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WO2020106625A1 - Composés et leurs utilisations - Google Patents

Composés et leurs utilisations

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Publication number
WO2020106625A1
WO2020106625A1 PCT/US2019/062025 US2019062025W WO2020106625A1 WO 2020106625 A1 WO2020106625 A1 WO 2020106625A1 US 2019062025 W US2019062025 W US 2019062025W WO 2020106625 A1 WO2020106625 A1 WO 2020106625A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
optionally substituted
subject
mmol
adenosine
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/US2019/062025
Other languages
English (en)
Inventor
Andrew J. Mcriner
Junyi Zhang
Yanbin Liu
Neil E. Westlund
Ying Zhang
Dawn M. TROAST
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.)
Xios Therapeutics Inc
Original Assignee
Xios Therapeutics Inc
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Filing date
Publication date
Application filed by Xios Therapeutics Inc filed Critical Xios Therapeutics Inc
Publication of WO2020106625A1 publication Critical patent/WO2020106625A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • the inflammatory response helps eliminate harmful agents from the body, including tumors. However, inflammation is also a non-specific response that can harm healthy tissue.
  • the cells involved in inflammation include immune cells (e.g., T cells, B cells, dendritic cells, macrophages, or granulocytes), the vascular endothelium, vascular smooth muscle cells, and fibroblasts. Inflammation is normally a localized action that results in isolation of the damaging agent and injured tissue.
  • immune checkpoint pathways inhibitory signaling networks provide a negative feedback mechanism that is important for immunomodulation and protection of healthy tissues from the damage of inflammatory responses.
  • the adenosine receptors are important immune checkpoints in cancer therapy.
  • the present disclosure relates to compositions and methods for the treatment of disorders related to adenosine or adenosine receptors, such as cancer.
  • the present invention features compounds useful to modulate levels of adenosine, e.g., in a subject in need thereof.
  • the compounds described herein modulate adenosine levels via antagonism of the adenosine A2A receptor.
  • the compounds described herein modulate adenosine levels via antagonism of the adenosine A ⁇ B receptor.
  • the compounds described herein modulate adenosine levels via antagonism of both the adenosine A2 A and A2B receptors.
  • the compounds described herein are useful in the treatment of disorders associated with an alteration in the activity level of the adenosine A2A receptor.
  • the compounds described herein are useful in the treatment of disorders associated with an alteration in the activity level of the adenosine A2B receptor.
  • the compounds of the invention alone or in combination with other pharmaceutically active agents, can be used for treating such disorders, which include cancer.
  • the invention provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula I:
  • R 1 , R 2 , and R 3 is, independently, H or optionally substituted C1-C6 alkyl
  • each of R 5 and R 6 is, independently, H or optionally substituted C1-C6 alkyl, or R 5 and R 6 , together with the atom to which each is attached, combine to form an optionally substituted C3-C10 carbocyclyl;
  • B is optionally substituted C 3 -Cio carbocyclylene or optionally substituted C3-C9 heterocyclylene;
  • L 2 is V " _r n ⁇
  • ml is 1 , 2, or 3;
  • n2 is 0, 1 , 2, or 3;
  • R 4 is optionally substituted C6-C10 aryl, optionally substituted C3-C9 heterocyclyl, optionally substituted C1-C9 heteroaryl, or optionally substituted C 1 -C 6 heteroalkyl,
  • R 4 is substituted C6-C10 aryl, optionally substituted C3-C9 heterocyclyl, optionally substituted C1 -C9 heteroaryl, or optionally substituted C1-C6 heteroalkyl.
  • R 1 is H. In some embodiments, R 1 is optionally substituted C1-C6 alkyl. In some embodiments,
  • R 2 is H. In some embodiments, R 2 is optionally substituted C1 -C6 alkyl. In
  • R 2 is A.
  • R 3 is H. In some embodiments, R 3 is optionally substituted C1 -C6 alkyl. In some embodiments,
  • L 1 is /
  • ml is 1 or 2. In some embodiments, ml is 1 . In some embodiments, ml is 2.
  • R 5 is H. In some embodiments, R 5 is optionally substituted C1-C6 alkyl. In
  • R 5 is A.
  • R 6 is H. In some embodiments, R 6 is optionally substituted C1-C6 alkyl. In
  • R 6 is A . In some embodiments, R 6 is H or A
  • R 5 and R 6 together with the atom to which each is attached, combine to form an optionally substituted C3-C10 carbocyclyl.
  • R 5 and R 6 together with the atom to which each is attached, combine to form an optionally substituted C3-C6 carbocyclyl. In some embodiments, R 5 and R 6 , together with the atom to which each is attached, combine to form an optionally substituted C3-C5 carbocyclyl.
  • B is optionally substituted C3-C10 carbocyclylene. In some embodiments,
  • B is optionally substituted C3-C9 heterocyclylene.
  • L 2 is . In some embodiments, L 2 is
  • m2 is 1 , 2, or 3. In some embodiments, m2 is 1 or 2. In some embodiments, m2 is 1 . In some embodiments, m2 is 2.
  • R 4 is optionally substituted C6-C10 aryl.
  • n 0, 1 , 2, 3, 4, or 5;
  • each R a is, independently, C1-C6 perfluoroalkyl or C3-C8 cycloalkyl.
  • each R a is, independently, , or
  • each R a is .
  • n 1 or 2.
  • R 4 is optionally substituted C3-C9 heterocyclyl.
  • o 0, 1 , 2, or 3;
  • each R b is, independently, halo or optionally substituted C1-C6 alkyl; and R 7 is H or optionally substituted C1-C6 alkyl.
  • R 4 is . , In some embodiments,
  • each R b is, independently, halo or C1-C6 alkyl.
  • o is 0 or 1 . In some embodiments, o is 0. In some embodiments, o is 1 .
  • R 7 is H. In some embodiments, R 7 is optionally substituted C1-C6 alkyl. In some embodiments,
  • R 4 is optionally substituted C1 -C9 heteroaryl.
  • p 0, 1 , 2, or 3;
  • q 0, 1 , 2, or 3;
  • each of X a , X b , X c , and X d is, independently, N, CH, or CR C ;
  • X e is O, S, NR 8 , or CR c R d ;
  • each R c is, independently, halo or optionally substituted C1-C6 alkyl
  • R 8 is H or optionally substituted C1-C6 alkyl.
  • R 4 is .
  • q is 0 or 1 . In some embodiments, q is 0. In some embodiments, q is 1 .
  • each of X a and X b is, independently, N or CH. In some embodiments, each of X c and X d is, independently, N or CH. In some embodiments, X e is O or S. In some
  • X e is NH or CH2.
  • X a is N. In some embodiments, X a is CH.
  • X b is N. In some embodiments, X b is CH.
  • X c is N. In some embodiments, X c is CH.
  • X d is N. In some embodiments, X d is CH.
  • X e is NH. In some embodiments, X e is CH2.
  • p is 0 or 1 . In some embodiments, p is 0. In some embodiments, p is 1 .
  • each R c is, independently, halo or C1-C6 alkyl.
  • R 8 is H. In some embodiments, R 8 is optionally substituted C1-C6 alkyl. In some embodiments,
  • R 4 is optionally substituted Ci-Ce heteroalkyl. In some embodiments,
  • the invention provides a compound, or a pharmaceutically acceptable salt thereof, selected from any one of compounds 1 -80 in Table 1 .
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising any of the foregoing compounds (e.g. a compound of Formula I, such as any of compounds 1-86 in Table 1 ) and a pharmaceutically acceptable excipient.
  • the invention provides a method for modulating the level of adenosine in a cell.
  • This method includes contacting a cell with an effective amount of any of the foregoing compounds or pharmaceutical compositions.
  • the invention provides a method for modulating the level of adenosine in a subject, the method comprising administering to the subject an effective amount of a compound of any of the foregoing compounds or pharmaceutical compositions.
  • the invention provides a method for the treatment of a disorder associated with adenosine (e.g., cancer) in a subject in need thereof, the method comprising administering an effective amount of any of the foregoing compounds or pharmaceutical compositions.
  • adenosine e.g., cancer
  • the invention provides a method for modulating the activity of the adenosine A2 A receptor in a cell.
  • This method includes contacting a cell with an effective amount of any of the foregoing compounds or pharmaceutical compositions.
  • the invention provides a method for modulating the activity of the adenosine A2 A receptor in a subject, the method comprising administering to the subject an effective amount of a compound of any of the foregoing compounds or pharmaceutical compositions.
  • the invention provides a method for the treatment of a disorder associated with the adenosine A2 A receptor (e.g., cancer) in a subject in need thereof, the method comprising administering an effective amount of any of the foregoing compounds or pharmaceutical compositions.
  • a disorder associated with the adenosine A2 A receptor e.g., cancer
  • the invention provides a method for modulating the activity of the adenosine A2 B receptor in a cell.
  • This method includes contacting a cell with an effective amount of any of the foregoing compounds or pharmaceutical compositions.
  • the invention provides a method for modulating the activity of the adenosine A2 B receptor in a subject, the method comprising administering to the subject an effective amount of a compound of any of the foregoing compounds or pharmaceutical compositions.
  • the invention provides a method for the treatment of a disorder associated with the adenosine A2B receptor (e.g., cancer) in a subject in need thereof, the method comprising administering an effective amount of any of the foregoing compounds or pharmaceutical compositions.
  • the invention provides a method for modulating the activity of the adenosine AZA and the adenosine ASB receptor in a cell.
  • This method includes contacting a cell with an effective amount of any of the foregoing compounds or pharmaceutical compositions.
  • the invention provides a method for modulating the activity of the adenosine A2A and the adenosine A2B receptor in a subject, the method comprising administering to the subject an effective amount of a compound of any of the foregoing compounds or pharmaceutical compositions.
  • the invention provides a method for the treatment of a disorder associated with the adenosine A2A and the adenosine A ⁇ B receptor (e.g., cancer) in a subject in need thereof, the method comprising administering an effective amount of any of the foregoing compounds or
  • the invention provides a method of modulating an immune response in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any of the foregoing compounds or pharmaceutical compositions.
  • the invention provides a method for modulating the activity of the dopamine D2 receptor in a cell, the method comprising contacting a cell with an effective amount of any of the foregoing compounds or pharmaceutical compositions.
  • the invention provides a method for modulating the activity of the dopamine D2 receptor in a subject, the method comprising administering to the subject an effective amount of a compound of any of the foregoing compounds or pharmaceutical compositions.
  • the invention provides a method of inhibiting inflammation in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the foregoing compounds or pharmaceutical compositions.
  • the invention provides a method of treating cancer in a subject, the method comprising administering to the subject an effective amount of any of the foregoing compounds or pharmaceutical compositions.
  • the method further comprises administering to the subject an additional anticancer therapy (e.g., an immunotherapy such as a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor, and/or adoptive T-cell transfer therapy, a chemotherapeutic or cytotoxic agent, and/or or radiotherapy).
  • an additional anticancer therapy e.g., an immunotherapy such as a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor, and/or adoptive T-cell transfer therapy, a chemotherapeutic or cytotoxic agent, and/or or radiotherapy.
  • the additional anticancer therapy and any of the foregoing compounds or pharmaceutical compositions are administered within 28 days of each other each in an amount that together are effective to treat the subject.
  • the subject has a compromised immune system.
  • the cancer has failed to respond to a previously administered an immunotherapy and/or the cancer is resistant to an immunotherapy.
  • the cancer is breast cancer such as triple negative breast cancer, colon cancer, renal cell cancer, non-small cell lung cancer, hepatocellular carcinoma, gastric cancer, ovarian cancer, pancreatic cancer, esophageal cancer, prostate cancer, sarcoma, glioblastoma, diffuse large B-cell lymphoma, leukemia (e.g., acute myeloid leukemia), or melanoma.
  • the cancer is melanoma.
  • the cancer is breast cancer.
  • the cancer is renal cell cancer.
  • the cancer is pancreatic cancer. In some embodiments of any of the foregoing methods, the cancer is non-small cell lung cancer. In some embodiments of any of the foregoing methods, the cancer is colon cancer. In some embodiments of any of the foregoing methods, the cancer is ovarian cancer. In some embodiments of any of the foregoing methods, the cancer is glioblastoma. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is prostate cancer. In some
  • the cancer is diffuse large B-cell lymphoma.
  • the cancer is leukemia (e.g., acute myeloid leukemia).
  • the cancer is a metastatic cancer, a migrating cancer, or a non-metastatic cell migration cancer.
  • the cancer is a drug resistant cancer or has failed to respond to a prior therapy (e.g., a cancer resistant to, or a cancer that has failed to respond to prior treatment with vemurafenib, dacarbazine, a CTLA4 inhibitor, a PD1 inhibitor, interferon therapy, a BRAF inhibitor, a MEK inhibitor, radiotherapy, temozolimide, irinotecan, a CAR-T therapy, herceptin, pertuzumab, tamoxifen, capecitabine, docetaxol, platinum agents (e.g., carboplatin), a taxane (e.g., paclitaxel and/or docetaxel), ALK inhibitors, MET inihibitors, pemetrexed, protein-bound paclitaxel (ABRAXANE®), doxorubicin, gemcitabine, bevacizumab, eribulin mesylate (
  • the cancer is melanoma (e.g., metastatic melanoma) that is resistant to, or has failed to respond to prior treatment with, vemurafenib, dacarbazine, interferon therapy, a CTLA- 4 inhibitor, a BRAF inhibitor, a MEK inhibitor, a PD1 inhibitor, a PDL-1 inhibitor, and/or a CAR-T therapy.
  • melanoma e.g., metastatic melanoma
  • a cancer is melanoma (e.g., metastatic melanoma) that is resistant to, or has failed to respond to prior treatment with, vemurafenib, dacarbazine, interferon therapy, a CTLA- 4 inhibitor, a BRAF inhibitor, a MEK inhibitor, a PD1 inhibitor, a PDL-1 inhibitor, and/or a CAR-T therapy.
  • the cancer is glioblastoma that is resistant to, or has failed to respond to prior treatment with, temozolimide, radiotherapy, bevacizumab, irinotecan, a VEGFR2 inhibitor, a CAR-T therapy, and/or an mTOR inhibitor.
  • the cancer is non-small cell lung cancer such as metastatic non-small cell lung cancer (e.g., EGFR-wild type non-small cell lung cancer and/or squamous non-small cell lung cancer) that is resistant to, or has failed to respond to prior treatment with, an EGFR inhibitor, platinum agents (e.g., carboplatin), bevacizumab, an ALK inhibitor, a MET inhibitor, a taxane (e.g., paclitaxel and/or doceltaxel), gemcitabine, pemetrexed, radiotherapy, a PD1 inhibitor, a PDL1 ihibitor, and/or a CAR-T therapy.
  • metastatic non-small cell lung cancer e.g., EGFR-wild type non-small cell lung cancer and/or squamous non-small cell lung cancer
  • platinum agents e.g., carboplatin
  • bevacizumab e.g., an ALK inhibitor
  • a MET inhibitor e
  • the cancer is a breast cancer (e.g., triple negative breast cancer) that is resistant to, or has failed to respond to prior treatment with, herceptin, pertuzumab, tamoxifen, capecitabine, docetaxel, carboplatin, paclitaxel, protein-bound paclitazel (ABRAXANE®), doxorubicin, gemcitabine, bevacizumab, eribuline mesylate (HALAVEN®), neratinib, a PARP inhibitor, a PD1 inhibitor, a PDL1 inhibitor, a CAR-T therapy, ARN810, and/or an mTOR inhibitor.
  • herceptin pertuzumab, tamoxifen, capecitabine
  • docetaxel carboplatin
  • paclitaxel protein-bound paclitazel
  • ABRAXANE® protein-bound paclitazel
  • doxorubicin gemcitabine
  • bevacizumab
  • the cancer is ovarian cancer (e.g., metastatic ovarian cancer) that is resistant to, or has failed to respond to prior treatment with, a PARP inhibitor, bevacizumab, platinum agents such as carboplatin, paclitaxel, docetaxel, topotecan, gemcitabine, a VEGR2 inhibitor, a folate receptor antagonist, a PD1 inhibitor, a PDL1 inhibitor, a CAR-T therapy, demcizumab, and/or fosbretabulin.
  • Compounds described herein also include isotopically-labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds described herein include and are not limited to 2 H, 3 H, 11 C, 13 C, 14 C, 36 CI, 18 F, 123
  • isotopically-labeled compounds are useful in drug and/or substrate tissue distribution studies.
  • substitution with heavier isotopes such as deuterium affords greater metabolic stability (for example, increased in vivo half- life or reduced dosage requirements).
  • substitution with positron emitting isotopes, such as 11 C, 18 F, 15 0 and 13 N is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • Isotopically-labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.
  • acyl represents a FI or an alkyl group, as defined herein, that is attached to a parent molecular group through a carbonyl group, as defined herein, and is exemplified by formyl (i.e., a carboxyaldehyde group), acetyl, trifluoroacetyl, propionyl, and butanoyl.
  • exemplary unsubstituted acyl groups include from 1 to 6, from 1 to 1 1 1 , or from 1 to 21 carbons.
  • alkyl refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of 1 to 20 carbon atoms (e.g., 1 to 16 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms).
  • An alkylene is a divalent alkyl group.
  • alkenyl refers to a straight- chain or branched hydrocarbon residue having a carbon-carbon double bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbon atoms).
  • alkynyl refers to a straight- chain or branched hydrocarbon residue having a carbon-carbon triple bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6, or 2 carbon atoms).
  • amino represents -N(R N1 )2, wherein each R N1 is, independently, FI, OH, NO2, N(R N2 )2, S0 2 0R N2 , S02R N2 , SOR N2 , an /V-protecting group, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), wherein each of these recited R N1 groups can be optionally substituted; or two R N1 combine to form an alkylene or heteroalkylene, and wherein each R N2 is, independently, H, alkyl, or aryl.
  • the amino groups of the invention can be an unsubstituted amino (i.e., - NH2) or a substituted amino (i.e., -N(R N1 )2).
  • aryl refers to an aromatic mono- or polycarbocyclic radical of 6 to 12 carbon atoms having at least one aromatic ring.
  • groups include, but are not limited to, phenyl, naphthyl, 1 ,2,3,4-tetrahydronaphthyl, 1 ,2-dihydronaphthyl, indanyl, and 1 H-indenyl.
  • arylalkyl represents an alkyl group substituted with an aryl group.
  • exemplary unsubstituted arylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C1-6 alkyl C6-10 aryl, C1-10 alkyl C6-10 aryl, or C1-20 alkyl Ce-io aryl), such as, benzyl and phenethyl.
  • the akyl and the aryl each can be further substituted with 1 , 2, 3, or 4 substituent groups as defined herein for the respective groups.
  • cyano represents a -CN group.
  • Carbocyclyl refers to a non-aromatic C3-12 monocyclic, bicyclic, or tricyclic structure in which the rings are formed by carbon atoms.
  • Carbocyclyl structures include cycloalkyl groups and unsaturated carbocyclyl radicals.
  • cycloalkyl refers to a saturated, non-aromatic, monovalent mono- or polycarbocyclic radical of three to ten, preferably three to six carbon atoms. This term is further exemplified by radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl.
  • halogen means a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical.
  • heteroalkyl refers to an alkyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur.
  • the heteroalkyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein for alkyl groups.
  • heteroalkyl groups are an“alkoxy” which, as used herein, refers alkyl-O- (e.g., methoxy and ethoxy).
  • a heteroalkylene is a divalent heteroalkyl group.
  • heteroalkenyl refers to an alkenyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur.
  • the heteroalkenyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein for alkenyl groups.
  • heteroalkenyl groups are an“alkenoxy” which, as used herein, refers alkenyl-O-.
  • a heteroalkenylene is a divalent heteroalkenyl group.
  • heteroalkynyl refers to an alkynyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur.
  • the heteroalkynyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein for alkynyl groups.
  • heteroalkynyl groups are an“alkynoxy” which, as used herein, refers alkynyl-O-.
  • a heteroalkynylene is a divalent heteroalkynyl group.
  • heteroaryl refers to an aromatic mono- or polycyclic radical of 5 to 12 atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N,
  • heteroaryl group is pyridyl, pyrazoyl, benzooxazolyl, benzoimidazolyl, benzothiazolyl, imidazolyl, oxaxolyl, and thiazolyl.
  • heteroarylalkyl represents an alkyl group substituted with a heteroaryl group.
  • exemplary unsubstituted heteroarylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C1-6 alkyl C2-9 heteroaryl, C1-10 alkyl C2-9 heteroaryl, or C1-20 alkyl C2-9 heteroaryl).
  • the akyl and the heteroaryl each can be further substituted with 1 , 2, 3, or 4 substituent groups as defined herein for the respective groups.
  • heterocycly denotes a mono- or polycyclic radical having 3 to 12 atoms having at least one ring containing one, two, three, or four ring heteroatoms selected from N, O or S, wherein no ring is aromatic.
  • heterocyclyl groups include, but are not limited to, morpholinyl, thiomorpholinyl, furyl, piperazinyl, piperidinyl, pyranyl, pyrrol id inyl, tetrahydropyranyl, tetrahydrofuranyl, and 1 ,3-dioxanyl.
  • heterocyclylalkyl represents an alkyl group substituted with a heterocyclyl group.
  • exemplary unsubstituted heterocyclylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as Ci-6 alkyl C2-9 heterocyclyl, C1-10 alkyl C2-9 heterocyclyl, or C1 -20 alkyl C2-9 heterocyclyl).
  • the akyl and the heterocyclyl each can be further substituted with 1 , 2, 3, or 4 substituent groups as defined herein for the respective groups.
  • hydroxyl represents an -OH group.
  • /V-protecting group represents those groups intended to protect an amino group against undesirable reactions during synthetic procedures. Commonly used /V-protecting groups are disclosed in Greene,“Protective Groups in Organic Synthesis,” 3 rd Edition (John Wiley &
  • /V-protecting groups include acyl, aryloyl, or carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4
  • nitrobenzoyl, and chiral auxiliaries such as protected or unprotected D, L or D, L-amino acids such as alanine, leucine, and phenylalanine; sulfonyl-containing groups such as benzenesulfonyl, and p- toluenesulfonyl; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl,
  • diisopropylmethoxycarbonyl isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxy carbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl, arylalkyl groups such as benzyl, triphenylmethyl, and benzyloxymethyl, and silyl groups, such as trimethylsilyl.
  • Preferred /V-protecting groups are alloc, formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).
  • nitro represents an -NO2 group.
  • thiol represents an -SH group.
  • alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl (e.g., cycloalkyl), aryl, heteroaryl, and heterocyclyl groups may be substituted or unsubstituted. When substituted, there will generally be 1 to 4 substituents present, unless otherwise specified.
  • Substituents include, for example: aryl (e.g., substituted and unsubstituted phenyl), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl), halogen (e.g., fluoro), hydroxyl, heteroalkyl (e.g., substituted and unsubstituted methoxy, ethoxy, or thioalkoxy), heteroaryl, heterocyclyl, amino (e.g., NH2 or mono- or dialkyl amino), azido, cyano, nitro, or thiol.
  • aryl e.g., substituted and unsubstituted phenyl
  • carbocyclyl e.g., substituted and unsubstituted cycloalkyl
  • halogen e.g., fluoro
  • hydroxyl hydroxyl
  • heteroalkyl e.g., substituted and unsubstituted
  • Aryl, carbocyclyl (e.g., cycloalkyl), heteroaryl, and heterocyclyl groups may also be substituted with alkyl (unsubstituted and substituted such as arylalkyl (e.g., substituted and unsubstituted benzyl)).
  • Compounds of the invention can have one or more asymmetric carbon atoms and can exist in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.
  • the optically active forms can be obtained for example by resolution of the racemates, by asymmetric synthesis or asymmetric chromatography (chromatography with a chiral adsorbents or eluant). That is, certain of the disclosed compounds may exist in various stereoisomeric forms.
  • Stereoisomers are compounds that differ only in their spatial arrangement.
  • Enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center. "Enantiomer” means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms and represent the configuration of substituents around one or more chiral carbon atoms. Enantiomers of a compound can be prepared, for example, by separating an enantiomer from a racemate using one or more well-known techniques and methods, such as, for example, chiral chromatography and separation methods based thereon.
  • Racemate or “racemic mixture” means a compound containing two enantiomers, wherein such mixtures exhibit no optical activity; i.e., they do not rotate the plane of polarized light.
  • “Geometric isomer” means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system.
  • Atoms (other than H) on each side of a carbon- carbon double bond may be in an E (substituents are on opposite sides of the carbon- carbon double bond) or Z (substituents are oriented on the same side) configuration.
  • "R,” “S,” “S*,” “R*,” “E,” “Z,” “cis,” and “trans,” indicate configurations relative to the core molecule.
  • Certain of the disclosed compounds may exist in atropisomeric forms.
  • Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers.
  • the compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from an isomeric mixture.
  • Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods.
  • the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9%) by weight relative to the other
  • stereoisomers When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight optically pure. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure. Percent optical purity is the ratio of the weight of the enantiomer or over the weight of the enantiomer plus the weight of its optical isomer. Diastereomeric purity by weight is the ratio of the weight of one diastereomer or over the weight of all the diastereomers.
  • the stereochemistry of a disclosed compound is named or depicted by structure
  • the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by mole fraction pure relative to the other stereoisomers.
  • the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by mole fraction pure.
  • the depicted or named diastereomer is at least 60%,
  • Percent purity by mole fraction is the ratio of the moles of the enantiomer or over the moles of the enantiomer plus the moles of its optical isomer.
  • percent purity by moles fraction is the ratio of the moles of the diastereomer or over the moles of the diastereomer plus the moles of its isomer.
  • diastereomer(s) or mixtures of diastereomers in which one or more diastereomer is enriched relative to the other diastereomers The invention embraces all of these forms.
  • the term“a” may be understood to mean“at least one”;
  • the term“or” may be understood to mean“and/or”;
  • the terms“comprising” and “including” may be understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps; and
  • the terms“about” and “approximately” may be understood to permit standard variation as would be understood by those of ordinary skill in the art; and (v) where ranges are provided, endpoints are included.
  • adenosine AZA receptor refers to the protein encoded by the adenosine AZA receptor
  • the adenosine A ⁇ A receptor refers to a peptide having the sequence of SEQ ID NO: 1 and/or a polypeptide with at least 90% identity (e.g., at least 95% identity, at least 98% identity, at least 99% identity) to SEQ ID NO: 1.
  • adenosine A2A receptor activity is measured by any method known in the art.
  • human adenosine A2 A receptor activity may be measured by a radioligand competition assay.
  • the ability of each test compound to compete for the radioligand binding at eight concentration points may be measured by scintillation counting. Data may be analyzed by non-linear regression to generate IC50 values and the inhibition constants (Ki) were calculated using the Cheng Prusoff equation.
  • adenosine A2B receptor refers to the protein encoded by the
  • the adenosine A ⁇ B receptor refers to a peptide having the sequence of SEQ ID NO: 2 and/or a polypeptide with at least 90% identity (e.g., at least 95% identity, at least 98% identity, at least 99% identity) to SEQ ID NO: 2.
  • adenosine AIB receptor activity is measured by any method known in the art.
  • human adenosine A2B receptor activity may be measured by a radioligand competition assay.
  • the ability of each test compound to compete for the radioligand binding at eight concentration points may be measured by scintillation counting. Data may be analyzed by non-linear regression to generate IC50 values and the inhibition constants (Ki) were calculated using the Cheng Prusoff equation.
  • the term“administration” refers to the administration of a composition (e.g., a compound or a preparation that includes a compound as described herein) to a subject or system.
  • Administration to an animal subject may be by any appropriate route.
  • administration may be bronchial (including by bronchial instillation), buccal, enteral, interdermal, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal,
  • cancer refers to a condition caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, and lymphomas.
  • a“combination therapy” or“administered in combination” means that two (or more) different agents or treatments are administered to a subject as part of a defined treatment regimen for a particular disease or condition.
  • the treatment regimen defines the doses and periodicity of administration of each agent such that the effects of the separate agents on the subject overlap.
  • the delivery of the two or more agents is simultaneous or concurrent and the agents may be co-form u I ated.
  • the two or more agents are not co-formulated and are administered together or in a sequential manner as part of a prescribed regimen.
  • administration of two or more agents or treatments in combination is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one agent or treatment delivered alone or in the absence of the other.
  • the effect of the two treatments can be partially additive, wholly additive, or greater than additive (e.g., synergistic).
  • Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues.
  • the therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination may be administered by intravenous injection while a second therapeutic agent of the combination may be administered orally.
  • a cancer“determined to be drug resistant,” as used herein, refers to a cancer that is drug resistant based on unresponsiveness or decreased responsiveness to a chemotherapeutic agent, or is predicted to be drug resistant based on a prognostic assay (e.g., a gene expression assay).
  • a“drug resistant” cancer is meant a cancer that does not respond, or exhibits a decreased response to, one or more chemotherapeutic agents (e.g., any agent described herein).
  • CTLA-4 inhibitor refers to a compound such as an antibody capable of inhibiting the activity of the protein that in humans is encoded by the CTLA4 gene.
  • CTLA-4 inhibitors include ipilimumab.
  • determining the level of a protein is meant the detection of a protein, or an mRNA encoding the protein, by methods known in the art either directly or indirectly.
  • Directly determining means performing a process (e.g., performing an assay or test on a sample or“analyzing a sample” as that term is defined herein) to obtain the physical entity or value.
  • Indirectly determining refers to receiving the physical entity or value from another party or source (e.g., a third party laboratory that directly acquired the physical entity or value).
  • Methods to measure protein level generally include, but are not limited to, western blotting, immunoblotting, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), immunoprecipitation, immunofluorescence, surface plasmon resonance, chemiluminescence, fluorescent polarization, phosphorescence, immunohistochemical analysis, matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry, liquid chromatography (LC)-mass spectrometry, microcytometry, microscopy, fluorescence activated cell sorting (FACS), and flow cytometry, as well as assays based on a property of a protein including, but not limited to, enzymatic activity or interaction with other protein partners.
  • Methods to measure mRNA levels are known in the art.
  • disorder related to the adenosine A2 A receptor refers to any disease or disorder that may derive a therapeutic benefit from modulation (e.g., inhibition) of the activity of the adenosine A ⁇ A receptor, e.g., cancer.
  • An“effective amount” of a compound may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the compound to elicit the desired response.
  • a therapeutically effective amount encompasses an amount in which any toxic or detrimental effects of the compound are outweighed by the therapeutically beneficial effects.
  • a therapeutically effective amount also encompasses an amount sufficient to confer benefit, e.g., clinical benefit.
  • the term“failed to respond to a prior therapy” or“refractory to a prior therapy,” refers to a cancer that progressed despite treatment with the therapy.
  • the term“inhibiting inflammation” refers to preventing inflammation or decreasing inflammation.
  • modulating an immune response is meant altering (e.g., stimulating or suppressing) an immune response.
  • the level of immune response may be measured using any method known in the art.
  • modulating the activity of a protein is meant increasing or decreasing the level of an activity related to the protein, or a related downstream effect.
  • the activity level a protein may be measured using any method known in the art.
  • modulating the activity of the adenosine receptor is meant increasing or decreasing the level of an activity related to the adenosine receptor (e.g., the adenosine AIA receptor, the adenosine A ⁇ B receptor, the adenosine Ai receptor, or the adenosine A3 receptor) , or a related downstream effect.
  • a non-limiting example of modulation of adenosine receptor includes increasing the level of immune cells in a subject by inhibiting the adenosine A2A receptor.
  • modulating the activity of the dopamine receptor is meant increasing or decreasing the level of an activity related to the dopamine receptor (e.g., the dopamine Di receptor or the dopamine D2 receptor), or a related downstream effect.
  • a non-limiting example of modulation of the dopamine receptor includes increasing the level of immune cells in a subject by inhibiting the dopamine D2 receptor.
  • level is meant a level of a protein, or mRNA encoding the protein, as compared to a reference.
  • the reference can be any useful reference, as defined herein.
  • a“decreased level” or an “increased level” of a protein is meant a decrease or increase in protein level, as compared to a reference (e.g., a decrease or an increase by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 150%, about 200%, about 300%, about 400%, about 500%, or more; a decrease or an increase of more than about 10%, about 15%, about 20%, about 50%, about 75%, about 100%, or about 200%, as compared to a reference; a decrease or an increase by less than about 0.01 -fold, about 0.02-fold, about
  • metastatic tumor refers to a tumor or cancer in which the cancer cells forming the tumor have a high potential to or have begun to, metastasize, or spread from one location to another location or locations within a subject, via the lymphatic system or via haematogenous spread, for example, creating secondary tumors within the subject. Such metastatic behavior may be indicative of malignant tumors. In some cases, metastatic behavior may be associated with an increase in cell migration and/or invasion behavior of the tumor cells.
  • cancers that can be defined as metastatic include but are not limited to non-small cell lung cancer, breast cancer, ovarian cancer, colorectal cancer, biliary tract cancer, bladder cancer, brain cancer including glioblastomas and medullablastomas, cervical cancer, choriocarcinoma, endometrial cancer, esophageal cancer, gastric cancer, hematological neoplasms, multiple myeloma, leukemia, intraepithelial neoplasms, livercancer, lymphomas, neuroblastomas, oral cancer, pancreatic cancer, prostate cancer, sarcoma, skin cancer including melanoma, basocellular cancer, squamous cell cancer, testicular cancer, stromal tumors, germ cel! tumors, thyroid cancer, and renal cancer.
  • “migrating cancer” refers to a cancer in which the cancer cells forming the tumor migrate and subsequently grow as malignant implants at a site other than the site of the original tumor.
  • the cancer cells migrate via seeding the surface of the peritoneal, pleural, pericardial, or subarachnoid spaces to spread into the body cavities; via invasion of the lymphatic system through invasion of lymphatic cells and transport to regional and distant lymph nodes and then to other parts of the body; via haematogenous spread through invasion of blood cells; or via invasion of the surrounding tissue.
  • Migrating cancers include metastatic tumors and cell migration cancers, such as ovarian cancer, mesothelioma, and primary lung cancer, each of which is characterized by cellular migration.
  • Non-metastatic cell migration cancer refers to cancers that do not migrate via the lymphatic system or via haematogenous spread.
  • PD-1 inhibitor refers to a compound such as an antibody capable of inhibiting the activity of the protein that in humans is encoded by the PDCD1 gene.
  • PD-1 inhibitors include nivolumab, pembrolizumab, pidilizumab, and BMS 936559.
  • PD-L1 inhibitor refers to a compound such as an antibody capable of inhibiting the activity of the protein that in humans is encoded by the CD274 gene.
  • Known PD-L1 inhibitors include atezolizumab and durvalumab.
  • compositions represents a composition containing a compound described herein formulated with a pharmaceutically acceptable excipient, and manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal.
  • Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other pharmaceutically acceptable formulation.
  • A“pharmaceutically acceptable excipient,” as used herein, refers any ingredient other than the compounds described herein (for example, a vehicle capable of suspending or dissolving the active compound) and having the properties of being substantially nontoxic and non-inflammatory in a patient.
  • Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, and waters of hydration.
  • excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C,
  • pharmaceutically acceptable salt means any pharmaceutically acceptable salt of the compound of formula (I).
  • pharmaceutically acceptable salts of any of the compounds described herein include those that are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al.,
  • the compounds of the invention may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts.
  • These salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the compounds of the invention be prepared from inorganic or organic bases.
  • the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases.
  • Suitable pharmaceutically acceptable acids and bases and methods for preparation of the appropriate salts are well-known in the art. Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases including inorganic and organic acids and bases.
  • Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate,
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.
  • a“reference” is meant any useful reference used to compare protein or mRNA levels.
  • the reference can be any sample, standard, standard curve, or level that is used for comparison purposes.
  • the reference can be a normal reference sample or a reference standard or level.
  • A“reference sample” can be, for example, a control, e.g., a predetermined negative control value such as a“normal control” or a prior sample taken from the same subject; a sample from a normal healthy subject, such as a normal cell or normal tissue; a sample (e.g., a cell or tissue) from a subject not having a disease; a sample from a subject that is diagnosed with a disease, but not yet treated with a compound of the invention; a sample from a subject that has been treated by a compound of the invention; or a sample of a purified protein (e.g., any described herein) at a known normal concentration.
  • a control e.g., a predetermined negative control value such as a
  • A“reference standard or level” is meant a value or number derived from a reference sample.
  • A“normal control value” is a pre-determ ined value indicative of non-disease state, e.g., a value expected in a healthy control subject. Typically, a normal control value is expressed as a range (“between X and Y”), a high threshold (“no higher than X”), or a low threshold (“no lower than X”).
  • a subject having a measured value within the normal control value for a particular biomarker is typical!'/ referred to as“within normal limits” for that biomarker.
  • reference standard or level can be a value or number derived from a normal subject not having a disease or disorder (e.g., cancer); a subject that has been treated with a compound of the invention.
  • the reference sample, standard, or level is matched to the sample subject sample by at least one of the following criteria: age, weight, sex, disease stage, and overall health.
  • a standard curve of levels of a purified protein, e.g., any described herein, within the normal reference range can also be used as a reference.
  • the term“subject” refers to any organism to which a composition in accordance with the invention may be administered, e.g., for experimental, diagnostic, prophylactic, and/or therapeutic purposes. Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans). A subject may seek or be in need of treatment, require treatment, be receiving treatment, be receiving treatment in the future, or be a human or animal who is under care by a trained professional for a particular disease or condition.
  • animal e.g., mammals such as mice, rats, rabbits, non-human primates, and humans.
  • a subject may seek or be in need of treatment, require treatment, be receiving treatment, be receiving treatment in the future, or be a human or animal who is under care by a trained professional for a particular disease or condition.
  • treat means both therapeutic treatment and prophylactic or preventative measures wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder, or disease, or obtain beneficial or desired clinical results.
  • Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of a condition, disorder, or disease; stabilized (i.e., not worsening) state of condition, disorder, or disease; delay in onset or slowing of condition, disorder, or disease progression; amelioration of the condition, disorder, or disease state or remission (whether partial or total), whether detectable or undetectable; an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of condition, disorder, or disease.
  • Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.
  • FIG 1. is a graph of the quantitation of IL-12 cytokine secreted from dendritic cells that had been differentiated and activated in the presence or absence of 5’-(N-ethylcarboxamido)adenosine (NECA) and compounds of the invention.
  • FIG. 2 is a graph of the quantitation of IL-6 cytokine secreted from dendritic cells that had been differentiated and activated in the presence or absence of NECA and compounds of the invention.
  • Recent immunotherapy approaches based on inhibiting immune checkpoint receptors offer a promising avenue to achieve robust, durable therapeutic responses in a number of solid tumors.
  • the suppression of tumor-specific T cells is orchestrated by both intrinsic and extrinsic factors including the production of immunosuppressive oncometabolites (e.g., tryptophan and adenosine) and by the activity of a variety of stromal myeloid and lymphoid cells.
  • the myeloid cells comprise various cell types, including neutrophils, macrophages, myeloid-derived suppressor cells (MDSCs) and dendritic cells (DCs) that regulate inflammation and immune state to maintain tissue homeostasis.
  • adenosine The action of adenosine is mediated by a family of G-protein coupled receptors (GPCR). Based on biochemical and pharmacological criteria, four subtypes of adenosine receptors have been described: A2A, A2B, Ai, and A3. The Ai and A3 receptors inhibit adenylyl cyclase, while the A2A and A2A receptors stimulate adenylyl cyclase.
  • GPCR G-protein coupled receptors
  • the adenosine A2 A receptor has dynamic expression pattern on a subset of immune cells and is an important checkpoint in cancer therapy. Most of the immunomodulatory effects of adenosine signaling are thought to be mediated through the high-affinity adenosine A2 A receptor, which is expressed primarily on T-cells, and through the low-affinity adenosine A2B receptor, which is expressed primarily on myeloid cells.
  • adenosine metabolism and signaling contributes to the resolution of tissue inflammation and modulation of adaptive T cell immunity in a healthy individual.
  • adenosine production is induced in response to hypoxia and its presence and downstream functions create an immunosuppressive state that is protective of a tumor rather than the patient.
  • blocking the adenosine signaling-mediated immune checkpoint is important.
  • the concentration of adenosine can reach levels as high as 100 pM within the tumor microenvironment.
  • the tumor microenvironment is thereby primed for immunosuppression by this metabolite exerting its functions through binding to A2 A receptors and A2B receptors expressed on primarily lymphoid and myeloid cells, respectively.
  • Adenosine binds to A2 A receptors with a high affinity, and low concentrations of adenosine are able to trigger a cAMP- dependent signaling cascade into T cells and NK cells that suppresses their immunosurveillance capabilities.
  • Small molecule antagonists of A2 A receptor rescue lymphocytes from the
  • A2 A receptor antagonists also act in synergy with checkpoint inhibitors to block tumor progression and metastases in animal models of cancer, demonstrating the immunosuppressive impact of endogenous adenosine in vivo.
  • the invention features compounds useful for modulating the activity of the adenosine A2 A receptor, e.g., for the treatment of cancer.
  • exemplary compounds described herein include compounds having a structure according to Formula I:
  • the compound has the structure of any one of compounds 1 -80 in Table 1.
  • the compounds described herein are useful in the methods of the invention and, while not bound by theory, are believed to exert their desirable effects through modulation of the levels of adenosine, for example, through their ability to modulate the level, status, and/or activity of an adenosine receptor (e.g., the adenosine A2A receptor and/or the adenosine A2B receptor) in mammals, e.g., humans.
  • an adenosine receptor e.g., the adenosine A2A receptor and/or the adenosine A2B receptor
  • An aspect of the present invention relates to methods of modulating an immune response in a subject in need thereof.
  • the compound is administered in an amount and for a time effective to stimulate an immune response in a subject in need thereof.
  • a further aspect of the present invention relates to inhibiting inflammation in a subject in need thereof.
  • the compound is administered in an amount and for a time effective to prevent inflammation in a subject in need thereof.
  • Another aspect of the present invention relates to methods of treating disorders related to the adenosine receptors (e.g., the adenosine A2 A receptors) such as cancer, in a subject in need thereof.
  • the compound is administered in an amount and for a time effective to result in one of (or more, e.g., 2 or more, 3 or more, 4 or more of): (a) reduced tumor size, (b) reduced rate of tumor growth, (c) increased tumor cell death (d) reduced tumor progression, (e) reduced number of metastases, (f) reduced rate of metastasis, (g) decreased tumor recurrence (h) increased survival of subject, or (i) increased progression free survival of subject.
  • adenosine receptors e.g., the adenosine A2 A receptors
  • the compound is administered in an amount and for a time effective to result in one of (or more, e.g., 2 or more, 3 or more, 4 or more of): (a)
  • Treating cancer can result in a reduction in size or volume of a tumor.
  • tumor size is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%,
  • Size of a tumor may be measured by any reproducible means of measurement.
  • the size of a tumor may be measured as a diameter of the tumor.
  • Treating cancer may further result in a decrease in number of tumors.
  • tumor number is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to number prior to treatment.
  • Number of tumors may be measured by any reproducible means of measurement, e.g., the number of tumors may be measured by counting tumors visible to the naked eye or at a specified magnification (e.g., 2x, 3x, 4x, 5x, 10x, or 50x).
  • Treating cancer can result in a decrease in number of metastatic nodules in other tissues or organs distant from the primary tumor site.
  • the number of metastatic nodules is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to number prior to treatment.
  • the number of metastatic nodules may be measured by any reproducible means of measurement.
  • the number of metastatic nodules may be measured by counting metastatic nodules visible to the naked eye or at a specified magnification (e.g., 2x, 10x, or 50x).
  • Treating cancer can result in an increase in average survival time of a population of subjects treated according to the present invention in comparison to a population of untreated subjects.
  • the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days).
  • An increase in average survival time of a population may be measured by any reproducible means.
  • An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with the compound of the invention.
  • An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with a pharmaceutically acceptable salt of the invention.
  • Treating cancer can also result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population.
  • the mortality rate is decreased by more than 2% (e.g., more than 5%, 10%, or 25%).
  • a decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with a pharmaceutically acceptable salt of the invention.
  • a decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with a pharmaceutically acceptable salt of the invention.
  • the compounds of the invention can be combined with one or more therapeutic agents.
  • the therapeutic agent can be one that treats or prophylactically treats any cancer described herein.
  • a compound of the invention can be used alone or in combination with an additional therapeutic agent, e.g., other agents that treat cancer or symptoms associated therewith, or in combination with other types of treatment to treat cancer.
  • the dosages of one or more of the therapeutic compounds may be reduced from standard dosages when administered alone. For example, doses may be determined empirically from drug combinations and permutations or may be deduced by isobolographic analysis (e.g., Black et al., Neurology 65:S3-S6, 2005). In this case, dosages of the compounds when combined should provide a therapeutic effect.
  • the second agent may be a checkpoint inhibitor.
  • the inhibitor of checkpoint is an inhibitory antibody (e.g., a monospecific antibody such as a monoclonal antibody).
  • the antibody may be, e.g., humanized or fully human.
  • the inhibitor of checkpoint is a fusion protein, e.g., an Fc-receptor fusion protein.
  • the inhibitor of checkpoint is an agent, such as an antibody, that interacts with a checkpoint protein.
  • the inhibitor of checkpoint is an agent, such as an antibody, that interacts with the ligand of a checkpoint protein.
  • the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA4 antibody such as ipilimumab/Yervoy or tremelimumab).
  • the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PD-1 (e.g., nivolumab/Opdivo®; pembrolizumab/Keytruda®;
  • the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PDL1 (e.g., MPDL3280A/RG7446; MEDI4736; MSB0010718C; BMS 936559).
  • the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor) of PDL2 (e.g., a PDL2/lg fusion protein such as AMP 224).
  • the inhibitor of checkpoint is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3 (e.g., MGA271 ), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG 3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1 , CHK2, A2 A receptor, A2B receptor, B-7 family ligands, or a combination thereof.
  • B7-H3 e.g., MGA271
  • B7-H4 BTLA
  • HVEM HVEM
  • TIM3 e.g., GAL9, LAG 3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1 , CHK2, A2 A receptor, A2B receptor, B-7 family ligands, or a combination thereof.
  • the first and second therapeutic agent are administered simultaneously or sequentially, in either order.
  • the first therapeutic agent may be administered immediately, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to, 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to hours 16, up to 17 hours, up 18 hours, up to 19 hours up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours up to 24 hours or up to 1-7, 1 -14, 1-21 or 1 -30 days before or after the second therapeutic agent.
  • the compounds of the invention are preferably formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo. Accordingly, in another aspect, the present invention provides a pharmaceutical composition comprising a compound of the invention in admixture with a suitable diluent, carrier, or excipient.
  • the compounds of the invention may be used in the form of the free base, in the form of salts, solvates, and as prodrugs. All forms are within the scope of the invention.
  • the described compounds or salts, solvates, or prodrugs thereof may be administered to a patient in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art.
  • the compounds of the invention may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, or transdermal administration and the pharmaceutical compositions formulated accordingly.
  • Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.
  • a compound of the invention may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet.
  • a compound of the invention may be incorporated with an excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, and wafers.
  • a compound of the invention may also be administered parenterally.
  • Solutions of a compound of the invention can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.
  • Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington’s Pharmaceutical Sciences (2003, 20 th ed.) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19), published in 1999.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that may be easily administered via syringe.
  • compositions for nasal administration may conveniently be formulated as aerosols, drops, gels, and powders.
  • Aerosol formulations typically include a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomizing device.
  • the sealed container may be a unitary dispensing device, such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use.
  • the dosage form comprises an aerosol dispenser
  • a propellant which can be a compressed gas, such as compressed air or an organic propellant, such as fluorochlorohydrocarbon.
  • the aerosol dosage forms can also take the form of a pump-atomizer.
  • compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, where the active ingredient is formulated with a carrier, such as sugar, acacia, tragacanth, gelatin, and glycerine.
  • a carrier such as sugar, acacia, tragacanth, gelatin, and glycerine.
  • Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base, such as cocoa butter.
  • the compounds of the invention may be administered to an animal, e.g., a human, alone or in combination with pharmaceutically acceptable carriers, as noted herein, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration, and standard pharmaceutical practice.
  • the dosage of the compounds of the invention, and/or compositions comprising a compound of the invention can vary depending on many factors, such as the pharmacodynamic properties of the compound; the mode of administration; the age, health, and weight of the recipient; the nature and extent of the symptoms; the frequency of the treatment, and the type of concurrent treatment, if any; and the clearance rate of the compound in the animal to be treated.
  • One of skill in the art can determine the appropriate dosage based on the above factors.
  • the compounds of the invention may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response. In general, satisfactory results may be obtained when the compounds of the invention are administered to a human at a daily dosage of, for example, between 0.05 mg and 3000 mg (measured as the solid form).
  • Dose ranges include, for example, between 10-1000 mg (e.g., 50-800 mg). In some embodiments, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of the compound is administered.
  • the dosage amount can be calculated using the body weight of the patient.
  • the dose of a compound, or pharmaceutical composition thereof, administered to a patient may range from 0.1 -50 mg/kg (e.g., 0.25-25 mg/kg).
  • the dose may range from 0.5-5.0 mg/kg (e.g., 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 mg/kg) or from 5.0-20 mg/kg (e.g., 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg/kg).
  • dichloromethane-methanol as eluent.
  • the product was repurified on silica (12g) using a gradient of dichloromethane-methanol as eluent.
  • the product was triturated with dichloromethane (4mL) overnight then filtered to afford 6-methyl-4-oxo-N-(3-(trifluoromethyl)benzyl)-3,4-dihydrofuro[2,3-d]pyrimidine-5- carboxamide (197mg) as a white solid.
  • the crude product product was purified by flash column chromatography on silica (24g) using a gradient of dichloromethane-ethyl acetate to afford 2-methyi-1-oxo-1 ,2,3,4-tetrahydroisoquinoline-5-carbonitrile (440mg).
  • Lithium aluminum hydride (76mg, 2.00mmol) was added to a solution of 1 -methyl-1 H-indazole-4- carboxamide (161 mg, 0.92mmol) in THF (6mL) and stirred for 5 minutes. The mixture was then heated at reflux for 1 hour before being cooled to 0 °C. Water (76pL), 15%aq. NaOH (76pL) and water (220pL) were added in succession and the mixture was diluted with DCM-methanol (9:1 ) and filtered through celite. The filtrate was concentrated under reduced pressure to afford (1 -methyl-1 H-indazol-4- yl)methanamine as a sticky brown solid (276mg) that was used without further purification.
  • PBMCs were prepared from fresh human blood using a LymphoprepTM kit and the purified PBMCs were resuspended in RPMI1640 media with 10% FBS. PBMCs were then stimulated to produce cytokines with the addition of anti-CD3/CD28 coated bead at a 1 :6 bead/cell ratio. A total of
  • 200,000 PBMC were added to each well of a 96-well plate along with either 150 nM or 300 nM NEC A and various concentrations of test compounds.
  • the PBMC plate was incubated for 24 hours at 37 °C and then an aliquot of the media was taken to read TNFa levels using a standard ELISA assay. IFNy levels were read using a standard ELISA assay after 48 hours of incubation. Percent recovery for each cytokine was calculated by comparing the cytokine concentration in the presence of compound to the
  • Example 51 Quantitation of IL-12 and IL-6 Cytokine Secreted from Dendritic Cells Treated with Compounds of the Invention
  • the A2 A and A ⁇ A /b antagonists were solubilized at 10 mM in DMSO and serially diluted to 400 pM in 2% DMSO. With the addition of 5 pl of these or the 2% DMSO working stock, the final
  • concentrations in a given well was either 0 or 10 pM of an antagonist.
  • the final concentration of DMSO was 0.1 % in all wells.
  • Cell were incubated for 5 days at 37°C in 6% CO2.
  • the immature DC were fully matured/activated by the addition of poly IC in 20 pl of media (Sigma #1530) to a final concentration of 20 pg/ml. After a further 24 h incubation, conditioned media was collected and frozen. A final 20x dilution of the conditioned media was evaluated for cytokines with the V-plex Proinflammatory Panel 1 (MSD #R15056).
  • IL-12 (FIG. 1 ) and IL-6 (FIG. 2) levels were measured in the conditioned media 24 h after immature DC had been activated with 20 pg/mL poly IC.
  • Immature DC had been differentiated from monocytes, and subsequently activated, in the presence or absence of 1 pM and 10 pM NECA, a nonhydrolyzable analog of adenosine, 10 pM of an A2A antagonist (compound 42), or 10 pM of a dual A2 A /A2 B antagonist (compound 84).
  • an AZA antagonist (compound 47) is not able to reverse the effect of NECA on the IL-12 and IL-6 levels, while a dual AZAIAZB antagonist (compound 84) is effective at reversing the effect of NECA on the IL-12 and IL-6 levels.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés utiles dans le traitement de troubles liés à l'adénosine ou au récepteur de l'adénosine.
PCT/US2019/062025 2018-11-19 2019-11-18 Composés et leurs utilisations Ceased WO2020106625A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009011617A2 (fr) * 2007-07-17 2009-01-22 'chemical Diversity Research Institute', Joint Stock Company Azahétérocycles annelés comprenant un fragment de pyrimidine, procédé de leur fabrication et inhibiteurs de pi3k kinases

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009011617A2 (fr) * 2007-07-17 2009-01-22 'chemical Diversity Research Institute', Joint Stock Company Azahétérocycles annelés comprenant un fragment de pyrimidine, procédé de leur fabrication et inhibiteurs de pi3k kinases

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
PUBCHEMCID-120162087, 15 June 2016 (2016-06-15), pages 2 *
PUBCHEM-CID-18775300, 4 December 2007 (2007-12-04), pages 2, XP058420518 *
PUBCHEM-CID-66663375, 30 November 2012 (2012-11-30), pages 2 *

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