US 12,331,036 B2
Heterocyclic RIP1 kinase inhibitors
Simon Shaw, Oakland, CA (US); Somasekhar Bhamidipati, Foster City, CA (US); and Vanessa Taylor, San Francisco, CA (US)
Assigned to RIGEL PHARMACEUTICALS, INC., South San Francisco, CA (US)
Filed by Rigel Pharmaceuticals, Inc., Indianapolis, IN (US)
Filed on Sep. 16, 2022, as Appl. No. 17/946,181.
Application 17/946,181 is a continuation of application No. 17/013,034, filed on Sep. 4, 2020, granted, now 11,479,543.
Claims priority of provisional application 63/004,290, filed on Apr. 2, 2020.
Claims priority of provisional application 63/004,301, filed on Apr. 2, 2020.
Claims priority of provisional application 63/004,319, filed on Apr. 2, 2020.
Claims priority of provisional application 63/001,016, filed on Mar. 27, 2020.
Claims priority of provisional application 62/932,404, filed on Nov. 7, 2019.
Claims priority of provisional application 62/897,223, filed on Sep. 6, 2019.
Prior Publication US 2023/0057341 A1, Feb. 23, 2023
Int. Cl. C07D 401/14 (2006.01); A61K 31/553 (2006.01); C07D 267/02 (2006.01); C07D 401/12 (2006.01); C07D 403/12 (2006.01); C07D 403/14 (2006.01); C07D 405/14 (2006.01); C07D 413/12 (2006.01); C07D 413/14 (2006.01); C07D 471/08 (2006.01); C07D 487/04 (2006.01); C07D 491/107 (2006.01); C07D 493/04 (2006.01)
CPC C07D 401/14 (2013.01) [A61K 31/553 (2013.01); C07D 267/02 (2013.01); C07D 401/12 (2013.01); C07D 403/12 (2013.01); C07D 403/14 (2013.01); C07D 405/14 (2013.01); C07D 413/12 (2013.01); C07D 413/14 (2013.01); C07D 471/08 (2013.01); C07D 487/04 (2013.01); C07D 491/107 (2013.01); C07D 493/04 (2013.01)] 7 Claims
 
1. A method for treating a disease in a subject, comprising administering to the subject (i) a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, a stereoisomer, an N-oxide, a tautomer, a hydrate, a solvate, an isotope, or a prodrug thereof; or (ii) a therapeutically effective amount of a pharmaceutical composition of a compound; wherein the subject has, or is suspected of having or developing, the disease, wherein the disease is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, or multiple sclerosis,
wherein the compound is:

OG Complex Work Unit Chemistry
wherein:
ring B is heteroaryl;
each R1 independently is -linker-R6 group, wherein the linker is Ra, provided that Ra is not H or D, and R6 is heterocyclyl, Rb, —C(Rf)3, or —C(Rf)═C(Rf)2;
R2 is Ra;
R3 is Ra;
R4 is C1-6 alkyl;
if present, each R4 independently is Re;
L is a heteroatom or Ra, provided that Ra is not H or D;
X is CH2 or O;
Z is heteroaryl;
m is 1, 2, 3, or 4;
n is 0, 1 or 2;
Ra is independently for each occurrence H or D, except for embodiments where L is Ra, or is C1-10aliphatic, C1-10haloaliphatic, C5-10aromatic, C3-6heterocyclic, or C3-10spiroheterocyclic;
Rb is independently for each occurrence —OH, —SH, —ORc, —SRc, —NRdRd, —Si(Ra)3, —C(O)OH, —C(O)ORc, —C(O)NRdRd, —OC(O)NRdRd, —OC(O)C1-10alkyl substituted with one or two NRdRd, carboxyl, or a combination thereof, and optionally further substituted with an aromatic moiety, —SH, —O-acyl, or —C(O)NH2;
Rc is independently for each occurrence C1-10alkyl, which can be substituted with 1, 2 or 3 Re, C2-10alkenyl, which can be substituted with 1, 2 or 3 Re, C2-10alkynyl, which can be substituted with 1, 2 or 3 Re, C3-6cycloalkyl, which can be substituted with 1, 2 or 3 Re, or C5-10aromatic, which can be substituted with 1, 2 or 3 Re;
Rd is independently for each occurrence H; C1-6alkyl, which can be substituted with 1, 2 or 3 Re or a C3-9heterocyclyl; C3-6cycloalkyl, which can be substituted with 1, 2 or 3 Re; C3-6heterocyclic, which can be substituted with 1, 2 or 3 Re; C5-10aryl, which can be substituted with 1, 2 or 3 Rb; C5-10heteroaryl, which can be substituted with 1, 2 or 3 Re; or two Rd groups together with the nitrogen bound thereto provide a C3-9heterocyclic, which can be substituted with one or more Re), or a C5-10heteroaryl, which can be substituted with one or more Re;
Re is independently for each occurrence halogen, C1-6alkyl, C2-10alkenyl, C2-10alkynyl, C1-6haloalkyl, C3-6cycloalkyl, C5-10heteroaryl, or —ORa; and
Rf is independently for each occurrence-alkyl-phosphate, Ra, Rb, or Re, or two Rf groups together with the carbon atom bound thereto provide a C2-6alkenyl group, a C3-6cycloalkyl group, which can be substituted with one or more Re, or a C3-10heterocyclic, which can be substituted with one or more Re or acyl.