Uses of salt-inducible kinase (sik) inhibitors

Abstract

The present disclosure provides methods of treating and/or preventing inflammatory bowel disease (IBD) and graft-versus-host disease (GVHD) using salt-inducible kinase (SIK) inhibitors, such as macrocyclic SIK inhibitors of Formula (I), imidazolyl SIK inhibitors of Formula (II), and urea and carbamate SIK inhibitors of Formula (III-A) (e.g., urea and carbamate SIK inhibitors of Formula (III)).

1 . A method of treating a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a salt-inducible kinase (SIK) inhibitor of any one of Formulae (I), (II), and (III-A), or a pharmaceutically acceptable salt thereof, wherein the disease is inflammatory bowel disease or graft-versus-host disease. 
     
     
         2 . (canceled) 
     
     
         3 . The method of  claim 1 , wherein the disease is inflammatory bowel disease. 
     
     
         4 . The method of  claim 3 , wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis. 
     
     
         5 . (canceled) 
     
     
         6 . The method of  claim 1 , wherein the disease is graft-versus-host disease. 
     
     
         7 . (canceled) 
     
     
         8 . A method of inhibiting the activity of a salt-inducible kinase (SIK) in a subject, the method comprising administering to the subject an effective amount of a SIK inhibitor of any one of Formulae (I), (II), and (III-A), or a pharmaceutically acceptable salt thereof. 
     
     
         9 . (canceled) 
     
     
         10 . A method of increasing the level of interleukin 10 (IL-10) in a subject, the method comprising administering to the subject an effective amount of a salt-inducible kinase (SIK) inhibitor of any one of Formulae (I), (II), and (III-A), or a pharmaceutically acceptable salt thereof. 
     
     
         11 . (canceled) 
     
     
         12 . A method of decreasing the level of a pro-inflammatory cytokine in a subject, the method comprising administering to the subject an effective amount of a salt-inducible kinase (SIK) inhibitor of any one of Formulae (I), (II), and (III-A), or a pharmaceutically acceptable salt thereof. 
     
     
         13 . (canceled) 
     
     
         14 . The method of  12 , wherein the pro-inflammatory cytokine is IL-1β, IL-6, IL-12, or TNF-α. 
     
     
         15 . A method of converting bone marrow-derived dentritic cells (BMDCs) to an anti-inflammatory phenotype in a subject, the method comprising administering to the subject an effective amount of a salt-inducible kinase (SIK) inhibitor of any one of Formulae (I), (II), and (III-A), or a pharmaceutically acceptable salt thereof. 
     
     
         16 - 20 . (canceled) 
     
     
         21 . The method of  claim 1 , wherein the SIK inhibitor is of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 Ring A is a substituted or unsubstituted phenyl ring or a substituted or unsubstituted, monocyclic, 5- to 6-membered heteroaryl ring, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; 
 each instance of R A  is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ; 
 each instance of R a  is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R a  groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; 
 k is 0, 1, 2, 3, or 4; 
 L is a substituted or unsubstituted, saturated or unsaturated C 3-10  hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —O—, —S—, —NR N —, —N═, or ═N—, wherein each instance of R N  is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted C 1-6  alkyl, or a nitrogen protecting group; 
 R B  is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted C 1-6  alkyl, or a nitrogen protecting group; 
 each of X A , X B , and X C  is independently N or CR X , wherein R X  is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ; 
 Y is —O— or —NR Y —, wherein R Y  is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted C 1-6  alkyl, or a nitrogen protecting group; 
 or when Y is —NR Y — and X A  is CR X , R Y  and R X  of X A  are joined to form a substituted or unsubstituted, monocyclic, 5- to 7-membered heterocyclic ring that is fused with Ring B; 
 each instance of R C  is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ; 
 m is 0, 1, 2, 3, 4, or 5; and 
 R D  is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 . 
 
       
     
     
         22 - 77 . (canceled) 
     
     
         78 . The method of  claim 21 , wherein the SIK inhibitor is of the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         79 . The method of  claim 21 , wherein the SIK inhibitor is of the formula: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         80 . The method of  claim 1 , wherein the SIK inhibitor is of Formula (II): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 each instance of R A  is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ; 
 each instance of R a  is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R a  are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; 
 j is 0, 1, or 2; 
 R B  is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group; 
 R C  is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted C 1-6  alkyl, or a nitrogen protecting group; 
 each instance of R D  is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ; 
 m is 0, 1, or 2; 
 R E  is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted C 1-6  alkyl, or a nitrogen protecting group; 
 each instance of R F  is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ; and 
 n is 0, 1, 2, 3, 4, or 5. 
 
       
     
     
         81 . The method of  claim 80 , wherein the SIK inhibitor is of Formula (II-A): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 each instance of R G  is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ; and 
 k is 0, 1, 2, 3, 4, or 5. 
 
       
     
     
         82 - 88 . (canceled) 
     
     
         89 . The method of  claim 80 , wherein the SIK inhibitor is of Formula (II-B): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 R H  is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted C 1-6  alkyl, or a nitrogen protecting group; 
 each instance of R J  is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ; 
 q is 0, 1, 2, 3, or 4; and 
 R K  is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 . 
 
       
     
     
         90 - 127 . (canceled) 
     
     
         128 . The method of  claim 80 , wherein the SIK inhibitor is of the formula: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         129 - 130 . (canceled) 
     
     
         131 . The method of  claim 1 , wherein the SIK inhibitor is of Formula (III-A): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 R G  is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, or of the formula: 
 
       
       
         
           
           
               
               
           
         
         
           each instance of R A  is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 , or two R A  groups are joined to form a substituted or unsubstituted carbocyclic ring, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted aryl ring, or substituted or unsubstituted heteroaryl ring; 
           each instance of R a  is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R a  groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; 
           k is 0, 1, 2, 3, 4, or 5; 
           R B  is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted C 1-6  alkyl, or a nitrogen protecting group; 
           each of X A , X B , and X C  is independently N or CR X , wherein each instance of R X  is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ; 
           or: X B  is CR X , and R G  and R X  of X B  are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; 
           R C  is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ; 
           R D  is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group; 
           Y is —O— or —NR Y —, wherein R Y  is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted C 1-6  alkyl, or a nitrogen protecting group; 
           Z is a bond or —C(R Z ) 2 —, wherein each instance of R Z  is independently hydrogen, halogen, or substituted or unsubstituted C 1-6  alkyl; 
           each instance of R E  is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —NR a S(═O)R a , —NR a S(═O)OR a , —NR a S(═O)N(R a ) 2 , —NR a S(═O) 2 R a , —NR a S(═O) 2 OR a , —NR a S(═O) 2 N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ; and 
           m is 0, 1, 2, 3, 4, or 5. 
         
       
     
     
         132 . The method of  claim 131 , wherein the SIK inhibitor is of Formula (III): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 each instance of R A  is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ; 
 each instance of R a  is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R a  groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; 
 k is 0, 1, 2, 3, 4, or 5; 
 R B  is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted C 1-6  alkyl, or a nitrogen protecting group; 
 each of X A , X B , and X C  is independently N or CR X , wherein each instance of R X  is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ; 
 R C  is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ; 
 R D  is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group; 
 Y is —O— or —NR Y —, wherein R Y  is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted C 1-6  alkyl, or a nitrogen protecting group; 
 each instance of R E  is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ; and 
 m is 0, 1, 2, 3, 4, or 5. 
 
       
     
     
         133 - 217 . (canceled) 
     
     
         218 . The method of  claim 131 , wherein the SIK inhibitor is of the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         219 . The method of  claim 131 , wherein the SIK inhibitor is of the formula: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         220 . (canceled)