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Msg  30458 of 30670  at  12/1/2023 6:32:26 PM  by

JBWIN


Building IP: EXEL Patent Appl "Heterocyclic Adenosine Receptor Antagonists"

 

Heterocyclic Adenosine Receptor Antagonists

DOCUMENT ID

US 20230382917 A1

DATE PUBLISHED

2023-11-30

INVENTOR INFORMATION

NAME

CITY

STATE

ZIP CODE

COUNTRY

Ma; Sunghoon
Foster City
CA
N/A
US
Wang; Yong
South San Francisco
CA
N/A
US
Xu; Wei
Danville
CA
N/A
US

APPLICANT INFORMATION

NAME
Exelixis, Inc.
CITY
Alameda
STATE
CA
ZIP CODE
N/A
COUNTRY
US
AUTHORITY
N/A
TYPE
obligated-assignee

APPLICATION NO

18/323510

DATE FILED

2023-05-25

DOMESTIC PRIORITY (CONTINUITY DATA)

parent US continuation 17201380 20210315 parent-grant-document US 11718622 child US 18323510

us-provisional-application US 62990105 20200316

US CLASS CURRENT:

1/1

CPC CURRENT

TYPE

CPC

DATE

CPCI
2013-01-01
CPCI
2013-01-01
CPCI
2013-01-01

Abstract

Heterocyclic compounds useful as antagonists of adenosine receptors, and methods of treatment of diseases using antagonists of adenosine receptors are disclosed herein. Also disclosed herein are pharmaceutical compositions and methods of administration of heterocyclic antagonists of adenosine receptors and processes for producing heterocyclic antagonists of adenosine receptors.

Background/Summary

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to U.S. Provisional Application Ser. No. 62/990,105, filed Mar. 16, 2020, the entire contents of which are incorporated by reference herein.

FIELD OF THE INVENTION

[0002] The present invention relates to heterocyclic compounds useful as antagonists of adenosine receptors, and further relates to methods of treatment of diseases using antagonists of adenosine receptors. The invention also relates to pharmaceutical compositions and methods of administration of heterocyclic antagonists of adenosine receptors. The invention also relates to processes for producing heterocyclic antagonists of adenosine receptors.

BACKGROUND OF THE INVENTION

[0003] Adenosine, an endogenous nucleoside that exists both intracellularly and extracellularly, regulates numerous important physiological functions such as the maintenance of cellular and tissue homeostasis (Borea, P. A. et al., Physiol Rev., 2018, 98, 1591-1625). In humans, four subtypes of adenosine receptors have been described: A1 (also known as ADORA1A), A2A (also known as ADORA2A), A2B (also known as ADORA2B), and A3 (also known as ADORA3). Whereas A1 and A2A are high affinity receptors for adenosine, A2B and A3 function as low affinity receptors. Through differential binding to specific receptors localized on the plasma membrane, adenosine can elicit varying pharmacological effects in different tissue systems.

[0004] In the immune system, adenosine signaling normally functions to limit inflammation and dampen the immune response, thus protecting tissues against excessive immune reactions (Allard, B. et al., Curr. Opin. Pharmacol., 2016, 29, 7-16). Many immune cell types express adenosine receptors and hence are directly regulated by adenosine. A2A adenosine receptor is primarily expressed on lymphoid-derived cells, including T effector cells, regulatory T cells, and natural killer cells. A2B adenosine receptor, in contrast, is primarily expressed on monocyte-derived cells, including myeloid-derived suppressor cells, tumor-associated macrophages, and dendritic cells. Binding of adenosine to A2A or A2B receptors on immune cells results in activation of adenylate cyclase, which catalyzes the production of intracellular cyclic AMP (cAMP). This increased intracellular cAMP in turn blocks the activation of immune effector cells and increases the number of immunosuppressive cells, thus suppressing the overall immune response (Livingstone, M. et al., Inflamm. Res., 2004, 53, 171-178).

[0005] Within the tumor microenvironment, adenosine levels are maintained at unusually high levels compared to normal physiological conditions (Blay, J. et al., Cancer Res., 1997, 57, 2602-2605). High adenosine levels function to suppress the anti-tumor immune response, thus promoting cancer progression. Enhanced production of adenosine within the tumor is primarily achieved via the overexpression of CD39 and CD73, two cell surface ectoenzymes that catalyze the breakdown of extracellular ATP to adenosine (Hammami, A. et al., Semin Immunol., 2019, 42, 101304). Many cell types within the tumor can express CD39 and CD73, including tumor cells, endothelial cells, mesenchymal stem cells, cancer-associated fibroblasts, T effector cells, regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells. Moreover, conditions inherent to a tumor such as hypoxia and inflammation can further upregulate the expression of CD39 and CD73, thus effectively sustaining adenosine production.

[0006] Given the importance of adenosine in creating and maintaining an immunosuppressive tumor microenvironment, inhibition of adenosine receptor signaling may be a viable anti-cancer strategy (Leone, R. D. et al., Cancer Immunol. Immunother., 2018, 67, 1271-1284). Indeed, targeted inhibition of A2A receptor has been shown to downregulate immunosuppressive signals that inactivate T effector cells, resulting in enhanced anti-tumor immune responses with subsequent tumor regression. Similarly, targeted inhibition of A2B receptor has been shown to enhance tumor antigen presentation, resulting in suppressed primary tumor growth and inhibited metastasis. That A2A and A2B receptor knockout mice are viable and fertile with no apparent growth abnormalities (Allard, B. et al., Curr. Opin. Pharmacol., 2016, 29, 7-16) suggests that pharmacological inhibition of either or both adenosine receptors may be a tolerable approach to restoring anti-cancer immunity.

SUMMARY OF THE INVENTION

[0007] In one aspect, the present invention provides a compound of formula I:

##STR00001## [0008] or a pharmaceutically acceptable salt thereof, wherein: [0009] Ring A is heteroaryl or aryl; [0010] R.sup.1 is H or alkyl optionally substituted with 1, 2, 3, or 4 independently selected R.sup.a substituents; [0011] R.sup.2 is H, alkyl, —COR″′, —CONR′R″, —COOR′, —SO.sub.2R′, —SO.sub.2NR′R″, or —SO.sub.2OR′, wherein the alkyl of R.sup.2 is optionally substituted with 1, 2, 3, or 4 independently selected R.sup.a substituents; [0012] R.sup.3 is H, alkyl, halo, —CN, or —CONR′R″, wherein the alkyl of R.sup.3 is optionally substituted with 1, 2, 3, or 4 independently selected R.sup.a substituents; [0013] or R.sup.2 and R.sup.3 together form 5-6 membered heterocycloalkyl or 5-6 membered heteroaryl, each of which is optionally substituted with 1, 2, 3, 4, or 5 independently selected R.sup.7 substituents, and wherein when R.sup.2 and R.sup.3 together form 6-membered heteroaryl, then R.sup.1 is absent; [0014] R.sup.4 is H, alkyl, halo, haloalkyl, —NR′R″, —COR′, —CONR′R″, —COOR′, SO.sub.2R′, —SO.sub.2NR′R″, —SO.sub.2OR′, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or —C.sub.1-4 alkylene-R.sup.b, wherein R.sup.b is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or —C.sub.1-4 alkylene-R.sup.b of R.sup.4 is optionally substituted with 1, 2, 3, or 4 independently selected R.sup.a substituents; [0015] each R.sup.5 is independently H, alkyl, halo, haloalkyl, alkoxy, —CN, —COR′, —CONR′R″, —COOR′, —SO.sub.2R′, —SO.sub.2NR′R″, —SO.sub.2OR′, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl wherein the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl of R.sup.5 is optionally substituted with 1, 2, 3, or 4 independently selected R.sup.a substituents; [0016] n is 0, 1, 2, 3, 4, or 5; [0017] one of Q.sub.1 and Q.sub.2 is N and the other is C; [0018] Z is N or CR.sup.6; [0019] R.sup.6 is H or alkyl, wherein the alkyl of R.sup.6 is optionally substituted with 1, 2, 3, or 4 independently selected R.sup.a substituents; [0020] each R.sup.7 is independently oxo, alkyl, halo, haloalkyl, hydroxy, alkoxy, hydroxyalkyl, cycloalkyl, or heterocycloalkyl, wherein each cycloalkyl and heterocycloalkyl of R.sup.7 is optionally and independently further substituted with 1, 2, or 3 of C.sub.1-4 alkyl, halo, C.sub.1-4 haloalkyl, hydroxy, or C.sub.1-4 alkoxy; [0021] R′ and R″ are each independently H or alkyl, wherein each alkyl of R′ and R″ is optionally substituted with 1, 2, 3, or 4 independently selected R.sup.a substituents; [0022] R″′ is alkyl, haloalkyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, cycloalkyl or heterocycloalkyl of R″′ is optionally substituted with 1, 2, 3, or 4 independently selected R.sup.a substituents; and [0023] each R.sup.a is independently alkyl, halo, haloalkyl, hydroxy, alkoxy, hydroxyalkyl, cycloalkyl, or heterocycloalkyl, wherein each cycloalkyl and heterocycloalkyl of R.sup.a is optionally and independently further substituted with 1, 2, or 3 of C.sub.1-4 alkyl, halo, C.sub.1-4 haloalkyl, hydroxy, or C.sub.1-4 alkoxy; [0024] wherein when R.sup.4 is H, aryl, or heteroaryl, then Ring A is furanyl.

[0025] Another aspect provides a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof as described herein, and a pharmaceutically acceptable carrier or excipient.

[0026] Another aspect provides a method of inhibiting an activity of an adenosine receptor, comprising contacting the receptor with a compound or a pharmaceutically acceptable salt thereof as described herein.

[0027] Another aspect provides a method of treating a disease or disorder in a patient, wherein the disease or disorder is associated with abnormal expression of A2A or A2B receptors, the method comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, as described herein.

[0028] Another aspect provides processes for producing a compound or a pharmaceutically acceptable salt thereof as described herein (e.g., compounds of formula I).



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