WO2024254440A1 - Composés de 5-cyano-1h-imidazole-2-carboxamide en tant qu'inhibiteurs de csf1r - Google Patents

Composés de 5-cyano-1h-imidazole-2-carboxamide en tant qu'inhibiteurs de csf1r Download PDF

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WO2024254440A1
WO2024254440A1 PCT/US2024/032992 US2024032992W WO2024254440A1 WO 2024254440 A1 WO2024254440 A1 WO 2024254440A1 US 2024032992 W US2024032992 W US 2024032992W WO 2024254440 A1 WO2024254440 A1 WO 2024254440A1
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compound
prodrug
disease
mmol
cancer
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Lloyd Mackenzie
Curtis Harwig
Laurence Burgess
Nicholas Saccomano
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Modulo Bio Inc
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Modulo Bio Inc
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Priority to EP24742713.1A priority Critical patent/EP4709719A1/fr
Priority to AU2024284488A priority patent/AU2024284488A1/en
Priority to CN202480051182.7A priority patent/CN121729411A/zh
Priority to JP2025571149A priority patent/JP2026519814A/ja
Publication of WO2024254440A1 publication Critical patent/WO2024254440A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems

Definitions

  • CSF1R Colony stimulating factor 1 receptor
  • M-CSFR macrophage colony- stimulating factor receptor
  • CD115 Cluster of Differentiation 115
  • CSF1R is a receptor that can be activated by two ligands: colony stimulating factor 1 (CSF-1) and interleukin-34 (IL- 34).
  • CSF1R is highly expressed in myeloid cells.
  • CSF1R signaling is necessary for the survival, proliferation, and differentiation of many myeloid cell types in vivo and in vitro.
  • CSF1R signaling is involved in many diseases and is targeted in therapies for cancer, neurodegeneration, and inflammatory bone diseases.
  • WO 2009/052237 describes compounds that inhibit protein kinases, especially c-fms kinase. The compounds are reported to be useful for treating certain cancers, metastasis of certain cancers, pain, and certain autoimmune diseases.
  • the invention provides a compound of formula (I): or a prodrug or a salt thereof, wherein: X is N, NR e , or CH; R 1 is selected from the group consisting of: wherein R 1 is optionally substituted with one or more groups independently selected from (C 1 - C6)alkyl and OH and R 1 is substituted with one or more groups independently selected from deuterium, chloro, and fluoro; or R 1 is R 2 or R 3 ; and is optionally substituted with one or more groups independently selected from D, Cl, F, OH, and (C1-C8)alkyl, where (C1-C8)alkyl is optionally substituted with one or more groups independently selected from D, Cl, F, OH; X 1 is NR a or S; R a is selected from H, (C1-C6)alkyl, (C1-C6)alkanoyl, and C1-C6)alkoxycarbonyl; R b is H, (C
  • the invention also provides a pharmaceutical composition comprising a compound of formula I or a prodrug or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition provides blood-brain barrier (BBB) permeability.
  • BBB blood-brain barrier
  • the invention also provides a method of treating a disease selected from the group consisting of osteoporosis, Paget's disease, rheumatoid arthritis and other forms of inflammatory arthritis, osteoarthritis, prosthesis failure, osteolytic sarcoma, myeloma, and tumor metastasis to bone in an animal, comprising administering to the animal a compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof.
  • the invention also provides a method of treating a disease initiated or progressed due to myeloid cell immune activation including but not limited to Monocyte, macrophage and microglia.
  • the invention also provides a method of treating a disease or disorder selected from the group consisting of glomerulonephritis, inflammatory bowel disease, prosthesis failure, sarcoidosis, congestive obstructive pulmonary disease, idiopathic pulmonary fibrosis, asthma, pancreatitis, HIV infection, COVID-19 (SARS-CoV-2), neurocognitive disorders, chemo brain cognitive impairment or cognitive dysfunction, psoriasis, diabetes, tumor related angiogenesis, age-related macular degeneration, diabetic retinopathy, restenosis, schizophrenia, Parkinson’s disease, Alzheimer’s disease, ⁇ Chronic Traumatic Encephalopathy, Huntington Disease, Progressive Bulbar Palsy, Progressive, Supranuclear Palsy, Lewy Body Disease, Myotonic Dystrophy , Ataxia
  • the invention also provides a method of treating pain in an animal, comprising administering to the animal a compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof.
  • the pain is skeletal pain caused by tumor metastasis or osteoarthritis, or visceral, inflammatory, or neurogenic pain.
  • the invention also provides a method of treating cancer in an animal, comprising administering to the animal a compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof.
  • the cancer is selected from the group consisting of ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, and hairy cell leukemia.
  • the invention also provides a method of treating or preventing cancer metastasis in an animal, comprising administering to the animal a compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof.
  • the cancer is selected from the group consisting of ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, and hairy cell leukemia.
  • the invention also provides a method of treating an autoimmune disease in an animal, comprising administering to the animal a compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof.
  • the autoimmune disease is selected from the group consisting of systemic lupus erythematosus, rheumatoid arthritis and other forms of inflammatory arthritis, psoriasis, Sjogren's syndrome, multiple sclerosis, and uveitis
  • the invention also provides a method for inhibiting the activity of c-fms kinase, comprising contacting the c-fms kinase a compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof.
  • the c-fms kinase is contacted with the compound or the salt in vitro.
  • the c-fms kinase is contacted with the compound of formula (I) or a pharmaceutically acceptable salt thereof in vivo.
  • the invention provides inhibitors of c-fms kinase that are not converted to biologically active metabolites in vivo.
  • the invention also provides a method of treating atherosclerosis in an animal, comprising administering to the animal a compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof.
  • the invention also provides a method of treating a disease selected from the group consisting of ALS, FTD, C9 related disease, Alzheimers, Parkinsons, MS, Huntington’s Disease, Giant Tenosynovial Carcinoma, and Epilepsy in an animal, comprising administering to the animal a compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof.
  • a disease selected from the group consisting of ALS, FTD, C9 related disease, Alzheimers, Parkinsons, MS, Huntington’s Disease, Giant Tenosynovial Carcinoma, and Epilepsy in an animal, comprising administering to the animal a compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof.
  • the invention also provides a method of treating ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, bladder cancer, pancreatic cancer, glioblastoma, melanoma, lymphoma, leukemia, or hairy cell leukemia in an animal, comprising administering to the animal a compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof.
  • the invention also provides a method of treating a disease selected from the group consisting of osteoporosis, Paget's disease, rheumatoid arthritis and other forms of inflammatory arthritis, osteoarthritis, prosthesis failure, osteolytic sarcoma, myeloma, Giant Tenosynovial Carcinoma, brain cancer and tumor metastasis to brain or bone in an animal, any advanced solid tumors and cancer tumor metastasis (especially to the brain, CNS, bone, or lymph nodes) in an animal, comprising administering to the animal a compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof.
  • a disease selected from the group consisting of osteoporosis, Paget's disease, rheumatoid arthritis and other forms of inflammatory arthritis, osteoarthritis, prosthesis failure, osteolytic sarcoma, myeloma, Giant Tenosynovial Carcinoma, brain cancer and tumor metastasis to brain or
  • the invention also provides a method of treating a disease selected from the group consisting of glomerulonephritis, inflammatory bowel disease, prosthesis failure, sarcoidosis, congestive obstructive pulmonary disease, idiopathic pulmonary fibrosis, asthma, pancreatitis, HIV infection, COVID-19 (SARS-CoV-2), Hepatitis, neurocognitive disorders, chemo brain cognitive impairment or cognitive dysfunction, psoriasis, diabetes, tumor related angiogenesis, age-related macular degeneration, diabetic retinopathy, restenosis, schizophrenia, Parkinson’s disease, Alzheimer’s disease, Chronic Traumatic Encephalopathy, Huntington Disease, Progressive Bulbar Palsy, Progressive Supranuclear Palsy, Lewy Body Disease, Myotonic Dystrophy, Ataxia Telangiectasia, Bovine Spongiform Encephalopathy, Kuru, Scrapie Anti-N- Methyl-D-Aspartate Receptor Encephalitis
  • the invention also provides a compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof for use in medical therapy.
  • the invention also provides a compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof for the prophylactic or therapeutic treatment of a disease selected from the group consisting of osteoporosis, Paget's disease, rheumatoid arthritis and other forms of inflammatory arthritis, osteoarthritis, prosthesis failure, osteolytic sarcoma, myeloma, and tumor metastasis to bone.
  • the invention also provides a compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof for the prophylactic or therapeutic treatment of a disease selected from the group consisting of glomerulonephritis, inflammatory bowel disease, prosthesis failure, sarcoidosis, congestive obstructive pulmonary disease, idiopathic pulmonary fibrosis, asthma, pancreatitis, HIV infection, COVID-19 (SARS-CoV-2), neurocognitive disorders, chemo brain cognitive impairment or cognitive dysfunction, psoriasis, diabetes, tumor related angiogenesis, age-related macular degeneration, diabetic retinopathy, restenosis, schizophrenia, Parkinson’s disease, Alzheimer’s disease, Chronic Traumatic Encephalopathy, Huntington Disease, Progressive Bulbar Palsy, Progressive, Supranuclear Palsy, Lewy Body Disease, Myotonic Dystrophy , Ataxia Telangiectasia, Bovine Spongiform Encephalopathy, Kuru, Scrapi
  • the invention also provides a compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof for the prophylactic or therapeutic treatment of pain.
  • the pain is skeletal pain caused by tumor metastasis or osteoarthritis, or visceral, inflammatory, or neurogenic pain.
  • the cancer is selected from the group consisting of ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, and hairy cell leukemia.
  • the invention also provides a compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof for treating or preventing cancer metastasis.
  • the cancer is selected from the group consisting of ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, and hairy cell leukemia.
  • the invention also provides a compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof for the prophylactic or therapeutic treatment an autoimmune disease.
  • the autoimmune disease is selected from the group consisting of systemic lupus erythematosus, rheumatoid arthritis and other forms of inflammatory arthritis, psoriasis, Sjogren's syndrome, multiple sclerosis, and uveitis.
  • the invention also provides a compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof for inhibiting the activity of c-fms kinase.
  • the invention also provides a compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof for the treatment of athlerosclerosis.
  • the invention also provides a compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof for the treatment of a disease selected from the group consisting of ALS, FTD, C9 related disease, Alzheimers, Parkinsons, MS, Huntington’s Disease, Giant Tenosynovial Carcinoma, and Epilepsy.
  • the invention also provides a compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof for the treatment of ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, bladder cancer, pancreatic cancer, glioblastoma, melanoma, lymphoma, leukemia, or hairy cell leukemia.
  • the invention also provides a compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof for the treatment of a disease selected from the group consisting of osteoporosis, Paget's disease, rheumatoid arthritis and other forms of inflammatory arthritis, osteoarthritis, prosthesis failure, osteolytic sarcoma, myeloma, Giant Tenosynovial Carcinoma, brain cancer and tumor metastasis to brain or bone in an animal, any advanced solid tumors and cancer tumor metastasis (especially to the brain, CNS, bone, or lymph nodes).
  • a disease selected from the group consisting of osteoporosis, Paget's disease, rheumatoid arthritis and other forms of inflammatory arthritis, osteoarthritis, prosthesis failure, osteolytic sarcoma, myeloma, Giant Tenosynovial Carcinoma, brain cancer and tumor metastasis to brain or bone in an animal, any advanced solid tumors and cancer tumor
  • the invention also provides a compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof for the treatment of a disease selected from the group consisting of glomerulonephritis, inflammatory bowel disease, prosthesis failure, sarcoidosis, congestive obstructive pulmonary disease, idiopathic pulmonary fibrosis, asthma, pancreatitis, HIV infection, COVID-19 (SARS-CoV-2), Hepatitis, neurocognitive disorders, chemo brain cognitive impairment or cognitive dysfunction, psoriasis, diabetes, tumor related angiogenesis, age-related macular degeneration, diabetic retinopathy, restenosis, schizophrenia, Parkinson’s disease, Alzheimer’s disease, Chronic Traumatic Encephalopathy, Huntington Disease, Progressive Bulbar Palsy, Progressive Supranuclear Palsy, Lewy Body Disease, Myotonic Dystrophy, Ataxia Telangiectasia, Bovine Spongiform Encephalopathy, Kuru, Scrapie Anti
  • the invention also provides the use of a compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof to prepare a medicament that is useful for treating a disease selected from the group consisting of osteoporosis, Paget's disease, rheumatoid arthritis and other forms of inflammatory arthritis, osteoarthritis, prosthesis failure, osteolytic sarcoma, myeloma, and tumor metastasis to bone in an animal.
  • a disease selected from the group consisting of osteoporosis, Paget's disease, rheumatoid arthritis and other forms of inflammatory arthritis, osteoarthritis, prosthesis failure, osteolytic sarcoma, myeloma, and tumor metastasis to bone in an animal.
  • the invention also provides the use of a compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof to prepare a medicament that is useful for treating a disease selected from the group consisting of glomerulonephritis, inflammatory bowel disease, prosthesis failure, sarcoidosis, congestive obstructive pulmonary disease, idiopathic pulmonary fibrosis, asthma, pancreatitis, HIV infection, COVID-19 (SARS-CoV-2), neurocognitive disorders, chemo brain cognitive impairment or cognitive dysfunction, psoriasis, diabetes, tumor related angiogenesis, age-related macular degeneration, diabetic retinopathy, restenosis, schizophrenia, Parkinson’s disease, Alzheimer’s disease, Chronic Traumatic Encephalopathy, Huntington Disease, Progressive Bulbar Palsy, Progressive, Supranuclear Palsy, Lewy Body Disease, Myotonic Dystrophy , Ataxia Telangiectasia, Bovine Spongiform Encephalopathy, Kur
  • the invention also provides the use of a compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof to prepare a medicament that is useful for treating pain in an animal.
  • the pain is skeletal pain caused by tumor metastasis or osteoarthritis, or visceral, inflammatory, or neurogenic pain.
  • the invention also provides the use of a compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof to prepare a medicament that is useful for treating cancer in an animal.
  • the cancer is ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, or hairy cell leukemia.
  • the invention also provides the use of a compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof to prepare a medicament that is useful for treating or preventing cancer metastasis in an animal.
  • the cancer is ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, or hairy cell leukemia.
  • the invention also provides the use of a compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof to prepare a formulation which optimizes exposure and other pharmacodynamic properties of the compound.
  • the invention also provides the use of a compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof to prepare a medicament that is useful for treating an autoimmune disease in an animal.
  • the autoimmune disease selected from the group consisting of systemic lupus erythematosus, rheumatoid arthritis and other forms of inflammatory arthritis, psoriasis, Sjogren's syndrome, multiple sclerosis, and uveitis.
  • the invention also provides the use of a compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof to prepare a medicament that is useful for inhibiting the activity of a c-fms kinase in an animal.
  • the invention also provides the use of a compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof to prepare a medicament that is useful for treating athlerosclerosis in an animal.
  • the invention also provides the use of a compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof to prepare a medicament that is useful for treating a disease selected from the group consisting of ALS, FTD, C9 related disease, Alzheimers, Parkinsons, MS, Huntington’s Disease, Giant Tenosynovial Carcinoma, and Epilepsy in an animal.
  • a disease selected from the group consisting of ALS, FTD, C9 related disease, Alzheimers, Parkinsons, MS, Huntington’s Disease, Giant Tenosynovial Carcinoma, and Epilepsy in an animal.
  • the invention also provides the use of a compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof to prepare a medicament that is useful for treating ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, bladder cancer, pancreatic cancer, glioblastoma, melanoma, lymphoma, leukemia, or hairy cell leukemia in an animal.
  • the invention also provides the use of a compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof to prepare a medicament that is useful for treating a disease selected from the group consisting of osteoporosis, Paget's disease, rheumatoid arthritis and other forms of inflammatory arthritis, osteoarthritis, prosthesis failure, osteolytic sarcoma, myeloma, Giant Tenosynovial Carcinoma, brain cancer and tumor metastasis to brain or bone in an animal, any advanced solid tumors and cancer tumor metastasis (especially to the brain, CNS, bone, or lymph nodes) in an animal.
  • a disease selected from the group consisting of osteoporosis, Paget's disease, rheumatoid arthritis and other forms of inflammatory arthritis, osteoarthritis, prosthesis failure, osteolytic sarcoma, myeloma, Giant Tenosynovial Carcinoma, brain cancer and tumor metastasis to brain or
  • the invention also provides the use of a compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof to prepare a medicament that is useful for treating a disease selected from the group consisting of glomerulonephritis, inflammatory bowel disease, prosthesis failure, sarcoidosis, congestive obstructive pulmonary disease, idiopathic pulmonary fibrosis, asthma, pancreatitis, HIV infection, COVID-19 (SARS-CoV-2), Hepatitis, neurocognitive disorders, chemo brain cognitive impairment or cognitive dysfunction, psoriasis, diabetes, tumor related angiogenesis, age-related macular degeneration, diabetic retinopathy, restenosis, schizophrenia, Parkinson’s disease, Alzheimer’s disease, Chronic Traumatic Encephalopathy, Huntington Disease, Progressive Bulbar Palsy, Progressive Supranuclear Palsy, Lewy Body Disease, Myotonic Dystrophy, Ataxia Telangiectasia, Bovine Spongiform Encephal
  • the invention also provides processes and intermediates disclosed herein that are useful for preparing a compound of formula I or a salt thereof.
  • Certain compounds are deuterated, chlorinated, or fluorinated in the group R 1 .
  • Deuteration, chlorination, or fluorination in the group R 1 may improve metabolic stability, potency, and/or in vivo efficacy relative to similar compounds with different R 1 substituents.
  • Certain compounds exhibit higher metabolic stabilities than the corresponding non- deuterated compounds.
  • Certain compounds exhibit superior in vivo pharmacokinetics than the corresponding non-deuterated compounds.
  • Certain compounds exhibit superior in vitro efficacies than the corresponding non- deuterated compounds.
  • Certain compounds exhibit higher metabolic stabilities than the corresponding non- fluorinated compounds.
  • Certain compounds exhibit superior in vivo pharmacokinetics than the corresponding non-fluorinated compounds. Certain compounds exhibit superior in vitro efficacies than the corresponding non- fluorinated compounds. Certain compounds exhibit higher metabolic stabilities than the corresponding non- chlorinated compounds. Certain compounds exhibit superior in vivo pharmacokinetics than the corresponding non- chlorinated compounds. Certain compounds exhibit superior in vitro efficacies than the corresponding non- chlorinated compounds.
  • halo or halogen is fluoro, chloro, bromo, or iodo.
  • Alkyl, alkoxy, etc. denote both straight and branched groups; but reference to an individual radical such as propyl embraces only the straight chain radical, a branched chain isomer such as isopropyl being specifically referred to.
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical, having the number of carbon atoms designated (i.e., C1-6 means one to six carbons).
  • alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, and n-hexyl.
  • (C 1 -C 6 )alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec- butyl, pentyl, 3-pentyl, or hexyl.
  • alkoxy refers to an alkyl groups attached to the remainder of the molecule via an oxygen atom (“oxy”).
  • (C1-C6)alkoxycarbonyl can be methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, or hexyloxycarbonyl.
  • protecting group refers to a substituent that is commonly employed to block or protect a particular functional group on a compound.
  • an "amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound.
  • Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9- fluorenylmethylenoxycarbonyl (Fmoc).
  • a "hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality.
  • Suitable protecting groups include acetyl and silyl.
  • a “carboxy-protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality.
  • Common carboxy- protecting groups include phenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2- (trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2- (diphenylphosphino)-ethyl, nitroethyl and the like.
  • protecting groups and their use see P.G.M. Wuts and T.W. Greene, Greene's Protective Groups in Organic Synthesis 4 th edition, Wiley-Interscience, New York, 2006.
  • a wavy line “ ” that intersects a bond in a chemical structure indicates the point of attachment of the bond that the wavy bond intersects in the chemical structure to the remainder of a molecule.
  • the terms “treat”, “treatment”, or “treating” to the extent it relates to a disease or condition includes inhibiting the disease or condition, eliminating the disease or condition, and/or relieving one or more symptoms of the disease or condition.
  • the terms “treat”, “treatment”, or “treating” also refer to both therapeutic treatment and/or prophylactic treatment or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as, for example, the development or spread of cancer.
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease or disorder, stabilized (i.e., not worsening) state of disease or disorder, delay or slowing of disease progression, amelioration or palliation of the disease state or disorder, and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • Those in need of treatment include those already with the disease or disorder as well as those prone to have the disease or disorder or those in which the disease or disorder is to be prevented.
  • “treat”, “treatment”, or “treating” does not include preventing or prevention
  • the phrase "therapeutically effective amount” or “effective amount” includes but is not limited to an amount of a compound of the that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
  • the term “mammal” as used herein refers to humans, higher non-human primates, rodents, domestic, cows, horses, pigs, sheep, dogs and cats. In one embodiment, the mammal is a human.
  • the term “patient” as used herein refers to any animal including mammals.
  • the patient is a mammalian patient.
  • the patient is a human patient.
  • the disclosure also includes "deuterated analogs" of compounds described herein in which from 1 to n hydrogens attached to a carbon atom is/are replaced by deuterium, in which n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound when administered to a mammal, particularly a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984).
  • Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.
  • Deuterium labeled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and/or an improvement in therapeutic index.
  • An 18 F, 3 H, or 11 C labeled compound may be useful for PET or SPECT or other imaging studies.
  • Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in a compound described herein. The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.
  • any atom specifically designated as a deuterium (D) is meant to represent deuterium.
  • D deuterium
  • the compound is enriched in deuterium at a given position above the natural abundance of deuterium.
  • the compound may be enriched by at least 2-times the natural abundance of deuterium.
  • the compound may be enriched by at least 10- times the natural abundance of deuterium.
  • the compound may be enriched by at least 100-times the natural abundance of deuterium.
  • the compound may be enriched by at least 1000-times the natural abundance of deuterium.
  • the compounds disclosed herein can also exist as tautomeric isomers in certain cases. Although only one delocalized resonance structure may be depicted, all such forms are contemplated within the scope of the invention. It is understood by one skilled in the art that this invention also includes any compound claimed that may be enriched at any or all atoms above naturally occurring isotopic ratios with one or more isotopes such as, but not limited to, deuterium ( 2 H or D). As a non-limiting example, a -CH 3 group may be substituted with -CD 3 .
  • the pharmaceutical compositions of the invention can comprise one or more excipients.
  • excipients refers generally to an additional ingredient that is combined with the compound of formula (I) or the pharmaceutically acceptable salt thereof to provide a corresponding composition.
  • excipients includes, but is not limited to: carriers, binders, disintegrating agents, lubricants, sweetening agents, flavoring agents, coatings, preservatives, and dyes. Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E.
  • the compounds of the invention can contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light.
  • the prefixes D and L, or R and S are used to denote the absolute configuration of the molecule about its chiral center(s).
  • the prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory.
  • a compound prefixed with (+) or d is dextrorotatory.
  • these stereoisomers are identical except that they are mirror images of one another.
  • a specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • racemic mixture A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
  • racemic mixture and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity. It will be appreciated by those skilled in the art that compounds of the invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism.
  • the present invention encompasses any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase.
  • optically active forms for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase.
  • the compound may be at least 51% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 60% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 80% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 90% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 95 the absolute stereoisomer depicted. In another embodiment, the compound may be at least 99% the absolute stereoisomer depicted.
  • R 1 is optionally substituted with one or more groups independently selected from (C 1 - C6)alkyl and OH and wherein R 1 is substituted with one or more groups independently selected from deuterium, chloro, and fluoro;
  • R a is H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, or (C 1 -C 6 )alkoxycarbonyl;
  • R b is H, (C1-C6)alkyl, (C1-C6)alkanoyl, or (C1-C6)alkoxycarbonyl;
  • R c is H, (C1-C6)alkyl, (C1-C6)alkanoyl, or (C1-C6)alkoxycarbonyl.
  • a specific value for R 1 is selected from the structures: wherein R 1 is optionally substituted with one or more OH and wherein R 1 is substituted with one or more one or more groups independently selected from deuterium, chloro, and fluoro.
  • a specific value for R 1 is selected from the structures: wherein R 1 is optionally substituted with one or more OH and wherein R 1 is substituted with one or more one or more groups independently selected from deuterium, chloro, and fluoro.
  • a specific value for R 1 is selected from the structures: wherein R 1 is optionally substituted with one or more OH and wherein R 1 is substituted with one or more one or more groups independently selected from deuterium, chloro, and fluoro.
  • a specific value for R 1 is selected from the structures: wherein R 1 is substituted with one or more one or more groups independently selected from deuterium, chloro, and fluoro.
  • a specific value for R 1 is selected from the structures: wherein R 1 is substituted with one or more one or more groups independently selected from deuterium, chloro, and fluoro.
  • a specific value for R 1 is selected from the structures: wherein R 1 is substituted with one or more one or more groups independently selected from deuterium, chloro, and fluoro.
  • a specific value for R 1 is selected from the structures: wherein R 1 is substituted with one or more deuterium.
  • a specific value for R 1 is selected from the structures: wherein R 1 is substituted with one or more deuterium.
  • a specific value for R 1 is selected from the structures: wherein R 1 is substituted with one or more deuterium.
  • a specific value for R 1 is selected from the structures: wherein R 1 is substituted with one or more groups independently selected from chloro and fluoro.
  • a specific value for R 1 is selected from the structures: wherein R 1 is substituted with one or more groups independently selected from chloro and fluoro.
  • a specific value for R 1 is selected from the structures: wherein R 1 is substituted with one or more groups independently selected from chloro and fluoro.
  • a specific value for R 1 has the structure: wherein R 1 is substituted with two or more deuterium.
  • a specific value for R 1 has the structure: wherein R 1 is substituted with three or more deuterium.
  • a specific value for R 1 has the structure: wherein R 1 is substituted with six or more deuterium.
  • a specific value for R 1 has the structure: wherein R 1 is substituted with twelve or more deuterium.
  • a specific value for R 1 is selected from the group consisting of: .
  • a specific value for R 1 is selected from the group consisting of:
  • a specific compound, prodrug, or salt is a compound of formula (III): or a prodrug or a salt thereof, wherein: R 1 is selected from the group consisting of: wherein R 1 is optionally substituted with one or more groups independently selected from OH deuterium, chloro, and fluoro; R a is H, (C1-C6)alkyl, (C1-C6)alkanoyl, or (C1-C6)alkoxycarbonyl; R b is H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, or (C 1 -C 6 )alkoxycarbonyl; and R c is H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, or (C 1 -C 6 )alkoxycarbonyl.
  • a specific compound, prodrug, or salt is a compound of formula (I): or a prodrug or a salt thereof, wherein: R 1 is selected from the group consisting of: wherein R 1 is optionally substituted with one or more groups independently selected from (C1- C 6 )alkyl and OH and wherein R 1 is substituted with one or more groups independently selected from deuterium, chloro, and fluoro; R a is H, (C1-C6)alkyl, (C1-C6)alkanoyl, or (C1-C6)alkoxycarbonyl; R b is H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, or (C 1 -C 6 )alkoxycarbonyl; and R c is H, (C1-C6)alkyl, (C1-C6)alkanoyl, or (C1-C6)alkoxycarbonyl.
  • R a is methoxycarbonyl. In one embodiment, R a is H. In one embodiment, R b is H or methyl. In one embodiment, R c is H, methyl, or ethyl. In one embodiment, X is N. In one embodiment, X is CH.
  • X 1 is NR a , O, or S
  • R a is selected from H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, and (C 1 -C 6 )alkoxycarbonyl
  • R 2 is optionally substituted with one or more groups independently selected from D, Cl, F, OH, and (C1-C6)alkyl, where (C1-C6)alkyl is optionally substituted with one or more groups independently selected from D, Cl, F, OH.
  • R 2 is: where R b and R c are independently selected from D, Cl, F, OH, and (C1-C6)alkyl, where (C1- C 6 )alkyl is optionally substituted with one or more groups independently selected from D, Cl, F, A specific value for R b and R c is independently selected from CH3, CH2F, and CH2OH.
  • the invention provides a compound of formula (III): or a prodrug or a salt thereof, wherein: X is N or CH; R 1 is selected from the group consisting of: wherein R 1 is optionally substituted with one or more groups independently selected from (C 1 - C6)alkyl and OH and wherein R 1 is substituted with one or more groups independently selected from deuterium, chloro, and fluoro; R a is H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, or (C 1 -C 6 )alkoxycarbonyl; R b is H, (C1-C6)alkyl, (C1-C6)alkanoyl, or (C1-C6)alkoxycarbonyl; and R c is H, (C1-C6)alkyl, (C1-C6)alkanoyl, or (C1-C6)alkoxycarbonyl.
  • the invention provides a compound of formula (I) or a prodrug or a salt thereof that is a compound of formula (II): or a prodrug or a salt thereof, wherein: X is N or CH; R 2 is: X 1 is NR a , O, or S; R a is selected from H, (C1-C6)alkyl, (C1-C6)alkanoyl, and (C1-C6)alkoxycarbonyl; is a single or double bond; and R 2 is optionally substituted with one or more groups independently selected from D, Cl, F, OH, and (C1-C6) alkyl, where (C1-C6)alkyl is optionally substituted with one or more groups independently selected from D, Cl, F, OH.
  • Certain Compounds e.g., certain compounds of formula (I) wherein R 1 includes a bridged bicyclic ring or certain compounds of formula (II) have improved kinase selectivity, potency, stability, pharmacokinetics, pharmacodynamics, penetration of the blood-brain barrier, chirality, and/or improvements in the activity of metabolites. Certain compounds may also elicit a unique microglia transcriptomic state that is beneficial. All of the exemplary compounds of Table 1 were prepared, characterized by LCMS [M+H] + (liquid chromatography mass spectroscopy) with detection of parent ion, and tested according to the assay described in Example 24.
  • Exemplary Formula I compounds have assay activity IC 50 values with the following ranges: more than seven compounds had an IC 50 ⁇ 10 nM; more than eleven compounds had an IC50 between 10nM and 100nM. Certain exemplary compounds demonstrate blood-brain barrier (BBB) permeability. Exemplary formula I compounds are shown in Table 1. Table 1 Exemplary compounds of formula (I)
  • a compound of formula (Ia), wherein R x is a protecting group can be converted to a corresponding compound of formula (I) by deprotecting the compound of formula (Ia) to provide the corresponding compound of formula (I).
  • the invention provides a method to prepare a compound of formula (I) comprising deprotecting a corresponding compound of formula (Ia), wherein R x is a protecting group to provide the compound of formula (I).
  • the invention also provides a compound of formula (Ia) wherein R x is a suitable protecting group.
  • R x is a trimethtlsilylethoxymethyl (SEM) group.
  • invention provides a method to prepare a compound of formula (I) comprising treating a corresponding compound of formula (Ia), wherein R x is a is a trimethtlsilylethoxymethyl (SEM) protecting group, with a fluoride source (e.g., tetrabutylammonium fluoride) to provide the compound of formula (I).
  • a fluoride source e.g., tetrabutylammonium fluoride
  • a salt of a compound of formula I can be useful as an intermediate for isolating or purifying a compound of formula I.
  • administration of a compound of formula I as a pharmaceutically acceptable acid or base salt may be appropriate.
  • Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, ⁇ - ketoglutarate, and ⁇ -glycerophosphate.
  • Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts. Salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
  • prodrug refers to those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
  • Prodrugs of the invention include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues, is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of a compound of the present invention. Additional types of prodrugs are also encompassed. For instance, a free carboxyl group of a compound of the invention can be derivatized as an amide or alkyl ester.
  • compounds of this invention comprising free hydroxy groups can be derivatized as prodrugs by converting the hydroxy group into a group such as, but not limited to, a phosphate ester, hemisuccinate, dimethylaminoacetate, or phosphoryloxymethyloxycarbonyl group, as outlined in Fleisher, D. et al., (1996) Improved oral drug delivery: solubility limitations overcome by the use of prodrugs Advanced Drug Delivery Reviews, 19:115.
  • Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups.
  • More specific examples include replacement of the hydrogen atom of the alcohol group with a group such as (C1-6)alkanoyloxymethyl, 1-((C1-6)alkanoyloxy)ethyl, 1-methyl-1-((C1- 6)alkanoyloxy)ethyl, (C1-6)alkoxycarbonyloxymethyl, N-(C1-6)alkoxycarbonylaminomethyl, succinoyl, (C 1-6 )alkanoyl, alpha-amino(C 1-4 )alkanoyl, arylacyl and alpha-aminoacyl, or alpha- aminoacyl-alpha-aminoacyl, where each alpha-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2, -P(O)(O(C1-6)alkyl)2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate).
  • prodrug derivatives see, for example, a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs," by H. Bundgaard p.113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992); d) H.
  • the compounds of formula I can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.
  • the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet.
  • a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier.
  • the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Such compositions and preparations should contain at least 0.1% of active compound.
  • compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form.
  • the amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.
  • the tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added.
  • binders such as gum tragacanth, acacia, corn starch or gelatin
  • excipients such as dicalcium phosphate
  • a disintegrating agent such as
  • the unit dosage form When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
  • the active compound may be incorporated into sustained-release preparations and devices.
  • the active compound may also be administered intravenously or intraperitoneally by infusion or injection.
  • Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
  • the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.
  • the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
  • the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
  • the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
  • Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like.
  • Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
  • Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use.
  • the resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
  • Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
  • useful dermatological compositions which can be used to deliver the compounds of formula I to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4,820,508).
  • Useful dosages of the compounds of formula I can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.
  • the amount of the compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
  • Compounds of the invention can also be administered in combination with other therapeutic agents, for example, checkpoint inhibitors, cholinesterase inhibitors, antibodies that target disease RNA and protein species, including but not limited to Amyloid beta, gene therapies, including, but not limited to, ASOs, siRNA, shRNA, AAV-based approaches, cell therapies, including, but not limited to, CRISPR, TALEN and ZFN), and compounds that modulate autophagy, ferroptosis, DNA damage repair, mis-folded protein, protein aggregation, apoptosis, mitochondria function, biogenesis, fusion/fission or the inflammasome.
  • other therapeutic agents for example, checkpoint inhibitors, cholinesterase inhibitors, antibodies that target disease RNA and protein species, including but not limited to Amyloid
  • 1,1,1-trifluoro-N-phenyl- N-(trifluoromethylsulfonyl)methanesulfonamide (2, 148.62 g, 416.0 mmol, 1.05 eq) was added at -70 °C.
  • the mixture was stirred at 20 °C for 10 h under N2.
  • the reaction mixture was quenched by NH4Cl (aqueous, 1000 mL) and extracted with EtOAc (1000 mL x 3).
  • the mixture was stirred at 25 °C for 12 hr.
  • the reaction mixture was diluted with water (500 mL) and extracted with EtOAc (200 mL x 2).
  • the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 2). The organic layers were combined, washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue without further purification.
  • Et. EtOAc gradient with a flow rate of 80 mL/min) to afford [1,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]- 8-oxabicyclo[3.2.1]octa-2,6-dien-3-yl]trifluoromethanesulfonate (19, 10 g, 18.36 mmol, 75.8 % yield) as a yellow oil that was used further as is.
  • Et. EtOAc gradient at a flow rate of 60 mL/min) to afford tert- butyl-[[5-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-8-oxabicyclo[3.2.1]octa-2,6-dien-1-yl]methoxy]-dimethyl-silane (INT-4, 4.6 g, 8.80 mmol, 95.9 % yield) as a yellow solid that was used further as is.
  • the mixture was stirred at 25 °C for 12 hr.
  • the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 2). The organic layers were combined, washed with brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash silica gel chromatography (ISCO®; 40 g SEPAFLASH® Silica Flash Column, with an eluent of 0 ⁇ 20 % Pet.
  • Et. EtOAc gradient at a flow rate of 60 mL/min) to afford N-[6-bromo-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]-4-cyano-1-(2- trimethylsilylethoxymethyl)imidazole-2-carboxamide (INT-5, 3.4 g, 6.41 mmol, 90.1 % yield) as a yellow solid that was used further as is.
  • the reaction mixture was filtered through a CELITETM pad and the filtrate was diluted with water (400 mL) and extracted with EtOAc (200 mL x 3). The organic layers were combined, washed with brine (300 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • the reaction mixture was diluted with NaHCO3 (saturated, aqueous, 10 mL) and extracted with DCM (10 mL x 3). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (SiO2, Pet.
  • the resulting residue was purified by Prep-HPLC (column: Waters Xbridge BEH C18100 x 30 mm x 10 ⁇ m; mobile phase:[water (NH 4 HCO 3 ) - ACN]; B%: gradient 50 %- 90 %, 8 min) to afford 2-(4,4-dimethylcyclohexen-1-yl)-6-[2,2,6,6- tetrakis(trideuteriomethyl)tetrahydropyran-4-yl]pyridin-3-amine (34, 0.2 g, 564.03 ⁇ mol, 64.12 % yield) as a white solid that was used further as is.
  • reaction mixture was concentrated under reduced pressure to remove DCM.
  • the residue was purified by Prep-HPLC (column: Phenomenex Luna C18100 x 40 mm x 5 ⁇ m; mobile phase: [water (TFA)-ACN]; gradient: 40 %-70 % B over 8 min) to afford title compound, 4-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[2,2,6,6- tetrakis(trideuteriomethyl)tetrahydropyran-4-yl]-3-pyridyl]-1H-imidazole-2-carboxamide (A-1) as a white solid (112.9 mg, 238.4 ⁇ mol, 57.6 % yield).
  • the reaction mixture was diluted with H 2 O (5 mL) and extracted with EtOAc (5 mL x 3). The organic layers were combined, washed with brine (5 mL x 3), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • the reaction mixture was diluted with NH4Cl (aqueous, 100 mL) and extracted with EtOAc (100 mL x 2). The organic layers were combined, washed with brine (150 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash silica gel chromatography (ISCO®; 220 g SEPAFLASH® Silica Flash Column, with an eluent of 0 ⁇ 20 % Pet.
  • Et. EtOAc gradient at a flow rate of 80 mL/min) to afford ethyl 7,9,9-trimethyl-1,4,8-trioxaspiro[4.5]decane-7- carboxylate (54, 5.7 g, 22.1 mmol, 77. % yield) as a yellow solid, that was used further as is and without further characterization.
  • reaction mixture was filtered and concentrated under reduced pressure to give, without further purification, (7,9,9-trimethyl-1,4,8-trioxaspiro[4.5]decan-7-yl)methanol (55, 4 g, 18.5 mmol, 83.8 % yield) as a yellow oil that was used further as is.
  • the mixture was stirred at 25 °C for 3 hr under blue LED lights.
  • the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 2). The organic layers were combined, washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • the mixture was stirred at 25 °C for 12 hr.
  • the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 2). The organic layers were combined, washed with brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • the reaction mixture was diluted with NH4Cl (aqueous, 300 mL) and extracted with EtOAc (200 mL x 2). The organic layers were combined, washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash silica gel chromatography (ISCO®; 330 g SEPAFLASH® Silica Flash Column with an eluent of 0 ⁇ 20 % Pet.
  • Et. EtOAc gradient at a flow rate of 80 mL/min) to afford 2-fluoro-8-oxabicyclo[3.2.1]oct-6-en-3-one (65, 5 g, 35.2 mmol, 24.3 % yield) as a yellow oil that was further used as is.
  • reaction mixture was concentrated under reduced pressure to give a residue to give, without further purification, 2-(4,4-dimethylcyclohexen-1-yl)-6-[2- fluoro-8-oxabicyclo[3.2.1]oct-6-en-3-yl]pyridin-3-amine (68, 230 mg, 389.88 ⁇ mol, 72.6 % yield, 75 % purity) as a TFA salt, as a yellow solid, that was used further as is.
  • Et. EtOAc gradient at a flow rate of 60 mL/min) to afford 4-cyano-N-[2- (4,4-dimethylcyclohexen-1-yl)-6-[2-fluoro-8-oxabicyclo[3.2.1]oct-6-en-3-yl]-3-pyridyl]-1-(2- trimethylsilylethoxymethyl)imidazole-2-carboxamide (69, 260 mg, 315.01 ⁇ mol, 45.0 % yield, 70 % purity) as a yellow oil that was used further as is.
  • reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 2). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by prep-HPLC (column: Phenomenex Luna C18100 x 40 mm x 5 ⁇ m; mobile phase: [H 2 O (0.1 % TFA) - ACN]; 35 % - 65 % B gradient over 8.0 min) to afford title compound, 5-cyano-N-[2-(4,4- dimethylcyclohexen-1-yl)-6-[2-fluoro-8-oxabicyclo[3.2.1]oct-6-en-3-yl]-3-pyridyl]-1H- imidazole-2-carboxamide (A-6, 49.8 mg, 111.3 ⁇ mol, 24.7 % yield) as a yellow oil.
  • Et. EtOAc gradient at a flow rate of 60 mL/min) to afford tert- butyl 7-[5-(tert-butoxycarbonylamino)-6-(4,4-dimethylcyclohexen-1-yl)-2-pyridyl]-3-oxa-9- azabicyclo[3.3.1]nonane-9-carboxylate (71, 580 mg, 1.10 mmol, 83.8 % yield) as a yellow solid that was used further as is.
  • the reaction mixture was diluted with water (20 mL) and extracted with DCM (20 mL x 2). The organic layers were combined, washed with brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to afford a residue.
  • the residue was purified by flash silica gel chromatography (ISCO®; 12 g SEPAFLASH® Silica Flash Column, with an eluent of 0 ⁇ 20 % Pet. Et.
  • the reaction mixture was diluted with H 2 O (5 mL) and extracted with EtOAc (8 mL x 3). The organic layers were combined, washed with brine(15 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , Pet. Et.
  • the reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (8 mL x 3). The organic layers were combined, washed with brine (15 mL), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • the reaction mixture was diluted with H 2 O (5 mL) and extracted with EtOAc (5 mL x 3). The organic layers were combined, washed with brine (5 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • Et. EtOAc gradient at a flow rate of 60 mL/min) to afford tert-butyl N- [6-[2,4-dichloro-8-oxabicyclo[3.2.1]oct-6-en-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)-3- pyridyl]carbamate (89, 150 mg, 312.87 ⁇ mol, 4.4 % yield) as a yellow solid, that was used further as is.
  • Et. EtOAc gradient at a flow rate of 60 mL/min) to afford 4-cyano-N-[6-[2,4-dichloro-8-oxabicyclo[3.2.1]oct-6-en-3-yl]-2-(4,4- dimethylcyclohexen-1-yl)-3-pyridyl]-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (91, 130 mg, 206.79 ⁇ mol, 71.3 % yield) as a yellow oil, which was used further as is.
  • reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 2). The organic layers were combined, washed with brine (20 mL), dried over Na 2 SO4, filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by prep-HPLC (column: Phenomenex Luna C18100 x 40 mm x 5 ⁇ m; mobile phase: [H2O (0.1% TFA) - ACN]; 60 % - 90 % B gradient over 8.0 min) to afford title compound, 5-cyano-N-[6-[2,4-dichloro-8- oxabicyclo[3.2.1]oct-6-en-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]-1H-imidazole-2- carboxamide (A-10, 42.8 mg, 85.87 ⁇ mol, 41.5 % yield) as a yellow oil.
  • the mixture was stirred at 25 °C for 12 hr under blue LED lights.
  • the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 2). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • the mixture was stirred at 25 °C for 12 h.
  • the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 2). The organic layers were combined, washed with brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 2). The organic layers were combined, washed with brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • the mixture was allowed to warm and further stirred at 20 °C for 16 hr under an N 2 atmosphere.
  • the reaction mixture was diluted with H 2 O (10 mL), extracted with DCM (6 mL x 3).
  • Et. EtOAc gradient at a flow rate of 60 mL/min) to afford N-[6-[1,5-bis[[tert- butyl(dimethyl)silyl]oxymethyl]-8-oxabicyclo[3.2.1]octa-2,6-dien-3-yl]-2-(4,4- dimethylcyclohexen-1-yl)-3-pyridyl]-4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2- carboxamide (98, 4.2 g, 4.96 mmol, 76.3 % yield) as a yellow oil that was used further as is.
  • the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (40 mL x 2). The organic layers were combined, washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • the mixture was stirred at 25 °C for 2 hr.
  • the reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 2). The organic layers were combined, washed with brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash silica gel chromatography (ISCO®; 12 g SEPAFLASH® Silica Flash Column, with an eluent of 0 ⁇ 20 % Pet.
  • Et. EtOAc gradient at a flow rate of 60 mL/min) to afford 3-[5-[[4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carbonyl]amino]-6-(4,4- dimethylcyclohexen-1-yl)-2-pyridyl]-5-(trifluoromethylsulfonyloxymethyl)-8- oxabicyclo[3.2.1]octa-3,6-dien-1-yl]methyltrifluoromethanesulfonate (100, 400 mg, 453.55 ⁇ mol, 93.4 % yield) was obtained as a yellow solid, where the 1 H NMR was consistent with the expected structure and the product was used further as is.
  • the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 2). The organic layers were combined, washed with brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash silica gel chromatography (ISCO®; 12 g SEPAFLASH® Silica Flash Column, with an eluent of 0 ⁇ 20 % Pet.
  • Et. EtOAc gradient at a flow rate of 60 mL/min) to afford N-[6- [1,5-bis(fluoromethyl)-8-oxabicyclo[3.2.1]octa-2,6-dien-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)- 3-pyridyl]-4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (101, 210 mg, 337.73 ⁇ mol, 74.5 % yield) as a yellow solid that was used further as is.
  • the reaction mixture was diluted with H 2 O (10 mL) and extracted with DCM (10 mL x 2). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • the mixture was further stirred at 25 °C for 16 hr under 34W blue LED lights.
  • the reaction mixture was quenched by NH4Cl (aqueous, 8 mL) and extracted with DCM (6 mL x 3). The organic layers were combined, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a residue.
  • the mixture was further stirred at 25 °C for 16 hr under 34W blue LED lights.
  • the reaction mixture was diluted with H 2 O (5 mL), extracted with EtOAc (4 mL x 3). The organic layers were combined, dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • the reaction mixture was quenched by H2O (20 mL) and extracted with EtOAc(20 mL x 2). The organic layers were combined, washed with brine (10 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash silica gel chromatography (ISCO®; 20 g SEPAFLASH® Silica Flash Column, with an eluent of 0 ⁇ 20 % Pet.
  • Et. EtOAc gradient at a flow rate of 80 mL/min) to afford tert-butyl-[[5- [[tert-butyl(dimethyl)silyl]oxymethyl]-2,3,6,7-tetradeuterio-3-deuteriooxy-8- oxabicyclo[3.2.1]octan-1-yl]methoxy]-dimethyl-silane (116, 1.6 g, 3.79 mmol, 99.0 % yield) as a yellow oil that was used further as is.
  • the mixture was stirred at 25 °C for 3 hr under blue LED lights.
  • the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x2). The organic layers were combined, washed with brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • Et. EtOAc gradient at a flow rate of 80 mL/min) to afford N-[6-[1,5- bis[[tert-butyl(dimethyl)silyl]oxymethyl]-2,3,6,7-tetradeuterio-8-oxabicyclo[3.2.1]octan-3-yl]-2- (4,4-dimethylcyclohexen-1-yl)-3-pyridyl]-4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole- 2-carboxamide (119, 240 mg, 280.9 ⁇ mol, 68.0 % yield) as a yellow solid that was used further as is.
  • the reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 2). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • the mixture was heated and stirred at 100 °C for 12 hr under N2.
  • the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 2). The organic layers were combined, washed with brine (80 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • Et. EtOAc at a flow rate of 60 mL/min) to afford N-[6-[1,5-bis[[tert- butyl(dimethyl)silyl]oxymethyl]-6,7-dideuterio-8-oxabicyclo[3.2.1]oct-2-en-3-yl]-2-(4,4- dimethylcyclohexen-1-yl)-3-pyridyl]-4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2- carboxamide (124, 260 mg, 305.75 ⁇ mol, 45.9 % yield) as a yellow solid, that was used further as is.
  • the reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 2). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • Et. EtOAc gradient at a flow rate of 40 mL/min) to afford [3-[5-[[4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carbonyl]amino]-6-(4,4- dimethylcyclohexen-1-yl)-2-pyridyl]-3,4,6,7-tetradeuterio-5- (trifluoromethylsulfonyloxymethyl)-8-oxabicyclo[3.2.1]octan-1-yl]methyltrifluoromethane- sulfonate (126, 200 mg, 224.72 ⁇ mol, 70.3 % yield) as a yellow solid that was used further as is.
  • the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (15 mL x 2). The organic layers were combined, washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash silica gel chromatography (ISCO®; 4 g SEPAFLASH® Silica Flash Column, with an eluent of 0 ⁇ 20 % Pet.
  • the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (15 mL x 2). The organic layers were combined, washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • Et. EtOAc gradient at a flow rate of 80 mL/min) to afford N-[4-bromo-2-(4,4-dimethylcyclohexen-1-yl)phenyl]-4-cyano-1-(2- trimethylsilylethoxymethyl)imidazole-2-carboxamide (130, 3.7 g, 6.99 mmol, 65.3 % yield) as a yellow oil, that was used further as is.
  • Et. EtOAc gradient at a flow rate of 60 mL/min) to afford N-[4-[1,5-bis[[tert- butyl(dimethyl)silyl]oxymethyl]-8-oxabicyclo[3.2.1]octa-2,6-dien-3-yl]-2-(4,4- dimethylcyclohexen-1-yl)phenyl]-4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2- carboxamide (131, 1.7 g, 2.01 mmol, 35.5 % yield) as a yellow oil that was used further as is.
  • the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (20 mL x 2). The organic layers were combined, washed with brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • Et. EtOAc gradient at a flow rate of 60 mL/min) to afford [3-[4- [[4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carbonyl]amino]-3-(4,4- dimethylcyclohexen-1-yl)phenyl]-5-(trifluoromethylsulfonyloxymethyl)-8- oxabicyclo[3.2.1]octa-3,6-dien-1-yl]methyltrifluoromethanesulfonate (133, 200 mg, 227.03 ⁇ mol, 70.0 % yield) as a yellow solid that was used further as is.
  • the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 2). The organic layers were combined, washed with brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash silica gel chromatography (ISCO®; 4 g SEPAFLASH® Silica Flash Column, with an eluent of 0 ⁇ 20 % Pet.
  • Et. EtOAc gradient at a flow rate of 60 mL/min) to afford N-[4- [1,5-bis(fluoromethyl)-8-oxabicyclo[3.2.1]octa-2,6-dien-3-yl]-2-(4,4-dimethylcyclohexen-1- yl)phenyl]-4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (134, 100 mg, 161.08 ⁇ mol, 71.0 % yield) as a yellow solid that was used further as is.
  • reaction mixture was diluted with H 2 O (10 mL) and extracted with DCM (10 mL x 2). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • the mixture was stirred at 25 °C for 3 hr under blue LED lights.
  • the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 2). The organic layers were combined, washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • Et. EtOAc gradient at a flow rate of 80 mL/min) to afford N-[4-[1,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-2,3,6,7-tetradeuterio-8- oxabicyclo[3.2.1]octan-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)phenyl]-4-cyano-1-(2- trimethylsilylethoxymethyl)imidazole-2-carboxamide (138, 1.1 g, 1.29 mmol, 59.9 % yield) as a yellow solid that was used further as is.
  • the reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 2). The organic layers were combined, washed with brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • Et. EtOAc with a flow rate of 80 mL/min) to afford 4-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-4- [2,3,6,7-tetradeuterio-1,5-bis(hydroxymethyl)-8-oxabicyclo[3.2.1]octan-3-yl]phenyl]-1-(2- trimethylsilylethoxymethyl)imidazole-2-carboxamide (139, 440 mg, 704.14 ⁇ mol, 66.8 % yield) as a yellow solid, that was used further as is.
  • Et. EtOAc gradient with a flow rate of 40 mL/min) to afford [3-[4-[[4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2- carbonyl]amino]-3-(4,4-dimethylcyclohexen-1-yl)phenyl]-3,4,6,7-tetradeuterio-5- (trifluoromethylsulfonyloxymethyl)-8-oxabicyclo[3.2.1]octan-1- yl]methyltrifluoromethanesulfonate (140, 380 mg, 427.45 ⁇ mol, 60.7 % yield) as a yellow solid that was used further as is.
  • the reaction mixture was diluted with water (10 mL) and extracted with DCM (15 mL x 2). The organic layers were combined, washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • Et.: EtOAc 1/0 to 0/1) to afford methyl 3-[4-(tert- butoxycarbonylamino)-3-(1,2-dideuterio-4,4-dimethyl-cyclohexyl)phenyl]-6,7-dideuterio-1,5- dimethyl-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (143, 1.4 g, 2.80 mmol, 74.3 % yield) as a white solid, where the 1 H NMR was consistent with the expected structure and the product was used further as is.
  • the reaction mixture was concentrated under reduced pressure to give a residue.
  • the residue was purified by Prep-HPLC (column: Phenomenex Luna C18100 x 40 mm x 5 um; mobile phase: [H 2 O (0.1 % TFA) - ACN]; 55 %-85 % B gradient over 8.0 min) to afford title compound 5- cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[1,5-dimethyl-8-oxabicyclo[3.2.1]octa-2,6-dien-3- yl]-3-pyridyl]-1H-imidazole-2-carboxamide (A-19, 0.0485 g, 106.46 ⁇ mol, 34.7 % yield) as yellow solid.
  • reaction mixture was concentrated under reduced pressure to give a residue.
  • residue was purified by prep-HPLC (column: Waters Xbridge C18150 x 50 mm x 10um; mobile phase: [H2O (10 mM NH4HCO3) - ACN]; 30 % - 70 % B gradient over 6.0 min) to afford title compound, 5-cyano-N- [2-(4,4-dimethylcyclohexen-1-yl)-6-(8-isopropyl-8-azabicyclo[3.2.1]octan-3-yl)-3-pyridyl]-1H- imidazole-2-carboxamide (A-20, 83.28 mg, 176.21 ⁇ mol, 45.1 % yield) as a white solid.
  • reaction mixture was stirred at 20 °C for 1 hr.
  • the reaction mixture was then diluted with MeOH (100 mL), then NaBH4 (2.28 g, 60.18 mmol, 2 eq) was added portion wise.
  • the reaction mixture was quenched with NH4Cl (30 mL) and extracted with EtOAc (100 mL x 3). The organic layers were combined, washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • reaction mixture was concentrated under reduced pressure to give a residue.
  • residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150 x 40 mm x 10 um; mobile phase: [H2O (10 mM NH4HCO3) - ACN]; 35 % - 75 % B gradient over 6.0 min) to afford title compound 5-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-(3,3,5,5-tetramethylpiperazin-1-yl)-3- pyridyl]-1H-imidazole-2-carboxamide (A-26, 0.0506 g, 109.62 ⁇ mol, 26.0 % yield) as a yellow solid.
  • reaction mixture was concentrated under reduced pressure to give a residue.
  • residue was purified by prep-HPLC (column: Phenomenex Luna C18100 x 30 mm x 5 um; mobile phase: [H 2 O (0.1 % TFA) - ACN]; 30 % - 60 % B gradient over 8.0 min) to afford title compound 5-cyano-N-[2- (4,4-dimethylcyclohexen-1-yl)-6-(4-ethyl-3,3,5,5-tetramethyl-piperazin-1-yl)-3-pyridyl]-1H- imidazole-2-carboxamide (A-29, 59.7 mg, 121.92 ⁇ mol, 39.8 % yield) as a white solid.
  • the reaction mixture was quenched by the addition of Na2SO4 (5 g, decahydrate). The resulting solid was collected by filtration, washed with EtOAc (10 mL x 3) and dried to obtain a residue.
  • EXAMPLE 36 4-[5-[(5-Cyano-1H-imidazole-2-carbonyl)amino]-6-(4,4-dimethylcyclohexen-1-yl)-2- pyridyl]-2,6,6-trimethyl-tetrahydropyran-2-carboxylic acid A-31 To a solution of ethyl 4-[5-[[4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2- carbonyl]amino]-6-(4,4-dimethylcyclohexen-1-yl)-2-pyridyl]-2,6,6-trimethyl-tetrahydropyran-2- carboxylate (202, 0.2 g, 307.74 ⁇ mol, 1 eq) in THF (3 mL) was added TBAF (1 M, 615.49 ⁇ L, 2 eq) at 20 °C, the mixture was stirred at 65 °C for 16 hr under N 2
  • reaction mixture was filtered and concentrated under reduced pressure to give a residue, without further purification, to afford 1,5-bis[[tert- butyl(dimethyl)silyl]oxymethyl]-8-oxabicyclo[3.2.1]octan-3-one (205, 5 g, crude) as a yellow oil.
  • the reaction mixture was quenched with water (8 mL) and extracted with EtOAc(5 mL x 2).
  • the reaction mixture was quenched with water (8 mL) and extracted with EtOAc(5 mL x 2).
  • the reaction mixture was quenched with H2O (100 mL) and extracted with EtOAc (150 mL x 3). The organic layers were combined, washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • reaction mixture was quenched with H 2 O (10 mL) and extracted with EtOAc (15 mL x 3). The organic layers were combined, washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • the resulting mixture was warmed and stirred at 100 °C for 12 hr under N2.
  • the reaction mixture was poured into NH4Cl (50 mL, aqueous) and extracted with EtOAc (50 mL x 3). The organic layers were combined, washed with brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • the reaction mixture was poured into NH4Cl (20 mL, aqueous) and extracted with EtOAc (20 mL x 3). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • reaction mixture was quenched by NH4Cl (30 mL, aqueous) and extracted with EtOAc(20 mL x 2). The organic layers were combined, washed with brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue, without further purification, to afford 1,5-bis[[tert- butyl(dimethyl)silyl]oxymethyl]-8-oxabicyclo[3.2.1]octan-3-ol (227, 5 g, 12.00 mmol, 99.5 % yield) as a yellow oil.
  • the reaction mixture was quenched by water (6 mL) and extracted with EtOAc (5 mL x 2).
  • the reaction mixture was quenched by water (10 mL) and extracted with DCM (6 mL x 3).
  • the resulting mixture was stirred at 25 °C for 2 hr.
  • the reaction mixture was poured into water (20 mL) and extracted with EtOAc (20 mL x 3).
  • the resulting mixture was stirred at 25 °C for 2 hrs.
  • the reaction mixture was poured into NH4Cl (50 mL, aqueous) and extracted with DCM (50 mL x 3). The organic layers were combined, washed with brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by column chromatography (SiO2, Pet. Et.
  • the resulting mixture was warmed and stirred at 40 °C for 2 hr.
  • the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3).
  • the resulting mixture was warmed and stirred at 60 °C for 3 hr.
  • the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL x 3). The organic layers were combined, washed with brine (20 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne un composé de formule (I) : ou un promédicament ou un sel de celui-ci, dans lequel R1, Rx, Ry, et X ont l'une quelconque des valeurs décrites dans la description, ainsi que des compositions comprenant un composé de formule (I). Les composés sont utiles en tant qu'inhibiteurs de kinase.
PCT/US2024/032992 2023-06-09 2024-06-07 Composés de 5-cyano-1h-imidazole-2-carboxamide en tant qu'inhibiteurs de csf1r Ceased WO2024254440A1 (fr)

Priority Applications (4)

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EP24742713.1A EP4709719A1 (fr) 2023-06-09 2024-06-07 Composés de 5-cyano-1h-imidazole-2-carboxamide en tant qu'inhibiteurs de csf1r
AU2024284488A AU2024284488A1 (en) 2023-06-09 2024-06-07 5-cyano-1h-imidazole-2-carboxamide compounds as csf1r inhibitors
CN202480051182.7A CN121729411A (zh) 2023-06-09 2024-06-07 作为csf1r抑制剂的5-氰基-1h-咪唑-2-甲酰胺化合物
JP2025571149A JP2026519814A (ja) 2023-06-09 2024-06-07 Ｃｓｆ１ｒ阻害剤としての５－シアノ－１ｈ－イミダゾール－２－カルボキサミド化合物

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US202363472202P 2023-06-09 2023-06-09
US63/472,202 2023-06-09
US202363540141P 2023-09-25 2023-09-25
US63/540,141 2023-09-25

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WO2024254440A1 true WO2024254440A1 (fr) 2024-12-12

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PCT/US2024/032992 Ceased WO2024254440A1 (fr) 2023-06-09 2024-06-07 Composés de 5-cyano-1h-imidazole-2-carboxamide en tant qu'inhibiteurs de csf1r

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EP (1) EP4709719A1 (fr)
JP (1) JP2026519814A (fr)
CN (1) CN121729411A (fr)
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WO (1) WO2024254440A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006047277A2 (fr) * 2004-10-22 2006-05-04 Janssen Pharmaceutica, N.V. Inhibiteurs de kinase c-fms
WO2009052237A1 (fr) * 2007-10-17 2009-04-23 Janssen Pharmaceutica, N.V. Inhibiteurs de la c-fms kinase
WO2014151258A1 (fr) * 2013-03-15 2014-09-25 Janssen Pharmaceutica Nv Dérivés de pyridine substitués utiles en tant qu'inhibiteurs de kinase c-fms

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006047277A2 (fr) * 2004-10-22 2006-05-04 Janssen Pharmaceutica, N.V. Inhibiteurs de kinase c-fms
WO2009052237A1 (fr) * 2007-10-17 2009-04-23 Janssen Pharmaceutica, N.V. Inhibiteurs de la c-fms kinase
WO2014151258A1 (fr) * 2013-03-15 2014-09-25 Janssen Pharmaceutica Nv Dérivés de pyridine substitués utiles en tant qu'inhibiteurs de kinase c-fms

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AU2024284488A1 (en) 2025-12-11
CN121729411A (zh) 2026-03-24
JP2026519814A (ja) 2026-06-18
EP4709719A1 (fr) 2026-03-18

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