Granted Patent B2

US 11,180,487 · App. 16/071,192 · Granted Nov 23, 2021

Inventors: Ian Stansfield (Issy-les Moulineaux, FR); Olivier Alexis Georges Querolle (Issy-les Moulineaux, FR); Virginie Sophie Poncelet (Issy-les Moulineaux, FR); Gerhard Max Gross (Beerse, BE); Edgar Jacoby (Beerse, BE); Lieven Meerpoel (Beerse, BE); Janusz Jozef Kulagowski (Harlow, GB); Calum Macleod (Harlow, GB); Samuel Edward Mann (Harlow, GB); Simon Richard Green (Harlow, GB); George Hynd (Harlow, GB)

Assignee: Janssen Pharmaceutica NV

C07D405/14A61P35/00C07D401/14C07D403/10C07D403/14C07D413/14C07F9/535

Abstract

Claims (172)

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, or C 1-6 alkyl substituted with one R 5 ;

Y represents CR 4 or N;

R 4 represents hydrogen or halo;

R 5 represents halo, 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 phenyl optionally substituted with 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 ; R 21 ; —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; C 2-6 alkenyl substituted with one R 13 ; C 2-6 alkynyl; and C 2-6 alkynyl substituted with one R 13 ;

R 10 represents —OH, —O—C 1-4 alkyl, —NR 11a R 11b 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;

R 21 represents 3,6-dihydro-2H-pyran-4-yl or 1,2,3,6-tetrahydro-4-pyridinyl, wherein 1,2,3,6-tetrahydro-4-pyridinyl may optionally be substituted on the N-atom with C 1-4 alkyl or 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, 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 , Het 4 , Het 7 and Het 8 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 , Het 4 , Het 7 and Het 8 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 a substituent each independently selected from the group consisting of C 1-4 alkyl, C 3-6 cycloalkyl and Het 7 ; 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-Het 8 ; 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 , 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 15a , R 17a and R 19a each independently represents hydrogen or C 1-4 alkyl;

R 14b , R 14d , R 15b , R 17b and R 19b each independently represents hydrogen; C 1-4 alkyl; C 3-6 cycloalkyl; —C(═O)—C 1-4 alkyl; C 1-4 alkyl substituted with one substituent selected from the group consisting of halo, —OH and —O—C 1-4 alkyl; —C(═O)—C 1-4 alkyl substituted with one substituent selected from the group consisting of halo, —OH and —O—C 1-4 alkyl; or —S(═O) 2 —C 1-4 alkyl;

R 20a and R 20b 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;

or a pharmaceutically acceptable addition salt, or a solvate thereof.

2. The compound according to claim 1 , wherein

Y represents CR 4 ;

R 5 represents Het 3a , —NR 6a R 6b , or —OR 7 ;

R 3 represents phenyl optionally substituted with 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)(═NR 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 ; R 21 ; —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 ;

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; and

R 14b , R 14d , 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.

3. The compound according to claim 1 , wherein

R 5 represents halo, —NR 6a R 6b , or —OR 7 ;

R 6a represents hydrogen;

R 6b represents —C(═O)—C 1-4 alkyl; or —S(═O) 2 —C 1-4 alkyl;

R 7 represents hydrogen, —C 1-4 alkyl-NR 8a R 8b , —C(═O)—R 9 , —S(═O) 2 —OH, or —(C═O)—CH(NH 2 )—C 1-4 alkyl-Ar 1 ;

R 8a represents hydrogen;

R 8b represents C 3-6 cycloalkyl;

R 3 represents phenyl optionally substituted with 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; —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 2-6 alkenyl substituted with one R 13 ; and C 2-6 alkynyl substituted with one R 13 ;

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;

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 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 —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, —O—C 1-4 alkyl, and —N(C 1-4 alkyl) 2 ;

Het 1b , Het 1e , Het 1g , Het 7 and Het 8 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 , Het 7 and Het 8 containing one or two heteroatoms each independently selected from O 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 and C 3-6 cycloalkyl; 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, and halo;

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 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 N-atoms;

wherein in case (b-1) contains one or two additional N-atoms, said one or two N-atoms may optionally be substituted with a substituent each independently selected from the group consisting of C 1-4 alkyl, C 3-6 cycloalkyl and Het 7 ; 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 —OH, cyano, C 1-4 alkyl, and C 1-4 alkyl-OH;

R 11b represents Het 1e ; C 1-4 alkyl; —C 1-4 alkyl-Het 5 ; —C 1-4 alkyl-Het 8 , C 1-4 alkyl substituted with one, two or three OH substituents; or C 3-6 cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo and —OH;

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, Ar 2 , or Het 1c ;

Ar 1 represents phenyl;

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 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; and

R 14b , R 14d , R 15b , R 17b and R 19b each independently represents hydrogen; C 1-4 alkyl; C 3-6 cycloalkyl; —C(═O)—C 1-4 alkyl; C 1-4 alkyl substituted with one substituent selected from the group consisting of —OH and —O—C 1-4 alkyl; or —S(═O) 2 —C 1-4 alkyl.

4. The compound according to claim 1 or 2 , wherein R 5 represents —NR 6a R 6b or —OR 7 ;

R 6a represents hydrogen;

R 6b represents —C(═O)—C 1-4 alkyl; or —S(═O) 2 —C 1-4 alkyl;

R 7 represents hydrogen, —C(═O)—R 9 , —S(═O) 2 —OH, or —(C═O)—CH(NH 2 )—C 1-4 alkyl-Ar 1 ;

R 9 represents C 1-4 alkyl, or C 1-4 alkyl substituted with one substituent selected from the group consisting of —NH 2 , —COOH, and Het 6 ;

R 3 represents phenyl optionally substituted with 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; —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 ; C 1-4 alkyl substituted with one, two or three halo atoms; C 1-4 alkyl substituted with one, two or three —OH substituents; and C 1-4 alkyl substituted with one R 13 ;

R 10 represents —OH, —NR 11a R 11b 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;

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 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 —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, —O—C 1-4 alkyl, and —N(C 1-4 alkyl) 2 ;

Het 1b , Het 1e , and Het 1g 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 and Het 1g containing one or two heteroatoms each independently selected from O 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 and C 3-6 cycloalkyl; 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 —OH substituents;

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 N-atom, or a N-linked 6- to 11-membered bicyclic saturated heterocyclyl, including fused, spiro and bridged cycles, optionally containing one or two additional N-atoms;

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 —OH, cyano, and C 1-4 alkyl-OH;

R 11b represents Het 1e ; C 1-4 alkyl; C 1-4 alkyl-Het 5 ; C 1-4 alkyl substituted with one, two or three OH substituents; or C 3-6 cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo and —OH;

R 13 represents —O—C 1-4 alkyl, —C(═O)NR 15a R 15b , —NR 19a R 19b , C 3-6 cycloalkyl, Het 1d , 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, C 3-6 cycloalkyl, Ar 2 , or Het 1c ;

Ar 1 represents phenyl;

Ar 2 represents phenyl optionally substituted with one C 1-4 alkyl;

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 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;

R 11a , R 14a , R 14c , R 15a and R 19a each independently represents hydrogen or C 1-4 alkyl;

R 14b , R 14d , R 15b , and R 19b each independently represents hydrogen; C 1-4 alkyl;

C 3-6 cycloalkyl; or C 1-4 alkyl substituted with one —O—C 1-4 alkyl.

5. The compound according to claim 1 or 2 , wherein

Y represents CR 4 ;

R 4 represents hydrogen;

R 5 represents —OR 7 ;

R 7 represents hydrogen or —C(═O)—R 9 ;

R 9 represents C 1-4 alkyl;

R 3 represents phenyl substituted with 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; —O—C 1-4 alkyl-R 12 ; —O—C 3-6 cycloalkyl; —O-Het 1b ; —NH—C(═O)—Het 1g ; and C 1-4 alkyl substituted with one R 13 ;

R 10 represents —NR 11a R 11b or Het 2 ;

Het 1g 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 1g containing one or two N-atoms;

wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with a C 1-4 alkyl substituent;

Het 1b 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 containing one or two N-atoms;

wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with a C 1-4 alkyl substituent; and

wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted on one ring C-atom with one halo substituent;

Het 2 represents a heterocyclyl of formula (b-1):

(b-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl wherein (b-1) may optionally be substituted on one C-atom with one —OH substituent;

R 11b represents C 1-4 alkyl;

R 13 represents —O—C 1-4 alkyl;

R 12 represents —O—C 1-4 alkyl; and

R 11a represents hydrogen.

6. The compound according to claim 1 or 2 , wherein

R 4 represents hydrogen;

R 5 represents —OR 7 ;

R 7 represents hydrogen or —C(═O)—R 9 ;

R 9 represents C 1-4 alkyl;

R 3 represents phenyl substituted with 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; —O—C 1-4 alkyl-R′ 2 ; —NH—C(═O)—Het 1g ; and C 1-4 alkyl substituted with one R 13 ;

R 10 represents —NR 11a R 11b or Het 2 ;

Het 1g 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 1g containing one or two N-atoms;

wherein said 4- to 7-membered monocyclic saturated heterocyclyl may optionally be substituted, where possible, on one or two ring N-atoms with a C 1-4 alkyl substituent;

Het 2 represents a heterocyclyl of formula (b-1):

(b-1) represents a N-linked 4- to 7-membered monocyclic saturated heterocyclyl wherein (b-1) may optionally be substituted on one C-atom with one —OH substituent;

R 11b represents C 1-4 alkyl;

R 13 represents —O—C 1-4 alkyl,

R 12 represents —O—C 1-4 alkyl; and

R 11a represents hydrogen.

7. The compound according to claim 1 or 2 , wherein

R 2 represents C 1-6 alkyl substituted with one R 5 ;

R 4 represents hydrogen;

R 5 represents —OR 7 ;

R 7 represents hydrogen; and

R 3 represents phenyl substituted with one, two or three substituents each independently selected from the group consisting of halo; cyano; and C 1-6 alkyl.

8. The compound according to any one of claims 1 to 6 , wherein

R 1 represents methyl;

R 2 represents methyl or —CH 2 —OH.

9. The compound according to any one of claims 1 to 4 , wherein

R 4 is hydrogen.

10. The compound according to any one of claims 1 to 6 , wherein

R 5 represents —OR 7 ; and

R 7 represents hydrogen.

11. The compound according to claim 1 or 2 , wherein

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;

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 .

12. The compound according claim 1 or 2 , wherein

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;

wherein in case (b-1) contains one additional N-atom, said N-atom 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 , —NR(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , and C 1-4 alkyl-OH.

13. The compound according to claim 1 , wherein the compound is selected from

tautomers and stereoisomeric forms thereof,

and the pharmaceutically acceptable addition salts, and the solvates thereof.

14. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 10 and 13 and a pharmaceutically acceptable carrier or diluent.

15. A method of treating 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 10 and 13 .

Assignments (9)

Priority Claims (2)

Continuity (1)