WO2020044206A1 - Heterocyclic amides as kinase inhibitors for use in the treatment cancer - Google Patents

Heterocyclic amides as kinase inhibitors for use in the treatment cancer Download PDF

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Publication number
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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French (fr)
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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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Publication of WO2020044206A1 publication Critical patent/WO2020044206A1/en

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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

Disclosed is a method of treating cancer in a human in need thereof, the method comprising administering to the human a RIP1 kinase inhibitor at a dose of about 50 mg to about 1600 mg. Also disclosed is a method of treating cancer in a human in need thereof, the method comprising administering to the human a RIP1 kinase inhibitor at a dose of about 50 mg to about 1600 mg, and administering to the human a PD1 antagonist thereof at a dose of about 200 mg.

Description

HETEROCYCLIC AMIDES AS KINASE INHIBITORS FOR USE IN THE TREATMENT CANCER
Field of the Invention
The present invention relates to heterocyclic amides that inhibit RIP1 kinase and methods of making and using the same. The present invention also relates to dosing of RIP1 kinase inhibitors and dosing of combinations of RIP 1 kinase inhibitors and at least one other therapeutically active agent and methods of using said dosing in the treatment of cancer.
Background of the Invention
Receptor-interacting protein- 1 (RIP1) kinase, originally referred to as RIP, 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.
The role for RIP 1 in cell signaling has been assessed under various conditions [including TLR3 (Nat Immunol. 5, 503-507 (2004)), TLR4 (J. Biol. Chem. 280, 36560- 36566 (2005)), TRAIL (FAS (J. Biol. Chem. 279, 7925-7933 (2004))], but is best understood in the context of mediating signals downstream of the death receptor TNFR1 (Cell 114, 181-190 (2003)). Engagement of the TNFR by TNF leads to its
oligomerization, and the recruitment of multiple proteins, including linear K63 -linked polyubiquitinated RIP1 (Mol. Cell 22, 245-257 (2006)), TRAF2/5 (J. Mol. Biol. 396, 528- 539 (2010)), TRADD (Nat. Immunol. 9, 1037-1046 (2008)) and cIAPs (Proc. Natl. Acad. Sci. USA. 105, 11778-11783 (2008)), to the cytoplasmic tail of the receptor. This complex which is dependent on RIP1 as a scaffolding protein (i.e. kinase independent), termed complex I, provides a platform for pro-survival signaling through the activation of the NFKB and MAP kinases pathways (Sci. Signal. 115, re4 (2010)). Alternatively, binding of TNF to its receptor under conditions promoting the deubiquitination of RIP 1 (by proteins such as A20 and CYLD or inhibition of the cIAPs) results in receptor internalization and the formation of complex II or DISC (death-inducing signaling complex) (Cell Death Dis.
2, e230 (2011)). Formation of the DISC, which contains RIP1, TRADD, FADD and caspase 8, results in the activation of caspase 8 and the onset of programmed apoptotic cell death also in a RIP1 kinase independent fashion (FEBS J 278, 877-887 (2012)). Apoptosis is largely a quiescent form of cell death; and is involved in routine processes such as development and cellular homeostasis.
Under conditions where the DISC forms and RIP3 is expressed, but apoptosis is inhibited (such as FADD/caspase 8 deletion, caspase inhibition or viral infection), a third RIP1 kinase-dependent possibility exists. 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)). As opposed to apoptosis, programmed necrosis (not to be confused with passive necrosis which is not programmed) results in the release of danger associated molecular patterns (DAMPs) from the cell. These DAMPs are capable of providing a“danger signal” to surrounding cells and tissues, eliciting proinflammatory responses including inflammasome activation, cytokine production and cellular recruitment (Nat. Rev. Immunol 8, 279-289 (2008)).
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
Ulcerative colitis and Crohn’s disease) (Nature 477, 330-334 (2011)), Psoriasis (Immunity 35, 572-582 (2011)), retinal-detachment-induced photoreceptor necrosis (PNAS 107, 21695-21700 (2010)), retinitis pigmentosa (Proc. Natl. Acad. Sci., 109:36, 14598-14603 (2012)), cerulein-induced acute pancreatits (Cell 137, 1100-1111 (2009)) and
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)). Other diseases or disorders regulated at least in part by RIP 1 -dependent apoptosis, necrosis or cytokine production include hematological and solid organ malignancies (Genes Dev. 27: 1640-1649 (2013), Cancer Cell 28, 582-598 2015);
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
Endocrinology (2015)). Blocking the actions of TNF at the TNF receptor has been shown to improve glucose homeostasis in animals and humans (Stagakis et ak, Arthritis Research & Therapy (2012)). Inhibition of RIP 1 has been implicated in protection against the RdlO mouse model of human retinitis pigmentosa (RP) (Y. Murakami et ak, PNAS
109(36): 14598-14603 (2012)). Inhibition of RIP1 has been implicated in protection against the experimental autoimmune encephalomyelitis (EAE) mouse model of human Multiple Sclerosis (MS) (D. Ofengeim et al. Cell Reports 10(11): 1836-1849, (2015)).
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/hί1061 (2004) and
Ofengeim, D. & Yuan, J . Nat. Rev. Mol. Cell Biol. 14, 727-736, doi: l0. l038/nrm3683 (2013)). 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 potent, selective, small molecule inhibitor of RIP 1 kinase activity would block RIP 1 -dependent cellular necrosis and might block suppressive macrophage polarization in cancer and thereby provide a therapeutic benefit in diseases or events associated with DAMPs, cell death, and/or inflammation as well as be useful in combination treatment with immuno-modulators. Thus, there is a need for new therapies with RIP1 kinase inhibitors and RIP1 kinase inhibitors with other therapeutically active agents, in particular, immuno-modulators .
Summary of the Invention In one aspect, a method of treating cancer in a human in need thereof is provided, the method comprising administering to the human a RIP 1 kinase inhibitor at a dose of about 50 mg to about 1600 mg.
In one aspect, a method of treating cancer in a human in need thereof is provided, the method 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.
Brief Description of the Drawings
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
It will be appreciated by those skilled in the art that the compounds of this invention, depending on further substitution, may exist in other tautomeric forms. It will be further appreciated by those skilled in the art that any of the RIP1 kinase inhibitor compounds useful in the methods of this invention, may exist in other tautomeric forms. All tautomeric forms of the compounds described herein are intended to be encompassed within the scope of the present invention. It is to be understood that any reference to a named compound or a structurally depicted compound is intended to encompass all tautomers of such compounds and any mixtures of tautomers thereof. It will also be appreciated by those skilled in the art that when A1 and A4 are C, and A2, A3, and A5 are each independently selected from N and NH, the compounds useful in this invention may exist as triazole tautomers represented by Formulas (I-A), (I-B) and (I-C):
Figure imgf000006_0001
(I-A) (I-B)
(I-C) The chemical names provided for the intermediate compounds and/or the compounds useful in this invention described herein may refer to any one of the tautomeric representations of such compounds (in some instances, such alternate names are provided within the experimentals). It is to be understood that any reference to a named compound (an intermediate compound or a compound useful in this invention) or a structurally depicted compound (an intermediate compound or a compound useful in this invention) is intended to encompass all tautomers of such compounds and any mixtures of tautomers thereof.
As used herein, the term“optionally substituted” indicates that the B phenyl group may be unsubstituted, or the phenyl group, may be substituted with one fluoro substituent. As used herein, 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.
In one embodiment, a compound disclosed in WO2014/125444 that inhibits RIP1 kinase is a compound of Formula (I):
Figure imgf000007_0001
(I) wherein:
X is O, S, SO, SOi, NH, CO, CH2, CF2, CH(CH3), CH(OH), or N(CH3);
Y is CHi or CH2CH2;
ZGs N, CH or CR1; Z2 is CH or CR2;
Z3 is N, CH or CR3;
Z4 is CH or CR4;
R1 is fluoro or methyl; one of R2 and R3 is halogen, cyano, (Ci-Ce)alkyl, halo(Ci-C4)alkyl,
(Ci-G,)alkoxy. halo(Ci-C4)alkoxy, hydroxyl, B(OH)2, -COOH, halo(Ci-C4)alkylC(OH)2-, (Ci-C4)alkoxy(Ci-C4)alkoxy, (Ci-C4)alkylS02-, (Ci-C4)alkylS02NHC(0)-, (Ci-C4)alkylC(0)NH-, ((Ci-C4)alkyl)((Ci-C4)alkyl)NC(0)-, (Ci-C4)alkyl0C(0)-, (Ci-C4)alkylC(0)N(Ci-C4)alkyl)-, (Ci-C4)alkylNHC(0)-,
(Ci-C4)alkoxy(C2-C4)alkylNHC(0)-, (Ci-C4)alkoxy(C2-C4)alkylC(0)NH-,
(Ci-C4)alkoxy(C2-C4)alkylNHC(0)NH-, (Ci-C4)alkylS02(C2-C4)alkylNHC(0)-,
(Ci-C4)alkylNHC(0)NH-, (Ci-C4)alkyl0C(0)NH-, hydroxy(Ci-C4)alkylOC(0)NH-, 5-6 membered heterocycloalkyl-C(O)-, 5-6 membered
heterocycloalkyl-(Ci-C4)alkyl-NHC(0)-, 5-6 membered heterocycloalkyl-(Ci-C4)alkoxy-, 3-6 membered cycloalkyl, 5-6 membered heteroaryl, or 5-6 membered heteroaryl-C(0)NH, wherein said 3-6 membered cycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl are optionally substituted by 1 or 2 substituents each independently selected from the group consisting of (Ci-C4)alkyl and -(Ci-C4)alkyl-CN; and the other of R2 and R3 is halogen, cyano or (Ci-G,)alkyl:
R4 is fluoro, chloro, methyl or trifluoromethyl;
R5 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 RA is (Ci-C4)alkyl; and
L is O, S, NH, N(CH3), CH2, CH2CH2, CH(CH3), CHF, CF2, CH20, CH2N(CH ), CH2NH, or CH(OH); B is an optionally substituted (C3-Ce)cycloalkyl, phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocycloalkyl; wherein said (C3-C6)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-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, nitro, and (Ci-C4)alkylC(0)-; or the moiety -L-B is (C3-C6)alkyl, (C3-C6)alkoxy, halo(C3-C6)alkoxy,
(C3-C6)alkenyl, or (C3-C6)alkenyloxy; or a salt, particularly, a pharmaceutically acceptable salt thereof. In another embodiment, a compound that inhibits RIP 1 kinase is a compound according to Formula (II):
Figure imgf000009_0001
wherein:
X is CHi or NH;
Z1 is CH;
Z2 is CH or CR2;
Z3 is CH; Z4 is CH or CR4;
R2 and R4 are each independently selected from chloro or fluoro;
R5 is H or methyl;
L is CHi;
A1 and A4 are C, and A2, A3, and A5 are each independently selected
from N and NH to form a triazolyl ring moiety,
B is a phenyl ring, optionally substituted by fluoro; or a salt, particularly a pharmaceutically acceptable salt, thereof.
Accordingly, included within the present invention are the compounds of Formula (I) or Formula (II), particularly, compounds of any one of Formula (I) or Formula (II), as defined herein, in any salt or non-salt form and any physical form thereof, and mixtures of various forms. While such are included within the present invention, it will be understood that the compounds of Formula (I) or Formula (II), particularly, compounds of any one of Formula (I) or Formula (II), as defined herein, in any salt or non-salt form, and in any physical form thereof, may have varying levels of activity, different bioavailabilities and different handling properties for formulation purposes.
In one embodiment of this invention, the compounds of Formula (II) do not include:
(S)-5-benzyl-N-(2-oxo-2, 3, 4, 5-tetrahydro- lH-benzo [b]azepin-3-yl)-4H-l, 2, 4-triazole-3- carboxamide;
(S)-5-benzyl-N-( 1 -methyl-2-oxo-2,3 ,4,5 -tetrahydro- lH-benzo [b] azepin-3 -yl)-4H- 1,2,4- triazole-3 -carboxamide ;
(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 (S)-5-benzyl-N-(7-chloro-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 salt thereof.
In one embodiment, there is provided a compound according to Formula (III):
Figure imgf000010_0001
wherein:
X is CHi or NH;
Z1 is CH;
Z2 is CH or CR2;
Z3 is CH; Z4 is CH or CR4;
R2 and R4 are each independently selected from chloro or fluoro; R5 is H or methyl; L is CHi;
A1 and A4 are C, and A2, A3, and A5 are each independently selected from N and NH (such that A1-A2-A3-A4-A5-A1 forms a triazolyl ring moiety),
B is a phenyl ring, optionally substituted by fluoro; or a salt, particularly a pharmaceutically acceptable salt, thereof; provided that the compound is not:
(S)-5-benzyl-N-(2-oxo-2, 3, 4, 5-tetrahydro- lH-benzo [b]azepin-3-yl)-4H-l, 2, 4-triazole-3- carboxamide;
(S)-5-benzyl-N-( 1 -methyl-2-oxo-2,3 ,4,5 -tetrahydro- lH-benzo [b] azepin-3 -yl)-4H- 1,2,4- triazole-3-carboxamide;
(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
(S)-5-benzyl-N-(7-chloro-2 -oxo-2, 3, 4, 5-tetrahydro- lH-benzo [b]azepin-3-yl)-4H-l, 2, 4- triazole-3 -carboxamide ; or a salt, particularly a pharmaceutically acceptable salt, thereof.
In one embodiment of the compounds of Formula (I), Formula (II), or
Formula (III), X is CH2. In another embodiment, X is NH.
In one embodiment of the compounds of Formula (I), (II) or (III), Z1, Z2,
Z3, and Z4 are each CH. In another embodiment, Z1, Z3, and Z4 are each CH
and Z2 is CR2. In another embodiment, Z1, Z2, and Z3 are each CH and Z4 is
CR4. In another embodiment, Z1 and Z3 are each CH, Z2 is CR2 and Z4 is CR4.
In one embodiment of the compounds useful in this invention, R2 is fluoro. In another embodiment, R2 is chloro.
In one embodiment of the compounds useful in this invention, R4 is
fluoro.
In one embodiment of the compounds useful in this invention, R5 is H.
In another embodiment, R5 is methyl. In one embodiment of the compounds useful in this invention, B is
unsubstituted phenyl.
In another embodiment, B is phenyl, substituted by a fluoro substituent.
In a specific embodiment, B is 2-fluorophenyl. In one embodiment, X is NH, Z1, Z2, Z3, and Z4 are each CH, R5 is
methyl, A1 and A4 are C, A2 and A5 are each independently selected from N and
NH, L is CH2 and B is a phenyl ring substituted by fluoro.
It will be appreciated that the present invention covers compounds of Formula (I), Formula (II), or Formula (III) as the free base, and as salts thereof, for example as a pharmaceutically acceptable salt thereof. In one embodiment, the invention relates to compounds of Formula (I), Formula (II), or Formula (III) in the form of a free base. In another embodiment, the invention relates to compounds of Formula (I), Formula (II), or Formula (III) or a pharmaceutically acceptable salt thereof. It will further be appreciated that compounds of Formula (I), Formula (II), or Formula (III) and salts thereof may exist in hydrated from, such as the monohydrate, dihydrate, or trihydrate.
Representative compounds useful in this invention include:
(S)-N-(9-fluoro-2-oxo-2,3 ,4,5 -tetrahydro- lH-benzo [b] [ 1 ,4] diazepin-3 -yl)-5 -(2- fluorobenzyl)-4H-l,2,4-triazole-3-carboxamide; or
(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; or a tautomer thereof; or a salt thereof, particularly a pharmaceutically acceptable salt thereof.
Representative compounds useful in this invention include a compound having the formula:
Figure imgf000013_0001
or a tautomer thereof; or a salt thereof, particularly a pharmaceutically acceptable salt thereof. In one embodiment, this invention is directed to (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 salt, particularly a pharmaceutically acceptable salt thereof. In one embodiment, the compound useful in this invention is (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. In another embodiment, the compound useful in this invention is a salt 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. In another embodiment, the compound useful in this invention is a pharmaceutically acceptable salt 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. In another embodiment, the compound useful in this invention is ((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 as the free base.
The compounds useful in this invention contain one asymmetric center (also referred to as a chiral center), a chiral carbon. The stereochemistry of the chiral carbon center present in compounds useful in this invention is generally represented in the compound names and/or in the chemical structures illustrated herein. Compounds useful in this invention containing a chiral center may be present as a racemic mixture,
enantiomerically enriched mixture, or as an enantiomerically pure individual stereoisomer.
An individual stereoisomer of a compound useful in this invention may be resolved (or mixtures of stereoisomers may be enriched) using methods known to those skilled in the art. For example, such resolution may be carried out (1) by formation of
diastereoisomeric salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer-specific reagent, for example by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent. The skilled artisan will appreciate that where the desired stereoisomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired form. Alternatively, a specific stereoisomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.
The invention also includes various deuterated forms of the compounds of Formula (I), Formula (II), and Formula (III). Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom. A person of ordinary skill in the art will know how to synthesize deuterated forms of the compounds of Formula (I), Formula (II), or Formula (III). For example, a-deuterated a-amino acids are commercially available or may be prepared by conventional techniques (see for example: Elemes, Y. and Ragnarsson, U. J. Chem. Soc., Perkin Trans. 1, 1996, 6, 537-40). Employing such compounds may allow for the preparation of compounds in which the hydrogen atom at a chiral center is replaced with a deuterium atom. Other commercially available deuterated starting materials may be employed in the preparation of deuterated analogs of the compounds useful in this invention (see for example: methyl - -amine available from Aldrich Chemical Co., Milwaukee, WI), or they may be synthesized using conventional techniques employing deuterated reagents (e.g. by reduction using lithium aluminum deuteride or sodium borodeuteride or by metal-halogen exchange followed by quenching with D2O or mcthanol-i/i).
The skilled artisan will appreciate that solvates (particularly, hydrates) of a compound of Formulas (I), (II), or (III), including solvates of salts of a compound of Formulas (I), (II), or (III), particularly a compound of any one of Formulas (I), (II), or (III), may be formed when solvent molecules are incorporated into the crystalline lattice during crystallization. The present invention includes within its scope all possible stoichiometric and non-stoichiometric salt and/or hydrate forms.
When a disclosed compound or its salt is named or depicted by structure, it is to be understood that the compound or salt, including solvates (particularly, hydrates) thereof, may exist in crystalline forms, non-crystalline forms or a mixture thereof. The compound or salt, or solvates (particularly, hydrates) thereof, may also exhibit polymorphism (i.e. the capacity to occur in different crystalline forms). These different crystalline forms are typically known as“polymorphs.” It is to be understood that when named or depicted by structure, the disclosed compound, or solvates (particularly, hydrates) thereof, also include all polymorphs thereof. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. One of ordinary skill in the art will appreciate that different polymorphs may be produced, for example, by changing or adjusting the conditions used in crystallizing/recrystallizing the compound.
It is to be understood that the references herein to a compound of Formulas (I), (II), or (III), or a salt thereof, includes a compound of Formulas (I), (II), or (III) as a free base or as a salt thereof, for example as a pharmaceutically acceptable salt thereof. Thus, in one embodiment, the invention is directed to a compound of Formulas (I), (II), or (III). In a further embodiment, the invention is directed to a pharmaceutically acceptable salt of a compound of Formulas (I), (II), or (III). In a further embodiment, the invention is directed to a compound of Formulas (I), (II), or (III), or a pharmaceutically acceptable salt thereof.
Because of their potential use in medicine, it will be appreciated that a salt of a compound of Formulas (I), (II), or (III) is preferably pharmaceutically acceptable. As used herein, the term“pharmaceutically acceptable” means a compound which is suitable for pharmaceutical use. Salts and solvates (e.g. hydrates and hydrates of salts) of the compounds of Formulas (I), (II), or (III) which are suitable for use in medicine are those wherein the counterion or associated solvent is pharmaceutically acceptable. Salts and solvates (e.g. hydrates and hydrates of salts) of the compounds useful in this invention which are suitable for use in medicine are those wherein the counterion or associated solvent is pharmaceutically acceptable. Salts and solvates having non-pharmaceutically acceptable counterions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds useful in this invention and their salts and solvates.
Pharmaceutically acceptable salts include, amongst others, those described in Berge, J. Pharm. Sci., 66, 1-19, (1977) or those listed in P.H. Stahl and C.G. Wermuth, editors, Handbook of Pharmaceutical Salts; Properties, Selection and Use, Second Edition Stahl/Wermuth: Wiley- VCH/VHCA (2011) (see
http://www.wiley.com/WileyCDA/WileyTitle/productCd-39063905 l9.html).
Suitable pharmaceutically acceptable salts can include acid addition salts.
Such acid addition salts can be formed by reaction of a compound of Formula (I), (II), or (III) (which, for example contains a basic amine or other basic functional group) with the appropriate acid, optionally in a suitable solvent such as an organic solvent, to give the salt which can be isolated by a variety of methods, including crystallization and filtration.
Salts may be prepared in situ during the final isolation and purification of a compound of Formula (I), (II), or (III). If a basic compound of Formula (I), (II), or (III) is isolated as a salt, the corresponding free base form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic base.
This invention also provides for the conversion of one salt of a compound useful in this invention, e.g., a hydrochloride salt, into another salt of a compound useful in this invention, e.g., a sulfate salt. This invention also provides for the conversion of one pharmaceutically acceptable salt of a compound useful in this invention into another pharmaceutically acceptable salt of a compound useful in this invention.
It will be understood that if a compound of Formula (I), (II), or (III)) contains one or more basic moieties, the stoichiometry of salt formation may include 1, 2 or more equivalents of acid. Such salts would contain 1, 2 or more acid counterions, for example, a dihydrochloride salt.
Stoichiometric and non-stoichiometric forms of a pharmaceutically acceptable salt of a compound of Formula (I), (II), or (III) are included within the scope of the invention, including sub-stoichiometric salts, for example where a counterion contains more than one acidic proton.
Certain compounds useful in this invention may form salts with one or more equivalents of an acid. The present invention includes within its scope all possible stoichiometric and non-stoichiometric salt forms.
It is to be further understood that the present invention includes within its scope all tautomeric forms of any free base form of the compounds useful in this invention as well as all possible stoichiometric and non-stoichiometric salt forms of all tautomeric forms of the compounds useful in this invention.
Representative pharmaceutically acceptable acid addition salts include, but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzene sulfonate (besylate), benzoate, bisulfate, bitartrate, butyrate, calcium edetate, camphorate, camphorsulfonate (camsylate), caprate (decanoate), caproate (hexanoate), caprylate (octanoate), cinnamate, citrate, cyclamate, digluconate, 2,5-dihydroxybenzoate, disuccinate, dodecylsulfate (estolate), edetate (ethylenediaminetetraacetate), estolate (lauryl sulfate), ethane- 1, 2-disulfonate (edisylate), ethane sulfonate (esylate), formate, fumarate, galactarate (mucate), gentisate (2,5-dihydroxybenzoate), glucoheptonate
(gluceptate), gluconate, glucuronate, glutamate, glutarate, glycerophosphorate, glycolate, hexylresorcinate, - 16 -ignaling, hydrabamine (/V./V'-di(dehydroabietyl)-ethylenediamine). hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, isobutyrate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, methanesulfonate (mesylate), methylsulfate, mucate, naphthalene- 1,5 -disulfonate (napadisylate), naphthalene-2-sulfonate (napsylate), nicotinate, nitrate, oleate, palmitate. / aminobcnzcncsulfonatc. p- aminosalicyclate, pamoate (embonate), pantothenate, pectinate, persulfate, phenylacetate, phenylethylbarbiturate, phosphate, polygalacturonate, propionate. / oluenesulfonate (tosylate), pyroglutamate, pyruvate, salicylate, sebacate, stearate, subacetate, succinate, sulfamate, sulfate, tannate, tartrate, teoclate (8-chlorotheophyllinate), thiocyanate, triethiodide, undecanoate, undecylenate, and valerate.
For solvates of the compounds of Formulas (I), (II), or (III), including solvates of salts of the compounds of Formulas (I), (II), or (III), that are in crystalline form, the skilled artisan will appreciate that pharmaceutically acceptable solvates may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization.
Solvates may involve nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and EtOAc, or they may involve water as the solvent that is incorporated into the crystalline lattice. Solvates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as“hydrates.” Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The invention includes all such solvates, particularly hydrates. Accordingly, a compound useful in this invention includes a compound of Formula (I), (II), or (III), or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a hydrate thereof, a hydrate of a pharmaceutically acceptable salt of a compound of Formula (I), (II), or (III), and particularly includes each compound described in the Examples. Thus, the invention provides a compound of Formula (I), (II), or (III), or a salt thereof, especially a pharmaceutically acceptable salt thereof, as a solvate, particularly as a hydrate, such as a monohydrate, dihydrate, or trihydrate.
Because the compounds useful in this invention are intended for use in
pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions.
A compound that inhibits RIP1 kinase, particularly 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. Provisional Patent Application No. 62/424047, filed November 18, 2016, U.S. Patent Application No. 15/424, 216, filed February 3, 2017 (US9,8l5,850), U.S. Patent Application No. 15/200, 058, filed July 1, 2016, (the disclosures of each of which are incorporated by reference herein) or a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, may be particularly useful for the treatment of RIP 1 kinase-mediated diseases or disorders. These RIP1 kinase-mediated diseases or disorders are diseases or disorders that are mediated by activation of RIP 1 kinase, and as such, are diseases or disorders where inhibition of RIP 1 kinase would provide benefit. Such RIP 1 kinase-mediated diseases or disorders are diseases/disorders which are likely to be regulated at least in part by programmed necrosis, apoptosis or the production of inflammatory cytokines, particularly: inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), psoriasis, retinal detachment, retinal degeneration, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, arthritis (including rheumatoid arthritis, spondyloarthritis, gout, juvenile idiopathic arthritis (systemic onset juvenile idiopathic arthritis (SoJIA)), psoriatic arthritis), systemic lupus erythematosus (SUE), Sjogren’s syndrome, systemic scleroderma, anti-phospholipid syndrome (APS), vasculitis, osteoarthritis, liver damage/diseases (non-alcohol steatohepatitis, alcohol steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary diseases, primary sclerosing cholangitis (PSC), acetaminophen toxicity, hepatotoxicity), kidney damage/injury (nephritis, renal transplant, surgery, adjuvant therapy following solid tumor resection, administration of nephrotoxic drugs e.g. 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), intracerebral hemorrhage, myocardial infarction (MI), atherosclerosis, Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), 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, Wegener’s granulomatosis, pulmonary sarcoidosis, Behcet’s disease, interleukin- 1 converting enzyme (ICE, also known as caspase-l) associated fever syndrome, chronic obstructive pulmonary disease (COPD), cigarette smoke-induced damage, cystic fibrosis, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), a neoplastic tumor, peridontitis, NEMO-mutations
(mutations of NF-kappa-B essential modulator gene (also known as IKK gamma or IKKG)), particularly, NEMO-deficiency syndrome, HOIL-l deficiency (also known as RBCK1) heme-oxidized IRP2 ubiquitin ligase-l deficiency), linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome, hematological and solid organ malignancies, bacterial infections and viral infections (such as influenza, staphylococcus, and mycobacterium (tuberculosis)), and Lysosomal storage diseases (particularly, Gaucher disease, and including GM2 gangliosidosis, alpha-mannosidosis, aspartylglucosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis, infantile free sialic acid storage disease, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic
leukodystrophy, mucopolysaccharidoses disorders, multiple sulfatase deficiency, Niemann- Pick disease, neuronal ceroid lipofuscinoses, Pompe disease, pycnodysostosis, Sandhoff disease, Schindler disease, sialic acid storage disease, Tay-Sachs, and Wolman disease), Stevens-Johnson syndrome, toxic epidermal necrolysis, glaucoma, spinal cord injury, fibrosis, complement-mediated cytotoxicity, pancreatic cancer (particularly metastatic adenocarcinoma of the pancreas, pancreatic ductal adenocarcinoma and/or malignancies of the endocrine cells in the pancreas), hepatocellular carcinoma, mesothelioma, melanoma, colorectal cancer, acute myeloid leukemia, metastasis, glioblastoma, breast cancer, gallbladder cancer, clear cell renal carcinoma (cc-RCC), non-small cell lung carcinoma (NSCLC), acute liver failure, radiation protection/mitigation (radiation induced necrosis), auditory disorders such as noise-induced hearing loss and drugs associated with ototoxicity such as cisplatin, or for the treatment of cells ex vivo to preserve vitality and function.
In this invention, RIP 1 kinase-mediated diseases or disorders are diseases or disorders that are mediated by activation of RIP 1 kinase, and as such, are diseases or disorders where inhibition of RIP 1 kinase would provide benefit. Such RIP1 kinase- mediated diseases or disorders are diseases/disorders which are likely to be regulated at least in part by programmed necrosis, apoptosis or the production of inflammatory cytokines, particularly inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), psoriasis, retinal detachment, retinal degeneration, retinitis pigmentosa, macular degeneration, age-related macular degeneration, pancreatitis, atopic dermatitis, arthritis (including rheumatoid arthritis, spondyloarthritis, gout, juvenile idiopathic arthritis (systemic onset juvenile idiopathic arthritis (SoJIA)), psoriatic arthritis), lupus, systemic lupus erythematosus (SLE), Sjogren’s syndrome, systemic scleroderma, anti-phospholipid syndrome (APS), vasculitis, osteoarthritis, liver damage/diseases (non-alcohol steatohepatitis (NASH), alcohol steatohepatitis (ASH), autoimmune hepatitis, autoimmune hepatobiliary diseases, primary sclerosing cholangitis (PSC), acetaminophen toxicity, hepatotoxicity), non-alcohol steatohepatitis (NASH), alcohol steatohepatitis (ASH), autoimmune hepatitis, non-alcoholic fatty liver disease (NAFLD), kidney damage/injury (nephritis, renal transplant, surgery, administration of nephrotoxic drugs e.g. 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 caspase-l) associated fever syndrome, chronic obstructive pulmonary disease (COPD), cigarette smoke-induced damage, cystic fibrosis, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), a neoplastic tumor, peridontitis, NEMO-mutations
(mutations of NF-kappa-B essential modulator gene (also known as IKK gamma or
IKKG)), particularly, NEMO-deficiency syndrome, HOIL-l deficiency (also known as RBCK1) heme-oxidized IRP2 ubiquitin ligase-l deficiency), linear ubiquitin chain
assembly complex (LUBAC) deficiency syndrome, hematological and solid organ
malignancies, bacterial infections and viral infections (such as influenza, staphylococcus, and mycobacterium (tuberculosis)), and Lysosomal storage diseases (particularly, Gaucher disease, and including GM2 gangliosidosis, alpha-mannosidosis, aspartylghicosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis, infantile free sialic acid storage disease, juvenile hexosaminidase A
deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic
leukodystrophy, mucopolysaccharidoses disorders, multiple sulfatase deficiency, Niemann- Pick disease, neuronal ceroid lipofuscinoses, Pompe disease, pycnodysostosis, Sandhoff disease, Schindler disease, sialic acid storage disease, Tay-Sachs, and Wolman disease), Stevens-Johnson syndrome, toxic epidermal necrolysis, glaucoma, spinal cord injury, fibrosis, complement-mediated cytotoxicity, pancreatic ductal adenocarcinoma,
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,
intracerebral hemorrhage, subarachnoid hemorrhage, acute liver failure and radiation protection/mitigation , auditory disorders such as noise-induced hearing loss and drugs associated with ototoxicity such as cisplatin, or for the treatment of cells ex vivo to
preserve vitality and function.
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. For example, 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.
The compounds useful in this invention may be particularly useful for the
amelioration of organ injury or damage sustained as a result of radiation therapy, or amelioration of spinal tissue injury or damage following spinal cord injury or amelioration of liver tissue injury or damage associated acute liver failure. The compounds useful in this invention may be particularly useful for amelioration of auditory disorders, such as noise-induced hearing loss or auditory disorders following the administration of ototoxic drugs or substances, e.g. cisplatin.
The compounds useful in this invention may be particularly useful for amelioration of solid organ tissue (particularly kidney, liver, and heart and/or lung) injury or damage following transplant or the administration of nephrotoxic drugs or substances e.g. cisplatin.
It will be understood that amelioration of such tissue damage may be achieved where possible, by pre-treatment with a compound of Formula (I), (II), or (III), or a
pharmaceutically acceptable salt thereof; 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.
Other RIP 1 kinase-mediated diseases or disorders suitable for treatment using the compounds useful in this invention include: hemorrhagic shock, trauma (including multiple trauma), traumatic brain injury, bums (thermal injury), Stevens-Johnson Syndrome / toxic epidermal necrolysis, heat stroke, acute pancreatitis, critical illness (in general),
chemotherapy, radiation injury, radiotherapy, sepsis, 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), 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. The compounds of Formulas (I), (II), or (III), or a pharmaceutically acceptable salt thereof, may be particularly useful for the prevention, delay of onset, amelioration, and/or treatment of diseases or disorders which result in RIP 1 -dependent inflammation of the gut epithelium, leading to bacterial translocation via blood or lymph to the systemic circulation. 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. It is anticipated that treatment of a patient suffering from one of such diseases or disorders (e.g., a bum injury) with a compound of Formulas (I), (II), or (III), or a pharmaceutically acceptable salt thereof, may prevent, delay the onset of, ameliorate or treat the resulting RIP 1 -dependent inflammation of the gut epithelium thereby preventing, delaying the onset of, or ameliorating the bacterial translocation via blood or lymph to the systemic circulation of the patient.
The compounds useful in this invention may be particularly useful for the treatment of 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, ischemia reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome, multiple sclerosis, and/or tumor necrosis factor receptor-associated periodic syndrome. The compounds useful in this invention, particularly the compounds of Formulas (I) or Formulas(II) or (II), or a pharmaceutically acceptable salt thereof, may be particularly useful for the treatment of the following RIP1 kinase-mediated diseases or disorders. In another embodiment, a compound that inhibits RIP1 kinase, particularly 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.
Provisional Patent Application No. 62/424047, filed November 18, 2016, U.S. Provisional Patent Application No. 62/585,267, filed November 13, 2017, U.S. Patent Application No. 15/424, 216, filed February 3, 2017 (US9,8l5,850), U.S. Patent Application No. 15/200, 058, filed July 1, 2016, (the disclosures of each of which are incorporated by reference herein) may be particularly useful for the treatment of the following RIP1 kinase-mediated diseases or disorders.
In one embodiment of this invention, the RIP1 kinase-mediated disease or disorder is a solid tumor.
In another embodiment, 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.
In yet another embodiment, 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.
In one embodiment, the human has a solid tumor.
Accordingly, in one embodiment, 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.
Provisional Patent Application No. 62/424,047, filed November 18, 2016, U.S. Provisional Patent Application No. 62/585,267 , filed November 13, 2017, U.S. Patent Application No. 15/424, 216, filed February 3, 2017 (US 9,815,850), U.S. Patent Application No. 15/200, 058, filed July 1, 2016, (the disclosures of each of which are incorporated by reference herein), and wherein the human has a solid tumor.
In another embodiment , this invention is directed to a method of treating a RIP 1 kinase-mediated cancer comprising administering a therapeutically effective amount of a compound that inhibits RIP 1 kinase in combination with at least one other therapeutically active agent, specifically, an immuno-modulator, to a human in need thereof, wherein the compound that inhibits RIP1 kinase is a compound of Formulas (I) and (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,
W02017/096301, WO2017/069279, and/or U.S. Provisional Patent Application No.
62/424,047, filed November 18, 2016, U.S. Provisional Patent Application No. 62/585,267, filed November 13, 2017, U.S. Patent Application No. 15/424, 216, filed February 3, 2017 (US9,8l5,850), U.S. Patent Application No. 15/200, 058, filed July 1, 2016, (the disclosures of each of which are incorporated by reference herein), and wherein the human has a solid tumor.
In one embodiment, the tumor is selected from head and neck cancer, gastric cancer, melanoma, renal cell carcinoma (RCC), esophageal cancer, non-small cell lung carcinoma (NSCUC), prostate cancer, colorectal cancer, ovarian cancer, pancreatic cancer, and pancreatic ductal adenocarcinoma. In one aspect, the human has one or more of the following: colorectal cancer (CRC), esophageal cancer, cervical, bladder, breast cancer, head and neck cancer, ovarian cancer, melanoma, renal cell carcinoma (RCC), EC squamous cell carcinoma, non-small cell lung carcinoma, mesothelioma, prostate cancer, and pancreatic ductal adenocarcinoma. In another aspect, the human has a liquid tumor such as diffuse large B cell lymphoma (DUBCU), multiple myeloma, chronic
lyphomblastic leukemia (CUE), follicular lymphoma, acute myeloid leukemia and chronic myelogenous leukemia.
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 T-cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, Hodgkin’s lymphoma, Non-Hodgkin’s lymphoma, lymphoblastic T cell lymphoma, Burkitt’s lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, lung cancer, vulval cancer, cervical cancer, endometrial cancer, cancer of the uterus, renal cancer (including kidney clear cell cancer, kidney papillary cancer, renal cell carcinoma), mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) and testicular cancer.
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.
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
promyelogenous or promyeloblastic) leukemia, acute myelomonocytic (or
myelomonoblastic) leukemia, acute monocytic (or monoblastic) leukemia, erythroleukemia and megakaryocytic (or megakaryoblastic) leukemia. These 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). 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
(RAEBT); as well as myelofibrosis (MFS) with or without agnogenic myeloid metaplasia. 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. 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). High-grade B-NHLs include Burkitt’s lymphoma (BL), Burkitt-like lymphoma, small non-cleaved cell lymphoma (SNCCL) and
lymphoblastic lymphoma. Other 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.
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. 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). Hematopoietic cancers may also include other cancers of additional hematopoietic cells, including polymorphonuclear leukocytes (or neutrophils), basophils, eosinophils, dendritic cells, platelets, erythrocytes and natural killer 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.
Accordingly, 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.
In another embodiment, 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.
In another embodiment, 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. In another embodiment, 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.
Specifically, 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
therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, with at least one other therapeutically active agent, to a human in need thereof.
In one specific embodiment, 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.
In another embodiment, 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. Specifically, this invention provides a compound described herein, or a pharmaceutically acceptable salt thereof, for use in therapy. More specifically, 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. More specifically, 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, for use in therapy.
In another embodiment, 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). In another embodiment, 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.
Specifically, 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-
1.2.4-triazole-3 -carboxamide, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a RIP 1 kinase-mediated disease or disorder (for example, a disease or disorder recited herein). This invention further provides (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, for use in the treatment of 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. Accordingly, 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. Specifically, 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. More specifically, 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. Specifically, 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. More specifically, 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. Specifically, 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, brain, liver, kidney), and limb ischemia), bowel ischemia (small intestine and large intestine), and cardiac surgery requiring cardio pulmonary bypass.
Other RIP1 kinase-mediated disease or disorders specifically suitable for treatment using a compound that inhibits RIP1 kinase, wherein the compound that inhibits RIP1 kinase 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.
Provisional Patent Application No. 62/424047, filed November 18, 2016, U.S. Patent Application No. 15/424, 216, filed February 3, 2017 (US 9,815,850), U.S. Patent
Application No. 15/200, 058, filed July 1, 2016, (the disclosures of each of which are incorporated by reference herein, or is a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, are diseases and disorders selected from pancreatic cancer, metastatic adenocarcinoma of the pancreas, pancreatic ductal adenocarcinoma, a malignancy of the endocrine cells in the pancreas, hepatocellular carcinoma, mesothelioma, melanoma, colorectal cancer, acute myeloid leukemia, metastasis, glioblastoma, breast cancer, gallbladder cancer, clear cell renal carcinoma, non small cell lung carcinoma, and radiation induced necrosis. Accordingly, in one embodiment, 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. In one embodiment, 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. In another embodiment, 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.
In another embodiment, a compound that inhibits RIP1 kinase is:
Figure imgf000033_0001
or a pharmaceutically acceptable salt thereof, or a tautomer thereof.
In another embodiment, a compound that inhibits RIP1 kinase is:
Figure imgf000033_0002
or a tautomer thereof.
In another embodiment, a compound that inhibits RIP1 kinase is:
Figure imgf000034_0001
or a pharmaceutically acceptable salt thereof, or a tautomer thereof.
In another embodiment, a compound that inhibits RIP1 kinase is:
Figure imgf000034_0002
or a tautomer thereof.
In another embodiment, a compound that inhibits RIP1 kinase is:
Figure imgf000034_0003
or a pharmaceutically acceptable salt thereof, or a tautomer thereof.
In another embodiment, a compound that inhibits RIP1 kinase is:
Figure imgf000034_0004
or a tautomer thereof.
In one embodiment, 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:
Figure imgf000035_0001
or a pharmaceutically acceptable salt, tautomer, stereoisomer or mixture of stereoisomers thereof, wherein:
R’ is H or optionally substituted C1-C6 alkyl; X1 and X2 together form an optionally substituted pyridyl:
Figure imgf000035_0002
YHsO;
Y2 is -0-;
R3 and R4 are independently H, halo, or optionally substituted C1-C6 alkyl, or R3 and R4 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-; -NR7- or C(R8)2-; R is H or optionally substituted C1-C6 alkyl; each R8 is independently H, halo, or optionally substituted C1-C6 alkyl, or two R8 together with the carbon atom to which they are attached, form an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; and R9 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 designated atom’s normal valence is not exceeded, selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido, carbamoyl, cyano, cycloalkyl, cycloalkylalkyl, guanadino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -NHNH2, =NNH2, imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfmyl, alkylsulfonyl, alkylsulfmyl, thiocyanate, -S(0)OH, -S(0)20H,
- 35 -ignaling- 35 -s, -SH, thioxo, N-oxide, Si(R100)3 wherein each R100 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 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and may comprise one or more oxo (C=0) or N-oxide (N-0-) moieties and/or a single ring or multiple rings wherein the multiple rings may be fused, bridged, or spiro; and each heteroaryl is independently an aromatic group having 1 to 20 ring carbon atoms, a single ring, multiple rings, or multiple fused rings, with one to five ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.
In one embodiment, a compound that inhibits RIP1 kinase is a compound having the formula:
Figure imgf000037_0001
or a pharmaceutically acceptable salt thereof.
In one embodiment, 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:
Figure imgf000038_0001
or a pharmaceutically acceptable salt thereof.
In one embodiment, a compound disclosed in W02017/004500 (now US
2017/0008877, the disclosure of which is incorporated by reference herein) that inhibits RIP 1 kinase is a compound having the formula:
Figure imgf000038_0002
or a pharmaceutically acceptable salt thereof, wherein
R1 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:
(a) 1 to 3 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-C6 cycloalkyl), and CH2CH2-(C3-C6 cycloalkyl); wherein if a nitrogen atom in the A ring is substituted, the substituent is not halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 thioalkyl, or cyano; (b) 1 substituent selected from the group consisting of C4-C6 heterocyclyl, C5-C6 heteroaryl, CH2-(C4-C6 heterocyclyl), CH2CH2-(C4-C6 heterocyclyl), CH2-(C5-C6 heteroaryl), CH2CH2-(C5-C6 heteroaryl); and optionally a second substituent selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; or
I two adjacent substituents which together form phenyl, C5-C6 heteroaryl, C4-C6 heterocyclyl or C4-C6 cycloalkyl; 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,
C1-C4 thioalkyl, or cyano; 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;
wherein the C ring is optionally substituted with:
(a) 1 to 4 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-C6 cycloalkyl), and CH2CH2-(C3-C6 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;
(b) 1 to 2 substituents selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, CH2(C4-C6 heterocyclyl), CH2CH2-(C4-C6 heterocyclyl), and unsubstituted C5-C6 heteroaryl; or
I two adjacent substituents which together form phenyl, C5-C6 heteroaryl, C4-C6 heterocyclyl or C4-C6 cycloalkyl;
Lis selected from the group consisting of a bond, 0, S, NH, NCH3, (Ckkjm, CH(CH3), C(CH3)2, CF2, CH2O, CH2S, CH(OH), CH2NH, and CH2N(CH3), or Lis absent such that the B ring and the C ring are fused; X is selected from the group consisting of CH2, C(CH3)2, CF2 and CHCF3;
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(CH3)2, C(CH3)2, CF2; and the C ring is phenyl. In another embodiment, a compound disclosed in W02017/004500 (now US
2017/0008877, the disclosure of which is incorporated by reference herein) that inhibits RIP1 kinase is:
(S)- l-benzyl-N-(4-methyl-5-oxo-5,6,7,8-tetrahydro-4H- pyrazolo[ l,5-a]
[1.3]diazepin-6-yl)-lH-l,2,4-triazole-3-carboxamide; (S)-l-benzyl-N-(4-methyl-5-oxo-2-(trifluoromethyl)-5,6,7,8- tetrahydro-4H- pyrazolo[ 1,5-a] [ 1 ,3 ]diazepin-6-yl)- 1H- 1 ,2,4-triazole-3 -carboxamide
(S)-N-((S)-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H- pyrazolo[l,5-a][l,3]diazepin-6- yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2- carboxamide;
(S)-l-benzyl-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8- tetrahydro-4H-pyrazolo[l,5- a] [l,3]diazepin-6-yl)-lH-l,2,4-triazole-3-carboxamide;
(S)-l- benzyl-N-(2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[l,5-a]
[1.3]diazepin-6-yl)-lH- 1,2,4- triazole-3-carboxamide; (S)-l-(2,6-difluorobenzyl)-N-(2,4-dimethyl-5-oxo-5,6,7,8- tetrahydro-4H- pyrazolo [ 1,5 -a] [ 1 ,3 ] diazepin-6-yl)- 1H- 1 , 2, 4-tri azole-3 -carboxamide ;
(S)-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H- pyrazolo[l,5-a]
[1.3]diazepin-6-yl)-l-(2,6-difluorobenzyl)-lH-l,2,4-triazole-3-carboxamide; (S)-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H- pyrazolo[l,5-a]
[1.3]diazepin-6-yl)-l-(3,5-difluorobenzyl)-lH-l,2,4-triazole-3-carboxamide;
(S)-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H- pyrazolo[l,5-a]
[1.3]diazepin-6-yl)-l-(2,5-difluorobenzyl)-lH-l,2,4-triazole-3-carboxamide;
(S)-l-(2,5-difluorobenzyl)-N-(2,4-dimethyl-5-oxo-5,6,7,8- tetrahydro-4H- pyrazolo[ 1,5 -a] [ 1 ,3 ]diazepin-6-yl)- 1H- 1 ,2,4-triazole-3 -carboxamide;
(S)-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H- pyrazolo[l,5-a]
[1.3]diazepin-6-yl)- l-(2,3-dichlorobenzyl)-lH- 1,2, 4-tri azole-3-carboxamide;
(S)-N-(2-cyclopropyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H- pyrazolo[l,5-a]
[1.3]diazepin-6-yl)- l-(2,4-dichlorobenzyl)-lH- 1,2, 4-tri azole-3-carboxamide; (S)-l-benzyl-N-(2-isopropyl-4-methyl-5-oxo-5,6,7,8- tetrahydro-4H-pyrazolo[l,5-a]
[1.3]diazepin-6-yl)-lH-l, 2, 4-triazole-3 -carboxamide;
(S)-N-(2-ethyl-4-methyl-5-oxo-5,6,7,8-tetrahydro-4H- pyrazolo| \ .5-a/
[ 1 ,3 ]diazepin-6-yl)- 1 -(2-fluorobenzyl)- 1H- l,2,4-triazole-3 -carboxamide;
I-5-(2-fluorophenyl)-N-((S)-4-methyl-5-oxo-5,6,7,8- tetrahydro-4H-pyrazolo[l,5- a][l,3]diazepin-6-yl)-6,7-dihydro-5H-pyrrolo[ l,2-b] [ l,2,4]triazole-2- carboxamide;
(5R)-5-phenyl-N-[(6S)-2,4-dimethyl-5-oxo-7,8-dihydro-6H- pyrazolo[l,5-a]
[1.3]diazepin-6-yl]-6,7-dihydro-5Hpyrrolo[ l,2-b][l,2,4]triazole-2- carboxamide; or (5R)-5-(2-fluorophenyl)-N-[(6S)-4-methyl-5-oxo-7,8-dihydro-6H-pyrazolo[l,5-a]
[1.3]diazepin-6-yl]-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2- carboxamide; or a pharmaceutically acceptable salt thereof. In one embodiment, a compound disclosed in WO2016/185423 (the disclosure of which is incorporated by reference herein) that inhibits RIP 1 kinase is a compound having the following formula:
Figure imgf000042_0001
wherein:
R1 is (Ci-C4)alkoxy-CH2-, phenyl(Ci-C4)alkoxy-CH2-, or a substituted or unsubstituted (C2-C6)alkyl, (C2-C4)alkynyl, (C3-Ce)cycloalkyl,
(C3-C6)cycloalkyl-(Ci-C4)alkyl- group, or a substituted or unsubstituted 5-6 membered heterocycloalkyl group further optionally substituted by halogen or (Ci-C4)alkyl,
wherein said substituted (C2-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-alkyl-, or 5-6 membered heterocycloalkyl group is substituted by 1, 2 or 3 substituents independently selected from hydroxyl, (benzyloxy)carbonyl)amino, cyano, halogen, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, (Ci-C4)alkyl-CO-, cyano(Ci-C4)alkyl-CO-, (Ci-C4)alkoxy-(Ci-C4)alkyl-CO-, (Ci-C4)alkoxy-CO-, (Ci-C4)alkylNHCO-, ((Ci-C4)alkyl)((Ci-C4)alkyl)NCO-, halo(Ci-C4)alkyl-CO-, optionally substituted (C3-C6)cycloalkyl-CO, optionally substituted
(C3-C6)cycloalkyl-(Ci-C4)alkyl-CO-, optionally substituted phenyl-CO, optionally substituted phenyl-SCh-, optionally substituted phenyl(Ci-C4)alkyl-CO-, optionally substituted 5-6 membered heteroaryl-CO, and optionally substituted 9-10 membered heteroaryl-CO-,
wherein said optionally substituted (C3-C6)cycloalkyl-CO-, optionally substituted (C3-C6)cycloalkyl-(Ci-C4)alkyl-CO-, optionally substituted phenyl-CO-, optionally substituted phenyl-S02-, optionally substituted phenyl(Ci-C4)alkyl-CO-, optionally substituted 5-6 membered heteroaryl-CO-, or optionally substituted 9-10 membered heteroaryl-CO- is optionally substituted by 1 or 2 substituents independently selected from halogen, cyano, (Ci-C4)alkyl, (Ci-C4)alkoxy, (Ci-C4)alkyl-CO-, halo(Ci-C4)alkyl, halo(Ci-C4)alkyl-CO, (C3-C6)cycloalkyl and 5-6 membered heterocycloalkyl; or
said substituted (C2-C4)alkynyl, (C3-Ce)cycloalkyl or 5-6 membered
heterocycloalkyl group is substituted by an optionally substituted phenyl, 5-6 membered heteroaryl or 9-membered heteroaryl group,
wherein said phenyl, 5-6 membered heteroaryl or 9-membered heteroaryl group is optionally substituted by 1 or 2 substituents independently selected from halogen, (Ci-C4)alkyl,
(Ci-GOalkyl-CO-, halo(Ci-C4)alkyl, and halo(Ci-C4)alkyl-CO-; R2 is a substituted or unsubstituted phenyl, (C3-Ce)cycloalkyl, 5-6 membered
oxygen-containing heterocycloalkyl, 5-6 membered heteroaryl, 9-membered heteroaryl, 9-10 membered carbocyclic-aryl, or 9-10 membered heterocyclic-aryl group,
wherein said substituted phenyl, (C3-Ce)cycloalkyl, 5-6 membered
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 R3 is H or halogen;
or a salt, particularly a pharmaceutically acceptable salt, thereof. In one embodiment, a compound disclosed in U.S. Provisional Patent Application
No. 62/424047, filed November 18, 2016 (and U.S. Provisional Patent Application No. 62/585,267, filed November 13, 2017, the disclosure of each of which is incorporated by reference herein), that inhibits RIP1 kinase is a compound having the following Formula:
Figure imgf000043_0001
wherein:
R1 is a substituted or unsubstituted 5-6 membered heteroaryl or 9-10 membered heteroaryl group,
wherein said substituted 5-6 membered heteroaryl or 9-10 membered heteroaryl group is substituted by 1 or 2 substituents independently selected from hydroxyl, cyano, halogen, (Ci-C4)alkyl, halo(Ci-C4)alkyl, hydroxy(Ci-C4)alkyl,
(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-,
H2NCO-(Ci-C4)alkyl-, ((Ci-C4)alkyl)NHCO-, (hydroxy-(Ci-C4)alkyl)NHCO-, (C3-C6)cycloalkyl-NHCO-, optionally substituted 5-6 membered
heterocycloalkyl-NHCO, ((Ci-C4)alkyl)((Ci-C4)alkyl)N-CO-,
(Ci-C4)alkyl-CONH-,
((Ci-C4)alkyl)((Ci-C4)alkyl)N-NHCO-, -CO2H, -C02(Ci-C4)alkyl,
(Ci-C4)alkylthio-, phenyl-(Ci-C4)alkylthio-, (Ci-C4)alkyl-S02-, phenyl, optionally substituted 5-6 membered heterocycloalkyl, and optionally substituted 5-6 membered heteroaryl group,
wherein said optionally substituted (Ci-C4)alkoxy is optionally substituted by hydroxyl, -CO2H, -CONH2, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; or said optionally substituted 5-6 membered heterocycloalkyl-CO-, optionally substituted 5-6 membered heterocycloalkyl, or optionally substituted 5-6 membered heteroaryl group is optionally substituted by (Ci-C4)alkyl or oxo; or said optionally substituted 5-6 membered heterocycloalkyl-NHCO- is optionally substituted by (Ci-C4)alkyl-CO-; and
R2 is a substituted or unsubstituted phenyl or 5-6 membered heteroaryl group,
wherein said substituted phenyl or 5-6 membered heteroaryl group is substituted by 1 or 2 substituents independently selected from halogen, (Ci-C4)alkyl,
(Ci-C4)alkoxy, and cyano;
or a pharmaceutically acceptable salt thereof.
These compounds may be prepared according to Scheme 1, Scheme 2, Scheme 3, Scheme 4, or analogous methods. Wittig reaction of an aryl aldehyde of Formula A with (triphenylphosphoranylidene)-acetaldehyde affords an unsaturated aldehyde of Formula B. Reaction of an aldehyde of Formula B with hydrazine provides a dihydropyrazole of Formula C. The coupling of l-(tert-butoxycarbonyl)piperidine-4-carboxybc acid with the dihydropyrazole of Formula C under amide bond forming conditions affords a compound of Formula D. Removal of the t-butoxy carbonyl group of a compound of Formula D affords a racemic piperdine of Formula E. Treatment of the racemic piperidine of Formula E with a chiral acid (e.g. (lR)-(-)-lO-camphorsulfonic acid) provides a chiral amine salt of Formula F. Reaction of a compound of Formula F with and aryl halide or aryl sulfone under nucleophilic aromatic substitution conditions provides a compound having the above formula. Alternatively, these compounds can be prepared through further transformation of a preexisting functional group. For example, as in Scheme 2, a compound possessing a carboxylate ester (Formula G) may be hydrolyzed to provide a new compound possessing a carboxylic acid (Formula H). Additionally, a compound of Formula H may be further transformed through an amide bond forming reaction to afford an alternate compound of possessing an amide (Formula J).
Alternatively, 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.
Scheme 1 : Synthesis of RIP 1 Inhibitor Compounds.
Figure imgf000046_0003
Scheme 2: Alternate Synthesis of RIP 1 Inhibitor Compounds.
Figure imgf000046_0001
Scheme 3: Alternate Synthesis of RIP 1 Inhibitor Compounds.
Figure imgf000046_0002
Scheme 4: Alternate Synthesis of RIP 1 Inhibitor Compounds.
Figure imgf000047_0001
In one embodiment, a compound that inhibits RIP1 kinase is:
(S)-( 1 -(4-(benzylthio)pyrimidin-2-yl)piperidin-4-yl)(5-phenyl-4, 5-dihydro- lH-pyrazol- 1 - yl)methanone;
2-(4-(5 -phenyl -4, 5 -dihydro- lH-pyrazole- 1 -carbonyl)piperidin- 1 -yl)pyrimidine-5 - carbonitrile;
( 1 -(4-methoxypyrimidin-2-yl)piperidin-4-yl)(5 -phenyl -4, 5 -dihydro- lH-pyrazol- 1 - yl)methanone; (5 -phenyl-4,5 -dihydro- lH-pyrazol- 1 -yl)( 1 -(4-phenylpyrimidin-2-yl)piperidin-4- yl)methanone;
2-(4-(5 -phenyl -4, 5 -dihydro- lH-pyrazole- 1 -carbonyl)piperidin- 1 -yl)pyrimidine-4- carbonitrile;
( 1 -(4-aminopyrimidin-2-yl)piperidin-4-yl)(5 -phenyl-4,5 -dihydro- lH-pyrazol- 1 - yl)methanone;
( 1 -(5 -methoxypyrimidin-2-yl)piperidin-4-yl)(5 -phenyl -4, 5 -dihydro- lH-pyrazol- 1 - yl)methanone;
(S)-(l-(5-(methylsulfonyl)pyrimidin-2-yl)piperidin-4-yl)(5-phenyl-4, 5-dihydro- lH- pyrazol- 1 -yl)methanone ; (S)-(l-(7H-purin-2-yl)piperidin-4-yl)(5-phenyl-4,5-dihydro-lH-pyrazol-l-yl)methanone;
(S)-methyl 2-(4-(5 -phenyl -4, 5-dihydro- lH-pyrazole- 1 -carbonyl)piperidin- 1 -yl)pyrimidine- 5-carboxylate;
(S)-( 1 -(2-aminopyrimidin-4-yl)piperidin-4-yl)(5 -phenyl-4,5 -dihydro- lH-pyrazol- 1 - yl)methanone; (S)-(l-(6-methoxypyrimidin-4-yl)piperidin-4-yl)(5-phenyl-4,5-dihydro-lH-pyrazol-l- yl)methanone;
(S)-(l-(5-methoxypyrimidin-2-yl)piperidin-4-yl)(5-phenyl-4,5-dihydro-lH-pyrazol-l- yl)methanone; (S)-6-(4-(5-phenyl-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin-l-yl)pyrimidine-4- carbonitrile;
(S)-(l-(2-(methylamino)pyrimidin-4-yl)piperidin-4-yl)(5-phenyl-4,5-dihydro-lH-pyrazol- l-yl)methanone;
(S)-(l-(4-(methylamino)pyrimidin-2-yl)piperidin-4-yl)(5-phenyl-4,5-dihydro-lH-pyrazol- l-yl)methanone;
(S)-(l-(2-methoxypyrimidin-4-yl)piperidin-4-yl)(5-phenyl-4,5-dihydro-lH-pyrazol-l- yl)methanone;
(S)-4-(4-(5-phenyl-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin-l-yl)pyrimidine-2- carbonitrile; (S)-2-(4-(5 -phenyl -4, 5 -dihydro- lH-pyrazole- 1 -carbonyl)piperidin- 1 -yl)pyrimidin-4(3H)- one;
(S)-( 1 -(6-aminopyrimidin-4-yl)piperidin-4-yl)(5 -phenyl-4,5 -dihydro- lH-pyrazol- 1 - yl)methanone;
(S)-(5 -phenyl-4,5 -dihydro- lH-pyrazol- 1 -yl)( 1 -(pyrazolo [ 1 ,5-a]pyrimidin-5 -yl)piperidin-4- yl)methanone;
(S)-(l-(imidazo[l,2-b]- 47 -ignaling- 47— 6-yl)piperidin-4-yl)(5-phenyl-4,5-dihydro-lH- pyrazol- 1 -yl)methanone ;
(S)-( 1 -(9-methyl-9H-purin-2-yl)piperidin-4-yl)(5 -phenyl -4, 5 -dihydro- lH-pyrazol- 1 - yl)methanone; (S)-2-(4-(5-phenyl-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin-l-yl)-5H-pyrrolo[2,3- d]pyrimidin-6(7H)-one; (S)-6-(4-(5 -phenyl -4, 5 -dihydro- lH-pyrazole- 1 -carbonyl)piperidin- 1 -yl)pyridazine-3- carboxamide;
(S)-(5-phenyl-4,5-dihydro-lH-pyrazol-l-yl)(l-(6-(trifluoromethyl)- 48 -ignaling- 48— 3- yl)piperidin-4-yl)methanone; (S)-(l-(4-amino-5-fluoropyrimidin-2-yl)piperidin-4-yl)(5-phenyl-4, 5-dihydro- lH-pyrazol- l-yl)methanone;
(S)-2-(4-(5-phenyl-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin-l-yl)pyrimidine-4- carboxamide;
(S)-2-(4-(5-phenyl-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin-l-yl)pyrimidine-4- carboxylic acid;
(S)-6-(4-(5-phenyl-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin-l-yl)nicotinamide;
(S)-6-(4-(5 -phenyl -4, 5 -dihydro- lH-pyrazole- 1 -carbonyl)piperidin- 1 -yl)pyrazine-2- carboxamide;
(S)-6-(4-(5-phenyl-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin-l-yl)pyrimidine-4- carboxamide;
(S)-(l-(6-amino-2 -methylpyrimidin-4-yl)piperidin-4-yl)(5-phenyl-4, 5-dihydro- lH-pyrazol- l-yl)methanone;
(S)-(l-(2-amino-6-methoxypyrimidin-4-yl)piperidin-4-yl)(5-phenyl-4,5-dihydro-lH- pyrazol- 1 -yl)methanone ; (S)-(l-(6-amino-2-methoxypyrimidin-4-yl)piperidin-4-yl)(5-phenyl-4,5-dihydro-lH- pyrazol- 1 -yl)methanone ;
(S)-N-(2-(4-(5-phenyl-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin-l-yl)pyrimidin-4- yl)acetamide;
(S)-6-(4-(5-phenyl-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin-l-yl)-lH-pyrazolo[3,4- d]pyrimidin-4(7H)-one;
(S)-(5 -phenyl-4, 5 -dihydro- lH-pyrazol-l-yl)( l-(6-phenylpyrazin-2-yl)piperidin-4- yl)methanone; (S)-(5-phenyl-4,5-dihydro-lH-pyrazol-l-yl)(l-(- 49 -ignaling- 49 -s-2-yl)piperidin-4- yl)methanone;
(S)-5-(4-(5-phenyl-4,5-dihydro- lH-pyrazole- 1 -carbonyl)piperidin- 1 -yl)pyrazine-2- carbonitrile; (S)-( 1 -(6-aminopyrazin-2-yl)piperidin-4-yl)(5 -phenyl -4, 5 -dihydro- lH-pyrazol- 1 - yl)methanone;
(S)-6-(4-(5 -phenyl -4, 5 -dihydro- lH-pyrazole- 1 -carbonyl)piperidin- 1 -yl)pyridazine-3- carbonitrile;
(S)-( 1 -(6-hydroxypyrimidin-4-yl)piperidin-4-yl)(5 -phenyl -4, 5 -dihydro- lH-pyrazol- 1 - yl)methanone;
(S)-3-(4-(5-phenyl-4,5-dihydro- lH-pyrazole- 1 -carbonyl)piperidin- 1 -yl)pyrazine-2- carbonitrile;
(S)-(l-(2-(methylthio)pyrimidin-4-yl)piperidin-4-yl)(5-phenyl-4,5-dihydro-lH-pyrazol-l- yl)methanone; (S)-(5 -phenyl -4, 5-dihydro- lH-pyrazol- l-yl)( l-(2-(trifluoromethyl)pyrimidin-4- yl)piperidin-4-yl)methanone;
(S)-6-(4-(5 -phenyl -4, 5 -dihydro- lH-pyrazole- 1 -carbonyl)piperidin- 1 -yl)pyrazine-2- carbonitrile;
(S)-(l-(6-methoxypyrazin-2-yl)piperidin-4-yl)(5-phenyl-4,5-dihydro-lH-pyrazol-l- yl)methanone;
(S)-( 1 -(6-methoxypyridazin-3 -yl)piperidin-4-yl)(5 -phenyl -4, 5 -dihydro- lH-pyrazol- 1 - yl)methanone;
(S)-4-(4-(5 -phenyl -4, 5 -dihydro- lH-pyrazole- 1 -carbonyl)piperidin- 1 -yl)pyrimidine-5 - carbonitrile; (S)-(5 -phenyl -4, 5-dihydro- lH-pyrazol- l-yl)( l-(6-(trifluoromethyl)pyrimidin-4- yl)piperidin-4-yl)methanone; (S)-(l-(lH-pyrazolo[3,4-d]pyrimidin-6-yl)piperidin-4-yl)(5-phenyl-4,5-dihydro-lH- pyrazol- 1 -yl)methanone ;
(S)-2-(4-(5 -phenyl -4, 5 -dihydro- lH-pyrazole- 1 -carbonyl)piperidin- 1 -yl)thiazole-4- carbonitrile; (S)-N-methyl-2-(4-(5-phenyl-4,5-dihydro- lH-pyrazole- 1 -carbonyl)piperidin- 1 -yl)thiazole-
4-carboxamide;
(S)-2-(4-(5 -phenyl -4, 5 -dihydro- lH-pyrazole- 1 -carbonyl)piperidin- 1 -yl)thiazole-5 - carboxamide;
(S)-2-(4-(5 -phenyl -4, 5 -dihydro- lH-pyrazole- 1 -carbonyl)piperidin- 1 -yl)thiazole-4- carboxamide;
(S)-( 1 -(5 -phenyl- 1 ,3 ,4-oxadiazol-2-yl)piperidin-4-yl)(5 -phenyl -4, 5 -dihydro- lH-pyrazol- 1 - yl)methanone;
(S)-( 1 -(4-ethoxypyrimidin-2-yl)piperidin-4-yl)(5-phenyl-4,5-dihydro- lH-pyrazol- 1 - yl)methanone; (S)-(l-(6-(methylthio)pyrimidin-4-yl)piperidin-4-yl)(5-phenyl-4,5-dihydro-lH-pyrazol-l- yl)methanone;
(S)-(l-(6-amino-2-(methylthio)pyrimidin-4-yl)piperidin-4-yl)(5-phenyl-4, 5-dihydro- lH- pyrazol- 1 -yl)methanone ;
(S)-(l-(6-amino-5-fluoropyrimidin-4-yl)piperidin-4-yl)(5-phenyl-4,5-dihydro-lH-pyrazol- l-yl)methanone;
(S)-3 -( 1 -( 1 -(pyrazolo [ 1 ,5 -a]pyrimidin-5 -yl)piperidine-4-carbonyl)-4,5 -dihydro- 1H- pyrazol-5 -yl)benzonitrile ;
(S)-5-(4-(5-phenyl-4,5-dihydro- lH-pyrazole- 1 -carbonyl)piperidin- 1 -yl)pyrazine-2- carboxamide; (S)-N-(6-(4-(5-phenyl-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin-l-yl)pyrazin-2- yl)acetamide; (S)-ethyl 2-(4-(5 -phenyl -4, 5 -dihydro- lH-pyrazole- 1 -carbonyl)piperidin- 1 -yl)oxazole-4- carboxylate;
(S)-ethyl 2-(4-(5 -phenyl -4, 5 -dihydro- lH-pyrazole- 1 -carbonyl)piperidin- 1 -yl)oxazole-5- carboxylate; (S)-(5 -phenyl-4, 5 -dihydro- lH-pyrazol-l-yl)(l -(5 -phenyloxazol-2-yl)piperidin-4- yl)methanone;
(S)-6-(4-(5-(3-cyanophenyl)-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin-l- yl)pyrimidine-4-carbonitrile;
(S)-3-( 1 -( 1 -(4-methoxypyrimidin-2-yl)piperidine-4-carbonyl)-4,5-dihydro- lH-pyrazol-5- yl)benzonitrile;
(S)-6-(4-(5-(3-cyanophenyl)-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin-l- yl)pyrimidine-4-carboxamide ;
(S)-2-(4-(5-(3-cyanophenyl)-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin-l- yl)pyrimidine-4-carboxamide ; (S)-3-( 1 -( 1 -(4-amino-5-fluoropyrimidin-2-yl)piperidine-4-carbonyl)-4, 5-dihydro- 1H- pyrazol-5 -yl)benzonitrile ;
(S)-3-(l-(l-(imidazo[l,2-b]- 51 -ignaling- 51— 6-yl)piperidine-4-carbonyl)-4,5-dihydro- 1 H-pyrazol-5 -y l)benzonitrile ;
(S)-4-(4-(5-(3-cyanophenyl)-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin-l- yl)pyrimidine-2-carbonitrile;
(S)-3-( 1 -( 1 -(2-methoxypyrimidin-4-yl)piperidine-4-carbonyl)-4,5-dihydro- lH-pyrazol-5- yl)benzonitrile;
(S)-3 -( 1 -( 1 -( lH-pyrazolo [3 ,4-d]pyrimidin-6-yl)piperidine-4-carbonyl)-4,5 -dihydro- 1H- pyrazol-5 -yl)benzonitrile ; (S)-(5-(3 ,5 -difluorophenyl)-4,5 -dihydro- lH-pyrazol- 1 -yl)( 1 -(5-methyl- 1 ,3 ,4-oxadiazol-2- yl)piperidin-4-yl)methanone; (S)-6-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin-l- yl)pyrimidine-4-carbonitrile;
(S)-(5-(3 ,5 -difluorophenyl)-4,5 -dihydro- lH-pyrazol- 1 -yl)( 1 -(4-methoxypyrimidin-2- yl)piperidin-4-yl)methanone; (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin-l-yl)-5H- pyrrolo [2,3 -d]pyrimidin-6(7H)-one;
(S)-( 1 -(4-amino-5-fluoropyrimidin-2-yl)piperidin-4-yl)(5 -(3 ,5 -difluorophenyl)-4,5 - dihydro- lH-pyrazol- 1 -yl)methanone;
(S)-(5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazol-l-yl)(l-(2-(methylthio)pyrimidin-4- yl)piperidin-4-yl)methanone;
(S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin-l- yl)pyrimidine-4-carboxamide ;
(S)-(l-(2 -aminopyrimidin-4-yl)piperidin-4-yl)(5-(3,5-difluorophenyl)-4, 5-dihydro- lH- pyrazol- 1 -yl)methanone ; (S)-6-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin-l- yl)pyrimidine-4-carboxamide ;
(S)-(l-(lH-pyrazolo[3,4-d]pyrimidin-6-yl)piperidin-4-yl)(5-(3,5-difluorophenyl)-4,5- dihydro- lH-pyrazol- 1 -yl)methanone;
(S)-(5 -(3 ,5 -difluorophenyl)-4, 5 -dihydro- lH-pyrazol- 1 -yl)( 1 -(imidazo [1,2- b]- 52 -ignabng- 52— 6-yl)piperidin-4-yl)methanone;
(S)-4-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin-l- yl)pyrimidine-5-carbonitrile;
(S)-4-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin-l- yl)pyrimidine-2-carbonitrile; (S)-(5 -(3 ,5 -difluorophenyl)-4, 5 -dihydro- lH-pyrazol- 1 -yl)( 1 -(pyrazolo [ 1 ,5 -a]pyrimidin-5- yl)piperidin-4-yl)methanone; (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazol-l-yl)(l-(6-methoxypyrimidin-4- yl)piperidin-4-yl)methanone;
(S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin-l- yl)pyrimidine-5-carbonitrile; (S)-(l-(4-aminopyrimidin-2-yl)piperidin-4-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-lH- pyrazol- 1 -yl)methanone ;
(S)-6-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin-l- yl)pyridazine -3 -carbonitrile ;
(S)-5-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin-l- yl)pyrazine-2-carbonitrile;
(S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin-l- yl)pyrimidine-5 -carboxamide ;
(S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin-l- yl)pyrimidin-4(3H)-one ; (S)-(l-(6-aminopyrimidin-4-yl)piperidin-4-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-lH- pyrazol- 1 -yl)methanone ;
(S)-(5-(3 ,5 -difluorophenyl)-4,5 -dihydro- lH-pyrazol- 1 -yl)( 1 -(2-methoxypyrimidin-4- yl)piperidin-4-yl)methanone;
(S)-(5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazol-l-yl)(l-(2-(methylamino)pyrimidin-4- yl)piperidin-4-yl)methanone;
(S)-(5-(2,5-difluorophenyl)-4,5-dihydro-lH-pyrazol-l-yl)(l-(5-methoxypyrimidin-2- yl)piperidin-4-yl)methanone,
(S)-2-(4-(5-(2,5-difluorophenyl)-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin-l- yl)pyrimidine-4-carboxamide ; (S)-5-(4-(5-(2,5-difluorophenyl)-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin-l- yl)pyrazine-2 -carbonitrile; (S)-6-(4-(5-(2,5-difluorophenyl)-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin-l- yl)pyrimidine-4-carbonitrile;
(S)-(5-(2,5 -difluorophenyl)-4, 5 -dihydro- lH-pyrazol- 1 -yl)( 1 -(6-methoxypyrimidin-4- yl)piperidin-4-yl)methanone; (S)-ethyl 2-(4-(5-(3, 5-difluorophenyl)-4, 5-dihydro- lH-pyrazole-l -carbonyl)piperidin-l- yl)oxazole-4-carboxylate;
(S)-ethyl 2-(4-(5-(3, 5-difluorophenyl)-4, 5-dihydro- lH-pyrazole-l -carbonyl)piperidin-l- yl)oxazole -5 -carboxylate ;
(S)-6-(4-(5-(5-fluoropyridin-3-yl)-4, 5-dihydro- lH-pyrazole-l-carbonyl)piperidin-l- yl)pyrimidine-4-carboxamide;
(S)-2-(4-(5-(5-fluoropyridin-3-yl)-4, 5-dihydro- lH-pyrazole-l-carbonyl)piperidin-l- yl)pyrimidine-4-carboxamide ;
(S)-(5 -(5 -fluoropyridin-3 -yl)-4, 5 -dihydro- lH-pyrazol- 1 -yl)( 1 -(2-methoxypyrimidin-4- yl)piperidin-4-yl)methanone; (S)-6-(4-(5-(5-fluoropyridin-3-yl)-4, 5-dihydro- lH-pyrazole-l-carbonyl)piperidin-l- yl)pyrimidine-4-carbonitrile;
(S)-(l-(4-amino-5-fluoropyrimidin-2-yl)piperidin-4-yl)(5-(5-fluoropyridin-3-yl)-4,5- dihydro- lH-pyrazol- 1 -yl)methanone;
(S)-(5 -(5 -fluoropyridin-3 -yl)-4, 5 -dihydro- lH-pyrazol- 1 -yl)( 1 -(6-methoxypyrimidin-4- yl)piperidin-4-yl)methanone;
(S)-(5 -(5 -fluoropyridin-3 -yl)-4, 5 -dihydro- lH-pyrazol- 1 -yl)( 1 -(2-(methylthio)pyrimidin-4- yl)piperidin-4-yl)methanone;
(S)-4-(4-(5-(5-fluoropyridin-3-yl)-4, 5-dihydro- lH-pyrazole-l-carbonyl)piperidin-l- yl)pyrimidine-2-carbonitrile; (S)-(5-(5-fluoropyridin-3-yl)-4,5-dihydro-lH-pyrazol-l-yl)(l-(pyrazolo[l,5-a]pyrimidin-5- yl)piperidin-4-yl)methanone; (S)-(5 -(5 -fluoropyridin-3 -yl)-4, 5 -dihydro- lH-pyrazol- 1 -yl)( 1 -(imidazo [1,2- b]- 55 -ignaling- 55— 6-yl)piperidin-4-yl)methanone;
(S)-N-(2-(4-(5-(2, 5-difluorophenyl)-4, 5-dihydro- lH-pyrazole-l-carbonyl)piperidin- 1- yl)pyrimidin-4-yl)acetamide; (S)-N-(6-(4-(5-phenyl-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin-l-yl)pyrimidin-4- yl)acetamide;
(S)-N-(6-(4-(5 -(3 ,5 -difluorophenyl)-4,5 -dihydro- lH-pyrazole- 1 -carbonyl)piperidin- 1 - yl)pyrimidin-4-yl)acetamide;
(S)-( 1 -(5 -fluoro-4-(4-methylpiperazin- 1 -yl)pyrimidin-2-yl)piperidin-4-yl)(5 -phenyl -4, 5 - dihydro- lH-pyrazol- 1 -yl)methanone;
(S)-(l-(2-(dimethylamino)pyrimidin-4-yl)piperidin-4-yl)(5-phenyl-4, 5-dihydro- lH- pyrazol- 1 -yl)methanone ;
(S)-2-(4-(5-(2,5-difluorophenyl)-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin-l- yl)pyrimidine-5 -carboxamide ; (S)-5-chloro-2-(4-(5-(5-fluoropyridin-3-yl)-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin- 1 -yl)pyrimidine-4-carboxamide;
(S)-N-cyclopropyl-2-(4-(5-phenyl-4,5-dihydro- lH-pyrazole- 1 -carbonyl)piperidin- 1 - yl)pyrimidine-4-carboxamide;
(S)-N-(2 -hydroxyethyl)-2-(4-(5-phenyl-4, 5-dihydro- lH-pyrazole- l-carbonyl)piperidin-l- yl)pyrimidine-4-carboxamide;
(S)-( 1 -(5 -fluoro-4-(2-morpholinoethoxy)pyrimidin-2-yl)piperidin-4-yl)(5 -phenyl -4, 5 - dihydro- lH-pyrazol- 1 -yl)methanone;
(S)-( 1 -(5 -hydroxypyrimidin-2-yl)piperidin-4-yl)(5 -phenyl -4, 5 -dihydro- lH-pyrazol- 1 - yl)methanone; (S)-( 1 -(6-(5 -methyl- 1 ,3 ,4-oxadiazol-2-yl)pyrimidin-4-yl)piperidin-4-yl)(5 -phenyl -4, 5 - dihydro- lH-pyrazol- 1 -yl)methanone; (S)-(l-(4-(hydroxymethyl)pyrimidin-2-yl)piperidin-4-yl)(5-phenyl-4,5-dihydro-lH- pyrazol- 1 -yl)methanone ;
(S)-2-(4-(5 -phenyl -4, 5 -dihydro- lH-pyrazole- 1 -carbonyl)piperidin- 1 -yl)pyrimidine-5 - carboxamide; (S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin-l- yl)oxazole -5 -carboxamide ;
(S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin-l- yl)oxazole -5 -carbonitrile ;
(S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin-l- yl)oxazole-4-carboxamide;
(S)-2-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin-l- yl)oxazole -4-carbonitrile ;
(S)-2-(4-(5 -phenyl -4, 5 -dihydro- lH-pyrazole- 1 -carbonyl)piperidin- 1 -yl)oxazole-4- carboxamide; (S)-2-(4-(5 -phenyl -4, 5 -dihydro- lH-pyrazole- 1 -carbonyl)piperidin- 1 -yl)oxazole-4- carbonitrile;
(S)-2-(4-(5 -phenyl -4, 5 -dihydro- lH-pyrazole- 1 -carbonyl)piperidin- 1 -yl)oxazole-5 - carbonitrile;
(S)-(l-(7H-purin-2-yl)piperidin-4-yl)(5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazol-l- yl)methanone;
(S)-(l-(4-(4,5-dihydro-lH-imidazol-2-yl)pyrimidin-2-yl)piperidin-4-yl)(5-phenyl-4,5- dihydro- lH-pyrazol- 1 -yl)methanone,
(S)-(4-methylpiperazin- 1 -yl)(2-(4-(5 -phenyl -4, 5 -dihydro- lH-pyrazole- 1 - carbonyl)piperidin- 1 -yl)pyrimidin-4-yl)methanone; (S)-N, N-diethyl-2-(4-(5-phenyl -4, 5-dihydro- lH-pyrazole- 1 -carbonyl)piperidin- 1 - yl)pyrimidine-4-carboxamide ; (S)-N’ ,N’ -dimethyl-2-(4-(5 -phenyl -4, 5 -dihydro- lH-pyrazole- 1 -carbonyl)piperidin- 1 - yl)pyrimidine-4-carbohydrazide ;
(S)-N-( 1 -acetylpiperidin-4-yl)-2-(4-(5-phenyl -4, 5-dihydro- lH-pyrazole- 1- carbonyl)piperidin- 1 -yl)pyrimidine-4-carboxamide ; (S)-(l-(4-(morphobne-4-carbonyl)pyrimidin-2-yl)piperidin-4-yl)(5 -phenyl -4,5 -dihydro- lH-pyrazol- 1 -yl)methanone;
(S)-(5 -phenyl-4,5 -dihydro- lH-pyrazol- 1 -yl)( 1 -(4-(piperazine- 1 -carbonyl)pyrimidin-2- yl)piperidin-4-yl)methanone;
(S)-2-(4-(5 -phenyl -4, 5 -dihydro- lH-pyrazole- 1 -carbonyl)piperidin- 1 -yl)-N-(piperidin-4- yl)pyrimidine-4-carboxamide;
(S)-(l-(4-(2H-tetrazol-5-yl)pyrimidin-2 -yl)piperidin-4-yl)(5-phenyl-4, 5-dihydro- lH- pyrazol- 1 -yl)methanone ;
(S)-(l-(4-(2H-tetrazol-5-yl)pyrimidin-2-yl)piperidin-4-yl)(5-(5-fluoropyridin-3-yl)-4,5- dihydro- lH-pyrazol- 1 -yl)methanone; 3-(5-fluoro-2-(4-((S)-5-phenyl-4, 5-dihydro- lH-pyrazole- l-carbony l)piperidin-l- yl)pyrimidin-4-yl)- 57 -ignaling- 57 -s-2-one;
3-(5-fluoro-2-(4-((S)-5-(5-fluoropyridin-3-yl)-4, 5-dihydro- lH-pyrazole- 1- carbonyl)piperidin-l-yl)pyrimidin-4-yl)- 57 -ignaling- 57 -s-2-one;
(S)-2-((2-(4-(5-phenyl-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin-l-yl)pyrimidin-4- yl)oxy)acetic acid;
(S)-(l-(4-((2H-tetrazol-5-yl)methoxy)-5-fluoropyrimidin-2-yl)piperidin-4-yl)(5-phenyl- 4,5-dihydro- lH-pyrazol- 1 -yl)methanone;
(S)-(l-(5-fluoro-4-(2-hydroxyethoxy)pyrimidin-2-yl)piperidin-4-yl)(5-phenyl-4,5-dihydro- lH-pyrazol- 1 -yl)methanone; (S)-( 1 -(6-ethynylpyrimidin-4-yl)piperidin-4-yl)(5 -phenyl-4,5 -dihydro- lH-pyrazol- 1 - yl)methanone; (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazol-l-yl)(l-(6-ethynylpyrimidin-4- yl)piperidin-4-yl)methanone;
(S)-3-( 1 -( 1 -(6-ethynylpyrimidin-4-yl)piperidine-4-carbonyl)-4,5-dihydro- lH-pyrazol-5- yl)benzonitrile; (S)-5 -fluoro-6-(4-(5 -phenyl-4,5 -dihydro- lH-pyrazole- 1 -carbonyl)piperidin- 1 - yl)pyrimidine-4-carboxylic acid;
(S)-5-fluoro-6-(4-(5-(5-fluoropyridin-3-yl)-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin- 1 -yl)pyrimidine-4-carboxamide;
(S)-5-fluoro-2-(4-(5-(5-fluoropyridin-3-yl)-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin- l-yl)pyrimidine-4-carboxamide;
(S)-5 -fluoro-2-(4-(5 -phenyl-4,5 -dihydro- lH-pyrazole- 1 -carbonyl)piperidin- 1 - yl)pyrimidine-4-carboxamide ;
(S)-N, N-diethyl-5-fluoro-6-(4-(5-phenyl-4, 5-dihydro- lH-pyrazole- l-carbonyl)piperidin-l- yl)pyrimidine-4-carboxamide ; (S)-6-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin-l-yl)-5- fluoropyrimidine-4-carboxylic acid;
(S)-6-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin-l-yl)-5- fluoropyrimidine-4-carboxamide ;
1-3 -(5-fluoro-2-(4-((S)-5 -(5 -fluoropyridin-3 -yl)-4, 5 -dihydro- lH-pyrazole- 1 - carbonyl)piperidin-l-yl)pyrimidin-4-yl)- 58 -ignaling- 58 -s-2-one;
(S)-2-((5 -fluoro-2-(4-(5-phenyl-4, 5 -dihydro- lH-pyrazole- 1 -carbonyl)piperidin- 1 - yl)pyrimidin-4-yl)oxy)acetamide;
(l-(4-(morpholin-3-yl)pyrimidin-2-yl)piperidin-4-yl)((S)-5-phenyl-4,5-dihydro-lH- pyrazol- 1 -yl)methanone ; (S)-2-(5 -fluoro-2-(4-(5-phenyl-4, 5 -dihydro- lH-pyrazole- 1 -carbonyl)piperidin- 1 - yl)pyrimidin-4-yl)acetamide; or a pharmaceutically acceptable salt thereof. Methods of Treatment
In one aspect, a method of treating cancer in a human in need thereof is provided, the method comprising administering to the human a RIP 1 kinase inhibitor at a dose of about 50 mg to about 1600 mg. In one aspect, a method of treating cancer in a human in need thereof is provided, the method 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.
In one aspect, there is provided a RIP1 kinase inhibitor, wherein the RIP1 kinase inhibitor is to be administered at a dose of about 50 mg to about 1600 mg.
In another aspect, a RIP1 kinase inhibitor for use in treating cancer is provided, wherein the RIP1 kinase inhibitor is to be administered at a dose of about 50 mg to about 1600 mg.
In one aspect, use of a RIP 1 kinase inhibitor in the manufacture of a medicament for treating cancer is provided, wherein the RIP 1 kinase inhibitor is to be administered at a dose of about 50 mg to about 1600 mg.
In one aspect, a pharmaceutical kit comprising about 50 mg to about 1600 mg of a RIP1 kinase inhibitor is provided.
In one aspect, a RIP 1 kinase inhibitor and a PD 1 antagonist for simultaneous or sequential use in treating cancer is provided, wherein the RIP1 kinase inhibitor is to be administered at a dose of about 50 mg to about 1600 mg, and the PD1 antagonist is to be administered at a dose of about 200 mg.
In another aspect, a RIP1 kinase inhibitor for use in treating cancer is provided, 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.
In one aspect, there is provided a PD 1 antagonist for use in treating cancer, wherein the PD 1 antagonist is to be administered at a dose of about 200 mg and is to be administered simultaneously or sequentially with a RIP1 kinase inhibitor at a dose of about 50 mg to about 1600 mg.
In another aspect, use of a RIP1 kinase inhibitor in the manufacture of a medicament for treating cancer is provided, 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.
In one aspect, use of a PD 1 antagonist in the manufacture of a medicament for treating cancer is provided, wherein the PD 1 antagonist is to be administered at a dose of about 200 mg and is to be administered simultaneously or sequentially with a RIP 1 kinase inhibitor at a dose of about 50 mg to about 1600 mg.
In another aspect, there is a provided a pharmaceutical kit comprising about 50 mg to about 1600 mg of a RIP1 kinase inhibitor and about 200 mg of a PD1 antagonist.
In one embodiment, 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,
100 mg, 200 mg, 400 mg, 800 mg, or 1600 mg. In one embodiment, the PD1 antagonist is administered at a dose of 200 mg.
In one embodiment, the PD 1 antagonist is an anti -PD 1 antibody or antigen binding portion thereof. In one embodiment, the anti-PDl antibody is a monoclonal antibody. In another embodiment, the anti-PDl antibody is humanized or human.
In one embodiment, the PD1 antagonist is pembrolizumab or nivolumab. In one embodiment, the PD1 antagonist is pembrolizumab. In another embodiment, the PD1 antagonist is nivolumab.
In one embodiment, the RIP1 kinase inhibitor is a compound of Formula (I), Formula (II) or Formula (III), or a pharmaceutically acceptable salt thereof.
In one embodiment, the RIP1 kinase inhibitor is (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 .
In one embodiment, the RIP 1 kinase inhibitor is Compound A or a
pharmaceutically acceptable salt thereof. The structure of Compound A is provided below:
Figure imgf000062_0001
In one embodiment, the RIP1 kinase inhibitor is administered orally. In another embodiment, the PD1 antagonist is administered intravenously.
In one embodiment, the RIP 1 kinase inhibitor is administered once, twice, three times, four times, or five times daily. In another embodiment, the RIP1 kinase inhibitor is administered once every 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, or 40 days.
In one embodiment, the RIP 1 kinase inhibitor is administered once, twice, three times, four times, or five times daily such that the total daily dose is about 50 mg to about 1600 mg. In one embodiment, the RIP1 kinase inhibitor is administered twice daily such that the total daily dose is about 100 mg, 200 mg, about 400 mg, about 800 mg, or about 1600 mg. In one embodiment, the RIP1 kinase inhibitor is administered in equally divided doses such that the total daily dose is about 100 mg (e.g., 50 mg per dose twice daily). In one embodiment, the RIP1 kinase inhibitor is administered orally twice daily in equally divided doses such that the total daily dose is about 100 mg.
In one embodiment, the PD 1 antagonist is administered once every 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, or 40 days.
In another embodiment, the PD 1 antagonist is administered once every week, once every two weeks, or once every three weeks. In one embodiment, the PD1 antagonist is administered once every three weeks.
In one aspect, there is provided a method of treating cancer in a human in need thereof, the method 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, wherein the RIP1 kinase inhibitor is:
Figure imgf000063_0001
or a pharmaceutically acceptable salt thereof.
In one aspect, there is provided a method of treating cancer in a human in need thereof, the method 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:
Figure imgf000063_0002
or a pharmaceutically acceptable salt thereof.
In another aspect, a RIP1 kinase inhibitor for use in treating cancer is provided, 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, wherein the RIP1 kinase inhibitor is
Figure imgf000063_0003
or a pharmaceutically acceptable salt thereof.
In another aspect, a RIP 1 kinase inhibitor and a PD 1 antagonist for simultaneous or sequential use in treating cancer is provided, 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
Figure imgf000064_0001
or a pharmaceutically acceptable salt thereof.
In another aspect, use of a RIP 1 kinase inhibitor in the manufacture of a medicament for treating cancer is provided, wherein the RIP1 kinase inhibitor is to be administered at a dose of dose of 50 mg, 100 mg, 200 mg, 400 mg, 800 mg, or 1600 mg and is to be administered simultaneously or sequentially with a PD1 antagonist at a dose of 200 mg, wherein the PD1 antagonist is pembrolizumab, and wherein the RIP1 kinase inhibitor is
Figure imgf000064_0002
or a pharmaceutically acceptable salt thereof.
In one embodiment, the human has a solid tumor. In one embodiment, the solid tumor is advanced solid tumor. In one embodiment, the cancer is selected from pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), and melanoma. In another embodiment, 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. In one aspect 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. In another aspect the human has 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.
As used herein, the terms“cancer,”“neoplasm,” and“tumor” are used
interchangeably and, in either the singular or plural form, refer 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, as used herein, 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. When referring to a type of cancer that normally manifests as a solid tumor, 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. Tumors may be a hematopoietic (or hematologic or hematological or blood-related) cancer, for example, cancers derived from blood cells or immune cells, which may be referred to as“liquid tumors.” 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.
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
promyelogenous or promyeloblastic) leukemia, acute myelomonocytic (or
myelomonoblastic) leukemia, acute monocytic (or monoblastic) leukemia, erythroleukemia and megakaryocytic (or megakaryoblastic) leukemia. These 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). 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
(RAEBT); as well as myelofibrosis (MFS) with or without agnogenic myeloid metaplasia. 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 Bcell 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. 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). High-grade B-NHLs include Burkitt’s lymphoma (BL), Burkitt-like lymphoma, small non-cleaved cell lymphoma (SNCCL) and
lymphoblastic lymphoma. Other 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.
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. 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). Hematopoietic cancers may also include other cancers of additional hematopoietic cells, including polymorphonuclear leukocytes (or neutrophils), basophils, eosinophils, dendritic cells, platelets, erythrocytes and natural killer 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.
“Treating” or“treatment” is intended to mean at least the mitigation of a disease or disorder in a patient. The methods of treatment for mitigation of a disease or disorder include the use of the compounds in this invention in any conventionally acceptable manner, for example for prevention, retardation, prophylaxis, therapy or cure of a RIP 1 kinase-mediated disease or disorder, as described hereinabove. In reference to a particular condition,“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.
As used herein,“prevention” is understood to refer to the prophylactic
administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof. The skilled artisan will appreciate that“prevention” is not an absolute term. Prophylactic therapy is appropriate, for example, when a subject is considered at high risk for developing cancer, such as when a subject has a strong family history of cancer or when a subject has been exposed to a carcinogen.
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.
A therapeutically“effective amount” is intended to mean that amount of a compound that, when administered to a patient in need of such treatment, is sufficient to effect treatment (e.g., an amount that will elicit the biological or medical response of a tissue, system, animal or human that is being sought). Thus, e.g., a therapeutically effective amount of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, is a quantity of an agent that, when administered to a human in need thereof, is sufficient to modulate and/or inhibit the activity of RIP 1 kinase such that a disease condition which is mediated by that activity is reduced, alleviated or prevented.
The term also includes within its scope amounts effective to enhance normal physiological function. Furthermore, the term“therapeutically effective amount” means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The amount of a given compound that will correspond to such an amount will vary depending upon factors such as the particular compound (e.g., the potency (pICso), efficacy (ECso), and the biological half-life of the particular compound), disease condition and its severity, the identity (e.g., age, size and weight) of the patient in need of treatment, but can nevertheless be routinely determined by one skilled in the art. Likewise, the 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 administration of a therapeutically effective amount of the combinations of the invention (or therapeutically effective amounts of each of the components of the combination) are advantageous over the individual component compounds in that the combinations provide one or more of the following improved properties when compared to the individual administration of a therapeutically effective amount of a component compound: i) a greater anticancer effect than the most active single agent, ii) synergistic or highly synergistic anticancer activity, iii) a dosing protocol that provides enhanced anticancer activity with reduced side effect profde, iv) a reduction in the toxic effect profile, v) an increase in the therapeutic window, or vi) an increase in the bioavailability of one or both of the component compounds.
For use in therapy, the compounds useful in this invention will be normally, but not necessarily, formulated into a pharmaceutical composition prior to administration to a patient.
Accordingly, 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. In one embodiment, there is provided 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. In another embodiment, there is provided 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, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
The compounds useful in this invention, particularly a compound that inhibits RIP1 kinase, particularly, the compounds of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, may be employed alone or in combination with one or more other therapeutic agents, e.g., pharmaceutically active compounds or biologic products (e.g., monoclonal antibodies). Combination therapies according to the present invention thus 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. Preferably, 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. In the treatment of the above noted diseases and disorders, it will be understood that 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.
As used herein,“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 . As used herein“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.
The term“antibody” is used herein in the broadest sense to refer to molecules with an immunoglobulin-like domain (for example IgG, IgM, IgA, IgD or IgE) and includes monoclonal, recombinant, polyclonal, chimeric, human, humanized, multispecific antibodies, including bispecific antibodies, and heteroconjugate antibodies; a single variable domain (e.g., VH, VHH, VL, domain antibody (dAb™)), antigen binding antibody fragments, Fab, F(ab’)2, Fv, disulphide linked Fv, single chain Fv, disulphide-linked scFv, diabodies, TANDABS™, etc. and modified versions of any of the foregoing.
As used herein the term“agonist” refers to an antigen binding protein, for example an ICOS binding protein, which upon contact with its ligand or receptor causes one or more of the following (1) stimulates or activates the receptor, (2) enhances, increases or promotes, induces or prolongs an activity, function or presence of the ligand or receptor and/or (3) enhances, increases, promotes or induces the expression of the ligand or receptor. An“agonist” or activating antibody is one that enhances or initiates signaling by the antigen to which it binds. In some embodiments, agonist antibodies cause or activate signaling without the presence of the natural ligand. 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. Thus, as used herein 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. In some embodiments, 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. As a result, the antagonism of CTLA-4 (e.g., antagonist anti-CTLA antibodies) and or agonizing B7.1/B7.2/CD28 may be useful to enhance immune response in the treatment of infection (e.g., acute and chronic) and tumor immunity.
As used herein the term“cross competes for binding” refers to any binding protein that will compete for binding to its binding target with any of the binding proteins of the present invention. Competition for binding between two molecules for one target can be tested by various methods known in the art including Flow cytometry, Meso Scale Discovery and ELISA. Binding can be measured directly, meaning two or more binding proteins can be put in contact with the target or interest and binding may be measured for one or each. Alternatively, binding of molecules or interest can be tested against the binding or natural ligand and quantitatively compared with each other.
An antigen binding fragment may be provided by means of arrangement of one or more CDRs on non-antibody protein scaffolds.“Protein Scaffold” as used herein includes but is not limited to an immunoglobulin (Ig) scaffold, for example an IgG scaffold, which may be a four chain or two chain antibody, or which may comprise only the Fc region of an antibody, or which may comprise one or more constant regions from an antibody, which constant regions may be of human or primate origin, or which may be an artificial chimera of human and primate constant regions.
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. For example, 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.
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.
The subclass of an antibody in part determines secondary effector functions, such as complement activation or Fc receptor (FcR) binding and antibody dependent cell cytotoxicity (ADCC) (Huber, et ak, Nature 229(5284): 419-20 (1971); Brunhouse, et ah, Mol Immunol 16(11): 907-17 (1979)). In identifying the optimal type of antibody for a particular application, the effector functions of the antibodies can be taken into account. For example, hlgGl antibodies have a relatively long half life, are very effective at fixing complement, and they bind to both FcyRI and FcyRII. In contrast, human IgG4 antibodies have a shorter half life, do not fix complement and have a lower affinity for the FcRs. Replacement of serine 228 with a proline (S228P) in the Fc region of IgG4 reduces heterogeneity observed with hIgG4 and extends the serum half life (Rabat, et ak,
“Sequences of proteins of immunological interest” 5.sup.th Edition (1991); Angal, et ak, Mol Immunol 30(1): 105-8 (1993)). A second mutation that replaces leucine 235 with a glutamic acid (L235E) eliminates the residual FcR binding and complement binding activities (Alegre, et al., J Immunol 148(11): 3461-8 (1992)). The resulting antibody with both mutations is referred to as IgG4PE. The numbering of the hIgG4 amino acids was derived from EU numbering reference: Edelman, G.M. et al., Proc. Natl. Acad. USA, 63, 78-85 (1969). PMID: 5257969. In one embodiment of the present invention ICOS antigen binding proteins comprising an IgG4 Fc region comprising the replacement S228P and L235E may have the designation IgG4PE. Thus, 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.
As used herein“immuno-modulators” refer to any substance including, but not limited to, antigen binding proteins and monoclonal antibodies that affects the immune system. Immuno-modulators can be used as anti-neoplastic agents for the treatment of cancer. Therefore,“immuno-modulators” are therapeutically active agents. For example, immuno-modulators include, but are not limited to, anti-CTLA-4 antibodies such as ipilimumab (YERVOY); anti-PD-l antibodies (Opdivo/nivolumab and
Keytruda/pembrolizumab); anti-PD-Ll antibodies ((TECENTRIQ (atezolizumab) IMFINZI (durvalumumab) and BAVENCIO (avelumab)). Other immuno-modulators include, but are not limited to, PD-l antibodies, CTLA4 antibodies; ICOS antibodies, OX-40 antibodies, PD-L1 antibodies, LAG3 antibodies, TIM-3 antibodies, 41BB antibodies and GITR antibodies.
Immuno-modulators may include any agents that block the interaction between PD-l and PD-L1, including, but not limited to antibodies directed to PD-l and/or PDL1.
In one aspect, the immuno-modulator is an anti-PD-Ll antibody. Anti-PD-Ll antibodies and methods of making the same are known in the art. Such antibodies to PD-L1 may be polyclonal or monoclonal, and/or recombinant, and/or humanized or fully human.
Exemplary PD-L1 antibodies are disclosed in US Patent Nos. 8,217,149, 8,383,796, 8,552,154, 9,212,224, and 8,779,108, and US Patent Appln. Pub. Nos. 20110280877, 2014/0341902 and 20130045201. Additional exemplary antibodies to PD-L1 (also referred to as CD274 or B7-H1) and methods for use are disclosed in US Patent Nos. 7,943,743, 8,168,179; and 7,595,048, WO2014055897, W02016007235 and US Patent Appln. Pub. Nos. 20130034559, 20130034559 and 20150274835. PD-L1 antibodies are in development as immuno-modulatory agents or immuno-modulators for the treatment of cancer. TECENTRIQ (atezolizumab) is a PD-L1 antibody approved for the treatment of people with metastatic non-small cell lung cancer (NSCLC) who have disease progression during or following platinum-containing chemotherapy, and have progressed on an appropriate FDA -approved targeted therapy if their tumor has EGFR or ALK gene abnormalities. IMFINZI (durvalumumab) is an antibody PD-L1 antibody that blocks the interaction of PD-L1 with PD-l and CD80.
In one embodiment, the antibody to PD-L1 is an antibody disclosed in US Patent No. 8,217,149. In another embodiment, the anti-PD-Ll antibody comprises the CDRs of an antibody disclosed in US Patent No. 8,217,149. In another embodiment, the antibody to PD-U1 is an antibody disclosed in US Patent No. 8,779,108. In another embodiment, the anti-PD-Ul antibody comprises the CDRs of an antibody disclosed in US Application No. 8,779,108. In another embodiment, the antibody to PD-U1 is an antibody disclosed in US Patent Appln. Pub. No. 20130045201. In another embodiment, the anti-PD-Ul antibody comprises the CDRs of an antibody disclosed in US Patent Appln. Pub. No. 20130045201. In one embodiment, the anti-PD-Ul antibody is BMS-936559 (MDX- 1105), which was described in WO 2007/005874. In another embodiment, the anti-PD- Ul antibody is MPDU3280A (RG7446). In another embodiment, the anti-PD-Ul antibody is MEDI4736, which is an anti-PD-Ul monoclonal antibody described in WO 2011/066389 and US 2013/034559. In another embodiment, the anti-PD-Ul antibody is TECENTRIQ™ (atezolizumab), which is an anti-PDUl cancer immunotherapy which was approved in the US in May 2016 for specific types of bladder cancer. In another embodiment, 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. Examples of 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.
Pat. No. 8,217,149, and US 2013/034559.
Other examples of mAbs that bind to human PD-U1, and useful in the treatment method, medicaments and uses of the present invention, are described in
WO2013/019906, W02010/077634 Al and US8383796. 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.
As used herein, 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. In some embodiments, a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L 1 to its binding partners. In a specific aspect, the PD-L1 binding antagonist inhibits binding of PD-L 1 to PD-l and/or B7-1. In some embodiments, PD-L1 binding antagonists include anti -PD-L 1 antibodies and antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, small molecule antagonist, polynucleotide antagonists, and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-L 1 with one or more of its binding partners, such as PD-l and/or B7-1. In one embodiment, a PD-L1 binding antagonist reduces the negative signal mediated by or through cell surface proteins expressed on T lymphocytes, and other cells, mediated signaling through PD-L1 or PD-l so as render a dysfunctional T-cell less dysfunctional. In some embodiments, a PD-L1 binding antagonist is an anti-PD-Ll antibody. In a specific aspect, an anti-PD-Ll antibody is YW243.55.S70. In another specific aspect, an anti-PD-Ll antibody is MDX-l 105. In still another specific aspect, an anti-PD-Ll antibody is MPDL3280A (atezolizumab). In still another specific aspect, an anti-PD-Ll antibody is MEDI4736 (durvalumab). In still another specific aspect, an anti- PD-Ll antibody is MSB001 0718C (avelumab). MDX-l 105, also known as BMS-936559, is an anti-PD-Ll antibody described in W02007/005874. Antibody YW243.55.S70 is an anti-PD-Ll antibody described in WO 2010/077634 and US 8,217,149, the entirety of each of which is incorporated herein by reference.
Additional 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,
PDL2, B7-DC, Btdc and CD273 for PD-L2. In any embodiments of the aspects or embodiments of the present invention in which a human individual is to be treated, 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. In some embodiments, 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. In some embodiments, the antigen binding fragment is selected from the group consisting of Fab, Fab’-SH, F(ab’)2, scFv and Fv fragments.
Examples of mAbs that bind to human PD-l, and useful in the various aspects and embodiments of the present invention, are described in US7488802, US7521051, US8008449, US8354509, US8168757, W02004/004771,
W02004/072286, W02004/056875, US2011/0271358 and US2018/0030137.
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. 1, pages 68-69 (2013) and which comprises the heavy and light chain amino acid sequences shown in Figure 7; the humanized antibodies h409Al l, h409Al6 and h409Al7, which are described in WO2008/156712, and AMP-514, which is being developed by Medimmune.
Other PD-l antagonists useful in the any of the aspects and embodiments of the present invention include an immunoadhesin that specifically binds to PD-l, and preferably specifically binds to human PD-l, e.g., a fusion protein containing the extracellular or PD-l binding portion of PD-L 1 or PD-L2 fused to a constant region such as an Fc region of an immunoglobulin molecule. Examples of immunoadhesion molecules that specifically bind to PD-l are described in WO2010/027827 and WO2011/066342. Specific fusion proteins useful as the PD-l antagonist in the treatment method, medicaments and uses of the present invention include AMP-224 (also known as B7-DCIg), which is 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.
In one embodiment, 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.
EXAMPLES
The following examples illustrate the invention. These examples are not intended to limit the scope of the present invention, but rather to provide guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of the present invention. While particular embodiments of the present invention are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the invention.
The reactions described herein are applicable for producing compounds useful in this invention having a variety of different substituent groups (e.g., R1, R2, etc.), as defined herein. The skilled artisan will appreciate that if a particular substituent is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions. The protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound. Suitable protecting groups and the methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley & Sons, NY (1999).
Names for the intermediate and final compounds described herein were generated using the software naming program ACD/Name Pro V6.02 available from Advanced Chemistry Development, Inc., 110 Yonge Street, l4th Floor, Toronto, Ontario, Canada, M5C 1T4 (http://www.acdlabs.com/) or the naming program in ChemDraw, Struct=Name Pro 12.0, as part of ChemBioDraw Ultra, available from Cambridge Soft. 100
CambridgePark Drive, Cambridge, MA 02140 USA (www.cambridgesoft.comf.
It will be appreciated by those skilled in the art that in certain instances these programs may name a structurally depicted compound as a tautomer of that compound. It is to be understood that any reference to a named compound or a structurally depicted compound is intended to encompass all tautomers of such compounds and any mixtures of tautomers thereof. In the following experimental descriptions, the following abbreviations may be used:
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
The compounds useful in this invention can be prepared using intermediate compounds and analogous methods to those disclosed in International Patent Application Publication No. WO2014/125444 and as hereinafter described.
Preparation 1
Ethyl 2-ethoxy-2-iminoacetate
Figure imgf000083_0001
To a solution of ethyl carbonocyanidate (40 g, 404 mmol) in DCM (200 mL) stirred under nitrogen at 0 °C was added a solution of HC1 (45 wt. %, 27.3 mL, 404 mmol) in EtOH dropwise over 15 min. The reaction mixture was stirred at 0 °C for 3 hr and allowed to stand overnight at -5 °C to -3 °C. To the resulting mixture was added DCM (250 mL) at 0 °C. TEA (113 mL, 807 mmol) in DCM (50 mL) was added dropwise over 30 min at 0 °C. The mixture was stirred for 30 min at 0 °C, and water (100 mL) was added at 0 °C. The resulting mixture was stirred for 5 min. The organic layer was separated, dried over sodium sulfate, and evaporated. Diethyl ether (50 mL) was added to the residue and the solid was filtered. The filtrate was dried to afford ethyl 2-ethoxy-2-iminoacetate as a pale yellow liquid (31.0 g, 214 mmol, 52.9 % yield). 'HNMR (400 MHz, CDCb) d 8.78 (s, 1H), 4.36-4.28 (m, 4H), 1.40-1.35 (m, 6H).
Preparation 2
Ethyl 2-amino-2-(2-(2-phenylacetyl)hydrazono)acetate
Figure imgf000083_0002
To 2-phenylacetohydrazide (39.5 g, 263 mmol) in ethanol (150 mL) was added ethyl 2- ethoxy-2-iminoacetate (39.5 g, 272 mmol) and diethyl ether (200 mL). The reaction mixture was stirred for 10 min and solid formed. The reaction mixture was stirred for 5 hours and diethyl ether (50 mL) was added. The resulting mixture was stirred for 17 hours. The solid was filtered, rinsed with diethyl ether, and dried to give ethyl 2-amino-2-(2-(2- phenylacetyl)hydrazono)acetate as a white solid (59 g, 85 % yield). The filtrate sat for 5 days and additional white solid precipitated out. The solid was filtered and dried to give 2- amino-2-(2-(2-phenylacetyl)hydrazono)acetate as a white solid (4.8 g) (92% total yield). MS ES+ m/z 250.1 [M+H]+; 'H NMR (400 MHz, DMSO-d6) d 9.95 (d, J=l7. l8 Hz, 1H), 7.13-7.37 (m, 5H), 6.50 (d, 2H), 4.24 (dq, J=7.07, 10.86 Hz, 2H), 3.86 (s, 1H), 3.50 (s,
1H), 1.27 (dt, J=7.07, 17.43 Hz, 3H).
Preparation 3 Ethyl 5-benzyl-4H-l,2,4-triazole-3-carboxylate
Figure imgf000084_0001
A solution of ethyl 2-imino-2-(2-(2-phenylacetyl)hydrazinyl)acetate (35 g, 140 mmol) in diphenyl ether (300 mL) was stirred for 4 hours under nitrogen at 200 °C. The reaction mixture was cooled to rt, diluted with diethyl ether (750 mL), and stirred for 15 minutes. The precipitate was filtered and dried to afford ethyl 5-benzyl-4H-l,2,4-triazole-3- carboxylate as a brown solid (29 g, 105 mmol, 74.6 % yield). MS ES+ m/z 232.1 [M+H]+; ¾ NMR (400 MHz, DMSO-de) d 14.4 (s, 1H), 7.34-7.25 (m, 5H), 4.31-4.26 (m, 2H), 4.13 (s, 2H), 1.28 (t, J= 6.8Hz, 3H). Preparation 4
5 -Benzyl -4H-1, 2, 4-triazole-3 -carboxylic acid
Figure imgf000085_0002
To ethyl 5-benzyl-4H-l,2,4-triazole-3-carboxylate (9.2 g) in water (100 mL) was added 2M aqueous LiOH (60 mL) dropwise over 20 min while maintaining the reaction temperature of about 20 °C. The reaction mixture was stirred at 20-25 °C for 3 hrs and then cooled in a MeOH-ice bath to -5 °C. 2M HC1 (70 mL) was added dropwise over 10 min maintaining the reaction temperature below 5 °C. The suspension was stirred at 0 °C for 30 min and the solids were collected by filtration. The solids were washed with ice cold water several times. The filter cake was air-dried on a filter funnel overnight to afford 5-benzyl- 4H-1, 2, 4-triazole-3 -carboxylic acid as a white solid (7.5g, 93 % yield). MS ES+ m/z 204.4 [M+H]+; ¾ NMR (400 MHz, DMSO-de) d 14.33 (s, 1H), 13.13 (br s, 1H), 7.33-7.20 (m, 5H), 4.10-4.03 (m, 2H).
Preparation 5
Ethyl 2-amino-2-(2-(2-(2-fluorophenyl)acetyl)hydrazono)acetate
Figure imgf000085_0001
2-(2-fluorophenyl)acetohydrazide (7.05 g, 41.9 mmol) was partially dissolved in ethanol (30 mL), and then ethyl 2-ethoxy-2-iminoacetate (6.39 g, 44.0 mmol) and diethyl ether (35 mL) were added. The reaction mixture was stirred for 0.5 hours, and diethyl ether (100 mL) was added. The resulting mixture was stirred for 18 hours. The solid was filtered off, rinsed with diethyl ether, and dried to give ethyl 2-amino-2-(2-(2-(2- fluorophenyl)acetyl)hydrazono)acetate as an off-white solid (10 g, 89% yield). MS ES+ m/z 268 [M+H]+; ¾ NMR (400 MHz, DMSO-de) d 9.80-10.25 (m, 1H), 7.25-7.43 (m, 2H), 7.09-7.21 (m, 2H), 6.42-6.60 (m, 2H), 4.23 (dq, .7=1.52, 7.07 Hz, 2H), 3.92 (s, 1H),
3.58 (s, 1H), 1.26 (dt, 7=5.05, 7.07 Hz, 3H).
Preparation 6
Ethyl 5-(2-fluorobenzyl)-4H- l,2,4-triazole-3-carboxylate
Figure imgf000086_0001
Ethyl 2-amino-2-(2-(2-(2-fluorophenyl)acetyl)hydrazono)acetate (10 g, 37.4 mmol) was suspended in Dowtherm® A (100 mL), heated at 180 °C for 4.5 hours, and cooled to room temperature. Hexanes (-200 mL) was added, and the mixture was stirred for 15 minutes. The solid precipitate was filtered, rinsed with hexanes, and dried to give ethyl 5-(2- fluorobenzyl)-4H-l,2,4-triazole-3-carboxylate as a light tan solid (8.51 g, 91% yield). MS ES+ m/z 250 [M+Hf; ¾ NMR (400 MHz, DMSO-de) d 14.50 (br s, 1H), 7.28-7.43 (m, 2H), 7.13-7.25 (m, 2H), 4.24-4.40 (m, 7=6.80 Hz, 2H), 4.17 (br s, 2H), 1.29 (t, 7=7.07 Hz, 3H).
Preparation 7
5-(2-Fluorobenzyl)-4H-l,2,4-triazole-3-carboxylic acid hydrochloride
Figure imgf000087_0001
To a suspension of ethyl 5-(2-fluorobenzyl)-4H-l,2,4-triazole-3-carboxylate (8.51 g, 33.1 mmol) in water (60 mL) was added a solution of lithium hydroxide (1.747 g, 72.9 mmol) in water (30 mL) dropwise. The mixture was stirred for 3 days at room temperature and was cooled in an ice water bath. Concentrated HC1 (10 mL, 60.0 mmol) was added dropwise until the mixture reached pH ~ 3. A solid precipitated from the mixture, and the mixture was stirred for 10 minutes. The precipitate was filtered, rinsed with cold water, and dried in high vacuum for 20 hrs to give 5-(2-fluorobenzyl)-4H-l,2,4-triazole-3-carboxylic acid hydrochloride (7.0 g, 85% yield) as a tan solid. MS ES+ m/z 222 [M+H]+; ¾ NMR (400 MHz, MeOD-d4) d 7.27-7.43 (m, 2H), 7.05-7.23 (m, 2H), 4.23 (s, 2H).
Example 1
(S)-N-(9-Fluoro-2 -oxo-2, 3,4, 5-tetrahydro-lH-benzo [b] [l, 4]diazepin-3-yl)-5-(2- fluorobenzyl)-4H-l, 2, 4-triazole-3 -carboxamide
Figure imgf000087_0002
Step 1 : (S)-2-((tert-Butoxycarbonyl)amino)-3-((3-fluoro-2-nitrophenyl)amino)propanoic acid
Figure imgf000088_0001
To a suspension of (S)-3-amino-2-((tert-butoxycarbonyl)amino)propanoic acid (7.33 g, 35.9 mmol) and l,3-difluoro-2-nitrobenzene (5.19 g, 32.6 mmol) in DMSO (80 mL), DIEA (19.94 mL, 114 mmol) was added and the mixture was stirred at room temperature for 5 days. The mixture was diluted with 200 mL water and extracted with ether (3 x 100 mL). The aqueous phase was acidified with 1N HC1 (120 mL, 120 mmol) to about pH 2. A deep orange oil separated which was extracted with EtOAc (3 x 50 mL). The organic layers were combined and washed with water (3 x 50 mL) and brine (2 x 50 mL), dried over sodium sulfate, and was concentrated in vacuo to afford (S)-2-((tert- butoxycarbonyl)amino)-3-((3-fluoro-2-nitrophenyl)amino)propanoic acid as a brown residue (10.91 g, 31.8 mmol, 97 % yield). MS ES+ m/z 244/288/366 for [M-Boc/M- tBu/M+Naf; Ή NMR (400 MHz, DMSO-t/e) d ppm
12.92 (br s, 1 H), 7.46 (m, 1 H), 7.21 - 7.36 (m, 2 H), 6.84 (d, 7=8.84 Hz, 1 H), 6.63 (dd, .7=11.62, 8.08 Hz, 1 H), 4.20 (m, 1 H), 3.66 (m, 1 H), 3.42 - 3.55 (m, 1 H), 1.36 (s, 9 H).
Step 2: (S)-3-((2-Amino-3-fluorophenyl)amino)-2-((tert-butoxycarbonyl)amino)propanoic acid
Figure imgf000088_0002
A solution of (S)-2-((tert-butoxycarbonyl)amino)-3-((3-fluoro-2- nitrophenyl)amino)propanoic acid (l0.9lg, 31.8 mmol) in ethyl acetate (63.6 ml) and ethanol (63.6 ml) was hydrogenated in the presence of 10% Pd/C (l .09g, 1.024 mmol) at 35 psi for 2 hours in a Parr shaker. The catalyst was filtered off. The solution was evaporated and co-evaporated with toluene to afford (S)-3-((2-amino-3- fluorophenyl)amino)-2-((tert-butoxycarbonyl)amino)propanoic acid as a brown solid foam (9.96g, 31.8 mmol, 100 % yield). MS ES+ m/z 314 [M+H]+; ¾ NMR (400 MHz, DMSO- de) d ppm 6.18-6.64 (m, 3 H), 4.21 (m, 1 H), 3.22-3.54 (m, 4 H), 1.35 (s, 9 H).
This material was used in Step 3 without further purification.
Step 3: (S)-tert-Butyl (9-fluoro-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b][l,4]diazepin-3- yl)carbamate
Figure imgf000089_0001
A solution of (S)-3-((2-amino-3-fluorophenyl)amino)-2-((tert- butoxycarbonyl)amino)propanoic acid (9.86g, 31.5 mmol) in ethyl acetate (100 mL) was submersed in an ice-water bath. To this solution was added DIEA (16.49 mL, 94 mmol) followed by 50% T3P® in ethyl acetate (28.1 mL, 47.2 mmol). The mixture was washed with water and brine, dried over sodium sulfate, and evaporated in vacuo to provide 7.55 g of crude product. The crude product was purified by normal phase column
chromatography (silica gel: 220 g column; eluent: eluent A = hexanes, eluent B = (EtOAc/EtOH 3/1), 0-60% B gradient) to afford (S)-tert-butyl (9-fluoro-2 -oxo-2, 3,4,5- tetrahydro-lH-benzo[b][l,4]diazepin-3-yl)carbamate as a pale yellow solid foam (5.99 g, 20.28 mmol, 64.5 % yield). MS ES+ m/z 196 [M-Boc+Hf; Ή NMR (400 MHz, DMSO- ck) d ppm 9.53 (s, 1 H), 6.90-7.04 (m, 2 H), 6.59-6.75 (m, 2 H), 5.87 (d, J= 5.56 Hz, 1 H), 4.20 (m, 1 H), 3.52 (m, 1 H), 3.38 (t, J=\ 1.12 Hz, 1 H), 1.37 (s, 9 H).
Step 4: (S)-3-Amino-9-fluoro-4,5-dihydro-lH-benzo[b] [l,4]diazepin-2(3H)-one dihydrochloride
Figure imgf000090_0001
A solution of (S)-tert-butyl (9-fluoro-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b][l,4]diazepin- 3-yl)carbamate (l .5g, 5.08 mmol) in 4M HCl/dioxane (30 ml, 120 mmol) was stirred at room temperature for 7 hrs. The reaction mixture was evaporated (co-evaporated with MeOH and ether). The resulting residue was dried to afford (S)-3-amino-9-fluoro-4,5- dihydro-lH-benzo[b][l,4]diazepin-2(3H)-one dihydrochloride as a pale yellow solid (l .523g, 5.21 mmol, 100 % yield). MS ES + m/z 196 [M+H]+; Tf NMR ^OO MHz, DMSO- de) d ppm 10.02 (s, 1 H), 8.55 (d, 7=4.04 Hz, 3 H), 6.99 (td, 7=8.15, 6.44 Hz, 1 H), 6.72 (d, .7=8.08 Hz, 1 H), 6.61-6.69 (m, 1 H), 4.09-4.24 (m, 1 H), 3.82 (dd, J=\ 1.12, 4.29 Hz, 1 H), 3.48 (t, 7=10.99 Hz, 1 H).
Step 5 : Ethyl 2-amino-2-(2-(2-(2-fluorophenyl)acetyl)hydrazono)acetate
Figure imgf000090_0002
2-(2-fluorophenyl)acetohydrazide (7.05 g, 41.9 mmol) was partially dissolved in ethanol (30 mL), and then ethyl 2-ethoxy-2-iminoacetate (6.39 g, 44.0 mmol) and diethyl ether (35 mL) were added. The reaction mixture was stirred for 0.5 hours, and diethyl ether (100 mL) was added. The resulting mixture was stirred for 18 hours. The solid was filtered off, rinsed with diethyl ether, and dried to give ethyl 2-amino-2-(2-(2-(2- fluorophenyl)acetyl)hydrazono)acetate as an off-white solid (10 g, 89% yield). MS ES+ m/z 268 [M+H]+; Tf NMR (400 MHz, DMSO-de) d 9.80-10.25 (m, 1H), 7.25-7.43 (m, 2H), 7.09-7.21 (m, 2H), 6.42-6.60 (m, 2H), 4.23 (dq, J=l .52, 7.07 Hz, 2H), 3.92 (s, 1H), 3.58 (s, 1H), 1.26 (dt, J=5.05, 7.07 Hz, 3H).
Step 6: Ethyl 5-(2-fluorobenzyl)-4H-l,2,4-triazole-3-carboxylate
Figure imgf000091_0001
Ethyl 2-amino-2-(2-(2-(2-fluorophenyl)acetyl)hydrazono)acetate (10 g, 37.4 mmol) was suspended in Dowtherm® A (100 mL), heated at 180 °C for 4.5 hours, and cooled to room temperature. Hexanes (-200 mL) was added, and the mixture was stirred for 15 minutes. The solid precipitate was filtered, rinsed with hexanes, and dried to give ethyl 5-(2- fluorobenzyl)-4H-l,2,4-triazole-3-carboxylate as a light tan solid (8.51 g, 91% yield). MS ES+ m/z 250 [M+Hf; ¾ NMR (400 MHz, DMSO-de) d 14.50 (br s, 1H), 7.28-7.43 (m, 2H), 7.13-7.25 (m, 2H), 4.24-4.40 (m, J=6.80 Hz, 2H), 4.17 (br s, 2H), 1.29 (t, J=7.07 Hz, 3H).
Step 7: 5-(2-Fluorobenzyl)-4H-l,2,4-triazole-3-carboxylic acid hydrochloride
Figure imgf000091_0002
To a suspension of ethyl 5-(2-fluorobenzyl)-4H-l,2,4-triazole-3-carboxylate (8.51 g, 33.1 mmol) in water (60 mL) was added a solution of lithium hydroxide (1.747 g, 72.9 mmol) in water (30 mL) dropwise. The mixture was stirred for 3 days at room temperature and was cooled in an ice water bath. Concentrated HC1 (10 mL, 60.0 mmol) was added dropwise until the mixture reached pH ~ 3. A solid precipitated from the mixture, and the mixture was stirred for 10 minutes. The precipitate was filtered, rinsed with cold water, and dried in high vacuum for 20 hrs to give 5-(2-fluorobenzyl)-4H-l,2,4-triazole-3-carboxylic acid hydrochloride (7.0 g, 85% yield) as a tan solid. MS ES+ m/z 222 [M+H]+; ¾ NMR (400 MHz, MeOH-d4)□ 7.27-7.43 (m, 2H), 7.05-7.23 (m, 2H), 4.23 (s, 2H).
Step 8: (S)-N-(9-Fluoro-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b][l,4]diazepin-3-yl)-5-(2- fluorobenzyl)-4H-l,2,4-triazole-3-carboxamide
Figure imgf000092_0001
A suspension of (S)-3-amino-9-fluoro-4,5-dihydro-lH-benzo[b] [l,4]diazepin-2(3H)-one dihydrochloride (200 mg, 0.685 mmol) and 5-(2-fluorobenzyl)-4H -l,2,4-triazole-3- carboxylic acid (216 mg, 0.753 mmol) in dichloromethane (4 mL) was submersed in an ice-water bath. To this suspension was added DIEA (0.717 mL, 4.11 mmol). The mixture was stirred for 15 min. 50% T3P® in EtOAc (0.611 mL, 1.027 mmol) was added dropwise, and the reaction mixture was stirred for 5 min. The mixture was diluted with 10 mL EtOAc, washed with water and brine, dried over sodium sulfate, and was evaporated. The crude material was purified by normal phase column chromatography (silica gel: 40 g column; eluent: eluent A = hexanes, eluent B = (EtOAc/EtOH 3/1), 0-70% B gradient).
The pooled clean fractions were evaporated in vacuo, and the residue was triturated with ether. The solid was filtered and dried for 40 hr in high vacuum at 70 °C to give (S)-N-(9- fluoro-2 -oxo-2, 3,4, 5-tetrahydro-lH-benzo [b] [l, 4]diazepin-3-yl)-5-(2-fluorobenzyl)-4H- 1 ,2,4-triazole-3 -carboxamide . MS ES+ m/z 399 [M+H]+; Ή NMR (400 MHz, DMSO-t/e) d ppm 14.63 (br s, 1 H), 9.79 (s, 1 H), 8.35 (br s, 1 H), 7.27-7.41 (m, 2 H), 7.19 (d, J=8.08 Hz, 2 H), 6.90-7.01 (m, 1 H), 6.67 (d, =8.08 Hz, 1 H), 6.60 (t, =9.09 Hz, 1 H), 6.24 (d, J= 5.56 Hz, 1 H), 4.57-4.69 (m, 1 H), 4.16 (br s, 2 H), 3.63-3.74 (m, 1 H), 3.47 (t, J= 9.85 Hz, 1 H).
Example 2
(S)-5-Benzyl-N-(7-chloro-2 -oxo-2, 3,4, 5-tetrahydro-lH-benzo[b]azepin-3-yl)-4H-l, 2,4- triazole -3 -carboxamide
Figure imgf000093_0001
To a solution of (S)-3-amino-4,5-dihydro-lH-benzo[b]azepin-2(3H)-one (50 g, 284 mmol) and 5 -benzyl -4H-1, 2, 4-triazole-3 -carboxylic acid (72.1 g, 355 mmol) in DCM (1500 ml) was added DIPEA (173 ml, 993 mmol) at 15 °C. The reaction mixture was stirred for 20 minutes and 2, 4, 6-tripropyl- 1,3, 5, 2, 4, 6-trioxatriphosphinane-2, 4, 6-trioxide (50 wt % T3P® in EtOAc, 236 ml, 397 mmol) was slowly added at 15 °C. The reaction was stirred overnight. The resulting solid was filtered, and the solid was washed with DCM. The solid was dried under vacuum at 50 °C overnight. The filtrate was concentrated under reduced pressure. To the resulting residue was added cold water. The mixture was stirred and a white solid precipitated out of solution. The white solid was collected and washed with water and ethyl ether. The solid was dried under vacuum at 50 °C for 3 days to afford (S)-5-benzyl-N-(2-oxo-2,3,4,5-tetrahydro-lH-benzo[b]azepin-3-yl)-4H-l,2,4-triazole-3- carboxamide (102 g, 282 mmol, 99 % yield). Ή NMR (MeOD-d4) d: 7.18-7.48 (m, 8H), 7.10 (d, J=7.6 Hz, 1H), 4.58 (m, 1H), 4.17 (s, 2H), 2.97 (m 1H), 2.77 (m, 1H), 2.67 (m, 1H), 2.23 (m, 1H). MS ES+ m/z 362 [M+H]+.
Step 2: (S)-5-Benzyl-N-(7-chloro-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b]azepin-3-yl)-4H- l,2,4-triazole-3-carboxamide
Figure imgf000094_0001
To a solution of (S)-5-benzyl-N-(2-oxo-2,3,4,5-tetrahydro-lH-benzo[b]azepin-3-yl)-4H- l,2,4-triazole-3-carboxamide (35 g, 97 mmol) in DMA (700 ml) was added NCS (14.87 g, 111 mmol) at 0 °C. The reaction mixture was stirred for 30 min, warmed to room temperature, and stirred for 5 hrs. A second portion of NCS (3.88 g, 29.1 mmol) was added to the reaction mixture. The resulting mixture was stirred for an additional 24 hrs. A third portion of NCS (1.293 g, 9.68 mmol) was added. The resulting mixture was stirred at room temperature for 16 h. The reaction was then quenched with cold water. The white solid was collected by filtration and washed with water 3 times to provide (S)-5-benzyl-N- (7-chloro-2 -oxo-2, 3,4, 5-tetrahydro-lH-benzo[b]azepin-3-yl)-4H- 1,2, 4-triazole-3- carboxamide (36 g, 91 mmol, 94 % yield). The product was air dried overnight.
Additional purification was achieved by suspending (S)-5-benzyl-N-(7-chloro-2-oxo- 2,3,4,5-tetrahydro-lH-benzo[b]azepin-3-yl)-4H-l,2,4-triazole-3-carboxamide (10 g, 25.3 mmol) in hot methanol (500 mL) for lh. The solution was then cooled to room temperature and filtered. The solid was washed with methanol (2 x 75 mL) to give (S)-5- benzyl-N-(7-chloro-2 -oxo-2, 3, 4, 5-tetrahydro-lH-benzo[b]azepin-3-yl)-4H-l, 2, 4-triazole- 3-carboxamide (7 g, 70% yield). MS ES+ m/z 396 and 398 [M+H]+; Ή NMR (DMSO-de) d: 10.06 (s, 1H), 8.31 (br s, 1H), 7.44 (d, J=2.5 Hz, 1H), 7.18-7.40 (m, 7H), 7.05 (d, J=8.6 Hz, 1H), 4.32 (dt, J=l 1.5, 7.9 Hz, 1H), 4.11 (s, 2H), 2.63-2.80 (m, 2H), 2.37-2.49 (m, 1H), 2.25 (br s, 1H). Example 3
(S)-5-(2-Fluorobenzyl)-N-(l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b][l,4]diazepin-3- yl)- 1H- 1 ,2,4-triazole-3-carboxamide
Figure imgf000095_0001
Step 1 : (S)-2-((tert-Butoxycarbonyl) amino)-3-((2-nitrophenyl)amino)propanoic acid
Figure imgf000095_0002
To a suspension of (S)-3-amino-2-((tert-butoxycarbonyl)amino)propanoic acid (200g, 979 mmol) and l-fluoro-2-nitrobenzene (138 g, 979 mmol) in DMF (2000 mF) stirred under nitrogen at room temp was added sodium bicarbonate (247 g, 2938 mmol). The reaction mixture was stirred at 70 °C for 24 hr. Water was then added (8 F). The aqueous layer was washed with diethyl ether (2 x 2 F), acidified with citric acid to pH < 5, and washed with EtOAc (2 x 2 F). The organic layers were combined. The combined organic layers were washed with water (2 x 2 F), washed with brine (2 F), dried over anhydrous Na2SC>4, filtered, and concentrated to afford (S)-2-((tert-butoxycarbonyl)amino)-3-((2- nitrophenyl)amino)propanoic acid as redish yellow solid (201 g, 615 mmol, 62.8 % yield). MS ES+ m/z 326 [M+Hf; ¾ NMR (DMSO-de) d 12.90 (br s, 1H), 8.15-8.26 (m, 1H), 8.07 (br d, J=8.6 Hz, 1H), 7.57 (br t, J=7.7 Hz, 1H), 7.30 (br d, J=7.7 Hz, 1H), 7.09 (d, J=8.6 Hz, 1H), 6.73 (t, J=7.7 Hz, 1H), 4.15-4.30 (m, 1H), 3.67-3.86 (m, 1H), 3.54 (ddd, J=l4.0, 8.7, 5.8 Hz, 1H), 1.2-1.34 (m, 9H).
ĭ95 Step 2: (S)-3-((2-Aminophenyl)amino)-2-((tert-butoxycarbonyl)amino)propanoic acid
Figure imgf000097_0001
To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-((2-nitrophenyl)amino)propanoic acid (80 g, 246 mmol) in methanol (1000 mL) in a Parr-shaker under nitrogen at room temp was added 10% Pd/C (50% wet) (10.47 g, 9.84 mmol). The reaction mixture was hydrogenated under 60 psi at 25 °C for 5 hr. The reaction mixture was filtered through a celite pad, the celite pad was washed with methanol (300 mL) followed by 10 % MeOH in DCM (2 X 300 mL). The filtrate was concentrated under reduced pressure to afforded (S)- 3-((2-aminophenyl)amino)-2-((tertbutoxycarbonyl)amino)propanoic acid (75 g, 216 mmol, 88 % yield) as a brown solid. MS ES+ m/z 296 [M+H]+; Ή NMR (DMSO-de) 5 7.11 (br d, J=8. l Hz, 1H), 6.63-6.85 (m, 1H), 6.4-6.62 (m, 5H), 4.10-4.27 (m, 1H), 3.24-3.45 (m, 4H), l.28-l .35(m, 9H).
Step 3: (S)-tert-Butyl (2-oxo-2,3,4,5-tetrahydro-lH-benzo[b] [l,4]diazepin-3-yl)carbamate
Figure imgf000097_0002
To a solution of (S)-3-((2-aminophenyl)amino)-2-((tert-butoxycarbonyl)amino)propanoic acid (150 g, 423 mmol) in DMSO (1500 mL) was added DIPEA (185 mL, 1058 mmol) and HATU (633 g, 1666 mmol). The resulting mixture was stirred at 25 °C for 3 hr, cooled in an ice-water bath, and diluted with cold water (5 L, added over ~ 10 minutes) with vigorous stirring. The organics were extracted with EtOAc (2 x 3 L). The combined organics were washed with water (2 L) and brine (2 L). The organic layer was dried over anhydrous NaiSCri. filtered, and concentrated in vacuo to give a residue (140 g). The residue was purified by normal phase column chromatography (60-120 mesh silica gel column; eluent: 10-40 % EtOAc in hexanes) to afforded (S)-tert-butyl (2-oxo-2, 3,4,5- tetrahydro-lH-benzo[b][l,4]diazepin-3-yl)carbamate as a pale brown solid (100 g, 341 mmol, 81 % yield). MS ES+ m/z 278 [M+H]+; ¾ NMR (DMSO-de) d 9.67 (s, 1H), 6.87- 6.94 (m, 2H), 6.77-6.86 (m, 2H), 6.69-6.76 (m, 1H), 5.59 (br d, J=5.5 Hz, 1H), 4.15 (br t, J= 11.3 Hz, 1H), 3.49 (dt, J=l0.7, 5.5 Hz, 1H), 3.31-3.37 (m, 1H), 1.37 (s, 9H).
Step 4: (S)-tert-Butyl (l-methyl-2-oxo-2,3,4,5-tetrahydro-lH-benzo[b][l,4]diazepin-3- yl)carbamate
Figure imgf000098_0001
To a suspension of 60% NaH in mineral oil (7.93 g, 198 mmol) in THF (300 mL) stirred under nitrogen at 25 °C was added a solution of (S)-tert-butyl (2-oxo-2,3,4,5-tetrahydro- lH-benzo[b][l,4]diazepin-3-yl)carbamate (50 g, 180 mmol) in THF (200 mL) dropwise over 5 min. The reaction mixture was stirred at 25 °C for 1 hr and then iodomethane (11.84 mL, 189 mmol) was added dropwise over 2 min. Then resulting reaction mixture was stirred at 25 °C for 48 hr and then water (1000 mL) was added. The reaction mixture was extracted with EtOAc (3 x 500 mL), and combined organic layers were dried over anhydrous NaiSOi. filtered, and concentrated in vacuo to afford (S)-tert-butyl (1 -methyl-2- oxo-2,3,4,5-tetrahydro-lH-benzo[b][l,4]diazepin-3-yl)carbamate as dark brown gum-like material (56 g, 111 mmol, 61.7 % yield). This material was used the next step without further purification. MS ES+ m/z 292 [M+H]+. Step 5: (S)-3-Amino-l-methyl-4,5-dihydro-lH-benzo[b][l,4]diazepin-2(3H)-one dihydrochloride
Figure imgf000099_0001
To a solution of (S)-tert-butyl (l-methyl-2-oxo-2,3,4,5-tetrahydro-lH- benzo[b][l,4]diazepin-3-yl)carbamate (179 g, 544 mmol) in DCM (1500 mL) was added 4M HC1 (680 mL, 2719 mmol) in l,4-dioxane at 0 °C. The reaction mixture was stirred at 25 °C for 24 hr and then was concentrated in vacuo. The resulting solid was triturated with diethyl ether (600 mL), fdtered, washed with diethyl ether (500 mL), and dried under vacuum to afford (S)-3-amino-l-methyl-4,5-dihydro-lH-benzo[b] [l,4]diazepin-2(3H)-one dihydrochloride as an off-white solid (151 g, 526 mmol, 97 % yield). MS ES+ m/z 192 [M+H]+; ¾ NMR (DMSO-de) d 8.40-8.60 (m, 5H), 7.40 (dd, J=7.8, 1.4 Hz, 1H), 7.12-7.30 (m, 3H), 3.96-4.07 (m, 1H), 3.90 (dd, J=l0.2, 6.5 Hz, 1H), 3.47-3.58 (m, 1H), 3.31 (s, 3H).
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
Figure imgf000099_0002
To a mixture of (S)-3-amino-l-methyl-4,5-dihydro-lH-benzo[b][l,4]diazepin-2(3H)-one dihydrochloride (100 g, 379 mmol) and 5-(2-fluorobenzyl)-4H-l,2,4-triazole-3-carboxylic acid (80 g, 360 mmol) in DCM (2000 mL) was added DIPEA (331 mL, 1893 mmol) and a > 50 wt. % solution of T3P in EtOAc (338 mL, 568 mmol) at 0 °C. Then resulting mixture was stirred at room temperature for 16 hr. The reaction was diluted with water (2000 mL) and extracted with DCM (2000 mL). The organic layer was washed with water (2 x 1500 mL) and brine (1 x 1500 mL), dried over anhydrous NaiSCri. filtered, and concentrated in vacuo to afforded (S)-5-(2-fluorobenzyl)-N-(l-methyl-2-oxo-2,3,4,5-tetrahydro-lH- benzo[b][l,4]diazepin-3-yl)-4H-l,2,4-triazole-3-carboxamide as brown solid (112 g, 257 mmol, 68.0 % yield). MS ES+ m/z 395 [M+H]+; ¾ NMR (DMSO-de) d 8.25 (br d, J=7.0 Hz, 1H), 7.24-7.40 (m, 3H), 7.04-7.23 (m, 3H), 6.90-7.04 (m, 2H), 5.38 (br d, J=5.5 Hz, 1H), 4.54-4.69 (m, 1H), 4.14 (s, 2H), 3.68 (dt, J=9.9, 5.8 Hz, 1H), 3.43-3.52 (m, 1H), 3.33- 3.40 (m, 1H), 3.27 (s, 3H).
Example 4
(,V)-5-Benzyl-N-(6,8-difluoro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo|b| | 1 ,4 |oxazepin-3- yl)- 1H- 1 ,2,4-triazole-3-carboxamide
Figure imgf000101_0001
Step 1 : Ethyl 2-ethoxy-2-iminoacetate
Figure imgf000101_0002
To a solution of ethyl carbonocyanidate (40 g, 404 mmol) in DCM (200 mL) stirred under nitrogen at 0 °C was added a solution of HC1 (45 wt%, 27.3 mL, 404 mmol) in EtOH dropwise over 15 min. The reaction mixture was stirred at 0 °C for 3 hr and allowed to stand overnight at -5 °C to 3 °C. To the resulting mixture was added DCM (250 mL) at 0 °C. TEA (113 mL, 807 mmol) in DCM (50 mL) was added dropwise over 30 min at 0 °C.
The mixture was stirred for 30 min at 0 °C, and water (100 mL) was added at 0 °C. The resulting mixture was stirred for 5 min. The organic layer was separated, dried over sodium sulfate, and evaporated. Diethyl ether (50 mL) was added to the residue and the solid was filtered. The filtrate was dried to afford ethyl 2-ethoxy-2-iminoacetate as a pale yellow liquid (31.0 g, 214 mmol, 52.9 % yield). 'HNMR (400 MHz, CDCb) d 8.78 (s, 1H), 4.36-4.28 (m, 4H), 1.40-1.35 (m, 6H).
Step 2: Ethyl 2-amino-2-(2-(2-phenylacetyl)hydrazono)acetate
Figure imgf000102_0001
To 2-phenylacetohydrazide (39.5 g, 263 mmol) in ethanol (150 mL) was added ethyl 2- ethoxy-2-iminoacetate (39.5 g, 272 mmol) and diethyl ether (200 mL). The reaction mixture was stirred for 10 min and solid formed. The reaction mixture was stirred for 5 hours and diethyl ether (50 mL) was added. The resulting mixture was stirred for 17 hours. The solid was filtered, rinsed with diethyl ether, and dried to give ethyl 2-amino-2-(2-(2- phenylacetyl)hydrazono)acetate as a white solid (59 g, 85 % yield). The filtrate sat for 5 days and additional white solid precipitated out. The solid was filtered and dried to give 2- amino-2-(2-(2-phenylacetyl)hydrazono)acetate as a white solid (4.8 g) (92% total yield). MS ES+ m/z 250.1 [M+H]+; 'H NMR (400 MHz, DMSO-de) d 9.95 (d, J=l7. l8 Hz, 1H), 7.13-7.37 (m, 5H), 6.50 (d, 2H), 4.24 (dq, J=7.07, 10.86 Hz, 2H), 3.86 (s, 1H), 3.50 (s,
1H), 1.27 (dt, J=7.07, 17.43 Hz, 3H).
Step 3: Ethyl 5-benzyl-4H-l,2,4-triazole-3-carboxylate
Figure imgf000102_0002
A solution of ethyl 2-imino-2-(2-(2-phenylacetyl)hydrazinyl)acetate (28 g, 120 mmol) in diphenyl ether (250 mL) was stirred for 4 hours under nitrogen at 200 °C. Reaction progress was monitored by TLC which showed absence of starting material in 4 h. The reaction mixture was cooled to rt, diluted with diethyl ether (750 mL), and stirred for 15 minutes. The precipitate was filtered and dried to afford ethyl 5 -benzyl -4H- 1,2, 4-triazole- 3-carboxylate as an off-white solid (25 g, 106 mmol, 89 % yield). MS ES+ m/z 232.1 [M+H]+; ¾ NMR (400 MHz, DMSO-de) d 14.4 (s, 1H), 7.34-7.25 (m, 5H), 4.31-4.26 (m, 2H), 4.13 (s, 2H), 1.28 (t , J= 6.8Hz, 3H).
Step 4: 5-Benzyl -4H-1, 2, 4-triazole-3-carboxylic acid
Figure imgf000103_0001
To ethyl 5-benzyl-4H-l,2,4-triazole-3-carboxylate (9.2 g) in water (100 mL) was added 2M aqueous LiOH (60 mL) dropwise over 20 min while maintaining the reaction temperature of about 20 °C. The reaction mixture was stirred at 20-25 °C for 3 hrs and then cooled in a MeOH-ice bath to -5 °C. 2M HC1 (70 mL) was added dropwise over 10 min maintaining the reaction temperature below 5 °C. The suspension was stirred at 0 °C for 30 min and the solids were collected by filtration. The solids were washed with ice cold water several times. The filter cake was air-dried on a filter funnel overnight to afford 5-benzyl- 4H-1, 2, 4-triazole-3 -carboxylic acid as a white solid (7.5g, 93 % yield). MS ES+ m/z 204.4 [M+H]+; ¾ NMR (400 MHz, DMSO-de) d 14.33 (s, 1H), 13.13 (br s, 1H), 7.33-7.20 (m,
5H), 4.10-4.03 (m, 2H).
Step 5: (.V)-2-(tcrt-Butoxycarbonylamino)-3-hydroxypropanoic acid
NaOH
Figure imgf000103_0002
To a stirred suspension of (S)-2 -amino-3 -hydroxypropanoic acid (100 g, 952 mmol, 1.0 eq) in dioxane (600 mL) and water (600 mL) under nitrogen at 0 °C was added NaOH (76 g, 1903 mmol, 2.0 eq) dropwise. The reaction mixture was stirred for 10 min. Boc anhydride (221 mL, 952 mmol, 1.0 eq) was added dropwise over 10 min. The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was acidified with 1.0 N HC1 to pH 2. The reaction mixture was extracted with ethyl acetate (3 x 500 mL). The organic phase was washed with brine (500 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to afford (S)-2-((tertbutoxycarbonyl)amino)-3-hydroxypropanoic acid as a colorless gum-like material (170 g, 78 % yield). MS ES+ m/z 205.9 [M+H]+; ¾ NMR (400 MHz, DMSO-de) d 6.72 (d, J= 8.4Hz, 1H), 4.00-3.94 (m, 1H), 3.62 (d, J = 4.8Hz, 2H), 1.38 (s, 9H).
Step 6: (.S)-2-(tcrt-Butoxycarbonylamino)-3-(3.5-difluoro-2-nitrophcnoxy)propanoic acid
Figure imgf000104_0001
To a stirred solution of Aliquat® 336 (13 g) in 2-MeTHF (100 mL) was added a solution of KOH (130 g) in water (130 mL) at rt. The mixture was cooled to -15 °C (with an external MeOH-ice bath), and a solution of the (S)-2-((tert-butoxycarbonyl)amino)-3- hydroxypropanoic acid (61 g) and 2,4,6-trifluoronitrobenzene (52 g) in 2-MeTHF (400 mF) was added dropwise over 35 min maintaining the reaction temperature below 0 °C (during the last 75 mF of this addition, the internal temperature was at +3 °C). Following the addition, the reaction mixture was stirred at about -2 °C for 25 min. The cooling bath was switched to a dilute dry ice-acetone bath (-60 °C).
The reaction mixture was quenched by addition of 85 % H3PO4 (185 mF) over 20 min maintaining the reaction temperature at -10 to 0 °C. The mixture was stirred a few min at rt and filtered. The filtrate layers were separated, and the organic phase was dried over MgSCL, filtered, and concentrated in vacuo (with a MeOH chase) to afford (S)-2-((tert- butoxycarbonyl)amino)-3-(3,5-difluoro-2-nitrophenoxy)propanoic acid of a pale yellow oil (130 g, 72% yield, 60% purity by UV). This material was used in the next step without further purification. MS ESI (m/z) 361.6 [M-H] .
Step 7 : (.V)-3-(2-Amino-3.5-difliiorophcnoxy)-2-(tcrt-butoxycarbonylamino)propanoic acid
Figure imgf000105_0001
To a solution of (,V)-2-((tert-butoxycarbonyl)amino)-3-(3.5-difhioro-2- nitrophenoxy)propanoic acid (70 g, 193 mmol) in ethanol (400 mL) under nitrogen was added 10% Pd/C (12.34 g, 11.59 mmol). The reaction mixture was subjected to 50 psi hydrogen atmosphere at ambient temperature for 4 h. The reaction mixture was filtered through Celite® bed, washed with ethyl acetate. The combined filtrate was concentrated in vacuo to afford (<S)-3-(2 -amino-3, 5-difluorophenoxy)-2-(tert- butoxycarbonylamino)propanoic acid (75 g, 80 % yield, 68% purity by UV) as crude product. The crude product was used in the next step without further purification. MS ES+ m/z 333.21 [M+H]+.
Step 8: (.Sj-tert-Butyl 6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3- ylcarbamate
Figure imgf000105_0002
To a stirred solution of (S)-3-(2 -amino-3, 5-difluorophenoxy)-2-((tertbutoxy carbonyl) amino)propanoic acid (90 g, 87 mmol) in DMSO (400 mL) was added HATU (45.2 g, 119 mmol) at rt. The reaction mixture was stirred at rt for 1.5 hours, and DIPEA (33.6 mL, 192 mmol) was added. The resulting mixture was stirred at rt for 4 hours and then poured into cold water to afford a precipitate. The solid material was collected by filtration. The solid material was purified by normal phase column chromatography (60-120 mesh silica gel; eluent: 15 % EtOAc in petroleum ether). Collected fractions were concentrated in vacuo to afford brown color solid. Petroleum ether (150 mL) was added, and the mixture was stirred at rt for a few minutes and filtered to give (S)-tert-butyl (6,8-difluoro-4-oxo-2,3,4,5- tetrahydrobenzo[b][l,4]oxazepin-3-yl)carbamate as an off white solid (l2g, 37.9 mmol, 43.7 % yield). MS ES+m/z 315.13 [M+Hf; Ή NMK (400 MHz, DMSO-de) d 9.84 (s,
1H), 7.22 (t, J= l0.4Hz, 1H), 7.09 (d, J=7.20 Hz, 1H), 6.98 (d, J= 9.60 Hz, 1H), 4.45-4.32 (m, 3H), 1.36 (s, 9H).
Step 9: (.Y)-tcrt-Butyl 6,8-difluoro-5-methyl-4-oxo-2,3,4,5- tetrahy drobenzo [b] [ 1 ,4] oxazepin-3 -yl)carbamate
Figure imgf000106_0001
To a solution of (S)-tert-butyl (6,8-difluoro-4-oxo-2,3,4,5- tetrahy drobenzo [b][ 1,4] oxazepin-3 -yl)carbamate (6.10 g, 19.41 mmol) in DMF (75 mL) was added cesium carbonate (8.85 g, 27.2 mmol). The reaction mixture was stirred for 5 minutes and then iodomethane (1.396 mL, 22.32 mmol) was added. The mixture was stirred for 2 hours and then cooled in an ice-water bath. Water (100 mL) was added quickly dropwise, which resulted in gum-like solid. The material was diluted with water (200 mL) and diethyl ether. The organic layer was separated, washed with brine, concentrated, and dried to give (S)-tert-butyl (6,8-difluoro-5-methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b][l,4]oxazepin-3-yl)carbamate as a pale pink-purple sticky foam (6.54 g, 98 % yield). MS ES+ m/z 229.3 [M-Boc+H]+; ¾ NMR (400 MHz, DMSO-de) d 7.37 (ddd, J=2.78, 9.16, 11.56 Hz, 1H), 7.21 (d, J=8.34 Hz, 1H), 7.03-7.12 (m, J=2.02, 9.09 Hz, 1H), 4.39-4.50 (m, J=8.08, 8.08 Hz, 1H), 4.29-4.36 (m, 2H), 3.17 (d, J=2.02 Hz, 3H), 1.35 (s, 9H).
Step 10: (,S)-3-Amino-6,8-difluoro-5-methyl-2,3-dihydrobenzo|b || 1 4 |oxazcpin-4(5H)-onc hydrochloride
Figure imgf000107_0001
To a suspension of (S)-tert-butyl (6,8-difluoro-5-methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b][l,4]oxazepin-3-yl)carbamate (25 g, 63.0 mmol) in DCM (150 mL) stirred under nitrogen at 0 °C was added 4.0 M HC1 (250 ml, 1000 mmol) in dioxane. The reaction mixture was stirred at rt for 4 hours. The reaction mixture was cooled to -5 C° and filtered. The solid was washed with ether (100 mL) and dried to give (S)-3-amino-6,8- difluoro-5-methyl-2,3-dihydrobenzo[b][l,4]oxazepin-4(5H)-one hydrochloride as an off white solid (15 g, 56.6 mmol, 90 % yield). MS ES+ m/z 228.88 [M+H]+; 1HNMR (400 MHz, DMSO-de) d 8.80 (s, 3H), 7.40 (t, J=8.8 Hz, 1H), 7.18 (d, J=8.8 Hz, 1H), 4.68-4.64 (m, 1H), 4.54-4.45 (m, 2H), 3.23 (d, J=2.0 Hz, 3H).
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
Figure imgf000108_0001
To a stirred solution of (,S)-3-amino-6.8-difluoro-5-methyl-2.3- dihydrobenzo[b][l,4]oxazepin-4(5H)-one hydrochloride (15.0 g, 56.7 mmol, 1.0 eq) and 5- benzyl-4H-l,2,4-triazole-3-carboxylic acid (12.67 g, 62.3 mmol, 1.1 eq) in DMF (150 mL) was added DIEA (39.6 mL, 227 mmol, 5.0 eq) and propyl phosphonic anhydride (54.1 g,
85 mmol, 1.5 eq) in EtOAc (50 %) dropwise over 15 min. The reaction mixture was stirred at ambient temperature for 2 h and then diluted with water (1000 mL). The resulting solid was filtered and dried. To the solid was added ethyl acetate (600 mL). The mixture was washed with saturated bicarbonate solution (300 mL) and brine (300 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to afford crude product (24.3 g). To the crude product was added EtOH (150 mL). The mixture was stirred at 80 °C for 10 min and then at rt for 2 days. The reaction mixture was filtered to collect crystalline solid. The solid was washed with cold EtOH (100 mL) and dried to afford (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 as white crystalline solid (17.5 g, 74.5 % yield). MS ES+ m/z 414.13
[M+H]+; ¾ NMR (400 MHz, DMSO-de) d 14.33 (s, 1H), 8.41 (s br, 1H), 7.41-7.22 (m, 6H), 7.12 (d, J=8.8Hz, 1H), 4.96-4.89 (m, 1H), 4.65 (s br, 1H), 4.44 (t, J=8.0Hz, 1H), 4.12 (s, 2H), 3.20 (s, 3H).
Example 5
(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
Figure imgf000109_0001
Step 1 : (E)-6,8-Difluoro-3,4-dihydronaphthalen-l(2H)-one oxime
Figure imgf000109_0002
To a solution of 6,8-difluoro-3,4-dihydronaphthalen-l(2H)-one (50 g, 274 mmol) in ethanol (500 mL) and water (167 mL) was added sodium acetate (33.8 g, 412 mmol) and hydroxylamine hydrochloride (28.6 g, 412 mmol). The reaction turned from a light pink to light yellow after hydroxylamine hydrochloride was added and a precipitate formed after 5 minutes. The reaction was stirred at room temperature for 2 hrs 20 min. To the reaction mixture was added water (500 mL). The solids were filtered and rinsed with water. The solid was dried to give (E)-6,8-difluoro-3,4-dihydronaphthalen-l(2H)-one oxime as an off- white solid (51.2 g). On sitting for 18 hours, a small amount of additional solid had precipitated from the filtrate. This solid was also filtered, washed with water, and dried to give additional (E)-6,8-difluoro-3,4-dihydronaphthalen-l(2H)-one oxime (0.95 g). Total yield 52.15 g (96 % yield). MS ES+ m/z 198 [M+H]+; 'H NMR (400 MHz, DMSO-de) d
11.33 (s, 1H), 7.09 (ddd, J=2.65, 9.35, 11.75 Hz, 1H), 7.00 (dd, J=l .39, 8.97 Hz, 1H), 2.61-2.77 (m, 4H), 1.71 (quin, J=6.38 Hz, 2H).
Step 2: (E)-6,8-Difluoro-3,4-dihydronaphthalen-l(2H)-one O-tosyl oxime
Figure imgf000109_0003
To a suspension of (E)-6,8-difluoro-3,4-dihydronaphthalen-l(2H)-one oxime (52.2 g, 265 mmol) in dichloromethane (600 mL) was added TEA (55.3 mL, 397 mmol). The reaction was cooled in an ice-water bath, and p-toluenesulfonyl chloride (53 g, 278 mmol) was added. The ice bath was removed, and the reaction mixture was stirred at room temperature for 22 hours. The reaction solution was washed with water (2 x 350 mL), 5 % citric acid, and brine. The mixture was concentrated under reduced pressure and dried to afford (E)-6,8-difluoro- 3,4-dihydronaphthalen-l(2H)-one O-tosyl oxime as an orange-tan solid (92.1 g, 96 % yield). MS ES+ m/z 352 [M+Hf; ¾ NMR (400 MHz, DMSO-de) d 7.86 (d, 7=8.34 Hz, 2H), 7.48 (d, 7=8.08 Hz, 2H), 7.19 (ddd, 7=2.53, 9.22, 11.49 Hz, 1H), 7.09 (dd, 7=1.39, 8.97 Hz, 1H), 2.82 (t, 7=6.57 Hz, 2H), 2.75 (t, 7=6.06 Hz, 2H), 2.42 (s, 3H), 1.71 (quin, 7=6.32 Hz, 2H).
Step 3: 7, 9-Difluoro-4, 5-dihydro- lH-benzo[b]azepin-2(3H)-one
Figure imgf000110_0001
To (E)-6,8-difluoro-3,4-dihydronaphthalen-l(2H)-one O-tosyl oxime (92.1 g, 262 mmol) was added trifluoroacetic acid (220 mL). The reaction mixture was heated in an Opti Therm metal heating mantle at 50 °C and stirred for 10 minutes. The internal temperature was about 35 °C and the heating mantle temperature was raised to 65 °C. After 5 minutes, the homogeneous reaction was dark brown and bubbled for about a minute and the internal temperature was about 70 °C. After 10 minutes, the reaction was cooled to room temperature and further cooled in an ice-water bath. 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. MS ES+ m/z 198 [M+H]+; ¾ NMR (400 MHz, DMSO-de) d 9.40 (s, 1H), 7.20 (ddd, 7=2.78, 9.16, 10.29 Hz, 1H), 7.06 (dd, .7=1.52, 8.84 Hz, 1H), 2.73 (t, 7=6.82 Hz, 2H), 2.05-2.20 (m, 4H). Step 4: 7,9-Difluoro-3-iodo-4,5-dihydro-lH-benzo[b]azepin-2(3H)-one
Figure imgf000111_0001
To a mixture of 7,9-difluoro-4,5-dihydro-lH-benzo[b]azepin-2(3H)-one (33.9 g, 172 mmol) in dichloromethane (400 mL) cooled in an ice/water bath was added TMEDA (51.9 mL, 344 mmol), followed by TMSI (46.8 mL, 344 mmol) dropwise over 25 minutes. The light brown solution was stirred in the ice-bath for 60 minutes, and then iodine (65.4 g, 258 mmol) was added. The reaction mixture was stirred in the ice-bath for another 60 minutes, quenched with aq. Sodium thiosulfate, and stirred for 15 minutes. The resulting solid was filtered, washed with water and dichloromethane, and dried under vacuum to give 7,9- difluoro-3-iodo-4,5-dihydro-lH-benzo[b]azepin-2(3H)-one (37.6 g, 66 % yield) as a tan solid. The organic layer from the filtrate was separated and combined with
dichloromethane washes. The combined organic layers were washed with water and brine, and concentrated under reduced pressure. The resulting solid was triturated in ethyl acetate (50 mL), filtered, and dried to give additional 7,9-difluoro-3-iodo-4,5-dihydro-lH- benzo[b]azepin-2(3H)-one as an off-white solid (15.7 g, 28% yield). MS ES+ m/z 324 [M+H]+; ¾ NMR (400 MHz, DMSO-de) d 9.85 (s, 1H), 7.24 (dt, J= 2.78, 9.60 Hz, 1H), 7.08 (dd, .7=1.52, 8.84 Hz, 1H), 4.63-4.75 (m, 1H), 2.66-2.81 (m, 3H), 2.53-2.64 (m, 1H).
Step 5: 3-Amino-7,9-difluoro-4,5-dihydro-lH-benzo[b]azepin-2(3H)-one
Figure imgf000112_0001
To a cloudy solution of 7,9-difluoro-3-iodo-4,5-dihydro-lH-benzo[b]azepin-2(3H)-one (53.2 g, 165 mmol) in N,N-dimethylformamide (400 mL) was added sodium azide (12.85 g, 198 mmol). The resulting was mixture stirred at room temperature for 45 minutes. To the reaction was added ice (300 mL) and then water (500 mL). The precipitation of a solid resulted. The reaction was stirred for 10 minutes and filtered to give 3-azido-7,9-difluoro- 4,5-dihydro-lH-benzo[b]azepin-2(3H)-one as a tan solid. This was washed with water and used without further purification or drying. To a sohT’ion of 3-azido-7,9-difluoro-4,5- dihydro-lH-benzo[b]azepin-2(3H)-one (direct from previous step) in tetrahydrofuran (400 mL) was added water (2 mL) and PPh3 resin (66 g, 3 mmol/g loading, 198 mmol). The reaction was stirred at room temperature for 24 h, filtered through a small celite plug to remove the resin, and rinsed with tetrahydrofuran. The filtrate was concentrated in vacuo. The resulting solid was triturated in Et20, filtered, and dried to give 3-amino-7,9-difluoro- 4,5-dihydro-lH-benzo[b]azepin-2(3H)-one as an off-white solid (28.43 g, 80 % yield over 2 steps). MS ES+ m/z 213 [M+H]+; ¾ NMR (400 MHz, DMSO-de) d 9.59 (br s, 1H), 7.20 (ddd, J=2.78, 9.22, 10.23 Hz, 1H), 7.02-7.11 (m, 1H), 3.15 (dd, J=7.96, 11.49 Hz, 1H), 2.61-2.74 (m, 2H), 2.17-2.33 (m, 1H), 1.76 (dtd, J=2.78, 6.46, 17.91 Hz, 1H), 1.62 (br s, 2H).
Step 6: (S)-3-Amino-7,9-difluoro-4,5-dihydro-lH-benzo[b]azepin-2(3H)-one
Figure imgf000112_0002
To a mechanically stirred solution of 3-amino-7,9-difluoro-4,5-dihydro-lH- benzo[b]azepin-2(3H)-one (28.4 g, 134 mmol) in isopropanol (1.25 L) at 70°C was added 2-hydroxy-5-nitrobenzaldehyde (0.671 g, 4.02 mmol). Within 1 minute, a thick precipitate formed. L-pyroglutamic acid (17.28 g, 134 mmol) was added. The reaction mixture turned bright yellow and was stirred at 70 °C for 5 days and then cooled to ~50°C. The solid was filtered and washed twice with isopropanol. The solid was suspended in hexanes, stirred, filtered, and dried to give (S)-3-amino-7,9-difluoro-4,5-dihydro-lH- benzo[b]azepin-2(3H)-one L-pyroglutamate salt as an off-white solid (37.97 g, % ee = 94.7 %). This material was suspended in 9: 1 ACN:water (600 mL) and heated at 70 °C for 18 hours. The suspension was cooled to ~40°C, filtered, washed with ACN, and dried to give (S)-3-amino-7,9-difluoro-4, 5-dihydro- lH-benzo[b]azepin-2(3H)-one L-pyroglutamate salt as a white solid (35.8 g, % ee = 100 %). The salt was stirred vigorously in a mixture of 15 mL cone. Ammonium hydroxide in 200 mL water for 7 minutes. The solid was filtered, re-suspended in a mixture of 15 mL cone. Ammonium hydroxide in 200 mL water for 7 minutes, and filtered. The solid was stirred in water (200 mL) for 15 min, filtered, and dried to give (S)-3-amino-7, 9-difluoro-4, 5-dihydro- lH-benzo[b]azepin-2(3H)-one as a white solid (20.0 g, 70% yield). MS ES+ m/z 213 [M+Hf; ¾ NMR (400 MHz, DMSO-de) d 9.59 (br. S., 1H), 7.15-7.29 (m, 1H), 7.07 (dd, J=L52, 8.84 Hz, 1H), 3.15 (dd, J=7.83, 11.62 Hz, 1H), 2.59-2.77 (m, 2H), 2.16-2.31 (m, 1H), 1.69-1.83 (m, 1H), 1.60 (br s, 2H).
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
Figure imgf000114_0001
To a mixture of (S)-3-amino-7,9-difluoro-4,5-dihydro-lH-benzo[b]azepin-2(3H)-one (19.1 g, 90 mmol), 5 -benzyl -4H-1, 2, 4-triazole-3 -carboxylic acid (22.65 g, 95 mmol), and DIEA (47.2 mL, 270 mmol) in dichloromethane (650 mL) cooled in an ice-water bath was added a > 50 wt. % solution of T3P in EtOAc (81 mL, 135 mmol) dropwise over 13 minutes. The mixture became more homogeneous during T3P addition. The ice bath was removed, and the reaction mixture was stirred at room temperature for 45 minutes becoming
homogeneous after 10 minutes. The reaction was diluted with 0.5 M HC1 (600 mL), and a solid precipitated from the organic phase. The 2 layers were separated. The organic phase, including the solid, were together treated with saturated sodium bicarbonate. The resulting organic and aqueous phases were shaken vigorously. The solid was filtered and washed with dichloromethane. The solid was stirred vigorously in water (600 mL) for 60 minutes, filtered, washed with water, and dried in a vacuum oven at 50 °C to give (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 as a white solid (33.1 g). The solid was re-suspended in water (700 mL) and stirred for 2 hours. The solid was filtered, washed with water, and dried in a vacuum oven at 50 °C to give (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 as a white solid (32.0 g, 88% yield). MS ES+ m/z 398 [M+H]+; Ή NMR (DMSO-de) d ppm Ή NMR (400 MHz, DMSO-de) d 13.98-15.03 (m, 1H), 9.96 (s, 1H), 7.90-8.85 (m, 1H), 7.20-7.39 (m, 6H), 7.15 (br d, .7=8.84 Hz, 1H), 4.34 (td, J=7.89, 11.49 Hz, 1H), 4.01-4.20 (m, 2H), 2.69-2.91 (m, 2H), 2.14-2.48 (m, 2H). Example 6
(S)-6-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin-l- yl)pyrimidine-4-carbonitrile
Figure imgf000115_0001
Step 1
To a solution of 3,5-difluorobenzaldehyde (50 g, 352 mmol) in THF (300 mL) stirred under nitrogen at rt was added (triphenylphosphoranylidene)acetaldehyde (118 g, 387 mmol). The reaction mixture was stirred at 80 °C for 15 h and evaporated in vacuo. The residue was purified by normal phase column chromatography (CyH/EtOAc 100/0 to 90/10) to afford 3-(3,5-difluorophenyl)acrylaldehyde (25.6 g, 91 mmol, purity: 60 %, recovery: 26 %) as a yellow powder. LCMS (m/z) 169 (M+H)+, retention time: 2.28 min, LC/MS Method 1. Step 2
To a solution of hydrazine monohydrate (11.1 mL, 228 mmol) in ethanol (30 mL) was added acetic acid (14.8 mL, 259 mmol) at rt. The reaction mixture was heated to 45 °C and solid 3-(3,5-difluorophenyl)acrylaldehyde (25.6 g, 152 mmol) was added portion-wise during 20 min. The reaction vessel was sealed and heated to 80 °C for 21 h. The reaction mixture was concentrated in vacuo. The yellow residue was purified by normal phase column chromatography [CyH/(EtOAc/EtOH 3: 1) 100/0 to 75/25] to afford 5-(3,5- difluorophenyl)-4,5-dihydro-lH-pyrazole (20 g, 110 mmol, purity: 63 %, recovery: 72 %) as an orange oil. LCMS (m/z) 183 (M+H)+, retention time: 1.89 min, LC/MS Method 1.
Step 3
To a solution of l-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (25.2 g, 110 mmol) in DCM (300 mL) were added PyBroP® (53.7 g, 115 mmol) and DIPEA (21.09 mL, 121 mmol) at rt. After stirring for 5 min, 5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazole (20 g, 110 mmol) was added. The reaction was stirred for 5 h and concentrated in vacuo. The residue was purified by normal phase column chromatography [CyH/(EtOAc/EtOH 3: 1) 100/0 to 50/50] to provide tert-butyl 4-(5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazole-l- carbonyl)piperidine-l-carboxylate. Tert-Butyl 4-(5-(3,5-difluorophenyl)-4,5-dihydro-lH- pyrazole-l-carbonyl)piperidine-l-carboxylatewas dissolved in DCM (500 mL) and a 3 M solution of HC1 in CPME (91 mL, 274 mmol) was added at rt. The reaction was stirred at rt for 24 h. The precipitate was filtered off, washed with DCM (2 x l50mL) and /PnO (3 x 200 mL) to give (5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazol-l-yl)(piperidin-4- yl)methanone, hydrochloride (20 g, 60.6 mmol, purity: 90 %, recovery: 55 %) as a cream powder. LCMS (m/z) 294 (M+H)+, retention time: 1.17 min, LC/MS Method 1.
Step 4
To a solution of (5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazol-l-yl)(piperidin-4- yl)methanone, hydrochloride (20 g, 60.6 mmol) in EtOH (50 mL) was added a 1 M solution of sodium hydroxide (79 mL, 79 mmol). The reaction mixture was stirred at rt for 30 min. DCM (150 mL) was added and the two layers were separated. The aqueous layer was extracted with DCM (2 x 150 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated in vacuo to give the free base as an oil (17.3 g). This residue was dissolved in EtOH (50 mL) and (lR)-(-)-lO-camphorsulfonic acid (14.09 g, 06.6 mmol) was added at rt. The resulting suspension was heated at 60 °C for 30 min. The solution was then evaporated to dryness and the partially crystalline crude solid was suspended and slurried in ethanol (50 mL) to fully convert it to a crystalline form, and this suspension was evaporated to dryness to give a light orange crystalline solid. This solid was recrystallized from EtOH (300 mL) to afford (S)-(5-(3,5-difluorophenyl)-4,5-dihydro- lH-pyrazol-l-yl)(piperidin-4-yl)methanone, lR-(-)-camphor-lO-sulphonic acid salt (7 g, 13.3 mmol, purity: 100 %, recovery: 22 %) as a white powder. LCMS (m/z) 294 (M+H)+, retention time: 1.17 min, LC/MS Method 1. Chiral HPLC Method 1 : 2.58 and 3.26 min, % ee = 99.2 %.
Step 5
Figure imgf000117_0001
To a suspension of (S)-(5-(3, 5-difluorophenyl)-4, 5-dihydro- lH-pyrazol-l-yl)(piperidin-4- yl)methanone, lR-(-)-camphor-lO-sulphonic acid salt (300 mg, 0.57 mmol) in MeCN (30 mL) was added 6-chloropyrimidine-4-carbonitrile (80 mg, 0.57 mmol) and DIPEA (0.25 mL, 1.43 mmol) The vessel was sealed and heated at 80°C for 2 h. The reaction mixture was evaporated in vacuo. This residue was purified by normal phase column
chromatography [CyH/(EtOAc/EtOH 3: 1) 100/0 to 70/30] A trituration into /PnO afforded, after filtration, (S)-6-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazole-l- carbonyl)piperidin-l-yl)pyrimidine-4-carbonitrile (130 mg, 0.33 mmol, purity: 100 %, recovery: 58 %) as a light yellow powder. LCMS (m/z) 397 (M+H)+, retention time: 2.48 min, LC/MS Method 1. 'HNMR (400 MHz, DMSO- 6) d ppm 8.54 (s, 1H), 7.57 (s, 1H), 7.26 (s, 1H), 7.12 (tt, J=9.4, 2.1 Hz, 1H), 6.84 (d, J=6.5 Hz, 2H), 5.34 (dd, J=l2.0, 4.9 Hz, 1H), 4.47 (br.s, 2H), 3.49 (ddd, J=l9.0, 12.0, 1.0 Hz, 1H), 3.43 (tt, J=l 1.4, 3.7 Hz, 1H), 3.13 (br s, 2H), 2.75 (ddd, J=l9.2, 4.9, 1.5 Hz, 1H), 1.95 (d, J=l2.7 Hz, 1H), 1.81 (d,
J= 12.7 Hz, 1H), 1.48 (m, 2H).
Example 7
In vitro Assay: A fluorescent polarization based binding assay was developed to quantitate interaction of novel test compounds at the ATP binding pocket of RIP1, by competition with a fluorescently labeled ATP competitive ligand. Table 1 lists examples of p IC’50 data for the noted compounds of the Examples. 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. Following the incubation, 5pL of the fluorescent labeled ligand solution, was added to each reaction, at twice the final assay concentration, and incubated at room temperature for at least 15 minutes. Finally, samples were read on an instrument capable of measuring fluorescent polarization. Test compound inhibition was expressed as percent inhibition of internal assay controls. For concentration response experiments, normalized data were fit and p IC’50 values determined using conventional techniques. Those of skill in the art will recognise that in vitro binding assays for functional activity are subject to experimental variability, accordingly, it is to be understood that the values given below are exemplary only. As determined using the above method, the compounds of Examples 1-6 exhibited a pICso between approximately 5.0 and 9.0.
Table 1.
Figure imgf000119_0001
In vivo Assay: 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.
Each test compound is run through the TNF/zVAD version of the model. For example, 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.
Example 8 Subcutaneous tumor efficacy
The efficacy of 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.
Table 2. Study Design
Figure imgf000120_0001
Note:
N: animal number
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.
Study endpoints: The major endpoints of the study include the following: 1) Tumor growth inhibition (TGI): TGI% is an indication of antitumor
effectiveness, and expressed as: 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.
2) Tumor and plasma collection at study end for further investigation. Experimental Methods
Cell Culture: 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.
Table 3. Medium information
Figure imgf000121_0001
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 80-120mm3 (around lOOmm3). 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.
Study Results
Table 4. Mean tumor growth inhibition (TGI) at model termination
Figure imgf000122_0001
Example 9
Protocol Title: A Phase I/II, Open-Label Study to Investigate the Safety, Clinical Activity, Pharmacokinetics, and Pharmacodynamics of Compound A Administered Alone and in Combination with Anticancer Agents Including Pembrolizumab in Adult Participants with Selected Advanced Solid Tumors
Short Title: First-time-in-human study of Compound A alone and in combination with other anticancer agents in adults with advanced solid tumors Rationale:
Pancreatic ductal adenocarcinoma (PDAC) is the 4th 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. Furthermore, in an unbiased screen, RIPK1 was identified as a top gene contributing to resistance to immunotherapy. These data suggest that the small molecule RIP 1 inhibitor Compound A may have therapeutic potential in multiple tumor types.
The Study described in Example 9 is a Phase 1 first-time -in-human (FTIH) study of Compound A alone and in combination with other anticancer agents including
pembrolizumab in participants with PDAC and other selected tumors, e.g. non-small cell lung cancer (NSCLC), triple negative breast cancer, or melanoma. 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.
Background
Inflammation and cell death are intimately linked, and an appropriate balance between the two is essential for maintaining tissue homeostasis. Tumorigenesis represents one of the best examples of the pathological consequences of a disruption in this balance, as dysregulated cross-talk between cell death and immune signaling in the tumor promotes immunosuppression and tissue-regeneration. To circumvent this miscommunication, much work has been done to develop immuno-therapies that directly activate the adaptive immune system to induce cytotoxicity and tumor regression. However, therapeutics that block immune checkpoints in T cells are only able to eradicate malignant cells if the T cells can infiltrate the tumor and effectively interact with proinflammatory innate immune cells (Garrido-Laguna 2015). The lack of efficacy of T cell based immuno-therapies in pancreatic ductal adenocarcinoma (Garrido-Laguna 2015) underscores the importance of targeting additional immunoregulatory pathways. Hallmarks of PDAC that contribute to this therapeutic barrier include the vast infiltrate of myeloid cells, and impenetrable desmoplasia (Scarlett 2013, Garrido-Laguna 2015, Engblom 2016). Tumor infiltrated myeloid cells often correlate with a worse patient prognosis and are increasingly recognized as key drivers of an immunosuppressive tumor microenvironment contributing to therapeutic resistance. For these reasons, immunomodulation of the myeloid cell population within tumors is an attractive target for next-generation therapeutics in PDAC (Scarlett 2013).
Recent work demonstrates a novel role for RIP1 kinase activity in recruiting immunosuppressive myeloid cells in PDAC (Seifert 2016). 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.
Inhibition of cIAP proteins prevent RIP1 ubiquitination, and in the absence of proapoptotic caspase activity, will lead to a RIP1 kinase dependent, pro-inflammatory programmed cell death termed necroptosis (Ofengeim 2013). Initially it was thought that inducing necroptosis in tumor cells could serve as a novel treatment for tumors resistant to apoptosis. However, increasing evidence reveals a detrimental effect of danger associated molecular patterns (DAMPs) released following necrosis or necroptosis within solid tumors (Fofti 2016), and necroptosis in endothelial cells promotes metastasis (Strilic 2016).
It is increasingly clear that there are a variety of RIP 1 driven processes that are independent of cell death including cytokine secretion (Najjar 2016), cell differentiation (Xin 2017), DNA stability (Chen 2014, Park 2009), extravasation (Hanggi 2018), and anchorage independent cell growth (Fiu 2016). Given these additional roles for RIP1 kinase activity, combined with the negative effects of necroptosis in solid tumors, it is not surprising that recent in vivo work shows a role for RIP 1 in promoting oncogenesis that contradicts earlier in vitro studies. Recent work from the Miller lab, for example, showed that RIP1 kinase activity leads to the recruitment of myeloid derived suppressor cells (MDSCs), tumor associated macrophages (TAMs) and IL-10 expressing T cells in a
CXCL1 and SAP130 dependent manner to promote pancreatic oncogenesis (Seifert 2016). This work has been expanded internally to show that therapeutic blockade of RIP1 kinase activity retarded tumor progression and decreased fibrosis within the remaining pancreatic tumor.
Preclinical PDAC models support the clinical hypothesis. The first models tested were the orthotopic KPC and transgenic KC models. In the former model, tumors are derived from a mouse harboring the same Kras and p53 mutations present in >90% of pancreatic cancer cases. In the latter, pancreatic intraepithelial (PanIN) lesions develop spontaneously due to a Kras mutation. Similar to human tumors, these tumors are fibrotic in nature and resistant to anti -PD 1. In both models, maintenance of >90% inhibition of
RIP1 in the periphery led to an approximate 50% decrease in tumor size. Concomitant with this efficacy, there was a significant decrease in the number of M2 -like TAMS.
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).
Compound A
Compound A has the following structure:
Figure imgf000125_0001
Compound A demonstrates consistent pharmacology across all the assays in the RIP 1 critical path. Compound A is a high-quality candidate with desirable physiochemical properties which result in excellent pharmacokinetic and safety profiles.
In vivo efficacy for Compound A could not be evaluated because it is not selective for non-primate RIP1. This necessitated the use of a tool compound, a potent mouse RIP1 inhibitor for evaluation of anti-tumor activity in a pancreatic tumor model. One dose was evaluated in the form of food-based dosing which resulted in approximately 50% tumor growth inhibition with blood concentration maintained above 90% RIP 1 inhibition during the entire dosing period. A dose of 100 mg when administered as 50 mg BID is anticipated to provide 97.4% RIP1 inhibition in the blood over the dosing interval in 50% of participants.
Pembrolizumab
Immunotherapy has emerged as a transformative anticancer therapeutic strategy over the past few years. In particular, the inhibition of negative T cell regulatory pathways with the checkpoint inhibitors has been very successful, first in the treatment of melanoma and, more recently, expanding to additional indications, including NSCLC. Ipilimumab and pembrolizumab are examples of these initial checkpoint inhibitors, which are mAbs that block the activity of the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and PD-l pathways, respectively, thereby freeing the T cell priming and T cell effector functions from their negative regulatory effects.
Pembrolizumab, a humanized monoclonal antibody against the PD-l protein, has been developed by Merck & Co for the treatment of patients with cancer. Pembrolizumab is approved for treatment of patients with melanoma in several countries; in the US and EU it is approved for the treatment of patients with advanced (unresectable or metastatic) melanoma in adults. Pembrolizumab has also been approved for treatment of patients with NSCLC in several countries; in the US it is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 as determined by an LDAapproved test and who have disease progression on or after platinum-containing chemotherapy. Patients with NSCLC and EGLR or ALK genomic tumor aberrations should also have disease progression on PDA-approved therapy for these aberrations prior to receiving
pembrolizumab. In the US, pembrolizumab is also approved for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck with disease progression on or after platinum-containing chemotherapy. Pembrolizumab has demonstrated initial clinical efficacy in single arm monotherapy trials in participants with non-small cell lung cancer, head and neck squamous cell
carcinoma, urothelial cancer, gastric cancer, triple negative breast cancer and Hodgkin’s Lymphoma as determined by response rate. Ongoing clinical trials are being conducted in advanced melanoma, NSCLC, head and neck cancer, urothelial cancer, gastric cancer, TNBC, Hodgkin’s lymphoma and a number of other advanced solid tumor indications and hematologic malignancies.
The dose of pembrolizumab planned to be studied in this trial is 200 mg Q3W.
Overall Design:
This is a FTIH, open-label, non-randomized, multicenter study designed to evaluate the safety, tolerability, PK, pharmacodynamics, and preliminary clinical activity of Compound A orally administered twice daily (BID) to participants with selected advanced or recurrent solid tumors.
The study will utilize a staged approach consisting of at least four parts.
In Part 1, Compound A monotherapy will be assessed in escalating doses in participants with advanced or metastatic pancreatic cancer. Part 2 will assess escalating doses of Compound A in combination with a fixed dose of pembrolizumab in participants with selected solid tumors that may include PD AC, NSCLC, triple-negative breast cancer, and/or melanoma.
Initiation of Part 2 will occur after emerging data from Part 1 demonstrate the safety of Compound A monotherapy. Part 2 will begin with a Compound A dose below the highest Part 1 dose shown to have an acceptable toxicity profile in at least 3 participants. Part 3 may evaluate the combination of one or more doses of Compound A and pembrolizumab in disease-specific expansion cohorts via protocol amendment. All available safety, pharmacodynamic, PK, and efficacy data will be used to select 1 or more doses of Compound A to evaluate in Part 3. The population of participants selected for Part 3 will also be determined by data emerging from Part 2. The protocol may be amended to include investigation of additional anticancer agent combinations with Compound A in Part 4. All participants in Parts 1 and 2 must be willing to undergo mandatory fresh biopsy collection at baseline, on treatment, and if feasible at the time of disease progression. Exploration of lower dose levels (or expansion of a previously tested dose level) will be allowed if agreed upon by the Medical Monitor and treating investigators. The
Neuenschwander Continual Reassessment Method (NCRM) (Neuenschwander 2008) will be used to guide dose escalation for monotherapy and the modified Toxicity Probability Interval (mTPI) procedure (Ji 2013) will be used for combination therapy. The final dose escalation decision will be made by the study team based on all available data, including biomarker and PK data and the safety profile of prior cohorts. Dose-escalation decisions will be documented in writing with copies maintained at each site and in the study files.
Criteria that may be considered in the determination of which dose level(s) to expand and which tumor types to enroll in Parts 3 and 4 may include target engagement and pharmacodynamic activity, tolerability, and clinical activity, including stable disease of at least 12 weeks. Unless otherwise specified, all response endpoints will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) vl.l; iRECIST will be used to determine treatment decisions. Number of Participants:
The study will enroll up to approximately 220 participants (Parts 1 and 2
[approximately 30 participants each], Parts 3 and 4 [approximately 80 each]) with tumor types that may include PDAC, NSCLC, triple-negative breast cancer, and/or melanoma. Treatment Groups and Duration:
The study includes a screening period, a treatment period, and a follow-up period. Participants will be screened for eligibility beginning approximately 21 days before the start of treatment. The maximum duration of treatment with Compound A alone and Compound A plus pembrolizumab will be 2 years. The follow-up period for safety assessments will be a minimum of 3 months from the date of the last dose of any study drug. The post-treatment follow-up period includes disease assessments every 12 weeks until documented PD, initiation of another anticancer therapy, or death. Following PD or initiation of another anticancer therapy, participants will be contacted every 12 weeks to assess survival status until death occurs.
Participants with confirmed PR or CR will be followed for response duration and may be eligible for additional treatment with Compound A at the time of
relapse/progression. The decision whether a participant will receive additional treatment will be discussed and agreed upon by the treating investigator and the Sponsor/Medical Monitor on a case-by-case basis.
In Part 1, 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.
Analyses:
No formal statistical hypothesis will be tested in the dose escalation phase.
For the combination therapy, in the dose expansion phase, the anti-tumor activity of combination therapy will be tested using the predictive probability design of Lee and Liu (Lee 2008). The response rates to be tested for null and alternative hypotheses for the secondary endpoint of overall response rate (ORR) will be specified prior to initiation of the expansion phase. These rates will depend on the target tumor type and the choice of anti -cancer agent.
Treatments
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo, or medical device(s) intended to be administered to a study participant according to the study protocol.
Treatments Administered
See FIG. 3 for Study Drug Characteristics.
Transition of Study Treatment from Capsules to Tablets
Participants will initially receive API capsules (size“00/1”, 5 mg to 75 mg) until the tablet formulation (25 mg/50 mg/200 mg) of the study treatment is manufactured and ready for distribution. The dose level at which this transition will occur will be designated the “transition” dose level. At the transition dose level, the safety of capsules compared with tablets will be assessed as follows. Three subjects will be dosed with capsules and evaluated for DLT. After the transition dose has met criteria for dose escalation with capsules as per the N-CRM method, an additional three participants will receive the same transition dose with tablets and will be evaluated for DLT. Once the safety of the transition dose has been established in tablets as per the N-CRM method, all participants still receiving capsules (including those receiving capsules at lower dose levels) will begin receiving tablets.
Study Visits
Visit Types
Screening: All screening assessments should be completed within 21 days prior to dosing start. Pregnancy testing 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. Screening assessments can be done over multiple office visits as needed.
Treatment: While on study drug(s), participants should have office visits per the Schedule of Activities and within the visit windows specified. One cycle is 21 days in length.
End of Treatment (EOT): The end-of-treatment (EOT) visit should be conducted within 30 days (+10 days) of the decision to discontinue study drug(s).
Follow up:
Response Follow-up (RFU): If study treatment has been permanently
discontinued in the absence of progressive disease, participants still in the study must have a RFU office visit every 12 weeks until disease progression, initiation of another anticancer treatment, or death.
- Aes and Concomitant Medications: All Aes and concurrent medications will be collected until at least 30 days after the last dose of study treatment (i.e., Aes and
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.
Survival Follow-up (SFU): The SFU telephone call should be completed every 12 weeks after documented disease progression or after initiation of another anticancer treatment. All participants still in the study should be contacted every 12 weeks (±2 weeks) until death occurs.
Visit Windows
All screening assessments should be completed within 21 days prior to dosing start.
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.
Telephone call on Week 1 Day 3 must be performed on the day indicated.
Week 2 through Week 7: Based on participant and clinic schedule, assessments can be ±3 days.
The Week 3 Day 1 PK collection is timed to permit evaluation of Compound A PK at steady-state dosing. If a participant is not receiving drug on Week 3 Day 1 (either as a consequence of a planned drug holiday or due to toxicity), then this PK collection should be rescheduled for a later timepoint when the participant is again being dosed at steady state, and the alternate collection date noted in the eCRF. Visits at Week 8 and beyond will be allowed to have a ±3-days window.
The EOT visit should be completed within 30 days (+10 days) after the last dose of study drug(s).
Assessments
This section lists the procedures and parameters of each planned study assessment. If assessments are scheduled for the same nominal time, it is recommended that the assessments should occur in the following order: l2-lead ECG, vital signs, and blood draws. The timing of the assessments should allow the blood draws to occur at the exact nominal time.
The timing and number of planned study assessments may be altered during the study based on newly available data (e.g., to obtain data closer to the time of peak plasma concentrations) to ensure appropriate monitoring for the following assessments: safety, PK, pharmacodynamic/biomarker, or other assessments.
The change in timing or addition of time points for any planned study assessments must be approved by the relevant GSK study team member and then archived in the Sponsor study and site study files, but this will not constitute a protocol amendment. The IRB/IEC will be informed of any safety issues that require alteration of the safety monitoring scheme or amendment of the informed consent form.
Protocol waivers or exemptions are not allowed except for immediate safety concerns. Therefore, adherence to the study design requirements are essential and required for study conduct.
Screening and Critical Baseline Assessments
All screening evaluations must be completed and reviewed to confirm that potential participants meet all eligibility criteria. The investigator will maintain a screening log to record details of all participants screened and to confirm eligibility or record reasons for screening failure, as applicable.
Demographic and Baseline Assessments
The following demographic parameters will be captured: year of birth, sex, race, and ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion criteria.
Procedures conducted as part of the participant’s routine clinical management (e.g., blood counts, ECG, and scans) and obtained prior to signing of the ICF may be utilized for screening or baseline purposes provided the procedure meets the protocol-defined criteria and has been performed in the timeframe specified.
Critical Baseline Assessments Cardiovascular medical history /risk factors (as detailed in the eCRF) will be assessed at screening.
Baseline Documentation of Target and Non-Target Lesions
All baseline lesion assessments must be performed within 21 days before the first dose. Measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all involved organs, should be identified as target lesions, and recorded and measured at baseline. These lesions should be selected based on their size (lesions with the longest diameter) and their suitability for accurate repeated measurements (either by imaging techniques or clinically).
• Lymph nodes that have a short axis of <10 mm are considered non-pathological and should not be recorded or followed.
• Pathological lymph nodes with short axis >10 mm but <15 mm are considered nonmeasurable-.
• Pathological lymph nodes with short axis >15 mm are considered measurable and can be selected as target lesions; however, lymph nodes should not be selected as target lesions when other suitable target lesions are available.
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue
components, that can be evaluated by computed tomography (CT) or magnetic resonance imaging (MRI) can be considered measurable. Bone scans,
fluorodeoxyglucose-positron-emission tomography (FDG-PET) scans or X-rays are not considered adequate imaging techniques to measure bone lesions.
• All other lesions (or sites of disease) 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.
Note: Cystic lesions thought to represent cystic metastases should not be selected as target lesions when other suitable target lesions are available.
Note: Measurable lesions that have been previously irradiated and have not been shown to be progressing following irradiation should not be considered as target lesions.
The following are required at baseline: A CT scan with contrast of the chest, abdomen, and pelvis, and other areas as indicated by the participant’s underlying disease, and clinical disease assessment for palpable lesions. For participants with head and neck cancer, a CT or MRI of the head and neck area is required. At each post-baseline assessment, evaluations of the sites of disease identified by these scans are required. NOTE: Although 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
contraindicated due to allergy to contrast agent, provided that the method used to document baseline status is used consistently throughout study treatment to facilitate direct comparison.
Confirmation of CR and PR are required per protocol. Confirmation assessments must be performed at least 4 weeks after the criteria for response were met initially and may be performed at the next protocol scheduled assessment. If a confirmation assessment is performed prior to the next protocol schedule assessment, the next protocol scheduled evaluation is still required (e.g., evaluations must occur at each protocol scheduled time point regardless of unscheduled assessments).
Disease Assessments
A participant’s disease status and determination of disease progression at postbaseline visits will be evaluated by the local investigators’ assessments of radiology by RECIST vl. l (Eisenhauer 2009) and iRECIST (Seymour 2017). A decision to discontinue treatment due to disease progression will be based upon iRECIST and the primary endpoint analysis will use RECIST. Scans will be collected and stored to allow for the option of central radiologic audit or review. Disease assessment modalities may include imaging (e.g., CT scan, MRI, bone scan, plain radiography) and physical examination (as indicated for palpable/superficial lesions).
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.
For post-baseline assessments, 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.
Adverse Events
The investigator and any designees are responsible for detecting, documenting, and reporting events that meet the definition of an adverse event (AE) or serious adverse event (SAE) and remain responsible for following up Aes that are serious, considered related to the study.
Assessment Guidelines by RECIST 1.1
Please note the following:
• The same diagnostic method, including use of contrast when applicable, must be used throughout the study to evaluate a lesion. Contrast agents must be used in accordance with the Image Acquisition Guidelines.
• All measurements should be taken and recorded in millimeters (mm), using a ruler or calipers.
• Ultrasound is not a suitable modality of disease assessment. If new lesions
are identified by ultrasound, confirmation by CT or MRI is required.
• Fluorodeoxyglucose (FDG)-PET is generally not suitable for ongoing
assessments of disease. However, 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
on CT/MRI or when a baseline FDG-PET was previously negative for the site of the new lesion. FDG-PET may also be used in lieu of a standard bone scan providing coverage allows interrogation of all likely sites of bone disease and FDG-PET is performed at all assessments. • If PET/CT is performed then the CT component can only be used for standard response assessments if performed to diagnostic quality, which includes the required anatomical coverage and prescribed use of contrast.
The method of assessment should be noted as CT on the eCRF.
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.
Guidelines for Evaluation of Disease Measurable and Non-measurable Definitions Measurable lesion: A non-nodal lesion that can be accurately measured in at least one dimension (longest dimension) of
• >10 mm with MRI or CT when the scan slice thickness is no greater than 5 mm. If the slice thickness is greater than 5 mm, 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).
• >10 mm caliper/ruler measurement by clinical exam or medical photography.
• >20 mm by chest X-ray.
• Additionally, lymph nodes can be considered pathologically enlarged and
measurable if >15 mm in the short axis when assessed by CT or MRI (slice thickness recommended to be no more than 5 mm). At baseline and follow-up, only the short axis will be measured.
Non-measurable lesion:
All other lesions including lesions too small to be considered measurable (longest diameter <10 mm or pathological lymph nodes with >10 mm and <15 mm short axis) as well as truly non-measurable lesions, which include: leptomeningeal disease, ascites, pleural or pericardial effusions, inflammatory breast disease, lymphangitic involvement of the skin or lung, abdominal masses/abdominal organomegaly identified by physical exam that is not measurable by reproducible imaging techniques
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:
non-measurable only disease is not allowed per protocol.
Evaluation of Response by iRECIST 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.
Clinical stability is defined as meeting all of the following:
• Absence of symptoms and signs indicating clinically significant progression of
disease · No decline in ECOG performance status
• No requirements for intensified management, including increased analgesia,
radiation, or other palliative care
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.
In 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.
If a participant has confirmed radiographic progression (iCPD) as defined below, 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.
Description of the iRECIST Process for Assessment of Disease Progression
Assessment at Screening and Prior to RECIST 1.1 Progression Until radiographic disease progression based on RECIST 1.1, there is no distinct iRECIST assessment.
Assessment and Decision at RECIST 1.1 Progression
For participants who show evidence of radiological PD by RECIST 1.1 the Investigator will decide whether to continue a participant on study intervention until repeat imaging is obtained (using iRECIST for participant management (see Table 11 and Figure 3). This decision should be based on the participant’s overall clinical condition.
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, including:
• Increase in the sum of diameters of target lesion(s) identified at baseline to >20% and >5 mm from nadir o Note: the iRECIST publication uses the terminology“sum of measurements”, but “sum of diameters” will be used in this protocol, consistent with the original RECIST 1.1 terminology.
• Unequivocal progression of non-target lesion(s) identified at baseline
Development of new lesion(s) iRECIST defines response categories, including iUPD (unconfirmed progressive disease) and iCPD (confirmed progressive disease). For purposes of iRECIST assessment, 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. At this visit, 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.
Assessment at the Confirmatory Imaging
At the confirmatory imaging visit assessment, 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).
Confirmation of Progression
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the following occurs:
• Any of the factors that were the basis for the initial iUPD show worsening o For target lesions, worsening is a further increase in the sum of diameters of
>5 mm, compared to any prior iUPD time point o For non-target lesions, worsening is any significant growth in lesions overall,
compared to a prior iUPD time point; this does not have to meet the
“unequivocal” standard of RECIST 1.1 o For new lesions, worsening is any of these:
• An increase in the new lesion sum of diameters by >5 mm from a prior
iUPD time point
• Visible growth of new non-target lesions · The appearance of additional new lesions
• Any new factor appears that would have triggered PD by RECIST 1.1 Persistent iUPD
Progression is considered not confirmed, and the overall response remains iUPD, if:
• None of the progression-confirming factors identified above occurs AND · The target lesion sum of diameters (initial target lesions) remains above the initial
PD threshold (by RECIST 1.1)
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.
Resolution of iUPD
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if:
• None of the progression-confirming factors identified above occurs, AND
• The target lesion sum of diameters (initial target lesions) is not above the initial PD
threshold.
The response is classified as iSD or iPR (depending on the sum of diameters of the target lesions), or iCR if all lesions resolve.
In this case, 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.
Management Following the Confirmatory Imaging
If repeat imaging does not confirm PD per iRECIST, as assessed by the Investigator, and the participant continues to be clinically stable, study intervention may continue and follow the regular imaging schedule. If PD is confirmed, participants will be discontinued from study intervention.
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, but 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 continue to be performed following the intervals as outlined.
Detection of Progression at Visits After Pseudo-Progression Resolves
After resolution of pseudo-progression (i.e., achievement of iSD/iPR/iCR), 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
progression has not resolved, iUPD results from any significant further growth of non-target lesions.
New lesions o New lesions appear for the first time
o Additional new lesions appear
o Previously identified new target lesions show an increase of > 5 mm in the new
lesion sum of diameters, from the nadir value of that sum o Previously identified non-target lesions show any significantgrowth
If any of the events above occur, 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. It will remain iUPD until either a decrease in the new lesion burden allows resolution to iSD or iPR, or until a confirmatory factor causes iCPD. Additional details about iRECIST are provided in the iRECIST publication [Seymour, 2017]
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Claims

Claims:
1. A method of treating cancer in a human in need thereof, the method comprising
administering to the human a RIP1 kinase inhibitor at a dose of about 50 mg to about 1600 mg.
2. A method of treating cancer in a human in need thereof, the method comprising
administering to the human a RIP1 kinase inhibitor at a dose of about 50 mg to about 1600 mg, and administering to the human a PD1 antagonist thereof at a dose of about 200 mg.
3. The method of claim 1 or 2, wherein the RIP1 kinase inhibitor is:
Figure imgf000147_0001
or a pharmaceutically acceptable salt thereof.
4. The method of any one of claims 2-3, wherein the PD1 antagonist is an anti -PD 1 antibody or antigen binding portion thereof.
5. The method of any one of claims 2-4, wherein the PD1 antagonist is pembrolizumab.
6. The method of any one of claims 2-5, wherein the PD1 antagonist is nivolumab.
7. The method of any one of claims 1-6, wherein the RIP1 kinase inhibitor is
administered at a dose of 50 mg, 100 mg, 200 mg, 400 mg, 800 mg, or 1600 mg.
8. The method of any one of claims 2-7, wherein the PD1 antagonist is administered at a dose of 200 mg.
9. The method of any one of claims 1-8, wherein the RIP1 kinase inhibitor is
administered orally.
10. The method of any one of claims 2-9, wherein the PD1 antagonist is administered intravenously.
11. The method of any one of claims 1-10, wherein the cancer is an advanced solid tumor.
12. The method of any one of claims 1-11 , wherein the cancer is pancreatic ductal
adenocarcinoma (PDA), non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), or melanoma.
13. The method of any one of claims 1-12, wherein the RIP1 kinase inhibitor is
administered twice daily.
14. The method of any one of claims 1-13, wherein the RIP1 kinase inhibitor is
administered twice daily such that the total daily dose is 100 mg, 200 mg, 400 mg, 800 mg, or 1600 mg.
15. The method of any one of claims 2-14, wherein the PD1 antagonist is administered once every three weeks.
16. A method of treating cancer in a human in need thereof, the method 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, wherein the RIP1 kinase inhibitor is:
Figure imgf000148_0001
or a pharmaceutically acceptable salt thereof.
17. A method of treating cancer in a human in need thereof, the method 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-PDl antibody or antigen binding portion thereof at a dose of 200 mg, wherein the anti-PDl antibody is pembrolizumab, and wherein the RIP1 kinase inhibitor is:
Figure imgf000149_0001
or a pharmaceutically acceptable salt thereof.
18. A RIP1 kinase inhibitor, wherein the RIP1 kinase inhibitor is to be administered at a dose of about 50 mg to about 1600 mg.
19. 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.
20. Use of a RIP1 kinase inhibitor in the manufacture of a medicament for treating cancer, wherein the RIP1 kinase inhibitor is to be administered at a dose of about 50 mg to about 1600 mg.
21. A pharmaceutical kit comprising about 50 mg to about 1600 mg of a RIP1 kinase inhibitor.
22. A RIP1 kinase inhibitor and a PD1 antagonist for simultaneous or sequential 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 the PD1 antagonist is to be administered at a dose of about 200 mg.
23. 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.
24. A PD1 antagonist for use in treating cancer, wherein the PD1 antagonist is to be
administered at a dose of about 200 mg and is to be administered simultaneously or sequentially with a RIP1 kinase inhibitor at a dose of about 50 mg to about 1600 mg.
25. Use of a RIP1 kinase inhibitor in the manufacture of a medicament for treating cancer, wherein the RIP1 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.
26. Use of a PD1 antagonist in the manufacture of a medicament for treating cancer,
wherein the PD1 antagonist is to be administered at a dose of about 200 mg and is to be administered simultaneously or sequentially with a RIP1 kinase inhibitor at a dose of about 50 mg to about 1600 mg.
27. A pharmaceutical kit comprising about 50 mg to about 1600 mg of a RIP1 kinase inhibitor and about 200 mg of a PD1 antagonist.
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