Chemical Compounds

Abstract

The invention is directed to substituted piperidine derivatives. Specifically, the invention is directed to compounds according to Formula IIII: wherein A, B, X, Y, L 1 , L 2 , L 3 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , z 2 , z 4 , z 5 , and z 6 are as defined herein, and salts thereof. The compounds of the invention are inhibitors of the ATF4 pathway and can be useful in the treatment of cancer, pre-cancerous syndromes and diseases associated with activated unfolded protein response pathways, such as Alzheimer's disease, spinal cord injury, traumatic brain injury, ischemic stroke, stroke, diabetes, Parkinson disease, Huntington's disease, Creutzfeldt-Jakob Disease, and related prion diseases, progressive supranuclear palsy, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular disease, inflammation, fibrosis, chronic and acute diseases of the liver, chronic and acute diseases of the lung, chronic and acute diseases of the kidney, chronic traumatic encephalopathy (CTE), neurodegeneration, dementia, cognitive impairment, atherosclerosis, ocular diseases, arrhythmias, in organ transplantation and in the transportation of organs for transplantation. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting the ATF4 pathway and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

1 . A compound according to Formula (III): 
       
         
           
           
               
               
           
         
         wherein:
 L 2  is selected from: a bond, —NH—, —O—, —S—, —S(O)—, —S(O) 2 —, substituted or unsubstituted C 1-8 alkylene or substituted or unsubstituted C 1-6 heteroalkylene, or L 2  is further taken together with B to form heterocycloalkyl; 
 L 3  is selected from: a bond, —NH—, —O—, —S—, —S(O)—, —S(O) 2 —, substituted or unsubstituted C 1-6 alkylene or substituted or unsubstituted C 1-6 heteroalkylene, or L 3  is further taken together with A to form heterocycloalkyl; 
 L 1  is selected from: a bond, —NH—, —C(R 7 )—, —O—, —S—, —S(O)—, —S(O) 2 —, substituted or: 
 unsubstituted C 1-6 alkylene and substituted or unsubstituted C 1-6 heteroalkylene; 
 R 1  is CH—, or R 1  is C— and taken together with R 3  and the nitrogen to which R 3  is attached, and optionally from 1 to 3 additional heteroatoms, to form a heterocycloalkyl, which is optionally substituted with from 1 to 5 substituents independently selected from:
 fluoro, chloro, C 1-6 alkyl, C 1-6 alkyl substituted 1 to 6 times by fluoro, C 1-4 alkoxy, C 1-4 alkoxy substituted 1 to 6 times by fluoro, oxo, and —NH 2 ; 
 
 
         R 3 , R 5  and R 6  and are independently hydrogen, fluoro, chloro, bromo, iodo, —OCH 3 , —OCH 2 Ph, —C(O)Ph, —CH 3 , —CF 3 , —CN, —S(O)CH 3 , —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —C(O)CH 3 , —CH(CH 3 ) 2 , —CCH, —CH 2 CCH, —SO 3 H, —SO 2 NH 2 , —NHC(O)NH 2 , —NHC(O)H, —NHOH, —OCF 3 , —OCHF 2 , substituted or unsubstituted C 1-6 alkylene, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, provided R 3  is absent when Z is a nitrogen linked heteroaryl; 
         R 2  and R 4  are independently NR 8 , O, or S; 
         R 7  is selected from: ═NR 8 , ═O, and ═S; 
         R 8  is selected from: hydrogen, C 1-6 alkyl and C 1-6 alkyl substituted 1 to 6 times by fluoro; 
         R 9  is selected from: hydrogen, fluoro, chloro, bromo, iodo, —OH, C 1-3 alkyl and C 1-3 alkyl substituted with from 1 to 3 substituents independently selected from: fluoro, oxo, —OH, and —NH 2 ; 
         A and B are independently aryl or heteroaryl; 
         z2 and z4 are independently 0 or 1; 
         z5 and z6 are independently an integer from 0 to 5; 
         X is absent or present as C 1-2 alkyl or C 1-2 alkyl substituted 1 to 2 times by fluoro, where the dotted lines represent optional bonds of the alkyl chain of X; 
         Y is absent or present as C 1-2 alkyl or C 1-2 alkyl substituted 1 to 2 times by fluoro, where the dotted lines represent optional bonds of the alkyl chain of Y; and 
         Z is nitrogen or a nitrogen linked heteroaryl; 
         or a salt thereof including a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The compound of  claim 1  represented by the following Formula (IV): 
       
         
           
           
               
               
           
         
         wherein:
 L 12  and L 13  are independently: —CH 2 —O—, —O—CH 2 —, —CH 2 —CH 2 —O—, —O—CH 2 —CH 2 —, 
 —CH 2 —CH 2 —CH 2 —O— and —O—CH 2 —CH 2 —CH 2 —; 
 L 11  is selected from: a bond, —CH 2 — and —C(O)—; 
 R 11  is CH— and R 13  is hydrogen, or R 1  1 is C— and taken together with R 13  and the nitrogen to which R 13  is attached form an oxazolidine, which is optionally substituted by oxo; 
 
         R 15  and R 16  are independently hydrogen or chloro; 
         R 12  and R 14  are O; 
         R 19  is selected from: hydrogen, fluoro, chloro, —OH, C 1-3 alkyl and C 1-3 alkyl substituted with from 1 to 3 substituents independently selected from: fluoro, oxo, and —OH; 
         z 12  and z 14  are independently 0 or 1; 
         z 15  and z 16  are independently an integer from 0 to 5; 
         X 1  is absent or present as C 1-2 alkyl or C 1-2 alkyl substituted 1 to 2 times by fluoro, where the dotted lines represent optional bonds of the alkyl chain of X; and 
         Y 1  is absent or present as C 1-2 alkyl or C 1-2 alkyl substituted 1 to 2 times by fluoro, where the dotted lines represent optional bonds of the alkyl chain of Y; 
       
       or a salt thereof including a pharmaceutically acceptable salt thereof. 
     
     
         3 . The compound of  claim 1  selected from:
 2-(4-chlorophenoxy)-N-(1-(2-(4-chlorophenoxy)acetyl)piperidin-4-yl)acetamide; 
 8-(2-(4-chlorophenoxy)acetyl)-3-(2-(4-chlorophenoxy)ethyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one; 
 2-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)propyl)piperidin-4-yl)acetamide; 
 2-(4-chlorophenoxy)-N-(1-(2-(4-chlorophenoxy)acetyl)piperidin-3-yl)acetamide; 
 N-(2-(4-chlorophenoxy)ethyl)-1-(3-(4-chlorophenoxy)propanoyl)piperidine-4-carboxamide; 
 2-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)propanoyl)piperidin-4-yl)acetamide; 
 2-(4-chlorophenoxy)-N-(1-(2-(4-chlorophenoxy)ethyl) piperidin-4-yl)acetamide; 
 2-(4-chlorophenoxy)-N-((1-(2-(4-chlorophenoxy)acetyl)piperidin-4-yl) methyl)acetamide; 
 N-(1-(2-((5-chloroisothiazol-3-y)oxy)ethyl) piperidin-4-y)-2-(4-chlorophenoxy)acetamide; 
 N-(1-(3-((5-chloroisothiazol-3-y)oxy)propyl) piperidin-4-yl)-2-(4-chlorophenoxy)acetamide; 
 2-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)-2-hydroxypropyl)piperidin-4-yl)acetamide; 
 (R)-2-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)-2-hydroxypropyl)piperidin-4-yl)acetamide; 
 (S)-2-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)-2-hydroxypropyl) piperidin-4-yl)acetamide; 
 2-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)-2-fluoropropyl)piperidin-4-yl)acetamide; 
 2-(4-chlorophenoxy)-N-(2-(3-(4-chlorophenoxy)-2-hydroxypropyl)-2-azabicyclo[2.2.1]heptan-5-yl)acetamide; 
 2-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)-2-methoxypropyl)piperidin-4-yl)acetamide; 
 2-(4-chlorophenoxy)-N-(1-(3-((6-chloropyridin-3-yl)oxy)propyl)piperidin-4-yl)acetamide; 
 2-(4-chlorophenoxy)-N-(2-(3-(4-chlorophenoxy)propyl)-2-azabicyclo[2.2.1]heptan-5-yl)acetamide; 
 N-(1-(3-(4-chlorophenoxy)propyl)piperidin-4-y)-2-((5-chloropyridin-2-yl)oxy)acetamide; 
 2-(4-chlorophenoxy)-N-(1-(3-((5-chloropyridin-2-yl)oxy)propyl)piperidin-4-yl)acetamide; 
 2-(4-chlorophenoxy)-N-(1-(3-(3,4-dichlorophenoxy)propyl)piperidin-4-yl)acetamide; 
 4-(2-((4-chlorophenoxy)methyl)-1H-imidazol-1-yl)-1-(3-(4-chlorophenoxy)propyl)piperidine; 
 2-(4-chlorophenoxy)-N-(1-(2-(4-chlorophenoxy)acetyl)-3-methylpiperidin-4-yl)acetamide; 
 N-(4-chlorophenethyl)-1-(2-(4-chlorophenoxy)acetyl) piperidine-4-carboxamide; 
 2-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)propanoyl)piperidin-4-yl)acetamide; 
 2-(4-chlorophenoxy)-N-(1-(4-(4-chlorophenyl)butanoyl)-3-fluoropiperidin-4-yl)acetamide; 
 2-(4-chlorophenoxy)-N-(1-(2-(4-chlorophenoxy)acetyl)piperidin-3-yl)acetamide; 
 2-(4-chlorophenoxy)-N-(2-(1-(2-(4-chlorophenoxy)acetyl)piperidin-3-yl)ethyl)acetamide; 
 N-((1-(2-(4-chlorophenoxy)acetyl)piperidin-3-yl)methyl)-2-((6-chloropyridin-3-yl)oxy)acetamide; 
 2-(4-chlorophenoxy)-N-(1-(2-(4-chlorophenoxy)acetyl)-3-fluoropiperidin-4-yl)acetamide; 
 2-(4-chlorophenoxy)-N-(2-(2-(4-chlorophenoxy)acetyl)-2-azabicyclo[2.2.1]heptan-5-yl)acetamide; 
 2-(4-chlorophenoxy)-N-(1-((1R,2R)-2-(4-chlorophenoxy)cyclopropane-1-carbonyl)piperidin-4-yl)acetamide; 
 2-(4-chlorophenoxy)-N-(1-((1R,2S)-2-(4-chlorophenoxy)cyclopropane-1-carbonyl)piperidin-4-yl)acetamide; 
 N-(1-((1 S,2R)-2-(4-chlorobenzyl)cyclopropane-1-carbonyl)piperidin-4-yl)-2-(4-chlorophenoxy)acetamide; 
 N-(1-((1R,2R)-2-(4-chlorobenzyl)cyclopropane-1-carbonyl)piperidin-4-yl)-2-(4-chlorophenoxy)acetamide; 
 2-(4-chlorophenoxy)-N-(1-(2-(4-chlorophenyl)cyclopropane-1-carbonyl)piperidin-4-yl)acetamide; 
 2-(4-chlorophenoxy)-N-(1-(4-(4-chlorophenyl)butanoyl)piperidin-4-yl)acetamide; 
 2-(4-chlorophenoxy)-N-(1-(2-(4-chlorophenoxy)ethyl)-3-methylpiperidin-4-yl)acetamide; 
 N,1-bis(2-(4-chlorophenoxy)ethyl)piperidine-4-carboxamide; 
 N-(2-(4-chlorophenoxy)ethyl)-1-(3-(4-chlorophenoxy)propyl)piperidine-4-carboxamide; 
 2-(4-chlorophenoxy)-N-(1-(2-(4-chlorophenoxy)ethyl)-3-hydroxypiperidin-4-yl)acetamide; 
 6-chloro-N-(1-(3-(4-chlorophenoxy)propyl)piperidin-4-yl)chromane-2-carboxamide; 
 N-(1-(3-(4-chlorophenoxy)propyl)piperidin-4-yl)-2-((6-chloropyridin-3-yl)oxy)acetamide; 
 N-(1-(3-(4-chlorophenoxy)propyl)piperidin-4-yl)-2-(3,4-dichlorophenoxy)acetamide; 
 N-(1-(3-(4-chlorophenoxy)propyl)piperidin-4-yl)-2-(2,4-dichlorophenoxy)acetamide; 
 2-(4-chlorophenoxy)-N-((1R,5S)-8-(3-(4-chlorophenoxy)propyl)-8-azabicyclo[3.2.1]octan-3-yl)acetamide; 
 2-(4-chlorophenoxy)-N-(1-(2-(3,4-dichlorophenoxy)ethyl)-3-fluoropiperidin-4-yl)acetamide; 
 N-(1-(2-(4-chlorophenoxy)ethyl)-3-fluoropiperidin-4-yl)-2-(3,4-dichlorophenoxy)acetamide; 
 2-(4-chlorophenoxy)-N-((1-(3-(4-chlorophenoxy)propyl)piperidin-4-yl)methyl)acetamide; 
 2-(4-chlorophenoxy)-N-(1-(2-(4-chlorophenoxy)ethyl)-3-fluoropiperidin-4-yl)acetamide; 
 4-(4-chlorophenoxy)-2-(4-(2-(4-chlorophenoxy)acetamido)piperidin-1-yl)butanoic acid; 
 2-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)propyl)-2-oxopiperidin-4-yl)acetamide; 
 4-(4-chlorophenoxy)-2-(4-(2-(3,4-dichlorophenoxy)acetamido)piperidin-1-yl)butanoic acid; 
 2-(4-(2-(4-chlorophenoxy)acetamido)piperidin-1-yl)-4-(3,4-dichlorophenoxy)butanoic acid; 
 N-(1-(3-(4-chlorophenoxy)propyl)piperidin-4-yl)-2-(4-(difluoromethoxy)phenoxy)acetamide; 
 N-(1-(3-(4-chlorophenoxy)propyl)piperidin-4-yl)-2-(4-cyclopropylphenoxy)acetamide; 
 2-(4-chlorophenoxy)-N-(1-(3-(4-chlorophenoxy)propyl)piperidin-4-yl)-N-methylacetamide; 
 4-(2-(4-chlorophenoxy)acetamido)-1-(3-(4-chlorophenoxy)propyl)piperidine-2-carboxylic acid; and 
 4-(2-(4-chlorophenoxy)acetamido)-1-(3-(4-chlorophenoxy)propyl)piperidine-2-carboxylic acid; 
 
       or a salt thereof including a pharmaceutically acceptable salt thereof. 
     
     
         4 . A pharmaceutical composition comprising a compound according to  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. 
     
     
         5 . A method of treating a disease selected from: cancer, pre-cancerous syndromes, Alzheimer's disease, spinal cord injury, traumatic brain injury, ischemic stroke, stroke, diabetes, Parkinson disease, Huntington's disease, Creutzfeldt-Jakob Disease, and related prion diseases, progressive supranuclear palsy, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular disease, inflammation, fibrosis, chronic and acute diseases of the liver, chronic and acute diseases of the lung, chronic and acute diseases of the kidney, chronic traumatic encephalopathy (CTE), neurodegeneration, dementia, cognitive impairment, atherosclerosis, ocular diseases, in organ transplantation and arrhythmias, in a mammal in need thereof, which comprises administering to such mammal a therapeutically effective amount of a compound as described in  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         6 . The method of  claim 5  wherein the mammal is a human. 
     
     
         7 - 8 . (canceled) 
     
     
         9 . The method according to  claim 5  wherein said cancer is selected from: brain (gliomas), glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate, sarcoma and thyroid. 
     
     
         10 - 11 . (canceled) 
     
     
         12 . The method of inhibiting the ATF4 pathway in a mammal in need thereof, which comprises administering to such mammal a therapeutically effective amount of a compound as described in  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         13 . The method of  claim 12  wherein the mammal is a human. 
     
     
         14 . A method of treating cancer in a mammal in need thereof, which comprises: administering to such mammal a therapeutically effective amount of
 a) a compound as described in  claim 1  or a pharmaceutically acceptable salt thereof; and   b) at least one anti-neoplastic agent.   
     
     
         15 . The method  claim 14 , wherein the at least one anti-neoplastic agent is selected from the group consisting of: anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis, inhibitors, immunotherapeutic agents, proapoptotic agents, cell cycle signaling inhibitors, proteasome inhibitors, and inhibitors of cancer metabolism. 
     
     
         16 . A pharmaceutical combination comprising:
 a) a compound as described in  claim 1  or a pharmaceutically acceptable salt thereof; and   b) at least one anti-neoplastic agent.   
     
     
         17 . (canceled) 
     
     
         18 . The method according to  claim 5  wherein said cancer is selected from: breast cancer, inflammatory breast cancer, ductal carcinoma, lobular carcinoma, colon cancer, pancreatic cancer, insulinomas, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, skin cancer, melanoma, metastatic melanoma, lung cancer, small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma, adenocarcinoma, large cell carcinoma, brain (gliomas), glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, head and neck, kidney, liver, melanoma, ovarian, pancreatic, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid,
 lymphoblastic T cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, Immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, 
 malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma, 
 neuroblastoma, bladder cancer, urothelial cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor), neuroendocrine cancers and testicular cancer. 
 
     
     
         19 . The method of  claim 18  wherein the mammal is a human. 
     
     
         20 . A process for preparing a pharmaceutical composition containing a pharmaceutically acceptable excipient and an effective amount of a compound as described in  claim 1  or a pharmaceutically acceptable salt thereof, which process comprises bringing the compound or a pharmaceutically acceptable salt thereof into association with a pharmaceutically acceptable excipient. 
     
     
         21 . The method according to  claim 5  wherein said pre-cancerous syndrome is selected from: cervical intraepithelial neoplasia, monoclonal gammapathy of unknown significance (MGUS), myelodysplastic syndrome, aplastic anemia, cervical lesions, skin nevi (pre-melanoma), prostatic intraepithleial (intraductal) neoplasia (PIN), Ductal Carcinoma in situ (DCIS), colon polyps and severe hepatitis or cirrhosis. 
     
     
         22 . (canceled) 
     
     
         23 . A method of treating ocular diseases in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound as described in  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         24 . A method according to  claim 23  wherein the ocular disease is selected from: rubeosis irides; neovascular glaucoma; pterygium; vascularized glaucoma filtering blebs; conjunctival papilloma; choroidal neovascularization associated with age-related macular degeneration (AMD), myopia, prior uveitis, trauma, or idiopathic; macular edema; retinal neovascularization due to diabetes; age-related macular degeneration (AMD); macular degeneration (AMD); ocular ischemic syndrome from carotid artery disease; ophthalmic or retinal artery occlusion; sickle cell retinopathy; retinopathy of prematurity; Eale's Disease; and VonHippel-Lindau syndrome. 
     
     
         25 . A method according to  claim 23  wherein the ocular disease is selected form: age-related macular degeneration (AMD) and macular degeneration. 
     
     
         26 . A method of treating neurodegeneration in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a compound of Formula I, as described in  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         27 . A method of preventing organ damage during the transportation of organs for transplantation, which comprises adding a compound as described in  claim 1  or a pharmaceutically acceptable salt thereof, to a solution housing the organ during transportation. 
     
     
         28 .- 35 . (canceled)