WO2018208727A1 - Analogues de nucléosides et de nucléotides en tant qu'inhibiteurs de cd73 et utilisations thérapeutiques associées - Google Patents

Analogues de nucléosides et de nucléotides en tant qu'inhibiteurs de cd73 et utilisations thérapeutiques associées Download PDF

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WO2018208727A1
WO2018208727A1 PCT/US2018/031512 US2018031512W WO2018208727A1 WO 2018208727 A1 WO2018208727 A1 WO 2018208727A1 US 2018031512 W US2018031512 W US 2018031512W WO 2018208727 A1 WO2018208727 A1 WO 2018208727A1
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alkyl
aryl
cycloalkyl
alkenyl
nrn
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PCT/US2018/031512
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Jian Liu
Linghang Zhuang
Heping Wu
Suxing Liu
Rumin Zhang
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Eternity Bioscience Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/23—Heterocyclic radicals containing two or more heterocyclic rings condensed among themselves or condensed with a common carbocyclic ring system, not provided for in groups C07H19/14 - C07H19/22

Definitions

  • the present invention relates to novel nucleoside and nucleotide compounds and pharmaceutical compositions containing these compounds useful as CD73 inhibitors for the treatment of cancer and other diseases mediated by CD73.
  • CD73 (also known as ecto-5' -nucleotidase) is a cell surface enzyme through a glycosyl phosphatidylinositol linkage to anchor onto the cell membrane and is expressed in different tissues, especially in the colon, kidney, brain, liver, heart, lung, spleen, lymph nodes, and bone marrow (Antonioli, L. et al, Trends Mol. Med. 2013 19: 355-367).
  • the enzymatic activity of CD73 is to catalyze the extracellular dephosphorylation of nucleoside monophosphates to their corresponding nucleosides (e.g., 5-AMP to adenosine).
  • CD73 exerts physiological influences mainly via its enzymatic nucleoside products, particularly adenosine in extracellular space, including epithelial ion and fluid transportation, tissue barrier function control, adaptation to hypoxia, ischemic preconditioning, anti-inflammation, and immune suppression signaling (Colgan, S.P., et al, Purinergic Signaling 2006 2: 351-360).
  • adenosine produces a broad range of physiological responses in the human body via interaction with adenosine receptors (receptor subtypes: Ai , A2A , A2B , and A3), including the vasodilation and atrioventricular conduction suppression properties in the cardiovascular system; the sedative, local neuronal excitability inhibition, anticonvulsant, and neuroprotective effects in the central nervous system (Dunwiddie, T.V., et al, Annu. Rev. Neurosci.
  • CD73 is broadly expressed in many cancer types (Antonioli, L. et al, Trends in Cancer 2016 2(2):95-109) and associated with many cancer types' poor prognosis (Allard, D., et al., Immunotherapy 2016 8(2), 145-163). CD73 promotes cancer metastasis (Yang, Q., et al., Pathol. Oncol. Res.
  • CD73 is found on the surface of macrophages, lymphocytes, regulatory T cells, myeloid-derived suppressor cells (MDSCs), and dendritic cells.
  • the extracellular adenosine mainly produced by CD73, can chronically accumulate in tumor microenvironment, activating adenosine receptors, promoting tumor-inducing mononuclear phagocytes, deregulating anti-tumor T cell response, expanding MDSCs population, triggering immune suppression and favoring the escape of cancer cells from immune surveillance, hence promoting cancer transformation and growth (Antonioli, L. et al, Nature Reviews Cancer 2013 13: 842-857).
  • CD73 new inhibitors which will provide new therapeutic approaches to limit tumor progression and metastasis, increase the efficacy of anti-cancer therapy, and treat cancer by decreasing extracellular adenosine level in tumor microenvironment to resume immune cells effective response against cancer cells.
  • CD73 inhibitors can be used to enhance immune response and treat adenosine and adenosine receptors related diseases or disorders, including neurological, neurodegenerative and CNS disorders and diseases, depression and Parkinson's disease, cerebral and cardiac ischaemic diseases, sleep disorders, fibrosis, immune and inflammatory disease, and cancer.
  • the present invention provides novel nucleoside and nucleotide compounds, and pharmaceutically acceptable compositions thereof, as effective inhibitors of CD73 for the treatment of diseases or disorders associated with CD73 activities, especially cancers and other diseases as further described herein.
  • A is O, S, CH 2 , Se, NH, N-alkyl, CHW (R, S, or racemic), or C(W) 2 , wherein W is F, CI, Br, or I;
  • Ri is H, OH, F, CI, Br, I, ORio, NH 2 , or N 3 ;
  • R 2 is H, Ci-4 alkyl, CH 2 F, CHF 2 , CF 3 , F, or CN;
  • R3 and R3' are independently selected from the group consisting of H, OH, C1-4 alkyl, C 2 -4 alkenyl, C 2-4 alkynyl , vinyl, N 3 , CN, CI, Br, F, I, N0 2 , OC(0)0(Ci -4 alkyl), OC(0)0(C 2-4 alkynyl), OC(0)0(C 2-4 alkenyl), OCi-io haloalkyl, O(aminoacyl), 0(Ci-io acyl), 0(Ci -4 alkyl), 0(C 2-4 alkenyl), S(Ci -4 acyl), S(Ci -4 alkyl), S(C 2-4 alkynyl), S(C 2-4 alkenyl), SO(Ci -4 acyl), SO(Ci- 4 alkyl), SO(C 2-4 alkynyl), SO(C 2-4 alkenyl), S0 2 (Ci -4
  • R is H, a lower alkyl, an optionally substituted alkyl (including lower alkyl), CN, vinyl, 0-(lower alkyl), hydroxyl lower alkyl, e.g.,, -(CH 2 ) p OH, where p is 1-6, including hydroxyl methyl (CH 2 OH), CH 2 F, N 3 , CH 2 CN, CH 2 N 3 , CH 2 NH 2 , CH 2 NHCH 3 , CH 2 N(CH 3 ) 2 , alkynyl (optionally substituted), or halogen, including F, CI, Br, or I;
  • Base is naturally occurring or modified purine or pyrimidine base represented by the following structures: wherein D is N or CH;
  • R5, R6, R7, Rs , and R9 are each independently selected from the group consisting of H, halogen, Cy, C alkyl, C haloalkyl, CN, ORn a , SRn a , C(0)Rn b , C(0)NRn c Rn d , C(0)ORna, OC(0)Rnb, OC(0)NRn c Rn d , NRn c Rn d , NRn c C(0)Rn b , NRn c C(0)ORn a , NRn c C(0)NRii c Riid, NRn c S(0)Rn b , NRn c S(0) 2 Riib, NRii c S(0)2NRn c Rn d , S(0)Rn b , S(0)NRii c Riid, S(0)2Riib, and S(0)2NRn c Rnd, wherein Ci-4 alkyl is optionally substituted by
  • Rio is H, -C(0)ORi 2 , -C(0)Ri3, phosphate, or a stabilized phosphate prodrug, H- phosphonate, including stabilized H-phosphonates, acyl, including optionally substituted phenyl and lower acyl, alkyl, including lower alkyl, O-substituted carboxyalkylamino or its peptide derivatives, sulfonate ester, including alkyl or arylalkyl sulfonyl, including methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted, a lipid, including a phospholipid, an L or D-amino acid, a carbohydrate, a peptide, a cholesterol, or other pharmaceutically acceptable leaving group which when administrated in vivo is capable of providing a compound wherein R3 is OH or phosphate;
  • Cy is selected from Ce- ⁇ aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, each of which is substituted with 1, 2, 3, or 4 substituents independently selected from halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, CN, N0 2 , ORna, SRna, C(0)Rnb, C(0)NncRiid, C(0)ORna, OC(0)Rnb, OC(0)NRn c Rn d , NRn c Rn d , NRn c C(0)Riib, NRn c C(0)ORii a , NRn c C(0)NRn c Rn d , NRn c S(0)Rn b , NRn c S(0) 2 Rn b , NRii c S(0) 2 Rn b , NRii c S(0) 2 R
  • Each Rna, Rub, Riic, Rn d is independently selected from H, Ci-6 alkyl, C 1-4 haloalkyl, C 2 -6 alkenyl, C 2- 6 alkynyl, Ce- ⁇ aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Ce- ⁇ aryl-Ci-4alkyl-, C3-10 cycloalkyl-Ci-4alkyl-, (5-10 membered heteroaryl)-Ci-4 alkyl-, or (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein said Ci-6 alkyl, C 2 -6 alkenyl, C 2 -6 alkynyl, Ce- ⁇ aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Ce- ⁇ aryl-Ci-4 alkyl-, C3-10 cycloalky
  • R12 and Ri3 are independently H, Ci-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl,
  • Z is -CR14R15R16, Ri6, -NR17R18, -OR19, or -SR19;
  • Ri4 and R15 are independently H, halogen (F, CI, Br, I), hydroxyl, or alkyl;
  • Rl6 IS P(0)(OR21a)R22P(0)(OR21b)(OR 2 l C ) ⁇ P(0)(NR23R24)R22P(0)( NR23R24) 2 ;
  • R2ia, R2ib, and R21C are each independently selected from hydrogen, n-alkyl; branched alkyl; cycloalkyl; and aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one or more functional groups independently selected from the group consisting of Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C i-6 alkoxy, F, CI, Br, I, nitro, cyano, Ci-6 haloalkyl, -N(R2i')2, Ci-6 acylamino, -NHSO2C1-6 alkyl, -S02N(R2i')2, COR21", and -SO2C1-6 alkyl; (R 21 ' is independently hydrogen or alkyl, which includes, but is not limited to, Ci-20 alkyl, Ci-10 alkyl, or Ci-6 alkyl, R21
  • R22 is CR25R26, NR27, or O;
  • R25 and R26 are independently H, OH, F, CI, Br, or alkyl
  • R27 is hydrogen or alkyl
  • R23 and R24 are independently H, Ci-ioalkyl, CR28aR28bC(0)R29, or R28a or R28b and R23 or R24 together are (CH2) n so as to form a cyclic ring that includes the adj oining N and C atoms, C(0)CR28aR28bNH(R 2 ia, R2ib, or R 2 i c ), where n is 2 to 4;
  • R29 is OR 30 , NH 2 , or NHOH
  • R 3 o is H, Ci-10 alkyl, Ci-10 alkyl optionally substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, or halogen, Ci-10 haloalkyl, C 3- io cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl;
  • Ri7 and Ris are independently H, alkyl, -CR14R15R16, or C(0)(CR 3 i a R 3 ib)g(C(0)) h R 3 2, wherein g is 0 to 3 and h is 0 to 1, or (CR 3 i a R 3 ib)iR3 3 , wherein i is 0 to 1;
  • R 3 i a and R 3 ib are independently H or C1-4 alkyl, said alkyl optionally substituted with hydroxyl;
  • R 3 2 is R29 or CR28aR28bNH(R 2 i a , R2ib, or R 2 ic);
  • R 33 is Ri6, aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl;
  • Rl9 IS Rl6, -CR14R15R16, CR 34 (C(0)R29)j(P(0)(OR21a)2)k, (C(0)R29)j(P(0)(OR21b) 2 )k, (C(0)R29)j(P(0)(OR2i c ) 2 )k, or CR 34 (C(0)R29)j(P(0)(NR 23 R 2 4)2)k, where j is 1 to 2 and k is 0 to 1; and
  • R 3 4 is H, alkyl, optionally substituted aryl, or substituted heteroaryl.
  • the present invention provides pharmaceutical compositions containing any of these novel compounds, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable carrier.
  • the present invention provides methods of treating cancer a disease or disorder associated with CD73 activity in a subject, the method comprising administering to the subject a therapeutically effective amount of any compound of the present invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof.
  • the compound of present invention is typically administered to a patient in a pharmaceutical formulation or dosage form that contains at least one pharmaceutically acceptable carrier.
  • the present invention provides use of the novel nucleoside and nucleotide compounds, or pharmaceutically acceptable salt, solvate or prodrugs thereof, in the manufacture of medicaments for treatment of a disease or disorder associated with CD73 activity.
  • the present disclosure provides compounds of formula (II):
  • Ri4 and R15 are independently selected from H, halogen (F, CI, Br, I), or alkyl;
  • Rl6 IS P(0)(OR 2 la)R22P(0)(OR21b)(OR 2 l C ) ⁇ P(0)(NR 23 R24)R22P(0)(NR23R24)2;
  • R2ia, R2ib, and R21 C are independently selected from hydrogen, n-alkyl; branched alkyl; cycloalkyl; or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 alkoxy, F, CI, Br, I, nitro, cyano, Ci-6 haloalkyl, -N(R2i')2, Ci-6 acylamino, -NHSO2C1-6 alkyl, -S0 2 N(R 2 i')2, COR21", and -SO2C1-6 alkyl; (R21 ' is independently hydrogen or alkyl, which includes, but is not limited to, Ci-20 alkyl, Ci-10 alkyl, or Ci-6 alkyl, R21" is -OR2i a ,
  • R25 and R26 are independently H, OH, F, CI, Br, or alkyl
  • R27 is hydrogen or alkyl
  • R23 and R24 are independently selected from H, Ci-ioalkyl, CR28aR28bC(0)R29, or R28a or R28b and R23 or R24 together are (CH2) n so as to form a cyclic ring that includes the adjoining N and C atoms, C(0)CR28aR28bNH(R2i a , R 2 ib, or R2ic), where n is 2 to 4;
  • R29 is OR30 , NH 2 , or NHOH
  • R30 is H, Ci-10 alkyl, Ci-10 alkyl optionally substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, or halogen, Ci-10 haloalkyl, C3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl.
  • the present disclosure provides compounds of formula (III):
  • Ri6 is P(0)(OR2ia)R22P(0)(OR2ib)(OR 2 i c ), or P(0)(NR 23 R24)R22P(0)( NR 23 R24)2;
  • R2ia, R2ib, and R21 C are independently selected from hydrogen, n-alkyl; branched alkyl; cycloalkyl; or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 alkoxy, F, CI, Br, I, nitro, cyano, Ci-6 haloalkyl, -N(R 2 i') 2 , C1-5 acylamino, -NHSO2C1-6 alkyl, -S0 2 N(R 2 i')2, COR21", and -SO2C1-6 alkyl; (R21 ' is independently hydrogen or alkyl, which includes, but is not limited to, Ci-20 alkyl, Ci-io alkyl, or Ci-6 alkyl, R2i"is -OR
  • R22 is CR25R26, NR27, or O;
  • R25 and R26 are independently H, OH, F, CI, Br, or alkyl
  • R27 is hydrogen or alkyl
  • R23 and R24 are independently selected from H, Ci-ioalkyl, CR28aR28bC(0)R29, or R28a or R28b and R23 or R24 together are (CH2) n so as to form a cyclic ring that includes the adjoining N and C atoms, C(0)CR28aR28bNH(R2i a , R 2 ib, or R2ic), where n is 2 to 4;
  • R29 is OR 30 , NH 2 , or NHOH
  • R 3 o is H, Ci-10 alkyl, Ci-10 alkyl optionally substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, or halogen, Ci-10 haloalkyl, C 3- io cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl.
  • Ri7 and Ri 8 are independently H, alkyl, -CR14R15R16, or C(0)(CR 3 i a R 3 ib)g(C(0))hR 3 2, where g is 0 to 3 and h is 0 to 1, or (CR 3 i a R 3 ib R 33 , where i is 0 to 1 ;
  • R 3 i a and R 3 1 ⁇ 2 are independently selected from H, or C1-4 alkyl, said alkyl groups optionally substituted with hydroxyl;
  • R 3 2 is R29, or CR2 8a R2 8 bNH(R 2 i a , R2ib, or R 2 i c );
  • R 33 is Ri6, aryl, such as phenyl, heteroaryl, such as pyridinyl, substituted aryl, or substituted heteroaryl;
  • Ri6 is P(0)(OR2ia)R22P(0)(OR2ib)(OR 2 i c ), or P(0)(NR 23 R 2 4)R22P(0)( NR 23 R 2 4) 2 ;
  • R2ia, R2ib, and R21 C are independently selected from hydrogen, n-alkyl; branched alkyl; cycloalkyl; or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 alkoxy, F, CI, Br, I, nitro, cyano, Ci-6 haloalkyl, -N(R 21 ') 2 , Ci-6 acylamino, -NHSO2C1-6 alkyl, -S0 2 N(R 2 i')2, COR21", and -SO2C1-6 alkyl; (R21 ' is independently hydrogen or alkyl, which includes, but is not limited to, Ci-20 alkyl, Ci-io alkyl, or Ci-6 alkyl, R2i"is -OR2i
  • R22 is CR25R26, NR27, or O;
  • R25 and R26 are independently H, OH, F, CI, Br, or alkyl
  • R27 is hydrogen or alkyl
  • R23 and R24 are independently H, Ci-ioalkyl, CR28aR28bC(0)R29, or R28a or R28b and R23 or R24 together are (CH2) n so as to form a cyclic ring that includes the adjoining N and C atoms, C(0)CR28aR28bNH(R2i a , R 2 ib, or R2ic), where n is 2 to 4;
  • R29 is OR30 , NH 2 , or NHOH
  • R30 is H, Ci-10 alkyl, Ci-10 alkyl optionally substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, or halogen, Ci-10 haloalkyl, C3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl.
  • Rl9 is Rl6, -CR14R15R16, CR34 (C(0)R 2 9)j(P(0)(OR 2 la, 21b, or 21c) 2 )k, ⁇ CR34
  • R34 is H, alkyl, optionally substituted aryl, or substituted heteroaryl
  • Rl6 IS P(0)(OR21a)R22P(0)(OR21b)(OR 2 l C ), ⁇ P(0)(NR23R24)R22P(0)(NR23R24) 2 ;
  • R2ia, R2ib, R21 C are independently selected from hydrogen, n-alkyl; branched alkyl; cycloalkyl; or aryl, which includes, but is not limited to, phenyl or naphthyl, where phenyl or naphthyl are optionally substituted with at least one of Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 alkoxy, F, CI, Br, I, nitro, cyano, Ci-6 haloalkyl, -N(R 2 i') 2 , C1-5 acylamino, -NHSO2C1-6 alkyl, -S0 2 N(R 2 i')2, COR21", and -SO2C1-6 alkyl; (R21 ' is independently hydrogen or alkyl, which includes, but is not limited to, Ci-20 alkyl, Ci-io alkyl, or Ci-6 alkyl, R2i"is -OR2
  • R22 is CR25R26, NR27, or O;
  • R25 and R26 are independently selected from H, OH, F, CI, Br, or alkyl;
  • R27 is hydrogen or alkyl
  • R23 and R24 are independently H, Ci-ioalkyl, CR28aR28bC(0)R29, R28a, or R28b; or alternatively R23 or R24 together are (CH2) n so as to form a cyclic ring that includes the adjoining N and C atoms, C(0)CR28aR28bNH(R2i a , R2ib, or R2ic), where n is 2 to 4;
  • R29 is OR 30 , NH 2 , or NHOH
  • R 3 o is H, Ci-10 alkyl, Ci-10 alkyl optionally substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, or halogen, Ci-10 haloalkyl, C 3 -io cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl.
  • compositions or formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration. Regardless of the route of administration selected, the active ingredient(s) are formulated into pharmaceutically acceptable dosage forms by methods known to those of skill in the art.
  • the amount of the active ingredient(s) which will be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration and all of the other factors described above.
  • the amount of the active ingredient(s) which will be combined with a carrier material to produce a single dosage form will generally be that amount of the active ingredient(s) which is the lowest dose effective to produce a therapeutic effect.
  • Methods of preparing pharmaceutical formulations or compositions include the step of bringing the active ingredient(s) into association with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly mixing the active ingredient(s) into liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Exemplary, non-limiting examples of formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or nonaqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of the active ingredient(s).
  • the prodrug(s), active ingredient(s) in their micronized form
  • one or more pharmaceutically-acceptable carriers known to those of skill in the art.
  • suitable aqueous and nonaqueous carriers include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • suitable mixtures thereof Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size, and by the use of surfactants.
  • compositions may also contain adjuvants such as wetting agents, emulsifying agents and dispersing agents. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like in the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • the absorption of the drug in order to prolong the effect of the active ingredient(s), it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the active ingredient(s) then depends upon its/their rate of dissolution which, in turn, may depend upon crystal size and crystalline form.
  • the formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a lyophilized condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use.
  • sterile liquid carrier for example water for injection
  • Extemporaneous injection solutions and suspensions maybe prepared from sterile powders, granules and tablets of the type described above. Any terms in the present application, unless specifically defined, will take the ordinary meanings as understood by a person of ordinary skill in the art.
  • aryl, cycloalkyl, heteroaryl, and heterocyclyl groups of the present disclosure may be substituted as described in each of their respective definitions.
  • aryl part of an arylalkyl group such as benzyl, may be substituted as described in the definition of the term "aryl.”
  • alkoxy refers to a CI -CIO, preferably C1-C6, alkyl group attached to the parent molecular moiety through an oxygen atom.
  • alkoxy group include, but are not limited to, methoxy (CH3O-), ethoxy (CH3CH2O-), and t- butoxy ((CH 3 ) 3 CO).
  • alkyl refers to a group derived from a straight or branched chain saturated hydrocarbon by removal of a hydrogen from one of the saturated carbons.
  • the alkyl group preferably contains from one to ten carbon atoms, more preferably one to six carbon atoms ("lower alkyl”), and sometimes even more preferably one to four carbon atoms.
  • Representative examples of alkyl group include, but are not limited to, methyl, ethyl, isopropyl, and tert-butyl.
  • aryl refers to a group derived from a C6-C12, preferably C6-C10, aromatic carbocycle by removal of a hydrogen atom from an aromatic ring.
  • the aryl group can be monocyclic, bicyclic or polycyclic. Preferred examples of aryl groups include phenyl and naphthyl.
  • cyano refers to -CN.
  • cycloalkyl refers to a group derived from a monocyclic saturated carbocycle, having preferably three to eight, more preferably three to six, carbon atoms, by removal of a hydrogen atom from the saturated carbocycle.
  • Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl. When a cycloalkyl group contains one or more double bond(s) in the ring, yet not aromatic, it forms a "cycloalkenyl" group.
  • halo and halogen, as used herein, refer to F, CI, Br, or I.
  • haloalkoxy refers to a C1-C6, preferably C1-C4, haloalkyl group attached to the parent molecular moiety through an oxygen atom.
  • haloalkyl refers to a C1-C10, preferably C 1-C6, more preferably C1-C4, alkyl group substituted by at least one halogen atom.
  • the haloalkyl group can be an alkyl group of which all hydrogen atoms are substituted by halogens.
  • Representative examples of haloalkyl include, but are not limited to, trifiuoromethyl (CF3-), 1-chloroethyl (CICH2CH2-), and 2,2,2-trifluoroethyl (CF3CH2-).
  • heteroaryl refers to a 5- to 10-membered, monocyclic or bicyclic aromatic group comprising one or more, preferably one to three, heteroatoms independently selected from nitrogen, oxygen, and sulfur in the aromatic ring(s).
  • heteroaryl rings have less aromatic character than their all- carbon counterparts.
  • a heteroaryl group need only have some degree of aromatic character.
  • heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, pyrimidinyl, furyl, thienyl, isoxazolyl, thiazolyl, isoxazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, benzisoxazolyl, benzothiazolyl, and benzothienyl.
  • heterocyclyl refers to a 3- to 10-membered monocyclic or bicyclic nonaromatic group comprising one or more, preferably one to three, heteroatoms independently selected from nitrogen, oxygen, and sulfur in the nonaromatic ring(s).
  • the heterocyclyl groups of the present disclosure can be attached to the parent molecular moiety through a carbon atom or a nitrogen atom in the group.
  • a heterocylcyl group can be saturated or unsaturated, for example, containing one or more double bond(s) in the ring.
  • heterocyclyl 5 groups include, but are not limited to, morpholinyl, oxazolidinyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuryl, thiomorpholinyl, and indolinyl, or the like.
  • hydroxy or "hydroxyl,” as used herein, refers to -OH.
  • nitro refers to -NO2.
  • any group for example, alkyl, alkenyl, "cycloalkyl,” “aryl,” “heterocyclyl,” or “heteroaryl”
  • the group is or is not substituted by from one to five, preferably one to three, substituents independently selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, oxo, acyl, cyano, nitro, and amino group, or the like, provided that such substitution would not violate the conventional bonding principles known to a person of ordinary skill in the art.
  • the phrase “optionally substituted” is used before a list of groups, it means that each one of the groups listed may be optionally substituted.
  • the compounds of the present disclosure can exist as pharmaceutically acceptable salts or solvates.
  • pharmaceutically acceptable salt means any nontoxic salt that, upon administration to a recipient, is capable of providing the compounds or the prodrugs of a compound of this invention.
  • the salts can be prepared during the final isolation and purification of the compounds or separately by reacting a suitable nitrogen atom with a suitable acid.
  • Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, hydrogen bisulfide as well as organic acids, such as para- toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, / ⁇ ara-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid acid, and related inorganic and organic acids.
  • organic acids such as para- toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascor
  • Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia 5 or an organic primary, secondary, or tertiary amine.
  • a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia 5 or an organic primary, secondary, or tertiary amine.
  • the cations of pharmaceutically acceptable salts include, but are not limited to, lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, Nmethylpiperidine, and N-methylmorpholine.
  • nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, Nmethylpiperidine, and N-methylmorpholine.
  • solvate means a physical association of a compound of this invention with one or more, preferably one to three, solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more, preferably one to three, solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are generally known in the art.
  • terapéuticaally effective amount refers to the total amount of each active component that is sufficient to show a meaningful patient benefit, e.g., a sustained reduction in viral load.
  • a meaningful patient benefit e.g., a sustained reduction in viral load.
  • the term refers to that ingredient alone.
  • the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially, or simultaneously.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
  • patient includes both human and other mammals.
  • treating refers to: (i) preventing a disease, disorder or condition from occurring in a patient that may be predisposed to the disease, disorder, and/or condition but has not yet been diagnosed as having it; (ii) inhibiting the disease, disorder, or condition, i.e., arresting its development; and (iii) relieving the disease, disorder, or condition, i.e., causing regression of the disease, disorder, and/or condition.
  • Alcohol 1-1 was prepared according to literature procedures. It underwent, but not limited to, three different treatments: (i) treated with methylenebis(phosphonic dichloride); (ii) converted to 1-2 with leaving groups (e.g., tosylate, mesylate, etc.) followed by treatment with corresponding tris(tetra-n-butylammonium) substituted methylenebis(phosphonic acid); or (iii) treated with corresponding diazo compounds catalyzed by rodium (II) acetate to afford corresponding 1-3.
  • Scheme 2
  • Amine 2-1 was prepared according to literature procedures. It was treated with, but not limited to, three different ways: (i) condensed with corresponding acids via standard conditions (e.g., EDCI, HOBt, DMAP) with or without further treatments including, but not limited to, hydrolysis, deprotection, or one more round of condensation with acids; (ii) underwent reductive amination with corresponding aldehydes and reducing agents (e.g., NaBH 4 ); (iii) displaced a leaving group (e.g., nosylate) in corresponding bisphosphonates to give corresponding 2-2.
  • standard conditions e.g., EDCI, HOBt, DMAP
  • reducing agents e.g., NaBH 4
  • displaced a leaving group e.g., nosylate
  • Phosphonate 3-1 was prepared according to literature procedures. It was treated with, but not limited to, a second phosphonate compound to afford 3-2, which was further converted to 3-3 via standard conditions.
  • Scheme 4
  • Halide (e.g., Br, or I) 4-1 was prepared according to literature procedures. It was treated with, but not limited to, two different pathways: (i) 4-1 underwent two consecutive displacement by corresponding substituted methylphosphonates to afford bisphosphonate 4-2, which was then converted to corresponding nucleotides 4-3 via standard conditions; (ii) 4-1 was converted to monophosphonate 4-4 with corresponding phosphite, which was displaced by corresponding substituted methylphosphonate to afford bisphosphonate 4-5 and further converted to corresponding nucleotide 4-6 via standard conditions.
  • 4-1 underwent two consecutive displacement by corresponding substituted methylphosphonates to afford bisphosphonate 4-2, which was then converted to corresponding nucleotides 4-3 via standard conditions
  • 4-1 was converted to monophosphonate 4-4 with corresponding phosphite, which was displaced by corresponding substituted methylphosphonate to afford bisphosphonate 4-5 and further converted to corresponding nucleotide 4-6 via standard conditions.
  • tert-Butyldimethylsilyl chloride (93mg, 0.62mmol) was added to a solution of 3b (200mg, 0.59mmol) and imidazole (80mg, 1.17mmol) in DMF (5 mL) The resulting mixture was stirred overnight at room temperature, and then concentrated in high vacuo.
  • Example 26
  • BIOLOGICAL ASSAYS CD73 Enzymatic Activity Assay (Assay 1): The CD73 enzymatic assay was performed using a Malachite Green phosphate Detection kit (R&D Systems). The procedure was modified from the kit manual. Compounds were diluted in DMSO first. 0.3ng recombinant human 5'-Nucleotidase/CD73 (R&D Systems) was incubated with or without tested compounds at various concentrations in assay buffer, which contained 20 mM HEPES (pH7.4), 137mM NaCl, 0.001% TW20. Final reaction volume was 12 ⁇ and DMSO concentration was adjusted to 1.25%.
  • the clear flat-bottom plate was incubated at 37°C for certain time (12m, 2h, 20h, 3d, 5d, 7d). After pre-incubation, 3 ⁇ of CMP dissolved in assay buffer was added to each reaction. Final CMP concentration was 45 ⁇ . The plate was then incubated at 37°C for 15 min. 3 ⁇ of Malachite Green Reagent A was added to each reaction. After 10 min of incubation at RT, 3ul of Malachite Green Reagent B was added to each reaction. After 20min of incubation at RT. Signal was read at OD620. IC50 value was calculated using appropriate programs in GraphPad Prism by plotting the logarithm of the compound concentration versus percent inhibition.
  • CD73 Cellular Activity Assay (Assay 2): SKOV3 cells were purchased from American Type Culture Collection. All cells were cultured in the recommended medium and serum concentration. Cells were seeded in 96-well plates at a density of 2500 - 5000 cells per well and cultured overnight at 37°C in a humidified atmosphere with 5% CO2. On the next day, cells were washed once using assay buffer (20 mM HEPES, 137 mM NaCl, 5.4 mM KC1, 1.3 mM CaCb, 4.2 mM NaHC0 3 , lmg/ml glucose), then incubated with compounds at various concentrations in 200 ⁇ assay buffer with 50 ⁇ CMP at 37°C for 4h.
  • assay buffer (20 mM HEPES, 137 mM NaCl, 5.4 mM KC1, 1.3 mM CaCb, 4.2 mM NaHC0 3 , lmg/ml glucose
  • DMSO concentration was adjusted to 0.1%. After incubation, 100 ⁇ of supernatant from each well was transferred to new clear flat-bottom 96-well plates. 20 ⁇ of Malachite Green Reagent A and Malachite Green Reagent B were added to each well subsequently and OD620 was recorded, following Malachite Green phosphate Detection kit manual. IC50 value was calculated using the same way as CD73 Enzymatic Activity Assay.

Abstract

L'invention concerne des composés et des analogues de nucléosides et de nucléotides, et des compositions pharmaceutiquement acceptables de ceux-ci, utilisés en tant qu'inhibiteurs de CD73 dans le traitement de maladies ou de troubles associés à l'activités de CD73, en particulier des cancers, ainsi que des procédés de préparation de ces composés.
PCT/US2018/031512 2017-05-08 2018-05-08 Analogues de nucléosides et de nucléotides en tant qu'inhibiteurs de cd73 et utilisations thérapeutiques associées WO2018208727A1 (fr)

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US11591355B2 (en) 2017-03-31 2023-02-28 Peloton Therapeutics Inc. CD73 inhibitors and uses thereof
EP3600273A4 (fr) * 2017-03-31 2021-01-20 Peloton Therapeutics, Inc. Inhibiteurs de cd73 et leurs utilisations
US11576922B2 (en) 2017-05-10 2023-02-14 Oric Pharmaceuticals, Inc. CD73 inhibitors
US11129841B2 (en) 2017-05-10 2021-09-28 Oric Pharmaceuticals, Inc. CD73 inhibitors
US11377469B2 (en) 2017-11-03 2022-07-05 Oric Pharmaceuticals, Inc. CD73 inhibitors
US11807658B2 (en) 2018-04-30 2023-11-07 Oric Pharmaceuticals, Inc. CD73 inhibitors
US11325938B2 (en) 2018-04-30 2022-05-10 Oric Pharmaceuticals, Inc. CD73 inhibitors
US20230022922A1 (en) * 2018-06-21 2023-01-26 Lijing Chen Ectonucleotidase inhibitors and methods of use thereof
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US11858957B2 (en) 2018-06-21 2024-01-02 Antengent Therapeutics Limited Ectonucleotidase inhibitors and methods of use thereof
CN112888696B (zh) * 2018-06-21 2024-04-16 德琪医疗有限公司 外核苷酸酶抑制剂及其使用方法
EP3810617A4 (fr) * 2018-06-21 2022-06-29 Calithera Biosciences, Inc. Inhibiteurs d'ectonucléotidases et leurs procédés d'utilisation
CN114206841A (zh) * 2019-04-15 2022-03-18 博奥阿迪斯生物科技公司 Cd73抑制剂
WO2020211668A1 (fr) * 2019-04-15 2020-10-22 Bioardis Llc Inhibiteurs de cd73
WO2020210938A1 (fr) * 2019-04-15 2020-10-22 Bioardis Llc Dérivés de quinazoline en tant qu'inhibiteurs de cd73
JP2022526147A (ja) * 2019-04-28 2022-05-23 アビスコ セラピューティクス カンパニー リミテッド Ｃｄ７３阻害剤、その製造方法と応用
CN113366008A (zh) * 2019-04-28 2021-09-07 上海和誉生物医药科技有限公司 一种cd73抑制剂，其制备方法和应用
AU2020264642B2 (en) * 2019-04-28 2023-05-25 Abbisko Therapeutics Co., Ltd. CD73 inhibitor, preparation method therefor and application thereof
CN113366008B (zh) * 2019-04-28 2023-06-23 上海和誉生物医药科技有限公司 一种cd73抑制剂，其制备方法和应用
WO2021011689A1 (fr) * 2019-07-16 2021-01-21 Oric Pharmaceuticals, Inc. Inhibiteurs de cd73
US11530236B2 (en) 2019-10-30 2022-12-20 Oric Pharmaceuticals, Inc. CD73 inhibitors
US11130778B2 (en) 2019-10-30 2021-09-28 Oric Pharmaceuticals, Inc. CD73 inhibitors
US11028120B2 (en) 2019-10-30 2021-06-08 Oric Pharmaceuticals, Inc. CD73 inhibitors
WO2021087136A1 (fr) * 2019-10-30 2021-05-06 Oric Pharmaceuticals, Inc. Inhibiteurs de cd73
WO2023201267A1 (fr) 2022-04-13 2023-10-19 Gilead Sciences, Inc. Polythérapie pour le traitement de cancers exprimant trop-2
CN115181148A (zh) * 2022-07-12 2022-10-14 南京工业大学 一种基于虫草素经衍生化具有抗肿瘤效应的化合物
WO2024012126A1 (fr) * 2022-07-12 2024-01-18 南京工业大学 Composé dérivé de cordycépine ayant un effet antitumoral

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