Methods of using cleavable drug conjugates and compositions thereof

Abstract

Methods of synthesizing and using base-labile drug conjugates and compositions thereof are disclosed.

1 . A method of treating a patient suffering from a disease selected from a cancer, autoimmune disease, and infectious disease, comprising administering to a patient in need thereof a compound of Formula (II) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         each A 1  is independently a moiety selected from Formula (A 1 a1), Formula (A 1 a2), Formula (A 1 a3), Formula (A 1 b1), Formula (A 1 b2), Formula (A 1 c1), Formula (A 1 c2), Formula (A 1 c3), Formula (A 1 d1), Formula (A 1 d2), Formula (A 1 d3), Formula (A 1 e1), Formula (A 1 f1), and Formula (A 1 f2): 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein:
 each R 8  and R 9  is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, phenyl, and benzyl; 
 each E is selected from F, Cl, Br, and I; and 
 each L 2  is selected from halogen, N-hydroxysuccinimidyl, substituted N-hydroxysuccinimidyl, phenol-yl, substituted phenol-yl, hydroxybenzotriazolyl, substituted hydroxybenzotriazolyl, imidazolyl, and substituted imidazolyl; 
 
         each X 1  and X 3  is independently selected from a covalent bond, C 1-20  alkanediyl, substituted C 1-20  alkanediyl, C 1-20  heteroalkanediyl, substituted C 1-20  heteroalkanediyl, C 3-12  cycloalkanediyl, substituted C 3-12  cycloalkanediyl, C 3-12  heterocycloalkanediyl, substituted C 3-12  heterocycloalkanediyl, C 4-20  alkanecycloalkanediyl, substituted C 4-20  alkanecycloalkanediyl, C 4-20  heteroalkanecycloalkanediyl, substituted C 4-20  heteroalkanecycloalkanediyl, C 6-20  arenediyl, substituted C 6-20  arenediyl, C 6-20  heteroarenediyl, substituted C 6-20  heteroarenediyl, C 7-20  alkanearenediyl, substituted C 7-20  alkanearenediyl, C 6-20  heteroalkanearenediyl, substituted C 6-20  heteroalkanearenediyl, and —(CH 2 ) n1 —(CH 2 —CH 2 —O) n2 —(CH 2 ) n3 —, wherein:
 each n1 and n3 is independently an integer selected from 0 to 5; and 
 each n2 is independently an integer selected from 1 to 25; 
 
         each X 2  is independently selected from a covalent bond, —O—, —S—, —NH—, —N═, —N═N—, —N═CH—, —SO—, —SO 2 —, —SO 2 NH—, —SS—, —C(O)—, —C(O)O—, —C(O)NH—, —C(O)S—, —C(O)NH—N═, —OP(O)(OH)O—, —OC(O)O—, —OC(O)NH—, —NHC(O)NH—, and —NHC(S)NH—; 
         each R 1  and R 2  is independently selected from hydrogen, C 1-6  alkyl, substituted C 1-6  alkyl, C 1-6  heteroalkyl, substituted C 1-6  heteroalkyl, C 6-10  aryl, substituted C 6-10  aryl, C 6-10  heteroaryl, and substituted C 6-10  heteroaryl; 
         D is selected from aminopterin, folitixorin, methotrexate, pemetrexed, pralatrexate, raltitrexed, pelitrexol, talotrexin, deoxycoformycin, cladribine, clofarabine, fludarabine, thioguanine, mercaptopurine, berubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, amrubicin, pirarubicin, zorubicin, mitoxantrone, banoxantrone, ledoxantrone, nortopixantrone, pixantrone, piroxantrone, sabarubicin, topixantrone, monomethyl auristatin E, monomethyl auristatin F, monomethyl dolastatin 10, dolastatin 15, belotecan, atiratecan, camptothecin, exatecan, irinotecan, namitecan, rubitecan, topotecan, demecolcine, duocarmycin A, duocarmycin SA, duocarmycin B, duocarmycin B1, abbeymycin, anthramycin, centanamycin, chicamycin, mazethramycin, porothramycin A, porothramycin B, sibanomycin, sibiromycin, trabectedin, calicheamicin γ1, calicheamicin T, esperamicin A1, esperamicin C, esperamicin D, dynemicin A, dynemicin H, dynemicin M, dynemicin N, dynemicin O, dynemicin P, dynemicin Q, dynemicin S, neocarzinostatin chromophore, uncialamycin, 21-aminoepothilone B, eribulin, hemiasterlin, HTI-286, kahalatide F, elsamitrucin, lucanthone, melphalan, mitoguazone, nimustine, procarbazine, dacarbazine, amsacrine, 5-amino-4-oxo-pentanoic acid, methyl 5-amino-4-oxo-pentanoate, actinomycin D, 7-aminoactinomycin D, bleomycin, mitomycin, staurosporine, desacetylvinblastine hydrazide, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, afatinib, apilimod, balamapimod, barasertib, bosutinib, canertinib, cevipabulin, crizotinib, dacomitinib, dasatinib, denibulin, dilmapimod, dinaciclib, dovitinib, dutacatib, duvoglustat, edotecarin, elisidepsin, entinostat, epetirimod, erlotinib, fingolimod, fostamatinib, gefitinib, golotimod, gusperimus, imatinib, imiquimod, intedanib, ispinesib, lapatinib, lenalidomide, linifanib, litronesib, losmapimod, metesind, mocetinostat, motesanib, masitinib, myriocin, neratinib, nilotinib, odanacatib, ombrabulin, pamapimod, panobinostat, pazopanib, plerixafor, pomalidomide, razupenem, resiquimod, sabarubicin, saracatinib, seliciclib, selumetinib, sotirimod, squalamine, tacedinaline, talabostat, taltobulin, telatinib, tipifarnib, tozasertib, vandetanib, vatalanib, veliparib, voreloxin, alvespimycin, amikacin, amphotericin B, arbekacin, astromicin, bacitracin, balofloxacin, bederocin, bekanamycin, besifloxacin, brodimoprim, ciprofloxacin, clinafloxacin, colistin, daptomycin, dibekacin, enoxacin, framycetin, garenoxacin, gatifloxacin, gemifloxacin, gentamicin, gentamicin, grepafloxacin, hamycin, hexetidine, hygromycin B, ibacitabine, iclaprim, isepamicin, kanamycin, lomefloxacin, lucimycin, lymecycline, mepartricin, moxifloxacin, natamycin, nemonoxacin, neomycin B, neomycin C, netilmicin, norfloxacin, nystatin, omadacycline, oritavancin, paromomycin, pazufloxacin, perimycin A, perimycin B, perimycin C, pipemidic acid, polymyxin B, puromycin, radezolid, retaspimycin, ribostamycin, rimocidin, sisomicin, sitafloxacin, sparfloxacin, spectinomycin, streptomycin, sulfacetamide, sulfadiazine, sulfadimethoxine, sulfadimidine, sulfafurazole, sulfalene, sulfamazone, sulfamerazine, sulfamethizole, sulfamethoxazole, sulfamethoxypyridazine, sulfametomidine, sulfametoxydiazine, sulfametrole, sulfamoxole, sulfanilamide, sulfaperin, sulfaphenazole, sulfapyridine, sulfathiazole, sulfathiourea, sulfisomidine, teicoplanin, telavancin, tanespimycin, temafloxacin, tetroxoprim, tigecycline, tobramycin, tosufloxacin, trimethoprim, trimethoprim, trovafloxacin, tyrothricin, ulifloxacin, valnemulin, vancomycin, verdamicin, and zabofloxacin; and 
         n5 is an integer selected from 1 to 20. 
       
     
     
         2 . The method of  claim 1 , wherein the cancer is selected from adrenal cortical cancer, anal cancer, aplastic anemia, bile duct cancer, bladder cancer, bone cancer, bone metastasis, a brain cancer, a central nervous system (CNS) cancer, a peripheral nervous system (PNS) cancer, breast cancer, cervical cancer, childhood Non-Hodgkin's lymphoma, colon and rectum cancer, endometrial cancer, esophagus cancer, Ewing's family of tumors, eye cancer, gallbladder cancer, a gastrointestinal carcinoid tumor, a gastrointestinal stromal tumor, gestational trophoblastic disease, hairy cell leukemia, Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, acute lymphocytic leukemia, acute myeloid leukemia, children's leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, liver cancer, lung cancer, a lung carcinoid tumor, Non-Hodgkin's lymphoma, male breast cancer, malignant mesothelioma, multiple myeloma, myelodysplastic syndrome, myeloproliferative disorders, nasal cavity and paranasal cancer, nasopharyngeal cancer, neuroblastoma, oral cavity and oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, a sarcoma, melanoma skin cancer, non-melanoma skin cancers, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, uterine cancer, transitional cell carcinoma, vaginal cancer, vulvar cancer, mesothelioma, squamous cell or epidermoid carcinoma, bronchial adenoma, choriocarcinoma, head and neck cancers, teratocarcinoma, and Waldenstrom's macroglobulinemia. 
     
     
         3 . The method of  claim 1 , wherein the autoimmune disease is selected from alopecia areata, ankylosing spondylitis, Chagas disease, chronic obstructive pulmonary disease, Crohns Disease, dermatomyositis, diabetes mellitus type 1, endometriosis, Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome, Hashimoto's disease, Hidradenitis suppurativa, Kawasaki disease, IgA nephropathy, idiopathic thrombocytopenic purpura, interstitial cystitis, lupus erythematosus, lupus nephritis, mixed connective tissue disease, morphea, multiple sclerosis, Myasthenia gravis, carcolepsy, meuromyotonia, Pemphigus vulgaris, Pernicious anaemia, psoriasis, psoriatic arthritis, polymyositis, primary biliary cirrhosis, relapsing polychondritis, rheumatoid arthritis, sarcoidosis, schizophrenia, scleroderma, Sjögren's syndrome, temporal arteritis, ulcerative colitis, vasculitis, and Wegener's granulomatosis. 
     
     
         4 . The method of  claim 1 , wherein the infectious disease is selected from a fungal disease, a bacterial disease, and a viral disease. 
     
     
         5 . The method of  claim 1  comprising administering a second therapeutic agent effective in treating a cancer, autoimmune disease, or infectious disease. 
     
     
         6 . The method of  claim 1 , wherein each A 1  is independently a moiety selected from Formula (A 1 a1a), Formula (A 1 a2a), Formula (A 1 a2b), Formula (A 1 a3a), Formula (A 1 a3b), Formula (A 1 b1a), Formula (A 1 b1b), Formula (A 1 b1c), Formula (A 1 b2a), Formula (A 1 b2b), Formula (A 1 b2c), Formula (A 1 c1), Formula (A 1 c2), Formula (A 1 c3), Formula (A 1 d1), Formula (A 1 d2), Formula (A 1 d3), Formula (A 1 e1), Formula (A 1 f1), and Formula (A 1 f2): 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         7 . The method of  claim 1 , wherein each X 1  and X 3  is independently selected from a covalent bond, C 1-20  alkanediyl, C 1-20  cycloalkanediyl, C 6-10  arenediyl, C 7-20  alkanearenediyl, and —(CH 2 ) n1 —(CH 2 —CH 2 —O) n2 —(CH 2 ) n3 —, wherein each n1 and n3 is independently an integer selected from 0 to 5 and each n2 is independently an integer selected from 1 to 25. 
     
     
         8 . The compound of  claim 1 , wherein each X 1  and X 3  is independently selected from a covalent bond, methane-diyl, ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl, hexane-1,6-diyl, benzene-diyl, methylbenzene-diyl, ethylbenzene-diyl, propylbenzene-diyl, methyl cyclohexane-diyl, —(CH 2 ) 2 —(CH 2 —CH 2 —O)(CH 2 )—, —(CH 2 ) 2 —(CH 2 —CH 2 O) 2 —(CH 2 )—, and —(CH 2 ) 2 —(CH 2 —CH 2 O) 3 —(CH 2 ) 2 —. 
     
     
         9 . The compound of  claim 1 , wherein each X 2  is selected from a covalent bond, —O—, —S—, —SO—, —SO 2 —, —SO 2 NH—, —SS—, —C(O)—, —C(O)O—, —C(O)NH—, —C(O)NH—N═, —OC(O)NH—, and —NHC(O)NH—. 
     
     
         10 . The method of  claim 1 , wherein each X 2  is selected from a covalent bond, —O—, —SO 2 NH—, —SS—, —C(O)—, —C(O)O—, and —C(O)NH—. 
     
     
         11 . The method of  claim 1 , wherein each R 1  and R 2  is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, and phenyl. 
     
     
         12 . The method of  claim 1 , wherein the compound is selected from the compound of Formula (II-A-1), Formula (II-A-2), Formula (II-A-3), Formula (II-A-4), Formula (II-A-5), Formula (II-A-6), Formula (II-A-7), Formula (II-A-8), Formula (II-A-9), and Formula (II-A-10): 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         13 . The compound of  claim 1 , wherein the compound is selected from the compound of Formula (II-B-1), Formula (II-B-2), Formula (II-B-3), Formula (II-B-4), Formula (II-B-5), Formula (II-B-6), Formula (II-B-7), Formula (II-B-8), Formula (II-B-9), Formula (II-B-10), Formula (II-B-11), Formula (II-B-12), and Formula (II-B-13): 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         14 . The compound of  claim 1 , wherein the compound is selected from Formula (II-a), Formula (II-b), Formula (II-c), Formula (II-d), Formula (II-e), Formula (II-f), Formula (II-g), Formula (II-h), Formula (II-i), Formula (II j), Formula (II-k), Formula (II-l), Formula (II-m), Formula (II-n), Formula (II-o), Formula (II-p), Formula (II-q), Formula (II-r), Formula (II-s), Formula (II-t), Formula (II-u), Formula (II-v), Formula (II-w), Formula (II-x), Formula (II-y), Formula (II-z), Formula (II-aa), Formula (II-ab), and Formula (II-ac), or a salt of any of the foregoing: