transfer
  • the assay buffer can contain 5 mM HEPES pH 7.4, 150 mM NaCl, 10 mM EDTA, 1 mM DTT, 0.05% BSA, 0.0025% (v/v) Igepal and 100 mM KF.
  • a Ras working solution is prepared in assay buffer containing typically 10 nM of the protein construct (e.g., GST-tagged hK-Ras G12C) and 2 nM of the FRET donor (e.g., antiGST-Eu(K) from Cisbio, France).
  • a SOS1 working solution is prepared in assay buffer containing typically 10 nM of the protein construct (e.g., His-hSOSl) and 10 nM of the FRET acceptor (e.g., anti-6His-XL665 from Cisbio, France).
  • An inhibitor control solution is prepared in assay buffer containing 10 nM of the FRET acceptor without the SOS1 protein.
  • a fixed reaction mixture with or without test compound is transferred into a 384-well plate. Ras working solution is added to all wells of the test plate. SOS1 working solution is added to all wells except for those that are subsequently filled with the inhibitor control solution. After approximately 60 min incubation, the fluorescence is measured with a MIOOOPro plate reader (Tecan) using HTRF detection (excitation 337 nm, emission 1 : 620nm, emission 2: 665nm). Compounds are tested in duplicate at different concentrations (for example, 10 pM, 2.5 pM, 0.63 pM, 0.16 pM, 0.04 pM, 0.01 pM test compound). The ratiometric data (i.e., emission 2 divided by emission 1) is used to calculate IC50 values against SOS1 using GraphPad Prism (GraphPad software).
  • MIA PaCa-2 ATCC CRL-1420
  • NCI-H1792 ATCC CRL-5895
  • cell lines comprise a G12C mutation and can be used to assess Ras cellular signaling in vitro, e.g., in response to a subject compound of the present disclosure.
  • This cellular assay can also be used to discern selective inhibition of subject compounds against certain types of Kras mutants, e.g., more potent inhibition against Kras G12D relative to Kras G12C mutant, by using MIA PaCa-2 (G12C driven tumor cell line) as a comparison.
  • Cell culture medium (comprising, for example, MIA PaCa-2 cells) is prepared with DMEM/Ham's F12 (e.g., with stable Glutamine, 10% FCS, and 2.5% Horse Serum).
  • NCI-H1792 culture medium is prepared with RPMI 1640 (e.g., with stable Glutamine) and 10% FCS.
  • a CellTiter-Glo (CTG) luminescent based assay (Promega) is used to assess growth of the cells, as a measurement of the ability of the compounds herein to inhibit Ras signaling in the cells.
  • the cells (e.g., 800-1200 per well) are seeded in their respective culture medium in standard tissue culture -treated ultra-low attachment surface 96-well format plates (Coming Costar #3474).
  • a dilution series e.g., a 9 point 3-fold dilution series
  • the compounds herein e.g., approximately 125 pl, final volume per well.
  • Cell viability can be monitored (e.g., approximately 5 days later) according to the manufacturer’s recommended instructions, where the CellTiter-Glo reagent is added (e.g., approximately 65 pL), vigorously mixed, covered, and placed on a plate shaker (e.g., approximately for 20 min) to ensure sufficient cell lysis prior to assessment of luminescent signal.
  • the IC50 values are determined using the four-parameter fit. The resulting IC50 value is a measurement of the ability of the compounds herein to reduce cell growth of Ras-driven cells as representative tumor cells.
  • Example 5 Inhibition of cell proliferation using SOS1 inhibitors in combination with amivantamab
  • EGFR mutant cell lines are available commercially, including Ba/F3-EGFR_Ex20_ASV insertion cells, Ba/F3 EGFR L858R/T790M cells, PC9-EGFR Exl9 E746_A750 cells, andH1975-EGFR L858R/T790M cells.
  • These exemplary cells can be maintained in a humidified incubator at 37 °C with 5% CO2 and grown in RPMI 1640 with 10% FBS (Gibco) and 50 IU mL' 1 penicillin/streptomycin (Gibco).
  • a CellTiter-Glo (CTG) luminescent based assay Promega
  • Cells (-300-1,200 per well) are seeded (using the same media) in standard tissue culture -treated 384-well format plates. The day after plating, cells are treated with a 9 point, 3 -fold dilution series of indicated compounds (40 pl, final volume per well) and growth inhibition is monitored -72 hours later (for BaF/3 EGFR mutant lines) or 5 days later for other cell lines according to the manufacturer’s recommended instructions, where 20 pl, of CellTiter-Glo reagent is added, vigorously mixed, covered, and placed on a plate shaker for 20 min to ensure complete cell lysis prior to assessment of luminescent signal. Growth inhibition of cells treated with a SOS1 inhibitor of the present disclosure in combination with amivantamab are monitored as stated above.
  • Example 6 Inhibition of tumor growth in EGFR exon 20 insertion murine model
  • mice are maintained under specific pathogen-free conditions, and food and water are provided ad libitum.
  • BALB/c nude (NCr) mice are implanted with respective tumor fragments (2-3 mm in diameter) on the flank.
  • Suitable exemplary PDX models include, but are not limited to, LU0858, LU0387 (ex20), LU3075 (ex20).
  • Ba/F3 EGFR mutant cell lines (1 x 10 6 cells) are harvested on the day of use and injected in growth-factor-reduced Matrigel/PBS (50% final concentration in 100 pL).
  • One flank is inoculated subcutaneously per mouse.
  • FIG. 1 shows that a SOS1 inhibitor of the present disclosure (Compound A) synergistically inhibits tumor growth in combination with amivantamab in EGFR exon 20 insertion lung cancer.
  • FIG. 3 shows that a SOS1 inhibitor of the present disclosure (Compound A) synergistically reduces tumor volume in combination with amivantamab in a PDX model (NSCLC-squamous, EGFR-Ex20 D772_N773insDNP) that is refractory to amivantamab.
  • Compound A synergistically reduces tumor volume in combination with amivantamab in a PDX model (NSCLC-squamous, EGFR-Ex20 D772_N773insDNP) that is refractory to amivantamab.
  • mice are maintained under specific pathogen-free conditions, and food and water are provided ad libitum.
  • BALB/c nude (NCr) mice are implanted with respective tumor fragments (2-3 mm in diameter) on the flank.
  • Nr nude
  • 1 x 10 6 cells are harvested on the day of use and injected in growth-factor-reduced Matrigel/PBS (50% final concentration in 100 pL).
  • One flank is inoculated subcutaneously per mouse. Mice are monitored daily, weighed twice weekly, and caliper measurements begin when tumors become visible. Animals are randomly assigned to treatment groups as indicated in FIG.
  • FIG. 2 shows that a SOS1 inhibitor of the present disclosure (Compound A) synergistically reduces tumor volume in combination with amivantamab in EGFR-mediated lung cancer, particularly MET amplified lung cancer.
  • Compound A synergistically reduces tumor volume in combination with amivantamab in EGFR-mediated lung cancer, particularly MET amplified lung cancer.
  • Example 8 Inhibition of tumor growth in EGFR L858R/T790M murine models
  • mice are maintained under specific pathogen-free conditions, and food and water are provided ad libitum.
  • Female 6- to 8-week old athymic BALB/c nude (NCr) nu/nu mice are used to inoculate EGFR L858R/T790M cell lines.
  • NHLB/c nude (NCr) nu/nu mice are used to inoculate EGFR L858R/T790M cell lines.
  • H1975 cells (5 x 10 6 ) or Ba/F3 EGFR mutant cells (1 x 10 6 ) are harvested on the day of use and injected in growth-factor-reduced Matrigel/PBS (50% final concentration in 100 pL).
  • One flank is inoculated subcutaneously per mouse. Mice are monitored daily, weighed twice weekly, and caliper measurements begin when tumors become visible.
  • Tumor volume is calculated by measuring two perpendicular diameters using the following formula: (L x w 2 ) 12, in which L and w refer to the length and width of the tumor diameter, respectively.
  • L and w refer to the length and width of the tumor diameter, respectively.
  • FIG. 5 shows that a SOS1 inhibitor of the present disclosure (Compound A) synergistically reduces tumor volume in combination with amivantamab in mice bearing H820 xenograft tumors, a papillary adenocarcinoma model that is refractory to osimertinib and exhibits EGFR L858R/T790M mutations and MET amplification, with 8 of 8 animals in the combination group showing complete responses.
  • FIG. 6 H820 xenograft tumors progress on amivantamab monotherapy, but when a S0S1 inhibitor of the present disclosure (Compound A) was added to the treatment regimen on day 22, tumors regressed, with 4 of 5 animals showing complete responses.
  • FIG. 1 SOS1 inhibitor of the present disclosure
  • Compound A synergistically reduces tumor volume in combination with amivantamab in mice bearing Ba/F3 tumors transduced with mutant EGFR containing triple mutations in L858R, T790M, and C797S.
  • EGFR mutant cell lines including Ba/F3-EGFR_Ex20_ASV insertion cells, Ba/F3 EGFR L858R/T790M cells, PC9-EGFR Exl9 E746_A750 cells, and H1975-EGFR L858R/T790M cells, and METamp cell lines, including H820 cells, are available commercially. These exemplary cells can be maintained in a humidified incubator at 37 °C with 5% CO2 and grown in RPMI 1640 with 10% FBS (Gibco) and 50 IU ml/ 1 penicillin/ streptomycin (Gibco).
  • CCG CellTiter-Glo
  • cells are treated with a 9 point, 3 -fold dilution series of either vehicle or (i) a SOS1 inhibitor of the present disclosure (e.g., Compound A) alone, (ii) amivantamab alone, or (iii) a combination of (i) and (ii) (40 id, final volume per well) and growth inhibition is monitored -72 hours later (for BaF/3 EGFR mutant lines) or 5 days later for other cell lines according to the manufacturer’s recommended instructions, where 20 pL of CellTiter-Glo reagent is added, vigorously mixed, covered, and placed on a plate shaker for 20 min to ensure complete cell lysis prior to assessment of luminescent signal. Growth inhibition of cells treated with a SOS1 inhibitor of the present disclosure alone or in combination with amivantamab are monitored as stated above.
  • a SOS1 inhibitor of the present disclosure e.g., Compound A
  • amivantamab alone
  • mice are maintained under specific pathogen-free conditions, and food and water are provided ad libitum.
  • BALB/c nude (NCr) mice are implanted with respective tumor fragments (2-3 mm in diameter) on the flank, such as CR9528 tumor fragments. Mice are monitored daily, weighed twice weekly, and caliper measurements begin when tumors become visible. Animals are randomly assigned to treatment groups as indicated in FIG. 4 by an algorithm that assigns animals to groups to achieve best case distributions of mean tumor size with lowest possible standard deviation.
  • Tumor volume is calculated by measuring two perpendicular diameters using the following formula: (L x w 2 ) / 2, in which L and w refer to the length and width of the tumor diameter, respectively.
  • FIG. 4 shows that a SOS1 inhibitor of the present disclosure (Compound A) synergistically inhibits tumor growth in combination with amivantamab in KRAS G12C-mediated colorectal cancer.

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Abstract

La présente divulgation concerne des composés et un sel pharmaceutiquement acceptable de ceux-ci, et des méthodes d'utilisation de ceux-ci. Les composés et les méthodes ont une gamme d'utilités en tant qu'agents thérapeutiques, diagnostiques et outils de recherche. En particulier, les compositions et les méthodes de la divulgation sont utiles pour réduire la sortie de signalisation de protéines oncogènes lorsqu'elles sont utilisées en combinaison avec un ou plusieurs autres agents thérapeutiques.
PCT/US2024/052876 2023-10-25 2024-10-24 Utilisation d'inhibiteurs de sos1 et d'amivantamab pour traiter le cancer Pending WO2025090810A1 (fr)

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