2,4-diamino-pyrimidine compounds and method for making and using the compounds

Abstract

Compounds within the scope of the present invention have a Formula 1or a salt or produg thereof, where ring A is selected from cycloaliphatic; ring B is aryl; R1 is selected from (C1-C10)alkyl, (C3-C10)cycloalkyl, halo, aryl, and heteroaryl; and R2 and R3 are independently selected from hydrogen and (C1-C6)alkyl. Disclosed compounds may have an IRAK4 IC50 of from 0.003 μM to 3.7 μM; a TAK1 IC50 of from 0.008 μM to 132 μM; and/or an IRAK4/TAK1 selectivity of from 1 to 450. Particular compounds may have an IRAK4/TAK1 selectivity of from 100 to 500. Disclosed compositions may be formulated as pharmaceutical compositions. A method for using the compounds and/or compositions also are disclosed. The method may comprise administering to a subject an effective amount of a compound within the scope of the present invention, particularly to selectively inhibit IRAK 1 and/or IRAK4 over TAK1.

We claim: 
     
         1 . A method for treating a proliferative disorder, comprising administering to a subject a therapeutically effective amount of a compound, or a composition comprising the compound, wherein the compound has a formula 1 
       
         
           
           
               
               
           
         
       
       or salt thereof, wherein:
 ring A is cycloaliphatic; 
 ring B is aryl; 
 R 1  is (C1-C10)alkyl, (C3-C10)cycloalkyl, halo, aryl, or heteroaryl; and 
 R 2  and R 3  are independently hydrogen or (C1-C6)alkyl. 
 
     
     
         2 . The method according to  claim 1  wherein the hyperproliferative disorder is a hyperproliferative skin disease. 
     
     
         3 . The method according to  claim 2  wherein the hyperproliferative disorder is epidermal hyperproliferation. 
     
     
         4 . The method according to  claim 1  wherein the hyperproliferative disorder is a hematological malignancy. 
     
     
         5 . The method according to  claim 4  where the hematological malignancy is leukemia, acute myeloid leukemia (AML), DLBCL, ABC DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma/leukemia, acute lymphocytic leukemia, or B-cell prolymphocytic leukemia. 
     
     
         6 . The method according to  claim 1 , wherein cycloaliphatic ring A is substituted with —CONH 2 . 
     
     
         7 . The method according to  claim 1 , wherein ring A is a carboxamide substituted (C6-C12) cycloalkyl, (C6-C12) cycloalkenyl, (C6-C12) bicycloalkyl or a (C6-C12) bicycloalkenyl ring. 
     
     
         8 . The method according to  claim 1 , wherein ring B is a mono-, di- or tri-substituted phenyl ring. 
     
     
         9 . The method according to  claim 1 , wherein ring B is substituted with a substituent selected from (C1-10)amide, (C3-C10)cycloamide, (C1-C10)alkyl, (C1-C10)alkoxyl, (C3-C10)cycloalkoxyl, halo, (C3-C10)cycloalkyl or (C3-C10)heterocycloalkyl. 
     
     
         10 . The method according to  claim 9 , wherein the substituent is methyl or fluoro. 
     
     
         11 . The method according to  claim 1 , wherein the A ring is selected from 
       
         
           
           
               
               
           
         
       
     
     
         12 . The method according to  claim 1 , wherein the B ring is selected from 
       
         
           
           
               
               
           
         
       
     
     
         13 . The method according to  claim 1 , wherein R 1  is aryl or heteroaryl. 
     
     
         14 . The method according to  claim 1 , wherein R 1  is F, CH 3 , 
       
         
           
           
               
               
           
         
       
     
     
         15 . The method according to  claim 1 , having a formula selected from 
       
         
           
           
               
               
           
         
       
       wherein the A ring, the B ring, R 1 , R 2  and R 3  are as stated in  claim 1 . 
     
     
         16 . The method according to  claim 11 , having a formula 
       
         
           
           
               
               
           
         
       
     
     
         17 . The method according to  claim 1 , having a formula selected from 
       
         
           
           
               
               
           
         
       
       wherein the A ring, the B ring, R 2  and R 3  are as stated in  claim 1 , and R 4  is selected from (C1-C6)alkyl, cyano, halo and hydrogen. 
     
     
         18 . The method according to  claim 17 , wherein R 4  is methyl or fluoro. 
     
     
         19 . The method according to  claim 1 , having a formula selected from 
       
         
           
           
               
               
           
         
       
       wherein the A ring, the B ring, and R 2  and R 3  are as stated in  claim 1 . 
     
     
         20 . The method according to  claim 15 , wherein (C1-C10)alkyl is methyl and (C1-C10)cycloalkyl is cyclopropyl. 
     
     
         21 . The method according to  claim 1 , wherein the compound is selected from:
 (1S,2S,3R,4R)-3-((5-(pyridin-3-yl)-2-((4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;   (2S,3R)-3-((2-((3-fluoro-4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)amino)-5-(pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;   (1S,2S,3R,4R)-3-((5-(pyridin-3-yl)-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;   (1S,2S,3R,4R)-3-((5-methyl-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;   (1S,2S,3R,4R)-3-((5-cyclopropyl-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;   (1S,2S,3R,4R)-3-((5-(furan-3-yl)-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;   (1S,2S,3R,4R)-3-((5-phenyl-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;   (1S,2S,3R,4R)-3-((5-(pyridin-3-yl)-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;   (1S,2S,3R,4R)-3-((5-(pyridin-4-yl)-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;   (1S,2S,3R,4R)-3-((5-(2-fluorophenyl)-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;   (1S,2S,3R,4R)-3-((5-(3-fluorophenyl)-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;   (1S,2S,3R,4R)-3-((5-(4-fluorophenyl)-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;   (1S,2S,3R,4R)-3-((5-(3-cyanophenyl)-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;   (1S,2S,3R,4R)-3-((5-(4-cyanophenyl)-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;   (1S,2S,3R,4R)-3-((5-(5-fluoropyridin-3-yl)-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;   (1S,2S,3R,4R)-3-((5-(2-fluoropyridin-4-yl)-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;   1S,2R)-2-((5-(3-cyanophenyl)-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide;   (1S,2S,3R,4R)-3-((5-bromo-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide; or   (1S,2S,3R,4R)-3-((5-bromo-2-((4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide.   
     
     
         22 . A method for treating a hyperproliferative skin disease or a hematological malignancy, comprising administering to a subject a therapeutically effective amount of a compound, or a composition comprising the compound, wherein the compound has a formula 1 
       
         
           
           
               
               
           
         
       
       or salt thereof, wherein:
 ring A is selected from 
 
       
         
           
           
               
               
           
         
         ring B is selected from 
       
       
         
           
           
               
               
           
         
         R 1  is (C1-C10)alkyl, (C3-C10)cycloalkyl, halo, aryl, or heteroaryl; and 
         R 2  and R 3  are independently hydrogen or (C1-C6)alkyl.