WO2022022600A1 - Immunomodulateurs, compositions et procédés associés - Google Patents

Immunomodulateurs, compositions et procédés associés Download PDF

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Publication number
WO2022022600A1
WO2022022600A1 PCT/CN2021/109089 CN2021109089W WO2022022600A1 WO 2022022600 A1 WO2022022600 A1 WO 2022022600A1 CN 2021109089 W CN2021109089 W CN 2021109089W WO 2022022600 A1 WO2022022600 A1 WO 2022022600A1
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Prior art keywords
methyl
oxazol
benzo
difluoromethoxy
biphenyl
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PCT/CN2021/109089
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English (en)
Inventor
Yiqian WANG
Yao ZHANG
Chunhui Zhang
Guangzhi Zhang
Lieming Ding
Jiabing Wang
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Betta Pharmaceuticals Co., Ltd
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Priority to CN202180045720.8A priority Critical patent/CN115884972A/zh
Publication of WO2022022600A1 publication Critical patent/WO2022022600A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the present invention relates to compounds that are inhibitors of PD-1/PD-L1 protein/protein interaction.
  • the present invention also relates to pharmaceutical compositions comprising such compounds and methods of using such compounds in the treatment of cancer, pre-cancerous syndromes and other diseases associated with inhibition of PD-1/PD-L1 protein/protein interaction.
  • Cancer immunotherapy has been increasingly utilized to treat advanced malignancies.
  • the signaling network of immune checkpoints has attracted considerable attention.
  • Several cancers are highly refractory to conventional chemotherapy.
  • the survival of tumors in several cases is assisted by checkpoint immunomodulation to maintain the imbalance between immune surveillance and cancer cell proliferation.
  • Immune checkpoint inhibitors are revolutionizing the treatment options and expectations for patients with cancer.
  • Programmed cell death-1 also known as CD279, is a cell surface receptor expressed on activated T cells, natural killer T cells, B cells, and macrophages. It functions as an intrinsic negative feedback system to prevent the activation of T-cells, which in turn reduces autoimmunity and promotes self-tolerance.
  • PD-1 is also known to play a critical role in the suppression of antigen-specific T cell response in diseases like cancer and viral infection.
  • the interaction between PD-1 and PD-L1 results in a decrease in tumor infiltrating lymphocytes, a decrease in T-cell receptor mediated proliferation, and immune evasion by the cancerous cells. Immune suppression can be reversed by inhibiting the local interaction of PD-1 with PD-L1, and the effect is additive when the interaction of PD-1 with PD-L2 is blocked as well.
  • potent small molecules that can have activity as inhibitors of the interaction of PD-L1 with PD-1, and thus may be useful for therapeutic administration to enhance immunity against cancer and/or infectious diseases.
  • These small molecules are expected to be useful as pharmaceuticals with desirable stability, solubility, bioavailability, therapeutic index and toxicity values that are crucial to become efficient medicines to promote human health.
  • the present invention relates to compounds that are used as inhibitors of the functional interaction between PD-L1 and PD-1.
  • Inhibitors of the interaction between PD-L1 and PD-1 are useful in the treatment of cancers and infectious diseases.
  • the compounds of the invention have the general structures as Formula (I) .
  • a compound of Formula (I) or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof,
  • R 1 and R 2 are each independently selected from halogen, CN, or C 1-4 alkyl;
  • R 3 is CN or C 1-3 haloalkyl
  • R 4 is selected from -CH 2 -Cy or - (CH 2 ) t -NR 5 R 6 ;
  • Cy is a group selected from
  • X is selected from C, N, O or S
  • R 5 and R 6 are each independently selected from H, C 1-6 alkyl, C 3-8 cycloalkyl, C 3-6 heterocycloalkyl, C 5-6 aryl or C 5-6 heteroaryl, wherein the C 1-6 alkyl, C 3-8 cycloalkyl, C 3-6 heterocycloalkyl, C 5-6 aryl and C 5-6 heteroaryl optionally substituted with one or more substitutents independently selected R 7 substituents; wherein the C 3-6 heterocycloalkyl and C 5-6 heteroaryl optionally comprising 1, 2 or 3 hetero atoms independently selected from N, S, or O;
  • R 1 and R 2 are -CH 3 , R 3 is CN; then one of R 5 and R 6 is H, the other is not
  • R a1 and R a2 together with the atoms to which they are attached form oxo, C 3-6 cycloalkyl or C 3-6 heterocycloalkyl, wherein the C 3-6 cycloalkyl andC 3-6 heterocycloalkyl optionally substituted with one or more substituents independently selected R e substituents; wherein the C 3-6 heterocycloalkyl optionally comprising 1, 2 or 3 hetero atoms independently selected from N, S, or O;
  • R d1 and R d2 are each independently selected from H or C 1-4 alkyl
  • R a3 is selected from H, halogen, hydroxyl, CN, C 1-4 alkyl, -C 1-4 alkoxyl, C 3-6 cycloalkyl or C 3-6 heterocycloalkyl, wherein the C 3-6 heterocycloalkyl optionally comprising 1, 2 or 3 hetero atoms independently selected from N, S, or O;
  • R 1 and R 2 are -CH 3 , R a3 is H; then R a1 and R a2 are not both -CH 3 ;
  • R c1 and R c2 are each independently selected from H, halogen, hydroxyl, oxo, CN, C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 alkoxyl, -CONR d1 R d2 , -CO-C 1-4 alkyl, -S (O) 2 -C 1-4 alkyl, -S (O) -C 1-4 alkyl, -O-C 1-4 alkyl, -O-C 1-4 haloalkyl or -C 1-4 alkyl-O-C 1-4 alkyl; or
  • R c1 and R c2 together with the atoms to which they are attached form C 3-6 cycloalkyl or C 3-6 heterocycloalkyl, the C 3-6 cycloalkyl and C 3-6 heterocycloalkyl optionally substituted with one or more substituents independently selected R e substituents; wherein the C 3-6 heterocycloalkyl optionally comprising 1, 2 or 3 hetero atoms independently selected from N, S, or O;
  • R c3 is selected from H, halogen, hydroxyl, oxo, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-6 alkynyl, C 1- 4 alkoxyl, C 3-6 cycloalkyl or C 3-6 heterocycloalkyl, wherein the C 3-6 heterocycloalkyl optionally comprising 1, 2 or 3 hetero atoms independently selected from N, S, or O;
  • R b1 and R b2 are each independently selected from H, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 alkoxyl, -C 1-4 alkyl-OH, -CO-NR f1 R f2 or -CO-C 1-4 alkyl; or
  • R b1 and R b2 together with the atoms to which they are attached form C 4-6 cycloalkyl or C 3-6 heterocycloalkyl, the C 4-6 cycloalkyl and C 3-6 heterocycloalkyl optionally substituted with one or more substituents independently selected R e substituents, wherein the C 3-6 heterocycloalkyl optionally comprising 1, 2 or 3 hetero atoms independently selected from N, S, or O;
  • R f1 and R f2 are each independently selected from H or C 1-4 alkyl
  • R b5 is selected from H, oxo, halogen, CN, C 1-4 alkyl, C 1-4 alkoxyl, C 2-4 alkenyl, C 3-6 cycloalkyl or C 3-6 heterocycloalkyl, wherein the C 3-6 heterocycloalkyl optionally comprising 1, 2 or 3 hetero atoms independently selected from N, S, or O;
  • R b3 is selected from H, oxo, C 1-4 alkyl or halogen
  • R b1 or R b2 is H, then the other is not H or -CH 3 ;
  • R e is selected from H, halogen, hydroxyl, oxo, CN, - (CH 2 ) y -NR j1 R j2 , -COR j1 , -NR j1 R j2 , - (CH 2 ) y -OR j1 , - (CH 2 ) y -CONR j1 R j2 , -S (O) 2 R j1 , -S (O) 2 NR j1 R j2 , -S (O) R j1 , -S (O) NR j1 R j2 , C 1-4 alkyl, C 1-4 alkoxyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 5-6 aryl , C 5-6 heteroaryl, C 3-6 cycloalkyl, C 3-10 heterocyclic ring, wherein the C 5-6 heteroaryl and C 3-10
  • R j1 and R j2 are each independently selected from H, halogen, C 1-4 alkyl, C 1-4 alkoxyl or C 2-6 alkenyl;
  • n, t and y are each independently selected from 0, 1, 2 or 3;
  • n is selected from 0, 1, 2, 3 or 4;
  • k is selected from 0, 1, 2, 3, 4 or 5;
  • q is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;
  • R 1 and R 2 are each independently selected from halogen, CN, or C 1-4 alkyl;
  • R 3 is CN or C 1-3 haloalkyl
  • R 4 is selected from -CH 2 -Cy or - (CH 2 ) t -NR 5 R 6 ;
  • Cy is a group selected from
  • X is selected from C, N, O or S
  • R 5 and R 6 are each independently selected from H, C 1-6 alkyl, C 3-8 cycloalkyl, C 3-6 heterocycloalkyl, C 5-6 aryl or C 5-6 heteroaryl, wherein the C 1-6 alkyl, C 3-8 cycloalkyl, C 3-6 heterocycloalkyl, C 5-6 aryl and C 5-6 heteroaryl optionally substituted with one or more substitutents independently selected R 7 substituents;
  • R 1 and R 2 are -CH 3 , R 3 is CN; then one of R 5 and R 6 is H, the other is not
  • R a1 and R a2 together with the atoms to which they are attached form oxo, C 3-6 cycloalkyl or C 3-6 heterocycloalkyl, the C 3-6 cycloalkyl and C 3-6 heterocycloalkyl optionally substituted with one or more substituents independently selected R e substituents; wherein the C 3-6 heterocycloalkyl optionally comprising 1, 2 or 3 hetero atoms independently selected from N, S, or O;
  • R d1 and R d2 are each independently selected from H or C 1-4 alkyl
  • R a3 is selected from H, halogen, hydroxyl, CN, C 1-4 alkyl, -C 1-4 alkoxyl, C 3-6 cycloalkyl or C 3-6 heterocycloalkyl;
  • R 1 and R 2 are -CH 3 , R a3 is H; then R a1 and R a2 are not both -CH 3 ;
  • R c1 and R c2 are each independently selected from H, halogen, hydroxyl, oxo, CN, C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 alkoxyl, -CONR d1 R d2 , -CO-C 1-4 alkyl, -S (O) 2 -C 1-4 alkyl, -S (O) -C 1-4 alkyl, -O-C 1-4 alkyl, -O-C 1-4 haloalkyl or -C 1-4 alkyl-O-C 1-4 alkyl; or
  • R c1 and R c2 together with the atoms to which they are attached form C 3-6 cycloalkyl or C 3-6 heterocycloalkyl, the C 3-6 cycloalkyl and C 3-6 heterocycloalkyl optionally substituted with one or more substituents independently selected R e substituents; wherein the C 3-6 heterocycloalkyl optionally comprising 1, 2 or 3 hetero atoms independently selected from N, S, or O;
  • R c3 is selected from H, halogen, hydroxyl, oxo, CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-6 alkynyl, C 1- 4 alkoxyl, C 3-6 cycloalkyl or C 3-6 heterocycloalkyl;
  • R b1 and R b2 are each independently selected from H, Br, C 1-4 alkyl, -CHF 2 , -CF 3 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 alkoxyl, -CO-NR f1 R f2 or -CO-C 1-4 alkyl; or
  • R b1 and R b2 together with the atoms to which they are attached form C 4-6 cycloalkyl or C 3-6 heterocycloalkyl, the C 4-6 cycloalkyl and C 3-6 heterocycloalkyl optionally substituted with one or more substituents independently selected R e substituents;
  • R f1 is selected from H or C 1-4 alkyl, and R f2 is C 1-4 alkyl;
  • R b5 is selected from H, oxo, halogen, CN, C 1-4 alkyl, C 1-4 alkoxyl, C 2-4 alkenyl, C 3-6 cycloalkyl or C 3-6 heterocycloalkyl;
  • R b3 is selected from H, oxo, C 1-4 alkyl or halogen
  • R b1 or R b2 is H, then the other is not H or -CH 3 ;
  • R e is selected from H, halogen, hydroxyl, oxo, CN, - (CH 2 ) y -NR j1 R j2 , -COR j1 , -NR j1 R j2 , - (CH 2 ) y -OR j1 , - (CH 2 ) y -CONR j1 R j2 , -S (O) 2 R j1 , -S (O) 2 NR j1 R j2 , -S (O) R j1 , -S (O) NR j1 R j2 , C 1-4 alkyl, C 1-4 alkoxyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 5-6 aryl , C 5-6 heteroaryl, C 3-6 cycloalkyl, C 3-10 heterocyclic ring, wherein the C 5-6 heteroaryl and C 3-10
  • R j1 and R j2 are each independently selected from H, halogen, C 1-4 alkyl, C 1-4 alkoxyl or C 2-6 alkenyl;
  • n, t and y are each independently selected from 0, 1, 2 or 3;
  • n is selected from 0, 1, 2, 3 or 4;
  • k is selected from 0, 1, 2, 3, 4 or 5;
  • q is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;
  • R f1 is selected from H or C 1-4 alkyl
  • R f2 is C 1-4 alkyl
  • R 5 and R 6 are each independently selected from H, C 1-6 alkyl, C 3-8 cycloalkyl, C 4-6 heterocycloalkyl, C 5-6 aryl, wherein the C 1-6 alkyl, C 3-8 cycloalkyl, C 4-6 heterocycloalkyl and C 5-6 aryl optionally substituted with one or more substitutents independently selected R 7 substituents, wherein the C 4-6 heterocycloalkyl optionally comprising 1, 2 or 3 hetero atoms independently selected from N or O.
  • R 5 and R 6 are each independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, C 5 heterocycloalkyl, C 6 aryl, wherein the C 1-3 alkyl, C 3-6 cycloalkyl, C 5 heterocycloalkyl and C 6 aryl optionally substituted with one or more substitutents independently selected R 7 substituents, wherein the C 5 heterocycloalkyl optionally comprising 1, 2 or 3 hetero atoms independently selected from N or O.
  • R 5 and R 6 are each independently selected from the group consisting of H, C 1-6 alkyl, H and/or C 1-6 alkyl substituted C 3-8 cycloalkyl, H and/or oxo substituted 5-membered hetercycloalkyl comprising 1-2 hetero atoms selected from N and O, wherein the C 1-6 alkyl optionally substituted with -NR j1 R j2 , H and/or oxo subustituted 5-membered heterocycloalkyl comprising 1-2 N hetero atoms, CN, pyridine, or CN substituted pyridine.
  • R 5 and R 6 are each independently selected from H, C 1-3 alkyl or C 3-6 cycloalkyl.
  • R 7 is selected from H, halogen, CN, OH, NO 2 , oxo, C 1-3 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, C 5-6 heterocycloalkyl, C 5-6 heteroaryl, -NR j1 R j2 , wherein the C 3-6 cycloalkyl, C 5-6 heterocycloalkyl and C 5-6 heteroaryl can be optionally substituted with H, oxo, CN or C 1-3 alkoxyl, wherein the C 5-6 heterocycloalkyl and C 5-6 heteroaryl optionally comprising 1, 2 or 3 hetero atoms independently selected from N or O.
  • R 7 is selected from H, C 1-3 alkyl or CN.
  • R 7 is selected from H or C 1-3 alkyl.
  • R 7 is selected from H or -CH 3 .
  • R 1 and R 2 are each independently selected from halogen or C 1-4 alkyl.
  • R 1 and R 2 are each independently selected from halogen or -CH 3 .
  • R 1 and R 2 are each independently selected from Cl or -CH 3 .
  • R 3 is selected from CN and F substituted C 1-3 alkyl.
  • R 3 is selected from CN or -CF 3 .
  • X is C or N.
  • R a1 and R a2 together with the atoms to which they are attached form C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl optionally substituted with one or more R e substituents, wherein the 3-6 membered heterocycloalkyl optionally comprising 1-2 hetero atoms independently selected from N, S, or O.
  • R a1 and R a2 together with the atoms to which they are attached form C 3-6 cycloalkyl or C 3-6 heterocycloalkyl, the C 3-6 cycloalkyl or C 3-6 heterocycloalkyl optionally substituted with one or more substituents independently selected R e substituents, wherein the C 3-6 heterocycloalkyl optionally comprising 1-2 hetero atoms independently selected from N, S, or O.
  • R a1 and R a2 are each independently selected from H, hydroxyl, C 1-3 alkyl, C 1-3 haloalkyl, halogen, CN, C 2-4 alkenyl, -C 1-4 alkoxyl, -C 1-3 alkyl-O-C 1-3 alkyl or C 5-6 heteroaryl, wherein the C 5-6 heteroaryl optionally comprising one N hetero atom; or
  • R a1 and R a2 together with the atoms to which they are attached form C 3-4 cycloalkyl or C 3-4 heterocycloalkyl, the C 3-4 cycloalkyl and C 3-4 heterocycloalkyl optionally substituted with one or more substituents independently selected R e substituents, wherein the C 3-4 heterocycloalkyl optionally comprising 1-2 hetero atoms independently selected from N, S, or O.
  • R a1 and R a2 are each independently selected from H, hydroxyl, C 1-3 alkyl, C 1-3 haloalkyl, halogen, CN, C 2-4 alkenyl, -C 1-4 alkoxyl, or -C 1-3 alkyl-O-C 1-3 alkyl, or
  • R a1 and R a2 together with the atoms to which they are attached form C 3-4 cycloalkyl or C 3-4 heterocycloalkyl, the C 3-4 cycloalkyl and C 3-4 heterocycloalkyl optionally substituted with one or more substituents independently selected R e substituents, wherein the C 3-4 heterocycloalkyl optionally comprising 1-2hetero atoms independently selected from N, S, or O.
  • R a1 and R a2 are each independently selected from H, hydroxyl, C 1-3 alkyl, C 1-3 haloalkyl, halogen, CN, C 2-4 alkenyl, -C 1-4 alkoxyl or -C 1-3 alkyl-O-C 1-3 alkyl, or
  • R a1 and R a2 together with the atoms to which they are attached form C 3-4 cycloalkyl optionally substituted with one or more substituents independently selected R e substituents.
  • R a3 is selected from H, C 1-3 alkyl or C 3-6 heterocycloalkyl optionally comprising 1, 2 or 3 hetero atoms independently selected from N, S, or O.
  • R a3 is selected from H, C 1-3 alkyl or C 4 heterocycloalkyl optionally comprising 1, 2 or 3 hetero atoms independently selected from N, S, or O.
  • the compound is not: ( (2- (3'- (7-cyano-5- ( (1, 1-difluoro-5-azaspiro [2.4] heptan-5-yl) methyl) benzo [d] oxazol-2-yl) -2, 2'-dimethyl- [1, 1'-biphenyl] -3-yl) -6- (difluoromethoxy) benzo [d] oxazol-5-yl) methyl) -L-proline.
  • R a3 is H
  • R a3 is -CH 3 .
  • R a3 is C 4 heterocycloalkyl comprising one O hetero atom.
  • R d1 and R d2 are each independently selected from H or -CH 3 .
  • R d1 and R d2 are H.
  • R b1 and R b2 are each independently selected from H, Br, C 1-4 alkyl, -CHF 2 , C 2-6 alkenyl, C 2-6 alkynyl, -CO-NR f1 R f2 or -CO-C 1-4 alkyl, or
  • R b1 and R b2 together with the atoms to which they are attached form C 4-6 cycloalkyl optionally substituted with one or more substituents independently selected R e substituents;
  • R b1 or R b2 is H, then the other is not H or -CH 3 .
  • R b1 and R b2 are each independently selected from H, Br, C 1-3 alkyl, -CHF 2 , C 2-4 alkenyl, C 1-3 alkoxyl, -CO-NR f1 R f2 or -CO-C 1-4 alkyl, or
  • R b1 and R b2 together with the atoms to which they are attached form C 4-6 cycloalkyl optionally substituted with one or more substituents independently selected R e substituents;
  • R b1 or R b2 is H, then the other is not H or -CH 3 .
  • R b1 and R b2 are each independently selected from H, Br, C 1-3 alkyl, -CHF 2 or C 2-4 alkenyl; or
  • R b1 and R b2 together with the atoms to which they are attached form C 6 cycloalkyl optionally substituted with one or more substituents independently selected R e substituents;
  • R b1 or R b2 is H, then the other is not H or -CH 3 .
  • R b1 and R b2 are each independently selected from H, Br, C 1-3 alkyl, -CHF 2 or C 2-4 alkenyl;
  • R b1 or R b2 is H, then the other is not H or -CH 3 .
  • R b1 and R b2 are each independently selected from H, Br, -CHF 2 or C 2-4 alkenyl.
  • R b3 is selected from H, oxo, -CH 3 or F.
  • R b3 is H.
  • R b5 is H
  • R c1 and R c2 are each independently selected from H, halogen, oxo, C 1-3 alkyl, C 1-3 alkoxyl, -S (O) 2 -C 1-3 alkyl or -CO-C 1-3 alkyl; or
  • R c1 and R c2 together with the atoms to which they are attached form oxo, C 3-6 cycloalkyl or C 3-6 heterocycloalkyl, the C 3-6 cycloalkyl or C 3-6 heterocycloalkyl optionally substituted with one or more substituents independently selected R e substituents.
  • R c1 and R c2 are each independently selected from H, halogen, C 1-6 alkyl, -S (O) 2 -C 1-4 alkyl or -CO-C 1-4 alkyl; or
  • R c1 and R c2 together with the atoms to which they are attached form C 3-6 cycloalkyl or C 3-6 heterocycloalkyl, the C 3-6 cycloalkyl and C 3-6 heterocycloalkyl optionally substituted with one or more substituents independently selected R e substituents.
  • R c1 and R c2 are each independently selected from H, halogen, C 1-3 alkyl or oxo, or
  • R c1 and R c2 together with the atoms to which they are attached form C 3-4 cycloalkyl optionally substituted with one or more substituents independently selected R e substituents.
  • R c1 and R c2 are each independently selected from H, halogen or C 1-3 alkyl.
  • R c1 and R c2 together with the atoms to which they are attached form C 4 cycloalkyl optionally substituted with one or more substituents independently selected R e substituents.
  • R c1 and R c2 are each independently selected from H, halogen or C 1-3 alkyl.
  • R c3 is selected from H, halogen, oxo or C 1-4 alkyl.
  • R c3 is selected from H or oxo.
  • R c3 is H
  • R c3 is oxo
  • R e is selected from H, halogen, hydroxyl, oxo, CN, -COR j1 , -S (O) 2 R j1 , C 1-4 alkyl, C 1-4 alkoxyl, C 2-6 alkenyl, C 5-6 aryl, C 3-6 cycloalkyl, the C 1-4 alkoxyl can be optionally substituted with H or halogen, and the C 2-6 alkenyl can be optionally substituted with H or C 5-6 aryl.
  • R e is selected from H, halogen, hydroxyl, oxo, CN, -COR j1 , -S (O) 2 R j1 , C 1-3 alkyl, C 1-3 alkoxyl, C 2-6 alkenyl, C 5-6 aryl, C 3-6 cycloalkyl, the C 1-3 alkoxyl can be optionally substituted with H or halogen, and the C 2-6 alkenyl can be optionally substituted with H or C 5-6 aryl.
  • R e is selected from H, halogen, phenyl, C 1-3 alkyl, C 1-3 alkoxyl unsubstituted or substituted with halogen.
  • R e is selected from H, halogen or CN.
  • R f1 is selected from H or -CH 3 .
  • R f2 is -CH 3 .
  • R j1 is selected from H or C 1-4 alkyl.
  • R j1 is selected from H or -CH 3 .
  • R j1 is H
  • n and y is 1.
  • t is 1 or 2.
  • t is 1.
  • n 0, 1 or 2.
  • k is 0 or 1.
  • q is 0, 1 or 2.
  • k is 1.
  • Cy is selected from:
  • the compound is of Formula (II) :
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of any of the present invention and a pharmaceutically acceptable excipient, such as hydroxypropyl methyl cellulose.
  • a pharmaceutically acceptable excipient such as hydroxypropyl methyl cellulose.
  • the said compound in a weight ratio to the said excipient within the range from about 0.0001 to about 10.
  • the present invention additionally provided a use of a pharmaceutical composition of Formula I for the preparation of a medicament for treating a disease in a subject.
  • the present invention further provides some preferred technical solutions with regard to above-mentioned uses.
  • a medicament thus prepared can be used for the treatment or prevention of, or for delaying or preventing onset or progression in, cancer, cancer metastasis, an immunological disorder.
  • the cancer is colon cancer, gastric cancer, thyroid cancer, lung cancer, leukemia, pancreatic cancer, melanoma, multiple melanoma, brain cancer, renal cancer, prostate cancer, ovarian cancer or breast cancer.
  • the present invention provided a method of inhibiting PD-1/PD-L1 interaction, said method comprising administering to a patient a compound, or a pharmaceutically acceptable salt or a stereoisomer thereof.
  • the present invention provided a method of treating a disease associated with inhibition of PD-1/PD-L1 interaction, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt or a stereoisomer thereof.
  • the disease is colon cancer, gastric cancer, thyroid cancer, lung cancer, leukemia, pancreatic cancer, melanoma, multiple melanoma, brain cancer, renal cancer, prostate cancer, ovarian cancer, or breast cancer.
  • the present invention provided a method of enhancing, stimulating and/or increasing the immune response in a patient, said method comprising administering to the patient in need thereof a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt or a stereoisomer thereof.
  • the present invention also provides a use of the present compound or its pharmaceutical composition for the preparation of a medicament.
  • the medicament is used for the treatment or prevention of cancer.
  • the cancer is colon cancer, gastric cancer, thyroid cancer, lung cancer, leukemia, pancreatic cancer, melanoma, multiple melanoma, brain cancer, renal cancer, prostate cancer, ovarian cancer or breast cancer.
  • the medicament is used as an inhibitor of PD-1/PD-L1 interaction.
  • halogen as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo.
  • halogen groups include F, Cl and Br.
  • alkyl includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties.
  • alkyl radicals include methyl, ethyl, propyl, isopropyl, cyclcopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclcobutyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclcopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl.
  • C 1-4 as in C 1-4 alkyl is defined to identify the group as having 1, 2, 3, or 4 carbon atoms in a linear or branched arrangement.
  • Alkenyl and alkynyl groups include straight, branched chain or cyclic alkenes and alkynes.
  • C 2-8 alkenyl and “C 2-8 alkynyl” means an alkenyl or alkynyl radicals having 2, 3, 4, 5, 6, 7 or 8 carbon atoms in a linear or brached arrangement.
  • Alkoxy radicals are oxygen ethers formed from the previously described straight, branched chain or cyclic alkyl groups.
  • aryl refers to an unsubstituted or substituted mono-or polycyclic ring system containing carbon ring atoms.
  • the preferred aryls are mono cyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls. The most preferred aryl is phenyl.
  • heterocycloalkyl represents an unsubstituted or substituted stable three to ten membered saturated monocyclic, spirocyclic, bridged bicyclic or fused bicyclic ring system which consists of carbon atoms and one to three heteroatoms selected from N, O and S.
  • the nitrogen or sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • the heterocyclyl group may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • C 3-10 heterocycloalkyl means 3-10 membered heterocycloalkyl which having 3-10 ring atoms wherein one or more (e.g., 2, 3 or 4) ring atoms are independentlu selected from N, O and S.
  • heterocyclyl groups include, but are not limited to azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazepinyl, azepinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone and oxadiazolyl.
  • heteroaryl represents an unsubstituted or substituted stable five or six membered monocyclic aromatic ring system or an unsubstituted or substituted nine or ten membered benzo-fused heteroaromatic ring system or bicyclic heteroaromatic ring system which consists of carbon atoms and from one to four heteroatoms selected from N, O or S, and wherein the nitrogen or sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • the heteroaryl group may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • C 5-6 heteroaryl means 5-6 membered heteroaryl which having 5-6 ring atoms wherein one or more (e.g., 2 or 3) ring atoms are independentlu selected from N, O and S.
  • heteroaryl groups include, but are not limited to thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl adeninyl, quinolinyl or isoquinoliny
  • alkenyloxy refers to the group -O-alkenyl, where alkenyl is defined as above.
  • alknyloxy refers to the group -O-alknyl, where alknyl is defined as above.
  • cycloalkyl to a cyclic saturated alkyl chain having from 3 to 12 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclobutyl, cyclobutyl.
  • substituted refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent (s) .
  • the substituent (s) is independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluromethoxy, ethoxy, propyloxy, iso-propyloxy, n-butyloxy, isobutyloxy, t-butyloxy, -SCH 3 , -SC 2 H 5 , formaldehyde group, -C (OCH 3 ) , cyano, nitro, CF 3 , -OCF 3 , amino, dimethylamino, methyl thio, sulfonyl and acetyl.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. Accordingly, pharmaceutical compositions containing the compounds of the present invention as the active ingredient as well as methods of preparing the instant compounds are also part of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents and such solvates are also intended to be encompassed within the scope of this invention.
  • substituted alkyl group examples include, but not limited to, 2-aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, methoxymethyl, pentafluoroethyl and piperazinylmethyl.
  • substituted alkoxy groups include, but not limited to, aminomethoxy, thrifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3-hydroxypropoxy.
  • the compounds of the present invention may also be present in the form of pharmaceutically acceptable salts.
  • the salts of the compounds of this invention refer to non-toxic “pharmaceutically acceptable salts” .
  • the pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts.
  • the pharmaceutically acceptable acidic/anionic salt generally takes a form in which the basic nitrogen is protonated with an inorganic or organic acid.
  • organic or inorganic acids include hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, saccharinic or trifluoroacetic.
  • Pharmaceutically acceptable basic/cationic salts include, and are not limited to aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium, sodium and zinc.
  • the present invention includes within its scope the prodrugs of the compounds of this invention.
  • such prodrugs will be functional derivatives of the compounds that are readily converted in vivo into the required compound.
  • the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the subject.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs” , ed. H. Bundgaard, Elsevier, 1985.
  • the present invention includes compounds described herein can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers.
  • the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.
  • the above Formula I are shown without a definitive stereochemistry at certain positions.
  • the present invention includes all stereoisomers of Formula I and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.
  • the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, except where specifically stated otherwise.
  • the present invention includes any possible solvates and polymorphic forms.
  • a type of a solvent that forms the solvate is not particularly limited so long as the solvent is pharmacologically acceptable.
  • water, ethanol, propanol, acetone or the like can be used.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
  • the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases.
  • Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous) , ferric, ferrous, lithium, magnesium, manganese (ic and ous) , potassium, sodium, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines.
  • Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N', N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine
  • the compound of the present invention When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, formic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.
  • citric, hydrobromic, formic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids particularly preferred are formic and hydrochloric acid.
  • the compounds of Formula I are intended for pharmaceutical use they are preferably provided in substantially pure form, for example at least 60%pure, more suitably at least 75%pure, especially at least 98%pure (%are on a weight for weight basis) .
  • compositions of the present invention comprise a compound represented by Formula I (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants.
  • the compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • the compounds represented by Formula I, or a prodrug, or a metabolite, or pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous) .
  • the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient.
  • compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as oil-in-water emulsion, or as a water-in-oil liquid emulsion.
  • the compound represented by Formula I, or a pharmaceutically acceptable salt thereof may also be administered by controlled release means and/or delivery devices.
  • the compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients.
  • the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
  • compositions of this invention may include a pharmaceutically acceptable carrier and a compound, or a pharmaceutically acceptable salt, of Formula I.
  • the compounds of Formula I, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
  • the pharmaceutical carrier employed can be, for example, a solid, liquid, or gas.
  • solid carriers include such as lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • liquid carriers include such as sugar syrup, peanut oil, olive oil, and water.
  • gaseous carriers include such as carbon dioxide and nitrogen.
  • oral liquid preparations such as suspensions, elixirs and solutions
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets.
  • oral solid preparations such as powders, capsules and tablets.
  • tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed.
  • tablets may be coated by standard aqueous or nonaqueous techniques.
  • a tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • Each tablet preferably contains from about 0.05mg to about 5g of the active ingredient and each cachet or capsule preferably containing from about 0.05mg to about 5g of the active ingredient.
  • a formulation intended for the oral administration to humans may contain from about 0.5mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
  • Unit dosage forms will generally contain between from about l mg to about 2g of the active ingredient, typically 25mg, 50mg, l00mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg, or l000mg.
  • compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water.
  • a suitable surfactant can be included such as, for example, hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
  • compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions.
  • the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions.
  • the final injectable form must be sterile and must be effectively fluid for easy syringability.
  • the pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol) , vegetable oils, and suitable mixtures thereof.
  • compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound represented by Formula I of this invention, or a pharmaceutically acceptable salt thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 5wt%to about 10wt%of the compound, to produce a cream or ointment having a desired consistency.
  • compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier (s) followed by chilling and shaping in molds.
  • the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient.
  • dosage levels on the order of from about 0.01mg/kg to about 150mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5mg to about 7g per patient per day.
  • colon cancer, rectal cancer, mantle cell lymphoma, multiple myeloma, breast cancer, prostate cancer, glioblastoma, squamous cell esophageal cancer, liposarcoma, T-cell lymphoma melanoma, pancreatic cancer, glioblastoma or lung cancer may be effectively treated by the administration of from about 0.01 to 50mg of the compound per kilogram of body weight per day, or alternatively about 0.5mg to about 3.5g per patient per day.
  • DDQ 2, 3-Dichloro-5, 6-dicyano-p-benzoquinone
  • DMSO Dimethyl sulfoxide
  • EA Ethyl acrylate
  • PE petroleum ether
  • Pd/C Palladium on carbon
  • TBAI Tetrabutylammonium Iodide
  • THF Tetrahydrofuran
  • Step 3 Preparation of methyl 2- (3-bromo-2-methylphenyl) -6-hydroxybenzo [d] oxazole-5-carboxylate
  • Step 4 Preparation of methyl 2- (3-bromo-2-methylphenyl) -6- (difluoromethoxy) benzo [d] oxazole-5-carboxylate
  • Methyl 2- (3-bromo-2-methylphenyl) -6-hydroxybenzo [d] oxazole-5-carboxylate (a-4) (10.0g) , sodium 2-bromo-2, 2-difluoroacetate (5.46g) , Cs 2 CO 3 (27.09g) , KI (4.59g) , TBAI (10.22g) was added into DMF (200mL) , The mixture was stirred at 100°C for 3 hrs. The reaction was diluted with DCM and washed with saturated NaCl solution.
  • Step 5 Preparation of (2- (3-bromo-2-methylphenyl) -6- (difluoromethoxy) benzo [d] oxazol-5-yl) methanol
  • Step 6 Preparation of 2- (3-bromo-2-methylphenyl) -6- (difluoromethoxy) benzo [d] oxazole-5-carbaldehyde
  • Step 7 Preparation of methyl ( (2- (3-bromo-2-methylphenyl) -6- (difluoromethoxy) benzo [d] oxazol-5-yl) methyl) -L-prolinate
  • Step 8 Preparation of methyl ( (6- (difluoromethoxy) -2- (2-methyl-3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) benzo [d] oxazol-5-yl) methyl) -L-prolinate
  • Methyl 3-cyano-4-hydroxybenzoate (9 g) was dissolved in a mixture of glacial AcOH (36 mL) and Ac 2 O (10 mL) . After cooling the clear solution to 10 °C (ice bath) , a mixture of concentrated HNO 3 (65%) (5 mL) in glacial AcOH (10 mL) was added over 1 h. The light brown solution was allowed to rise to 15-20 °C and stirring was continued for a further 1h. The reaction solution was poured into H 2 O (30mL) . The precipitate was filtered and rinsed with small amounts of H 2 O. Then the crude product was poured into MeOH (20mL) with stirring. The precipitate was filtered, rinsed with small amounts of MeOH, dried under vacuum to get the tilte product 4.7 g.
  • Step 3 Preparation of methyl 2- (3-bromo-2-methylphenyl) -7-cyanobenzo [d] oxazole-5-carboxylate
  • Step 5 Preparation of methyl ( (2- (3'- (7-cyano-5- (hydroxymethyl) benzo [d] oxazol-2-yl) -2, 2'-dimethyl- [1, 1'-biphenyl] -3-yl) -6- (difluoromethoxy) benzo [d] oxazol-5-yl) methyl) -L-prolinate
  • Step 6 Preparation of methyl ( (2- (3'- (5- (chloromethyl) -7-cyanobenzo [d] oxazol-2-yl) -2, 2'-dimethyl- [1, 1'-biphenyl] -3-yl) -6- (difluoromethoxy) benzo [d] oxazol-5-yl) methyl) -L-prolinate
  • Step 7 Preparation of methyl ( (2- (3'- (7-cyano-5- ( (3-methyleneazetidin-1-yl) methyl) benzo [d] oxazol-2-yl) -2, 2'-dimethyl- [1, 1'-biphenyl] -3-yl) -6- (difluoromethoxy) benzo [d] oxazol-5-yl) methyl) -L-prolinate
  • Step 8 Preparation of ( (2- (3'- (7-cyano-5- ( (3-methyleneazetidin-1-yl) methyl) benzo [d] oxazol-2-yl) -2, 2'-dimethyl- [1, 1'-biphenyl] -3-yl) -6- (difluoromethoxy) benzo [d] oxazol-5-yl) methyl) -L-proline
  • Methyl 4-hydroxy-3- (trifluoromethyl) benzoate (4.5 g) was dissolved in a mixture of glacial AcOH (20 mL) and Ac 2 O (8 mL) . After cooling the clear solution to 10 °C (ice bath) , a mixture of concentrated HNO 3 (65%) (5 mL) in glacial AcOH (6 mL) was added over 1 h. The light brown solution was allowed to rise to 15-20 °C and stirring was continued for a further 1h. The reaction solution was poured into H 2 O (26 mL) . The precipitate was filtered and rinsed with small amounts of H 2 O. Then the crude product was poured into MeOH (15mL) with stirring. The precipitate was filtered, rinsed with small amounts of MeOH, dried under vacuum to get the tilte product 3 g.
  • Step 3 Preparation of methyl 2- (3-bromo-2-methylphenyl) -7- (trifluoromethyl) benzo [d] oxazole-5-carboxylate
  • Step 4 Preparation of (2- (3-bromo-2-methylphenyl) -7- (trifluoromethyl) benzo [d] oxazol-5-yl) methanol
  • Step 5 Preparation of methyl ( (6- (difluoromethoxy) -2- (3'- (5- (hydroxymethyl) -7- (trifluoromethyl) benzo [d] oxazol-2-yl) -2, 2'-dimethyl- [1, 1'-biphenyl] -3-yl) benzo [d] oxazol-5-yl) methyl) -L-prolinate
  • Step 6 Preparation of methyl ( (2- (3'- (5- (chloromethyl) -7- (trifluoromethyl) benzo [d] oxazol-2-yl) -2, 2'-dimethyl- [1, 1'-biphenyl] -3-yl) -6- (difluoromethoxy) benzo [d] oxazol-5-yl) methyl) -L-prolinate
  • Step 7 Preparation of methyl ( (6- (difluoromethoxy) -2- (3'- (5- ( (3-ethylazetidin-1-yl) methyl) -7- (trifluoromethyl) benzo [d] oxazol-2-yl) -2, 2'-dimethyl- [1, 1'-biphenyl] -3-yl) benzo [d] oxazol-5-yl) methyl) -L-prolinate
  • Step 8 Preparation of ( (6- (difluoromethoxy) -2- (3'- (5- ( (3-ethylazetidin-1-yl) methyl) -7- (trifluoromethyl) benzo [d] oxazol-2-yl) -2, 2'-dimethyl- [1, 1'-biphenyl] -3-yl) benzo [d] oxazol-5-yl) methyl) -L-proline
  • the compounds of table 1 were prepared in a similar manner to Examples 1-2 via different reaction starting materials and suitable reagents.
  • the comparison example 1 and 2 were prepared in the manner essentially as described for Example 7 and Example 10 in WO2018119266.
  • the comparison example 3 and 4 were prepared in a similar manner to Examples 1-2 via different reaction starting materials and suitable reagents.
  • the assays were conducted in a standard black 384-well polystyrene plate with a final volume of 20 ⁇ L. Inhibitors were first serially diluted in DMSO and then added to the plate wells before the addition of other reaction components. The final concentration of DMSO in the assay was 1%. Add 100 nL/well of compound to the 384 reaction plate (6008280, PerkinElmer) with Echo and centrifuge at 1000 rpm for 1 minute.
  • IC 50 values in the following ranges: “*” stands for “0.1nM ⁇ IC 50 ⁇ 5nM” ; “**” stands for “5nM ⁇ IC 50 ⁇ 50nM” ; “***” stands for “IC 50 >50nM” .
  • Time of blood collection 30 min, 2 h, 4 h. approximately 0.1 mL of whole blood was collected from retro-orbital venous plexus, and placed into tubes that contained K 2 -EDTA as an anticoagulant.
  • the whole blood was centrifuged at 4°C and 4000 rpm for 10 min.
  • the plasma was transferred into centrifuge tubes, and stored at -20°C untill being analyzed. Concentrations of test compounds in the plasma samples were analyzed with liquid chromatography-tandem mass spectrometry (LC-MS/MS) . Plasma concentration-time data of individual animals was analyzed using Microsoft Excel 2010. The data is shown in Table 4.
  • NA not avaliable, not detectable
  • the exemplified compounds of the present invention display unexpectedly better pharmacokinetic properties than the known compounds, Com. EX. No. 1and Com. EX. No. 2.
  • PD-1 /PD-L1 Blockade Bioassay contains two cells: PD-1 Effector Cells, which are the Jurkat T cells expressing hPD-1 and luciferase reporter genes; PD-L1 aAPC /CHO-K1 Cells, which are the CHO-K1 cells expressing hPD-L1 and activate TCR's cell surface proteins.
  • the antibody or small molecule compound is incubated with these two cells for a period of time, and the amount of the product is detected using Bio-Glo Luciferase reagent and chemiluminescence method to reflect the influence of antibody or small molecule compound on PD-1 /PD-L1 interaction.
  • Assay buffer 49.5 mL RPMI-1640; 0.5 mL FBS
  • Positive control antibody Atezolizumab was diluted to 4 ⁇ g/ml with assay buffer. 4 ⁇ g /ml was used as the first concentration, and a 2.5-fold gradient dilution was performed, with a total of 9 concentration gradients, and the 10th concentration was used as the assay buffer control;
  • EC 50 value which is provided in Table 5.
  • Compounds of the present disclosure as exemplified in the Examples, showed IC 50 values in the following ranges: “A” stands for “0.1nM ⁇ IC 50 ⁇ 500nM” ; “B” stands for “500nM ⁇ IC 50 ⁇ 1000nM” .
  • EX No. EC 50 (nM) EX No. EC 50 (nM) Com. EX. No. 3 4697 44 285 Com. EX. No. 4 3225 46 218 1 113 48 B 2 A 49 219 17 A 50 135 19 129 51 144 20 B 52 100 22 B 53 352 23 B 54 B 24 A 55 201 25 B 57 A 26 B 59 99 27 25 60 B 28 108 61 A 29 136 64 B 30 244 65 A 32 A 67 B 33 110 70 65.79 34 A 72 B 35 205 74 B 36 359 75 40 37 166 76 B 39 A 77 B 40 A 90 181 41 79 92 B 42 B

Abstract

L'invention concerne des composés de formule (I), des procédés d'utilisation des composés en tant qu'immunomodulateurs et des compositions pharmaceutiques comprenant de tels composés. Les composés sont utiles dans le traitement, la prévention ou l'amélioration de maladies ou de troubles tels que le cancer ou les infections.
PCT/CN2021/109089 2020-07-31 2021-07-29 Immunomodulateurs, compositions et procédés associés WO2022022600A1 (fr)

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CN110582493A (zh) * 2016-12-22 2019-12-17 因赛特公司 作为免疫调节剂的苯并噁唑衍生物
WO2020156323A1 (fr) * 2019-01-31 2020-08-06 Betta Pharmaceuticals Co., Ltd Immunomodulateurs, compositions et procédés associés

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Publication number Priority date Publication date Assignee Title
CN110582493A (zh) * 2016-12-22 2019-12-17 因赛特公司 作为免疫调节剂的苯并噁唑衍生物
WO2020156323A1 (fr) * 2019-01-31 2020-08-06 Betta Pharmaceuticals Co., Ltd Immunomodulateurs, compositions et procédés associés

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