US 12,172,984 B2
Pyrazolopyridine derivatives and uses thereof
Simone Bonazzi, Cambridge, MA (US); Artiom Cernijenko, Cambridge, MA (US); Jennifer Stroka Cobb, Stow, MA (US); Natalie Alysia Dales, Arlington, MA (US); Janetta Dewhurst, Framingham, MA (US); Matthew James Hesse, Oakland, CA (US); Rama Jain, Danville, CA (US); John Ryan Kerrigan, Wakefield, MA (US); Hasnain Ahmed Malik, Boston, MA (US); James R. Manning, Emeryville, CA (US); Gary O'Brien, Maynard, MA (US); Andrew W. Patterson, Somerville, MA (US); Noel Marie-France Thomsen, Chelmsford, MA (US); and Pamela Yf Ting, Somerville, MA (US)
Assigned to NOVARTIS AG, Basel (CH)
Filed by Novartis AG, Basel (CH)
Filed on Sep. 1, 2023, as Appl. No. 18/460,428.
Application 18/460,428 is a division of application No. 17/693,759, filed on Mar. 14, 2022, granted, now 11,787,785.
Claims priority of provisional application 63/164,130, filed on Mar. 22, 2021.
Claims priority of provisional application 63/161,139, filed on Mar. 15, 2021.
Prior Publication US 2024/0158374 A1, May 16, 2024
Int. Cl. C07D 403/14 (2006.01); A61P 7/00 (2006.01); C07D 405/14 (2006.01); C07D 417/14 (2006.01)
CPC C07D 403/14 (2013.01) [A61P 7/00 (2018.01); C07D 405/14 (2013.01); C07D 417/14 (2013.01)] 30 Claims
 
1. A method of treating or preventing a disorder that is affected by the reduction of WIZ protein levels in a subject in need thereof; inhibiting, reducing, or eliminating the activity of WIZ protein or WIZ protein expression in a subject in need thereof; inducing or promoting fetal hemoglobin in a subject in need thereof; reactivating fetal hemoglobin production or expression in a subject in need thereof; increasing fetal hemoglobin expression in a subject in need thereof; treating a hemoglobinopathy, a sickle cell disease, or beta-thalassemia in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I″) or a pharmaceutically acceptable salt thereof, wherein:

OG Complex Work Unit Chemistry
custom character is a single bond or a double bond;
X is selected from CH, CF, and N;
Rx is selected from hydrogen, C1-C6alkyl, halo, C1-C6alkoxyl, and C3-C8cycloalkyl;
R′ is selected from hydrogen and C1-C6alkyl;
R1 is selected from hydrogen and C1-C6alkyl;
each R2 is independently selected from C1-C6alkyl, C1-C6haloalkyl, halo, and oxo, wherein the C1-C6alkyl is substituted with 0-1 occurrence of R2a; or 2 R2 on non-adjacent carbon atoms together with the non-adjacent carbon atoms to which they are attached form a bridging ring;
R2a is selected from C1-C6alkoxyl and hydroxyl;
R3 is selected from hydrogen, C1-C8alkyl, C2-C6alkenyl, —SO2R4, C1-C6haloalkyl, —C(═O)—O—(R5), —C(═O)—(R6), C3-C10cycloalkyl, and a 4- to 10-membered heterocyclyl comprising 1-2 heteroatoms independently selected from N, O and S, wherein the C1-C8alkyl and C1-C6haloalkyl are each independently substituted with 0-3 occurrences of R3a, and wherein the C3-C10cycloalkyl and 4- to 10-membered heterocyclyl are each independently substituted with 0-3 occurrences of R3b;
or
R3 together with the nitrogen atom to which it is attached and R2 together with the carbon atom to which it is attached form a 5- or 6-membered heterocyclyl comprising 0-1 additional heteroatom selected from N, O and S, which 5- or 6-membered heterocyclyl is substituted with 0-2 occurrences of an oxo group;
each R3a is independently selected from C3-C10cycloalkyl, a 4- to 10-membered heterocyclyl comprising 1-2 heteroatoms independently selected from N, O and S, a 5- to 10-membered heteroaryl comprising 1-4 heteroatoms independently selected from N, O, and S, C6-C10aryl, C1-C6alkoxyl, hydroxyl, and —C(═O)—NR7R8, wherein the C3-C10cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl and C6-C10aryl are substituted with 0-4 occurrences of R3b;
each R3b is independently selected from C1-C6alkoxyl, halo, C1-C6haloalkyl, C1-C6haloalkoxyl, C1-C6alkyl, —CN, —SO2NR7R8, —SO2R4, and hydroxyl;
R4 is selected from C3-C8cycloalkyl, C1-C6alkyl, a 4- to 6-membered heterocyclyl comprising 1-2 heteroatoms independently selected from N, O and S, C6-C10aryl, and —NR4bR4c, wherein the C1-C6alkyl is substituted with 0-1 occurrence of R4a;
R4a is selected from C3-C8cycloalkyl, C6-C10aryl, and C1-C6alkoxyl;
R4b is selected from hydrogen, and C1-C6alkyl;
R4c is selected from hydrogen, C1-C6alkyl, and C3-C8cycloalkyl;
R5 is selected from C1-C6alkyl, C3-C8cycloalkyl, and C6-C10aryl;
R6 is selected from C1-C6alkyl, C3-C8cycloalkyl, C6-C10aryl, a 4- to 10-membered heterocyclyl comprising 1-2 heteroatoms independently selected from N, O and S, and —NR4bR4c wherein the C1-C6alkyl is substituted with 0-1 occurrence of R6a, the C3-C8cycloalkyl is substituted with 0-1 occurrence of R6b and the 4- to 10-membered heterocyclyl is substituted with 0-1 occurrence of C1-C6alkyl;
R6a is selected from C6-C10aryl and C3-C8cycloalkyl;
R6b is selected from halo, C1-C6haloalkyl, C1-C6haloalkoxyl, and C1-C6alkyl;
R7 is selected from hydrogen and C1-C6alkyl;
R8 is selected from hydrogen and C1-C6alkyl;
or
R7 and R8 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl comprising 0-1 additional heteroatom selected from N, O, and S;
n is 0, 1, 2, 3 or 4;
m is 0, 1 or 2; and
p is 0 or 1.