US 12,357,603 B2
Acyl sulfonamides for treating cancer
Léa Aurelie Bouché, Berlin (DE); Daniel Korr, Berlin (DE); Antonius ter Laak, Berlin (DE); Ernesto Amaury Fernandez-Montalvan, Le Pecq (FR); Naomi Barak, Berlin (DE); Roman Hillig, Berlin (DE); Roland Neuhaus, Berlin (DE); Matyas Gorjanacz, Berlin (DE); Vera Pütter, Berlin (DE); Stefan Niklaus Gradl, Berlin (DE); Simon Anthony Herbert, Berlin (DE); Steven James Ferrara, Cambridge, MA (US); Craig Strathdee, Watertown, MA (US); and Jacob Jaffe, Cambridge, MA (US)
Assigned to Bayer Aktiengesellschaft, Leverkusen (DE); and The Broad Institute, Inc., Cambridge, MA (US)
Appl. No. 17/605,818
Filed by Bayer Aktiengesellschaft, Leverkusen (DE); and The Broad Institute, Inc., Cambridge, MA (US)
PCT Filed Apr. 20, 2020, PCT No. PCT/EP2020/060962
§ 371(c)(1), (2) Date Oct. 22, 2021,
PCT Pub. No. WO2020/216701, PCT Pub. Date Oct. 29, 2020.
Claims priority of provisional application 62/838,477, filed on Apr. 25, 2019.
Prior Publication US 2022/0226279 A1, Jul. 21, 2022
Int. Cl. A61K 31/343 (2006.01); A61K 31/351 (2006.01); A61K 31/357 (2006.01); A61K 31/381 (2006.01); A61K 31/4025 (2006.01); A61K 31/4035 (2006.01); A61K 31/4155 (2006.01); A61K 31/4245 (2006.01); A61K 31/443 (2006.01); A61K 31/4525 (2006.01); A61K 31/4709 (2006.01); A61K 31/5025 (2006.01); A61P 35/00 (2006.01); C07D 307/85 (2006.01); C07D 333/70 (2006.01); C07D 405/04 (2006.01); C07D 405/12 (2006.01); C07D 407/12 (2006.01); C07D 413/12 (2006.01); C07D 487/04 (2006.01)
CPC A61K 31/343 (2013.01) [A61K 31/351 (2013.01); A61K 31/357 (2013.01); A61K 31/381 (2013.01); A61K 31/4025 (2013.01); A61K 31/4035 (2013.01); A61K 31/4155 (2013.01); A61K 31/4245 (2013.01); A61K 31/443 (2013.01); A61K 31/4525 (2013.01); A61K 31/4709 (2013.01); A61K 31/5025 (2013.01); A61P 35/00 (2018.01); C07D 307/85 (2013.01); C07D 333/70 (2013.01); C07D 405/04 (2013.01); C07D 405/12 (2013.01); C07D 407/12 (2013.01); C07D 413/12 (2013.01); C07D 487/04 (2013.01)] 17 Claims
 
1. A compound of formula (I)

OG Complex Work Unit Chemistry
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.
 
17. A method of treating comprising administering an effective amount of at least one compound of general formula (I) to a subject in need thereof according to claim 1 wherein the cancer is selected from lung cancer, breast cancer, bladder cancer, uterine cancer, endometrial cancer, prostate cancer and leukemia.