WO2020044206A1 - Amides hétérocycliques utiles en tant qu'inhibiteurs de kinases destinés à être utilisés dans le traitement du cancer - Google Patents

Amides hétérocycliques utiles en tant qu'inhibiteurs de kinases destinés à être utilisés dans le traitement du cancer Download PDF

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WO2020044206A1
WO2020044206A1 PCT/IB2019/057160 IB2019057160W WO2020044206A1 WO 2020044206 A1 WO2020044206 A1 WO 2020044206A1 IB 2019057160 W IB2019057160 W IB 2019057160W WO 2020044206 A1 WO2020044206 A1 WO 2020044206A1
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dose
dihydro
kinase inhibitor
compound
rip1 kinase
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PCT/IB2019/057160
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English (en)
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Jill Marinis ANBARI
Michael Reilly
Mukesh K. MAHAJAN
Chetan RATHI
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Glaxosmithkline Intellectual Property Development Limited
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • Receptor-interacting protein- 1 (RIP1) kinase is a TKL family serine/threonine protein kinase involved in innate immune signaling.
  • RIP1 kinase is a RHIM domain containing protein, with an N-terminal kinase domain and a C- terminal death domain (Trends Biochem. Sci. 30, 151-159 (2005)).
  • the death domain of RIP1 mediates interaction with other death domain containing proteins including Fas and TNFR-l (Cell 81, 513-523 (1995)), TRAIL-R1 and TRAIL-R2 (Immunity 7, 821-830 (1997)) and TRADD (Immunity 4, 387-396, (1996)), while the RHIM domain is crucial for binding other RHIM domain containing proteins such as TRIF (Nat Immunol. 5, 503-507 (2004)), DAI (EMBO Rep. 10, 916-922 (2009)) and RIP3 (J. Biol. Chem. 274, 16871- 16875 (1999); Curr. Biol. 9, 539-542 (1999)) and exerts many of its effects through these interactions.
  • RIP1 is a central regulator of cell signaling, and is involved in mediating both pro-survival and programmed cell death pathways which will be discussed below.
  • RIP3 can now enter this complex, become phosphorylated by RIP1 and initiate a caspase -independent programmed necrotic cell death through the activation of MLKL and PGAM5 (Cell 148, 213-227 (2012)); (Cell 148, 228- 243 (2012)); (Proc. Natl. Acad. Sci. USA. 109, 5322-5327 (2012)).
  • DAMPs danger associated molecular patterns
  • Dysregulation of RIP 1 kinase-mediated programmed cell death has been linked to various inflammatory diseases, as demonstrated by use of the RIP3 knockout mouse (where RIP 1 -mediated programmed necrosis is completely blocked) and by Necrostatin-l (a tool inhibitor of RIP 1 kinase activity with poor oral bioavailability).
  • the RIP3 knockout mouse has been shown to be protective in inflammatory bowel disease (including
  • Sepsis/systemic inflammatory response syndrome (SIRS) (Immunity 35, 908-918 (2011)).
  • Necrostatin-l has been shown to be effective in alleviating ischemic brain injury (Nat. Chem. Biol. 1, 112-119 (2005)), retinal ischemia/reperfusion injury (J. Neurosci. Res. 88, 1569-1576 (2010)), Huntington’s disease (Cell Death Dis. 2 el 15 (2011)), renal ischemia reperfusion injury (Kidney Int. 81, 751-761 (2012)), cisplatin induced kidney injury (Ren. Fail. 34, 373-377 (2012)) and traumatic brain injury (Neurochem. Res. 37, 1849-1858 (2012)).
  • pancreatic cancer (Nature 532, 245-249 (2016), Nature 536, 215-218 (2016)), bacterial infections and viral infections (Cell Host & Microbe 15, 23-35 (2014)) (including, but not limited to, tuberculosis and influenza (Cell 153, 1-14, (2013)) and Lysosomal storage diseases (particularly, Gaucher Disease, Nature Medicine Advance Online Publication, 19 January 2014, doi: 10. l038/nm.3449). Inflammation is known to be a contributing factor in the pathogenesis of diabetes and obesity (Chen. et. ak, International Journal of
  • RIP1 is a serine/threonine protein kinase closely aligned with RIP3 in that their co association results in necroptosis (Shutinoski, B. et al. Cell Death Differ. 23, 1628-1637, doi: 10. l038/cdd.20l6.51 (2016)). However, RIP1 additionally drives NF-kB and MAP kinase signaling in response to inflammatory stimuli independently of its association with RIP3 (Meylan, E. et al. Nat. Immunol. 5, 503-507, doi: 10.1038/h ⁇ 1061 (2004) and
  • RIP1 is also a putative master upstream regulator of TLR signaling (Ofengeim, D. & Yuan, J.). Hence, RIP1 may have pleiotropic influences on suppressive macrophage polarization in cancer.
  • a method of treating cancer in a human in need thereof comprising administering to the human a RIP 1 kinase inhibitor at a dose of about 50 mg to about 1600 mg.
  • FIG. 1 A shows the temperature loss over time in mice after oral pre-dosing with the compound of Example 6 or vehicle followed by simultaneous i.v. administration of mouse TNF and zVAD.
  • FIG. 1B shows the temperature loss in mice 3 hours after oral pre-dosing with the compound of Example 6 or vehicle followed by simultaneous i.v. administration of mouse TNF and zVAD.
  • FIG. 2A shows subcutaneous pancreatic tumor model with Example 6 alone or in combination with anti -PD 1 antibody.
  • FIG. 2B shows subcutaneous bladder tumor model with Example 6 alone or in combination with anti -PD 1 antibody.
  • FIG. 3 is a table showing Study Drug Characteristics.
  • FIG. 4 is a plot showing orthotopic tumor pharmacokinetics of Example 6. Detailed Description of the Invention
  • the term“optionally substituted” indicates that the B phenyl group may be unsubstituted, or the phenyl group, may be substituted with one fluoro substituent.
  • the terms“compound(s) of the invention” or“compound(s) of this invention” mean a compound of Formula (I), particularly a compound of any one of Formula (I), as defined herein, in any form, i.e., any salt or non-salt form (e.g., as a free acid or base form, or as a salt, particularly a pharmaceutically acceptable salt thereof) and any physical form thereof (e.g., including non-solid forms (e.g., liquid or semi-solid forms), and solid forms (e.g., amorphous or crystalline forms, specific polymorphic forms, solvate forms, including hydrate forms (e.g., mono-, di-and hemi- hydrates)), and mixtures of various forms.
  • a compound disclosed in WO2014/125444 that inhibits RIP1 kinase is a compound of Formula (I):
  • Y is CHi or CH2CH2
  • Z 2 is CH or CR 2 ;
  • Z 3 is N, CH or CR 3 ;
  • Z 4 is CH or CR 4 ;
  • R 1 is fluoro or methyl; one of R 2 and R 3 is halogen, cyano, (Ci-Ce)alkyl, halo(Ci-C 4 )alkyl,
  • R 4 is fluoro, chloro, methyl or trifluoromethyl
  • R 5 is H or methyl;
  • A is phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocycloalkyl, wherein the carbonyl moiety and L are substituted 1,3 on ring A;
  • m is 0 or m is 1 and
  • R A is (Ci-C4)alkyl;
  • L is O, S, NH, N(CH 3 ), CH 2 , CH 2 CH 2 , CH(CH 3 ), CHF, CF 2 , CH 2 0, CH 2 N(CH ), CH 2 NH, or CH(OH);
  • B is an optionally substituted (C 3 -Ce)cycloalkyl, phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocycloalkyl; wherein said (C 3 -C 6 )cycloalkyl, phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocycloalkyl is unsubstituted or is substituted by one or two substituents each independently selected from halogen, (Ci-C 4 )alkyl, halo(Ci-C 4 )alkyl, (Ci-C 4 )alkoxy, halo(Ci-C4)alkoxy, nitro, and (Ci-C4)alkylC(0)-; or the moiety -
  • a compound that inhibits RIP 1 kinase is a compound according to Formula (II):
  • X is CHi or NH
  • Z 1 is CH
  • Z 2 is CH or CR 2 ;
  • Z 3 is CH;
  • Z 4 is CH or CR 4 ;
  • R 2 and R 4 are each independently selected from chloro or fluoro
  • R 5 is H or methyl
  • L is CHi
  • a 1 and A 4 are C, and A 2 , A 3 , and A 5 are each independently selected
  • B is a phenyl ring, optionally substituted by fluoro; or a salt, particularly a pharmaceutically acceptable salt, thereof.
  • the compounds of Formula (II) do not include:
  • cisplatin acute kidney injury (AKI)) Celiac disease, autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP), transplant rejection (rejection of transplant organs, tissues and cells), ischemia reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome (SIRS), cerebrovascular accident (CVA, stroke), myocardial infarction (MI), atherosclerosis, Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), neonatal brain injury, neonatal hypoxic brain injury, ischemic brain injury, traumatic brain injury allergic diseases (including asthma and atopic dermatitis), peripheral nerve injury, bums, multiple sclerosis, type I diabetes, type II diabetes, obesity, Wegener’s granulomatosis, pulmonary sarcoidosis, Behcet’s disease, interleukin- 1 converting enzyme (ICE, also known as caspas
  • NF-kappa-B essential modulator gene also known as IKK gamma
  • hepatocellular carcinoma mesothelioma, melanoma, metastasis, breast cancer, non-small cell lung carcinoma (NSCLC), radiation induced necrosis (acute radiation syndrome, radiation induced mucositis), ischemic kidney damage, ophthalmologic ischemia,
  • the treatment of the above-noted diseases/disorders may concern, more specifically, the amelioration of organ injury or damage sustained as a result of the noted diseases/disorders.
  • the compounds useful in this invention may be particularly useful for amelioration of brain tissue injury or damage following ischemic brain injury or traumatic brain injury, or for amelioration of heart tissue injury or damage following myocardial infarction, or for amelioration of brain tissue injury or damage associated with Huntington’s disease, Alzheimer’s disease or Parkinson’s disease, or for amelioration of liver tissue injury or damage associated with non-alcohol steatohepatitis, alcohol steatohepatitis, autoimmune hepatitis autoimmune hepatobiliary diseases, or primary sclerosing cholangitis, or overdose of acetaminophen.
  • tissue damage for example, by pre-treatment of a patient prior to administration of cisplatin or pre-treatment of an organ or the organ recipient prior to transplant surgery.
  • Amelioration of such tissue damage may be achieved by treatment with a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, during transplant surgery.
  • Amelioration of such tissue damage may also be achieved by short-term treatment of a patient with a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, after transplant surgery.
  • ARDS Aboratory Distress Syndrome
  • intestinal obstruction liver cirrhosis
  • organ transplantation for donors and recipients
  • major abdominal operations abdominal aortic aneurysm repair, large bowel resections, ischemia-reperfusion injury (including organ (gut, brain, liver, kidney) ischemia, and limb ischemia), bowel ischemia (small intestine and large intestine), and cardiac surgery requiring cardio-pulmonary bypass.
  • ischemia-reperfusion injury including organ (gut, brain, liver, kidney) ischemia, and limb ischemia
  • bowel ischemia small intestine and large intestine
  • cardiac surgery requiring cardio-pulmonary bypass.
  • These diseases or disorders include hemorrhagic shock, trauma (including multiple trauma), traumatic brain injury, bums (thermal injury), heat stroke, acute pancreatitis, critical illness (in general), pneumonias, chemotherapy, radiation injury, radiotherapy, sepsis, septic shock, Stevens-Johnson syndrome, toxic epidermal necrolysis, stroke, stroke-associated pneumonia, Systemic Inflammatory Response Syndrome (SIRS), Multi-Organ Dysfunction Syndrome (MODS), Acute Respiratory Distress Syndrome (ARDS), intestinal obstruction, liver cirrhosis, organ transplantation (for donors and recipients), surgery, major abdominal operations, abdominal aortic aneurysm repair, large bowel resections, ischemia-reperfusion injury (including organ (gut, brain, liver, kidney) ischemia, and limb ischemia), bowel ischemia (small intestine and large intestine), and cardiac surgery requiring cardio-pulmonary bypass.
  • trauma including multiple trauma
  • traumatic brain injury including multiple trauma
  • bums thermal injury
  • the RIP1 kinase-mediated disease or disorder is a solid tumor.
  • this invention is directed to a method of treating a RIP1 kinase-mediated disease or disorder comprising administering a therapeutically effective amount of a compound that inhibits RIP 1 kinase to a human in need thereof.
  • this invention is directed to a method of treating a RIP 1 kinase-mediated disease or disorder comprising administering a therapeutically effective amount of a compound that inhibits RIP1 kinase in combination with an immuno- modulator a human in need thereof.
  • the human has a solid tumor.
  • this invention is directed to a method of treating a RIP 1 kinase-mediated disease or disorder comprising administering a therapeutically effective amount of a compound that inhibits RIP1 kinase to a human in need thereof, wherein the compound that inhibits RIP 1 kinase is a compound of Formulas (I) (a compound of WO2014/125444) and Formula (II), or a pharmaceutically acceptable salt thereof, or is a compound disclosed in W02005/077344 (US7,49l,743), W02007/075772, W02010/07556 (US9,586,880), WO2012/125544, WO2014/125444, WO2016/094846 (now US9,499,52l), W02016/101887, WO2016/185423, W02017/004500 (now US 2017/0008877), US9,643,977, WO2017/096301, WO2017/069279, and/or U.S
  • the present disclosure also relates to a method for treating or lessening the severity of a cancer selected from: brain (gliomas), glioblastomas, astrocytomas, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, triple negative breast cancer, inflammatory breast cancer, Wilm’s tumor, Ewing’s sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, head and neck cancer (including squamous cell carcinoma of head and neck), kidney cancer, lung cancer (including lung squamous cell carcinoma, lung adenocarcinoma, lung small cell carcinoma, and non-small cell lung carcinoma), liver cancer (including hepatocellular carcinoma), melanoma, ovarian cancer, pancreatic cancer (including squamous pancreatic cancer), prostate cancer, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid cancer, lymphoblastic
  • leukemias such as chronic myelocytic leukemia, acute myelocytic leukemia, chronic lymphocytic leukemia and acute lymphocytic leukemia
  • plasma cell malignancies such as multiple myeloma, MGUS and Waldenstrom’s macroglobulinemia
  • lymphomas such as non-Hodgkin’s lymphoma, Hodgkin’s lymphoma; and the like.
  • myelomonoblastic leukemia acute monocytic (or monoblastic) leukemia, erythroleukemia and megakaryocytic (or megakaryoblastic) leukemia.
  • leukemias may be referred together as acute myeloid (or myelocytic or myelogenous) leukemia (AML).
  • Myeloid malignancies also include myeloproliferative disorders (MPD) which include, but are not limited to, chronic myelogenous (or myeloid) leukemia (CML), chronic myelomonocytic leukemia (CMML), essential thrombocythemia (or thrombocytosis), and polcythemia vera (PCV).
  • CML chronic myelogenous leukemia
  • CMML chronic myelomonocytic leukemia
  • PCV polcythemia vera
  • Myeloid malignancies also include myelodysplasia (or myelodysplastic syndrome or MDS), which may be referred to as refractory anemia (RA), refractory anemia with excess blasts (RAEB), and refractory anemia with excess blasts in transformation
  • RA refractory anemia
  • RAEB refractory anemia with excess blasts
  • RAEB refractory anemia with excess blasts
  • RAEBT myelofibrosis
  • MFS myelofibrosis
  • specific examples of clinical conditions based on hematologic tumors include leukemias such as chronic myelocytic leukemia, acute myelocytic leukemia, chronic lymphocytic leukemia and acute lymphocytic leukemia; plasma cell malignancies such as multiple myeloma, MGUS and Waldenstrom’s macroglobulinemia; lymphomas such as non-Hodgkin’s lymphoma, Hodgkin’s lymphoma; and the like.
  • Hematopoietic cancers also include lymphoid malignancies, which may affect the lymph nodes, spleens, bone marrow, peripheral blood, and/or extranodal sites.
  • Lymphoid cancers include B-cell malignancies, which include, but are not limited to, B-cell non- Hodgkin’s lymphomas (B-NHLs).
  • B-NHLs may be indolent (or low-grade), intermediate- grade (or aggressive) or high-grade (very aggressive).
  • Indolent B cell lymphomas include follicular lymphoma (FL); small lymphocytic lymphoma (SLL); marginal zone lymphoma (MZL) including nodal MZL, extranodal MZL, splenic MZL and splenic MZL with villous lymphocytes; lymphoplasmacytic lymphoma (LPL); and mucosa-associated-lymphoid tissue (MALT or extranodal marginal zone) lymphoma.
  • FL follicular lymphoma
  • SLL small lymphocytic lymphoma
  • MZL marginal zone lymphoma
  • LPL lymphoplasmacytic lymphoma
  • MALT mucosa-associated-lymphoid tissue
  • Intermediate-grade B-NHLs include mantle cell lymphoma (MCL) with or without leukemic involvement, diffuse large cell lymphoma (DLBCL), follicular large cell (or grade 3 or grade 3B) lymphoma, and primary mediastinal lymphoma (PML).
  • MCL mantle cell lymphoma
  • DLBCL diffuse large cell lymphoma
  • follicular large cell or grade 3 or grade 3B lymphoma
  • PML primary mediastinal lymphoma
  • High-grade B-NHLs include Burkitt’s lymphoma (BL), Burkitt-like lymphoma, small non-cleaved cell lymphoma (SNCCL) and
  • B-NHLs include immunoblastic lymphoma (or immunocytoma), primary effusion lymphoma, HIV associated (or AIDS related) lymphomas, and post-transplant lymphoproliferative disorder (PTLD) or lymphoma.
  • B- cell malignancies also include, but are not limited to, chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), Waldenstrom’s macroglobulinemia (WM), hairy cell leukemia (HCL), large granular lymphocyte (LGL) leukemia, acute lymphoid (or lymphocytic or lymphoblastic) leukemia, and Castleman’s disease.
  • Hematopoietic cancers also include Hodgkin’s lymphoma (or disease) including classical Hodgkin’s lymphoma, nodular sclerosing Hodgkin’s lymphoma, mixed cellularity Hodgkin’s lymphoma, lymphocyte predominant (LP) Hodgkin’s lymphoma, nodular LP Hodgkin’s lymphoma, and lymphocyte depleted Hodgkin’s lymphoma.
  • Hodgkin’s lymphoma or disease
  • classical Hodgkin’s lymphoma including classical Hodgkin’s lymphoma, nodular sclerosing Hodgkin’s lymphoma, mixed cellularity Hodgkin’s lymphoma, lymphocyte predominant (LP) Hodgkin’s lymphoma, nodular LP Hodgkin’s lymphoma, and lymphocyte depleted Hodgkin’s lymphoma.
  • LP lymphocyte predominant
  • Hematopoietic cancers also include plasma cell diseases or cancers such as multiple myeloma (MM) including smoldering MM, monoclonal gammopathy of undetermined (or unknown or unclear) significance (MGUS), plasmacytoma (bone, extramedullary), lymphoplasmacytic lymphoma (LPL), Waldenstrom’s Macroglobulinemia, plasma cell leukemia, and primary amyloidosis (AL).
  • MM multiple myeloma
  • MGUS monoclonal gammopathy of undetermined (or unknown or unclear) significance
  • MGUS monoclonal gammopathy of undetermined (or unknown or unclear) significance
  • plasmacytoma bone, extramedullary
  • LPL lymphoplasmacytic lymphoma
  • Waldenstrom’s Macroglobulinemia plasma cell leukemia
  • AL primary amyloidosis
  • Hematopoietic cancers may also include other cancers of additional hematopoietic cells
  • Tissues which include hematopoietic cells referred herein to as“hematopoietic cell tissues” include bone marrow; peripheral blood; thymus; and peripheral lymphoid tissues, such as spleen, lymph nodes, lymphoid tissues associated with mucosa (such as the gut-associated lymphoid tissues), tonsils, Peyer’s patches and appendix, and lymphoid tissues associated with other mucosa, for example, the bronchial linings.
  • one embodiment of this invention is directed to a method of inhibiting RIP1 kinase comprising contacting said kinase with a compound useful in this invention.
  • this invention is directed to a method of inhibiting RIP1 kinase comprising contacting a cell with a compound useful in this invention.
  • Another embodiment of this invention is directed to a method of treating a RIP 1 kinase-mediated disease or disorder (specifically, a disease or disorder recited herein) comprising administering a therapeutically effective amount of a compound that inhibits RIP 1 kinase to a human in need thereof.
  • Another embodiment of this invention is directed to a method of treating a RIP 1 kinase-mediated disease or disorder (specifically, a disease or disorder recited herein) comprising administering a therapeutically effective amount of a compound that inhibits RIP 1 kinase with at least one other therapeutically active agent to a human in need thereof.
  • the invention is directed to a method of treating a RIP1 kinase-mediated disease or disorder comprising administering a therapeutically effective amount of a compound useful in this invention, particularly a compound of Formula (I), (II), or (III), or a salt, particularly a pharmaceutically acceptable salt thereof, to a human in need thereof.
  • the invention is directed to a method of treating a RIP 1 kinase-mediated disease or disorder comprising administering a therapeutically effective amount of a compound useful in this invention, particularly a compound of Formula (I), (II), or (III), or a salt, particularly a pharmaceutically acceptable salt thereof, with at least one other therapeutically active agent to a human in need thereof.
  • this invention provides a method of treating a RIP 1 kinase-mediated disease or disorder (specifically, a disease or disorder recited herein) comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, to a human in need thereof. More specifically, this invention provides a method of treating a RIP1 kinase-mediated disease or disorder (specifically, a disease or disorder recited herein) comprising administering a
  • the invention is directed to a method of treating a RIP 1 kinase-mediated disease or disorder (specifically, a disease or disorder recited herein) comprising administering a therapeutically effective amount of (S)-5-(2-fluorobenzyl)-N- ( 1 -methyl -2 -oxo-2, 3 ,4,5 -tetrahydro- lH-benzo [b] [ 1 ,4]diazepin-3 -yl)- 1H- 1 ,2,4-triazole-3 - carboxamide, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, to a human in need thereof.
  • a RIP 1 kinase-mediated disease or disorder specifically, a disease or disorder recited herein
  • this invention provides a compound that inhibits RIP1 kinase for use in therapy.
  • This invention also provides a compound useful in this invention, particularly a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in therapy.
  • this invention provides a compound described herein, or a pharmaceutically acceptable salt thereof, for use in therapy.
  • this invention provides (S)-5-(2-fluorobenzyl)-N-(l-methyl-2- oxo-2,3,4,5-tetrahydro-lH-benzo[b][l,4]diazepin-3-yl)-lH-l,2,4-triazole-3-carboxamide, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, for use in therapy.
  • this invention provides a compound that inhibits RIP1 kinase for use in the treatment of a RIP1 kinase -mediated disease or disorder (for example, a disease or disorder recited herein).
  • this invention provides a compound that inhibits RIP 1 kinase with at least one other therapeutically active agent for use in the treatment of a RIP 1 kinase-mediated disease or disorder (for example, a disease or disorder recited herein).
  • This invention particularly provides a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in the treatment of a RIP 1 kinase-mediated disease or disorder.
  • This invention particularly provides a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, with at least one other therapeutically active agent, for use in the treatment of a RIP 1 kinase-mediated disease or disorder.
  • this invention provides a compound described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a RIP1 kinase- mediated disease or disorder. More specifically, this invention provides (S)-5-(2- fluorobenzyl)-N-( 1 -methyl-2-oxo-2,3,4,5-tetrahydro- lH-benzo[b] [ 1 ,4]diazepin-3-yl)- 1H-
  • a RIP 1 kinase-mediated disease or disorder for example, a disease or disorder recited herein.
  • This invention specifically provides for the use of a compound that inhibits RIP1 kinase as an active therapeutic substance.
  • This invention specifically provides for the use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, as an active therapeutic substance. More specifically, this invention provides for the use of a compound described herein for the treatment of a RIP1 kinase-mediated disease or disorder.
  • the invention provides for the use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, as an active therapeutic substance in the treatment of a human in need thereof with a RIP 1 kinase-mediated disease or disorder.
  • this invention provides the invention provides for the use of (S)- 5-(2-fluorobenzyl)-N-(l-methyl-2 -oxo-2, 3, 4, 5-tetrahydro-lH-benzo [b][l,4]diazepin-3-yl)- lH-l,2,4-triazole-3-carboxamide, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, as an active therapeutic substance in the treatment of a human in need thereof with a RIP1 kinase-mediated disease or disorder.
  • this invention provides the invention provides for the use of (S)-5-(2-fluorobenzyl)-N-(l-methyl-2-oxo- 2,3,4,5-tetrahydro-lH-benzo[b][l,4]diazepin-3-yl)-lH-l,2,4-triazole-3-carboxamide, or a tautomer thereof, as an active therapeutic substance in the treatment of a human in need thereof with a RIP1 kinase-mediated disease or disorder.
  • the invention further provides for the use of a compound that inhibits RIP 1 kinase in the manufacture of a medicament for the treatment of a RIP 1 kinase-mediated disease or disorder, for example the diseases and disorders recited herein.
  • the invention further provides for the use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a RIP 1 kinase-mediated disease or disorder.
  • the invention provides for the use of a compound described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a RIP1 kinase-mediated disease or disorder.
  • the invention provides for the use of (S)-5-(2-fluorobenzyl)- N-(l-methyl-2 -oxo-2, 3, 4, 5-tetrahydro-lH-benzo [b][l, 4]diazepin-3-yl)-lH-l, 2, 4-triazole-3- carboxamide, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a RIP1 kinase-mediated disease or disorder, for example the diseases and disorders recited herein.
  • the invention provides forthe use of (S)-5-(2-fluorobenzyl)-N-(l-methyl-2-oxo-2,3,4,5-tetrahydro-lH- benzo[b][l,4]diazepin-3-yl)-lH-l,2,4-triazole-3-carboxamide, or a tautomer thereof, in the manufacture of a medicament for the treatment of a RIP1 kinase-mediated disease or disorder, for example the diseases and disorders recited herein.
  • RIP 1 kinase-mediated disease or disorders specifically suitable for treatment using a compound that inhibits RIP1 kinase are diseases and disorders selected from inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), psoriasis, retinal detachment, retinitis pigmentosa, arthritis (including rheumatoid arthritis,
  • spondyloarthritis gout, osteoarthritis, and systemic onset juvenile idiopathic arthritis (SoJIA)
  • transplant rejection organ transplantation (for donors and recipients), multiple sclerosis, tumor necrosis factor receptor-associated periodic syndrome, multiple organ dysfunction syndrome (MODS), thermal injury/bum, systemic inflammatory response syndrome (SIRS), radiation injury, radiotherapy, chemotherapy, pneumonias, hemorrhagic shock, trauma (including multiple trauma), traumatic brain injury, acute pancreatitis, critical illness (in general), sepsis, septic shock, Stevens-Johnson syndrome, toxic epidermal necrolysis, stroke, heat stroke, stroke-associated pneumonia, Multi-Organ Dysfunction Syndrome (MODS), Acute Respiratory Distress Syndrome (ARDS), intestinal obstruction, liver cirrhosis, surgery, major abdominal operations, abdominal aortic aneurysm repair, large bowel resections, ischemia reperfusion injury (including ischemia reperfusion injury of solid organs, (gut,
  • a compound that inhibits RIP1 kinase is (S)-5-(2- fluorobenzyl)-N-( 1 -methyl-2-oxo-2,3,4,5-tetrahydro- lH-benzo[b] [ 1 ,4]diazepin-3-yl)- 1H- l,2,4-triazole-3-carboxamide or (S)-5-benzyl-N-(7,9-difluoro-2-oxo-2,3,4,5-tetrahydro-lH- benzo[b]azepin-3-yl)-4H-l,2,4-triazole-3-carboxamide; or a tautomer thereof; or a pharmaceutically acceptable salt thereof.
  • a compound that inhibits RIP1 kinase is (S)-5-benzyl-N-(5- methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)-4H-l,2,4-triazole-3- carboxamide; or a tautomer thereof; or a pharmaceutically acceptable salt thereof.
  • a compound that inhibits RIP1 kinase is (S)-5-benzyl-N-(5-methyl-4- oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)-4H-l,2,4-triazole-3-carboxamide; or a tautomer thereof.
  • a compound that inhibits RIP1 kinase is:
  • a compound that inhibits RIP1 kinase is:
  • a compound that inhibits RIP1 kinase is: or a pharmaceutically acceptable salt thereof, or a tautomer thereof.
  • a compound that inhibits RIP1 kinase is:
  • a compound that inhibits RIP1 kinase is:
  • a compound disclosed in US 9,815,850 (U.S. Patent Application No. 15/424,216, the disclosure of which is incorporated by reference herein) that inhibits RIP 1 kinase is a compound having the formula:
  • R’ is H or optionally substituted C1-C6 alkyl; X 1 and X 2 together form an optionally substituted pyridyl:
  • Y 2 is -0-
  • R 3 and R 4 are independently H, halo, or optionally substituted C1-C6 alkyl, or R 3 and R 4 together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring;
  • A is an optionally substituted cycloalkyl, optionally substituted heterocyclyl ring or optionally substituted heteroaryl ring;
  • L is absent, -0-, -S-, -S(O)-, -S(0) 2 -; -NR 7 - or C(R 8 ) 2 -;
  • R is H or optionally substituted C1-C6 alkyl; each R 8 is independently H, halo, or optionally substituted C1-C6 alkyl, or two R 8 together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; and
  • R 9 is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; wherein each optionally substituted pyridyl, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl ring is independently optionally substituted by one or more substituents, provided that the
  • each R 100 is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, -OC(0)R, and -C(0)OR, wherein R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; and further wherein: each cycloalkyl is independently a saturated or partially unsaturated cyclic alkyl group of from 3 to 20 ring carbon atoms having a single ring or multiple rings, wherein the cycloalkyl may be fused, bridged, or spiro; each heterocyclyl is independently a saturated or unsaturated cyclic alkyl group of from 2 to 20 ring carbon atoms with one to five
  • a compound that inhibits RIP1 kinase is a compound having the formula:
  • a compound disclosed in US9,499,52l (the disclosure of which is incorporated by reference herein, corresponding to WO2016/094846) that inhibits RIP1 kinase is a compound having the formula: or a pharmaceutically acceptable salt thereof.
  • R 1 is selected from the group consisting of H and unsubstituted C1-C4 alkyl; the A ring is selected from the group consisting of cyclopropyl, 6 membered aryl, and 5 to 6 membered heteroaryl having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; wherein the A ring is optionally substituted with:
  • the B ring is tetrazolyl or a 5 to 6 membered heteroaryl having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; wherein the B ring is optionally substituted with 1 to 2 substituents selected from the group consisting of halogen, C1-C4 alkyl, C3-C4 cycloalkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C44 haloalkoxy and cyano; and wherein if a nitrogen atom in the B ring is substituted, the substituent is not halogen, C1-C4 alkoxy, C1-C4 haloalkoxy,
  • the C ring is selected from the group consisting of phenyl, 5 to 6 membered heteroaryl, 5 to 7 membered cycloalkyl, and 5 to 7 membered heterocyclyl;
  • substituents selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 thioalkyl, cyano, phenyl, benzyl, CH2-(C3-C 6 cycloalkyl), and CH2CH2-(C3-C 6 cycloalkyl); wherein if a nitrogen atom in the C ring is substituted, the substituent is not halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 thioalkyl, or cyano;
  • Z 1 is N ⁇ m is 1 or 4; and n is 1; provided that if the A ring is 6 membered aryl or 6 membered heteroaryl, Lis absent such that the B ring and the C ring are fused; further provided that if the A ring is a 5 to 6 membered heteroaryl having 3 heteroatoms, two of said heteroatoms must be nitrogen; further provided that if the A ring is unsubstituted 6 membered aryl and Lis absent, the fused B, and C rings are not unsubstituted indolyl or indolyl substituted by one or two halogen atoms; and further provided that if the B ring is tetrazolyl, Lis selected from the group consisting of CFh, CFlfLFF) CH(CH 3 )2, C(CH 3 )2, CF2; and the C ring is phenyl.
  • a compound disclosed in W02017/004500 now US
  • oxygen-containing heterocycloalkyl 5-6 membered heteroaryl, 9-membered heteroaryl, 9-10 membered carbocyclic-aryl, or 9-10 membered heterocyclic-aryl group,
  • heterocycloalkyl 5-6 membered heteroaryl, 9-membered heteroaryl, 9-10 membered carbocyclic-aryl, or 9-10 membered heterocyclic-aryl group is substituted by 1, 2 or 3 substituents independently selected from halogen, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, and cyano; and R 3 is H or halogen;
  • R 1 is a substituted or unsubstituted 5-6 membered heteroaryl or 9-10 membered heteroaryl group
  • (C2-C4)alkynyl optionally substituted (Ci-C4)alkoxy, optionally substituted 5-6 membered heterocycloalkyl-CO-, fused 5-6 membered heterocycloalkyl, H2N-, ((Ci-C4)alkyl)-NH-, ((Ci-C4)alkyl)((Ci-C4)alkyl)N-, H2NCO-,
  • heterocycloalkyl-NHCO ((Ci-C4)alkyl)((Ci-C4)alkyl)N-CO-,
  • R 2 is a substituted or unsubstituted phenyl or 5-6 membered heteroaryl group
  • substituted phenyl or 5-6 membered heteroaryl group is substituted by 1 or 2 substituents independently selected from halogen, (Ci-C 4 )alkyl,
  • a compound can be prepared from a compound of Formula J according to Scheme 3. Reaction of the primary amide of a compound of Formula J with phosphorous oxychloride provides a compound possessing a nitrile (Formula K). Alternatively, a compound may be prepared from another compound possessing a preexisting halogen (Formula F) according to Scheme 4. Reaction of a compound of Formula F with a primary or secondary amine under nucleophilic aromatic substitution conditions provides a compound of Formula M.
  • a method of treating cancer in a human in need thereof comprising administering to the human a RIP 1 kinase inhibitor at a dose of about 50 mg to about 1600 mg.
  • a method of treating cancer in a human in need thereof comprising administering to the human a RIP 1 kinase inhibitor at a dose of about 50 mg to about 1600 mg, and administering to the human a PD 1 antagonist at a dose of about 200 mg.
  • a RIP1 kinase inhibitor wherein the RIP1 kinase inhibitor is to be administered at a dose of about 50 mg to about 1600 mg.
  • a RIP1 kinase inhibitor for use in treating cancer wherein the RIP1 kinase inhibitor is to be administered at a dose of about 50 mg to about 1600 mg.
  • a pharmaceutical kit comprising about 50 mg to about 1600 mg of a RIP1 kinase inhibitor is provided.
  • a RIP1 kinase inhibitor for use in treating cancer wherein the RIP1 kinase inhibitor is to be administered at a dose of about 50 mg to about 1600 mg and is to be administered simultaneously or sequentially with a PD1 antagonist at a dose of about 200 mg.
  • a RIP1 kinase inhibitor in the manufacture of a medicament for treating cancer, wherein the RIP 1 kinase inhibitor is to be administered at a dose of about 50 mg to 1600 mg and is to be administered simultaneously or sequentially with a PD1 antagonist at a dose of about 200 mg.
  • a pharmaceutical kit comprising about 50 mg to about 1600 mg of a RIP1 kinase inhibitor and about 200 mg of a PD1 antagonist.
  • the RIP 1 kinase inhibitor is administered at a dose of about 100 mg to about 1600 mg. In one embodiment, the RIP1 kinase inhibitor is administered at a dose of 50 mg,
  • the PD1 antagonist is pembrolizumab or nivolumab. In one embodiment, the PD1 antagonist is pembrolizumab. In another embodiment, the PD1 antagonist is nivolumab.
  • the RIP1 kinase inhibitor is administered orally. In another embodiment, the PD1 antagonist is administered intravenously.
  • a method of treating cancer in a human in need thereof comprising administering to the human a RIP1 kinase inhibitor at a dose of 50 mg, 100 mg, 200 mg, 400 mg, 800 mg, or 1600 mg, and administering to the human an anti-PD 1 antibody or antigen binding portion thereof at a dose of 200 mg, wherein the anti-PD 1 antibody is pembrolizumab, and wherein the RIP1 kinase inhibitor is:
  • a RIP 1 kinase inhibitor and a PD 1 antagonist for simultaneous or sequential use in treating cancer wherein the RIP1 kinase inhibitor is to be administered at a dose of 50 mg, 100 mg, 200 mg, 400 mg, 800 mg, or 1600 mg, and the PD 1 antagonist is to be administered at a dose of 200 mg, wherein the PD 1 antagonist is pembrolizumab, and wherein the RIP1 kinase inhibitor is or a pharmaceutically acceptable salt thereof.
  • the human has a solid tumor.
  • the solid tumor is advanced solid tumor.
  • the cancer is selected from pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), and melanoma.
  • the cancer is selected from head and neck cancer, squamous cell carcinoma of the head and neck (SCCHN), gastric cancer, melanoma, renal cell carcinoma (RCC), esophageal cancer, non-small cell lung carcinoma, prostate cancer, colorectal cancer, ovarian cancer and pancreatic cancer.
  • the human has one or more of the following: SCCHN, colorectal cancer (CRC), esophageal, cervical, bladder, breast, head and neck, ovarian, melanoma, renal cell carcinoma (RCC), EC squamous cell, non-small cell lung carcinoma, mesothelioma, and prostate cancer.
  • SCCHN colorectal cancer
  • CRC colorectal cancer
  • RRC renal cell carcinoma
  • EC squamous cell non-small cell lung carcinoma
  • mesothelioma mesothelioma
  • prostate cancer a liquid tumor such as diffuse large B cell lymphoma (DLBCL), multiple myeloma, chronic lyphomblastic leukemia (CLL), follicular lymphoma, acute myeloid leukemia and chronic myelogenous leukemia.
  • DLBCL diffuse large B cell lymphoma
  • CLL chronic lyphomblastic leukemia
  • a cancer cell refers to cells that have undergone a malignant transformation that makes them pathological to the host organism.
  • Primary cancer cells can be readily distinguished from non-cancerous cells by well-established techniques, particularly histological examination.
  • the definition of a cancer cell includes not only a primary cancer cell, but any cell derived from a cancer cell ancestor. This includes metastasized cancer cells, and in vitro cultures and cell lines derived from cancer cells.
  • a“clinically detectable” tumor is one that is detectable on the basis of tumor mass; e.g., by procedures such as computed tomography (CT) scan, magnetic resonance imaging (MRI), X-ray, ultrasound or palpation on physical examination, and/or which is detectable because of the expression of one or more cancer-specific antigens in a sample obtainable from a patient.
  • CT computed tomography
  • MRI magnetic resonance imaging
  • X-ray X-ray
  • ultrasound or palpation e.g., ultrasound or palpation on physical examination
  • the cancer may be any cancer in which an abnormal number of blast cells or unwanted cell proliferation is present or that is diagnosed as a hematological cancer, including both lymphoid and myeloid malignancies.
  • Myeloid malignancies include, but are not limited to, acute myeloid (or myelocytic or myelogenous or myeloblastic) leukemia (undifferentiated or differentiated), acute promyeloid (or promyelocytic or
  • myelomonoblastic leukemia acute monocytic (or monoblastic) leukemia, erythroleukemia and megakaryocytic (or megakaryoblastic) leukemia.
  • leukemias may be referred together as acute myeloid (or myelocytic or myelogenous) leukemia (AML).
  • Myeloid malignancies also include myeloproliferative disorders (MPD) which include, but are not limited to, chronic myelogenous (or myeloid) leukemia (CML), chronic myelomonocytic leukemia (CMML), essential thrombocythemia (or thrombocytosis), and polycythemia vera (PCV).
  • CML chronic myelogenous leukemia
  • CMML chronic myelomonocytic leukemia
  • PCV polycythemia vera
  • Hematopoietic cancers also include lymphoid malignancies, which may affect the lymph nodes, spleens, bone marrow, peripheral blood, and/or extranodal sites.
  • Lymphoid cancers include B-cell malignancies, which include, but are not limited to, B-cell non- Hodgkin’s lymphomas (B-NHLs). B-NHLs may be indolent (or low-grade), intermediate- grade (or aggressive) or high-grade (very aggressive).
  • Intermediate-grade B-NHLs include mantle cell lymphoma (MCL) with or without leukemic involvement, diffuse large cell lymphoma (DLBCL), follicular large cell (or grade 3 or grade 3B) lymphoma, and primary mediastinal lymphoma (PML).
  • MCL mantle cell lymphoma
  • DLBCL diffuse large cell lymphoma
  • follicular large cell or grade 3 or grade 3B lymphoma
  • PML primary mediastinal lymphoma
  • High-grade B-NHLs include Burkitt’s lymphoma (BL), Burkitt-like lymphoma, small non-cleaved cell lymphoma (SNCCL) and
  • B-NHLs include immunoblastic lymphoma (or immunocytoma), primary effusion lymphoma, HIV associated (or AIDS related) lymphomas, and post-transplant lymphoproliferative disorder (PTLD) or lymphoma.
  • B- cell malignancies also include, but are not limited to, chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), Waldenstrom’s macroglobulinemia (WM), hairy cell leukemia (HCL), large granular lymphocyte (LGL) leukemia, acute lymphoid (or lymphocytic or lymphoblastic) leukemia, and Castleman’s disease.
  • NHL may also include T-cell non-Hodgkin’s lymphoma s(T-NHLs), which include, but are not limited to T-cell non-Hodgkin’s lymphoma not otherwise specified (NOS), peripheral T-cell lymphoma (PTCL), anaplastic large cell lymphoma (ALCL), angioimmunoblastic lymphoid disorder (AILD), nasal natural killer (NK) cell / T-cell lymphoma, gamma/delta lymphoma, cutaneous T cell lymphoma, mycosis fungoides, and Sezary syndrome.
  • T-NHLs T-cell non-Hodgkin’s lymphoma s(T-NHLs)
  • Hematopoietic cancers also include Hodgkin’s lymphoma (or disease) including classical Hodgkin’s lymphoma, nodular sclerosing Hodgkin’s lymphoma, mixed cellularity
  • “treating” means: (1) to ameliorate the condition or one or more of the biological manifestations of the condition, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition (3) to alleviate one or more of the symptoms, effects or side effects associated with the condition or one or more of the symptoms, effects or side effects associated with the condition or treatment thereof, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition.
  • the compounds useful in this invention may be administered by any suitable route of administration, including both systemic administration and topical administration.
  • Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation.
  • Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion.
  • Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion.
  • Inhalation refers to administration into the patient’s lungs whether inhaled through the mouth or through the nasal passages.
  • Topical administration includes application to the skin.
  • duration of treatment and the time period of administration (time period between dosages and the timing of the dosages, e.g., before/with/after meals) of the compound will vary according to the identity of the mammal in need of treatment (e.g., weight), the particular compound and its properties (e.g., pharmacokinetic properties), disease or disorder and its severity and the specific composition and method being used, but can nevertheless be determined by one of skill in the art.
  • the invention also is directed to pharmaceutical compositions comprising a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising (S)-5-(2-fluorobenzyl)-N-(l-methyl- 2-oxo-2,3,4,5-tetrahydro-lH-benzo[b][l,4]diazepin-3-yl)-lH-l,2,4-triazole-3- carboxamide, or a tautomer thereof, and at least one pharmaceutically acceptable excipient.
  • combination therapies according to the present invention comprise the administration of at least one compound that inhibits RIP1 kinase, particularly a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, and at least one other therapeutically active agent, specifically one or two other therapeutically active agents, more specifically one other therapeutically active agent.
  • the other therapeutically active agent administered in combination with a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof includes any agent that is considered as a“standard of care” therapy for that disease or disorder. Many of such standard of care therapies are described hereinbelow.
  • “antigen binding protein” is any protein, including but not limited to antibodies, domains and other constructs described herein, that binds to an antigen, such as PD-l, or PDL-l .
  • “antigen binding portion” of an antigen binding protein would include any portion of the antigen binding protein capable of binding to its target, including but not limited to, an antigen binding antibody fragment.
  • Agonist activity can be measured in vitro by various assays know in the art such as, but not limited to, measurement of cell signaling, cell proliferation, immune cell activation markers, cytokine production. Agonist activity can also be measured in vivo by various assays that measure surrogate end points such as, but not limited to the measurement of T cell proliferation or cytokine production.
  • an“agonist antibody” is an antibody that upon contacting its target elicits at least one of the activities of an agonist.
  • Agonist antibodies or antigen binding proteins of the present invention include, but are not limited to, agonist ICOS antibodies and agonist OX-40 antibodies.
  • A“blocking” antibody or an“antagonist” antibody is one that inhibits or reduces a biological activity of the antigen it binds.
  • blocking antibodies or antagonist antibodies substantially or completely inhibit the biological activity of the antigen.
  • the anti-PD-l, anti-PD-Ll antibodies of the invention block the signaling through PD-l and restores a functional response by T-cells from a dysfunctional state to antigen stimulation.
  • Anti-CTLA4 antibodies of the present invention block inhibits TCR- and CD-28 mediated signal transduction. CTLA-4 engagement results in the inhibition of IL-2 synthesis and progression through the cell cycle and termination of T-cell responses.
  • the protein scaffold may be an Ig scaffold, for example an IgG, or IgA scaffold.
  • the IgG scaffold may comprise some or all the domains of an antibody (i.e. CH1, CH2, CH3, VH, VL).
  • the antigen binding protein may comprise an IgG scaffold selected from IgGl, IgG2, IgG3, IgG4 or IgG4PE.
  • the scaffold may be IgGl .
  • the scaffold may consist of, or comprise, the Fc region of an antibody, or is a part thereof.
  • the protein scaffold may be a derivative of a scaffold selected from the group consisting of CTLA-4, lipocalin, Protein A derived molecules such as Z-domain of Protein A (Affibody, SpA), A-domain (Avimer/Maxibody); heat shock proteins such as GroEl and GroES; transferrin (trans-body); ankyrin repeat protein (DARPin); peptide aptamer; C-type lectin domain (Tetranectin); human g-crystallin and human ubiquitin (affilins); PDZ domains; scorpion toxin kunitz type domains of human protease inhibitors; and fibronectin/adnectin; which has been subjected to protein engineering in order to obtain binding to an antigen, such as ICOS, other than the natural ligand.
  • Protein A derived molecules such as Z-domain of Protein A (Affibody, SpA), A-domain (Avimer/Maxibody); heat shock proteins such as GroEl and GroES;
  • Antigen binding site refers to a site on an antigen binding protein which is capable of specifically binding to an antigen, this may be a single variable domain, or it may be paired VH/VL domains as can be found on a standard antibody.
  • Single-chain Fv (ScFv) domains can also provide antigen-binding sites.
  • the term“epitope-binding domain” refers to a domain that specifically binds to a region of an antigen known as the epitope independently of a different domain.
  • the term multi-specific antigen binding protein refers to antigen binding proteins which comprise at least two different antigen binding sites. Each of these antigen-binding sites will be capable of binding to a different epitope, which may be present on the same antigen or different antigens.
  • the multi-specific antigen binding protein will have specificity for more than one antigen, for example two antigens, or for three antigens, or for four antigens.
  • ICOS antigen binding proteins comprising an IgG4 Fc region comprising the replacement S228P and L235E may have the designation IgG4PE.
  • an ICOS binding protein having the heavy chain variable region H2 and the light chain variable region L5 and an IgG4PE Fc region will be designated as H2L5 IgG4PE or synonymously as H2L5 hIgG4PE.
  • anti-PD-Ul antibody is YW243.55.S70 which is an anti-PD-Ul described in WO 2010/077634 and U.S. Pat. No. 8,217,149.
  • anti-PD-Ul antibodies useful for the methods of this invention, and methods for making thereof are described in PCT patent application WO 2010/077634, WO 2007/005874, WO 2011/066389, U.S.
  • Specific anti-human PD-U1 mAbs useful as the PD-l antagonist in the treatment method, medicaments and uses of the present invention include MPDU3280A, BMS-936559, MEDI4736, MSB0010718C.
  • a“PD-U1 binding antagonist” is a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-L1 with either one or more of its binding partners, such as PD-l and/or B7-1.
  • a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L 1 to its binding partners.
  • the PD-L1 binding antagonist inhibits binding of PD-L 1 to PD-l and/or B7-1.
  • PD-l antagonist examples of other therapeutic agents (anti-neoplastic agent or immuno-modulators) for use in combination or co-administered with a RIP1 inhibitor compound are PD-l antagonist.
  • PD-l antagonist means any chemical compound or biological molecule that blocks binding of PD-L 1 expressed on a cancer cell to PD-l expressed on an immune cell (T cell, B cell or NKT cell) and preferably also blocks binding of PD-L2 expressed on a cancer cell to the immune-cell expressed PD-L
  • Alternative names or synonyms for PD-l and its ligands include: PDCD1, PD1, CD279 and SLEB2 for PD- 1; PDCD1L1, PDL1, B7H1, B7-4, CD274 and B7-H for PD-L1; and PDCD1L2,
  • the PD-l antagonist blocks binding of human PD-L1 to human PD-l, and preferably blocks binding of both human PD-L1 and PD-L2 to human PD-L
  • Human PD-l amino acid sequences can be found in NCBI Locus No.: NP 005009.
  • Human PD-L1 and PD-L2 amino acid sequences can be found in NCBI Locus No.: NP_054862 and NP_0795 l5, respectively.
  • PD-l antagonists useful in any of the aspects of the present invention include a monoclonal antibody (mAb), or antigen binding fragment thereof, which specifically binds to PD-l or PD-L1, and preferably specifically binds to human PD-l or human PD-L1.
  • the mAb may be a human antibody, a humanized antibody or a chimeric antibody, and may include a human constant region.
  • the human constant region is selected from the group consisting of IgGl, IgG2, IgG3 and IgG4 constant regions, and in preferred embodiments, the human constant region is an IgGl or IgG4 constant region.
  • the antigen binding fragment is selected from the group consisting of Fab, Fab’-SH, F(ab’)2, scFv and Fv fragments.
  • Specific anti -human PD- 1 mAbs useful as the PD- 1 antagonist in any of the aspects and embodiments of the present invention include: MK-3475, a humanized IgG4 mAb with the structure described in WHO Drug Information, Vol. 27, No. 2, pages 161-162 (2013) and which comprises the heavy and light chain amino acid sequences shown in Figure 6; nivolumab, a human IgG4 mAb with the structure described in WHO Drug Information, Vol. 27, No.
  • immunoadhesion molecules that specifically bind to PD-l are described in WO2010/027827 and WO2011/066342.
  • AMP-224 also known as B7-DCIg
  • B7-DCIg a PD-U2-FC fusion protein and binds to human PD-l.
  • KEYTRUDA/pembrolizumab is an anti-PD- 1 antibody marketed for the treatment of lung cancer by Merck. The amino acid sequence of pembrolizumab and methods of using are disclosed in US Patent No 8.168.757.
  • any mouse or chimeric sequences of any anti-PD- 1 of a combination of the invention, or a method or use thereof, are engineered to make a humanized antibody.
  • Opdivo/nivolumab is a fully human monoclonal antibody marketed by Bristol Myers Squibb directed against the negative immunoregulatory human cell surface receptor PD-l (programmed death-l or programmed cell death-l/PCD-l) with immunopotentiation activity.
  • Nivolumab binds to and blocks the activation of PD-l, an Ig superfamily transmembrane protein, by its ligands PD-L1 and PD-L2, resulting in the activation of T- cells and cell-mediated immune responses against tumor cells or pathogens.
  • Activated PD- 1 negatively regulates T-cell activation and effector function through the suppression of PI3K/Akt pathway activation.
  • Other names for nivolumab include: BMS-936558, MDX- 1106, and ONO-4538. The amino acid sequence for nivolumab and methods of using and making are disclosed in US Patent No. US 8.008.449.
  • Step 6 (S)-5-(2-Fluorobenzyl)-N-(l-methyl-2-oxo-2,3,4,5-tetrahydro-lH- benzo [b] [ 1 ,4]diazepin-3 -yl)- 1H- 1 ,2,4-triazole-3 -carboxamide
  • Step 6 (.S)-2-(tcrt-Butoxycarbonylamino)-3-(3.5-difluoro-2-nitrophcnoxy)propanoic acid
  • Step 7 (.V)-3-(2-Amino-3.5-difliiorophcnoxy)-2-(tcrt-butoxycarbonylamino)propanoic acid
  • Step 8 (.Sj-tert-Butyl 6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3- ylcarbamate
  • Step 10 (,S)-3-Amino-6,8-difluoro-5-methyl-2,3-dihydrobenzo
  • Step 11 (S)-5-Benzyl-N-(6,8-difluoro-5-methyl-4-oxo-2, 3,4,5- tetrahydrobenzo[b][l,4]oxazepin-3-yl)-4H-l,2,4-triazole-3-carboxamide
  • Step 1 (E)-6,8-Difluoro-3,4-dihydronaphthalen-l(2H)-one oxime
  • Step 3 7, 9-Difluoro-4, 5-dihydro- lH-benzo[b]azepin-2(3H)-one
  • the reaction mixture was quenched with cold water (1000 mL) over 5 minutes. The reaction mixture was stirred vigorously for 30 minutes in an ice bath. The resulting precipitate was filtered and washed with water. The crude material was stirred in 10% diethyl ether/hexanes (500 mL), filtered, suspended in 25% diethyl ether/hexanes (500 mL), filtered, and suspended in diethyl ether (250 mL). The resulting solid was filtered and dried in a vacuum oven to give 7,9-difluoro-4,5-dihydro-lH- benzo[b]azepin-2(3H)-one (33.9 g, 60 % yield) as a light brown solid.
  • Step 7 (S)-5-Benzyl-N-(7,9-difluoro-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b]azepin-3-yl)- 4H- 1 ,2,4-triazole-3 -carboxamide
  • the FP assay involves a fluorescent labeled ligand (l4-(2- ⁇ [3-( ⁇ 2- ⁇ [4-(cyanomethyl)phenyl]amino ⁇ -6-[(5- cyclopropyl- lH-pyrazol-3 -yl)amino] -4-pyrimidinyl ⁇ amino)propyl] amino ⁇ -2-oxoethyl)- 16, 16,18,18-tetramethyl-6,7,7a,8a,9, 10,16,18- octahydrobenzo[2”,3”]indolizino[8”,7”:5’,6’]pyrano[3’,2’:3,4]pyrido[l,2-a]indol-5-ium- 2-sulfonate at a final assay concentration of 5nM.
  • His-GST-RipKl(l-375) was purified from a Baculovirus expression system and was used at a final assay concentration of lOnM. Both the enzyme and ligand were prepared in buffer consisting of 50mM HEPES pH 7.5, lOmM NaCl, 50mM MgCl2, 0.5mM DTT, and 0.02% CHAPS. Test compounds were prepared in neat DMSO and lOOnL was dispensed to individual wells of a multiwell plate. Next, 5uL His-GST-RipKl(l-375) was added to the test compounds at twice the final assay concentration, and incubated at room temperature for 10 minutes.
  • the efficacy of RIP 1 inhibitors may be tested in mice in vivo using a TNF -driven systemic inflammatory response syndrome model (Duprez, L., et al., Immunity 35(6):908-9l8 (2011)).
  • the model is run in a long modality (using TNF alone i.v.) which results in the termination of the study in ⁇ 7-8 hrs (under IACUC guidelines for moribund endpoints) or a short modality (using TNF plus the caspase inhibitor zVAD i.v.) which is terminated at ⁇ 2.5 -3 hrs (under IACUC guidelines for moribund endpoints).
  • TNF (or TNF/zVAD) induced manifestations include temperature loss, the production of numerous cytokines (including IF-6, IF-lb, MIRIb, and MIP2) in the periphery, liver and intestinal inflammation and an increase of markers of cellular (FDH and CK) and liver damage (AST and AFT) in the serum. Inhibition of these TNF (or TNF/zVAD) induced manifestations can be shown by orally or i.v. pre-dosing with selected compounds useful in this invention.
  • mice 7 mice per group are pre-dosed intravenously with vehicle or test compound 15 minutes before i.v. administration of mouse TNF (1.25 mg/kg/mouse) and zVAD (16.7 mg/kg/mouse) simultaneously. Temperature loss in mice is measured by rectal probe. The study is terminated when the control group became moribund, per our IACUC protocol. Representative data for the compound of Example 6 are provided in FIGS. 1A and 1B.
  • RIP 1 inhibition was tested in 12 different murine (6-8 week old) syngeneic subcutaneous tumor models. RIP1 inhibition was tested as a single agent in all models, with anti-PDl combination arms added to the five of the final models.
  • Dosing volume adjust dosing volume based on body weight (10 pl/g). Treatment regimen may be changed per BW (body weight) loss.
  • the interval of BID dosing is 8 hours.
  • TGI Tumor growth inhibition
  • TGI (%) l00 x (l-T/C).
  • T and C are the mean tumor volume of the treated and control groups, respectively, on a given day.
  • the 12 syngenic cell lines were maintained in vitro with different medium (indicated in Table 3) at 37 °C in an atmosphere of 5% CO2 in air.
  • the tumor cells were routinely subcultured twice weekly.
  • the cells in an exponential growth phase were harvested and counted for tumor inoculation.
  • Each mouse was inoculated subcutaneously with tumor cells in 0.1 mL of PBS for tumor development. The treatments were started when the mean tumor size reached approximately 80-120mm 3 (around lOOmm 3 ).
  • the test article (Example 6 or anti -PD 1 (anti mouse PD-l antibody (clone RPM1-14), BioXcell) administration and the animal numbers in each study group are shown in the experimental design Table 2. The date of tumor cell inoculation is denoted as day 0.
  • Pancreatic ductal adenocarcinoma is the 4 th leading cause of cancer deaths worldwide with a 5-year survival rate of less than 5%.
  • a major therapeutic barrier for PDAC is the highly immunosuppressive myeloid infiltrate that is a hallmark of the pancreatic tumor microenvironment (TME). This immunosuppressive innate infiltrate is largely responsible for PDAC resistance to current immunotherapies that target the adaptive immune system. To overcome this barrier, the next generation of
  • immunotherapies for pancreatic cancer and other tumors with a similar cellular phenotype will need to modulate the innate infiltrate to increase sensitivity to T cell checkpoint inhibitors.
  • Nonclinical evidence suggests that there is therapeutic potential for inhibition of receptor interacting protein 1 (RIP1), encoded by the RIPK1 gene, across multiple therapeutic areas, including oncology.
  • RIP1 kinase activity in pancreatic oncogenesis reveals that within the pancreatic TME, RIP 1 inhibition leads to the replacement of tumor- permissive myeloid infiltrates with innate cells that promote an effective anti-tumor response by the adaptive immune system.
  • RIPK1 was identified as a top gene contributing to resistance to immunotherapy.
  • pembrolizumab in participants with PDAC and other selected tumors, e.g. non-small cell lung cancer (NSCLC), triple negative breast cancer, or melanoma.
  • NSCLC non-small cell lung cancer
  • melanoma triple negative breast cancer
  • These tumor types were chosen based on preclinical evidence supporting a role for RIP 1 kinase activity promoting oncogenesis and/or their phenotypic similarity to PDAC characterized by high infiltrates of immunosuppressive innate infiltrates.
  • the study includes up to 4 parts: Parts 1 and 2 will be conducted as dose escalation as monotherapy and in combination with pembrolizumab), Part 3 will explore dose expansion with pembrolizumab, and Part 4 will explore dose expansion of Compound A in combination with other anticancer therapies.
  • RIP1 is a ubiquitous kinase but is only active upon homeostatic disruptions. In its ubiquinated form, RIP1 provides a scaffolding function essential to pro-survival NF-kB signaling that is required for vitality.
  • Macrophages present in the tumor after RIP1 inhibition were polarized to a more Ml -like anti -tumor phenotype (Seifert 2016). Furthermore, RIP1 inhibition markedly upregulated T-cell infiltration and PD-l expression on the T cells in the TME. Functionally, this sensitized tumors to checkpoint blockade with anti-PD 1. In a third subcutaneous model using pan02 cells, inhibiting RIP1 >90% in the periphery also led to an approximate 50% reduction in tumor size. Similarly, the addition of anti-PD 1 increased the efficacy in this model. Further, the RIP1 inhibitor of Example 6 penetrated orthotopic tumors (FIG. 4).
  • dose escalation for Compound A monotherapy will begin with a total daily dose of 100 mg Compound A administered by mouth in two equally divided doses (50 mg po BID). Planned dose levels are 100, 200, 400, 800, and 1600 mg per day but intermediate doses or schedules other than BID may be explored if exposure differs significantly from that predicted, if there is excessive toxicity, or if further evaluation of pharmacodynamic markers to aid dose selection is warranted.
  • Dose escalation of Compound A in combination with 200 mg pembrolizumab (Part 2) will begin with a Compound A dose below the highest Part 1 dose shown to have acceptable toxicity profile in at least 3 participants.
  • Concomitant Medications All Aes and concurrent medications will be collected from study day 1 until at least 30 days after the last dose of study treatment (i.e., at least through the EOT visit). AESIs will be collected starting day 1, while SAEs will be recorded from the time a participant consents to participate in the study. All AESIs and SAEs and any concurrent medications relevant to the reported AESIs and SAEs will be collected until at least 90 days after the last dose of study treatment. If another anticancer agent is started during the 90-day reporting period, only AESI and SAEs that occur within 30 days from the last dose of study drug(s) should be recorded.
  • Pregnancy testing for screening must be completed 7 days prior to dosing start and checked again on Day 1 within 24 hours before the first dose of study drug.
  • Week 1 Visits for Week 1 Days 1 and 2 must be performed on the day indicated.
  • Lymph nodes that have a short axis of ⁇ 10 mm are considered non-pathological and should not be recorded or followed.
  • CT computed tomography
  • MRI magnetic resonance imaging
  • FDG-PET fluorodeoxyglucose-positron-emission tomography
  • All other lesions should be identified as non-target and should also be recorded at baseline. Non-target lesions will be grouped by organ. Measurements of these lesions are not required, but the presence or absence of each should be noted throughout follow-up.
  • a CT or MRI of the head and neck area is required.
  • evaluations of the sites of disease identified by these scans are required.
  • CT scan is preferred, MRI may be used as an alternative method of baseline disease assessment, especially for participants for whom a CT scan is
  • the baseline disease assessment will be completed within 21 days prior to the first dose of Compound A. Post-baseline disease assessments must be performed after the mandatory biopsies. Assessments must be performed on a calendar schedule and should not be affected by dose interruptions/delays.
  • a window of +7 days is permitted to allow for flexibles cheduling. Participants whose disease responds (either CR or PR) should have a confirmatory disease assessment performed at least 4 weeks after the date of assessment during which the response was first demonstrated. Participants whose disease progresses (PD) must have a confirmatory scan performed at least 4 weeks after the date of assessment during which the first indication of PD was demonstrated. If the last radiographic assessment was more than 12 weeks prior to the participant’s withdrawal from study and PD has not been documented, a disease assessment should be obtained at the time of withdrawal from the study. To ensure comparability between the baseline and subsequent assessments, the same method of assessment and the same technique will be used when assessing response throughout the study.
  • FDG-PET can be useful in confirming new sites of disease where a positive FDG-PET scans correlates with the new site of disease present
  • Clinical Examination Clinically detected lesions will only be considered measurable when they are superficial (e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a ruler/calipers to measure the size of the lesion, is required.
  • CT and MRI Contrast enhanced CT with 5 mm contiguous slices is recommended. Minimum size of a measurable baseline lesion should be twice the slice thickness, with a minimum lesion size of 10 mm when the slice thickness is 5 mm. MRI is acceptable, but when used, the technical specification of the scanning sequences should be optimized for the evaluation of the type and site of disease and lesions must be measured in the same anatomic plane by use of the same imaging examinations. Whenever possible, the same scanner should beused.
  • X-ray In general, X-ray should not be used for target lesion measurements owing to poor lesion definition. Lesions on chest X-ray may be considered measurable if they are clearly defined and surrounded by aerated lung; however, chest CT is preferred over chest X-ray.
  • Brain Scan If brain scans are required, then contrast enhanced MRI is preferable to contrast enhanced CT.
  • the minimum size of a measurable lesion must be at least double the slice thickness (e.g., if the slice thickness is 10 mm, a measurable lesion must be >20 mm).
  • lymph nodes can be considered pathologically enlarged and
  • Measurable disease The presence of at least one measurable lesion. Palpable lesions that are not measurable by radiologic or photographic evaluations may not be utilized as the only measurable lesion. Non-Measurable only disease: The presence of only non-measurable lesions. Note:
  • iRECIST is based on RECIST 1.1, but adapted to account for the unique tumor response seen with immunotherapeutic drugs. iRECIST will be used to assess tumor response and progression, and make treatment decisions. When clinically stable, participants should not be discontinued until progression is confirmed according to the rules described below. This allowance to continue treatment despite initial radiologic PD takes into account the observation that some participants can have a transient tumor flare in the first few months after the start of immunotherapy, and then experience subsequent disease response. These data will be captured in the clinical database.
  • Any participant deemed clinically unstable may be discontinued from study intervention at site-assessed first radiologic evidence of PD. It is strongly preferred to obtain the repeat tumor imaging, when feasible, for confirmation of PD by iRECIST.
  • a clinically unstable participant if the Investigator decides to continue treatment, following consultation with the Sponsor medical monitor, the participant may continue to receive study intervention.
  • the tumor assessment should be repeated at least 4 weeks and up to 8 weeks later to confirm PD by iRECIST. If repeat imaging does not confirm PD per iRECIST and the participant continues to be clinically stable, study intervention may continue and follow the regular imaging schedule or as clinically indicated. If PD is confirmed, participants will be discontinued from study intervention.
  • radiographic progression iCPD
  • study intervention should be discontinued; however, if the participant is achieving a clinically meaningful benefit, continuation of study intervention may be considered following consultation with the Sponsor. In this case, if study intervention is continued, tumor imaging should follow the regular imaging schedule or as clinically indicated.
  • Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, including:
  • iRECIST defines response categories, including iUPD (unconfirmed progressive disease) and iCPD (confirmed progressive disease).
  • iUPD unconfirmed progressive disease
  • iCPD confirmed progressive disease
  • the first visit showing progression according to RECIST 1.1 will be assigned a visit (overall) response of iUPD, regardless of which factors caused the progression.
  • target and non-target lesions identified at baseline by RECIST 1.1 will be assessed as usual.
  • New lesions will be classified as measurable or non-measurable, using the same size thresholds and rules as for baseline lesion assessment in RECIST 1.1. From measurable new lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions - Target. The sum of diameters of these lesions will be calculated, and kept distinct from the sum of diameters for target lesions at baseline. All other new lesions will be followed qualitatively as New Lesions - Non-target.
  • the participant will be classified as progression confirmed (with an overall response of iCPD), or as showing persistent unconfirmed progression (with an overall response of iUPD), or as showing disease stability or response (iSD/iPR/iCR).
  • Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging on which iUPD is seen. This may correspond to the next visit in the original visit schedule.
  • the assessment of the subsequent confirmation imaging proceeds in an identical manner, with possible outcomes of iCPD, iUPD, and iSD/iPR/iCR.
  • the response is classified as iSD or iPR (depending on the sum of diameters of the target lesions), or iCR if all lesions resolve.
  • the initial iUPD is considered to be pseudo-progression, and the level of suspicion for progression is“reset”. This means that the next visit that shows radiographic progression, whenever it occurs, is again classified as iUPD by iRECIST, and the confirmation process is repeated before a response of iCPD can be assigned.
  • study intervention may continue and follow the regular imaging schedule. If PD is confirmed, participants will be discontinued from study intervention.
  • iUPD is indicated by any of the following events:
  • Target lesions o Sum of diameters reaches the PD threshold (>20% and >5 mm increase from nadir) either for the first time, or after resolution of previous pseudo-progression.
  • the nadir is always the smallest sum of diameters seen during the entire trial, either before or after an instance of pseudo-progression.
  • Non-target lesions o If non-target lesions have never shown unequivocal progression, doing so for the first-time results in iUPD. o If non-target lesions have shown previous unequivocal progression, and this
  • iUPD results from any significant further growth of non-target lesions.
  • the overall response for that visit is iUPD, and the iUPD evaluation process (see Assessment at the Confirmatory Imaging above) is repeated. Progression must be confirmed before iCPD can occur.
  • the decision process is identical to the iUPD confirmation process for the initial PD, with one exception: if new lesions occurred at a prior instance of iUPD, and at the confirmatory imaging the burden of new lesions has increased from its smallest value (for new target lesions, the sum of diameters is >5 mm increased from its nadir), then iUPD cannot resolve to iSD or iPR.

Abstract

L'invention concerne une méthode de traitement du cancer chez un sujet humain qui en a besoin, la méthode consistant à administrer au sujet humain un inhibiteur de la RIP1 kinase à une dose d'environ 50 mg à environ 1 600 mg. La présente invention concerne une méthode de traitement du cancer chez un sujet humain qui en a besoin, la méthode consistant à administrer au sujet humain un inhibiteur de la RIP1 kinase à une dose d'environ 50 mg à environ 1 600 mg, et à administrer au sujet humain un antagoniste de PD1 associé à une dose d'environ 200 mg.
PCT/IB2019/057160 2018-08-29 2019-08-26 Amides hétérocycliques utiles en tant qu'inhibiteurs de kinases destinés à être utilisés dans le traitement du cancer WO2020044206A1 (fr)

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