Compositions and methods for treating cancer

Abstract

The present disclosure relates to compounds that are capable of penetrating the blood brain barrier to modulate the activity of EGFR tyrosine kinase. The disclosure further relates to methods of treating glioblastoma and other EGFR-mediated cancers, such as those that have been determined to have altered glucose metabolism in the presence of inhibitors. The present disclosure also provides methods of administering to a subject a glucose metabolism inhibitor and a cytoplasmic p53 stabilizer.

1 - 115 . (canceled) 
     
     
         116 . A method of treating central nervous system (CNS) cancer, comprising administering a therapeutically effective amount of a compound of Formula A or pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein n is 1 or 2; 
         R is —OH or —N(R 1 )R 2 ; 
         wherein R 1  and R 2  are independently alkyl or hydrogen; or R 1  and R 2  combine to form a 5- or 6-membered heterocyclyl optionally containing an additional —O— or —N(R 3 ) ring atom, wherein R 3  is alkyl. 
       
     
     
         117 . The method of  claim 116 , wherein the compound is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         118 . The method of  claim 116 , wherein the compound or pharmaceutically acceptable salt thereof is formulated as a pharmaceutical composition comprising a compound of  claim 116  and a pharmaceutically acceptable excipient. 
     
     
         119 . The method of  claim 116 , wherein the CNS cancer comprises a primary malignant brain tumor. 
     
     
         120 . The method  claim 119 , wherein the primary malignant brain tumor comprises an astrocytoma, a pilocytic astrocytoma, a pleomorphic xanthoastrocytoma, a diffuse astrocytoma, an anaplastic astrocytoma, a glioblastoma, a ganglioglioma, an oligodendroglioma, or an ependymoma. 
     
     
         121 . The method of  claim 120 , wherein the primary malignant brain tumor is a glioblastoma. 
     
     
         122 . The method of  claim 116 , wherein the CNS cancer comprises a CNS metastasis. 
     
     
         123 . The method of  claim 122 , wherein the CNS metastasis comprises a brain metastasis, a leptomeningeal metastasis, a choroidal metastasis, or a spinal cord metastasis. 
     
     
         124 . The method of  claim 116 , wherein the method reduces cancer cell proliferation. 
     
     
         125 . A method of treating a central nervous system (CNS) metastasis from a primary cancer comprising administering a therapeutically effective amount of a compound of Formula A, or pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein n is 1 or 2; and 
         R is —OH or —N(R 1 )R 2 ; 
         wherein R 1  and R 2  are independently alkyl or hydrogen; or R 1  and R 2  combine to form a 5- or 6-membered heterocyclyl optionally containing an additional —O— or —N(R 3 ) ring atom, wherein R 3  is alkyl. 
       
     
     
         126 . The method of  claim 125 , wherein the compound is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         127 . The method of  claim 125 , wherein the method reduces cancer cell proliferation. 
     
     
         128 . The method of  claim 125 , wherein the compound or pharmaceutically acceptable salt thereof is formulated as a pharmaceutical composition comprising a compound of  claim 125  and a pharmaceutically acceptable excipient. 
     
     
         129 . The method of  claim 125 , wherein the CNS metastasis comprises a brain metastasis, a leptomeningeal metastasis, a choroidal metastasis, or a spinal cord metastasis. 
     
     
         130 . The method of  claim 125 , wherein the primary cancer comprises a bladder cancer, bone cancer, breast cancer, cardiac cancer, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, fibrosarcoma, gastric cancer, gastrointestinal cancer, head, spine and neck cancer, Kaposi's sarcoma, kidney cancer, leukemia, liver cancer, lymphoma, melanoma, multiple myeloma, pancreatic cancer, penile cancer, testicular germ cell cancer, thymoma carcinoma, thymic carcinoma, lung cancer, ovarian cancer, or prostate cancer. 
     
     
         131 . The method of  claim 125 , wherein the primary cancer is lung cancer. 
     
     
         132 . A method of treating lung cancer, comprising administering a therapeutically effective amount of a compound of Formula A or pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein n is 1 or 2; and 
         R is —OH or —N(R 1 )R 2 ; 
         wherein R 1  and R 2  are independently alkyl or hydrogen; or R 1  and R 2  combine to form a 5- or 6-membered heterocyclyl optionally containing an additional —O— or —N(R 3 ) ring atom, wherein R 3  is alkyl. 
       
     
     
         133 . The method of  claim 132 , wherein the compound is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         134 . The method of  claim 132 , wherein the compound or pharmaceutically acceptable salt thereof is formulated as a pharmaceutical composition comprising a compound of  claim 132  and a pharmaceutically acceptable excipient. 
     
     
         135 . The method of  claim 132 , wherein the lung cancer comprises a CNS metastasis. 
     
     
         136 . A method of reducing cancer cell proliferation comprising administering a therapeutically effective amount of a compound of Formula A or pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein n is 1 or 2; and 
         R is —OH or —N(R 1 )R 2 ; 
         wherein R 1  and R 2  are independently alkyl or hydrogen; or R 1  and R 2  combine to form a 5- or 6-membered heterocyclyl optionally containing an additional —O— or —N(R 3 ) ring atom, wherein R 3  is alkyl. 
       
     
     
         137 . The method of  claim 136 , wherein the compound is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         138 . The method of  claim 136 , wherein the compound or pharmaceutically acceptable salt thereof is formulated as a pharmaceutical composition comprising a compound of  claim 136  and a pharmaceutically acceptable excipient. 
     
     
         139 . A method of treating glioblastoma comprising administering a therapeutically effective amount of a compound having the structure: 
       
         
           
           
               
               
           
         
       
     
     
         140 . The method of  claim 139 , wherein the compound is provided as a pharmaceutically acceptable salt. 
     
     
         141 . A method of making a compound or a pharmaceutically acceptable salt thereof, according to Scheme 1 or Scheme 2: 
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
         wherein: 
         X is Q, S, or NH; 
         Z is aryl or heteroaryl; 
         R 1  is alkyl; 
         R 2a  and R 2b  are each independently selected from hydrogen, alkyl, halo, CN, and NO 2 ; 
         R 3  is hydrogen, alkyl, or acyl; 
         R 4  is alkoxy; 
         R 3  is alkyl; 
         R 21  is an alkyl substituted with a leaving group, e.g., a haloalkyl or sulfonylalkyl; 
         B is a base; 
         Nu is a nitrogen-containing heterocycle (e.g., having at least one N—H bond), aminoalkyl, or hydroxyalkyl; 
         Sv 1  is a solvent; and 
         n is 0-3.