Small molecules for the treatment of autoimmune diseases and cancer

Abstract

Disclosed herein are quinazolinyl compounds, compositions, and methods of use thereof. The compounds may be used in the treatment of autoimmune disorders or cancer.

1 . (canceled) 
     
     
         2 . A compound of Formula (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         X 1  is —(CH 2 ) o — or a covalent bond; 
         o is an integer equal to 1, 2, 3, 4, 5, or 6; 
         X 2  is hydrogen and X 3  is represented by Formula (IX3): 
       
       
         
           
           
               
               
           
         
         
           where 
           X a  is selected from the group consisting of CH and N; 
           m is independently an integer selected from 0, 1, 2, 3, or 4; 
           n is independently an integer selected from 0, 1, 2, 3, or 4; 
           X b  is selected from the group consisting of CH 2 , —NR a , NH, O, S, and SO 2 ; 
           l is an integer selected from 0, 1, or 2; 
           each instance of R a , where present, is independently selected from the group consisting of amino, —OH, halogen, cyano, hydroxy, optionally substituted C 1 -C 6  alkyl, C-carboxy, and optionally substituted C 1 -C 6  alkoxy(C 1 -C 6 )alkyl; and 
           wherein each R a  can be provided at any position of the “A” ring by replacing one or more —H atoms of any carbon or nitrogen atom present within the “A” ring; 
         
         X 4  is selected from the group consisting of —CN, —OR 1 , —SR 1 , halogen, optionally substituted C 1 -C 10  alkyl, optionally substituted C 1 -C 10  alkenyl, optionally substituted C 1 -C 10  alkynyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 6-10 membered aryl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl, and —NR 2 R 3 ; 
         R 1  is hydrogen or an optionally substituted C 1 -C 10  alkyl; 
         each of R 2  and R 3  is independently selected from hydrogen and optionally substituted C 1-10  alkyl; or alternatively, R 2  and R 3  attached to the same nitrogen atom may be together with the atom to which they are attached, form an optionally substituted 3-10 membered heterocyclyl or an optionally substituted 5-10 membered heteroaryl; 
         R 4  is represented by one of: —OR 9  or (heterocyclyl)alkynyl;
 where 
 R 9  is selected from the group consisting of hydrogen, C 1 -C 3  alkyl, optionally substituted 2-10 membered heteroalkyl, optionally substituted (carbocyclyl)alkyl, optionally substituted (heterocyclyl)alkyl, optionally substituted (aryl)alkyl, optionally substituted (heteroaryl)alkyl, and (amino)C 1 -C 6  alkyl; 
 
         R 5  is selected from the group consisting of hydrogen, halogen, and —OMe; 
         provided that, if X 3  is 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
          R 5  is —OMe, and R a , where present, is methyl, isopropyl, cyclopropyl, cyclohexyl, or —CH 2 -cyclohexyl, then X 4  is not optionally substituted cyclohexyl, an optionally substituted 5-membered to 7-membered heterocyclyl, an optionally substituted furanyl, or an optionally substituted pyrrolyl; 
         A is selected from the group consisting of N, CH, or CH 2 ; and 
         r is an integer equal to 0 or 1. 
       
     
     
         3 . The compound of  claim 2 , wherein:
 A is CH;   r is 0; and   n is 1 and m is 1, n is 1 and m is 3, or n is 2 and m is 2.   
     
     
         4 . The compound of  claim 3 , wherein X b  is —NH, —NR a , O or SO 2 . 
     
     
         5 . The compound of  claim 4 , where R 4  is —OR 9 . 
     
     
         6 . The compound of  claim 5 , where R 9  is an optionally substituted 2-10 membered heteroalkyl. 
     
     
         7 . The compound of  claim 4 , where R 4  is one of the following structures: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 2 , wherein 
       
         
           
           
               
               
           
         
       
       is represented by the following one of the following structures: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 2 , wherein X 4  is represented by Formula (IX4): 
       
         
           
           
               
               
           
         
         X f  is selected from the group consisting of CH and N; 
         b is independently an integer selected from 1, 2, and 3; 
         c is independently an integer selected from 0, 1, 2, and 3; 
         d is independently an integer selected from 0, 1, 2, and 3; 
         X g  is selected from the group consisting of CH 2 , NH, O, and SO 2 ; 
         R f  is optionally present and can be provided at any position of the “D” ring by replacing one or more —H of any carbon or nitrogen atom present within the “D” ring; and 
         R f  is selected from the group consisting of halogen, amino, —OH, optionally substituted C 1 -C 6  alkyl, and C-carboxy. 
       
     
     
         10 . The compound of  claim 9 , wherein the optional substitutions of the “D” ring are selected from one or more of amino, —OH, optionally substituted C 1 -C 6  alkyl, and halogen. 
     
     
         11 . The compound of  claim 2 , wherein X 4  is an optionally substituted 5-membered heteroaryl. 
     
     
         12 . The compound of  claim 2 , wherein X 4  is represented by: 
       
         
           
           
               
               
           
         
         any one of which may be optionally substituted by replacing one or more —H atoms of any carbon or nitrogen atom present on X 4 . 
       
     
     
         13 . The compound of  claim 2 , wherein X 1  is a covalent bond. 
     
     
         14 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 2  and a pharmaceutically acceptable excipient. 
     
     
         15 . A method of treating or ameliorating inflammation in a subject in need thereof, comprising administering a compound of  claim 2  to the subject. 
     
     
         16 . The method of  claim 15 , wherein the administration downregulates expression of a pro-inflammatory gene and degrades extracellular matrix signaling pathways. 
     
     
         17 . The method of  claim 16 , wherein the pro-inflammatory gene is Ccl2, Ccl3, Ccl7, Ccl9, Csf3, Csf3r, Cxcl1, Cxcl2, Cxcl3, Cxcl5, Il1a, Il1b, Il1r2, Il11, Il13ra2, Il6, Mmp3, Osm, Osmr, Ptgs2, Stc1, or Tnfrsf11b. 
     
     
         18 . A method of treating or ameliorating inflammation in a subject in need thereof, comprising administering a compound of Formula (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         X 1  is —(CH 2 ) o — or a covalent bond; 
         o is an integer equal to 1, 2, 3, 4, 5, or 6; 
         X 2  is hydrogen and X 3  is represented by Formula (IX3): 
       
       
         
           
           
               
               
           
         
         
           where 
           X a  is selected from the group consisting of CH and N; 
           m is independently an integer selected from 0, 1, 2, 3, or 4; 
           n is independently an integer selected from 0, 1, 2, 3, or 4; 
           X b  is selected from the group consisting of CH 2 , —NR a , NH, O, S, and SO 2 ; 
           l is an integer selected from 0, 1, or 2; 
           each instance of R a , where present, is independently selected from the group consisting of amino, —OH, halogen, cyano, hydroxy, optionally substituted C 1 -C 6  alkyl, C-carboxy, and optionally substituted C 1 -C 6  alkoxy(C 1 -C 6 )alkyl; and 
           wherein each R a  can be provided at any position of the “A” ring by replacing one or more —H atoms of any carbon or nitrogen atom present within the “A” ring; 
         
         X 4  is selected from the group consisting of halogen, optionally substituted 3-10 membered carbocyclyl, optionally substituted 6-10 membered aryl, optionally substituted 3-10 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl, and —NR 2 R 3 ; 
         each of R 2  and R 3  is independently selected from hydrogen and optionally substituted C 1-10  alkyl; or alternatively, R 2  and R 3  attached to the same nitrogen atom may be together with the atom to which they are attached, form an optionally substituted 3-10 membered heterocyclyl or an optionally substituted 5-10 membered heteroaryl; 
         R 4  is represented by one of: —OR 9  or (heterocyclyl)alkynyl;
 where 
 R 9  is selected from the group consisting of hydrogen, C 1 -C 3  alkyl, optionally substituted 2-10 membered heteroalkyl, optionally substituted (carbocyclyl)alkyl, optionally substituted (heterocyclyl)alkyl, optionally substituted (aryl)alkyl, optionally substituted (heteroaryl)alkyl, and (amino)C 1 -C 6  alkyl; 
 
         R 5  is —OMe; 
         A is CH; and 
         r is 0. 
       
     
     
         19 . The method of  claim 18 , where R 4  is —OR 9 , where R 9  is selected from the group consisting of optionally substituted 2-10 membered heteroalkyl, optionally substituted (heterocyclyl) alkyl, and optionally substituted (heteroaryl)alkyl. 
     
     
         20 . The method of  claim 18 , wherein administration downregulates expression of a pro-inflammatory gene and degrades extracellular matrix signaling pathways. 
     
     
         21 . The method of  claim 20 , wherein the pro-inflammatory gene is Ccl2, Ccl3, Ccl7, Ccl9, Csf3, Csf3r, Cxcl1, Cxcl2, Cxcl3, Cxcl5, Il1a, Il1b, Il1r2, Il11, Il13ra2, Il6, Mmp3, Osm, Osmr, Ptgs2, Stc1, or Tnfrsf11b.