RU2011113236A - NEW CHEMICAL COMPOUNDS FOR TREATMENT OF ONCOLOGICAL DISEASES - Google Patents

Abstract

 1. Compounds of general formula I, their tautomers, an individual isomer or mixture of isomers, a pharmaceutically acceptable salt, solvate or hydrate thereof:! ! where X1 represents N, CRt 1; X2 is N, CRt 2, X3 is N, CRt 3, X4 is N, CH; X1, X2, X3 and X4 are independently selected; preferably X1 = CRt 1, X2 = CRt 2, X3 = CRt 3, X4 = CH; ! Rt 1 represents —H, halogen, —R1, —OR2, —NHR2, —SR2, —C (O) CH3, —C (O) CH2CH3, —CH2C (O) CH3, —CH2OH, —CH2CH2OH, —CH2CH2CH2OH , -CH2OCH3, -CH2CH2OCH3, -CH2OCH2CH3, -CH2SH, -CH2SCH3, -CH2SCH2CH3, -CH2CH2SCH3, -CN, -COOH, -CONH2, -C (O) NHCH3, -NHC (O) CH3; preferably Rt 1 = —H, —Cl, —R1, —OR2, —CH2 OCH3, —SCH3; ! Rt 2 represents —H, halogen, —CH3, —CH2CH3, —CH = CH2, —NH2, —NHCH3, —OH, —OCH3, —SH, —SCH3; preferably Rt 2 = —H; ! Rt 3 represents —H, halogen, —CN, —NO2, —R6, —OR4, —NR4R5, —C (O) YR4, —OC (O) YR4, —NR4C (O) YR4, —SC (O) YR4, -NR4C (= S) YR4, -OC (= S) YR4, -C (= S) YR4, -YC (= NR5) YR4, -YP (= O) (YR6) (YR6), -Si ( R6) 3, -NR4SO2R4, -S (O) rR4, -SO2NR4R5, -NR SO2NR4R5, where Y is independently selected and is a chemical bond, -O-, -S-, -NR5-; preferably Rt 3 = —H, —NR4R5, —OR4, —R6, —CO (Y) R4; ! R1 represents alkyl, alkenyl, alkynyl, cycloalkyl containing from 1 to 4 carbon atoms and any substituents (however, the total number of heavy atoms in the group R1 should not exceed 4); preferably R1 = CH3, CH2CH3, CH2CH2CH3, C = CHCH3, cyclopropyl; ! R2 represents alkyl, alkenyl, alkynyl containing from 1 to 3 carbon atoms and any substituents (however, the total number of heavy atoms in the group R2 should not exceed 3); preferably R2 = CH3, CH2CH3; ! cycle A is a 5- or 6-membered aryl or heteroaryl ring optionally substituted with 1-4 Ra groups; ! cycle B is a 5- or 6-membered aryl or heteroaryl ring optionally substituted with 1-5 Rb groups; ! Ra and Rb are independently selected and represent

Claims (5)

1. Compounds of general formula I, their tautomers, an individual isomer or mixture of isomers, a pharmaceutically acceptable salt, solvate or hydrate thereof:

where X ₁ represents N, CR _t ¹ ; X ₂ represents N, CR _t ² , X ₃ represents N, CR _t ³ , X ₄ represents N, CH; X ¹ , X ² , X ³ and X ⁴ are independently selected; preferably X ¹ = CR _t ¹ , X ² = CR _t ² , X ³ = CR _t ³ , X ⁴ = CH; R _t ¹ represents —H, halogen, —R ¹ , —OR ² , —NHR ² , —SR ² , —C (O) CH ₃ , —C (O) CH ₂ CH ₃ , —CH ₂ C (O ) CH ₃ , -CH ₂ OH, -CH ₂ CH ₂ OH, -CH ₂ CH ₂ CH ₂ OH, -CH ₂ OCH ₃ , -CH ₂ CH ₂ OCH ₃ , -CH ₂ OCH ₂ CH ₃ , -CH ₂ SH, —CH ₂ SCH ₃ , —CH ₂ SCH ₂ CH ₃ , —CH ₂ CH ₂ SCH ₃ , —CN, —COOH, —CONH ₂ , —C (O) NHCH ₃ , —NHC (O) CH ₃ ; preferably R _t ¹ = —H, —Cl, —R ¹ , —OR ² , —CH ₂ OCH ₃ , —SCH ₃ ; R _t ² represents —H, halogen, —CH ₃ , —CH ₂ CH ₃ , —CH = CH ₂ , —NH ₂ , —NHCH ₃ , —OH, —OCH ₃ , —SH, —SCH ₃ ; preferably R _t ² = —H; R _t ³ represents —H, halogen, —CN, —NO ₂ , —R ⁶ , —OR ⁴ , —NR ⁴ R ⁵ , —C (O) YR ⁴ , —OC (O) YR ⁴ , —NR ⁴ C (O) YR ⁴ , -SC (O) YR ⁴ , -NR ⁴ C (= S) YR ⁴ , -OC (= S) YR ⁴ , -C (= S) YR ⁴ , -YC (= NR ⁵ ) YR ⁴ , -YP (= O) (YR ⁶ ) (YR ⁶ ), -Si (R ⁶ ) ₃ , -NR ⁴ SO ₂ R ⁴ , -S (O) _r R ⁴ , -SO ₂ NR ⁴ R ⁵ , —NR SO ₂ NR ⁴ R ⁵ , where Y is independently selected and is a chemical bond, —O—, —S—, —NR ⁵ -; preferably R _t ³ = —H, —NR ⁴ R ⁵ , —OR ⁴ , —R ⁶ , —CO (Y) R ⁴ ; R ¹ represents alkyl, alkenyl, alkynyl, cycloalkyl containing from 1 to 4 carbon atoms and any substituents (however, the total number of heavy atoms in the group R ¹ should not exceed 4); preferably R ¹ = CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , C = CHCH ₃ , cyclopropyl; R ² represents alkyl, alkenyl, alkynyl containing from 1 to 3 carbon atoms and any substituents (however, the total number of heavy atoms in the group R ² should not exceed 3); preferably R ² = CH ₃ , CH ₂ CH ₃ ; cycle A is a 5- or 6-membered aryl or heteroaryl ring optionally substituted with 1-4 R ^a groups; cycle B is a 5- or 6-membered aryl or heteroaryl ring optionally substituted with 1-5 R ^b groups; R ^a and R ^b are independently selected and are —H, halogen, —CN, —NO ₂ , —R ⁶ , —OR ⁴ , —NR ⁴ R ⁵ , —C (O) YR ⁴ , —OC (O) YR ⁴ , -NR ⁴ C (= S) YR ⁴ , -SC (O) YR ⁴ , -NR ⁴ C (= S) YR ⁴ , -OC (= S) YR ⁴ , -C (= S) YR ⁴ , -YC (= NR ⁵ ) YR ⁴ , -YP (= O) (YR ⁶ ) YR ⁶ ), -Si (R ⁶ ) ₃ , -NR ⁴ O ₂ R ⁴ , -S (O) _r R ⁴ , - SO ₂ NR ⁴ R ⁵ , —NR ⁴ SO ₂ NR ⁴ R ⁵ , where Y is independently selected and is a chemical bond, —O—, —S—, —NR ⁵ -; L ¹ represents NR ³ C (O) or C (O) NR ³ ; R ³ , R ⁴ and R ⁵ are independently selected and are H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl or heteroaryl; also the NR ⁴ R ⁵ group may be a 5- or 6-membered saturated, partially saturated or unsaturated cycle, which optionally may contain substituents and also have 0-2 additional heteroatoms selected from N, O and S (O) _r ; in each case, R ⁶ is independently selected and is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl or heteroaryl; each of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl or heteroaryl groups may optionally be substituted; r is selected from 0, 1 or 2; m is 0, 1, 2, 3, 4; p is 0, 1, 2, 3, 4 or 5. 2. Compounds of general formula II, their tautomers, an individual isomer or mixture of isomers, a pharmaceutically acceptable salt, solvate or hydrate thereof:

where Z represents N, CH; X ₁ represents N, CR _t ¹ ; X ₂ represents N, CR _t ² , X ₃ represents N, CR _t ³ , X ⁴ represents N, CH; X ¹ , X ² , X ³ and X ⁴ are independently selected; preferably X ¹ = X ⁴ and X ² = X ³ , Z = CH; X ₁ and X ₃ at the same time are not equal to N; R _t ¹ represents —H, halogen, —R ¹ , —OR ² , —NHR ² , —SR ² , —C (O) CH ₃ , —C (O) CH ₂ CH ₃ , —CH ₂ C (O ) CH ₃ , -CH ₂ OH, -CH ₂ CH ₂ OH, -CH ₂ CH ₂ CH ₂ OH, -CH ₂ OCH ₃ , -CH ₂ CH ₂ OCH ₃ , -CH ₂ OCH ₂ CH ₃ , -CH ₂ SH, —CH ₂ SCH ₃ , —CH ₂ SCH ₂ CH ₃ , —CH ₂ CH ₂ SCH ₃ , —CN, —COOH, —CONH ₂ , —C (O) NHCH ₃ , —NHC (O) CH ₃ ; preferably R _t ¹ = —H, —Cl, —R ¹ , —OR ² , —CH ₂ OCH ₃ , —SCH ₃ ; R _t ² represents —H, halogen, —CH ₃ , —CH ₂ CH ₃ , —CH = CH ₂ , —NH ₂ , —NHCH ₃ , —OH, —OCH ₃ , —SH, —SCH ₃ ; preferably R _t ² = —H, —CH ₃ ; R _t ³ represents —H, halogen, —CN, —NO ₂ , —R ⁶ , —OR ⁴ , —NR ⁴ R ⁵ , —C (O) YR ⁴ , —OC (O) YR ⁴ , —NR ⁴ C (O) YR ⁴ , -SC (O) YR ⁴ , -NR ⁴ C (= S) YR ⁴ , -OC (= S) YR ⁴ , -C (= S) YR ⁴ , -YC (= NR ⁵ ) YR ⁴ , -YP (= O) (YR ⁶ ) (YR ⁶ ), -Si (R ⁶ ) ₃ , -NR ⁴ SO ₂ R ⁴ , -S (O) _r R ⁴ , SO ₂ NR ⁴ R ⁵ , —NR ⁴ SO ² NR ⁴ R ⁵ , where Y is independently selected and is a chemical bond, —O—, —S—, —NR ⁵ -; preferably R _t ³ = —NR ⁴ R ⁵ , —OR ⁴ , —R ⁶ , —CO (Y) R ⁴ ; R ¹ represents alkyl, alkenyl, alkynyl, cycloalkyl containing from 1 to 4 carbon atoms and any substituents (however, the total number of heavy atoms in the group R ¹ should not exceed 4); preferably R ¹ = CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , C≡CHCH ₃ ; R ² represents alkyl, alkenyl, alkynyl containing from 1 to 3 carbon atoms and any substituents (however, the total number of heavy atoms in the group R ² should not exceed 3); preferably R ² = CH ₃ , CH ₂ CH ₃ ; cycle A is a 5- or 6-membered aryl or heteroaryl ring optionally substituted with 1-4 R ^a groups; cycle B is a 5- or 6-membered aryl or heteroaryl ring optionally substituted with 1-5 R ^b groups; R ^a and R ^b are independently selected and are —H, halogen, —CN, —NO ₂ , —R ⁶ , —OR ⁴ , —NR ⁴ R ⁵ , —C (O) YR ⁴ , —OC (O) YR ⁴ , -NR ⁴ C (O) YR ⁴ , -SC (O) YR ⁴ , -NR ⁴ C (= S) YR ⁴ , -OC (= S) YR ⁴ , -C (= S) YR ⁴ , - YC (= NR ⁵ ) YR ⁴ , YP (= O) (YR ⁶ ) YR ⁶ ), -Si (R ⁶ ) ₃ , -NR ⁴ SO ₂ R ⁴ , -S (O) _r R ⁴ , -SO ₂ NR ⁴ R ⁵ , —NR ⁴ SO ₂ NR ⁴ R ⁵ , where Y is independently selected and is a chemical bond, —O—, —S—, —NR ⁵ -; L ¹ represents NR ³ C (O) or C (O) NR ³ ; R ³ , R ⁴ and R ⁵ are independently selected and are H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl or heteroaryl; also the NR ⁴ R ⁵ group may be a 5- or 6-membered saturated, partially saturated or unsaturated cycle, which optionally may contain substituents and also have 0-2 additional heteroatoms selected from N, O and S (O) _r ; in each case, R ⁶ is independently selected and is alkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl or heteroaryl; each of said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl or heteroaryl groups may optionally be substituted; r is selected from 0, 1 or 2; m is 0, 1, 2, 3, 4; p is 0, 1, 2, 3, 4 or 5. 3. The use of an effective amount of any of the compounds according to claims 1 and 2 in mammals for the treatment and / or prevention of cancer, including the introduction of a therapeutically effective amount of any of the compounds from claims 1 to 2, or their pharmacologically acceptable salts, hydrates or solvates. 4. The use of an effective amount of any of the compounds according to claims 1 and 2 in mammals for the treatment and / or prevention of the disease, based on the inhibition of kinase by the compound according to claims 1 and 2, and comprising administering a therapeutically effective amount of the compound or its pharmacologically acceptable salt to the needy human or animal. 5. A pharmaceutical composition comprising any of the compounds of claims 1 and 2, or pharmacologically acceptable salts, hydrates or solvates thereof, and a pharmacologically acceptable carrier, solvent or excipient.