Substituted imidazo[1, 2-a]pyridin-2-ylamine compounds, and pharmaceutical compositions and methods of use thereof

Abstract

Provided herein are substituted imidazo[1,2-a]pyridin-2-ylamine compounds, for example, of formula (A), and pharmaceutical compositions thereof; and methods of their use for treating, preventing, or ameliorating one or more symptoms of a Janus kinase-mediated disease.

1 . A compound of formula (A): 
       
         
           
           
               
               
           
         
         or a stereoisomer, enantiomer, mixture of enantiomers, mixture of diastereomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
 L 1  is hydrogen or —C(O)R 2 ; 
 R 1  at each occurrence is independently (a) cyano, halogen, or nitro; (b) C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 10  cycloalkyl, C 6 -C 10  aryl, heteroaryl, or heterocyclyl; or (c) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(NR 1a )NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(═NR 1a )NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a S(O)R 1d , —R 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —SR 1a , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ; 
 R 2  is C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 10  cycloalkyl, C 6 -C 10  aryl, heteroaryl, or heterocyclyl; 
 R A  is C 3 -C 10  cycloalkyl, C 6 -C 10  aryl, heteroaryl, or heterocyclyl; 
 R L  is hydrogen, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 10  cycloalkyl, C 6 -C 10  aryl, heteroaryl, or heterocyclyl; 
 each R 1a , R 1b , R 1c , and R 1d  is independently hydrogen, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 10  cycloalkyl, C 6 -C 10  aryl, heteroaryl, or heterocyclyl; or R 1a  and R 1c  together with the C and N atoms to which they are attached form heterocyclyl; or R 1b  and R 1c  together with the N atom to which they are attached form heterocyclyl; and 
 n is an integer of 0, 1, 2, 3, or 4; 
 wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with one or more substituents Q, where each Q is independently selected from (a) oxo, cyano, halogen, and nitro; (b) C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 10  cycloalkyl, C 6 -C 10  aryl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more substituents Q a ; and (c) —C(O)R a , —C(O)OR a , —C(O)NR b R c , —C(NR a )NR b R c , —OR a , —OC(O)R a , —OC(O)OR a , —OC(O)NR b R c , —OC(═NR a )NR b R c , —OP(O)(OR a ) 2 , —OS(O)R a , —OS(O) 2 R a , —OS(O)NR b R c , —S(O) 2 NR b R c , —NR b R c , —NR a C(O)R d , —NR a C(O)OR d , —NR a C(O)NR b R c , —NR a C(═NR d )NR b R c , —NR a S(O)R d , —NR a S(O) 2 R d , —NR a S(O)NR b R c , —NR a S(O) 2 NR b R c , —SR a , —S(O)R a , —S(O) 2 R a , —S(O)NR b R c , and —S(O) 2 NR b R c , where each R a , R b , R c , and R d  is independently (i) hydrogen; (ii) C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 10  cycloalkyl, C 6 -C 10  aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; or (iii) R b  and R c  together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q a ; 
 
         wherein each Q a  is independently selected from the group consisting of (a) oxo, cyano, halogen, and nitro; (b) C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 10  cycloalkyl, C 6 -C 10  aryl, heteroaryl, and heterocyclyl; and (c) —C(O)R f , —C(O)OR f , —C(O)NR g R h , —C(NR f )NR g R h , —OR f , —OC(O)R f , —OC(O)OR f , —OC(O)NR g R h , —OC(═NR f )NR g R h , —OS(O)R f , —OS(O) 2 R f , —OS(O)NR g R h , —OS(O) 2 NR g R h , —NR g R h , —NR f C(O)R k , —NR f C(O)OR k , —NR f C(O)NR g R h , —NR f C(═NR k )NR g R h , —NR f S(O)R k , —NR f S(O) 2 R k , —NR f S(O)NR g R h , —NR f S(O) 2 NR g R h , —SR f , —S(O)R f , —S(O) 2 R f , —S(O)NR g R h , and —S(O) 2 NR g R h ; where each R f , R g , R h , and R k  is independently (i) hydrogen; (ii) C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 10  cycloalkyl, C 6 -C 10  aryl, heteroaryl, and heterocyclyl; or (iii) R g  and R h  together with the N atom to which they are attached form heterocyclyl. 
       
     
     
         2 . The compound of  claim 1 , wherein R A  is C 6 -C 10  aryl or heteroaryl, each of which is optionally substituted with one or more substituents Q. 
     
     
         3 . The compound of  claim 1 , wherein R A  is C 6 -C 10  aryl, optionally substituted with one or two substituents Q. 
     
     
         4 . The compound of  claim 1 , wherein the compound is a compound of formula (C): 
       
         
           
           
               
               
           
         
         or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein:
 L 2  is a single bond, —O—, —NR 6 —, —C(O)—, —C(O)O—, —OC(O)—, —CONR 6 —, —NR 6 CO—, —S(O) 2 —, —NR 6 SO 2 —, or —SO 2 NR 6 —; 
 m is an integer of 0, 1, 2, 3, 4, 5, or 6; 
 n is an integer of 0, 1, 2, or 3; 
 i is an integer of 0, 1, 2, 3, or 4; 
 R 3  is (a) cyano, halogen, or nitro; (b) C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 10  cycloalkyl, C 6 -C 10  aryl, heteroaryl, or heterocyclyl; or (c) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(NR 1a )NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(═NR 1a )NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —SR 1a , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ; 
 
         R 4  at each occurrence is independently (a) hydrogen, cyano, halogen, or nitro; (b) C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 10  cycloalkyl, C 6 -C 10  aryl, heteroaryl, or heterocyclyl; or (c) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(NR 1a )NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(═NR 1a )NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —SR 1a , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ; or two R 4  groups together with the C atom to which they are attached form C 3 -C 10  cycloalkyl or heterocyclyl; 
         R 5  at each occurrence is independently (a) cyano, halogen, or nitro; (b) C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 10  cycloalkyl, C 6 -C 10  aryl, heteroaryl, or heterocyclyl; or (c) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(NR 1a )NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(═NR 1a )NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a S(O)R 1d , —R 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —SR 1a , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c , 
         R 6  at each occurrence is independently hydrogen, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 10  cycloalkyl, C 6 -C 10  aryl, heteroaryl, or heterocyclyl; and 
         each R 1a , R 1b , R 1c , and R 1d  is independently hydrogen, C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 10  cycloalkyl, C 6 -C 10  aryl, heteroaryl, or heterocyclyl; or R 1a  and R 1c  together with the C and N atoms to which they are attached form heterocyclyl; or R 1b  and R 1c  together with the N atom to which they are attached form heterocyclyl; 
         wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with one or more substituents Q, where each Q is independently selected from (a) oxo, cyano, halogen, and nitro; (b) C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 10  cycloalkyl, C 6 -C 10  aryl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more substituents Q a ; and (c) —C(O)R a , —C(O)OR a , —C(O)NR b R c , —C(NR a )N b R c , —OR a , —OC(O)R a , —OC(O)OR a , —OC(O)NR b R c , —OC(═NR a )NR b R c , —OS(O)R a , —OS(O) 2 R a , —OS(O)NR b R c , —S(O) 2 NR b R c , —NR b R c , —NR a C(O)R d , —NR a C(O)OR d , —NR a C(O)NR b R c , —NR a C(═NR d )NR b R c , —NR a S(O)R d , —NR a S(O) 2 R d , —NR a S(O)NR b R c , —NR a S(O) 2 NR b R c , —SR a , —S(O)R a , —S(O) 2 R a , —S(O)NR b R c , and —S(O) 2 NR b R c , where each R a , R b , R c , and R d  is independently (i) hydrogen; (ii) C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 10  cycloalkyl, C 6 -C 10  aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q a ; or (iii) R b  and R c  together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q a ; 
         wherein each Q a  is independently selected from the group consisting of (a) oxo, cyano, halogen, and nitro; (b) C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 10  cycloalkyl, C 6 -C 10  aryl, heteroaryl, and heterocyclyl; and (c) —C(O)R f , —C(O)OR f , —C(O)NR g R h , —C(NR f )NR g R h , —OR f , —OC(O)R f , —OC(O)OR f , —OC(O)NR g R h , —OC(═NR f )NR g R h , —OS(O)R f , —OS(O) 2 R f , —OS(O)NR g R h , —OS(O) 2 NR g R h , —NR g R h , —NR f C(O)R k , —NR f C(O)OR k , R f C(O)NR g R h , —NR f C(═NR k )R g R h , —NR f S(O)R k , —NR f S(O) 2 R k , —NR f S(O)NR g R h , —NR f S(O) 2 NR g R h , —SR f , —S(O)R f , —S(O) 2 R f , —S(O)NR g R h , and —S(O) 2 NR g R h ; where each R f , R g , R h , and R k  is independently (i) hydrogen; (ii) C 1 -C 8  alkyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 3 -C 10  cycloalkyl, C 6 -C 10  aryl, heteroaryl, and heterocyclyl; or (iii) R g  and R h  together with the N atom to which they are attached form heterocyclyl. 
       
     
     
         5 . The compound of  claim 4 , wherein the compound is a compound of formula (D): 
       
         
           
           
               
               
           
         
         or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 
       
     
     
         6 . The compound of  claim 4 , wherein the compound is a compound of formula (E): 
       
         
           
           
               
               
           
         
         or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 
       
     
     
         7 . The compound of  claim 1 , wherein R L  is hydrogen. 
     
     
         8 . The compound of  claim 1 , wherein L 1  is hydrogen. 
     
     
         9 . The compound of  claim 1 , wherein L 1  is —C(O)R 2 . 
     
     
         10 . The compound of  claim 9 , wherein R 2  is C 1 -C 8  alkyl, C 3 -C 10  cycloalkyl, or heterocyclyl; each of which is optionally substituted with one or more substituents Q. 
     
     
         11 . The compound of  claim 9 , wherein R 2  is C 1 -C 8  alkyl, optionally substituted with one or more substituents Q. 
     
     
         12 . The compound of  claim 11 , wherein R 2  is isopropyl. 
     
     
         13 . The compound of  claim 9 , wherein R 2  is C 3 -C 10  cycloalkyl, optionally substituted with one or more substituents Q. 
     
     
         14 . The compound of  claim 13 , wherein R 2  is cyclopropyl or cyclobutyl, each of which is optionally substituted with one or more substituents Q. 
     
     
         15 . The compound of  claim 13 , wherein R 2  is cyclopropyl. 
     
     
         16 . The compound of  claim 1 , wherein n is an integer of 1. 
     
     
         17 . The compound of  claim 1 , wherein R 1  is halogen or C 1 -C 8  alkyl, where the alkyl is optionally substituted with one or more substituents Q. 
     
     
         18 . The compound of  claim 17 , wherein R 1  is chloro or methyl. 
     
     
         19 . The compound of  claim 1 , wherein n is an integer of 0. 
     
     
         20 . The compound of  claim 4 , wherein R 3  is (a) cyano; (b) heterocyclyl, which is optionally substituted with one or more substituents Q; (c) —NR 1b R 1c , —NR 1a C(O)R 1d , —OR 1a , or —NR 1a S(O) 2 R 1d . 
     
     
         21 . The compound of  claim 20 , wherein R 3  is heterocyclyl, optionally substituted with one or more substituents Q. 
     
     
         22 . The compound of  claim 21 , wherein R 3  is 4-, 5, or 6-membered heterocyclyl, each of which is optionally substituted with one or more substituents Q. 
     
     
         23 . The compound of  claim 21 , wherein R 3  is 4-membered heterocyclyl, optionally substituted with one or more substituents Q. 
     
     
         24 . The compound of  claim 21 , wherein R 3  is 6-membered heterocyclyl, optionally substituted with one or more substituents Q. 
     
     
         25 . The compound of  claim 21 , wherein R 3  is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, or thiomorpholino, each of which is optionally substituted with one or more substituents Q. 
     
     
         26 . The compound of  claim 21 , wherein R 3  is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, or thiomorpholino, each of which is optionally substituted with one or two substituents Q. 
     
     
         27 . The compound of  claim 21 , wherein each substituent Q is independently selected from oxo, cyano, hydroxyl, and C 1 -C 8  alkyl, where the alkyl is optionally substituted with one or more substituents Q a . 
     
     
         28 . The compound of  claim 21 , wherein R 3  is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, or thiomorpholino, each of which is optionally substituted with one or two substituents Q, where each substituent Q is independently selected from oxo, cyano, hydroxyl, and methyl. 
     
     
         29 . The compound of  claim 20 , wherein R 3  is cyano, cyanomethylphenylamino, 3,3,3-trifluoropropanamido, hydroxypyrrolidinyl, piperidinyl, cyanopiperidinyl, morpholino, methyl-piperazinyl, 1,1-dioxidothiomorpholino, methoxy, dimethylazetidinyl, or cyclopropanesulfonamido. 
     
     
         30 . The compound of  claim 20 , wherein R 3  is cyano, 2-cyanomethylphenyl-amino, 3,3,3-trifluoropropanamido, 3-hydroxypyrrolidin-1-yl, (R)-3-hydroxypyrrolidin-1-yl, (S)-3-hydroxypyrrolidin-1-yl, piperidin-1-yl, 4-cyanopiperidin-1-yl, morpholin-4-yl, 4-methyl-piperazin-1-yl, 1,1-dioxidothiomorpholin-4-yl, methoxy, 3,3-dimethylazetidin-1-yl, or cyclopropanesulfonamido. 
     
     
         31 . The compound of  claim 4 , wherein m is an integer of 1. 
     
     
         32 . The compound of  claim 4 , wherein R 4  at each occurrence is hydrogen or C 1 -C 8  alkyl, where the alkyl is optionally substituted with one or more substituents Q. 
     
     
         33 . The compound of  claim 4 , wherein two R 4  groups together with the C atom to which they are attached form C 3 -C 10  cycloalkyl, which is optionally substituted with one or more substituents Q. 
     
     
         34 . The compound of  claim 33 , wherein two R 4  groups together with the C atom to which they are attached form cyclopropyl, which is optionally substituted with one or more substituents Q. 
     
     
         35 . The compound of  claim 4 , wherein m is an integer of 0. 
     
     
         36 . The compound of  claim 4 , wherein L 2  is a single bond. 
     
     
         37 . The compound of  claim 4 , wherein L 2  is a single bond; m is an integer of 1; and R 4  at each occurrence is hydrogen. 
     
     
         38 . The compound of  claim 4 , wherein L 2  is —C(O)—. 
     
     
         39 . The compound of  claim 4 , wherein L 2  is —C(O)— and m is an integer of 0. 
     
     
         40 . The compound of  claim 4 , wherein i is an integer of 1. 
     
     
         41 . The compound of  claim 4 , wherein R 5  is halogen or C 1 -C 8  alkyl, where the alkyl is optionally substituted with one or more substituents Q. 
     
     
         42 . The compound of  claim 41 , wherein R 5  is fluoro, chloro, or methyl. 
     
     
         43 . The compound of  claim 4 , wherein i is an integer of 0. 
     
     
         44 . The compound of  claim 1 , selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and isotopic variants thereof; and pharmaceutically acceptable salts, solvates, and prodrugs thereof. 
       
     
     
         45 . A pharmaceutical composition comprising the compound of  claim 1 , and a pharmaceutically acceptable excipient. 
     
     
         46 . The pharmaceutical composition of  claim 45 , wherein the pharmaceutical composition is formulated for single dose administration. 
     
     
         47 . The pharmaceutical composition of  claim 45 , wherein the pharmaceutical composition is formulated as an oral, parenteral, or intravenous dosage form. 
     
     
         48 . The pharmaceutical composition of  claim 47 , wherein the oral dosage form is a tablet or capsule. 
     
     
         49 . The pharmaceutical composition of  claim 45 , further comprising a second therapeutic agent. 
     
     
         50 . A method for treating, preventing, or ameliorating one or more symptoms of a Janus kinase-mediated disorder, disease, or condition in a subject, comprising administering to the subject the compound of  claim 1 . 
     
     
         51 - 57 . (canceled) 
     
     
         58 . The method of  claim 50 , wherein the disorder, disease, or condition is rheumatoid arthritis, asthma, psoriasis, juvenile idiopathic arthritis, Crohn's diseases, ulcerative colitis, inflammatory bowel disease, lupus, alopecia, dry eyes, organ transplant rejection, or a proliferative disease. 
     
     
         59 . (canceled) 
     
     
         60 . The method of  claim 50 , wherein the disorder, disease, or condition is allergy, alopecia areata, amyotrophic lateral sclerosis, ankylosing spondylitis, arthritis, rheumatoid arthritis, juvenile idiopathic arthritis, asthma, atopic dermatitis, Behcet's disease, celiac disease, colitis, chronic obstructive pulmonary disease, Crohn's disease, dry eyes, an inflammatory bowel disease, leukemia, lymphoma, myelofibrosis, multiple sclerosis, osteoarthritis, polycythemia, primary biliary cirrhosis, psoriasis, rhinitis, sicca syndrome, Sjögren's syndrome, a solid tumor, systemic lupus erythematosus, transplant rejection, ulcerative colitis, or vitiligo. 
     
     
         61 - 64 . (canceled) 
     
     
         65 . A method of inhibiting the activity of a Janus kinase, comprising contacting the kinase with the compound of  claim 1 .