US 2023/0142285 A1Published application

Substituted straight chain spiro derivatives

AssigneeJanssen Pharmaceutica NV

InventorsWei CAI, Xuedong DAI, Oliver Alexis Georges QUEROLLE, Johannes Wilhelmus John F. THURING, Yingtao LIU, Lianzhu LIU, Yanping XU, Liqiang FU, Ming LI, Lichao FANG, Xianguin DENG, Qiwu ZHAO, Kangying LI, Alicia Tee Fuay NG, Nicolas Freddy J. DARVILLE, Edward CLEATOR, Gregor Thomas URBANIETZ, William Marc MATON, Vineet PANDA

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Abstract

The present invention relates to pharmaceutical agents useful for therapy and/or prophylaxis in a mammal, pharmaceutical composition comprising such compounds, and their use as menin/MLL protein/protein interaction inhibitors, useful for treating diseases such as cancer, including but not limited to leukemia, myelodysplastic syndrome (MDS), and myeloproliferative neoplasms (MPN); and diabetes.

A compound of Formula (I)

or a tautomer or a stereoisomeric form thereof, wherein
R1a represents —C(═O)—NRxaRxb;
Het;
or
Het represents a 5- or 6-membered monocyclic aromatic ring containing one, two or three nitrogen atoms and optionally a carbonyl moiety;
wherein said 5- or 6-membered monocyclic aromatic ring is optionally substituted with one or two substituents selected from the group consisting of C3-6cycloalkyl and C1-4alkyl;
Rxa and Rxb are each independently selected from the group consisting of hydrogen, C1-4alkyl and C3-6cycloalkyl;
R1b represents F or Cl;
Y1 represents —CR5aR5b—, —O— or —NR5c—;
R2 is selected from the group consisting of hydrogen, halo, C1-4alkyl, —O—C1-4alkyl, and —NR7aR7b;
U represents N or CH;
n1, n2, n3 and n4 are each independently selected from 1 and 2;
X1 represents CH, and X2 represents N;
R4 represents isopropyl;
R5a, R5b, R5c, R7a, and R7b, are each independently selected from the group consisting of hydrogen, C1-4alkyl and C3-6cycloalkyl;
R3 represents —C1-6alkyl-NR8aR8b, —C1-6alkyl-C(═O)—NR9aR9b, —C1-6alkyl-OH, or —C1-6alkyl-NR11—C(═O)—O—C1-4alkyl-O—C(═O)—C1-4alkyl;
wherein each of the C1-4alkyl or C1-6alkyl moieties in the R3 definitions independently of each other may be substituted with one, two or three substituents each independently selected from the group consisting of cyano, halo, —OH, and —O—C1-4alkyl;
R8a and R8b are each independently selected from the group consisting of hydrogen;
C1-6alkyl;
—C(═O)—C1-4alkyl;
—C(═O)—O—C1-4alkyl;
—C(═O)—NR12aR12;
and C1-4alkyl substituted with one, two or three substituents each independently selected from the group consisting of —OH, cyano, halo, —S(═O)2—C1-4alkyl, —O—C1-4alkyl, —C(═O)—NR10aR10b, and —NR10c—C(═O)—C1-4alkyl;
R9a, R9b, R10a, R10b, R10c, R11, R12a, and R12b are each independently selected from the group consisting of hydrogen and C1-6alkyl;
or a pharmaceutically acceptable salt or a solvate thereof.

22 more elements

Abstract

Claims21