Compositions and methods for inhibiting arginase activity

Abstract

The invention relates to a novel class of compounds that exhibit activity inhibitory activity toward arginase, and pharmaceutical compositions comprising the compounds of the invention. Also provided herein are methods of treating cancer with the arginase inhibitors of the invention.

We claim: 
     
         1 . A compound having a structure of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof; 
         wherein: 
         R a  is H or is selected from optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl; 
         R b  is H or is selected from optionally substituted alkyl, alkenyl, alkynyl, acyl, —C(O)O(alkyl), and —C(O)O(aryl); 
         each R c  is independently selected from H or alkyl, or two occurrences of R c  are taken together with the intervening —O—B—O— atoms to form an optionally substituted boron-containing ring; 
         X is O or S; 
         R 1  and R 2  are each independently selected from H and optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl; 
         R 1  and R 2  are taken together with the intervening atoms to form an optionally substituted 5- to 7-membered ring; and 
         R 3  is H or optionally substituted alkyl; 
         or R 1  and R 3  are taken together with the intervening atoms to form an optionally substituted 5- to 7-membered ring; 
         wherein the compound is not: 
       
       
         
           
           
               
               
           
         
       
     
     
         2 . The compound of  claim 1 , having a structure of formula (Ia): 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1 , having a structure of formula (Ib): 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , having a structure of formula (Ic): 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 1 , having a structure of formula (Id): 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 1 , having a structure of formula (Ie): 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 1 , having a structure of formula (If): 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 1 , having a structure of formula (Ig): 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 1 , having a structure of formula (Ih): 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of any one of  claims 1 - 3 , wherein R 2  is H. 
     
     
         11 . The compound of any one of  claims 1 - 10 , wherein R a  is H or optionally substituted alkyl. 
     
     
         12 . The compound of  claim 11 , wherein R a  is H. 
     
     
         13 . The compound of any one of  claims 1 - 12 , wherein R b  is H or optionally substituted alkyl or acyl. 
     
     
         14 . The compound of  claim 13 , wherein R b  is H. 
     
     
         15 . The compound of any one of  claims 1 - 14 , wherein, for each occurrence, R c  is H. 
     
     
         16 . The compound of any one of  claims 1 - 14 , wherein two occurrences of R c  are taken together to form an optionally substituted dioxaborolane, dioxaborolanone, dioxaborolandione, dioxaborinane, dioxaborinanone, or dioxaborinandione. 
     
     
         17 . The compound of any one of  claims 1 - 15 , wherein X is O. 
     
     
         18 . The compound of any one of  claims 1 - 17 , wherein if R 1  is H, then R 3  is not benzyl. 
     
     
         19 . The compound of any one of  claims 1 - 18 , wherein R 1  is H. 
     
     
         20 . The compound of any one of  claims 1 - 18 , wherein if R 1  is benzyl, then R 3  is not methyl. 
     
     
         21 . The compound of any one of  claims 1 - 17  and  20 , wherein R 1  is optionally substituted aralkyl, heteroaralkyl, (cycloalkyl)alkyl, or (heterocycloalkyl)alkyl. 
     
     
         22 . The compound of any one of  claims 1 - 17  and  20 , wherein R 1  is optionally substituted aralkyl or heteroaralkyl. 
     
     
         23 . The compound of  claim 22 , wherein R 1  is benzyl. 
     
     
         24 . The compound of  claim 22 , wherein R 1  is not benzyl substituted by —CF 3 . 
     
     
         25 . The compound of  claim 22 , wherein R 1  is heteroaralkyl, such as —CH 2 -(1H-imidazol-4-yl). 
     
     
         26 . The compound of any one of  claims 1 - 17 , wherein R 1  is optionally substituted alkyl, alkenyl, or alkynyl. 
     
     
         27 . The compound of  claim 26 , wherein R 1  is alkyl, optionally substituted by one or more substituents independently selected from hydroxy, halo, haloalkyl, alkoxy, —SH, —S-(alkyl), —SeH, —Se-(alkyl), aryl, heteroaryl, cycloalkyl, heterocycloalkyl, amino, carboxylic acid, ester, guanidino, and amido. 
     
     
         28 . The compound of  claim 27 , wherein R 1  is alkyl, optionally substituted by one or more substituents independently selected from hydroxy, halo, haloalkyl, alkoxy, —SH, —S-(alkyl), —SeH, —Se-(alkyl), heteroaryl, cycloalkyl, heterocycloalkyl, amino, carboxylic acid, ester, guanidino, and amido. 
     
     
         29 . The compound of  claim 28 , wherein R 1  is alkyl, optionally substituted by one or more substituents independently selected from hydroxy, alkoxy, haloalkyl, and —S-(alkyl). 
     
     
         30 . The compound of any one of  claims 1 - 17 , wherein R 1  is selected from optionally substituted cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. 
     
     
         31 . The compound of any one of  claims 1 - 17 , wherein R 1  is an amino acid side chain of Arg, His, Lys, Asp, Glu, Ser, Thr, Asn, Gln, Cys, Sec, Gly, Ala, Val, Ile, Leu, Met, Phe, Tyr, or Trp. 
     
     
         32 . The compound of any one of  claims 1 - 31 , wherein R 3  is H. 
     
     
         33 . The compound of any one of  claims 1 - 17 , wherein R 1  and R 3  are taken together with the intervening atoms to form a substituted 5-membered ring. 
     
     
         34 . The compound of any one of  claims 1 - 17 , wherein R 1  and R 3  are taken together with the intervening atoms to form an optionally substituted 6- or 7-membered ring. 
     
     
         35 . The compound of  claim 34 , wherein R 1  and R 3 , taken together with the intervening atoms, do not form a tetrahydroisoquinolinyl ring. 
     
     
         36 . The compound of  claim 1 , having a structure selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof. 
     
     
         37 . A pharmaceutical composition comprising a compound of any one of  claims 1 - 36  and a pharmaceutically acceptable carrier. 
     
     
         38 . A method of treating or preventing cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of  claims 1 - 36  or a pharmaceutical composition of  claim 37 . 
     
     
         39 . The method of  claim 38 , wherein the cancer is 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 Tumor, 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, Sezary Syndrome, Skin Cancer, Small Cell Lung Cancer, Small Intestine Cancer, Soft Tissue Sarcoma, Squamous Cell Carcinoma, Squamous Neck Cancer with Occult Primary, 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. 
     
     
         40 . The method of  claim 39 , wherein the cancer is selected from acute myeloid leukemia (AML), bladder cancer, breast cancer, colorectal cancer, chronic myelogenous leukemia (CML), esophageal cancer, gastric cancer, lung cancer, melanoma, mesothelioma, non-small cell lung carcinoma (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, and skin cancer. 
     
     
         41 . The method of any one of  claims 38 - 40 , further comprising conjointly administering one or more additional chemotherapeutic agents. 
     
     
         42 . The method of  claim 41 , wherein the one or more additional chemotherapeutic agents includes aminoglutethimide, amsacrine, anastrozole, asparaginase, AZD5363,  Bacillus  Calmette-Guérin vaccine (bcg), bicalutamide, bleomycin, bortezomib, buserelin, busulfan, campothecin, capecitabine, carboplatin, carfilzomib, carmustine, chlorambucil, chloroquine, cisplatin, cladribine, clodronate, cobimetinib, colchicine, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, demethoxyviridin, dexamethasone, dichloroacetate, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, epirubicin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, gemcitabine, genistein, goserelin, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, lenalidomide, letrozole, leucovorin, leuprolide, levamisole, lomustine, lonidamine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, metformin, methotrexate, miltefosine, mitomycin, mitotane, mitoxantrone, MK-2206, nilutamide, nocodazole, octreotide, olaparib, oxaliplatin, paclitaxel, pamidronate, pazopanib, pentostatin, perifosine, plicamycin, pomalidomide, porfimer, procarbazine, raltitrexed, rituximab, rucaparib, selumetinib, sorafenib, streptozocin, sunitinib, suramin, talazoparib, tamoxifen, temozolomide, temsirolimus, teniposide, testosterone, thalidomide, thioguanine, thiotepa, titanocene dichloride, topotecan, trametinib, trastuzumab, tretinoin, veliparib, vinblastine, vincristine, vindesine, or vinorelbine. 
     
     
         43 . The method of  claim 41 , wherein the one or more additional chemotherapeutic agents includes abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, atezolizumab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab, pidilizumab, rituximab, ticilimumab, samalizumab, or tremelimumab. 
     
     
         44 . The method of  claim 41 , wherein the one or more additional chemotherapeutic agents includes abagovomab, adecatumumab, afutuzumab, anatumomab mafenatox, apolizumab, blinatumomab, catumaxomab, durvalumab, epratuzumab, inotuzumab ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, nivolumab, ocaratuzumab, olatatumab, pembrolizumab, pidilizumab, ticilimumab, samalizumab, or tremelimumab. 
     
     
         45 . The method of  claim 44 , wherein the one or more additional chemotherapeutic agents includes ipilimumab, nivolumab, pembrolizumab, or pidilizumab. 
     
     
         46 . The method of any one of  claims 38 - 45 , wherein the method further comprises administering one or more non-chemical methods of cancer treatment, such as radiation therapy, surgery, thermoablation, focused ultrasound therapy, cryotherapy, or a combination of the foregoing.