Rad51 inhibitors

Abstract

This application is directed to inhibitors of RAD51 represented by the following structural formula, and methods for their use, such as to treat cancer, autoimmune diseases, immune deficiencies, or neurodegenerative diseases.

1 . A compound represented by the following structural formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 the thiazole ring is optionally substituted with —F or —Cl; 
 Cy is —(C 3 -C 7 )cycloalkyl, bridged (C 6 -C 12 ) cycloalkyl, or a 4-10 membered heterocyclic ring, each of which is optionally substituted with one or more groups selected from the group consisting of halogen, —OH, (C 1 -C 4 )alkyl, and (C 1 -C 4 )alkoxy; 
 when X 5  is connected with a nitrogen ring atom of Cy, X 5  is absent; 
 when X 5  is connected with a carbon ring atom of Cy, X 5  is NR a  or O; 
 X 6  is NR a  or O; 
 R 1  is (C 1 -C 5 )alkyl optionally substituted with —OH; 
 R 3  is (C 1 -C 5 )alkyl, —CH 2 -phenyl, —(C 3 -C 7 )cycloalkyl, —CH 2 —(C 3 -C 7 )cycloalkyl, —CH 2 -monocyclic 3-7 membered heterocyclic ring, or monocyclic 3-7 membered heterocyclic ring, wherein the (C 1 -C 5 )alkyl, —(C 3 -C 7 )cycloalkyl, phenyl or monocyclic 3-7 membered heterocyclic ring represented by R 3  or in the group represented by R 3  is optionally substituted with one or more groups selected from the group consisting of halogen, —OH, (C 1 -C 4 )alkyl, halomethyl, halomethoxy, —CN, and (C 1 -C 4 )alkoxy; 
 R 2  is —NR a C(O)O(C 1 -C 4 )alkyl; —NR a C(O)NR a (C 1 -C 4 )alkyl; —NR a C(O)O(C 2 -C 4 )alkenyl; —NR a C(O)NR a (C 2 -C 4 )alkenyl; —NR a C(O)O—(C 3 -C 6 )cycloalkyl; —NR a C(O)NR a —(C 3 -C 7 )cycloalkyl; —NR a C(O)O-phenyl; —NR a C(O)NR a -phenyl; —NR a C(O)O-monocyclic 3-7 membered heterocyclic ring; —NR a C(O)NR a -monocyclic 3-7 membered heterocyclic ring; —NR a C(O)O-monocyclic 5-6 membered heteroaromatic ring; —NR a C(O)NR a -monocyclic 5-6 membered heteroaromatic ring; 
 wherein the (C 1 -C 4 )alkyl and the (C 2 -C 4 )alkenyl in the group represented by R 2  are each optionally and independently substituted with one or more groups selected from the group consisting of halogen, N 3 , —OR a , —NR a R a , —(C 3 -C 6 )cycloalkyl, phenyl, a monocyclic 3-7 membered heterocyclic ring, and a monocyclic 5-6 membered heteroaromatic ring; 
 wherein the (C 3 -C 7 )cycloalkyl in the group represented by R 2  is optionally substituted with one or more groups selected from the group consisting of halogen, —CH 3 , ═O, —OR a  and —NR a R a ; 
 wherein the phenyl in the group represented by R 2  is optionally substituted with one or more groups selected from the group consisting of halogen, —CH 3 , halomethyl, halomethoxy, —CN, —OR a , and —N 3 ; 
 wherein the heterocyclic ring in the group represented by R 2  is optionally substituted with one or more groups selected from the group consisting of ═O, halogen, —OR a , —CH 3 , halomethyl, and halomethoxy; 
 wherein the heteroaromatic ring in the group represented by R 2  is optionally substituted with one or more groups selected from the group consisting of halogen, —CN, —CH 3 , halomethyl, halomethoxy, —OR a  and —NR a R a ; and 
 each R a  is independently —H or —CH 3 . 
 
       
     
     
         2 .- 34 . (canceled) 
     
     
         35 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         36 . A method of treating cancer, the method comprising administering to a subject in need thereof an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         37 . The method of  claim 36 , wherein the cancer is selected from the group consisting of lymphoma, leukemia, and a plasma cell neoplasm. 
     
     
         38 . The method of  claim 37 , wherein the lymphoma selected from the group consisting of Non-Hodgkin's lymphoma, Burkitt's lymphoma, small lymphocytic lymphoma, lymphoplasmacytic lymphoma, MALT lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, and T-cell lymphoma. 
     
     
         39 . The method of  claim 37 , wherein the leukemia selected from the group consisting of acute lymphoblastic leukemia (ALL), Burkitt's leukemia; B-cell leukemia, B-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), and T-cell acute lymphoblastic leukemia (T-ALL). 
     
     
         40 . The method of  claim 37 , wherein the plasma cell neoplasm selected from the group consisting of multiple myeloma, plasma cell myeloma, plasma cell leukemia, and plasmacytoma. 
     
     
         41 . The method of  claim 36 , wherein the cancer is selected from the group consisting of carcinoma and sarcoma. 
     
     
         42 . The method of  claim 41 , wherein the carcinoma selected from the group consisting of colon cancer, liver cancer, gastric cancer, intestinal cancer esophageal cancer, breast cancer, ovarian cancer, head and neck cancer, lung cancer, and thyroid cancer. 
     
     
         43 . The method of  claim 36 , wherein the cancer is selected from the group consisting of colon cancer, endometrial cancer, stomach cancer, pancreatic cancer, kidney/ureter tract cancer, hepatobiliary tract cancer, gastric tract cancer, prostate cancer, ovarian cancer, gallbladder duct cancer, brain cancer, small intestine cancer, breast cancer, and skin cancer. 
     
     
         44 . The method of  claim 36 , wherein the cancer is characterized by mutations in mutS homologue 6 (MSH6). 
     
     
         45 .- 47 . (canceled) 
     
     
         48 . The method of  claim 36 , further comprising the step of co-administering to the subject an effective amount of a DNA repair inhibitor, a DNA damage response (DDR) inhibitor, a DNA damaging agent or an immunomodulatory agent. 
     
     
         49 . The method of  claim 48 , wherein the DNA damaging agent is selected from the group consisting of: exposure to a DNA damaging chemical; exposure to a chemotherapeutic agent; exposure to a radiochemotherapy, and exposure to ionizing or ultraviolet radiation. 
     
     
         50 . The method of  claim 36 , wherein the subject is determined to have an increased level and/or activity of a DNA damage process or DNA editing enzyme. 
     
     
         51 . The method of  claim 48 , wherein the immunomodulatory agent is selected from the group consisting of immune checkpoint modulators, Toll-like receptor (TLR) agonists, cell-based therapies, cytokines and cancer vaccines. 
     
     
         52 . The method of  claim 50 , wherein the DNA editing enzyme is selected from the group consisting of activation induced cytidine deaminase (AID or AICDA), APOBEC2, APOBEC3A, APOBEC3C, APOBEC3D, APOBEC3F, APOBEC3G, APOBEC3H, APOBEC4, a Type 1 Topoisomerase, a Type 2 Topoisomerase, Recombination Activating Gene 1 (RAG 1), and Recombination Activating Gene 2 (RAG2). 
     
     
         53 . The method of  claim 36 , wherein blood cells obtained from the subject have been determined to have a detectable level of activation-induced cytidine deaminase (AID). 
     
     
         54 . The method of  claim 36 , wherein B cells obtained from the subject have been determined to have a detectable level of activation-induced cytidine deaminase (AID). 
     
     
         55 . The method of  claim 53 , wherein the detectable level of activation-induced cytidine deaminase (AID) is statistically significantly higher than the level of AID expressed in unactivated B-cells or normal non-immune cells from a healthy subject. 
     
     
         56 . A compound selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.