Positive allosteric modulators of the muscarinic acetylcholine receptor m4

Abstract

Disclosed herein are tricyclic compounds, including pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine-8-amine, pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine-4-amine, pyrazino[2′,3′:4,5]thieno[3,2-d]pyrimidin-4-amine, pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine, and pyrimido[4′,5′:4,5]furo[2,3-c]pyridazin-8-amine compounds, which may be useful as positive allosteric modulators of the muscarinic acetylcholine receptor M4 (mAChR M4). Also disclosed herein are methods of making the compounds, pharmaceutical compositions comprising the compounds, and methods of treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction using the compounds and compositions.

What is claimed is: 
     
         1 . A compound of formula (I) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         B is O or S; 
         X is N or CR 1 ; 
         Z is N or CR 3 ; 
         R 1  is selected from hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, halo, and —OR b ; 
         R 2  is selected from hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -hydroxyalkyl, C 1 -C 4 -acetoxyalkyl, halo, and —OR b ; 
         R 3  is selected from hydrogen and C 1 -C 4 -alkyl; 
         R 4  and R 5  are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heteroalkyl, heterocycle, and —(CR c R d ) n —Y, each of which may be optionally substituted; 
         or R 4  and R 5  are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic ring; 
         R 6  is selected from hydrogen and C 1 -C 4 -alkyl; 
         each Y is independently selected from halo, —OR, —SR, —C(O)R, —C(O)OR, —S(O)R, —SO 2 R, —NR 2 , —C(O)NR 2 , —NRC(O)R, —S(O) 2 NR 2 , —NRS(O) 2 R, aryl, heteroaryl, cycloalkyl, and heterocycle, each of which may be optionally substituted; 
         n is 1, 2, 3, 4, 5, 6, 7, or 8; 
         R b  is selected from hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocycle; 
         R c  and R d  are each independently selected from hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, and halo; and 
         each R is independently selected from hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl, heteroaryl, heteroarylalkyl, and heteroalkyl, each of which may be optionally substituted. 
       
     
     
         2 . The compound of  claim 1 , wherein the compound is a compound of formula (Ia): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         3 . The compound of  claim 1 , wherein the compound is a compound of formula (Ib): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         4 . The compound of any one of  claims 1 - 3 , wherein
 X is N.   
     
     
         5 . The compound of any one of  claims 1 - 3 , wherein
 X is CR 1 .   
     
     
         6 . The compound of  claim 5 , wherein
 R 1  is hydrogen.   
     
     
         7 . The compound of  claim 5 , wherein
 R 1  is C 1 -C 4  alkyl.   
     
     
         8 . The compound of  claim 7 , wherein
 R 1  is methyl.   
     
     
         9 . The compound of any one of  claims 1 - 8 , wherein
 R 2  is selected from hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, halo, and —OR b .   
     
     
         10 . The compound of any one of  claims 1 - 8 , wherein
 R 2  is hydrogen.   
     
     
         11 . The compound of any one of  claims 1 - 8 , wherein
 R 2  is selected from C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, halo, and —OR b .   
     
     
         12 . The compound of any one of  claims 1 - 8 , wherein
 R 2  is C 1 -C 4  alkyl.   
     
     
         13 . The compound of  claim 12 , wherein
 R 2  is methyl.   
     
     
         14 . The compound of any one of  claims 1 - 8 , wherein
 R 2  is halo.   
     
     
         15 . The compound of  claim 14 , wherein
 R 2  is chloro.   
     
     
         16 . The compound of any one of  claims 1 - 8 , wherein
 R 2  is —OR b .   
     
     
         17 . The compound of  claim 16 , wherein
 R b  is C 1 -C 4  alkyl.   
     
     
         18 . The compound of  claim 17 , wherein
 R b  is methyl.   
     
     
         19 . The compound of any one of  claims 1 - 18 , wherein
 Z is CR 3 .   
     
     
         20 . The compound of  claim 19 , wherein
 R 3  is C 1 -C 4  alkyl.   
     
     
         21 . The compound of  claim 20 , wherein
 R 3  is methyl.   
     
     
         22 . The compound of  claim 21 , wherein
 R 3  is hydrogen.   
     
     
         23 . The compound of any one of  claims 1 - 18 , wherein
 Z is N.   
     
     
         24 . The compound of any one of  claims 1 - 23 , wherein
 R 4  is hydrogen or alkyl; and   R 5  is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heteroalkyl, heterocycle, and —(CR c R d ) n —Y, each of which may be optionally substituted.   
     
     
         25 . The compound of  claim 24 , wherein
 R 4  is selected from hydrogen and methyl;   R 5  is selected from C 1 -C 4  alkyl, C 3 -C 6  cycloalkyl, a 3- to 6-membered heterocycle having one heteroatom selected from N and O, and —(CR c R d ) n —Y;   n is 1, 2 or 3;   R c  and R d  are each hydrogen;   Y is selected from —OR, aryl, C 3 -C 6  cycloalkyl, a 5- to 6-membered heteroaryl having 1 or 2 heteroatoms independently selected from N, O and S, a 3- to 6-membered heterocycle having one or two heteroatoms independently selected from N, O and S, sulfanyl, —COR, —C(O)NR 2 , and —SO 2 R;   wherein each alkyl, aryl, cycloalkyl, heteroaryl and heterocycle is independently unsubstituted or substituted with 1 or 2 substituents independently selected from C 1 -C 4  alkyl, C 1 -C 4  hydroxyalkyl, C 1 -C 4  alkoxy, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, C 1 -C 4 -aminoalkyl, —CONR 2 , halo, hydroxy, aryl, C 3 -C 6  cycloalkyl, a 3- to 6-membered heterocycle having one heteroatom independently selected from N and O, and a 5- to 6-membered heteroaryl having 1 or 2 heteroatoms independently selected from N, O and S; and   each R is independently selected from hydrogen, C 1 -C 4  alkyl, C 1 -C 4  hydroxyalkyl, C 1 -C 4  haloalkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, C 3 -C 6  cycloalkyl, a 5- to 6-membered heteroaryl group having 1, 2 or 3 heteroatoms independently selected from N, S and O, a 3- to 6-membered heterocycle having one or two heteroatoms independently selected from N and O, or a bicyclic heterocycle, C 3 -C 6  cycloalkyl.   
     
     
         26 . The compound of  claim 24 , wherein
 R 4  is selected from hydrogen and methyl;   R 5  is selected from C 1 -C 4  alkyl, C 3 -C 6  cycloalkyl, a 3- to 6-membered heterocycle having one heteroatom selected from N and O, and —(CR c R d ) n —Y;   n is 1, 2 or 3;   R c  and R d  are each hydrogen;   Y is selected from —OR, aryl, C 3 -C 6  cycloalkyl, and a 5- to 6-membered heteroaryl having 1 or 2 heteroatoms independently selected from N, O and S; and   R is C 1 -C 4  alkyl;   wherein each aryl, cycloalkyl, heteroaryl and heterocycle is independently unsubstituted or substituted with 1 or 2 substituents independently selected from C 1 -C 4  alkyl, C 1 -C 4  hydroxyalkyl, C 1 -C 4  alkoxy, halo, hydroxy, aryl, C 3 -C 6  cycloalkyl, a 3- to 6-membered heterocycle having one heteroatom independently selected from N and O, and a 5- to 6-membered heteroaryl having 1 or 2 heteroatoms independently selected from N, O and S.   
     
     
         27 . The compound of any one of  claims 1 - 23 , wherein
 R 4  and R 5  are taken together with the nitrogen atom to which they are attached to form an azetidinyl, pyrrolidinyl, piperidinyl or piperazinyl group, which may be optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heteroalkyl, heterocycle, oxo, and —(CR c R d ) p —Y, wherein p is 0, 1, 2, 3, 4, 5, 6, 7, or 8.   
     
     
         28 . The compound of  claim 27 , wherein
 R 4  and R 5  are taken together with the nitrogen atom to which they are attached to form an azetidinyl, pyrrolidinyl, piperidinyl or piperazinyl group, each of which is independently unsubstituted or substituted with 1 or 2 substituents independently selected from C 1 -C 4  alkyl, C 3 -C 6  cycloalkyl, aryl, a 5- to 6-membered heteroaryl having 1 or 2 heteroatoms independently selected from N, O and S, a 3- to 6-membered heterocycle having one heteroatom independently selected from N and O, oxo, and —(CR c R d ) p —Y;   p is 0 or 1;   R c  and R d  are each hydrogen;   each Y is independently selected from C 1 -C 4  alkyl, aryl, —OR, —NR 2 ; and   each R is independently selected from hydrogen, C 1 -C 4  alkyl, aryl, and a 5- to 6-membered heteroaryl having 1 or 2 heteroatoms independently selected from N, O and S;   wherein each aryl, cycloalkyl, heteroaryl and heterocycle is independently unsubstituted or substituted with 1 or 2 substituents independently selected from C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, cyano, and halo.   
     
     
         29 . The compound of any one of  claims 1 - 28 , wherein
 R 6  is hydrogen.   
     
     
         30 . The compound of  claim 1 , wherein the compound is a compound of formula (Ic): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 2  is selected from C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, halo, and —OR b . 
       
     
     
         31 . The compound of  claim 1 , wherein the compound is a compound of formula (Id): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 7  is selected from hydrogen, C 1 -C 4  alkyl, and halo; 
         R 8  is optionally substituted aryl, heteroaryl, aryloxy, or heteroaryloxy; and 
         m is 1, 2, or 3. 
       
     
     
         32 . The compound of  claim 1 , wherein the compound is a compound of formula (Ie): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 7  is selected from hydrogen, C 1 -C 4  alkyl and halo; and 
         R 8  is optionally substituted aryl or heteroaryl. 
       
     
     
         33 . The compound of  claim 32 , wherein R 8  is optionally substituted phenyl. 
     
     
         34 . The compound of  claim 1 , wherein the compound is a compound of formula (If): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         A is a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl or heterocycle; and 
         R 9  is an optionally substituted aryl or heteroaryl. 
       
     
     
         35 . The compound of  claim 1 , wherein the compound is a compound of formula (Ig): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  is C 1 -C 4 -alkyl; 
         R 2  is selected from hydrogen and halo; and 
         R 3  is C 1 -C 4 -alkyl. 
       
     
     
         36 . The compound of  claim 35 , wherein:
 R 1  is methyl;   R 2  is chloro; and   R 3  is methyl.   
     
     
         37 . The compound of  claim 1 , wherein the compound is a compound of formula (Ih): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 2  is C 1 -C 4 -alkyl; and 
         R 3  is C 1 -C 4 -alkyl. 
       
     
     
         38 . The compound of  claim 1 , wherein the compound is a compound of formula (Ii): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         A is selected from aryl, cycloalkyl, heterocyclyl and heteroaryl; 
         q is 1, 2 or 3; and 
         each R 9  is independently selected from alkyl, halo, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, sulfanyl, —(CR c R d ) p —Y, —OR, —SR, —C(O)R, —C(O)OR, —S(O)R, —SO 2 R, —NR 2 , —C(O)NR 2 , and —S(O) 2 NR 2 , each of which may be optionally substituted. 
       
     
     
         39 . The compound of  claim 38 , wherein
 A is selected from phenyl, a C 3 -C 6  cycloalkyl, a 3- to 6-membered heterocycle having one or two heteroatoms independently selected from N, S and O, and a 5- to 6-membered heteroaryl having 1 or 2 heteroatoms independently selected from N, O and S.   
     
     
         40 . The compound of any one of  claims 38 - 39 , wherein
 each R 9  is independently selected from C 1 -C 6  alkyl, halo, C 1 -C 6  hydroxyalkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, phenyl, C 3 -C 6  cycloalkyl, a 3- to 6-membered heterocycle having one or two heteroatoms independently selected from N, O and S, a 5- to 6-membered heteroaryl having 1 or 2 heteroatoms independently selected from N, O and S, —(CR c R d ) p —Y, —OR, —C(O)R, —C(O)NR 2 , and —SO 2 R;   each Y is independently selected from C 3 -C 6  cycloalkyl, a 3- to 6-membered heterocycle having one or two heteroatoms independently selected from N, O and S, and a 5- to 6-membered heteroaryl having 1 or 2 heteroatoms independently selected from N, O and S;   p is 1;   R c  and R d  are hydrogen;   each R is independently selected from hydrogen, C 1 -C 6  alkyl, hydroxy, C 3 -C 6  cycloalkyl, a 3- to 6-membered heterocycle having one or two heteroatoms independently selected from N, O and S, and a 5- to 6-membered heteroaryl having 1 or 2 heteroatoms independently selected from N, O and S; and   each alkyl, phenyl, cycloalkyl, heterocyclyl and heteroaryl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from halo, hydroxy, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, C 3 -C 6  cycloalkyl, C 1 -C 4  alkoxy and C 1 -C 4  haloalkoxy.   
     
     
         41 . The compound of any one of  claims 30 - 40 , wherein
 R 6  is hydrogen.   
     
     
         42 . The compound of  claim 1 , selected from the group consisting of:
 N,N,3,4-tetramethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   N-cyclohexyl-3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   3,4-dimethyl-N-(tetrahydro-2H-pyran-4-yl)pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   3,4-dimethyl-8-(piperidin-1-yl)pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine;   N-cyclobutyl-3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   3,4-dimethyl-8-(pyrrolidin-1-yl)pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine;   3,4-dimethyl-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azetidin-3-yl)pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   8-(4-cyclopropylpiperazin-1-yl)-3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine;   8-(azetidin-1-yl)-3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine;   8-(3-azabicyclo[3.1.0]hexan-3-yl)-3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine;   1-(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)-N,N-dimethylpyrrolidin-3-amine;   N-(2-methoxyethyl)-N,3,4-trimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   6-(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)-2-oxa-6-azaspiro[3.3]heptane;   8-(3-(methoxymethyl)azetidin-1-yl)-3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine;   8-methyl-4-(pyrrolidin-1-yl)pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine;   4-(3,3-difluoropyrrolidin-1-yl)-8-methylpyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine;   8-methyl-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azetidin-3-yl)pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine;   4-(azetidin-1-yl)-8-methylpyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine;   6-(8-methylpyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-yl)-2-oxa-6-azaspiro[3.3]heptane;   N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)azetidin-3-yl)pyrazino[2′,3′:4,5]thieno[3,2-d]pyrimidin-4-amine;   8-(3,3-difluoroazetidin-1-yl)-3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine;   3,4-dimethyl-N-(1-(6-(trifluoromethyl)pyridin-3-yl)azetidin-3-yl)pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   3,4-dimethyl-N-(1-phenylpyrrolidin-3-yl)pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   3,4-dimethyl-8-(3-(pyridin-4-yl)azetidin-1-yl)pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine;   N-cyclopropyl-3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   N-(2-(4-methoxyphenyl)cyclopropyl)-3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   N-(3-fluoro-4-methoxybenzyl)-3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   3,4-dimethyl-8-(3-phenylpyrrolidin-1-yl)pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine;   N-(4-(2-fluoropyridin-3-yl)benzyl)-3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   8-(3-(4-fluorophenoxy)azetidin-1-yl)-3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine;   8-(3-(2-fluorophenoxy)azetidin-1-yl)-3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine;   8-(3-(3-fluorophenoxy)azetidin-1-yl)-3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine;   3,4-dimethyl-8-(3-phenoxyazetidin-1-yl)pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine;   1-(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)-3-methylazetidin-3-ol;   1-(3-((3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino)azetidin-1-yl)ethan-1-one;   1-(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)azetidin-3-one;   8-chloro-N-(3,3-difluorocyclobutyl)-7,9-dimethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   8-chloro-N-cyclopropyl-7,9-dimethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   2-[4-[[(8-chloro-7,9-dimethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-yl)amino]methyl]phenyl]propan-2-ol;   8-chloro-N-(2,2-dimethylcyclopropyl)-7,9-dimethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   8-chloro-N-(2-ethylcyclopropyl)-7,9-dimethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   4-(azetidin-1-yl)-8-chloro-7,9-dimethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine;   8-chloro-N,N,7,9-tetramethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   8-chloro-N,7,9-trimethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   8-chloro-7,9-dimethyl-N-propyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   8-chloro-N-isobutyl-7,9-dimethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   8-chloro-N-ethyl-7,9-dimethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   8-chloro-7,9-dimethyl-4-pyrrolidin-1-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine;   8-chloro-N-cyclobutyl-7,9-dimethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   8-chloro-N-cyclopentyl-7,9-dimethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   8-chloro-N-[2-(3,4-difluorophenyl)cyclopropyl]-7,9-dimethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   8-chloro-N-(cyclobutylmethyl)-7,9-dimethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   8-chloro-N-(3-methoxypropyl)-7,9-dimethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   8-chloro-7,9-dimethyl-N-[(2-methylpyrimidin-5-yl)methyl]pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   N-cyclobutyl-7,9-dimethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   7,9-dimethyl-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine;   2-[3-[[(7,9-dimethylpyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-yl)amino]methyl]phenyl]propan-2-ol;   N-[1-(5-isopropoxypyrimidin-2-yl)azetidin-3-yl]-7,9-dimethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   N-[1-(5-fluoropyrimidin-2-yl)azetidin-3-yl]-7,9-dimethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   N-[1-(2,5-dichloro-4-pyridyl)azetidin-3-yl]-7,9-dimethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   N-[2-(3,4-difluorophenyl)cyclopropyl]-7,9-dimethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   N-cyclopropyl-7,9-dimethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   N-[1-(5-fluoropyrimidin-2-yl)azetidin-3-yl]-3,4-dimethyl-pyrimido[4′,5′:4,5]furo[2,3-c]pyridazin-8-amine;   1-[4-[[(3,4-dimethylpyrimido[4′,5′:4,5]furo[2,3-c]pyridazin-8-yl)amino]methyl]phenyl]cyclobutanol;   2-[4-[[(3,4-dimethylpyrimido[4′,5′:4,5]furo[2,3-c]pyridazin-8-yl)amino]methyl]phenyl]propan-2-ol;   1-[3-[[(3,4-dimethylpyrimido[4′,5′:4,5]furo[2,3-c]pyridazin-8-yl)amino]methyl]phenyl]cyclobutanol;   2-[3-[[(3,4-dimethylpyrimido[4′,5′:4,5]furo[2,3-c]pyridazin-8-yl)amino]methyl]phenyl]propan-2-ol;   N-cyclopropyl-3,4-dimethyl-pyrimido[4′,5′:4,5]furo[2,3-c]pyridazin-8-amine;   N-cyclobutyl-3,4-dimethyl-pyrimido[4′,5′:4,5]furo[2,3-c]pyridazin-8-amine;   N-cyclopentyl-3,4-dimethyl-pyrimido[4′,5′:4,5]furo[2,3-c]pyridazin-8-amine;   3,4-dimethyl-N-(2-oxaspiro[3.3]heptan-6-yl)pyrimido[4′,5′:4,5]furo[2,3-c]pyridazin-8-amine;   N-(3,3-difluorocyclobutyl)-3,4-dimethyl-pyrimido[4′,5′:4,5]furo[2,3-c]pyridazin-8-amine;   3,4-dimethyl-8-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimido[4′,5′:4,5]furo[2,3-c]pyridazine;   2-[5-[[(3,4-dimethylpyrimido[4′,5′:4,5]furo[2,3-c]pyridazin-8-yl)amino]methyl]-2-pyridyl]propan-2-ol;   N-[(3-fluoro-4-methoxy-phenyl)methyl]-3,4-dimethyl-pyrimido[4′,5′:4,5]furo[2,3-c]pyridazin-8-amine;   2-[4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]phenyl]propan-2-ol;   N-(2-(4-methoxyphenyl)cyclopropyl)-3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   N-(3-fluoro-4-methoxybenzyl)-3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   N-(4-(2-fluoropyridin-3-yl)benzyl)-3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   1-(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)-3-methyl-azetidin-3-ol;   N-[1-(2,3-difluorophenyl)pyrrolidin-3-yl]-3,4-dimethyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   N-[1-(3-chloro-5-cyclopropyl-2-pyridyl)azetidin-3-yl]-3,4-dimethyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   N-[1-(6-cyclopropyl-2-methyl-3-pyridyl)azetidin-3-yl]-3,4-dimethyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   N-[1-(5-fluoropyrimidin-2-yl)azetidin-3-yl]-3,4-dimethyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   N-[1-(2,5-dichloro-4-pyridyl)azetidin-3-yl]-3,4-dimethyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   N-[1-(5-cyclopropylpyrazin-2-yl)azetidin-3-yl]-3,4-dimethyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   tert-butyl 3-[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]azetidine-1-carboxylate;   N-(azetidin-3-yl)-3,4-dimethyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   N-[1-(5-isopropoxypyrimidin-2-yl)azetidin-3-yl]-3,4-dimethyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   N-[[6-(difluoromethoxy)-3-pyridyl]methyl]-3,4-dimethyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   N-[[4-(cyclopropylmethoxy)-3-fluoro-phenyl]methyl]-3,4-dimethyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   3,4-dimethyl-N-[[4-(pentafluoro-16-sulfanyl)phenyl]methyl]pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   3,4-dimethyl-N-[(4-methylsulfonylphenyl)methyl]pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   N-[(3,4-dimethoxyphenyl)methyl]-3,4-dimethyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   1-(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)azetidin-3-amine;   N-[1-(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)azetidin-3-yl]acetamide;   N-[1-(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)azetidin-3-yl]pyridine-4-carboxamide;   1-(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)-3-methyl-azetidin-3-amine;   (3R)-1-(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)pyrrolidin-3-amine;   2-[4-[1-[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]ethyl]phenyl]propan-2-ol;   1-[4-[1-[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]ethyl]phenyl]cyclobutanol;   1-[3-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]phenyl]cyclobutanol;   3-cyclopropyl-1-(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)azetidin-3-ol;   1-(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)azetidine-3-carboxamide;   8-(2,6-diazaspiro[3.3]heptan-2-yl)-3,4-dimethyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine;   2-[5-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]-2-pyridyl]propan-2-ol;   2-[4-[[(3,4-dimethylpyrimido[4,5]thieno[1,2-c]pyridazin-8-yl)amino]methyl]-3-fluoro-phenyl]propan-2-ol;   3,4-dimethyl-N-[[4-(morpholinomethyl)phenyl]methyl]pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   3,4-dimethyl-N-[[4-(2-pyridyl)phenyl]methyl]pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   3,4-dimethyl-N-[[4-(2-pyridyloxy)phenyl]methyl]pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   3,4-dimethyl-N-[[4-(4-methylpiperazin-1-yl)phenyl]methyl]pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   2-[4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]-2-fluoro-phenyl]propan-2-ol;   2-[4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]phenyl]-1,1,1-trifluoro-propan-2-ol;   1-[4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]phenyl]cyclobutanol;   2-[4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]-3-fluoro-phenyl]butan-2-ol;   2-[4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]phenyl]butan-2-ol;   2-[1-[[4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]phenyl]methyl]pyrrolidin-2-yl]propan-2-ol;   3,4-dimethyl-N-[(4-piperazin-1-ylphenyl)methyl]pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   N-[2-(3,4-difluorophenyl)cyclopropyl]-3,4-dimethyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   N-[[4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl]methyl]-3,4-dimethyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   N-[(2,6-difluoro-4-methoxy-phenyl)methyl]-3,4-dimethyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   [4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]phenyl]-pyrrolidin-1-yl-methanone;   [4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]phenyl]-morpholino-methanone;   [4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]phenyl]-(2-oxa-6-azaspiro[3.3]heptan-6-yl)methanone;   [4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]phenyl]-(1-piperidyl)methanone;   3-azabicyclo[3.1.0]hexan-3-yl-[4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]phenyl]methanone;   [4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]phenyl]-[3-(methoxymethyl)azetidin-1-yl]methanone;   [4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]phenyl]-[(3S)-3-fluoropyrrolidin-1-yl]methanone;   [4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]phenyl]-[(3R)-3-fluoropyrrolidin-1-yl]methanone;   (4,4-difluoro-1-piperidyl)-[4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]phenyl]methanone;   azetidin-1-yl-[4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]phenyl]methanone;   N-cyclopropyl-4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]-N-methyl-benzamide;   N-cyclopropyl-4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]benzamide;   (3,3-difluoropyrrolidin-1-yl)-[4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]phenyl]methanone;   N-[(4-methoxyphenyl)methyl]-3,4-dimethyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   N-[(3,5-difluoro-4-methoxy-phenyl)methyl]-3,4-dimethyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   2-[4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)-methyl-amino]methyl]phenyl]propan-2-ol;   2-[1-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]-3-bicyclo[1.1.1]pentanyl]propan-2-ol;   N-(3-fluoro-1-bicyclo[1.1.1]pentanyl)-3,4-dimethyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   methyl 1-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]bicyclo[1.1.1]pentane-3-carboxylate;   N-[1-(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)azetidin-3-yl]-3-isocyano-pyridin-2-amine;   2-[2-(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)isoindolin-5-yl]propan-2-ol;   1-cyclopropyl-1-[4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]phenyl]ethanol;   3-[4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]phenyl]pentan-3-ol;   4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]-N-methyl-benzamide;   3,4-dimethyl-N-[[6-(trifluoromethyl)-3-pyridyl]methyl]pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   N-[(4,6-dimethyl-3-pyridyl)methyl]-3,4-dimethyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   N-[(5,6-dimethyl-3-pyridyl)methyl]-3,4-dimethyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]-N-(1-methylcyclopropyl)benzamide;   N-cyclobutyl-4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]benzamide;   4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]-N-(3-fluorocyclobutyl)benzamide;   N-(3,3-difluorocyclobutyl)-4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]benzamide;   N-cyclopentyl-4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]benzamide;   4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]-N-(2-oxaspiro[3.3]heptan-6-yl)benzamide;   4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]-N-isopropyl-benzamide;   (3,3-difluoroazetidin-1-yl)-[4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]phenyl]methanone;   4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]-N-[(1R)-2,2,2-trifluoro-1-methyl-ethyl]benzamide;   4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]-N-(3-hydroxy-1,2,2-trimethyl-propyl)benzamide;   N-cyclohexyl-4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]benzamide;   N-(4,4-dimethylcyclohexyl)-4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]benzamide;   N-[1-(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)azetidin-3-yl]-2,3-difluoro-pyridin-4-amine;   N-[2-(3,5-dichloro-2-pyridyl)-2-azaspiro[3.3]heptan-6-yl]-3,4-dimethyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   N-[2-(3-chloro-5-fluoro-2-pyridyl)-2-azaspiro[3.3]heptan-6-yl]-3,4-dimethyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   N-[2-(5-chloro-3-fluoro-2-pyridyl)-2-azaspiro[3.3]heptan-6-yl]-3,4-dimethyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   3,4-dimethyl-N-[2-(5-methylpyrimidin-2-yl)-2-azaspiro[3.3]heptan-6-yl]pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   3,4-dimethyl-N-[2-[(2-methylpyrimidin-5-yl)methyl]-2-azaspiro[3.3]heptan-6-yl]pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   3,4-dimethyl-N-[2-[[2-(trifluoromethyl)pyrimidin-5-yl]methyl]-2-azaspiro[3.3]heptan-6-yl]pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   1-[6-[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]-2-azaspiro[3.3]heptan-2-yl]-3,3,3-trifluoro-propan-1-one;   [6-[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]-2-azaspiro[3.3]heptan-2-yl]-tetrahydropyran-4-yl-methanone;   1-[6-[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]-2-azaspiro[3.3]heptan-2-yl]hexan-1-one;   2-[1-(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)pyrrolidin-3-yl]propan-2-ol;   [6-[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]-2-azaspiro[3.3]heptan-2-yl]-[4-(trifluoromethyl)phenyl]methanone;   1-(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)-N-[4-(trifluoromethyl)phenyl]pyrrolidine-3-carboxamide;   1-(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)-N-(2-pyridyl)pyrrolidine-3-carboxamide;   2-[5-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]-2-fluoro-phenyl]propan-2-ol;   N-cyclopropyl-5-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]-2-fluoro-benzamide;   N-cyclobutyl-5-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]-2-fluoro-benzamide;   N-cyclopentyl-5-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]-2-fluoro-benzamide;   5-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]-2-fluoro-N-isopropyl-benzamide;   5-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]-2-fluoro-N-isobutyl-benzamide;   N-(2,2-dimethylcyclopropyl)-5-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]-2-fluoro-benzamide;   5-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]-2-fluoro-N-[(1R)-2,2,2-trifluoro-1-methyl-ethyl]benzamide;   5-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]-2-fluoro-N-(3-fluorocyclobutyl)benzamide;   N-(3,3-difluorocyclobutyl)-5-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]-2-fluoro-benzamide;   5-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]-2-fluoro-N-(3-hydroxy-1,2,2-trimethyl-propyl)benzamide;   5-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]-2-fluoro-N-(2-methoxyethyl)benzamide;   5-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]-2-fluoro-N-methyl-benzamide;   2-[2-chloro-4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]phenyl]propan-2-ol;   2-[3-chloro-4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]phenyl]propan-2-ol;   3,4-dimethyl-N-[[4-(2-thienyl)phenyl]methyl]pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   3,4-dimethyl-N-[[4-(1H-pyrrol-2-yl)phenyl]methyl]pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   3,4-dimethyl-N-[[4-(1-methylpyrazol-3-yl)phenyl]methyl]pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   3,4-dimethyl-N-[[4-(2-methylpyrazol-3-yl)phenyl]methyl]pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   4-[3-(methoxymethyl)azetidin-1-yl]-7,9-dimethyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine;   6-(7,9-dimethylpyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-yl)-2-oxa-6-azaspiro[3.3]heptane;   4-(3-azabicyclo[3.1.0]hexan-3-yl)-7,9-dimethyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine;   4-(azetidin-1-yl)-7,9-dimethyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine;   4-(3,3-difluoroazetidin-1-yl)-7,9-dimethyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine;   7,9-dimethyl-4-pyrrolidin-1-yl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine;   N-cyclobutyl-7,9-dimethyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine;   7,9-dimethyl-4-[3-(4-pyridyl)azetidin-1-yl]pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine;   N-[2-(4-methoxyphenyl)cyclopropyl]-7,9-dimethyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine;   N-[[6-(difluoromethoxy)-3-pyridyl]methyl]-7,9-dimethyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine;   7,9-dimethyl-N-[(4-methylsulfonylphenyl)methyl]pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine;   7,9-dimethyl-N-[(2-methylpyrimidin-5-yl)methyl]pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine;   2-[4-[[(7,9-dimethylpyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-yl)amino]methyl]phenyl]propan-2-ol;   7,9-dimethyl-N-[1-[5-(trifluoromethyl)pyrimidin-2-yl]azetidin-3-yl]pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine;   1-[4-[3-[(7,9-dimethylpyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-yl)amino]azetidin-1-yl]-2-pyridyl]cyclobutanol;   3-chloro-4-methyl-8-pyrrolidin-1-yl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine;   3-chloro-N-cyclobutyl-4-methyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   3-chloro-N-[[6-(difluoromethoxy)-3-pyridyl]methyl]-4-methyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   3-chloro-N-[(3-fluoro-4-methoxy-phenyl)methyl]-4-methyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   2-[4-[[(3-chloro-4-methyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]phenyl]propan-2-ol;   3-chloro-4-methyl-N-[1-[5-(trifluoromethyl)pyrimidin-2-yl]azetidin-3-yl]pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   8-chloro-9-methyl-4-pyrrolidin-1-yl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine;   8-chloro-4-(3,3-difluoropyrrolidin-1-yl)-9-methyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine;   1-(8-chloro-9-methyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-yl)azetidine-3-carbonitrile;   8-chloro-4-[3-(methoxymethyl)azetidin-1-yl]-9-methyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine;   4-(3-azabicyclo[3.1.0]hexan-3-yl)-8-chloro-9-methyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine;   8-chloro-4-(3-fluoropyrrolidin-1-yl)-9-methyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine;   4-(azetidin-1-yl)-8-chloro-9-methyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine;   6-(8-chloro-9-methyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-yl)-2-oxa-6-azaspiro[3.3]heptane;   8-chloro-4-(3,3-difluoroazetidin-1-yl)-9-methyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine;   8-chloro-9-methyl-4-[3-(4-pyridyl)azetidin-1-yl]pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine;   8-chloro-N-[1-(5-fluoropyrimidin-2-yl)azetidin-3-yl]-9-methyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine;   8-chloro-9-methyl-N-(1-methylcyclopropyl)pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine;   8-chloro-N-(2,2-dimethylcyclopropyl)-9-methyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine;   8-chloro-N-cyclobutyl-9-methyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine;   4-[[(8-chloro-9-methyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-yl)amino]methyl]-N,N-dimethyl-benzamide;   8-chloro-N-[(3,5-dimethoxyphenyl)methyl]-9-methyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine;   8-chloro-N-[1-(2,5-dichloro-4-pyridyl)azetidin-3-yl]-9-methyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine;   8-chloro-9-methyl-N-[[4-(morpholinomethyl)phenyl]methyl]pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine;   8-chloro-N-[(2,2-dimethyl-3H-benzofuran-5-yl)methyl]-9-methyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine;   8-chloro-N-(1,3-dihydroisobenzofuran-5-ylmethyl)-9-methyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine;   8-chloro-N-(6,7-dihydro-5H-cyclopenta[b]pyridin-3-ylmethyl)-9-methyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine;   8-chloro-N-[2-(4-methoxyphenyl)cyclopropyl]-9-methyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine;   8-chloro-9-methyl-N-[(4-methylsulfonylphenyl)methyl]pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine;   8-chloro-9-methyl-N-[(2-methylpyrimidin-5-yl)methyl]pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine;   1-[4-[3-[(8-chloro-7,9-dimethyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-yl)amino]azetidin-1-yl]-2-pyridyl]cyclobutanol;   2-[4-[[(8-chloro-7,9-dimethyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-yl)amino]methyl]phenyl]propan-2-ol;   8-chloro-7,9-dimethyl-N-[1-[5-(trifluoromethyl)pyrimidin-2-yl]azetidin-3-yl]pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   8-chloro-7,9-dimethyl-4-pyrrolidin-1-yl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine;   8-chloro-N-cyclobutyl-7,9-dimethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   8-chloro-N-(3,3-difluorocyclobutyl)-7,9-dimethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   8-chloro-N-cyclopropyl-7,9-dimethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   8-chloro-N-cyclopentyl-7,9-dimethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   8-chloro-N-[2-(3,4-difluorophenyl)cyclopropyl]-7,9-dimethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   8-chloro-7,9-dimethyl-N-[(4-methylsulfonylphenyl)methyl]pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   8-chloro-N-(cyclobutylmethyl)-7,9-dimethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   8-chloro-N-(3-methoxypropyl)-7,9-dimethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   2-[4-[[(8-chloro-7,9-dimethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-yl)amino]methyl]phenyl]propan-2-ol;   8-chloro-7,9-dimethyl-N-[(2-methylpyrimidin-5-yl)methyl]pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   8-chloro-N-[(3-fluoro-4-methoxy-phenyl)methyl]-7,9-dimethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   8-chloro-7,9-dimethyl-4-pyrrolidin-1-yl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine;   8-chloro-4-(3,3-difluoropyrrolidin-1-yl)-7,9-dimethyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine;   1-(8-chloro-7,9-dimethyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-yl)azetidine-3-carbonitrile;   4-(3-azabicyclo[3.1.0]hexan-3-yl)-8-chloro-7,9-dimethyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine;   8-chloro-4-(3-fluoropyrrolidin-1-yl)-7,9-dimethyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine;   4-(azetidin-1-yl)-8-chloro-7,9-dimethyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine;   6-(8-chloro-7,9-dimethyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-yl)-2-oxa-6-azaspiro[3.3]heptane;   8-chloro-4-(3,3-difluoroazetidin-1-yl)-7,9-dimethyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine;   8-chloro-7,9-dimethyl-4-[3-(4-pyridyl)azetidin-1-yl]pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine;   8-chloro-N-[1-(5-fluoropyrimidin-2-yl)azetidin-3-yl]-7,9-dimethyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine;   8-chloro-7,9-dimethyl-N-(1-methylcyclopropyl)pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine;   8-chloro-N-(2,2-dimethylcyclopropyl)-7,9-dimethyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine;   8-chloro-N-cyclobutyl-7,9-dimethyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine;   8-chloro-N-[(3,4-dimethoxyphenyl)methyl]-7,9-dimethyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine;   8-chloro-N-[(4-imidazol-1-ylphenyl)methyl]-7,9-dimethyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine;   8-chloro-7,9-dimethyl-N-[[4-(morpholinomethyl)phenyl]methyl]pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine;   8-chloro-N-[(2,2-dimethyl-3H-benzofuran-5-yl)methyl]-7,9-dimethyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine;   8-chloro-7,9-dimethyl-N-[(2-methylpyrimidin-5-yl)methyl]pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine;   8-chloro-7,9-dimethyl-N-[1-[5-(trifluoromethyl)pyrimidin-2-yl]azetidin-3-yl]pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine;   8-chloro-7,9-dimethyl-N-(tetrahydrofuran-3-ylmethyl)pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine;   8-chloro-N-(3,3-difluorocyclobutyl)-7,9-dimethyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine;   8-chloro-N-cyclopropyl-7,9-dimethyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine;   1-[4-[[(8-chloro-7,9-dimethyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-yl)amino]methyl]phenyl]cyclobutanol;   1-[3-[[(8-chloro-7,9-dimethyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-yl)amino]methyl]phenyl]cyclobutanol;   2-[4-[[(8-chloro-7,9-dimethyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-yl)amino]methyl]-2-fluoro-phenyl]propan-2-ol;   2-[4-[[(8-chloro-7,9-dimethyl-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-yl)amino]methyl]-3-fluoro-phenyl]propan-2-ol;   2-[4-[[(3-methoxy-4-methyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]phenyl]propan-2-ol;   3-methoxy-4-methyl-8-pyrrolidin-1-yl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine;   3-methoxy-4-methyl-N-[1-[5-(trifluoromethyl)pyrimidin-2-yl]azetidin-3-yl]pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   8-chloro-N-(2,2-dimethylcyclopropyl)-7,9-dimethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   8-chloro-N-(2-ethylcyclopropyl)-7,9-dimethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   8-chloro-7,9-dimethyl-N-propyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   8-chloro-N-isobutyl-7,9-dimethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   8-chloro-N-ethyl-7,9-dimethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   2-[3-[[(8-chloro-7,9-dimethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-yl)amino]methyl]phenyl]propan-2-ol;   N-[1-(5-fluoropyrimidin-2-yl)azetidin-3-yl]-7,9-dimethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   N-[1-(2,5-dichloro-4-pyridyl)azetidin-3-yl]-7,9-dimethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   7,9-dimethyl-N-[1-[5-(trifluoromethyl)pyrazin-2-yl]azetidin-3-yl]pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   7,9-dimethyl-N-[(4-methylsulfonylphenyl)methyl]pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   N-cyclobutyl-7,9-dimethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   N-[2-(3,4-difluorophenyl)cyclopropyl]-7,9-dimethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   N-cyclopropyl-7,9-dimethyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidin-4-amine;   7,9-dimethyl-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine;   1-[4-[[(3,4-dimethylpyrimido[4′,5′:4,5]furo[2,3-c]pyridazin-8-yl)amino]methyl]phenyl]cyclobutanol;   2-[4-[[(3,4-dimethylpyrimido[4′,5′:4,5]furo[2,3-c]pyridazin-8-yl)amino]methyl]phenyl]propan-2-ol;   1-[3-[[(3,4-dimethylpyrimido[4′,5′:4,5]furo[2,3-c]pyridazin-8-yl)amino]methyl]phenyl]cyclobutanol;   2-[3-[[(3,4-dimethylpyrimido[4′,5′:4,5]furo[2,3-c]pyridazin-8-yl)amino]methyl]phenyl]propan-2-ol;   N-cyclopropyl-3,4-dimethyl-pyrimido[4′,5′:4,5]furo[2,3-c]pyridazin-8-amine;   N-cyclobutyl-3,4-dimethyl-pyrimido[4′,5′:4,5]furo[2,3-c]pyridazin-8-amine;   N-cyclopentyl-3,4-dimethyl-pyrimido[4′,5′:4,5]furo[2,3-c]pyridazin-8-amine;   3,4-dimethyl-N-(2-oxaspiro[3.3]heptan-6-yl)pyrimido[4′,5′:4,5]furo[2,3-c]pyridazin-8-amine;   N-(3,3-difluorocyclobutyl)-3,4-dimethyl-pyrimido[4′,5′:4,5]furo[2,3-c]pyridazin-8-amine;   3,4-dimethyl-8-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimido[4′,5′:4,5]furo[2,3-c]pyridazine;   2-[5-[[(3,4-dimethylpyrimido[4′,5′:4,5]furo[2,3-c]pyridazin-8-yl)amino]methyl]-2-pyridyl]propan-2-ol;   N-[(4-methoxyphenyl)methyl]-3,4-dimethyl-pyrimido[4′,5′:4,5]furo[2,3-c]pyridazin-8-amine;   N-[(2,6-difluoro-4-methoxy-phenyl)methyl]-3,4-dimethyl-pyrimido[4′,5′:4,5]furo[2,3-c]pyridazin-8-amine;   N-[(3,5-difluoro-4-methoxy-phenyl)methyl]-3,4-dimethyl-pyrimido[4′,5′:4,5]furo[2,3-c]pyridazin-8-amine;   2-[4-[[(3,4-dimethylpyrimido[4′,5′:4,5]furo[2,3-c]pyridazin-8-yl)amino]methyl]phenyl]-1,1,1-trifluoro-propan-2-ol;   N-[1-(3,4-difluorophenyl)azetidin-3-yl]-3,4-dimethyl-pyrimido[4′,5′:4,5]furo[2,3-c]pyridazin-8-amine 2-chloro-N-cyclopropyl-4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]benzamide;   N-[1-(3,5-dichloro-2-pyridyl)azetidin-3-yl]-3,4-dimethyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   N-[1-(5-chloro-3-fluoro-2-pyridyl)azetidin-3-yl]-3,4-dimethyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   2-chloro-N-cyclobutyl-4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]benzamide;   2-chloro-N-cyclopentyl-4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]benzamide;   2-chloro-4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]-N-isopropyl-benzamide;   2-chloro-N-(2,2-dimethylcyclopropyl)-4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]benzamide;   2-chloro-4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]-N-[(1R)-2,2,2-trifluoro-1-methyl-ethyl]benzamide;   2-chloro-4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]-N-(3-fluorocyclobutyl)benzamide;   2-chloro-N-(3,3-difluorocyclobutyl)-4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]benzamide;   2-chloro-4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]-N-[1-[1-(hydroxymethyl)cyclopropyl]ethyl]benzamide;   2-chloro-4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]-N-(2-methoxyethyl)benzamide;   2-chloro-4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]-N-methyl-benzamide;   3,4-dimethyl-N-[(4-thiazol-2-ylphenyl)methyl]pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   3,4-dimethyl-N-[(3-pyrimidin-2-ylphenyl)methyl]pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   3,4-dimethyl-N-[(3-pyrazol-1-ylphenyl)methyl]pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   8-[(3S)-3-[(2-chloro-4-pyridyl)oxy]pyrrolidin-1-yl]-3,4-dimethyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine;   3,4-dimethyl-8-[(3S)-3-[(2-methyl-4-pyridyl)oxy]pyrrolidin-1-yl]pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine;   3,4-dimethyl-8-[(3S)-3-[[2-(trifluoromethyl)-4-pyridyl]oxy]pyrrolidin-1-yl]pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine;   3,4-dimethyl-8-[(3S)-3-(3-pyridyloxy)pyrrolidin-1-yl]pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine;   5-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)(methyl)amino]methyl]-2-fluoro-N-methyl-benzamide;   2-[4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]-2-methyl-phenyl]propan-2-ol;   2-[4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]-3-methyl-phenyl]propan-2-ol;   8-[(3R)-3-[(2-chloro-4-pyridyl)oxy]pyrrolidin-1-yl]-3,4-dimethyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine;   3,4-dimethyl-8-[(3R)-3-[[2-(trifluoromethyl)-4-pyridyl]oxy]pyrrolidin-1-yl]pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine;   3,4-dimethyl-8-[(3R)-3-[(2-methyl-4-pyridyl)oxy]pyrrolidin-1-yl]pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine;   3-[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]-1-(4-fluorophenyl)cyclobutanol;   3,4-dimethyl-8-[(3R)-3-(3-pyridyloxy)pyrrolidin-1-yl]pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine;   3,4-dimethyl-N-[[4-(1-methylpyrrol-2-yl)phenyl]methyl]pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   N-[[4-(2,4-dimethylpyrazol-3-yl)phenyl]methyl]-3,4-dimethyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   N-[[4-(2-ethylpyrazol-3-yl)phenyl]methyl]-3,4-dimethyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   N-[[2-fluoro-4-(2-methylpyrazol-3-yl)phenyl]methyl]-3,4-dimethyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   3,4-dimethyl-N-[(4-pyrazol-1-ylphenyl)methyl]pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   8-[4-[(2-chloro-4-pyridyl)oxy]-1-piperidyl]-3,4-dimethyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine;   8-[3-[(2-chloro-4-pyridyl)oxymethyl]pyrrolidin-1-yl]-3,4-dimethyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine;   8-[3-[(2-chloro-4-pyridyl)oxymethyl]azetidin-1-yl]-3,4-dimethyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine;   8-[3-[(2-chloro-4-pyridyl)oxy]azetidin-1-yl]-3,4-dimethyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine;   3,4-dimethyl-8-(3-pyrazin-2-yloxyazetidin-1-yl)pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine;   8-[3-[(4,6-dimethyl-3-pyridyl)oxy]azetidin-1-yl]-3,4-dimethyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine;   1,1,1,3,3,3-hexadeuterio-2-[4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]phenyl]propan-2-ol;   2-[(3R)-1-(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)pyrrolidin-3-yl]propan-2-ol;   2-[(3S)-1-(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)pyrrolidin-3-yl]propan-2-ol;   5-[1-(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)azetidin-3-yl]oxypyridine-2-carbonitrile;   3,4-dimethyl-8-[3-(3-pyridyloxy)azetidin-1-yl]pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine;   3,4-dimethyl-8-[3-(1-methylpyrazol-4-yl)oxyazetidin-1-yl]pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine;   3,4-dimethyl-8-[(3S,4R)-3-methyl-4-[(2-methyl-4-pyridyl)oxy]pyrrolidin-1-yl]pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine;   3,4-dimethyl-8-[(3S)-3-(2-pyridyloxy)pyrrolidin-1-yl]pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine;   3,4-dimethyl-8-[(3S)-3-[[5-(trifluoromethyl)-2-pyridyl]oxy]pyrrolidin-1-yl]pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine;   3,4-dimethyl-8-[(3S)-3-pyrazin-2-yloxypyrrolidin-1-yl]pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine;   3,4-dimethyl-8-[(3S)-3-[[6-(trifluoromethyl)-3-pyridyl]oxy]pyrrolidin-1-yl]pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine;   4-[(3S)-1-(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)pyrrolidin-3-yl]oxybenzonitrile;   3,4-dimethyl-8-[(3S)-3-[(6-methyl-3-pyridyl)oxy]pyrrolidin-1-yl]pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine;   3,4-dimethyl-8-[(2R,4S)-2-methyl-4-[(2-methyl-4-pyridyl)oxy]pyrrolidin-1-yl]pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine;   3,4-dimethyl-8-[3-(4-pyridyloxy)-3-(trifluoromethyl)pyrrolidin-1-yl]pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazine;   N-[[4-(1-methoxy-1-methyl-ethyl)phenyl]methyl]-3,4-dimethyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   2-[4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]-3-fluoro-phenyl]-2-methyl-propan-1-ol;   2-[4-[dideuterio-[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]phenyl]propan-2-ol;   3,4-dimethyl-N-[[4-[1-methyl-1-(trideuteriomethoxy)ethyl]phenyl]methyl]pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   N-[[4-(1-amino-1-methyl-ethyl)phenyl]methyl]-3,4-dimethyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   N-[(1,1-dimethyl-3H-isobenzofuran-5-yl)methyl]-3,4-dimethyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   2-[4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]phenyl]propane-1,2-diol;   3,4-dimethyl-N-[[4-(oxetan-3-yl)phenyl]methyl]pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-amine;   2-[4-[[(3,4-dimethylpyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl)amino]methyl]phenyl]-2-methyl-propan-1-ol;   [8-[[4-(2-hydroxypropan-2-yl)benzyl]amino]-4-methyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-3-yl]methyl acetate; and   2-[4-[[[3-(hydroxymethyl)-4-methyl-pyrimido[4′,5′:4,5]thieno[2,3-c]pyridazin-8-yl]amino]methyl]phenyl]propan-2-ol,   or a pharmaceutically acceptable salt thereof.   
     
     
         43 . The compound of any one of  claims 1 - 41 , wherein the compound is isotopically labeled. 
     
     
         44 . The compound of  claim 43 , wherein R 1  is deuterium. 
     
     
         45 . The compound of  claim 43 , wherein R 3  is deuterium. 
     
     
         46 . The compound of  claim 43 , wherein R 6  is deuterium. 
     
     
         47 . The compound of  claim 43 , wherein
 R 4  is hydrogen;   R 5  is —(CR c R d ) n —Y;   R c  is deuterium; and   R d  is deuterium.   
     
     
         48 . The compound of  claim 43 , wherein
 R 4  is hydrogen;   R 5  is —(CR c R d ) n —Y;   n is 1;   Y is phenyl that is substituted with a C 1 -C 4 -hydroxyalkyl or a C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl group, wherein at least one hydrogen of the C 1 -C 4 -hydroxyalkyl or a C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl group is deuterium.   
     
     
         49 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of  claims 1 - 48 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         50 . A method for treating a neurological and/or psychiatric disorder associated with muscarinic acetylcholine receptor dysfunction in a mammal, comprising a step of administering to the mammal a therapeutically effective amount a compound of any one of  claims 1 - 48 , or pharmaceutically acceptable salt thereof. 
     
     
         51 . The method of  claim 50 , wherein the disorder is associated with a mAChR M 4  dysfunction. 
     
     
         52 . The method of  claim 50 , wherein the disorder is a neurological and/or psychiatric disorder associated with mAChR M 4  dysfunction. 
     
     
         53 . The method of  claim 50 , wherein the disorder is selected from Alzheimer's disease, schizophrenia, a sleep disorder, a pain disorder, and a cognitive disorder. 
     
     
         54 . The method of  claim 53 , wherein the disorder is Alzheimer's disease. 
     
     
         55 . The method of  claim 50 , wherein the disorder is selected from psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders such as severe major depressive disorder; mood disorders associated with psychotic disorders, acute mania, depression associated with bipolar disorder, mood disorders associated with schizophrenia, behavioral manifestations of mental retardation, autistic disorder, movement disorders, Tourette's syndrome, akinetic-rigid syndrome, movement disorders associated with Parkinson's disease, tardive dyskinesia, drug induced and neurodegeneration based dyskinesias, attention deficit hyperactivity disorder, cognitive disorders, dementias, and memory disorders. 
     
     
         56 . A kit comprising a compound of any one of  claims 1 - 48 , or pharmaceutically acceptable salt thereof, and one or more of: (a) at least one agent known to increase mAChR M 4  activity; (b) at least one agent known to decrease mAChR M 4  activity; (c) at least one agent known to treat a disorder associated with cholinergic activity; (d) instructions for treating a disorder associated with cholinergic activity; (e) instructions for treating a disorder associated with mAChR M 4  receptor activity; and (f) instructions for administering the compound in connection with cognitive or behavioral therapy.