Combination cancer therapy using chk inhibitor

Abstract

Disclosed is the use of a checkpoint kinase (CHK) inhibitor in combination with i) an immunotherapeutic agent or a therapeutic agent targeting a cancer-promoting/sustaining molecule, and optionally ii) a chemotherapeutic agent such as gemcitabine, in cancer treatment.

1 . A method for treating a cancer in a subject in need thereof, comprising administering a subject in need thereof an therapeutically effective amount of a compound of formula I or the pharmaceutically acceptable salt thereof, in combination with an immunotherapeutic agent or a therapeutic agent targeting a cancer-promoting molecule, 
       
         
           
           
               
               
           
         
         wherein Y is NH, O, S, or CH 2 ; 
         R 1  is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         wherein X is CH 2 , NH, S, or O, 
         R 8 =—H, —NH 2 , —OH, —N(R 4 R 5 ), —C(R 4 R 5 ) 1-7 NR 6 R 7 , —C(R 4 R 5 ) 1-7 OR 6 , or —N(R 4 )NR 5 R 6 , 
         wherein R 4 , R 5 , R 6 , and R 7  are independently H, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl with or without nuclear heteroatoms such as O, S, and N; optionally substituted aryl, or optionally substituted heteroaromatic, 
         R 9 , R 10 , R 11 , R 12 , and R 13  are independently H, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl with or without nuclear heteroatoms such as O, S or N; optionally substituted aryl, or optionally substituted heteroaromatic, 
         R 2  is selected from a group consisting of H, OH, NH 2 , OR 14 , NR 14 R 15 , alkyl, aryl, heteroaryl, cycloalkyl, arylalkyl, heterocyclyl, heterocyclylalkyl, alkenyl, and alkynyl, 
         wherein R 14  and R 15  are independently H, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl with or without nuclear heteroatoms such as O, S, N; optionally substituted aryl, or optionally substituted heteroaromatic, and 
         R 3  is selected from a group consisting of H, alkyl, aryl, heteroaryl, cycloalkyl, arylalkyl, heterocyclyl, heterocyclylalkyl, alkenyl, and alkynyl. 
       
     
     
         2 . The method according to  claim 2 , wherein R 3  is selected from the group consisting of 
       
         
           
           
               
               
           
         
         wherein R 16 , R 17 , and R 18  are independently H; F, Cl, Br, I; C 3-8 cycloalkyl of C 1 -C 8 alkyls, C 3 -C 8  cycloalkyls, aryls, and heteroaryls; —OR 19 ; —SR 19 ; —NR 19 R 20 ; —S(O)R 19 ; —S(O) 2 R 19 ; —S(O) 2 NR 19 R 20 ; —C(O)NR 19 R 20 ; —N(R 19 )C(O)R 20 ; —N(R 19 )S(O) 2 R 20 ; —N(R 19 )C(O)N(R 20 R 21 ); N(R 19 )C(O)OR 20 ; optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryalkyl, optionally substituted heterocyclyl, optionally substituted heteterocyclylalkyl; optionally substituted alkenyl, or optionally substituted alkynyl; 
         where R 19 , R 20 , and R 21  are independently H, C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, optionally substituted aryl, optionally substituted alkylaryl, or optionally substituted heteroaryl, or R 16 , R 17 , and R 21  are independently part of a fused ring containing 0-3 heteroatoms selected from N, O, and S. 
       
     
     
         3 . The method according to  claim 1 , wherein Y is NH. 
     
     
         4 . The method according to  claim 1 , wherein Y is O. 
     
     
         5 . The method according to  claim 1 , wherein Y is S. 
     
     
         6 . The method according to  claim 1 , wherein Y is CH 2 . 
     
     
         7 . The method according to  claim 1 , wherein the compound of formula I is selected from the group consisting of
 2-(4-fluorophenyl)-4-(3-piperidineamino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-chlorophenyl)-4-(3-piperidineamino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-bromophenyl)-4-(3-piperidineamino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-fluorophenyl)-4-(3-tetrahydropyran-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-chlorophenyl)-4-(3-tetrahydropyran-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-bromophenyl)-4-(3-tetrahydropyran-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-fluorophenyl)-4-(3-tetrahydrothiapyran-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-chlorophenyl)-4-(3-tetrahydrothiapyran-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-bromophenyl)-4-(3-tetrahydrothiapyran-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-chlorophenyl)-4-(2-piperidine-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-chlorophenyl)-4-(2-piperidine-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-chlorophenyl)-4-(S-3-piperidine-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-chlorophenyl)-4-(R-3-piperidine-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-chlorophenyl)-4-(3-piperidine-amino)-thieno[2,3-d]pyridazine-7-N-methyl-carboxylic acid amide,   2-(4-chlorophenyl)-4-(3-piperidine-amino)-thieno[2,3-d]pyridazine-7-N,N-dimethyl-carboxyli-c acid amide,   2-(4-chlorophenyl)-4-(3-tetrahydrothiapyran-amino)-thieno[2,3-d]pyridazine-7-N-methyl-carboxylic acid amide,   2-(4-chlorophenyl)-4-(3-tetrahydrothiapyran-amino)-thieno[2,3-d]pyridazine-7-N,N-dimethyl-carboxylic acid amide,   2-(4-chlorophenyl)-4-(3-tetrahydropyran-amino)-thieno[2,3-d]pyridazine-7-N-methyl-carboxylic acid amide,   2-(4-chlorophenyl)-4-(3-tetrahydropyran-amino)-thieno[2,3-d]pyridazine-7-N,N-dimethyl-carboxylic acid amide,   2-(4-fluorophenyl)-4-(3-tetrahydropyrrol-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-chlorophenyl)-4-(3-tetrahydropyrrol-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-bromophenyl)-4-(3-tetrahydropyrrol-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-fluorophenyl)-4-(3-tetrahydrofuran-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-chlorophenyl)-4-(3-tetrahydrofuran-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-bromophenyl)-4-(3-tetrahydrofuran-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-fluorophenyl)-4-(3-tetrahydrothieno-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-chlorophenyl)-4-(3-tetrahydrothieno-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-bromophenyl)-4-(3-tetrahydrothieno-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-chlorophenyl)-4-(2-tetrahydropyrrol-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-chlorophenyl)-4-(S-3-tetrahydropyrrol-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-chlorophenyl)-4-(R-3-tetrahydropyrrol-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-chlorophenyl)-4-(3-tetrahydropyrrol-amino)-thieno[2,3-d]pyridazine-7-N-methyl-carboxylic acid amide,   2-(4-chlorophenyl)-4-(3-tetrahydropyrrol-amino)-thieno[2,3-d]pyridazine-7-N,N-dimethyl-carboxylic acid amide,   2-(4-chlorophenyl)-4-(3-tetrahydrothieno-amino)-thieno[2,3-d]pyridazine-7-N-methyl-carboxylic acid amide,   2-(4-chlorophenyl)-4-(3-tetrahydrothieno-amino)-thieno[2,3-d]pyridazine-7-N,N-dimethyl-carboxylic acid amide,   2-(4-chlorophenyl)-4-(3-tetrahydrofuran-amino)-thieno[2,3-d]pyridazine-7-N-methyl-carboxylic acid amide,   2-(4-chlorophenyl)-4-(3-tetrahydrofuran-amino)-thieno[2,3-d]pyridazine-7-N,N-dimethyl-carboxylic acid amide,   2-(4-fluorophenyl)-4-(3-pyridin-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-chlorophenyl)-4-(3-pyridin-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-bromophenyl)-4-(3-pyridin-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-fluorophenyl)-4-(3-α-pyran-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-chlorophenyl)-4-(3-α-pyran-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-bromophenyl)-4-(3-α-pyran-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-fluorophenyl)-4-(3-α-thiapyran-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-chlorophenyl)-4-(3-α-thiapyran-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-bromophenyl)-4-(3-α-thiapyran-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-chlorophenyl)-4-(2-pyridin-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide 2-(4-chlorophenyl)-4-(4-pyridin-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide 2-(4-chlorophenyl)-4-(S-3-pyridin-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-chlorophenyl)-4-(R-3-pyridin-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-chlorophenyl)-4-(3-pyridin-amino)-thieno[2,3-d]pyridazine-7-N-methyl-carboxylic acid amide,   2-(4-chlorophenyl)-4-(3-pyridin-amino)-thieno[2,3-d]pyridazine-7-N,N-dimethyl-carboxylic acid amide,   2-(4-chlorophenyl)-4-(3-thiapyran-amino)-thieno[2,3-d]pyridazine-7-N-methyl-carboxylic acid amide,   2-(4-chlorophenyl)-4-(3-thiapyran-amino)-thieno[2,3-d]pyridazine-7-N,N-dimethyl-carboxylic acid amide,   2-(4-chlorophenyl)-4-(3-pyran-amino)-thieno[2,3-d]pyridazine-7-N-methyl-carboxylic acid amide,   2-(4-chlorophenyl)-4-(3-pyran-amino)-thieno[2,3-d]pyridazine-7-N,N-dimethyl-carboxylic acid amide,   2-(4-fluorophenyl)-4-(3-pyrrol-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-chlorophenyl)-4-(3-pyrrol-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-bromophenyl)-4-(3-pyrrol-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-fluorophenyl)-4-(3-furan-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-chlorophenyl)-4-(3-furan-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-bromophenyl)-4-(3-furan-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-fluorophenyl)-4-(3-thieno-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-chlorophenyl)-4-(3-thieno-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-bromophenyl)-4-(3-thieno-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-chlorophenyl)-4-(2-pyrrol-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-chlorophenyl)-4-(S-3-pyrrol-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-chlorophenyl)-4-(R-3-pyrrol-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(4-chlorophenyl)-4-(3-pyrrol-amino)-thieno[2,3-d]pyridazine-7-N-methyl-carboxylic acid amide,   2-(4-chlorophenyl)-4-(3-pyrrol-amino)-thieno[2,3-d]pyridazine-7-N,N-dimethyl-carboxylic acid amide,   2-(4-chlorophenyl)-4-(3-thieno-amino)-thieno[2,3-d]pyridazine-7-N-methyl-carboxylic acid amide,   2-(4-chlorophenyl)-4-(3-thieno-amino)-thieno[2,3-d]pyridazine-7-N,N-dimethyl-carboxylic acid amide,   2-(4-chlorophenyl)-4-(3-furan-amino)-thieno[2,3-d]pyridazine-7-N-methyl-carboxylic acid amide,   2-(4-chlorophenyl)-4-(3-furan-amino)-thieno[2,3-d]pyridazine-7-N,N-dimethyl-carboxylic acid amide,   2-(3-fluorophenyl)-4-(3-piperidineamino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-chlorophenyl)-4-(3-piperidineamino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-bromophenyl)-4-(3-piperidineamino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-chlorophenyl)-4-(3-piperibine-amino)-thieno[2,3-d]pyridazine-7-N,N-dimethyl-carboxylic acid amide,   2-(3-chlorophenyl)-4-(3-tetrahydrothiapyran-amino)-thieno[2,3-d]pyridazine-7-N-methyl-carboxylic acid amide,   2-(3-chlorophenyl)-4-(3-tetrahydrothiapyran-amino)-thieno[2,3-d]pyridazine-7-N,N-dimethyl-carboxylic acid amide,   2-(3-chlorophenyl)-4-(3-tetrahydropyran-amino)-thieno[2,3-d]pyridazine-7-N-methyl-carboxylic acid amide,   2-(3-chlorophenyl)-4-(3-tetrahydropyran-amino)-thieno[2,3-d]pyridazine-7-N,N-dimethyl-carboxylic acid amide,   2-(3-fluorophenyl)-4-(3-tetrahydropyrrol-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-chlorophenyl)-4-(3-tetrahydropyrrol-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-bromophenyl)-4-(3-tetrahydropyrrol-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-fluorophenyl)-4-(3-tetrahydrofuran-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-chlorophenyl)-4-(3-tetrahydrofuran-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-bromophenyl)-4-(3-tetrahydrofuran-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-fluorophenyl)-4-(3-tetrahydrothieno-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-chlorophenyl)-4-(3-tetrahydrothieno-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-bromophenyl)-4-(3-tetrahydrothieno-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-chlorophenyl)-4-(2-tetrahydropyrrol-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-chlorophenyl)-4-(S-3-tetrahydropyrrol-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-chlorophenyl)-4-(R-3-tetrahydropyrrol-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-chlorophenyl)-4-(3-tetrahydropyrrol-amino)-thieno[2,3-d]pyridazine-7-N-methyl-carboxylic acid amide,   2-(3-chlorophenyl)-4-(3-tetrahydropyrrol-amino)-thieno[2,3-d]pyridazine-7-N,N-dimethyl-carboxylic acid amide,   2-(3-fluorophenyl)-4-(3-pyridin-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-chlorophenyl)-4-(3-pyridin-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-bromophenyl)-4-(3-pyridin-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-fluorophenyl)-4-(3-α-pyran-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-chlorophenyl)-4-(3-α-pyran-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-bromophenyl)-4-(3-α-pyran-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-fluorophenyl)-4-(3-α-thiapyran-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-chlorophenyl)-4-(3-α-thiapyran-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-bromophenyl)-4-(3-α-thiapyran-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-chlorophenyl)-4-(2-pyridin-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-chlorophenyl)-4-(4-pyridin-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-chlorophenyl)-4-(S-3-pyridin-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-chlorophenyl)-4-(R-3-pyridin-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-chlorophenyl)-4-(3-pyridin-amino)-thieno[2,3-d]pyridazine-7-N-methyl-carboxylic acid amide,   2-(3-chlorophenyl)-4-(3-pyridin-amino)-thieno[2,3-d]pyridazine-7-N,N-dimethyl-carboxylic acid amide,   2-(3-chlorophenyl)-4-(3-thiapyran-amino)-thieno[2,3-d]pyridazine-7-N-methyl-carboxylic acid amide,   2-(3-chlorophenyl)-4-(3-thiapyran-amino)-thieno[2,3-d]pyridazine-7-N,N-dimethyl-carboxylic acid amide,   2-(3-chlorophenyl)-4-(3-pyran-amino)-thieno[2,3-d]pyridazine-7-N-methyl-carboxylic acid amide,   2-(3-chlorophenyl)-4-(3-pyran-amino)-thieno[2,3-d]pyridazine-7-N,N-dimethyl-carboxylic acid amide,   2-(3-fluorophenyl)-4-(3-pyrrol-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-chlorophenyl)-4-(3-pyrrol-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-bromophenyl)-4-(3-pyrrol-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-fluorophenyl)-4-(3-furan-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-chlorophenyl)-4-(3-furan-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-bromophenyl)-4-(3-furan-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-fluorophenyl)-4-(3-thieno-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-chlorophenyl)-4-(3-thieno-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-bromophenyl)-4-(3-thieno-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-chlorophenyl)-4-(2-pyrrol-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-chlorophenyl)-4-(S-3-pyrrol-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-chlorophenyl)-4-(R-3-pyrrol-amino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-chlorophenyl)-4-(3-pyrrol-amino)-thieno[2,3-d]pyridazine-7-N-methyl-carboxylic acid amide,   2-(3-chlorophenyl)-4-(3-pyrrol-amino)-thieno[2,3-d]pyridazine-7-N,N-dimethyl-carboxylic acid amide,   2-(3-chlorophenyl)-4-(3-thieno-amino)-thieno[2,3-d]pyridazine-7-N-methyl-carboxylic acid amide,   2-(3-chlorophenyl)-4-(3-thieno-amino)-thieno[2,3-d]pyridazine-7-N,N-dimethyl-carboxylic acid amide,   2-(3-chlorophenyl)-4-(3-furan-amino)-thieno[2,3-d]pyridazine-7-N-methyl-carboxylic acid amide,   2-(3-chlorophenyl)-4-(3-furan-amino)-thieno[2,3-d]pyridazine-7-N,N-dimethyl-carboxylic acid amide,   2-(4-fluorophenyl)-4-(3-piperidinemethyl)-thieno[2,3-d] pyridazinyl-7-formamide;   2-(4-chlorophenyl)-4-(3-piperidinemethyl)-thieno[2,3-d] pyridazinyl-7-formamide;   2-(4-bromophenyl)-4-(3-piperidinemethyl)-thieno[2,3-d] pyridazinyl-7-formamide;   2-(4-fluorophenyl)-4-(3-tetrahy dropyranmethyl)-thieno[2,3-d]pyridazinyl-7-formamide;   2-(4-chlorophenyl)-4-(3-tetrahydropyranmethyl)-thieno[2,3-d]pyridazinyl-7-formamide;   2-(4-bromophenyl)-4-(3-tetrahydropyranmethyl)-thieno[2,3-d]pyridazinyl-7-formamide;   2-(4-fluorophenyl)-4-(3-tetrahydrothiapyranmethyl)-thieno[2,3-d]pyridazinyl-7-formamide;   2-(4-chlorophenyl)-4-(3-tetrahydrothiapyranmethyl)-thieno[2,3-d]pyridazinyl-7-formamide;   2-(4-bromophenyl)-4-(3-tetrahydrothiapyranmethyl)-thieno[2,3-d]pyridazinyl-7-formamide;   2-(4-chlorophenyl)-4-(2-piperidinemethyl)-thieno[2,3-d] pyridazinyl-7-formamide;   2-(4-chlorophenyl)-4-(4-piperidinemethyl)-thieno[2,3-d] pyridazinyl-7-formamide;   2-(4-chlorophenyl)-4-(S-3-piperidinemethyl)-thieno[2,3-d] pyridazinyl-7-formamide;   2-(4-chlorophenyl)-4-(R-3-piperidinemethyl)-thieno[2,3-d] pyridazinyl-7-formamide;   2-(4-chlorophenyl)-4-(3-piperidinemethyl)-thieno [2,3-d]pyridazinyl-7-N-methyl-formamide;   2-(4-chlorophenyl)-4-(3-piperidinemethyl)-thieno[2,3-d]pyridazinyl-7-N,N-dimethyl-7-formamide;   2-(4-chlorophenyl)-4-(3-tetrahydrothiapyranmethyl)-thieno[2,3-d]pyridazinyl-7-N-methyl-formamide;   2-(4-chlorophenyl)-4-(3-tetrahydrothiapyranmethyl)-thieno[2,3-d]pyridazinyl-7-N,N-dimethyl-7-formamide;   2-(4-chlorophenyl)-4-(3-tetrahy dropyranmethyl)-thieno[2,3-d]pyridazinyl-7-N-methyl-formamide;   2-(4-chlorophenyl)-4-(3-tetrahy dropyranmethyl)-thieno[2,3-d]pyridazinyl-7-N,N-dimethyl-7-formamide;   2-(4-fluorophenyl)-4-(3-pyrrolidinemethyl)-thieno[2,3-d] pyridazinyl-7-formamide;   2-(4-chlorophenyl)-4-(3-pyrrolidinemethyl)-thieno[2,3-d] pyridazinyl-7-formamide;   2-(4-bromophenyl)-4-(3-pyrrolidinemethyl)-thieno[2,3-d] pyridazinyl-7-formamide;   2-(4-fluorophenyl)-4-(3-tetrahy drofuranmethyl)-thieno[2,3-d]pyridazinyl-7-formamide;   2-(4-chlorophenyl)-4-(3-tetrahydrofuranmethyl)-thieno[2,3-d]pyridazinyl-7-formamide;   2-(4-bromophenyl)-4-(3-tetrahydrofuranmethyl)-thieno[2,3-d]pyridazinyl-7-formamide;   2-(4-fluorophenyl)-4-(3-tetrahydrothiophenemethyl)-thieno[2,3-d]pyridazinyl-7-formamide;   2-(4-chlorophenyl)-4-(3-tetrahydrothiophenemethyl)-thieno[2,3-d]pyridazinyl-7-formamide;   2-(4-bromophenyl)-4-(3-tetrahydrothiophenemethyl)-thieno[2,3-d]pyridazinyl-7-formamide;   2-(4-chlorophenyl)-4-(3-pyrrolidinemethyl)-thieno[2,3-d] pyridazinyl-7-formamide;   2-(4-chlorophenyl)-4-(S-3-pyrrolidinemethyl)-thieno[2,3-d]pyridazinyl-7-formamide;   2-(4-chlorophenyl)-4-(R-3-pyrrolidinemethyl)-thieno[2,3-d]pyridazinyl-7-formamide;   2-(4-chlorophenyl)-4-(3-pyrrolidinemethyl)-thieno[2,3-d]pyridazinyl-7-N-methyl-formamide;   2-(4-chlorophenyl)-4-(3-pyrrolidinemethyl)-thieno[2,3-d]pyridazinyl-7-N,N-dimethyl-formamide;   2-(4-chlorophenyl)-4-(3-tetrahydrothiophenemethyl)-thieno[2,3-d]pyridazinyl-7-N-methyl-formamide;   2-(4-chlorophenyl)-4-(3-tetrahydrothiophenemethyl)-thieno[2,3-d]pyridazinyl-7-N,N-dimethyl-formamide;   2-(4-chlorophenyl)-4-(3-tetrahydrofuranmethyl)-thieno[2,3-d]pyridazinyl-7-N-methyl-formamide;   2-(4-chlorophenyl)-4-(3-tetrahy drofuranmethyl)-thieno[2,3-d]pyridazinyl-7-N,N-dimethyl-formamide;   2-(4-fluorophenyl)-4-(3-pyridinemethyl)-thieno[2,3-d] pyridazinyl-7-formamide;   2-(4-chlorophenyl)-4-(3-pyridinemethyl)-thieno[2,3-d] pyridazinyl-7-formamide;   2-(4-bromophenyl)-4-(3-pyridinemethyl)-thieno[2,3-d] pyridazinyl-7-formamide;   2-(4-fluorophenyl)-4-(3-α-pyranmethyl)-thieno[2,3-d] pyridazinyl-7-formamide;   2-(4-chlorophenyl)-4-(3-α-pyranmethyl)-thieno[2,3-d] pyridazinyl-7-formamide;   2-(4-bromophenyl)-4-(3-α-pyranmethyl)-thieno[2,3-d] pyridazinyl-7-formamide;   2-(4-fluorophenyl)-4-(3-α-thiopyranmethyl)-thieno[2,3-d] pyridazinyl-7-formamide;   2-(4-chlorophenyl)-4-(3-α-thiopyranmethyl)-thieno[2,3-d] pyridazinyl-7-formamide;   2-(4-bromophenyl)-4-(3-α-thiopyranmethyl)-thieno[2,3-d] pyridazinyl-7-formamide;   2-(4-chlorophenyl)-4-(2-pyridinemethyl)-thieno[2,3-d] pyridazinyl-7-formamide;   2-(4-chlorophenyl)-4-(4-pyridinemethyl)-thieno[2,3-d] pyridazinyl-7-formamide;   2-(4-chlorophenyl)-4-(3-pyridinemethyl)-thieno[2,3-d]pyridazinyl-7-N-methyl formamide;   2-(4-chlorophenyl)-4-(3-pyridinemethyl)-thieno[2,3-d]pyridazinyl-7-N,N-dimethyl formamide;   2-(4-chlorophenyl)-4-(3-thiopyranylmethyl)-thieno[2,3-d]pyridazinyl-7-N-methyl formamide;   2-(4-chlorophenyl)-4-(3-thiopyranylmethyl)-thieno[2,3-d]pyridazinyl-7-N,N-dimethyl formamide;   2-(4-chlorophenyl)-4-(3-pyranmethyl)-thieno[2,3-d]pyridazinyl-7-N-methyl formamide;   2-(4-chlorophenyl)-4-(3-pyranmethyl)-thieno[2,3-d]pyridazinyl-7-N,N-dimethyl formamide;   2-(4-fluorophenyl)-4-(3-pyrrolemethyl)-thieno[2,3-d] pyridazinyl-7-formamide;   2-(4-chlorophenyl)-4-(3-pyrrolemethyl)-thieno[2,3-d] pyridazinyl-7-formamide;   2-(4-bromophenyl)-4-(3-pyrrolemethyl)-thieno[2,3-d] pyridazinyl-7-formamide;   2-(4-fluorophenyl)-4-(3-furanmethyl)-thieno[2,3-d] pyridazinyl-7-formamide;   2-(4-chlorophenyl)-4-(3-furanmethyl)-thieno[2,3-d] pyridazinyl-7-formamide;   2-(4-bromophenyl)-4-(3-furanmethyl)-thieno[2,3-d] pyridazinyl-7-formamide;   2-(4-fluorophenyl)-4-(3-thiaphenemethyl)-thieno[2,3-d] pyridazinyl-7-formamide;   2-(4-chlorophenyl)-4-(3-thiaphenemethyl)-thieno[2,3-d] pyridazinyl-7-formamide;   2-(4-bromophenyl)-4-(3-thiaphenemethyl)-thieno[2,3-d] pyridazinyl-7-formamide;   2-(4-chlorophenyl)-4-(2-pyrrolemethyl)-thieno[2,3-d] pyridazinyl-7-formamide;   2-(4-chlorophenyl)-4-(3-pyrrolemethyl)-thieno[2,3-d]pyridazinyl-7-N-methyl formamide;   2-(4-chlorophenyl)-4-(3-pyrrolemethyl)-thieno[2,3-d]pyridazinyl-7-N,N-dimethyl formamide;   2-(4-chlorophenyl)-4-(3-thiaphenemethyl)-thieno[2,3-d]pyridazinyl-7-N-methyl formamide;   2-(4-chlorophenyl)-4-(3-thiaphenemethyl)-thieno[2,3-d]pyridazinyl-7-N,N-dimethyl formamide;   2-(4-chlorophenyl)-4-(3-furanmethyl)-thieno[2,3-d]pyridazinyl-7-N-methyl formamide;   2-(4-chlorophenyl)-4-(3-furanmethyl)-thieno[2,3-d]pyridazinyl-7-N,N-dimethyl formamide; and   2-(3,5-dichlorophenyl)-4-(3-piperidinemethyl)-thieno[2,3-d]pyridazinyl-7-formamide.   
     
     
         8 . The method according to  claim 7 , wherein the compound of formula I is selected from the group consisting of
 2-(3-fluorophenyl)-4-(3-piperidineamino)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-fluorophenyl)-4-(3-piperidinyloxy)-thieno[2,3-d]pyridazine-7-carboxylic acid amide,   2-(3-fluorophenyl)-4-(3-piperidinylthio)-thieno[2,3-d]pyridazine-7-carboxylic acid amide, and   2-(3,5-dichlorophenyl)-4-(3-piperidinemethyl)-thieno[2,3-d]pyridazinyl-7-formamide.   
     
     
         9 . The method according to  claim 1 , wherein the immunotherapeutic agent or the therapeutic agent targeting a cancer-promoting molecule is an inhibitor of PD-1, PD-L1, CTLA-4, HER-2, CD20, CD33, or CD52. 
     
     
         10 . The method according to  claim 9 , wherein the immunotherapeutic agent or the therapeutic agent targeting a cancer-promoting molecule is an antibody targeting PD-1, PD-L1, CTLA-4, HER-2, CD20, CD33, or CD52, or an antibody-drug conjugate (ADC) or a CAR-T cell targeting PD-L1, HER-2, CD20, CD33, and/or CD52. 
     
     
         11 . The method according to  claim 10 , wherein the antibody targeting PD-1 is selected from the group consisting of Nivolumab, Pembrolizumab and Toripalimab. 
     
     
         12 . The method according to  claim 10 , wherein the antibody targeting PD-L1 is selected from the group consisting of Atezolizumab, Druvalumab and Avelumab. 
     
     
         13 . The method according to  claim 1 , wherein the subject is further administered with a chemotherapeutic agent. 
     
     
         14 . The method according to  claim 13 , wherein the chemotherapeutic agent is selected from the group consisting of cisplatin, pemetrexed, gemcitabine, cytarabine, hydroxycarbamide, temozolomide, irinotecan, cyclophosphamide, mitoxantrone, etoposide, folinic acid, fludarabine, and fluorouracil. 
     
     
         15 . The method according to  claim 1 , wherein the cancer is a solid cancer selected from the group consisting of lung, prostate, ovarian, brain, breast, skin, bladder, colon, gastrointestinal, head and neck, gastric, pancreas, neurologic, renal, and liver cancer. 
     
     
         16 . The method according to  claim 1 , wherein the cancer is a hematological cancer selected from the group consisting of lymphocytic leukemia, myeloid leukemia, non-Hodgkin lymphoma, and Hodgkin lymphoma.