Selectively substituted quinoline compounds

Abstract

Embodiments of the disclosure relate to selectively substituted quinolone compounds that act as antagonists or inhibitors for Toll-like receptors 7 and/or 8, and their use in pharmaceutical compositions effective for treatment of systemic lupus erythematosus (SLE) and lupus nephritis.

1 - 7 . (canceled) 
     
     
         8 . A method for treatment of systemic lupus erythematosus, cutaneous lupus, neuropsychiatric lupus, or lupus, comprising administering a pharmaceutically effective amount of two or more compounds or pharmaceutically acceptable salts according to Formula (I): 
       
         
           
           
               
               
           
         
         wherein at least one of R 1  and R 2  is —H, methyl, or ethyl, and the other is
 H, or the other is 
 C 1 -C 6  alkyl that is optionally substituted with:
 —OH, methoxy, ethoxy, —OCH(CH 3 ) 2 , —O(CH 2 ) 2 CH 3 , phenyl, furanyl, —O(CH 2 ) 2 OH, phenoxy, methylthio, —F, —N(CH 3 ) 2 , cyano, pyridinyloxy, fluorophenoxy, isochromanyl, phenol, benzylamino, —NHCH 3 , oxo-, amino, carboxyl, 7-member spiroaminyl, a three to six member cycloalkyl, saturated or unsaturated and optionally including one or more heteroatoms selected from O and N, and optionally substituted at one or more C or N atoms by methyl, cyano, fluoro, methylamino, or trifluoromethyl; or the other is 
 
 C 3 -C 7  cycloalkane, saturated or unsaturated, optionally bridged, optionally including one or more heteroatoms selected from O, S, and N, and optionally substituted at one or more C or N atoms by methyl, ethyl, pyridinyl, azetidinyl, acetamidyl, carboxamidyl, cyano, fluoro, methylamino, or trifluoromethyl; or 
 
         R 1  and R 2 , together with the nitrogen atom to which they are attached, form an 8 to 11 member spirodiamine, an 8 member bicyclodiamine, a 7 member spiroxamine, a piperidinyl optionally substituted with ethyl, or a four to six member cycloalkyl, optionally substituted with at least one of carboxamidyl, aminomethyl, methyl, (ethylamino)methyl, (dimethylamino)methyl, dimethylamino, (methylamino)methyl, and amino; and wherein
 R 3  is —H or methyl. 
 
       
     
     
         9 . The method of  claim 8 , wherein said two or more compounds are administered as pharmaceutically acceptable salts. 
     
     
         10 . A method for antagonizing at least one of Toll-like receptor 7 (TLR7) and Toll-like receptor 7 (TLR8), comprising administering a pharmaceutically effective amount of two or more compounds or pharmaceutically acceptable salts according to Formula (I): 
       
         
           
           
               
               
           
         
         wherein at least one of R 1  and R 2  is —H, methyl, or ethyl, and the other is
 —H; or the other is 
 C 1 -C 6  alkyl that is optionally substituted with:
 —OH, methoxy, ethoxy, —OCH(CH 3 ) 2 , —O(CH 2 ) 2 CH 3 , phenyl, furanyl, —O(CH 2 ) 2 OH, phenoxy, methylthio, —F, —N(CH 3 ) 2 , cyano, pyridinyloxy, fluorophenoxy, isochromanyl, phenol, benzylamino, —NHCH 3 , oxo-, amino, carboxyl, 7-member spiroaminyl, a three to six member cycloalkyl, saturated or unsaturated and optionally including one or more heteroatoms selected from O and N, and optionally substituted at one or more C or N atoms by methyl, cyano, fluoro, methylamino, or trifluoromethyl; or the other is 
 
 C 3 -C 7  cycloalkane, saturated or unsaturated, optionally bridged, optionally including one or more heteroatoms selected from O, S, and N, and optionally substituted at one or more C or N atoms by methyl, ethyl, pyridinyl, azetidinyl, acetamidyl, carboxamidyl, cyano, fluoro, methylamino, or trifluoromethyl; or 
 
         R 1  and R 2 , together with the nitrogen atom to which they are attached, form an 8 to 11 member spirodiamine, an 8 member bicyclodiamine, a 7 member spiroxamine, a piperidinyl optionally substituted with ethyl, or a four to six member cycloalkyl, optionally substituted with at least one of carboxamidyl, aminomethyl, methyl, (ethylamino)methyl, (dimethylamino)methyl, dimethylamino, (methylamino)methyl, and amino; and wherein
 R 3  is —H or methyl. 
 
       
     
     
         11 . (canceled) 
     
     
         12 . A pharmaceutical composition comprising two or more compounds or pharmaceutically acceptable salts according to Formula (I): 
       
         
           
           
               
               
           
         
         wherein at least one of R 1  and R 2  is —H, methyl, or ethyl, and the other is
 —H; or the other is 
 C 1 -C 6  alkyl that is optionally substituted with:
 —OH, methoxy, ethoxy, —OCH(CH 3 ) 2 , —O(CH 2 ) 2 CH 3 , phenyl, furanyl, —O(CH 2 ) 2 OH, phenoxy, methylthio, —F, —N(CH 3 ) 2 , cyano, pyridinyloxy, fluorophenoxy, isochromanyl, phenol, benzylamino, —NHCH 3 , oxo-, amino, carboxyl, 7-member spiroaminyl, a three to six member cycloalkyl, saturated or unsaturated and optionally including one or more heteroatoms selected from O and N, and optionally substituted at one or more C or N atoms by methyl, cyano, fluoro, methylamino, or trifluoromethyl; or the other is 
 
 C 3 -C 7  cycloalkane, saturated or unsaturated, optionally bridged, optionally including one or more heteroatoms selected from O, S, and N, and optionally substituted at one or more C or N atoms by methyl, ethyl, pyridinyl, azetidinyl, acetamidyl, carboxamidyl, cyano, fluoro, methylamino, or trifluoromethyl; or 
 
         R 1  and R 2 , together with the nitrogen atom to which they are attached, form an 8 to 11 member spirodiamine, an 8 member bicyclodiamine, a 7 member spiroxamine, a piperidinyl optionally substituted with ethyl, or a four to six member cycloalkyl, optionally substituted with at least one of carboxamidyl, aminomethyl, methyl, (ethylamino)methyl, (dimethylamino)methyl, dimethylamino, (methylamino)methyl, and amino; and wherein
 R 3  is —H or methyl 
 and at least one pharmaceutically acceptable carrier. 
 
       
     
     
         13 - 18 . (canceled) 
     
     
         19 . The method of  claim 10 , wherein the method is used for treatment of systemic lupus erythematosus or lupus nephritis. 
     
     
         20 . The method of  claim 11 , wherein the method is used for treatment of systemic lupus erythematosus or lupus nephritis. 
     
     
         21 . The method of  claim 8 , wherein one of the two or more compounds or pharmaceutically acceptable salts according to Formula (I) is (2R,6R)-4-(8-cyanoquinolin-5-yl)-N-((3S,4R)-4-fluoropyrrolidin-3-yl)-6-methylmorpholine-2-carboxamide or a pharmaceutically acceptable salt thereof. 
     
     
         22 . The method of  claim 10 , wherein one of the two or more compounds or pharmaceutically acceptable salts according to Formula (I) is (2R,6R)-4-(8-cyanoquinolin-5-yl)-N-((3S,4R)-4-fluoropyrrolidin-3-yl)-6-methylmorpholine-2-carboxamide or a pharmaceutically acceptable salt thereof. 
     
     
         23 . The pharmaceutical composition of  claim 12 , wherein one of the two or more compounds or pharmaceutically acceptable salts according to Formula (I) is (2R,6R)-4-(8-cyanoquinolin-5-yl)-N-((3S,4R)-4-fluoropyrrolidin-3-yl)-6-methylmorpholine-2-carboxamide or a pharmaceutically acceptable salt thereof.