US 12,258,342 B2
Class of DNA gyrase and/or topoisomerase IV inhibitors with activity against gram-positive and gram-negative bacteria
Tihomir Tomašič, Trzin (SI); Nace Zidar, Ljubljana (SI); Martina Durcik, Dutovlje (SI); Janez Ilaš, Škofljica (SI); Anamarija Zega, Ljubljana (SI); Cristina Durante Cruz, Helsinki (FI); Päivi Tammela, Helsinki (FI); Csaba Pál, Szeged (HU); Ákos József Nyerges, Szekesfehervar (HU); Danijel Kikelj, Ljubljana (SI); and Lucija Peterlin Mašič, Medvode (SI)
Assigned to Univerza v Ljubljani, Ljubljana (SI); and Szegedi Biológiai Kutatóközpont, Szeged (HU)
Appl. No. 17/272,871
Filed by Univerza v Ljubljani, Ljubljana (SI); and Szegedi Biológiai Kutatóközpont, Szeged (HU)
PCT Filed Sep. 3, 2019, PCT No. PCT/EP2019/073412
§ 371(c)(1), (2) Date Mar. 2, 2021,
PCT Pub. No. WO2020/048949, PCT Pub. Date Mar. 12, 2020.
Claims priority of application No. 100918 (LU), filed on Sep. 3, 2018.
Prior Publication US 2021/0323957 A1, Oct. 21, 2021
Int. Cl. C07D 417/12 (2006.01); A61P 31/04 (2006.01); C07D 417/14 (2006.01)
CPC C07D 417/12 (2013.01) [A61P 31/04 (2018.01); C07D 417/14 (2013.01)] 22 Claims
 
1. A compound of formula (I):

OG Complex Work Unit Chemistry
wherein:
R1, R2, and R3 are each independently selected from H, halogen, —CN, —CF3, amino, methylamino, ethylamino, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxy, and optionally substituted C3-6 cycloalkyl; wherein two of R1, R2, and R3 are halogen;
R4 is (CH2)0-6-A wherein A is H, carboxyl, NR6R7 or is selected from optionally substituted monocyclic C3-7 cycloalkyl, optionally substituted monocyclic C3-7 cycloalkenyl, optionally substituted saturated or unsaturated monocyclic 3-7 membered heterocycle, optionally substituted saturated or unsaturated fused bicyclic 8-10 membered-heterocycle, optionally substituted C6-10 aryl and optionally substituted 5-10 membered heteroaryl;
R5 is (hydroxyimino)methyl, —CO—C1-6 alkyl, —CO—C2-6 alkenyl, —CO—C2-6 alkynyl, carboxyl, —COO—C1-6 alkyl, —CONR6R7, —OCONR6R7, —OCO—C1-6 alkyl, —COO—C1-6 alkyl-COO—C1-6 alkyl, —CONHCH(CO2R7)R6, —(CH2)0-6OH, —O—C1-6 alkyl, hydroxyl-C1-6 alkyl, heterocyclyl, aryl, —C(═NOR7) C1-6 alkyl, —C(═NOR7)NR6R7, —S(O)pNR6R7, —S(O)p-C1-6 alkyl-CONHR7, —C(O)NHS(O)p-C1-6 alkyl, —C(O)NHS(O)p-aryl, —CH2CH(COOR6)OH, —C1-6 alkyl-CH(NR6R7) COOR6 or —C1-6 alkyl-CH(NR6R7)CONR6R7), wherein any alkyl, alkenyl, alkynyl, heterocyclyl or aryl may be optionally substituted;
R6 and R7 are independently at each occurrence selected from H and optionally substituted C1-6 alkyl;
or R6 and R7 may together with the nitrogen to which they are attached form a 5 or 6-membered heterocyclic ring, optionally substituted with 1 or 2 substituents independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, hydroxyl, C1-6 alkoxy, halogen, cyano, nitro, carboxyl, hydroxy-C1-6 alkyl-, C1-6 alkoxy-C1-6 alkyl, halogen-C1-6 alkyl-, difluoromethyl, trifluoromethyl, formyl, —CO—C1-6 alkyl, —COO—C1-6 alkyl, —C(O)NH2, —C(O)NH—C1-6 alkyl, —C(O)N [C1-6 alkyl]2, —SO2NH2, —SO2NH—C1-6 alkyl, —SO2N [C1-6 alkyl]2 and —S(O) p-C1-6 alkyl;
p is (independently at each occurrence) 0, 1 or 2;
X1 is S, O or NH;
X2, X3 and X4 are each independently selected from N or C—R8;
R8 is H, hydroxy, halogen, carboxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, (CH2)mO—C1-6 alkyl, (CH2)mS—C1-6 alkyl, (CH2)mS(═O)—C1-6 alkyl, (CH2)mO(CH2)m—C3-7 cycloalkyl, (CH2)m—C3-7 cycloalkyl, (CH2)mO(CH2)maryl, (CH2)mO(CH2)m-5-10-membered heterocycle, (CH2)m-5-10-membered heterocycle, halogen-C1-6 alkyl, cyano or (CH2)mNR9R10, wherein each m is an integer independently selected from 0, 1, 2 and 3, and wherein any alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle or aryl may be optionally substituted;
R9 and R10 are each independently selected from H or C1-6 alkyl, C3-6 cycloalkyl and 4-6-membered heterocyclyl, wherein any alkyl, cycloalkyl or heterocyclyl may be optionally substituted, or R9 and R10 join together to form an optionally substituted 4-6-membered heterocyclyl and where each m is an integer independently selected from 0, 1, 2 and 3;
or a pharmaceutically acceptable salt, racemate, diastereomer, enantiomer, ester, carbamate, sulphate, or phosphate thereof.