Jak1 selective inhibitors and uses thereof

Abstract

The new 1H-furo[3,2-b]imidazo[4,5-d]pyridine derivatives are selective Jak1 kinase inhibitors useful in treating disorders related to Jak1 activities such as autoimmune diseases or disorders, inflammatory diseases or disorders, and cancer or neoplastic diseases or disorders.

What is claimed: 
     
       1. A compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein R 1  is H, halo, or C 1-3  alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, CN, OR, NHR, NRR′, N(R)C(═O)R′, N(R)C(═O)(0)R′, N(R)C(═O)(O)R′, OC(═O)NRR′, C(═O)R, C(═O)NRR′, N(R)S(O) 2 R′, S(O) 2 R, and S(O) 2 NRR′;
 R 2  is H, halo, or C 1-3  alkyl; 
 Cy is C 3-7  cycloalkyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of R 3 , oxo, halo, OH, CN, OR, NHR, NRR′, N(R)C(═O)R′, N(R)C(═O)(O)R′, OC(═O)NRR′, C(═O)R, C(═O)NRR′, N(R)S(O) 2 R′, S(O) 2 R, and S(O) 2 NRR′, wherein R 3  is C 1-3  alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, CN, OR, NHR, NRR′, N(R)C(═O)R′, N(R)C(═O)(O)R′, OC(═O)NRR′, C(═O)R, C(═O)NRR′, N(R)S(O) 2 R′, S(O) 2 R, and S(O) 2 NRR′; and 
 R and R′ are each independently H, or C 1-3  alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, and CN. 
 
       
     
     
       2. The compound of  claim 1 , wherein Cy is C 5-7  cycloalkyl, or 5-7 membered heterocyclyl, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of R 3 , oxo, halo, OH, CN, OR, NHR, NRR′, N(R)C(═O)R′, N(R)C(═O)(O)R′, OC(═O)NRR′, C(═O)R, C(═O)NRR′, N(R)S(O) 2 R′, S(O) 2 R, and S(O) 2 NRR′, wherein R 3  is C 1-3  alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, CN, OR, NHR, NRR′, N(R)C(═O)R′, N(R)C(═O)(O)R′, OC(═O)NRR′, C(═O)R, C(═O)NRR′, N(R)S(O) 2 R′, S(O) 2 R, and S(O) 2 RR′. 
     
     
       3. The compound of  claim 1 , wherein R 2  is hydrogen. 
     
     
       4. The compound of  claim 1 , wherein the compound is selected from the group consisting of:
 trans-4-[2-[(R)-1-Hydroxyethyl]-1H-furo[3,2-b]imidazo[4,5-d]pyridin-1-yl] cyclohexanecarbonitrile (1), 
 trans-4-[2-(Hydroxymethyl)furo[3,2-b]imidazo[4,5-d]pyridin-1-yl] cyclohexanecarbonitrile (2), 
 2-[trans-4-[2-[(R)-1-Hydroxyethyl]furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]cyclohexyl] acetonitrile (3), 
 2-[(2R,5S)-5-[2-[(R)-1-Hydroxyethyl]furo[3,2-b]imidazo[4,5-d]pyridin-1-yl] tetrahydropyran-2-yl]acetonitrile (4), 
 3-[2-[(R)-1-Hydroxyethyl]-1H-furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (5), 
 (R)-4-[2-(1-Hydroxyethyl)-1H-furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]-N-(2,2,2-trifluoroethyl)piperidine-1-carboxamide (6), 
 2-[(2R,5S)-5-[2-(Hydroxymethyl)furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (7), 
 2-[(2S,5S)-5-[2-(Hydroxymethyl)furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (8), 
 2-[(2R,5S)-5-[2-Ethylfuro[3,2-b]imidazo[4,5-d]pyridin-1-yl] tetrahydropyran-2-yl]acetonitrile (9), 
 2-[(2R,5S)-5-[2-Furo[3,2-b]imidazo[4,5-d] pyridin-1-yl] tetrahydropyran-2-yl]acetonitrile (10), and 
 2-[(2R,5S)-5-[2-Methylfuro [3,2-b] imidazo [4,5-d] pyridin-1-yl] tetrahydropyran-2-yl] acetonitrile (11). 
 2-[(2R,5S)-5-[2-Ethylfuro[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (9), 
 2-[(2R,5S)-5-[2-Furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (10), and 
 2-[(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (11).  
 
     
     
       5. A method of treating rheumatoid arthritis in a subject comprising administering to the subject a compound of  claim 1 . 
     
     
       6. A compound of formula A1-14: 
       
         
           
           
               
               
           
         
       
     
     
       7. A process, comprising contacting a compound of formula V: 
       
         
           
           
               
               
           
         
         and a compound of formula VI: 
       
       
         
           
           
               
               
           
         
         in the presence of a (C 1-6 ) 3  alkyloxonium tetrafluoroborate at a sufficient temperature, and for a sufficient time to produce a compound of formula I: 
       
       
         
           
           
               
               
           
         
         wherein R 1  is H, halo, or C 1-3  alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, CN, OR, NHR, NRR′, N(R)C(═O)R′, N(R)C(═O)(O)R′, OC(═O)NRR′, C(═O)R, C(═O)NRR′, N(R)S(O) 2 R′, S(O) 2 R, and S(O) 2 NRR′;
 R 2  is H; 
 Cy is C 3-7  cycloalkyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of R 3 , oxo, halo, OH, CN, OR, NHR, NRR′, N(R)C(═O)R′, N(R)C(═O)(O)R′, OC(═O)NRR′, C(═O)R, C(═O)NRR′, N(R)S(O) 2 R′, S(O) 2 R, and S(O) 2 NRR′, wherein R 3  is C 1-3  alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, CN, OR, NHR, NRR′, N(R)C(═O)R′, N(R)C(═O)(O)R′, OC(═O)NRR′, C(═O)R, C(═O)NRR′, N(R)S(O) 2 R′, S(O) 2 R, and S(O) 2 NRR′; and 
 R and R′ are each independently H, or C 1-3  alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, and CN. 
 
       
     
     
       8. The process of  claim 7 , wherein the (C 1-6 ) 3  alkyloxonium tetrafluoroborate reagent is triethyloxonium tetrafluoroborate. 
     
     
       9. The process of  claim 7 , wherein the compound of formula V is prepared by a process comprising reducing a compound of formula VII: 
       
         
           
           
               
               
           
         
         in the presence of a hydrogenation catalyst and hydrogen gas at a sufficient temperature, a sufficient pressure and for a sufficient time to produce a compound of formula V. 
       
     
     
       10. The process of  claim 9 , wherein the hydrogenation catalyst is palladium on carbon. 
     
     
       11. The process of  claim 9 , wherein the compound of formula VII is prepared by a process comprising contacting a compound of formula A1-14: 
       
         
           
           
               
               
           
         
         and a compound of formula VIII:
   Cy-NH 2    VIII
 
 
         in the presence of a base at a sufficient temperature, and for a sufficient time to produce the compound of formula VII. 
       
     
     
       12. The process of  claim 11 , wherein the base is N,N-Diisopropylethylamine. 
     
     
       13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Cy is C 5-7  cycloalkyl, or 5-7 membered heterocyclyl, each optionally substitutued with 1, 2, or 3 substituents independently selected from the group consisting of R 3 , oxo, halo, OH, CN, OR, NHR, NRR′, N(R)C(═O)R′, N(R)C(═O)(O)R′, OC(═O)NRR′, C(═O)R, C(═O)NRR′, N(R)S(O) 2 R′, S(O) 2 R, and S(O) 2 NRR′, wherein R 3  is C 1-3  alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, CN, OR, NHR, NRR′, N(R)C(═O)R′, N(R)C(═O)(O)R′, OC(═O)NRR′, C(═O)R, C(═O)NRR′, N(R)S(O) 2 R′, S(O) 2 R, and S(O) 2 NRR′.  
     
     
       14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2  is hydrogen. 
     
     
       15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound or pharmaceutically acceptable salt is selected from the group consisting of:
 2-[(2R,5S)-5-[2-Ethylfuro[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (9),   2-[(2R,5S)-5-[2-Furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (10),   2-[(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (11), and   pharmaceutically acceptable salts thereof.    
     
     
       16. A compound that is 2-[(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (11). 
     
     
       17. A pharmaceutically acceptable salt that is a pharmaceutically acceptable salt of 2-[(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (11). 
     
     
       18. A method of treating rheumatoid arthritis in a subject in need thereof comprising administering to the subject in need thereof an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof. 
     
     
       19. A compound of formula A1-14: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       20. A process, comprising contacting a compound of formula V: 
       
         
           
           
               
               
           
         
         and a compound of formula VI: 
       
       
         
           
           
               
               
           
         
         in the presence of a (C 1-6  alkyl) 3 oxonium tetrafluoroborate at a sufficient temperature, and for a sufficient time to produce a compound of formula I: 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein R 1  is H, halo, or C 1-3  alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, CN, OR, NHR, NRR′, N(R)C(═O)R′, N(R)C(═O)(O)R′, OC(═O)NRR′, C(═O)R, C(═O)NRR′, N(R)S(O) 2 R′, S(O) 2 R, and S(O) 2 NRR′;
 R 2  is H; 
 Cy is C 3-7  cycloalkyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of R 3 , oxo, halo, OH, CN, OR, NHR, NRR′, N(R)C(═O)R′, N(R)C(═O)(O)R′, OC(═O)NRR′, C(═O)R, C(═O)NRR′, N(R)S(O) 2 R′, S(O) 2 R, and S(O) 2 NRR′, wherein R 3  is C 1-3  alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, CN, OR, NHR, NRR′, N(R)C(═O)R′, N(R)C(═O)(O)R′, OC(═O)NRR′, C(═O)R, C(═O)NRR′, N(R)S(O) 2 R′, S(O) 2 R, and S(O) 2 NRR′; and 
 R and R′are each independently H, or C 1-3  alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, and CN. 
 
       
     
     
       21. The process of claim 20, wherein Cy is C 5-7  cycloalkyl or 5-7 membered heterocyclyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of R 3 , oxo, halo, OH, CN, OR, NHR, NRR′, N(R)C(═O)R′, N(R)C(═O)(O)R′, OC(═O)NRR′, C(═O)R, C(═O)NRR′, N(R)S(O) 2 R′, S(O) 2 R, and S(O) 2 NRR′, wherein R 3  is C 1-3  alkyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, OH, CN, OR, NHR, NRR′, N(R)C(═O)R′, N(R)C(═O)(O)R′, OC(═O)NRR′, C(═O)R, C(═O)NRR′, N(R)S(O) 2 R′, S(O) 2 R, and S(O) 2 NRR′.  
     
     
       22. The process of claim 20, wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:
 2-[(2R,5S)-5-[2-Ethylfuro[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (9),   2-[(2R,5S)-5-[2-Furo[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (10),   2-[(2R,5S)-5-[2-Methylfuro[3,2-b]imidazo[4,5-d]pyridin-1-yl]tetrahydropyran-2-yl]acetonitrile (11), and   pharmaceutically acceptable salts thereof.