C19 scaffolds and steroids and methods of use and manufacture thereof

Abstract

The present disclosure relates to stereodefined polycyclic (e.g., tetracyclic) compounds that contain quaternary centers at one or multiple ring fusions, synthetic methods for preparing such compounds, and methods of using such compounds to treat a disease, such as a brain tumor and, particularly, a glioma.

1 - 12 . (canceled) 
     
     
         13 . A compound or salt thereof, wherein the compound has a structure corresponding to Formula (I-A1.1), (I-A2.1), (I-A3.1), (I-A4.1), (II-A1.1), (II-A2.1), (II-A3.1), (II-A4.1), OR(III-D1): 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein n is an integer selected from the group consisting of 0, 1, 2, 3, and 4; 
         m is an integer selected from the group consisting of 0, 1, 2, and 3; 
         each R A  is independently selected from the group consisting of hydrogen, C 1-10 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl, C 1-10 -haloalkyl, halogen, —OR AX , SR AY , —S(O) 2 NR Z1 R Z2 , —S(O) 2 R Z1 , —S(O)R Z1 , —NR Z1 R Z2 , —N(R Z1 )C(O)R Z2 , —N(R Z1 )S(O) 2 R Z2 , C 6-10 -aryl, and 5- to 10-membered heteroaryl,
 wherein R AX  is hydrogen, C 1-6 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynl, C 1-10 -haloalkyl, —C(O)—C 1-10 -alkyl, —C(O)—C 6-10 -aryl, —C(O)-heteroaryl, —C(O)—O—C 1-10 -alkyl, —C(O)—O—C 6-10 -aryl, —C(O)—O-heteroaryl, —C(O)—NR Z1 R Z2 , —S(O) 2 NR Z1 R Z2 , —S(O) 2 R Z1 , C 6-10 -aryl, or 5- to 10-membered heteroaryl, 
 wherein R AY  is hydrogen, C 1-6 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynl, C 1-10 -haloalkyl, —C(O)—C 1-10 -alkyl, —C(O)—C 6-10 -aryl, —C(O)-heteroaryl, C 6-10 -aryl, or 5- to 10-membered heteroaryl, 
 wherein each of R Z1  and R Z2  are independently hydrogen, C 1-10 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl, C 1-10 -haloalkyl, C 6-10 -aryl, 5- to 10-membered heteroaryl, hydroxy, or C 1-6 -alkoxy; 
 
         R 9  is selected from the group consisting of hydrogen, C 1-10 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl, C 1-10 -haloalkyl, halogen, —(CH 2 ) m —C 6-10 -aryl, and —(CH 2 ) m -5- to 10-membered heteroaryl; 
         R 10  is selected from the group consisting of hydrogen, C 1-10 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl, C 1-10 -haloalkyl, halogen, —(CH 2 ) m —C 6-10 -aryl, and —(CH 2 ) m -5- to 10-membered heteroaryl; 
         R 13  is selected from the group consisting of C 1-10 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl, C 1-10 -haloalkyl, —(CH 2 ) m -C 6-10 -aryl, and —(CH 2 ) m -5- to 10-membered heteroaryl; 
         each of R 17A  and R 17B  are independently selected from the group consisting of hydrogen, C 1-10 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl, C 1-10 -haloalkyl, halogen, hydroxy, C 1-6 -alkoxy, C 1-10 -alkyl-C(O), —C(O)—C 1-10 -alkyl, —C(O)—C 1-10 -hydroxyalkyl, —C(O)—C 1-10 -alkyl-C 6-10 -aryl, —C(O)—C 1-10 -alkyl-heteroaryl, —C(O)—C 6-10 -aryl, —C(O)-heteroaryl, —O—C(O)—C 1-6 -alkyl, C 6-10 -aryl, and 5- to 10-membered heteroaryl, or R 17A  and R 17B  together form an oxo; 
         R D  is selected from the group consisting of hydrogen, C 1-6 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl, C 1-10 -haloalkyl, —C(O)—C 1-10 -alkyl, —C(O)—C 6-10 -aryl, —C(O)-heteroaryl, —C(O)—O—C 1-10 -alkyl, —C(O)—O—C 6-10 -aryl, —C(O)—O-heteroaryl, —C(O)—NR Z1 R Z2 , C 6-10 -aryl, and 5- to 10-membered heteroaryl; 
         each   independently represents a single bond or a double bond; and 
         wherein any C 6-10 -aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen, hydroxy, C 1-6 -alkyl, C 1-6 -haloalkyl, or C 1-6 -alkoxy. 
       
     
     
         14 . The compound or salt of  claim 13 , wherein the compound has a structure corresponding to: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         15 . The compound or salt of  claim 13 , wherein the compound has a structure corresponding to: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         16 . The compound or salt of  claim 13 , wherein the compound has a structure corresponding to: 
       
         
           
           
               
               
           
         
       
     
     
         17 . A method for treating a disease or condition selected from cancer, inflammation, neurodegeneration, spinal cord injury (SCI), multiple sclerosis (MS), Parkinson's disease (PD), or Alzheimer's disease (AD), the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt or prodrug of  claim 13 . 
     
     
         18 . The method of  claim 17 , wherein the disease is cancer and the cancer is breast cancer, prostate cancer, ovarian cancer, acute myeloid leukemia, or glioma. 
     
     
         19 . A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt or prodrug of  claim 13  and a pharmaceutically acceptable excipient. 
     
     
         20 . A composition comprising a compound or a pharmaceutically acceptable salt or prodrug of  claim 13 , wherein the composition has not more than 15% of an enantiomeric impurity. 
     
     
         21 . The compound or salt of  claim 13 , wherein the compound has a structure corresponding to Formula (I-A1.1), (I-A2.1), (I-A3.1), or (I-A4.1). 
     
     
         22 . The compound or salt of  claim 21 , wherein n is 0, R AX  is C 1-6 -alkyl, R 9  is C 1-10 -alkyl, C 1-10 -haloalkyl, halogen, or —(CH 2 ) m —C 6-10 -aryl, R 13  is C 1-10 -alkyl, C 1-10 -haloalkyl, or —(CH 2 ) m —C 6-10 -aryl, R 17A  and R 17B  are selected from the group consisting of hydrogen, C 1-6 -alkyl, hydroxy, C 1-6 -alkoxy, and —C(O)—C 1-10 -alkyl, and R D  is hydrogen or C 1-6 -alkyl. 
     
     
         23 . The compound or salt of  claim 22 , wherein R 9  is C 1-10 -alkyl and R 13  is C 1-10 -alkyl. 
     
     
         24 . The compound or salt of  claim 13 , wherein the compound has a structure corresponding to Formula (II-A1.1), (II-A2.1), (II-A3.1), or (II-A4.1) 
     
     
         25 . The compound or salt of  claim 24 , wherein n is 0, R 10  is C 1-10 -alkyl, C 1-10 -haloalkyl, halogen, or —(CH 2 ) m —C 6-10 -aryl, R 13  is C 1-10 -alkyl, C 1-10 -haloalkyl, or —(CH 2 ) m —C 6-10 -aryl, R 17A  and R 17B  are selected from the group consisting of hydrogen, C 1-6 -alkyl, hydroxy, C 1-6 -alkoxy, and —C(O)—C 1-10 -alkyl, and R D  is hydrogen or C 1-6 -alkyl. 
     
     
         26 . The compound or salt of  claim 25 , wherein R 10  is C 1-10 -alkyl and R 13  is C 1-10 -alkyl. 
     
     
         27 . The compound or salt of  claim 13 , wherein the compound has a structure corresponding to Formula (III-D1). 
     
     
         28 . The compound or salt of  claim 27 , wherein R 10  is C 1-10 -alkyl, C 1-10 -haloalkyl, halogen, or —(CH 2 ) m —C 6-10 -aryl, R 13  is C 1-10 -alkyl, C 1-10 -haloalkyl, or —(CH 2 ) m —C 6-10 -aryl, and R 17A  and R 17B  are selected from the group consisting of hydrogen, C 1-6 -alkyl, hydroxy, C 1-6 -alkoxy, and —C(O)—C 1-10 -alkyl. 
     
     
         29 . The compound or salt of  claim 28 , wherein R 10  is C 1-10 -alkyl and R 13  is C 1-10 -alkyl.