US2023151016A1PendingUtilityA1
Pyrrolidine-pyrazoles as pyruvate kinase activators
Assignee: GLOBAL BLOOD THERAPEUTICS INCPriority: Feb 8, 2021Filed: Jan 17, 2023Published: May 18, 2023
Est. expiryFeb 8, 2041(~14.5 yrs left)· nominal 20-yr term from priority
C07D 487/04A61P 7/06
68
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Claims
Abstract
The subject matter described herein is directed to pyruvate kinase activating compounds of Formula I and pharmaceutical salts thereof, methods of preparing the compounds, pharmaceutical compositions comprising the compounds and methods of administering the compounds for the treatment of diseases associated with PKR and/or PKM2, such as pyruvate kinase deficiency, sickle cell disease, and beta-thalassemia.
Claims
exact text as granted — not AI-modified1 . A compound of Formula I:
wherein,
R a1 is hydroxy, C 1 -C 3 alkoxy, hydroxy-C 1 -C 3 alkoxy, or hydroxy-C 1 -C 3 alkyl;
R a2 is hydrogen or C 1 -C 3 alkyl;
or R a1 and R a2 , together with the carbon atom to which they are each attached, form a 4- to 5-membered heterocyclyl;
R c is phenyl or pyridinyl, each optionally substituted with one or two substituents independently selected in each instance from the group consisting of halo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, hydroxy-C 1 -C 3 alkoxy, (C 1 -C 3 alkoxy)-C 1 -C 3 alkoxy, hydroxy-C 1 -C 3 alkyl, and (C 1 -C 3 alkoxy)-C 1 -C 3 alkyl; and
R b is a thiazol-2(3H)-one or a 5-membered heteroaryl ring, each optionally substituted with one, two, or three substituents independently selected in each instance from the group consisting of C 1 -C 3 alkyl, halo-C 1 -C 3 alkyl, halo-C 1 -C 3 alkoxy, halo, C 1 -C 3 alkoxy, (C 1 -C 3 alkoxy)-C 1 -C 3 alkyl, (C 1 -C 3 -alkoxy)-C 1 -C 3 alkoxy, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocyclyl, phenyl, and 5- or 6-membered heteroaryl; or a pharmaceutically acceptable salt thereof.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R a1 is hydroxy-C 1 -C 3 alkyl.
3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R a1 is —OH, —CH 2 OH, —CH(OH)CH 3 , —OCH 3 , or —OCH 2 CH 2 OH.
4 . The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R a1 is —CH 2 OH.
5 . The compound of any one of claims 1 - 4 , or a pharmaceutically acceptable salt thereof, wherein R a2 is hydrogen or —CH 3 .
6 . The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R a2 is hydrogen.
7 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R a1 and R a2 , together with the carbon atom to which they are each attached, form an oxetanyl ring.
8 . The compound of any one of claims 1 - 7 , or a pharmaceutically acceptable salt thereof, wherein R c is phenyl or pyridinyl, each optionally substituted with one or two halos.
9 . The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein R c is phenyl or pyridinyl, each optionally substituted with one halo.
10 . The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein R c is phenyl or pyridinyl, each optionally substituted with fluoro or chloro.
11 . The compound of any one of claims 8 - 10 , or a pharmaceutically acceptable salt thereof, wherein R c is phenyl, 2-fluorophenyl, 2-chlorophenyl, or pyridin-2-yl.
12 . The compound of any one of claims 1 - 11 , or a pharmaceutically acceptable salt thereof, wherein R c is
wherein, X is CH or N; and
R c is hydrogen, fluoro, or chloro.
13 . The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein R c is
14 . The compound of any one of claims 1 - 13 , wherein R c is phenyl.
15 . The compound of any one of claims 1 - 7 , or a pharmaceutically acceptable salt thereof, wherein R c is phenyl substituted ortho with C 1 -C 3 alkyl, (C 1 -C 3 -alkoxy)-C 1 -C 3 alkoxy, C 1 -C 3 alkoxy, or hydroxy-C 1 -C 3 alkoxy.
16 . The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein R c is phenyl substituted ortho with —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —OCH 3 , —OCH 2 CH 3 , methoxy-C 1 -C 3 alkoxy, —OCH 2 CH 2 OH, or —OCH 2 CH 2 CH 2 OH.
17 . The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein R c is phenyl substituted ortho with —CH 2 CH 3 , —OCH 3 , —OCH 2 CH 2 OH, or —OCH 2 CH 2 OCH 3 .
18 . The compound of any one of claims 1 - 17 , or a pharmaceutically acceptable salt thereof, wherein R b is a thiazol-2(3H)-one or a 5-membered heteroaryl ring substituted with one or two substituents, each independently selected from the group consisting of C 1 -C 3 alkyl, halo-C 1 -C 3 alkoxy, halo-C 1 -C 3 alkyl, (C 1 -C 3 alkoxy)-C 1 -C 3 alkyl, C 1 -C 3 alkoxy, phenyl, and 4- to 6-membered heterocyclyl.
19 . The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein R b is a thiazol-2(3H)-one or a 5-membered heteroaryl ring substituted with one or two substituents, each independently selected from the group consisting of —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , fluoro-C 1 -C 3 alkyl, fluoro-C 1 -C 3 alkoxy, phenyl, 5-membered heterocyclyl, methoxy-C 1 -C 3 alkyl, —OCH 2 CH 3 , and —OCH 3 .
20 . The compound of claim 19 , or a pharmaceutically acceptable salt thereof, wherein R b is a thiazol-2(3H)-one or a 5-membered heteroaryl ring substituted with one or two substituents, each independently selected from the group consisting of —CH 3 , —CH 2 CH 3 , —CF 3 , —CH 2 CHF 2 , —CH 2 CH 2 CF 3 , —CHF 2 , —OCH 2 CHF 2 , phenyl, —OCH 2 CF 3 , —CH 2 CF 3 , —CH 2 CH 2 F, —CH 2 CH 2 OCH 3 , —OCH 2 CH 3 , —OCH 3 , and tetrahydrofuranyl.
21 . The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein R b is a 5-membered heteroaryl ring substituted with one halo-C 1 -C 3 alkyl and optionally further substituted with one C 1 -C 3 alkyl.
22 . The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein R b is a 5-membered heteroaryl ring substituted with one substituent selected from the group consisting of C 1 -C 3 alkyl and halo-C 1 -C 3 alkyl.
23 . The compound of claim 22 , or a pharmaceutically acceptable salt thereof, wherein R b is a 5-membered heteroaryl ring substituted with one halo-C 1 -C 3 alkyl.
24 . The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein R b is a 5-membered heteroaryl ring substituted with two substituents, each independently selected from the group consisting of C 1 -C 3 alkyl and halo-C 1 -C 3 alkyl.
25 . The compound of claim 24 , or a pharmaceutically acceptable salt thereof, wherein R b is a 5-membered heteroaryl ring substituted with one C 1 -C 3 alkyl and one halo-C 1 -C 3 alkyl.
26 . The compound of any one of claims 1 - 25 , or a pharmaceutically acceptable salt thereof, wherein R b is a 5-membered heteroaryl ring comprising one, two, or three nitrogen ring atoms.
27 . The compound of claim 26 , wherein the 5-membered heteroaryl ring of R b is pyrazolyl, imidazolyl, pyrrolyl, oxazolyl, triazolyl, or thiazolyl.
28 . The compound of claim 27 , or a pharmaceutically acceptable salt thereof, wherein the 5-membered heteroaryl ring of R b is pyrazolyl.
29 . The compound of any one of claims 1 - 28 , or a pharmaceutically acceptable salt thereof, wherein R b is
wherein, R b1 is halo-C 1 -C 3 alkyl, methoxy-C 1 -C 3 alkyl, C 1 -C 3 alkyl, hydrogen, or tetrahydrofuranyl; and
R b2 is hydrogen, halo-C 1 -C 3 alkyl, or C 1 -C 3 alkyl.
30 . The compound of any one of claims 1 - 29 , or a pharmaceutically acceptable salt thereof, wherein R b is
31 . The compound of claim 29 or 30 , or a pharmaceutically acceptable salt thereof, wherein R b1 is halo-C 1 -C 3 alkyl; and R b2 is hydrogen or C 1 -C 3 alkyl.
32 . The compound of any one of claims 29 - 31 , or a pharmaceutically acceptable salt thereof, wherein R b2 is hydrogen.
33 . The compound of any one of claims 29 - 31 , or a pharmaceutically acceptable salt thereof, wherein R b2 is C 1 -C 3 alkyl.
34 . The compound of claim 33 , or a pharmaceutically acceptable salt thereof, wherein R b2 is —CH 3 .
35 . The compound of any one of claims 29 - 34 , or a pharmaceutically acceptable salt thereof, wherein R b1 is fluoro-C 1 -C 3 alkyl.
36 . The compound of claim 35 , or a pharmaceutically acceptable salt thereof, wherein R b1 is —CHF 2 , —CH 2 CH 2 CF 3 , —CH 2 CH 2 F, —CH 2 CHF 2 , or —CH 2 CF 3 .
37 . The compound of claim 29 or 30 , or a pharmaceutically acceptable salt thereof, wherein R b1 is C 1 -C 3 alkyl; and R b2 is fluoro-C 1 -C 3 alkyl.
38 . The compound of claim 37 , or a pharmaceutically acceptable salt thereof, wherein R b1 is —CH 2 CH 3 ; and R b2 is —CF 3 .
39 . The compound of claim 29 or 30 , or a pharmaceutically acceptable salt thereof, wherein R b1 is —CH 2 CH 2 OCH 3 or tetrahydrofuranyl; and R b2 is hydrogen.
40 . The compound of claim 27 , or a pharmaceutically acceptable salt thereof, wherein the 5-membered heteroaryl ring of R b is thiazolyl.
41 . The compound of claim 40 , or a pharmaceutically acceptable salt thereof, wherein R b is
wherein, R b3 is halo-C 1 -C 3 alkoxy, C 1 -C 3 alkyl, halo-C 1 -C 3 alkyl, or C 1 -C 3 alkoxy; and
R b4 is hydrogen or C 1 -C 3 alkyl.
42 . The compound of claim 41 , or a pharmaceutically acceptable salt thereof, wherein R b is
43 . The compound of claim 41 or 42 , or a pharmaceutically acceptable salt thereof, wherein R b3 is —CH 3 , —CH 2 CH 2 CF 3 , —OCH 2 CHF 2 , —OCH 2 CHF 3 , —OCH 3 , or —OCH 2 CH 3 ; and R b4 is —CH 3 .
44 . The compound of any one of claims 1 - 25 , or a pharmaceutically acceptable salt thereof, wherein R b is a 5-membered heteroaryl ring, wherein the 5-membered heteroaryl ring of R b is thiophenyl.
45 . The compound of claim 44 , or a pharmaceutically acceptable salt thereof, wherein R b is
wherein, R b5 is halo, C 1 -C 3 alkyl, phenyl, or halo-C 1 -C 3 alkyl.
46 . The compound of claim 45 , or a pharmaceutically acceptable salt thereof, wherein R b is
47 . The compound of claim 45 or 46 , or a pharmaceutically acceptable salt thereof, wherein R b5 is phenyl, —CH 2 CH 3 , —CF 3 , bromo, or —CH 2 CH 2 CF 3 .
48 . The compound of claim 1 , selected from Table 1, or a pharmaceutically acceptable salt thereof.
49 . A pharmaceutical composition comprising a compound of any one of claims 1 - 48 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
50 . A method of treating a disease or disorder associated with modulation of pyruvate kinase (PKR) and/or PKM2 in a subject, comprising administering to the subject an effective amount of a compound of any one of claims 1 - 48 , or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 49 .
51 . A method of activating PKR and/or PKM2 in a subject, comprising administering to the subject an effective amount of a compound of any one of claims 1 - 48 , or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 49 .
52 . A method of treating a subject afflicted with a disease associated with decreased activity of PKR and/or PKM2, comprising administering to the subject an effective amount of a compound of any one of claims 1 - 48 , or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 49 .
53 . The method of claim 52 , wherein the disease is selected from the group consisting of sickle cell disease, sickle cell anemia, thalassemia, hereditary non-spherocytic hemolytic anemia, hemolytic anemia, hereditary spherocytosis, hereditary elliptocytosis, abetalipoproteinemia, paroxysmal nocturnal hemoglobinuria, acquired hemolytic, cancer, and anemia of chronic diseases.
54 . The method of claim 53 , wherein the disease is selected from the group consisting of sickle cell disease and thalassemia.
55 . The method of claim 54 , wherein the thalassemia is beta-thalassemia.Join the waitlist — get patent alerts
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