Inhibitors of integrated stress response pathway

Abstract

The present disclosure relates generally to therapeutic agents that may be useful as inhibitors of Integrated Stress Response (ISR) pathway.

1 - 20 . (canceled) 
     
     
         21 . A compound of formula (VI): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein:
 R 24  is hydrogen or —C(O)OH; 
 R 25  is hydrogen or halogen; 
 L 7  is selected from the group consisting of 
 
       
       
         
           
           
               
               
           
         
         
            wherein the * represents the attachment point to A 7 , and the # represents the attachment point to the remainder of the molecule; 
           L 8  is selected from the group consisting of 
         
       
       
         
           
           
               
               
           
         
         
            wherein the * represents the attachment point to A 8 , and the # represents the attachment point to the remainder of the molecule; 
           A 7  is selected from the group consisting of phenyl, naphthyl, pyridyl, pyrazinyl, quinolinyl, benzofuranyl, 2,3-dihydrobenzofuranyl, benzothiazolyl, and 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, wherein each of the phenyl, naphthyl, pyridyl, pyrazinyl, quinolinyl, benzofuranyl, 2,3-dihydrobenzofuranyl, benzothiazolyl, or 3,4-dihydro-2H-benzo[b][1,4]oxazinyl is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halogen, CN, —NO 2 , C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, —O—C 1 -C 6  alkyl, —O—C 1 -C 6  haloalkyl, and C 1 -C 6  haloalkyl; 
           A 8  is selected from the group consisting of phenyl, naphthyl, pyridyl, pyrazinyl, quinolinyl, benzofuranyl, 2,3-dihydrobenzofuranyl, benzothiazolyl, and 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, wherein each of the phenyl, naphthyl, pyridyl, pyrazinyl, quinolinyl, benzofuranyl, 2,3-dihydrobenzofuranyl, benzothiazolyl, or 3,4-dihydro-2H-benzo[b][1,4]oxazinyl is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halogen, CN, —NO 2 , C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, —O—C 1 -C 6  alkyl, —O—C 1 -C 6  haloalkyl, and C 1 -C 6  haloalkyl. 
         
       
     
     
         22 . A compound of formula (VII): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein:
 R 26  is hydrogen or —C(O)OH; 
 R 27  is hydrogen or halogen; 
 L 9  is selected from the group consisting of 
 
       
       
         
           
           
               
               
           
         
         
            wherein the * represents the attachment point to A 9 , and the # represents the attachment point to the remainder of the molecule; 
           L 10  is selected from the group consisting of 
         
       
       
         
           
           
               
               
           
         
         
            wherein the * represents the attachment point to A 10 , and the # represents the attachment point to the remainder of the molecule; 
           A 9  is selected from the group consisting of phenyl, naphthyl, pyridyl, pyrazinyl, quinolinyl, benzofuranyl, 2,3-dihydrobenzofuranyl, benzothiazolyl, and 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, wherein each of the phenyl, naphthyl, pyridyl, pyrazinyl, quinolinyl, benzofuranyl, 2,3-dihydrobenzofuranyl, benzothiazolyl, or 3,4-dihydro-2H-benzo[b][1,4]oxazinyl is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halogen, CN, —NO 2 , C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, —O—C 1 -C 6  alkyl, —O—C 1 -C 6  haloalkyl, and C 1 -C 6  haloalkyl; 
           A 10  is selected from the group consisting of phenyl, naphthyl, pyridyl, pyrazinyl, quinolinyl, benzofuranyl, 2,3-dihydrobenzofuranyl, benzothiazolyl, and 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, wherein each of the phenyl, naphthyl, pyridyl, pyrazinyl, quinolinyl, benzofuranyl, 2,3-dihydrobenzofuranyl, benzothiazolyl, or 3,4-dihydro-2H-benzo[b][1,4]oxazinyl is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halogen, CN, —NO 2 , C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, —O—C 1 -C 6  alkyl, —O—C 1 -C 6  haloalkyl, and C 1 -C 6  haloalkyl. 
         
       
     
     
         23 . A compound of formula (VIII): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein:
 R 28  is hydrogen or —C(O)OH; 
 R 29  is hydrogen or halogen; 
 L 11  is selected from the group consisting of 
 
       
       
         
           
           
               
               
           
         
         
            wherein the * represents the attachment point to A 11 , and the # represents the attachment point to the remainder of the molecule; 
           L 12  is selected from the group consisting of 
         
       
       
         
           
           
               
               
           
         
         
            wherein the * represents the attachment point to A 12 , and the # represents the attachment point to the remainder of the molecule; 
           A 11  is selected from the group consisting of phenyl, naphthyl, pyridyl, pyrazinyl, quinolinyl, benzofuranyl, 2,3-dihydrobenzofuranyl, benzothiazolyl, and 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, wherein each of the phenyl, naphthyl, pyridyl, pyrazinyl, quinolinyl, benzofuranyl, 2,3-dihydrobenzofuranyl, benzothiazolyl, or 3,4-dihydro-2H-benzo[b][1,4]oxazinyl is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halogen, CN, —NO 2 , C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, —O—C 1 -C 6  alkyl, —O—C 1 -C 6  haloalkyl, and C 1 -C 6  haloalkyl; 
           A 12  is selected from the group consisting of phenyl, naphthyl, pyridyl, pyrazinyl, quinolinyl, benzofuranyl, 2,3-dihydrobenzofuranyl, benzothiazolyl, and 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, wherein each of the phenyl, naphthyl, pyridyl, pyrazinyl, quinolinyl, benzofuranyl, 2,3-dihydrobenzofuranyl, benzothiazolyl, or 3,4-dihydro-2H-benzo[b][1,4]oxazinyl is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halogen, CN, —NO 2 , C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, —O—C 1 -C 6  alkyl, —O—C 1 -C 6  haloalkyl, and C 1 -C 6  haloalkyl; 
           provided that the compound of formula (VIII) is not 
         
       
       
         
           
           
               
               
           
         
       
     
     
         24 - 56 . (canceled) 
     
     
         57 . The compound of  claim 21 , or a pharmaceutically acceptable salt thereof, wherein R 24  and R 25  are each hydrogen. 
     
     
         58 . The compound of  claim 21 , or a pharmaceutically acceptable salt thereof, wherein A 7  is phenyl optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halogen, CN, —NO 2 , C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, —O—C 1 -C 6  alkyl, —O—C 1 -C 6  haloalkyl, and C 1 -C 6  haloalkyl. 
     
     
         59 . The compound of  claim 21 , or a pharmaceutically acceptable salt thereof, wherein A 7  is phenyl optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halogen and C 1 -C 6  haloalkyl. 
     
     
         60 . The compound of  claim 21 , or a pharmaceutically acceptable salt thereof, wherein L 7  is selected from the group consisting of, 
       
         
           
           
               
               
           
         
         wherein the * represents the attachment point to A 7 , and the # represents the attachment point to the remainder of the molecule. 
       
     
     
         61 . The compound of  claim 21 , or a pharmaceutically acceptable salt thereof, wherein L 7  is selected from the group consisting of 
       
         
           
           
               
               
           
         
         wherein the * represents the attachment point to A 7 , and the # represents the attachment point to the remainder of the molecule. 
       
     
     
         62 . The compound of  claim 21 , or a pharmaceutically acceptable salt thereof, wherein L 8  is selected from the group consisting of 
       
         
           
           
               
               
           
         
         wherein the * represents the attachment point to A 8 , and the # represents the attachment point to the remainder of the molecule. 
       
     
     
         63 . The compound of  claim 21 , or a pharmaceutically acceptable salt thereof, wherein A 8  is selected from the group consisting of phenyl, naphthyl, pyridyl, pyrazinyl, quinolinyl, benzofuranyl, 2,3-dihydrobenzofuranyl, and 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, wherein each of the phenyl, naphthyl, pyridyl, pyrazinyl, quinolinyl, benzofuranyl, 2,3-dihydrobenzofuranyl, or 3,4-dihydro-2H-benzo[b][1,4]oxazinyl is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halogen, CN, —NO 2 , C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, —O—C 1 -C 6  alkyl, —O—C 1 -C 6  haloalkyl, and C 1 -C 6  haloalkyl. 
     
     
         64 . The compound of  claim 21 , or a pharmaceutically acceptable salt thereof, wherein A 8  is selected from the group consisting of phenyl, naphthyl, pyridyl, pyrazinyl, quinolinyl, benzofuranyl, 2,3-dihydrobenzofuranyl, and 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, wherein each of the phenyl, naphthyl, pyridyl, pyrazinyl, quinolinyl, benzofuranyl, 2,3-dihydrobenzofuranyl, or 3,4-dihydro-2H-benzo[b][1,4]oxazinyl is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halogen, CN, —O—C 1 -C 6  haloalkyl, and C 1 -C 6  haloalkyl. 
     
     
         65 . The compound of  claim 21 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         66 . The compound of  claim 21 , or a pharmaceutically acceptable salt thereof, wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         67 . The compound of  claim 21 , or a pharmaceutically acceptable salt thereof, wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         68 . The compound of  claim 21 , or a pharmaceutically acceptable salt thereof, wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         69 . The compound of  claim 21 , or a pharmaceutically acceptable salt thereof, wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         70 . A pharmaceutical composition comprising a compound of  claim 21 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         71 . A method of treating a disease or disorder mediated by an integrated stress response (ISR) pathway in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound of  claim 21 , or a pharmaceutically acceptable salt thereof. 
     
     
         72 . The method of  claim 71 , wherein the compound, or the pharmaceutically acceptable salt thereof, is administered in combination with a therapeutically effective amount of one or more additional anti-cancer agents. 
     
     
         73 . The method of  claim 71 , wherein the disease or disorder is mediated by phosphorylation of eIF2α and/or the guanine nucleotide exchange factor (GEF) activity of eIF2B. 
     
     
         74 . The method of  claim 71 , wherein the disease or disorder is mediated by a decrease in protein synthesis. 
     
     
         75 . The method of  claim 71 , wherein the disease or disorder is mediated by the expression of ATF4, CHOP or BACE-1. 
     
     
         76 . The method of  claim 71 , wherein the disease or disorder is a neurodegenerative disease, an inflammatory disease, an autoimmune disease, a metabolic syndrome, a cancer, a vascular disease, an ocular disease, a musculoskeletal disease, or a genetic disorder. 
     
     
         77 . The method of  claim 71 , wherein the disease is vanishing white matter disease, childhood ataxia with CNS hypomyelination, intellectual disability syndrome, Alzheimer's disease, prion disease, Creutzfeldt-Jakob disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS) disease, cognitive impairment, frontotemporal dementia (FTD), traumatic brain injury, postoperative cognitive dysfunction (PCD), neuro-otological syndromes, hearing loss, Huntington's disease, stroke, chronic traumatic encephalopathy, spinal cord injury, dementias or cognitive impairment, arthritis, psoriatic arthritis, psoriasis, juvenile idiopathic arthritis, asthma, allergic asthma, bronchial asthma, tuberculosis, chronic airway disorder, cystic fibrosis, glomerulonephritis, membranous nephropathy, sarcoidosis, vasculitis, ichthyosis, transplant rejection, interstitial cystitis, atopic dermatitis or inflammatory bowel disease, Crohn's disease, ulcerative colitis, celiac disease, systemic lupus erythematosus, type 1 diabetes, multiple sclerosis, rheumatoid arthritis, alcoholic liver steatosis, obesity, glucose intolerance, insulin resistance, hyperglycemia, fatty liver, dyslipidemia, hyperlipidemia, type 2 diabetes, pancreatic cancer, breast cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, urothelial cancer, endometrial cancer, ovarian cancer, cervical cancer, renal cancer, esophageal cancer, gastrointestinal stromal tumor (GIST), multiple myeloma, cancer of secretory cells, thyroid cancer, gastrointestinal carcinoma, chronic myeloid leukemia, hepatocellular carcinoma, colon cancer, melanoma, malignant glioma, glioblastoma, glioblastoma multiforme, astrocytoma, dysplastic gangliocytoma of the cerebellum, Ewing's sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, ductal adenocarcinoma, adenosquamous carcinoma, nephroblastoma, acinar cell carcinoma, lung cancer, non-Hodgkin's lymphoma, Burkitt's lymphoma, chronic lymphocytic leukemia, monoclonal gammopathy of undetermined significance (MGUS), plasmocytoma, lymphoplasmacytic lymphoma, acute lymphoblastic leukemia, Pelizaeus-Merzbacher disease, atherosclerosis, abdominal aortic aneurism, carotid artery disease, deep vein thrombosis, Buerger's disease, chronic venous hypertension, vascular calcification, telangiectasia or lymphoedema, glaucoma, age-related macular degeneration, inflammatory retinal disease, retinal vascular disease, diabetic retinopathy, uveitis, rosacea, Sjogren's syndrome or neovascularization in proliferative retinopathy, hyperhomocysteinemia, skeletal muscle atrophy, myopathy, muscular dystrophy, muscular wasting, sarcopenia, Duchenne muscular dystrophy (DMD), Becker's disease, myotonic dystrophy, X-linked dilated cardiomyopathy, spinal muscular atrophy (SMA), Down syndrome, MEHMO syndrome, metaphyseal chondrodysplasia, Schmid type (MCDS), depression, or social behavior impairment. 
     
     
         78 . A method of producing a protein, comprising contacting a eukaryotic cell comprising a nucleic acid encoding the protein with the compound of  claim 21 , or salt thereof. 
     
     
         79 . The method of  claim 78 , comprising culturing the cell in an in vitro culture medium comprising the compound or salt. 
     
     
         80 . A method of culturing a eukaryotic cell comprising a nucleic acid encoding a protein, comprising contacting the eukaryotic cell with an in vitro culture medium comprising the compound of  claim 21 , or salt thereof. 
     
     
         81 . The method of  claim 80 , wherein the nucleic acid encoding the protein is a recombinant nucleic acid. 
     
     
         82 . The method of  claim 80 , wherein the cell is a human embryonic kidney (HEK) cell or a Chinese hamster ovary (CHO) cell. 
     
     
         83 . The method of  claim 80 , wherein the cell is a yeast cell, a wheat germ cell, an insect cell, a rabbit reticulocyte, a cervical cancer cell, a baby hamster kidney cell, a murine myeloma cell, an HT-1080 cell, a PER.C6 cell, a plant cell, a hybridoma cell, or a human blood derived leukocyte. 
     
     
         84 . A method of producing a protein, comprising contacting a cell-free protein synthesis (CFPS) system comprising eukaryotic initiation factor 2 (eIF2) and a nucleic acid encoding a protein with the compound of  claim 21 , or salt thereof. 
     
     
         85 . The method of  claim 84 , wherein the protein is an antibody or a fragment thereof. 
     
     
         86 . The method of  claim 84 , wherein the protein is a recombinant protein, an enzyme, an allergenic peptide, a cytokine, a peptide, a hormone, erythropoietin (EPO), an interferon, a granulocyte-colony stimulating factor (G-CSF), an anticoagulant, or a clotting factor. 
     
     
         87 . The method of  claim 84 , comprising purifying the protein. 
     
     
         88 . An in vitro cell culture medium, comprising the compound of  claim 21 , or salt thereof, and nutrients for cellular growth. 
     
     
         89 . The cell culture medium of  claim 88 , comprising a eukaryotic cell comprising a nucleic acid encoding a protein. 
     
     
         90 . The cell culture medium of  claim 88 , further comprising a compound for inducing protein expression. 
     
     
         91 . The cell culture medium of  claim 88 , wherein the nucleic acid encoding the protein is a recombinant nucleic acid. 
     
     
         92 . The cell culture medium of  claim 88 , wherein the protein is an antibody or a fragment thereof. 
     
     
         93 . The cell culture medium of  claim 88 , wherein the protein is a recombinant protein, an enzyme, an allergenic peptide, a cytokine, a peptide, a hormone, erythropoietin (EPO), an interferon, a granulocyte-colony stimulating factor (G-CSF), an anticoagulant, or a clotting factor. 
     
     
         94 . The cell culture medium of  claim 88 , wherein the eukaryotic cell is a human embryonic kidney (HEK) cell or a Chinese hamster ovary (CHO) cell. 
     
     
         95 . The cell culture medium of  claim 88 , wherein the cell is a yeast cell, a wheat germ cell, an insect cell, a rabbit reticulocyte, a cervical cancer cell, a baby hamster kidney cell, a murine myeloma cell, an HT-1080 cell, a PER.C6 cell, a plant cell, a hybridoma cell, or a human blood derived leukocyte. 
     
     
         96 . A cell-free protein synthesis (CFPS) system comprising eukaryotic initiation factor 2 (eIF2) and a nucleic acid encoding a protein with the compound of  claim 21 , or salt thereof. 
     
     
         97 . The CFPS system of  claim 96 , comprising a eukaryotic cell extract comprising eIF2. 
     
     
         98 . The CFPS system of  claim 96 , further comprising eIF2B. 
     
     
         99 . The CFPS system of  claim 96 , wherein the protein is an antibody or a fragment thereof. 
     
     
         100 . The CFPS system of  claim 96 , wherein the protein is a recombinant protein, an enzyme, an allergenic peptide, a cytokine, a peptide, a hormone, erythropoietin (EPO), an interferon, a granulocyte-colony stimulating factor (G-CSF), an anticoagulant, or a clotting factor.