Triazole benzamide derivatives and the compositions and methods of treatment regarding the same

Abstract

The present disclosure is directed to triazole benzamide compounds of formula (I) and formula (II), pharmaceutical compositions thereof and methods for modulating or activating a Parkin ligase The present disclosure is also directed to methods of treating and/or reducing the incidence of diseases or conditions related to the activation of Parkin ligase. R 1 , R 2 , R 3 , M 1 , M 2 , M 3 , L 1 , L 2 , and L 3 are as defined herein.

1 - 83 . (canceled) 
     
     
         84 . A compound of formula (II): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof, wherein:
 M 1  and M 2  are each independently selected from a bond, —NR 4 —, —NR 4 C(O)—, —C(O)NR 4 —, provided that M 1  and M 2  are not both —NR 4 — or both a bond; 
 R 1  and R 2  are each independently selected from a cycloalkyl, aryl, heterocyclyl, or heteroaryl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with one or more R 5a , provided that R 1  and R 2  are not 1,3-dioxoisoindolin-2-yl; 
 R 3  is selected from an alkyl, alkenyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with one or more R 5a ; 
 R 4  is each independently H or alkyl; 
 R 5a  is each independently I, Br, Cl, F, CN, NH 2 , NHR 6 , NO 2 , NR 6a R 6a , OH, OR 6a , or R 6a ; and 
 R 6a  is each independently alkyl or haloalkyl; or alternatively two R 6a  on the same N atom can together form a 3-6 membered N-heterocyclyl. 
 
     
     
         85 . The compound of  claim 84 , wherein, M 1  is a bond and M 2  is —NR 4 — or —NR 4 C(O)—. 
     
     
         86 . The compound of  claim 85 , wherein R 4  is H or C1-C3 alkyl. 
     
     
         87 . The compound of  claim 84 , wherein, M 2  is a bond and M 1  is —NR 4 — or —NR 4 C(O)—. 
     
     
         88 . The compound of  claim 87 , wherein R 4  is H or C1-C3 alkyl. 
     
     
         89 . The compound of  claim 84 , wherein R 1 , R 2 , and R 3  in formula (I) are each independently selected from phenyl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl, wherein each phenyl, heteroaryl and heterocyclyl is optionally substituted with one or more R 5a . 
     
     
         90 . The compound of  claim 89 , wherein R 1  and R 2  is each independently phenyl, pyridyl, pyrimidinyl, 
       
         
           
           
               
               
           
         
       
       each optionally substituted with one or more R 5a . 
     
     
         91 . The compound of  89 , wherein at least one of R 1  and R 2  is pyridyl, optionally substituted with one or more R 5a . 
     
     
         92 . The compound of  claim 91 , wherein at least one of R 1  and R 2  is 2-pyridyl, optionally substituted with one or more R 5a . 
     
     
         93 . The compound of  claim 89 , wherein R 3  is phenyl optionally substituted with one or more R 5a . 
     
     
         94 . The compound of  claim 89 , wherein R 5a  is methyl, I, Br, Cl, F, CN, NH 2 , NO 2 , OH, OCF 3 , or OMe. 
     
     
         95 . The compound of  claim 84 , wherein the compound has one of the following structures: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         96 . The compound of  claim 84 , wherein the compound has one of the following structures: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         97 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient and a compound of  claim 84 . 
     
     
         98 . The pharmaceutical composition of  claim 97 , wherein the compound has one of the following structures: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         99 . The pharmaceutical composition of  claim 97 , further comprising one additional therapeutically active agent. 
     
     
         100 - 110 . (canceled) 
     
     
         111 . A method of treating a disease or a condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (II): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof, wherein:
 M 1  and M 2  are each independently selected from a bond, —NR 4 —, —NR 4 C(O)—, —C(O)NR 4 —, provided that M 1  and M 2  are not both —NR 4 — or both a bond; 
 R 1  and R 2  are each independently selected from a cycloalkyl, aryl, heterocyclyl, or heteroaryl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with one or more R 5a , provided that R 1  and R 2  are not 1,3-dioxoisoindolin-2-yl; 
 R 3  is selected from an alkyl, alkenyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with one or more R 5a ; 
 R 4  is each independently H or alkyl; 
 R 5a  is each independently I, Br, Cl, F, CN, NH 2 , NHR 6 , NO 2 , NR 6a R 6a , OH, OR 6a , or R 6a ; and 
 R 6a  is each independently alkyl or haloalkyl; or alternatively two R 6a  on the same N atom can together form a 3-6 membered N-heterocyclyl. 
 
     
     
         112 . The method of  claim 111 , wherein the disease or the condition is cancer. 
     
     
         113 . The method of  claim 112 , wherein the cancer is Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Adrenocortical Carcinoma, AIDS-Related Cancers, Kaposi Sarcoma, Lymphoma, Anal Cancer, Appendix Cancer, Astrocytomas, Childhood Atypical Teratoid/Rhabdoid Tumor, Basal Cell Carcinoma, Skin Cancer (Nonmelanoma), Childhood Bile Duct Cancer, Extrahepatic Bladder Cancer, Bone Cancer, Ewing Sarcoma Family of Tumors, Osteosarcoma and Malignant Fibrous Histiocytoma, Brain Stem Glioma, Brain Tumors, Embryonal Tumors, Germ Cell Tumors, Craniopharyngioma, Ependymoma, Bronchial Tumors, Burkitt Lymphoma (Non-Hodgkin Lymphoma), Carcinoid Tumor, Gastrointestinal Carcinoma of Unknown Primary, Cardiac (Heart) Tumors, Lymphoma, Primary, Cervical Cancer, Childhood Cancers, Chordoma, Chronic Lymphocytic Leukemia, Chronic Myelogenous Leukemia, Chronic Myeloproliferative Neoplasms Colon Cancer, Colorectal Cancer, Cutaneous T-Cell Lymphoma, Ductal Carcinoma In Situ, Endometrial Cancer, Ependymoma, Esophageal Cancer, Esthesioneuroblastoma, Ewing Sarcoma, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, Eye Cancer, Intraocular Melanoma, Retinoblastoma, Fibrous Histiocytoma of Bone, Malignant, and Osteosarcoma, Gallbladder Cancer, Gastric (Stomach) Cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Stromal Tumors, Extragonadal Cancer, Ovarian Cancer, Testicular Cancer, Gestational Trophoblastic Disease, Glioma, Brain Stem Cancer, Hairy Cell Leukemia, Head and Neck Cancer, Heart Cancer, Hepatocellular (Liver) Cancer, Histiocytosis, Langerhans Cell Cancer, Hodgkin Lymphoma, Hypopharyngeal Cancer, Intraocular Melanoma, Islet Cell Tumors, Pancreatic Neuroendocrine Tumors, Kaposi Sarcoma, Kidney Cancer, Renal Cell Cancer, Wilms Tumor and Other Childhood Kidney Tumors, Langerhans Cell Histiocytosis, Laryngeal Cancer, Leukemia, Chronic Lymphocytic Cancer, Chronic Myelogenous Cancer, Hairy Cell Cancer, Lip and Oral Cavity Cancer, Liver Cancer (Primary), Lobular Carcinoma In Situ (LCIS), Lung Cancer, Non-Small Cell Cancer, Small Cell Cancer, Lymphoma, Cutaneous T-Cell (Mycosis Fungoides and Sezary Syndrome), Hodgkin Cancer, Non-Hodgkin Cancer, Macroglobulinemia, Waldenström, Male Breast Cancer, Malignant Fibrous Histiocytoma of Bone and Osteosarcoma, Melanoma, Intraocular (Eye) Cancer, Merkel Cell Carcinoma, Mesothelioma, Malignant, Metastatic Squamous Neck Cancer with Occult Primary, Midline Tract Carcinoma Involving NUT Gene, Mouth Cancer, Multiple Endocrine Neoplasia Syndromes, Multiple Myeloma/Plasma Cell Neoplasm, Mycosis Fungoides, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Neoplasms, Myelogenous Leukemia, Chronic, Myeloid Leukemia, Acute, Myeloma Multiple, Chronic Myeloproliferative Neoplasms, Nasal Cavity and Paranasal Sinus Cancer, Nasopharyngeal Cancer, Neuroblastoma, Non-Hodgkin Lymphoma, Non-Small Cell Lung Cancer, Oral Cancer, Oral Cavity Cancer, Lip and Oropharyngeal Cancer, Osteosarcoma and Malignant Fibrous Histiocytoma of Bone, Epithelial Cancer, Low Malignant Potential Tumor, Pancreatic Cancer, Pancreatic Neuroendocrine Tumors (Islet Cell Tumors), Papillomatosis, Paraganglioma, Parathyroid Cancer, Penile Cancer, Pharyngeal Cancer, Pheochromocytoma, Pituitary Tumor, Plasma Cell Neoplasm/Multiple Myeloma, Pleuropulmonary Blastoma, Primary Central Nervous System Lymphoma, Rectal Cancer, Renal Cell (Kidney) Cancer, Retinoblastoma, Rhabdomyosarcoma, Salivary Gland Cancer, Sarcoma, Ewing Cancer, Kaposi Cancer, Osteosarcoma (Bone Cancer), Soft Tissue Cancer, Uterine Cancer, Sezary Syndrome, Skin Cancer, Childhood Melanoma, Merkel Cell Carcinoma, Nonmelanoma, Small Cell Lung Cancer, Small Intestine Cancer, Soft Tissue Sarcoma, Squamous Cell Carcinoma, Skin Cancer (Nonmelanoma), Childhood Squamous Neck Cancer with Occult Primary, Metastatic Cancer, Stomach (Gastric) Cancer, T-Cell Lymphoma, Cutaneous Cancer, Testicular Cancer, Throat Cancer, Thymoma and Thymic Carcinoma, Thyroid Cancer, Transitional Cell Cancer of the Renal Pelvis and Ureter, Unknown Primary, Carcinoma of Childhood, Unusual Cancers of Childhood, Urethral Cancer, Uterine Cancer, Endometrial Cancer, Uterine Sarcoma, Vaginal Cancer, Vulvar Cancer, Waldenström Macroglobulinemia, Wilms Tumor, or Women's Cancers. 
     
     
         114 . The method of  claim 112 , wherein the cancer is colon cancer, lung cancer, or ovarian cancer. 
     
     
         115 . The method of  claim 111 , wherein the compound has one of the following structures: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         116 . The method of  claim 111 , wherein the compound has one of the following structures: 
       
         
           
           
               
               
           
         
       
       r a pharmaceutically acceptable salt or solvate thereof. 
     
     
         117 - 123 . (canceled) 
     
     
         124 . The compound of  claim 84 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         125 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient and the compound of  claim 124 , or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         126 . The method of  claim 111 , wherein the wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         127 . The method of  claim 126 , wherein the disease or the condition is cancer. 
     
     
         128 . The method of  claim 127 , wherein the cancer is colon cancer, lung cancer, or ovarian cancer.