[go: up one dir, main page]

WO2018208727A1 - Nucleoside and nucleotide analogues as cd73 inhibitors and therapeutic uses thereof - Google Patents

Nucleoside and nucleotide analogues as cd73 inhibitors and therapeutic uses thereof Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
aryl
cycloalkyl
alkenyl
nrn
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2018/031512
Other languages
French (fr)
Inventor
Jian Liu
Linghang Zhuang
Heping Wu
Suxing Liu
Rumin Zhang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eternity Bioscience Inc
Original Assignee
Eternity Bioscience Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eternity Bioscience Inc filed Critical Eternity Bioscience Inc
Publication of WO2018208727A1 publication Critical patent/WO2018208727A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Genetics & Genomics (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Biotechnology (AREA)
  • Biochemistry (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Immunology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Nucleoside and nucleotide compounds and analogues, and pharmaceutically acceptable compositions thereof, as inhibitors of CD73 for the treatment of diseases or disorders associated with CD73 activities, especially cancers, and methods of preparing these compounds are disclosed.

Description

NUCLEOSIDE AND NUCLEOTIDE ANALOGUES AS CD73 INHIBITORS AND
THERAPEUTIC USES THEREOF
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority under 35 U. S.C. § 1 19(e) to U. S. Provisional Patent Application Serial No. 62/503,035, filed on May 8, 2017, the disclosure of which is incorporated herein by reference in its entirety.
TECHNICAL FIELD OF THE INVENTION
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.
BACKGROUND OF INVENTION
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).
As a ubiquitous extracellular signaling molecule with neuromodulating properties, 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. 2001 24:31-55); the bronchoconstriction effects in the respiratory system (Pauwels, R., et al, Drug Development Research 1993 28: 318-321); and the mediation of immune/inflammatory responses in the immune system (Hasko, G, et al, "A Key Link between Metabolism and Brain Activity" 2013 233-251). 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. 2013 19: 81 1 -814) and chemoresistance (Loi, S., et al, PNAS 2013 1 10(27): 1 1091 -1 1096). In the immune system, 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).
Accordingly, there is need to identify and develop 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.
Because of a wide range of physiological functions of adenosine in human body, 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.
SUMMARY OF THE INVENTION
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.
In one aspect, the present disclosure provides compounds of formula (I):
Figure imgf000003_0001
or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:
A is O, S, CH2, 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, NH2, or N3;
R2 is H, Ci-4 alkyl, CH2F, CHF2, CF3, F, or CN;
R3 and R3' are independently selected from the group consisting of H, OH, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl , vinyl, N3, CN, CI, Br, F, I, N02, OC(0)0(Ci-4 alkyl), OC(0)0(C2-4 alkynyl), OC(0)0(C2-4 alkenyl), OCi-io haloalkyl, O(aminoacyl), 0(Ci-io acyl), 0(Ci-4 alkyl), 0(C2-4 alkenyl), S(Ci-4 acyl), S(Ci-4 alkyl), S(C2-4 alkynyl), S(C2-4 alkenyl), SO(Ci-4 acyl), SO(Ci-4 alkyl), SO(C2-4 alkynyl), SO(C2-4 alkenyl), S02(Ci-4 acyl), S02(Ci-4 alkyl), S02(C2-4 alkynyl), S02(C2-4 alkenyl), OSCOMCM acyl), OS(0)2(Ci-4 alkyl), OS(0)2(C2-4 alkenyl), NH2, NH(Ci-4 alkyl), NH(C2-4 alkenyl), NH(C2-4 alkynyl), NH(Ci4acyl), N(Ci-4alkyl)2, and N(Ci- i8acyl)2, wherein alkyl, alkynyl, alkenyl, and vinyl are each optionally substituted by N3, CN, one to three halogen(Cl, Br, F, I), N02, C(0)0(Ci-4 alkyl), C(0)0(C2-4 alkynyl), C(0)0(C2-4 alkenyl), 0(Ci-4 acyl), 0(Ci-4 alkyl), 0(C2-4 alkenyl), S(Ci-4 acyl), S(Ci-4 alkyl), S(C2-4 alkynyl), S(C2-4 alkenyl), SO(Ci-4 acyl), SO(Ci-4 alkyl), SO(C2-4 alkynyl), SO(C2- alkenyl), S02(Ci- acyl), S02(Ci- alkyl), S02(C2- alkynyl), S02(C24 alkenyl), OS(0)2(Ci- acyl), OS(0)2(Ci4 alkyl), 03S(C24 alkenyl), NH2, NH(Ci- alkyl), NH(C2- alkenyl), NH(C2- alkynyl), NH(Ci-4 acyl), N(Ci-4 alkyl)2, N(Ci-4 acyl)2, and OR10; or R3 and R3 ' can be linked together to form a vinyl optionally substituted by one or two functional groups independently selected from the group consisting of N3, CN, CI, Br, F, I, and N02;
R is H, a lower alkyl, an optionally substituted alkyl (including lower alkyl), CN, vinyl, 0-(lower alkyl), hydroxyl lower alkyl, e.g.,, -(CH2)pOH, where p is 1-6, including hydroxyl methyl (CH2OH), CH2F, N3, CH2CN, CH2N3, CH2NH2, CH2NHCH3, CH2N(CH3)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:
Figure imgf000004_0001
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, ORna, SRna, C(0)Rnb, C(0)NRncRnd, C(0)ORna, OC(0)Rnb, OC(0)NRncRnd, NRncRnd, NRncC(0)Rnb, NRncC(0)ORna, NRncC(0)NRiicRiid, NRncS(0)Rnb, NRncS(0)2Riib, NRiicS(0)2NRncRnd, S(0)Rnb, S(0)NRiicRiid, S(0)2Riib, and S(0)2NRncRnd, wherein Ci-4 alkyl is optionally substituted by 1, 2 or 3 substituents independently selected from H, halogen, Cy, Ci-4 haloalkyl, CN, ORna, SRna, C(0)Rnb, C(0)NRncRiid, C(0)ORna, OC(0)Rnb, OC(0)NRncRnd, NRncRnd, NRncC(0)Riib, NRncC(0)ORiia, NRncC(0)NRiicRnd, NRncS(0)Rnb, NRncS(0)2Riib, NRiicS(0)2NRiicRiid, S(0)Rnb, S(0)NRncRnd, S(0)2Riib, S(0)2NRncRnd, lower alkyl of Ci-6, optionally substituted alkyl of Ci-i2 , halogenated lower alkyl of Ci-6 such as CF3 and CH2CH2F, lower alkenyl of C2-6 such as CH=CH2, halogenated lower alkenyl of C2-6, lower alkynyl of C2-6, halogenated lower alkynyl of C2-6, lower alkoxy of Ci-6, such as CH2OH and CH2CH2OH, halogenated lower alkoxy of Ci-6, C02H, C02Rna, CONH2, CONRncRnd, CH=CHC02H, and CH=CHC02Rna;
Rio is H, -C(0)ORi2, -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-ιο 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, N02, ORna, SRna, C(0)Rnb, C(0)NncRiid, C(0)ORna, OC(0)Rnb, OC(0)NRncRnd, NRncRnd, NRncC(0)Riib, NRncC(0)ORiia, NRncC(0)NRncRnd, NRncS(0)Rnb, NRncS(0)2Rnb, NRiicS(0)2NRncRiid, S(0)Rnb, S(0)NRncRnd, S(0)2Rnb, and S(0)2NRncRnd;
Each Rna, Rub, Riic, Rnd is independently selected from H, Ci-6 alkyl, C 1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, Ce-ιο aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Ce-ιο 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, C2-6 alkenyl, C2-6 alkynyl, Ce-ιο aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Ce-ιο aryl-Ci-4 alkyl-, C3-10 cycloalkyl-Ci4 alkyl-, (5-10 membered heteroaryl)-Ci-4 alkyl-, or (4-10 membered heterocycloalkyl)-Ci-4 alkyl- is optionally substituted with 1,2,3,4, or 5 substituents independently selected from halogen, Ci- 4 alkyl, C haloalkyl, C M cyanoalkyl, CN, N02, OR12, SR12, C(0)Ri2, C(0)NRi2Ri3, C(0)ORi2, OC(0)Ri2, OC(0)NRi2Ri3, NR12R13, NRi2C(0)Ri3, NRi2C(0)ORi3, NRi2C(0)NRi2Ri3, NRi2S(0)Ri3, NRi2S(0)2Ri3, NRi2S(0)2NRi2Ri3, S(0)R12, S(0)NRi2Ri3, S(0)2Ri2, and S(0)2NRi2Ri3;
R12 and Ri3 are independently H, Ci-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl,
Ce-ιο aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Ce- 10 aryl-Ci-4alkyl-, C3-10 cycloalkyl-Ci-4alkyl-, (5-10 membered heteroaryl)-Ci-4 alkyl-, or (4- 10 membered heterocycloalkyl)-Ci-4 alkyl-, wherein said Ci-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, Ce-ιο aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Ce-ιο aryl-Ci-4 alkyl-, C3-10 cycloalkyl-Ci-4 alkyl-, (5-10 membered heteroaryl)-Ci-4 alkyl-, or (4-10 membered heterocycloalkyl)-Ci-4 alkyl- is optionally substituted with 1,2,3,4, or 5 substituents independently selected from Cy, halogen, C1-4 alkyl, Ci-4 haloalkyl, C1-4 cyanoalkyl, CN, NO2;;
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)(OR2lC) ΟΓ 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; (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 -OR2ia, -OR2111, -
Figure imgf000006_0001
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(R2ia, R2ib, or R2ic), where n is 2 to 4;
R28a and R28b are (i) independently selected from H, Ci-10 alkyl, cycloalkyl, - (CH2)C(NR28')2, Ci-6 hydroxyalkyl, -CH2SH, -(CH2)2S(0)dMe, -(CH2)3NHC(=NH)NH2, (1H- indol-3-yl)methyl, (lH-imidazol-4-yl)methyl, -(CH2)eCOR28", aryl, and aryl C 1-3 alkyl, said aryl groups optionally substituted with a group selected from hydroxyl, Ci-10 alkyl, Ci-6 alkoxy, halogen, nitro and cyano; (ii) R.28a and R.28b both are Ci-6 alkyl; (iii) R28a and R28b together are (CH2)f so as to form a spiro ring; (iv) R28a is H, and R28b and R23 or R24 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms; (v) R28b is H, and R28a and R23 or R24 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to 3, f is 2 to 5, n is 2 to 4, and where R28' is independently H or Ci-6 alkyl, and R28" is -OR2ia, -OR21b, -OR21C, or -N(R28')2); (vi) R28a is H, and R28b is H, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, -CH(CH3)CH2CH3, - CH2Ph, -CH2-indol-3-yl, -CH2CH2SCH3, -CH2CO2H, -CH2C(0)NH2, -CH2CH2COOH, - CH2CH2C(0)NH2, -CH2CH2CH2CH2NH2, -CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4'-OH)-Ph), CH2SH, or lower cycloalkyl; or (vii) R28a is H, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2Ph, -CH2-indol-3-yl, - CH2CH2SCH3, -CH2CO2H, -CH2C(0)NH2, -CH2CH2COOH, -CH2CH2C(0)NH2, - CH2CH2CH2CH2NH2, -CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4'-OH)-Ph), CH2SH, or lower cycloalkyl, and R28b is H, where R28' is independently H, or alkyl, which includes, but is not limited to, Ci-20 alkyl, Ci-10 alkyl, or Ci-6 alkyl, R28" is -OR2ia, -OR2ib, -OR2ic, or -N(R28')2);
R29 is OR30, NH2, or NHOH;
R3o 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-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)(CR3iaR3ib)g(C(0))hR32, wherein g is 0 to 3 and h is 0 to 1, or (CR3iaR3ib)iR33, wherein i is 0 to 1;
R3ia and R3ib are independently H or C1-4 alkyl, said alkyl optionally substituted with hydroxyl;
R32 is R29 or CR28aR28bNH(R2ia, R2ib, or R2ic);
R33 is Ri6, aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl;
Rl9 IS Rl6, -CR14R15R16, CR34(C(0)R29)j(P(0)(OR21a)2)k, (C(0)R29)j(P(0)(OR21b)2)k, (C(0)R29)j(P(0)(OR2ic)2)k, or CR34 (C(0)R29)j(P(0)(NR23R24)2)k, where j is 1 to 2 and k is 0 to 1; and
R34 is H, alkyl, optionally substituted aryl, or substituted heteroaryl. In another aspect, 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.
In another aspect, 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.
In another aspect, 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.
Other aspects and embodiments of the present invention will be better appreciated through the following description, examples, and claims.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present disclosure provides compounds of formula (II):
Figure imgf000008_0001
(I D,
or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein A, Base, Ri, R2, R3, R3', and R are defined in formula I;
Ri4 and R15 are independently selected from H, halogen (F, CI, Br, I), or alkyl;
Rl6 IS P(0)(OR2la)R22P(0)(OR21b)(OR2lC) ΟΓ P(0)(NR23R24)R22P(0)(NR23R24)2;
R2ia, R2ib, and R21C 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, -S02N(R2i')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 -OR2ia, - OR2ib, -OR21C or -N(R2i')2); 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(R2ia, R2ib, or R2ic), where n is 2 to 4;
R28a and R28b are (i) independently selected from H, Ci-10 alkyl, cycloalkyl, - (CH2)C(NR28')2, Ci-6 hydroxyalkyl, -CH2SH, -(CH2)2S(0)dMe, -(CH2)3NHC(=NH)NH2, (1H- indol-3-yl)methyl, (lH-imidazol-4-yl)methyl, -(CH2)eCOR28", aryl and aryl C1-3 alkyl, said aryl groups optionally substituted with a group selected from hydroxyl, Ci-10 alkyl, Ci-6 alkoxy, halogen, nitro and cyano; (ii) R28a and R28b both are Ci-6 alkyl; (iii) R28a and R28b together are (CH2)f so as to form a spiro ring; (iv) R28a is H and R28b and R23 or R24 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms; (v) R28b is H and R28a and R23 or R24 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to 3, f is 2 to 5, n is 2 to 4, and where R28' is independently H, or Ci-6 alkyl and R28" is -OR2ia, -OR2ib, -OR21C, or -N(R28')2); (vi) R28a is H, and R28b is H, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, -CH(CH3)CH2CH3, - CH2Ph, -CH2-indol-3-yl, -CH2CH2SCH3, -CH2CO2H, -CH2C(0)NH2, -CH2CH2COOH, - CH2CH2C(0)NH2, -CH2CH2CH2CH2NH2, -CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4'-OH)-Ph), CH2SH, or lower cycloalkyl; or (vii) R28a is H, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2Ph, -CH2-indol-3-yl, - CH2CH2SCH3, -CH2CO2H, -CH2C(0)NH2, -CH2CH2COOH, -CH2CH2C(0)NH2, - CH2CH2CH2CH2NH2, -CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4'-OH)-Ph), CH2SH, or lower cycloalkyl and R28b is H, where R28' is independently H, or alkyl, which includes, but is not limited to, Ci-20 alkyl, Ci-10 alkyl, or Ci-6 alkyl, R28" is -OR2ia, -OR2ib, -OR2ic, or -N(R28')2);
R29 is OR30 , NH2, or NHOH; and
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. In another embodiment, the present disclosure provides compounds of formula (III):
Figure imgf000010_0001
or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein A, Base, Ri, R2, R3, R3 ' , and R are defined in formula I;
Ri6 is P(0)(OR2ia)R22P(0)(OR2ib)(OR2ic), or P(0)(NR23R24)R22P(0)( NR23R24)2;
R2ia, R2ib, and R21C 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, C1-5 acylamino, -NHSO2C1-6 alkyl, -S02N(R2i')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 -OR2ia, - OR2ib, -OR21C or -N(R2i')2);
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(R2ia, R2ib, or R2ic), where n is 2 to 4;
R28a and R28b are (i) independently selected from H, Ci-io alkyl, cycloalkyl, - (CH2)C(NR28')2, Ci-6 hydroxyalkyl, -CH2SH, -(CH2)2S(0)dMe, -(CH2)3NHC(=NH)NH2, (1H- indol-3-yl)methyl, (lH-imidazol-4-yl)methyl, -(CH2)eCOR28", aryl and aryl C1-3 alkyl, said aryl groups optionally substituted with a group selected from hydroxyl, Ci-io alkyl, Ci-6 alkoxy, halogen, nitro and cyano; (ii) R28a and R28b both are Ci-6 alkyl; (iii) R28a and R28b together are (CH2)f so as to form a spiro ring; (iv) R28a is H and R28b and R23 or R24 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms; (v) R28b is H and R28a and R23 or R24 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to 3, f is 2 to 5, n is 2 to 4, and where R28' is independently H, or Ci-6 alkyl and R28" is -OR2ia, -OR2ib, -OR21C, or -N(R28')2); (vi) R28a is H, and R28b is H, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, -CH(CH3)CH2CH3, - CH2Ph, -CH2-indol-3-yl, -CH2CH2SCH3, -CH2CO2H, -CH2C(0)NH2, -CH2CH2COOH, - CH2CH2C(0)NH2, -CH2CH2CH2CH2NH2, -CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4'-OH)-Ph), CH2SH, or lower cycloalkyl; or (vii) R28a is H, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2Ph, -CH2-indol-3-yl, - CH2CH2SCH3, -CH2CO2H, -CH2C(0)NH2, -CH2CH2COOH, -CH2CH2C(0)NH2, - CH2CH2CH2CH2NH2, -CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4'-OH)-Ph), CH2SH, or lower cycloalkyl and R28b is H, where R28' is independently H, or alkyl, which includes, but is not limited to, Ci-20 alkyl, Ci-10 alkyl, or Ci-6 alkyl, R28" is -OR2ia, -OR2ib, -OR2ic, or -N(R28')2);
R29 is OR30 , NH2, or NHOH; and
R3o 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-io cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl.
In another embodiment, the present disclosure provides compounds of formula (IV):
Figure imgf000011_0001
or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein A, Base, Ri, R2, R3, R3', and R4 are defined in formula I;
Ri7 and Ri8 are independently H, alkyl, -CR14R15R16, or C(0)(CR3iaR3ib)g(C(0))hR32, where g is 0 to 3 and h is 0 to 1, or (CR3iaR3ib R33, where i is 0 to 1 ;
R3ia and R3½ are independently selected from H, or C1-4 alkyl, said alkyl groups optionally substituted with hydroxyl;
R32 is R29, or CR28aR28bNH(R2ia, R2ib, or R2ic);
R33 is Ri6, aryl, such as phenyl, heteroaryl, such as pyridinyl, substituted aryl, or substituted heteroaryl;
Ri6 is P(0)(OR2ia)R22P(0)(OR2ib)(OR2ic), or P(0)(NR23R24)R22P(0)( NR23R24)2;
R2ia, R2ib, and R21C 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(R21')2, Ci-6 acylamino, -NHSO2C1-6 alkyl, -S02N(R2i')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 -OR2ia, - OR2ib, -OR21C or -N(R2i')2);
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(R2ia, R2ib, or R2ic), where n is 2 to 4;
R28a and R28b are (i) independently selected from H, Ci-10 alkyl, cycloalkyl, - (CH2)C(NR28')2, Ci-6 hydroxyalkyl, -CH2SH, -(CH2)2S(0)dMe, -(CH2)3NHC(=NH)NH2, (1H- indol-3-yl)methyl, (lH-imidazol-4-yl)methyl, -(CH2)eCOR28", aryl, and aryl C 1-3 alkyl, said aryl groups optionally substituted with a group selected from hydroxyl, Ci-10 alkyl, Ci-6 alkoxy, halogen, nitro and cyano; (ii) R28a and R28b both are Ci-6 alkyl; (iii) R28a and R28b together are (CH2)f so as to form a spiro ring; (iv) R28a is H and R28b and R23 or R24 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms; (v) R28b is H and R28a and R23 or R24 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to 3, f is 2 to 5, n is 2 to 4, and where R28' is independently H, or Ci-6 alkyl and R28" is -OR2ia, -OR2ib, -OR21C, or -N(R28')2); (vi) R28a is H, and R28b is H, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, -CH(CH3)CH2CH3, - CH2Ph, -CH2-indol-3-yl, -CH2CH2SCH3, -CH2CO2H, -CH2C(0)NH2, -CH2CH2COOH, - CH2CH2C(0)NH2, -CH2CH2CH2CH2NH2, -CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4'-OH)-Ph), CH2SH, or lower cycloalkyl; or (vii) R28a is H, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2Ph, -CH2-indol-3-yl, - CH2CH2SCH3, -CH2CO2H, -CH2C(0)NH2, -CH2CH2COOH, -CH2CH2C(0)NH2, - CH2CH2CH2CH2NH2, -CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4'-OH)-Ph), CH2SH, or lower cycloalkyl and R28b is H, where R28' is independently H, or alkyl, which includes, but is not limited to, Ci-20 alkyl, Ci-10 alkyl, or Ci-6 alkyl, R28" is -OR2ia, -OR2ib, -OR2ic, or -N(R28')2);
R29 is OR30 , NH2, or NHOH; and
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.
In another embodiment, the present disclosure provides compounds of formula (V):
Figure imgf000013_0001
or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein A, Base, Ri, R2, R3, R3 ' , nd aR4 are defined in formula I;
Rl9 is Rl6, -CR14R15R16, CR34 (C(0)R29)j(P(0)(OR2la, 21b, or 21c)2)k, ΟΓ CR34
(C(0)R29)j(P(0)(NR23R24)2)k, where j is 1 to 2 and k is 0 to 1;
R34 is H, alkyl, optionally substituted aryl, or substituted heteroaryl;
Rl6 IS P(0)(OR21a)R22P(0)(OR21b)(OR2lC), ΟΓ P(0)(NR23R24)R22P(0)(NR23R24)2;
R2ia, R2ib, R21C 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, C1-5 acylamino, -NHSO2C1-6 alkyl, -S02N(R2i')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 -OR2ia, - OR2ib, -OR21C or -N(R2i')2);
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(R2ia, R2ib, or R2ic), where n is 2 to 4;
R28a and R28b are (i) independently selected from H, Ci-10 alkyl, cycloalkyl, - (CH2)C(NR28')2, Ci-6 hydroxyalkyl, -CH2SH, -(CH2)2S(0)dMe, -(CH2)3NHC(=NH)NH2, (1H- indol-3-yl)methyl, (lH-imidazol-4-yl)methyl, -(CH2)eCOR28", aryl and aryl C1-3 alkyl, said aryl groups optionally substituted with a group selected from hydroxyl, Ci-10 alkyl, Ci-6 alkoxy, halogen, nitro and cyano; (ii) R28a and R28b both are Ci-6 alkyl; (iii) R28a and R28b together are (CH2)f so as to form a spiro ring; (iv) R28a is H and R28b and R23 or R24 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms; (v) R.28b is H and R.28a and R23 or R24 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to 3, f is 2 to 5, n is 2 to 4, and where R28' is independently H, or Ci-6 alkyl and R28" is -OR2ia, -OR2it>, -OR21C, or -N(R28')2); (vi) R28a is H, and R28b is H, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, -CH(CH3)CH2CH3, - CH2Ph, -CH2-indol-3-yl, -CH2CH2SCH3, -CH2CO2H, -CH2C(0)NH2, -CH2CH2COOH, - CH2CH2C(0)NH2, -CH2CH2CH2CH2NH2, -CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4'-OH)-Ph), CH2SH, or lower cycloalkyl; or (vii) R28a is H, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2Ph, -CH2-indol-3-yl, - CH2CH2SCH3, -CH2CO2H, -CH2C(0)NH2, -CH2CH2COOH, -CH2CH2C(0)NH2, - CH2CH2CH2CH2NH2, -CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4'-OH)-Ph), CH2SH, or lower cycloalkyl and R28b is H, where R28' is independently H, or alkyl, which includes, but is not limited to, Ci-20 alkyl, Ci-10 alkyl, or Ci-6 alkyl, R28" is -OR2ia, -OR2ib, -OR2ic, or -N(R28')2);
R29 is OR30 , NH2, or NHOH; and
R3o 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-io cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl.
Yet other aspects and embodiments may be found in the description and claims provided herein and any reasonable combinations thereof.
Pharmaceutical 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. In general, 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).
In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the prodrug(s), active ingredient(s) (in their micronized form) is/are mixed with one or more pharmaceutically-acceptable carriers known to those of skill in the art. Examples of suitable aqueous and nonaqueous carriers which may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and 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.
These 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.
In some cases, 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. 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.
As used herein, the singular forms "a", "an", and "the" include plural reference unless the context clearly dictates otherwise.
Unless stated otherwise, all aryl, cycloalkyl, heteroaryl, and heterocyclyl groups of the present disclosure may be substituted as described in each of their respective definitions. For example, the aryl part of an arylalkyl group, such as benzyl, may be substituted as described in the definition of the term "aryl."
The term "alkoxy," as used herein, refers to a CI -CIO, preferably C1-C6, alkyl group attached to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy group include, but are not limited to, methoxy (CH3O-), ethoxy (CH3CH2O-), and t- butoxy ((CH3)3CO).
The term "alkyl," as used herein, 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.
The term "aryl," as used herein, 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.
The term "cyano," as used herein, refers to -CN.
The term "cycloalkyl," as used herein, 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.
The terms "halo" and "halogen," as used herein, refer to F, CI, Br, or I.
The term "haloalkoxy," as used herein, refers to a C1-C6, preferably C1-C4, haloalkyl group attached to the parent molecular moiety through an oxygen atom.
The term "haloalkyl," as used herein, 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-).
The term "heteroaryl," as used herein, 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). As is well known to those skilled in the art, heteroaryl rings have less aromatic character than their all- carbon counterparts. Thus, for the purposes of the invention, a heteroaryl group need only have some degree of aromatic character. Illustrative examples of 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.
The term "heterocyclyl," as used herein, 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. Examples of heterocyclyl 5 groups include, but are not limited to, morpholinyl, oxazolidinyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydrofuryl, thiomorpholinyl, and indolinyl, or the like.
The terms "hydroxy" or "hydroxyl," as used herein, refers to -OH.
The term "nitro," as used herein, refers to -NO2.
The term "oxo," as used herein, refers to "=0".
When any group, for example, alkyl, alkenyl, "cycloalkyl," "aryl," "heterocyclyl," or "heteroaryl", is said to be "optionally substituted," unless specifically defined, it means that 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. When 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. The term "pharmaceutically acceptable salt," as used herein, 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.
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. 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.
The term "solvate," as used herein, 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.
The term "therapeutically effective amount," as used herein, 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. When applied to an individual active ingredient, administered alone, the term refers to that ingredient alone. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially, or simultaneously.
The term "pharmaceutically acceptable," as used herein, 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.
The term "patient" includes both human and other mammals.
The term "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. Synthetic Methods
The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes that illustrate the methods by which the compounds of the invention may be prepared. Other reaction schemes could be readily devised by those skilled in the art based on the present disclosure.
Sch me 1
Figure imgf000019_0001
Rh2(OAC)4
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
(i)
acid
EDCI, HOBt, DMAP
Figure imgf000020_0001
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., NaBH4); (iii) displaced a leaving group (e.g., nosylate) in corresponding bisphosphonates to give corresponding 2-2.
Scheme 3
Figure imgf000020_0002
3-2 3-3
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
Figure imgf000021_0001
4-6
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.
Alternately, PG of 3-1 and 4-1 in Scheme 3 and 4 was replaced with corresponding base and followed the similar conditions described in scheme 3 and 4 to afford corresponding nucleotides, respectively.
EXAMPLES
The compounds and processes of the present invention will be better understood in connection with the following illustrative, non-limiting examples.
Figure imgf000022_0001
Step 1A
la (100 mg, 0.37 mmol) and benzaldehyde (0.23ml, 2.22 mmol) were added sequentially to a solution of magnesium methylate (319mg, 3.7 mmol) in methanol (5.6 mL). The reaction mixture was stirred for 3 h at 55 °C, followed by addition of sodium borohydride (112mg, 2.96 mmol). After 30 min stirring at room temperature, the reaction mixture was adjusted to pH=7 with cone. HCl and concentrated in vacuo. Water (3 mL) was added to the residue and the mixture was extracted with ethyl acetate (30 mL). The organic layer was dried with magnesium sulfate, filtered, and concentrated in vacuo to give the title product lb as colorless solids (83mg, 63%). MS (ESI): m/z =360 [M+H]+. ¾ MR (500 MHz, DMSO-i/6) δ 8.51 (t, J = 6.4 Hz, 1H), 8.40 (s, 1H), 8.22 (s, 1H), 7.33 (d, J =7.6 Hz, 2H), 7.29 (t, J = 7.5 Hz, 2H), 7.24 - 7.16 (m, 1H), 6.24 (dd, J = 17.1, 2.9 Hz, 1H), 5.73 (d, J = 6.1 Hz, 1H), 5.44 (d, J= 50 Hz, 1H), 5.25 (t, J= 5.5 Hz, 1H), 4.81 - 4.61 (m, 2H), 4.49 (dq, 7=17.5, 5.9 Hz, 1H), 3.98 (dt, 7= 6.4, 3.2 Hz, 1H), 3.74 (dt, 7= 12.3, 3.3 Hz, 1H), 3.58 (dt, 7 = 12.2, 4.7 Hz, 1H); 19F NMR (282 MHz, DMSO-^6) δ-204.3.
Step IB
tert-Butyldimethylsilyl chloride (44mg, 0.292mmol) was added to a solution of lb (lOOmg, 0.28mmol) and imidazole (38mg, 0.56mmol) in DMF (5 mL) The resulting mixture was stirred overnight at room temperature. After removal of solvent in vacuo, the residue was purified by column chromatography to give the title product lc as pale yellow oil (72.4mg, 55%). MS (ESI): m/z =474 [M+H]+. ¾ NMR (500 MHz, DMSO-^6) δ 8.49 (s, 1H), 8.29 (s, 1H), 8.21 (s, 1H), 7.38 - 7.24 (m, 4H), 7.20 (t, 7= 7.2 Hz, 1H), 6.24 (d, 7 = 18.5 Hz, 1H), 5.72 (d, 7 = 6.5 Hz, 1H), 5.45 (d, 7 = 55 Hz, 1H), 4.69 (d, 7 = 7.5 Hz, 1H), 4.59 (ddd, 7 = 22.4, 11.3, 7.0 Hz, 2H), 4.00 - 3.91 (m, 2H), 3.77(dd, 7 = 11.6, 3.5 Hz, 1H), 0.81 (s, 9H), - 0.01 (d, 7= 15.6 Hz, 6H).
Step 1C
To a mixture of lc (600 mg, 1.27 mmol) and 3,4-dihydro-2H-pyran (2.08mL, 22.8mmol) in dioxane (10 mL) was added p-toluenesulfonic acid (362.4mg, 1.90 mmol), and the mixture was kept at room temperature for 45 min. The excess of p-toluenesulfonic acid was neutralized with 1 M NaHCC , and the reaction mixture was concentrated in vacuo. The residue was partitioned between CH2CI2 and water; the organic layer was separated and concentrated in vacuo. The residue was chromatographed on a column of silica gel to give the title compound Id as a mixture of two diastereomers (587 mg, 83%): MS (ESI): m/z =558 [M+H]+.
Step ID
Id (840mg, 1.51mmol) was dissolved in TBAF (1M in THF, 8.5mL), and the solution was stirred at room temperature for 2.5h. The reaction mixture was quenched with aq. sat. NaHC03, extracted with CH2CI2, concentrated and purified by column chromatography to give the title product le as a mixture of two diastereomers as off-white solids (580mg, 87%). MS (ESI): m/z =444 [M+H]+. ¾ NMR (500 MHz, DMSO-^6) δ 8.51 (s, 2H), 8.42 (d, 7 = 5.7 Hz, 2H), 8.22 (s, 2H), 7.36 - 7.25 (m, 8H), 7.20 (t, 7= 7.2 Hz, 2H), 6.28 (m, 2H), 5.67 (d, 7 = 50 Hz, 1H), 5.46 (d, 7= 55 Hz, 1H), 5.31 (dt, 7= 16.6, 5.6 Hz, 2H), 4.84 - 4.79 (m, 2H), 4.70 (s, 2H), 4.68 - 4.49 (m, 4H), 4.17 - 4.08 (m, 2H), 3.83-3.77 (m, 4H), 3.63-3.60 (m, 2H), 3.53 - 3.38 (m, 2H), 1.77 - 1.63 (m, 4H), 1.61 - 1.45 (m, 8H). Step IE
To the mixture of le (49.5mg, O. l lmmol) in pyridine (1.5mL) was added mesyl chloride (O.OlmL, 0.14mmol). After 30min stirring at room temperature, the reaction was quenched with EtOH (1.5mL), and concentrated in vacuo. The resulted residue was subject to chromatography to give the title product If (20.3mg, 35%). MS (ESI): m/z =522 [M+H]+.
Step IF
If (20.3 mg, 0.04 mmol) was added in one portion to a solution of tris(tetrabutyl ammonium) methyl enebis(phosphonate) prepared according to the literature procedure (Pankiewicz, K.W., et al., J. Med. Chem. 2002 45: 703-712) (54mg, 0.06 mmol) in DMSO (l .OmL). The mixture was kept at room temperature for 2 h, diluted with water (2.0mL), and purified by reverse-phased HPLC to give the title product lg (5 mg, 21%). MS (ESI): m/z =602 [M+H]+. ¾ NMR (500 MHz, Deuterium Oxide) δ 8.55 (s, 1H), 8.32 (s, 1H), 7.44 - 7.34 (m, 6H), 6.51 - 6.42 (m, 1H), 5.48 (d, J = 54.4 Hz, 1H), 4.85 (d, J = 7.5 Hz, 2H), 4.40-4.20 (m, 3H), 3.97-3.94 (m, 2H), 3.62 - 3.53 (m, 1H), 2.20 (t, J = 18.6 Hz, 2H), 1.80 (d, J = 9.5 Hz, 2H), 1.59 - 1.37 (m, 4H); 31P MR (203 MHz, Deuterium Oxide) δ 18.2, 15.1; 19F NMR (282 MHz, Deuterium Oxide) δ-204.3.
Step 1G
A mixture of lg (4.2mg, 0.007mmol), Dowex50WX8/H+ resin (5mg), and water (ImL) was stirred at room temperature for 2h. The mixture was then neutralized by 50mM NH4CO3 and concentrated in high vacuo before reverse-phased HPLC purification to give the title product 1 as white solids (1.6mg, 44.2%): MS (ESI): m/z =518 [M+H]+; ¾ NMR (500 MHz, Deuterium Oxide) δ 8.47 (s, 1H), 8.23 (s, 1H), 7.53 - 7.35 (m, 5H), 7.34 (d, J= 7.2Hz, 1H), 6.42 (d, J = 17.0 Hz, 1H), 5.41 (d, J= 55.2 Hz, 1H), 5.05-4.75 (m, 3H), 4.37 (d, J = 7.3 Hz, 1H), 4.30 (s, 2H), 2.33- 1.94 (m, 2H); 31P NMR (203 MHz, Deuterium Oxide) δ 21.2, 12.3.
Exam le 2
Figure imgf000025_0001
Step 2A
To a solution of Id from Example 1 (267mg,0.48mmol) and DMAP (6mg, 0.048mmol) in THF (5mL) under argon was added Boc20 (630mg, 2.89mmol). After 12 h stirring at room temperature, the reaction mixture was concentrated in vacuo. The residue was diluted with ethyl acetate (300ml), washed with HCl (IN aq. solution, 5ml) and aq. saturated NaCl (6ml) in sequence, dried over anhy.Na2S04. After filtration and removal of the solvents in vacuo, the residues was purified by column chromatography to afford the title product 2a as white solids (208mg, 66%): MS (ESI): m/z =658 [M+H]+.
Step 2B
2a (237.6mg, 0.36mmol) was dissolved in a solution of TBAF in THF (1M, 2mL), and the solution was further stirred at room temperature for 2.5h. The reaction mixture was then quenched with aq. sat. NaHC03, extracted with CH2C12 (3x1 OmL), concentrated in vacuo, and purified by column chromatography to give the title product 2b (157mg, 80%): MS (ESI): m/z =544 [M+H]+; ¾ NMR (500 MHz, DMSO-^6) δ 8.80 - 8.73 (m, 2H), 7.33 - 7.19 (m, 5H), 6.39 (dd, J = 17.4, 6.3 Hz, 1H), 5.67 (d, J = 50 Hz, 1H), 5.16 (s, 2H), 4.84 - 4.79 (m, 1H), 4.61 (m, 1H), 4.19 - 4.09 (m, 2H), 3.82-3.78 (m, 2H), 3.68 - 3.57 (m, 1H), 3.48 (td, J= 11.8, 6.2 Hz, 1H), 1.77 - 1.48 (m, 6H), 1.35 (s, 9H). Step 2C
Ethyl 2-diazo-2-(diethoxyphosphoryl) acetate prepared according to the literature procedure (Takaharu, H. et al., Bioorganic and Medicinal Chemistry 2013 21(17): 5488 - 5502) (26.4mg, O. l lmmol) and Rh2(OAc)4 (6.6mg, 0.015mmol) were added to a solution of 2b (41mg, 0.075mmol) in toluene (2mL). After 48h stirring at 100-110 °C under Ar, the reaction mixture was cooled to room temperature, concentrated in vacuo. The residue was purified by column chromatography to give the title product 2c as a mixture of isomers of reddish oil (32.9mg, 57%): MS (ESI): m/z =766 [M+H]+.
Step 2D
To a solution of 2c (30mg, 0.039mmol) in CH2C12 (3mL) was added trifluoroacetic acid (ImL, 13mmol) at 0 °C. After 3h stirring at room temperature, the reaction mixture was neutralized with aq. sat. Na2C03, concentrated in vacuo, and purified by column chromatography to give the title product 2d (20mg, 88%): MS (ESI): m/z =582 [M+H]+.
Step 2E
To a solution of ethyl 2d (19.5mg, 0.033mmol) in CH2C12 (ImL) was added TMSBr (0.07mL, 0.53mmol) at room temperature. After 24 h stirring at room temperature, the volatile solvents were evaporated and a solution of ethanokwater (v:v=l : l, ImL) was added to the residue. After 30min further stirring, the solvents were evaporated and the residue was subject to reverse-phased HPLC to give the title product 2 as a pair of diastereoisomers with 1 : 1 ratio as white solids (6.8mg, 39%): MS(ESI) m/z =526 [M+H]+; ¾ NMR (500 MHz, Deuterium Oxide) δ 8.67 (s, 1H), 8.50 (s, 1H), 8.22 (s, 2H), 7.39 (d, J = 8.4 Hz, 10H), 7.33 (d, J = 6.9 Hz, 2H), 6.40 (d, J = 16.7 Hz, 2H), 5.54 (d, J = 14.0 Hz, 1H), 5.44 (d, J =13.9 Hz, 1H), 4.37 (s, 2H), 4.15 (m, 6H), 4.02 - 3.85 (m, 4H), 3.80 (m, 2H), 1.14 (m, 6H); 31P NMR (203 MHz, Deuterium Oxide) δ 7.80, 7.78. Example 3
Figure imgf000027_0001
Step 3 A
A mixture of 3a (lOOmg, 0.37mmol),benzylamine (0.04mL, 0.37mmol), Et3N (0.05mL, 0.37mmol) in ethanol (5mL) was stirred at 60 °C for 18 h. The reaction mixture was concentrated in vacuo and the white solid residues were purified by column chromatography to give the title product 3b as white foams (112mg, 89%): MS (ESI): m/z =342 [M+H]+; ¾ NMR (500 MHz, DMSO-^6) δ 8.45 (s, 1H), 8.36 (s, 1H), 8.19 (s, 1H), 7.30 (dt, J = 15.0, 7.5Hz, 4H), 7.20 (t, J = 7.1 Hz, 1H), 6.40 - 6.30 (m, 1H), 5.31 (d, J = 3.9 Hz, 1H), 5.22 (t, J = 5.3 Ηζ,ΙΗ), 4.70 (s, 2H), 4.40 (s, 1H), 3.92 - 3.84 (m, 1H), 3.61 (dt, J = 8.8, 4.2 Hz, 1H), 3.51 (dt, 7=11.5, 5.5 Hz, 1H), 2.73 (dt, 7= 12.7, 6.2 Hz, 1H), 2.30 - 2.21 (m, 1H).
Step 3B
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. The residue was purified by column chromatography to give the title product 3c as pale yellow oil (147mg, 55%): MS (ESI): m/z =456 [M+H]+; ¾ NMR (500 MHz, DMSO-i/6) δ 8.41 (s, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 7.35 - 7.24 (m, 4H), 7.23 - 7.16 (m, 1H), 6.35 (t, 7 = 6.6 Hz, 1H), 5.35 (d, J= 4.2 Hz, 1H), 4.69 (s, 2H), 4.42 (dq, 7 =7.8, 4.1 Hz, 1H), 3.87 (q, 7 = 4.3 Hz, 1H), 3.81 (dd, 7 = 11.1, 4.6 Hz, 1H), 3.69 (dd, 7= 11.1, 4.7Hz, 1H), 2.75 (dt, 7= 13.0, 6.4 Hz, 1H), 2.31 (ddd, 7= 13.2, 6.5, 3.9 Hz, 1H), 0.84 (s, 9H), 0.01 (s, 6H).
Step 3C
Benzoyl chloride (0.66ml, 5.58mmol) was added dropwise to an ice-cold solution of
3c (457mg, lmmol), triethylamine (0.78mL, 5.58mmol) and dimethylaminopyridine (68mg, 0.56mmol) in dichloromethane (15 mL). The resulting mixture was stirred at room temperature overnight, followed by addition of aq. sat. NaHCCb (30 mL). The organic and aqueous layers were then separated and the aqueous phase was further extracted twice with dichloromethane (2 x 20mL). The combined organic layers were dried over anhy. magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography to give the title product 3d as white solids (603mg, 91%): MS (ESI): m/z =664 [M+H]+; ¾ NMR (500 MHz, DMSO-^6) δ 8.61 (d, 7 = 15.3 Hz, 2H), 8.06 - 8.00 (m, 2H), 7.73 - 7.66 (m,lH), 7.56 (t, 7 = 7.8 Hz, 2H), 7.45 - 7.30 (m, 5H), 7.22 (ddt, 7 = 21.4, 14.7, 7.4 Hz, 5H), 6.49 (dd, 7 = 7.8, 6.3 Hz, 1H), 5.61 (dt, 7 = 6.4, 2.5 Hz, 1H), 5.52 (s, 2H), 4.27 (td, 7= 4.8, 2.4 Hz, 1H), 3.89 - 3.77 (m, 2H), 3.16-3.10 (m, 1H), 2.71 (ddd, 7= 14.2, 6.3, 2.5 Hz, 1H), 0.78 (s, 9H), -0.07 (d, 7= 1.9 Hz, 6H).
Step 3D
To a stirred solution of 3d (262mg, 0.39mmol) in THF (lOmL), was added aqueous trifluoroacetic acid (0.6mL, TFA/H20, 1 : 1) at 0 °C. After stirring at room temperature for 3 h, the reaction mixture was neutralized with saturated aqueous NaHCC (lOmL) and diluted with ethyl acetate (15mL). After separation, the organic phase was washed with water (2x20mL), dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified by column chromatography to give the title product 3e as white solids (193mg, 90%): MS (ESI): m/z =550 [M+H]+; ¾ NMR (500 MHz, DMSO-^6) δ 8.72 (s, 1H), 8.60 (s, 1H), 8.07 - 8.01 (m, 2H), 7.75 - 7.66 (m, lH), 7.56 (t, 7= 7.8 Hz, 2H), 7.44 - 7.31 (m, 5H), 7.30 - 7.15 (m, 5H), 6.51 (dd, 7 = 8.5, 5.9 Ηζ, ΙΗ), 5.60 (dt, 7 = 6.1, 1.8 Hz, 1H), 5.52 (s, 2H), 5.18 (brs, 1H), 4.25 (td, 7 = 4.4, 1.9 Hz, 1H), 3.71 - 3.61 (m, 2H), 3.05 (ddd, 7= 14.4, 8.7, 6.1 Hz, 1H), 2.67 (ddd, 7= 14.1, 5.9, 1.8 Ηζ, ΙΗ). Step 3E
Diethyl 2-diazomalonate (24mg, 0.13mmol) and Rh2(OAc)4 (9mg, 0.02mmol) were added to a solution of 3e (54mg, 0. lmmol) in toluene (1.5mL). The reaction mixture was stirred at 100 °C for 1.5h under Ar. The reaction was cooled to room temperature, concentrated in vacuo, and the residue was purified by column chromatography to give the title compound 3f as colorless solids (29.3mg, 41%): MS (ESI): m/z =708 [M+H]+; ¾ NMR (500 MHz, DMSO-^6) δ 8.77 (s, 1H), 8.58 (s, 1H), 8.08 - 8.02 (m, 2H), 7.74 - 7.67 (m,lH), 7.57 (t, J = 7.8 Hz, 2H), 7.43 - 7.32 (m, 5H), 7.30 - 7.15 (m, 5H), 6.58 (dd, J = 8.6, 6.0 Ηζ, ΙΗ), 5.68 (dt, J = 6.0, 1.7 Hz, 1H), 5.53 (s, 2H), 4.92 (s, 1H), 4.46 (td, J = 3.6, 1.6 Hz, 1H), 4.26 -4.10 (m, 4H), 3.92 - 3.79 (m, 2H), 3.00 (ddd, J= 14.2, 8.7, 5.9 Hz, 1H), 2.74 (ddd, J= 14.1, 6.0, 1.7 Hz, 1H), 1.17 (td, J= 7.1, 4.4 Hz, 6H).
Step 3F
To a solution of 3f (13mg, 0.018mmol) in MeOH (1.5mL) was added 7N NH3 in MeOH (0.2mL) at 0 °C. After 18 h stirring at room temperature, the reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography to give the title product 3 (3mg, 38%): MS (ESI): m/z =442 [M+H]+; ¾ NMR (500 MHz, Methanol-i/4) δ 8.31 (s, 1H), 8.26 (s, 1H), 7.38 (d, J= 7.2 Hz, 2H), 7.31 (t, J = 6.9 Hz, 2H), 7.25 (d, J= 7.0 Hz, 1H), 6.44 (t,J = 6.3 Hz, 1H), 4.81 (s, 2H), 4.69 (s, 1H), 4.16 (s, 1H), 3.85 (s, 3H), 3.03 - 2.90 (m, 1H), 2.53 - 2.40 (m, 1H).
Example 4
Figure imgf000029_0001
To a solution of 3f (13mg, 0.018mmol) in EtOH (lmL) at room temperature was added NaOEt (21% in EtOH, O. lmL). After 1.5h stirring at room temperature, the reaction mixture was quenched with IN HCl to pH=7. After removal of solvents in vacuo, the residue was purified by HPLC to give the title product 4 (5mg, 63%): MS (ESI): m/z =444 [M+H]+; ¾ NMR (500 MHz, Methanol-i/4) δ 8.48 (s, 1H), 8.26 (s, 1H), 7.38 (d, J = 7.4 Hz, 2H), 7.31 (t, J= 7.5 Hz, 2H), 7.24 (t, J= 7.3 Hz, 1H), 6.46 (t, J= 5.5 Hz, 1H), 4.80 (s, 2H), 4.63 (s, 1H), 4.17 (m, 2H), 3.70 (m, 2H), 2.84 (d, J= 14.8 Hz, 1H), 2.47 (d, J= 6.8 Hz, 1H). xample 5
Figure imgf000030_0001
Step 5A
A mixture of 5a (lOOmg, 0.35 mmol), benzylamine (0.04ml, 0.35mmol), Et3N (0.05ml, 0.35mmol) in ethanol (5mL) was stirred at 60 °C for 18 h. After cooled to room temperature, the reaction mixture was concentrated in vacuo and the residue was purified by column chromatography to give the title product 5b as white solids (100.5mg, 80%): MS (ESI): m/z =358 [M+H]+; ¾ MR (500 MHz, DMSO-^6) δ 8.49 (s, 1H), 8.38 (s, 1H), 8.20 (s, 1H), 7.33-7.27 (m, 4H), 7.22-7.19 (m, 1H), 5.88 (d, J = 6.2 Hz, 1H), 5.46 (d, J = 6.1 Hz, 1H), 5.41-5.38 (m, 1H), 5.20 (d, J = 6.2 Hz, 1H), 4.70 (s, 2H), 4.63-4.60 (m, 1H), 4.14 (d, J =3.0 Hz, 1H), 3.96 (d, J= 3.0 Hz, 1H), 3.67 (d, J= 12.1 Hz, 1H), 3.54 (ddd, J= 11.7, 7.2, 3.5
Step 5B
A mixture of 5b (2.8g, 7.8mmol), 2,2-dimethoxypropane (lOmL, 81.8mmol), and p- toluenesulfonic acid monohydrate (1.86g, 9.8mmol) in acetone (78mL) was stirred at room temperature for 16 h. Then, sodium bicarbonate (2.6g, 31.4mmol) and water (50mL) were added, and the reaction mixture was stirred for 2h. The reaction mixture was extracted with ethyl acetate (3xl00mL). The combined organic layers were dried over anhy. sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography to give 5c as white solids (2. lg, 67%): MS (ESI): m/z =398 [M+H]+.
Step 5C
To a solution of 5c (lOOmg, 0.25mmol) and ethyl 2-diazo-2-(diethoxyphosphoryl) acetate (lOOmg, 0.40mmol) in toluene (3mL) was added iH Acb (4.4mg, O.Ol mmol). The rnixiure was degassed, and then heated at 170 C for 20min with microwave under nitrogen. The reaction mixture was concentrated in vacuo and the residue was purified by reverse- phased HPLC to afford 5d as brown solids (26mg, 18%): MS (ESI): m/z =580 [M+H]+.
Step 5D
To a solution of 5d (26mg,0.045mmol) in CH3CN (3mL) was added TMSBr
(0.05mL), The reaction mixture was stirred at 0 °C for 14h, concentrated in vacuo, and purified by reverse-phased HPLC to afford 5 as white solids (0.8mg, 3%): MS (ESI): m/z =524 [M+H]+. Example 6
Figure imgf000031_0001
The purification of 5 by reverse-phased HPLC also afforded 6 as white solids (0.5mg, 2%): MS (ESI): m/z =552 [M+H]+. Exam le 7
Figure imgf000031_0002
Step 7 A
To a solution of 5c (50mg, 0.125mmol) and diethyl 2-diazomalonate (50mg, 0.2mmol) in toluene (5ml) was added Rh2(OAc)4 (2.2mg,0.005rarnol). The mixture was degassed and then heated at 105 °C under nitrogen for 12h.The solvent was removed under reduced pressure, then the crude product was purified by reverse-phased HPLC to afford 7 a as brown solids (13mg, 18.5%): MS (ESI): m/z =556 [M+H]+.
Step 7B
To a solution of 7a (13mg, 0.025mmol) in CH2C12 (2mL) was added TFA (0.5mL) at 0 °C. After 3h stirring at room temperature for 3h, the reaction mixture was concentrated to afford 7b (13mg, 100%): MS (ESI): m/z =516 [M+H]+.
Step 7C
To a solution of 7b (13mg, 0.025mmol) in THF (2mL) was added aqueous NaOH (2N, 0.5mL) at 0 °C and stirred at room temperature for 12h. After removal of solvent, the aqueous phase was adjusted to pH=3 by IN aqueous HC1 and purified by reverse-phased HPLC to afford 7 as white solids (2.0mg, 20%): MS (ESI): m/z =458 [M-H]\
Example 8
Figure imgf000032_0001
Step 8A
To a solution of 7a (18.5mg, 0.033mmol) and DMAP (0.4mg, 0.003mmol) in THF (1.5mL) was added Boc20 (32mg, 0.15mmol) under argon, and then was stirred at room temperature for 12h. After concentration in vacuo, the residue was purified by column chromatography to afford 8a as white solids (13mg, 62%): MS (ESI): m/z =656 [M+H]+. Step 8B
To a solution of 8a (13mg, 0.019mmol) in DMF (3mL) was added Cs:>CCh (19 5mg, O.Oommol). The reaction mixture had been stirred at room temperature for 30min, before addition of benzyl bromide (6.8mg, 0,04mmol) at room temperature. The reaction mixture was heated and stirred at 60 °C for 12h. After removal of solvent, the residue was purified by column chromatography to afford 8b as yellow oil (3mg, 20%): MS (ESI): m/z =746 [M+H]+.
Step 8C
To a solution of 8b (3mg, 0.004mmol) in CH2C12 (1.5mL) was added TFA (0.1 mL) at 0 °C. After 3h stirring at room temperature, the reaction mixture was concentrated in vacuo to afford 8c (2.4mg, 100%): MS (ESI): m/z =606 [M+H]+.
Step 8D
Follow the same procedure as the step 7C in the example 7 to afford 8 as white solids (2mg, 31%): MS (ESI): m/z =548 [M-H]\
Example 9
Figure imgf000033_0001
Step 9A
A mixture of 5a (2g, 6.98 mmol), benzhydrylamine (1.28g, 6.98mmol), Et3N (lml, 6.98mmol) in ethanol (50mL) was stirred at 60 °C for 18 h. After cooled to room temperature, the reaction mixture was concentrated in vacuo and the residue was purified by column chromatography to give the title product 9a as white solids (750mg, 25%): MS (ESI): m/z =434 [M+H]+.
Step 9B
A mixture of 9a (750mg, 1.73mmol), 2,2-dimethoxypropane (2.2mL, 18.2mmol), and /?-toluenesulfonic acid monohydrate (410mg, 2.2mmol) in acetone (18mL) was stirred at room temperature for 16 h. Then, sodium bicarbonate (580mg) and water (1 lmL) were added, and the reaction mixture was stirred for 2h. The reaction mixture was extracted with ethyl acetate (3x20mL). The combined organic layers were dried over anhy. sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography to give 9b as white solids (760mg, 92.5%): MS (ESI): m/z =474 [M+H]+.
Step 9C
To a solution of 9b (50mg, O. l lmmol) and ethyl 2-diazo-2-(diethoxyphosphoryl) acetate (43.4mg, 0.17mmol) in toluene (3mL) was added RiWOAc (4.4mg, O.Olmmol). The mixture was degassed, and then heated at 170 °C for 20min with microwave under nitrogen. The reaction mixture was concentrated in vacuo and the residue was purified by reverse- phased HPLC to afford 9c (35mg, 47.4%): MS (ESI): m/z =696 [M+H]+.
Step 9D
To a solution of 9c (20mg, 0.03mmol) in CH2C12 (2mL) was added TFA (0.2mL) at 0°C, and the resulting mixture was stirred at 0°C overnight. The reaction mixture was concentrated in vacuo at 0°C to give 9d as red oil (18mg, 100%), which was used directly in the next step: MS (ESI): m/z =656 [M+H]+.
Step 9E
To a solution of 9d (18mg, 0.03mmol) in CH3CN (2mL) was added TMSBr (0.1 mL) dropwise at 0°C. After 16h stirring at 0°C, the reaction mixture was purified by reverse- phased HPLC to afford 9 as white solids (0.2mg, 1.2%): MS (ESI): m/z =600 [M+H]+. Experiment 10
Figure imgf000035_0001
Step 10A
To a solution of 5c (159mg, 0.4 mmol) in THF (5mL) was added phthalimide
(60.5mg, 0.4 mmol) and triphenylphosphine (105mg, 0.4 mmol). After 10 min stirring at room temperature, DEAD (70mg,1.7 mmol) was added to the mixture and the mixture was stirred overnight. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography to afford 10a as white solids (204mg, 97%): MS (ESI): m/z =527 [M+H]+.
Step 10B
To a solution of 10a (204mg, 0.39mmol) and DMAP (4.7mg, 0.039mmol) in THF (5mL) under argon was added Boc20 (511mg, 2.34mmol). The reaction was stirred at room temperature for 12h. After removal of the solvent in vacuo, the residue was diluted with ethyl acetate (50ml), washed with HC1(1N, 5mL) and saturated aqueous NaCl (6ml) in sequence, dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The residue was purified by column chromatography to afford 10b as white solids (161mg, 66%): MS (ESI): m/z =626 [M+H]+; ¾ NMR (500 MHz, DMSO-^6) δ 8.68 (s, 1H), 8.45 (s, 1H), 7.82-7.79 (m, 2H), 7.75-7.73 (m, 2H), 7.34 - 7.25 (m, 4H), 7.20 (t, J = 7.1 Hz, 1H), 6.30 (d, J = 1.8 Hz, 1H), 5.51 (dd, J = 6.2, 1.8 Hz, 1H), 5.20 (dd, J = 6.2, 3.7 Hz, 1H), 5.14 (s, 2H), 4.41 (td, J = 6.0, 3.8 Hz, 1H), 3.87 (d, J= 6.1 Hz, 2H), 1.43 (s, 6H), 1.37 (s, 9H).
Step IOC
To a solution of 10b (321mg, 0.51mmol) in EtOH (7mL) was added ethylenediamine
(0.17mL, 1.15mmol). After 6h stirring at 70 °C, the reaction mixture was concentrated and the residue was purified by column chromatography to afford 10c as colorless oil (214mg, 84%): MS (ESI): m/z =497 [M+H]+; 1H NMR (500 MHz, DMSO-^6) δ 8.79 (s, 1H), 8.75 (s, 1H), 7.35 - 7.23 (m, 4H), 7.22 - 7.15 (m,lH), 6.19 (d, J = 3.0 Hz, 1H), 5.47 (dd, J = 6.2, 3.0 Hz, 1H), 5.16 (s, 2H), 4.99 (dd, J = 6.3, 2.7Hz, 1H), 4.12 (qd, J = 7.8, 6.8, 3.9 Hz, 2H), 3.17 (d, J= 4.9 Hz, 1H), 2.68 (dd, J= 5.9, 1.4 Hz, 2H), 1.54 (s, 3H), 1.35 (s, 9H), 1.33 (s, 3H).
Step 10D
To a solution of lOd (1.23mL, 6.67mmol) in CH3OH (12mL) was slowly added aqueous NaOH solution (2N, 3mL) at 0 °C. The resulting mixture was stirred at room temperature for 24h and then concentrated in vacuo. The residue was diluted with water (15mL), washed with diethyl ether (15mL), acidified with HC1 (2N, 4mL), and extracted with CH2C12 (2x15mL). The combined organic layers were further washed with water (15mL), saturated brine (15mL), dried with anhydrous Na2S04, filtered, and concentrated to afford lOe (392mg, 28.8%): MS (ESI): m/z =205 [M+H]+. Step 10E
To a solution of 10c (102mg, 0.205mmol), lOe (51mg, 0.246mmol) in CH2C12 (2mL) was added EDCI (51mg, 0.267mmol), HOBt (36mg, 0.267mmol), and DMAP (38mg, 0.308mmol) in sequence at room temperature. After 16h stirring at room temperature, the reaction mixture was concentrated and the residue was purified by column chromatography to afford lOf as colorless oil (136.9mg, 97.6%): MS (ESI): m/z =683 [M+H]+.
Step 10F To a solution of lOf (66.6mg, 0.098mmol) in CH2C12 (2mL) was added TFA (0.2mL) dropwise at 0°C and the reaction mixture was stirred at 0°C for 48h. The major component in the mixture was the methyl ester of TM. The mixture was concentrated at 0°C and the residue was purified by reverse-phased HPLC to afford 10 as white solids (2mg, 8.2%): MS (ESI): m/z =489 [M+H]+.
Exam le 11
Figure imgf000037_0001
Step 11A
To a mixture of lOf (67.6mg, 0.099mmol), hydroxylamine HC1 salt (34.4mg,
0.495mmol) in methanol (2mL) was added Hunig's base (64.0mg, 0.495mmol) at room temperature. After 12h stirring at room temperature, the reaction mixture concentrated and purified by reverse-phased HPLC to afford 11a as white solids (10.7mg, 15.8%): MS (ESI): m/z =684 [M+H]+; 1HNMR (500 MHz, DMSO-^) δ 10.89 (s, 1H), 9.08 (s, 1H), 8.76 (s, 1H), 8.73 (s, 1H), 8.23 (t, J = 6.0 Hz, 1H), 7.32 (d, J = 7.3 Hz, 2H), 7.29 - 7.23 (m, 2H), 7.22 - 7.15 (m, 1H), 6.25 (d, J = 2.7 Hz, 1H), 5.48 (dd, J = 6.4, 2.7 Hz, 1H), 5.16 (s, 2H), 4.98 (dd, J = 6.4, 3.4 Hz, 1H), 4.56 (d, J = 6.4 Hz, 1H), 4.40 - 4.18 (m, 2H), 3.46 - 3.26 (m , 2H), 1.53 (s, 3H), 1.38 (s, 3H), 1.35 (s, 9H), 1.31 (d, J = 2.2 Hz, 6H). Step 1 IB
To a solution of 11a (23mg, 33.6μιηο1) in CH2C12 (2mL) was added TFA (0.2mL) at 0°C and the reaction mixture was stirred at 0°C for 72h. The mixture was concentrated and the residue was purified by reverse-phased HPLC to afford 11 as white solids (4.6mg, 27.2%): MS (ESI): m/z =504 [M+H]+.
Example 12
Figure imgf000038_0001
Step 12A
To a solution of 10c (250mg, 0.503mmol) and 3-methoxy-3-oxopropanoic acid (72mg,
0.604mmol) in CH2C12 (3mL) was added EDCI (125mg, 0.654mmol), HOBt (89mg, 0.654mmol) and DMAP (93mg, 0.755mmol) in sequence. After 12h stirring at room temperature, the reaction mixture concentrated and purified by column chromatography to afford 12a as white solids (171.8mg, 57.3%): MS (ESI): m/z =597 [M+H]+. Step 12B
To a solution of 12a (46mg, 0.077mmol) in CH2C12 (2mL) was added TFA (0.15mL) at 0 °C. After 16h stirring at 0 °C, the reaction mixture was concentrated at 0 °C, and purified by reverse-phased HPLC to afford 12b as white solids (6mg, 34%): MS (ESI): m/z =457 [M+H]+. Step 12C
To a solution of 12b (20mg, 0.044mmol) in CH3OH (2mL) and THF (lmL) was added NaOH (2N, lmL) at room temperature. After 16h stirring at room temperature, the reaction mixture was concentrated. The residue was acidified to pH=3 with HCl (2N) before purification by reverse-phased HPLC to afford 12 as white solids (8mg, 41.3%): MS (ESI): m/z =443 [M+H]+.
Exam le 13
Figure imgf000039_0001
Step 13 A
To a solution of 12a (20mg, 0.034mmol) and hydroxylamine HCl salt (11.6mg, 0.17mmol) in CH3OH (2mL) was added Hunig's base (22mg, 0.17mmol) at room temperature. The resulting solution was stirred at room temperature for 48h before purification with reverse-phased HPLC to afford 13a as white solids (9.2mg, 46.0%): MS (ESI): m/z =598 [M+H]+.
Step 13B
To a stirred solution of 13a (7.9mg, 0.013mmol) in CH2CI2 (lmL) was added TFA
(O. lmL) dropwise at 0°C and the reaction mixture was stirred at 0°C for 16hs. The mixture was concentrated and the residue was purified by reverse-phased HPLC to afford 13 as white solids (1.3mg, 21.5%): MS (ESI): m/z =458 [M+H]+. Examples 14 to 20 (Table 1) were prepared from 10c and corresponding acid based on the similar conditions described in steps 12A-12C of example 12.
Table 1. Compounds of formula:
Figure imgf000039_0002
Figure imgf000040_0001
Example 21
Figure imgf000041_0001
Step 21 A
To a solution of 10c (91.6mg, 0.18mmol), monomethyl glutarate (27mg, 0.18mmol), and HOBt (29.2mg, 0.22mmol) in DMF (lmL) were added EDCI (41.4mg, 0.22mmol) and N, N- diisopropylethylamine (0.08ml, 0.45mmol) in sequence. After 24h stirring at room temperature, the reaction mixture was concentrated in vacuo and the residue was purified by column chromatography to afford 21a (78mg, 70%): MS (ESI): m/z =625 [M+H]+. Step 2 IB
To a solution of 21a (65mg, O. lmmol) in THF (1.5mL) was added an aqueous solution of LiOH (IM, 1.5mL). The reaction mixture was stirred at room temperature for 16hs, adjusted pH=7 with HCl (IN), concentrated to get rid of THF in vacuo, extracted with ethyl acetate (3x1 OmL), dried over anhydrous Na2S04, filtered, concentrated, and the residue was purified by column chromatography to give 21b (15.7mg, 37%): MS (ESI): m/z =611 [M+H]+.
Step 21C
To a solution of 21b (15.7mg, 0.026mmol), dimethyl L-aspartate hydrochloride (5.1mg, 0.026mmol), and HOBt (4.2mg, 0.031mmol) in DMF (lmL) were added EDCI (6mg, 0.031mmol) and N, N- diisopropylethylamine (0.01ml, 0.065mmol) in sequence. After 24h stirring at room temperature, the reaction mixture was concentrated in vacuo and the residue was purified by column chromatography to afford 21c (l l . lmg, 57%): MS (ESI): m/z =754 [M+H]+.
Step 2 ID
To a stirred solution of 21c (l l . lmg, 0.015mmol) in CH2CI2 (lmL) was added TFA
(O. lmL) dropwise at 0°C and the reaction mixture was stirred at 0°C for 16hs. The mixture was concentrated and the residue was purified by reverse-phased HPLC to afford 22 as white solids (1.5mg, 16.3%): MS (ESI): m/z =614 [M+H]+. Example 22
Figure imgf000042_0001
Example 22 was prepared from 10c and methyl hydrogen succinate based on the same conditions described in steps 21A-21D of example 21 : MS (ESI): m/z =600 [M+H]+.
Example 23
Figure imgf000042_0002
Step 23 A
A mixture of 10c (72.3mg, 0.15mmol), methyl 6-formylpicolinate (148mg, 0.9mmol) in methanol (2.24 mL containing magnesium methylate 0.146g, 1.69 mmol) was stirred at 55 °C for 3 hs before cooled down to room temperature. Then sodium borohydride (45mg, 1.2 mmol)was slowly added to the mixture and the reduction reaction was continued to stir at room temperature for 30 min. The reaction mixture was adjusted to pH=7 with HC1 and concentrated in vacuo. The residue was purified by column chromatography to afford 23a get a mixture of methyl ester and acid of the product (52mg, 54%): MS (ESI): m/z =646 [M+H]+.
Step 23B
To a solution of 23a (52mg, 0.08mmol) in THF (l .OmL) was added aqueous solution
LiOH (1M, ImL). After 6h stirring at room temperature, the reaction mixture was adjusted pH =7 with HC1 (IN), concentrated in vacuo to remove THF, extracted with ethyl acetate (3x5mL). The combined organic layers were dried over anhydrous Na2S04, filtered, and the residue was purified by column chromatography to afford 23b (20mg, 40%) : MS (ESI): m/z =632 [M+H]+.
Step 23 C
To a stirred solution of 23b (15mg, 0.024mmol) in CH2C12 (ImL) was added TFA (O. lmL) dropwise at 0°C and the reaction mixture was stirred at 0°C for 16hs. The mixture was concentrated and the residue was purified by reverse-phased HPLC to afford 23 (2mg, 17%): MS (ESI): m/z =492 [M+H]+.
Example 24
Figure imgf000044_0001
Figure imgf000044_0002
Step 24A
To a slurry of 24a (2.0g, 12.9mmol) in CH3OH (50mL) was added thionyl chloride (3mL) dropwise at 0°C. The resulting mixture was stirred at 60°C for 16hs, cooled to room temperature, concentrated in vacuo to afford 24b as yellow solids (3.26g, 100%): MS (ESI): m/z =170 [M+H]+.
Step 24B
To a solution of 12a (26.6mg, 0.446mmol) in CH3OH (2mL) and THF (ImL) was added NaOH (2N, ImL) at 0°C. After 2.5h stirring at 0°C, the reaction mixture was concentrated at 0°C, diluted with water (5mL), washed with ethyl ether (5mL), and acidified to pH=3 with 2N HC1. The resulting white slurry was extracted with ethyl acetate (2x5mL). The combined organic layers were washed with saturated brine (5mL), dried over anhydrous Na2S04 , then concentrated to afford 24c as white solids (23mg, 86%): MS (ESI): m/z =583 [M+H]+; 1HNMR (500 MHz, DMSO-d6) 512.48 (s, 1H), 8.77 (s, 1H), 8.73 (s, 1H), 8.28 (t, J = 5.9 Hz, 1H), 7.36 - 7.30 (m, 2H), 7.29 - 7.24 (m, 2H), 7.22 - 7.14 (m, 1H), 6.24 (d, J = 2.9 Hz, 1H), 5.45 (dd, J = 6.3, 3.0 Hz, 1H), 5.17 (s, 2H), 4.94 (dd, J = 6.3, 3.3 Hz, 1H), 4.19 (td, J = 5.9, 3.3 Hz, 1H), 3.46 - 3.25 (m, 2H), 3.22 - 3.06 (m, 2H), 1.54 (s, 3H), 1.36 (s, 9H), 1.31 (s, 3H). Step 24C
A mixture of 24c (48mg, 0.082mmol), 17b (25mg, 0.12mmol), EDCI (24mg, 0.12mmol), HOBt (17mg, 0.12mmol), DMAP (30mg, 0.24mmol) in CH2C12 (2mL) was stirred at room temperature for 12hs. After concentration in vacuo, the reaction mixture was purified by flash chromatography to afford 24d as white solids (36mg, 60%): MS (ESI): m/z =734 [M+H]+.
Step 24D
To a solution of 24d (36mg, 0.049mmol) in CH2C12 (2mL) was added TFA (O. lmL) dropwise at 0°C. After 48h stirring at 0°C, the reaction mixture was concentrated to afford 24e (12mg, 41%) as white solids: MS (ESI): m/z =594 [M+H]+. Step 24E
To a solution of 24e (19.6mg, 0.033mmol) in CH3OH (2mL) and THF (ImL) was added aqueous NaOH (2N, ImL) dropwise at 0°C. The reaction mixture was stirred at 0°C for 2h, concentrated in vacuo, and acidified to pH=3 with aqueous HC1 (2N). The resulting slurry was diluted with DMF (ImL) and purified by reverse-phased HPLC to afford 24 as white solids (12.2mg, 63.8%): MS (ESI): m/z =580 [M+H]+.
Example 25
Figure imgf000045_0001
Example 25 (4.8mg, 25%), as white solids, was prepared from 24c (20mg, 0.034mmol) and (S)-methionine methyl ester based on the same conditions described in steps 24C-E of example 24: MS (ESI): m/z =574 [M+H]+. Example 26
Figure imgf000046_0001
HN'Bn
: 26
HO OH
Step 26 A
To a solution of LDA (2M in THF, 8.9mL, 17.8mmol) in THF (17mL) was added diisopropyl methylphosphonate 26a (lg, 5.55mmol) dropwise at -78°C under N2. The mixture had been stirred for 30 minutes at -78°C before the addition of diethyl (hydroxymethyl) phosphonate (1.12g, 6.66mmol). After 30min stirring at -78°C and 4h stirring at room temperature, the reaction mixture was quenched with AcOH (1.67g, 27.8mmol) and concentrated in vacuo. To the residue were added NaHC03 (2.33g) and ethyl acetate (50mL) and the mixture was extracted with water(3x50mL). The combined aqueous layers were saturated with NaCl and extracted with CH2CI2 (3x50mL). The combined organic layers were dried over anhydrous Na2S04, filtered, and concentrated in vacuo to afford 26b as yellow oil (1.47g, 87.6%): MS (ESI): m/z =303 [M+H]+.
Step 26B
To a solution of 26b (197mg, 0.65mmol) in CH2Cl2(2mL) was added Hunig's base (lOlmg, 0.78mmol) under N2 and a solution of 2-nitrobenzenesulfonyl chloride (159mg, 0.72mmol) in CH2CI2 (lmL) in sequence at 0°C. After 16h stirring at room temperature, the reaction mixture was purified by flash chromatography to give 26c as yellow oil (135mg, 42.6%): MS (ESI): m/z =488 [M+H]+.
Step 26C
To a solution of 26c (66.4mg, 0.136mmol) and 10c (135mg, 0.272mmol) in DMF (2mL) was added Hunig's base (70.3mg, 0.544mmol) under N2. The reaction mixture was stirred at 80°C for 6h, cooled to room temperature, poured into water (lOmL), and extracted with ethyl acetate (3x1 OmL). The organic layers were combined, washed with water (2x1 OmL), dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to give 26d as white foams (73mg, 68.7%): MS (ESI): m/z =781 [M+H]+.
Step 26D
To a solution of 26d (36.3mg, 46.5μιηο1) in CH2CI2 (2mL) was added TFA (0.15mL) dropwise at 0°C. The mixture was stirred at 0°C over 4 days. The mixture was concentrated in vacuo to afford 26e without further purification for next step: MS (ESI): m/z =641 [M+H]+.
Step 26E
To a stirred solution of 26e (14.8mg, 0.023mmol) in CH3CN (2mL) was added TMSI (0.2mL) dropwise at 0°C for 48hs. The reaction mixture was quenched with 2mL of saturated aqueous NaHCC (2mL) and purified by reverse-phased HPLC to give 26 as white solids (3.1mg, 25.3%): MS (ESI): m/z =529 [M+H]+.
Example 27
Step 27A
To a mixture of 26d (36.7mg, 0.047mmol), K2C03 (20mg, 0.141mmol) in DMF (lmL) was added iodomethane (20mg, 0.141mmol). After 6h stirring at room temperature, the reaction mixture was filtered and the filtrate was purified by reverse-phased HPLC to give 27a as white solids (1 lmg, 29.4%): MS (ESI): m/z =795 [M+H]+.
Step 27B
To a solution of 27a (l lmg, 0.014mmol) in CH2C12 (2mL) was added TFA (0.15mL) dropwise at 0°C . The reaction mixture was stirred at 0°C for 48h. The reaction mixture was concentrated to give 27b (9.7mg, 100%): MS (ESI): m/z =695 [M+H]+. Step 27C
To a solution of 27b (9.7mg, 0.014mol) in CH3CN (2mL) was added TMSI (O. lmL) dropwise at 0°C. After 16hs stirring at 0°C, the reaction mixture was quenched with aqueous saturated NaHC03 (2mL) and purified by reverse-phased HPLC to give 27 as white solids (1.4mg, 17.4%): MS (ESI): m/z =583 [M+H]+.
Example 28
Figure imgf000048_0001
28
28 was prepared according to the similar method to prepare 26: ¾ NMR (500 MHz, Methanol-^) δ 8.09 (s, 1H), 7.29 (d, J= 8.0 Hz, 2H), 7.20 (q, J= 9.5, 7.7 Hz, 2H), 7.12 (m, 1H), 6.12 (d, J= 11.2 Hz, 1H), 5.38 (m, 2H), 4.44 - 4.38 (m, 2H), 4.19 (q, 1H), 3.39 (d, J = 12.5 Ηζ, ΙΗ), 3.24 (m, 1H), 3.03 - 2.94 (m, 2H), 2.09 (m, 1H), 1.48 (d, J= 8.8 Hz, 3H). 31P NMR (500 MHz, Methanol-^) δ 24.51 (s), 19.40 (s). MS (ESI): m/z =577 [M+H]+.
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 μΐ 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 μΐ of CMP dissolved in assay buffer was added to each reaction. Final CMP concentration was 45 μΜ. The plate was then incubated at 37°C for 15 min. 3 μΐ 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 NaHC03, lmg/ml glucose), then incubated with compounds at various concentrations in 200 μΐ assay buffer with 50 μΜ CMP at 37°C for 4h. Final DMSO concentration was adjusted to 0.1%. After incubation, 100 μΐ of supernatant from each well was transferred to new clear flat-bottom 96-well plates. 20 μΐ 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.
The results of assays 1 and 2 are shown in Table 2 (+ means >1000nM, ++ means ΙΟΟηΜ to ΙΟΟΟηΜ, +++ means <100nM).
Table 2. Summary of results of assays 1 and 2.
Figure imgf000049_0001
Example No. Assay 1 Assay 2
6 + +
7 + +
8 + +
9 ++ +
10 + +
11 ++ +
12 + +
13 ++ +
14 + +
15 + +
16 + +
17 + +
18 + +
19 + +
20 + +
21 + +
22 + +
23 + +
24 + +
25 + +
26 +++ ++
27 + +
28 +++ +++
The foregoing preferred embodiments and examples are provided for illustration only and are not intended to limit the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art based on the present disclosure, and such changes and modifications, including, without limitation, those relating to the chemical structures, substituents, derivatives, formulations and/or methods of preparation, may be made without departure from the spirit and scope of the present invention.

Claims

What is claimed is:
1. A compound of formula (I):
Figure imgf000051_0001
or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:
A is O, S, CH2, Se, NH, N-alkyl, CHW, or C(W)2, wherein W is F, CI, Br, or I;
Ri is H, OH, F, CI, Br, I, ORio, NH2, or N3;
R2 is H, Ci-4 alkyl, CH2F, CHF2, CF3, F, or CN;
R3 and R3' are each independently H, OH, C 14 alkyl, C2-4 alkenyl, C2-4 alkynyl , vinyl, N3, CN, CI, Br, F, I, N02, OC(0)0(Ci-4 alkyl), OC(0)0(C2-4 alkynyl), OC(0)0(C2-4 alkenyl), OCi-io haloalkyl, O(aminoacyl), O(Ci-io acyl), 0(Ci-4 alkyl), 0(C2- alkenyl), S(Ci- acyl), S(Ci-4 alkyl), S(C2-4 alkynyl), S(C2-4 alkenyl), SO(Ci-4 acyl), SO(Ci-4 alkyl), SO(C2-4 alkynyl), SO(C2-4 alkenyl), S02(Ci-4 acyl), S02(Ci-4 alkyl), S02(C2-4 alkynyl), S02(C2-4 alkenyl), OSCOMCM acyl), OSCOMCM alkyl), OS(0)2(C2- alkenyl), NH2, NH(Ci-4 alkyl), NH(C2-4 alkenyl), NH(C2-4 alkynyl), NH(Ci-4acyl), N(Ci-4alkyl)2, or N(Ci-i8acyl)2, wherein alkyl, alkynyl, alkenyl, and vinyl are each optionally substituted by N3, CN, one to three halogen(Cl, Br, F, I), N02, C(0)0(Ci-4 alkyl), C(0)0(C2-4 alkynyl), C(0)0(C2-4 alkenyl), 0(Ci-4 acyl), 0(Ci- alkyl), 0(C2- alkenyl), S(Ci- acyl), S(Ci- alkyl), S(C24 alkynyl), S(C2- alkenyl), SO(Ci- acyl), SO(Ci- alkyl), SO(C2- alkynyl), SO(C2- alkenyl), S02(Ci- acyl), S02(Ci- alkyl), S02(C2-4 alkynyl), S02(C2- alkenyl), OS(0)2(Ci-4 acyl), OS(0)2(Ci-4 alkyl), 03S(C2-4 alkenyl), NH2, NH(Ci-4 alkyl), NH(C2- alkenyl), NH(C2-4 alkynyl), NH(Ci-4 acyl), N(Ci-4 alkyl)2, N(Ci-4 acyl)2, or OR10, or R3 and R3' can be linked together to form a vinyl optionally substituted by one or two substituents independently selected from the group consisitn of N3, CN, CI, Br, F, I, and N02;
R is H, an optionally substituted alkyl (including lower alkyl), CN, vinyl, 0-(lower alkyl), hydroxyl lower alkyl -(CH2)pOH, where p is 1-6, CH2F, N3, CH2CN, CH2N3, CH2NH2, CH2NHCH3, CH2N(CH3)2, alkynyl (optionally substituted), or halogen; Base is naturally occurring or modified purine or pyrimidine base represented by any one of the following structures:
Figure imgf000052_0001
wherein: D is N or CH;
R.5, ¾, R-7, R-8, and R9 are each independently selected from the group consisting of H, halogen, Cy, C alkyl, CM haloalkyl, CN, ORiia, SRiia, C(0)Rnb, C(0)NRl lcRiid,
C(0)ORna, OC(0)Riib, OC(0)NRncRnd, NRncRnd, NRncC(0)Rnb, NRncC(0)ORna, NRncC(0)NRiicRiid, NRncS(0)Rnb, NRncS(0)2Riib, NRiicS(0)2NRncRnd, S(0)Rnb, S(0)NRiicRiid, S(0)2Riib, and S(0)2NRncRnd, wherein said C1-4 alkyl is optionally substituted by 1, 2 or 3 substituents independently selected from halogen, Cy, C1-4 haloalkyl, CN, ORna, SRna, C(0)Rnb, C(0)NRncRiid, C(0)ORna, OC(0)Rnb, OC(0)NRncRnd, NRncRiid, NRncC(0)Riib, NRncC(0)ORna, NRncC(0)NRncRnd, NRncS(0)Rnb,
NRiicS(0)2Riib, NRiicS(0)2NRncRiid, S(0)Rnb, S(0)NRncRnd, S(0)2Riib, S(0)2NRncRiid, optionally substituted Ci-12 alkyl , halogenated Ci-6 alkyl, C2-6 alkenyl, halogenated C2-6 alkenyl, C2-6 alkynyl, halogenated C2-6 alkynyl, Ci-6 alkoxy, halogenated Ci-6 alkoxy, C02Riia, CONRncRiid, and CH=CHC02Riia;
Rio is H, -C(0)ORi2, -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 Ce-ιο 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 the group consisting of halogen, C1-4 alkyl, C 1-4 haloalkyl, C1-4 cyanoalkyl, CN, N02, ORna, SRna, C(0)Rnb, C(0)NncRiid, C(0)ORna, OC(0)Rnb, OC(0)NRncRnd, NRncRiid, NRncC(0)Riib, NRncC(0)ORna, NRncC(0)NRncRnd, NRncS(0)Rnb,
NRiicS(0)2Riib, NRiicS(0)2NRncRiid, S(0)Rnb, S(0)NRncRnd, S(0)2Riib, and
S(0)2NRncRiid; Riia, Rub, Riic, and Rnd are each independently selected from the group consisting of H, Ci-6 alkyl, Ci-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, Ce-ιο aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Ce-ιο aryl-Ci-4alkyl-, C3-10 cycloalkyl-Ci-4alkyl-, (5-10 membered heteroaryl)-Ci4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-4 alkyl-, wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ce-ιο aryl, C3- 10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Ce-ιο aryl-Ci-4 alkyl-, C3-10 cycloalkyl-Ci-4 alkyl-, (5-10 membered heteroaryl)-Ci-4 alkyl-, or (4-10 membered heterocycloalkyl)-Ci-4 alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halogen, C1-4 alkyl, Ci-4 haloalkyl, C1-4 cyanoalkyl, CN, NO2, OR12, SR12, C(0)Ri2, C(0)NRi2Ri3, C(0)ORi2, OC(0)Ri2, OC(0)NRi2Ri3,
NR12R13, NRi2C(0)Ri3, NRi2C(0)ORi3, NRi2C(0)NRi2Ri3, NRi2S(0)Ri3, NRi2S(0)2Ri3, NRi2S(0)2NRi2Ri3, S(0)Ri2, S(0)NRi2Ri3, S(0)2Ri2, and S(0)2NRi2Ri3;
R12 and Ri3, at each occurrence, are independently H, Ci-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, Ce-ιο aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Ce-ιο aryl-Ci-4alkyl-, C3-10 cycloalkyl-Ci-4alkyl-, (5-10 membered heteroaryl)-Ci-4 alkyl-, or (4-10 membered heterocycloalkyl)-Ci-4 alkyl-, wherein said Ci-6 alkyl, C 14 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, Ce-ιο aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Ce-ιο aryl-Ci-4 alkyl-, C3-10 cycloalkyl-Ci-4 alkyl-, (5-10 membered heteroaryl)-Ci-4 alkyl-, or (4-10 membered heterocycloalkyl)-Ci-4 alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, CN, and NO2;
Z is CR14R15R16, Ri6, NR17R18, OR19, or SR19;
Ri4 and R15 are independently H, halogen, hydroxyl, or alkyl;
Rl6 IS P(0)(OR21a)R22P(0)(OR21b)(OR21c) ΟΓ P(0)(NR23R24)R22P(0)( NR23R24)2; R2ia, R2ib, and R21C are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, and aryl, where the aryl is optionally substituted with one or more substituents independently selected from the group consisting of Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 alkoxy, F, CI, Br, I, nitro, cyano, C 1-6 haloalkyl, -N(R21')2, Ci-6 acylamino, - NHSO2C1-6 alkyl, -S02N(R2i')2, COR21", and -SO2C1-6 alkyl;
R21' is independently hydrogen or alkyl;
R21" is -OR12, -OR12, -OR12, or -N(Ri2)2;
R22 is CR25R26, NR27, S, or O;
R25 and R26 are each independently H, OH, F, CI, Br, I, or alkyl;
R27 is hydrogen or alkyl; R.23 and R24 are each 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 or C atom, C(0)CR28aR28bNH(R2ia, R2ib, or R2ic), where n is 2 to 4;
R28a and R28b (i) are independently selected from the group consisting of H, Ci-io alkyl, cycloalkyl, -(CH2)C(NR28')2, Ci< hydroxyalkyl, -CH2SH, -(CH2)2S(0)dMe, -
(CH2)3NHC(=NH)NH2, (lH-indol-3-yl)methyl, (lH-imidazol-4-yl)methyl, -(CH2)eCOR28", aryl, and aryl C1-3 alkyl, wherein said aryl groups are each optionally substituted with a group selected from hydroxyl, Ci-10 alkyl, Ci-6 alkoxy, halogen, nitro and cyano; or (ii) are both independently Ci-6 alkyl; or (iii) together with the carbon atom to which they attach form
(CH2)f so as to form a spiro ring; or alternatively, (iv) R28a is H, and R28b and R23 or R24 together form (CH2)n so as to form a cyclic ring that includes the adj oining N and C atoms; or (v) R28b is H, and R28a and R23 or R24 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to 3, f is 2 to 5, n is 2 to 4, and where R28' is independently H or Ci-6 alkyl; and R28" is -OR2ia, -OR2ib, -OR21C, or -N(R28')2); or (vi) R28a is H, and R28b is H, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, -
CH(CH3)CH2CH3, -CH2Ph, -CH2-indol-3-yl, -CH2CH2SCH3, -CH2CO2H, -CH2C(0)NH2, - CH2CH2COOH, -CH2CH2C(0)NH2, -CH2CH2CH2CH2NH2, -CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4'-OH)-Ph), CH2SH, or lower cycloalkyl; or (vii) R28a is H, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2Ph, -CH2- indol-3-yl, -CH2CH2SCH3, -CH2CO2H, -CH2C(0)NH2, -CH2CH2COOH, -CH2CH2C(0)NH2, -CH2CH2CH2CH2NH2, -CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH,
CH(OH)CH3, CH2((4'-OH)-Ph), CH2SH, or lower cycloalkyl, and R28b is H, where R28' is independently H or alkyl, and R28" is -OR2ia, -OR2ib, -OR21C, or -N(R28')2;
R29 is OR30 , NH2, or NHOH;
R30 is H, Ci-10 alkyl, Ci-io haloalkyl, C3-10 cycloalkyl, cycloalkyl alkyl,
cycloheteroalkyl, aminoacyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl, wherein the Ci-10 alkyl is optionally substituted with a lower alkyl, alkoxy, di(lower alkyl)- amino, or halogen;
Ri7 and Ri8 are independently selected from the group consisting of H, - CR14R15R16, alkyl, C(0)(CR3iaR3ib)g(C(0))hR32, where g is 0 to 3 and h is 0 to 1, and
(CR3iaR3ib)iR33, where i is 0 to 1 ;
R3ia and R3ib are independently H or C 1-4 alkyl, wherein said alkyl is optionally substituted with hydroxyl;
R32 is R29 or CR28aR28bNH(R2ia, R2ib, or R2ic); R33 is Ri6, aryl, heteroaryl, substituted aryl, or substituted heteroaryl;
Rl9 is Rl6, -CR14R15R16, CR34(C(0)R29)j(P(0)(OR21a, 21b, or 21C)2)k, ΟΓ CR34
(C(0)R29)j(P(0)(NR23R24)2)k, where j is 1 to 2 and k is 0 to 1 ; and
R34 is H, alkyl, optionally substituted aryl, or substituted heteroaryl.
2. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
Figure imgf000055_0001
Ri4 and R15 are independently H, halogen, hydroxyl, or alkyl;
Rl6 IS P(0)(OR21a)R22P(0)(OR21b)(OR21c) ΟΓ P(0)(NR23R24)R22P(0)(NR23R24)2;
R2ia, R2ib, and R21C are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, and aryl, optionally substituted with at least one of Ci-6 alkyl, C2- 6 alkenyl, C2-6 alkynyl, C i-6 alkoxy, F, CI, Br, I, nitro, cyano, Ci-6 haloalkyl, -N(R21')2, Ci-6 acylamino, -NHSO2C1-6 alkyl, -S02N(R2i')2, COR21", and -SO2C1-6 alkyl; and wherein R21 ' is independently hydrogen or alkyl, and R2i"is -OR2ia, -OR21b, -OR21C, or -N(R21')2;
R22 is CR25R26, NR27, S, or O;
R25 and R26 are independently H, OH, F, CI, Br, I, 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(R2ia, R2ib, or R2ic), where n is 2 to 4;
R28a and R28b are (i) independently selected from H, Ci-10 alkyl, cycloalkyl, - (CH2)C(NR28')2, Ci-e hydroxyalkyl, -CH2SH, -(CH2)2S(0)dMe, -(CH2)3NHC(=NH)NH2, (1H- indol-3-yl)methyl, (lH-imidazol-4-yl)methyl, -(CH2)eCOR28", aryl and aryl C1-3 alkyl, said aryl groups optionally substituted with a group selected from hydroxyl, Ci-10 alkyl, Ci-6 alkoxy, halogen, nitro and cyano; (ii) R28a and R28b both are Ci-6 alkyl; (iii) R28a and R28b together are (CH2)f so as to form a spiro ring; (iv) R28a is H and 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; (v) R28b is H and R28a and R23 or R24 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to 3, f is 2 to 5, n is 2 to 4, and where R28' is independently H, or Ci-6 alkyl and R28" is -OR2ia, -OR2ib, -OR21C, or -N(R28')2); (vi) R28a is H, and R28b is H, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, -CH(CH3)CH2CH3, - CH2Ph, -CH2-indol-3-yl, -CH2CH2SCH3, -CH2CO2H, -CH2C(0)NH2, -CH2CH2COOH, - CH2CH2C(0)NH2, -CH2CH2CH2CH2NH2, -CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4'-OH)-Ph), CH2SH, or lower cycloalkyl; or (vii) R28a is H, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2Ph, -CH2-indol-3-yl, - CH2CH2SCH3, -CH2C02H, -CH2C(0)NH2, -CH2CH2COOH, -CH2CH2C(0)NH2, - CH2CH2CH2CH2NH2, -CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH,
CH(OH)CH3, CH2((4'-OH)-Ph), CH2SH, or lower cycloalkyl and R28b is H, where R28' is independently H, or alkyl, which includes, but is not limited to, Ci-2o alkyl, Ci-10 alkyl, or Ci-6 alkyl, R28" is -OR2ia, -OR2ib, -OR2ic, or -N(R28')2);
R29 is OR30 , NH2, or NHOH; and
R3o is H, Ci-10 alkyl, Ci-io haloalkyl, C3 -io cycloalkyl, cycloalkyl alkyl,
cycloheteroalkyl, aminoacyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl, wherein Ci-10 alkyl is optionally substituted with a lower alkyl, alkoxy, di(lower alkyl)- amino, or halogen,.
3. The compound of claim 1, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:
Z is R½;
Ri6 is P(0)(OR2ia)R22P(0)(OR2ib)(OR2ic) or P(0)(NR23R24)R22P(0)( NR23R24)2;
R2ia, R2ib, and R2ic are independently hydrogen, alkyl, cycloalkyl, or aryl, 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, - NHS02Ci-6 alkyl, -S02N(R2i')2, COR2i", and -S02Ci-6 alkyl;
R21' is independently hydrogen or alkyl;
R2i"is -OR2ia, -OR2ib, -OR2ic, or -N(R2i')2;
R22 is CR25R26, NR27, S, or O;
R25 and R26 are H, OH, F, CI, Br, I, 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(R2ia, R2ib, or R2ic), where n is 2 to 4;
R28a and R28b are (i) independently selected from H, Ci-10 alkyl, cycloalkyl, - (CH2)C(NR28')2, Ci-e hydroxyalkyl, -CH2SH, -(CH2)2S(0)dMe, -(CH2)3NHC(=NH)NH2, (1H- indol-3-yl)methyl, (lH-imidazol-4-yl)methyl, -(CH2)eCOR28", aryl and aryl Ci-3 alkyl, said aryl groups optionally substituted with a group selected from hydroxyl, Ci-10 alkyl, Ci-6 alkoxy, halogen, nitro and cyano; (ii) R28a and R28b both are Ci-6 alkyl; (iii) R28a and R28b together are (CH2)f so as to form a spiro ring; (iv) R28a is H and R28b and R23 or R24 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms; (v) R28b is H and R.28a and R23 or R24 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to 3, f is 2 to 5, n is 2 to 4, and where R28' is independently H, or Ci-6 alkyl and R28" is -OR2ia, -OR2it>, -OR21C, or -N(R28')2); (vi) R28a is H, and R28b is H, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, -CH(CH3)CH2CH3, - CH2Ph, -CH2-indol-3-yl, -CH2CH2SCH3, -CH2CO2H, -CH2C(0)NH2, -CH2CH2COOH, - CH2CH2C(0)NH2, -CH2CH2CH2CH2NH2, -CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4'-OH)-Ph), CH2SH, or lower cycloalkyl; or (vii) R28a is H, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2Ph, -CH2-indol-3-yl, - CH2CH2SCH3, -CH2CO2H, -CH2C(0)NH2, -CH2CH2COOH, -CH2CH2C(0)NH2, - CH2CH2CH2CH2NH2, -CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH,
CH(OH)CH3, CH2((4'-OH)-Ph), CH2SH, or lower cycloalkyl and R28b is H, where R28' is independently H, or alkyl, which includes, but is not limited to, Ci-20 alkyl, Ci-10 alkyl, or Ci-6 alkyl, R28" is -OR2ia, -OR2ib, -OR2ic, or -N(R28')2);
R29 is OR30 , NH2, or NHOH; and
R3o is H, Ci-10 alkyl, Ci-io haloalkyl, C3-io cycloalkyl, cycloalkyl alkyl,
cycloheteroalkyl, aminoacyl, aryl, heteroaryl, substituted aryl, or substituted heteroaryl, wherein the Ci-10 alkyl is optionally substituted with a lower alkyl, alkoxy, di(lower alkyl)- amino, or halogen.
4. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:
Z is NRivRis;
Ri7 and Ri8 are independently selected from the group consisting of H, alkyl, - CR14R15R16, C(0)(CR3iaR3ib)g(C(0))hR32, and (CR3iaR3ib)iR33, wherein g is 0 to 3, h is 0 to 1, and i is 0 to 1 ;
Ri4 and R15 are independently H, halogen, hydroxyl, or alkyl;
Rl6 IS P(0)(OR21a)R22P(0)(OR21b)(OR21c) ΟΓ P(0)(NR23R24)R22P(0)(NR23R24)2;
R2ia, R2ib, and R21C are independently selected from hydrogen, alkyl, cycloalkyl, and aryl, where said aryl is 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(R21')2, Ci-6 acylamino, - NHSO2C1-6 alkyl, -S02N(R2i')2, COR21", and -SO2C1-6 alkyl;
R21' is independently hydrogen or alkyl;
R2i"is -OR2ia, -OR2ib, -OR2ic, or -N(R2i')2;
R22 is CR25R26, NR27, or O;
R25 and R26 are independently H, OH, F, CI, Br, or alkyl; R.27 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(R2ia, R2ib, or R2ic), where n is 2 to 4;
R28a and R28b are (i) independently selected from H, Ci-10 alkyl, cycloalkyl, -
(CH2)C(NR28')2, Ci-e hydroxyalkyl, -CH2SH, -(CH2)2S(0)dMe, -(CH2)3NHC(=NH)NH2, (1H- indol-3-yl)methyl, (lH-imidazol-4-yl)methyl, -(CH2)eCOR28", aryl and aryl C1-3 alkyl, said aryl groups optionally substituted with a group selected from hydroxyl, Ci-10 alkyl, Ci-6 alkoxy, halogen, nitro and cyano; (ii) R28a and R28b both are Ci-6 alkyl; (iii) R28a and R28b together are (CH2)f so as to form a spiro ring; (iv) R28a is H and 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; (v) R28b is H and R28a and R23 or R24 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to 3, f is 2 to 5, n is 2 to 4, and where R28' is independently H, or Ci-6 alkyl and R28" is -OR2ia, -OR2ib, -OR21C, or -N(R28')2); (vi) R28a is H, and R28b is H, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, -CH(CH3)CH2CH3, - CH2Ph, -CH2-indol-3-yl, -CH2CH2SCH3, -CH2CO2H, -CH2C(0)NH2, -CH2CH2COOH, - CH2CH2C(0)NH2, -CH2CH2CH2CH2NH2, -CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4'-OH)-Ph), CH2SH, or lower cycloalkyl; or (vii) R28a is H, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2Ph, -CH2-indol-3-yl, - CH2CH2SCH3, -CH2CO2H, -CH2C(0)NH2, -CH2CH2COOH, -CH2CH2C(0)NH2, - CH2CH2CH2CH2NH2, -CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH,
CH(OH)CH3, CH2((4'-OH)-Ph), CH2SH, or lower cycloalkyl and R28b is H, where R28' is independently H, or alkyl, which includes, but is not limited to, Ci-20 alkyl, Ci-10 alkyl, or Ci-6 alkyl, R28" is -OR2ia, -OR2ib, -OR2ic, or -N(R28')2);
R29 is OR30 , NH2, 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-io haloalkyl, C3-10 cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl.
R3ia and R3ib are independently H or C 1-4 alkyl, wherein said alkyl is optionally substituted with hydroxyl;
R32 is R29 or CR28aR28bNH(R2ia, R2ib, or R2ic);
R33 is Ri6, aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl;
5. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:
Rl9 IS Rl6, -CR14R15R16, CR34(C(0)R29)j(P(0)(OR2la, 21b, or 21C)2)k, ΟΓ CR34
(C(0)R29)j(P(0)(NR23R24)2)k, where j is 1 to 2 and k is 0 to 1 ;
Ri4 and R15 are independently H, halogen (F, CI, Br, I), hydroxyl, or alkyl;
Rl6 IS P(0)(OR21a)R22P(0)(OR21b)(OR21c), ΟΓ P(0)(NR23R24)R22P(0)(NR23R24)2;
R2ia, R2ib, and R21C 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(R21')2, Ci-6 acylamino, -NHSO2C1-6 alkyl, -S02N(R2i ')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, R2i"is -OR2ia, - OR2ib, -OR21C or -N(R2i')2);
R22 is CR25R26, NR27, S, or O;
R25 and R26 are independently H, OH, F, CI, Br, I, 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(R2ia, R2ib, or R2ic), where n is 2 to 4;
R28a and R28b are (i) independently selected from H, Ci-10 alkyl, cycloalkyl, - (CH2)C(NR28')2, Ci-e hydroxyalkyl, -CH2SH, -(CH2)2S(0)dMe, -(CH2)3NHC(=NH)NH2, (1H- indol-3-yl)methyl, (lH-imidazol-4-yl)methyl, -(CH2)eCOR28", aryl and aryl C1-3 alkyl, said aryl groups optionally substituted with a group selected from hydroxyl, Ci-10 alkyl, Ci-6 alkoxy, halogen, nitro and cyano; (ii) R28a and R28b both are Ci-6 alkyl; (iii) R28a and R28b together are (CH2)f so as to form a spiro ring; (iv) R28a is H and 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; (v) R28b is H and R28a and R23 or R24 together are (CH2)n so as to form a cyclic ring that includes the adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to 3, f is 2 to 5, n is 2 to 4, and where R28' is independently H, or Ci-6 alkyl and R28" is -OR2ia, -OR2ib, -OR21C, or -N(R28')2); (vi) R28a is H, and R28b is H, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, -CH(CH3)CH2CH3, - CH2Ph, -CH2-indol-3- yl, -CH2CH2SCH3, -CH2CO2H, -CH2C(0)NH2, -CH2CH2COOH, -CH2CH2C(0)NH2, -CH2C H2CH2CH2NH2, -CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4'-OH)-Ph), CH2SH, or lower cycloalkyl; or (vii) R28a is H, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2Ph, -CH2-indol-3-yl, -CH2CH2SCH3, -CH2C02H, - CH2C(0)NH2, -CH2CH2COOH, -CH2CH2C(0)NH2, -CH2CH2CH2CH2NH2, - CH2CH2CH2NHC(NH)NH2, CH2-imidazol-4-yl, CH2OH, CH(OH)CH3, CH2((4'-OH)-Ph), CH2SH, or lower cycloalkyl and R28b is H, where R2s' is independently H, or alkyl, which includes, but is not limited to, Ci-2o alkyl, Ci-10 alkyl, or Ci-6 alkyl, R2s" is -OR2ia, -OR2ib, - OR2ic, or -N(R28')2);
R29 is OR30 , NH2, or NHOH;
R3o is H, Ci-10 alkyl, Ci-10 alkyl optionally substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino, or halogen, Ci-io haloalkyl, C3-io cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, aryl, such as phenyl, heteroaryl, such as, pyridinyl, substituted aryl, or substituted heteroaryl.
R34 is H, alkyl, optionally substituted aryl, or substituted heteroaryl;
6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein A is oxygen (O) or carbon (C ).
7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein one of Ri and R2 is hydrogen and the other is OH or halogen.
8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein one of R3 and R3' is hydrogen and the other is OH.
9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R4 is H.
10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt, solvate or prodrug there
"Base" is either
Figure imgf000060_0001
wherein D, R5, R6 are as defined in claim 1.
11. The compound of claim 10, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:
R5 is Cy, C i-4 alkyl, ORiia, SRi ia, or NRncRi id, wherein C1-4 alkyl is optionally substituted by 1, 2 or 3 substituents independently selected from halogen, Cy, C i-6 alkyl, C 1-4 haloalkyl, CN, ORna, SRna, C(0)Rnb, C(0)NRncRnd, C(0)ORna, OC(0)Rnb, OC(0)NRncRiid, NRiicRnd, NRncC(0)Rnb, NRncC(0)ORna, NRncC(0)NRiicRnd, NRiicS(0)Riib, NRiicS(0)2Riib, NRiicS(0)2NRiicRiid, S(0)Rnb, S(0)NRncRnd, S(0)2Riib, S(0)2NRiicRiid, lower alkenyl of C2-6 such as CH=CH2, halogenated lower alkenyl of C2-6, lower alkynyl of C2-6, halogenated lower alkynyl of C2-6, lower alkoxy of Ci-6, such as CH2OH and CH2CH2OH, halogenated lower alkoxy of Ci-6, C02H, C02Riia, CONH2, CONRiicRnd, CH=CHC02H, and CH=CHC02Riia; Cy, C alkyl, C haloalkyl, ORna, SRna; and
R¾ is H, halogen, Cl -4 alkyl, C haloalkyl, CN, ORna, or SRna;
Riia, Rub, Riic, and Rna are each independently selected from the group consisting of H, Ci-6 alkyl, C haloalkyl, C2-6 alkenyl, C2-6 alkynyl, Ce-ιο aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Ce-ιο aryl-Ci-4alkyl-, C3-10 cycloalkyl-Ci-4alkyl-, (5-10 membered heteroaryl)-Ci-4 alkyl-, and (4-10 membered heterocycloalkyl)-Ci-4 alkyl-, wherein said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ce-ιο aryl, C3- 10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Ce-ιο aryl-Ci-4 alkyl-, C3-10 cycloalkyl-Ci-4 alkyl-, (5-10 membered heteroaryl)-Ci-4 alkyl-, or (4-10 membered heterocycloalkyl)-Ci-4 alkyl- is optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from halogen, C alkyl, C M haloalkyl, C M cyanoalkyl, CN, NO2, OR12, SR12, C(0)Ri2, C(0)NRi2Ri3, C(0)ORi2, OC(0)Ri2, OC(0)NRi2Ri3, NR12R13, NRi2C(0)Ri3, NRi2C(0)ORi3, NRi2C(0)NRi2Ri3, NRi2S(0)Ri3, NRi2S(0)2Ri3, NRi2S(0)2NRi2Ri3, S(0)Ri2, S(0)NRi2Ri3, S(0)2Ri2, and S(0)2NRi2Ri3; and
R12 and Ri3 are independently H, Ci-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, Ce-ιο aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Ce- 10 aryl-Ci-4alkyl-, C3-10 cycloalkyl-Ci-4alkyl-, (5-10 membered heteroaryl)-Ci-4 alkyl-, or (4- 10 membered heterocycloalkyl)-Ci-4 alkyl-, wherein said Ci-6 alkyl, C M haloalkyl, C2-6 alkenyl, C2-6 alkynyl, Ce-ιο aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, Ce-ιο aryl-Ci-4 alkyl-, C3-10 cycloalkyl-Ci-4 alkyl-, (5-10 membered heteroaryl)-Ci-4 alkyl-, or (4-10 membered heterocycloalkyl)-Ci-4 alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy, halogen, C M alkyl, C M haloalkyl, C M cyanoalkyl, CN, and NC . The compound of claim 1 1, having a formula selected from the group consisting
Figure imgf000062_0001
13. The compound of claim 12, wherein R5 is cyclopentanaminyl or (S)-l- phenylethanaminyl; and R.6 is chloro.
14. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate or prodrug thereof, selected from the exemplified compounds 1 to 28.
15. A composition comprising a compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable carrier.
16. A method of treating a disease or disorder modulated by adenosine and adenosine receptors, especially activity of CD73, comprising administering to a subj ect in need of treatment a therapeutically effective amount of a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a composition of claim 15
17. The method of claim 16, wherein the disease or disorder is selected from the group consisting of 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.
PCT/US2018/031512 2017-05-08 2018-05-08 Nucleoside and nucleotide analogues as cd73 inhibitors and therapeutic uses thereof Ceased WO2018208727A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201762503035P 2017-05-08 2017-05-08
US62/503,035 2017-05-08

Publications (1)

Publication Number Publication Date
WO2018208727A1 true WO2018208727A1 (en) 2018-11-15

Family

ID=64105396

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2018/031512 Ceased WO2018208727A1 (en) 2017-05-08 2018-05-08 Nucleoside and nucleotide analogues as cd73 inhibitors and therapeutic uses thereof

Country Status (1)

Country Link
WO (1) WO2018208727A1 (en)

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020146795A1 (en) 2019-01-11 2020-07-16 Omeros Corporation Methods and compositions for treating cancer
WO2020185859A1 (en) 2019-03-12 2020-09-17 Arcus Biosciences, Inc. Treatment of oncogene-driven cancers
WO2020205527A1 (en) 2019-03-29 2020-10-08 Arcus Biosciences, Inc. Treatment of cancer utilizing an identified adenosine fingerprint
WO2020211668A1 (en) * 2019-04-15 2020-10-22 Bioardis Llc Cd73 inhibitors
EP3600273A4 (en) * 2017-03-31 2021-01-20 Peloton Therapeutics, Inc. CD73 INHIBITORS AND THEIR USES
WO2021011689A1 (en) * 2019-07-16 2021-01-21 Oric Pharmaceuticals, Inc. Cd73 inhibitors
WO2021087136A1 (en) * 2019-10-30 2021-05-06 Oric Pharmaceuticals, Inc. Cd73 inhibitors
CN112888696A (en) * 2018-06-21 2021-06-01 卡利泰拉生物科技公司 Exonucleotidase inhibitors and methods of use thereof
CN113366008A (en) * 2019-04-28 2021-09-07 上海和誉生物医药科技有限公司 CD73 inhibitor, preparation method and application thereof
US11129841B2 (en) 2017-05-10 2021-09-28 Oric Pharmaceuticals, Inc. CD73 inhibitors
US11325938B2 (en) 2018-04-30 2022-05-10 Oric Pharmaceuticals, Inc. CD73 inhibitors
US11377469B2 (en) 2017-11-03 2022-07-05 Oric Pharmaceuticals, Inc. CD73 inhibitors
CN115181148A (en) * 2022-07-12 2022-10-14 南京工业大学 Compound with anti-tumor effect based on cordycepin through derivatization
WO2023201267A1 (en) 2022-04-13 2023-10-19 Gilead Sciences, Inc. Combination therapy for treating trop-2 expressing cancers
GB2627905A (en) * 2022-07-12 2024-09-04 Nanjing University Of Technology Cordycepin-derivatized compound with anti-tumor effect
US12187758B2 (en) 2022-03-15 2025-01-07 Rome Therapeutics, Inc. Compounds and methods for treating disease
US12331068B2 (en) 2018-05-31 2025-06-17 Peloton Therapeutics, Inc. Compositions and methods for inhibiting CD73
WO2025137640A1 (en) 2023-12-22 2025-06-26 Gilead Sciences, Inc. Azaspiro wrn inhibitors
WO2025162964A1 (en) 2024-01-30 2025-08-07 Institut National de la Santé et de la Recherche Médicale Methods for the treatment of endometriosis

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20010033862A1 (en) * 1988-07-07 2001-10-25 Hostetler Karl Y. Methods of treating viral infections using antiviral liponucleotides
US20130109850A1 (en) * 2010-04-28 2013-05-02 Isis Pharmaceuticals, Inc Modified 5' diphosphate nucleosides and oligomeric compounds prepared therefrom

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20010033862A1 (en) * 1988-07-07 2001-10-25 Hostetler Karl Y. Methods of treating viral infections using antiviral liponucleotides
US20130109850A1 (en) * 2010-04-28 2013-05-02 Isis Pharmaceuticals, Inc Modified 5' diphosphate nucleosides and oligomeric compounds prepared therefrom

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE PUBCHEM 16 September 2004 (2004-09-16), XP055546675, Database accession no. 6022 *

Cited By (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11591355B2 (en) 2017-03-31 2023-02-28 Peloton Therapeutics Inc. CD73 inhibitors and uses thereof
EP3600273A4 (en) * 2017-03-31 2021-01-20 Peloton Therapeutics, Inc. CD73 INHIBITORS AND THEIR USES
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
US12331068B2 (en) 2018-05-31 2025-06-17 Peloton Therapeutics, Inc. Compositions and methods for inhibiting CD73
US11858957B2 (en) 2018-06-21 2024-01-02 Antengent Therapeutics Limited Ectonucleotidase inhibitors and methods of use thereof
CN112888696B (en) * 2018-06-21 2024-04-16 德琪医疗有限公司 Exonuclease inhibitors and methods of use thereof
US20230022922A1 (en) * 2018-06-21 2023-01-26 Lijing Chen Ectonucleotidase inhibitors and methods of use thereof
CN112888696A (en) * 2018-06-21 2021-06-01 卡利泰拉生物科技公司 Exonucleotidase inhibitors and methods of use thereof
IL279475B1 (en) * 2018-06-21 2025-09-01 Calithera Biosciences Inc Ectonucleotidase inhibitors and methods of using them
EP3810617A4 (en) * 2018-06-21 2022-06-29 Calithera Biosciences, Inc. Ectonucleotidase inhibitors and methods of use thereof
WO2020146795A1 (en) 2019-01-11 2020-07-16 Omeros Corporation Methods and compositions for treating cancer
WO2020185859A1 (en) 2019-03-12 2020-09-17 Arcus Biosciences, Inc. Treatment of oncogene-driven cancers
WO2020205527A1 (en) 2019-03-29 2020-10-08 Arcus Biosciences, Inc. Treatment of cancer utilizing an identified adenosine fingerprint
CN114206841A (en) * 2019-04-15 2022-03-18 博奥阿迪斯生物科技公司 CD73 inhibitor
WO2020210938A1 (en) * 2019-04-15 2020-10-22 Bioardis Llc Quinazoline derivatives as cd73 inhibitors
WO2020211668A1 (en) * 2019-04-15 2020-10-22 Bioardis Llc Cd73 inhibitors
AU2020264642B2 (en) * 2019-04-28 2023-05-25 Abbisko Therapeutics Co., Ltd. CD73 inhibitor, preparation method therefor and application thereof
JP2022526147A (en) * 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 inhibitor, its manufacturing method and application
CN113366008B (en) * 2019-04-28 2023-06-23 上海和誉生物医药科技有限公司 A kind of CD73 inhibitor, its preparation method and application
JP7627966B2 (en) 2019-04-28 2025-02-07 アビスコ セラピューティクス カンパニー リミテッド CD73 inhibitors, their production methods and applications
JP2023145547A (en) * 2019-04-28 2023-10-11 アビスコ セラピューティクス カンパニー リミテッド Cd73 inhibitor, preparation method therefor and application thereof
JP2023145548A (en) * 2019-04-28 2023-10-11 アビスコ セラピューティクス カンパニー リミテッド Cd73 inhibitor, preparation method therefor and application thereof
JP7627967B2 (en) 2019-04-28 2025-02-07 アビスコ セラピューティクス カンパニー リミテッド CD73 inhibitors, their production methods and applications
US12157755B2 (en) 2019-04-28 2024-12-03 Abbisko Therapeutics Co., Ltd. CD73 inhibitor, preparation method therefor and application thereof
CN113366008A (en) * 2019-04-28 2021-09-07 上海和誉生物医药科技有限公司 CD73 inhibitor, preparation method and application thereof
JP7557522B2 (en) 2019-07-16 2024-09-27 オリック ファーマシューティカルズ，インク． CD73 inhibitors
WO2021011689A1 (en) * 2019-07-16 2021-01-21 Oric Pharmaceuticals, Inc. Cd73 inhibitors
JP2022540890A (en) * 2019-07-16 2022-09-20 オリック ファーマシューティカルズ，インク． CD73 inhibitor
US11028120B2 (en) 2019-10-30 2021-06-08 Oric Pharmaceuticals, Inc. CD73 inhibitors
CN116854758A (en) * 2019-10-30 2023-10-10 欧瑞克制药公司 CD73 inhibitors
US12018043B2 (en) 2019-10-30 2024-06-25 Oric Pharmaceuticals, Inc. CD73 inhibitors
US12454544B2 (en) 2019-10-30 2025-10-28 Oric Pharmaceuticals, Inc. CD73 inhibitors
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
WO2021087136A1 (en) * 2019-10-30 2021-05-06 Oric Pharmaceuticals, Inc. Cd73 inhibitors
US12187758B2 (en) 2022-03-15 2025-01-07 Rome Therapeutics, Inc. Compounds and methods for treating disease
WO2023201267A1 (en) 2022-04-13 2023-10-19 Gilead Sciences, Inc. Combination therapy for treating trop-2 expressing cancers
WO2024012126A1 (en) * 2022-07-12 2024-01-18 南京工业大学 Cordycepin-derivatized compound with anti-tumor effect
US12215123B2 (en) 2022-07-12 2025-02-04 Nanjing Tech University Cordycepin-based derivatized compound with anti-tumor effect
GB2627905B (en) * 2022-07-12 2025-06-25 Nanjing University Of Technology Cordycepin-based derivatized compound with anti-tumor effect
CN115181148A (en) * 2022-07-12 2022-10-14 南京工业大学 Compound with anti-tumor effect based on cordycepin through derivatization
GB2627905A (en) * 2022-07-12 2024-09-04 Nanjing University Of Technology Cordycepin-derivatized compound with anti-tumor effect
WO2025137640A1 (en) 2023-12-22 2025-06-26 Gilead Sciences, Inc. Azaspiro wrn inhibitors
WO2025162964A1 (en) 2024-01-30 2025-08-07 Institut National de la Santé et de la Recherche Médicale Methods for the treatment of endometriosis

Similar Documents

Publication Publication Date Title
WO2018208727A1 (en) Nucleoside and nucleotide analogues as cd73 inhibitors and therapeutic uses thereof
TWI660967B (en) 4&#39;-substituted nucleoside reverse transcriptase inhibitors
AU2018305614B2 (en) Piperazine heteroaryl derivative, preparation method therefor and use of same in medicine
CN106459009B (en) Hepatitis C virus inhibitor and its pharmaceutical use
CN112888696B (en) Exonuclease inhibitors and methods of use thereof
AU2006242920A1 (en) 2-amido-6-amino-8-oxopurine derivatives as Toll-Like receptor modulators for the treatment of cancer and viral infections, such as hepatitis C
BR112020013141A2 (en) oxy-fluoropiperidine as a kinase inhibitor
KR20130064064A (en) Stereoselective synthesis of phosphorus containing actives
CZ20021223A3 (en) Purine derivatives
CN115887465A (en) Methods of treating arenaviridae and coronaviridae virus infections
JP2015205910A (en) Novel nucleic acid prodrugs and methods of use thereof
CN116265462B (en) Heterocyclic compound with antitumor activity and application thereof
ZA200202725B (en) Purine derivatives.
CN114555620A (en) Novel galactoside inhibitors of galectins
KR20200043407A (en) Diarylthiohydantoin compound as an androgen receptor antagonist
CN114075200A (en) JAK inhibitor compounds for the treatment of severe pneumonia
JP6767011B2 (en) Nucleoside derivative with physiological activity such as anti-DNA virus activity
WO2018082503A1 (en) Heterocyclic compound and preparation method and application thereof
CN113164506B (en) Dinucleotide compounds and prodrugs thereof
TWI638825B (en) Compounds for inhibiting cancer and virus
Guo et al. Discovery of pyrimidine nucleoside dual prodrugs and pyrazine nucleosides as novel anti-HCV agents
CN113166190B (en) Oligonucleotides and prodrugs
TW202220991A (en) Spiro compound, comprising pharmacuetical composition and application thereof
TWI804016B (en) Thienopyridine compound, comprising pharmacuetical composition and application thereof
RU2842251C2 (en) Heterocyclic compound having anticancer activity, and use thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18797767

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18797767

Country of ref document: EP

Kind code of ref document: A1