US 12,152,030 B2
Polycyclic compound inhibiting MNK1 and MNK2
Bing Li, Shanghai (CN)
Assigned to NOVOSTAR PHARMACEUTICALS, LTD., Shanghai (CN)
Appl. No. 17/414,408
Filed by NOVOSTAR PHARMACEUTICALS, LTD., Shanghai (CN)
PCT Filed Dec. 4, 2019, PCT No. PCT/CN2019/123077
§ 371(c)(1), (2) Date Jun. 16, 2021,
PCT Pub. No. WO2020/155842, PCT Pub. Date Aug. 6, 2020.
Claims priority of application No. 201910087247.4 (CN), filed on Jan. 29, 2019.
Prior Publication US 2022/0041602 A1, Feb. 10, 2022
Int. Cl. C07D 471/22 (2006.01)
CPC C07D 471/22 (2013.01) 10 Claims
 
1. A compound of formula (I):

OG Complex Work Unit Chemistry
or a stereoisomer, tautomer, prodrug, solvate, hydrate, stable isotope derivative or pharmaceutically acceptable salt thereof, wherein:
A is —CR7—;
X is —(CR1aR1b)p-M-(CR2aR2b)q—, wherein M is a chemical bond or selected from the group consisting of —N(R9)—, —O—, —S—, —C(O)—, —S(O)—, —S(O)2—, —C(O)NH—, or —NHC(O)—;
p and q are each independently 0, 1 or 2;
Y is selected from the group consisting of —N(R8)—, —O—, —S—, —C(O)—, —S═O, —S(O)2—, or —CHR9—;
W1 and W2 are independently selected from the group consisting of O, S or N—OR′, wherein R′ is C1-C8 alkyl;
R1 is selected from the group consisting of hydrogen, —OH, acetyl, C1-C8 alkyl, —C(O)(C1-C8 alkyl), —C(O)(C3-C8 cycloalkyl), —COOH, —C(O)O—(C1-C8) alkyl, C3-C8 cycloalkyl, 5-12 membered aryl, 5-12 membered heteroaryl, or 5-12 membered heterocyclyl;
n is 1, 2 or 3;
R2 and R3 are each independently selected from the group consisting of hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C10 aryl, 5-12 membered heteroaryl, C1-C4 alkylene-(5-12) membered heteroaryl, C3-C8 cycloalkyl, C1-C4 alkylene-(C3-C8)cycloalkyl, 5-12 membered heterocyclyl, C1-C4 alkylene-(5-12) membered heterocyclyl; or R2 and R3 together with the carbon atom connected thereto form the radicals selected from the group consisting of: C3-C10 monocyclic alkyl, C3-C10 bicyclic or polycyclic alkyl, 5-12 membered heteromonocyclic alkyl containing 1-3 N, O or S atoms, 5-12 membered heterobicyclic or heteropolycyclic alkyl containing 1-3 N, O or S atoms;
R1a, R1b, R2a and R2b are each independently selected from the group consisting of hydrogen, halogen, hydroxy, —SH, hydroxy-(C1-C4) alkylene, cyano, C1-C4 alkyl, C1-C4 alkoxy;
R4 is independently selected from the group consisting of hydrogen, halogen, hydroxy, —SH, hydroxy-(C1-C4) alkylene, cyano, C1-C4 alkyl, C1-C4 alkoxy, —C(O)(C1-C8 alkyl), —C(O)(C3-C8 cycloalkyl), —COOH, —C(O)O—(C1-C8) alkyl, —S(C1-C8 alkyl), C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C6-C10 aryl, 5-12 membered heteroaryl or 5-12 membered heterocyclyl;
R5, R6 and R7 are each independently selected from the group consisting of —H, —OH, —CN, —SR10, halogen, —S(O)2(C1-C8)alkyl, —NH—S(O)2(C1-C8)alkyl, —C(O)N(R10)2, —NHC(O)R10, —N(R10)2, —(C1-C4 alkylene)N(R10)2, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, —O(C1-C8 alkyl), —O(C1-C8 haloalkyl), —O(C1-C8 alkylene)NHR10, —O(C1-C8 alkylene)N(R10)2, C6-C10 aryl, 5-12 membered heteroaryl, C1-C4 alkylene-(5-12) membered heteroaryl, C3-C8 monocyclic alkyl, C1-C4 alkylene-(C3-C8)cycloalkyl, 5-12 membered heterocyclyl, C1-C4 alkylene-(5-12) membered heterocyclyl; or R5 and R7 together with the carbon atom connected thereto form C6-C10 aryl, 5-12 membered heteroaryl, C3-C8 cycloalkyl, 5-12 membered heterocyclyl;
R10 is selected from the group consisting of —H, —OH, —C(O)O(C1-C8 alkyl), —C(O)(C1-C8 alkyl), —C(O)—NH2, —C(O)—NH (C1-C8 alkyl), —NH—C(O)(C1-C8 alkyl), NH2—C(O)—(C1-C4 alkylene), —S(C1-C8 alkyl), acetyl, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —O(C1-C8 alkyl), —(C1-C8 haloalkyl), C1-C8 alkylamino, —C(O)(C1-C8 alkyl), —C(O)(C3-C8 cycloalkyl), —C(O)O—(C1-C8 alkyl), C3-C8 cycloalkyl, C6-C10 aryl, 5-12 membered heteroaryl or 5-12 membered heterocyclyl;
wherein, each of alkyl, alkylene, cycloalkyl, aryl, heteroaryl, heterocyclyl, amino are optionally substituted with 1, 2 or 3 J groups, the J group is selected from the group consisting of —SR9, —S(O) R9, —S(O) 2R9, —S(O)N(R9)2, —N(R9)2, —C(O)OR9, —C(O)R9, —C(O)—N(R9)2, hydroxy, cyano, halogen, acetyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, haloalkyl, —S—(C1-C4 alkyl), cyano-(C1-C4 alkylene), C1-C4 alkylamino, NH2—C(O)—(C1-C4) alkylene, N(R9)2—C(O)—(C1-C4)alkylene, —CHR9—C(O)—(C1-C4) alkyl, —C(O)—(C1-C4) alkyl, 5-12 membered heterocyclyl, C1-C4 alkylene-(5-12) membered heterocyclyl, C3-C8 cycloalkyl, C1-C4 alkylene-(C3-C8)cycloalkyl, C2-C4 alkylene-(C3-C8)cycloalkyl, —CHR9—C(O)—(C3-C8)cycloalkyl, —C(O)—(C3-C8)cycloalkyl, —CHR9—C(O)—(C6-C10)aryl, —CHR9—(C6-C10)aryl, —C(O)—(C6-C10)aryl, —CHR9—C(O)—(5-12) membered heterocyclyl, —C(O)-(5-12) membered heterocyclyl; or two J groups connected to the same atom forming oxo (═O); and
R8 and R9 are hydrogen, C1-C4 alkyl, hydroxy-(C1-C4) alkyl, C3-C8 cycloalkyl, 5-12 membered heterocyclyl, —NH2 or —OH.