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US-20260125378-A2 - Heterocyclic Compounds

US20260125378A2US 20260125378 A2US20260125378 A2US 20260125378A2US-20260125378-A2

Abstract

Disclosed herein is a compound of Formula (I) having the following structure for activating T cells, promoting T cell proliferation, and/or exhibiting antitumor activity, a method of using the compounds disclosed herein for treating cancer, and a pharmaceutical composition comprising the same.

Inventors

  • Guoliang Zhang
  • Zhikun NI
  • JIANZHUANG MIAO
  • Zhi Zhang
  • Ce Wang

Assignees

  • BEONE MEDICINES I GMBH

Dates

Publication Date
20260507
Application Date
20250729

Claims (20)

  1. 1 . A compound of formula (I), or a pharmaceutically acceptable salt, a tautomer, a stereoisomer, an enantiomer, an isotopologue, or a prodrug thereof, wherein X 1 is C or N, each of X 2 and X 3 is independently selected from —N— or —CH—; X 4 is N, O or S; R 1 is hydrogen, deuterium, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl, provided that R 2 is absent when X 1 is N; R 4 is hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl, provided that R 4 is absent when X 4 is O or S; R 5 is hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl, R 5a —C(O)—, R 5a —C(O)O—, R 5a —O—C(O)—, R 5a —C(O)NR 5b —, R 5a —NR 5b —C(O)—, or R 5a —SO 2 —, wherein R 5a and R 5b are each independently hydrogen, alkyl, or cycloalkyl; each of R 7 , R 9 , R 8 , and R 10 is independently hydrogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxyl, substituted or unsubstituted cycloalkyl, —C(O)R 7a , or -alkyl-C(O)R 7a , and wherein R 7a is hydrogen, alkyl, or alkoxy, provided that at least one of R 7 and R 9 is not hydrogen; or R 7 and R 9 are each hydrogen and R 8 and R 10 together form a bridge containing at least one —CH 2 -moiety in addition to the two bridgehead atoms; or R 8 and R 10 are each hydrogen and R 7 and R 9 together form a bridge containing at least one —CH 2 -moiety in addition to the two bridgehead atoms; L 1 is a direct bond, —O—, —N(R L )—, substituted or unsubstituted alkyl, -alkylene or —C(O)—, wherein R L is hydrogen or alkyl; Cy 1 is unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, or unsubstituted or substituted heteroaryl, wherein Cy 1 is optionally substituted with 1 to 5 substituents R 3a , wherein R 3a is selected from deuterium, alkoxy, alkyl, halogen, oxo, R 3b —SO 2 —, cycloalkyl, cyano, R 3b —C(O)—N(R 3c )—, N(R 3b R 3c )—C(O)—, N(R 3b R 3c ), R 3b —O—C(O)—, cycloalkyl or heterocyclyl; optionally wherein two R 3a connect to the same carbon and together form a spirocyclic ring; optionally wherein two R 3a form a fused ring with Cy 1 , wherein R 3a is unsubstituted or substituted with cyano, alkoxy, alkyl, halogen, or hydroxy; and wherein R 3b and R 3c are each independently hydrogen or alkyl.
  2. 2 . The compound according to claim 1 , which is a compound of any one of formulas (IA1), (IB1) or (IC1): wherein the variables are defined as herein.
  3. 3 . The compound according to claim 1 , which is a compound of any one of formula (IA2), (IB2) or (IC2): wherein the variables are defined as herein.
  4. 4 . The compound according to claim 1 , which is a compound of any one of formula (IA3), (IB3) or (IC3): wherein the variables are defined as herein.
  5. 5 . The compound according to claim 1 , which is a compound of any one of formula (IA4), (IB4) or (IC4): wherein the variables are defined as herein.
  6. 6 . The compound according to claim 1 , which is a compound of formula (II): or a pharmaceutically acceptable salt, a tautomer, a stereoisomer, an enantiomer, an isotopologue, or a prodrug thereof, wherein X 1 is Cor N, X 4 is N, O or S; R 1 is hydrogen, deuterium, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl, provided that R 2 is absent when X 1 is N; R 4 is hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl, provided that R 4 is absent when X 4 is O or S; R 5 is hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl, R 5a —C(O)—, R 5a —C(O)O—, R 5a —O—C(O)—, R 5a —C(O)NR 5b —, R 5a —NR 5b —C(O)—, or R 5a —SO 2 —, wherein R 5a and R 5b are each independently hydrogen, alkyl, or cycloalkyl; each of R 7 , and R 9 is independently hydrogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxyl, substituted or unsubstituted cycloalkyl, —C(O)R 7a , or -alkyl-C(O)R 7a , and wherein R 7a is hydrogen, alkyl, or alkoxy, provided that at least one of R 7 and R 9 is not hydrogen; or R 7 and R 9 together form a bridge containing at least one —CH 2 -moiety in addition to the two bridgehead atoms; L 1 is a direct bond, —O—, —N(R L )—, substituted or unsubstituted alkyl, -alkylene or —C(O)—, wherein R L is hydrogen or alkyl; m is 0, 1, 2 or 3, n is 0 or 1 wherein R 3a is selected from deuterium, alkoxy, alkyl, halogen, oxo, R 3b —SO 2 —, cycloalkyl, cyano, R 3b —C(O)—N(R 3c )—, N(R 3b R 3c )—C(O)—, N(R 3b R 3c ), R 3b —O—C(O)—, cycloalkyl or heterocyclyl; optionally wherein two R 3a connect to the same carbon and together form a spirocyclic ring; optionally wherein two R 3a form a fused ring with Cy 1 , wherein R 3a is unsubstituted or substituted with cyano, alkoxy, alkyl, halogen, or hydroxy; and wherein R 3b and R 3c are each independently hydrogen or alkyl.
  7. 7 . The compound according to any one of claims 1 to 6 , wherein R 1 is hydrogen, or substituted or unsubstituted alkyl.
  8. 8 . The compound according to any one of claims 1 to 7 , wherein R 1 is hydrogen, or C 1-4 alkyl optionally substituted with deuterium, halogen, hydroxy, alkoxy or cycloalkyl; preferably R 1 is hydrogen, or C 1-4 alkyl optionally substituted with deuterium, halogen, hydroxy, alkoxy or cycloalkyl; more preferably R 1 is hydrogen, or C 1-3 alkyl optionally substituted with deuterium, or halogen; even more preferably R 1 is hydrogen, methyl, methyl-d3, ethyl, isopropyl, 2-hydroxyethyl, 2-methoxyethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, or cyclopropylmethyl.
  9. 9 . The compound according to claim 8 , wherein R 2 is hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxyl or cyano; preferably R 2 is hydrogen, F, Br, Cl or CN.
  10. 10 . The compound according to any one of claims 1 to 9 , wherein R 4 is hydrogen, halogen or alkyl, wherein the alkyl is optionally substituted with deuterium, halogen or —OR 4a , wherein R 4a is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl is optionally substituted with —C 1-6 aklyl, —C 1-6 alkoxy or —C 3-8 cycloalkyl; preferably R 4 is hydrogen, or C 1-3 alkyl optionally substituted with deuterium, or halogen; more preferably R 4 is hydrogen, fluoro, chloro, bromo, methyl, methyl-d3, trifluoromethyl, ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, propyl, cyclopropyl.
  11. 11 . The compound according to any one of claims 1 to 10 , wherein R 5 is hydrogen, alkyl, alkenyl or alkynyl, wherein said alkyl is unsubstituted or substituted with cyano; preferably R 5 is C 1-4 alkyl, C 2-4 alkenyl or C 2-4 alkynyl, wherein said alkyl is substituted with cyano; more preferably R 5 is C 1-4 alkyl, wherein said alkyl is substituted with cyano.
  12. 12 . The compound according to any one of claims 1 to 11 , wherein each of R 7 and R 9 is independently hydrogen, alkyl, or —C(O)R 7a , wherein said alkyl is unsubstituted or substituted with halogen, cyano, hydroxy, or alkoxy, and wherein R 7a is hydrogen, alkyl, or alkoxy; preferably each of R 7 and R 9 is independently C 1-2 alkyl.
  13. 13 . The compound according to claim 12 , wherein R 7 and R 9 are each independently hydrogen, methyl, ethyl, methoxymethyl, 1-hydroxyethyl, 2-methoxyethyl, cyanomethyl, hydroxyethyl, hydroxymethyl, methoxycarbonyl, difluoromethyl, provided that at least one of R 7 and R 9 is not hydrogen.
  14. 14 . The compound according to any one of claims 1 to 13 , wherein R 8 and R 10 are each hydrogen; R 7 is methyl; and R 9 is methyl; R 8 and R 10 are each hydrogen; R 7 is ethyl; and R 9 is ethyl; R 8 and R 10 are each hydrogen; R 7 is methyl; and R 9 is ethyl; or R 8 and R 10 are each hydrogen; R 7 is ethyl, and R 9 is methyl; R 8 and R 10 are each hydrogen; R 7 is methoxymethyl, and R 9 is methyl, ethyl or methoxymethyl.
  15. 15 . The compound according to any one of claims 1 to 14 , wherein L 1 is a direct bond, —O—, —N(R L )—, -alkylene- or —C(O)—, wherein R 1 is hydrogen or alkyl and wherein said -alkylene- is unsubstituted or substituted with deuterium, halogen, alkoxy, alkynyl or heterocyclyl; preferably L 1 is a direct bond, —O—, —N(R 1 )—, -alkylene- or —C(O)—, wherein R L is hydrogen or alkyl; preferably L 1 is C 1-4 alkylene, preferably C 1-2 alkylene; more preferably L 1 is a direct bond, —CH 2 —, —CH(CH 3 )—, —CH(CD 3 )-, —CH(CH 2 CH 3 )—, —CH(CHF 2 )—, —CH(prop-1-ynyl)-, —N(H)—, —N(CH 3 )—, —O—, —CH(C(O)—NHCH 2 CH 2 OCH 3 )— or —C(CH 3 ) 2-.
  16. 16 . The compound according to any one of claims 1 to 5 and 7 to 15 , wherein Cy 1 is aryl, heterocyclyl, heterocyclyl, heteroaryl, or cycloalkyl, each of which is unsubstituted or substituted with one, two, three, or four substituents R 3a , wherein R 3a is selected from deuterium, alkoxy, alkyl, halogen, R 3b —SO 2 —, cycloalkyl, cyano, R 3b —C(O)—N(R 3c )—, N(R 3b R 3c )—C(O)—, N(R 3b R 3c ), R 3b —O—C(O)—, or heterocyclyl, wherein said alkyl moiety in the group alkyl or alkoxy is unsubstituted or substituted with halogen, alkoxy, hydroxy, or cyano; said cycloalkyl or heterocyclyl is unsubstituted or substituted with alkoxy, alkyl, halogen, or hydroxy, wherein R 3b and R 3c are each independently hydrogen or alkyl.
  17. 17 . The compound according to claim 16 , wherein Cy 1 is unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, or unsubstituted or substituted heteroaryl; preferably Cy 1 is optionally substituted with one, two or three substituents R 3a , wherein R 3a is selected from deuterium, fluoro, bromo, chloro, methyl, difluoromethyl, trifluoromethoxy, methoxy, methoxymethyl, trifluoromethyl, methylsulfonyl, difluoro, ethoxy, isopropyl, isopropoxy, difluoromethoxy, cyclopropyl, 2,2-difluorocyclopropyl, 1-fluorocyclopropyl, 2-fluorocyclopropyl, cyclobutyl, 1-hydroxyethyl, 2-hydroxyethyl, ethyl, 1,1-difluoroethyl, cyano, dimethoxy, dichloro, acetamido, 1-methoxyethyl, cyanomethyl, carbamoyl, methoxycarbonyl, dimethylcarbamoyl, (difluoromethoxy)methyl, amino, 1-(difluoromethoxy)ethyl, azetidin-1-yl, 2-methoxypropan-2-yl, 1-methoxycyclopropyl, oxetan-3-yl, 1-methylazetidin-3-yl, 1-hydroxyazetidin-3-yl, 2-cyanoethyl, 2-cyanopropan-2-yl, hydroxymethyl, 3-hydroxypropyl, 2-hydroxypropan-2-yl, or 2-fluoropropan-2-yl.
  18. 18 . The compound according to claim 16 , wherein Cy 1 is aryl, which is unsubstituted or substituted with one, two or three substituents R 3a , wherein R 3a is selected from alkoxy, halogen-substituted alkoxy, alkoxyalkyl-, alkyl, alkenyl, halogen-substituted alkyl, halogen, R 3b —SO 2 —, cycloalkyl, hydroxyalkyl-, cyano, R 3b —C(O)—N(R 3c )—, cyano-substituted alkyl, N(R 3b R 3c )—C(O)—, R 3b —O—C(O)—, heterocyclylalkyl- or heterocyclyl, said cycloalkyl or heterocyclyl is unsubstituted or substituted with alkoxy, alkyl, halogen, or hydroxy, wherein R 3b and R 3c are each independently hydrogen or alkyl.
  19. 19 . The compound according to claim 18 , wherein Cy 1 is phenyl, which is substituted with one or two R 3a , wherein R 3a is fluoro, chloro, bromo; methyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, methoxymethyl, 1-methoxyethyl, ethyl, propyl, isopropyl, tert-butyl, 2-hydroxypropan-2-yl, 1-hydroxy-2-methylpropan-2-yl, 2-cyanopropan-2-yl, morpholinomethyl; prop-1-en-2-yl; cyclopropyl, 1-methylcyclopropyl; methoxy, difluoromethoxy, trifluoromethoxy, 1,1-difluoroethoxy, isopropoxy; oxetan-3-yl, morpholino, 2-oxa-6-azaspiro[3,3]heptan-6-yl; or methylcarbamoyl.
  20. 20 . The compound according to claim 16 , wherein Cy 1 is a monocyclic 5- to 9-membered heterocyclyl or a bicyclic 7- to 10-membered heterocyclyl which is unsubstituted or substituted with one, two, three or four R 3a (provided that the valency theory has been met), wherein R 3a is selected from deuterium, alkoxy, alkyl, halogen, R 3b —SO 2 —, cycloalkyl, cyano, R 3b —C(O)—N(R 3c )—, N(R 3b R 3c )—C(O)—, N(R 3b R 3c ), R 3b —O—C(O)—, oxo or heterocyclyl, wherein said alkyl moiety in the group alkyl or alkoxy is unsubstituted or substituted with halogen, alkoxy, hydroxy, or cyano; said cycloalkyl or heterocyclyl is unsubstituted or substituted with alkoxy, alkyl, halogen, or hydroxy, wherein R 3b and R 3c are each independently hydrogen or alkyl; preferably, R 3a is selected from alkoxy, halogen-substituted alkoxy, alkoxyalkyl-, alkyl, halogen-substituted alkyl, halogen, R 3b —SO 2 —, cycloalkyl, hydroxyalkyl-, cyano, R 3b C(O)—N(R 3c )—, cyano-substituted alkyl, N(R 3b R 3c )—C(O)—, R 3b —O—C(O)—, or heterocyclyl, said cycloalkyl or heterocyclyl is unsubstituted or substituted with alkoxy, alkyl, halogen, or hydroxy, wherein R 3b and R 3c are each independently hydrogen or alkyl; preferably, said monocyclic 5- to 9-membered heterocyclyl is tetrahydrofuranyl, tetrahydropyranyl, 1,4-dioxanyl, piperidinyl, piperazinyl, or dihydropyridinyl, each of which is unsubstituted or substituted with one, two or three R 3a as disclosed herein; preferably Cy 1 is tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl, 1,4-dioxan-2-yl, 1,4-dioxan-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, piperazin-4-yl, 1,2-dihydropyridin-3-yl, 1,2-dihydropyridin-4-yl, 1,2-dihydropyridin-5-yl, or 1,2-dihydropyridin-6-yl.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of International Application No. PCT/CN2024/075494, filed on Feb. 2, 2024, which claims priority to International Application No. PCT/CN2023/074235, filed on Feb. 2, 2023, the disclosures of each of which are hereby incorporated by reference in their entireties. SEQUENCE LISTING This application contains a Sequence Listing, which has been submitted electronically in XML format. The XML file entitled “2024 May 15_01368-0102-00PCT_Sequence listing as filed,” was created on May 15, 2025, and is 6,531 bytes in size. The Sequence Listing is incorporated herein by reference in its entirety. FIELD OF THE DISCLOSURE Disclosed herein is a compound of Formula (I) for activating T cells, promoting T cell proliferation, and/or exhibiting antitumor activity, a method of using the compounds disclosed herein for treating cancer, and a pharmaceutical composition comprising the same. BACKGROUND OF THE DISCLOSURE Diacylglycerol kinases (DGKs) are a family of lipid kinases that phosphorylates and converts diacylglycerol (DAG) into phosphatidic acid (PA). As the substrate of DGKs, DAG is generated from inositol phospholipids and other phospholipids at the plasma membrane by phospholipase C (PLC) hydrolysis in response to the activation of various cell-surface receptors, including G-protein coupled receptors (GPCR) and immunoreceptor tyrosine-based activation motif (ITAM)-bearing receptors (Rhee, Sue Goo. Annual review of biochemistry. 2001, 70.1:281-312). DAG is one of the key intracellular second messengers that recruits and activates many downstream effectors including protein kinase C (PKC), protein kinase D (PKD) families, and Ras guanyl nucleotide releasing proteins (RasGRPs), which in turn activates NF-κB and extracellular regulated kinase (ERK) pathways (Mérida, Isabel, et al. Biochemical Journal. 2008, 409.1:1-18, Joshi, Rohan P., et al. International Journal of Molecular Sciences. 2013, 14.4:6649-6673). By consuming DAG, DGK controls and tunes the threshold and duration of DAG mediated signaling. Mammalian DGK family comprises 10 different members, in which DGKα, DGKζ and DGKδ are the three major isoforms that are abundantly expressed in lymphoid tissues (Joshi, Rohan P., et al. International Journal of Molecular Sciences. 2013, 14.4:6649-6673). Cancer immunotherapy is a type of cancer treatment to manipulate and boost host immune system to recognize and attack cancer cells. A vast majority of studies have focused on targeting immune checkpoint inhibitors, such as CTLA-4 and PD-1/PD-L1, to reinvigorate exhausted CD8+ T cells within tumor sites. It was emerged that peripheral T cell tolerance, which under normal circumstances prevents detrimental autoimmune disease, can be hijacked by tumors to prevent anti-tumor immune response during carcinogenesis (Nüssing, Simone, et al. Frontiers in Immunology. 2020, 11:2461). T cell anergy is one of the most important mechanisms of T cell tolerance and has been reported to occur in tumor infiltrated T cells, which contributes to the immunosuppressive nature of tumor microenvironment (Abe, Brian T., and Fernando Macian. Oncoimmunology. 2013, 2.2: e22679). Anergy-associated transcription factor early growth response gene2 (Egr2) directly binds to Dgka and Dgkz promoter and increases their expression (Zheng, Yan, et al. Journal of Experimental Medicine 2012, 209.12:2157-2163; Zheng, Yan, et al. Molecular Immunology. 2013, 55.3-4:283-291). In anergic T cells, both DGKa and DGK play critical roles to negatively regulate DAG-signaling downstream of TCR and reduce the strength of TCR activation (Chen, Shelley S., et al. Frontiers in Cell and Developmental Biology. 2016, 4:130). Thus, immune cell expressed DGKα and DGKζ were investigated as potential targets to reverse the hyporesponsiveness of the tumor infiltrated T cells. It was demonstrated that genetic deletion of DGKα or DGKζ enhanced cytokine production and proliferation of T cells (Olenchock, Benjamin A., et al. Nature immunology. 2006, 7.11:1174-1181; Zhong, Xiao-Ping, et al. Nature immunology. 2003, 4.9:882-890). DGKα or DGKζ single knockout in both mouse or human chimeric antigen receptor (CAR)-T cells showed superior effector function as determined by enhanced in vitro cytotoxicity and cytokine secretion when cocultured with antigen expressing titled cells (Riese, Matthew J., et al. Cancer Research. 2013, 73.12:3566-3577; Jung, In-Young, et al. Cancer Research. 2018, 78.16:4692-4703). MesoCAR-transduced DGKα or DGKζ deficient T cells also showed significantly elevated in vivo activity against mesotheliomas (Riese, Matthew J., et al. Cancer Research. 2013, 73.12:3566-3577). DGKζ−/− mice showed enhanced tumor suppressive efficacy with both orthotopic and subcutaneously implanted models (Wesley, Erin M., et al. Immunohorizons. 2018, 2.4:107-118; Wee, Susan, et al. AACR; Cancer Res 2019; 79 (13 Suppl): Abstract nr 936). Besides the T cell regulatory functi