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US-12624022-B2 - Heterocyclic immunomodulators as PDL1 checkpoint inhibitor

US12624022B2US 12624022 B2US12624022 B2US 12624022B2US-12624022-B2

Abstract

The disclosure describes pyridinone-containing inhibitors of PD-L1, pharmaceutical compositions comprising these compounds, chemical processes for preparing these compounds, and their use in the treatment of infectious diseases and cancer.

Inventors

  • David Craig McGowan
  • Edgar Jacoby

Assignees

  • Janssen Sciences Ireland Unlimited Company

Dates

Publication Date
20260512
Application Date
20200605
Priority Date
20190607

Claims (16)

  1. 1 . A compound of Formula (I), or a stereoisomer or tautomeric form thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is a ring optionally substituted with one or more substituents selected from the group consisting of halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl, NR x R y , NR x C(═O)R y , NR x CO 2 R y , NR x C(═O)NR x R y , OC(═O)NR x R y , O-(6 to 10-membered aryl), O-(5 to 10-membered heteroaryl), and a ring; R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 11 are independently selected from the group consisting of H, halogen, C 1-4 alkyl and C 1-4 alkyl substituted with one or more F; R 8 and R 9 are independently selected from the group consisting of H, C 1-6 alkyl and C 1-6 heteroalkyl, wherein each of the C 1-6 alkyl and C 1-6 heteroalkyl is optionally substituted with one or more substituents selected from the group consisting of C 1-4 alkyl, OH, OCH 3 , —CO 2 H, —CO 2 C 1-4 alkyl, C 3-6 heterocycle, aryl and heteroaryl, wherein the C 3-6 heterocycle is optionally substituted with one or more substituent selected from the group consisting of oxo, OH and CO 2 H; with the proviso that R 8 and R 9 are not both H; or R 8 and R 9 are connected together to form a C 3-6 heterocycle optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, oxo, OH and CO 2 H; R 10 is selected from the group consisting of H, CN, halogen, C 1-6 alkyl, OC 1-6 alkyl, C 1-6 alkyl-CO 2 H, C 1-6 alkyl-CO 2 —C 1-6 alkyl, C 1-6 alkyl-C(O)NH 2 , C 1-6 alkyl-CO—NHC 1-6 alkyl, C 1-6 alkyl-C(O)N(C 1-6 alkyl) 2 , C(═O)NR x R y , SO 2 —C 1-6 alkyl, aryl and heteroaryl; wherein the aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of CN, halogen, C 1-6 alkyl, OC 1-6 alkyl, C 1-6 alkyl-CO 2 H, C 1-6 alkyl-CO 2 —C 1-6 alkyl, C 1-6 alkyl-C(O)NH 2 , C 1-6 alkyl-CO—NHC 1-6 alkyl, C 1-6 alkyl-C(O)N(C 1-6 alkyl) 2 , C(═O)NR x R y and SO 2 —C 1-6 alkyl; X is N or CR 12 ; R 12 is selected from the group consisting of H, F, Cl, CN, C(═O)NR x R y , aryl and heteroaryl, wherein the aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of CN, halogen, C 1-6 alkyl, OC 1-6 alkyl, C 1-6 alkyl-CO 2 H, C 1-6 alkyl-CO 2 —C 1-6 alkyl, C 1-6 alkyl-C(O)NH 2 , C 1-6 alkyl-CO—NHC 1-6 alkyl, C 1-6 alkyl-C(O)N(C 1-6 alkyl) 2 , C(═O)NR x R y and SO 2 —C 1-6 alkyl; and R x and R y are independently selected from the group consisting of H and C 1-6 alkyl.
  2. 2 . The compound of claim 1 , wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 11 are independently selected from the group consisting of H and C 1-4 alkyl.
  3. 3 . The compound of claim 1 , wherein R 6 is C 1-4 alkyl or Cl.
  4. 4 . The compound of claim 1 , wherein R 6 is Cl, R 2 , R 3 , R 4 , R 5 , R 7 and R 11 are H.
  5. 5 . The compound of claim 1 , wherein R 1 is formula,
  6. 6 . The compound of claim 1 , wherein R 8 is H and R 9 is C 1-6 alkyl substituted with OH and CO 2 H.
  7. 7 . The compound of claim 1 , wherein R 8 and R 9 are connected together to form a C 3-6 heterocycle substituted with OH and CO 2 H.
  8. 8 . The compound of claim 7 , wherein the C 3-6 heterocycle is pyrrolidine.
  9. 9 . The compound of claim 1 , wherein R 10 is CN and X is N.
  10. 10 . The compound of claim 1 , wherein R 10 is H and X is N.
  11. 11 . The compound of claim 1 , wherein the IC 50 is equal or less than 5 μM in amplified luminescent proximity homogeneous assay (ALPHA)-LISA.
  12. 12 . A compound selected from the group consisting of or a stereoisomer or tautomeric form thereof, or a pharmaceutically acceptable salt thereof.
  13. 13 . A compound selected from the group consisting of or a stereoisomer or tautomeric form thereof, or a pharmaceutically acceptable salt thereof.
  14. 14 . A pharmaceutical composition, comprising the compound or the pharmaceutically acceptable salt of claim 1 and at least one pharmaceutically acceptable carrier.
  15. 15 . A method of inhibiting PD-L1 in a subject in need thereof, comprising administering to the subject an effective amount of the compound or the pharmaceutically acceptable salt of claim 1 .
  16. 16 . A process for preparing a compound of Formula (I) according to claim 1 , comprising reacting a compound of formula (II) with an amine of formula (III), in the presence of sodium cyanoborohydride, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and X are defined as in claim 1 .

Description

CROSS REFERENCE TO RELATED APPLICATION This application is a Section 371 of International Application No. PCT/EP2020/065646, filed on Jun. 5, 2020, which published in the English language on Dec. 10, 2020 under International Publication No. WO2020/245372 A1, which claims priority to EP Patent Application No. 19179072.4 filed on Jun. 7, 2019, the disclosures of which are incorporated herein by reference in their entireties. BACKGROUND Programmed death-ligand 1 (PD-L1) is a 40 kDa immune checkpoint protein encoded in humans by the CD274 gene. Upon binding to its receptor PD-1, which is expressed on activated B cells, T cells, and myeloid cells, PD-L1 initiates signaling pathways that lead to downregulation of T cell proliferation and activation, facilitating tumor cell escape from T cell-mediated immune surveillance, thereby contributing to cancer severity and progression. PD-L1 expression has been shown on a wide variety of solid tumors (e.g., breast, lung, colon, ovarian, melanoma, bladder, liver, salivary, stomach, gliomas, thyroid, thymic epithelial, head, and neck (Brown J A et al., 2003. J. Immunol. 170:1257-66; Dong H et al. 2002. Nat. Med. 8:793-800; Hamanishi J, et al. 2007. Proc. Natl. Acad. Sci. USA 104:3360-65; Strome S E et al. 2003. Cancer Res. 63:6501-5; Inman B A et al. 2007. Cancer 109:1499-505; Konishi J et al. 2004. Clin. Cancer Res. 10:5094-100; Nakanishi J et al. 2007. Cancer Immunol. Immunother. 56:1173-82)), and the protein has arisen as an attractive target for the development of anti-cancer therapeutics. PD-L1 expression is further involved in the evasion of immune responses involved in infectious diseases (e.g., chronic viral infections including HBV and HIV). As such, PD-L1 also serves as a therapeutic target for the treatment of a variety of infectious diseases. Therapeutic efficacy of PD-L1 antagonists (and of PD-1 antagonists) has been validated in clinical trials. However, response rates remain low. For example, Opdivo® (Nivolumab) treatment achieved a 26% objective response rate (ORR) across the 27 clinical trials analyzed (Tie Y et al., 2016 Int. J. Cancer. 140:948-58). Accordingly, there is a need in the art for effective treatments for PD-L1-associated diseases. SUMMARY The present disclosure is directed to the general and preferred embodiments defined, respectively, by the independent and dependent claims appended hereto, which are incorporated by reference herein. In particular, the present disclosure is directed to compounds of Formula (I): including the stereoisomers or tautomeric forms thereof, or a pharmaceutically acceptable salt thereof, wherein R1 is a ring optionally substituted with one or more substituents selected from halogen, CN, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C1-6heteroalkyl, NRxRy, NRxC(═O)Ry, NRxCO2Ry, NRxC(═O)NRxRy, OC(═O)NRxRy, O-(6 to 10-membered aryl), O-(5 to 10-membered heteroaryl), and a ring;R2, R3, R4, R5, R6, R7 and R11 are independently selected from H, halogen, C1-4alkyl and C1-4alkyl substituted with one or more F;R8 and R9 are independently selected from H, C1-6alkyl and C1-6heteroalkyl, each of C1-6alkyl and C1-6heteroalkyl being optionally substituted with one or more substituents selected from C1-4alkyl, OH, OCH3, —CO2H, —CO2C1-4alkyl, C3-6heterocycle, aryl and heteroaryl; wherein C3-6heterocycle is optionally substituted with one or more substituent selected from oxo, OH and CO2H;with the proviso that R8 and R9 are not both H;or wherein R8 and R9 are connected together to form a C3-6heterocycle optionally substituted with one or more substituents selected from C1-6alkyl, oxo, OH and CO2H; R10 is selected from H, CN, halogen, C1-6alkyl, OC1-6alkyl, C1-6alkyl-CO2H, C1-6alkyl-CO2—C1-6-alkyl, C1-6alkyl-C(O)NH2, C1-6alkyl-CO—NHC1-6alkyl, C1-6alkyl-C(O)N(C1-6alkyl)2, C(═O)NRxRy, SO2—C1-6alkyl, aryl and heteroaryl;wherein aryl and heteroaryl are optionally substituted with one or more substituents selected from CN, halogen, C1-6alkyl, OC1-6alkyl, C1-6alkyl-CO2H, C1-6alkyl-CO2—C1-6alkyl, C1-6 alkyl-C(O)NH2, C1-6alkyl-CO—NHC1-6alkyl, C1-6alkyl-C(O)N(C1-6alkyl)2, C(═O)NRxRy and SO2—C1-6 alkyl;X is N or CR12;R12 is selected from H, F, Cl, CN, C(═O)NRxRy, aryl and heteroaryl,wherein aryl and heteroaryl are optionally substituted with one or more substituents selected from CN, halogen, C1-6alkyl, OC1-6alkyl, C1-6alkyl-CO2H, C1-6alkyl-CO2—C1-6alkyl, C1-6alkyl-C(O)NH2, C1-6alkyl-CO—NHC1-6alkyl, C1-6alkyl-C(O)N(C1-6alkyl)2, C(═O)NRxRy and SO2—C1-6alkyl; and Rx and Ry are independently selected from H and C1-6alkyl. In embodiments, the compounds of Formula (I) are compounds selected from those species described or exemplified in the detailed description below. The present disclosure is also directed to pharmaceutical compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof. Pharmaceutical compositions may further comprise a pharmaceutically acceptable carrier. The present disclosure is als