US 12,478,621 B2
Substituted aminoquinolones as dgkalpha inhibitors for immune activation
Norbert Schmees, Berlin (DE); Lars Wortmann, Biberbach an der Riß (DE); Dennis Kirchhoff, Berlin (DE); Thi Thanh Uyen Nguyen, Berlin (DE); Nicolas Werbeck, Freiburg (DE); Ulf Bömer, Glienicke (DE); Kirstin Petersen, Berlin (DE); Christina Kober, Lollar (DE); Detlef Stöckigt, Potsdam (DE); Christian Lechner, Berlin (DE); Robin Michael Meier, Wain (DE); Simon Anthony Herbert, Berlin (DE); Isabel Patrizia Kerschgens, Zürich (CH); Dirk Kosemund, Berlin (DE); Rienk Offringa, Heidelberg (DE); Mareike Grees, Berlin (DE); and Benjamin Bader, Berlin (DE)
Assigned to Deutsches Krebsforschungszentrum, (DE); Bayer Pharma Aktiengesellschaft, (DE); and Bayer Aktiengesellschaft, (DE)
Appl. No. 17/780,890
Filed by Bayer Aktiengesellschaft, Leverkusen (DE); Bayer Pharma Aktiengesellschaft, Berlin (DE); and Deutsches Krebsforschungszentrum, Heidelberg (DE)
PCT Filed Nov. 24, 2020, PCT No. PCT/EP2020/083198
§ 371(c)(1), (2) Date May 27, 2022,
PCT Pub. No. WO2021/105117, PCT Pub. Date Jun. 3, 2021.
Claims priority of application No. 19212252 (EP), filed on Nov. 28, 2019; and application No. 20181065 (EP), filed on Jun. 19, 2020.
Prior Publication US 2023/0148194 A1, May 11, 2023
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 31/4545 (2006.01); A61K 31/4709 (2006.01); A61K 31/4725 (2006.01); A61K 31/496 (2006.01); A61K 31/498 (2006.01); A61K 31/55 (2006.01); A61K 45/06 (2006.01); A61P 35/00 (2006.01); A61P 37/04 (2006.01); C07D 401/04 (2006.01); C07D 401/14 (2006.01); C07D 405/14 (2006.01); C07D 413/14 (2006.01); C07D 417/14 (2006.01)
CPC A61K 31/4545 (2013.01) [A61K 31/4709 (2013.01); A61K 31/4725 (2013.01); A61K 31/496 (2013.01); A61K 31/498 (2013.01); A61K 31/55 (2013.01); A61K 45/06 (2013.01); A61P 35/00 (2018.01); A61P 37/04 (2018.01); C07D 401/04 (2013.01); C07D 401/14 (2013.01); C07D 405/14 (2013.01); C07D 413/14 (2013.01); C07D 417/14 (2013.01)] 17 Claims
 
1. A compound of general formula (I):

OG Complex Work Unit Chemistry
wherein:
R1 is selected from the group consisting of cyano, —C(═O)NH2, —C(═O)N(H)CH3, —C(═O)N(H)C2H5, —C(═O)N(CH3)2, and —C(═O)OR15;
R2 is selected from the group consisting of phenyl, naphthyl, and 5- to 10-membered heteroaryl,
wherein the 5- to 10-membered heteroaryl group is connected to the rest of the molecule via a carbon atom of said 5- to 10-membered heteroaryl group,
wherein the phenyl, naphthyl, and 5- to 10-membered heteroaryl group each optionally substituted, one, two, three, or four times,
wherein each substituent is independently selected from the group consisting of a halogen atom, C1-C6-alkyl, C3-C6-cycloalkyl, C1-C6-hydroxyalkyl, C1-C6-haloalkyl, (C1-C2-alkoxy)-(C1-C6-alkyl)-, C1-C6-alkoxy, (C1-C2 alkoxy)-(C1-C6-alkoxy)-, C1-C6-haloalkoxy, C3-C6-cycloalkyloxy, phenoxy, —SR14, —S(═O)R14, —S(═O)2R14, —P(═O)(R14)2, cyano, hydroxy, —N(R9)(R10), —C(═O)N(R9)(R10), —C(═O)R11, —N(R12)C(═O)R13, —N(R12)S(═O)2R14, —N═S(═NH)(R14)2, —N═S(═O)(R14)2, 4- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkenyl, (4- to 7-membered heterocycloalkyl)oxy, phenyl, and 5- or 6-membered heteroaryl,
or two substituents of said phenyl group, when they are attached to adjacent ring atoms, are linked to one another in such a way that they jointly form a group selected from the group consisting of —(CH2)3—, —CH2—CH(OH)—CH2—, —(CH2)4—, —O—(CH2)2—, —(CH2)2—O—, —CH2—CH(CH3)—O—, —CH2—O—CH2—, —O—(CH2)3—, —(CH2)3—O—, —CH2—O—(CH2)2—, —(CH2)2—O—CH2—, —O—CH2—O—, —O—C(CH3)2—O—, —O—(CH2)2—O—, —N(R18)—C(═O)—(C(R18)(R19))m—, —N(R18)—C(═O)—(C(CH3)2)—, —N(R18)—(C(R18)(R19))m—, —N(R18)—C(═O)—O—, and —N(R18)—C(═O)—N(R18)—,
wherein said 4- to 7-membered heterocycloalkyl group and
5- to 7-membered heterocycloalkenyl group are connected to the rest of the molecule via a carbon atom of said
4- to 7-membered heterocycloalkyl group or
5- to 7-membered heterocycloalkenyl group,
wherein said 4- to 7-membered heterocycloalkyl group,
5- to 7-membered heterocycloalkenyl group, and
(4- to 7-membered heterocycloalkyl)oxy group are optionally substituted, one, two, or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, C1-C2-alkyl, C1-C2-haloalkyl, cyano, hydroxy, C1-C2-alkoxy, C3-C4-cycloalkyl, —N(R9)(R10), and oxo,
wherein said C1-C6-alkyl and C1-C6-alkoxy groups are optionally substituted with a group selected from the group consisting of C3-C4-cycloalkyl, phenyl, and 4- to 7-membered heterocycloalkyl,
wherein said 4- to 7-membered heterocycloalkyl group is connected to the rest of the molecule via a carbon atom of said 4- to 7-membered heterocycloalkyl group,
wherein said 4- to 7-membered heterocycloalkyl group is optionally substituted, one, two or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, C1-C2-alkyl, C1-C2-haloalkyl, cyano, hydroxy, C1-C2-alkoxy, C3-C4-cycloalkyl, —N(R9)(R10), and oxo, wherein the phenyl group is optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, C1-C2-alkyl, C1-C2-haloalkyl, cyano, hydroxy, C1-C2-alkoxy, C3-C4-cycloalkyl, and —N(R9)(R10),
wherein the C3-C4-cycloalkyl group is optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, and hydroxy,
wherein said C3-C6-cycloalkyl group is optionally substituted, one or two times, wherein each substituent is independently a halogen atom or a C1-C4-alkyl group,
and
wherein said phenyl, phenoxy, and 5- or 6-membered heteroaryl group are optionally substituted, one or two times, each substituent independently selected from the group consisting of a halogen atom, C1-C2-alkyl, C1-C2-haloalkyl, cyano, hydroxy, C1-C2-alkoxy, C3-C4-cycloalkyl, and —N (R9)(R10);
R3 is selected from the group consisting of a hydrogen atom, a halogen atom, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C4-C6-cycloalkenyl, C1-C6-hydroxyalkyl, C1-C6-haloalkyl, (C1-C2-alkoxy)-(C1-C6-alkyl)-, C1-C6-alkoxy, (C1-C2 alkoxy)-(C1-C6-alkoxy)-, C1-C4-haloalkoxy, C3-C6-cycloalkyloxy, phenoxy, —SR14, —S(═O)R14, —S(═O)2R14, cyano, hydroxy, —N(R9)(R10), —C(═O)N(R9)(R10), —C(═O)R11, —N(R12)C(═O)R13, —N(R12)S(═O)2R14, —N═S(═NH)(R14)2, —N═S(═O)(R14)2, —P(═O)(R14)2, 4- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkenyl, (4- to 7-membered heterocycloalkyl)oxy, phenyl, and 5- or 6-membered heteroaryl,
wherein said 4- to 7-membered heterocycloalkyl group and 5- to 7-membered heterocycloalkenyl group are connected to the rest of the molecule via a carbon atom of said 4- to 7-membered heterocycloalkyl group or 5- to 7-membered heterocycloalkenyl group,
wherein said 4- to 7-membered heterocycloalkyl group, 5- to 7-membered heterocycloalkenyl group, and (4- to 7-membered heterocycloalkyl)oxy group are optionally substituted, one, two, or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, C1-C2-alkyl, C1-C2-haloalkyl, cyano, hydroxy, C1-C2-alkoxy, C3-C4-cycloalkyl, —N(R9)(R10), and oxo,
wherein said C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, and C1-C6-alkoxy groups are optionally substituted with a group selected from the group consisting of C3-C4-cycloalkyl, phenyl, and 4- to 7-membered heterocycloalkyl,
wherein said 4- to 7-membered heterocycloalkyl group is connected to the rest of the molecule via a carbon atom of said 4- to 7-membered heterocycloalkyl group,
wherein said 4- to 7-membered heterocycloalkyl group is optionally substituted, one, two, or three times, each substituent independently selected from the group consisting of a halogen atom, C1-C2-alkyl, C1-C2-haloalkyl, cyano, hydroxy, C1-C2-alkoxy, C3-C4-cycloalkyl, —N(R9)(R10), and oxo,
wherein the phenyl group is optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, C1-C2-alkyl, C1-C2-haloalkyl, cyano, hydroxy, C1-C2-alkoxy, C3-C4-cycloalkyl, and —N(R9)(R10),
wherein the C3-C4-cycloalkyl group is optionally substituted, one or two times, each substituent independently selected from the group consisting of a halogen atom, cyano, and hydroxy,
wherein said C2-C6-alkenyl group is optionally substituted with a C1-C4-haloalkyl group,
wherein said C3-C6-cycloalkyl and C4-C6-cycloalkenyl groups are optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, C1-C4-alkyl, and C1-C4-haloalkyl,
wherein said phenyl, phenoxy, and 5- or 6-membered heteroaryl groups are optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, C1-C2-alkyl, C1-C2-haloalkyl, cyano, hydroxy, C1-C2-alkoxy, C3-C4-cycloalkyl and —N(R9)(R10);
R4 is selected from the group consisting of a hydrogen atom, a halogen atom, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C4-C6-cycloalkenyl, C1-C6-hydroxyalkyl, C1-C6-haloalkyl, (C1-C2-alkoxy)-(C1-C6-alkyl)-, C1-C6-alkoxy, (C1-C2 alkoxy)-(C1-C6-alkoxy)-, C1-C4-haloalkoxy, —O—(C1-C4-alkyl)-C(═O)OR15, —O—(C1-C4-alkyl)-C(═O)N(R9)(R10), C3-C6-cycloalkyloxy, —S(═O)R14, —S(═O)2R14, cyano, nitro, hydroxy, —N(R9)(R10), —N(R16)(R17), —N(R16)(R20), —C(═O)N(R9)(R10), —C(═O)R11, —N(R12)C(═O)R13, —N(R12)S(═O)2R14, —N═S(═NH)(R14)2, —N═S(═O)(R14)2, —P(═O)(R14)2, 4- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkenyl, (4- to 7-membered heterocycloalkyl)oxy, phenyl, and 5- or 6-membered heteroaryl,
wherein said 4- to 7-membered heterocycloalkyl group and 5- to 7-membered heterocycloalkenyl group are connected to the rest of the molecule via a carbon atom of said 4- to 7-membered heterocycloalkyl group, or 5- to 7-membered heterocycloalkenyl group,
wherein said 4- to 7-membered heterocycloalkyl group, 5- to 7-membered heterocycloalkenyl group, and
(4- to 7-membered heterocycloalkyl)oxy group are optionally substituted, one, two, or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, C1-C2-alkyl,
C1-C2-haloalkyl, cyano, hydroxy, C1-C2-alkoxy, C3-C4-cycloalkyl, —N(R9)(R10), and oxo,
wherein said C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, and C1-C6-alkoxy groups are optionally substituted with C3-C4-cycloalkyl or 4- to 7-membered heterocycloalkyl,
wherein said 4- to 7-membered heterocycloalkyl group is connected to the rest of the molecule via a carbon atom of said 4- to 7-membered heterocycloalkyl group,
wherein said 4- to 7-membered heterocycloalkyl group is optionally substituted, one, two, or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, C1-C2-alkyl, C1-C2-haloalkyl, cyano, hydroxy, C1-C2-alkoxy, C3-C4-cycloalkyl, —N(R9)(R10), and oxo,
wherein the C3-C4-cycloalkyl group is optionally substituted, one or two times, wherein each substituent is independently selected from a halogen atom, cyano, and hydroxy,
wherein said C1-C6-alkoxy group is optionally substituted with an oxiran-2-yl group,
wherein said C3-C6-cycloalkyl and C4-C6-cycloalkenyl groups are optionally substituted, one or two times, wherein each substituent is independently a halogen atom or a C1-C4-alkyl group,
wherein said phenyl and 5- or 6-membered heteroaryl groups are optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, C1-C2-alkyl, C1-C2-haloalkyl, cyano, hydroxy, C1-C2-alkoxy, C3-C4-cycloalkyl, and —N(R9)(R10);
R5 is selected from the group consisting of a hydrogen atom, a halogen atom, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C4-C6-cycloalkenyl, C1-C6-hydroxyalkyl, C1-C6-haloalkyl, (C1-C2-alkoxy)-(C1-C6-alkyl)-, C1-C6-alkoxy, (C1-C2 alkoxy)-(C2-C6-alkoxy)-, C1-C4-haloalkoxy, C3-C6-cycloalkyloxy, phenoxy, —SR14, —S(═O)R14, —S(═O)2R14, cyano, hydroxy, —N(R9)(R10), —C(═O)N(R9)(R10), —C(═O)R11, —N(R12)C(═O)R13, —N(R12)S(═O)2R14, —N═S(═NH)(R14)2, —N═S(═O)(R14)2, —P(═O)(R14)2, 4- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkenyl, (4- to 7-membered heterocycloalkyl)oxy, phenyl, and 5- or 6-membered heteroaryl,
wherein said 4- to 7-membered heterocycloalkyl group and 5- to 7-membered heterocycloalkenyl group are connected to the rest of the molecule via a carbon atom of said 4- to 7-membered heterocycloalkyl group or 5- to 7-membered heterocycloalkenyl group,
wherein said 4- to 7-membered heterocycloalkyl group, 5- to 7-membered heterocycloalkenyl group, and (4- to 7-membered heterocycloalkyl)oxy group are optionally substituted, one, two, or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, C1-C2-alkyl, C1-C2-haloalkyl, cyano, hydroxy, C1-C2-alkoxy, C3-C4-cycloalkyl, —N(R9)(R10), and oxo,
wherein said C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, and C1-C6-alkoxy groups are optionally substituted with a group selected from the group consisting of C3-C4-cycloalkyl, phenyl, and 4- to 7-membered heterocycloalkyl,
wherein said 4- to 7-membered heterocycloalkyl group is connected to the rest of the molecule via a carbon atom of said 4- to 7-membered heterocycloalkyl group, and
wherein said 4- to 7-membered heterocycloalkyl group is optionally substituted, one, two, or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, —C2-alkyl, C1-C2-haloalkyl, cyano, hydroxy, C1-C2-alkoxy, C3-C4-cycloalkyl, —N(R9)(R10), and oxo,
wherein the phenyl group is optionally substituted, one or two times,
wherein each substituent is independently selected from the group consisting of a halogen atom, C1-C2-alkyl, C1-C2-haloalkyl, cyano, hydroxy, C1-C2-alkoxy, C3-C4-cycloalkyl, and —N(R9)(R10), and
wherein the C3-C4-cycloalkyl group is optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, cyano, and hydroxy,
wherein said C3-C6-cycloalkyl and C4-C6-cycloalkenyl groups are optionally substituted, one or two times, wherein each substituent is independently a halogen atom or a C1-C4-alkyl group,
wherein said phenyl, phenoxy, and 5- or 6-membered heteroaryl groups are optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, C1-C2-alkyl, C1-C2-haloalkyl, cyano, hydroxy, C1-C2-alkoxy, C3-C4-cycloalkyl, and —N(R9)(R10);
R6 is selected from the group consisting of a hydrogen atom, a fluorine atom, C1-C4-alkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy, hydroxy, and oxo;
R7 is selected from the group consisting of a hydrogen atom, a halogen atom, C1-C4-alkyl, C1-C4-alkoxy, hydroxy, and cyano;
R8 is methyl or ethyl;
R9 and R10 are each independently selected from the group consisting of a hydrogen atom, C1-C4-alkyl, C2-C4-hydroxyalkyl, N≡C—(C1-C4-alkyl)-, (C1-C4-alkoxy)-(C2-C4-alkyl)-, C3-C4-cycloalkyl and C2-C4-haloalkyl, or
R9 and R10 together with the nitrogen to which they are attached form a nitrogen containing 4- to 7-membered heterocycloalkyl group,
wherein said nitrogen containing 4- to 7-membered heterocycloalkyl group is optionally substituted, one, two, or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, C1-C4-alkyl, C3-C4-cycloalkyl, hydroxy and oxo,
or
two substituents, which are attached to the same carbon atom of said nitrogen containing 4- to 7-membered heterocycloalkyl group, together with the carbon atom to which they are attached, form a 4- to 7-membered heterocycloalkyl group,
wherein said 4- to 7-membered heterocycloalkyl group is optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, C1-C4-alkyl, C3-C4-cycloalkyl, C1-C4-haloalkyl, hydroxy, and oxo;
R11 is selected from the group consisting of a hydrogen atom, C1-C4-alkyl, C1-C4-hydroxyalkyl, C1-C4-haloalkyl, phenyl, and 5- or 6-membered heteroaryl,
wherein said phenyl group and 5- or 6-membered heteroaryl group are optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, C1-C2-alkyl, C1-C2-haloalkyl, cyano, hydroxy, C1-C2-alkoxy, C3-C4-cycloalkyl, and —N(R9)(R10);
R12 is a hydrogen atom or a C1-C4-alkyl group;
R13 is selected from the group consisting of a hydrogen atom, C1-C6-alkyl, phenyl, and 5- or 6-membered heteroaryl,
wherein said phenyl group and 5- or 6-membered heteroaryl group are optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, C1-C2-alkyl, C1-C2-haloalkyl, cyano, hydroxy, C1-C2-alkoxy, C3-C4-cycloalkyl, and —N(R9)(R10);
R14 is selected from the group consisting of C1-C6-alkyl, C1-C6-haloalkyl, C3-C6-cycloalkyl, phenyl, and 5- or 6-membered heteroaryl,
wherein said phenyl group and 5- or 6-membered heteroaryl group are optionally substituted, one or two times, wherein each substituent is independently selected from the group consisting of a halogen atom, C1-C2-alkyl, C1-C2-haloalkyl, cyano, hydroxy, C1-C2-alkoxy, C3-C4-cycloalkyl, and —N(R9)(R10);
R15 is a hydrogen atom or a C1-C4-alkyl group;
R16 is selected from the group consisting of a hydrogen atom, C1-C4-alkyl, C3-C4-cycloalkyl, and C2-C4-haloalkyl;
R17 is a 4- to 7-membered heterocycloalkyl group,
wherein said 4- to 7-membered heterocycloalkyl group is optionally substituted, one, two, or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, C1-C4-alkyl, C3-C4-cycloalkyl, C1-C4-alkoxy, hydroxy and oxo,
wherein said 4- to 7-membered heterocycloalkyl group is connected to the rest of the molecule via a carbon atom of the 4- to 7-membered heterocycloalkyl group;
R18 is selected from the group consisting of a hydrogen atom, methyl, and ethyl;
R19 is selected from the group consisting of a hydrogen atom, methyl, and ethyl;
R20 is a (4- to 7-membered heterocycloalkyl)-(C1-C4-alkyl)-group,
wherein the (4- to 7-membered heterocycloalkyl) part of said group is optionally substituted, one, two, or three times, wherein each substituent is independently selected from the group consisting of a halogen atom, C1-C4-alkyl, C3-C4-cycloalkyl, C1-C4-alkoxy, hydroxy, and oxo;
m is 1, 2, or 3; and
n is 1, 2, or 3,
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of any of the foregoing.