Combination therapy comprising an alk2 inhibitor and a jak2 inhibitor

Abstract

Provided herein are compounds, pharmaceutical compositions comprising such compounds, and methods of using such compounds to treat diseases or disorders associated with JAK2 and/or ALK2.

1 - 24 . (canceled) 
     
     
         25 . A pharmaceutical combination comprising
 (i) a JAK2 inhibitor that is 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile   or a pharmaceutically acceptable salt thereof; and   (ii) an ALK2 inhibitor that is 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-(3-(tetrahydro-2H-pyran-4-yl)-3-aza-bicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide   or a pharmaceutically acceptable salt thereof.   
     
     
         26 . (canceled) 
     
     
         27 . The pharmaceutical combination of  claim 25 , wherein the JAK2 inhibitor is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof. 
     
     
         28 . (canceled) 
     
     
         29 . The pharmaceutical combination of  claim 25 , wherein the ALK2 inhibitor is 2-amino-N-(4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo-[3.1.0]hexan-1-yl)phenyl)nicotinamide, or a pharmaceutically acceptable salt thereof. 
     
     
         30 . (canceled) 
     
     
         31 . A pharmaceutical composition comprising an ALK2 inhibitor that is 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-(3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide, a pharmaceutically acceptable carrier, and a JAK2 inhibitor that is 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile
 or a pharmaceutically acceptable salt thereof.   
     
     
         32 - 33 . (canceled) 
     
     
         34 . The pharmaceutical composition of  claim 31 , wherein the JAK2 inhibitor is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof. 
     
     
         35 - 38 . (canceled) 
     
     
         39 . The pharmaceutical composition of  claim 31 , wherein the ALK2 inhibitor is 2-amino-N-(4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo-[3.1.0]hexan-1-yl)phenyl)nicotinamide, or a pharmaceutically acceptable salt thereof. 
     
     
         40 . (canceled) 
     
     
         41 . A method of treating myelofibrosis (MF) comprising administering to a subject in need thereof an ALK2 inhibitor that is 2-amino-N-(4-hydroxy-bicyclo-[2.2.2]octan-1-yl)-5-(4-(3-(tetrahydro-2H-pyran-4-yl)-3-aza-bicyclo[3.1.0]-hexan-1-yl)phenyl)nicotinamide
 or a pharmaceutically acceptable salt thereof;   wherein the compound is administered as a monotherapy.   
     
     
         42 . The method of  claim 41 , wherein the compound is 2-amino-N-(4-hydroxy-bicyclo-[2.2.2]octan-1-yl)-5-(4-(1R,5S)-(3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]-hexan-1-yl)phenyl)nicotinamide, or a pharmaceutically acceptable salt thereof, wherein the compound is administered as a monotherapy. 
     
     
         43 . A method of treating myelofibrosis (MF)-induced anemia comprising administering to a subject in need thereof a JAK2 inhibitor that is 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile
 or a pharmaceutically acceptable salt thereof;   and an ALK2 inhibitor that is 2-amino-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)-5-(4-(3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide   or a pharmaceutically acceptable salt thereof.   
     
     
         44 . The method of  claim 43 , wherein
 the JAK2 inhibitor of Formula I is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt.   
     
     
         45 . The method of  claim 43 , wherein thereof the ALK2 inhibitor of Formula II 2-amino-N-(4-hydroxy-bicyclo-[2.2.2]octan-1-yl)-5-(4-(1R,5S)-(3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo[3.1.0]-hexan-1-yl)phenyl)nicotinamide, or a pharmaceutically acceptable salt or hydrate thereof. 
     
     
         46 . The method of  claim 43 , wherein the ALK2 inhibitor and JAK2 inhibitor are administered in a single formulation. 
     
     
         47 . The method of  claim 46 , further comprising a pharmaceutically acceptable carrier. 
     
     
         48 . The method of  claim 43 , wherein the ALK2 inhibitor and JAK2 inhibitor are administered separately. 
     
     
         49 . The method of  claim 43 , wherein the treatment comprises administering the ALK2 inhibitor and the JAK2 inhibitor at substantially the same time. 
     
     
         50 . The method of  claim 43 , wherein the treatment comprises administering the ALK2 inhibitor and the JAK2 inhibitor at different times. 
     
     
         51 . The method of  claim 50 , wherein the ALK2 inhibitor is administered to the subject, followed by administration of the JAK2 inhibitor. 
     
     
         52 . The method of  claim 50 , wherein the JAK2 inhibitor is administered to the subject, followed by administration of the ALK2 inhibitor. 
     
     
         53 . The method of  claim 41 , wherein the myelofibrosis is selected from the group consisting of primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis. 
     
     
         54 . The pharmaceutical combination of  claim 25 , wherein the JAK2 inhibitor is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, and the ALK2 inhibitor is 2-amino-N-(4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo-[3.1.0]hexan-1-yl)phenyl)nicotinamide, or a pharmaceutically acceptable salt thereof. 
     
     
         55 . The pharmaceutical composition of  claim 31 , wherein the JAK2 inhibitor is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, and the ALK2 inhibitor is 2-amino-N-(4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo-[3.1.0]hexan-1-yl)phenyl)nicotinamide, or a pharmaceutically acceptable salt thereof. 
     
     
         56 . The method of  claim 43 , wherein the JAK2 inhibitor is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, and the ALK2 inhibitor is 2-amino-N-(4-hydroxybicyclo-[2.2.2]octan-1-yl)-5-(4-((1R,5S)-3-(tetrahydro-2H-pyran-4-yl)-3-azabicyclo-[3.1.0]hexan-1-yl)phenyl)nicotinamide, or a pharmaceutically acceptable salt thereof.