US 12,357,603 B2 · Acyl sulfonamides for treating cancer

Abstract

The present invention provides acyl sulfonamide compounds of general formula (I): in which X, R1, R2, R3, R4, R5, R6′ Ra and Rb are as described and defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds, and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of hyperproliferative disorders, as a sole agent or in combination with other active ingredients as well as methods of treating and/or prophylaxing diseases, particularly cancer, more particularly cancer in which KAT6A and/or KAT6B is focally amplified, said method comprising administering an effective amount of at least one compound of formula (I) to a subject in need thereof.

A compound of formula (I)

wherein
X is an oxygen atom;
R1 is selected from a hydrogen atom, a halogen atom, a cyano group, a nitro group, a R7R8N— group, a C1-C6-alkyl group, a C3-C8-cycloalkyl group, a C1-C6-alkoxy group, a C1-C6-haloalkyl group, a heterocycloalkyl group, a phenyl group, a naphthyl group and a heteroaryl group,
wherein said heterocycloalkyl group is connected to the rest of the molecule via a carbon atom of said heterocycloalkyl group,
wherein said phenyl, naphthyl, heterocycloalkyl or heteroaryl group is optionally substituted with one or more substituents independently selected from a halogen atom, a cyano group, a nitro group, a C1-C6-alkyl group, a C1-C6-hydroxyalkyl group, a C1-C6-alkylsulfanyl group, a C1-C6-haloalkyl group, a C1-C6-alkoxy group, a C1-C6-haloalkoxy group, a C2-C6-alkenyl group, a C2-C6-alkynyl group, a C3-C8-cycloalkyl group, a C4-C8-cycloalkenyl group, a C3-C8-cycloalkoxy group, a R7R8N— group, a heterocycloalkyl group, a phenyl group, a naphthyl group and a heteroaryl group,
wherein said heterocycloalkyl group is connected to the rest of the molecule via a carbon atom of said heterocycloalkyl group;
R2 is selected from a hydrogen atom, a halogen atom, a cyano group, a nitro group, a R7R8N— group, a C1-C6-alkyl group, a C3-C8-cycloalkyl group, a C1-C6-alkoxy group, a C1-C6-haloalkyl group, a heterocycloalkyl group, a phenyl group, a naphthyl group and a heteroaryl group,
wherein said heterocycloalkyl group is connected to the rest of the molecule via a carbon atom of said heterocycloalkyl group,
wherein said phenyl, naphthyl, heterocycloalkyl or heteroaryl group is optionally substituted with one or more substituents independently selected from a halogen atom, a cyano group, a nitro group, a C1-C6-alkyl group, a C1-C6-hydroxyalkyl group, a C1-C6-alkylsulfanyl group, a C1-C6-haloalkyl group, a C1-C6-alkoxy group, a C1-C6-haloalkoxy group, a C2-C6-alkenyl group, a C2-C6-alkynyl group, a C3-C8-cycloalkyl group, a C4-C8-cycloalkenyl group, a C3-C8-cycloalkoxy group, a R7R8N— group, a heterocycloalkyl group, a phenyl group, a naphthyl group and a heteroaryl group,
wherein said heterocycloalkyl group is connected to the rest of the molecule
via a carbon atom of said heterocycloalkyl group;
R3 is selected from a hydrogen atom, a halogen atom, a cyano group, a nitro group, a R7R8N— group, a C1-C6-alkyl group, a C3-C8-cycloalkyl group, a C1-C6-alkoxy group, a C1-C6-haloalkyl group, a heterocycloalkyl group, a phenyl group, a naphthyl group and a heteroaryl group,
wherein said heterocycloalkyl group is connected to the rest of the molecule via a carbon atom of said heterocycloalkyl group,
wherein said phenyl, naphthyl, heterocycloalkyl or heteroaryl group is optionally substituted with one or more substituents independently selected from a halogen atom, a cyano group, a nitro group, a C1-C6-alkyl group, a C1-C6-hydroxyalkyl group, a C1-C6-alkylsulfanyl group, a C1-C6-haloalkyl group, a C1-C6-alkoxy group, a C1-C6-haloalkoxy group, a C2-C6-alkenyl group, a C2-C6-alkynyl group, a C3-C8-cycloalkyl group, a C4-C8-cycloalkenyl group, a C3-C8-cycloalkoxy group, a R7R8N— group, a heterocycloalkyl group, a phenyl group, a naphthyl group and a heteroaryl group,
wherein said heterocycloalkyl group is connected to the rest of the molecule
via a carbon atom of said heterocycloalkyl group;
R4 is selected from a hydrogen atom, a halogen atom, a C1-C6-alkyl group and a C3-C8-cycloalkyl group;
R5 is selected from a hydrogen atom and a C1-C6-alkyl group;
R6 is selected from a C1-C6-alkyl group, a phenyl group, a naphthyl group, a heteroaryl group, a (phenyl)-(C1-C6-alkyl)- group, a (naphthyl)-(C1-C6-alkyl)- group, a (heteroaryl)-(C1-C6-alkyl)- group, a (heterocycloalkyl)-(C1-C6-alkyl)- group and a heterocycloalkyl group,
wherein said heterocycloalkyl group is connected to the rest of the molecule via a carbon atom of said heterocycloalkyl group,
wherein said phenyl, naphthyl, heteroaryl or heterocycloalkyl group is each optionally substituted with one or more substituents independently selected from a halogen atom, a cyano group, a nitro group, a hydroxy group, a C1-C6-alkyl group, a C1-C6-hydroxyalkyl group, a C1-C6-alkylsulfanyl group, a C1-C6-haloalkyl group, a C1-C6-alkoxy group, a C1-C6-haloalkoxy group, a C2-C6-alkenyl group, a C2-C6-alkynyl group, a C3-C8-cycloalkyl group, a C4-C8-cycloalkenyl group, a C3-C8-cycloalkoxy group, a (C1-C2-alkyl)-O—(C1-C2-alkyl)-O— group, a (C3-C8-cycloalkyl)-(C1-C2-alkyl)-O— group, a (C3-C8-halocycloalkyl)-(C1-C2-alkyl)-O— group, a C1-C6-thioalkyl group, a heterocycloalkyl group, a (heterocycloalkyl)-O— group, a R7R8N— group, a (R7R8N)—(S(═O)2)— group, a (C1-C2-alkyl)-(S(═O)2)— group, a CH3—C(═O)—CH2— group, a (R7R8N)—(C1-C6-alkyl)-(C═O)—NH— group, a (R7R8N)—(C1-C6-alkyl)- group, a (R7R8N)—(C1-C6-alkyl)-O— group, a R9OOC— group, a phenyl group, a naphthyl group, a (phenyl)-(C1-C2-alkyl)-O— group, a (phenyl)-O— group, a heteroaryl group and a heteroaryl-(C1-C2-alkyl)- group,
wherein said heterocycloalkyl group is connected to the rest of the molecule via a carbon atom of said heterocycloalkyl group,
wherein said phenyl, naphthyl, heteroaryl or heterocycloalkyl group is each optionally substituted with one or more substituents independently selected from a halogen atom, a cyano group, a nitro group, a C1-C6-alkyl group, a C1-C6-hydroxyalkyl group, a C1-C6-alkylsulfanyl group, a C1-C6-haloalkyl group, a C1-C6-alkoxy group, a C1-C6-haloalkoxy group, a C2-C6-alkenyl group, a C2-C6-alkynyl group, a C3-C8-cycloalkyl group, a C4-C8-cycloalkenyl group, a C3-C8-cycloalkoxy group, a heterocycloalkyl group, a R7R8N— group, a (R7R8N)—(S═O)2— group, a (R7R8N)—(C1-C6-alkyl)-(C═O)—NH— group, a (R7R8N)—(C1-C6-alkyl)- group, and a R9OOC— group,
wherein said heterocycloalkyl group is connected to the rest of the molecule via a carbon atom of said heterocycloalkyl group;
R7 and R8 are each independently selected from a hydrogen atom, a C1-C6-alkyl group, a C3-C8-cycloalkyl group, a C1-C6-haloalkyl group, a HC(═O)— group, a (C1-C2-alkyl)-(C(═O))— group, a (C1-C6-alkyl) C(═O)— group, a (C1-C6-haloalkyl) C(═O)— group, a (C3-C8-cycloalkyl)-(C1-C6-alkyl)- group, a C1-C6-hydroxyalkyl group, a (C1-C6-alkoxy)-(C1-C6-alkyl)- group, a (phenyl)-(S═O)2— group, a (C1-C6-alkyl)-(S═O)2— group, a (C1-C6-haloalkyl)-(S═O)2— group, a R9OOC— group, a phenyl group, a heterocycloalkyl group and a heteroaryl group, wherein said heterocycloalkyl group is connected to the rest of the molecule via a carbon atom of said heterocycloalkyl group,
wherein said phenyl, heteroaryl or heterocycloalkyl group is each optionally substituted with one or more substituents independently selected from a halogen atom, a cyano group, a nitro group, a C1-C6-alkyl group, a C1-C6-hydroxyalkyl group, a C1-C6-alkylsulfanyl group, a C1-C6-haloalkyl group, a C1-C6-alkoxy group, a C1-C6-haloalkoxy group, a C2-C6-alkenyl group, a C2-C6-alkynyl group, a C3-C8-cycloalkyl group, a C4-C8-cycloalkenyl group, a C3-C8-cycloalkoxy group, a C1-C6-thioalkyl group, a heterocycloalkyl group, and a R9OOC— group,
wherein said heterocycloalkyl group is connected to the rest of the molecule via a carbon atom of said heterocycloalkyl group;
or R7 and R8 together with the nitrogen atom to which they are attached form a 4- to 7-membered nitrogen-containing heterocycloalkyl group, wherein said heterocycloalkyl group optionally contains one, two or three further heteroatoms independently selected from nitrogen, oxygen and sulfur and/or is optionally substituted with one or more substituents independently selected from a halogen atom, a cyano group, a nitro group, a C1-C6-alkyl group, a C1-C6-hydroxyalkyl group, a C1-C6-alkylsulfanyl group, a C1-C6-haloalkyl group, a C1-C6-alkoxy group, a C1-C6-haloalkoxy group, a C2-C6-alkenyl group, a C2-C6-alkynyl group, a C3-C8-cycloalkyl group, a C4-C8-cycloalkenyl group, a C3-C8-cycloalkoxy group, a C1-C6-thioalkyl group, a heterocycloalkyl group and a R9OOC— group,
wherein said heterocycloalkyl group is connected to the rest of the molecule via a carbon atom of said heterocycloalkyl group;
R9 is selected from a hydrogen atom, a C1-C6-alkyl group and a C3-C8-cycloalkyl group;
Ra and Rb are each independently selected from a hydrogen atom, a C1-C6-alkyl group, a C3-C8-cycloalkyl group, a C1-C6-haloalkyl group, a HC(═O)— group, a (C1-C6-alkyl) C(═O)— group, a (C1-C6-haloalkyl) C(═O)— group, a (C3-C8-cycloalkyl)-(C1-C6-alkyl)- group, a C1-C6-hydroxyalkyl group, a (C1-C6-alkoxy)-(C1-C6-alkyl)- group, a heterocycloalkyl group, a heteroaryl group and a phenyl group,
wherein said heterocycloalkyl group is connected to the rest of the molecule via a carbon atom of said heterocycloalkyl group,
wherein said phenyl, heteroaryl or heterocycloalkyl group is each optionally substituted with one or more substituents independently selected from a halogen atom, a cyano group, a nitro group, a C1-C6-alkyl group, a C1-C6-hydroxyalkyl group, a C1-C6-alkylsulfanyl group, a C1-C6-haloalkyl group, a C1-C6-alkoxy group, a C1-C6-haloalkoxy group, a C2-C6-alkenyl group, a C2-C6-alkynyl group, a C3-C8-cycloalkyl group, a C4-C8-cycloalkenyl group, a C3-C8-cycloalkoxy group, a C1-C6-thioalkyl group, a heterocycloalkyl group, a R7R8N— group, a (R7R8N)—(S═O)2— group, a (R7R8N)—(C1-C6-alkyl)-(C═O)—NH— group, a (R7R8N)—(C1-C6-alkyl)- group and a R9OOC— group,
wherein said heterocycloalkyl group is connected to the rest of the molecule via a carbon atom of said heterocycloalkyl group;
or Ra and Rb together with the nitrogen atom to which they are attached form a 4- to 7-membered nitrogen-containing heterocycloalkyl group,
or R1 and one of Ra and Rb, together with the carbon and the nitrogen atom to which they are respectively attached form a 5- to 7-membered nitrogen-containing heterocycloalkyl group,
or R2 and one of Ra and Rb, together with the carbon and the nitrogen atom to which they are respectively attached form a 5- to 7-membered nitrogen-containing heterocycloalkyl group,
wherein said 4- to 7-membered or 5- to 7-membered nitrogen-containing heterocycloalkyl group optionally contains one, two or three further heteroatoms independently selected from nitrogen, oxygen and sulfur and/or is optionally substituted one, two or three times, each substituent independently selected from a halogen atom or a group selected from cyano, hydroxy, a C1-C2-alkyl group, a C1-C2-haloalkyl group, a C1-C2-alkoxy group, a C3-C4-cycloalkyl group, a (H2N)—(C═O)— group and oxo;
or a tautomer, or a salt thereof, or a salt of a tautomer, or a mixture of same.

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Acyl sulfonamides for treating cancer

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Acyl sulfonamides for treating cancer

Life of this patent

Abstract

Claims17