Heterocyclic inhibitors of glutaminase

Abstract

The invention relates to novel heterocyclic compounds and pharmaceutical preparations thereof. The invention further relates to methods of treatment using the novel heterocyclic compounds of the invention.

1 - 71 . (canceled) 
     
     
         72 . A compound having a structure of formula I, 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         L represents CH 2 SCH 2 , CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 2 , CH 2 S, SCH 2 , CH 2 NHCH 2 , CH═CH, or 
       
       
         
           
           
               
               
           
         
          wherein any hydrogen atom of a CH or CH 2  unit may be replaced by alkyl or alkoxy, any hydrogen of an NH unit may be replaced by alkyl, and any hydrogen atom of a CH 2  unit of CH 2 CH 2 , CH 2 CH 2 CH 2  or CH 2  may be replaced by hydroxy; 
         X, independently for each occurrence, represents S, O or CH═CH, wherein any hydrogen atom of a CH unit may be replaced by alkyl; 
         Y, independently for each occurrence, represents H or CH 2 O(CO)R 7 ; 
         R 7 , independently for each occurrence, represents H or substituted or unsubstituted alkyl, alkoxy, aminoalkyl, alkylaminoalkyl, heterocyclylalkyl, or heterocyclylalkoxy; 
         Z represents R 3 (CO); 
         R 1  and R 2  each independently represent H, alkyl, alkoxy or hydroxy; 
         R 3 , independently for each occurrence, represents substituted or unsubstituted alkyl, hydroxyalkyl, aminoalkyl, acylaminoalkyl, alkenyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroaryloxyalkyl or C(R 8 )(R 9 )(R 10 ), N(R 4 )(R 5 ) or OR 6 , wherein any free hydroxyl group may be acylated to form C(O)R 7 , and further wherein each occurrence of R 3  is not identical; 
         R 4  and R 5  each independently represent H or substituted or unsubstituted alkyl, hydroxyalkyl, acyl, aminoalkyl, acylaminoalkyl, alkenyl, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl, wherein any free hydroxyl group may be acylated to form C(O)R 7 ; 
         R 6 , independently for each occurrence, represents substituted or unsubstituted alkyl, hydroxyalkyl, aminoalkyl, acylaminoalkyl, alkenyl, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl, wherein any free hydroxyl group may be acylated to form C(O)R 7 ; and 
         R 8 , R 9  and R 10  each independently represent H or substituted or unsubstituted alkyl, hydroxy, hydroxyalkyl, amino, acylamino, aminoalkyl, acylaminoalkyl, alkoxycarbonyl, alkoxycarbonylamino, alkenyl, alkoxy, alkoxyalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl, or R 8  and R 9  together with the carbon to which they are attached, form a carbocyclic or heterocyclic ring system, wherein any free hydroxyl group may be acylated to form C(O)R 7 , and wherein at least two of R 8 , R 9  and R 10  are not H. 
       
     
     
         73 . The compound of  claim 72 , wherein L represents CH 2 SCH 2 , CH 2 CH 2 , CH 2 S or SCH 2 . 
     
     
         74 . The compound of  claim 72 , wherein L represents CH 2 CH 2 . 
     
     
         75 . The compound of any one of  claims 72 - 74 , wherein Y represents H. 
     
     
         76 . The compound of any one of  claims 72 - 75 , wherein X, independently for each occurrence, represents S or CH═CH, wherein any hydrogen atom of a CH unit may be replaced by alkyl. 
     
     
         77 . The compound of any one of  claims 72 - 76 , wherein R 1  and R 2  each represent H. 
     
     
         78 . The compound of any one of  claims 72 - 77 , wherein R 3 , independently for each occurrence, represents substituted or unsubstituted arylalkyl, heteroarylalkyl, cycloalkyl or heterocycloalkyl. 
     
     
         79 . The compound of any one of  claims 72 - 78 , wherein R 3 , independently for each occurrence, represents C(R 8 )(R 9 )(R 10 ), wherein R 8  represents substituted or unsubstituted aryl, arylalkyl, heteroaryl or heteroaralkyl, R 9  represents H, and R 10  represents hydroxy, hydroxyalkyl, alkoxy or alkoxyalkyl. 
     
     
         80 . The compound of  claim 79 , wherein R 8  represents substituted or unsubstituted aryl, arylalkyl, or heteroaryl. 
     
     
         81 . The compound of  claim 79  or  80 , wherein R 10  represents hydroxy, hydroxyalkyl, or alkoxy. 
     
     
         82 . The compound of any one of  claims 72 - 77 , wherein at least one R 3  represents substituted or unsubstituted heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, or heteroaryloxyalkyl. 
     
     
         83 . The compound of  claim 72 , wherein L represents CH 2 SCH 2 , CH 2 CH 2 , CH 2 S or SCH 2 , Y represents H, X represents S, R 1  and R 2  each represent H, and R 3 , independently for each occurrence, represents substituted or unsubstituted arylalkyl, heteroarylalkyl, cycloalkyl or heterocycloalkyl. 
     
     
         84 . The compound of  claim 72 , wherein L represents CH 2 SCH 2 , CH 2 CH 2 , CH 2 S or SCH 2 , Y represents H, X represents S, R 1  and R 2  each represent H, and R 3 , independently for each occurrence, represents C(R 8 )(R 9 )(R 10 ), wherein R 8  represents substituted or unsubstituted aryl, arylalkyl, heteroaryl or heteroaralkyl, R 9  represents H, and R 10  represents hydroxy, hydroxyalkyl, alkoxy or alkoxyalkyl. 
     
     
         85 . The compound of  claim 84 , wherein L represents CH 2 CH 2 . 
     
     
         86 . The compound of  claim 84  or  85 , wherein R 8  represents substituted or unsubstituted aryl, arylalkyl or heteroaryl. 
     
     
         87 . The compound of  claim 86 , wherein R 8  represents substituted or unsubstituted aryl. 
     
     
         88 . The compound of any one of  claims 84 - 87 , wherein R 10  represents hydroxy, hydroxyalkyl or alkoxy. 
     
     
         89 . The compound of  claim 88 , wherein R 10  represents hydroxyalkyl. 
     
     
         90 . The compound of  claim 72 , wherein L represents CH 2 CH 2 , Y represents H, X, independently for each occurrence, represents S or CH═CH, R 1  and R 2  each represent H, and R 3 , independently for each occurrence, represents arylalkyl, heteroarylalkyl, cycloalkyl or heterocycloalkyl. 
     
     
         91 . A pharmaceutical composition comprising one or more pharmaceutically acceptable excipients and the compound of any one of  claims 72 - 90 . 
     
     
         92 . The pharmaceutical composition of  claim 91 , wherein the compound is present as a pharmaceutically acceptable salt. 
     
     
         93 . A method of treating cancer or an immunological or neurological disease comprising administering a compound of any one of  claims 72 - 90 . 
     
     
         94 . The method of  claim 93 , wherein the compound is administered as a pharmaceutically acceptable salt. 
     
     
         95 . The method of  claim 93  or  94 , wherein the cancer comprises Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Adrenocortical Carcinoma, Anal Cancer, Appendix Cancer, Atypical Teratoid/Rhabdoid Tumor, Basal Cell Carcinoma, Bile Duct Cancer, Bladder Cancer, Bone Cancer, Brain Tumor, Astrocytoma, Brain and Spinal Cord Tumors, Brain Stem Glioma, Central Nervous System Atypical Teratoid/Rhabdoid Tumor, Central Nervous System Embryonal Tumors, Breast Cancer, Bronchial Tumors, Burkitt Lymphoma, Carcinoid Tumor, Carcinoma of Unknown Primary, Central Nervous System Cancer, Cervical Cancer, Childhood Cancers, Chordoma, Chronic Lymphocytic Leukemia (CLL), Chronic Myelogenous Leukemia (CML), Chronic Myeloproliferative Disorders, Colon Cancer, Colorectal Cancer, Craniopharyngioma, Cutaneous T-Cell Lymphoma, Ductal Carcinoma In Situ (DCIS), Embryonal Tumors, Endometrial Cancer, Ependymoblastoma, Ependymoma, Esophageal Cancer, Esthesioneuroblastoma, Ewing Sarcoma, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, Eye Cancer, Fibrous Histiocytoma of Bone, Gallbladder Cancer, Gastric Cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Stromal Tumors (GIST), Germ Cell Tumor, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Ovarian Germ Cell Tumor, Gestational Trophoblastic Tumor, Glioma, Hairy Cell Leukemia, Head and Neck Cancer, Heart Cancer, Hepatocellular Cancer, Histiocytosis, Langerhans Cell Cancer, Hodgkin Lymphoma, Hypopharyngeal Cancer, Intraocular Melanoma, Islet Cell Tumors, Kaposi Sarcoma, Kidney Cancer, Langerhans Cell Histiocytosis, Laryngeal Cancer, Leukemia, Lip and Oral Cavity Cancer, Liver Cancer, Lobular Carcinoma In Situ (LCIS), Lung Cancer, Lymphoma, AIDS-Related Lymphoma, Macroglobulinemia, Male Breast Cancer, Medulloblastoma, Medulloepithelioma, Melanoma, Merkel Cell Carcinoma, Malignant Mesothelioma, Metastatic Squamous Neck Cancer with Occult Primary, Midline Tract Carcinoma Involving NUT Gene, Mouth Cancer, Multiple Endocrine Neoplasia Syndrome, Multiple Myeloma/Plasma Cell Neoplasm, Mycosis Fungoides, Myelodysplastic Syndrome, Myelodysplastic/Myeloproliferative Neoplasm, Chronic Myelogenous Leukemia (CML), Acute Myeloid Leukemia (AML), Myeloma, Multiple Myeloma, Chronic Myeloproliferative Disorder, Nasal Cavity Cancer, Paranasal Sinus Cancer, Nasopharyngeal Cancer, Neuroblastoma, Non-Hodgkin Lymphoma, Non-Small Cell Lung Cancer, Oral Cancer, Oral Cavity Cancer, Lip Cancer, Oropharyngeal Cancer, Osteosarcoma, Ovarian Cancer, Pancreatic Cancer, Papillomatosis, Paraganglioma, Paranasal Sinus Cancer, Nasal Cavity Cancer, Parathyroid Cancer, Penile Cancer, Pharyngeal Cancer, Pheochromocytoma, Pineal Parenchymal Tumors of Intermediate Differentiation, Pineoblastoma, Pituitary Tumor, Plasma Cell Neoplasm, Pleuropulmonary Blastoma, Breast Cancer, Primary Central Nervous System (CNS) Lymphoma, Prostate Cancer, Rectal Cancer, Renal Cell Cancer, Renal Pelvis Cancer, Ureter Cancer, Transitional Cell Cancer, Retinoblastoma, Rhabdomyosarcoma, Salivary Gland Cancer, Sarcoma, Sézary Syndrome, Skin Cancer, Small Cell Lung Cancer, Small Intestine Cancer, Soft Tissue Sarcoma, Squamous Cell Carcinoma, Squamous Neck Cancer with Occult Primary, Metastatic, Stomach Cancer, Supratentorial Primitive Neuroectodermal Tumors, T-Cell Lymphoma, Testicular Cancer, Throat Cancer, Thymoma, Thymic Carcinoma, Thyroid Cancer, Transitional Cell Cancer of the Renal Pelvis and Ureter, Gestational Trophoblastic Tumor, Unknown Primary, Unusual Cancer of Childhood, Urethral Cancer, Uterine Cancer, Uterine Sarcoma, Waldenström Macroglobulinemia, or Wilms Tumor. 
     
     
         96 . The method of any one of  claims 93 - 95 , wherein the method comprises conjointly administering one or more chemotherapeutic agents. 
     
     
         97 . The method of  claim 96 , wherein the one or more chemotherapeutic agents includes aminoglutethimide, amsacrine, anastrozole, asparaginase, Bacillus Calmette-Guérin vaccine (bcg), bicalutamide, bleomycin, buserelin, busulfan, campothecin, capecitabine, carboplatin, carmustine, chlorambucil, chloroquine, cisplatin, cladribine, clodronate, colchicine, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, demethoxyviridin, dichloroacetate, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, epirubicin, estradiol, estramustine, etoposide, everolimus, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, gemcitabine, genistein, goserelin, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, ironotecan, letrozole, leucovorin, leuprolide, levamisole, lomustine, lonidamine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, metformin, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, nocodazole, octreotide, oxaliplatin, paclitaxel, pamidronate, pentostatin, perifosine, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, sorafenib, streptozocin, sunitinib, suramin, tamoxifen, temozolomide, temsirolimus, teniposide, testosterone, thioguanine, thiotepa, titanocene dichloride, topotecan, trastuzumab, tretinoin, vinblastine, vincristine, vindesine, or vinorelbine. 
     
     
         98 . The method of  claim 96 , wherein the one or more chemotherapeutic agents is selected from the combinatorial therapies listed in Table 1. 
     
     
         99 . The method of any one of  claims 93 - 98 , wherein the method further comprises administering a non-chemical method of cancer treatment. 
     
     
         100 . The method of  claim 99 , wherein the non-chemical method of cancer treatment comprises radiation therapy. 
     
     
         101 . The method of  claim 99 , wherein the non-chemical method of cancer treatment comprises surgery, thermoablation, focused ultrasound therapy, cryotherapy, or any combination of the foregoing. 
     
     
         102 . The compound of  claim 72 , having a structure of the formula, 
       
         
           
           
               
               
           
         
       
     
     
         103 . The compound of  claim 102 , wherein R 3 , independently for each occurrence, represents substituted or unsubstituted alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.