Bis-octahydrophenanthrene carboxamides and protein conjugates thereof

Abstract

Provided herein are compounds, compositions and methods for the treatment of diseases and disorders associated with the liver X receptor, including bis-octahydrophenanthrene carboxamides and protein (e.g., antibody) drug conjugates thereof.

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, wherein
 each of Q 1  and Q 2  is independently —CH—, —C(O)—, —C(H)(OH)—, —C(OH) 2 —, —SO 2 —, —SO—, —PO(OR 11 )—, —PO(NR 11 NR 12 )—, —NR 11 —, or —N═; 
 W is —CH 2 —, —N(H)—, or —O—; 
 R 1  is independently —H, —OR 6 , —H, —NH 2 , alkyl, or —OP(O)(OR 6 ) 2 ; 
 R 2  is independently —H, —OH, —OR 11 , halide, —SO 2 NR 11 R 12 , —CONR 11 R 12 , —CH 2 NH 2 , R 3 , R 4 , R 5 , or —O—R 5 ; 
 wherein R 1  and R 2  are not simultaneously —H; 
 R 3  is —N(R 6 ) 2 ; 
 R 4  is —X—Y—Z; 
 X is selected from the group consisting of —O— and —N(H)—; 
 Y is selected from the group consisting of alkylene, substituted alkylene (will include oxo, i.e. ═O substitution), heteroalkylene, and substituted heteroalkylene; 
 Z is selected from the group consisting of —OH and —NH 2 ; 
 R 5  is alkyl, heterocycloalkyl, or substituted heterocycloalkyl, wherein each heterocycloalkyl or substituted heterocycloalkyl comprises one, two, or three heteroatoms selected from nitrogen and oxygen, and includes at least one —OH and —CH 2 OH, or at least one primary or secondary nitrogen; 
 each R 6  is, independently in each instance, —H, an amino acid residue, an N-alkyl amino acid residue, a peptide, a biodegradable moiety, or alkyl; 
 each R 7  is independently halo, C 1-6  alkyl, C 1-6  alkoxy, —CN, O-glucose, O-amino acid residue, and O-PEG n , wherein each n is an integer from 0-3; and 
 each R 11  and R 12  are independently —H, alkyl, and aryl. 
 
       
     
     
         2 . The compound of  claim 1  according to Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof, wherein
 each of Q 1  and Q 2  is independently —CH 2 —, —C(O)—, —C(H)(OH)—, or —C(OH) 2 —; 
 W is —CH 2 —, —N(H)—, or —O—; 
 R 1  is independently —H, —OH, —NH 2 , alkyl, or —OP(O)(OR 6 ) 2 ; 
 R 2  is independently —H, —OH, —CH 2 NH 2 , R 3 , R 4 , R 5 , or —O—R 5 ; 
 wherein R 1  and R 2  are not simultaneously —H; 
 R 3  is —N(R 6 ) 2 ; 
 R 4  is —X—Y—Z; 
 X is selected from the group consisting of —O— and —N(H)—; 
 Y is selected from the group consisting of alkylene, substituted alkylene (will include oxo, i.e. ═O substitution), heteroalkylene, and substituted heteroalkylene; 
 Z is selected from the group consisting of —OH and —NH 2 ; 
 R 5  is alkyl, heterocycloalkyl, or substituted heterocycloalkyl, wherein each heterocycloalkyl or substituted heterocycloalkyl comprises one, two, or three heteroatoms selected from nitrogen and oxygen, and includes at least one —OH and —CH 2 OH, or at least one primary or secondary nitrogen; 
 each R 6  is, independently in each instance, —H, an amino acid residue, an N-alkyl amino acid residue, a peptide, or alkyl; and 
 each R 7  is independently halo, C 1-6  alkyl, C 1-6  alkoxy, —CN, O-glucose, O-amino acid residue, and O-PEG n , wherein each n is an integer from 0-3. 
 
       
     
     
         3 . The compound of  claim 1  according to Formula Ia: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof. 
       
     
     
         4 . The compound of  claim 1  wherein Q 1  is —CH 2 — and Q 2  is —C(O)—. 
     
     
         5 . The compound of  claim 1  wherein Q 1  is —C(H)(OH)— and Q 2  is —C(O)—. 
     
     
         6 . The compound of  claim 1  wherein Q 1  is —C(O)— and Q 2  is —C(O)—. 
     
     
         7 . The compound of  claim 1  wherein Q 1  is —C(O)— and Q 2  is —CH 2 —. 
     
     
         8 . The compound of  claim 1  wherein Q 1  is —C(O)— and Q 2  is —C(H)(OH)—. 
     
     
         9 . The compound of  claim 1  wherein W is —CH 2 —. 
     
     
         10 . The compound of  claim 1  wherein W is —O—. 
     
     
         11 . The compound of  claim 1  wherein W is —NH—. 
     
     
         12 . The compound of  claim 1  wherein R 1  is —H and R 2  is R 3 , R 4 , R 5 , or —O—R 5 . 
     
     
         13 . The compound of  claim 1  wherein R 1  is —OH and R 2  is R 3 , R 4 , R 5 , or —O—R 5 . 
     
     
         14 . The compound of  claim 1  wherein R 1  is —OH or —OP(O)(OR 6 )(OH) and R 2  is —H. 
     
     
         15 . The compound of  claim 1  according to Formula Ib: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, or stereoisomeric form thereof. 
       
     
     
         16 . The compound of  claim 1  wherein R 1  is —OH. 
     
     
         17 . The compound of  claim 1  wherein R 2  is —O—(CH 2 ) n —Z and n is an integer from 1 to 4. 
     
     
         18 . The compound of  claim 1  wherein R 2  is —N(H)C(O)—(CH 2 )) n —NH 2  and n is an integer from 1 to 4. 
     
     
         19 . The compound of  claim 1  wherein R 2  is —N(H)C(O)—(CRR) n —NH 2 ; each R is —H—, —OH or —CH 2 OH; and n is an integer from 1 to 4. 
     
     
         20 . The compound of  claim 1  wherein R 2  is N-piperazinyl. 
     
     
         21 . The compound of  claim 1  wherein R 2  is —N(R 6 ) 2 . 
     
     
         22 . The compound of  claim 1  wherein R 2  is N-serinyl. 
     
     
         23 . The compound of  claim 1  wherein R 2  is O-glycosyl. 
     
     
         24 . The compound of  claim 1  wherein R 1  is —OP(O)(OR 6 )(OH) and R 1  is —NH 2 . 
     
     
         25 . The compound of  claim 1  selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate or stereoisomeric form thereof. 
       
     
     
         26 . A linker-payload comprising the compound of  claim 1  bonded to a linker. 
     
     
         27 . The linker-payload of  claim 1  wherein the linker is bonded to an oxygen or a primary or secondary nitrogen of the compound of the preceding claims. 
     
     
         28 . The linker-payload of  claim 26 , selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         29 . An antibody-drug-conjugate comprising the compound of  claim 1  bonded to an antibody, or an antigen binding fragment thereof. 
     
     
         30 . A compound of Formula A 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, or stereoisomeric form thereof, wherein
 L is a linker; 
 BA is a binding agent; 
 k is an integer from 1 to 30; 
 each of Q 1  and Q 2  is independently —CH—, —C(O)—, —C(H)(OH)—, or —C(OH) 2 —; 
 W is —CH 2 —, —N(H)—, or —O—; 
 R is independently —H, —OH, or —OP(O)(OR 6 )(OH); and 
 each R 6  is, independently in each instance, —H, an amino acid residue, a peptide, or alkyl; and 
 each R 7  is independently halo, C 1-6  alkyl, C 1-6  alkoxy, —CN, O-glucose, O-amino acid residue, and O-PEG n , wherein each n is an integer from 0-3. 
 
       
     
     
         31 . A pharmaceutical composition comprising the compound, linker-payload, or antibody-drug-conjugate of  claim 1  and a pharmaceutically acceptable excipient, carrier, or diluent. 
     
     
         32 . A method for the treatment of dyslipidemia, a metabolic disease, inflammation, or a neurodegenerative disease in a subject comprising the administration to the subject of an effective treatment amount of a compound of  claim 1 . 
     
     
         33 . A method for the treatment of dyslipidemia in a subject comprising the administration to the subject of an effective treatment amount of a compound of  claim 1 . 
     
     
         34 . A method for the treatment of a metabolic disease in a subject comprising the administration to the subject of an effective treatment amount of  claim 1 . 
     
     
         35 . A method for the treatment of inflammation in a subject comprising the administration to the subject of an effective treatment amount of a compound of  claim 1 . 
     
     
         36 . A method for the treatment of a neurodegenerative disease in a subject comprising the administration to the subject of an effective treatment amount of  claim 1 . 
     
     
         37 - 53 . (canceled)