3-[(1h-pyrazol-r-yl)oxy]pyrazin-2-amine compounds as hpk1 inhibitor and use thereof

Abstract

Disclosed herein is 3-[(1H-pyrazol-4-yl) oxy] pyrazin-2-amine compounds of Formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions comprising thereof. Also disclosed is a method of modulating, e.g., inhibiting or treating HPK1 related disorders or diseases including cancer by using the compound disclosed herein

1 . A compound of Formula (I) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, 
         wherein
 X is N or CR 2 , wherein R 2  is selected from hydrogen, —C 1-8 alkyl, —C 2-8 alkynyl, halogen, cycloalkyl, aryl, heterocyclyl, heteroaryl, —NR c R d , —OR a , —(CR a R b ) n —R d , —(CR a R b ) n —NR c R d , —(CR a R b ) n —CONR c R d , —CONR c —(CR a R b ) n —R d , —(CR a R b ) n —NR c COR d , —NR c —CO—(CR a R b ) n —R d , —(CR a R b ) n —SO 2 — NR c R d , —(CR a R b ) n —SO 2 —R d , —SO 2 —NR c —(CR a R b ) n —R d , —(CR a R b ) n  NR c —CS—NR d R e , or —(CR a R b ) n —NR c —CO—NR d R e ; each of said —C 1-8 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted with at least one R f ; 
 R 1  and R 3  are each independently selected from hydrogen, —C 1-8 alkyl, halogen, cycloalkyl, aryl, heterocyclyl, heteroaryl, —NR c R d , —OR d , —SiR a R b R c , —(CR a R b ) n —R d , —(CR a R b ) n —NR c R d , —(CR a R b ) n —CONR c R a , —CONR c —(CR a R b )—R a , —(CR a R b ) n —NR c COR a , —NR c —CO—(CR a R b ) n —R d , —(CR a R b ) n —SO 2 —NR c R d , —(CR a R b ) n  NR c —SO 2 —R a , —SO 2 —NR c —(CR a R b ) n —R a , or —(CR a R b ) n —NR c —CO—NR a R c , wherein each of said —C 1-8 alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted with at least one R f ; 
 R 4  is selected from hydrogen, —C 1-8 alkyl, cycloalkyl, heterocyclyl comprising one, two or three heteroatoms independently selected from nitrogen, oxygen or sulfur as ring member(s), wherein each of said —C 1-8 alkyl, cycloalkyl or heterocyclyl are optionally substituted with R f ; 
 each R f  is independently selected from oxo, halogen, —C 1-8 alkyl, hydroxy, —NR 1c R 1d , —C 1-8 alkoxy, or heterocyclyl, said heterocyclyl or —C 1-8 alkyl is optionally substituted with at least one R g , wherein R 1c  and R 1d  are each independently hydrogen or —C 1-8 alkyl; 
 R 51 , R 52 , R 61 , R 62 , R 71 , R 72 , R 81 , R 82  and R 9  are each independently selected from hydrogen, halogen, —C 1-8 alkyl, or —C 1-8 alkoxy; or 
 R 51  and R 61 , R 51  and R 62 , R 52  and R 61 , or R 52  and R 62 , together with the atoms to which they are attached, form a 7- to 12-membered bridged heterocyclyl, wherein the bridge contains 1-6 atoms selected from carbon, oxygen, nitrogen or sulfur; 
 R a  and R b  are each independently hydrogen, —C 1-8 alkyl or heterocyclyl; or 
 R a  and R b , together with the carbon atom to which they are attached, form a 3- to 6-membered ring comprising 0, 1 or 2 heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as the ring member(s); 
 R c , R d  and R e  are each independently hydrogen, —C 1-8 alkyl, aryl, CN, hydroxyl, —C 1-8 alkoxy, cycloalkyl, heterocyclyl, heteroaryl or —NR 1c R 1d , wherein each of said —C 1-8 alkyl, cycloalkyl, aryl or heterocyclyl or heteroaryl is optionally substituted with at least one R g , wherein R 1c  and R 1d  are each independently hydrogen or —C 1-8 alkyl; 
 each R g  is independently selected from oxo, hydroxy, halogen, haloalkyl, —C 1-8 alkyl, —C 1-8 alkoxy, cycloalkyl or heterocyclyl; and 
 
         n is each independently 0, 1, 2, 3 or 4. 
       
     
     
         2 . The compound according to  claim 1 , wherein
 X is N or CR 2 , wherein R 2  is selected from hydrogen, —C 1-8 alkyl, —C 2-8 alkynyl, C 3-7 cycloalkyl, aryl, 5- to 6-membered heteroaryl comprising one, two or three heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as the ring member(s), 3- to 7-membered heterocyclyl comprising one, two or three heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as the ring member(s), —NR c R d , —(CR a R b ) n —R d , —(CR a R b ) n —NR c R d , —(CR a R b ) n —CONR c R d , —CONR c —(CR a R b ) n —R d , —(CR a R b ) n —NR c COR d , —(CR a R b ) n —SO 2 —NR c R d , —(CR a R b ) n —NR c —CO—NR d R e , —(CR a R b ) n —NR c —CS—NR d R e , —(CR a R b ) n —NR c —SO 2 —R d  or —(CR a R b ) n —NR c —CO—NR d R e ; each of said —C 1-8 alkyl, C 3-7 cycloalkyl, aryl, 3- to 7-membered heterocyclyl or 5- to 6-membered heteroaryl is optionally substituted with at least one R f ;   R 1  is selected from hydrogen, —C 1-8 alkyl, halogen, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, 3-to 7-membered heterocyclyl comprising one, two or three heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as the ring member(s), —NR c R d , or —OR d ; each of said —C 1-8 alkyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, or 3- to 7-membered heterocyclyl is optionally substituted with at least one R f ;   R 3  is selected from hydrogen, —C 1-8 alkyl, C 3-7 cycloalkyl, 3- to 7-membered heterocyclyl comprising one, two or three heteroatoms independently selected from nitrogen, oxygen, silicon or optionally oxidized sulfur as the ring member(s), —(CR a R b ) n —NR c R d , —(CR a R b ) n —CONR c R d , —SiR a R b R c , —(CR a R b ) n —NR c COR d , —CONR c —(CR a R b ) n —R d , —(CR a R b ) n —SO 2 —NR c R d , —SO 2 —NR c —(CR a R b ) n —R a , —(CR a R b ) n —NR c —SO 2 —R a , —(CR a R b ) n —NR c —CO—NR d R e , or —(CR a R b ) n —NR c R d , wherein said —C 1-8 alkyl, C 3-7 cycloalkyl, 3- to 7-membered heterocyclyl is optionally substituted with at least one R f ;   R 4  is selected from hydrogen, —C 1-8 alkyl, C 3-7 cycloalkyl, 3- to 7-membered heterocyclyl comprising one, two or three heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as the ring member(s); each said —C 1-8 alkyl, C 3-7 cycloalkyl or 3- to 7-membered heterocyclyl is optionally substituted with R f ;   
       each R f  is independently selected from oxo, halogen, —C 1-8 alkyl, hydroxy, —NR 1c R 1d , —C 1-8 alkoxy, 3- to 7-membered heterocyclyl; said heterocyclyl or —C 1-8 alkyl is optionally substituted with at least one R 9 , wherein R 1c  and R 1d  are each independently hydrogen or —C 1-8 alkyl;
 R 51 , R 52 , R 61 , R 62 , R 71 , R 72 , R 81  and R 82  are each independently selected from hydrogen, halogen, —C 1-8 alkyl, or —C 1-8 alkoxy; or 
 R 51  and R 61 , R 51  and R 62 , R 52  and R 61 , or R 52  and R 62 , together with the atoms to which they are attached, form a 7- to 12-membered bridged heterocyclyl, wherein the bridge contains 1-6 atoms selected from carbon, oxygen, nitrogen or sulfur; 
 
       R a  and R b  are each independently hydrogen, —C 1-8 alkyl or heterocyclyl; or
 R a  and R b , together with the carbon atom to which they are attached, form a 3- to 6-membered ring comprising 0, 1 or 2 heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as the ring member(s); 
 
       R c , R d  and R e  are each independently hydrogen, —C 1-8 alkyl, 5-to 6 membered heteroaryl, aryl, CN, hydroxyl, —C 1-8 alkoxy, C 3-7 cycloalkyl, 3- to 7-membered heterocyclyl comprising one, two or three heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur, or —NR 1c R 1d ; 
       each said —C 1-8 alkyl, 5-to 6 membered heteroaryl, C 3-7 cycloalkyl, aryl or 3- to 7-membered heterocyclyl is optionally substituted with at least one R g ; wherein R 1c  and R 1d  are each independently hydrogen or —C 1-8 alkyl; each R f  is independently selected from oxo, hydroxy, halogen, —C 1-8 alkyl, —C 1-8 alkoxy, or 3- to 7-membered heterocyclyl; and 
       n is each independently 0, 1, 2, 3 or 4. 
     
     
         3 . The compound according to  claim 1 , wherein
 R 1  is selected from halogen, —NR c R d , or —OR c , —C 1-4 alkyl, C 3-6 cycloalkyl, 4- to 6-membered C-linked heterocyclyl comprising one to three heteroatoms selected from nitrogen, oxygen, silicon or sulfur, 4- to 6-membered Si-linked heterocyclyl comprising 0, 1 or 2 additional heteroatoms selected from nitrogen, oxygen, or sulfur, 5-, 6- or 7-membered N-linked heterocyclyl comprising 0, 1 or 2 additional heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring member(s), or 5- to 6-membered heteroaryl;   wherein each of said —C 1-4 alkyl, C 3-6 cycloalkyl, 4- to 6-membered C-linked heterocyclyl, 4- to 6-membered Si-linked heterocyclyl or 5-, 6- or 7-membered N-linked heterocyclyl or 5- to 6-membered heteroaryl is optionally substituted with at least one substituent selected from halogen, hydroxy, oxo, —NH(C 1-4 alkyl) or —C 1-4 alkyl; R c  and R d  are each independently hydrogen or —C 1-4 alkyl.   
     
     
         4 . The compound according to  claim 1 , wherein
 R 1  is selected from hydrogen, methyl, tert-butyl, ethyl, n-propyl, iso-propyl, cyclopropyl, 2-methylpropyl, butyl, pentyl, hexyl, chloro, fluoro, methoxy, —CHF 2 , —NHCH 3 , —N(C 2 H 5 ) 2 , —OCH(CH 3 ) 2 ,   S(O) 2 —NHCH 3 , —Si(CH 3 ) 2 OH, —Si(C 2 H 5 ) 2 OH, —CH(CH 3 ) 2 OH, —CH 2 OCH 3     
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         5 . The compound according to  claim 1 , wherein
 X is —CR 2 , wherein R 2  is selected from hydrogen, —C 1-4 alkyl, aryl, 5- to 6-membered heteroaryl comprising one, two or three heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur, 3- to 7-membered heterocyclyl comprising one, two or three heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur, —(CH 2 ) n —CONHR a , —CONH—(CH 2 ) n —R a , —CONH—R d , —(CH 2 ) n —NHR d , —(CH 2 ) n —NHCOR a , —(CH 2 ) n —R a , —SO 2 —NH—(CH 2 ) n —R a , —(CH 2 ) n —SO 2 —NHR d , —(CH 2 ) n —NH—CO—NR d R e , —(CH 2 ) n —NH—CS—NR d R e , or —(CH 2 ) n —NH—SO 2 —R a ; wherein each of said aryl, 5- to 6-membered heteroaryl or 3- to 7-membered heterocyclyl is optionally substituted with at least one selected from —C 1-4 alkyl or oxo; and n is 1 or 2;   
       R d  and R e  each are independently selected from hydrogen, hydroxy, —C 1-4 alkyl, phenyl, —C 1-4 alkoxy, C 3-6  cycloalkyl, aryl, 5- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl or —NR 1c R 1d , wherein each of said —C 1-4 alkyl, C 3-6  cycloalkyl, aryl 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl is optionally substituted with at least one halogen, CF 3 , —C 1-4 alkyl or oxo; 
       R 1c  and R 1d  are each independently hydrogen or —C 1-4 alkyl. 
     
     
         6 . The compound according to  claim 5 , wherein
 R 2  is selected from hydrogen hydroxyl, methyl, halogen,   
       
         
           
           
               
               
           
         
       
       —CONHCH 3 , —CONHOCH 3 , 
       
         
           
           
               
               
           
         
       
       —SO 2 NHCH 3 , —CH 2 NHCONHCH 3 , —CH 2 NHCSNHCH 3 , —CH 2 NHCOCH 3 , —CH 2 NHSO 2 CH 3 , —CH 2 NHCONHC 2 H 5 , 
       
         
           
           
               
               
           
         
       
       —C 2 H 4 NHSO 2 CH 3 , —CH 2 SO 2 NHCH 3 , —CH 2 NHCH 2 CF 3 , —CH 2 NHCONHCH 2 CF 3 , —CH 2 NHCONHC(CH 3 ) 3 , —CH 2NHCOCN(CH   3 ) 2 , 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         7 . The compound according to  claim 1 , wherein
 R 3  is selected from hydrogen, —C 1-4 alkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocyclyl comprising one to three heteroatoms selected from nitrogen, oxygen, silicon or sulfur, —(CH 2 ) n —CONHR d , —CONH—(CH 2 ) n —R d , —CONH—R d , —(CH 2 ) n —NHCOR d , —SO 2 —NH—(CH 2 ) n —R a , —(CH 2 ) n —SO 2 —NHR d , —(CH 2 ) n —NH—CO—NR d R e , —(CH 2 ) n  NH—SO 2 —R a , —SiR a R b R c ,   
       
         
           
           
               
               
           
         
       
       or 5- to 6-membered heteroaryl, wherein said —C 1-4 alkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocyclyl or 5- to 6-membered heteroaryl is optionally substituted with —C 1-4 alkyl, halogen, oxo or hydroxy;
 n is 0, 1 or 2; 
 R d  and R e  are each independently selected from hydrogen, —C 1-4 alkyl, phenyl, —C 1-4 alkoxy, CN, C 3-6 cycloalkyl, 5- to 6-membered heterocyclyl, or —NR 1c R 1d , wherein each said —C 1-4 alkyl, C 3-6 cycloalkyl, aryl or 5- to 6-membered heterocyclyl is optionally substituted with at least one of —C 1-4 alkyl, halogen or oxo; and R 1c  and R 1d  are each independently hydrogen or —C 1-4 alkyl. 
 
     
     
         8 . The compound according to  claim 7 , wherein
 R 3  is selected from methyl, ethyl, propyl, cyclopropyl, CH(OH)CH 3 , —C(OH)(CH 3 ) 2 , —SO 2 NHCH 3 , —SO 2 NH 2 , —SO 2 NHC 2 H 5 , —CH(OH)CF 3 , —C(OH)(CF 3 ) 2 , —C(OH)(CH 3 ) 2 , Si(CH 3 ) 2 OH, —Si(C 2 H 5 ) 2 OH, —CH 2 NHCH 3 ,   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         9 . The compound according to  claim 1 , wherein R 4  is selected from C 3-6 cycloalkyl, or —C 1-4 alkyl optionally substituted with 4- to 6-membered monocyclic heterocyclyl. 
     
     
         10 . The compound according to  claim 1 , wherein
 R 4  is selected from methyl, ethyl, isopropyl, cyclopropyl, or   
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound according to  claim 1 , wherein R 51 , R 52 , R 61 , and R 62  are hydrogen. 
     
     
         12 . The compound according to  claim 1 , wherein R 51  and R 61 , together with the atoms to which they are attached, form an 8-membered bridged heterocyclyl, wherein the bridge contains two carbon atoms (i.e., —CH 2 —CH 2 —); and R 52  and R 62  are hydrogen. 
     
     
         13 . The compound according to  claim 1 , wherein R 71 , R 72 , R 81  and R 82  and R 9  are hydrogen. 
     
     
         14 . The compound according to  claim 1 , being a compound of Formula (II), 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3  and R 4  are defined as in  claim 1 . 
       
     
     
         15 . A compound selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. 
       
     
     
         16 . A pharmaceutical composition comprising the compound of  claim 1  or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. 
     
     
         17 . A method of treating cancer, comprising administering a subject in need thereof a therapeutically effective amount of the compound of  claim 1  or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. 
     
     
         18 . A method of treating cancer, comprising administering a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of  claim 16 .