Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/28—Compounds containing heavy metals
  • A61K31/282—Platinum compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4196—1,2,4-Triazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/433—Thidiazoles
• • 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
  • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/24—Heavy metals; Compounds thereof
  • A61K33/243—Platinum; Compounds thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
  • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
  • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
  • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
  • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
  • G01N33/57407—Specifically defined cancers
  • G01N33/57449—Specifically defined cancers of ovaries
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
  • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
  • A61K51/04—Organic compounds
  • A61K51/0404—Lipids, e.g. triglycerides; Polycationic carriers
  • A61K51/0408—Phospholipids

Definitions

• Metabolic deregulation is a hallmark of cancer as tumors exhibit an increased demand for nutrients and macromolecules to fuel their rapid proliferation.
• Glutamine the most abundant amino acid in circulation, plays an essential role in providing cancer cells with biosynthetic intermediates required to support proliferation and survival.
• tumor cells utilize glutaminolysis, or the enzymatic conversion of glutamine to glutamate, as a nutrient source for amino acid and nucleotide synthesis, and a carbon skeleton to fuel ATP and NADPH synthesis through the TCA cycle.
• glutamine metabolism plays a critical role in multiple metabolic events to generate energy and maintain cellular redox balance.
• Products of glutaminolysis are used in maintaining cellular redox homeostasis as glutamate can be converted into glutathione, the major intracellular antioxidant.
• Cancer cells require a constant source of biomass and macro-molecules to support cell division and reducing agents to maintain redox homeostasis. While many of these building blocks are provided through aerobic glycolysis, many cancer cells have evolved a dependence on glutamine metabolism for growth and survival.
• GLS-1 mitochondrial glutaminase
• GLS-1 mitochondrial glutaminase
• GLS-1 Both forms of GLS-1 are thought to bind to the inner membrane of the mitochondrion in mammalian cells, although at least one report suggests that glutaminase may exist in the intramembrane space, dissociated from the membrane. GLS is frequently overexpressed in human tumors and has been shown to be positively regulated by oncogenes such as Myc. Consistent with the observed dependence of cancer cell lines on glutamine metabolism, pharmacological inhibition of GLS offers the potential to target Gin addicted tumors. Such targeted treatment, however, is hampered by the lack of clinical biomarkers to identify sensitive patient populations.
• the present invention is based, in part, on the discovery of a mechanism whereby tumor cells with a specific metabolic dependence on the activity of glutaminase to generate intracellular pools of glutamate are uniquely sensitive to glutaminase inhibition. Conversely, cells which have alternative mechanisms for generating glutamate define a specific patient population that may be insensitive to glutaminase inhibitors.
• the invention comprises a method of treating cancer in a subject whose cancer cells express low levels of asparagine synthetase (ASNS), as defined by an Histophathology Score (H-score) of 0 - 100 (both inclusive) by
• ASNS asparagine synthetase
• immunohistochemical staining comprising administering a glutaminase- 1 (GLS-1) inhibitor to said subject.
• the invention comprises a method of treating a subject having a disorder, such as a cancer or tumor.
• the method comprises determining the concentration or expression of ASNS in said cancer or tumor of said subject; and administering a glutaminase-1 (GLS-1) inhibitor to said subject if the level of ASNS is quantified as an H-score of less than or equal to 100 by immunohistochemical staining.
• the method comprises optionally obtaining a biological sample from a subject, determining that the concentration or expression of ASNS in said sample from said subject is low and administering a glutaminase-1 (GLS-1) inhibitor to said subject.
• the invention comprises a method of stratifying a subject for response to GLS inhibitor therapy.
• the method comprises determining that the concentration of ASNS or its expression levels in a tumor or in cancer cells of said subject are low and administering a glutaminase inhibitor to said subject.
• the subject in need of treatment may be afflicted with a disorder or a condition, for example, cancer, including, but not limited to, bladder cancer, bone marrow cancer, breast cancer, cancer of the central nervous system, cervical cancer, colon cancer, endometrial cancer, cancer of the gastric system, head and neck cancer, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, muscle cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, thyroid cancer, or a variant thereof.
• the cancer is ovarian, skin, liver, prostate, breast, colon, lung, head and neck cancers or a lymphoma.
• the cancer is ovarian cancer, for example, high-grade serous ovarian cancer (HGSOC).
• the GLS-1 inhibitor may, for example, be a selective inhibitor of GLS-1.
• FIG. 1(a) shows the the potent and specific inhibition of glutaminase-1 (GLS-1) by compound 1.
• x-axis concentration of compound 1 (M);
• y-axis activity (relative to control);
• IC50 5.8 nm.
• FIG. 1(b) shows that target engagement for OVCAR8 can be measured after treatment with compound 1.
• the glutamate : glutamine ratio is depicted for DMSO (1.) and Compound 1 (2.).
• FIG. 1(c) shows that target engagement for OVCAR429 can be measured after treatment with compound 1.
• the glutamate : glutamine ratio is depicted for DMSO (1.) and Compound 1 (2.).
• FIG. 1(d) shows that target engagement for IGROVl can be measured after treatment with compound 1.
• the glutamate : glutamine ratio is depicted for DMSO (1.) and Compound 1 (2.).
• FIG. 1(e) shows that target engagement for OVCAR4 can be measured after treatment with compound 1.
• the glutamate : glutamine ratio is depicted for DMSO (1.) and Compound 1 (2.).
• FIG. 3(a) shows that differential response to GLS-1 inhibition is observed in OVCA lines. Viability (relative to DMSO) of IGROVl is plotted as a function of Compound 1 (uM). [019] FIG. 3(b) shows that differential response to GLS-1 inhibition is observed in OVCA lines. Viability (relative to DMSO) of OVCAR4 is plotted as a function of Compound 1 concentration (uM).
• FIG. 4 shows a waterfall plot depicting differential response to GLS-1 inhibition in a broad panel of OVCA lines.
• IC50 (uM) at 72 h is plotted for several cell lines.
• a subset of OVCA lines show low nM sensitivity to GLSi while others do not show any response.
• FIG. 5 shows that metabolic alterations result in an altered redox balance in response to treatment of OVCAR429 (1.) and OVCAR8 (2.) with compound 1.
• Metabolite fold change (log 2) is plotted for various metabolites involved in: TCA (i , glutamate synthesis (ii); purine (in); and pentose phosphate (iv) pathways.
• FIG. 6 shows that metabolic alterations result in an altered redox balance in response to treatment of OVCAR4 (1.) and IGROV l (2.) with compound 1.
• Metabolite fold change (log 2) is plotted for various metabolites involved in: TCA (i), glutamate synthesis (ii); purine (Hi); and pentose phosphate (iv) pathways.
• FIG. 7 shows that glutathione levels are decreased after treatment with compound 1 (2.) compared to DMSO (1.). Shown are the glutathione levels (uM) for responders (i) OVCAR420 (a); OVCAR429 (b); OVCAR8 (c); and a non-responder (ii) OVCAR4 (d).
• FIG. 8(a) shows that the loss of glutathione (GSH) after treatment with compound 1, a GLS-1 inhibitor (GLS li), leads to an accumulation of intracellular reactive oxygen species (ROS) in OVCAR420 cells.
• GSH glutathione
• GLS-1 inhibitor GLS-1 inhibitor
• FIG. 8(b) shows that the loss of glutathione (GSH) after treatment with compound 1, a GLS-1 inhibitor (GLS li), leads to an accumulation of intracellular reactive oxygen species (ROS) in OVCAR429 cells.
• GSH glutathione
• GLS-1 inhibitor GLS-1 inhibitor
• FIG. 11 shows that the GLSli induces oxidative stress that leads to accumulation of DNA damage, y-axis is ⁇ 2 ⁇ foci, normalized to DMSO.
• y-axis is ⁇ 2 ⁇ foci, normalized to DMSO.
• FIG. 12(a) shows that application of exogenous GSH to responder cell line OVCAR420 rescues proliferation defects induced by compound 1. Viability upon application of cell-permeable GSH (1.) is shown, along with a control (2) without GSH treatment.
• FIG. 12 shows that application of exogenous GSH to responder cell line
• OVCAR429 rescues proliferation defects induced by compound 1. Viability upon application of cell-permeable GSH (1.) is shown, along with a control (2) without GSH treatment.
• ASNS asparagine synthetase
• FIG. 13 shows key metabolic pathways that determine the production and fate of glutamine (GLU).
• FIG. 14 shows the ASNS levels by reverse phase protein array (RPPA) expression analysis in responder (a) and non-responder (b) OVCA cell lines.
• RPPA reverse phase protein array
• FIG. 15 shows the Western blot of ASNS expression across a panel of OVCA cell lines.
• FIG. 16(a) shows western blot of ASNS for ASNS over-expression study.
• OV8 (1.); ASNS OE (2.); ASNS OE 1 : 10 (3.); ASNS OE (1 : 100).
• FIG. 16(b) shows western blot of GAPDH for over-expression study.
• OV8 (1.); ASNS OE (2.); ASNS OE 1 : 10 (3.); ASNS OE (1 : 100).
• FIG. 16(c) plots viability, normalized to DMSO, for OV8 (1.); OV8 ASNS OE (2.); OV8 ASNS OE 1 : 10 (3.); and OV8 ASNS OE 1 : 100 (4.).
• FIGS. 17(a) shows ASNS western blot for ASNS knockdown study. NTC (1.) and ASNS KD (2 ).
• FIGS. 17(b) shows Hsp90 western blot for ASNS knockdown study. NTC (1.) and ASNS KD (2 ). [044]
• FIG. 17(c) shows ASNS immunohistochemical (IHC) antibody validation.
• FIG. 17(d) shows ASNS immunohistochemical (IHC) antibody validation.
• FIGS. 18(a) shows IHC assay for responder OVCAR420.
• FIGS. 18(b) shows IHC assay for responder OVCAR429.
• FIGS. 18(c) shows IHC assay for non-responder OVCAR4.
• FIGS. 18(d) shows IHC assay for non-responder A2780 (d).
• FIGS. 19(a) shows tissue microarrays from ovarian cancer patientswith low ASNS expressing TMA cores.
• FIGS. 19(b) shows tissue microarrays from ovarian cancer patientswith high ASNS expressing TMA cores.
• FIG. 19(c) shows provides quantification of patients with different levels of ASNS expression from ASNS scoring.
• FIG. 20(b) shows that GLS-1 inhibition inhibits tumor progression in an orthotopic model of ovarian cancer.
• Vehicle (1.); Compound 2 100 mpk (2.); Paclitaxel 15 mpk (3.); and Compound 2 + Paclitaxel (4.); y-axis combined nodule weight (g).
• FIG. 22(a) shows phospho-histone H3 stain for Compound 1.
• FIG. 22(b) shows phospho-histone H3 stain for vehicle.
• FIG. 22(c) shows pathologist score for vehicle (1.) and Compound 1 (2.).
• FIG. 23(a) shows scoring of patients samples using a traditional pathologist's scale of 0-3.
• FIG. 23(b) shows example stains of TMA cores having low ASNS expression.
• FIG. 23 (c) shows example stains of TMA cores having ASNS expression
• FIG. 24 (a) shows a summary of scoring from TMA cores, which reveals 40% of patients with no or low ASNS expression, and another 20% with medium levels of ASNS expression. Both populations would be predicted to respond to GLS inhibition.
• FIG. 24(b) shows that growth of an ASNSiow PDX model is inhibited in vivo following treatment with GLSi. Vehicle (1.); Compound 2 100 mpk (2.); Paclitaxel 15 mpk (3.); and Compound 2 + Paclitaxel (4.).
• FIG. 25(a) shows production of glutathione and subsequent reduction of reactive oxygen species (ROS).
• FIG. 25(b) shows that reduction of reactive oxygen species (ROS) levels can be reduced in responders by treatment with a GLS inhibitor, thus increasing ROS levels.
• ROS reactive oxygen species
• FIG. 25(c) shows that non-responders circumvent GLS inhibition by utilizing aspartate as an alternate feedstock for glutathione synthesis.
• the present invention is based, in part, on the discovery of biomarkers and mechanisms that indicate responsiveness to glutaminase (GLS) inhibitor treatment.
• a molecular mechanism has been identified that stratifies cancer patients for treatment and indicates responsiveness to GLS inhibition.
• the inventors have discovered that some cancer cells are sensitive to GLS inhibition.
• the inventors have also discovered that cells that express high levels of asparagine synthetase (ASNS) are resistant to inhibition of GLS.
• ASNS asparagine synthetase
• cells for example, tumor cells, which are sensitive to GLS-1 inhibition display a dependence on reduced glutathione, the major endogenous antioxidant comprised of glycine, cysteine, and glutamine-derived glutamate. Inhibition of GLS-1 reduces the steady state levels of glutathione, thus shifting the redox balance of such cells. Consistent with this model, treatment of a subset of HGSOC cell lines with a potent GLS-1 inhibitor reduces intracellular levels of glutamate and glutathione and inhibits cell growth through a mechanism that involves reactive oxygen species (ROS)- induced DNA damage.
• ROS reactive oxygen species
• HGSOC cell lines expressing high levels of ASNS the enzyme that metabolizes aspartate to glutamate and asparagine, failed to respond to GLS-1 inhibitor treatment.
• ASNS the enzyme that metabolizes aspartate to glutamate and asparagine
• These non-responder cells maintain glutamate and glutathione pools in the presence of GLS-1 inhibition through the activity of ASNS, and presumably utilize ASNS- derived glutamate to produce glutathione. Consequently, ASNS levels function as a negative indicator of response to GLS-1 inhibition, thus, serving as a patient stratification biomarker.
• the invention comprises a method of treating a tumor or a cancer in a subject.
• the invention comprises a method of treating a tumor or a cancer in a subject wherein the tumor or cancer cells in said subject express low levels of asparagine synthetase (ASNS), comprising administering a glutaminase inhibitor to said subject.
• ASNS asparagine synthetase
• the invention comprises a method of treating a subject having a disorder, such as a cancer or tumor.
• the method comprises determining that the concentration or expression of ASNS in said cancer or tumor of said subject is low and administering a glutaminase inhibitor to said subject.
• H-score Histophathology Score
• the invention comprises treating cancer in a subpopulation of subjects, the subpopulation being characterized by a low level of ASNS in the subjects, and administering a glutaminase inhibitor to the subjects in the subpopulation.
• the level of ASNS in the subjects in the subpopulation is quantified as an H-score by immunohistochemical staining.
• the H-score of subjects in the subpopulation is less than or equal to 150.
• the H-score of subjects in the subpopulation is less than or equal to 125.
• the H-score of subjects in the subpopulation is less than or equal to 100.
• Embodiment 1 A method for treatment of a disorder in a subject characterized by a low level of expression or concentration of asparagine synthetase (ASNS), said treatment comprising administering one or more glutathione lowering agents to said subject.
• ASNS asparagine synthetase
• Embodiment 2 A method for treatment of a disorder in a subpopulation of subjects, said subjects in said subpopulation being characterized by a low level of expression or concentration of ASNS, said treatment comprising administering one or more glutathione lowering agents to said subjects.
• Embodiment 3 A method of stratifying a subject for response to GLS-1 inhibitor therapy, comprising determination of a low level of expression or concentration of ASNS in said subject, and administering one or more glutathione lowering agents to said subject.
• Embodiment 4 A method comprising the treatment of a subject having a disorder in need of treatment, comprising determination of the expression or concentration or asparagine synthetase (ASNS) in the subject, and administering one or more glutathione lowering agents to said subject if said subject displays a low level of expression or concentration of ASNS.
• ASNS asparagine synthetase
• Embodiment 5 The method of any one of Embodiments 1-4, further comprising obtaining a biological sample or samples from said subject or subjects.
• Embodiment 6 The method of Embodiment 4, further comprising determining the level or concentration of ASNS from said biological sample or samples.
• Embodiment 7 The method of any one of Embodiments 1-6, wherein said disorder is chosen from a cancer or a tumor.
• Embodiment 8 The method of Embodiment 6, wherein said disorder is a cancer.
• Embodiment 9 The method of Embodiment 8, wherein said cancer is chosen from Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML),
• Duct Cancer including Extrahepatic
• Bladder Cancer including Bladder Cancer, Bone Cancer (including Breaste Cancer).
• Brain Tumor such as Astrocytomas
• Neuroectodermal Tumors and Pineoblastoma Breast Cancer, Bronchial Tumors, Burkitt Lymphoma, Basal Cell Carcinoma, Bile Duct Cancer (including Extrahepatic), Bladder Cancer, Bone Cancer (including Osteosarcoma and Malignant Fibrous Histiocytoma), Carcinoid Tumor, Carcinoma of Unknown Primary, Central Nervous System (such as Atypical Teratoid/Rhabdoid Tumor, Embryonal Tumors and Lymphoma), Cervical Cancer, Childhood Cancers, Chordoma, Chronic Lymphocytic Leukemia (CLL), Chronic
• CML Myelogenous Leukemia
• CML Chronic Myeloproliferative Disorders
• Colon Cancer Colorectal Cancer
• Craniopharyngioma Cutaneous T-Cell Lymphoma (Mycosis Fungoides and Sezary Syndrome)
• Duct Bile (Extrahepatic)
• Ductal Carcinoma In situ DCIS
• Embryonal Tumors Central Nervous System
• Endometrial Cancer Ependymoblastoma, Ependymoma, Esophageal Cancer, Esthesioneuroblastoma, Ewing Sarcoma Family of Tumors, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, Eye Cancer (like Intraocular Melanoma, Retinoblastoma), Fibrous
• Macroglobulinemia Waldenstrom, Male Breast Cancer, Malignant Fibrous Histiocytoma of Bone and Osteosarcoma, Medulloblastoma, Medulloepithelioma, Melanoma (including Intraocular (Eye)), Merkel Cell Carcinoma, Mesothelioma (Malignant), Metastatic Squamous Neck Cancer with Occult Primary, Midline Tract Carcinoma Involving NUT Gene, Mouth Cancer, Multiple Endocrine Neoplasia Syndromes, Multiple Myeloma/Plasma Cell Neoplasm, Mycosis Fungoides, Myelodysplasia Syndromes,
• Myelodysplastic/Myeloproliferative Neoplasms Myelogenous Leukemia, Chronic (CML), Myeloid Leukemia, Acute (AML), Myeloma and Multiple Myeloma, Myeloproliferative Disorders (Chronic), Nasal Cavity and Paranasal Sinus Cancer, Nasopharyngeal Cancer, Neuroblastoma, Non-Hodgkin Lymphoma, Non-Small Cell Lung Cancer, Oral Cancer, Oral Cavity Cancer, Lip and, Oropharyngeal Cancer, Osteosarcoma and Malignant Fibrous Histiocytoma of Bone, Ovarian Cancer (such as Epithelial, Germ Cell Tumor, Low
• Pancreatic Cancer including Islet Cell Tumors
• Papillomatosis including Islet Cell Tumors
• Paraganglioma including Islet Cell Tumors
• Paranasal Sinus and Nasal Cavity Cancer including Islet Cell Tumors
• Parathyroid Cancer including Islet Cell Tumors
• Penile Cancer Pharyngeal Cancer
• Pheochromocytoma Pineal Parenchymal Tumors of Intermediate Differentiation
• Embodiment 10 The method of Embodiment 8, wherein said cancer is chosen from high grade serous (HGSOC), epithelial, germ cell tumor, and low malignant potential tumor.
• HSSOC high grade serous
• epithelial epithelial
• germ cell tumor germ cell tumor
• low malignant potential tumor low malignant potential tumor
• Embodiment 11 The method of Embodiment 8, wherein said cancer is chosen from ovarian, skin, liver, prostate, breast, colon, lung, head and neck cancers and lymphoma.
• Embodiment 12 The method of Embodiment 11, wherein said cancer is ovarian cancer.
• Embodiment 13 The method of Embodiment 12, wherein said ovarian cancer is high-grade serous ovarian cancer (HGSOC).
• HGSOC high-grade serous ovarian cancer
• Embodiment 14 The method of Embodiment 13, wherein said ovarian cancer is nonresectable or relapsed HGSOC.
• Embodiment 15 The method of Embodiment 7, wherein said disorder is a tumor or tumors.
• Embodiment 16 The method of any one of Embodiments 1-15, wherein said low level of expression or concentration of ASNS is a low level of expression of ASNS.
• Embodiment 17 The method of Embodiment 16, wherein said tumor or tumors of said subject or subjects is characterized by a low level of expression of ASNS.
• Embodiment 18 The method of any one of Embodiments 1-15, wherein said low level of expression or concentration of ASNS is a low concentration of ASNS.
• Embodiment 19 The method of Embodiment 16, wherein which said tumor or tumors of said subject or subjects is characterized by a low concentration of ASNS.
• Embodiment 20 The method of either one of Embodiment 18 or 19, in which said concentration of ASNS is less than or equal to 150 by immunohistochemical staining.
• Embodiment 21 The method of either one of Embodiment 18 or 19, in which said concentration of ASNS is less than or equal to 125 by immunohistochemical staining.
• Embodiment 22 The method of either one of Embodiment 18 or 19, in which said concentration of ASNS is less than or equal to 100 by immunohistochemical staining.
• Embodiment 23 The method of either one of Embodiment 18 or 19, in which said concentration of ASNS is less than or equal to 95 by immunohistochemical staining.
• Embodiment 24 The method of either one of Embodiment 18 or 19, in which said concentration of ASNS is less than or equal to 90 by immunohistochemical staining.
• Embodiment 25 The method of either one of Embodiment 18 or 19, in which said concentration of ASNS is less than or equal to 85 by immunohistochemical staining.
• Embodiment 26 The method of either one of Embodiment 18 or 19, in which said concentration of ASNS is less than or equal to 80 by immunohistochemical staining.
• Embodiment 27 The method of either one of Embodiment 18 or 19, in which said concentration of ASNS is less than or equal to 75 by immunohistochemical staining.
• Embodiment 28 The method of either one of Embodiment 18 or 19, in which said concentration of ASNS is less than or equal to 70 by immunohistochemical staining.
• Embodiment 29 The method of either one of Embodiment 18 or 19, in which said concentration of ASNS is less than or equal to 65 by immunohistochemical staining.
• Embodiment 30 The method of either one of Embodiment 18 or 19, in which said concentration of ASNS is less than or equal to 60 by immunohistochemical staining.
• Embodiment 31 The method of either one of Embodiment 18 or 19, in which said concentration of ASNS is less than or equal to 55 by immunohistochemical staining.
• Embodiment 32 The method of either one of Embodiment 18 or 19, in which said concentration of ASNS is less than or equal to 50 by immunohistochemical staining.
• Embodiment 33 The method of either one of Embodiment 18 or 19, in which said concentration of ASNS is less than or equal to 45 by immunohistochemical staining.
• Embodiment 34 The method of either one of Embodiment 18 or 19, in which said concentration of ASNS is less than or equal to 40 by immunohistochemical staining.
• Embodiment 35 The method of either one of Embodiment 18 or 19, in which said concentration of ASNS is less than or equal to 35 by immunohistochemical staining.
• Embodiment 36 The method of either one of Embodiment 18 or 19, in which said concentration of ASNS is less than or equal to 30 by immunohistochemical staining.
• Embodiment 37 The method of either one of Embodiment 18 or 19, in which said concentration of ASNS is less than or equal to 25 by immunohistochemical staining.
• Embodiment 38 The method of either one of Embodiment 18 or 19, in which said concentration of ASNS is less than or equal to 20 by immunohistochemical staining.
• Embodiment 39 The method of either one of Embodiment 18 or 19, in which said concentration of ASNS is less than or equal to 15 by immunohistochemical staining.
• Embodiment 40 The method of either one of Embodiment 18 or 19, in which said concentration of ASNS is less than or equal to 10 by immunohistochemical staining.
• Embodiment 41 The method of any one of Embodiments 1-40, wherein said one or more glutathione lowering agents comprises one or more compounds that inhibit glutathione production or activity.
• Embodiment 42 The method of Embodiment 41, wherein said one or more glutathione lowering agents comprises one or more compounds that inhibit glutathione production.
• Embodiment 43 The method of Embodiment 41, wherein said one or more glutathione lowering agents comprises one or more compounds that inhibit glutathione activity.
• Embodiment 44 The method of any one of Embodiments 1-43, wherein said one or more glutathione lowering agents comprises one or more compounds that inhibits amino acid or glutathione transport.
• Embodiment 45 The method of Embodiment 44, wherein said one or more glutathione lowering agents comprises one or more compounds that inhibits amino acid transport.
• Embodiment 46 The method of Embodiment 44, wherein said one or more glutathione lowering agents comprises one or more compounds that inhibits glutathione transport.
• Embodiment 47 The method of any one of Embodiments 1-46, wherein said one or more glutathione lowering agents comprises one or more glutaminase inhibitor.
• Embodiment 48 The method of Embodiment 47, wherein said one or more glutaminase inhibitor comprises one or more GLS-1 inhibitors.
• Embodiment 49 The method of Embodiment 48, wherein said one or more GLS- 1 inhibitors comprises one or more selective GLS-1 inhibitors.
• Embodiment 50 The method of Embodiment 48, wherein said one or more glutathione lowering agents comprises one or more GLS-1 inhibitors chosen from the group consisting of: a) (S)-2-hydroxy-2-phenyl-N-(5-(4-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)- pyridazin-3-yl)butyl)-l ,3,4-thiadiazol-2-yl)acetamide,
• Embodiment 51 The method of Embodiment 48, wherein said one or more glutathione lowering agents comprises two or more GLS-1 inhibitors chosen from the group consisting of:
• Embodiment 52 The method of Embodiment 48, wherein said one or more glutathione lowering agents comprises (S)-2-hydroxy-2-phenyl-N-(5-(4-(6-(2-(3- (trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl)-l,3,4-thiadiazol-2-yl)acetamide, or a salt or polymorph thereof.
• Embodiment 53 The method of Embodiment 48, wherein said one or more glutathione lowering agents comprises N,N'-(5,5'-(2,2'-thiobis(ethane-2,l-diyl))bis(l,3,4- thiadiazole-5,2-diyl))bis(2-phenylacetamide), or a salt or polymorph thereof.
• Embodiment 54 The method of Embodiment 48, wherein said one or more glutathione lowering agents comprises (S)-2-hydroxy-2-(pyridin-2-yl)-N-(5-(4-(6-(2-(3- (trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl)-l,3,4-thiadiazol-2-yl)acetamide, or a salt or polymorph thereof.
• Embodiment 55 The method of Embodiment 48, wherein said one or more glutathione lowering agents comprises N,N'-(5,5'-(2,2'-sulfonylbis(ethane-2,l-diyl))bis(l,3,4- thiadiazole-5,2-diyl))bis(2-(pyridin-2-yl)acetamide), or a salt or polymorph thereof.
• Embodiment 56 The method of Embodiment 48, wherein said one or more glutathione lowering agents comprises N-methyl-l- ⁇ 4-[6-(2- ⁇ 4-[3-(trifluoromethoxy)- phenyl]pyridin-2-yl ⁇ acetamido)pyridazin-3-yl]butyl ⁇ -lH-l,2,3-triazole-4-carboxamide, or a salt or polymorph thereof.
• Embodiment 57 The method of Embodiment 48, wherein said one or more glutathione lowering agents comprises l-(2-fluoro-4-(5-(2-(pyridin-2-yl)acetamido)- 1,3,4- thiadiazol-2-yl)butyl)-N-((4-(trifluoromethyl)pyridin-2-yl)methyl)-lH-l,2,3-triazole-4- carboxamide, or a salt or polymorph thereof.
• Embodiment 58 The method of Embodiment 48, wherein said one or more glutathione lowering agents comprises l-(2-fluoro-4-(6-(2-(4-(trifluoromethyl)pyridin-2- yl)acetarmdo)pyridazin-3-yl)butyl)-N-methyl-lH-l,2,3 riazole-4-carboxamide, or a salt or polymorph thereof.
• Embodiment 59 The method of Embodiment 48, wherein said one or more glutathione lowering agents comprises N-(pyridin-2-ylmethyl)-5-(3-(6-(2-(3- (trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)pyrrolidin- 1 -yl)- 1 ,3,4-thiadiazole-2- carboxamide, or a salt or polymorph thereof.
• Embodiment 60 The method of Embodiment 48, wherein said one or more glutathione lowering agents comprises (R)-l-(2-fluoro-4-(6-(2-(4-(3-(trifluoromethoxy)- phenyl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-lH-l,2,3-triazole-4- carboxamide, or a salt or polymorph thereof.
• Embodiment 61 The method of Embodiment 48, wherein said one or more glutathione lowering agents comprises (R)-l-(2-fluoro-4-(6-(2-(4-(trifluoromethyl)pyridin-2- yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-lH-l,2,3 riazole-4-carboxamide, or a salt or polymorph thereof.
• Embodiment 62 The method of Embodiment 48, wherein said one or more glutathione lowering agents comprises (R)-l-(2-fluoro-4-(6-(2-(6-methyl-4- (trifluoromethyl)pyridin-2-yl)acetamido)pyridazin-3-yl)but l)-N-methyl-lH-l,2,3-triazole-4- carboxamide, or a salt or polymorph thereof.
• Embodiment 63 The method of Embodiment 48, wherein said one or more glutathione lowering agents comprises (R)-l-(4-(6-(2-(4-(cyclopropyldifluoromethyl)pyridin- 2-yl)acetainido)pyridazin-3-yl)-2-fluorobut l)-N-methyl-lH-l,2,3-triazole-4-carboxamide, or a salt or polymorph thereof.
• Embodiment 64 The method of Embodiment 48, wherein said one or more glutathione lowering agents comprises (R)-l-(4-(6-(2-(4-(3,3-difluorocyclobutoxy)pyridin-2- yl)acetainido)pyridazin-3-yl)-2-fluorobutyl)-N-methyl-lH-l,2,34riazole-4-carboxamide, or a salt or polymorph thereof.
• Embodiment 65 The method of Embodiment 48, wherein said one or more glutathione lowering agents comprises (R)-l-(2-fluoro-4-(6-(2-(l-(3-(trifluoromethoxy)- phenyl)-lH-imidazol-4-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-lH-l,2,3-triazole-4- carboxamide, or a salt or polymorph thereof.
• Embodiment 66 The method of Embodiment 48, wherein said one or more glutathione lowering agents comprises l-(4-(6-(2-(4-cyclobutoxypyridin-2-yl)acetamido)- pyridazin-3-yl)but l)-N-methyl-lH-l,2,3-triazole-4-carboxamide, or a salt or polymorph thereof.
• Embodiment 67 The method of Embodiment 48, wherein said one or more glutathione lowering agents comprises l-(4-(6-(2-(4-cyclobutoxypyridin-2-yl)acetamido)- pyridazin-3-yl)-2-fluorobutyl)-N-methyl-lH-l,2,3-triazole-4-carboxarnide, or a salt or polymorph thereof.
• Embodiment 68 The method of Embodiment 48, wherein said one or more glutathione lowering agents comprises l-(4-(6-(2-(4-(3,3-difluorocyclobutoxy)pyridin-2- yl)acetarmdo)pyridazin-3-yl)butyl)-N-methyl-lH-l,2,3 riazole-4-carboxamide, or a salt or polymorph thereof.
• Embodiment 69 The method of Embodiment 48, wherein said one or more glutathione lowering agents comprises l-(4-(6-(2-(4-(3,3-difluorocyclobutoxy)pyridin-2- yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-N-methyl-lH-l,2,3-triazole-4-carboxamide, or a salt or polymorph thereof.
• Embodiment 70 The method of Embodiment 48, wherein said one or more glutathione lowering agents comprises (R)-l-(4-(6-(2-(4-cyclopropylpyridin-2-yl)acetamido)- pyridazin-3-yl)-2-fluorobutyl)-N-methyl-lH-l,2,3-triazole-4-carboxarnide, or a salt or polymorph thereof.
• Embodiment 71 The method of Embodiment 48, wherein said one or more glutathione lowering agents comprises 5-(3-(6-(2-(pyridin-2-yl)acetamido)pyridazin-3- yl)pyrrolidin-l-yl)-N-((4-(trifluoromethyl)pyridin-2-yl)methyl)-l,3,4-thiadiazole-2- carboxamide, or a salt or polymorph thereof.
• Embodiment 72 The method of Embodiment 48, wherein said one or more glutathione lowering agents comprises N,N'-(5,5'-(cyclohexane-l,3-diyl)bis(l,3,4- thiadiazole-5,2-diyl))bis(2-phenylacetamide), or a salt or polymorph thereof.
• Embodiment 73 The method of Embodiment 48, wherein said one or more glutathione lowering agents comprises N,N'-(5,5'-((lS,3S)-cyclohexane-l,3-diyl)bis(l,3,4- thiadiazole-5,2-diyl))bis(2-phenylacetamide), or a salt or polymorph thereof.
• Embodiment 74 The method of Embodiment 48, wherein said one or more glutathione lowering agents comprises N,N'-(5,5'-((lR,3R)-cyclohexane-l,3-diyl)bis(l,3,4- thiadiazole-5,2-diyl))bis(2-phenylacetamide), or a salt or polymorph thereof.
• Embodiment 75 The method of Embodiment 48, wherein said one or more glutathione lowering agents comprises Compound 1 :
• Embodiment 76 The method of Embodiment 48, wherein said one or more glutathione lowering agents comprises Compound 2:
• Embodiment 77 The method of Embodiment 48, wherein said one or more glutathione lowering agents comprises a compound of Formula I:
• n is chosen from 3, 4, and 5;
• each R x and R y is independently chosen from alkyl, cyano, H, and halo, wherein two R x groups together with the atoms to which they are attached optionally form a cycloalkyl ring;
• a 1 and A 2 are independently chosen from C-H, C-F, and N;
• R 1 and R 4 are independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, hydroxyl, C(R ) 2 C(0)R 3 , C(R ) 2 C(0)N(R ) 2 , C(R ) 2 N(R ) 2 ,
• R 2 is chosen from alkyl, heterocycloalkyl, cyano, cycloalkyl, H, halo, and haloalkyl, wherein R 1 and R 2 together with the atoms to which they are attached optionally form an form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with between 0 and 3 R z groups;
• each R 3 is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, and hydroxyl, wherein each R 3 may be optionally substituted with between 0 and 3 R z groups, wherein two R 3 groups together with the atoms to which they are attached optionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with between 0 and 3 R z groups;
• each R z group is independently chosen from alkenyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl, alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, alkylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl, aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyan
• haloalkoxyheteroarylalkyl haloalkoxyheteroarylalkyl, haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl, haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl, haloalkylcycloalkylalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl, haloalkylheterocycloalkyl,
• haloalkylheterocycloalkylalkyl haloaryl, haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl, halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy,
• haloheteroaryl haloheteroarylalkyl, haloheteroarylalkyloxy, haloheteroaryloxy,
• haloheterocycloalkyl haloheterocycloalkylalkyl, haloheterocycloalkylalkyloxy,
• each R 6 is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, and hydroxyl, wherein two R 6 groups together with the atoms to which they are attached optionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with between 0 and 3 R x groups; and
• Z is heteroaryl, which may be optionally substituted.
• Embodiment 78 The method of Embodiment 77, wherein:
• Z 1 is chosen from C and N;
• Z 2 , Z 3 , and Z 4 are independently chosen from N, O, S, and CH, wherein at least one of Z 1 , Z 2 , Z 3 , and Z 4 is chosen from N, O, and S.
• Embodiment 79 The method of Embodiment 77, wherein:
• Z 1 is chosen from C and N;
• Z 2 is chosen from N, CH, and C(O);
• Z 3 , and Z 4 are independently chosen from N and CH, wherein at least one of Z 1 , Z 2 , Z 3 , and Z 4 is N;
• R 5 is chosen from alkyl, heterocycloalkyl, cyano, cycloalkyl, H, halo, and haloalkyl, wherein R 4 and R 5 together with the atoms to which they are attached optionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with between 0 and 3 R z groups.
• Embodiment 80 The method of Embodiment 48, wherein said one or more glutathione lowering agents comprises a compound of Formula II:
• n is chosen from 3, 4, and 5;
• each R x and R y is independently chosen from alkyl, cyano, H, and halo, wherein two R x groups together with the atoms to which they are attached optionally form a cycloalkyl ring;
• a 1 and A 2 are independently chosen from N and CH;
• a 3 is chosen from N and CR 2 ;
• R 1 is chosen from alkenyl, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl,
• R 1 may be optionally substituted with between 0 and 3 R z groups;
• R 2 is chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl,
• heterocycloalkylalkyl hydroxyl, C(0)N(R ) 2 , C(0)C(R ) 3 , C(0)OH, C(0)OC(R ) 3 , wherein R 1 and R 2 together with the atoms to which they are attached optionally form an form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with between 0 and 3 R z groups;
• each R 3 is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, and hydroxyl, wherein each R 3 may be optionally substituted with between 0 and 3 R z groups, wherein two R 3 groups together with the atoms to which they are attached optionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with between 0 and 3 R z groups;
• R 4 is chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl,
• heterocycloalkylalkyl hydroxyl, N(R ) 2 , NR C(0)C(R ) 3 , NR C(0)OC(R ) 3 ,
• R 4 may be optionally substituted with between 0 and 3 R z groups;
• each R z group is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, halo, haloalkyl, heteroaryl, heteroarylalkyl,
• heterocycloalkyl heterocycloalkylalkyl, hydroxyl, oxo, N(R 6 ) 2 , NR 6 C(0)C(R 6 ) 3 ,
• each R 6 is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, and hydroxyl, wherein two R 6 groups together with the atoms to which they are attached optionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with between 0 and 3 R x groups; and
• Embodiment 81 The method of Embodiment 80, wherein:
• Z 1 is chosen from C and N;
• Z 2 , Z 3 , and Z 4 are independently chosen from N, O, S, and CH, wherein at least one of Z 1 , Z 2 , Z 3 , and Z 4 is chosen from N, O, and S.
• Embodiment 82 The method of Embodiment 80, wherein:
• Z 2 is chosen from N, CH, and C(O);
• Z 3 , and Z 4 are independently chosen from N and CH, wherein at least one of Z 1 , Z 2 , Z 3 , and Z 4 is N;
• R 5 is chosen from alkyl, heterocycloalkyl, cyano, cycloalkyl, H, halo, and haloalkyl, wherein R 4 and R 5 together with the atoms to which they are attached optionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with between 0 and 3 R z groups.
• Embodiment 83 The method of Embodiment 48, wherein said one or more glutathione lowering agents comprises a compound of Formula III:
• n is chosen from 3, 4, and 5;
• each R x and R Y is independently chosen from alkyl, cyano, H, and halo, or two R x groups together with the atoms to which they are attached optionally form a cycloalkyl ring;
• a 1 is chosen from C and N;
• a 2 , A 3 , and A 4 are independently chosen from N, O, S, and CH, wherein at least one of A 1 , A 2 , A 3 , and A 4 is chosen from N, O, and S;
• R 1 and R 2 are each independently chosen from alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein R 1 and R 2 each may be optionally substituted with one to three R z groups, wherein R 1 and R 2 together with the atoms to which they are attached optionally form an heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with one to three R z groups;
• R 3 is chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl,
• heterocycloalkylalkyl hydroxyl, C(R 4 ) 2 C(0)R 4 , C(R 4 ) 2 C(0)N(R 4 ) 2 , C(R 4 ) 2 N(R 4 ) 2 ,
• each R 4 is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, and hydroxyl, wherein each R 4 may be optionally substituted with one to three R z groups, wherein two R 4 groups together with the atoms to which they are attached optionally form an heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with one to three R z groups;
• each R z group is independently chosen from alkenyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl, alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, alkylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl, aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyan
• haloalkoxyheteroarylalkyl haloalkoxyheteroarylalkyl, haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl, haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl, haloalkylcycloalkylalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl, haloalkylheterocycloalkyl,
• haloalkylheterocycloalkylalkyl haloaryl, haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl, halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy,
• haloheteroaryl haloheteroarylalkyl, haloheteroarylalkyloxy, haloheteroaryloxy, haloheterocycloalkyl, haloheterocycloalkylalkyl, haloheterocycloalkylalkyloxy,
• each R 5 is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein two R 5 groups together with the atoms to which they are attached optionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with one to three R x groups; and
• Z is a monocyclic heteroaryl, which may be optionally substituted.
• Embodiment 84 The method of Embodiment 83, wherein:
• Z 1 is chosen from C and N;
• Z 2 , Z 3 , and Z 4 are independently chosen from N, O, S, and CH, wherein at least one of Z 1 , Z 2 , Z 3 , and Z 4 is chosen from N, O, and S.
• Embodiment 85 The method of Embodiment 83, wherein:
• Z 2 is chosen from N and CH;
• Z 3 , and Z 4 are independently chosen from N and CH, wherein at least one of Z 1 , Z 2 , Z 3 , and Z 4 is N;
• R 6 is chosen from, alkyl, cyano, cycloalkyl, H, halo, haloalkyl, and heterocycloalkyl, wherein R 3 and R 6 groups together with the atoms to which they are attached optionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with one to three R z groups.
• Embodiment 86 The method of Embodiment 48, wherein said one or more glutathione lowering agents comprises a compound of Formula IIIc:
• R x is chosen from fiuoro and H;
• R 1 is chosen from alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein R 1 may be optionally substituted with one to three R z groups;
• each R 4 is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, and hydroxyl, wherein R 4 may be optionally substituted with one to three R z groups;
• each R z group is independently chosen from alkenyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl, alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, alkylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl, aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyan
• haloalkoxyheteroarylalkyl haloalkoxyheteroarylalkyl, haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl, haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl, haloalkylcycloalkylalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl, haloalkylheterocycloalkyl,
• haloalkylheterocycloalkylalkyl haloaryl, haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl, halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy,
• haloheteroaryl haloheteroarylalkyl, haloheteroarylalkyloxy, haloheteroaryloxy,
• haloheterocycloalkyl haloheterocycloalkylalkyl, haloheterocycloalkylalkyloxy,
• each R 5 is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein two R 5 groups together with the atoms to which they are attached optionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with one to three R x groups.
• Embodiment 87 The method of Embodiment 86, wherein R 1 is methyl.
• Embodiment 88 The method of Embodiment 48, wherein said one or more glutathione lowering agents comprises a compound of Formula IIIc-1 :
• R x is chosen from fluoro and H
• R 1 is chosen from alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein R 1 may be optionally substituted with one to three R z groups;
• each R 4 is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, and hydroxyl, wherein R 4 may be optionally substituted with one to three R z groups;
• each R z group is independently chosen from alkenyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl, alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, alkylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl, aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyan
• haloalkoxyheteroarylalkyl haloalkoxyheteroarylalkyl, haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl, haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl, haloalkylcycloalkylalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl, haloalkylheterocycloalkyl,
• haloalkylheterocycloalkylalkyl haloaryl, haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl, halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy,
• haloheteroaryl haloheteroarylalkyl, haloheteroarylalkyloxy, haloheteroaryloxy,
• haloheterocycloalkyl haloheterocycloalkylalkyl, haloheterocycloalkylalkyloxy,
• each R 5 is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein two R 5 groups together with the atoms to which they are attached optionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with one to three R x groups.
• Embodiment 89 The method of Embodiment 48, wherein said one or more glutathione lowering agents comprises a compound of Formula IIIc-2:
• R x is chosen from fluoro and H
• R 1 is chosen from alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein R 1 may be optionally substituted with one to three R z groups; each R 4 is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, and hydroxyl, wherein R 4 may be optionally substituted with one to three R z groups;
• each R z group is independently chosen from alkenyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl, alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, alkylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl, aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyan
• haloalkoxyheteroarylalkyl haloalkoxyheteroarylalkyl, haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl, haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl, haloalkylcycloalkylalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl, haloalkylheterocycloalkyl,
• haloalkylheterocycloalkylalkyl haloaryl, haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl, halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy,
• haloheteroaryl haloheteroarylalkyl, haloheteroarylalkyloxy, haloheteroaryloxy,
• haloheterocycloalkyl haloheterocycloalkylalkyl, haloheterocycloalkylalkyloxy,
• each R 5 is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein two R 5 groups together with the atoms to which they are attached optionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with one to three R x groups.
• Embodiment 90 The method of Embodiment 48, wherein said one or more glutathione lowering agents comprises a compound of Formula Hid:
• R x is chosen from fiuoro and H;
• each of R Z1 and R Z2 is independently chosen from alkenyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxy cycloalkyl, alkoxy cycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl, alkoxyheterocycloalkyl,
• alkoxyheterocycloalkylalkyl alkyl, alkylaryl, alkylarylalkyl, alkylcycloalkyl,
• haloalkoxyheterocycloalkyl haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl, haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl, haloalkylcycloalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl, haloalkylheterocycloalkyl, haloalkylheterocycloalkylalkyl, haloaryl, haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl, halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy, haloheteroaryl, haloheteroarylal
• haloheteroarylalkyloxy haloheteroaryloxy, haloheteroaryloxy, haloheterocycloalkyl, haloheterocycloalkylalkyl, haloheterocycloalkylalkyloxy, haloheterocycloalkyloxy, heteroaryl, heteroarylalkyl, heteroarylhaloalkyl, heteroaryloxy, heterocycloalkyl,
• heterocycloalkylalkyl heterocycloalkylalkyloxy, heterocycloalkylhaloalkyl
• heterocycloalkyloxy hydroxyl, and oxo.
• Embodiment 91 The method of Embodiment 90, wherein:
• R x is chosen from fiuoro and H.
• each of R Z1 and R Z2 is independently chosen from alkyl, cycloalkyl,
• cycloalkylhaloalkyl cycloalkyloxy, H, haloalkoxy, haloalkoxyaryl, haloalkyl,
• Embodiment 92 The method of Embodiment 90, wherein: R x is chosen from fluoro and H; and e 3 ⁇ 4. cp3 ,
• Embodiment 93 The method of Embodiment 48, wherein said one or more glutathione lowering agents comprises a compound of Formula Hie:
• R x is chosen from fluoro and H
• R Z1 is chosen from alkenyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl, alkoxy cycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl,
• alkoxyheteroarylalkyl alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, alkylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl, aryl, arylalkyloxy, arylhaloalkyl, aryloxy, cyano, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, cycloalkylhaloalkyl, cycloalkyloxy, H, halo, haloalkoxy, haloalkoxyalkyl, haloalkoxyaryl, haloalk
• haloalkoxyheteroarylalkyl haloalkoxyheteroarylalkyl, haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl, haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl, haloalkylcycloalkylalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl, haloalkylheterocycloalkyl,
• haloalkylheterocycloalkylalkyl haloaryl, haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl, halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy,
• haloheteroaryl haloheteroarylalkyl, haloheteroarylalkyloxy, haloheteroaryloxy,
• haloheterocycloalkyl haloheterocycloalkylalkyl, haloheterocycloalkylalkyloxy,
• Embodiment 94 The method of any one of Embodiments 48-50 and 52-93, wherein said one or more glutathione lowering agents comprises exactly one GLS-1 inhibitor.
• Embodiment M-l A method of treating cancer in a subject whose cancer cells express low levels of asparagine synthetase (ASNS), as defined by an Histophathology Score (H-score) of less than or equal to 100 by immunohistochemical staining, comprising administering a glutaminase-1 (GLS-1) inhibitor to said subject.
• ASNS asparagine synthetase
• H-score Histophathology Score
• Embodiment M-2 A method of treating a subject having a cancer or a tumor in need of treatment comprising:
• Embodiment M-3 The method of Embodiment M-2, wherein the tumor is cancerous.
• Embodiment M-4 The method of Embodiment M-l or Embodiment M-3, wherein the cancer is: bladder cancer, bone marrow cancer, breast cancer, cancer of the central nervous system, cervical cancer, colon cancer, endometrial cancer, cancer of the gastric system, head and neck cancer, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, muscle cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, thyroid cancer, or a variant thereof.
• the cancer is: bladder cancer, bone marrow cancer, breast cancer, cancer of the central nervous system, cervical cancer, colon cancer, endometrial cancer, cancer of the gastric system, head and neck cancer, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, muscle cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, thyroid cancer, or a variant thereof.
• Embodiment M-5 The method of Embodiment M-4, wherein the cancer is ovarian, skin, liver, prostate, breast, colon, lung, head and neck cancers or a lymphoma.
• Embodiment M-6 The method of Embodiment M-4, wherein the cancer is ovarian cancer.
• Embodiment M-7 The method of Embodiment M-6, wherein the ovarian cancer is high-grade serous ovarian cancer (HGSOC).
• HGSOC high-grade serous ovarian cancer
• Embodiment M-8 The method of Embodiment M-7, wherein the ovarian cancer is nonresectable or relapsed HGSOC.
• Embodiment M-9 The method of Embodiment M-l or Embodiment M-2, wherein the GLS-1 inhibitor is a selective inhibitor of GLS-1.
• Embodiment M-10 The method of Embodiment M-l or Embodiment M-2, wherein the GLS-1 inhibitor binds an allosteric pocket on the solvent exposed region of the GLS-1 dimer in the binding pocket present in the vicinity of Leu321, Phe322, Leu323, and Tyr394 from both monomers.
• Embodiment M-ll The method of Embodiment M-l or Embodiment M-2, wherein the GLS-1 inhibitor is selected from the list of compounds p rovided in Table 1.
• Embodiment M-12 The method of Embodiment M-l or Embodiment M-2, wherein the GLS-1 inhibitor is compound 1 or compound 2.
• Embodiment M-13 The method of claim Embodiment M-l or Embodiment M-2, wherein the subject is human.
• Embodiment M-14 The method of claim Embodiment M-l or Embodiment M-3, further comprising administering another pharmaceutically active compound.
• Embodiment M-15 The method of claim Embodiment M-14, wherein the other pharmaceutically active compound is an anti-cancer agent.
• Embodiment M-16 The method of claim Embodiment M-15, wherein the anticancer agent is chosen from a platinum-based agent, a taxane-based agent, an
• Embodiment M-17 The method of claim Embodiment M-15, wherein the targeted therapy is an inhibitor of MEK kinase, HSP90, CDK4, or the mTOR pathway.
• Embodiment M-18 The method of claim Embodiment M-l or Embodiment M-3, wherein the method further comprises administering non-chemical methods of cancer treatment.
• Embodiment M-19 The method of Embodiment M-18, wherein the method further comprises administering radiation therapy.
• Embodiment M-20 The method of Embodiment M-18, wherein the method further comprises administering surgery, thermoablation, focused ultrasound therapy, cryotherapy, or any combination thereof.
• a GLS-1 inhibitor or a compound that inhibits glutathione production for use as a medicament in the treatment of a disorder, for example, a tumor or cancer, in need of treatment, in a subject in whose tumors or cancer cells the concentration or expression level of ASNS is low.
• the tumor is cancerous and the concentration or expression level of ASNS in the tumor of the subject is low.
• the cancer may be any one of the types of cancers provided below.
• the cancer is ovarian, skin, liver, prostate, breast, colon, lung, head and neck cancers or a lymphoma.
• the cancer is ovarian cancer, for example HGSOC, Epithelial, Germ Cell Tumor, and Low Malignant Potential Tumor.
• GLS-1 inhibitor or a compound that inhibits glutathione production for use in the manufacture of a medicament for the treatment of a disorder in need of treatment, in a subject subject in whose tumor or cancer cells the concentration or expression level of ASNS is low.
• the disorder is a cancer.
• the cancer may be any cancer now known, or later discovered, including, but not limited to, Acute Lymphoblastic
• ALL Leukemia
• AML Acute Myeloid Leukemia
• Adrenocortical Carcinoma AIDS- Related Cancers
• Anal Cancer Appendix Cancer, Atypical Teratoid/Rhabdoid Tumor, Basal Cell Carcinoma, Bile Duct Cancer (including Extrahepatic), Bladder Cancer, Bone Cancer (including Osteosarcoma and Malignant Fibrous
• Brain Tumor such as Astrocytomas, Brain and Spinal Cord Tumors, Brain Stem Glioma, Central Nervous System Atypical Teratoid/Rhabdoid Tumor, Central Nervous System Embryonal Tumors, Craniopharyngioma, Ependymoblastoma, Ependymoma, Medulloblastoma, Medulloepithelioma, Pineal Parenchymal Tumors of Intermediate
• Brain Tumor such as Astrocytomas, Brain and Spinal Cord Tumors, Brain Stem Glioma, Central Nervous System Atypical Teratoid/Rhabdoid Tumor, Central Nervous System Embryonal Tumors, Craniopharyngioma, Ependymoblastoma, Ependymoma, Medulloblastoma, Medulloepithelioma, Pineal Parenchymal Tumors of Intermediate
• Lymphoma Mycosis Fungoides and Sezary Syndrome
• Duct Bile (Extrahepatic)
• Ductal Carcinoma In situ DCIS
• Embryonal Tumors Central Nervous System
• Endometrial Cancer Ependymoblastoma, Ependymoma, Esophageal Cancer, Esthesioneuroblastoma, Ewing Sarcoma Family of Tumors, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, Eye Cancer (like Intraocular Melanoma,
• Retinoblastoma Fibrous Histiocytoma of Bone (including Malignant and Osteosarcoma), Gallbladder Cancer, Gastric (Stomach) Cancer, Gastrointestinal Carcinoid Tumor,
• Gastrointestinal Stromal Tumors GIST
• Germ Cell Tumor Extracranial, Extragonadal, Ovarian
• Gestational Trophoblastic Tumor Glioma, Hairy Cell Leukemia, Head and Neck Cancer, Heart Cancer, Hepatocellular (Liver) Cancer, Histiocytosis, Langerhans Cell, Hodgkin Lymphoma, Hypopharyngeal Cancer, Intraocular Melanoma, Islet Cell Tumors (Endocrine, Pancreas), Kaposi Sarcoma, Kidney (including Renal Cell), Langerhans Cell Histiocytosis, Laryngeal Cancer, Leukemia (including Acute Lymphoblastic (ALL), Acute Myeloid (AML), Chronic Lymphocytic (CLL), Chronic Myelogenous (CML), Hairy Cell), Lip and Oral Cavity Cancer, Liver Cancer (Primary), Lobular Carcinoma In Situ (LCIS), Lung Cancer (Non-Small Cell and Small Cell
• Cutaneous T-Cell Mycosis Fungoides and Sezary Syndrome
• Hodgkin Non-Hodgkin
• Primary Central Nervous System CNS
• Macroglobulinemia Waldenstrom, Male Breast Cancer
• Malignant Fibrous Histiocytoma of Bone and Osteosarcoma Medulloblastoma, Medulloepithelioma, Melanoma (including Intraocular (Eye)), Merkel Cell Carcinoma, Mesothelioma (Malignant), Metastatic Squamous Neck Cancer with Occult Primary, Midline Tract Carcinoma Involving NUT Gene, Mouth Cancer, Multiple Endocrine Neoplasia Syndromes, Multiple Myeloma/Plasma Cell Neoplasm, Mycosis Fungoides, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Neoplasms, Myelogenous Leukemia, Chronic (CML), Myeloid Leukemia, A
• Nasopharyngeal Cancer Neuroblastoma, Non-Hodgkin Lymphoma, Non-Small Cell Lung Cancer, Oral Cancer, Oral Cavity Cancer, Lip and, Oropharyngeal Cancer, Osteosarcoma and Malignant Fibrous Histiocytoma of Bone, Ovarian Cancer (such as Epithelial, Germ Cell Tumor, Low Malignant Potential Tumor and High Grade Serous Ovarian Cancer), Pancreatic Cancer (including Islet Cell Tumors), Papillomatosis, Paraganglioma, Paranasal Sinus and Nasal Cavity Cancer, Parathyroid Cancer, Penile Cancer, Pharyngeal Cancer,
• Ovarian Cancer such as Epithelial, Germ Cell Tumor, Low Malignant Potential Tumor and High Grade Serous Ovarian Cancer
• Pancreatic Cancer including Islet Cell Tumors
• Papillomatosis Paraganglioma, Paranasal Sinus and Nasal Cavity Cancer, Parathyroid Cancer, Penile Cancer
• Retinoblastoma Retinoblastoma, Rhabdomyosarcoma, Salivary Gland Cancer, Sarcoma (like Ewing Sarcoma Family of Tumors, Kaposi, Soft Tissue, Uterine), Sezary Syndrome, Skin Cancer (such as Melanoma, Merkel Cell Carcinoma, Nonmelanoma), Small Cell Lung Cancer, Small Intestine Cancer, Soft Tissue Sarcoma, Squamous Cell Carcinoma, Squamous Neck Cancer with Occult Primary, Metastatic, Stomach (Gastric) Cancer, Supratentorial Primitive
• Neuroectodermal Tumors T-Cell Lymphoma (Cutaneous, Mycosis Fungoides and Sezary Syndrome), Testicular Cancer, Throat Cancer, Thymoma and Thymic Carcinoma, Thyroid Cancer, Transitional Cell Cancer of the Renal Pelvis and Ureter, Trophoblastic Tumor (Gestational), Unknown Primary, Unusual Cancers of Childhood, Ureter and Renal Pelvis, Transitional Cell Cancer, Urethral Cancer, Uterine Cancer, Endometrial, Uterine Sarcoma, Waldenstrom Macroglobulinemia and Wilms Tumor, or a variant thereof.
• the cancer is ovarian, skin, liver, prostate, breast, colon, lung, head and neck cancers, a lymphoma, or a variant thereof.
• the cancer is ovarian cancer.
• the cancer is high-grade serous ovarian cancer (HGSOC).
• the cancer is nonresectable or relapsed HGSOC.
• the invention comprises a method of treating a tumor or a cancer in a subject whose tumor or cancer cells express low levels of ASNS comprising administering a glutaminase inhibitor to said subject.
• the level of ASNS as measured by immunohistochemistry is quantified with an H-score of less than or equal to 100.
• the cancer may be any of the cancers listed above.
• the cancer is ovarian, skin, liver, prostate, breast, colon, lung, head and neck cancers or a lymphoma.
• the cancer is ovarian cancer, for example, high-grade serous ovarian cancer (HGSOC).
• the cancer is nonresectable or relapsed HGSOC.
• GLS-1 reduces the steady state levels of glutathione, thus shifting the redox balance of the cells. This inhibits cell growth through a mechanism that involves reactive oxygen species (ROS)-induced DNA damage.
• ROS reactive oxygen species
• Asparagine synthetase or ASNS or aspartate- ammonia ligase is a chiefly cytoplasmic enzyme that generates asparagine from aspartate, while converting glutamine to glutamate. Attempts to reduce cellular levels of glutamate (and ultimately glutathione) by GLS-1 inhibitors would have little, or no, overall effect if the reduction is countered through the activity of ASNS, and ASNS-derived glutamate to produce glutathione.
• the levels of ASNS must be below certain levels.
• the level of ASNS is quantified by immunohistochemistry and calculated as an H-score. An H-score of 0 - 100 (inclusive) or less than or equal to 100 would indicate response to GLS inhibition.
• H-score Calculation of a Histophathology Score or H-score is known to one of skill in the art.
• expression of ASNS protein in tumor cells is detected or measured, for example, using microscopy and immunohistochemistry (IHC) and the H-score is determined therefrom. Based on the intensity of staining, the sample is, for example, scored at 4 different levels, on a scale of 0 to 3+, for ASNS protein expression.
• IHC immunohistochemistry
• H-score is used to mean an immunohistology score for ASNS expression in a tumor sample.
• the degree of IHC staining, if any, in each subcellular compartment in tumor cells is captured for ASNS.
• the degree or intensity of staining is classified into 4 levels that are assigned a score from 0 (no staining) to 3+ (greatest degree or most intense staining).
• This algorithm includes capturing the percentage of tumor cells stained at each intensity level. A semi-quantitative intensity scale ranging from 0 for no staining, to 3+ for the most intense staining, is used. All of this information is used to calculate the H-Score. This score is more representative of the staining of the entire tumor on the section. Although given sections may share the same simple intensity score, there is a difference between a 3+ case with only 10% of the cells staining as compared to a 3+ case where greater than 90% of the cells are staining. This difference is easily picked up using the H-Score method.
• the H-score is less than or equal to 150. In another embodiment, the H- score is 0 - 125 (both inclusive). In another embodiment, the H-score is less than or equal to 125. In some embodiments, the H-score is 0 - 100 (both inclusive). In some embodiments, the H-score is less than or equal to 100. In some embodiments, the H-score is less than 100.
• the H-score is less than or equal to 95. In some embodiments, the H-score is less than or equal to 90. In some embodiments, the H-score is less than or equal to 85. In some embodiments, the H-score is less than or equal to 80. In some embodiments, the H-score is less than or equal to 75. In some embodiments, the H scose is less than or equal to 70. In some embodiments, the H-score is less than or equal to 65. In some embodiments, the H-score is less than or equal to 60. In some embodiments, the H-score is less than or equal to 55. In some embodiments, the H-score is less than or equal to 50.
• the H-score is less than or equal to 45. In some embodiments, the H-score is less than or equal to 40. In some embodiments, the H-score is less than or equal to 35. In some embodiments, the H-score is less than or equal to 30. In some embodiments, the H-score is less than or equal to 25. In some embodiments, the H-score is less than or equal to 20. In some embodiments, the H-score is less than or equal to 15. In some embodiments, the H-score is less than or equal to 10.
• the GLS li is a selective inhibitor of GLS-1.
• the GLS li binds an allosteric pocket on the solvent exposed region of the GLS-1 dimer in the binding pocket present in the vicinity of Leu321 , Phe322, Leu323, and Tyr394 from both monomers.
• the GLS li is compound 1. In certain embodiments, the GLS li is compound 2. In certain embodiments, the GLS-1 inhibitor is selected from the list of compounds provided in Table 1 below. In certain embodiments, the compound is chosen from any combination of the compounds provided in Table 1, or a salt or polymorph thereof. For example, in certain embodiments, the GLS li is chosen from any two, three, four, five, six, seven, eight, none or ten of the compounds provided in Table 1 , or a salt or polymorph thereof.
• the subj ect is human.
• methods disclosed herein further comprise administering another pharmaceutically active compound.
• the disorder to be treated is a cancer and the other pharmaceutically active compound is an anti-cancer agent.
• the anti-cancer agent is a chosen from a platinum-based agent, a taxane-based agent, an immunotherapy, an immune-oa targeted therapy.
• the targeted therapy is an inhibitor of MEK kinase, HSP90, CDK4, or the mTOR pathway.
• methods disclosed herein further comprise administering non-chemical methods of cancer treatment.
• the method further comprises administering radiation therapy.
• the method further comprises administering surgery, thermoablation, focused ultrasound therapy, cryotherapy, or any combination thereof.
• methods disclosed herein administer the active agent (e.g., a compound that inhibits glutathione production, glutaminase-1 inhibitor, or selective GLS li) as a pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier.
• the pharmaceutical composition is formulated for oral administration.
• pharmaceutical composition is formulated as a tablet or capsule.
• the pharmaceutical composition is formulated for parenteral administration.
• any embodiment disclosed herein may be combined with any one or more of these embodiments to form a new compound or class of compounds, or pharmaceutical composition comprising it, or method of use employing it, provided the combination is not mutually exclusive.
• a combination embodiment wherein the subject is human and the disorder in need of treatment is cancer is valid because the recited limitations are not mutually exclusive.
• the term "and/or" when used in a list of two or more items, means that any one of the listed items can be employed by itself or in combination with any one or more of the listed items.
• the expression “A and/or B” is intended to mean either or both of A and B, i.e. , A alone, B alone or A and B in combination.
• the expression “A, B and/or C” is intended to mean A alone, B alone, C alone, A and B in combination, A and C in
• disease as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder,” “syndrome,” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.
• combination therapy means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.
• GLS-1 inhibitor and “GLSli” are used interchangeably herein to refer to a compound that exhibits an IC50 with respect to GLS-1 activity of no more than about 100 ⁇ and more typically not more than about 50 ⁇ , as measured in the GLS-1 enzyme assay described generally herein below.
• IC50 is that concentration of inhibitor that reduces the activity of an enzyme (e.g. , GLS-1) to half-maximal level. Certain compounds disclosed herein have been discovered to exhibit inhibition against GLS-1.
• compounds will exhibit an IC50 with respect to GLS-1 of no more than about 10 ⁇ ; in further embodiments, compounds will exhibit an IC50 with respect to GLS-1 of no more than about 5 ⁇ ; in yet further embodiments, compounds will exhibit an IC50 with respect to GLS-1 of not more than about 1 ⁇ ; in yet further embodiments, compounds will exhibit an IC50 with respect to GLS-1 of not more than about 200 nM, as measured in the GLS-1 enzymatic assay described herein.
• inhibitor selective for GLS-1 and a “selective inhibitor of GLS-1” are used interchangeably herein and refer to inhibitors that are about 100 times more selective for GLS-1 than for GLS-2 as measured in any assay known to one of skill in the art that measures the activity of the enzyme.
• An example of such an assay includes, but is not limited to, the GLS-1 enzyme assay (GLS-1 Enzymatic Activity Assay) described below.
• glutathione lowering agent is used herein to refer to a compound that reduces glutathione levels.
• the glutathione lowering agent inhibits amino acid or glutathione transport.
• the glutathione lowering agent inhibits amino acid or glutathione activity.
• the compound is a glutaminase inhibitor.
• the glutathione lowering agent is a GLS-1 inhibitor.
• terapéuticaally acceptable refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
• treatment of a patient is intended to include prevention, prophylaxis, attenuation, amelioration and therapy. Treatment may also include prevention of disease. Prevention of a disease may involve complete protection from disease, for example as in the case of prevention of infection with a pathogen, or may involve prevention of disease progression. For example, prevention of a disease may not mean complete foreclosure of any effect related to the diseases at any level, but instead may mean prevention of the symptoms of a disease to a clinically significant or detectable level.
• Prevention of diseases may also mean prevention of progression of a disease to a later stage of the disease.
• subject and “patient” are used interchangeably herein to mean all mammals including humans. Examples of subjects include, but are not limited to, humans, monkeys, dogs, cats, horses, cows, goats, sheep, pigs, and rabbits. In one embodiment, the patient is a human.
• acyl refers to a carbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, or any other moiety were the atom attached to the carbonyl is carbon.
• An “acetyl” group refers to a -C(0)CH3 group.
• An “alkylcarbonyl” or “alkanoyl” group refers to an alkyl group attached to the parent molecular moiety through a carbonyl group. Examples of such groups include
• acyl groups include formyl, alkanoyl and aroyl.
• alkenyl refers to a straight- chain or branched-chain hydrocarbon radical having one or more double bonds and containing from 2 to 20 carbon atoms. In certain embodiments, the alkenyl will comprise from 2 to 6 carbon atoms.
• alkenyl radicals examples include ethenyl, propenyl, 2-methylpropenyl, 1,4- butadienyl and the like. Unless otherwise specified, the term "alkenyl" may include
• alkenylene groups.
• alkoxy refers to an alkyl ether radical, wherein the term alkyl is as defined below.
• suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like.
• alkyl refers to a straight- chain or branched-chain alkyl radical containing from 1 to 20 carbon atoms. In certain embodiments, the alkyl will comprise from 1 to 10 carbon atoms. In further embodiments, the alkyl will comprise from 1 to 6 carbon atoms. Alkyl groups may be optionally substituted as defined herein.
• alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, noyl and the like.
• alkylene refers to a saturated aliphatic group derived from a straight or branched chain saturated hydrocarbon attached at two or more positions, such as methylene (-CH2-). Unless otherwise specified, the term “alkyl” may include “alkylene” groups.
• alkylamino refers to an alkyl group attached to the parent molecular moiety through an amino group. Suitable alkylamino groups may be mono- or dialkylated, forming groups such as, for example, N-methylamino, N-ethylamino, N,N-dimethylamino, ⁇ , ⁇ -ethylmethylamino and the like.
• alkylidene refers to an alkenyl group in which one carbon atom of the carbon-carbon double bond belongs to the moiety to which the alkenyl group is attached.
• alkylthio refers to an alkyl thioether (R-S-) radical wherein the term alkyl is as defined above and wherein the sulfur may be singly or doubly oxidized.
• suitable alkyl thioether radicals include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like.
• alkynyl refers to a straight- chain or branched chain hydrocarbon radical having one or more triple bonds and containing from 2 to 20 carbon atoms. In certain embodiments, the alkynyl comprises from 2 to 6 carbon atoms. In further embodiments, the alkynyl comprises from 2 to 4 carbon atoms.
• alkynylene refers to a carbon-carbon triple bond attached at two positions such as ethynylene (-C: : :C-, -C ⁇ C-).
• alkynyl radicals examples include ethynyl, propynyl, hydroxypropynyl, butyn-l -yl, butyn-2-yl, pentyn-l-yl, 3-methylbut n-l-yl, hexyn-2-yl, and the like.
• alkynyl may include "alkynylene” groups.
• acylamino as used herein, alone or in combination, embraces an acyl group attached to the parent moiety through an amino group.
• An example of an “acylamino” group is acetylamino (CH3C(0)NH-).
• amino refers to— NRR', wherein R and R' are independently selected from the group consisting of hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may themselves be optionally substituted. Additionally, R and R' may combine to form heterocycloalkyl, either of which may be optionally substituted.
• aryl as used herein, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such poly cyclic ring systems are fused together.
• aryl embraces aromatic groups such as phenyl, naphthyl, anthracenyl, and phenanthryl.
• arylalkenyl or “aralkenyl,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkenyl group.
• arylalkoxy or “aralkoxy,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkoxy group.
• arylalkyl or “aralkyl,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkyl group.
• arylalkynyl or “aralkynyl,” as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkynyl group.
• arylalkanoyl or “aralkanoyl” or “aroyl,” as used herein, alone or in combination, refers to an acyl radical derived from an aryl-substituted alkanecarboxylic acid such as benzoyl, napthoyl, phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4- phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like.
• aryloxy refers to an aryl group attached to the parent molecular moiety through an oxy.
• carbamate refers to an ester of carbamic acid (-NHCOO-) which may be attached to the parent molecular moiety from either the nitrogen or acid end, and which may be optionally substituted as defined herein.
• 0-carbamyl as used herein, alone or in combination, refers to a -OC(0)NRR', group with R and R' as defined herein.
• N-carbamyl as used herein, alone or in combination, refers to a ROC(0)NR'- group, with R and R' as defined herein.
• carbonyl when alone includes formyl [-C(0)H] and in combination is a -C(O)- group.
• carboxyl or “carboxy,” as used herein, refers to -C(0)OH or the corresponding “carboxylate” anion, such as is in a carboxylic acid salt.
• An "O-carboxy” group refers to a RC(0)0- group, where R is as defined herein.
• a “C-carboxy” group refers to a -C(0)OR groups where R is as defined herein.
• cycloalkyl or, alternatively, “carbocycle,” as used herein, alone or in combination, refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl group wherein each cyclic moiety contains from 3 to 12 carbon atom ring members and which may optionally be a benzo fused ring system which is optionally substituted as defined herein.
• the cycloalkyl will comprise from 5 to 7 carbon atoms.
• cycloalkyl groups examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronapthyl, indanyl, octahydronaphthyl, 2,3-dihydro-lH- indenyl, adamantyl and the like.
• "Bicyclic” and "tricyclic” as used herein are intended to include both fused ring systems, such as decahydronaphthalene, octahydronaphthalene as well as the multicyclic (multicentered) saturated or partially unsaturated type. The latter type of isomer is exemplified in general by, bicyclo[l,l,l]pentane, camphor, adamantane, and bicyclo[3,2,l]octane.
• esters refers to a carboxy group bridging two moieties linked at carbon atoms.
• ether refers to an oxy group bridging two moieties linked at carbon atoms.
• halo or halogen
• haloalkoxy refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.
• haloalkyl refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals.
• a monohaloalkyl radical for one example, may have an iodo, bromo, chloro or fluoro atom within the radical.
• Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals.
• haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,
• dichlorofluoromethyl difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
• Haloalkylene refers to a haloalkyl group attached at two or more positions. Examples include fiuoromethylene
• heteroalkyl refers to a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, fully saturated or containing from 1 to 3 degrees of unsaturation, consisting of the stated number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
• the heteroatom(s) O, N and S may be placed at any interior position of the heteroalkyl group. Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3.
• heteroaryl refers to a 3 to 15 membered unsaturated heteromonocyclic ring, or a fused monocyclic, bicyclic, or tricyclic ring system in which at least one of the fused rings is aromatic, which contains at least one atom selected from the group consisting of O, S, and N.
• the heteroaryl will comprise from 5 to 7 carbon atoms.
• the term also embraces fused poly cyclic groups wherein heterocyclic rings are fused with aryl rings, wherein heteroaryl rings are fused with other heteroaryl rings, wherein heteroaryl rings are fused with heterocycloalkyl rings, or wherein heteroaryl rings are fused with cycloalkyl rings.
• heteroaryl groups include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, benzothienyl, chromonyl,
• tetrazolopyridazinyl tetrahydroisoquinolinyl
• thienopyridinyl furopyridinyl
• pyrrolopyridinyl exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl and the like.
• heterocycloalkyl and, interchangeably, “heterocycle,” as used herein, alone or in combination, each refer to a saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic, or tricyclic heterocyclic group containing at least one heteroatom as a ring member, wherein each the heteroatom may be independently selected from the group consisting of nitrogen, oxygen, and sulfur
• the hetercycloalkyl will comprise from 1 to 4 heteroatoms as ring members.
• the hetercycloalkyl will comprise from 1 to 4 heteroatoms as ring members.
• hetercycloalkyl will comprise from 1 to 2 heteroatoms as ring members. In certain embodiments, the hetercycloalkyl will comprise from 3 to 8 ring members in each ring. In further embodiments, the hetercycloalkyl will comprise from 3 to 7 ring members in each ring. In yet further embodiments, the hetercycloalkyl will comprise from 5 to 6 ring members in each ring.
• Heterocycloalkyl and “heterocycle” are intended to include sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclic fused and benzo fused ring systems; additionally, both terms also include systems where a heterocycle ring is fused to an aryl group, as defined herein, or an additional heterocycle group.
• heterocycle groups include aziridinyl, azetidinyl, 1 ,3 -benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[l ,3]oxazolo[4,5- bjpyridinyl, benzothiazolyl, dihydroindolyl, dihy-dropyridinyl, 1 ,3-dioxanyl, 1 ,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like.
• the heterocycle groups may be optionally substituted unless specifically prohibited.
• hydrazinyl as used herein, alone or in combination, refers to two amino groups joined by a single bond, i.e., -N-N-.
• hydroxyalkyl refers to a hydroxy group attached to the parent molecular moiety through an alkyl group.
• isocyanato refers to a -NCO group.
• isothiocyanato refers to a -NCS group.
• linear chain of atoms refers to the longest straight chain of atoms independently selected from carbon, nitrogen, oxygen and sulfur.
• lower aryl as used herein, alone or in combination, means phenyl or naphthyl, either of which may be optionally substituted as provided.
• lower heteroaryl means either 1) monocyclic heteroaryl comprising five or six ring members, of which between one and four the members may be heteroatoms selected from the group consisting of O, S, and N, or 2) bicyclic heteroaryl, wherein each of the fused rings comprises five or six ring members, comprising between them one to four heteroatoms selected from the group consisting of O, S, and N.
• lower cycloalkyl means a monocyclic cycloalkyl having between three and six ring members. Lower cycloalkyls may be unsaturated. Examples of lower cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
• lower heterocycloalkyl as used herein, alone or in combination, means a monocyclic heterocycloalkyl having between three and six ring members, of which between one and four may be heteroatoms selected from the group consisting of O, S, and N.
• lower heterocycloalkyls include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, and morpholinyl.
• Lower heterocycloalkyls may be unsaturated.
• lower amino refers to— NRR', wherein R and R' are independently selected from the group consisting of hydrogen, lower alkyl, and lower heteroalkyl, any of which may be optionally substituted. Additionally, the R and R' of a lower amino group may combine to form a five- or six-membered heterocycloalkyl, either of which may be optionally substituted.
• mercaptyl as used herein, alone or in combination, refers to an RS- group, where R is as defined herein.
• nitro refers to -N02.
• perhaloalkoxy refers to an alkoxy group where all of the hydrogen atoms are replaced by halogen atoms.
• perhaloalkyl refers to an alkyl group where all of the hydrogen atoms are replaced by halogen atoms.
• sulfonate refers the -SO3H group and its anion as the sulfonic acid is used in salt formation.
• thia and thio refer to a - S- group or an ether wherein the oxygen is replaced with sulfur.
• the oxidized derivatives of the thio group namely sulfinyl and sulfonyl, are included in the definition of thia and thio.
• thiol as used herein, alone or in combination, refers to an -SH group.
• thiocarbonyl when alone includes thioformyl -C(S)H and in combination is a -C(S)- group.
• N-thiocarbamyl refers to an ROC(S)NR'- group, with R and R' as defined herein.
• 0-thiocarbamyl refers to a -OC(S)NRR', group with R and R' as defined herein.
• thiocyanato refers to a -CNS group.
• trihalomethanesulfonamido refers to a X3CS(0)2NR- group with X is a halogen and R as defined herein.
• trihalomethanesulfonyl refers to a X3CS(0)2- group where X is a halogen.
• trihalomethoxy refers to a X3CO- group where X is a halogen.
• trimethysilyl as used herein, alone or in combination, refers to a silicone group substituted at its three free valences with groups as listed herein under the definition of substituted amino. Examples include trimethysilyl, tert-butyldimethylsilyl, triphenylsilyl and the like.
• any definition herein may be used in combination with any other definition to describe a composite structural group.
• the trailing element of any such definition is that which attaches to the parent moiety.
• the composite group alkylamido would represent an alkyl group attached to the parent molecule through an amido group
• the term alkoxyalkyl would represent an alkoxy group attached to the parent molecule through an alkyl group.
• substituents of an "optionally substituted” group may include, without limitation, one or more substituents independently selected from the following groups or a particular designated set of groups, alone or in combination: lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower
• heterocycloalkyl lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester, lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, lower alkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lower haloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonic acid, trisubstituted silyl, N 3 , SH, SCFb, C(0)CH3, CO2CH3, CO2H, pyridinyl, thiophene
• Two substituents may be joined together to form a fused five-, six-, or seven-membered carbocyclic or heterocyclic ring consisting of zero to three heteroatoms, for example forming methylenedioxy or ethylenedioxy.
• An optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and monosubstituted (e.g., -CH2CF3).
• substituents are recited without qualification as to substitution, both substituted and unsubstituted forms are encompassed.
• R or the term R' refers to a moiety selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl and heterocycloalkyl, any of which may be optionally substituted.
• Asymmetric centers exist in the compounds disclosed herein. These centers are designated by the symbols “R” or “S,” depending on the configuration of substituents around the chiral carbon atom. It should be understood that the disclosure encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric, and epimeric forms, as well as d-isomers and 1 -isomers, and mixtures thereof.
• Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art.
• Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art.
• the compounds disclosed herein may exist as geometric isomers. The present disclosure includes all cis, trans, syn, anti,
• compounds may exist as tautomers; all tautomeric isomers are provided by this disclosure. Additionally, the compounds disclosed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms.
• bond refers to a covalent linkage between two atoms, or two moieties when the atoms joined by the bond are considered part of larger substructure.
• a bond may be single, double, or triple unless otherwise specified.
• a dashed line between two atoms in a drawing of a molecule indicates that an additional bond may be present or absent at that position.
• the compounds disclosed herein can exist as therapeutically acceptable salts.
• the present disclosure includes compounds listed above in the form of salts, including acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable. However, salts of non- pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question. Basic addition salts may also be formed and be pharmaceutically acceptable.
• Pharmaceutical Salts Properties, Selection, and Use (Stahl, P. Heinrich. Wiley -VCHA, Zurich, Switzerland, 2002).
• terapéuticaally acceptable salt represents salts or zwitterionic forms of the compounds disclosed herein which are water or oil-soluble or dispersible and therapeutically acceptable as defined herein.
• the salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound in the form of the free base with a suitable acid.
• Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate,
• basic groups in the compounds disclosed herein can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides.
• acids which can be employed to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Salts can also be formed by coordination of the compounds with an alkali metal or alkaline earth ion.
• the present disclosure contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, and the like.
• Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine.
• a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine.
• the cations of therapeutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, ⁇ , ⁇ -dibenzylphenethylamine, 1 -ephenamine, and ⁇ , ⁇ '-dibenzylethylenediamine.
• Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.
• a salt of a compound can be made by reacting the appropriate compound in the form of the free base with the appropriate acid.
• the compound is a compound that inhibits glutathione production or activity. In certain embodiments, the compound inhibits amino acid or glutathione transport. In some embodiments, the compound is a glutaminase inhibitor.
• the compound is a GLS-1 inhibitor, for example, a selective inhibitor of GLS-1. It is known that GLS-1 forms a tetramer (PNAS 2012, 109, 7705).
• the GLSli occupies an allosteric pocket on the solvent exposed region between two GLS-1 dimers. The GLSli may, for example, bind GLS-1 in an allosteric pocket on the solvent exposed region of the GLS-1 dimer in the binding pocket present in the vicinity of amino acids Leu 321, Phe322, Leu323, and Tyr394 from both monomers.
• the inventors propose that key interactions are made within a hydrophobic cluster that comprises Leu321, Phe322, Leu323, and Tyr394 from both monomers which forms the allosteric pocket. Binding of the glutaminase inhibitor, for example, a GLSli, induces a dramatic conformational change near the catalytic site rendering the enzyme inactive.
• the compound is compound 2
• the compound (and its molecular mass) is provided in Table 1 below, or a salt or polymorph thereof.
• the compound is chosen from any combination of the compounds provided in Table 1 below, or a salt or polymorph thereof.
• the compound is chosen from any two, three, four, five, six, seven, eight, nine or ten of the compounds provided in Table 1 below, or a salt or polymorph thereof.
• the compound is (S)-2-hydroxy-2-phenyl-N-(5-(4-(6-(2- (3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl)-l ,3,4-thiadiazol-2- yl)acetamide, or a salt or polymorph thereof.
• the compound is ⁇ , ⁇ '- (5,5'-(2,2' hiobis(ethane-2,l -diyl))bis(l ,3,44hiadiazole-5,2-diyl))bis(2-phenylacetamide), or a salt or polymorph thereof.
• the compound is (S)-2-hydroxy-2- (pyridin-2-yl)-N-(5-(4-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)but l)- l,3,4-thiadiazol-2-yl)acetamide, or a salt or polymorph thereof.
• the compound is N,N'-(5,5'-(2,2'-sulfonylbis(ethane-2, l-diyl))bis(l,3,4-thiadiazole-5,2- diyl))bis(2-(pyridin-2-yl)acetamide), or a salt or polymorph thereof.
• the compound is N-methyl-l- ⁇ 4-[6-(2- ⁇ 4-[3-(trifluoromethoxy)phenyl]pyridin-2- yl ⁇ acetamido)pyridazin-3-yl]but l ⁇ -lH-l ,2,3-triazole-4-carboxarnide, or a salt or polymorph thereof.
• the compound is l-(2-fluoro-4-(5-(2-(pyridin-2- yl)acetamido)-l ,3,4-thiadiazol-2-yl)butyl)-N-((4-(trifluoromethyl)pyridin-2-yl)methyl)-lH- l,2,3-triazole-4-carboxamide, or a salt or polymorph thereof.
• the compound is 1 -(2-fluoro-4-(6-(2-(4-(trifluoromethyl)pyridin-2-yl)acetamido)pyridazin-3- yl)butyl)-N-methyl-lH-l ,2,3-triazole-4-carboxamide, or a salt or polymorph thereof.
• the compound is N-(pyridin-2-ylmethyl)-5-(3-(6-(2-(3- (trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)pyrrolidin- 1 -yl)- 1 ,3,4-thiadiazole-2- carboxamide, or a salt or polymorph thereof.
• the compound is (R)-l- (2-fluoro-4-(6-(2-(4-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetamido)pyridazin-3- yl)butyl)-N-methyl-lH-l ,2,3-triazole-4-carboxamide, or a salt or polymorph thereof.
• the compound is (R)-l -(2-fluoro-4-(6-(2-(4-(trifluoromethyl)pyridin-2- yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-lH-l,2,3 riazole-4-carboxamide, or a salt or polymorph thereof.
• the compound is (R)-l -(2-fluoro-4-(6-(2-(6- methyl-4-(trifluoromethyl)pyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-lH-l ,2,3- triazole-4-carboxamide, or a salt or polymorph thereof.
• the compound is (R)-l -(4-(6-(2-(4-(cyclopropyldifluoromethyl)pyridin-2- yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-N-methyl-lH-l ,2,3-triazole-4-carboxamide, or a salt or polymorph thereof.
• the compound is (R)-l -(4-(6-(2-(4-(3,3- difluorocyclobutoxy)pyridin-2-yl)acetaniido)pyridazin-3-yl)-2-fluorobut l)-N-methyl-lH- l,2,3-triazole-4-carboxamide, or a salt or polymorph thereof.
• the compound is (R)-l -(2-fluoro-4-(6-(2-(l -(3-(trifluoromethoxy)phenyl)-lH-imidazol-4- yl)acetarmdo)pyridazin-3-yl)butyl)-N-methyl-lH-l,2,3 riazole-4-carboxamide, or a salt or polymorph thereof.
• the compound is l -(4-(6-(2-(4- cyclobutoxypyridin-2-yl)acetamido)pyridazin-3-yl)butyl)-N-methyl-lH-l,2,3-triazole-4- carboxamide, or a salt or polymorph thereof.
• the compound is l -(4- (6-(2-(4-cyclobutoxypyridin-2-yl)acetamido)pyridazin-3-yl)-2-fluorobutyl)-N-methyl-lH- l,2,3-triazole-4-carboxamide, or a salt or polymorph thereof.
• the compound is 1 -(4-(6-(2-(4-(3,3-difluorocyclobutoxy)pyridin-2-yl)acetamido)pyridazin-3- yl)butyl)-N-methyl-lH-l ,2,3-triazole-4-carboxamide, or a salt or polymorph thereof.
• the compound is l-(4-(6-(2-(4-(3,3-difluorocyclobutoxy)pyridin-2- yl)acetarmdo)pyridazin-3-yl)-2-fluorobutyl)-N-methyl-lH-l,2,34riazole-4-carboxamide, or a salt or polymorph thereof.
• the compound is (R)-l -(4-(6-(2-(4- cyclopropylpyridin-2-yl)acetamido)pyridazin-3-yl)-2-fluorobut l)-N-methyl-lH-l ,2,3- triazole-4-carboxamide, or a salt or polymorph thereof.
• the compound is 5-(3-(6-(2-(pyridin-2-yl)acetamido)pyridazin-3-yl)pyrrolidin-l -yl)-N-((4- (trifluoromethyl)pyridin-2-yl)methyl)-l,3,4-thiadiazole-2-carboxamide, or a salt or polymorph thereof.
• the compound is N,N'-(5,5'-(cyclohexane-l ,3- diyl)bis(l ,3,4-thiadiazole-5,2-diyl))bis(2-phenylacetamide), or a salt or polymorph thereof.
• the compound is N,N'-(5,5'-((l S,3S)-cyclohexane-l,3-diyl)bis(l ,3,4- thiadiazole-5,2-diyl))bis(2-phenylacetamide), or a salt or polymorph thereof.
• the compound is N,N'-(5,5'-((lR,3R)-cyclohexane-l,3-diyl)bis(l ,3,4- thiadiazole-5,2-diyl))bis(2-phenylacetamide), or a salt or polymorph thereof.
• the GLS li is disclosed in United States Patent
• the GLS-1 inhibitor is of Formula I: or a salt thereof, wherein:
• n is chosen from 3, 4, and 5;
• each R x and R y is independently chosen from alkyl, cyano, H, and halo, wherein two R x groups together with the atoms to which they are attached optionally form a cycloalkyl ring;
• a 1 and A 2 are independently chosen from C-H, C-F, and N;
• R 1 and R 4 are independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, hydroxyl, C(R ) 2 C(0)R 3 , C(R ) 2 C(0)N(R ) 2 , C(R ) 2 N(R ) 2 ,
• R 2 is chosen from alkyl, heterocycloalkyl, cyano, cycloalkyl, H, halo, and haloalkyl, wherein R 1 and R 2 together with the atoms to which they are attached optionally form an form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with between 0 and 3 R z groups;
• each R 3 is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, and hydroxyl, wherein each R 3 may be optionally substituted with between 0 and 3 R z groups, wherein two R 3 groups together with the atoms to which they are attached optionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with between 0 and 3 R z groups;
• each R z group is independently chosen from alkenyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl, alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, alkylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl, aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyan
• haloalkoxyheteroarylalkyl haloalkoxyheteroarylalkyl, haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl, haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl, haloalkylcycloalkylalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl, haloalkylheterocycloalkyl,
• haloalkylheterocycloalkylalkyl haloaryl, haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl, halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy,
• haloheteroaryl haloheteroarylalkyl, haloheteroarylalkyloxy, haloheteroaryloxy,
• haloheterocycloalkyl haloheterocycloalkylalkyl, haloheterocycloalkylalkyloxy,
• each R 6 is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, and hydroxyl, wherein two R 6 groups together with the atoms to which they are attached optionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with between 0 and 3 R x groups; and
• Z is heteroaryl, which may be optionally substituted.
• the GLS-1 inhibitor is of Formula la:
• n is chosen from 3, 4, and 5;
• each R x and R y is independently chosen from alkyl, cyano, H, and halo, wherein two R x groups together with the atoms to which they are attached optionally form a cycloalkyl ring;
• a 1 and A 2 are independently chosen from C-H, C-F, and N;
• Z 1 is chosen from C and N;
• Z 2 , Z 3 , and Z 4 are independently chosen from N, O, S, and CH, wherein at least one of Z 1 , Z 2 , Z 3 , and Z 4 is chosen from N, O, and S;
• R 1 and R 4 are independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, hydroxyl, C(R ) 2 C(0)R 3 , C(R ) 2 C(0)N(R ) 2 , C(R ) 2 N(R ) 2 ,
• R 2 is chosen from alkyl, heterocycloalkyl, cyano, cycloalkyl, H, halo, and haloalkyl, wherein R 1 and R 2 together with the atoms to which they are attached optionally form an form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with between 0 and 3 R z groups;
• each R 3 is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, and hydroxyl, wherein each R 3 may be optionally substituted with between 0 and 3 R z groups, wherein two R 3 groups together with the atoms to which they are attached optionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with between 0 and 3 R z groups;
• each R z group is independently chosen from alkenyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl, alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, alkylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl, aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyan
• haloalkoxyheteroarylalkyl haloalkoxyheteroarylalkyl, haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl, haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl, haloalkylcycloalkylalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl, haloalkylheterocycloalkyl,
• haloalkylheterocycloalkylalkyl haloaryl, haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl, halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy,
• haloheteroaryl haloheteroarylalkyl, haloheteroarylalkyloxy, haloheteroaryloxy, haloheterocycloalkyl, haloheterocycloalkylalkyl, haloheterocycloalkylalkyloxy,
• each R 6 is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, and hydroxyl, wherein two R 6 groups together with the atoms to which they are attached optionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with between 0 and 3 R x groups.
• n is chosen from 3, 4, and 5;
• each R x and R y is independently chosen from alkyl, cyano, H, and halo, wherein two R x groups together with the atoms to which they are attached optionally form a cycloalkyl ring;
• a 1 and A 2 are independently chosen from C-H, C-F, and N;
• Z 1 is chosen from C and N;
• Z 2 is chosen from N, CH, and C(O);
• Z 3 , and Z 4 are independently chosen from N and CH, wherein at least one of Z 1 , Z 2 , Z 3 , and Z 4 is N;
• R 1 and R 4 are independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, hydroxyl, C(R ) 2 C(0)R 3 , C(R ) 2 C(0)N(R ) 2 , C(R ) 2 N(R ) 2 ,
• R 2 and R 5 are chosen from alkyl, heterocycloalkyl, cyano, cycloalkyl, H, halo, and haloalkyl, wherein R 1 and R 2 together with the atoms to which they are attached optionally form an form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with between 0 and 3 R z groups, wherein R 4 and R 5 together with the atoms to which they are attached optionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with between 0 and 3 R z groups; each R 3 is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycl
• each R z group is independently chosen from alkenyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl, alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, alkylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl, aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyan
• haloalkoxyheteroarylalkyl haloalkoxyheteroarylalkyl, haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl, haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl, haloalkylcycloalkylalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl, haloalkylheterocycloalkyl,
• haloalkylheterocycloalkylalkyl haloaryl, haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl, halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy,
• haloheteroaryl haloheteroarylalkyl, haloheteroarylalkyloxy, haloheteroaryloxy,
• haloheterocycloalkyl haloheterocycloalkylalkyl, haloheterocycloalkylalkyloxy,
• each R 6 is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, and hydroxyl, wherein two R 6 groups together with the atoms to which they are attached optionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with between 0 and 3 R x groups.
• the GLS li is disclosed in United States Patent
• n is chosen from 3, 4, and 5;
• each R x and R y is independently chosen from alkyl, cyano, H, and halo, wherein two R x groups together with the atoms to which they are attached optionally form a cycloalkyl ring;
• a 1 and A 2 are independently chosen from N and CH;
• a 3 is chosen from N and CR 2 ;
• R 1 is chosen from alkenyl, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl,
• R 1 may be optionally substituted with between 0 and 3 R z groups;
• R 2 is chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl,
• heterocycloalkylalkyl hydroxyl, C(0)N(R ) 2 , C(0)C(R ) 3 , C(0)OH, C(0)OC(R ) 3 , wherein R 1 and R 2 together with the atoms to which they are attached optionally form an form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with between 0 and 3 R z groups;
• each R 3 is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, and hydroxyl, wherein each R 3 may be optionally substituted with between 0 and 3 R z groups, wherein two R 3 groups together with the atoms to which they are attached optionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with between 0 and 3 R z groups;
• R 4 is chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, hydroxyl, N(R ) 2 , NR C(0)C(R ) 3 , NR C(0)OC(R ) 3 ,
• R 4 may be optionally substituted with between 0 and 3 R z groups;
• each R z group is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, halo, haloalkyl, heteroaryl, heteroarylalkyl,
• heterocycloalkyl heterocycloalkylalkyl, hydroxyl, oxo, N(R 6 ) 2 , NR 6 C(0)C(R 6 ) 3 ,
• NR 6 C(0)OC(R 6 ) 3 NR 6 C(0)N(R 6 ) 2 , NR 6 S(0)C(R 6 ) 3 , NR 6 S(0) 2 C(R 6 ) 3 , C(0)N(R 6 ) 2 , S(0)N(R 6 ) 2 , S(0) 2 N(R 6 ) 2 , C(0)C(R 6 ) 3 , SC(R 6 ) 3 , S(0)C(R 6 ) 3 , and S(0) 2 C(R 6 ) 3 ;
• each R 6 is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, and hydroxyl, wherein two R 6 groups together with the atoms to which they are attached optionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with between 0 and 3 R x groups; and
• Z is heteroaryl, which may be optionally substituted.
• n is chosen from 3, 4, and 5;
• each R x and R y is independently chosen from alkyl, cyano, H, and halo, wherein two R x groups together with the atoms to which they are attached optionally form a cycloalkyl ring;
• a 1 and A 2 are independently chosen from N and CH;
• a 3 is chosen froni N and CR 2 ;
• Z 1 is chosen from C and N;
• Z 2 , Z 3 , and Z 4 are independently chosen from N, O, S, and CH, wherein at least one of Z 1 , Z 2 , Z 3 , and Z 4 is chosen from N, O, and S;
• R 1 is chosen from alkenyl, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl,
• R 1 may be optionally substituted with between 0 and 3 R z groups;
• R 2 is chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl,
• heterocycloalkylalkyl hydroxyl, C(0)N(R ) 2 , C(0)C(R ) 3 , C(0)OH, C(0)OC(R ) 3 , wherein R 1 and R 2 together with the atoms to which they are attached optionally form an form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with between 0 and 3 R z groups;
• each R 3 is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, and hydroxyl, wherein each R 3 may be optionally substituted with between 0 and 3 R z groups, wherein two R 3 groups together with the atoms to which they are attached optionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with between 0 and 3 R z groups;
• R 4 is chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl,
• heterocycloalkylalkyl hydroxyl, N(R 3 ) 2 , NR 3 C(0)C(R ) 3 , NR 3 C(0)OC(R ) 3 ,
• R 4 may be optionally substituted with between 0 and 3 R z groups;
• each R z group is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, halo, haloalkyl, heteroaryl, heteroarylalkyl,
• heterocycloalkyl heterocycloalkylalkyl, hydroxyl, oxo, N(R 6 ) 2 , NR 6 C(0)C(R 6 ) 3 ,
• each R 6 is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, and hydroxyl, wherein two R 6 groups together with the atoms to which they are attached optionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with between 0 and 3 R x groups.
• the GLS-1 inhibitor is of Formula lib:
• n is chosen from 3, 4, and 5;
• each R x and R y is independently chosen from alkyl, cyano, H, and halo, wherein two R x groups together with the atoms to which they are attached optionally form a cycloalkyl ring;
• a 1 and A 2 are independently chosen from N and CH;
• a 3 is chosen from N and CR 2 ;
• Z 1 is chosen from C and N;
• Z 2 is chosen from N, CH, and C(O);
• Z 3 , and Z 4 are independently chosen from N and CH, wherein at least one of Z 1 , Z 2 , Z 3 , and Z 4 is N;
• R 1 is chosen from alkenyl, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl,
• R 1 may be optionally substituted with between 0 and 3 R z groups;
• R 2 is chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl,
• heterocycloalkylalkyl hydroxyl, C(0)N(R 3 ) 2 , C(0)C(R ) 3 , C(0)OH, C(0)OC(R ) 3 , wherein R 1 and R 2 together with the atoms to which they are attached optionally form an form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with between 0 and 3 R z groups;
• each R 3 is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, and hydroxyl, wherein each R 3 may be optionally substituted with between 0 and 3 R z groups, wherein two R 3 groups together with the atoms to which they are attached optionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with between 0 and 3 R z groups;
• R 4 is chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, hydroxyl, N(R ) 2 , NR C(0)C(R ) 3 , NR C(0)OC(R ) 3 ,
• R 4 may be optionally substituted with between 0 and 3 R z groups;
• R 5 is chosen from alkyl, heterocycloalkyl, cyano, cycloalkyl, H, halo, and haloalkyl, wherein R 4 and R 5 together with the atoms to which they are attached optionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with between 0 and 3 R z groups;
• each R z group is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, halo, haloalkyl, heteroaryl, heteroarylalkyl,
• heterocycloalkyl heterocycloalkylalkyl, hydroxyl, oxo, N(R 6 ) 2 , NR 6 C(0)C(R 6 ) 3 ,
• each R 6 is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, and hydroxyl, wherein two R 6 groups together with the atoms to which they are attached optionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with between 0 and 3 R x groups.
• the GLS li is disclosed inUnited States Patent Application Publication No. US 2016/0009704, published January 14, 2016.
• n is chosen from 3, 4, and 5;
• each R x and R Y is independently chosen from alkyl, cyano, H, and halo, or two R x groups together with the atoms to which they are attached optionally form a cycloalkyl ring;
• a 1 is chosen from C and N;
• a 2 , A 3 , and A 4 are independently chosen from N, O, S, and CH, wherein at least one of A 1 , A 2 , A 3 , and A 4 is chosen from N, O, and S;
• R 1 and R 2 are each independently chosen from alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein R 1 and R 2 each may be optionally substituted with one to three R z groups, wherein R 1 and R 2 together with the atoms to which they are attached optionally form an heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with one to three R z groups;
• R 3 is chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl,
• heterocycloalkylalkyl hydroxyl, C(R 4 ) 2 C(0)R 4 , C(R 4 ) 2 C(0)N(R 4 ) 2 , C(R 4 ) 2 N(R 4 ) 2 ,
• each R 4 is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, and hydroxyl, wherein each R 4 may be optionally substituted with one to three R z groups, wherein two R 4 groups together with the atoms to which they are attached optionally form an heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with one to three R z groups;
• each R z group is independently chosen from alkenyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl, alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, alkylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl, aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyan
• haloalkylheterocycloalkylalkyl haloaryl, haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl, halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy,
• haloheteroaryl haloheteroarylalkyl, haloheteroarylalkyloxy, haloheteroaryloxy,
• haloheterocycloalkyl haloheterocycloalkylalkyl, haloheterocycloalkylalkyloxy,
• each R 5 is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein two R 5 groups together with the atoms to which they are attached optionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with one to three R x groups; and
• Z is a monocyclic heteroaryl, which may be optionally substituted.
• the GLS-1 inhibitor is of Formula Ilia:
• n is chosen from 3, 4, and 5;
• each R x and R Y is independently chosen from alkyl, cyano, H, and halo, or two R x groups together with the atoms to which they are attached optionally form a cycloalkyl ring;
• a 1 and Z 1 are independently chosen from C and N;
• a 2 , A 3 , A 4 , Z 2 , Z 3 , and Z 4 are independently chosen from N, O, S, and CH, wherein at least one of A 1 , A 2 , A 3 , and A 4 and at least one of Z 1 , Z 2 , Z 3 , and Z 4 is chosen from N, O, and
• R 1 and R 2 are each independently chosen from alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein R 1 and R 2 each may be optionally substituted with one to three R z groups, wherein R 1 and R 2 together with the atoms to which they are attached optionally form an heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with one to three R z groups;
• R 3 is chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl,
• heterocycloalkylalkyl hydroxyl, C(R 4 ) 2 C(0)R 4 , C(R 4 ) 2 C(0)N(R 4 ) 2 , C(R 4 ) 2 N(R 4 ) 2 ,
• each R 4 is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, and hydroxyl, wherein each R 4 may be optionally substituted with one to three R z groups, wherein two R 4 groups together with the atoms to which they are attached optionally form an heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with one to three R z groups;
• each R z group is independently chosen from alkenyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl, alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, alkylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl, aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyan
• haloalkoxyheteroarylalkyl haloalkoxyheteroarylalkyl, haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl, haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl, haloalkylcycloalkylalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl, haloalkylheterocycloalkyl,
• haloalkylheterocycloalkylalkyl haloaryl, haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl, halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy,
• haloheteroaryl haloheteroarylalkyl, haloheteroarylalkyloxy, haloheteroaryloxy, haloheterocycloalkyl, haloheterocycloalkylalkyl, haloheterocycloalkylalkyloxy,
• each R 5 is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein two R 5 groups together with the atoms to which they are attached optionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with one to three R x groups.
• the GLS-1 inhibitor is of Formula Illb:
• n is chosen from 3, 4, and 5;
• each R x and R Y is independently chosen from alkyl, cyano, H, and halo, or two R x groups together with the atoms to which they are attached optionally form a cycloalkyl ring;
• a 1 is chosen from C and N;
• a 2 , A 3 , and A 4 are independently chosen from N, O, S, and CH, wherein at least one of A 1 , A 2 , A 3 , and A 4 is chosen from N, O, and S;
• Z 2 , Z 3 and Z 4 are independently chosen from N and CH, wherein at least one of Z 1 , Z 2 , Z 3 , and Z 4 is N;
• R 1 and R 2 are each independently chosen from alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein R 1 and R 2 each may be optionally substituted with one to three R z groups, wherein R 1 and R 2 together with the atoms to which they are attached optionally form an heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with one to three R z groups;
• R 3 is chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl,
• heterocycloalkylalkyl hydroxyl, C(R 4 ) 2 C(0)R 4 , C(R 4 ) 2 C(0)N(R 4 ) 2 , C(R 4 ) 2 N(R 4 ) 2 ,
• each R 4 is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, and hydroxyl, wherein each R 4 may be optionally substituted with one to three R z groups, wherein two R 4 groups together with the atoms to which they are attached optionally form an heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with one to three R z groups;
• each R z group is independently chosen from alkenyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl, alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, alkylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl, aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyan
• haloalkoxyheteroarylalkyl haloalkoxyheteroarylalkyl, haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl, haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl, haloalkylcycloalkylalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl, haloalkylheterocycloalkyl,
• haloalkylheterocycloalkylalkyl haloaryl, haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl, halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy,
• haloheteroaryl haloheteroarylalkyl, haloheteroarylalkyloxy, haloheteroaryloxy,
• haloheterocycloalkyl haloheterocycloalkylalkyl, haloheterocycloalkylalkyloxy,
• each R 5 is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein two R 5 groups together with the atoms to which they are attached optionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with one to three R x groups; and
• R 6 is chosen from, alkyl, cyano, cycloalkyl, H, halo, haloalkyl, and heterocycloalkyl, wherein R 3 and R 6 groups together with the atoms to which they are attached optionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with one to three R z groups.
• the GLS-1 inhibitor is of Formula IIIc:
• R x is chosen from fluoro and H
• R 1 is chosen from alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein R 1 may be optionally substituted with one to three R z groups;
• each R 4 is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, and hydroxyl, wherein R 4 may be optionally substituted with one to three R z groups;
• each R z group is independently chosen from alkenyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl, alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, alkylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl, aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyan
• haloalkoxyheteroarylalkyl haloalkoxyheteroarylalkyl, haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl, haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl, haloalkylcycloalkylalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl, haloalkylheterocycloalkyl,
• haloalkylheterocycloalkylalkyl haloaryl, haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl, halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy,
• haloheteroaryl haloheteroarylalkyl, haloheteroarylalkyloxy, haloheteroaryloxy,
• haloheterocycloalkyl haloheterocycloalkylalkyl, haloheterocycloalkylalkyloxy,
• each R 5 is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein two R 5 groups together with the atoms to which they are attached optionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with one to three R x groups.
• the GLSli is of Formula IIIc as shown above, or a salt thereof, wherein R 1 is methyl.
• the GLS-1 inhibitor is of Formula IIIc-1 :
• R x is chosen from fluoro and H
• R 1 is chosen from alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein R 1 may be optionally substituted with one to three R z groups; each R 4 is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, and hydroxyl, wherein R 4 may be optionally substituted with one to three R z groups;
• each R z group is independently chosen from alkenyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl, alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, alkylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl, aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyan
• haloalkoxyheteroarylalkyl haloalkoxyheteroarylalkyl, haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl, haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl, haloalkylcycloalkylalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl, haloalkylheterocycloalkyl,
• haloalkylheterocycloalkylalkyl haloaryl, haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl, halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy,
• haloheteroaryl haloheteroarylalkyl, haloheteroarylalkyloxy, haloheteroaryloxy,
• haloheterocycloalkyl haloheterocycloalkylalkyl, haloheterocycloalkylalkyloxy,
• each R 5 is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein two R 5 groups together with the atoms to which they are attached optionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with one to three R x groups.
• the GLS-1 inhibitor is of Formula IIIc-2:
• R x is chosen from fluoro and H
• R 1 is chosen from alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein R 1 may be optionally substituted with one to three R z groups;
• each R 4 is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, and hydroxyl, wherein R 4 may be optionally substituted with one to three R z groups;
• each R z group is independently chosen from alkenyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl, alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, alkylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl, aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyan
• haloalkoxyheteroarylalkyl haloalkoxyheteroarylalkyl, haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl, haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl, haloalkylcycloalkylalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl, haloalkylheterocycloalkyl,
• haloalkylheterocycloalkylalkyl haloaryl, haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl, halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy,
• haloheteroaryl haloheteroarylalkyl, haloheteroarylalkyloxy, haloheteroaryloxy,
• haloheterocycloalkyl haloheterocycloalkylalkyl, haloheterocycloalkylalkyloxy,
• each R 5 is independently chosen from alkenyl, alkoxy, alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein two R 5 groups together with the atoms to which they are attached optionally form an aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, which may be optionally substituted with one to three R x groups.
• the GLS-1 inhibitor is of Formula Hid:
• R x is chosen from fluoro and H
• each of R Z1 and R Z2 is independently chosen from alkenyl, alkoxy, alkoxy alkyl, alkoxyaryl, alkoxyarylalkyl, alkoxy cycloalkyl, alkoxy cycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl, alkoxyheterocycloalkyl,
• alkoxyheterocycloalkylalkyl alkyl, alkylaryl, alkylarylalkyl, alkylcycloalkyl,
• haloalkoxyheterocycloalkyl haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl, haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl, haloalkylcycloalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl, haloalkylheterocycloalkyl, haloalkylheterocycloalkylalkyl, haloaryl, haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl, halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy, haloheteroaryl, haloheteroarylal
• the GLS-1 inhibitor is of Formula Hid as shown above, or a salt thereof, wherein:
• R x is chosen from fiuoro and H.
• each of R Z1 and R Z2 is independently chosen from alkyl, cycloalkyl,
• cycloalkylhaloalkyl cycloalkyloxy, H, haloalkoxy, haloalkoxyaryl, haloalkyl,
• the GLS-1 inhibitor is of Formula Hid as shown above, or a salt thereof, wherein:
• R Z1 and R Z2 are independe chosen fr m HH, 3 ⁇ 4 °Y
• the GLS-1 inhibitor is of Formula Hie:
• R x is chosen from fiuoro and H;
• R Z1 is chosen from alkenyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxy cycloalkyl, alkoxy cycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl,
• alkoxyheteroarylalkyl alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, alkylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl, aryl, arylalkyloxy, arylhaloalkyl, aryloxy, cyano, cycloalkyl, cycloalkylalkyl, cycloalkylalkyloxy, cycloalkylhaloalkyl, cycloalkyloxy, H, halo, haloalkoxy, haloalkoxyalkyl, haloalkoxyaryl, haloalk
• haloalkylheterocycloalkylalkyl haloaryl, haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl, halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy,
• haloheteroaryl haloheteroarylalkyl, haloheteroarylalkyloxy, haloheteroaryloxy,
• haloheterocycloalkyl haloheterocycloalkylalkyl, haloheterocycloalkylalkyloxy,
• the GLS-1 inhibitor is a compound or a salt thereof, wherein the compound is chosen from
• the GLS li is one as disclosed in United States Patent Application Publication No. US 2017/0001996 filed January 5, 2017.
• the GLS-1 inhibitor is of Formula IV:
• n is chosen from 1 and 2;
• R 1 is chosen from NR C(0)R 3 , NR C(0)OR 3 , NR C(0)N(R ) 2 , C(0)N(R ) 2 , and
• each R 3 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl,
• cycloalkylalkyl H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl,
• each R 3 may be optionally substituted with one to three R x groups, wherein two R 3 groups together with the atoms to which they are attached optionally form an heteroaryl or heterocycloalkyl ring, which may be optionally substituted with one to three R x groups;
• R 2 is chosen from NR 4 C(0)R 4 , NR 4 C(0)OR 4 , NR 4 C(0)N(R 4 ) 2 , C(0)N(R 4 ) 2 and
• each R 4 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl,
• cycloalkylalkyl H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and
• each R 4 may be optionally substituted with one to three R x groups, wherein two R 4 groups together with the atoms to which they are attached optionally form an heteroaryl or heterocycloalkyl ring, which may be optionally substituted with one to three R x groups;
• each R x group is independently chosen from alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl, alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, alkylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl,aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyano, cycloalkyl, cycloalkylalkyl, cycl
• haloalkoxyheteroarylalkyl haloalkoxyheteroarylalkyl, haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl, haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl, haloalkylcycloalkylalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl, haloalkylheterocycloalkyl,
• haloalkylheterocycloalkylalkyl haloaryl, haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl, halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy,
• haloheteroaryl haloheteroarylalkyl, haloheteroarylalkyloxy, haloheteroaryloxy,
• haloheterocycloalkyl haloheterocycloalkylalkyl, haloheterocycloalkylalkyloxy,
• each R 5 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl, cycloalkyl, hydroxyl, oxo, N(R 5 ) 2 , NR 5 C(0)R 5 , NR 5 C(0)OR 5 , NR 5 C(0)N(R 5 ) 2 , C(0)N(R 5 ) 2 , and C(0)R 5 ; each R 5 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl,
• cycloalkylalkyl H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and
• heterocycloalkylalkyl which may be optionally substituted with one to three R z groups;
• R z is chosen from alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl;
• A is a monocyclic heteroaryl, which may be optionally substituted with one to three R z groups;
• Z is a monocyclic heteroaryl, which may be optionally substituted with one to three R z groups.
• the GLS li is disclosed in United States Patent
• the GLS-1 inhibitor is of Formula IV a:
• n is chosen from 1 and 2;
• R 1 is chosen from NR C(0)R 3 , NR C(0)OR 3 , NR C(0)N(R ) 2 , C(0)N(R ) 2 , and
• each R 3 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl,
• cycloalkylalkyl H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl,
• each R 3 may be optionally substituted with one to three R x groups, wherein two R 3 groups together with the atoms to which they are attached optionally form an heteroaryl or heterocycloalkyl ring, which may be optionally substituted with one to three R x groups;
• R 2 is chosen from NR 4 C(0)R 4 , NR 4 C(0)OR 4 , NR 4 C(0)N(R 4 ) 2 , C(0)N(R 4 ) 2 and
• each R 4 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl,
• cycloalkylalkyl H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and
• each R 4 may be optionally substituted with one to three R x groups, wherein two R 4 groups together with the atoms to which they are attached optionally form an heteroaryl or heterocycloalkyl ring, which may be optionally substituted with one to three R x groups;
• each R x group is independently chosen from alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl, alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, alkylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl,aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyano, cycloalkyl, cycloalkylalkyl, cycl
• haloalkoxyheteroarylalkyl haloalkoxyheteroarylalkyl, haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl, haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl, haloalkylcycloalkylalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl, haloalkylheterocycloalkyl,
• haloalkylheterocycloalkylalkyl haloaryl, haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl, halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy,
• haloheteroaryl haloheteroarylalkyl, haloheteroarylalkyloxy, haloheteroaryloxy,
• haloheterocycloalkyl haloheterocycloalkylalkyl, haloheterocycloalkylalkyloxy,
• each R 5 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl,
• cycloalkylalkyl H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and
• heterocycloalkylalkyl which may be optionally substituted with one to three R z groups;
• R z is chosen from alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl.
• the GLS-1 inhibitor is of Formula IVb:
• n is chosen from 1 and 2;
• R 3 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein each R 3 may be optionally substituted with one to three R x groups;
• R 4 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein each R 4 may be optionally substituted with one to three R x groups;
• each R x group is independently chosen from alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl, alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, alkylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl,aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyano, cycloalkyl, cycloalkylalkyl, cycl
• haloalkoxyheteroarylalkyl haloalkoxyheteroarylalkyl, haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl, haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl, haloalkylcycloalkylalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl, haloalkylheterocycloalkyl,
• haloalkylheterocycloalkylalkyl haloaryl, haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl, halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy,
• haloheteroaryl haloheteroarylalkyl, haloheteroarylalkyloxy, haloheteroaryloxy,
• haloheterocycloalkyl haloheterocycloalkylalkyl, haloheterocycloalkylalkyloxy,
• each R 5 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl, cycloalkyl, cycloalkyl, hydroxyl, oxo, N(R 5 )2, NR 5 C(0)R 5 , NR 5 C(0)OR 5 , NR 5 C(0)N(R 5 ) 2 , C(0)N(R 5 ) 2 , and C(0)R 5 ; each R 5 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl,
• cycloalkylalkyl H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and
• heterocycloalkylalkyl which may be optionally substituted with one to three R z groups;
• R z is chosen from alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl.
• the GLS-1 inhibitor is of Formula IVc:
• n is chosen from 1 and 2;
• R 3 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein each R 3 may be optionally substituted with one to three R x groups;
• R 4 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein each R 4 may be optionally substituted with one to three R x groups;
• each R x group is independently chosen from alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl, alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, alkylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl,aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyano, cycloalkyl, cycloalkylalkyl, cycl
• haloalkoxyheteroarylalkyl haloalkoxyheteroarylalkyl, haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl, haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl, haloalkylcycloalkylalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl, haloalkylheterocycloalkyl,
• haloalkylheterocycloalkylalkyl haloaryl, haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl, halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy,
• haloheteroaryl haloheteroarylalkyl, haloheteroarylalkyloxy, haloheteroaryloxy,
• each R 5 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl,
• cycloalkylalkyl H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and
• heterocycloalkylalkyl which may be optionally substituted with one to three R z groups;
• R z is chosen from alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl.
• the GLS-1 inhibitor is of Formula IVd:
• n is chosen from 1 and 2;
• R 3 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein each R 3 may be optionally substituted with one to three R x groups;
• R 4 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein each R 4 may be optionally substituted with one to three R x groups;
• each R x group is independently chosen from alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl, alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, alkylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl,aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyano, cycloalkyl, cycloalkylalkyl, cycl
• haloalkoxyheteroarylalkyl haloalkoxyheteroarylalkyl, haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl, haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl, haloalkylcycloalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl, haloalkylheterocycloalkyl, haloalkylheterocycloalkylalkyl, haloaryl, haloarylalkyl, haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl, halocycloalkylalkyl, halocycloalkylalkyloxy, halocycl
• haloheteroaryl haloheteroarylalkyl, haloheteroarylalkyloxy, haloheteroaryloxy,
• haloheterocycloalkyl haloheterocycloalkylalkyl, haloheterocycloalkylalkyloxy,
• each R 5 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl,
• cycloalkylalkyl H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and
• heterocycloalkylalkyl which may be optionally substituted with one to three R z groups;
• R z is chosen from alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl.
• the GLS-1 inhibitor is of Formula IVe:
• n is chosen from 1 and 2;
• R 3 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein each R 3 may be optionally substituted with one to three R x groups;
• R 4 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, wherein each R 4 may be optionally substituted with one to three R x groups;
• each R x group is independently chosen from alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyarylalkyl, alkoxycycloalkyl, alkoxycycloalkylalkyl, alkoxyhaloalkyl, alkoxyheteroaryl, alkoxyheteroarylalkyl, alkoxyheterocycloalkyl, alkoxyheterocycloalkylalkyl, alkyl, alkylaryl, alkylarylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylheteroaryl, alkylheteroarylalkyl, alkylheterocycloalkyl, alkylheterocycloalkylalkyl,aryl, arylalkyl, arylalkyloxy, arylhaloalkyl, aryloxy, cyano, cycloalkyl, cycloalkylalkyl, cycl
• haloalkoxyheteroarylalkyl haloalkoxyheteroarylalkyl, haloalkoxyheterocycloalkyl, haloalkoxyheterocycloalkylalkyl, haloalkyl, haloalkylaryl, haloalkylarylalkyl, haloalkylcycloalkyl, haloalkylcycloalkylalkylalkyl, haloalkylheteroaryl, haloalkylheteroarylalkyl, haloalkylheterocycloalkyl,
• haloalkylheterocycloalkylalkyl haloaryl, haloarylalkyl, haloarylalkyloxy, haloaryloxy, halocycloalkyl, halocycloalkylalkyl, halocycloalkylalkyloxy, halocycloalkyloxy,
• haloheteroaryl haloheteroarylalkyl, haloheteroarylalkyloxy, haloheteroaryloxy,
• haloheterocycloalkyl haloheterocycloalkylalkyl, haloheterocycloalkylalkyloxy,
• each R 5 is independently chosen from alkyl, aryl, arylalkyl, cycloalkyl,
• cycloalkylalkyl H, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and
• heterocycloalkylalkyl which may be optionally substituted with one to three R z groups;
• R z is chosen from alkyl, aryl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, H, halo, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl.
• the GLSli is one as disclosed in US 2017/0174661, published June 22, 2017.
• the GLSli is one as disclosed in WO2013/078123 or Mol Cancer Ther 2014; 13:890-901.
• the GLS-1 inhibitor is of Formula Al,
• Y independently for each occurrence, represents H or CH20(CO)R.7;
• Rj independently for each occurrence, represents H or substituted or unsubstituted alkyl, alkoxy, aminoalkyl, alkylaminoalkyl, heterocyclylalkyl, arylalkyl, or
• Z represents H or R3(CO);
• Ri and R2 each independently represent H, alkyl, alkoxy or hydroxy
• R3 independently for each occurrence, represents substituted or unsubstituted alkyl, hydroxyalkyl, aminoalkyl, acylaminoalkyl, alkenyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroaryloxyalkyl or C(R8)(R9)(Rio), N(R4)(Rs) or OR6, wherein any free hydroxyl group may be acylated to form C(0)R7;
• R4 and R5 each independently represent H or substituted or unsubstituted alkyl, hydroxyalkyl, acyl, aminoalkyl, acylaminoalkyl, alkenyl, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl, wherein any free hydroxyl group may be acylated to form C(0)R7;
• R6 independently for each occurrence, represents substituted or unsubstituted alkyl, hydroxyalkyl, aminoalkyl, acylaminoalkyl, alkenyl, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl, wherein any free hydroxyl group may be acylated to form C(0)R7; and
• R8, R9 and Rio each independently represent H or substituted or unsubstituted alkyl, hydroxy, hydroxyalkyl, amino, acylamino, aminoalkyl, acylaminoalkyl, alkoxy carbonyl, alkoxy carbonylamino, alkenyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl, or Rs and R9 together with the carbon to which they are attached, form a carbocyclic or heterocyclic ring system, wherein any free hydroxyl group may be acylated to form C(0)R7, and wherein at least two of Rs, R9 and Rio are not H.
• the GLSli is one as disclosed in WO2014/078645.
• the GLS-1 inhibitor is of Formula A2,
• Y independently for each occurrence, represents H or CH20(CO)R7;
• Rj independently for each occurrence, represents H or substituted or unsubstituted alkyl, alkoxy, aminoalkyl, alkylaminoalkyl, heterocyclylalkyl, arylalkyl, or
• Z represents H or R3(CO);
• Ri and R2 each independently represent H, alkyl, alkoxy or hydroxy
• R3 represents substituted or unsubstituted alkyl, hydroxyalkyl, aminoalkyl, acylaminoalkyl, alkenyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroaryloxyalkyl or C(R8)(R9)(Rio), N(R4)(Rs) or OR6, wherein any free hydroxyl group may be acylated to form C(0)R7;
• R4 and R5 each independently for each occurrence represent H or substituted or unsubstituted alkyl, hydroxyalkyl, acyl, aminoalkyl, acylaminoalkyl, alkenyl, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,
• heterocyclylalkyl heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl, wherein any free hydroxyl group may be acylated to form C(0)R7;
• R6 represents substituted or unsubstituted alkyl, hydroxyalkyl, aminoalkyl, acylaminoalkyl, alkenyl, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl, wherein any free hydroxyl group may be acylated to form C(0)R7; R.8, R.9 and Rio each independently for each occurrence represent H or substituted or unsubstituted alkyl, hydroxy, hydroxyalkyl, amino, acylamino, aminoalkyl, acylaminoalkyl, alkoxycarbonyl, alkoxy carbonylamino, alkenyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, ary
• R11 represents aryl, arylalkyl, aryloxy, aryloxyalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl, wherein the aryl or heteroaryl ring is substituted with either -OCHF2 or -OCF3 and is optionally further substituted, or R11 represents
• R12 and Ri3 each independently respresent H or substituted or unsubstituted alkyl, hydroxy, hydroxyalkyl, amino, acylamino, aminoalkyl, acylaminoalkyl, alkoxycarbonyl, alkoxy carbonylamino, alkenyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl, wherein any free hydroxyl group may be acylated to form C(0)R7, and wherein both of R12 and R13 are not H; and
• Ri4 represents aryl, arylalkyl, aryloxy, aryloxyalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl, wherein the aryl or heteroaryl ring is substituted with either -OCHF2 or -OCF3 and is optionally further substituted.
• the GLSli is one as disclosed in WO2014/079011.
• the GLS-1 inhibitor is of Formula A3,
• X is C3-C7 cycloalkylene
• each Ri and R 2 is independently -NH 2 , -N(R 3 )-C(0)-R 4 , -C(0)-N(R 3 )-R 4 , N(R 3 )- C(0)-0-R 4 , -N(R 3 )-C(0)-N(R 3 )-R 4 or -N(R 3 )-C(0)-SR 4 ;
• each R 3 is independently hydrogen, Ci-6 alkyl or aryl
• each R 4 is independently Ci-6 alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, or heterocyclyl, each of which is substituted with 0-3 occurrences of R5;
• each R5 is independently Ci-6 alkyl, Ci-6 alkoxy, Ci-6 thioalkoxy, Ci-6 haloalkyl, C 3 -7 cycloalkyl, C 3 -7 cycloalkylalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclylalkyl, heterocyclyl, cyano, halo, oxo, -OH, -OCF 3 , -SO2-C1-6 alkyl, -NO2, -N(Rv)-C(0)- Ci-6 alkyl, - N(R 7 ) 2 , or two adjacent R5 moieties, taken together with the atoms to which they are attached form a heterocyclyl;
• each R6 is independently hydrogen, fluoro, Ci-6 alkyl, -OH, -NH2, -NH(CH 3 ),
• each R7 is independently hydrogen or Ci-6 alkyl
• n 0, 1, or 2;
• n 0, 1, or 2;
• 0 is 1, 2 or 3;
• p 1, 2 or 3.
• the GLSli is one as disclosed in WO2014/081925A1 or US2014/0142081A1.
• the GLS-1 inhibitor is of Formula A4,
• each R 3 and R 3a is independently hydrogen, Ci-6 alkyl or aryl
• each R 4 is independently Ci-6 alkyl, Ci-6 alkenyl, aryl, heteroaryl, aralkyl,
• heteroaralkyl heterocyclylalkyl, heterocyclyl, cycloalkyl or cycloalkylalkyl, each of which is substituted with 0-3 occurrences of R5, or two adjacent R5 moieties, taken together with the atoms to which they are attached form a heterocyclyl, heteroaryl, cycloalkyl or aryl;
• each R6 is independently hydrogen, fluoro, OH or Ci-6 alkyl
• each R7 is independently hydrogen, Ci-6 alkyl, -OH, -SH, cyano, halo, -CF 3 ,OCF 3 , - SO2-C1-6 alkyl, -NO2, -N(R 7 )-C(0)-Ci- 6 alkyl, -N(R 6 ) 2 or Ci-e alkoxy;
• n 1 , 2 or 3;
• 0 is 1, 2 or 3;
• p 1 , 2 or 3.

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