Inhibitors of RAD52 Recombination Protein and Methods Using Same

Abstract

The present invention includes novel RAD52 inhibitors for preventing or treating cancers in a subject in need thereof. The present invention further includes a method of preventing or treating cancers in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the invention. In certain embodiments, the subject is further administered at least one additional therapeutic agent.

1 . A compound of formula (I), or a salt, solvate, tautomer, enantiomer, diastereomer, or N-oxide thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 X at position 1 and X at position 3 are N, or X at position 1 is CH and X at position 3 is CH or N; 
 R 1  is selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         Y is O or S; 
         R 2  is —NR 4 R 5 ; 
         R 3  is selected from the group consisting of hydrogen, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )heteroalkyl, —F, —Cl, —Br, —I, —CN, —NO 2 , —OR 7 , —SR 7 , —S(═O)R 7 , —S(═O) 2 R 7 , —C(═O)R 7 , —OC(═O)R 7 , and —CO 2 R 7 ; 
         each occurrence of R 4  and R 5  is independently selected from the group consisting of hydrogen, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )heteroalkyl, aryl, and heteroaryl, wherein the aryl or heteroaryl group is optionally substituted;
 or R 4  and R 5  in R 1 , together with the nitrogen to which R 4  and R 5  are connected, form a 3-10 membered heterocycloalkyl, 
 
         each occurrence of R 6  is independently selected from the group consisting of —(C 1 -C 6 )alkyl, —(C 1 -C 6 )heteroalkyl, —OR 7 , 3-10 membered heterocycloalkyl, aryl, and heteroaryl, wherein the 3-10 membered heterocycloalkyl, aryl or heteroaryl group is optionally substituted; 
         each occurrence of R 7  is independently selected from the group consisting of H, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )heteroalkyl, —(C 3 -C 6 )cycloalkyl, -4-10 membered heterocycloalkyl, aryl, and —(C 5 -C 10 )heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally substituted. 
       
     
     
         2 . The compound of  claim 1 , wherein one of the following applies:
 (a) R 1  is   
       
         
           
           
               
               
           
         
       
       and R 2  is; 
       
         
           
           
               
               
           
         
         (b) R 1  is 
       
       
         
           
           
               
               
           
         
       
       and R 2  is 
       
         
           
           
               
               
           
         
         (c) R 1  is 
       
       
         
           
           
               
               
           
         
       
       and R 2  is 
       
         
           
           
               
               
           
         
         (d) R 1  is 
       
       
         
           
           
               
               
           
         
       
       and R 2  is 
       
         
           
           
               
               
           
         
         (e) R 1  is 
       
       
         
           
           
               
               
           
         
       
       and R 2  is 
       
         
           
           
               
               
           
         
       
       or
 (f) R 1  is 
 
       
         
           
           
               
               
           
         
       
       and R 2  is 
       
         
           
           
               
               
           
         
       
     
     
         3 . A pharmaceutical composition comprising at least one compound of  claim 1 , or a salt, solvate, tautomer, enantiomer, diastereomer, or N-oxide thereof, and at least one pharmaceutically acceptable carrier. 
     
     
         4 . The compound of  claim 1 , wherein the compound is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a salt, solvate, tautomer, enantiomer, diastereomer, or N-oxide thereof. 
       
     
     
         5 . The composition of  claim 3 , further comprising at least one additional therapeutic agent that treats or prevents cancer. 
     
     
         6 . A method of treating or ameliorating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a salt, solvate, tautomer, enantiomer, diastereomer, or N-oxide thereof: 
       
         
           
           
               
               
           
         
       
       wherein in (I):
 X at position 1 and X at position 3 are N, or X at position 1 is CH and X at position 3 is CH or N; 
 R 1  is selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         Y is O or S; 
         R 2  is —NR 4 R 5 ; 
         R 3  is selected from the group consisting of hydrogen, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )heteroalkyl, —F, —Cl, —Br, —I, —CN, —NO 2 , —OR 7 , —SR 7 , —S(═O)R 7 , —S(═O) 2 R 7 , —C(═O)R 7 , —OC(═O)R 7 , and —CO 2 R 7 ; 
         each occurrence of R 4  and R 5  is independently selected from the group consisting of hydrogen, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )heteroalkyl, aryl, and heteroaryl, wherein the aryl or heteroaryl group is optionally substituted;
 or R 4  and R 5  in R 1 , together with the nitrogen to which R 4  and R 5  are connected, form a 3-10 membered heterocycloalkyl, 
 
         each occurrence of R 6  is independently selected from the group consisting of —(C 1 -C 6 )alkyl, —(C 1 -C 6 )heteroalkyl, —OR 7 , 3-10 membered heterocycloalkyl, aryl, and heteroaryl, wherein the 3-10 membered heterocycloalkyl, aryl or heteroaryl group is optionally substituted; 
         each occurrence of R 7  is independently selected from the group consisting of H, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )heteroalkyl, —(C 3 -C 6 )cycloalkyl, -4-10 membered heterocycloalkyl, aryl, and —(C 5 -C 10 )heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally substituted. 
       
     
     
         7 . The method of  claim 6 , wherein the method further comprises administering to the subject at least one additional therapeutic agent that treats or ameliorates cancer. 
     
     
         8 . The method of  claim 6 , wherein the compound is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a salt, solvate, tautomer, enantiomer, diastereomer, or N-oxide thereof. 
     
     
         9 . The method of  claim 6 , wherein the cancer is selected from the group consisting of squamous cell cancer, lung cancer, vulval cancer, thyroid cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, and head and neck cancer. 
     
     
         10 . The method of  claim 9 , wherein the cancer is ovarian cancer or breast cancer. 
     
     
         11 . The method of  claim 10 , wherein the human has mutations in at least one selected from the group consisting of BRCA1 and BRCA2. 
     
     
         12 . A method of preventing or treating a RAD52 related disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of  claim 1 . 
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
     
     
         13 . The method of  claim 12 , wherein the RAD52 related disease or disorder comprises cancer. 
     
     
         14 . The method of  claim 12 , the method further comprising administering to the subject at least one additional therapeutic agent that treats or prevents cancer. 
     
     
         15 . The method of  claim 12 , wherein the compound is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a salt, solvate, tautomer, enantiomer, diastereomer, or N-oxide thereof. 
     
     
         16 . The method of  claim 12 , wherein the cancer is selected from the group consisting of squamous cell cancer, lung cancer, vulval cancer, thyroid cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, and head and neck cancer. 
     
     
         17 . The method of  claim 16 , wherein the cancer is ovarian cancer or breast cancer. 
     
     
         18 . The method of  claim 17 , wherein the human has mutations in at least one selected from the group consisting of BRCA1 and BRCA2. 
     
     
         19 . A compound of formula (IX), or a salt, solvate, tautomer, enantiomer, diastereomer, or N-oxide thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 3  is selected from the group consisting of hydrogen, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )heteroalkyl, —F, —Cl, —Br, —I, —CN, —NO 2 , —OR 7 , —SR 7 , —S(═O)R 7 , —S(═O) 2 R 7 , —C(═O)R 7 , —OC(═O)R 7 , and —CO 2 R 7 ; 
 each occurrence of R 4  and R 5  is independently selected from the group consisting of hydrogen, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )heteroalkyl, aryl, and heteroaryl, wherein the aryl or heteroaryl group is optionally substituted; 
 or R 4  and R 5  in R 1 , together with the nitrogen to which R 4  and R 5  are connected, form a 3-10 membered heterocycloalkyl; 
 each occurrence of R 7  is independently selected from the group consisting of H, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )heteroalkyl, —(C 3 -C 6 )cycloalkyl, -4-10 membered heterocycloalkyl, aryl, and —(C 5 -C 10 )heteroaryl, wherein the alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is optionally substituted; and 
 X is N or CH. 
 
     
     
         20 . The compound of  claim 19 , wherein the compound is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       or a salt, solvate, tautomer, enantiomer, diastereomer, or N-oxide thereof.