Enhancement of anti-tumor activity of shp2 inhibitor pyrimidinone in combination with novel cancer medicines in cancers

A combination comprising a compound represented by formula (I):

• or a tautomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein:
• X is OH or N,
• R1 is —CH3,
• R2 and R3 are independently selected from the group consisting of hydrogen and C1-4alkyl,
• Q is C or N,
• wherein when Q is C, then either:
• (i) R4 is amino, aminoC1-4alkyl, or monoC1-4alkylamino,
• R5 is hydrogen, C1-4alkyl, halogen, hydroxyC1-4alkyl, C1-4alkoxy, haloC1-4alkyl, or C1-4alkoxyC1-4alkyl,
• or
• (ii) R4 and R5 together with Q form a four- to six-membered ring that can optionally contain 1 to 3 heteroatoms or groups independently selected from the group consisting of N, O, S, NH, C(O), and S(O)m, and said ring formed by R4 and R5 can be unsubstituted or substituted with 1 to 4 groups independently selected from the group consisting of amino, halogen, haloC1-4alkyl, hydroxyl, methoxy, methylamino, and C1-4alkyl, and m is selected from the group consisting of 1 and 2, and
• wherein when Q is N, then:
• R4 is absent, and
• R5 is hydrogen,
• R6 and R7 are independently selected from the group consisting of halogen, C1-4alkyl, hydroxyC1-4alkyl, and hydroxyl, provided that when Q is N, then R6 or R7 is not halogen or hydroxyl,
• or any two groups selected from the group consisting of R2, R3, R6, and R7 together form a one- to three-membered bridge group selected from the group consisting of C1-3alkylene, C2-3alkenylene, methylene-NRq-methylene, and methylene-O-methylene, wherein the bridge group is optionally substituted with a group selected from the group consisting of C1-4alkyl, hydroxyl and halogen, and Rq is selected from the group consisting of hydrogen and C1-4alkyl,
• or R4 and R7 form a four- to six-membered ring containing a N atom,
• or R5 and R7 form a three- to six-membered ring,
• or R6 and R7 form a direct bond,
• a is selected from the group consisting of 0, 1 and 2,
• b is selected from the group consisting of 0, 1 and 2,
• c is selected from the group consisting of 0, 1 and 2,
• or Q is C, c is 2, R4 is hydrogen, and the two R7 join to form a 4 to 6-membered nitrogen containing ring,
• Ring A is either:
• (i) a five-membered nitrogen-containing heterocyclic ring wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from the group consisting of N, O, and S, or
• (ii) a six-membered aromatic nitrogen-containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from the group consisting of N, O, and S, or
• (iii) a six-membered non-aromatic nitrogen-containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from the group consisting of N and S,
• R8 is selected from the group consisting of hydrogen, C1-4alkyl, haloC1-4alkyl, and halogen,
• R9 is selected from the group consisting of hydrogen and halogen,
• R10 is selected from the group consisting of haloC1-4alkyl, C1-4alkyl, halogen, hydrogen, and C1-4alkoxy,
• R11 are independently selected from the group consisting of halogen, cyano, cyanoC1-4alkyl, hydroxyl, oxo (═O), C1-4alkyl optionally substituted with a five- or six-membered heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of O, N, and S, haloC1-4alkyl, C1-4alkoxy, hydroxylC1-4alkyl, C1-4alkoxyC1-4alkyl, C1-4alkylsulfone, amino, monoC1-4alkylamino, diC1-4alkylamino, aminoC1-4alkyl, —C1-4alkylene-C(═O)NH(2-q)(C1-6alkyl)q), —C1-4alkylene-NHC(═O)C1-6alkyl, sulfonamide, sulfonamideC1-4alkyl, 3 to 6-membered cycloalkyl, C1-4alkyl substituted with 3 to 6-membered cycloalkyl, a five- or six-membered unsaturated heterocyclic group containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of O, N, and S, and an optionally substituted four- to six-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of O, N, and S where the optional substituent is selected from C1-4alkyl,
• q is selected from the group consisting of 0, 1, and 2, and
• d is selected from the group consisting of 0, 1, and 2, and
• at least one additional compound having an antitumor effect, at least one tautomer thereof, at least one solvate thereof, or at least one pharmaceutically acceptable salt thereof, selected from the group consisting of molecular targeted drugs and cytotoxic drugs.

An antitumor effect enhancer for at least one additional compound having an antitumor effect, at least one tautomer thereof, at least one solvate thereof, or at least one pharmaceutically acceptable salt thereof, selected from the group consisting of molecular targeted drugs and cytotoxic drugs,

• the antitumor effect enhancer comprising a compound represented by formula (I)
• or a tautomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein:
• X is CH or N,
• R1 is —CH3,
• R2 and R3 are independently selected from the group consisting of hydrogen and C1-4alkyl,
• Q is C or N,
• wherein when Q is C, then either:
• (i) R4 is amino, aminoC1-4alkyl, or monoC1-4alkylamino,
• R5 is hydrogen, C1-4alkyl, halogen, hydroxyC1-4alkyl, C1-4alkoxy, haloC1-4alkyl, or C1-4alkoxyC1-4alkyl,
• or
• (ii) R4 and R5 together with Q form a four- to six-membered ring that can optionally contain 1 to 3 heteroatoms or groups independently selected from the group consisting of N, O, S, NH, C(O), and S(O)m, and said ring formed by R4 and R5 can be unsubstituted or substituted with 1 to 4 groups independently selected from the group consisting of amino, halogen, haloC1-4alkyl, hydroxyl, methoxy, methylamino, and C1-4alkyl, and m is selected from the group consisting of 1 and 2, and
• wherein when Q is N, then:
• R4 is absent, and
• R5 is hydrogen,
• R6 and R7 are independently selected from the group consisting of halogen, C1-4alkyl, hydroxyC1-4alkyl, and hydroxyl, provided that when Q is N, then R6 or R7 is not halogen or hydroxyl,
• or any two groups selected from the group consisting of R2, R3, R6 and R7 together form a one- to three-membered bridge group selected from the group consisting of C1-3alkylene, C2-3alkenylene, methylene-NRq-methylene and methylene-O-methylene, wherein the bridge group is optionally substituted with a group selected from the group consisting of C1-4alkyl, hydroxyl, and halogen, and Rq is selected from the group consisting of hydrogen and C1-4alkyl,
• or R4 and R7 form a four- to six-membered ring containing a N atom,
• or R5 and R7 form a three- to six-membered ring,
• or R6 and R7 form a direct bond,
• a is selected from the group consisting of 0, 1, and 2,
• b is selected from the group consisting of 0, 1, and 2,
• c is selected from the group consisting of 0, 1, and 2,
• or Q is C, c is 2, R4 is hydrogen, and the two R7 join to form a 4 to 6-membered nitrogen containing ring,
• Ring A is either:
• (i) a five-membered nitrogen-containing heterocyclic ring wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from the group consisting of N, O, and S, or
• (ii) a six-membered aromatic nitrogen-containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from the group consisting of N, O, and S, or
• (iii) a six-membered non-aromatic nitrogen-containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from the group consisting of N and S,
• R8 is selected from the group consisting of hydrogen, C1-4alkyl, haloC1-4alkyl, and halogen,
• R9 is selected from the group consisting of hydrogen and halogen,
• R10 is selected from the group consisting of haloC1-4alkyl, C1-4alkyl, halogen, hydrogen, and C1-4alkoxy,
• R11 are independently selected from the group consisting of halogen, cyano, cyanoC1-4alkyl, hydroxyl, oxo (═O), C1-4alkyl optionally substituted with a five- or six-membered heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of O, N, and S, haloC1-4alkyl, C1-4alkoxy, hydroxylC1-4alkyl, C1-4alkoxyC1-4alkyl, C1-4alkylsulfone, amino, monoC1-4alkylamino, diC1-4alkylamino, aminoC1-4alkyl, —C1-4alkylene-C(═O)NH(2-q)(C1-6alkyl)q), —C1-4alkylene-NHC(═O)C1-6alkyl, sulfonamide, sulfonamideC1-4alkyl, 3 to 6-membered cycloalkyl, C1-4alkyl substituted with 3 to 6-membered cycloalkyl, a five- or six-membered unsaturated heterocyclic group containing 1, 2, 3, or 4 heteroatoms selected from the group consisting of O, N, and S, and an optionally substituted four- to six-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of O, N, and S where the optional substituent is selected from C1-4alkyl,
• q is selected from the group consisting of 0, 1 and 2, and
• d is selected from the group consisting of 0, 1 and 2,
• as an active ingredient.

An antitumor agent comprising a compound represented by formula (I)

• or a tautomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein:
• X is CH or N,
• R1 is —CH3,
• R2 and R3 are independently selected from the group consisting of hydrogen and C1-4alkyl,
• Q is C or N,
• wherein when Q is C, then either:
• (i) R4 is amino, aminoC1-4alkyl, or monoC1-4alkylamino, R5 is hydrogen, C1-4alkyl, halogen, hydroxyC1-4alkyl, C1-4alkoxy, haloC1-4alkyl, or C1-4alkoxyC1-4alkyl,
• or
• (ii) R4 and R5 together with Q form a four- to six-membered ring that can optionally contain 1 to 3 heteroatoms or groups independently selected from the group consisting of N, O, S, NH, C(O), and S(O)m, and said ring formed by R4 and R5 can be unsubstituted or substituted with 1 to 4 groups independently selected from the group consisting of amino, halogen, haloC1-4alkyl, hydroxyl, methoxy, methylamino, and C1-4alkyl, and m is selected from the group consisting of 1 and 2, and
• wherein when Q is N, then:
• R4 is absent, and
• R5 is hydrogen,
• R6 and R7 are independently selected from the group consisting of halogen, C1-4alkyl, hydroxyC1-4alkyl, and hydroxyl, provided that when Q is N, then R6 or R7 is not halogen or hydroxyl,
• or any two groups selected from the group consisting of R2, R3, R6, and R7 together form a one- to three-membered bridge group selected from the group consisting of C1-3alkylene, C2-3alkenylene, methylene-NRq-methylene, and methylene-O-methylene, wherein the bridge group is optionally substituted with a group selected from the group consisting of C1-4alkyl, hydroxyl and halogen, and Rq is selected from the group consisting of hydrogen and C1-4alkyl,
• or R4 and R7 form a four- to six-membered ring containing a N atom,
• or R5 and R7 form a three- to six-membered ring,
• or R6 and R7 form a direct bond,
• a is selected from the group consisting of 0, 1, and 2,
• b is selected from the group consisting of 0, 1, and 2,
• c is selected from the group consisting of 0, 1, and 2,
• or Q is C, c is 2, R4 is hydrogen, and the two R7 join to form a 4 to 6-membered nitrogen containing ring,
• Ring A is either:
• (i) a five-membered nitrogen-containing heterocyclic ring wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from the group consisting of N, O, and S, or
• (ii) a six-membered aromatic nitrogen-containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from the group consisting of N, O, and S, or
• (iii) a six-membered non-aromatic nitrogen-containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from the group consisting of N and S,
• R8 is selected from the group consisting of hydrogen, C1-4alkyl, haloC1-4alkyl, and halogen,
• R9 is selected from the group consisting of hydrogen and halogen,
• R10 is selected from the group consisting of haloC1-4alkyl, C1-4alkyl, halogen, hydrogen, and C1-4alkoxy,
• R11 are independently selected from the group consisting of halogen, cyano, cyanoC1-4alkyl, hydroxyl, oxo (═O), C1-4alkyl optionally substituted with a five- or six-membered heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of O, N, and S, haloC1-4alkyl, C1-4alkoxy, hydroxylC1-4alkyl, C1-4alkoxyC1-4alkyl, C1-4alkylsulfone, amino, monoC1-4alkylamino, diC1-4alkylamino, aminoC1-4alkyl, —C1-4alkylene-C(═O)NH(2-q)(C1-6alkyl)q), —C1-4alkylene-NHC(═O)C1-6alkyl, sulfonamide, sulfonamideC1-4alkyl, 3 to 6-membered cycloalkyl, C1-4alkyl substituted with 3 to 6-membered cycloalkyl, a five- or six-membered unsaturated heterocyclic group containing 1, 2, 3, or 4 heteroatoms selected from the group consisting of O, N, and S, and an optionally substituted four- to six-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of O, N, and S where the optional substituent is selected from C1-4alkyl,
• q is selected from the group consisting of 0, 1, and 2, and
• d is selected from the group consisting of 0, 1, and 2,
• wherein the antitumor agent is concomitantly used with at least one additional compound having an antitumor effect, at least one tautomer thereof, at least one solvate thereof, or at least one pharmaceutically acceptable salt thereof, selected from the group consisting of molecular targeted drugs and cytotoxic drugs.

A method of treating a tumor comprising administering a compound represented by formula (I)

• or a tautomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein:
• X is CH or N,
• R1 is —CH3,
• R2 and R3 are independently selected from the group consisting of hydrogen and C1-4alkyl,
• Q is C or N,
• wherein when Q is C, then either:
• (i) R4 is amino, aminoC1-4alkyl or monoC1-4alkylamino,
• R5 is hydrogen, C1-4alkyl, halogen, hydroxyC1-4alkyl, C1-4alkoxy, haloC1-4alkyl, or C1-4alkoxyC1-4alkyl,
• or
• (ii) R4 and R5 together with Q form a four- to six-membered ring that can optionally contain 1 to 3 heteroatoms or groups independently selected from the group consisting of N, O, S, NH, C(O), and S(O)m, and said ring formed by R4 and R5 can be unsubstituted or substituted with 1 to 4 groups independently selected from the group consisting of amino, halogen, haloC1-4alkyl, hydroxyl, methoxy, methylamino, and C1-4alkyl, and m is selected from the group consisting of 1 and 2, and
• wherein when Q is N, then:
• R4 is absent, and
• R5 is hydrogen,
• R6 and R7 are independently selected from the group consisting of halogen, C1-4alkyl, hydroxyC1-4alkyl, and hydroxyl, provided that when Q is N, then R6 or R7 is not halogen or hydroxyl,
• or any two groups selected from the group consisting of R2, R3, R6, and R7 together form a one- to three-membered bridge group selected from the group consisting of C1-3alkylene, C2-3alkenylene, methylene-NRq-methylene, and methylene-O-methylene, wherein the bridge group is optionally substituted with a group selected from the group consisting of C1-4alkyl, hydroxyl, and halogen, and Rq is selected from the group consisting of hydrogen and C1-4alkyl,
• or R4 and R7 form a four- to six-membered ring containing a N atom,
• or R5 and R7 form a three- to six-membered ring,
• or R6 and R7 form a direct bond,
• a is selected from the group consisting of 0, 1, and 2,
• b is selected from the group consisting of 0, 1, and 2,
• c is selected from the group consisting of 0, 1, and 2,
• or Q is C, c is 2, R4 is hydrogen, and the two R7 join to form a 4 to 6-membered nitrogen containing ring,
• Ring A is either:
• (i) a five-membered nitrogen-containing heterocyclic ring wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from the group consisting of N, O, and S, or
• (ii) a six-membered aromatic nitrogen-containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from the group consisting of N, O, and S, or
• (iii) a six-membered non-aromatic nitrogen-containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from the group consisting of N and S,
• R8 is selected from the group consisting of hydrogen, C1-4alkyl, haloC1-4alkyl, and halogen,
• R9 is selected from the group consisting of hydrogen and halogen,
• R10 is selected from the group consisting of haloC1-4alkyl, C1-4alkyl, halogen, hydrogen, and C1-4alkoxy,
• R11 are independently selected from the group consisting of halogen, cyano, cyanoC1-4alkyl, hydroxyl, oxo (═O), C1-4alkyl optionally substituted with a five- or six-membered heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of O, N, and S, haloC1-4alkyl, C1-4alkoxy, hydroxylC1-4alkyl, C1-4alkoxyC1-4alkyl, C1-4alkylsulfone, amino, monoC1-4alkylamino, diC1-4alkylamino, aminoC1-4alkyl, —C1-4alkylene-C(═O)NH(2-q)(C1-6alkyl)q), —C1-4alkylene-NHC(═O)C1-6alkyl, sulfonamide, sulfonamideC1-4alkyl, 3 to 6-membered cycloalkyl, C1-4alkyl substituted with 3 to 6-membered cycloalkyl, a five- or six-membered unsaturated heterocyclic group containing 1, 2, 3, or 4 heteroatoms selected from the group consisting of O, N, and S, and an optionally substituted four- to six-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of O, N, and S where the optional substituent is selected from C1-4alkyl,
• q is selected from the group consisting of 0, 1, and 2, and
• d is selected from the group consisting of 0, 1, and 2, and at least one additional compound having an antitumor effect, at least one tautomer thereof, at least one solvate thereof, or at least one pharmaceutically acceptable salt thereof, selected from the group consisting of molecular targeted drugs and cytotoxic drugs.

A kit for malignant tumor treatment comprising a compound represented by formula (I)

• or a tautomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein:
• X is CH or N,
• R1 is —CH3,
• R2 and R3 are independently selected from the group consisting of hydrogen and C1-4alkyl,
• Q is C or N,
• wherein when Q is C, then either:
• (i) R4 is amino, aminoC1-4alkyl, or monoC1-4alkylamino,
• R5 is hydrogen, C1-4alkyl, halogen, hydroxyC1-4alkyl, C1-4alkoxy, haloC1-4alkyl, or C1-4alkoxyC1-4alkyl,
• or
• (ii) R4 and R5 together with Q form a four- to six-membered ring that can optionally contain 1 to 3 heteroatoms or groups independently selected from the group consisting of N, O, S, NH, C(O), and S(O)m, and said ring formed by R4 and R5 can be unsubstituted or substituted with 1 to 4 groups independently selected from the group consisting of amino, halogen, haloC1-4alkyl, hydroxyl, methoxy, methylamino, and C1-4alkyl, and m is selected from the group consisting of 1 and 2, and
• wherein when Q is N, then:
• R4 is absent, and
• R5 is hydrogen,
• R6 and R7 are independently selected from the group consisting of halogen, C1-4alkyl, hydroxyC1-4alkyl, and hydroxyl, provided that when Q is N, then R6 or R7 is not halogen or hydroxyl,
• or any two groups selected from the group consisting of R2, R3, R6, and R7 together form a one- to three-membered bridge group selected from the group consisting of C1-3alkylene, C2-3alkenylene, methylene-NRq-methylene, and methylene-O-methylene, wherein the bridge group is optionally substituted with a group selected from the group consisting of C1-4alkyl, hydroxyl, and halogen, and Rq is selected from the group consisting of hydrogen and C1-4alkyl,
• or R4 and R7 form a four- to six-membered ring containing a N atom,
• or R5 and R7 form a three- to six-membered ring,
• or R6 and R7 form a direct bond,
• a is selected from the group consisting of 0, 1, and 2,
• b is selected from the group consisting of 0, 1, and 2,
• c is selected from the group consisting of 0, 1, and 2,
• or Q is C, c is 2, R4 is hydrogen, and the two R7 join to form a 4 to 6-membered nitrogen containing ring,
• Ring A is either:
• (i) a five-membered nitrogen-containing heterocyclic ring wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from the group consisting of N, O, and S, or
• (ii) a six-membered aromatic nitrogen-containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from the group consisting of N, O, and S, or
• (iii) a six-membered non-aromatic nitrogen-containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from the group consisting of N and S,
• R8 is selected from the group consisting of hydrogen, C1-4alkyl, haloC1-4alkyl and halogen,
• R9 is selected from the group consisting of hydrogen and halogen,
• R10 is selected from the group consisting of haloC1-4alkyl, C1-4alkyl, halogen, hydrogen, and C1-4alkoxy,
• R11 are independently selected from the group consisting of halogen, cyano, cyanoC1-4alkyl, hydroxyl, oxo (═O), C1-4alkyl optionally substituted with a five- or six-membered heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of O, N, and S, haloC1-4alkyl, C1-4alkoxy, hydroxylC1-4alkyl, C1-4alkoxyC1-4alkyl, C1-4alkylsulfone, amino, monoC1-4alkylamino, diC1-4alkylamino, aminoC1-4alkyl, —C1-4alkylene-C(═O)NH(2-q)(C1-6alkyl)q), —C1-4alkylene-NHC(═O)C1-6alkyl, sulfonamide, sulfonamideC1-4alkyl, 3 to 6-membered cycloalkyl, C1-4alkyl substituted with 3 to 6-membered cycloalkyl, a five- or six-membered unsaturated heterocyclic group containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of O, N, and S, and an optionally substituted four- to six-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of O, N, and S where the optional substituent is selected from C1-4alkyl,
• q is selected from the group consisting of 0, 1, and 2, and
• d is selected from the group consisting of 0, 1, and 2
• and at least one additional compound having an antitumor effect, at least one tautomer thereof, at least one solvate thereof, or at least one pharmaceutically acceptable salt thereof, selected from the group consisting of molecular targeted drugs and cytotoxic drugs.