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CA-3181922-C - CD73 INHIBITING 2,4-DIOXOPYRIMIDINE COMPOUNDS

CA3181922CCA 3181922 CCA3181922 CCA 3181922CCA-3181922-C

Abstract

The present disclosure provides pyrimidine dione compounds of Formula (I) (see formula I): and pharmaceutically acceptable salts thereof, and more particularly the compound (see above compound): or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions thereof, for treating cancer, including solid tumors. The compounds can be used alone or in combination with other anti-cancer agents.

Inventors

  • Mark J. Bartlett
  • Michael R. Mish
  • Scott D. Schroeder
  • Nathan D. Shapiro
  • Dustin S. Siegel
  • Doris T. Tang
  • Hai Yang
  • Gregory F. Chin
  • Michael O. Clarke
  • Jennifer L. Cosman
  • Deeba Ensan
  • Bindu Goyal
  • Stephen Ho
  • Hon C. Hui
  • Richard L. Mackman

Assignees

  • GILEAD SCIENCES, INC.

Dates

Publication Date
20260505
Application Date
20210429
Priority Date
20200501

Claims (10)

  1. CLAIMS: 1.A compound selected from the group consisting of: , , , , , , , , , , , , , , , , , 90163700 1254 , , , , , and .
  2. 2. A pharmaceutically acceptable salt of the compound of claim 1.
  3. 3.The compound, which is: , or a pharmaceutically acceptable salt thereof.
  4. 4. The compound, which is: .
  5. 5. A pharmaceutically acceptable salt of the compound, which is: 90163700 1255 .
  6. 6. A pharmaceutical composition comprising a compound of claim 1 or 4, or a pharmaceutically acceptable salt of claim 2 or 5, and a pharmaceutically acceptable carrier or excipient.
  7. 7. A combination comprising the pharmaceutical composition of claim 6, and one or more additional therapeutic agents or therapies.
  8. 8. The combination of claim 7, wherein the one or more additional therapeutic agents or therapies is independently an anti-neoplastic agent, chemotherapy, radiation therapy, or resection therapy.
  9. 9. The combination of claim 7, wherein the additional therapeutic agent is independently rituximab, doxorubicin, gemcitabine, nivolumab, pembrolizumab, atezolizumab or ipilimumab.
  10. 10. The combination of claim 7, wherein the one or more additional therapeutic agents or therapies is a PD-1 or PD-L1 inhibitor.

Description

CD73 INHIBITING 2,4-DIOXOPYRIMIDINE COMPOUNDS CROSS-REFERENCES TO RELATED APPLICATIONS [0001] This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 63/018,774, filed on May 1, 2020, and of U.S. Provisional Application No. 63/149,803, filed on February 16, 2021, which are hereby incorporated herein by reference in their entireties for all purposes. BACKGROUND OF THE INVENTION [0002] The glycosyl-phosphatidylinositol-anchored CD73 antigen (also known as Cluster of Differentiation 73, ecto-5 '-nucleotidase, ecto-5'-NT, 5'-NT, and NTSE) is considered the ratelimiting enzyme in the generation of extracellular adenosine (Stagg J, Smyth MJ. Extracellular adenosine triphosphate and adenosine in cancer. Oncogene. 2010;29:5346-58. doi:10.1038/onc.2010.292). CD73 is a 70-kDa glycosylphosphatidylinositol (GPI)-anchored protein normally expressed on endothelial cells and subsets of hematopoietic cells. CD73, together with CD39, regulates adenosine triphosphate (ATP) metabolism. CD39 (NTPDase-1) converts ATP into AMP, with only trace amounts of ADP being released, while CD73 catalyzes the conversion of AMP to adenosine (Ado). [0003] Extracellular Ado accumulates in cancerous tissues and constitutes an important mechanism of tumor immune escape. Among other effects, tumor-derived Ado profoundly inhibits infiltrating effector T cells. ATP degradation into Ado through CD39 and CD73 coexpressed on murine Treg (regulatory CD4+ T cells) has been shown as responsible for tumor immunosuppression. [0004] CD73 can be found constitutively expressed at high levels on various types of cancer cells. CD73-generated adenosine is assumed to suppress adaptive anti-tumor immune responses thereby promoting tumor growth and metastasis. And studies in animal models have shown that blockade of CD73 activity suppresses tumor growth and prolongs survival by promoting antitumor adaptive immunity (Forte et al. (2012) J Immunol. 189(5):2226-33). Given the need for cancer treatments, new compositions and methods for regulating CD73 activity and related therapeutic agents is needed. This disclosure meets this and other needs. BRIEF SUMMARY OF THE INVENTION [0005] In one embodiment, the present disclosure provides a compound of Formula (I): 1 90163700 WO 2021/222522 (I) or a pharmaceutically acceptable salt thereof, wherein PCT/0S2021/029828 Y is a bond, -C1-6alkyl, -C2-6alkenyl, -C2-6alkynyl, -C3-1cycloalkyl, -C1-6alkyl-O-, -C1- 6alkyl-O-C1-6alkyl, -O-C1-6alkyl, -O-C1-6alkyl-O-, -C3-1cycloalkyl-O-, -O-C3_ 1cycloalkyl, -C3-1cycloalkyl-C1-3alkyl, -S(=0)2-, -S(=0)2CH2-, -CH2S(=0)2-, - N(Ra)-, -N(Ra)CH2-, -C1-6alkyl-N(Rb)-, -C3-1cycloalkyl-N(Rb)-, -N(Ra)C(=O)-, - C1-3alkylN(Ra)C(=O)-, heterocycloalkyl-C(=O)-, heterocycloalkyl-N(H)C(=O)-, heterocycloalkyl, heterocycloalkyl-C1-6alkyl-O-, or heterocycloalkyl-0-, wherein each alkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one to four halogens and is further optionally substituted with one or two groups independently selected from -CN, -C1-3alkyl and -C1-3haloalkyl; one or two of Z1, Z2 and Z3 is CR2 and the remaining one or two of Z1, Z2, and Z3 is N; one of W1 and W2 is N and the other is C; R1 is hydrogen, -CN, -C1-6alkyl, -C3-1cycloalkyl, -C6-12aryl, -C1-6alkyl-C6-12aryl, -C1- 6alkyl-heteroaryl, heterocycloalkyl, heteroaryl, or -C1-6alkyl-O-C1-6alkyl, wherein each alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one to three halogens and is further optionally substituted with one or two R3; R2 is each independently hydrogen, halogen, -CN, -C1-6alkyl, -C3-10cycloalkyl, -O-C1- 6alkyl, -C(=O)OR\ -C(=O)heterocycloalkyl, -C(=O)N(Rb)C6-12aryl, - C(=O)N(Rb)heteroaryl, -C(=O)N(Rb)(Rb), -C1-6alkyl-S(=0)2C6-12aryl, -N(Rb)(Rb), -C6-12aryl, heterocycloalkyl, or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one to three halogens and is further optionally substituted with one to three R4; R3 is halogen, -CN, -C1-6alkyl, -C3-1cycloalkyl, -C1-3alkyl-C3-1cycloalkyl, -C1-3alkylheterocycloalkyl, -N(Rb)(Rb), -N(H)C(=O)O-RC, -C(=O)N(Rb)(Rb), -C(=O)OC1- 6alkyl, -C(=O)OC1-6alkylC6-12aryl, -C(=O)C1-3alkyl, -C(=O)C3-1cycloalkyl, - C( =O)heterocycloalkyl, -OC( =O)heterocycloalkyl, -OC( =O)N(H)C1-6alkyl, - OC(=O)N(H)C3-1cycloalkyl, -OC(=O)OC1-6alkyl, -OC(=O)N(H)C6-12aryl, or - ORC, wherein each alkyl, cycloalkyl, heterocycloalkyl, or aryl is optionally 2 WO 2021/222522 PCT/0S2021/029828 substituted with one to three halogens and is further optionally substituted with one or two R\ R4 is halogen, -CN, -ORC, -C1-6alkyl, -N(Rb)(Rb), or -C1-6haloalkyl; Ra is each independently hydrogen, or -C1-3alkyl; Rb is each independently hydrogen, -C1-6alkyl, -C1-6haloalkyl, -C1-6alkyl-C3-1cycloalkyl, - C3-1cycloalkyl-C1-6haloalkyl, -C3-1cycloalkyl, -C3-1halocycloalkyl, or -C(=O)C1- 6alkyl; and Re is each independently hydrogen, -C1-6alkyl, -C1-6haloalkyl, -C3-1cycloalkyl, -C1-3