US 12,459,957 B2
Therapeutic compounds and methods
Samantha Alyson Green, South San Francisco, CA (US); Jessica Marie Grandner, South San Francisco, CA (US); Steven Thomas Staben, South San Francisco, CA (US); Neri Amara, South San Francisco, CA (US); Vishva M. Dixit, South San Francisco, CA (US); and Elisia Villemure, South San Francisco, CA (US)
Assigned to GENENTECH, INC., South San Francisco, CA (US)
Filed by GENENTECH, INC., South San Francisco, CA (US)
Filed on May 8, 2024, as Appl. No. 18/657,963.
Application 18/657,963 is a division of application No. 17/862,963, filed on Jul. 12, 2022, granted, now 12,006,331.
Claims priority of provisional application 63/222,288, filed on Jul. 15, 2021.
Prior Publication US 2025/0109142 A1, Apr. 3, 2025
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 498/04 (2006.01); A61K 9/08 (2006.01); A61K 9/12 (2006.01); A61K 9/20 (2006.01); A61K 9/48 (2006.01); A61K 47/02 (2006.01); A61K 47/06 (2006.01); A61K 47/10 (2017.01); A61K 47/12 (2006.01); C07D 519/00 (2006.01); C07F 9/6561 (2006.01)
CPC C07D 498/04 (2013.01) [A61K 9/08 (2013.01); A61K 9/12 (2013.01); A61K 9/2013 (2013.01); A61K 9/2018 (2013.01); A61K 9/2027 (2013.01); A61K 9/2054 (2013.01); A61K 9/2059 (2013.01); A61K 9/485 (2013.01); A61K 9/4858 (2013.01); A61K 9/4866 (2013.01); A61K 47/02 (2013.01); A61K 47/06 (2013.01); A61K 47/10 (2013.01); A61K 47/12 (2013.01); C07D 519/00 (2013.01); C07F 9/6561 (2013.01)] 20 Claims
OG exemplary drawing
 
1. A method for treating a symptom of a disease associated with the activity of glycolytic enzyme phosphofructokinase-1 liver type in an animal, comprising administering to the animal a compound of formula (I):

OG Complex Work Unit Chemistry
or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein:
R1 is —NRaRb or a 5-10 membered heteroaryl that is optionally substituted with one or more groups Rc;
R2 is a 6-10 membered aryl that is optionally substituted with one or more groups Rr; or R2 is a 5-10 membered heteroaryl that is that is optionally substituted with one or more groups Rs; or R2 is a 3-10 membered heterocycle that is that is optionally substituted with one or more groups R2;
Ra is (C1-C6)alkyl, (C3-C6)cycloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C3-C6)cycloalkyl(C1-C6)alkyl, (C2-C6)alkynylcarbonyl, 3-6 membered heterocycle, or a 5-6 membered heteroaryl that is optionally substituted with one or more groups Rf; wherein each (C1-C6)alkyl, (C3-C6)cycloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C3-C6)cycloalkyl(C1-C6)alkyl, (C2-C6)alkynylcarbonyl, and 3-6 membered heterocycle is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, cyano, (C2-C6)alkenyl, (C2-C6)alkynyl, C(═O)NRmRn, and (C1-C6)alkyl that is optionally substituted with one or more groups independently selected form the group consisting of halo, hydroxy, cyano, —NRmRn, and —C(═O)NRmRn;
Rb is H or (C1-C6)alkyl;
each Rc is independently selected from the group consisting of cyano, —NRdRe, —C(═O)NRdRe, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C6)alkyl, (C1-C6)alkoxy, and (C1-C6)alkanoyl, wherein each (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C6)alkyl, (C1-C6)alkoxy and (C1-C6)alkanoyl is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, carboxy, and cyano;
Rd and Re are each independently selected from the group consisting of H and (C1-C6)alkyl; or Rd and Re taken together with the nitrogen to which they are attached form a 3-6 membered heterocyclic ring that is optionally substituted with one or more groups independently selected from the group consisting of halo and (C1-C6)alkyl;
each Rf is independently selected from the group consisting of halo, hydroxy,
cyano, —NRgRh, —C(═O)NgRh, and (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, carboxy, —NRgRh, —C(═O)NRgRh, and cyano;
Rg and Rh are each independently selected from the group consisting of H and (C1-C6)alkyl; or Rg and Rh taken together with the nitrogen to which they are attached form a 3-6 membered heterocyclic ring that is optionally substituted with one or more groups independently selected from the group consisting of halo and (C1-C6)alkyl;
Rm is H or (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, carboxy, cyano, and oxo;
Rn is H or (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, carboxy, cyano, and oxo;
each Rr is independently selected from the group consisting of halo, hydroxy, cyano, —NRtRu, —C(═O)NRtRu, —S(O)2NRtRu, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, —N(H)S(O)2Rx, —S(O)2Rx, (C2-C6)alkenyl, and (C2-C6)alkynyl, wherein each (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, (C2-C6)alkenyl, and (C2-C6)alkynyl is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, carboxy, —NRtRu, —C(═O)NRtRu, —S(O)2NRtRu, —S(O)2Rx, and cyano;
each Rs is independently selected from the group consisting of halo,
cyano, —NRvRw, —C(═O)NRvRw, —S(O)2NRvRw, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkylthio, 3-6 membered heterocycle, and —S(O)2Ry, wherein each (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, 3-6 membered heterocycle, and (C1-C6)alkylthio, is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, carboxy, —NRtRu, —C(═O)NRtRu, S(O)2NRvRw, —S(O)2Ry, and cyano;
Rt and Ru are each independently selected from the group consisting of H, (C1-C6)alkyl, (C1-C6)alkanoyl, and (C2-C6)alkynylcarbonyl; or Rt and Ru taken together with the nitrogen to which they are attached form a 3-6 membered heterocyclic ring that is optionally substituted with one or more groups independently selected from the group consisting of halo and (C1-C6)alkyl;
Rv and Rw are each independently selected from the group consisting of H, (C1-C6)alkyl, and (C1-C6)alkanoyl; or Ry and Rw taken together with the nitrogen to which they are attached form a 3-6 membered heterocyclic ring that is optionally substituted with one or more groups independently selected from the group consisting of halo and (C1-C6)alkyl;
Rx is H or (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, carboxy, cyano, and oxo;
Ry is H or (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, carboxy, cyano, and oxo; and
each Rz is independently selected from the group consisting of oxo, halo, hydroxy, and (C1-C6)alkyl that is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, carboxy, —NRtRu, —C(═O)NRtRu, S(O)2NRvRw, —S(O)2Ry, cyano, and oxo;
provided the compound is not:

OG Complex Work Unit Chemistry
wherein the disease associated with the activity of glycolytic enzyme phosphofructokinase-1 liver type is cancer, diabetes, a caspase-associated auto-inflammatory condition, pulmonary disease, a systemic autoimmune disease, atherosclerosis, thrombosis, multiple sclerosis, Alzheimer's disease, psoriasis, or pulmonary fibrosis.