Tricyclic carbamate jak inhibitors

Abstract

The present disclosure relates to 2,4-pyrimidinediamines substituted with tricyclic carbamates and the compositions and methods using these compounds in the treatment of conditions in which modulation of the JAK pathway or inhibition of JAK kinases, such as JAK2 or JAK3, is therapeutically useful.

What is claimed is: 
     
         1 . A method for inhibiting JAK activity in a cell, comprising contacting the cell with a therapeutically effective amount of a compound having a formula I 
       
         
           
           
               
               
           
         
         a tautomer, N-oxide, or salt thereof, wherein:
 ring A is aryl or heteroaryl; 
 n is 0 or 1; 
 p is 0, 1, 2 or 3 when ring A is monocyclic aryl or heteroaryl or p is 0, 1, 2, 3, 4, or 5 when ring A is bicyclic or tricyclic aryl or heteroaryl; 
 X is selected from the group consisting of alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halo, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; 
 Y is O or S; 
 Z is O; 
 W is hydrogen, —SO 2 N(R 4 )R 5 , -alk-SO 2 N(R 4 )R 5 , —N(R 4 )SO 2 R 5 , or -alk-N(R 4 )SO 2 R 5 ; 
 -alk- is selected from the group consisting of straight or branched chain C 1-6  alkylene group, and straight or branched chain substituted C 1-6  alkylene group; 
 R 1  is hydrogen or C 1-3  alkyl; 
 each R 2  independently is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkenyl, substituted cycloalkenyl, alkynyloxy, amino, substituted amino, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, aminocarbonyl, aminocarbonyloxy, carboxyl, carboxyl ester, (carboxyl ester)oxy, nitro, halo, and oxo, wherein if R 2  is oxo, then the oxo substituent is attached to a nonaromatic portion of ring A; or 
 R 3  is hydrogen or C 1-3  alkyl; 
 R 4  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyl and M + , wherein M +  is a counterion selected from the group consisting of K + , Na + , Li +  and  + N(R 8 ) 4 , wherein each R 8  is independently hydrogen or alkyl, and the nitrogen of —SO 2 N(R 4 )R 5  or —N(R 4 )SO 2 R 5  is N − ; and 
 R 5  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, amino, alkylamino, dialkylamino, cycloalkylamino, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and acyl; or 
 R 4  and R 5  together with the intervening atom or atoms bound thereto form a heterocyclic or a substituted heterocyclic group. 
 
       
     
     
         2 . The method of  claim 1 , wherein contacting is in vitro. 
     
     
         3 . The method of  claim 1 , wherein the JAK activity is JAK 2 activity. 
     
     
         4 . The method of  claim 1 , wherein contacting comprises administering to a subject a therapeutically effective amount of the compound. 
     
     
         5 . The method of  claim 4 , wherein the subject has a disease associated with JAK 2 activity and wherein the disease is selected from leukemia, lymphoma, multiple myeloma, transplant rejection, bone marrow transplant applications, autoimmune diseases, inflammation, myeloproliferative disorders, polycythemia vera disorder, essential thrombocythemia disorder and primary myelofibrosis. 
     
     
         6 . The method of  claim 1 , wherein R 1  is hydrogen. 
     
     
         7 . The method of  claim 6 , wherein Y is O and R 3  is hydrogen. 
     
     
         8 . The method of  claim 7 , wherein W is hydrogen. 
     
     
         9 . The method of  claim 8 , wherein the compound has a formula IIa or IIb: 
       
         
           
           
               
               
           
         
       
     
     
         10 . The method of  claim 7 , wherein the compound has a formula IIIa or IIIb: 
       
         
           
           
               
               
           
         
         wherein W is not hydrogen. 
       
     
     
         11 . The method of  claim 10 , wherein ring A is phenyl. 
     
     
         12 . The method of  claim 11 , wherein X is alkyl or halo. 
     
     
         13 . The method of  claim 12 , wherein X is methyl or chloro. 
     
     
         14 . The method of  claim 13 , wherein W is -alk-N(R 4 )SO 2 R 5 . 
     
     
         15 . The method of  claim 14 , wherein alk is —CH 2 — or —CH 2 CH 2 —. 
     
     
         16 . The method of  claim 15 , according to formula IVa or IVb: 
       
         
           
           
               
               
           
         
         wherein q is 1 or 2. 
       
     
     
         17 . The method of  claim 1 , wherein the compound is selected from
 5-Chloro-N4-[4-[2-[N-(cyclopropylsulfonyl)amino]ethyl]phenyl]-N2-[(3aR,8aS)-2-oxo-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-5-yl]-2,4-pyrimidinediamine;   5-Methyl-N2-[(3aR,8aS)-2-oxo-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-5-yl]-N4-(2,2,4-trimethyl-3-oxo-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine;   N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-methyl-N2-[(3aR,8aS)-2-oxo-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-5-yl]-2,4-pyrimidinediamine;   5-Methyl-N4-(4-methyl-3-oxo-2H-benz[1,4]thiazin-6-yl)-N2-[(3aR,8aS)-2-oxo-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-5-yl]-2,4-pyrimidinediamine;   5-Methyl-N2-[(3aR,8aS)-2-oxo-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-5-yl]-N4-(2,2,4-trimethyl-3-oxo-5-pyrido[1,4]oxazin-6-yl)-2,4-pyrimidinediamine;   5-Methyl-N4-(4-propyl-3-oxo-2H-benz[1,4]oxazin-6-yl)-N2-[(3aR,8aS)-2-oxo-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-5-yl]-2,4-pyrimidinediamine;   5-Methyl-N2-[(3aR,8aS)-2-oxo-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-5-yl]-N4-(2,2,4-trimethyl-3-oxo-benz[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;   5-Chloro-N4-[4-[[N-(cyclopropylsulfonyl)amino]methyl]phenyl]-N2-[(3aR,8aS)-2-oxo-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-5-yl]-2,4-pyrimidinediamine;   5-Methyl-N2-[(3aS,8aR)-2-oxo-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-5-yl]-N4-(2,2,4-trimethyl-3-oxo-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine;   5-Chloro-N2-[(3aS,8aR)-2-oxo-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-5-yl]-N4-(2,2,4-trimethyl-3-oxo-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine;   N4-(2,2-Dimethyl-4-ethyl-3-oxo-benz[1,4]oxazin-6-yl)-5-methyl-N2-[(3aS,8aR)-2-oxo-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-5-yl]-2,4-pyrimidinediamine;   5-Chloro-N4-(2,2-dimethyl-4-ethyl-3-oxo-benz[1,4]oxazin-6-yl)-N2-[(3aS,8aR)-2-oxo-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-5-yl]-2,4-pyrimidinediamine;   N4-(2,2-Dimethyl-3-oxo-4H-benz[1,4]oxazin-6-yl)-5-methyl-N2-[(3aS,8aR)-2-oxo-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-5-yl]-2,4-pyrimidinediamine;   5-Chloro-N4-[3-[[(1,1-dimethylethyl)amino]sulfonyl]phenyl]-N2-[(3aS,8aR)-2-oxo-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-5-yl]-2,4-pyrimidinediamine;   N4-[4-[[N-(Cyclopropylsulfonyl)amino]methyl]phenyl]-5-methyl-N2-[(3aS,8aR)-2-oxo-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-5-yl]-2,4-pyrimidinediamine;   5-Chloro-N4-[4-[[N-(cyclopropylsulfonyl)amino]methyl]phenyl]-N2-[(3aS,8aR)-2-oxo-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-5-yl]-2,4-pyrimidinediamine;   5-Chloro-N4-[4-[[N-(cyclopropylsulfonyl)amino]methyl]-2-methylphenyl]-N2-[(3aS, 8aR)-2-oxo-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-5-yl]-2,4-pyrimidinediamine;   N4-[4-[[N-(Cyclopropylsulfonyl)amino]methyl]-5-methyl-N2-[(3aS,8aR)-2-oxo-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-5-yl]-2,4-pyrimidinediamine;   5-Chloro-N4-(indan-4-yl]-5-methyl-N2-[(3aS,8aR)-2-oxo-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-5-yl]-2,4-pyrimidinediamine;   N4-(Indan-4-yl]-5-methyl-N2-[(3aS,8aR)-2-oxo-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-5-yl]-2,4-pyrimidinediamine;   5-Chloro-N2-[(3aS,8aR)-2-oxo-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-5-yl]-N4-(5,6,7,8-tetrahydronaphthalen-1-yl)2,4-pyrimidinediamine;   5-Methyl-N2-[(3aS,8aR)-2-oxo-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-5-yl]-N4-(5,6,7,8-tetrahydronaphthalen-1-yl)-2,4-pyrimidinediamine;   N4-(1,4-Benzodioxan-5-yl)-5-chloro-N2-[(3aS,8aR)-2-oxo-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-5-yl]-2,4-pyrimidinediamine;   N4-(1,4-Benzodioxan-5-yl)-5-methyl-N2-[(3aS,8aR)-2-oxo-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-5-yl]-2,4-pyrimidinediamine;   5-Chloro-N4-(2,2-difluoro-1,3-benzodioxol-4-yl)-N2-[(3aS,8aR)-2-oxo-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-5-yl]-2,4-pyrimidinediamine;   5-Fluoro-N2-[(3aR,8aS)-2-oxo-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-5-yl]-N4-[4-(pyridin-2-ylmethoxy)phenyl]-2,4-pyrimidinediamine;   5-Methyl-N2-[(3aR,8aS)-2-oxo-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-5-yl]-N4-[4-(pyridin-2-ylmethoxy)phenyl]-2,4-pyrimidinediamine;   5-Methyl-N2-[(3aS,8aR)-2-oxo-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-5-yl]-N4-[4-(pyridin-2-ylmethoxy)phenyl]-2,4-pyrimidinediamine;   5-Fluoro-N2-[(3aR,8aS)-2-oxo-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-5-yl]-N4-[4-[2-(pyridin-4-yl)ethyl]phenyl]-2,4-pyrimidinediamine;   5-Fluoro-N2-[(3aS,8aR)-2-oxo-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-5-yl]-N4-[4-(pyridin-2-ylmethoxy)phenyl]-2,4-pyrimidinediamine;   5-Methyl-N2-[(3aR,8aS)-2-oxo-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-5-yl]-N4-[4-(pyridin-3-ylmethoxy)phenyl]-2,4-pyrimidinediamine;   5-Methyl-N2-[(3aS,8aR)-2-oxo-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-5-yl]-N4-[4-(pyridin-3-ylmethoxy)phenyl]-2,4-pyrimidinediamine;   5-Fluoro-N2-[(3aS,8aR)-2-oxo-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-5-yl]-N4-[4-[2-(pyridin-4-yl)ethyl]phenyl]-2,4-pyrimidinediamine;   5-Chloro-N4-(indan-4-yl]-5-methyl-N2-[(3aR,8aS)-2-oxo-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-5-yl]-2,4-pyrimidinediamine;   N4-(Indan-4-yl]-5-methyl-N2-[(3aR,8aS)-2-oxo-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-5-yl]-2,4-pyrimidinediamine;   5-Chloro-N2-[(3aR,8aS)-2-oxo-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-5-yl]-N4-(5,6,7,8-tetrahydronaphthalen-1-yl)2,4-pyrimidinediamine;   5-Methyl-N2-[(3aR,8aS)-2-oxo-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-5-yl]-N4-(5,6,7,8-tetrahydronaphthalen-1-yl)-2,4-pyrimidinediamine;   5-Methyl-N2-[(4aR,9aS)-3-oxo-2,3,4,4a,9a-hexahydroindeno[2,1-b][1,4]oxazin-6-yl]-N4-(2,2,4-trimethyl-3-oxo-benz[1,4]oxazin-6-yl)-2,4-pyrimidinediamine;   N4-[4-[[N-(Cyclopropylsulfonyl)amino]methyl]phenyl]-5-methyl-N2-[(4aR,9aS)-3-oxo-2,3,4,4a,9a-hexahydroindeno[2,1-b][1,4]oxazin-6-yl]-2,4-pyrimidinediamine; or   5-Chloro-N4-[4-[[N-(cyclopropylsulfonyl)amino]methyl]phenyl]-N2-[(4aR,9aS)-3-oxo-2,3,4,4a,9a-hexahydroindeno[2,1-b][1,4]oxazin-6-yl]-2,4-pyrimidinediamine.   
     
     
         18 . The method of  claim 4 , wherein the compound is administered in combination with or adjunctive to an immunosuppressive therapy selected from a corticosteroid, an alkylating agent, a calcineurin inhibitor, or an inhibitor of inosine monophosphate dehydrogenase. 
     
     
         19 . The method of  claim 4 , wherein the compound is administered in combination with or adjunctive to an immunosuppressive therapy selected from mercaptopurine, prednisone, methylprednisolone, prednisolone, cyclophosphamide, cyclosporine, sirolimus, tacrolimus, mycophenolate, mycophenolate mofetil, azathioprine; antilymphocyte globulin, antithymocyte globulin, monoclonal anti-T-cell antibodies, or irradiation. 
     
     
         20 . The method of  claim 4 , wherein the compound is administered in combination with a therapeutically effective amount of one or more chemotherapeutic agents selected from paclitaxel, cyclophosphamide, 5-fluorouracil, cisplatin, carboplatin, methotrexate, or imatinib. 
     
     
         21 . The method of  claim 5 , wherein the disease or condition associated with JAK2 activity is leukemia. 
     
     
         22 . A method of inhibiting an activity of a JAK2 kinase, comprising contacting the JAK2 kinase with an amount of a compound of formula I, or a tautomer, N-oxide, or salt thereof, effective to inhibit an activity of the JAK2 kinase 
       
         
           
           
               
               
           
         
         wherein:
 ring A is aryl or heteroaryl; 
 n is 0 or 1; 
 p is 0, 1, 2 or 3 when ring A is monocyclic aryl or heteroaryl or p is 0, 1, 2, 3, 4, or 5 when ring A is bicyclic or tricyclic aryl or heteroaryl; 
 X is selected from the group consisting of alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halo, nitro, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; 
 Y is O or S; 
 Z is O; 
 W is hydrogen, —SO 2 N(R 4 )R 5 , -alk-SO 2 N(R 4 )R 5 , —N(R 4 )SO 2 R 5 , or -alk-N(R 4 )SO 2 R 5 ; 
 -alk- is selected from the group consisting of straight or branched chain C 1-6  alkylene group, and straight or branched chain substituted C 1-6  alkylene group; 
 R 1  is hydrogen or C 1-3  alkyl; 
 each R 2  independently is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkenyl, substituted cycloalkenyl, alkynyloxy, amino, substituted amino, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, aminocarbonyl, aminocarbonyloxy, carboxyl, carboxyl ester, (carboxyl ester)oxy, nitro, halo, and oxo, wherein if R 2  is oxo, then the oxo substituent is attached to a nonaromatic portion of ring A; or 
 R 3  is hydrogen or C 1-3  alkyl; 
 R 4  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyl and M + , wherein M +  is a counterion selected from the group consisting of K + , Na + , Li +  and  + N(R 8 ) 4 , wherein each R 8  is independently hydrogen or alkyl, and the nitrogen of —SO 2 N(R 4 )R 5  or —N(R 4 )SO 2 R 5  is N − ; and 
 R 5  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, amino, alkylamino, dialkylamino, cycloalkylamino, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and acyl; or 
 R 4  and R 5  together with the intervening atom or atoms bound thereto form a heterocyclic or a substituted heterocyclic group. 
 
       
     
     
         23 . The method of  claim 22 , wherein the JAK2 kinase is in a subject and the method further comprises administering the compound to the subject.