WO2019123219A1 - Forme de sel cristalline de (s)-5-benzyl-n-(5-méthyl-4-oxo-2,3,4,5-tétrahydrobenzo[b][1,4]oxazépin-3-yl)-4h-1,2,4-triazole-3-carboxamide - Google Patents

Forme de sel cristalline de (s)-5-benzyl-n-(5-méthyl-4-oxo-2,3,4,5-tétrahydrobenzo[b][1,4]oxazépin-3-yl)-4h-1,2,4-triazole-3-carboxamide Download PDF

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WO2019123219A1
WO2019123219A1 PCT/IB2018/060206 IB2018060206W WO2019123219A1 WO 2019123219 A1 WO2019123219 A1 WO 2019123219A1 IB 2018060206 W IB2018060206 W IB 2018060206W WO 2019123219 A1 WO2019123219 A1 WO 2019123219A1
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Prior art keywords
compound
crystalline form
disease
oxo
carboxamide
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Lotfi Derdour
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GlaxoSmithKline Intellectual Property Development Ltd
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GlaxoSmithKline Intellectual Property Development Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a methane sulfonic acid (MSA) salt of a heterocyclic amide derivative, to pharmaceutical compositions comprising the same and its use as a therapeutic agent for treating a number of diseases or conditions.
  • the present invention relates to the methane sulfonic acid (MSA) salt of (,Y)-5-benzyl-/V-(5- methyl-4-oxo-2,3,4,5-tetrahydrobenzo[6][l,4]oxazepin-3-yl)-4i7-l,2,4-triazole-3- carboxamide, in particular in crystalline form, pharmaceutical compositions comprising the same and its use as a therapeutic agent for treating a number of diseases or conditions for which a RIP-l inhibitor is indicated.
  • the present invention relates to the methane sulfonic acid (MSA) salt of (,Y)-5- benzyl-A-(5-methyl-4-oxo-2, 3, 4, 5-tetrahydrobenzo[6] [l,4]oxazepin-3-yl)-4i7-l, 2,4- triazole-3 -carboxamide (herein referred to as“Compound B”), in particular a crystalline form thereof.
  • MSA methane sulfonic acid
  • Compound A is represented by Structure (I):
  • Compound B is represented by Structure (II):
  • Compound A may be useful for inhibiting RIP1, and for treating diseases such as inflammatory bowel disease, including Crohn's disease and ulcerative colitis. Compound A may also be useful for treating diseases such as psoriasis and rheumatoid arthritis and for treatment of bum injuries.
  • the methane sulfonic acid (MSA) salt of ( ⁇ S)-5-benzyl-/V-(5-methyl-4-oxo-2, 3,4,5- tetrahydrobenzo[6][l,4]oxazepin-3-yl)-4i7-l,2,4-triazole-3-carboxamide (herein referred to as“Compound B”), in particular a crystalline form thereof, may show an improved profile over known RIP1 inhibitors in that it may possess, for example, one or more of the following properties:
  • improved developability and handling e.g. desirable solubility profile, pharmacokinetics and pharmacodynamics
  • Figure 1 shows an 1H NMR Spectrum of Compound B as prepared by the small- scale preparation (Example 2) .
  • Figure 2 shows a differential scanning calorimetry (DSC) trace of Compound B as prepared by the small-scale preparation (Example 2).
  • Figure 3 shows an 1H NMR Spectrum of Compound B as prepared by the large- scale preparation (Example 3) .
  • Figure 4 shows an X ray powder diffraction (XRPD) pattern of Compound B as prepared by the large-scale preparation (Example 3).
  • Figure 5 shows a microscope image of Compound B as prepared by the small- scale preparation (Example 2).
  • Figure 6 shows an overlay of the DSC trace of Compound B as prepared by the small-scale preparation (Example 2) with the DSC trace of Compound B as prepared by the large-scale preparation (Example 3).
  • the present invention is directed to a methanesulfonic acid (MSA) salt of (,Y)-5- benzyl-/V-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo
  • oxazepin-3-yl)-4//- 1.2.4- triazole-3 -carboxamide herein referred to as Compound B
  • Compound B a methanesulfonic acid
  • Compound A as used herein is intended to represent ( ⁇ S)-5-benzyl-/V-(5-methyl-4-oxo-2, 3,4,5- tetrahydrobenzo [6] [ 1 ,4]oxazepin-3 -y ⁇ )- H- 1 ,2,4-triazole-3 -carboxamide (free base) .
  • MSA methane sulfonic acid
  • Compound B methane sulfonic acid
  • Compound B in particular crystalline forms thereof, wherein the crystalline form is characterized by an 1 H NMR spectrum substantially in accordance with Fig. 1 and/or Fig. 3.
  • Compound B in crystalline form as characterized by a DSC trace substantially in accordance with Fig. 2.
  • Compound B in crystalline form as characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with Fig. 4. Also described is Compound B in crystalline form, as characterized by diffraction data substantially in accordance with Table 1
  • the present invention provides a methanesulfonic acid (MSA) salt of (.Y)-5-bcnzyl-A-(5-mcthyl-4-oxo-2 3.4.5-tctrahydrobcnzo
  • MSA methanesulfonic acid
  • the present invention provides a methanesulfonic acid (MSA) salt of (.Y)-5-bcnzyl-A-(5-mcthyl-4-oxo-2 3.4.5-tctrahydrobcnzo
  • MSA methanesulfonic acid
  • the present invention provides a methanesulfonic acid (MSA) salt of (.Y)-5-bcnzyl-A-(5-mcthyl-4-oxo-2 3.4.5-tctrahydrobcnzo
  • MSA methanesulfonic acid
  • the present invention provides a methane sulfonic acid (MSA) salt (.Y)-5-bcnzyl-A-(5-mcthyl-4-oxo-2 3.4.5-tctrahydrobcnzo
  • MSA methane sulfonic acid
  • the present invention provides a methane sulfonic acid (MSA) salt (,V)-5-benzyl-/V-(5-methyl-4-oxo-2.3.4.5-tetrahydrobenzo
  • MSA methane sulfonic acid
  • the present invention provides a methane sulfonic acid (MSA) salt (,V)-5-benzyl-/V-(5-methyl-4-oxo-2.3.4.5-tetrahydrobenzo
  • MSA methane sulfonic acid
  • the present invention provides a methane sulfonic acid (MSA) salt (,V)-5-benzyl-/V-(5-methyl-4-oxo-2.3.4.5-tetrahydrobenzo
  • MSA methane sulfonic acid
  • the present invention provides a methane sulfonic acid (MSA) salt (,V)-5-benzyl-/V-(5-methyl-4-oxo-2.3.4.5-tetrahydrobenzo
  • the present invention provides a methane sulfonic acid (MSA) salt (,V)-5-benzyl-/V-(5-methyl-4-oxo-2.3.4.5-tetrahydrobenzo
  • MSA methane sulfonic acid
  • DSC differential scanning calorimetry
  • the present invention provides a methane sulfonic acid (MSA) salt (,V)-5-benzyl-/V-(5-methyl-4-oxo-2.3.4.5-tetrahydrobenzo
  • MSA methane sulfonic acid
  • the present invention provides a methane sulfonic acid (MSA) salt (,V)-5-benzyl-/V-(5-methyl-4-oxo-2.3.4.5-tetrahydrobenzo
  • the present invention provides a methane sulfonic acid (MSA) salt (,V)-5-benzyl-/V-(5-methyl-4-oxo-2.3.4.5-tetrahydrobenzo
  • MSA methane sulfonic acid
  • the present invention provides a methane sulfonic acid (MSA) salt (,V)-5-benzyl-/V-(5-methyl-4-oxo-2.3.4.5-tetrahydrobenzo
  • MSA methane sulfonic acid
  • the salt of Compound A is preferably a pharmaceutically acceptable salt. Accordingly, Compound B is a pharmaceutically acceptable salt of Compound A. Furthermore, the crystalline form of Compound A is preferably a pharmaceutically acceptable crystalline form. Accordingly, Compound B is a pharmaceutically acceptable crystalline form of Compound A.
  • a ⁇ NMR spectrum will be understood to comprise a peak (expressed in ppm) of “about” a value specified herein when the ⁇ NMR spectrum comprises a peak within ⁇
  • a ⁇ NMR spectrum that is“substantially as shown in Fig. 1 and/or Fig. 3” provided herein is a ⁇ NMR spectrum that would be considered by one skilled in the art to represent a compound possessing the same crystal form as the compound that provided the ⁇ NMR spectrum with that of the Figures provided herein. That is, the ⁇ NMR spectrum may be identical to that with that of the Figures provided herein, or more likely it may be somewhat different.
  • Such a ⁇ NMR spectrum may not necessarily show each of the peaks of any one of the spectra presented herein, and/or may show a slight change in appearance, intensity, or a shift in position of said peaks resulting from differences in the conditions involved in obtaining the data.
  • a person skilled in the art is capable of determining if a sample of a crystalline compound has the same form as, or a different form from, a form disclosed herein by comparison of their ⁇ NMR spectra.
  • oxazepin-3-yl)-4//- 1.2.4-triazole-3-carboxamide Compound B
  • Fig. 1 and/or Fig. 3 and using expertise and knowledge in the art, readily determine whether the ⁇ NMR spectrum of the sample is substantially as shown in Fig. 1 and/or Fig 3.
  • An XRPD pattern will be understood to comprise a diffraction angle (expressed in degrees 2Q) of“about” a value specified herein when the XRPD pattern comprises a diffraction angle within ⁇ 0.2 degrees 2Q of the specified value. Further, it is well known and understood to those skilled in the art that the apparatus employed, humidity, temperature, orientation of the powder crystals, and other parameters involved in obtaining an XRPD pattern may cause some variability in the appearance, intensities, and positions of the lines in the diffraction pattern.
  • An X-ray powder diffraction pattern that is “substantially in accordance” with that of the Figures provided herein is an XRPD pattern that would be considered by one skilled in the art to represent a compound possessing the same crystal form as the compound that provided the XRPD pattern of the Figures.
  • the XRPD pattern may be identical to that of Figure 4, or more likely it may be somewhat different.
  • Such an XRPD pattern may not necessarily show each of the lines of the diffraction patterns presented herein, and/or may show a slight change in appearance, intensity, or a shift in position of said lines resulting from differences in the conditions involved in obtaining the data.
  • a person skilled in the art is capable of determining if a sample of a crystalline compound has the same form as, or a different form from, a form disclosed herein by comparison of their XRPD patterns.
  • one skilled in the art can overlay an XRPD pattern of a sample of a methane sulfonic acid (MSA) salt of (.V)- 5-benzyl-/V-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo
  • MSA methane sulfonic acid
  • XRPD pattern of the sample is substantially in accordance with the XRPD patern of Compound B. If the XRPD patern is substantially in accordance with Fig. 4, the sample form can be readily and accurately identified as having the same crystal form as Compound B. Similarly, a person skilled in the art is capable of determining if a given diffraction angle (expressed in °20) obtained from an XRPD patern is at about the same position as a recited value.
  • a methane sulfonic acid (MSA) salt of (,Y)-5-benzyl-/V-(5-methyl-4-oxo-2. 3,4,5-tetrahydrobenzo[6][l,4]oxazepin-3-yl)-4i7-l,2,4-triazole-3-carboxamide may be characterized by a combination of the analytical data characterising each and all of the aforementioned embodiments.
  • oxazepin-3-yl)-4//- 1.2.4-triazole-3-carboxamide (Compound B) in crystalline form is characterised by an a 3 ⁇ 4 NMR spectrum substantially as shown in Fig.
  • 2,4- triazole-3 -carboxamide (Compound B) in crystalline solid state form is characterised by an X-ray powder diffraction (XRPD) patern comprising diffraction angles, expressed in degrees 2Q, at about 5.2, 8.9, 10.4, 12.7, 14.5, 15.4, 15.7, 16.6, 17.8, 18.1, 19.2, 19.7, 20.9, 20.4, 21.8, 22, 22.4, 23, 23.4, 24.2, 25, 25.2, 25.5, 26.9, 27.4, 28.3, 28.6, 29.6, 32.5, 33.6, 34.6, 34.9 and 35.9 degrees 20 ( ⁇ 0.2°) and a ⁇ NMR spectrum substantially as shown in Fig. 1 and/or Fig 3.
  • XRPD X-ray powder diffraction
  • the term“compound(s) of the invention” means the methane sulfonic acid (MSA) salt of (,Y)-5-benzyl-/V-(5-methyl-4-oxo-2.3.4.5- tetrahydrobenzo[6][l,4]oxazepin-3-yl)-477-l,2,4-triazole-3-carboxamide (Compound B), and in some embodiments, specifically the crystalline form of Compound B as characterized by the 1H NMR spectrum substantially in accordance with Fig. l and/or Fig.
  • MSA methane sulfonic acid
  • the compounds of this invention may be particularly useful for the treatment of RIP1 kinase-mediated diseases or disorders.
  • 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.
  • 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 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),
  • 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 or IKKG
  • NEMO-deficiency syndrome NEMO-deficiency syndrome
  • HOIL-l deficiency also known as RBCK1
  • IRP2 ubiquitin ligase-l deficiency heme-oxidized IRP2 ubiquitin ligase-l deficiency
  • LUBAC linear ubiquitin chain assembly complex
  • 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, galactosiabdosis, GM
  • the compounds of the invention may be particularly useful for the treatment of the following RIP 1 kinase- mediated diseases or disorders: 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, systemic onset juvenile idiopathic arthritis (SoJIA), psoriatic arthritis), lupus, systemic lupus
  • erythematosus SLE
  • Sjogren Sjogren
  • systemic scleroderma anti-phospholipid syndrome
  • APS anti-phospholipid syndrome
  • 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-alcholic steatohepatitis (NASH), alcoholic 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, 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
  • the compounds of the invention may be particularly useful for the treatment of the following RIP 1 kinase- mediated diseases or disorders, that is, diseases/disorders which are likely to be regulated at least in part by RIP1 kinase activity, particularly inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), asthma, cigarette smoke-induced damage, cystic fibrosis, psoriasis, retinal detachment, retinal degeneration, retinitis pigmentosa, macular degeneration, atopic dermatitis, bum injury, periodontitis, a bacterial or viral infection (an infection with a pathogen including but not limited to influenza, staphylococcus, and/or mycobacterium (tuberculosis), systemic scleroderma (particularly, topical treatment of hardened and/or tightened skin areas), and
  • the compounds of the invention may be useful for the treatment of glaucoma.
  • the compounds of the invention may be particularly useful for treatment of pancreatic ductal
  • adenocarcinoma hepatocellular carcinoma, mesothelioma, or melanoma.
  • the compounds of the invention may be particularly useful for the treatment of the following RIP 1 kinase- mediated disease or disorder: rheumatoid arthritis, inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), and psoriasis.
  • 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 of 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 of 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 of 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 of this invention may be particularly useful for amelioration of solid organ tissue
  • tissue damage may be achieved where possible, by pre-treatment with particularly Compound B, or Compound B in crystalline form; 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 particularly Compound B, or Compound B in crystalline form, during transplant surgery.
  • Amelioration of such tissue damage may also be achieved by short-term treatment of a patient with Compound B, or Compound B in crystalline form, after transplant surgery.
  • the compounds of the invention may be useful for the treatment of retinal detachment, macular degeneration, and retinitis pigmentosa.
  • the compounds of the invention may be useful for the treatment of multiple sclerosis.
  • the compounds of the invention may be useful for the treatment of traumatic brain injury.
  • the compounds of the invention, particularly Compound B, or Compound B in crystalline form may be useful for the treatment of Huntington's Disease, Alzheimer's Disease, amyotrophic lateral sclerosis, and Niemann-Pick disease.
  • the compounds of the invention may be useful for the treatment of amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), and Alzheimer’s disease.
  • ALS amyotrophic lateral sclerosis
  • PSP progressive supranuclear palsy
  • Alzheimer’s disease amyotrophic lateral sclerosis
  • the compounds of the invention may be useful for the treatment of age-related macular degeneration.
  • the treatment of retinal detachment, macular degeneration, retinitis pigmentosa, multiple sclerosis, traumatic brain injury, Huntington's Disease, Alzheimer's Disease, amyotrophic lateral sclerosis, and Niemann-Pick disease may concern, more specifically, the amelioration of organ injury or damage sustained as a result of these
  • the compounds of this invention may be particularly useful for amelioration of brain tissue injury or damage following traumatic brain injury, or for amelioration of brain tissue injury or damage associated of Huntington's Disease, Alzheimer's Disease, amyotrophic lateral sclerosis, and Niemann-Pick disease.
  • the compounds of the invention may be useful for the treatment of retinal detachment, macular degeneration, and retinitis pigmentosa, and the amelioration of brain tissue injury or damage as a result of multiple sclerosis, traumatic brain injury, Huntington's Disease, Alzheimer's Disease, amyotrophic lateral sclerosis, and Niemann-Pick disease.
  • the compounds of the invention may be useful for the treatment of Crohn’s disease, ulcerative colitis, psoriasis, rheumatoid arthritis, spondyloarthritis, systemic onset juvenile idiopathic arthritis (SoJIA), and osteoarthritis.
  • Compound B may be useful for the treatment of psoriasis, rheumatoid arthritis, and ulcerative and colitis.
  • the compounds of this invention may be useful for the treatment of lupus, inflammatory bowel disease (IBD), Crohn’s disease, and ulcerative colitis.
  • the compounds of the invention, particularly Compound B, or Compound B in crystalline form may be useful for the treatment of cerebrovascular accident (CVA, stroke), Huntington’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), traumatic brain injury, multiple sclerosis, Gaucher disease, Niemann-Pick disease, and spinal cord injury.
  • CVA cerebrovascular accident
  • ALS amyotrophic lateral sclerosis
  • the compounds of the invention may be useful for the treatment of amyotrophic lateral sclerosis (ALS).
  • ALS amyotrophic lateral sclerosis
  • the compounds of the invention may be useful for the treatment of multiple sclerosis.
  • the compounds of the invention may be useful for the treatment of pancreatic ductal adenocarcinoma (PDAC), metastasis, melanoma, breast cancer, non-small cell lung carcinoma (NSCLC), and radiation induced necrosis.
  • PDAC pancreatic ductal adenocarcinoma
  • NSCLC non-small cell lung carcinoma
  • the compounds of the invention may be useful for the treatment of pancreatic ductal adenocarcinoma (PDAC), metastasis, melanoma, breast cancer, and non-small cell lung carcinoma (NSCLC).
  • PDAC pancreatic ductal adenocarcinoma
  • NSCLC non-small cell lung carcinoma
  • the compounds of the invention may be useful for the treatment of pancreatic ductal adenocarcinoma (PDAC).
  • PDAC pancreatic ductal adenocarcinoma
  • the compounds of the invention may be useful for the treatment of intracerebral hemorrhage and subarachnoid hemorrhage.
  • the compounds of the invention may be useful for the treatment of type II diabetes and obesity.
  • the compounds of the invention may be useful for the treatment of atherosclerosis.
  • the compounds of the invention may be useful for the treatment of vasculitis.
  • the compounds of the invention may be useful for the treatment of bums.
  • the compounds of the invention, particularly Compound B, or Compound B in crystalline form may be useful for the treatment of ischemic kidney damage, ophthalmologic ischemia, intracerebral hemorrhage, and subarachnoid hemorrhage.
  • the compounds of the invention may be useful for the treatment of non-alcholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), autoimmune hepatitis, and non alcoholic fatty liver disease (NAFLD).
  • NASH non-alcholic steatohepatitis
  • ASH alcoholic steatohepatitis
  • NAFLD non alcoholic fatty liver disease
  • the compounds of the invention may be particularly useful for the treatment of the following RIP 1 kinase- mediated diseases or disorders.
  • the human has a solid tumor.
  • the tumor is selected from head and neck cancer, gastric cancer, melanoma, renal cell carcinoma (RCC), esophageal cancer, non-small cell lung carcinoma (NSCLC), prostate cancer, colorectal cancer, ovarian cancer, pancreatic cancer, and pancreatic ductal adenocarcinoma.
  • 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.
  • CRC colorectal cancer
  • RNC renal cell carcinoma
  • EC squamous cell carcinoma non small cell lung carcinoma
  • mesothelioma prostate cancer
  • pancreatic ductal adenocarcinoma adenocarcinoma
  • 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.
  • DLBCL diffuse large B cell lymphom
  • 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.
  • 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 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
  • 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.
  • myelodysplasia or myelodysplastic syndrome or MDS
  • MDS myelodysplasia
  • RA refractory anemia
  • RAEB refractory anemia with excess blasts
  • RAEBT refractory anemia with excess blasts in transformation
  • MFS myelofibrosis
  • 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).
  • High-grade B-NHLs include Burkitt’s lymphoma (BL), Burkitt-like lymphoma, small non-cleaved cell lymphoma (SNCCL) and lymphoblastic lymphoma.
  • 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 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.
  • 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 RIP 1 kinase comprising contacting said kinase with a compound of the invention.
  • this invention is directed to a method of inhibiting RIP1 kinase comprising contacting a cell with a compound of the 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 RIP1 kinase to a human in need thereof.
  • the invention is directed to 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 of the invention, to a human in need thereof.
  • the invention is directed to a method of treating a RIP1 kinase-mediated disease or disorder (specifically, a disease or disorder recited herein) comprising administering a
  • MSA methane sulfonic acid
  • 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 a methane sulfonic acid (MSA) salt of (,Y)-5-benzyl-/V-(5-methyl-4-oxo-2.3.4.5- tetrahydrobenzo [6] [ 1 ,4]oxazepin-3 -y ⁇ )- H- 1 ,2,4-triazole-3 -carboxamide in crystalline form, to a human in need thereof.
  • MSA methane sulfonic acid
  • the invention is directed to a method of treating Crohn’s disease, ulcerative colitis, psoriasis, rheumatoid arthritis, spondyloarthritis, psoriatic arthritis and/or bum injuries comprising administering a therapeutically effective amount of a methane sulfonic acid (MSA) salt of (ri)-5-benzyl-/V-(5-methyl-4-oxo-2, 3,4,5 - tetrahydrobenzo [6] [ 1 ,4]oxazepin-3 -y ⁇ )- H- 1 ,2,4-triazole-3 -carboxamide in crystalline form, to a human in need thereof.
  • MSA methane sulfonic acid
  • the invention is directed to a method of treating ulcerative colitis comprising administering a therapeutically effective amount of a methane sulfonic acid (MSA) salt of ( ⁇ S)-5-benzyl-/V-(5-methyl-4-oxo-2, 3,4,5- tetrahydrobenzo [6] [ 1 ,4]oxazepin-3 -y ⁇ )- H- 1 ,2,4-triazole-3 -carboxamide in crystalline form, to a human in need thereof.
  • MSA methane sulfonic acid
  • the invention is directed to a method of treating psoriasis comprising administering a therapeutically effective amount of a methane sulfonic acid (MSA) salt of (ri)-5-benzyl-A-(5 -methyl -4-oxo-2, 3,4,5 - tetrahydrobenzo [6] [ 1 ,4]oxazepin-3 -y ⁇ )- H- 1 ,2,4-triazole-3 -carboxamide in crystalline form, to a human in need thereof.
  • MSA methane sulfonic acid
  • the invention is directed to a method of treating rheumatoid arthritis comprising administering a therapeutically effective amount of a methane sulfonic acid (MSA) salt of ( ⁇ S)-5-benzyl-/V-(5-methyl-4-oxo-2, 3,4,5 - tetrahydrobenzo [6] [ 1 ,4]oxazepin-3 -y ⁇ )- H- 1 ,2,4-triazole-3 -carboxamide in crystalline form, to a human in need thereof.
  • MSA methane sulfonic acid
  • this invention provides a compound that inhibits RIP1 kinase for use in therapy.
  • This invention also provides a compound of the invention, for use in therapy. More specifically, this invention provides a methane sulfonic acid (MSA) salt of (.V)-5-benzyl-/V-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo
  • MSA methane sulfonic acid
  • this invention provides a methane sulfonic acid (MSA) salt of (ri)-5-benzyl-A-(5-methyl-4-oxo-2, 3,4,5- tetrahydrobenzo [6] [ 1 ,4]oxazepin-3 -y ⁇ )- H- 1 ,2,4-triazole-3 -carboxamide in crystalline form for use in therapy.
  • MSA methane sulfonic acid
  • this invention provides a compound that inhibits RIP 1 kinase for use in the treatment of a RIP1 kinase-mediated disease or disorder (for example, a disease or disorder recited herein).
  • This invention particularly provides a compound of the invention for use in the treatment of a RIP 1 kinase-mediated disease or disorder (for example, a disease or disorder recited herein).
  • this invention provides a methane sulfonic acid (MSA) salt of ( ⁇ S)-5 -benzyl-/V-(5-methyl-4-oxo-2, 3,4,5 - tetrahydrobenzo
  • MSA methane sulfonic acid
  • this invention provides a methane sulfonic acid (MSA) salt of (,V)-5-benzyl-/V-(5-methyl-4-oxo-2.3.4.5-tetrahydrobenzo
  • MSA methane sulfonic acid
  • this invention provides a methane sulfonic acid (MSA) salt of (.V)-5-benzyl-/V-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo
  • this invention provides a methane sulfonic acid (MSA) salt of (.V)-5-benzyl-/V-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo
  • MSA methane sulfonic acid
  • this invention provides a methane sulfonic acid (MSA) salt of (.V)-5-benzyl-/V-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo
  • this invention provides a methane sulfonic acid (MSA) salt of (.V)-5-benzyl-/V-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo
  • 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 the invention, 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 (for example, a disease or disorder recited herein).
  • this invention provides for the use of a methane sulfonic acid (MSA) salt of(.S)-5-benzyl-/V-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo
  • MSA methane sulfonic acid
  • this invention provides for the use of a methane sulfonic acid (MSA) salt of(,Y)-5-benzyl-/V-(5-methyl-4-oxo-2.3.4.5- tetrahydrobenzo
  • MSA methane sulfonic acid
  • 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 RIP1 kinase-mediated disease or disorder (for example, a disease or disorder recited herein).
  • the invention further provides for the use of a compound of the inventionin the manufacture of a medicament for the treatment of a RIP1 kinase-mediated disease or disorder (for example, a disease or disorder recited herein).
  • the invention provides for the use of a methane sulfonic acid (MSA) salt of (,S)-5-benzyl-/V-(5-methyl-4-oxo-2.3.4.5- tctrahydrobcnzo
  • MSA methane sulfonic acid
  • the invention provides for the use of a methane sulfonic acid (MSA) salt of (,Y)-5-benzyl-/V-(5- mcthyl-4-oxo-2.3.4.5-tctrahydrobcnzo
  • MSA methane sulfonic acid
  • this invention provides Compound B, or Compound B in crystalline form, for use in the treatment of inflammatory bowel disease. In another embodiment, this invention provides Compound B, or Compound B in crystalline form, for use in the treatment of Crohn's disease. In another embodiment, this invention provides Compound B, or Compound B in crystalline form, for use in the treatment of ulcerative colitis. In another embodiment, this invention provides Compound B, or Compound B in crystalline form, for use in the treatment of psoriasis. In another embodiment, this invention provides Compound B, or Compound B in crystalline form for use in the treatment of retinal detachment. In another embodiment, this invention provides
  • this invention provides Compound B, or Compound B in crystalline form, for use in the treatment of retinitis pigmentosa.
  • this invention provides Compound B, or Compound B in crystalline form, for use in the treatment of arthritis.
  • this invention provides a compound Compound B, or Compound B in crystalline form, for use in the treatment of rheumatoid arthritis.
  • this invention provides Compound B, or Compound B in crystalline form for use in the treatment of
  • this invention provides Compound B, or Compound B in crystalline form, for use in the treatment of gout. In another embodiment, this invention provides Compound B, or Compound B in crystalline form, for use in the treatment of systemic onset juvenile idiopathic arthritis. In another embodiment, this invention provides Compound B, or Compound B in crystalline form for use in the treatment of transplant rejection. In another embodiment, this invention provides
  • Compound B or Compound B in crystalline form for use in the treatment of ischemia reperfusion injury of solid organs.
  • Compound B, or Compound B in crystalline form may be employed alone or in combination with other therapeutic agents.
  • Combination therapies thus comprise the administration Compound B, or Compound B in crystalline form, and at least one other therapeutically active agent.
  • Compound B, or Compound B in crystalline form, and the other therapeutically active agent(s) may be administered together in a single
  • the amounts of Compound B, or Compound B in crystalline form, and the other therapeutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • a combination comprising a Compound B, or Compound B in crystalline form, together with one or more other therapeutically active agents.
  • a combination comprising Compound B in crystalline form as characterized by the ⁇ NMR spectrum substantially in accordance with Fig.1 and/or Fig. 3, together with one or more other therapeutically active agents.
  • a combination comprising Compound B in crystalline form as characterized by the DSC trace substantially in accordance with Fig. 2, together with one or more other therapeutically active agents.
  • a combination comprising Compound B in crystalline form as characterized by the diffraction data substantially in accordance with Table 1 together with one or more other therapeutically active agents.
  • a combination comprising Compound B in crystalline form as characterized by the XRPD pattern substantially in accordance with Fig.4, together with one or more other therapeutically active agents.
  • Compound B, or Compound B in crystalline form, or a pharmaceutical composition comprising Compound B, or Compound B in crystalline form may be used in combination with or include one or more other therapeutic agents, for example an anti-inflammatory agent and/or an anti-TNF agent.
  • Treatment of RIP 1 -mediated disease conditions may be achieved using a compound of the invention, particularly Compound B, or Compound B in crystalline form, as a monotherapy, or in dual or multiple combination therapy, particularly for the treatment of refractory cases, such as in combination with other anti-inflammatory and/or anti-TNF agents, which may be administered in therapeutically effective amounts as is known in the art.
  • Combination therapies according to the present invention thus comprise the administration of at least one compound of the invention, particularly Compound B, or Compound B in crystalline form, and at least one other theraputically active agent.
  • amelioration of tissue damage may be achieved by treatment with particularly Compound B, or Compound B in crystalline form, and at least one other therapeutically active agent during transplant surgery.
  • Amelioration of tissue damage may also be achieved by short-term treatment of a patient with particularly Compound B, or Compound B in crystalline form, and at least one other therapeutic ally active agent after transplant surgery.
  • Amelioration of tissue damage ex vivo that is ex vivo preservation of tissues, organs and cells may also be achieved by short-term treatment of tissues, organs and cells with particularly Compound B, or Compound B in crystalline form, and at least one other therapeutic ally active agent, prior to or during transplant surgery.
  • a compound that inhibits RIP1 kinase, particularly Compound B, or Compound B in crystalline form, may be administered in combination with other anti-inflammatory agents for any of the indications above, including oral or topical corticosteroids, anti-TNF agents, 5-aminosalicyclic acid and mesalamine preparations, hydroxy cloroquine, thiopurines, methotrexate, cyclophosphamide, cyclosporine, calcineurin inhibitors, mycophenolic acid, mTOR inhibitors, JAK inhibitors, Syk inhibitors, anti-inflammatory biologic agents, including anti-IL6 biologies, anti-ILl agents, anti-ILl7 biologies, anti- CD22, anti-integrin agents, anti-IFNa, anti-CD20 or CD4 biologies and other cytokine inhibitors or biologies to T-cell or B-cell receptors or interleukins.
  • anti-inflammatory agents including anti-IL6 biologies, anti-ILl
  • antiplatelets e.g., aspirin, clopidogrel (Plavix®), dipyridamole (Persantine®), ticolpidine (Ticlid®); aspirin and omeprazole (Y sprala®), anticoagulants (e.g., warfarin (Coumadin®), heparin®, dabigitran (Pradaxa®), apixaban (Eliquis®), rivaroxaban®), antihypertensives - diruetics (e.g., Hygroton®, Diuril®, Lasix®, Esidrix®, Hydrodiuril®, Microzide®, Lozol®, Mykrox®, Zaroxolyn®, Midarmar®, Aldactone®, Dyrenium®, Bumex®, Moduretic®, Aldatazide®, Dyazide
  • antiplatelets e.g., aspirin, clopidogrel (Plavix
  • a compound that inhibits RIP 1 kinase may be administered in combination with a broad-spectrum antibiotic (such as vacomycin) or other anti-MRSA therapy (cefeprime (Maxipime®), piperacillin/tazobactam(Zosyn®), carbapenem (imipenem, meropenem, doripenem), quinolones (ciprofloxacin, levofloxacin, ofloxacin, moxifloxacin, etc.), or low dose steroids such as hydrocortisones.
  • a broad-spectrum antibiotic such as vacomycin
  • other anti-MRSA therapy cefeprime (Maxipime®)
  • piperacillin/tazobactam(Zosyn®) piperacillin/tazobactam(Zosyn®)
  • carbapenem imipenem, meropenem, doripenem
  • quinolones ciprofloxacin, levofloxacin, oflox
  • a compound that inhibits RIP1 kinase particularly Compound B, or Compound B in crystalline form, may be administered in combination with
  • vedolizumab Entyvio®
  • alicaforsen alicaforsen
  • remestemcel-L Prochymal®
  • etrobzumab eldelumab
  • bertilimumab vedolizumab
  • a compound that inhibits RIP1 kinase may be administered in combination with ixekizumab, tildrakizumab (MK-3222), secukinumab (AIN457), Alefacept
  • a compound that inhibits RIP1 kinase may be administered in combination with an antimicrobial agent, (such as chlorhexidine (Peridex®, PerioChip®, PerioGard®, etc.)) or an antibiotic (such as doxycycline (Vibrox®, Periostat®, Monodox®, Oracea®, Doryx®, etc.), or minocycline (Dynacin®, Minocin®, Arestin®, Dynacin®, etc.).
  • an antimicrobial agent such as chlorhexidine (Peridex®, PerioChip®, PerioGard®, etc.)
  • an antibiotic such as doxycycline (Vibrox®, Periostat®, Monodox®, Oracea®, Doryx®, etc.), or minocycline (Dynacin®, Minocin®, Arestin®, Dynacin®, etc.).
  • a compound that inhibits RIP1 kinase may be administered in combination with an inhaled corticosteroid (ICS) such as fluticasone proprionate (Flovent®), fluticasone furoate (Veramyst®/Avamys®), beclomethasone dipropionate (QVAR®), budesonide (Pulmicort), trimcinolone acetonide (Azmacort®), flunisolide (Aerobid®), mometasone fuorate (Asmanex® Twisthaler®), or Ciclesonide (Alvesco®), a long acting beta agonist (LABA) such as formoterol fumarate (Foradil®), salmeterol xinafoate (Serevent®), indacaterol (Arcapta®Neohaler®); a combination of an ICS and LABA (such as fluticasone proprionate (Flovent®), fluticasone furoate (Vera
  • masitinib protein tyrosine kinase inhibitor
  • AMG 853 CRTH2/D-prostanoid receptor antangonist
  • E004 epinephrine inhalation aerosol
  • reslizumab reslizumab
  • PDE combination phosphodiesterase
  • PDE PDE-3 and (PDE)-4 inhibitor
  • a compound that inhibits RIP1 kinase may be administered in combination with a LABA (such as salmeterol xinafoate (Serevent), aformoterol tartrate (Brovana®), formoterol fumarate inhalation powder (Foradil®), indacterol maleate (Arcapta®
  • a LABA such as salmeterol xinafoate (Serevent), aformoterol tartrate (Brovana®), formoterol fumarate inhalation powder (Foradil®), indacterol maleate (Arcapta®
  • Neohaler® a long-acting inhaled anticholinergic (or muscarinic antagonist, such as umeclidinium (Incruse Ellipta®), tiotropium bromide (Spiriva®), and aclidinium bromide (Tudorza® Pressair®), a phosphodiesterase (PDE-r) inhibitor (such as roflumilast, Daliresp®), a combination ICS/LABA (such as fluticasone furoate and vilanterol (Breo Ellipta®/Relvar Ellipta®), fluticasone propionate/salmeterol (Advair®),
  • a phosphodiesterase (PDE-r) inhibitor such as roflumilast, Daliresp®
  • PDE-r phosphodiesterase
  • combination ICS/LABA such as fluticasone furoate and vilanterol (Breo Ellipta®/Relvar Ellipta®), fluticas
  • budesonide/formoterol (Symbicort®), mometasone/formoterol (Dulera®), or fluticasone propionate/eformoterol fumarate dehydrate (Flutiform®); an antimuscarinic such as such as ipratropium bromide (Atrovent®); an antimuscarinic in combination with a beta-agonist such as ipratropium bromide/albuterol (Combivent® Respimat®); a long-acting antimuscarinic such as umeclidinium bromide (Incruse®) or tiotropium bromide
  • SCH527123 a CXCR2 antagonist
  • NVA23-7 glycoprronium bromide
  • NVA149 glycoprronium bromide and indacaterol maleate
  • QVA149 Ultibro® Breezhaler®
  • a compound that inhibits RIP1 kinase may be administered in combination with an antimycobacterial agent (such as isoniazid (INH), ehambutol (Myambutol®), rifampin (Rifadin®), and pyrazinamide (PZA)) a bactericidal antibiotic (such as rifabutin (Mycobutin®) or rifapentine (Priftin®)), an aminoglycoside (Capreomycin®), a fluorquinolone (levofloxacin, moxifloxicin, ofloxacin), thioamide (ehionamide), cyclosporine (Sandimmune®), para-aminosalicyclic acid
  • an antimycobacterial agent such as isoniazid (INH), ehambutol (Myambutol®), rifampin (Rifadin®), and pyrazinamide (PZA)
  • a bactericidal antibiotic such as rifabut
  • a compound that inhibits RIP1 kinase may be administered in combination with an oral corticosteroid (such as prednisolone (Delatsone®, Orapred, Millipred, Omnipred, Econopred, Flo-Pred), an immunosuppressive agent (such as methotrexate (Rhuematrex®, Trexall®), cyclosporine (Sandimmune®), anti-thymocyte globulin (Atgam®), mycophenolate mofetil (CellCept®), cyclophosphamide (Cytoxan®), FK506 (tacrolimus), thalidomide (Thalomid®), chlorambucil (Feukeran®), azathioprine (Imuran®, Azasan®)), a calcium channel blocker (such as nifedip), a prednisolone (Delatsone®, Orapred, Millipred,
  • a compound that inhibits RIP1 kinase may be administered in combination with a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator (ivacftor (Kalydeco®)) a mucolytic agent (such as domase alpha
  • pancreatic enzymes such as Pancrelipase (Creon®, Pancreaze®, Ultresa®, Zenpep®)
  • a bronchodilator such as albuterol (AccuNeb®, ProAir®, Proventil HFA®, VoSpire ER®, Ventolin HFA®)
  • an antibiotic including inhaled, oral or parenteral, such as tobramycin solution for inhalation (TOBI®, Bethkis®, TOBI
  • Podhaler® aztreonam inhalation (Azactam®, Cayston®), colistimethate sodium (Coly- Mycin®), cephalosporins (cefadroxil monohydrate (Duricef®), cefazolin (Kefzol®), cephalexin (Keflex®), cefazolin (Ancef®, etc.), fluoroquinolones (moxifloxacin, levofloxacin, gemifloxacin, etc.), azithromycin (Zithromax®), gentamicin (Garamycin®), piperacillin/tazobacam (Zosyn®), cephalexin (Keflex), ceftazidime (Fortaz, Tazicef), ciprofloxin (Cipro XR, Proquin XR), trimethoprim/sulfamethoxazolyl (Bactrim DS, Septra DS), chloramphenicol)), or
  • a compound that inhibits RIP 1 kinase may be administered in combination with a ciliary neurtotrophic growth factor (NT-50 l-CNTF) or gene transfer agent, UshStat®.
  • NT-50 l-CNTF ciliary neurtotrophic growth factor
  • UshStat® ciliary neurtotrophic growth factor
  • a compound that inhibits RIP 1 kinase may be administered in combination with opthalmalic intravitreal injections (afibercept (Eylea®)) or with an anti- vascular endothelial growth factor (VEGF) inhibitor (such as ranibizumab (Lucentis®) or pegaptanib sodium (Macugen®)), a ciliary neurotrophic growth factor agent (NT501), iSONEP®, or bevacizumab (Avastin®).
  • VEGF vascular endothelial growth factor
  • a compound that inhibits RIP1 kinase may be administered in combination with a trivalent (IIV3) inactivated influenza vaccine (such as Afluria®, Fluarix®, Flucelvax®, FluLaval®, Fluvirin®, Fluzone®), a quadrivalent (IIV4) inactivated influenza vaccine (such as Fluarix® Quadrivalent, Flulaval® Quadrivalent, Fluzone® Quadrivalent), a trivalent recombinant influenza vaccine (such as FluBlok®), a quadrivalent live attenuated influenza vaccine (such as FluMist® Quadrivalent), an antiviral agent (such as oseltamivir (Tamiflu®), zanamivir (Relenza®), rimantadine (Flumadine®), or amantadine (Symmetrel®)), or Fluad®, Fludase, FluNhance®, Preflucel, or
  • a compound that inhibits RIP1 kinase particularly Compound B, or Compound B in crystalline form, may be
  • antibiotic such as a b-Lactam cephalosporin
  • sulfamethoxazolyl and trimethoprim (Bacrim®, Septra®,) sulfasalazine (Azulfidine®), acetyl sulfisoxazolyl (Gantrisin®, etc.), or vancomycin (Vancocin®)).
  • a compound that inhibits RIP1 kinase may be administered in combination with a high-dose corticosteroid (such as prednisone (Deltasone®), methylprednisolone (SoluMedrol®) etc.) a calcineurin inhibitor (such as cyclosporine (Sandimmune®, Neoral®, Gengraf®), tacrolimus (Prograf®, Astragraf XL®)), an mTor inhibitor (such as sirolimus (Rapamune®) or everolimus (Afmitor®)), an anti-proliferative agent (such as azathioprine (Imuran®, Azasan®), mycophenolate mofetil (CellCept®), or mycophenolate sodium (Myfortic®)), a monoclonal antibody (such as muromonab-CD3 (Orthoclone OKT3®)
  • a corticosteroid such as prednisone (Delta
  • a compound that inhibits RIP 1 kinase may be administered in combination with a topical immunomodulator or calcineurin inhibitor (such as
  • a topical corticosteroid such as hydrocortizone (Synacort®, Westcort®), betamethasone (Diprolene®), flurandrenolide (Cordan®), fluticasone (Cutivate®), triamcinolone (Kenalog®), fluocinonide (Lidex®), and clobetasol (Temovate®)
  • an oral corticosteroid such as hydrocortisone (Cortef®), methylprednisolone (Medrol®), or prednisolone (Pediapred®, Prelone®), an oral corticosteroid (such as hydrocortisone (Cortef®), methylprednisolone (Medrol®), or prednisolone (Pediapred®, Prelone®), an
  • immunosuppressant such as cyclosporine (Neoral®) or interferon gamma (Alferon N®, Infergen®, Intron A, Roferon-A®)
  • an antihistamine for itching such as Atarax®, Vistaril®, Benadryl®
  • an antibiotic such as penicillin derivatives flucloxacillin
  • Floxapen® or dicloxacillin (Dynapen®), erythromycin (Eryc®, T-Stat®, Erythra- Derm®, etc.)), anon-steroidal immunosuppressive agent (such as azathioprine (Imuran®, Azasan®), methotrexate (Rhuematrex®, Trexall®), cyclosporin (Sandimmune®), or mycophenolate mofetil (CellCept®)).
  • anon-steroidal immunosuppressive agent such as azathioprine (Imuran®, Azasan®), methotrexate (Rhuematrex®, Trexall®), cyclosporin (Sandimmune®), or mycophenolate mofetil (CellCept®)
  • a compound that inhibits RIP 1 kinase may be administered in combination with NSAIDs, DMARDs such as Sulfasalazine®, Methotrexate®, and corticosteroids; prednisolone delayed-release tablets (Rayos®), TNF inhibitors (Enbrel®, Remicade®, Humira® and Simponi®), or IL-17A (Cosentyx®).
  • NSAIDs such as Sulfasalazine®, Methotrexate®, and corticosteroids
  • prednisolone delayed-release tablets Rayos®
  • TNF inhibitors Enbrel®, Remicade®, Humira® and Simponi®
  • IL-17A Cosentyx®
  • a compound that inhibits RIP 1 kinase may be administered in combination with NSAIDs such as Celebrex®, diclofenac (Voltaran®), ibuprofen (Advil®, Motrin®), naproxen (Aleve, Naprosyn®), corticosteroids (prednisone, glucocorticoids), Methotrexate®, or biologies (ankinra (Kineret®), tocilizumab (Actemra®), canakinumab (ILARIS®)).
  • NSAIDs such as Celebrex®, diclofenac (Voltaran®), ibuprofen (Advil®, Motrin®), naproxen (Aleve, Naprosyn®), corticosteroids (prednisone, glucocorticoids), Methotrexate®, or biologies (ankinra (Kineret®), tocilizumab (Actemra®), canakinuma
  • a compound that inhibits RIP 1 kinase may be administered in combination with analgesics and NSAIDs (acetaminophen, opioid narcotics (e.g., tramadol®, Vicodin®, Darvon®, Percocet®); ibuprofen and famotidine (Duexis®);
  • analgesics and NSAIDs acetaminophen, opioid narcotics (e.g., tramadol®, Vicodin®, Darvon®, Percocet®); ibuprofen and famotidine (Duexis®);
  • a compound that inhibits RIP 1 kinase may be administered in combination with tetrabenazine (Xenazine®), antipsychotic drugs (haloperidol (Haldol®), chlorpromazine HCL (Thorazine®), risperidone (Risperdal®) and quetiapine (Seroquel®)), drugs to suppress chorea
  • Xenazine® tetrabenazine
  • antipsychotic drugs haloperidol (Haldol®), chlorpromazine HCL (Thorazine®), risperidone (Risperdal®) and quetiapine (Seroquel®)
  • a compound that inhibits RIP 1 kinase may be administered in combination with Donepzil hydrocholoride (Aricept®), Rivastigmine tartrate (Exelon®), caprylidene (Axona®), butoconazole nitrate 2% (Femstat 3®), Galantamine hydrobromide
  • a compound that inhibits RIP 1 kinase may be administered in combination with a glutamate blocker (Riluzole (Rilutek®)).
  • a compound that inhibits RIP 1 kinase may be administered in combination with quinidine (Nuedexta®), anticholinergics (amitriptyline®, Artane®, scopolamine patch (Transderm Scop®)), sympathomimetics (pseudoephedrine), mucolytics (guaifenesin), or analgesics (tramadol (Ultram®); ketorolac (Toradol®); morphine; fentanyl patch (Duragesic®)).
  • quinidine Nuedexta®
  • anticholinergics amitriptyline®, Artane®, scopolamine patch (Transderm Scop®)
  • sympathomimetics pseudoephedrine
  • mucolytics guaifenesin
  • analgesics tramadol (Ultram®); ketorolac (Toradol®); morphine; fentanyl
  • a compound that inhibits RIP 1 kinase may be administered in combination with corticosteroids (prednisone, methylprednisolone), Interferon Beta 1 -A (Avonex®, Extavia®, Rebif®, Betaseron®), peginterferon beta- 1 A (Plegridy®), Glatiramer acetate (Copaxone®); glatiramer acetate (Glatopa® - generic equivalent of Copaxone); Dimethyl fumarate (Tecfidera®); Fingolimod (Gilenya®); teriflunomide (Aubagio®); dalfampridine (Ampyra®); daclizumab (Zinbryta); alemtuzumab
  • a compound that inhibits RIP 1 kinase may be administered in combination with enzyme replacement therapy (imiglucerase (Cerezyme®), velaglucerase alfa (VPRIV®), taliglucerase alfa (Elelyso®)) or substrate reduction therapy (miglustat (Zavesca®), eliglustat (Cerdelga®)).
  • enzyme replacement therapy imiglucerase (Cerezyme®), velaglucerase alfa (VPRIV®), taliglucerase alfa (Elelyso®)
  • substrate reduction therapy miglustat (Zavesca®), eliglustat (Cerdelga®)
  • a compound that inhibits RIP 1 kinase may be administered in combination with bone marrow transplant, enzyme replacement therapy, gene therapy, miglustat (Zavesca®), Arimoclomol (BRX-345), NCT02612129, Hydroxypropyl-beta- cyclodexin (HPbCD), NCT01747135, or Hydroxypropyl- -cyclodextrin (VTS-2702) (NCT02534844).
  • a compound that inhibits RIP 1 kinase may be administered in combination with Tocilizumab (Actemra®), Arava, sulfasalazine delayed release tablets (Azulfidine EN-tabs®, Bextra, certolizumab pegol (Cimzia®), ibuprofen and famotidine (Duexis®), naproxen sodium (Etodolac®), adalimumab (Elumira®), Kineret; etodolac (Lodine®), naproxen sodium (Naprelan), abatacept (Orencia), prednisone (Rayos®), inflimimab (Remicade®), golimuma (Simponi®), rofecoxib (Vioxx®), tofacitinib (Xeljanz®), methot
  • a compound that inhibits RIP 1 kinase may be administered in combination with alicafosen, Mesalamine (Asacol®),
  • balsalazide disodium (Colazal®), vedolizumab (Entyvio®), golimumab (Simponi®), budesonide (Uceris®), adalimumab (Elumira®), RG-7413 (alpha4beta7 integrin), CNTO- 1275 (ustekinumab), biosimiar infliximab (Remsima (Inflectra®)), BMS eldelumab (CXCL 10), or Immune Pharma bertilimumab (CCR3).
  • a compound that inhibits RIP 1 kinase may be administered in combination with Remestemcel-L (Prochymal®), vedolizumab (Entyvio®), ustekinumab (Stelara®), certolizumab pegol (Cimzia®), natalizumab (Tysabri®), budesonide (Entocort EC®), anti-inflammatories (mesalamine (Lialda®, Apriso®, Canasa®, Asacol®, Rowasa®), sulfasalazine (Azulfidine®)), steroids (hydrocortisone, prednisone), immunosuppressants (methotrexate (Trexall®, Rasuvo®, Rheumatrex®), infliximab (Remicade®), azathioprine (Azasan®,
  • mercaptopurine Purinethol®, Purixan®
  • cyclosporine Genegraf®, Neoral®
  • tacrolimus Astagraf XL®, Hecoria®
  • antibiotics metalronidazole (Flagyl®, Metrogel®, Noritate®, MetroCream®, Rosadan®, MetroLotion®);
  • the at least one other therapeutically active agent is selected from a thrombolytic agent, a tissue plasminogen activator, an
  • the at least one other therapeutically active agent is selected from heparin, coumadin, clopidrogel, dipyridamole, ticlopidine HCL, eptifibatide, and aspirin.
  • the RIP1 kinase mediated disease or disorder treated with these agents is a cerebrovascular accident.
  • the at least one other therapeutically active agent is selected from broad-spectrum antibiotic, anti-MRSA therapy and a low dose steroid.
  • the at least one other therapeutically active agent is selected from vacomycin, cefeprime, a combination of piperacillin and tazobactam, imipenem, meropenem, doripenem, ciprofloxacin, levofloxacin, ofloxacin, moxifloxacin, and hydrocortisone.
  • the RIP1 kinase mediated disease or disorder treated with these agents is systemic inflammatory response syndrome.
  • the at least one other therapeutically active agent is alicaforse or remestemcel-L.
  • the RIP1 kinase mediated disease or disorder treated with these agents is Crohn’s disease or ulcerative colitis.
  • the at least one other therapeutically active agent is ixekizumab, or tildrakizumab.
  • the RIP1 kinase mediated disease or disorder treated with these agents is psoriasis.
  • the at least one other therapeutically active agent is an antimicrobial agent or an antibiotic. In another embodiment, the at least one other therapeutically active agent is selected from chlorhexidine, doxycycline and minocycline. In one embodiment, the RIP1 kinase mediated disease or disorder treated with these agents is periodonitis.
  • the at least one other therapeutically active agent is selected from an inhaled corticosteroid, a long acting beta agonist, a combination of an inhaled corticosteroid and a long acting beta agonist, a short acting beta agonist, a leukotriene modifier, an anti-IgE, a methylxanthine bronchodilator, a mast cell inhibitor, and a long-acting muscarinic antagonist.
  • the at least one other therapeutically active agent is selected from fluticasone proprionate, beclomethasone dipropionate, budesonide, trimcinolone acetonide, flunisolide, mometasone fuorate, or ciclesonide, formoterol fumarate, salmeterol xinafoate, a combination of fluticasone furoate and vilanterol, a combination of formoterol and budesonide inhalation, a combination of beclomethasone dipropionate and formoterol, a combination of fluticasone propionate and salmeterol, albuterol sulfate, levalbuterol tartrate, a combination of ipratropium bromide and albuterol, ipratropium bromide, montelukast sodium, zafirlukast, zileuton, omalizumab theophylline, cromulyn sodium, nedocromil sodium
  • the at least one other therapeutically active agent is selected from protein tyrosine kinase inhibitor, a CRTH2/D-prostanoid receptor antangonist, an epinephrine inhalation aerosol, and a combination of a phosphodiesterase -3 inhibitor and a
  • therapeutically active agent is selected from masitinib, AMG 853, indacaterol, E004, a combination of fluticasone furoate and fluticasone proprionate, a combination of vinanterol fluticasone furoate, a combination of fluticasone propionate and eformoterol fumarate dehydrate, reslizumab, salbutamol, tiotropium bromide, a combination of formoterol and budesonide, fluticasone furoate, VR506, lebrikizumab, and RPL554.
  • the RIP1 kinase mediated disease or disorder treated with these agents is asthma.
  • the at least one other therapeutically active agent is selected from a long acting beta agonist, a long-acting inhaled anticholinergic or muscarinic antagonist, a phosphodiesterase inhibitor, a combination an inhaled corticosteroid long acting beta agonist, a short acting beta agonist, and an inhaled corticosteroid.
  • the at least one other therapeutically active agent is selected from salmeterol xinafoate, a combination of umeclidinium and vilanterol, umeclidinium, aformoterol tartrate, formoterol fumarate, indacterol maleate, a combination of fluticasone propionate and eformoterol fumarate dehydrate, tiotropium bromide, aclidinium bromide, roflumilast, a combination of fluticasone furoate and vilanterol, a combination of fluticasone propionate and salmeterol, a combination of budesonide and formoterol, a combination of mometasone and formoterol, a combination of ipratropium bromide and albuterol sulfate, a combination of albuterol and ipratropium, ipratropium bromide, albuterol sulfate, budesonide, fluticasone
  • the at least one other therapeutically active agent is selected from SCH527123, glycoprronium bromide, a combination of glycopyrronium bromide and indacaterol maleate, a combination of glycopyrrolate and formoterol fumarate, indacaterol maleate, olodaterol, tiotropium, olodaterol, and a combination of aclidinium and formoterol.
  • the RIP1 kinase mediated disease or disorder treated with these agents is COPD.
  • the at least one other therapeutically active agent is an antimycobacterial agent or a bactericidal antibiotic.
  • the at least one other therapeutically active agent is selected from isoniazid, ehambutol, rifampin, pyrazinamide, rifabutin, rifapentine, capreomycin, levofloxacin, moxifloxicin, ofloxacin, ehionamide, cycloserine, kanamycin, streptomycin, viomycin, bedaquiline fumarate, PNU- 100480, and delamanid.
  • the RIP1 kinase mediated disease or disorder treated with these agents is a mycobacterium infection.
  • the at least one other therapeutically active agent is selected from an oral corticosteroid, anti-thymocyte globulin, thalidomide, chlorambucil, a calcium channel blocker, a topical emollient, an ACE inhibitor, a serotonin reuptake inhibitor, an endothelin- 1 receptor inhibitor, an anti-fibrotic agent, a proton-pump inhibitor or imatinib, ARG201, and tocilizumab.
  • the at least one other therapeutically active agent is selected from prednisolone, anti-thymocyte globulin, FK506 (tacrolimus), thalidomide, chlorambucil, nifedipine, nicardipine, nitroglycerin ointment, lisinopril, diltaizem, fluoxetine, bosentan, epoprostenol, colchicines, para- aminobenzoic acid, dimethyl sulfoxide, D-penicillamine, interferon alpha, interferon gamma (INF-g)), omeprazole, metoclopramide, lansoprazole, esomeprazole, pantoprazole, rabeprazole, imatinib, ARG201, and tocilizumab.
  • the RIP1 kinase mediated disease or disorder treated with these agents is systemic scleroderma.
  • the at least one other therapeutically active agent is selected from a cystic fibrosis transmembrane conductance regulator potentiator, a mucolytic agent, pancreatic enzymes, a bronchodilator, an antibiotic, or
  • the at least one other therapeutically active agent is selected from ivacftor, domase alpha, pancrelipase, albuterol, tobramycin, aztreonam, colistimethate sodium, cefadroxil monohydrate, cefazolin, cephalexin, cefazolin, moxifloxacin, levofloxacin, gemifloxacin, azithromycin, gentamicin, piperacillin/tazobacam, ceftazidime, ciprofloxin,
  • the RIP1 kinase mediated disease or disorder treated with these agents is cystic fibrosis.
  • the at least one other therapeutically active agent is a ciliary neurtotrophic growth factor or a gene transfer agent.
  • the at least one other therapeutically active agent is NT-501-CNTF or a gene transfer agent encoding myosin VIIA (MY07A).
  • the RIP1 kinase mediated disease or disorder treated with these agents is retinitis pigmentosa.
  • the at least one other therapeutically active agent is selected from opthalmalic intravitreal injections, an anti-vascular endothelial growth factor inhibitor, and a ciliary neurotrophic growth factor agent.
  • the at least one other therapeutically active agent is selected from afibercept, ranibizumab, pegaptanib sodium, NT501, humanized sphingomab, and bevacizumab.
  • the RIP1 kinase mediated disease or disorder treated with these agents is macular degeneration.
  • the at least one other therapeutically active agent is selected from a trivalent (IIV3) inactivated influenza vaccine, a quadrivalent (IIV4) inactivated influenza vaccine, a trivalent recombinant influenza vaccine, a quadrivalent live attenuated influenza vaccine, an antiviral agent, or inactivated influenza vaccine.
  • the at least one other therapeutically active agent is selected from oseltamivir, zanamivir, rimantadine, or amantadine.
  • the RIP1 kinase mediated disease or disorder treated with these agents is influenza.
  • the at least one other therapeutically active agent is selected from a b-Lactam, nafcillin, sulfamethoxazolylm, trimethoprim, sulfasalazine, acetyl sulfisoxazolyl, and vancomycin.
  • the RIP1 kinase mediated disease or disorder treated with these agents is a staphylococcus infection.
  • the at least one other therapeutically active agent is selected from a monoclonal antibody, a polyclonal anti-T-cell antibody, an anti thymocyte gamma globulin-equine antibody, an antithymocyte globulin-rabbit antibody, an anti-CD40 antagonist, a JAK inhibitor, and an anti-TCR murine mAb.
  • the at least one other therapeutically active agent is selected from muromonab-CD3, ASKP-1240, ASP015K, and TOL101.
  • the RIP1 kinase mediated disease or disorder treated with these agents is transplant rejection.
  • the at least one other therapeutically active agent is selected from a topical immunomodulator or calcineurin inhibitor, a topical corticosteroid, an oral corticosteroid, an interferon gamma, an antihistamine, or an antibiotic.
  • the at least one other therapeutically active agent is selected from pimecrolimus, tacrolimus, hydrocortizone, betamethasone, flurandrenolide, fluticasone, triamcinolone, fluocinonide, clobetasol, hydrocortisone, methylprednisolone, prednisolone, an interferon alpha protein, a recombinant synthetic type I interferon, interferon alpha-2a, interferon alpha-2b, hydroxyzine, diphenhydramine, flucloxacillin, dicloxacillin, and erythromycin.
  • the RIP1 kinase mediated disease or disorder treated with these agents is atopic dermatitis.
  • a compound that inhibits RIP 1 kinase may be administered to a patient in need thereof, in combination with at least one other therapy and/or with at least one other active therapeutic agent that is considered standard of care (U.S. Department of Health and Human Services, Agency for Healthcare Research and Quality, National Guideline Clearinghouse, https://www.guideline.gov/ and World Health Organization,
  • a compound that inhibits RIP 1 kinase, particularly Compound B, or Compound B in crystalline form, may be administered to a patient in need thereof, in combination with at least one other active therapeutic agent, wherein the at least one other active therapeutic agent is: a corticosteroid [administered orally, topically, by injection, or as a suppository; prednisone, methylprednisolone, prednisolone, budesonide, betamethasone,
  • mercaptopurine a JAK inhibitor
  • tofacitinib Baracitinib
  • an NSAID aspirin, acetaminophen, ibuprofen, naproxen (naproxen sodium), etodolac, celecoxib, diclofenac, meloxicam
  • an anti-IL6 biologic agent tocilizumab
  • an anti-ILl biologic agent anakinra, canakinumab, rilonacept
  • an anti-ILl 2 or IL23 biologic agent ustekinumab, risankizumab, guselkumab, tildrakizumab
  • an anti-CD6 biologic agent itolizumab
  • an anti-integrin agent natabzumab (Tysabri®), etrobzumab
  • an anti-ILl 7 biologic agent secukinumab, ixekizumab, brodalumab
  • Examples of other active therapeutic agents that may be used in combination with a compound of this invention for the treatment of ulcerative colitis and/or Crohn’s disease include vedolizumab, etrobzumab, eldelumab, or bertilimumab.
  • biologic agents examples include abatacept, belimumab, and alicafosen.
  • active therapeutic agent examples include baracitinib and Remestemcel-L.
  • a compound that inhibits RIP 1 kinase, particularly Compound B, or Compound B in crystalline form, may be administered to a pediatric or an adult patient in need thereof, in combination with at least one other therapy, for example, in combination with UVA and/or UVB phototherapy as indicated for the treatment of psoriasis.
  • a therapeutically "effective amount” is intended to mean that amount of Compound B, or Compound B in crystalline form, that when administered to a patient in need of such treatment, is sufficient to effect treatment, as defined herein.
  • a therapeutically effective amount of Compound B, or Compound B in crystalline form is a quantity of Compound B or Compound B in crystalline form, 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 RIP1 is reduced, alleviated or prevented.
  • the weight refers to the equivalent weight of Compound A (free base) and does not include the additional weight provided by the salt.
  • Compound B or Compound B in crystalline form, that will correspond to such an amount will vary depending upon factors such as the efficacy, biological half-life, 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.
  • 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 Compound B, or Compound B in crystalline form, will vary according to the identity of the mammal in need of treatment (e.g., weight), the particular salt form 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 terns "treating” or “treatment” are 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 RIP1 kinase-mediated disease or disorder, as described hereinabove.
  • the compounds of the 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.
  • the compounds of the invention may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan.
  • suitable dosing regimens including the duration such regimens are administered, for a compound of the invention depend on the disease or disorder being treated, the severity of the disease or disorder being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or overtime as individual patient needs change.
  • Total daily dosages range from 1 mg to 2000 mg of Compound B or Compound B in crystalline form, preferably, total daily dosages range from 1 mg to 250 mg of
  • the compounds of the invention will be normally, but not necessarily, formulated into a pharmaceutical composition, or administration unit, prior to administration to a patient. Accordingly, the invention also is directed to a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier and/or excipient. The invention also is directed to an administration unit comprising a compound of the invention and a pharmaceutically acceptable carrier and/or excipient.
  • the invention is further directed to a pharmaceutical composition comprising Compound B, or Compound B in crystalline form, and a pharmaceutically acceptable carrier and/or excipient.
  • the invention is also directed to an administration unit comprising Compound B, or Compound B in crystalline form, and a pharmaceutically acceptable carrier and/or one or more pharmaceutically acceptable excipients. More specifically, this invention is directed to a pharmaceutical composition comprising Compound B, or Compound B in crystalline form, as characterized by the ⁇ NMR spectrum substantially in accordance with Fig. 1 and/or Fig. 3 and a pharmaceutically acceptable carrier and/or excipient.
  • this invention is also directed to a pharmaceutical composition comprising Compound B, or Compound B in crystalline form as characterized by the DSC trace substantially in accordance with Fig. 2 and a pharmaceutically acceptable carrier and/or excipient.
  • This invention is also directed to a pharmaceutical composition comprising Compound B, or Compound B in crystalline form, as characterized by the XRPD pattern substantially in accordance with Fig. 4 and a pharmaceutically acceptable carrier and/or excipient.
  • this invention is also directed to a pharmaceutical composition comprising Compound B, or Compound B in crystalline form, as characterized by the diffraction data substantially in accordance with Table 1, and a pharmaceutically acceptable carrier and/or excipient.
  • compositions or administration units of the invention may be prepared and packaged in bulk form wherein an effective amount of a compound of the invention can be extracted and then given to the patient such as with powders, syrups, and solutions for injection.
  • the pharmaceutical compositions or administration units of the invention may be prepared and packaged in unit dosage form.
  • one or more tablets or capsules may be administered.
  • a dose of the pharmaceutical composition contains at least a therapeutically effective amount of a compound of the invention.
  • the pharmaceutical compositions or administration units may contain from 1 mg to 1000 mg of Compound B or Compound B in crystalline form.
  • the administration unit according to the invention comprises a therapeutically effective amount of Compound B, or Compound B in crystalline form, wherein at least 10 % by weight of said therapeutically effective amount of Compound B, or Compound B in crystalline form, or at least 30 % by weight, or at least 40 % by weight, or at least 50 % by weight, or at least 60% by weight, or at least 70 % by weight, or at least 80 % by weight, or at least 90 % by weight, or at least 95 % by weight, or at least 96 % by weight, or at least 97 % by weight, or at least 98 % by weight, or at least 99 % by weight of said therapeutically effective amount of Compound B or Compound B in crystalline form, is present as a pharmaceutically acceptable crystalline form of Compound B.
  • the administration unit according to the invention comprises a therapeutically effective amount of Compound B, or Compound B in crystalline form, wherein at least 10 /o by weight of said therapeutically effective amount of Compound B, or at least 30 /o by weight, or at least 40 % by weight, or at least 50 % by weight, or at least 60% by weight, or at least 70 % by weight, or at least 80 % by weight, or at least 90 % by weight, or at least 95 % by weight, or at least 96 % by weight, or at least 97 % by weight, or at least 98 % by weight, or at least 99 % by weight of said therapeutically effective amount of Compound B, or Compound B in crystalline form, is present as a pharmaceutically acceptable crystalline form of Compound B as characterized by the 1H NMR spectrum substantially in accordance with Fig. 1 and/or Fig. 3.
  • the administration unit according to the invention comprises a therapeutically effective amount of Compound B, or Compound B in crystalline form, wherein at least 10 /o by weight of said therapeutically effective amount of Compound B, or at least 30 /o by weight, or at least 40 % by weight, or at least 50 % by weight, or at least 60% by weight, or at least 70 % by weight, or at least 80 % by weight, or at least 90 % by weight, or at least 95 % by weight, or at least 96 % by weight, or at least 97 % by weight, or at least 98 % by weight, or at least 99 % by weight of said therapeutically effective amount of Compound B, or Compound B in crystalline form, is present as a pharmaceutically acceptable crystalline form of Compound B as characterized by the DSC trace substantially in accordance with Fig. 2.
  • the administration unit according to the invention comprises a therapeutically effective amount of Compound B, or Compound B in crystalline form, wherein at least 10 /o by weight of said therapeutically effective amount of Compound B, or at least 30 / o by weight, or at least 40 % by weight, or at least 50 % by weight, or at least 60% by weight, or at least 70 % by weight, or at least 80 % by weight, or at least 90 % by weight, or at least 95 % by weight, or at least 96 % by weight, or at least 97 % by weight, or at least 98 % by weight, or at least 99 % by weight of said therapeutically effective amount of Compound B, or Compound B in crystalline form, is present as a pharmaceutically acceptable crystalline form of Compound B as characterized by the XRPD pattern substantially in accordance with Fig. 4.
  • the administration unit according to the invention comprises a therapeutically effective amount of Compound B or Compound B in crystalline form, wherein at least 10 /o by weight of said therapeutically effective amount of Compound B, or at least 30 / o by weight, or at least 40 % by weight, or at least 50 % by weight, or at least 60% by weight, or at least 70 % by weight, or at least 80 % by weight, or at least 90 % by weight, or at least 95 % by weight, or at least 96 % by weight, or at least 97 % by weight, or at least 98 % by weight, or at least 99 % by weight of said therapeutically effective amount of Compound B, or Compound B in crystalline form, is present as a pharmaceutically acceptable crystalline form of Compound B as characterized by diffraction data substantially in accordance with Table 1.
  • the relative content of Compound B, or Compound B in crystalline form can be determined by standard analysis known to the skilled artisan. Suitable methods include but are not limited to thermal analysis, HPLC
  • not more than 90 % by weight of said therapeutically effective amount of Compound B is non-crystalline (e.g., amorphous).
  • not more than 80 % by weight, or not more than 70 % by weight, or not more than 60 % by weight, or not more than 50 % by weight, or not more than 40 %by weight, or not more than 30 % by weight, or not more than 20 % by weight, or not more than 10 % by weight of said therapeutically effective amount of Compound B is amorphous.
  • not more than 5 % by weight, or not more than 4 % by weight, or not more than 3% by weight, or not more than 2 % by weight, or not more than 1 % by weight, or not more than 0.5 % by weight, or not more than 0.2 % by weight, or not more than 0.1 % by weight of said therapeutically effective amount of Compound B is amorphous.
  • the total content of amorphous Compound B, as well as the relative content of the crystalline form of Compound B can be determined by standard analysis known to the skilled artisan. Suitable methods include but are not limited to thermal analysis, HPLC and XRPD (see e.g. K.D. Harris, Powder diffraction crystallography of molecular solids, Top Curr.
  • unit dosage forms containing from 1 mg to 1000 mg of Compound B, or Compound B in crystalline form, may be administered one, two, three, or four times per day, preferably one, two, or three times per day, and more preferably, one or two times per day, to effect treatment of a RIP 1 kinase-mediated disease or disorder.
  • compositions or administration units of the invention typically contain Compound B, or Compound B in crystalline form.
  • pharmaceutical compositions or administration units of the invention may optionally further comprise one or more additional pharmaceutically active compounds.
  • “Pharmaceutically acceptable carrier(s)” means any one or more compounds and/or compositions that are of sufficient purity and quality for use in the formulation of the compound of the invention that, when appropriately administered to a human, do not produce an adverse reaction, and that are used as a vehicle for a drug substance (i.e. a compound of the present invention).
  • Carriers may include excipients, diluents, granulating and/or dispersing agents, surface active agents and/or emulsifiers, binding agents, preservatives, buffering agents, lubricating agents, and natural oils.
  • pharmaceutically acceptable excipient(s) means a material, composition or vehicle involved in giving form or consistency to the composition.
  • Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided.
  • each excipient must of course be of sufficiently high purity to render it pharmaceutically acceptable.
  • the compounds of the invention and the pharmaceutically acceptable carrier(s) and/or excipient(s) will typically be formulated into a dosage form adapted for administration to the patient by the desired route of administration.
  • Conventional dosage forms include those adapted for (1) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as aerosols and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.
  • Suitable pharmaceutically acceptable carrier(s) and/or excipient(s) will vary depending upon the particular dosage form chosen.
  • suitable pharmaceutically acceptable excipients may be chosen for a particular function that they may serve in the composition.
  • certain pharmaceutically acceptable carrier(s) and/or excipient(s) may be chosen for their ability to facilitate the production of uniform dosage forms.
  • Certain pharmaceutically acceptable carrier(s) and/or excipient(s) may be chosen for their ability to facilitate the production of stable dosage forms.
  • pharmaceutically acceptable carrier(s) and/or excipient(s) may be chosen for their ability to facilitate the carrying or transporting the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body.
  • Certain pharmaceutically acceptable excipients may be chosen for their ability to enhance patient compliance.
  • Suitable pharmaceutically acceptable carrier(s) and/or excipient(s) include the following types of carrier(s) and excipient(s): diluents, fillers, binders, disintegrants, lubricants, gbdants, granulating agents, coating agents, wetting agents, solvents, co solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents.
  • certain pharmaceutically acceptable carrier(s) and/or excipient(s) may serve more than one function and may serve alternative functions depending on how much of the carrier(s) and/or excipient(s) is present in the formulation and what other ingredients are present in the formulation.
  • Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically acceptable carrier(s) and/or excipient(s) in appropriate amounts for use in the invention.
  • suitable pharmaceutically acceptable carrier(s) and/or excipient(s) there are a number of resources that are available to the skilled artisan which describe pharmaceutically acceptable carrier(s) and/or excipient(s) and may be useful in selecting suitable pharmaceutically acceptable carrier(s) and/or excipient(s). Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).
  • compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington’s Pharmaceutical Sciences (Mack Publishing
  • another embodiment of this invention is a method of preparing a pharmaceutical composition or administration unit comprising the step of admixing Compound B, or Compound B in crystalline form, with one or more pharmaceutically acceptable carrier(s) and/or excipient(s).
  • a method of preparing a pharmaceutical composition or administration unit comprising the step of admixing Compound B, or Compound B in crystalline form, as characterized by the 1H NMR spectrum substantially in accordance with Fig. 1 and/or Fig. 3, with one or more pharmaceutically acceptable carriers and/or excipients.
  • a method of preparing a pharmaceutical composition or administration unit comprising the step of admixing Compound B, or Compound B in crystalline form, as characterized by the DSC trace substantially in accordance with Fig. 2, with one or more pharmaceutically acceptable carriers and/or excipients.
  • a method of preparing a pharmaceutical composition or administration unit comprising the step of admixing Compound B, or Compound B in crystalline form as characterized by the XRPD pattern substantially in accordance with Fig. 4, with one or more pharmaceutically acceptable carriers and/or excipients.
  • a method of preparing a pharmaceutical composition or administration unit comprising the step of admixing Compound B, or Compound B in crystalline form, as characterized by the diffraction data substantially in accordance with Table 1, with one or more
  • the invention is directed to a solid oral dosage form such as a tablet or capsule comprising an effective amount of a compound of the invention and a diluent or filler.
  • Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. com starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate.
  • the oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g.
  • the oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose.
  • the oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc.
  • the DSC thermogram in Fig 2 shows no thermal event up until l80°C and exhibits an endotherm with an onset temperature at about 191.09 °C.
  • onset temperature of the endotherm may vary depending on the experimental conditions.
  • Microscope image of the methane sulfonic acid (MSA) salt of (.V)-5-bcnzyl-A-(5-mcthyl-4-oxo-2 3,4,5-tetrahydrobenzo[6][l,4]oxazepin-3-yl)- 477-1, 2, 4-triazole-3 -carboxamide (Compound B) was obtained using a polarized light microscope Nikon eclipse 80i equipped with a Nikon DS-Ril camera head, and is shown on Figure 5 .
  • the microscope images shows a faceted and birefringent crystal which confirms the crystallinity of the solid isolated.
  • the resultant suspension was left to age under stirring for 60 min at 35°C. After the agering was complete, an additional 8 ml (0.8 vol_eq) of the solution of MSA in acetone (Containing 0.744 mol_eq. of MSA) was added to the solution of Compound A/acetone over the course of 120 min while keeping the suspension temperature at 35°C. The resultant suspension was left to age for 30 min at 35°C then it was cooled to 10 °C over 30 min. The resultant suspension was then left to age for a further 10 min then it was filtered under vacuum. The filter cake was dried in a vacuum at 50°C until a constant weight was achieved to provide Compound B in a 87.9% yield as a crystalline solid.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une nouvelle forme de sel de (S)-5-benzyl-N-(5-méthyl-4-oxo-2,3,4,5-tétrahydrobenzo[b][1,4]oxazépin-3-yl)-4H-1,2,4-triazole-3-carboxamide, en particulier des formes cristallines associées et des compositions pharmaceutiques les contenant. L'invention concerne également des procédés de préparation correspondants et des procédés d'utilisation associés.
PCT/IB2018/060206 2017-12-20 2018-12-17 Forme de sel cristalline de (s)-5-benzyl-n-(5-méthyl-4-oxo-2,3,4,5-tétrahydrobenzo[b][1,4]oxazépin-3-yl)-4h-1,2,4-triazole-3-carboxamide Ceased WO2019123219A1 (fr)

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Citations (2)

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Publication number Priority date Publication date Assignee Title
WO2014125444A1 (fr) 2013-02-15 2014-08-21 Glaxosmithkline Intellectual Property Development Limited Amides hétérocycliques à utiliser en tant qu'inhibiteurs de kinase
WO2016128936A1 (fr) * 2015-02-13 2016-08-18 Glaxosmithkline Intellectual Property Development Limited Formes cristallines de (s)-5-benzyl-n-(5-méthyl-4-oxo-2,3,4,5-tétrahydrobenzo[b][1,4]oxazépine-3-yl)-4h-1,2,4-triazole-3-carboxamide

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WO2014125444A1 (fr) 2013-02-15 2014-08-21 Glaxosmithkline Intellectual Property Development Limited Amides hétérocycliques à utiliser en tant qu'inhibiteurs de kinase
US20150353533A1 (en) 2013-02-15 2015-12-10 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides as kinase inhibitors
WO2016128936A1 (fr) * 2015-02-13 2016-08-18 Glaxosmithkline Intellectual Property Development Limited Formes cristallines de (s)-5-benzyl-n-(5-méthyl-4-oxo-2,3,4,5-tétrahydrobenzo[b][1,4]oxazépine-3-yl)-4h-1,2,4-triazole-3-carboxamide

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