Cyanoindoline derivatives as nik inhibitors

Abstract

Fused aromatic bicyclic substituted 5-(2-amino-4-pyrimidinyl)-cyanoindoline derivatives (I) useful for therapy and/or prophylaxis in a mammal, and in particular to inhibitors of NF-KB-inducing kinase (NIK—also known as MAP3K14) useful for treating diseases such as cancer, inflammatory disorders, metabolic disorders and autoimmune disorders. The invention is also directed to pharmaceutical compositions comprising such compounds, and to the use of such compounds or pharmaceutical compositions for the prevention or treatment of diseases such as cancer, inflammatory disorders, metabolic disorders including obesity and diabetes, and autoimmune disorders.

1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
         a tautomer or a stereoisomeric form thereof, wherein 
         R 1  represents C 1-4 alkyl; 
         R 2  represents C 1-6 alkyl, C 1-6 alkyl substituted with one R 5 , or C 1-6 alkyl substituted with one, two or three fluoro atoms; 
         Y represents CR 4  or N; 
         R 4  represents hydrogen or halo; 
         R 5  represents Het 3a , —NR 6a R 6b , or —OR 7 ; 
         R 6a  represents hydrogen or C 1-4 alkyl; 
         R 6b  represents hydrogen; C 1-4 alkyl; C 3-6 cycloalkyl; —C(═O)—C 1-4 alkyl; —C(═O)-Het 4 ; 
         —S(═O) 2 —C 1-4 alkyl; —C(═O)—C 1-4 alkyl substituted with one substituent selected from the group consisting of —OH and —NR 16a R 16b ; or C 1-4 alkyl substituted with one substituent selected from the group consisting of —OH and —S(═O) 2 —C 1-4 alkyl; 
         R 7  represents hydrogen, C 1-4 alkyl, —C 1-4 alkyl-NR 8a R 8b , —C(═O)—R 9 , —S(═O) 2 —OH, —P(═O) 2 —OH, —(C═O)—CH(NH 2 )—C 1-4 alkyl-Ar 1 , or —C 1-4 alkyl-Het 3b ; 
         R 8a  represents hydrogen or C 1-4 alkyl; 
         R 8b  represents hydrogen, C 1-4 alkyl, or C 3-6 cycloalkyl; 
         R 9  represents C 1-6 alkyl, or C 1-6 alkyl substituted with one substituent selected from the group consisting of —NH 2 , —COOH, and Het 6 ; 
         R 16a  and R 16b  each independently represents hydrogen, C 1-4 alkyl or C 3-6 cycloalkyl; 
         R 3  represents 
         a) a fused bicyclic ring system of formula (1a-1) or (1a-2): 
       
       
         
           
           
               
               
           
         
         ring A1 represents phenyl or a 6-membered heteroaromatic ring containing 1 or 2 N-atoms; 
         ring A2 represents 2-oxo-1,2-dihydropyridin-3-yl; 
         ring B1 represents a 4- to 7-membered saturated heterocyclyl containing one or two heteroatoms each independently selected from O, S, S(═O) p  and N; 
         wherein (1a-1) and (1a-2) may optionally be substituted on the ring carbon atoms with in total one, two or three substituents each independently selected from the group consisting of halo; cyano; oxo; —OH; C 1-6 alkyl; —O—C 1-4 alkyl; —C(═O)—R 10 ; 
         —S(═O) 2 —C 1-4 alkyl; —S(═O)(═N—R 20a )—C 1-4 alkyl; —O—C 1-4 alkyl substituted with one, two or three halo atoms; —O—C 1-4 alkyl-R 2 ; C 3-6 cycloalkyl; —O—C 3-6 cycloalkyl; Het 1a ; —O-Het 1b ; R 18 ; —P(═O)—(C 1-4 alkyl) 2 ; —NH—C(═O)—C 1-4 alkyl; —NH—C(═O)-Het 1g ; —NR 17a R 17b ; 
         C 1-4 alkyl substituted with one, two or three halo atoms; C 1-4 alkyl substituted with one, two or three —OH substituents; C 1-4 alkyl substituted with one R 13 ; C 1-4 alkyl substituted with one R 18 ; C 2-6 alkenyl; and C 2-6 alkenyl substituted with one R 13 ; 
         wherein ring A2 may optionally be substituted, where possible, on the N-atom with a substituent selected from the group consisting of C 1-6 alkyl; C 3-6 cycloalkyl; Het 1a ; R 18 ; C 1-4 alkyl substituted with one, two or three halo atoms; C 1-4 alkyl substituted with one, two or three —OH substituents; C 1-4 alkyl substituted with one R 13 ; C 1-4 alkyl substituted with one R 18 ; C 2-6 alkenyl; and C 2-6 alkenyl substituted with one R 13 ; provided that when Het 1a  or R 18  are directly attached to the N-atom of ring A2, said Het 1a  or R 18  are attached to the N-atom via a ring carbon atom; and 
         wherein ring B1 may optionally be substituted, where possible, on one or two ring N-atoms with a substituent each independently selected from the group consisting of C 1-6 alkyl; C 3-6 cycloalkyl; Het 1a ; R 18 ; C 1-4 alkyl substituted with one, two or three halo atoms; C 1-4 alkyl substituted with one, two or three —OH substituents; C 1-4 alkyl substituted with one R 13 ; C 1-4 alkyl substituted with one R 18 ; —(C═O)—C 1-4 alkyl; 
         —C(═O)NR 14g R 14h ; —C(═O)—C 1-4 alkyl-NR 14i R 14j ; —C(═O)—C(═O)—NR 14k R 14l ; C 2-6 alkenyl; and C 2-6 alkenyl substituted with one R 13 ; provided that when Het 1a  or R 18  are directly attached to the N-atom of ring B1, said Het 1a  or R 18  are attached to the N-atom via a ring carbon atom; or 
         b) a fused bicyclic ring system of formula (2a-1): 
       
       
         
           
           
               
               
           
         
         ring A represents pyrazolyl optionally substituted with one substituent selected from the group consisting of C 1-4 alkyl, —C 1-4 alkyl-O—C 1-4 alkyl, and C 1-4 alkyl substituted with one, two or three halo atoms; 
         ring B represents a C 5-7 cycloalkyl or a 5- to 7-membered saturated heterocyclyl containing one or two heteroatoms each independently selected from O and N; 
         wherein said C 5-7 cycloalkyl or 5- to 7-membered saturated heterocyclyl may optionally be substituted on one or two ring carbon atoms with one or two substituents each independently selected from the group consisting of C 1-4 alkyl, —C 1-4 alkyl-O—C 1-4 alkyl and —C 1-4 alkyl-OH, or one ring carbon atom may optionally be substituted with oxo; and 
         wherein said 5- to 7-membered saturated heterocyclyl may optionally be substituted on one or two ring N-atoms with a substituent each independently selected from the group consisting of C 1-6 alkyl; C 3-6 cycloalkyl; C 1-4 alkyl substituted with one, two or three halo atoms; C 1-4 alkyl substituted with one, two or three —OH substituents; C 1-4 alkyl substituted with one R 13 ; —(C═O)—C 1-4 alkyl; —C(═O)NR 14g R 14h ; 
         C(═O)—C 1-4 alkyl-NR 14i R 14j ; or 
         c) a fused 6- to 11-membered bicyclic heteroaromatic ring system containing one or two heteroatoms each independently selected from O, S, and N; 
         wherein said fused 6- to 11-membered bicyclic heteroaromatic ring system may optionally be substituted on the ring carbon atoms with in total one, two or three substituents each independently selected from the group consisting of halo; cyano; C 1-6 alkyl; —O—C 1-4 alkyl; —C(═O)—R 10 ; —S(═O) 2 —C 1-4 alkyl; —S(═O)(═N—R 20a )—C 1-4 alkyl; —O—C 1-4 alkyl substituted with one, two or three halo atoms; —O—C 1-4 alkyl-R 12 ; C 3-6 cycloalkyl; —O—C 3-6 cycloalkyl; Het 1a ; —O-Het 1b ; R 18 ; —P(═O)—(C 1-4 alkyl) 2 ; —NH—C(═O)—C 1-4 alkyl; —NH—C(═O)-Het 1g ; —NR 17a R 17b ; C 1-4 alkyl substituted with one, two or three halo atoms; C 1-4 alkyl substituted with one, two or three —OH substituents; C 1-4 alkyl substituted with one R 13 ; C 1-4 alkyl substituted with one R 18 ; C 2-6 alkenyl; and C 2-6 alkenyl substituted with one R 13 ; and 
         wherein said fused 6- to 11-membered bicyclic heteroaromatic ring system may optionally be substituted, where possible, on one ring N-atom with a substituent selected from the group consisting of C 1-6 alkyl; C 3-6 cycloalkyl; Het 1a ; R 18 ; C 1-4 alkyl substituted with one, two or three halo atoms; C 1-4 alkyl substituted with one, two or three —OH substituents; C 1-4 alkyl substituted with one R 13 ; C 1-4 alkyl substituted with one R 18 ; —(C═O)—C 1-4 alkyl; —C(═O)NR 14g R 14h ; —C(═O)—C 1-4 alkyl-NR 14i R 14j ; —C(═O)—C(═O)—NR 14k R 14l ; C 2-6 alkenyl; and C 2-6 alkenyl substituted with one R 13 ; 
         provided that when Het 1a  or R 18  are directly attached to a N-atom, said Het 1a  or R 18  are attached to the N-atom via a ring carbon atom; 
         R 10  represents —OH, —O—C 1-4 alkyl, —NR 11a R 1b  or Het 2 ; 
         R 18  represents a 5-membered aromatic ring containing one, two or three N-atoms; 
         wherein said 5-membered aromatic ring may optionally be substituted with one substituent selected from the group consisting of C 1-4 alkyl and C 3-6 cycloalkyl; 
         Het 1a , Het 1c  and Het 1d  each independently represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O, S, S(═O) p  and N; or a 6- to 11-membered bicyclic saturated heterocyclyl, including fused, spiro and bridged cycles, containing one, two or three heteroatoms each independently selected from O, S, S(═O) p  and N; 
         wherein said 4- to 7-membered monocyclic saturated heterocyclyl or said 6- to 11-membered bicyclic saturated heterocyclyl may optionally be substituted, where possible, on one, two or three ring N-atoms with a substituent each independently selected from the group consisting of C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkyl substituted with one substituent selected from the group consisting of —OH and —O—C 1-4 alkyl; and 
         wherein said 4- to 7-membered monocyclic saturated heterocyclyl or said 6- to 11-membered bicyclic saturated heterocyclyl may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of —OH, oxo, halo, C 1-4 alkyl, cyano, —C(═O)—C 1-4 alkyl, —O—C 1-4 alkyl, —NH 2 , —NH(C 1-4 alkyl), and —N(C 1-4 alkyl) 2 ; 
         Het 1b , Het 1e , Het 1g  and Het 4  each independently represents a 4- to 7-membered monocyclic saturated heterocyclyl, attached to the remainder of the molecule of Formula (I) through any available ring carbon atom, said Het 1b , Het 1e , Het 1g  and Het 4  containing one or two heteroatoms each independently selected from O, S, S(═O) p  and N; 
         wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with a substituent each independently selected from the group consisting of C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkyl substituted with one substituent selected from the group consisting of —OH and —O—C 1-4 alkyl; and 
         wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of —OH, halo, C 1-4 alkyl, cyano, —C(═O)—C 1-4 alkyl, —O—C 1-4 alkyl, —NH 2 , —NH(C 1-4 alkyl), and —N(C 1-4 alkyl) 2 ; 
         Het 2  represents a heterocyclyl of formula (b-1): 
       
       
         
           
           
               
               
           
         
         (b-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional heteroatom selected from O, S, S(═O) p  and N, or a N-linked 6- to 11-membered bicyclic saturated heterocyclyl, including fused, spiro and bridged cycles, optionally containing one or two additional heteroatoms each independently selected from O, S, S(═O) p  and N; 
         wherein in case (b-1) contains one or two additional N-atoms, said one or two N-atoms may optionally be substituted with C 1-4 alkyl; and 
         wherein (b-1) may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of halo, —OH, cyano, C 1-4 alkyl, —O—C 1-4 alkyl, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , and C 1-4 alkyl-OH; 
         R 11b  represents hydrogen; Het 1e ; C 1-4 alkyl; C 1-4 alkyl-Het 5 ; C 1-4 alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C 1-4 alkyl; C 3-6 cycloalkyl; or C 3-6 cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C 1-4 alkyl; 
         R 13  represents —O—C 1-4 alkyl, —C(═O)NR 15a R 15b , —NR 19a R 19b , C 3-6 cycloalkyl, Het 1d , —S(═O) 2 —C 1-4 alkyl, —S(═O)(═N—R 20c )—C 1-4 alkyl, or —C(═O)-Het 1f ; 
         R 12  represents —OH, —O—C 1-4 alkyl, —NR 14a R 14b , —C(═O)NR 14c R 14d , —S(═O) 2 —C 1-4 alkyl, —S(═O)(═N—R 20b )—C 1-4 alkyl, C 3-6 cycloalkyl, Ar 2 , or Het 1c ; 
         Ar 1  represents phenyl optionally substituted with one hydroxy; 
         Ar 2  represents phenyl optionally substituted with one C 1-4 alkyl; 
         Het 3a , Het 3b , Het 5 , Het 6  and Het 1f  each independently represents a heterocyclyl of formula (c-1): 
       
       
         
           
           
               
               
           
         
         (c-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl optionally containing one additional heteroatom selected from O, S, S(═O) p  and N; 
         wherein in case (c-1) contains one additional N-atom, said additional N-atom may optionally be substituted with C 1-4 alkyl or C 3-6 cycloalkyl; and 
         wherein (c-1) may optionally be substituted on one or two ring C-atoms atoms with one or two substituents each independently selected from the group consisting of halo, C 1-4 alkyl, and C 3-6 cycloalkyl; 
         R 11a , R 14a , R 14c , R 14g , R 14i , R 14k , R 15a , R 17a  and R 19a  each independently represents hydrogen or C 1-4 alkyl; 
         R 14b , R 14d , R 14h , R 14j , R 14l , R 15b , R 17b  and R 19b  each independently represents hydrogen; C 1-4 alkyl; C 3-6 cycloalkyl; or C 1-4 alkyl substituted with one substituent selected from the group consisting of halo, —OH and —O—C 1-4 alkyl; 
         R 20a , R 20b  and R 20c  each independently represents hydrogen; C 1-4 alkyl; C 3-6 cycloalkyl; or 
         C 1-4 alkyl substituted with one substituent selected from the group consisting of —OH and —O—C 1-4 alkyl; 
         p represents 1 or 2; 
         and the pharmaceutically acceptable addition salts, and the solvates thereof. 
       
     
     
         2 . The compound according to  claim 1 , wherein R 3  represents a fused bicyclic ring system of formula (1a-1) or (1a-2): 
       
         
           
           
               
               
           
         
         ring A1 represents phenyl or a 6-membered heteroaromatic ring containing 1 or 2 N-atoms; 
         ring A2 represents 2-oxo-1,2-dihydropyridin-3-yl; 
         ring B1 represents a 4- to 7-membered saturated heterocyclyl containing one or two heteroatoms each independently selected from O, S, S(═O) p  and N; 
         wherein (1a-1) and (1a-2) may optionally be substituted on the ring carbon atoms with in total one, two or three substituents each independently selected from the group consisting of halo; cyano; oxo; —OH; C 1-6 alkyl; —O—C 1-4 alkyl; —C(═O)—R 10 ; —S(═O) 2 —C 1-4 alkyl; —S(═O)(═N—R 20a )—C 1-4 alkyl; —O—C 1-4 alkyl substituted with one, two or three halo atoms; —O—C 1-4 alkyl-R 12 ; C 3-6 cycloalkyl; —O—C 3-6 cycloalkyl; Het 1a ; —O-Het 1b ; R 18 ; —P(═O)—(C 1-4 alkyl) 2 ; —NH—C(═O)—C 1-4 alkyl; —NH—C(═O)-Het 1g ; —NR 17a R 17b ; C 1-4 alkyl substituted with one, two or three halo atoms; C 1-4 alkyl substituted with one, two or three —OH substituents; C 1-4 alkyl substituted with one R 13 ; C 1-4 alkyl substituted with one R 18 ; C 2-6 alkenyl; and C 2-6 alkenyl substituted with one R 13 ; 
         wherein ring A2 may optionally be substituted, where possible, on the N-atom with a substituent selected from the group consisting of C 1-6 alkyl; C 3-6 cycloalkyl; Het 1a ; R 18 ; C 1-4 alkyl substituted with one, two or three halo atoms; C 1-4 alkyl substituted with one, two or three —OH substituents; C 1-4 alkyl substituted with one R 13 ; C 1-4 alkyl substituted with one R 18 ; C 2-6 alkenyl; and C 2-6 alkenyl substituted with one R 13 ; provided that when Het 1a  or R 18  are directly attached to the N-atom of ring A2, said Het 1a  or R 18  are attached to the N-atom via a ring carbon atom; and 
         wherein ring B1 may optionally be substituted, where possible, on one or two ring N-atoms with a substituent each independently selected from the group consisting of C 1-6 alkyl; C 3-6 cycloalkyl; Het 1a ; R 18 ; C 1-4 alkyl substituted with one, two or three halo atoms; C 1-4 alkyl substituted with one, two or three —OH substituents; C 1-4 alkyl substituted with one R 13 ; C 1-4 alkyl substituted with one R 18 ; —(C═O)—C 1-4 alkyl; —C(═O)NR 14g R 14h ; —C(═O)—C 1-4 alkyl-NR 14i R 14j ; —C(═O)—C(═O)—NR 14k R 14l ; C 2-6 alkenyl; and C 2-6 alkenyl substituted with one R 13 ; provided that when Het 1a  or R 18  are directly attached to the N-atom of ring B1, said Het 1a  or R 18  are attached to the N-atom via a ring carbon atom. 
       
     
     
         3 . The compound according to  claim 1  or  2 , wherein
 R 5  represents —OR 7 ; 
 R 7  represents hydrogen, C 1-4 alkyl, —C 1-4 alkyl-NR 8a R 8b , —C(═O)—R 9 , —(C═O)—CH(NH 2 )— or C 1-4 alkyl-Ar 1 ; 
 R 9  represents C 1-6 alkyl, or C 1-6 alkyl substituted with one substituent selected from the group consisting of —NH 2 , and —COOH; 
 R 3  represents a fused bicyclic ring system of formula (1a-1): 
 
       
         
           
           
               
               
           
         
         ring A1 represents phenyl or a 6-membered heteroaromatic ring containing 1 or 2 N-atoms; 
         ring B represents a 4- to 7-membered saturated heterocyclyl containing one or two heteroatoms each independently selected from O, S, S(═O) p  and N; 
         wherein (1a-1) may optionally be substituted on the ring carbon atoms with in total one, two or three substituents each independently selected from the group consisting of halo; cyano; oxo; C 1-6 alkyl; —O—C 1-4 alkyl; —C(═O)—R 10 ; —S(═O) 2 —C 1-4 alkyl; —O—C 1-4 alkyl substituted with one, two or three halo atoms; —O—C 1-4 alkyl-R 12 ; C 3-6 cycloalkyl; —O—C 3-6 cycloalkyl; —NH—C(═O)—C 1-4 alkyl; —NR 17a R 17b ; C 1-4 alkyl substituted with one, two or three halo atoms; C 1-4 alkyl substituted with one, two or three —OH substituents; C 1-4 alkyl substituted with one R 13 ; C 2-6 alkenyl; and C 2-6 alkenyl substituted with one R 13 ; and 
         wherein ring B1 may optionally be substituted, where possible, on one or two ring N-atoms with a substituent each independently selected from the group consisting of C 1-6 alkyl; C 3-6 cycloalkyl; C 1-4 alkyl substituted with one, two or three halo atoms; C 1-4 alkyl substituted with one, two or three —OH substituents; C 1-4 alkyl substituted with one R 13 ; —(C═O)—C 1-4 alkyl; —C(═O)NR 14g R 14h ; —C(═O)—C 1-4 alkyl-NR 14i R 14j ; —C(═O)—C(═O)—NR 14k R 14l ; C 2-6 alkenyl; and C 2-6 alkenyl substituted with one R 13 ; 
         R 10  represents —OH, —O—C 1-4 alkyl, or —NR 11a R 11b ; 
         R 11b  represents hydrogen; C 1-4 alkyl; C 1-4 alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, —OH and —O—C 1-4 alkyl; C 3-6 cycloalkyl; or C 3-6 cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, 
         —OH and —O—C 1-4 alkyl; 
         R 13  represents —O—C 1-4 alkyl, —C(═O)NR 15a R 15b , —NR 19a R 19b , C 3-6 cycloalkyl, or —S(═O) 2 —C 1-4 alkyl; 
         R 12  represents —OH, —O—C 1-4 alkyl, —NR 14a R 14b , —C(═O)NR 14c R 14d , —S(═O) 2 —C 1-4 alkyl, C 3-6 cycloalkyl, or Ar 2 . 
       
     
     
         4 . The compound according to  claim 1  or  2 , wherein
 R 5  represents —OR 7 ; 
 R 7  represents hydrogen; 
 R 3  represents a fused bicyclic ring system of formula (1a-1): 
 
       
         
           
           
               
               
           
         
         ring A1 represents phenyl or a 6-membered heteroaromatic ring containing 1 or 2 N-atoms; 
         ring B1 represents a 4- to 7-membered saturated heterocyclyl containing one or two heteroatoms each independently selected from O and N; 
         wherein (1a-1) may optionally be substituted on the ring carbon atoms with in total one, two or three substituents each independently selected from the group consisting of halo; C 1-6 alkyl; —O—C 1-4 alkyl; —C(═O)—Ro; —O—C 1-4 alkyl-R 12 ; —NR 17a R 17b ; C 1-4 alkyl substituted with one, two or three —OH substituents; C 1-4 alkyl substituted with one R 13 ; C 2-6 alkenyl; and C 2-6 alkenyl substituted with one R 13 ; and 
         wherein ring B1 may optionally be substituted, where possible, on one or two ring N-atoms with a substituent each independently selected from the group consisting of C 1-6 alkyl; C 1-4 alkyl substituted with one R 13 ; —(C═O)—C 1-4 alkyl; —C(═O)—C 1-4 alkyl-NR 14i R 14j ; and —C(═O)—C(═O)—NR 14k R 14l ; 
         R 10  represents —NR 11a R 11b ; 
         R 11b  represents C 1-4 alkyl; 
         R 13  represents —O—C 1-4 alkyl, —C(═O)NR 15a R 15b , or C 3-6 cycloalkyl; 
         R 12  represents C 3-6 cycloalkyl; 
         R 11a , R 14i , R 14k , R 15a , and R 17a  each independently represents hydrogen or C 1-4 alkyl; 
         R 14j , R 14l , R 15b , and R 17b  each independently represents hydrogen or C 1-4 alkyl. 
       
     
     
         5 . The compound according to  claim 1  or  2 , wherein
 R 2  represents C 1-6 alkyl substituted with one R 5 ; 
 R 5  represents —OR 7 ; 
 R 7  represents hydrogen; 
 R 3  represents a fused bicyclic ring system of formula (1a-1): 
 
       
         
           
           
               
               
           
         
         ring A1 represents phenyl or a 6-membered heteroaromatic ring containing 1 N-atom; 
         ring B1 represents a 4- to 7-membered saturated heterocyclyl containing one heteroatom selected from O and N; 
         wherein (1a-1) may optionally be substituted on the ring carbon atoms with in total one, two or three substituents each independently selected from the group consisting of —O—C 1-4 alkyl; —O—C 1-4 alkyl-R 12 ; and C 1-4 alkyl substituted with one R 13 ; and 
         wherein ring B may optionally be substituted, where possible, on one N-atom with a C 1-6 alkyl substituent; 
         R 13  represents C 3-6 cycloalkyl; 
         R 12  represents C 3-6 cycloalkyl. 
       
     
     
         6 . The compound according to  claim 1 , wherein R 3  represents a fused bicyclic ring system of formula (2a-1): 
       
         
           
           
               
               
           
         
         ring A represents pyrazolyl optionally substituted with one substituent selected from the group consisting of C 1-4 alkyl, —C 1-4 alkyl-O—C 1-4 alkyl, and C 1-4 alkyl substituted with one, two or three halo atoms; 
         ring B represents a C 5-7 cycloalkyl or a 5- to 7-membered saturated heterocyclyl containing one or two heteroatoms each independently selected from O and N; 
         wherein said C 5-7 cycloalkyl or 5- to 7-membered saturated heterocyclyl may optionally be substituted on one or two ring carbon atoms with one or two substituents each independently selected from the group consisting of C 1-4 alkyl, —C 1-4 alkyl-O—C 1-4 alkyl and —C 1-4 alkyl-OH, or one ring carbon atom may optionally be substituted with oxo; and 
         wherein said 5- to 7-membered saturated heterocyclyl may optionally be substituted on one or two ring N-atoms with a substituent each independently selected from the group consisting of C 1-6 alkyl; C 3-6 cycloalkyl; C 1-4 alkyl substituted with one, two or three halo atoms; C 1-4 alkyl substituted with one, two or three —OH substituents; C 1-4 alkyl substituted with one R 13 ; —(C═O)—C 1-4 alkyl; —C(═O)NR 14g R 14h ; —C(═O)—C 1-4 alkyl-NR 14i R 14j . 
       
     
     
         7 . The compound according to  claim 6 , wherein
 R 1  represents C 1-4 alkyl;   R 2  represents C 1-6 alkyl substituted with one R 5 ;   R 5  represents —OR 7 ;   R 7  represents hydrogen;   R 3  represents a fused bicyclic ring system of formula (2a-1):   
       
         
           
           
               
               
           
         
         ring A represents pyrazolyl optionally substituted with one substituent selected from the group consisting of C 1-4 alkyl, and —C 1-4 alkyl-O—C 1-4 alkyl; 
         ring B represents a C 5-7 cycloalkyl or a 5- to 7-membered saturated heterocyclyl containing one or two heteroatoms each independently selected from O and N; 
         wherein said C 5-7 cycloalkyl or 5- to 7-membered saturated heterocyclyl may optionally be substituted on one ring carbon atom with one or two C 1-4 alkyl substituents, or one ring carbon atom may optionally be substituted with oxo; and 
         wherein said 5- to 7-membered saturated heterocyclyl may optionally be substituted on one or two ring N-atoms with a C 1-6 alkyl substituent. 
       
     
     
         8 . The compound according to  claim 6 , wherein
 R 1  represents C 1-4 alkyl;   R 2  represents C 1-6 alkyl substituted with one R 5 ;   R 5  represents —OR 7 ;   R 7  represents hydrogen;   R 3  represents a fused bicyclic ring system of formula (2a-1):   
       
         
           
           
               
               
           
         
         ring A represents pyrazolyl; 
         ring B represents a 6-membered saturated heterocyclyl containing one heteroatom selected from O and N; 
         wherein said 6-membered saturated heterocyclyl may optionally be substituted on one ring carbon atom with one C 1-4 alkyl substituent, or one ring carbon atom may optionally be substituted with oxo; and 
         wherein said 5- to 7-membered saturated heterocyclyl may optionally be substituted on one N-atom with a C 1-6 alkyl substituent. 
       
     
     
         9 . The compound according to  claim 8 , wherein
 R 3  represents a fused bicyclic ring system selected from the following structures:   
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound according to  claim 1 , wherein R 3  represents a fused 6- to 11-membered bicyclic heteroaromatic ring system containing one or two heteroatoms each independently selected from O, S, and N;
 wherein said fused 6- to 11-membered bicyclic heteroaromatic ring system may optionally be substituted on the ring carbon atoms with in total one, two or three substituents each independently selected from the group consisting of halo; cyano; C 1-6 alkyl; —O—C 1-4 alkyl; —C(═O)—R 10 ; —S(═O) 2 —C 1-4 alkyl; —S(═O)(═N—R 20a )—C 1-4 alkyl; —O—C 1-4 alkyl substituted with one, two or three halo atoms; —O—C 1-4 alkyl-R 12 ; C 3-6 cycloalkyl; —O—C 3-6 cycloalkyl; Het 1a ; —O-Het 1b ; R 18 ; —P(═O)—(C 1-4 alkyl) 2 ; —NH—C(═O)—C 1-4 alkyl; —NH—C(═O)-Het 1g ; —NR 17a R 17b ; C 1-4 alkyl substituted with one, two or three halo atoms; C 1-4 alkyl substituted with one, two or three —OH substituents; C 1-4 alkyl substituted with one R 13 ; C 1-4 alkyl substituted with one R 18 ; C 2-6 alkenyl; and C 2-6 alkenyl substituted with one R 13 ; and   wherein said fused 6- to 11-membered bicyclic heteroaromatic ring system may optionally be substituted, where possible, on one ring N-atom with a substituent selected from the group consisting of C 1-6 alkyl; C 3-6 cycloalkyl; Het 1a ; R 18 ; C 1-4 alkyl substituted with one, two or three halo atoms; C 1-4 alkyl substituted with one, two or three —OH substituents; C 1-4 alkyl substituted with one R 13 ; C 1-4 alkyl substituted with one R 18 ; —(C═O)—C 1-4 alkyl; —C(═O)NR 14g R 14h ; —C(═O)—C 1-4 alkyl-NR 14i R 14j ; —C(═O)—C(═O)—NR 14k R 14l ; C 2-6 alkenyl; and C 2-6 alkenyl substituted with one R 13 ; provided that when Het 1a  or R 18  are directly attached to a N-atom, said Het 1a  or R 18  are attached to the N-atom via a ring carbon atom.   
     
     
         11 . The compound according to  claim 10 , wherein
 R 5  represents —NR 6a R 6b , or —OR 7 ;   R 6b  represents hydrogen; C 1-4 alkyl; C 3-6 cycloalkyl; or —C(═O)—C 1-4 alkyl;   R 7  represents hydrogen, C 1-4 alkyl, or —C 1-4 alkyl-NR 8a R 8b ;   R 3  represents a fused 6- to 11-membered bicyclic heteroaromatic ring system containing one or two heteroatoms each independently selected from O, S, and N;   wherein said fused 6- to 11-membered bicyclic heteroaromatic ring system may optionally be substituted on the ring carbon atoms with in total one, two or three substituents each independently selected from the group consisting of halo; cyano; C 1-6 alkyl; —O—C 1-4 alkyl; C 1-4 alkyl substituted with one, two or three halo atoms; C 1-4 alkyl substituted with one, two or three —OH substituents; C 1-4 alkyl substituted with one R 13 ; C 2-6 alkenyl; and C 2-6 alkenyl substituted with one R 13 ; and   wherein said fused 6- to 11-membered bicyclic heteroaromatic ring system may optionally be substituted, where possible, on one ring N-atom with a substituent selected from the group consisting of C 1-6 alkyl; C 3-6 cycloalkyl; C 1-4 alkyl substituted with one, two or three halo atoms; C 1-4 alkyl substituted with one, two or three —OH substituents; C 1-4 alkyl substituted with one R 13 ; C 1-4 alkyl substituted with one R 18 ; C 2-6 alkenyl; and C 2-6 alkenyl substituted with one R 13 ;   Het 1d  represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O, S, S(═O) p  and N;   wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with a substituent each independently selected from the group consisting of C 1-4 alkyl, C 3-6 cycloalkyl, and C 1-4 alkyl substituted with one substituent selected from the group consisting of —OH and —O—C 1-4 alkyl; and   wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted on one, two or three ring C-atoms with one or two substituents each independently selected from the group consisting of —OH, halo, C 1-4 alkyl, cyano, —O—C 1-4 alkyl, —NH 2 , —NH(C 1-4 alkyl), and —N(C 1-4 alkyl) 2 ;   R 13  represents —O—C 1-4 alkyl, —C(═O)NR 15a R 15b , —NR 19a R 19b , C 3-6 cycloalkyl, or Het 1d .   
     
     
         12 . The compound according to  claim 10 , wherein
 R 1  represents C 1-4 alkyl;   R 5  represents —OR 7 ;   R 7  represents hydrogen;   R 3  represents a fused 6- to 11-membered bicyclic heteroaromatic ring system containing one or two heteroatoms each independently selected from O, S, and N;   wherein said fused 6- to 11-membered bicyclic heteroaromatic ring system may optionally be substituted on the ring carbon atoms with in total one, two or three halo substituents; and   wherein said fused 6- to 11-membered bicyclic heteroaromatic ring system may optionally be substituted, where possible, on one ring N-atom with a substituent selected from the group consisting of C 1-4 alkyl substituted with one, two or three —OH substituents; C 1-4 alkyl substituted with one R 13 ;   Het 1d  represents a 4- to 7-membered monocyclic saturated heterocyclyl containing one or two heteroatoms each independently selected from O, S, S(═O) p  and N;   R 13  represents —O—C 1-4 alkyl, —C(═O)NR 15a R 15b , or Het 1d ;   R 15a  represents hydrogen or C 1-4 alkyl;   R 15b  represents C 1-4 alkyl.   
     
     
         13 . The compound according to  claim 10 , wherein
 R 1  represents C 1-4 alkyl;   R 5  represents —OR 7 ;   R 7  represents hydrogen;   R 3  represents a fused 9-membered bicyclic heteroaromatic ring system containing one N-atom;   wherein said fused 6- to 11-membered bicyclic heteroaromatic ring system may optionally be substituted on the ring carbon atoms with in total one, two or three halo substituents; and   wherein said fused 6- to 11-membered bicyclic heteroaromatic ring system may optionally be substituted, where possible, on one ring N-atom with a substituent selected from the group consisting of C 1-4 alkyl substituted with one, two or three —OH substituents; C 1-4 alkyl substituted with one R 13 ;   R 13  represents —O—C 1-4 alkyl, or —C(═O)NR 15a R 15b ;   R 15a  represents hydrogen or C 1-4 alkyl;   R 15b  represents C 1-4 alkyl.   
     
     
         14 . The compound according to any one of  claims 1  to  13 , wherein
 R 1  represents methyl; and 
 R 2  represents methyl or —CH 2 —OH. 
 
     
     
         15 . The compound according to any one of  claims 1  to  14 , wherein
 Y represents CR 4 . 
 
     
     
         16 . The compound according to any one of  claims 1  to  15 , wherein R 4  represents hydrogen. 
     
     
         17 . The compound according to any one of  claims 1  to  14 , wherein
 Y represents N. 
 
     
     
         18 . The compound according to  claim 1 , wherein the compound is selected from compounds 21, 25, 32, 34, 35, 1b, 2b, 3b, 17b, 3c, and 8c,
 tautomers and stereoisomeric forms thereof,   and the pharmaceutically acceptable addition salts, and the solvates thereof.   
     
     
         19 . A pharmaceutical composition comprising a compound as claimed in any one of  claims 1  to  18  and a pharmaceutically acceptable carrier or diluent. 
     
     
         20 . A compound as claimed in any one of  claims 1  to  18  for use as a medicament. 
     
     
         21 . A compound as claimed in any one of  claims 1  to  18  for use in the prevention or treatment of cancer. 
     
     
         22 . A pharmaceutical composition as claimed in  claim 19  for use in the prevention or treatment of cancer. 
     
     
         23 . A method of treating or preventing a cell proliferative disease in a warm-blooded animal which comprises administering to the said animal an effective amount of a compound as claimed in any one of  claims 1  to  18 .