US 12,065,447 B2
Heterocyclic amide for inhibiting RIP1 kinase and uses thereof
Bing Zhou, Shanghai (CN); Wei Tang, Shanghai (CN); Xiangbo Yang, Shanghai (CN); Huimin Lu, Shanghai (CN); Mengying Gao, Shanghai (CN); Yaxi Yang, Shanghai (CN); and Huijin Feng, Shanghai (CN)
Assigned to SHANGHAI INSTITUTE OF MATERIA MEDICA, CHINESE ACADEMY OF SCIENCES, Shanghai (CN)
Filed by SHANGHAI INSTITUTE OF MATERIA MEDICA, CHINESE ACADEMY OF SCIENCES, Shanghai (CN)
Filed on Oct. 8, 2022, as Appl. No. 18/045,149.
Application 18/045,149 is a division of application No. 17/289,642, granted, now 11,498,927, previously published as PCT/CN2019/109899, filed on Oct. 8, 2019.
Claims priority of application No. 201811301267.9 (CN), filed on Nov. 2, 2018; and application No. 201910712428.1 (CN), filed on Aug. 2, 2019.
Prior Publication US 2023/0167129 A1, Jun. 1, 2023
Int. Cl. C07D 513/04 (2006.01); A61P 37/06 (2006.01); C07D 401/12 (2006.01); C07D 401/14 (2006.01); C07D 413/12 (2006.01); C07D 413/14 (2006.01); C07D 417/12 (2006.01); C07D 417/14 (2006.01); C07D 487/04 (2006.01)
CPC C07D 513/04 (2013.01) [A61P 37/06 (2018.01); C07D 401/12 (2013.01); C07D 401/14 (2013.01); C07D 413/12 (2013.01); C07D 413/14 (2013.01); C07D 417/12 (2013.01); C07D 417/14 (2013.01); C07D 487/04 (2013.01)] 9 Claims
 
1. A compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, enantiomer, diastereomer, atropisomer, optical isomer, racemate, polymorph, solvate or isotopically labeled compound thereof:

OG Complex Work Unit Chemistry
wherein
X is S, SO,

OG Complex Work Unit Chemistry
Y is C1-C2 alkylene;
Ring A is a benzene ring, a 5-6 membered heteroaromatic ring, a 5-6 membered non-aromatic heterocyclic ring or

OG Complex Work Unit Chemistry
and the carbonyl moiety and L1 connected to Ring A are in meta-positions;
RA is H or C1-C4 alkyl;
L1 is C3-C6 alkyl, C3-C6 alkoxy, halogenated C3-C6 alkoxy, C3-C6 alkenyl, C3-C6 alkenyloxy, or

OG Complex Work Unit Chemistry
wherein
L is O, S, NH, N(CH3), CH2, CH2CH2, CH(CH3), CHF, CF2, CH2O, CH2N(CH3), CH2NH or CH(OH);
Ring B is a C3-C6 cycloalkyl, phenyl, 5-6 membered heteroaryl or 5-6 membered non-aromatic heterocyclyl, wherein the C3-C6 cycloalkyl, the phenyl, the 5-6 membered heteroaryl and the 5-6 membered non-aromatic heterocyclyl are each independently unsubstituted or substituted with one or two substituents each independently selected from the group consisting of halogen, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkoxy, nitro and C1-C4 alkyl C(O)—;
R2 is H or CH3;
Ring M is independently a C6-C10 aromatic ring or a 5-10 membered heteroaromatic ring;
R1 representative 1-3 substituents each independently being H, halogen, —OH, —CN, —COOH,
Ct-Co alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C10 alkoxyalkyl, C2-C10 haloalkoxyalkyl, C1-C6 hydroxyalkyl, —B(OH)2, —S(O)n1Ra, —N(Ra)2, —C(═O)N(Ra)2, —NHC(═O)Ra, —NHC(═O)ORa, —NHC(═O)C(═O)N(R1)2, —NHC(═O)C(═O)ORa, —NHC(═O)N(Ra)2, —NHC(═O)NRaC(═O)N(Ra)2, —NHC(═O)NRaS(O)2ORa, —NHC(═O)NRaS(O)2N(Ra)2, —NHC(═S)N(Ra)2, —NHC(═N—C≡N)NRa, —NHC(═N—C≡N)SRa, —NHS(O)n1Ra, Ma, —(C1-C6 alkylene)-B(OH)2, —(C1-C6 alkylene)-S(O)n1Ra, —(C1-C6 alkylene)-N(Ra)2, —(C1-C6 alkylene)-C(═O)N(Ra)2, —(C1-C6 alkylene)-NHC(═O)Ra, —(C1-C6 alkylene)-NHC(═O)ORa, —(C1-C6 alkylene)-NHC(═O)C(═O)N(Ra)2, —(C1-C6 alkylene)-NHC(═O)C(═O)ORa, —(C1-C6 alkylene)-NHC(═O)N(Ra)2, —(C1-C6 alkylene)-NHC(═O)NRaC(═O)N(Ra)2, —(C1-C6 alkylene)-NHC(═O)NRAS(O)2ORa, —(C1-C6 alkylene)-NHC(═O)NRaS(O)2N(Ra)2, —(C1-C6 alkylene)-NHC(═S)N(Ra)2, —(C1-C6 alkylene)-NHC(═N—C≡N)NRa, —(C1-C6 alkylene)-NHC(═N—C≡N)SRa, —(C1-C6 alkylene)-NHS(O)n1Ra, —(C1-C6 alkylene)-Ma, —OMa, —SMa, or —N(Ra)Ma;
Ra at each occurrence is independently hydrogen, C1-C6 alkyl, C6-C10 aryl, 5-10 membered heteroaryl, 3-10 membered non-aromatic heterocyclyl, C3-C10 cycloalkyl, or C5-C10 cycloalkenyl, wherein the C1-C6 alkyl, the C6-C10 aryl, the 5-10 membered heteroaryl, the 3-10 membered non-aromatic heterocyclyl, the C3-C10 cycloalkyl and the C5-C10 cycloalkenyl are each independently unsubstituted or substituted with one or two selected from the group consisting of amino, hydroxyl, C1-C4 alkoxy, C1-C6 alkyl, C3-C10 cycloalkyl, and CN;
Ma at each occurrence is independently C6-C10 aryl, 5-10 membered heteroaryl, 3-10 membered non-aromatic heterocyclyl, C3-C10 cycloalkyl, or C3-C10 cycloalkenyl, wherein the C6-C10 aryl, the 5-10 membered heteroaryl, the 3-10 membered non-aromatic heterocyclyl, the C3-C10 cycloalkyl, and the C3-C10 cycloalkenyl are each independently unsubstituted or substituted with one or two selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 alkoxy, and —CN;
n1 at each occurrence is independently 0, 1 or 2;
R is each independently hydrogen, C1-C10 alkyl, C6-C10 aryl, 5-10 membered heteroaryl, 3-10 membered non-aromatic heterocyclyl, C3-C10 cycloalkyl, or C3-C10 cycloalkenyl, wherein the C1-C10 alkyl, the C6-C10 aryl, the 5-10 membered heteroaryl, the 3-10 membered non-aromatic heterocyclyl, the C3-C10 cycloalkyl, and the C3-C10 cycloalkenyl are each independently unsubstituted or substituted with 1 to 4 Mds;
Md at each occurrence is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, —CN, NO2, SCF3, oxo, —OMe, —OC(O)Mh, —OC(O)NMfMg, —SMe, —S(O)2Me, —S(O)2NMfMg, —C(O)Me, —C(O)-(5-10 membered monocyclic heterocyclic ring), —C(O)-(5-10-membered monocyclic heteroaryl), —C(O)OMe, —C(O)NMfMg, —NMfMg, —N(Me)C(O)Mh, —N(Me)S(O)2M, —N(M)C(O)OMh, —N(M)C(O)NMfMg, —(C1-C6 alkylene)-OMe, —(C1-C6 alkylene)-OC(O)Mh, —(C1-C6 alkylene)-OC(O)NMfMg, —(C1-C6 alkylene)-S(O)2Me, —(C1-C6 alkylene)-S(O)2NMfM9, —(C1-C6 alkylene)-C(O)Me, —(C1-C6 alkylene)-C(O)OMh, —(C1-C6 alkylene)-C(O)NMfMg, —(C1-C6 alkylene)-NMfMg, —(C1-C6 alkylene)-N(Me)C(O)M, —(C1-C6 alkylene)-N(Me)S(O)2Mh, —(C1-C6 alkylene)-N(Me)C(O)OMh, —(C1-C6 alkylene)-N(Me)C(O)NMfMg, —(C1-C6 alkylene)-CN, C6-C10 aryl, 5-10 membered heteroaryl, 3-10 membered non-aromatic heterocyclyl, C3-C10 cycloalkyl, or C3-C10 cycloalkenyl, wherein the C6-C10 aryl, the 5-10 membered heteroaryl, the 3-10 membered non-aromatic heterocyclyl, the C3-C10 cycloalkyl and the C3-C10 cycloalkenyl are each independently unsubstituted or substituted by one or two substituents each independently selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 alkoxy, and —CN;
Me, Mf, Mg and Mh at each occurrence are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, or 3-10 membered non-aromatic heterocyclyl, wherein the Ct-Co alkyl, the C1-C10 cycloalkyl, the C6-C10 aryl, the 5-10 membered heteroaryl, and the 3-10 membered non-aromatic heterocyclyl are each independently unsubstituted or substituted by one or two substituents each independently selected from the group consisting of halogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, —CN, —S(O)2(C1-C4 alkyl), and —C(O)(C1-C4 alkyl); or
two Mds together with the ring atoms to which they are connected, form a 3-8 membered saturated or unsaturated ring.