US 12,358,907 B2
Substituted pyrrolidine amides III
Florian Jakob, Aachen (DE); Jo Alen, Averbode (BE); Sebastian Krüger, Aachen (DE); Daniela Friebe, Düsseldorf (DE); Stephanie Hennen, Aachen (DE); and Philipp Barbie, Berlin (DE)
Assigned to GRÜNENTHAL GMBH, Aachen (DE)
Appl. No. 17/422,257
Filed by GRÜNENTHAL GMBH, Aachen (DE)
PCT Filed Jan. 13, 2020, PCT No. PCT/EP2020/050626
§ 371(c)(1), (2) Date Jul. 12, 2021,
PCT Pub. No. WO2020/144375, PCT Pub. Date Jul. 16, 2020.
Claims priority of application No. 19151406 (EP), filed on Jan. 11, 2019; application No. 19152282 (EP), filed on Jan. 17, 2019; and application No. 19181203 (EP), filed on Jun. 19, 2019.
Prior Publication US 2022/0089573 A1, Mar. 24, 2022
Int. Cl. C07D 417/14 (2006.01); C07D 401/14 (2006.01); C07D 403/10 (2006.01); C07D 403/12 (2006.01); C07D 403/14 (2006.01); C07D 409/14 (2006.01); C07D 413/14 (2006.01); C07D 471/04 (2006.01)
CPC C07D 417/14 (2013.01) [C07D 401/14 (2013.01); C07D 403/10 (2013.01); C07D 403/12 (2013.01); C07D 403/14 (2013.01); C07D 409/14 (2013.01); C07D 413/14 (2013.01); C07D 471/04 (2013.01)] 18 Claims
 
1. A compound according to general formula (I),

OG Complex Work Unit Chemistry
wherein
R1 represents phenyl; —C1-6-alkylene-phenyl; 5 or 6-membered heteroaryl; —C1-6-alkylene- (5 or 6-membered heteroaryl) or —C1-10-alkyl;
R1′ represents H; —C1-10-alkyl; or —C3-10-cycloalkyl;
R2 represents —C(═O)—C1-10-alkyl; —C(═O)—C3-10-cycloalkyl; —C(═O)—C1-6-alkylene-C3-10-cycloalkyl; —C(═O)-(3 to 7 membered heterocycloalkyl); —C(═O)—C1-6-alkylene- (3 to 7 membered heterocycloalkyl); —C(═O)-phenyl; —C(═O)—C1-6-alkylene-phenyl; —C(═O)-(5 or 6-membered heteroaryl); —C(═O)—C1-6-alkylene- (5 or 6-membered heteroaryl); —S(═O)1-2—C1-10-alkyl; —S(═O)1-2—C3-10-cycloalkyl; —S(═O)1-2—C1-6-alkylene-C3-10-cycloalkyl; —S(═O) 1-2-(3 to 7 membered heterocycloalkyl); —S(═O)1-2—C1-6-alkylene- (3 to 7 membered heterocycloalkyl); —S(═O)1-2-phenyl; —S(═O)1-2—C1-6-alkylene-phenyl; —S(═O)1-2— (5 or 6-membered heteroaryl); or —S(═O)1-2—C1-6-alkylene-(5 or 6-membered heteroaryl);
R3 and R3′ independently from one another represent H; F; Cl; —C1-10-alkyl; —C3-6-cycloalkyl; —CH2—C3-6-cycloalkyl; 3 to 7 membered heterocycloalkyl; —CH2-(3 to 7 membered heterocycloalkyl); —CH2-phenyl; or —CH2-(5 or 6-membered heteroaryl);
or R3 and R3′ together with the carbon atom to which they are bound form a C3-10-cycloalkyl; or
3 to 7 membered heterocycloalkyl;
R4 represents-phenyl; —C1-6-alkylene-phenyl; —5 or 6-membered heteroaryl; or —C1-6-alkylene-(5 or 6-membered heteroaryl);
A, X, Y and Z independently from one another represent N or CH;
wherein at least one of R1, R3 and R3′ is not H;
wherein —C1-10-alkyl and —C1-6-alkylene- in each case independently from one another is linear or branched, saturated or unsaturated;
wherein —C1-10-alkyl, —C1-6-alkylene-, —C3-10-cycloalkyl and 3 to 7 membered heterocycloalkyl in each case independently from one another are unsubstituted or mono- or polysubstituted with one or more substituents selected from —F; —Cl; —Br; —I; —CN; —C1-6-alkyl; —CF3; —CF2H; —CFH2; —CF2Cl; —CFCl2; —C(═O)—C1-6-alkyl; —C(═O)—OH; —C(═O)—OC1-6-alkyl; —C(═O)—NH2; —C(═O)—NH(C1-6-alkyl); —C(═O)—N(C1-6-alkyl)2; —OH; ═O; —OCF3; —OCF2H; —OCFH2; —OCF2Cl; —OCFCl2; —O—C1-6-alkyl; —O—C(═O)—C1-6-alkyl; —O—C(═O)—O—C1-6-alkyl; —O—(CO)—NH(C1-6-alkyl); —O—C(═O)—N(C1-6-alkyl)2; —O—S(═O)2—NH2; —O—S(═O)2—NH(C1-6-alkyl); —O—S(═O)2—N(C1-6-alkyl)2; —NH2; —NH(C1-6-alkyl); —N(C1-6-alkyl)2; —NH—C(═O)—C1-6-alkyl; —NH—C(═O)—O—C1-6-alkyl; —NH—C(═O)—NH2; —NH—C(═O)—NH(C1-6-alkyl); —NH—C(═O)—N(C1-6-alkyl)2; —N(C1-6-alkyl)-C(═O)—C1-6-alkyl; —N(C1-6-alkyl)-C(═O)—O—C1-6-alkyl; —N(C1-6-alkyl)-C(═O)—NH2; —N(C1-6-alkyl)-C(═O)—NH(C1-6-alkyl); —N(C1-6-alkyl)-C(═O)—N(C1-6-alkyl)2; —NH—S(═O)2OH; NH—S(═O)2—C1-6-alkyl; —NH—S(═O)2—O—C1-6-alkyl; —NH—S(═O)2—NH2; —NH—S(═O)2—NH(C1-6-alkyl); —NH—S(═O)2N(C1-6-alkyl)2; —N(C1-6-alkyl)-S(═O)2—OH; —N(C1-6-alkyl)-S(═O)2—C1-6-alkyl; —N(C1-6-alkyl)-S(═O)2—O—C1-6-alkyl; —N(C1-6-alkyl)-S(═O)2—NH2; —N(C1-6-alkyl)-S(═O)2—NH(C1-6-alkyl); —N(C1-6-alkyl)-S(═O)2—N(C1-6-alkyl)2; —SCF3; —SCF2H; —SCFH2; —S—C1-6-alkyl; —S(═O)—C1-6-alkyl; —S(═O)2—C1-6-alkyl; —S(═O)2—OH; —S(═O)2—O—C1-6-alkyl; —S(═O)2—NH2; —S(═O)2—NH(C1-6-alkyl); —S(═O)2—N(C1-6-alkyl)2; —C3-6-cycloalkyl; 3 to 6-membered heterocycloalkyl; phenyl; 5 or 6-membered heteroaryl; —O—C3-6-cycloalkyl; —O-(3 to 6-membered heterocycloalkyl); —O-phenyl; —O-(5 or 6-membered heteroaryl); —C(═O)—C3-6-cycloalkyl; —C(═O)-(3 to 6-membered heterocycloalkyl); —C(═O)-phenyl; —C(═O)— (5 or 6-membered heteroaryl); —S(═O)2—(C3-6-cycloalkyl); —S(═O)2—(3 to 6-membered heterocycloalkyl); —S(═O)2- phenyl or —S(═O)2—(5 or 6-membered heteroaryl);
wherein phenyl and 5 or 6-membered heteroaryl in each case independently from one another are unsubstituted or mono- or polysubstituted with one or more substituents selected from —F; —Cl; —Br; —I; —CN; —C1-6-alkyl; —CF3; —CF2H; —CFH2; —CF2Cl; —CFCl2; —C1-4-alkylene-CF3; —C1-4-alkylene-CF2H; —C1-4-alkylene-CFH2; —C(═O)—C1-6-alkyl; —C(═O)—OH; —C(═O)—OC1-6-alkyl; —C(═O)—NH(OH); —C(═O)—NH2; —C(═O)—NH(C1-6-alkyl); —C(═O)—N(C1-6-alkyl)2; —OH; ═O; —OCF3; —OCF2H; —OCFH2; —OCF2Cl; —OCFCl2; —O—C1-6-alkyl; —O—C3-6-cycloalkyl; —O-(3 to 6-membered heterocycloalkyl); —NH2; —NH(C1-6-alkyl); —N(C1-6-alkyl)2; —NH—C(═O)—C1-6-alkyl; —N(C1-6-alkyl)-C(═O)—C1-6-alkyl; —NH—C(═O)—NH2; —NH—C(═O)—NH(C1-6-alkyl); —NH—C(═O)—N(C1-6-alkyl)2; —N(C1-6-alkyl)-C(═O)—NH(C1-6-alkyl); —N(C1-6-alkyl)-C(═O)—N(C1-6-alkyl)2; —NH—S(═O)2—C1-6-alkyl; —SCF3; —S—C1-6-alkyl; —S(═O)—C1-6-alkyl; —S(═O)2—C1-6-alkyl; —S(═O)2—NH2; —S(═O)2—NH(C1-6-alkyl); —S(═O)2—N(C1-6-alkyl)2; —C3-6-cycloalkyl; —C1-4-alkylene-C3-6-cycloalkyl; 3 to 6-membered heterocycloalkyl; —C1-4-alkylene- (3 to 6-membered heterocycloalkyl); phenyl or 5 or 6-membered heteroaryl;
in the form of the free compound or a physiologically acceptable salt thereof;
with the proviso that the following compounds are excluded:
N-[(2R,3S)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-cyclopropanecarboxylic acid amide;
N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-cyclopropanecarboxylic acid amide;
N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxylic acid amide;
N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-5-methyl-[1,2,4]oxadiazole-3-carboxylic acid amide;
N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-4-methyl-thiazole-5-carboxylic acid amide;
N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-thiazole-4-carboxylic acid amide; and
N-[(2S,3R)-4,4-Dimethyl-1-[1-(1-methyl-6-oxo-1H-pyridin-3-yl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-5-methyl-thiazole-4-carboxylic acid amide.