RU2009128188A - BICYCLIC HETEROCYCLIC COMPOUNDS AS FGFR INHIBITORS - Google Patents

Abstract

 1. The compound of formula (I)! ! where X1, X2, and X3 are each independently selected from carbon or nitrogen so that at least one of X1-X3 is nitrogen; ! X4 is CR3 or nitrogen; ! X5 is CR6, nitrogen, or C = O; ! provided that not more than three of X1-X5 are nitrogen; ! represents a single or double bond so that at least one bond in the 5-membered ring system is a double bond; ! R3 represents hydrogen, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C3-6 cycloalkyl, C3-6 cycloalkenyl, cyano, halogen C1-6 alkyl, halogen C1-6 alkoxy or = O; ! A represents an aromatic or non-aromatic carbocyclic or heterocyclic group, which optionally can be substituted with one or more (for example, 1, 2 or 3) Ra groups; ! R1 is -NHCONR4R5, -NHCOOR4, -NH-CO- (CH2) n-NR4R5, -NH- (CH2) n-CONR4R5, -NH-CO- (CH2) n-COOR4, -NH-CO- (CH2 ) n-CSOR4, -NHSO2R4, NHSO2NR4R5, -NHCSNR4R5, -NHCOR4, -NHCSR4, -NHCSSR4, -NHC (= NR4) NR5, NHC (= NR4) R5, -NH-C (= NH2) -NH-CO R4, -NHCSOR4 or -NHCOSR4; ! R4 and R5 independently represent hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C1-6 alkanol, halogen C1-6 alkyl, - (CH2) n-NRxRy , - (CH2) S-COORZ, - (CH2) nO- (CH2) m-OH, - (CH2) n-aryl, - (CH2) nO-aryl, - (CH2) n-heterocyclyl or - (CH2) nO-heterocyclyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, aryl and heterocyclyl groups may optionally be substituted with one or more (e.g., 1, 2 or 3 ) by groups Ra; ! Rx, Ry and Rz independently represent hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkanol, -COOC1-6 alkyl, hydroxy, C1-6 alkoxy, halogen C1-6 alkyl, -CO - (CH2) n-C1-6 alkoxy, C1-6 alkylamino, C3-8 cycloalkyl or C3-8 cycloalkenyl; ! R2 and R6 are independently represent�

Claims (22)

1. The compound of formula (I)

, where X ₁ , X ₂ and X _{3 are} each independently selected from carbon or nitrogen so that at least one of X ₁ -X ₃ is nitrogen; X ₄ represents CR ³ or nitrogen; X ₅ represents CR ⁶ , nitrogen, or C = O; with the proviso that not more than three of X ₁ -X ₅ are nitrogen;

represents a single or double bond so that at least one bond in the 5-membered ring system is a double bond; R ³ represents hydrogen, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkenyl, cyano, halogen C _1-6 alkyl, haloC _1-6 alkoxy or = O; A represents an aromatic or non-aromatic carbocyclic or heterocyclic group, which optionally may be substituted with one or more (e.g., 1, 2 or 3) R ^a groups; R ¹ is —NHCONR ⁴ R ⁵ , —NHCOOR ⁴ , —NH-CO- (CH ₂ ) _n —NR ⁴ R ⁵ , —NH- (CH ₂ ) _n —CONR ⁴ R ⁵ , —NH-CO- ( CH ₂ ) _n -COOR ⁴ , -NH-CO- (CH ₂ ) _n -CSOR ⁴ , -NHSO ₂ R ⁴ , NHSO ₂ NR ⁴ R ⁵ , -NHCSNR ⁴ R ⁵ , -NHCOR ⁴ , -NHCSR ⁴ , - NHCSSR ⁴ , -NHC (= NR ⁴ ) NR ⁵ , NHC (= NR ⁴ ) R ⁵ , -NH-C (= NH ₂ ) -NH-CO-R ⁴ , -NHCSOR ⁴ or -NHCOSR ⁴ ; R ⁴ and R ⁵ independently represent hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, C _1-6 alkanol, halogen C _1-6 alkyl, - (CH ₂ ) _n -NR ^x R ^y , - (CH ₂ ) _S -COOR ^Z , - (CH ₂ ) _n -O- (CH ₂ ) _m -OH, - (CH ₂ ) _n -aryl, - (CH ₂ ) _n -O-aryl, - (CH ₂ ) _n -heterocyclyl or - (CH ₂ ) _n -O-heterocyclyl, wherein said C _{1-6 is} alkyl, C _{2-6 is} alkenyl, C _{2-6 is} alkynyl , C _3-8 cycloalkyl, C _3-8 cycloalkenyl, aryl and heterocyclyl groups may optionally be substituted with one or more (e.g. 1, 2 or 3) R ^a groups; R ^x , R ^y and R ^z independently represent hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkanol, -COOC _1-6 alkyl, hydroxy, C _1-6 alkoxy, haloC _1-6 alkyl, -CO- (CH ₂ ) _n -C _1-6 alkoxy, C _1-6 alkylamino, C _3-8 cycloalkyl or C _3-8 cycloalkenyl; R ² and R ⁶ independently represent halogen, hydrogen, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, -C≡N, C _3-8 cycloalkyl, C _{3- 8} cycloalkenyl, -NHSO ₂ R ^W , -CH = N-OR ^W , an aryl or heterocyclyl group, wherein said C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl and heterocyclyl groups may optionally be substituted one or more R ^b groups, provided that R ² and R ⁶ both cannot simultaneously be hydrogen; R ^W represents hydrogen or C _1-6 alkyl; R ^a represents halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, -OR ^x , - (CH ₂ ) _n -OC _{1- 6} alkyl, -O- (CH ₂ ) _n -OR ^x , halogen C _1-6 alkyl, halogen C _1-6 alkoxy, C _1-6 alkanol, = O, = S, nitro, Si (R ^x ) ₄ , - ( CH ₂ ) _s -CN, -SR ^x , -SO-R ^x , -SO ₂ -R ^x , -COR ^x , - (CR ^x R ^y ) _s -COOR ^z , - (CH ₂ ) _s -CONR ^x R ^y , - (CH ₂ ) _s -NR ^x R ^y , - (CH ₂ ) _s -NR ^x COR ^y , - (CH ₂ ) _s -NR ^x SO ₂ -R ^y , - (CH ₂ ) _s -NH- SO ₂ -NR ^x R ^y , -OCONR ^x R ^y , - (CH ₂ ) _s -NR ^x CO ₂ R ^y , -O- (CH ₂ ) _s -CR ^x R ^y - (CH ₂ ) _t -OR ^z or - (CH ₂ ) _s —SO ₂ NR ^x R ^y groups; R ^b represents an R ^a group or an -Y-carbocyclyl or -Z-heterocyclyl group, wherein said carbocyclyl and heterocyclyl groups may optionally be substituted with one or more (e.g., 1, 2 or 3) R ^a groups; Y and Z independently represent a bond, -CO- (CH ₂ ) _s -, -COO-, - (CH ₂ ) _n -, -NR ^x - (CH ₂ ) _n -, - (CH ₂ ) _n -NR ^x -, -CONR ^x -, -NR ^x CO-, -SO ₂ NR ^x -, -NR ^x SO ₂ -, -NR ^x CONR ^y -, -NR ^x CSNR ^y -, -O- (CH ₂ ) _s - , - (CH ₂ ) _s —O—, S—, —SO— or - (CH ₂ ) _s —SO ₂ -; m and n independently represent an integer having a value of 1-4; s and t independently represent an integer having a value of 0-4; or a pharmaceutically acceptable salt or solvate thereof, provided that the compound of formula (I) cannot be: 3- (3-acetamidophenyl) -6- (4-methylphenyl) pyrazolo (1,5a) -pyrimidine; 3- (3-acetamidophenyl) -6- (4-methoxyphenyl) pyrazolo (1,5a) -pyrimidine; N- (4- {6- [3- (4-fluorophenyl) -1H-4-pyrazolyl] imidazo [1,2-a] pyridin-3-yl} phenyl) methanesulfonamide; N- (4- {6- [3- (4-fluorophenyl) -1-trityl-1H-4-pyrazolyl] imidazo [1,2-a] pyridin-3-yl} phenyl) methanesulfonamide; N-cyclohexyl-N '- {2-fluoro-4- [6- (1-trityl-1H-4-pyrazolyl) imidazo [1,2-a] pyridin-3-yl] phenyl} urea; N- {2-fluoro-4- [6- (1-trityl-1H-4-pyrazolyl) imidazo [1,2-a] pyridin-3-yl] phenyl} -N'-isopropylurea; N-cyclohexyl-N '- {2-fluoro-4- [6- (1H-4-pyrazolyl) imidazo [1,2-a] pyridin-3-yl] phenyl} urea; N-12-fluoro-4- [6- (1H-4-pyrazolyl) imidazo [1,2-a] pyridin-3-yl] phenyl} -N'-isopropylurea or N1- {2-fluoro-4- [6- (1H-4-pyrazolyl) imidazo [1,2-a] pyridin-3-yl] phenyl} -4-fluorobenzamide. 2. The compound according to claim 1, where X ₁ , X _2, and X _{3 are} each independently selected from carbon or nitrogen so that at least one of X ₁ -X ₃ is nitrogen; X ₄ represents CR ³ or nitrogen; X ₅ represents CH, nitrogen or C = O; with the proviso that not more than three of X ₁ -X ₅ are nitrogen;

represents a single or double bond; R ³ represents hydrogen or = O; A represents an aromatic or non-aromatic carbocyclic or heterocyclic group, which optionally may be substituted with one or more (e.g., 1, 2 or 3) R ^a groups; R ¹ represents —NHCONR ⁴ R ⁵ , —NHCOOR ⁴ , —NH — CO— (CH ₂ ) _n —NR ⁴ R ⁵ , —NH — CO— (CH ₂ ) _n —COOR ⁴ , —NHSO ₂ R ^4, or -NHCSNR ⁴ R ⁵ ; R ⁴ and R ⁵ independently represent hydrogen, C _1-6 alkyl, C _1-6 alkanol, - (CH ₂ ) _n -NR ^x R ^y , - (CH ₂ ) _n -aryl or halogen C _1-6 alkyl; R ^x , R ^y and R ^z independently represent hydrogen, C _1-6 alkyl, C _1-6 alkanol, hydroxy, C _1-6 alkoxy, halogen C _1-6 alkyl or -CO- (CH ₂ ) _n -C _{1 -6} alkoxy; R ² represents an aryl or heterocyclyl group optionally substituted with one or more R ^b groups; R ^a represents halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkenyl, -OR ^x , -O- (CH ₂ ) _n -OR ^x , halogen C _1-6 alkyl, halogen C _1-6 alkoxy, C _1-6 alkanol, = O, = S, nitro, - (CH ₂ ) _s —CN, —SR ^x , —SO — R ^x , —SO ₂ -R ^x , -COR ^x , - (CR ^x R ^y ) _s -COOR ^z , - (CH ₂ ) _s -CONR ^x R ^y , - (CH ₂ ) _s -NR ^x R ^y , - (CH ₂ ) _s -NR ^x COR ^y , - (CH ₂ ) _s -NR ^x SO ₂ -R ^y , -OCONR ^x R ^y , - (CH ₂ ) _s -NR ^x CO ₂ R ^y , -O- (CH ₂ ) _s - CR ^x R ^y - (CH ₂ ) _t -OR ^z or - (CH ₂ ) _s -SO ₂ NR ^x R ^y groups; R ^b represents an —Y-aryl or —Z-heterocyclyl group, wherein said aryl and heterocyclyl groups may optionally be substituted with one or more (eg, 1, 2 or 3) R ^a groups; with the proviso that when R ² represents a group other than hydrogen, X ₅ represents CH or C = O; Y and Z independently represent a bond, CO, - (CH ₂ ) _n -, -NR ^x - (CH ₂ ) _n -, -O- or -O- (CH ₂ ) _s -; m and n independently represent an integer having a value of 1-4; s and t independently represent an integer having a value of 0-4; aryl is a carbocyclic ring; and heterocyclyl is a heterocyclic ring. 3. The compound according to claim 1, where A represents a phenyl or pyridyl group, optionally substituted by one or more R ^a groups. 4. The compound according to claim 1, where A represents phenyl or pyridyl, substituted by a group R ¹ at 5 position and optionally further substituted by one group R ^a at 3 position. 5. The compound according to claim 1, where R ¹ represents —NHCONR ⁴ R ⁵ . 6. The compound according to claim 1, where R ¹ represents —NHCONHCH ₂ CF ₃ or —NHCONHCH ₂ CH ₃ . 7. The compound according to claim 1, where R ² represents an aryl or heterocyclyl group optionally substituted with one or more R ^a groups. 8. The compound according to claim 1, where R ² represents an aryl group optionally substituted with halogen, a -Z-heterocyclyl group, or - (CR ^x R ^y ) _s -COOR ^z , where said heterocyclyl group may optionally be substituted with a group C _{1- 6} alkyl or - (CR ^x R ^y ) _s —COOR ^Z or R ² represents a heterocyclyl group optionally substituted = O, = S, halogen, C _1-6 alkyl, halogen C _1-6 alkyl, C _3-8 cycloalkyl , - (CH ₂ ) _s -NR ^x R ^y , -OR ^X , - (CH ₂ ) _n -OC _1-6 alkyl, -COR ^x , - (CR ^x R ^y ) _s -COOR ^z , -SR ^x , -SO ₂ -R ^x , - (CH ₂ ) _s -NR ^x R ^y , - (CH ₂ ) _s -SO ₂ NR ^x R ^y or C _1-6 alkanol. 9. The compound according to claim 1, where R ² represents oxazole, oxadiazole, triazole, tetrazole, thiadiazole or oxathiadiazole, optionally substituted by one or more methyl, ethyl or -S-methyl groups. 10. The compound according to claim 1, where Y and Z independently represent a bond, CO, —CH ₂ -, - (CH ₂ ) ₂ , - (CH ₂ ) _3, or —O—. 11. The compound according to claim 1, where X ₁ -X _{5 are} determined by the following ring systems

12. The compound according to claim 1, where X ₁ -X _{5 are} determined by the following ring system

13. The compound according to claim 1, which is a compound selected from examples 2-17, 19, 24, 26-62, 64-67, 75, 77-97, 100-109, 111-115, 117, 119- 131, 133-156, 158-166 and 168-422. 14. The compound according to claim 1, where the compound is a compound of formula (Id)

, where R ^a , R ² , R ⁵ and q are as defined in claim 1, J and L are independently selected from carbon or nitrogen. 15. The compound of claim 8, where R ² represents a 5-membered heterocyclyl group, optionally substituted = O, = S, halogen, C _1-6 alkyl, halogen C _1-6 alkyl, C _3-8 cycloalkyl, - (CH ₂ ) _s -NR ^x R ^y , -OR ^X , - (CH ₂ ) _n -OC _1-6 alkyl, -COR ^x , - (CR ^x R ^y ) _s -COOR ^z , -SR ^x , -SO ₂ - R ^x , - (CH ₂ ) _s -NR ^x R ^y , - (CH ₂ ) _s -SO ₂ NR ^x R ^y or C _1-6 alkanol. 16. A method of obtaining a compound of formula (I) according to claim 1, including: (i) the interaction of the compounds of formula (XX) or (XXI)

, or a protected form of this compound with a suitable substituted isocyanate or a suitable substituted amine in the presence of carbonyldiimidazole (CDI); or (ii) the interaction of the compounds of formula (XX) or (XXI)

, or a protected form of this compound with a suitable substituted aldehyde or ketone; or (iii) the interaction of the compounds of formula (XX) or (XXI)

, where X _1-5 , A and R ² have the meanings defined above; or a protected form of this compound with a suitable substituted carboxylic acid or reactive derivative; or (iv) the interaction of the compounds of formula (V) and (VI)

, and subsequent removal of any protective group present; and, optionally, then converting one compound of formula (I) into another compound of formula (I). 17. A pharmaceutical composition comprising a compound of formula (I) according to claim 1. 18. A method of treating a disease mediated by FGFR kinase, comprising administering to a subject in need thereof a compound of formula (II)

, where X ₁ -X ₅ and A have the meanings defined for the compounds of formula (I); u is an integer having a value from 0 to 2; R ^1a represents —NHCONR ⁴ R ⁵ , —NHCOOR ⁴ , —NH — CO— (CH ₂ ) _n —NR ⁴ R ⁵ , —NH— (CH ₂ ) _n —CONR ⁴ R ⁵ , —NH-CO- ( CH ₂ ) _n -COOR ⁴ , -NH-CO- (CH ₂ ) _n -CSOR ⁴ , -NHSO ₂ R ⁴ , -NHSO ₂ SR ⁴ , -NHSO ₂ NR ⁴ R ⁵ , -NHCSNR ⁴ R ⁵ , -NHCOR ⁴ , -NHCSR ⁴ , -NHCSSR ⁴ , -NR ⁴ R ⁵ , -C (= NR ⁴ ) NR ⁵ , halogen, C _1-6 alkyl, aryl, -CO-aryl, heterocyclyl, -CO-heterocyclyl, -CONR ⁴ R ⁵ , - (CH ₂ ) _n —NR ⁴ COR ⁵ , - (CH ₂ ) _S —CN, —OR ⁴ or —COOR ⁴ , wherein said aryl and heterocyclyl groups may optionally be substituted with one or more (e.g., 1 , 2 or 3) R ^a groups defined for compounds of formula (I); R ⁴ and R ⁵ are as defined for compounds of formula (I), provided that when one of R ⁴ and R ⁵ is hydrogen, the other is a group other than α-aryl or β-heterocyclyl; R ² is as defined for compounds of formula (I). 19. The method of treating a disease according to claim 18, wherein the compound of formula (II) is a compound selected from examples 1, 18, 20-23, 25, 63, 68-69, 70-74, 76, 98-99, 110 , 116, 118, 132, 157, 167 and 235. 20. A method of preventing or treating cancer, comprising administering to a subject in need thereof a compound of formula (I) according to claim 1. 21. The compound according to claim 1 for use in therapy. 22. The use of a compound according to claim 1 for the manufacture of a medicament for the prevention or treatment of cancer.