Chiral Indole Compounds and Their Use

Abstract

The present disclosure relates to indole compounds and pharmaceutical compositions thereof, and their use in stimulating the immune system of patients in need thereof and in treating cancer.

1 - 27 . (canceled) 
     
     
         28 . A method of stimulating or modulating the immune system in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Structural Formula 8c or Structural Formula 8d, or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein 
         R 4 , R 5 , R 6 , and R 7 , are each, independently, selected from the group consisting of hydrogen and halo; 
         R o  is hydrogen, deuterium, alkyl, aryl, or acyl; and 
         R N  is H, CN, alkyl, alkenyl, alkynyl, aryl, alkanoyl, carbonyloxy, carbonylthio, carbonylamino, or a phosphate moiety. 
       
     
     
         29 . The method of  claim 28 , wherein R o  is H, alkyl, or acyl. 
     
     
         30 . (canceled) 
     
     
         31 . The method of  claim 28 , wherein R o  is substituted or unsubstituted C 1 -C 6  acyl, wherein the substituted or unsubstituted C 1 -C 6  acyl can be a substituted C 2 , C 3 , C 4 , C 5 , or C 6  acyl, optionally interrupted by O, S, or NR (in which NR can be N-C1-C6 alkyl), wherein the substituent is a halo, carboxyl, amino, hydroxyl, alkoxy, or phosphonate moiety. 
     
     
         32 . The method of  claim 28 , wherein at least one of R 4 , R 5 , R 6 , and R 7  is F, Cl, or Br, and the others of R 4 , R 5 , R 6 , and R 7  are hydrogen. 
     
     
         33 . (canceled) 
     
     
         34 . The method of  claim 28 , wherein R 5  is F or Cl, and R 4 , R 6 , and R 7  are hydrogen. 
     
     
         35 . The method of  claim 28 , wherein R 6  is F or Cl, and R 4 , R 5 , and R 7  are hydrogen. 
     
     
         36 . The method of  claim 28 , wherein R 7  is F or Cl, and R 4 , R 5 , and R 6  are hydrogen. 
     
     
         37 - 39 . (canceled) 
     
     
         40 . The method of  claim 28 , wherein R 5  and R 6  are F or Cl, and R 4  and R 7  are hydrogen. 
     
     
         41 . The method of  claim 28 , wherein R 5  and R 7  are F or Cl, and R 4  and R 6  are hydrogen. 
     
     
         42 . The method of  claim 28 , wherein R 6  and R 7  are F or Cl, and R 4  and R 5  are hydrogen. 
     
     
         43 - 45 . (canceled) 
     
     
         46 . The method of  claim 28 , wherein each of R 4 , R 5 , R 6 , and R 7  is hydrogen. 
     
     
         47 . The method of  claim 28 , wherein R N  is a phosphate moiety. 
     
     
         48 - 62 . (canceled) 
     
     
         63 . The method of  claim 28 , wherein the compound gf Structural Formula 8d has the structure 
       
         
           
           
               
               
           
         
         or is a pharmaceutically acceptable salt thereof. 
       
     
     
         64 . The method of  claim 28 , wherein the compound gf Structural Formula 8c has the structure 
       
         
           
           
               
               
           
         
         or is a pharmaceutically acceptable salt thereof. 
       
     
     
         65 . (canceled) 
     
     
         66 . The method of  claim 28 , wherein the compound is administered as a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier. 
     
     
         67 . (canceled) 
     
     
         68 . The method of  claim 28 , wherein the compound decreases IL-21 level in the patient. 
     
     
         69 . The method of  claim 68 , wherein the patient has cancer. 
     
     
         70 . A method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Structural Formula 8c or Structural Formula 8d, or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein 
         R 4 , R 5 , R 6 , and R 7 , are each, independently, selected from the group consisting of hydrogen and halo; 
         R o  is hydrogen, deuterium, alkyl, aryl, or acyl; and 
         R N  is H, CN, alkyl, alkenyl, alkynyl, aryl, alkanoyl, carbonyloxy, carbonylthio, carbonylamino, or a phosphate moiety. 
       
     
     
         71 . The method of  claim 70 , wherein the cancer is selected from the group consisting of lymphoma, leukemia, myeloma, prostate cancer, lung cancer, ovarian cancer, cervical cancer, breast cancer, skin cancer, colorectal cancer, stomach cancer, pancreatic cancer, liver cancer, kidney cancer, bladder cancer, soft tissue cancer, glioma, and head and neck cancer. 
     
     
         72 . The method of  claim 70 , further comprising administering to the patient another cancer therapeutic agent. 
     
     
         73 - 74 . (canceled) 
     
     
         75 . A method of making a compound of Structural Formula 9, or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         Z 1  is N or CR 4 , Z 2  is N or CR 5 , Z 3  is N or CR 6 , Z 4  is N or CR 7 , Z 5  is N or CR 8 , Z 6  is N or C, Z 7  is N or C, wherein no more than two of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , and Z 7  are N; 
         R 4 , R 5 , R 6 , R 7 , R 8 , and R 9  are each independently selected from the group consisting of hydrogen, deuterium, halo, amino, hydroxy, cyano, formyl, furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio, halothiocarbonylthio, and —S(O) n R 11  (n=0 to 2, R 11  is directly connected to S), wherein R 11  is selected from the group consisting of hydrogen, deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio; 
         R 3  is selected from the group consisting of deuterium, cyano, formyl, furyl, nitro, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, C 1 -C 6  acyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio, halothiocarbonylthio, and —S(O) n R 10  (n=0 to 2, R 10  is directly connected to S), wherein R 10  is selected from the group consisting of hydrogen, deuterium, halo, amino, hydroxy, thiol, cyano, formyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, acyloxy, alkoxy, haloalkoxy, thioalkoxy, halothioalkoxy, alkanoyl, haloalkanoyl, thioalkanoyl, halothioalkanoyl, carboxy, carbonyloxy, halocarbonyloxy, carbonylthio, halocarbonylthio, thiocarbonyloxy, halothiocarbonyloxy, thiocarbonylthio, and halothiocarbonylthio; 
         R 3a  is selected from the group consisting of hydrogen, deuterium, cyano, or C 1 -C 6  alkyl; 
         R o  is hydrogen, deuterium, alkyl, aryl, or acyl; 
         each R N  is H, CN, alkyl, alkenyl, alkynyl, aryl, alkanoyl, carbonyloxy, carbonylthio, carbonylamino, or a phosphate moiety; 
         and optionally, adjacent R groups, together, can form a three- to twelve-membered ring; comprising: 
         (i) contacting a compound of Structural Formula 10 with (S)-2-methylpropane-2-sulfinamide in the presence of a catalyst to yield a compound of Structural Formula 11; 
       
       
         
           
           
               
               
           
         
         (ii) contacting a compound of Structural Formula 11 with one or more alkylating agent(s) to yield a compound of Structural Formula 12; 
       
       
         
           
           
               
               
           
         
         (iii) contacting a compound of Structural Formula 12 with a compound of Structural Formula 13 in the presence of an organolithium base to yield a compound of Structural Formula 14; 
       
       
         
           
           
               
               
           
         
         (iv) subjecting a compound of Structural Formula 14 to acid-base hydrolysis to obtain a compound of Structural Formula 9. 
       
     
     
         76 - 84 . (canceled)