P13 Kinase Antagonists

Abstract

The present invention provides novel PI3-Kinase antagonists and methods of use thereof.

1 . A compound having the formula: 
       
         
           
           
               
               
           
         
       
       wherein
 q is an integer from 0 to 5; 
 z is an integer from 0 to 10; 
 X is ═CH— or ═N—; 
 L 1  is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; 
 R 1  and R 2  are independently halogen, —CN, —OR 5 , —S(O) n R 6 , —NR 7 R 8 , —C(O)R 9 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein n is independently an integer from 0 to 2; 
 R 3 , and R 4  are independently hydrogen, halogen, —CN, —OR 5 , —S(O) n R 6 , —NR 7 R 8 , —C(O)R 9 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 5  is independently hydrogen, —C(O)R 10 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 6  is independently hydrogen, —NR 11 R 12 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein if n is 1 or 2 then R 6  is other than hydrogen; 
 R 7  is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 8  is independently hydrogen, —S(O) n R 13 , —C(O)R 14 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 9  is independently —NR 15 R 16 , hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 10  is independently hydrogen, —NR 17 R 18 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 14  is independently hydrogen, —NR 19 R 20 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and 
 R 11 , R 12 , R 13 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20  are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 
 
     
     
         2 . The compound of  claim 1 , wherein R 1  is halogen, substituted or unsubstituted halo(C 1 -C 6 )alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl(C 1 -C 6 )alkyl, or substituted or unsubstituted heteroaryl(C 1 -C 6 )alkyl. 
     
     
         3 . The compound of  claim 1 , wherein R 1  is halogen, substituted or unsubstituted phenyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted thiophenyl, or substituted or unsubstituted benzothiophenyl, substituted or unsubstituted indolyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted 1H-pyrrolo[2,3-c]pyridinyl, substituted or unsubstituted 1H-pyrrolo[2,3-b]pyridinyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted cylcohexyl, substituted or unsubstituted morpholino, substituted or unsubstituted piperidinyl, or substituted or unsubstituted tetrahydropyridinyl. 
     
     
         4 . The compound of  claim 3 , wherein R 1  is phenyl, furanyl, pyrrolyl, thiophenyl, or benzothiophenyl, each of which are optionally substituted with one or more R 21  substituent(s), wherein R 21  is independently
 (1) halogen, —CN, —OR 22 —C(O)R 23 , —NR 24 R 25 , —S(O) w NR 26 R 27 , or —S(O) w R 28 , wherein w is an integer from 0 to 2, and R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , and R 28  are independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, arylalkyl, or heteroarylalkyl, optionally substituted with unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted cycloalkyl-alkyl, unsubstituted heterocycloalkyl-alkyl, unsubstituted arylalkyl, or unsubstituted heteroarylalkyl; or   (2) (C 1 -C 10 )alkyl, 2 to 10 membered heteroalkyl, C 3 -C 8  cycloalkyl, 3 to 8 membered heterocycloalkyl, aryl or heteroaryl optionally substituted with halogen, —OH, —CN, —NH 2 , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted cycloalkyl-alkyl, unsubstituted heterocycloalkyl-alkyl, unsubstituted arylalkyl, or unsubstituted heteroarylalkyl.   
     
     
         5 . The compound of  claim 4 , wherein R 1  phenyl substituted at the meta and para positions, or substituted at the meta and meta positions. 
     
     
         6 . The compound of  claim 5 , wherein R 21  is halogen or —OR 22 . 
     
     
         7 . The compound of  claim 6 , wherein R 21  is fluorine and R 22  is hydrogen or methyl. 
     
     
         8 . The compound of  claim 1 , wherein q is 1. 
     
     
         9 . The compound of  claim 1 , wherein z is 1. 
     
     
         10 . The compound of  claim 1 , wherein R 2  is halogen, —OH, —CN, —NH 2 , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted cycloalkyl-alkyl, unsubstituted heterocycloalkyl-alkyl, unsubstituted arylalkyl, or unsubstituted heteroarylalkyl. 
     
     
         11 . The compound of  claim 1 , wherein R 2  is halogen or unsubstituted alkyl. 
     
     
         12 . The compound of  claim 1 , wherein R 2  is fluorine or unsubstituted C 1 -C 4  alkyl. 
     
     
         13 . The compound of  claim 1 , wherein R 3  is halogen, —OH, —CN, —NH 2 , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted cycloalkyl-alkyl, unsubstituted heterocycloalkyl-alkyl, unsubstituted arylalkyl, or unsubstituted heteroarylalkyl. 
     
     
         14 . The compound of  claim 1 , wherein R 3  is unsubstituted alkyl. 
     
     
         15 . The compound of  claim 1 , wherein R 3  is unsubstituted C 1 -C 4  alkyl. 
     
     
         16 . The compound of  claim 1 , wherein R 4  is halogen, —OH, —CN, —NH 2 , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, arylalkyl, or heteroarylalkyl. 
     
     
         17 . The compound of  claim 1 , wherein R 2  and R 3  are independently unsubstituted C 1 -C 4  alkyl; R 4  is NH 2 ; q is 1; and z is 1. 
     
     
         18 . The compound of  claim 1 , wherein L 1  is substituted or unsubstituted alkylene. 
     
     
         19 . The compound of  claim 1 , wherein L 1  is substituted or unsubstituted alkynylene. 
     
     
         20 . The compound of  claim 1 , wherein L 1  is substituted or unsubstituted methylene, substituted or unsubstituted ethylene, substituted or unsubstituted propylene, substituted or unsubstituted butylene, substituted or unsubstituted ethynylene, or substituted or unsubstituted prop-2-ynylene. 
     
     
         21 . The compound of  claim 20 , wherein R 1  is —CN, —OR 5 , —NR 7 R 8 , R 21 -substituted or unsubstituted cycloalkyl, R 21 -substituted or unsubstituted aryl, R 21 -substituted or unsubstituted heteroaryl, R 2 -substituted or unsubstituted C 1 -C 4  alkyl, wherein
 R 21  is halogen, —OR 22 , —NR 24 R 25 , or unsubstituted C 1 -C 4  alkyl and   R 5 , R 7 , R 8 , R 22 , R 24  and R 25  are independently hydrogen or unsubstituted C 1 -C 4  alkyl.   
     
     
         22 . A pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         23 . A method of decreasing the catalytic activity of a PI3-Kinase, the method comprising the step of contacting said PI3-Kinase with an activity decreasing amount of a PI3-Kinase affinity pocket binding antagonist. 
     
     
         24 . The method of  claim 23 , wherein said antagonist is a PI3-Kinase affinity pocket quinazolinone antagonist. 
     
     
         25 . The method of  claim 23 , wherein the PI3-Kinase is p110 δ kinase. 
     
     
         26 . A method of decreasing the catalytic activity of a PI3-Kinase, the method comprising the step of contacting said PI3-Kinase with an activity decreasing amount of a compound having the formula: 
       
         
           
           
               
               
           
         
       
       wherein
 q is an integer from 0 to 5; 
 z is an integer from 0 to 10; 
 X is ═CH— or ═N—; 
 L 1  is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; 
 R 1  and R 2  are independently halogen, —CN, —OR 5 , —S(O) n R 6 , —NR 7 R 8 , —C(O)R 9 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein n is independently an integer from 0 to 2; 
 R 3 , and R 4  are independently hydrogen, halogen, —CN, —OR 5 , —S(O) n R 6 , —NR 7 R 8 , —C(O)R 9 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 5  is independently hydrogen, —C(O)R 10 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 6  is independently hydrogen, —NR 11 R 12 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein if n is 1 or 2 then R 6  is other than hydrogen; 
 R 7  is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 8  is independently hydrogen, —S(O) n R 13 , —C(O)R 14 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 9  is independently —NR 15 R 16 , hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 10  is independently hydrogen, —NR 17 R 18 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 14  is independently hydrogen, —NR 19 R 20 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and 
 R 11 , R 12 , R 13 , R 15 , R 16 , R 17 , R 18 R 19 , and R 20  are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 
 
     
     
         27 . A method of treating a disease mediated by p110 δ kinase activity in a subject in need of such treatment, said method comprising administering to said subject a therapeutically effective amount of a PI3-Kinase affinity pocket binding antagonist. 
     
     
         28 . The method of  claim 27 , wherein said antagonist is a PI3-Kinase affinity pocket quinazolinone antagonist. 
     
     
         29 . The method of  claim 27 , wherein the disease is a hematologic malignancy, inflammation, autoimmune disease, or cardiovascular disease. 
     
     
         30 . The method of  claim 27 , wherein the disease is a hematologic malignancy, or autoimmune disease. 
     
     
         31 . The method of  claim 27 , wherein the disease is acute myelogenous leukemia, chronic myelogenous leukemia, mastocytosis, chronic lymphocytic leukemia, multiple myeloma, or myelodysplastic syndrome. 
     
     
         32 . The method of  claim 27 , wherein the disease is rheumatoid arthritis, systemic lupus erythematosus, or asthma. 
     
     
         33 . A method of treating a disease mediated by p110 δ kinase activity in a subject in need of such treatment, said method comprising administering to said subject a therapeutically effective amount of a compound having the formula: 
       
         
           
           
               
               
           
         
       
       wherein
 q is an integer from 0 to 5; 
 z is an integer from 0 to 10; 
 X is ═CH— or ═N—; 
 L 1  is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; 
 R 1  and R 2  are independently halogen, —CN, —OR 5 , —S(O) n R 6 , —NR 7 R 8 , —C(O)R 9 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein n is independently an integer from 0 to 2; 
 R 3 , and R 4  are independently hydrogen, halogen, —CN, —OR 5 , —S(O) n R 6 , —NR 7 R 8 , —C(O)R 9 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 5  is independently hydrogen, —C(O)R 10 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 6  is independently hydrogen, —NR 11 R 12 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein if n is 1 or 2 then R 6  is other than hydrogen; 
 R 7  is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 8  is independently hydrogen, —S(O) n R 13 , —C(O)R 14 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 9  is independently —NR 15 R 16 , hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 10  is independently hydrogen, —NR 17 R 18 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 14  is independently hydrogen, —NR 19 R 20 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and 
 R 11 , R 12 , R 13 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20  are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 
 
     
     
         34 . A method of disrupting the function of a leukocyte or disrupting a function of an osteoclast, said method comprising contacting said leukocyte or said osteoclast with a function disrupting amount of a PI3-Kinase affinity pocket binding antagonist. 
     
     
         35 . The method of  claim 34 , wherein said antagonist is a PI3-Kinase affinity pocket quinazolinone antagonist. 
     
     
         36 . A method of disrupting the function of a leukocyte or disrupting a function of an osteoclast, said method comprising contacting said leukocyte or said osteoclast with a function disrupting amount of a compound having the formula 
       
         
           
           
               
               
           
         
       
       wherein
 q is an integer from 0 to 5; 
 z is an integer from 0 to 10; 
 X is ═CH— or ═N—; 
 L 1  is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; 
 R 1  and R 2  are independently halogen, —CN, —OR 5 , —S(O) n R 6 , —NR 7 R 8 , —C(O)R 9 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein n is independently an integer from 0 to 2; 
 R 3 , and R 4  are independently hydrogen, halogen, —CN, —OR 5 , —S(O) n R 6 , —NR 7 R 8 , —C(O)R 9 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 5  is independently hydrogen, —C(O)R 10 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 6  is independently hydrogen, —NR 11 R 12 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein if n is 1 or 2 then R 6  is other than hydrogen; 
 R 7  is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 8  is independently hydrogen, —S(O) n R 13 —C(O)R 14 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 9  is independently —NR 15 R 16 , hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 10  is independently hydrogen, —NR 17 R 18 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 14  is independently hydrogen, —NR 19 R 20 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and 
 R 11 , R 12 , R 13 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20  are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.