Pharmaceutical composition comprising a quinazoline compound

Abstract

There is provided herein compounds of formula (I), (XXI), (XXII) and (XXIII) as defined herein, and salts thereof, for use in the treatment of colorectal and / or lung cancer.

Description

This article provides compounds of formulas (I), (XXI), (XXII), and (XXIII) as defined herein, and their salts, for the treatment of colorectal cancer and / or lung cancer. Abstract

Claims

CLAIMS1. A compound of the formula (I) or a salt thereof, for use in the treatment of colorectal cancer and / or lung cancer,wherein in formula (I),A is CRAor N,RAis H, optionally substituted C1-3 alkyl or cyano,Q is CRQor N,RQis H, halogen, optionally substituted C1-3 alkyl, C3-6 cycloalkyl or vinyl,E is CH or N,R1is naphthyl optionally substituted with one or two groups selected from the group consisting of optionally substituted C1-3 alkyl, cyano, OH and halogen, or R1is a group selected from the group consisting of the formula (II), the formula (III) and the formula (IV) below,Rla, Rlband Rlc, which are the same as or different from each other, are H, optionally substituted C1-3 alkyl, vinyl or halogen,R2is -V1-V2or W,V1is a bond, -CH2-, -O-, -S- or -N(RV1)-,RV1is H or optionally substituted C1-3 alkyl,V2is the formula (V) or the formula (VI) below,(V) (VI)W is the formula (VII) or the formula (VII-2) below or 7-membered to 9- membered bridged heterocycloalkyl containing one to two nitrogen atoms,each R2a, which is the same as or different from each other, are OH, OCH3, F or optionally substituted C1-3 alkyl, where R2ais attached only to a carbon atom that is an atom forming a ring selected from the group consisting of an azetidine ring represented by the formula (V), a pyrrolidine ring represented by the formula (VI), a piperidine ring represented by the formula (VII) and a piperazine ring represented by the formula (VII-2), m is an integer of 0 to 2,R3is optionally substituted C1-6 alkyl, optionally substituted heterocycloalkyl or optionally substituted heteroaryl,X is a bond, -CH2-, -O-, -S- or -NR4X-,R4Xis H or optionally substituted C1-3 alkyl,Y1is -©-(optionally substituted C1-3 alkylene)-*Y2, -S-(optionally substituted Ci- 3 alkylene)-*Y2, -SC>2-(optionally substituted C1-3 alkylene)-*Y2, -NRY-(optionally substituted C1-3 alkylene)-*Y2, -(optionally substituted C1-3 alkylene)-O-*Y2, -(optionally substituted C1-3 alkylene)-S-*Y2, -(optionally substituted C1-3 alkylene)-SC>2-*Y2or - (optionally substituted C1-3 alkylene)-NRY-*Y2(*Y2represents a linking moiety to Y2),RYis H or optionally substituted C1-3 alkyl,Y2is a bond, optionally substituted phenylene or optionally substituted heteroarylene,Linker is one group chemically linking Y2to EUB, andEUB is a group capable of binding to one E3 ubiquitin ligase selected from the group consisting of cereblon, IAP, MDM2, DCAF11, DCAF15, DCAF16, BIRC2, KEAP1,RNF4, RNF114, FEM1B and AhR.

2. The compound or a salt thereof, for use according to Claim 1, wherein EUB is a group capable of binding to cereblon.

3. The compound or a salt thereof, for use according to Claim 1 or Claim 2, wherein EUB is the formula (XV) below,( X V)G is CRGor N,RGis H or Ci-6 alkyl,Z is one group selected from the group consisting of the formulae (Z-1), (Z- 2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7), (Z-8), (Z-9), (Z-10), (Z-ll), (Z-12), (Z-13), (Z- 14), (Z-15), (Z-16), (Z-17), (Z-18), (Z-19), (Z-20), (Z-21), (Z-22) and (Z-23) below, wherein ring Bl and ring B2 in the formulae (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7), (Z-8), (Z-9), (Z-10), (Z-ll), (Z-12), (Z-13), (Z-14), (Z-15), (Z-16), (Z- 17), (Z-18), (Z-19), (Z-20), (Z-21), (Z-22) and (Z-23) form a bond with Linker, provided that when G is N, Z is one group selected from the group consisting of the formulae (Z-16), (Z-17), (Z-18), (Z-19), (Z-20), (Z-21), (Z-22) and (Z-23),each RZ1, which is the same as or different from each other, is optionally substituted Ci-6 alkyl, halogen, cyano, -OH, -O-(optionally substituted Ci-6 alkyl), -S- (optionally substituted Ci-6 alkyl), -NH-(optionally substituted Ci-6 alkyl) or -N- (optionally substituted Ci-6 alkyl)?, n is an integer of 0 to 2,RZ2, RZ3and RZ4, which are the same as or different from each other, are H or optionally substituted Ci-6 alkyl,M is a bond, -O-, -S-, -N(RM)- or optionally substituted C1-3 alkylene,RMis H or optionally substituted C1-3 alkyl, ring Bl is a benzene ring or a 6-membered hetero ring, wherein Rzland Linker form a bond with a carbon atom forming the ring Bl, and ring B2 is a benzene ring or a 5- or 6-membered hetero ring, wherein M, Rzland Linker form a bond with a carbon atom forming the ring B2.

4. The compound or a salt thereof, for use according to any one of Claims 1 to3, wherein EUB is the formula (XV) below,( X V)G is CH or N,Z is one group selected from the group consisting of the formulae (Z-l), (Z- 4), (Z-5), (Z-ll), (Z-14), (Z-15), (Z-16), (Z-18), (Z-19), (Z-20), (Z-22) and (Z-23), wherein ring Bl and ring B2 in the formulae (Z-l), (Z-4), (Z-5), (Z-ll), (Z- 14), (Z-15), (Z-16), (Z-18), (Z-19), (Z-20), (Z-22) and (Z-23) form a bond with Linker, provided that when G is N, Z is one group selected from the group consisting of the formulae (Z-16), (Z-18), (Z-19), (Z-20), (Z-22) and (Z-23),RZ1is C1-6 alkyl or halogen, n is an integer of 0 or 1,RZ2and RZ4, which are the same as or different from each other, are H or Ci-6 alkyl,M is a bond or C1-3 alkylene, ring Bl is a benzene ring or a pyridine ring, wherein Rzland Linker form a bond with a carbon atom forming the ring Bl, and ring B2 is a benzene ring or a pyridine ring, wherein M, Rzland Linker form a bond with a carbon atom forming the ringB2.

5. The compound or a salt thereof, for use according to any one of Claims 1 to 4, wherein A is CH or N, Q is CRQ,RQis C3-6 cycloalkyl,E is CH,R1is the formula (II) below,Rlaand Rlc, which are the same as or different from each other, are C1-3 alkyl or halogen,R2is -V1-V2or W, V1is a bond, -CH2-, -O-, -S- or -N(RV1)-, RV1is C1-3alkyl optionally substituted with one group selected from the group consisting of C3-6cycloalkyl, halogen and -OH, V2is the formula (V-2) or (VI-2) below,R3is C1-6 alkyl optionally substituted with one group selected from the group consisting of -O-(C1-6 alkyl), -S-(C1-6 alkyl), -N-(C1-6 alkyl)2 and heterocycloalkyl or optionally substituted heterocycloalkyl, X is -O- or -NR4X-, R4Xis C1-3 alkyl, Y1is -O-(C1-3 alkylene)-*Y2or -(C1-3 alkylene)-O-*Y2(*Y2represents a linking moiety to Y2), Y2is phenylene or pyridinediyl, Linker is -(L1-L2-L3-L4)-,L1, L2, L3and L4, which are the same as or different from each other, are one group selected from the group consisting of a bond, C=O, -O-, -S-, -SO2-, -NRL-, acetylene-1,2-diyl, optionally substituted heterocycloalkylene, optionally substituted heteroarylene, saturated 7-membered to 9-membered spiroheterocycloalkylene containing one or two nitrogen atoms, saturated 7-membered to 9-membered bridged heterocycloalkylene containing two nitrogen atoms and optionally substituted C1-6alkylene, and RL is H or C1-6alkyl.

6. The compound or a salt thereof, for use according to any one of Claims 1 to 5, wherein R1is the formula (II) below,R1ais halogen, and R1cis C1-3 alkyl, R2is -V1-V2or W, V1is a bond, -O- or -N(RV1)-, RV1is C1-3 alkyl, V2is the formula (VI-2) below,W is the formula (XII) below,R3is C1-6 alkyl optionally substituted with one group selected from the group consisting of -O(C1-6 alkyl), oxetanyl, tetrahydrofuranyl and tetrahydropyranyl, oxetanyl, tetrahydrofuranyl or tetrahydropyranyl, X is -O-,Y1is -O-(C1-3 alkylene)-*Y2(*Y2represents a linking moiety to Y2), Y2is phenylene, Linker is -(L1-L2-L3-L4)-, L1is C=O, L2is piperidinediyl optionally substituted with C1-3 alkyl, piperazinediyl optionally substituted with C1-3 alkyl, pyrrolidinediyl optionally substituted with C1-3alkyl, 3,8-diazabicyclo[3.2.1]octanediyl or 2,6-diazaspiro[3.4]octanediyl, L3is a bond, -N(RL3)-, C1-3alkylene or piperazinediyl, L4is a bond, -N(RL4)-, -O-, piperazinediyl or C1-3 alkylene, RL3is H or C1-3 alkyl, RL4is H or C1-3 alkyl, EUB is the formula (XV) below,( X V) G is CH or N, Z is one group selected from the group consisting of the formulae (Z-1), (Z- 5), (Z-11), (Z-14), (Z-15), (Z-16), (Z-20), (Z-22) and (Z-23), wherein ring B1 and ring B2 in the formulae (Z-1), (Z-5), (Z-11), (Z-14), (Z- 15), (Z-16), (Z-20), (Z-22) and (Z-23) form a bond with Linker, provided that when G is N, Z is one group selected from the group consisting of the formulae (Z-16), (Z-20), (Z-22) and (Z-23),^^Z ^20 ^^ ^Z ^22 ^^ ^Z ^23 ^RZ1is C1-3 alkyl or halogen, n is an integer of 0 or 1, RZ2is C1-3alkyl, M is a bond or C1-3 alkylene, ring B1 is a benzene ring or a pyridine ring, wherein RZ1and Linker form a bond with a carbon atom forming the ring B1, and ring B2 is a benzene ring or a pyridine ring, wherein M, RZ1and Linker form a bond with a carbon atom forming the ring B2.

7. The compound or a salt thereof, for use according to any one of Claims 1 to 6, wherein Q is CRQ, RQis cyclopropyl, R1is the formula (II-2) below,W is the formula (XII) below,R3is C1-3 alkyl optionally substituted with -OCH3 or tetrahydrofuranyl, tetrahydrofuranyl or tetrahydropyranyl, Y1is -O-(methylene)-*Y2(*Y2represents a linking moiety to Y2), Linker is one group selected from the group consisting of the formulae (L-1), (L-2), (L-3), (L-4), (L-5) and (L-7) below, wherein C=O in the formulae (L-1), (L-2), (L-3), (L-4), (L-5) and (L-7) forms a bond with Y2,L' is -O-, -(C1-3 alkylene)-NH-, -N(CH3)(C1-3 alkylene)-, piperazinediyl or -(C1-3alkylene)-piperazinediyl, L'' is a bond, C1-3alkylene or -(C1-3alkylene)-O-, RL2is H or C1-3alkyl, EUB is the formula (XV) below,( X V) G is CH or N, and Z is one group selected from the group consisting of the formulae (Z-1A), (Z- 1B), (Z-5A), (Z-5B), (Z-14A), (Z-14B), (Z-14C), (Z-15A), (Z-16A), (Z-16B), (Z-16C), (Z-16D), (Z-20A), (Z-22A), (Z-23A), (Z-23B), (Z-23C), (Z-23D), (Z-23E) and (Z-23F) below, wherein a benzene ring or a 6-membered hetero ring in the formulae (Z-1A), (Z-1B), (Z-5A), (Z-5B), (Z-14A), (Z-14B), (Z-14C), (Z-15A), (Z-16A), (Z-16B), (Z- 16C), (Z-16D), (Z-20A), (Z-22A), (Z-23A), (Z-23B), (Z-23C), (Z-23D), (Z-23E) and (Z-23F) form a bond with Linker, provided that when G is N, Z is one group selected from the group consisting of (Z-16A), (Z-16B), (Z-16C), (Z-16D), (Z-20A), (Z-22A), (Z-23A), (Z-23B), (Z-23C), (Z-23D), (Z-23E) and (Z-23F).^^Z ^16B ^ ^ ^Z ^ ^6C ^^ ^Z ^ ^6D ^8. The compound or a salt thereof, for use according to any one of Claims 1 to 7, wherein R2is -V1-V2or W, V1is -O-, V2is the formula (VI-2) below,W is the formula (XII) below,R3is n-propyl optionally substituted with -OCH3 or tetrahydropyranyl, Linker is the formula (L-5A) or (L-7A) below.(X V)G is CH or N, and Z is one group selected from the group consisting of the formulae (Z-1A), (Z- 14B), (Z-15A), (Z-16A) and (Z-22A) below,wherein a benzene ring or a 6-membered hetero ring in the formulae (Z-1A), (Z-14B), (Z-15A), (Z-16A) and (Z-22A) forms a bond with Linker, provided that when G is N, Z is (Z-16A) or (Z-22A).

9. The compound or salt thereof, for use according to any one of Claims 1 to 8, wherein EUB is the formula (XV) below,( X V) G is CRGor N, RGis H or C1-6alkyl, Z is one group selected from the group consisting of the formulae (Z-1), (Z- 2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7), (Z-8), (Z-9), (Z-10), (Z-11), (Z-12), (Z-13), (Z- 14), (Z-15), (Z-16), (Z-17), (Z-18), (Z-19), (Z-20), (Z-21), (Z-22), (Z-23), (Z-24), (Z-25), (Z-26) and (Z-27) below, wherein ring B1 and ring B2 in the formulae (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7), (Z-8), (Z-9), (Z-10), (Z-11), (Z-12), (Z-13), (Z-14), (Z-15), (Z-16), (Z- 17), (Z-18), (Z-19), (Z-20), (Z-21), (Z-22), (Z-23), (Z-24), (Z-25), (Z-26) and (Z-27) form a bond with Linker, provided that when G is N, Z is one group selected from the group consisting of the formulae (Z-1), (Z-16), (Z-17), (Z-18), (Z-19), (Z-20), (Z-21), (Z-22), (Z-23), (Z-24), (Z-25), (Z-26) and (Z-27),each RZ1, which is the same as or different from each other, is optionally substituted C1-6 alkyl, halogen, cyano, -OH, -O-(optionally substituted C1-6 alkyl), -S- (optionally substituted C1-6 alkyl), -NH-(optionally substituted C1-6 alkyl) or -N- (optionally substituted C1-6alkyl)2, n is an integer of 0 to 2, RZ2, RZ3, RZ4and RZ5, which are the same as or different from each other, are H or optionally substituted C1-6 alkyl, M is a bond, -O-, -S-, -N(RM)- or optionally substituted C1-3 alkylene, RMis H or optionally substituted C1-3alkyl, ring B1 is a benzene ring or a 6-membered hetero ring, wherein RZ1and Linker form a bond with a carbon atom forming the ring B1, and ring B2 is a benzene ring or a 5- or 6-membered hetero ring, wherein M, RZ1and Linker form a bond with a carbon atom forming the ring B2.

10. The compound or salt thereof, for use according to any one of Claims 1 to 9, wherein A is CH or N, Q is CRQ,RQis cyclopropyl, R1is the formula (II-2) below, , CH3)-, a (VI-2) below,W is the formula (VII-4) or (XII) below,R3is C1-3alkyl optionally substituted with -OCH3or tetrahydrofuranyl, tetrahydrofuranyl or tetrahydropyranyl, X is -O-, Y1is -O-(methylene)-*Y2(*Y2represents a linking moiety to Y2), Y2is phenylene, Linker is one group selected from the group consisting of the formulae (L-1), (L-2), (L-3), (L-4), (L-5) and (L-7) below, wherein C=O in the formulae (L-1), (L-2), (L-3), (L-4), (L-5) and (L-7) forms a bond with Y2,, L' is -O-, -(C1-3 alkylene)-NH-, -N(CH3)(C1-3 alkylene)-, piperazinediyl or -(C1-3alkylene)-piperazinediyl, L'' is a bond, C1-3alkylene or -(C1-3alkylene)-O-, RL2is H or C1-3 alkyl, EUB is the formula (XV) below,( X V) G is CH or N, and Z is one group selected from the group consisting of the formulae (Z-1A), (Z- 1B), (Z-5A), (Z-5B), (Z-14A), (Z-14B), (Z-14C), (Z-15A), (Z-16A), (Z-16B), (Z-16C), (Z-16D), (Z-20A), (Z-22A), (Z-23A), (Z-23B), (Z-23C), (Z-23D), (Z-23E), (Z-23F) and (Z-24A) below,^^Z ^16B ^ ^ ^Z ^ ^6C ^^ ^Z ^ ^6D ^, wherein a benzene ring or a 6-membered hetero ring in the formulae (Z-1A), (Z-1B), (Z-5A), (Z-5B), (Z-14A), (Z-14B), (Z-14C), (Z-15A), (Z-16A), (Z-16B), (Z- 16C), (Z-16D), (Z-20A), (Z-22A), (Z-23A), (Z-23B), (Z-23C), (Z-23D), (Z-23E) and (Z-23F) form a bond with Linker, and a benzene ring in the formula (Z-24A) forms a bond with Linker, provided that when G is N, Z is one group selected from the group consisting of (Z-1A), (Z-16A), (Z-16B), (Z-16C), (Z-16D), (Z-20A), (Z-22A), (Z-23A), (Z-23B), (Z-23C), (Z-23D), (Z-23E), (Z-23F) and (Z-24A).

11. The compound or a salt thereof, for use according to any one of Claims 1 to 10, wherein the compound of the formula (I) is selected from the group consisting of:5-[(8-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2- yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8- yl}oxy)methyl]benzoyl}-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl]-2-(2,6- dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione, 3-(5-{[(3S)-4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4- yl)oxy]quinazolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1-yl]methyl}-3- methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione, 3-(5-{[(3S)-4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2- methoxypropoxy]quinazolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1- yl]methyl}-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione, 3-[5-({(3S)-4-[4-({[(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4- yl)-2-[(2S)-2-methoxypropoxy]-4-{[(3S)-pyrrolidin-3-yl]oxy}quinolin-8- yl]oxy}methyl)benzoyl]-3-methylpiperazin-1-yl}methyl)-3-methyl-2-oxo-2,3- dihydro-1H-benzimidazol-1-yl]piperidine-2,6-dione, 1-(6-{[(3S)-4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4- yl)oxy]quinazolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1-yl]methyl}-1- methyl-1H-indazol-3-yl)-1,3-diazinane-2,4-dione, 3-(5-{[(3S)-4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2- methoxypropoxy]quinolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1- yl]methyl}-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione, 3-(5-{[(3S)-4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4- yl)oxy]quinazolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1-yl]methyl}-1-oxo- 1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione and 1-(7-{[(3S)-4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5- diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4- yl)oxy]quinazolin-8-yl}oxy)methyl]benzoyl}-3-methylpiperazin-1- yl]methyl}imidazo[1,2-a]pyridin-3-yl)-1,3-diazinane-2,4-dione.

12. A pharmaceutical composition, for treating colorectal and / or lung cancer, comprising a compound of formula (I), or a salt thereof, as defined in any one of Claims 1 to 11 and one or more pharmaceutically acceptable excipient.

13. Use of a compound of formula (I) or a salt thereof, as defined in any one ofClaims 1 to 11 for the manufacture of a medicament for the treatment of colorectal cancer and / or lung cancer.

14. A method for treating colorectal cancer and / or lung cancer, the method comprising administering a pharmaceutically effective amount of a compound of formula (I), or a salt thereof, as defined in any one of Claims 1 to 11 to a subject in need thereof.

15. The compound for use, pharmaceutical composition, use, or method as defined in any one of Claims 1 to 11, wherein the colorectal cancer and / or lung cancer is a G12D mutant KRAS-positive cancer.