Substituted aminothiazoles as dgkzeta inhibitors for immune activation

Abstract

The present invention covers aminothiazole compounds of general formula (I): in which R1, R2, R3 and R4 are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment and/or prophylaxis of diseases, in particular of diacylglycerol kinase zeta (DGKζ) regulated disorders, as a sole agent or in combination with other active ingredients.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is a phenyl or 6-membered heteroaryl group optionally substituted, one, two, or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, hydroxy, cyano, nitro, C 1 -C 6 -alkyl, (phenyl)-(C 1 -C 3 -alkyl)-, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, (phenyl)-(C 1 -C 3 -alkoxy)-, C 1 -C 6 -haloalkoxy, and —N(R 5 )(R 6 ),
 wherein the phenyl groups in said (phenyl)-(C 1 -C 3 -alkyl)- and (phenyl)-(C 1 -C 3 -alkoxy)- groups are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, dimethylamino and trifluoromethoxy, 
 or two substituents attached to adjacent carbon atoms of said phenyl or 6-membered heteroaryl group together form a bivalent group selected from the group consisting of —(CH 2 ) 3 —, —(CH 2 ) 4 —, —(CH 2 ) 2 —O—, —(CH 2 ) 3 —O—, —CH 2 —O—CH 2 —, —(CH 2 ) 2 —O—CH 2 —, —O—CH 2 —O—, —O—CH 2 —CH 2 —O—, —O—CF 2 —O—, —O—CH 2 -CF 2 —O—, and —O—CF 2 —CF 2 —O—, or 
 
         R 1  is a 5-membered heteroaryl group optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, C 1 -C 3 -alkyl, and C 1 -C 3 -alkoxy;
 R 2  is 
 
       
       
         
           
           
               
               
           
         
         
           
             wherein “*” indicates the point of attachment to the nitrogen atom to which R 2  is attached; 
           
           R 3  is methyl or —NH 2;    
         
         R 4  is a 5-membered heteroaryl group optionally substituted one or two times,
 wherein each substituent is independently selected from the group consisting of a halogen atom, C 1 -C 6 -alkyl, ((R 9 )O)—(C 1 -C 3 -alkyl)-, ((R 10 )(R 11 )N)—(C 1 -C 3 -alkyl)-, (C 3 -C 7 -cycloalkyl)-(C 1 -C 3 -alkyl)-, C 3 -C 7 -cycloalkyl, —OR 9 , —N(R 10 )(R 11 ), —C(═O)—N(R 15 )(R 16 ), —C(═O)—OR 17 , phenyl and 5- or 6-membered heteroaryl,
 wherein the phenyl group and the 5- or 6-membered heteroaryl group are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl, ((R 22 )(R 23 )N)—C 1 -C 3 -alkyl, —OR 9 , —N(R 10 )(R 11 ), and —C(═O)—N(R 15 )(R 16 ); 
 
 
         R 5  and R 6  are each independently selected from the group consisting of hydrogen atom, C 1 -C 4 -alkyl, (C 1 -C 4 -alkyl)-C(═O)—, C 3 -C 4 -cycloalkyl and (phenyl)-(C 1 -C 3 -alkyl)-, or 
         R 5  and R 6 , together with the nitrogen atom to which they are attached, form a monocyclic nitrogen containing 4- to 7-membered heterocycloalkyl group which is optionally substituted one, two or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, oxo, hydroxy, C 1 -C 4 -alkyl, (C 1 -C 4 -alkyl)-C(═O)—, C 3 -C 4 -cycloalkyl and C 1 -C 4 -alkoxy;
 R 7  is a hydrogen atom or a C 1 -C 2 -alkyl group; 
 R 8  is selected from the group consisting of —C(═O)—NH 2  and —S(═O) 2 —NH 2 ; 
 
         R 9  selected from the group consisting of a hydrogen atom, C 1 -C 6 -alkyl, (C 3 -C 7 -cycloalkyl)-(C 1 -C 3 -alkyl)-, (phenyl)-(C 1 -C 3 -alkyl)-, (5- or 6-membered heteroaryl)-(C 1 -C 3 -alkyl)-, C 1 -C 6 -haloalkyl, C 2 -C 4 -hydroxyalkyl, (C 1 -C 3 -alkoxy)-C 2 -C 3 -alkyl-, ((C 1 -C 3 -alkyl)-C(═O)—O)—C 2 -C 3 -alkyl-, —C(R 18 )(R 19 )—C(═O)—OR 17 , —C(R 18 )(R 19 )—C(═O)—N(R 20 )(R 21 ), —C(═O)—N(R 20 )(R 21 ), C 3 -C 7 -cycloalkyl, phenyl and 5- or 6-membered heteroaryl group,
 wherein C 3 -C 7 -cycloalkyl, and the C 3 -C 7 -cycloalkyl within said (C 3 -C 7 -cycloalkyl)-(C 1 -C 3 -alkyl)— group is optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, oxo, cyano, C 1 -C 2 -alkyl and C 1 -C 2 -haloalkyl, 
 and wherein the phenyl group within said (phenyl)-(C 1 -C 3 -alkyl)— group and said phenyl group itself, and the 5- or 6-membered heteroaryl group within said (5- or 6-membered heteroaryl)-(C 1 -C 3 -alkyl)— group and said 5- or 6-membered heteroaryl group itself, are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, dimethylamino and trifluoromethoxy; 
 
         R 10  and R 11  are each independently selected from the group consisting of a hydrogen atom, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 2 -C 4 -hydroxyalkyl, (C 1 -C 3 -alkoxy)-C 2 -C 3 -alkyl-, ((R 22 )(R 23 )N)—C 2 -C 3 -alkyl, (C 3 -C 7 -cycloalkyl)-(C 1 -C 3 -alkyl)-, (C 1 -C 4 -alkyl)-C(═O)—, C 3 -C 7 -cycloalkyl, (C 3 -C 7 -cycloalkyl)-C(═O)—, (phenyl)-(C 1 -C 3 -alkyl)-, (phenyl)-(C 1 -C 3 -alkyl)-C(═O)—, (phenyl)-(C 1 -C 3 -alkyl)-O—C(═O)—, phenyl, and a 5- or 6-membered heteroaryl group,
 wherein C 3 -C 7 -cycloalkyl, and the C 3 -C 7 -cycloalkyl within said (C 3 -C 7 -cycloalkyl)-(C 1 -C 3 -alkyl)- and (C 3 -C 7 -cycloalkyl)-C(═O)— groups are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, cyano, C 1 -C 2 -alkyl and C 1 -C 2 -haloalkyl,
 and wherein said phenyl and said 5- or 6-membered heteroaryl group, and the phenyl groups within said (phenyl)-(C 1 -C 3 -alkyl)-, (phenyl)-(C 1 -C 3 -alkyl)-C(═O)—, and (phenyl)-(C 1 -C 3 -alkyl)-O—C(═O)— groups, are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, dimethylamino and trifluoromethoxy, or 
 
 
         R 10  and R 11 , together with the nitrogen atom to which they are attached, form a monocyclic nitrogen containing 4- to 7-membered heterocycloalkyl group or a bicyclic nitrogen containing 5- to 11-membered heterocycloalkyl group, which are optionally substituted one, two or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, oxo, hydroxy, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, (C 1 -C 4 -alkyl)-C(═O)—, C 3 -C 7 -cycloalkyl, C 1 -C 4 -alkoxy, —N(R 22 )(R 23 ), and monocyclic 4- to 7-membered heterocycloalkyl; 
         R 15  and R 16  are each independently selected from the group consisting of a hydrogen atom, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -hydroxyalkyl, (cyano)-C 1 -C 4 -alkyl-, (C 1 -C 4 -alkoxy)-C 2 -C 3 -alkyl-, (C 1 -C 4 -haloalkoxy)-C 2 -C 3 -alkyl-, (phenoxy)-C 2 -C 3 -alkyl-, (C 3 -C 7 -cycloalkyl)-(C 1 -C 3 -alkyl)-, C 3 -C 7 -cycloalkyl, bicyclic C 5 -C 11 -cycloalkyl, monocyclic 4- to 7-membered heterocycloalkyl, (phenyl)-(C 1 -C 3 -alkyl)-, phenyl, and 5- or 6-membered heteroaryl,
 wherein C 3 -C 7 -cycloalkyl, the C 3 -C 7 -cycloalkyl within said (C 3 -C 7 -cycloalkyl)-(C 1 -C 3 -alkyl)- group, the bicyclic C 5 -C 11 -cycloalkyl and the monocyclic 4- to 7-membered heterocycloalkyl groups are optionally substituted one, two or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, oxo, hydroxy, C 1 -C 4 -alkyl, (C 1 -C 4 -alkyl)-C(═O)—, C 3 -C 4 -cycloalkyl and C 1 -C 4 -alkoxy, 
 and wherein the phenyl and the 5- or 6-membered heteroaryl groups, including the phenyl groups within said (phenoxy)-C 2 -C 3 -alkyl- and (phenyl)-(C 1 -C 3 -alkyl)- groups, are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, dimethylamino and trifluoromethoxy, or 
 
         R 15  and R 16 , together with the nitrogen atom to which they are attached, form a monocyclic nitrogen containing 4- to 7-membered heterocycloalkyl group which is optionally substituted one, two or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, oxo, hydroxy, C 1 -C 4 -alkyl, (C 1 -C 4 -alkyl)-C(═O)—, C 3 -C 4 -cycloalkyl and C 1 -C 4 -alkoxy;
 R 17  represents a C 1 -C 4 -alkyl group; 
 
         R 18  and R 19  are each independently a hydrogen atom or a C 1 -C 4 -alkyl group; 
         R 20  is selected from the group consisting of a hydrogen atom, C 1 -C 6 -alkyl, C 3 -C 4 -alkenyl, C 3 -C 4 -alkynyl, C 1 -C 3 -alkoxy, C 3 -C 7 -cycloalkyl, bicyclic C 5 -C 11 -cycloalkyl, adamantyl, monocyclic 4- to 7-membered heterocycloalkyl, bicyclic 5- to 11-membered heterocycloalkyl, phenyl, naphthyl, and 5- to 10-membered heteroaryl,
 wherein said C 1 -C 6 -alkyl group is optionally substituted one, two or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, hydroxy, cyano, C 1 -C 3 -alkoxy, —N(R 22 )(R 23 ), C 3 -C 7 -cycloalkyl, bicyclic C 5 -C 11 -cycloalkyl, adamantyl, monocyclic 4- to 7-membered heterocycloalkyl, bicyclic 5- to 11-membered heterocycloalkyl, phenyl, and 5- to 10-membered heteroaryl, said phenyl and 5- to 10-membered heteroaryl substituents themselves being optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, dimethylamino and trifluoromethoxy, 
 and wherein C 3 -C 7 -cycloalkyl, bicyclic C 5 -C 11 -cycloalkyl, adamantyl, monocyclic 4- to 7-membered heterocycloalkyl and bicyclic 5- to 11-membered heterocycloalkyl are optionally substituted one, two, or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, oxo, hydroxy, C 1 -C 4 -alkyl, (C 1 -C 4 -alkyl)-C(═O)—, C 3 -C 4 -cycloalkyl and C 1 -C 4 -alkoxy, 
 and wherein said phenyl, naphthyl and 5- to 10-membered heteroaryl groups are optionally substituted one, two, or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, —N(R 22 )(R 23 ) and —C(═O)—N(R 24 )(R 25 ), 
 R 21  is a hydrogen atom or a C 1 -C 4 -alkyl group, or 
 
         R 20  and R 21 , together with the nitrogen atom to which they are attached, form a monocyclic nitrogen containing 4- to 7-membered heterocycloalkyl group which is optionally benzocondensed, and which is optionally substituted one, two, or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, oxo, hydroxy, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, (phenyl)-(C 1 -C 3 -alkyl)-, (C 1 -C 4 -alkyl)-C(═O)—, C 3 -C 4 -cycloalkyl, C 1 -C 4 -alkoxy, C 1 -C 3 -haloalkoxy, —N(R 22 )(R 23 ) and —C(═O)—N(R 24 )(R 25 );
 R 22  and R 23  are each independently selected from the group consisting of a hydrogen atom, C 1 -C 2 -alky, and (C 1 -C 2 -alkyl)-C(═O)—, and 
 R 24  and R 25  are each independently a hydrogen atom or a C 1 -C 4 -alkyl group, 
 or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 
 
       
     
     
         2 . The compound according to  claim 1 , wherein:
 R 1  is a phenyl or pyridinyl group optionally substituted, one, two, or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, hydroxy, cyano, nitro, C 1 -C 4 -alkyl, (phenyl)-(C 1 -C 2 -alkyl)-, C 1 -C 4 -halo alkyl, C 1 -C 4 -alkoxy, (phenyl)-(C 1 -C 2 -alkoxy)-, C 1 -C 4 -haloalkoxy, and —N(R 5 )(R 6 ),
 wherein the phenyl groups in said (phenyl)-(C 1 -C 2 -alkyl)- and (phenyl)-(C 1 -C 2 -alkoxy)- groups are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, methyl, trifluoromethyl and methoxy, 
 or two substituents attached to adjacent carbon atoms of said phenyl or pyridinyl group together form a bivalent group selected from the group consisting of —(CH 2 ) 3 —, —(CH 2 ) 4 —, —(CH 2 ) 2 —O—, —(CH 2 ) 3 —O—, —CH 2 —O—CH 2 —, —O—CH 2 —O—, —O—CH 2 —CH 2 —O—, and —I—CF 2 —O—, or 
   R 1  represents a pyrazolyl group optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, C 1 -C 2 -alkyl, and C 1 -C 2 -alkoxy;
 R 2  is 
   
       
         
           
           
               
               
           
         
         
           
             wherein “*” indicates the point of attachment to the nitrogen atom to which R 2  is attached; 
           
           R 3  is methyl or —NH 2 ; 
         
         R 4  is a 5-membered heteroaryl group selected from the group consisting of oxazolyl, isoxazolyl, thiazolyl, isothiazolyl and oxadiazolyl, optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, C 1 -C 4 -alkyl, ((R 9 )O)—(C 1 -C 3 -alkyl)-, ((R 10 )(R 11 )N)—(C 1 -C 3 -alkyl)-, (C 3 -C 7 -cycloalkyl)-(C 1 -C 3 -alkyl)-, C 3 -C 7 -cycloalkyl, —OR 9 ,) —N(R 10 )(R 11 ), —C(═O)—N(R 15 )(R 16 ), —C(═O)—OR 17 , phenyl and 5- or 6-membered heteroaryl,
 wherein the phenyl group and the 5- or 6-membered heteroaryl group are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, cyano, C 1 -C 2 -alkyl, C 1 -C 2 -fluoroalkyl, —OR 9 , —N(R 10 )(R 11 ) and —C(═O)—N(R 15 )(R 16 ); 
 
         R 5  and R 6  are each independently selected from the group consisting of a hydrogen atom, C 1 -C 2 -alkyl and (C 1 -C 2 -alkyl)-C(═O)—, or 
         R 5  and R 6 , together with the nitrogen atom to which they are attached, form a monocyclic nitrogen containing 4- to 7-membered heterocycloalkyl group which is optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, oxo, hydroxy, C 1 -C 2 -alkyl and (C 1 -C 2 -alkyl)-C(═O)—;
 R 7  is a hydrogen atom or a C 1 -C 2 -alkyl group; 
 R 8  is a —C(═O)—NH 2  group; 
 
         R 9  is selected from the group consisting of a hydrogen atom, C 1 -C 4 -alkyl, (C 3 -C 7 -cycloalkyl)-(C 1 -C 2 -alkyl)-, (phenyl)-(C 1 -C 2 -alkyl)-, C 1 -C 4 -haloalkyl, C 2 -C 3 -hydroxyalkyl, (C 1 -C 2 -alkoxy)-C 2 -alkyl-, ((C 1 -C 2 -alkyl)-C(═O)—O)—C 2 -alkyl-, —C(═O)—N(R 20 )(R 21 ), C 3 -C 7 -cycloalkyl and phenyl,
 wherein C 3 -C 7 -cycloalkyl, and the C 3 -C 7 -cycloalkyl within said (C 3 -C 7 -cycloalkyl)-(C 1 -C 2 -alkyl)— group is optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, oxo and methyl, 
 and wherein the phenyl group within said (phenyl)-(C 1 -C 2 -alkyl)— group and said phenyl group itself are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, cyano, methyl, trifluoromethyl and methoxy; 
 
         R 10  and R 11  are each independently selected from the group consisting of a hydrogen atom, C 1 -C 2 -alkyl, C 1 -C 2 -haloalkyl, C 2 -C 3 -hydroxyalkyl, (C 1 -C 2 -alkoxy)-C 2 -alkyl-, ((R 22 )(R 23 )N)—C 2 -alkyl, (C 3 -C 7 -cycloalkyl)-(C 1 -C 2 -alkyl)-, (C 1 -C 2 -alkyl)-C(═O)—, C 3 -C 7 -cycloalkyl, (C 3 -C 7 -cycloalkyl)-C(═O)—, (phenyl)-(C 1 -C 2 -alkyl)-, (phenyl)-(C 1 -C 2 -alkyl)-C(═O)—, and (phenyl)-(C 1 -C 2 -alkyl)-O—C(═O)—,
 wherein C 3 -C 7 -cycloalkyl, and the C 3 -C 7 -cycloalkyl within said (C 3 -C 7 -cycloalkyl)-(C 1 -C 2 -alkyl)- and (C 3 -C 7 -cycloalkyl)-C(═O)— groups are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, cyano, C 1 -C 2 -alkyl and C 1 -C 2 -haloalkyl, 
 and wherein the phenyl groups within said (phenyl)-(C 1 -C 2 -alkyl)-, (phenyl)-(C 1 -C 2 -alkyl)-C(═O)—, and (phenyl)-(C 1 -C 2 -alkyl)-O—C(═O)— groups are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, methyl, trifluoromethyl and methoxy, or 
 
         R 10  and R 11 , together with the nitrogen atom to which they are attached, form a monocyclic nitrogen containing 4- to 7-membered heterocycloalkyl group, or a bicyclic nitrogen containing 5- to 10-membered heterocycloalkyl group, which are optionally substituted one, two or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, oxo, hydroxy, C 1 -C 2 -alkyl, C 1 -C 2 -haloalkyl, (C 1 -C 2 -alkyl)-C(═O)—, C 1 -C 2 -alkoxy, —N(R 22 )(R 23 ), and monocyclic 4- to 7-membered heterocycloalkyl; 
         R 15  and R 16  are each independently selected from the group consisting of a hydrogen atom, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -hydroxyalkyl, (cyano)-C 1 -C 4 -alkyl-, (C 1 -C 4 -alkoxy)-C 2 -C 3 -alkyl-, (C 1 -C 4 -haloalkoxy)-C 2 -C 3 -alkyl-, (C 3 -C 7 -cycloalkyl)-(C 1 -C 3 -alkyl), C 3 -C 7 -cycloalkyl, bicyclic C 5 -C 11 -cycloalkyl, monocyclic 4- to 7-membered heterocycloalkyl, (phenyl)-(C 1 -C 3 -alkyl)-, phenyl and 5- or 6-membered heteroaryl,
 wherein C 3 -C 7 -cycloalkyl, the C 3 -C 7 -cycloalkyl within said (C 3 -C 7 -cycloalkyl)-(C 1 -C 3 -alkyl)- group, the bicyclic C 5 -C 11 -cycloalkyL and the monocyclic 4- to 7-membered heterocycloalkyl groups are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, oxo, C 1 -C 2 -alkyl, (C 1 -C 2 -alkyl)-C(═O)—, and cyclopropyl, 
 and wherein the phenyl and the 5- or 6-membered heteroaryl groups, including the phenyl group within said (phenyl)-(C 1 -C 3 -alkyl)- group, are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, methyl, trifluoromethyl and methoxy, or 
 
         R 15  and R 16 , together with the nitrogen atom to which they are attached, form a monocyclic nitrogen containing 4- to 7-membered heterocycloalkyl group which is optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, oxo, C 1 -C 2 -alkyl, and (C 1 -C 2 -alkyl)-C(═O)—;
 R 17  is a C 1 -C 4 -alkyl group; 
 
         R 20  is selected from the group consisting of a hydrogen atom, C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, monocyclic 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl,
 wherein said C 1 -C 6 -alkyl group is optionally substituted one, two or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, hydroxy, cyano, C 1 -C 3 -alkoxy, —N(R 22 )(R 23 ), C 3 -C 7 -cycloalkyl, monocyclic 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, wherein said phenyl and 5- to 6-membered heteroaryl substituents are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, methyl, trifluoromethyl and methoxy, 
 and wherein C 3 -C 7 -cycloalkyl and monocyclic 4- to 7-membered heterocycloalkyl are optionally substituted one or two or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, oxo, hydroxy, C 1 -C 2 -alkyl, and (C 1 -C 2 -alkyl)-C(═O)—, 
 and wherein said phenyl and 5- to 6-membered heteroaryl groups are optionally substituted one, two or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, C 1 -C 2 -alkyl, C 1 -C 2 -haloalkyl, C 1 -C 2 -alkoxy, C 1 -C 2 -haloalkoxy, —N(R 22 )(R 23 ), and —C(═O)—N(R 24 )(R 25 ), 
 R 21  is a hydrogen atom or a C 1 -C 2 -alkyl group, or 
 
         R 20  and R 21 , together with the nitrogen atom to which they are attached, form a monocyclic nitrogen containing 4- to 7-membered heterocycloalkyl group which is substituted one, two or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, oxo, hydroxy, C 1 -C 2 -alkyl, C 1 -C 2 -haloalkyl, (phenyl)-(C 1 -C 2 -alkyl)-, (C 1 -C 2 -alkyl)-C(═O)—, C 3 -C 4 -cycloalkyl, C 1 -C 2 -alkoxy, C 1 -C 2 -haloalkoxy, —N(R 22 )(R 23 ) and —C(═O)—N(R 24 )(R 25 );
 R 22  and R 23  are each independently selected from the group consisting of a hydrogen atom, C 1 -C 2 -alky, and (C 1 -C 2 -alkyl)-C(═O)—, and 
 R 24  and R 25  are each independently a hydrogen atom or a C 1 -C 2 -alkyl group, 
 or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 
 
       
     
     
         3 . The compound according to  claim 1 , wherein:
 R 1  is a phenyl or pyridinyl group optionally substituted, one, two, or three times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, hydroxy, cyano, C 1 -C 4 -alkyl, C 1 -C 2 -fluoroalkyl, C 1 -C 2 -alkoxy, (phenyl)-(C 1 -C 2 -alkoxy)-, C 1 -C 2 -fluoroalkoxy and —N(R 5 )(R 6 ), or two substituents attached to adjacent carbon atoms of said phenyl or pyridinyl group together form a bivalent group selected from the group consisting of —(CH 2 ) 3 —, —O—CH 2 —O— and —O—CF 2 —O—, or   R 1  is a pyrazolyl group optionally substituted with one methyl group,
 R 2  is 
   
       
         
           
           
               
               
           
         
         
           
             wherein “*” indicates the point of attachment to the nitrogen atom to which R 2  is attached; 
           
           R 3  is from methyl or —NH 2 ; 
         
         R 4  is 
       
       
         
           
           
               
               
           
         
         wherein “#” indicates the point of attachment to the carbonyl group to which R 4  is attached,
 and wherein 
 
         R 4a  and R 4b  are each independently selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, C 1 -C 4 -alkyl, ((R 9 )O)—(C 1 -C 2 -alkyl)-, ((R 10 )(R 11 )N)—(C 1 -C 2 -alkyl)-, (C 3 -C 7 -cycloalkyl)-(C 1 -C 2 -alkyl)-, C 3 -C 7 -cycloalkyl, —OR 9 , —N(R 10 )(R 11 ), —C(═O)—N(R 15 )(R 16 ), —C(═O)—OR 17 , phenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl,
 wherein the phenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, cyano, C 1 -C 2 -alkyl, —OR 9 , —N(R 10 )(R 11 ), and —C(═O)—N(R 15 )(R 16 ); 
 
         R 5  and R 6  are each a hydrogen atom or a C 1 -C 2 -alkyl group, or 
         R 5  and R 6 , together with the nitrogen atom to which they are attached, form a monocyclic nitrogen containing 4- to 7-membered heterocycloalkyl group which is optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, hydroxy and C 1 -C 2 -alkyl;
 R 7  is a hydrogen atom or a C 1 -C 2 -alkyl group; 
 R 8  is a —C(═O)—NH 2  group; 
 
         R 9  is selected from the group consisting of a hydrogen atom, C 1 -C 2 -alkyl, benzyl, C 1 -C 2 -fluoroalkyl, C 2 -hydroxyalkyl, (C 1 -C 2 -alkoxy)-C 2 -alkyl-, ((C 1 -C 2 -alkyl)-C(═O)—O)—C 2 -alkyl-, —C(═O)—N(R 20 )(R 21 ), and phenyl,
 wherein the phenyl group within said benzyl group and said phenyl group itself are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, cyano and methyl; 
 
         R 10  and R 11  are each independently selected from the group consisting of a hydrogen atom, C 1 -C 2 -alkyl, C 1 -C 2 -fluoroalkyl, (C 3 -C 5 -cycloalkyl)-(C 1 -C 2 -alkyl)-(C 1 -C 2 -alkyl)-C(═O)—, C 3 -C 7 -cyclo alkyl, C 3 -C 7 -cycloalkyl-(C═O)—, (phenyl)-(C 1 -C 2 -alkyl)-, (phenyl)-(C 1 -C 2 -alkyl)-C(═O)—, and (phenyl)-(C 1 -C 2 -alkyl)-O—C(═O)—,
 wherein C 3 -C 7 -cycloalkyl, and the C 3 -C 5 -cycloalkyl within said (C 3 -C 5 -cycloalkyl)-(C 1 -C 2 -alkyl)- and the C 3 -C 7 -cycloalkyl within the C 3 -C 7 -cycloalkyl-(C═O)— groups are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, cyano, C 1 -C 2 -alkyl and C 1 -C 2 -fluoroalkyl, 
 and wherein the phenyl groups within said (phenyl)-(C 1 -C 2 -alkyl)-, (phenyl)-(C 1 -C 2 -alkyl)-C(═O)—, and (phenyl)-(C 1 -C 2 -alkyl)-O—C(═O)— groups are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom and a methyl group, or 
 
         R 10  and R 11 , together with the nitrogen atom to which they are attached, form a monocyclic nitrogen containing 4- to 7-membered heterocycloalkyl group which is optionally substituted one, two or three times, wherein each substituent is independently selected from the group consisting of a fluorine atom, cyano, oxo, C 1 -C 2 -alkyl, C 1 -C 2 -fluoroalkyl and (C 1 -C 2 -alkyl)-C(═O)—; 
         R 15  and R 16  are each independently selected from the group consisting of a hydrogen atom, C 1 -C 4 -alkyl, C 1 -C 3 -fluoroalkyl, (cyano)-C 1 -C 2 -alkyl-, (C 1 -C 4 -alkoxy)-C 2 -C 3 -alkyl-, (C 1 -C 2 -fluoroalkoxy)-C 2 -C 3 -alkyl-, (C 3 -C 5 -cycloalkyl)-(C 1 -C 2 -alkyl)-, C 3 -C 5 -cycloalkyl, phenyl, pyrazolyl, pyridinyl and pyrimidinyl,
 wherein C 3 -C 5 -cycloalkyl, and the C 3 -C 5 -cycloalkyl within said (C 3 -C 5 -cycloalkyl)-(C 1 -C 2 -alkyl)— group are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of methyl and cyclopropyl, 
 and wherein the phenyl, pyrazolyl, pyridinyl and pyrimidinyl are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, methyl, trifluoromethyl and methoxy, or 
 
         R 15  and R 16 , together with the nitrogen atom to which they are attached, form a monocyclic nitrogen containing 4- to 7-membered heterocycloalkyl group which is optionally substituted once with a substituent selected from the group consisting of a fluorine atom, oxo, C 1 -C 2 -alkyl and CH 3 —C(═O)—;
 R 17  is a C 1 -C 2 -alkyl group; 
 
         R 20  is a hydrogen atom, C 1 -C 3 -alkyl, or phenyl,
 wherein said C 1 -C 3 -alkyl group is optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, hydroxy, C 1 -C 3 -alkoxy and phenyl, said phenyl itself being optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, and a methyl group, 
 and wherein said phenyl group is optionally substituted one, two, or three times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, methyl, trifluoromethyl, methoxy, and trifluoromethoxy; 
 R 21  is a hydrogen atom or a C 1 -C 2 -alkyl group; or 
 
         R 20  and R 21 , together with the nitrogen atom to which they are attached, form a monocyclic nitrogen containing 4- to 7-membered heterocycloalkyl group which is optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, oxo, hydroxy, C 1 -C 2 -alkyl, C 1 -C 2 -fluoroalkyl, benzyl, (C 1 -C 2 -alkyl)-C(═O)—, and C 3 -C 4 -cycloalkyl,
 or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 
 
       
     
     
         4 . The compound according to  claim 1 , wherein:
 R 1  is a phenyl or pyridinyl group optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, methyl, difluoromethyl, trifluoromethyl, methoxy, benzyloxy, difluoromethoxy and trifluoromethoxy,
 or two substituents attached to adjacent carbon atoms of said phenyl or pyridinyl group together form a bivalent group —O—CF 2 —O—; 
 R 2  is 
   
       
         
           
           
               
               
           
         
         
           
             wherein “*” indicates the point of attachment to the nitrogen atom to which R 2  is attached; 
           
           R 3  is methyl or —NH 2 ; 
         
         R 4  is 
       
       
         
           
           
               
               
           
         
         
           wherein “#” indicates the point of attachment to the carbonyl group to which R 4  is attached,
 and wherein 
 
         
         R 4a  is selected from the group consisting of a chlorine atom, a bromine atom, ((R 9 )O)—(C 1 -C 2 -alkyl)-, ((R 10 )(R 11 )N)—(C 1 -C 2 -alkyl)-, (C 3 -C 5 -cycloalkyl)-(C 1 -C 2 -alkyl)-, C 3 -C 5 -cycloalkyl, —OR 9 , —C(═O)—N(R 15 )(R 16 ), and phenyl,
 wherein the phenyl group is optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, and a methyl group, or 
 
         R 4  is 
       
       
         
           
           
               
               
           
         
         
           wherein “#” indicates the point of attachment to the carbonyl group to which R 4  is attached,
 and wherein 
 
         
         R 4b  is selected from the group consisting of C 1 -C 4 -alkyl, C 3 -C 5 -cycloalkyl, —C(═O)—N(R 15 )(R 16 ), and phenyl,
 wherein the phenyl group is optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, cyano, C 1 -C 2 -alkyl, and —OR 9 ; 
 R 7  is a hydrogen atom or a C 1 -C 2 -alkyl group; 
 R 8  is a —C(═O)—NH 2  group; 
 
         R 9  is selected from the group consisting of a hydrogen atom, C 1 -C 2 -alkyl, benzyl, C 1 -C 2 -fluoroalkyl, (C 1 -C 2 -alkoxy)-C 2 -alkyl-, ((C 1 -C 2 -alkyl)-C(═O)—O)—C 2 -alkyl-, —C(═O)—N(R 20 )(R 21 ) and phenyl,
 wherein the phenyl group within said benzyl group and said phenyl group itself are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, cyano and methyl; 
 
         R 10  and R 11  are each independently selected from the group consisting of a hydrogen atom, C 1 -C 2 -alkyl, (C 3 -C 5 -cycloalkyl)-(C 1 -C 2 -alkyl)-, C 3 -C 7 -cycloalkyl and (phenyl)-(C 1 -C 2 -alkyl)-O—C(═O)—,
 wherein C 3 -C 7 -cycloalkyl, and the C 3 -C 5 -cycloalkyl within said (C 3 -C 5 -cycloalkyl)-(C 1 -C 2 -alkyl)— group are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, cyano, methyl, and C 1 -fluoroalkyl, 
 and wherein the phenyl group within said (phenyl)-(C 1 -C 2 -alkyl)-O—C(═O)— group is optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, and a methyl group, or 
 
         R 10  and R 11 , together with the nitrogen atom to which they are attached, form a monocyclic nitrogen containing 4- to 7-membered heterocycloalkyl group which is optionally substituted one, two or three times, wherein each substituent is independently selected from the group consisting of a fluorine atom, cyano, methyl, and C 1 -fluoroalkyl; 
         R 15  and R 16  are each independently selected from the group consisting of a hydrogen atom, C 1 -C 4 -alkyl, C 1 -C 2 -fluoroalkyl, (C 1 -C 4 -alkoxy)-C 2 -C 3 -alkyl-, (C 1 -C 2 -fluoroalkoxy)-C 2 -C 3 -alkyl-, (C 3 -C 05 -cycloalkyl)-(C 1 -C 2 -alkyl)-, C 3 -C 5 -cycloalkyl, phenyl and pyridinyl,
 wherein C 3 -C 5 -cycloalkyl, and the C 3 -C 5 -cycloalkyl within said (C 3 -C 5 -cycloalkyl)-(C 1 -C 2 -alkyl)— group are optionally substituted one or two times, wherein each substituent is independently a fluorine atom or a methyl group, 
 and wherein the phenyl and pyridinyl groups are optionally substituted one or two times, wherein each substituent is independently elected from the group consisting of a fluorine atom, a chlorine atom, methyl, trifluoromethyl, and methoxy; 
 
         R 20  is benzyl or phenyl,
 wherein said phenyl group, and the phenyl group within said benzyl group, is optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom and a methyl group, and 
 R 21  or a hydrogen atom or a methyl group, 
 or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 
 
       
     
     
         5 . The compound according to  claim 1 , wherein:
 R 1  is   
       
         
           
           
               
               
           
         
         
           wherein “**” indicates the point of attachment to the nitrogen atom to which R 1  is attached; 
         
         R 2  is 
       
       
         
           
           
               
               
           
         
         
           wherein “*” indicates the point of attachment to the nitrogen atom to which R 2  is attached; 
           R 3  is methyl or —NH 2 ; 
         
         R 4  is 
       
       
         
           
           
               
               
           
         
         
           wherein “#” indicates the point of attachment to the carbonyl group to which R 4  is attached,
 and wherein 
 
         
         R 4a  is selected from the group consisting of ((R 9 )O)—(C 1 -alkyl)-, ((R 10 )(R 11 )N)—(C 1 -alkyl)-, (C 3 -C 5 -cycloalkyl)-(C 1 -alkyl)-, C 3 -C 5 -cycloalkyl, —OR 9 , —C(═O)—N(R 15 )(R 16 ), and phenyl,
 wherein the phenyl group is optionally substituted one or two times, wherein each substituent is independently selected from a fluorine atom, a chlorine atom, and a methyl group, or 
 
         R 4  is 
       
       
         
           
           
               
               
           
         
         
           wherein “#” indicates the point of attachment to the carbonyl group to which R 4  is attached,
 and wherein 
 
         
         R 4b  is selected from C 1 -C 4 -alkyl, C 3 -C 5 -cycloalkyl and phenyl,
 wherein the phenyl group is optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, cyano, C 1 -C 2 -alkyl and —OR 9 ; 
 R 7  is a hydrogen atom or a C 1 -C 2 -alkyl group; 
 R 8  is a —C(═O)—NH 2  group; 
 
         R 9  is selected from the group consisting of a hydrogen atom, C 1 -C 2 -alkyl, benzyl, C 1 -C 2 -fluoroalkyl, (C 1 -C 2 -alkoxy)-C 2 -alkyl-, ((C 1 -C 2 -alkyl)-C(═O)—O)—C 2 -alkyl- and phenyl,
 wherein the phenyl group within said benzyl group and said phenyl group itself are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, cyano, and methyl; 
 
         R 10  and R 11  are each independently selected from the group consisting of a hydrogen atom, C 1 -C 2 -alkyl, C 3 -C 7 -cycloalkyl, and (benzyl)-O—C(═O)—,
 wherein C 3 -C 7 -cycloalkyl is optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, methyl, and trifluoromethyl, 
 and wherein the phenyl group within said (benzyl)-O—C(═O)— group is optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom and a methyl group, or 
 
         R 10  and R 11 , together with the nitrogen atom to which they are attached, form a monocyclic nitrogen containing 4- to 7-membered heterocycloalkyl group which is optionally substituted one, two or three times, wherein each substituent is independently selected from the group consisting of a fluorine atom, cyano, methyl, and trifluoromethyl; 
         R 15  and R 16  are each independently selected from the group consisting of a hydrogen atom, C 1 -C 4 -alkyl, C 1 -C 2 -fluoroalkyl, (C 1 -C 4 -alkoxy)-C 2 -alkyl-, (C 1 -C 2 -fluoroalkoxy)-C 2 -alkyl-, C 3 -C 5 -cycloalkyl, phenyl, and pyridinyl,
 wherein C 3 -C 5 -cycloalkyl is optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom and a methyl group; 
 Y 1  is —C(H)═, —C(F)═, —C(Cl)═, —C(CN)═, or —N═, and 
 R 26  is selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, methyl, difluoromethyl, trifluoromethyl, methoxy, benzyloxy, difluoromethoxy, and trifluoromethoxy, 
 or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 
 
       
     
     
         6 . The compound according to  claim 1 , wherein:
 R 1  is   
       
         
           
           
               
               
           
         
         
           wherein “**” indicates the point of attachment to the nitrogen atom to which R 1  is attached; 
           R 2  is 
         
       
       
         
           
           
               
               
           
         
         
           
             wherein “*” indicates the point of attachment to the nitrogen atom to which R 2  is attached; 
           
           R 3  is methyl or —NH 2 ; 
         
         R 4  is 
       
       
         
           
           
               
               
           
         
         
           wherein “#” indicates the point of attachment to the carbonyl group to which R 4  is attached,
 and wherein 
 
         
         R 4a  is selected from the group consisting of a chlorine atom, a bromine atom, ((R 9 )O)—(C 1 -alkyl)-, C 3 -C 5 -cycloalkyl, —OR 9 , and —C(═O)—N(R 15 )(R 16 ), or 
         R 4  is 
       
       
         
           
           
               
               
           
         
         
           wherein “#” indicates the point of attachment to the carbonyl group to which R 4  is attached,
 and wherein 
 
         
         R 4b  is selected from the group consisting of C 1 -C 4 -alkyl, C 3 -C 5 -cycloalkyl, and phenyl,
 wherein the phenyl group is optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, and a methyl group; 
 R 7  is a hydrogen atom or a C 1 -C 2 -alkyl group; 
 R 8  is a —C(═O)—NH 2  group; 
 
         R 9  is selected from the group consisting of C 1 -C 2 -alkyl, benzyl, C 1 -C 2 -fluoroalkyl, and phenyl,
 wherein the phenyl group within said benzyl group and said phenyl group itself are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, cyano, and methyl; 
 
         R 15  and R 16  are each independently selected from the group consisting of a hydrogen atom, C 1 -C 2 -alkyl, C 3 -C 5 -cycloalkyl, phenyl, and pyridinyl,
 wherein C 3 -C 5 -cycloalkyl is optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom and a methyl group; 
 Y 1  is C(H)═, —C(F)═, —C(Cl)═ or —N═, and 
 R 26  is selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, difluoromethyl, methoxy, benzyloxy, difluoromethoxy, and trifluoromethoxy, 
 or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 
 
       
     
     
         7 . The compound according to  claim 1 , wherein:
 R 1  is   
       
         
           
           
               
               
           
         
         
           wherein “**” indicates the point of attachment to the nitrogen atom to which R 1  is attached; 
           R 2  is 
         
       
       
         
           
           
               
               
           
         
         
           wherein “*” indicates the point of attachment to the nitrogen atom to which R 2  is attached; 
           R 3  is —NH 2 ; 
         
         R 4  is 
       
       
         
           
           
               
               
           
         
         
           wherein “#” indicates the point of attachment to the carbonyl group to which R 4  is attached,
 and wherein 
 
         
         R 4a  selected from the group consisting of a chlorine atom, a bromine atom, ((R 9 )O)—(C 1 -alkyl)-, C 3 -C 5 -cycloalkyl, —OR 9 , and —C(═O)—N(R 15 )(R 16 ), or 
         R 4  is 
       
       
         
           
           
               
               
           
         
         
           wherein “#” indicates the point of attachment to the carbonyl group to which R 4  is attached,
 and wherein 
 
         
         R 4b  is selected from the group consisting of C 1 -C 4 -alkyl, C 3 -C 5 -cycloalkyl, and phenyl,
 wherein the phenyl group is optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, and a methyl group; 
 R 7  is a methyl group; 
 R 8  is a —C(═O)—NH 2  group; 
 
         R 9  is selected from the group consisting of C 1 -C 2 -alkyl, benzyl, C 1 -C 2 -fluoroalkyl, and phenyl,
 wherein the phenyl group within said benzyl group and said phenyl group itself are optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom, a chlorine atom, cyano, and methyl; 
 
         R 15  and R 16  are each independently selected from the group consisting of a hydrogen atom, C 1 -C 2 -alkyl, C 3 -C 5 -cycloalkyl, phenyl, and pyridinyl,
 wherein C 3 -C 05 -cycloalkyl is optionally substituted one or two times, wherein each substituent is independently selected from the group consisting of a fluorine atom and a methyl group; 
 Y 1  is C(H)═, —C(F)═, —C(Cl)═, or —N═, and 
 R 26  is selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, difluoromethyl, methoxy, benzyloxy, difluoromethoxy, and trifluoromethoxy, 
 or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 
 
       
     
     
         8 . The compound according to  claim 1 , which is selected from the group consisting of:
 rac-2-(N-[4-amino-5-[3-(4-chlorophenyl)-1,2,4-oxadiazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propenamide;   rac-2-(N-[4-amino-5-(3-benzyloxyisoxazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide;   rac-2-(N-[4-amino-5-(3-phenylisoxazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide;   (R)-2-(N-[4-amino-5-(3-phenylisoxazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide;   (S)-2-(N-[4-amino-5-(3-phenylisoxazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide;   rac-2-(N-[4-amino-5-[3-(2,4-dichlorophenyl)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide;   rac-2-(N-[4-amino-5-[3-(4-chlorophenyl)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide;   rac-2-(N-[4-amino-5-(3-bromoisoxazole-5-carbonyl)thiazol-2-yl]-4-fluoro -anilino)propanamide;   (R)-2-(N-[4-amino-5-(3-bromoisoxazole-5-carbonyl)thiazol-2-yl]-4-fluoro -anilino)propanamide;   (S)-2-(N-[4-amino-5-(3-bromoisoxazole-5-carbonyl)thiazol-2-yl]-4-fluoro -anilino)propanamide;   rac-2-(N-[4-amino-5-[3-(3-pyridyl)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide;   rac-2-(N-[4-amino-5-[3-(4-pyridyl)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide;   rac-ethyl 5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]isoxazole-3-carboxylate;   rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-phenyl-isoxazole-3-carboxamide;   5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-[(cis)-2-fluorocyclopropyl]isoxazole-3-carboxamide (mixture of stereoisomers);   rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(1-methylpyrazol-4-yl)isoxazole-3-carboxamide;   rac-2-(N-[4-amino-5-[3-(morpholine-4-carbonyl)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide;   rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-pyrimidin-5-yl-isoxazole-3-carboxamide;   rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-cyclopropyl-isoxazole-3-carboxamide;   rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(4-pyridyl)isoxazole-3-carboxamide;   rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(2,2-difluoroethyl)isoxazole-3-carboxamide;   rac-2-(N-[4-amino-5-[3-(azetidine-1-carbonyl)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide;   rac-2-(N-[4-amino-5-[3-(pyrrolidine-1-carbonyl)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide;   rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(3-pyridyl)isoxazole-3-carboxamide;   rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-cyclobutyl-isoxazole-3-carboxamide;   rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(cyclopropylmethyl)isoxazole-3-carboxamide:   rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(2,2,2-trifluoroethyl)isoxazole-3-carboxamide;   rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(1-cyclopropylcyclopropyl)isoxazole-3-carboxamide;   rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-cyclopentyl-isoxazole-3-carboxamide;   rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(2-tert-butoxyethyl)isoxazole-3-carboxamide;   rac-2-(N-[4-amino-5-[3-(piperidine-1-carbonyl)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide;   rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(2-pyridyl)isoxazole-3-carboxamide;   rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-[2-(trifluoromethoxy)ethyl]isoxazole-3-carboxamide;   rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(1-methylcyclobutyl)isoxazole-3-carboxamide;   (R)-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(1-methylcyclobutyl)isoxazole-3-carboxamide;   (S)-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(1-methylcyclobutyl)isoxazole-3-carboxamide;   rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(1-bicyclo[1.1.1]pentanyl)isoxazole-3-carboxamide;   rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(3,3-difluorocyclobutyl)isoxazole-3-carboxamide;   (R)-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(3,3-difluorocyclobutyl)isoxazole-3-carboxamide;   (S)-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(3,3-difluorocyclobutyl)isoxazole-3-carboxamide;   5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(3,3-difluorocyclopentyl)isoxazole-3-carboxamide (mixture of stereoisomers);   rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-isopropyl-isoxazole-3-carboxamide;   rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(cyanomethyl)isoxazole-3-carboxamide;   5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(2-methoxy-1-methyl-ethyl)isoxazole-3-carboxamide (mixture of stereoisomers);   5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(2,2-dimethylcyclopentyl)isoxazole-3-carboxamide (mixture of stereoisomers);   5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(cis-3-fluorocyclobutyl)isoxazole-3-carboxamide (mixture of stereoisomers);   rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(1-methylcyclopentyl)isoxazole-3-carboxamide;   rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-[2-fluoro-1-(fluoromethyl)ethyl]isoxazole-3-carboxamide;   5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(2,2-difluoro-1-methyl-ethyl)isoxazole-3-carboxamide (mixture of stereoisomers);   5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(trans-3-fluorocyclobutyl)isoxazole-3-carboxamide (mixture of stereoisomers);   5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]-N-(3,3-dimethylcyclopentyl)isoxazole-3-carboxamide (mixture of stereoisomers);   rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-3,4-difluoro-anilino)thiazole-5-carbonyl]-N-(1-methylcyclobutyl)isoxazole-3-carboxamide;   (R)-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-3,4-difluoro-anilino)thiazole-5-carbonyl]-N-(1-methylcyclobutyl)isoxazole-3-carboxamide;   (S)-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-3,4-difluoro-anilino)thiazole-5-carbonyl]-N-(1-methylcyclobutyl)isoxazole-3-carboxamide;   rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-3,4-difluoro-anilino)thiazole-5-carbonyl]-N-(3,3-difluorocyclobutyl)isoxazole-3-carboxamide;   (R)-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-3,4-difluoro-anilino)thiazole-5-carbonyl]-N-(3,3-difluorocyclobutyl)isoxazole-3-carboxamide;   (S)-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-3,4-difluoro-anilino)thiazole-5-carbonyl]-N-(3,3-difluorocyclobutyl)isoxazole-3-carboxamide;   rac-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-3,4-difluoro-anilino)thiazole-5-carbonyl]-N-cyclopentyl-isoxazole-3-carboxamide;   (R)-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-3,4-difluoro-anilino)thiazole-5-carbonyl]-N-cyclopentyl-isoxazole-3-carboxamide;   (S)-5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-3,4-difluoro-anilino)thiazole-5-carbonyl]-N-cyclopentyl-isoxazole-3-carboxamide;   rac-2-(N-[4-amino-5-(3-cyclopentylisoxazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide;   rac-2-(N-[4-amino-5-[3-(difluoromethoxy)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide;   rac-2-(N-[4-amino-5-(3-isopropyl-1,2,4-oxadiazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide;   rac-2-(N-[4-amino-5-(3-phenylisothiazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide;   rac-2-(N-[4-amino-5-(3-phenyl-1,2,4-oxadiazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide;   rac-2-(N-[4-amino-5-(3-methyl-1,2,4-oxadiazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide;   rac-2-(N-[4-amino-5-(3-tert-butyl-1,2,4-oxadiazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide;   rac-2-(N-[4-amino-5-[3-(2-pyridyl)-1,2,4-oxadiazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide;   rac-2-(N-[4-amino-5-[3-(3-fluorophenyl)-1,2,4-oxadiazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide;   rac-2-(N-[4-amino-5-[3-(2,3-dimethylphenyl)-1,2,4-oxadiazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide;   rac-2-(N-[4-amino-5-(3-cyclopropyl-1,2,4-oxadiazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide;   rac-2-(N-[4-amino-5-[3-(1-methylpyrazol-4-yl)-1,2,4-oxadiazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide;   rac-2-(N-[4-amino-5-(3-cyclopentyl-1,2,4-oxadiazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide;   rac-2-(N-[4-amino-5-[3-[[cyclopentyl(methyl)amino]methyl]isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide;   rac-2-(N-[4-amino-5-[3-[[(1-methylcyclopentyl)amino]methyl]isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide;   rac-2-(N-[4-amino-5-[3-[(cyclopentylamino)methyl]isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide;   rac-2-(N-[4-amino-5-[3-(1-piperidylmethyl)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide;   rac-2-(N-[4-amino-5-[3-[(4-cyanophenoxy)methyl]isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide;   rac-2-(N-[4-amino-5-[3-(hydroxymethyl)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide;   rac-[5-[4-amino-2-(N-(2-amino-1-methyl-2-oxo-ethyl)-4-fluoro-anilino)thiazole-5-carbonyl]isoxazol-3-yl]methyl N-phenylcarbamate;   rac-2-(N-[4-amino-5-[3-(2-fluorophenyl)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide;   rac-2-(N-[4-amino-5-[3-(2-pyridyl)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide;   rac-2-(N-[4-amino-5-[3-[4-(trifluoromethoxy)phenyl]isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide;   rac-2-(N-[4-amino-5-[3-(2-methoxyphenyl)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide;   rac-2-(N-[4-amino-5-[3-(6-methoxy-3-pyridyl)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide;   rac-2-(N-[4-amino-5-(1-phenyltriazole-4-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide:   rac-2-(N-[4-amino-5-[3-[(3-fluoro azetidin-1-yl)methyl]isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide;   rac-2-(N-[4-amino-5-[3-[(3,3-difluoroazetidin-1-yl)methyl]isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide;   rac-2-(N-[4-amino-5-[3-[(4,4-difluoro-1-piperidyl)methyl]isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide;   2-(N-[4-amino-5-[3-[(4,4-difluoro-3-methyl-1-piperidyl)methyl]isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide (mixture of stereoisomers);   2-(N-[4-amino-5-[3-[(3-fluoropyrrolidin-1-yl)methyl]isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide (mixture of stereoisomers);   rac-2-(N-[4-Amino-5-(3-hydroxyisoxazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide;   rac-2(N-[4-amino-5-[3-(cyclobutoxy)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide;   rac-2-(N-[4-amino-5-[3-(cyclobutylmethoxy)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propanamide;   rac-2-(N-[4-Amino-5-[3-(4,4-difluorocyclohexoxy)isoxazole-5-carbonyl]thiazol-2-yl]-4-fluoro-anilino)propenamide; and   rac-2-(N-[4-amino-5-(3-isopropoxyisoxazole-5-carbonyl)thiazol-2-yl]-4-fluoro-anilino)propanamide,   or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.   
     
     
         9 . A method of treatment or prophylaxis of a disease, comprising administering the compound of  claim 1 , or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, to a mammal in need thereof. 
     
     
         10 . A pharmaceutical composition comprising the compound of  claim 1 , or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same; and one or more pharmaceutically acceptable excipients. 
     
     
         11 . A pharmaceutical combination comprising:
 the compound of  claim 1 , or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, and   one or more immune checkpoint inhibitors.   
     
     
         12 . The pharmaceutical combination according to  claim 11 , wherein the one or more immune checkpoint inhibitors comprise a aPD-1-L1 axis antagonist. 
     
     
         13 . The pharmaceutical combination according to  claim 11 , wherein the one or more immune checkpoint inhibitors is an inhibitor of DGKα. 
     
     
         14 .- 15 . (canceled) 
     
     
         16 . The method of  claim 9 , wherein the disease is cancer, a condition with dysregulated immune response, or a disorder associated with aberrant DGKζ signaling. 
     
     
         17 . The method of  claim 9 , wherein the mammal is a human. 
     
     
         18 . The method of  claim 16 , wherein the disease is a liquid tumor. 
     
     
         19 . The method of  claim 16 , wherein the disease is a solid tumor.