Use of pyrazolopyrimidine derivatives for the treatment of pi3k-delta related disorders

Abstract

The present application provides methods of treating PI3Kδ related disorders using compounds of Formula I: or pharmaceutically acceptable salts thereof.

1 . A method of treating a disease selected from autoimmune hemolytic anemia pemphigus, and myelofibrosis in a patient, comprising administering to said patient a therapeutically effective amount of a compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 R 2  is C 1-6  alkyl or C 1-6  haloalkyl; 
 R 4  is halo, OH, CN, C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  alkoxy, or C 1-4  haloalkoxy; 
 R 5  is halo, OH, CN, C 1-4  alkyl, C 1-4  haloalkyl, C 1-4  alkoxy, or C 1-4  haloalkoxy; 
 Cy is selected from C 3-7  cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 independently selected R 3  groups; 
 each R 3  is independently selected from Cy 1 , —(C 1-3  alkylene)-Cy 1 , halo, CN, NO 2 , C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, OR a1 , SR a1 , C(═O)R b1 , C(═O)NR c1 R d1 , C(═O)OR a1 , OC(═O)R b1 OC(═O)NR c1 R d1 , NR c1 R d1 , NR c1 C(═O)R b1 , NR c1 C(═O)OR b1 , NR c1 C(═O)NR c1 R d1 , C(═NR e )R b1 , C(═NR e )NR c1 R d1 , NR c1 C(═NR e )NR c1 R d1 , NR c1 S(═O)R b1 , NR c1 S(═O) 2 NR c1 R d1 , S(═O)R b1 , S(═O) 2 R b1 , and S(═O) 2 NR c1 R d1 ; wherein said C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 11  groups; 
 
         each Cy 1  is independently selected from C 3-7  cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 independently selected R 11  groups; 
         each R a1 , R c1 , and R d1  is independently selected from H, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl; wherein said C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, 4-7 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl are each optionally substituted with 1, 2, or 3 independently selected R 11  groups; 
         each R b1  is independently selected from C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl; wherein said C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are each optionally substituted with 1, 2, or 3 independently selected R 11  groups; 
         or R c1  and R d1  together with the N atom to which they are attached form a 4-, 5-, 6-, or 7 membered heterocycloalkyl group, which is optionally substituted with —OH or C 1-3  alkyl; 
         each R e  is independently selected from H, CN, OH, C 1-4  alkyl, and C 1-4  alkoxy; and 
         each R 11  is independently selected from OH, NO 2 , CN, halo, C 1-3  alkyl, C 2-3  alkenyl, C 2-3  alkynyl, C 1-3  haloalkyl, cyano-C 1-3  alkyl, HO—C 1-3  alkyl, C 1-3  alkoxy-C 1-3  alkyl, C 3-7  cycloalkyl, C 1-3  alkoxy, C 1-3  haloalkoxy, amino, C 1-3  alkylamino, di(C 1-3  alkyl)amino, thio, C 1-3  alkylthio, C 1-3  alkylsulfinyl, C 1-3  alkylsulfonyl, carbamyl, C 1-3  alkylcarbamyl, di(C 1-3  alkyl)carbamyl, carboxy, C 1-3  alkylcarbonyl, C 1-4  alkoxycarbonyl, C 1-3  alkylcarbonylamino, C 1-3  alkylsulfonylamino, aminosulfonyl, C 1-3  alkylaminosulfonyl, di(C 1-3  alkyl)aminosulfonyl, aminosulfonylamino, C 1-3  alkylaminosulfonylamino, di(C 1-3  alkyl)aminosulfonylamino, aminocarbonylamino, C 1-3  alkylaminocarbonylamino, and di(C 1-3  alkyl)aminocarbonylamino. 
       
     
     
         2 . The method of  claim 1 , wherein R 2  is C 1-3  alkyl or C 1-3  fluoroalkyl. 
     
     
         3 . The method of  claim 1 , wherein R 2  is methyl, ethyl, or 2,2-difluoromethyl. 
     
     
         4 . The method of  claim 1 , wherein R 2  is methyl. 
     
     
         5 . The method of  claim 1 , wherein R 2  is ethyl. 
     
     
         6 . The method of  claim 1 , wherein R 4  is halo, CN, or C 1-3  alkyl. 
     
     
         7 . The method of  claim 1 , wherein R 4  is F, Cl, CN, or methyl. 
     
     
         8 . The method of  claim 1 , wherein R 4  is F. 
     
     
         9 . The method of  claim 1 , wherein R 4  is Cl. 
     
     
         10 . The method of  claim 1 , wherein R 4  is CN. 
     
     
         11 . The method of  claim 1 , wherein R 4  is methyl. 
     
     
         12 . The method of  claim 1 , wherein R 5  is halo, CN, or C 1-3  alkyl. 
     
     
         13 . The method of  claim 1 , wherein R 5  is Cl, CN, or methyl. 
     
     
         14 . The method of  claim 1 , wherein R 5  is Cl. 
     
     
         15 . The method of  claim 1 , wherein R 5  is CN. 
     
     
         16 . The method of  claim 1 , wherein R 5  is methyl. 
     
     
         17 . The method of  claim 1 , wherein Cy is selected from C 3-6  cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 independently selected R 3  groups. 
     
     
         18 . The method of  claim 1 , wherein Cy is 4-6 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 independently selected R 3  groups. 
     
     
         19 . The method of  claim 1 , wherein Cy is selected from a cyclopropyl ring, a phenyl ring, an azetidine ring, a pyrrolidine ring, a piperidine ring, 3-oxo-morpholin-6-yl, 2-oxo-pyrrolidin-4-yl, 2-oxo-oxazolidin-4-yl, 2-oxo-oxazolidin-5-yl, a pyrazole ring, a pyridine ring, and a pyrimidine ring, each of which is optionally substituted with 1, 2, 3, or 4 independently selected R 3  groups. 
     
     
         20 . The method of  claim 1 , wherein:
 each R 3  is independently selected from Cy 1 , —(C 1-3  alkylene)-Cy 1 , halo, CN, C 1-6  alkyl, OR a1 , NR c1 R d1 , C(═O)R b1 , C(═O)OR a1 , C(═O)NR c1 R d1 , and S(═O) 2 R b1 , wherein said C 1-6  alkyl is optionally substituted with 1, 2, 3, or 4 independently selected R 11  groups;   each Cy 1  is independently C 3-7  cycloalkyl, which is optionally substituted with 1, 2, 3, or 4 independently selected R 11  groups;   each R a1 , R c1 , and R d1  is independently selected from H and C 1-6  alkyl, wherein said C 1-6  alkyl is optionally substituted with 1, 2, or 3 independently selected R 11  groups;   each R b1  is independently C 1-6  alkyl, which is optionally substituted with 1, 2, or 3 independently selected R 11  groups; and   each R 11  is independently OH, CN, halo, cyano-C 1-3  alkyl, C 1-3  haloalkoxy, amino, C 1-3  alkylamino, di(C 1-3  alkyl)amino, C 1-3  alkylcarbonyl, C 1-3  alkoxycarbonyl, carbamyl, C 1-3  alkylcarbamyl, or di(C 1-3  alkyl)carbamyl.   
     
     
         21 . The method of  claim 1 , wherein:
 R 2  is C 1-3  alkyl or C 1-3  fluoroalkyl;   R 4  is halo, CN, or C 1-3  alkyl;   R 5  is halo, CN, or C 1-3  alkyl;   Cy is selected from C 3-6  cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 independently selected R 3  group;   each R 3  is independently selected from Cy 1 , —(C 1-3  alkylene)-Cy 1 , halo, CN, C 1-6  alkyl, OR a1 , NR c1 R d1 , C(═O)R b1 , C(═O)OR a1 , C(═O)NR c1 R d1 , and S(═O) 2 R b1 , wherein said C 1-6  alkyl is optionally substituted with 1, 2, 3, or 4 independently selected R 11  groups;   each Cy 1  is independently C 3-7  cycloalkyl, which is optionally substituted with 1, 2, 3, or 4 independently selected R 11  groups;   each R a1 , R c1 , and R d1  is independently selected from H and C 1-6  alkyl, wherein said C 1-6  alkyl is optionally substituted with 1, 2, or 3 independently selected R 11  groups;   each R b1  is independently C 1-6  alkyl, which is optionally substituted with 1, 2, or 3 independently selected R 11  groups; and   each R 11  is independently OH, CN, halo, cyano-C 1-3  alkyl, C 1-3  haloalkoxy, amino, C 1-3  alkylamino, di(C1-3 alkyl)amino, C 1-3  alkylcarbonyl, C 1-3  alkoxycarbonyl, carbamyl, C 1-3  alkylcarbamyl, or di(C 1-3  alkyl)carbamyl.   
     
     
         22 . The method of  claim 1 , wherein:
 R 2  is methyl, ethyl, or 2,2-difluoromethyl;   R 4  is F, Cl, CN, or methyl;   R 5  is Cl, CN, or methyl;   Cy is selected from C 3-6  cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl, each of which is optionally substituted with 1, 2, 3, or 4 independently selected R 3  group;   each R 3  is independently selected from Cy 1 , —(C 1-3  alkylene)-Cy 1 , halo, CN, C 1-6  alkyl, OR a , NR c1 R d1 , C(═O)R b1 , C(═O)OR a1 , C(═O)NR c1 R d1 , and S(═O) 2 R b1 , wherein said C 1-6  alkyl is optionally substituted with 1, 2, 3, or 4 independently selected R 11  groups;   each Cy 1  is independently C 3-7  cycloalkyl, which is optionally substituted with 1, 2, 3, or 4 independently selected R 11  groups;   each R a1 , R c1 , and R d1  is independently selected from H and C 1-6  alkyl, wherein said C 1-6  alkyl is optionally substituted with 1, 2, or 3 independently selected R 11  groups;   each R b1  is independently C 1-6  alkyl, which is optionally substituted with 1, 2, or 3 independently selected R 11  groups; and   each R 11  is independently OH, CN, halo, cyano-C 1-3  alkyl, C 1-3  haloalkoxy, amino, C 1-3  alkylamino, di(C 1-3  alkyl)amino, C 1-3  alkylcarbonyl, C 1-3  alkoxycarbonyl, carbamyl, C 1-3  alkylcarbamyl, or di(C 1-3  alkyl)carbamyl.   
     
     
         23 . The method of  claim 1 , wherein:
 R 2  is methyl, ethyl, or 2,2-difluoromethyl;   R 4  is F, Cl, CN, or methyl;   R 5  is Cl, CN, or methyl;   Cy is selected from a cyclopropyl ring, a phenyl ring, an azetidine ring, a pyrrolidine ring, a piperidine ring, 3-oxo-morpholin-6-yl, 2-oxo-pyrrolidin-4-yl, 2-oxo-oxazolidin-4-yl, 2-oxo-oxazolidin-5-yl, a pyrazole ring, a pyridine ring, and a pyrimidine ring, each of which is optionally substituted with 1, 2, 3, or 4 independently selected R 3  groups   each R 3  is independently selected from Cy 1 , —(C 1-3  alkylene)-Cy 1 , halo, C 1-6  alkyl, OR a1 , NR c1 R d1 , C(═O)R b1 , C(═O)OR a1 , C(═O)NR c1 R d1 , and S(═O) 2 R b1 , wherein said C 1-6  alkyl is optionally substituted with 1, 2, 3, or 4 independently selected R 11  groups;   each Cy 1  is independently selected from cyclopropyl and cyclobutyl, each of which is optionally substituted with 1, 2, 3, or 4 independently selected R 11  groups;   each R a1 , R c1 , and R d1  is independently selected from H and C 1-4  alkyl; wherein said C 1-4  alkyl is optionally substituted with 1, 2, or 3 independently selected R 11  groups;   each R b1  is independently C 1-4  alkyl, which is optionally substituted with 1, 2, or 3 independently selected R 11  groups;   each R 11  is independently OH, CN, halo, cyano-C 1-3  alkyl, C 1-3  alkoxy-C 1-3  alkyl, C 1-3  alkoxy, C 1-3  haloalkoxy, amino, C 1-3  alkylamino, di(C 1-3  alkyl)amino, C 1-3  alkylcarbonyl, C 1-4  alkoxycarbonyl, carbamyl, C 1-3  alkylcarbamyl, or di(C 1-3  alkyl)carbamyl.   
     
     
         24 . The method of  claim 1 , wherein the compound is a compound of Formula II: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         25 . The method of  claim 1 , wherein the compound is a compound of Formula III: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         26 . The method of  claim 1 , wherein the compound is a compound of Formula IV: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 G is NH, n is 1, and V is O; or 
 G is NH, n is 0, and V is O or CH 2 ; or 
 G is O, n is 0 and V is NH. 
 
       
     
     
         27 . The method of  claim 1 , wherein the compound is a compound of Formula IVa: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         28 . The method of  claim 1 , wherein the compound is a compound of Formula IVb: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         29 . The method of  claim 1 , wherein the compound is a compound of Formula IVc: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         30 . The method of  claim 1 , wherein the compound is a compound of Formula IVd: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         31 . (canceled) 
     
     
         32 . The method of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the starred carbon in Formula I: 
       
         
           
           
               
               
           
         
         is a chiral carbon and said compound or said salt is the (S)-enantiomer. 
       
     
     
         33 . The method of  claim 1 , wherein the compound is selected from:
 1-{1-[5-Chloro-3-(1-isopropylazetidin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;   1-{1-[3-(1-Acetylazetidin-3-yl)-5-chloro-2-methoxy-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;   1-{1-[5-Chloro-2-methoxy-4-methyl-3-(1-propionylazetidin-3-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;   1-(1-{5-Chloro-3-[1-(cyclopropylmethyl)azetidin-3-yl]-2-methoxy-4-methylphenyl}ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;   1-{1-[5-chloro-2-methoxy-4-methyl-3-(1-methylazetidin-3-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;   1-{1-[5-Chloro-3-(1-ethylazetidin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;   1-{1-[5-Chloro-3-(1-isobutylazetidin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;   1-{1-[3-(1-sec-butylazetidin-3-yl)-5-chloro-2-methoxy-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;   1-(1-{5-Chloro-2-methoxy-3-[1-(2-methoxyethyl)azetidin-3-yl]-4-methylphenyl}ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;   3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N-methylazetidine-1-carboxamide;   5-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide;   1-{1-[5-Chloro-4-fluoro-3-(1-isopropylazetidin-3-yl)-2-methoxyphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;   5-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide;   4-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide;   4-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)-N-methylpicolinamide;   4-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N-(2-hydroxyethyl)pyridine-2-carboxamide;   4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N-(2-hydroxyethyl)-N-methylpyridine-2-carboxamide;   2-(4-(3-(1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)-1H-pyrazol-1-yl)ethanol;   3′-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5′-chloro-3-fluoro-2′-methoxy-N,N,6′-trimethylbiphenyl-4-carboxamide;   3′-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5′-chloro-3-fluoro-2′-methoxy-N,6′-dimethylbiphenyl-4-carboxamide;   5-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)-N-(2-hydroxyethyl)picolinamide;   4-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N-(2-hydroxyethyl)-N-methylpyridine-2-carboxamide;   4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-cyano-2-methoxy-6-methylphenyl}-N-(2-hydroxyethyl)-N-methylpyridine-2-carboxamide;   5-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide;   4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[5-(methylsulfonyl)pyridin-3-yl]benzonitrile;   5-(3-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-6-cyano-2-ethoxyphenyl)-N,N-dimethylpicolinamide   5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylnicotinamide   5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide;   1-{1-[5-Chloro-4-fluoro-3-(1-isopropylazetidin-3-yl)-2-methoxyphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;   (2S)-1-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-fluoro-2-methoxyphenyl}azetidin-1-yl)propan-2-ol;   2-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-fluoro-2-methoxyphenyl}azetidin-1-yl)ethanol;   1-{1-[5-Chloro-4-fluoro-2-methoxy-3-(1-oxetan-3-ylazetidin-3-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;   1-{1-[5-Chloro-2-ethoxy-3-(1-isopropylazetidin-3-yl)-4-methylphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;   2-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}azetidin-1-yl)ethanol;   (2S)-1-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}azetidin-1-yl)propan-2-ol;   (2S)-1-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}azetidin-1-yl)-1-oxopropan-2-ol;   (2S)-1-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)propan-2-ol;   2-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)ethanol;   (3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)acetonitrile;   1-(1-{5-Chloro-2-methoxy-4-methyl-3-[1-(2,2,2-trifluoroethyl)azetidin-3-yl]phenyl}ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;   (2R)-2-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)-N-methylpropanamide;   2-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)-3,3,3-trifluoropropan-1-ol;   (2R)-3-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)-1,1,1-trifluoropropan-2-ol;   (2S)-1-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)-1-oxopropan-2-ol;   (2R)-1-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)-1-oxopropan-2-ol;   1-{1-[5-Chloro-2-ethoxy-4-fluoro-3-(1-isopropylazetidin-3-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;   1-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}azetidin-1-yl)-2-methylpropan-2-ol;   1-(1-{5-Chloro-2-ethoxy-4-fluoro-3-[1-(2,2,2-trifluoroethyl)azetidin-3-yl]phenyl}ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;   (2S)-1-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}azetidin-1-yl)propan-2-ol;   (2R)-2-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)propan-1-ol;   1-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)-2-methylpropan-2-ol;   (2R)-2-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)-N,N-dimethylpropanamide;   [1-{3-3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidin-1-yl)cyclobutyl]acetonitrile;   1-{1-[5-Chloro-2-methoxy-4-methyl-3-(1-methylpiperidin-4-yl)phenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;   1-(4-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}piperidin-1-yl)-2-methylpropan-2-ol;   3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}cyclobutanol;   5-(3-(1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)-N,N-dimethylpicolinamide;   1-[1-(5-Chloro-3-{1-[2-(dimethylamino)ethyl]-1H-pyrazol-4-yl}-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;   2-[(5-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}pyridin-2-yl)amino]ethanol;   2-(5-(3-(1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)pyridin-2-yloxy)ethanol;   5-(3-(1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-(2,2-difluoroethoxy)-6-methylphenyl)-N,N-dimethylpicolinamide;   5-(3-(1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpicolinamide;   4-(3-(1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-methoxy-6-methylphenyl)-N,N-dimethylpicolinamide;   2-(4-(3-(1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-methylphenyl)-1H-pyrazol-1-yl)acetamide;   6-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylnicotinamide;   5-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-4-methoxy-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)benzonitrile;   1-(1-(5-chloro-2-methoxy-4-methyl-3-(pyrimidin-5-yl)phenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;   1-(1-(3-(2-aminopyrimidin-5-yl)-5-chloro-2-methoxy-4-methylphenyl)ethyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;   4-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-ethoxybenzonitrile;   4-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-(1-methylazetidin-3-yl)benzonitrile;   4-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[1-(2-hydroxyethyl)azetidin-3-yl]benzonitrile;   4-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-{1-[(2S)-2-hydroxypropyl]azetidin-3-yl}benzonitrile;   tert-Butyl 2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}azetidin-1-yl)-2-methylpropanoate;   4-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[1-(2-hydroxy-1,1-dimethylethyl)azetidin-3-yl]benzonitrile;   2-(3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}azetidin-1-yl)-2-methylpropanamide;   4-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[1-(2-hydroxy-2-methylpropanoyl)azetidin-3-yl]benzonitrile;   4-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-methoxybenzonitrile;   4-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-methoxy-2-(1-methylazetidin-3-yl)benzonitrile;   4-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-2-[1-(2-hydroxyethyl)azetidin-3-yl]-3-methoxybenzonitrile;   4-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-2-{1-[(2S)-2-hydroxypropyl]azetidin-3-yl}-3-methoxybenzonitrile;   4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-2-[1-(2-hydroxy-1-methylethyl)azetidin-3-yl]-3-methoxybenzonitrile;   2-(1-Acetylazetidin-3-yl)-4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-methoxybenzonitrile;   4-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-methoxy-2-[1-(methylsulfonyl)azetidin-3-yl]benzonitrile;   Methyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-methoxyphenyl}azetidine-1-carboxylate;   3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-methoxyphenyl}-N-(tert-butyl)azetidine-1-carboxamide;   3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-methoxyphenyl}azetidine-1-carboxamide;   3-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-methoxyphenyl}-N,N-dimethylazetidine-1-carboxamide;   1-{1-[4,5-Dichloro-3-(1-ethylazetidin-3-yl)-2-methoxyphenyl]ethyl}-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine;   4-[1-(4-Amino-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]-6-chloro-3-ethoxy-2-(1-isopropylazetidin-3-yl)benzonitrile;   4-[-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-{1-[(2S)-2-hydroxypropyl]azetidin-3-yl}-3-methoxy-6-methylbenzonitrile;   4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-[6-(1-hydroxy-1-methylethyl)pyridin-3-yl]benzonitrile;   4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-pyrrolidin-1-ylbenzonitrile;   4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-(3-methoxyazetidin-1-yl)benzonitrile;   4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-3-ethoxy-2-(1-isopropylazetidin-3-yl)-6-methylbenzonitrile;   4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-3-ethoxy-2-[1-(2-hydroxy-2-methylpropyl)azetidin-3-yl]-6-methylbenzonitrile;   4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-3-ethoxy-2-[1-(2-hydroxy-2-methylpropanoyl)azetidin-3-yl]-6-methylbenzonitrile;   4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}pyrrolidin-2-one;   4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-(2-oxo-1,3-oxazolidin-5-yl)benzonitrile;   6-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}morpholin-3-one;   5-{3-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-1,3-oxazolidin-2-one;   4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}pyrrolidin-2-one;   4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-6-chloro-3-ethoxy-2-(5-oxopyrrolidin-3-yl)benzonitrile;   4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}-1,3-oxazolidin-2-one;   5-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}-1,3-oxazolidin-2-one; and   4-(1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-chloro-2-(1-(2-hydroxypropyl)azetidin-3-yl)-3-methoxybenzonitrile;   or a pharmaceutically acceptable salt of any of the aforementioned.   
     
     
         34 - 36 . (canceled) 
     
     
         37 . The method of  claim 1 , wherein the compound is 4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}pyrrolidin-2-one, or a pharmaceutically acceptable salt thereof. 
     
     
         38 . The method of  claim 1 , wherein the compound is (S)-4-(3-((S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one, or a pharmaceutically acceptable salt thereof. 
     
     
         39 . The method of  claim 1 , wherein the compound is (R)-4-(3-((S)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one, or a pharmaceutically acceptable salt thereof. 
     
     
         40 . The method of  claim 1 , wherein the compound is (S)-4-(3-((R)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one, or a pharmaceutically acceptable salt thereof. 
     
     
         41 . The method of  claim 1 , wherein the compound is (R)-4-(3-((R)-1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-5-chloro-2-ethoxy-6-fluorophenyl)pyrrolidin-2-one, or a pharmaceutically acceptable salt thereof. 
     
     
         42 . The method of  claim 1 , wherein the disease is autoimmune hemolytic anemia. 
     
     
         43 . The method of  claim 37 , wherein the disease is autoimmune hemolytic anemia. 
     
     
         44 . The method of  claim 38 , wherein the disease is autoimmune hemolytic anemia. 
     
     
         45 . The method of  claim 39 , wherein the disease is autoimmune hemolytic anemia. 
     
     
         46 . The method of  claim 40 , wherein the disease is autoimmune hemolytic anemia. 
     
     
         47 . The method of  claim 41 , wherein the disease is autoimmune hemolytic anemia. 
     
     
         48 . The method of  claim 1 , wherein the disease is pemphigus. 
     
     
         49 . The method of  claim 37 , wherein the disease is pemphigus. 
     
     
         50 . The method of  claim 38 , wherein the disease is pemphigus. 
     
     
         51 . The method of  claim 39 , wherein the disease is pemphigus. 
     
     
         52 . The method of  claim 40 , wherein the disease is pemphigus. 
     
     
         53 . The method of  claim 41 , wherein the disease is pemphigus. 
     
     
         54 . The method of  claim 1 , wherein the disease is myelofibrosis. 
     
     
         55 . The method of  claim 37 , wherein the disease is myelofibrosis. 
     
     
         56 . The method of  claim 38 , wherein the disease is myelofibrosis. 
     
     
         57 . The method of  claim 39 , wherein the disease is myelofibrosis. 
     
     
         58 . The method of  claim 40 , wherein the disease is myelofibrosis. 
     
     
         59 . The method of  claim 41 , wherein the disease is myelofibrosis.