WO2021146631A1 - Composés hétérocycliques en tant qu'antagonistes de l'adénosine - Google Patents

Composés hétérocycliques en tant qu'antagonistes de l'adénosine Download PDF

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WO2021146631A1
WO2021146631A1 PCT/US2021/013740 US2021013740W WO2021146631A1 WO 2021146631 A1 WO2021146631 A1 WO 2021146631A1 US 2021013740 W US2021013740 W US 2021013740W WO 2021146631 A1 WO2021146631 A1 WO 2021146631A1
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alkylene
optionally substituted
halogen
compound
oxo
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PCT/US2021/013740
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English (en)
Inventor
Son Minh Pham
Jayakanth Kankanala
Pradeep S. Jadhavar
Baban Mohan MULIK
Farha KHAN
Sreekanth A. RAMACHANDRAN
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Nuvation Bio Inc.
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Publication of WO2021146631A1 publication Critical patent/WO2021146631A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • This disclosure relates generally to therapeutics for treatment mediated through a G- protein-coupled receptor (GPCR) signaling pathway and, more particularly, to compounds that inhibit an adenosine receptor (such as an A2A antagonist).
  • GPCR G- protein-coupled receptor
  • the disclosure also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compounds or compositions in the treatment of a disease associated with a GPCR signaling pathway.
  • Adenosine receptors are distributed throughout the body and are responsible for numerous biological functions.
  • the seven trans-membrane G-protein-coupled receptors (GPCRs) have been divided into four different subtypes: A 1 , A 2A , A 2B , and A3 .
  • the A 2A and A 2B ARs stimulate activity of the adenylyl cyclase, inducing an increase of cAMP levels.
  • a 2A ARs have a distinct tissue localization, different biochemical pathways, and specihc pharmacological prohles.
  • Adenosine is one of the human body’s most important neuromodulators in both the central and the peripheral nervous systems. Adenosine is released from tumor cells and its concentration in the extracellular fluid of tumors can reach immunosuppressive levels (Blay et al. (1997), Cancer Res., 57(13), pp. 2602-5). The extracellular fluid of solid carcinomas contains immunosuppressive concentrations of adenosine. Id. This increase in adenosine concentration is a result of increases in CD73 (ecto-5 '-nucleotidase) and CD39 (nucleoside triphosphate dephosphorylase) enzymes, which are responsible for directly catabolizing ATP into adenosine.
  • CD73 ecto-5 '-nucleotidase
  • CD39 nucleoside triphosphate dephosphorylase
  • adenosine as an endogenous immunoregulator in cancer pathogenesis: where to go?
  • CAR chimeric antigen receptor
  • Blockade of striatal adenosine A 2A receptor reduces, through a presynaptic mechanism, quinolinic acid-induced excitotoxicity: possible relevance to neuroprotective interventions in neurodegenerative diseases of the striatum, J. Neurosci, 22(5) pp. 1967-75, Gessi et al. (2011). Adenosine receptors and cancer. Biochim Biophys Acta,
  • a 2A and A3 subtypes appear promising targets for therapeutic development.
  • activation of A 2A receptors leads to immunosuppressive effects, which decreases anti-tumoral immunity and thereby encourages tumor growth.
  • the A 2B receptor is another potential target for therapeutic development. Autocrine/paracrine stimulation of A 2B expressed on tumor cells is believed to enhance their metastatic potential and A 2B blockade may reduce tumor metastasis in an immune-independent manner (Beavis et al. (2013). Blockade of A 2A receptors potently suppresses the metabolism of CD73 + Tumors. Proc. Natl. Acad. 5c/., 110(36) pp. 14711-6). A 2B expression also correlates with relapse-free survival (RFS) in triple negative breast cancer suggesting that this pathway may be clinically relevant.
  • RFS relapse-free survival
  • a 2B blockade also has the potential to modulate the immunosuppressive properties of tumor-associated immune cells including dendritic cells and myeloid-derived suppressor cells (MDSCs) (Cekic et al. (2011). Adenosine A2B receptor blockade slows growth of bladder and breast tumors. J. Immunol. 188(1 ), pp. 198-205; Sorrentino et al. (2015). Myeloid-derived suppressor cells contribute to A 2B adenosine receptor-induced VEGF production and angiogenesis in a mouse melanoma model. Oncotarget 6(29), pp. 27478-89; Iannone et al. (2013). Blockade of A 2B adenosine receptor reduces tumor growth and immune suppression mediated by myeloid-derived suppressor cells in a mouse model of melanoma. Neoplasia, 15(12), pp. 1400-9.
  • MDSCs myeloid-derived suppressor cells
  • a compound of formula (I), or a salt thereof is provided herein.
  • Q is an optionally substituted -O-(C 1 -C 3 alkylene)5- to 10-membered heteroaryl, an optionally substituted -C(O)N(R Qa )-(C 1 -C 3 alkylene) 5- to 10-membered heteroaryl, an optionally substituted -N(R Qa )-(C 1 -C 3 alkylene) 5- to 10-membered heteroaryl, optionally substituted -(C 1 -C 3 alkylene)-N(R Qa )5- to 10-membered heteroaryl, optionally substituted - (C 1 -C 3 alkylene)-O-5- to 10-membered heteroaryl, optionally substituted -O-(C 1 -C 3 alkylene)- NR Q 1a -5- to 10-membered heteroaryl, optionally substituted - NR Qa -(C 1 -C 3 alkylene)-O-5- to 10- membered heteroaryl, optionally substituted -
  • n is 2. In certain such embodiments, some embodiments wherein n is 2, 3 or 4, at least two of the R 3 moieties are different from each other. In some embodiments where n is 2, 3 or 4, at least one of the R 3 moieties is halo, such as chloro. In some embodiments where n is 2, 3 or 4, at least one of the R 3 moieties is C 1 -C 6 alkyl, such as methyl. In certain such embodiments, n is 2, wherein one R 3 moiety is halo and another
  • R 3 moiety is C 1 -C 6 alkyl.
  • a compound of formula (I) or (I'), or a salt thereof is provided.
  • the method comprises administering to the individual an effective amount of a compound of formula (I) or (I'), or a salt thereof.
  • the compound of formula (I) or (I') or a salt thereof is administered to the individual in combination with another therapeutic agent.
  • the compound of formula (I) or (I') or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing is administered to the individual in combination with another therapeutic agent.
  • compositions comprising (A) a compound detailed herein, such as a compound of formula (I) or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and (B) a pharmaceutically acceptable carrier or excipient.
  • pharmaceutical compositions comprising (A) a compound detailed herein, such as a compound of formula (I), and (B) a pharmaceutically acceptable carrier or excipient. Kits comprising a compound detailed herein or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing and instructions for use are also provided. Kits comprising a compound detailed herein or a salt thereof and instructions for use are also provided.
  • a compound detailed herein or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing is also provided for the manufacture of a medicament for the treatment of cancer.
  • Compounds as detailed herein or a pharmaceutically acceptable salt thereof are also provided for the manufacture of a medicament for the treatment of cancer.
  • the alkenyl group may be in “cis” or “trans” configurations, or alternatively in “E” or “Z” configurations.
  • Particular alkenyl groups are those having 2 to 20 carbon atoms (a “C 2 -C 20 alkenyl”), having 2 to 8 carbon atoms (a “C 2 -C 8 alkenyl”), having 2 to 6 carbon atoms (a “C 2 -C 6 alkenyl”), or having 2 to 4 carbon atoms (a “C 2 - C 4 alkenyl”).
  • alkenyl examples include, but are not limited to, groups such as ethenyl (or vinyl), prop-l-enyl, prop-2-enyl (or allyl), 2-methylprop-l-enyl, but-l-enyl, but-2-enyl, but-3- enyl, buta-l,3-dienyl, 2-methylbuta-l,3-dienyl, homologs and isomers thereof, and the like.
  • groups such as ethenyl (or vinyl), prop-l-enyl, prop-2-enyl (or allyl), 2-methylprop-l-enyl, but-l-enyl, but-2-enyl, but-3- enyl, buta-l,3-dienyl, 2-methylbuta-l,3-dienyl, homologs and isomers thereof, and the like.
  • alkyl refers to and includes saturated linear and branched univalent hydrocarbon structures and combination thereof, having the number of carbon atoms designated (i.e., C 1 -C 10 means one to ten carbons). Particular alkyl groups are those having 1 to 20 carbon atoms (a “C 1 -C 20 alkyl”).
  • alkyl groups are those having 1 to 8 carbon atoms (a “C 1 -C 8 alkyl”), 3 to 8 carbon atoms (a “C 3 -C 8 alkyl”), 1 to 6 carbon atoms (a “C 1 -C 6 alkyl”), 1 to 5 carbon atoms (a “C 1 -C 5 alkyl”), or 1 to 4 carbon atoms (a “C 1 -C 4 alkyl”).
  • alkyl examples include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • Alkylene refers to the same residues as alkyl, but having bivalency. Particular alkylene groups are those having 1 to 6 carbon atoms (a “C 1 -C 6 alkylene”), 1 to 5 carbon atoms (a “C 1 -C 5 alkylene”), 1 to 4 carbon atoms (a “C 1 -C 4 alkylene”) or 1 to 3 carbon atoms (a “C 1 -C 3 alkylene”).
  • alkylene examples include, but are not limited to, groups such as methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), butylene (-CH 2 CH 2 CH 2 CH 2 -), isopropylene (-CH 2 C(H)(CH 3 )CH 2 -), and the like.
  • Alkynyl refers to an unsaturated linear or branched univalent hydrocarbon chain or combination thereof, having at least one site of acetylenic unsaturation (i.e., having at least one moiety of the formula CoC) and having the number of carbon atoms designated (i.e., C 2 -C 10 means two to ten carbon atoms).
  • Particular alkynyl groups are those having 2 to 20 carbon atoms (a “C 2 -C 20 alkynyl”), having 2 to 8 carbon atoms (a “C 2 -C 8 alkynyl”), having 2 to 6 carbon atoms (a “C 2 -C 6 alkynyl”), or having 2 to 4 carbon atoms (a “C 2 - C4 alkynyl”).
  • alkynyl examples include, but are not limited to, groups such as ethynyl (or acetylenyl), prop-l-ynyl, prop-2-ynyl (or propargyl), but-l-ynyl, but-2-ynyl, but-3-ynyl, homologs and isomers thereof, and the like.
  • aryl refers to and includes polyunsaturated aromatic hydrocarbon groups.
  • Aryl may contain additional fused rings (e.g., from 1 to 3 rings), including additionally fused aryl, heteroaryl, cycloalkyl, and/or heterocyclyl rings.
  • the aryl group contains from 6 to 14 annular carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, and the like.
  • cycloalkyl refers to and includes cyclic univalent hydrocarbon structures, which may be fully saturated, mono- or polyunsaturated, but which are non-aromatic, having the number of carbon atoms designated (e.g., C 1 -C10 means one to ten carbons). Cycloalkyl can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantyl, but excludes aryl groups. A cycloalkyl comprising more than one ring may be fused, spiro or bridged, or combinations thereof. A preferred cycloalkyl is a cyclic hydrocarbon having from 3 to 13 annular carbon atoms.
  • a more preferred cycloalkyl is a cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a "C 3 -C 8 cycloalkyl").
  • cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, norbornyl, and the like.
  • Halo or “halogen” refers to elements of the Group 17 series having atomic number 9 to 85.
  • Preferred halo groups include fluoro, chloro, bromo and iodo. Where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be but are not necessarily the same halo; thus 4-chloro-3 -fluorophenyl is within the scope of dihaloaryl.
  • perhaloalkyl An alkyl group in which each hydrogen is replaced with a halo group is referred to as a “perhaloalkyl.”
  • a preferred perhaloalkyl group is trifluoroalkyl (-CF3).
  • perhaloalkoxy refers to an alkoxy group in which a halogen takes the place of each H in the hydrocarbon making up the alkyl moiety of the alkoxy group.
  • An example of a perhaloalkoxy group is trifluoromethoxy (-OCF3).
  • heteroaryl refers to and includes unsaturated aromatic cyclic groups having from 1 to 10 annular carbon atoms and at least one annular heteroatom, including but not limited to heteroatoms such as nitrogen, oxygen and sulfur, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule at an annular carbon or at an annular heteroatom.
  • Heteroaryl may contain additional fused rings (e.g., from 1 to 3 rings), including additionally fused aryl, heteroaryl, cycloalkyl, and/or heterocyclyl rings.
  • heteroaryl groups include, but are not limited to, pyridyl, pyrimidyl, thiophenyl, furanyl, thiazolyl, and the like.
  • heteroaryl groups also include, but are not limited to, pyridyl, pyrimidyl, thiophenyl, furanyl, thiazolyl, oxazolyl, isoxazolyl, thiophenyl, pyrrolyl, pyrazolyl, 1,3,4- oxadiazolyl, imidazolyl, isothiazolyl, triazolyl, 1,3,4-thiadiazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, pyrazolopyridinyl, indazolyl, benzothiazolyl, benzooxazolyl or benzoimidazolyl and the like.
  • a heteroaryl containing at least one additional fused ring that is nonaromatic is attached to the parent structure at an annular atom of the additional ring.
  • a heteroaryl containing at least one additional ring that is nonaromatic is attached to the parent structure at an annular atom of the aromatic ring.
  • heterocycle refers to a saturated or an unsaturated non- aromatic group having from 1 to 10 annular carbon atoms and from 1 to 4 annular heteroatoms, such as nitrogen, sulfur or oxygen, and the like, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
  • a heterocyclyl group may have a single ring or multiple condensed rings, but excludes heteroaryl groups.
  • a heterocycle comprising more than one ring may be fused, spiro or bridged, or any combination thereof. In fused ring systems, one or more of the fused rings can be aryl, cycloalyl or heterocyclyl.
  • heterocyclyl groups include, but are not limited to, tetrahydropyranyl, dihydropyranyl, piperidinyl, piperazinyl, pyrrolidinyl, thiazolinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, 2,3-dihydrobenzo[b]thiophen-2-yl, 4-amino-2- oxopyrimidin-l(2H)-yl, and the like.
  • a heterocyclyl containing at least one additional ring (such as a fused additional ring) that does not contain a heteroatom is attached to the parent structure at an annular atom of the additional ring.
  • a heterocyclyl containing at least one additional ring (such as a fused additional ring) that does not contain a heteroatom is attached to the parent structure at an annular atom of the ring containing a heteroatom.
  • Optionally substituted unless otherwise specified means that a group may be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4 or 5) of the substituents listed for that group in which the substituents may be the same of different.
  • an optionally substituted group has one substituent.
  • an optionally substituted group has two substituents.
  • an optionally substituted group has three substituents.
  • an optionally substituted group has four substituents.
  • an optionally substituted group has 1 to 2, 2 to 5, 3 to 5, 2 to 3, 2 to 4, 3 to 4, 1 to 3, 1 to 4 or 1 to 5 substituents.
  • a “pharmaceutically acceptable carrier” refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is non toxic to a subject.
  • a pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative.
  • treatment or “treating” is an approach for obtaining beneficial or desired results including clinical results.
  • beneficial or desired results include, but are not limited to, one or more of the following: decreasing symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, delaying the progression of the disease, and/or prolonging survival of individuals.
  • beneficial or desired results include shrinking a tumor (reducing tumor size); decreasing the growth rate of the tumor (such as to suppress tumor growth); reducing the number of cancer cells; inhibiting, retarding or slowing to some extent and preferably stopping cancer cell infiltration into peripheral organs; inhibiting (slowing to some extent and preferably stopping) tumor metastasis; inhibiting tumor growth; preventing or delaying occurrence and/or recurrence of tumor; and/or relieving to some extent one or more of the symptoms associated with the cancer.
  • beneficial or desired results include preventing or delaying occurrence and/or recurrence, such as of unwanted cell proliferation.
  • “delaying development of a disease” means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease (such as cancer). This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease. For example, a late stage cancer, such as development of metastasis, may be delayed.
  • an “effective dosage” or “effective amount” of compound or salt thereof or pharmaceutical composition is an amount sufficient to effect beneficial or desired results.
  • beneficial or desired results include results such as eliminating or reducing the risk, lessening the severity of, or delaying the onset of the disease, including biochemical, histological and/or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease.
  • beneficial or desired results include ameliorating, palliating, lessening, delaying or decreasing one or more symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication such as via targeting, delaying the progression of the disease, and/or prolonging survival.
  • an effective amount comprises an amount sufficient to cause a tumor to shrink and/or to decrease the growth rate of the tumor (such as to suppress tumor growth) or to prevent or delay other unwanted cell proliferation.
  • an effective amount is an amount sufficient to delay development.
  • an effective amount is an amount sufficient to prevent or delay occurrence and/or recurrence.
  • an effective amount can be administered in one or more administrations, in the case of cancer, the effective amount of the drug or composition may: (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, retard, slow to some extent and preferably stop cancer cell infiltration into peripheral organs; (iv) inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay occurrence and/or recurrence of tumor; and/or (vii) relieve to some extent one or more of the symptoms associated with the cancer.
  • An effective dosage can be administered in one or more administrations.
  • an effective dosage of compound or a salt thereof, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. It is intended and understood that an effective dosage of a compound or salt thereof, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an “effective dosage” may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved.
  • the term "individual” is a mammal, including humans.
  • An individual includes, but is not limited to, human, bovine, horse, feline, canine, rodent, or primate.
  • the individual is human.
  • the individual (such as a human) may have advanced disease or lesser extent of disease, such as low tumor burden.
  • the individual is at an early stage of a proliferative disease (such as cancer).
  • the individual is at an advanced stage of a proliferative disease (such as an advanced cancer).
  • references to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”. [0035] It is understood that aspects and variations described herein also include “consisting” and/or “consisting essentially of’ aspects and variations.
  • A is 5- to 10-membered heteroaryl optionally substituted by R 3 ;
  • B is a phenyl optionally substituted by R 3 , or a 5- to 6-membered heteroaryl optionally substituted by R 4 ;
  • Q 1 is 5- to 10-membered heteroarylene, -(C 1 -C 3 alkylene) (5- to 10-membered heteroarylene), -CH 2 -, -O-, -S-, -S(O) 2 - , -S(O) 2 NR 1a -, -NR 1a S(O) 2 -, -NR 1a -, -C(O)-, -NR 1a C(O)- , -NR 1a C(O)NR 1b -, -C(O)O-, -C(O)ONR 1a -, -C(O)NR 1a -, -(C 1 -C 3 alkylene)NR 1a -, -(C 1 -C 3 alkylene)0-, or a bond, wherein the heteroarylene
  • Q 2 is -CH 2 -, -O-, -S-, -S(O) 2 - , -S(O) 2 NR 1a -, -NR 1a S(O) 2 -, -NR 1a -, -C(O)-, -NR 1a C(O)- , -NR 1a C(O)NR 1b -, -C(O)O-, -C(O)ONR 1a -, -C(O)NR 1a or a bond; provided that Q 1 and Q 2 are not a bond at the same time;
  • L is a bond or C 1 -C 4 alkylene optionally substituted by R 4 ;
  • D is C6-C10 aryl, 5- to 10-membered heteroaryl, C 3 -C 8 cycloalkyl or 3- to 10-membered heterocyclyl, wherein each of which is optionally substituted by one or more R 2 ;
  • R 1a and R 1b are each independently hydrogen, C 3 -C 6 cycloalkyl or C 1 -C 6 alkyl optionally substituted by oxo, -OH or halogen;
  • each R 2 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, oxo, -CN, -OR 2a , -NR 2b R 2c , -C(O)R 2a , -C(O)OR 2a , -C(O)NR 2b R 2c , -NR 2a C(O)R 2b , -S(O)R 2a , -S(O)
  • R 2a , R 2b and R 2c is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 - C 6
  • each R 4 is independently oxo or R 3 ;
  • R 5 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl or 3- to 6-membered heterocyclyl, wherein each of which is optionally substituted by halogen, oxo, -CN, -OR 8 , -NR 8 R 9 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 8 R 9 , -NR 8 C(O)R 9 , -S(O)R 8 , -S(O) 2 R 8 , -S(O) 2 NR 8 R 9 , -NR 8 S(O) 2 R 9 , or C 1 -C 6 alkyl optionally substituted by oxo, -OH or halogen;
  • R 6 and R 7 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl or 3- to 6-membered heterocyclyl, wherein each of which is optionally substituted by halogen, oxo, -CN, -OR 8 , -NR 8 R 9 , -C(O)R 8 , -C(O)OR 8 ,
  • R 8 and R 9 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl or 3- to 6-membered heterocyclyl, wherein each of which is optionally substituted by halogen, OH, oxo or NH 2 ; or R 8 and R 9 are taken together with the atom to which they attached to form a 3- to 6-membered heterocyclyl optionally substituted by halogen, oxo or C 1 -C 6 alkyl optionally substituted by halogen, OH, oxo or NH 2 ; and
  • R 10 , R 11 and R 12 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 - C 6 alkynyl, C 3 -C 6 cycloalkyl or 3- to 6-membered heterocyclyl, wherein each of which is optionally substituted by halogen, OH, oxo or NH 2 ; or R 11 and R 12 are taken together with the atom to which they attached to form a 3- to 6-membered heterocyclyl optionally substituted by halogen, oxo or C 1 -C 6 alkyl optionally substituted by halogen, OH, oxo or NH 2 .
  • A is 5- to 6-membered heteroaryl optionally substituted by R 3 provided that A is other than an optionally substituted 2-pyridyl such as 4-hydroxy-2-pyridyl optionally further substituted by R 3 .
  • A is 4-pyridyl optionally substituted by R 3 ;
  • B is a phenyl optionally substituted by R 3 , or a 5- to 6-membered heteroaryl optionally substituted by R 4 ;
  • Q 1 is 5- to 10-membered heteroarylene, -(C 1 -C 3 alkylene) (5- to 10-membered heteroarylene), -CH 2 -, -O-, -S-, -S(O) 2 - , -S(O) 2 NR 1a -, -NR 1a S(O) 2 -, -NR 1a -, -C(O)-, -NR 1a C(O)- , -NR 1a C(O)NR 1b -, -C(O)O-, -C(O)ONR 1a -, -C(O)NR 1a or a bond, wherein the heteroarylene is optionally substituted by C 1 -C 6 alkyl, -
  • Q 2 is -CH 2 -, -O-, -S-, -S(O) 2 - , -S(O) 2 NR 1a -, -NR 1a S(O) 2 -, -NR 1a -, -C(O)-, -NR 1a C(O)- , -NR 1a C(O)NR 1b -, -C(O)O-, -C(O)ONR 1a -, -C(O)NR 1a or a bond; provided that Q 1 and Q 2 are not a bond at the same time;
  • L is a bond or C 1 -C 4 alkylene optionally substituted by R 4 ;
  • D is C6-C10 aryl, 5- to 10-membered heteroaryl, C 3 -C 8 cycloalkyl or 3- to 10-membered heterocyclyl, wherein each of which is optionally substituted by one or more R 2 ;
  • R 1a and R 1b are each independently hydrogen, C 3 -C 6 cycloalkyl or C 1 -C 6 alkyl optionally substituted by oxo, -OH or halogen;
  • each R 2 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, oxo, -CN, -OR 2a , -NR 2b R 2c , -C(O)R 2a , -C(O)OR 2a , -C(O)NR 2b R 2c , -NR 2a C(O)R 2b , -S(O)R 2a ,
  • R 5 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl or 3- to 6-membered heterocyclyl, wherein each of which is optionally substituted by halogen, oxo, -CN, -OR 8 , -NR 8 R 9 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 8 R 9 , -NR 8 C(O)R 9 , -S(O)R 8 , -S(O) 2 R 8 , -S(O) 2 NR 8 R 9 , -NR 8 S(O) 2 R 9 , or C 1 -C 6 alkyl optionally substituted by oxo, -OH or halogen;
  • R 6 and R 7 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl or 3- to 6-membered heterocyclyl, wherein each of which is optionally substituted by halogen, oxo, -CN, -OR 8 , -NR 8 R 9 , -C(O)R 8 , -C(O)OR 8 ,
  • R 8 and R 9 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl or 3- to 6-membered heterocyclyl, wherein each of which is optionally substituted by halogen, OH, oxo or NH 2 ; or R 8 and R 9 are taken together with the atom to which they attached to form a 3- to 6-membered heterocyclyl optionally substituted by halogen, oxo or C 1 -C 6 alkyl optionally substituted by halogen, OH, oxo or NH 2 ; and
  • R 10 , R 11 and R 12 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 - C 6 alkynyl, C 3 -C 6 cycloalkyl or 3- to 6-membered heterocyclyl, wherein each of which is optionally substituted by halogen, OH, oxo or NH2; or R 11 and R 12 are taken together with the atom to which they attached to form a 3- to 6-membered heterocyclyl optionally substituted by halogen, oxo or C 1 -C 6 alkyl optionally substituted by halogen, OH, oxo or NH2.
  • A is 5- to 6-membered heteroaryl optionally substituted by R 3 ;
  • B is a phenyl optionally substituted by R 3 , or a 5- to 6-membered heteroaryl optionally substituted by R 4 ;
  • Q 1 is 5- to 10-membered heteroarylene, -(C 1 -C 3 alkylene) (5- to 10-membered heteroarylene), -CH 2 -, -O-, -S-, -S(O) 2 - , -S(O) 2 NR 1a -, -NR 1a S(O) 2 -, -NR 1a -, -C(O)-, -NR 1a C(O)- , -NR 1a C(O)NR 1b -, -C(O)O-, -C(O)ONR 1a -, -C(O)NR 1a or a bond, wherein the heteroarylene is optionally substituted by C 1 -C 6 alkyl, -OH or halogen,
  • Q 2 is -CH 2 -, -O-, -S-, -S(O) 2 - , -S(O) 2 NR 1a -, -NR 1a S(O) 2 -, -NR 1a -, -C(O)-, -NR 1a C(O)- , -NR 1a C(O)NR 1b -, -C(O)O-, -C(O)ONR 1a -, -C(O)NR 1a or a bond; provided that Q 1 and Q 2 are not a bond at the same time;
  • L is a bond or C 1 -C 4 alkylene optionally substituted by R 4 ;
  • D is C 6 -C 10 aryl, 5- to 10-membered heteroaryl, C 3 -C 8 cycloalkyl or 3- to 10-membered heterocyclyl, wherein each of which is optionally substituted by one or more R 2 ;
  • R 1a and R 1b are independently hydrogen, C 3 -C 6 cycloalkyl or C 1 -C 6 alkyl optionally substituted by oxo, -OH or halogen;
  • each R 2 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, oxo, -CN, -OR 2a , -NR 2b R 2c , -C(O)R 2a , -C(O)OR 2a , -C(O)NR 2b R 2c , -NR 2a C(O)R 2b , -S(O)R 2a ,
  • each R 4 is independently oxo or R 3 ;
  • R 5 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl or 3- to 6-membered heterocyclyl, wherein each of which is optionally substituted by halogen, oxo, -CN, -OR 8 , -NR 8 R 9 , -C(O)R 8 , -C(O)OR 8 , -C(O)NR 8 R 9 , -NR 8 C(O)R 9 , -S(O)R 8 , -S(O) 2 R 8 , -S(O) 2 NR 8 R 9 , -NR 8 S(O) 2 R 9 , or C 1 -C 6 alkyl optionally substituted by oxo, -OH or halogen;
  • R 6 and R 7 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl or 3- to 6-membered heterocyclyl, wherein each of which is optionally substituted by halogen, oxo, -CN, -OR 8 , -NR 8 R 9 , -C(O)R 8 , -C(O)OR 8 ,
  • R 8 and R 9 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl or 3- to 6-membered heterocyclyl, wherein each of which is optionally substituted by halogen, OH, oxo or NH 2 ; or R 8 and R 9 are taken together with the atom to which they attached to form a 3- to 6-membered heterocyclyl optionally substituted by halogen, oxo or C 1 -C 6 alkyl optionally substituted by halogen, OH, oxo or NH 2 ;
  • R 10 , R 11 and R 12 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 - C 6 alkynyl, C 3 -C 6 cycloalkyl or 3- to 6-membered heterocyclyl, wherein each of which is optionally substituted by halogen, OH, oxo or NH 2 ; or R 11 and R 12 are taken together with the atom to which they attached to form a 3- to 6-membered heterocyclyl optionally substituted by halogen, oxo or C 1 -C 6 alkyl optionally substituted by halogen, OH, oxo or NH2 .
  • a compound of formula (I), or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing (1) when Q 1 is -O-, -NR 1a -, or -C(O)NR 1a -, then R 2 is not methyl, ethyl, halogen, oxo, -CF3, -OH, -OCH 3 , -CN, -C(O)OCH 3 , -C(O)OC2H5, -NH2 or -NHCH 3 ; and (2) when Q 1 is a bond or -CH 2 -, then R 2 is not C 1 -C 6 alkyl optionally substituted by halogen, -OH or oxo.
  • the compound is not 3-((4- (ethylamino)furan-3-yl)thio)-5,6-di(pyridin-3-yl)pyrazin-2-amine, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
  • a compound of formula (I) or a salt thereof wherein the compound is not 3-((4- (ethylamino)furan-3-yl)thio)-5,6-di(pyridin-3-yl)pyrazin-2-amine or a salt thereof.
  • Q 1 is 5- to 10-membered heteroarylene. In some embodiments, Q 1 is -(C 1 -C 3 alkylene)(5- to 10-membered heteroarylene). In some embodiments, Q 1 is -O-. In some embodiments, Q 1 is -S-. In some embodiments Q 1 is -S(O) 2 -. In some embodiments, Q 1 is -S(O) 2 NR 1a -. In some embodiments, Q 1 is -NR 1a S(O) 2 -. In some embodiments, Q 1 is -NR 1a -. In some embodiments, Q 1 is -C(O)-. In some embodiments, Q 1 is -NR 1a C(O)-.
  • Q 1 is -C(O)O-. In some embodiments, Q 1 is -C(O)ONR 1a -. In some embodiments, Q 1 is -C(O)NR 1a . In some embodiments, Q 1 is a bond. In some embodiments, R 1a is hydrogen.
  • Q 2 is -O-. In some embodiments, Q 2 is -S-. In some embodiments, Q 2 is -S(O) 2 -. In some embodiments, Q 2 is -S(O) 2 NR 1a -. In some embodiments, Q 2 is -NR 1a S(O) 2 -. In some embodiments, Q 2 is -NR 1a -. In some embodiments, Q 2 is -C(O)-. In some embodiments, Q 2 is -NR 1a C(O)-. In some embodiments, Q 2 is -C(O)O-. In some embodiments, Q 2 is -C(O)ONR 1a -. In some embodiments, Q 2 is -C(O)NR 1a . In some embodiments, Q 2 is a bond.
  • Q 1 is a bond and Q 2 is -O-, -S-, -S(O) 2 - , -S(O) 2 NR 1a - , -NR 1a S(O) 2 -, -NR 1a -, -C(O)-, -NR 1a C(O)- , -NR 1a C(O)NR 1b -, -C(O)O-, -C(O)ONR 1a - or -C(O)NR 1a .
  • Q 2 is a bond and Q 1 is -O-, -S-, -S(O) 2 - , -S(O) 2 NR 1a - , -NR 1a S(O) 2 -, -NR 1a -, -C(O)-, -NR 1a C(O)- , -NR 1a C(O)NR 1b -, -C(O)O-, -C(O)ONR 1a - or -C(O)NR 1a .
  • Q 1 is 5- to 10-membered heteroarylene and Q 2 is -O-, -S- , -S(O)2- , -S(O) 2 NR 1a -, -NR 1a S(O) 2 -, -NR 1a -, -C(O)-, -NR 1a C(O)- , -NR 1a C(O)NR 1b -, -C(O)O-, -C(O)ONR 1a -, -C(O)NR 1a or a bond.
  • Q 1 is -(C 1 -C 3 alkylene)(5- to 10- membered heteroarylene) and Q 2 is -O-, -S-, -S(O) 2 - , -S(O) 2 NR 1a -, -NR 1a S(O) 2 -, -NR 1a -, -C(O)- , -NR 1a C(O)- , -NR 1a C(O)NR 1b -, -C(O)O-, -C(O)ONR 1a -, -C(O)NR 1a or a bond.
  • Q 1 is -C(O)NR 1a ; and Q 2 is a bond.
  • L is a bond.
  • L is C 1 -C 4 alkylene, for example, -CH 2 -, - CH 2 CH 2 -, and - CH 2 CH 2 CH 2 -.
  • L is C 1 -C 4 alkylene optionally substituted by R 4 .
  • C 1 -C 3 or C 1 -C 4 alkylene is a linear alkylene.
  • C 1 - C 3 or C 1 -C 4 alkylene is a branched alkylene, such as -CH(CH 3 )- and -C(CH 3 ) 2 -.
  • -(C 1 -C 3 alkylene)( 5- to 6-membered heteroaryl) is -CH(CH 3 )-pyridyl.
  • D is C6-C10 aryl optionally substituted by one or more R 2 .
  • D is 5- to 10-membered heteroaryl optionally substituted by one or more R 2 .
  • D is C 3 -C 8 cycloalkyl optionally substituted by one or more R 2 .
  • D is 3- to 10-membered heterocyclyl optionally substituted by one or more R 2 .
  • D is C6-C10 aryl optionally substituted by one or more R 2 , wherein each R 2 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, -CN,
  • D is C 6 -C 10 aryl optionally substituted by halogen, -CN, -OR 2a , -NR 2b R 2c , -C(O)R 2a , -C(O)OR 2a ,
  • D is phenyl optionally substituted by halogen, -CN, -OR 2a , -NR 2b R 2c , -C(O)R 2a , -C(O)OR 2a , -C(O)NR 2b R 2c , -NR 2a C(O)R 2b , -S(O)R 2a , -S(O) 2 R 2a , -S(O) 2 NR 2b R 2c , -NR 2a S(O) 2 R 2b , -(C 1 -C 3 alkylene)OR 2a or C 1 -C 6 alkyl optionally substituted by oxo, -OH or halogen.
  • D is 5- to 10-membered heteroaryl optionally substituted by one or more R 2 , wherein each R 2 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halogen, oxo, -CN, -OR 2a , -NR 2b R 2c , -C(O)R 2a , -C(O)OR 2a ,
  • D is 5- to 10-membered heteroaryl optionally substituted by halogen, oxo, -CN, -OR 2a , -NR 2b R 2c , -C(O)R 2a , -C(O)OR 2a , -C(O)NR 2b R 2c , -NR 2a C(O)R 2b , -S(O)R 2a , -S(O) 2 R 2a , -S(O) 2 NR 2b R 2c , - NR 2a S(O) 2 R 2b , -(C 1 -C 3 alkylene)OR 2a or C 1 -C 6 alkyl optionally substituted by oxo, -OH or halogen.
  • D is pyridyl optionally substituted by halogen, oxo, -CN, -OR 2a , -NR 2b R 2c , -C(O)R 2a , -C(O)OR 2a , -C(O)NR 2b R 2c , -NR 2a C(O)R 2b , -S(O)R 2a , -S(O) 2 R 2a , -S(O) 2
  • NR 2b R 2c -NR 2a S(O) 2 R 2b , -(C 1 -C 3 alkylene)OR 2a or C 1 -C 6 alkyl optionally substituted by oxo, -OH or halogen.
  • D is pyridyl substituted by C 1 -C 6 alkyl optionally substituted by oxo, -OH or halogen.
  • D is independently C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, -NR 2b R 2c , -C(O)NR 2b R 2c ,
  • Q 1 , Q 2 , L and D together are group, which is selected from the group consisting of:
  • L and D may be combined with each A and/or B the same as if each and every combination of with A and/or B were specifically and individually listed.
  • A is 4-pyridyl optionally substituted by R 3 .
  • R 3 optionally substituted by R 3 .
  • n is 2, 3 or 4
  • at least two of the R 3 moieties are different from each other.
  • at least one of the R 3 moieties is halo, such as chloro.
  • at least one of the R 3 moieties is C 1 -C 6 alkyl, such as methyl.
  • n is 2, and wherein one R 3 moiety is halo and another R 3 moiety is C 1 -C 6 alkyl. In some such embodiments,
  • B is an unsubstituted phenyl. In some embodiments, B is a phenyl optionally substituted by R 3 . In some embodiments, B is a phenyl substituted by 1 to 3 R 3 which R 3 groups may be the same or different. In other embodiments, B is a 5- to 6-membered heteroaryl optionally substituted by R 4 . In other embodiments, B is a 5- to 6-membered heteroaryl substituted by 1 to 3 R 4 which R 4 may be the same or different.
  • the 5- to 6-membered heteroaryl of B is a 5-membered heteroaryl selected from the group consisting of furanyl, oxazolyl, thiophenyl, pyrazolyl, isoxazolyl, 1,3,4-oxadiazolyl, imidazolyl, thiazolyl, isothiazolyl, triazolyl, 1,3,4-thiadiazolyl and tetrazolyl, which 5-membered heteroaryl is optionally substituted by 1 to 3 R 4 which R 4 groups may be the same or different.
  • the 5- to 6-membered heteroaryl of B is a 6-membered heteroaryl selected from the group consisting of pyridyl, pyridazinyland pyrimidinyl which 6-membered heteroaryl is optionally substituted to 1 to 3 R 4 which R 4 groups may be the same or different [0055]
  • B is an unsubstituted phenyl.
  • B is a phenyl optionally substituted by R 3 .
  • B is a phenyl substituted by 1 to 3 R 3 which R 3 groups may be the same or different.
  • B is a 5- to 6-membered heteroaryl optionally substituted by R 4 .
  • B is a 5- to 6-membered heteroaryl substituted by 1 to 3 R 4 which R 4 may be the same or different.
  • the 5- to 6-membered heteroaryl of B is a 5-membered heteroaryl selected from the group consisting of furanyl, oxazolyl, thiophenyl, pyrazolyl, isoxazolyl, 1,3,4-oxadiazolyl, imidazolyl, thiazolyl, isothiazolyl, triazolyl, 1,3,4-thiadiazolyl and tetrazolyl, which 5-membered heteroaryl is optionally substituted by 1 to 3 R 4 which R 4 groups may be the same or different.
  • the 5- to 6-membered heteroaryl of B is a 6-membered heteroaryl selected from the group consisting of pyridyl and pyrimidinyl which 6-membered heteroaryl is optionally substituted to 1 to 3 R 4 which R 4 groups may be the same or different.
  • R 4 is R 3 and R 3 is selected from the group consisting of halogen
  • R 4 is R 3 and R 3 is selected from the group consisting of halogen and C 1 -C 6 alkyl optionally substituted by halogen.
  • each R 3 of B in one aspect is independently selected from the group consisting of halogen, -CN, -OR 5 , -NR 6 R 7 , -C(O)R 5 , C 3 -C 6 cycloalkyl and C 1 -C 6 alkyl optionally substituted by halogen.
  • each R 3 of B is independently selected from the group consisting of halogen and C 1 -C 6 alkyl optionally substituted by halogen (e.g., CF3).
  • B is a phenyl substituted with 1 to 3 halo groups which may be the same or different.
  • B is phenyl, fluoro-phenyl, di-fluoro-phenyl, chloro-phenyl, di-chloro-phenyl or (fluoro)(chloro)-phenyl.
  • B is selected from the group consisting of:
  • B is a phenyl substituted with 1 to 3 halo groups which may be the same or different.
  • B is phenyl, fluoro-phenyl, di-fluoro-phenyl, chloro-phenyl, di-chloro-phenyl or (fluoro)(chloro)-phenyl.
  • B is selected from the group consisting of:
  • B is a 5-membered heteroaryl substituted with 0 to 3 R 4 groups which may be the same or different. In some embodiments, B is a 5-membered heteroaryl substituted with 0 to 3 R 3 groups which may be the same or different. In one such aspect, B is a 5-membered heteroaryl substituted with 1 R 3 group. In another such aspect, B is a 5-membered heteroaryl substituted with 2 R 3 groups, which may be the same or different. In another such aspect, B is a 5-membered heteroaryl substituted with 3 R 3 groups, which may be the same or different.
  • B is a 5-membered heteroaryl selected from the group ; wherein the wavy lines denote attachment points to the parent molecule. It is understood that means that the B ring can be substituted with 0, 1, 2, or 3 R 3 groups, as valence permits (e.g., when the maximum number of allowed substituents is 2, the B ring can be substituted with 0, 1, or 2 R 3 groups).
  • B is a 5-membered heteroaryl substituted with 0 to 3 R 3 groups which may be the same or different.
  • B is a 5-membered heteroaryl selected lines denote attachment points to the parent molecule. It is understood that means that the B ring can be substituted with 0, 1, 2, or 3 R 3 groups, as valence permits (e.g., when the maximum number of allowed substituents is 2, the B ring can be substituted with 0, 1 , or 2 R 3 groups).
  • B is a 5-membered heteroaryl selected from the group
  • B is a 5-membered heteroaryl selected from the group
  • B is a pyridyl or pyrimidyl optionally substituted by 1 to 3 R 4 , which R 4 may be the same or different.
  • B is a pyridyl or pyrimidyl optionally substituted by 1 to 3 halo groups which may be the same or different.
  • B is a 6-membered heteroaryl selected from the group consisting of: the parent molecule.
  • B is a pyridyl or pyrimidyl optionally substituted by 1 to 3 R 4 , which R 4 may be the same or different. In some embodiments, B is a pyridyl or pyrimidyl optionally substituted by 1 to 3 R 3 , which R 3 may be the same or different. In some embodiments, B is a pyridyl or pyrimidyl optionally substituted by 1 to 3 halo groups which may be the same or different. In some embodiments, B is a 6-membered heteroaryl selected from the group consisting of:
  • B is selected from the group consisting of: wherein the wavy lines denote attachment points to the parent molecule.
  • B is selected from the group consisting of: some embodiments, B is selected from the group consisting of: wherein the wavy lines denote attachment points to the parent molecule. [0066] In some embodiments, . In some embodiments, B is some embodiments, B is . ,
  • each description of B may be combined with each description of R 1 and/or R 2 the same as if each and every combination were specifically and individually listed. It is similarly understood that each description of B may be combined with each description of A (and further with each description of R 1 and R 2 ) the same as if each and every combination were specifically and individually listed.
  • B is as defined in any variation herein
  • R 1 and R 2 are as defined in any variation herein and A is 4-pyridyl optionally substituted by R 3 .
  • salts of compounds referred to herein such as pharmaceutically acceptable salts.
  • the invention also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms of the compounds described.
  • a compound as detailed herein may in one aspect be in a purified form and compositions comprising a compound in purified forms are detailed herein.
  • Compositions comprising a compound as detailed herein or a salt thereof are provided, such as compositions of substantially pure compounds.
  • a composition containing a compound as detailed herein or a salt thereof is in substantially pure form.
  • substantially pure intends a composition that contains no more than 35 % impurity, wherein the impurity denotes a compound other than the compound comprising the majority of the composition or a salt thereof.
  • a composition of substantially pure compound or a salt thereof wherein the composition contains no more than 25 %, 20%, 15%, 10%, or 5% impurity. In some embodiments, a composition of substantially pure compound or a salt thereof is provided wherein the composition contains or no more than 3 %, 2%, 1% or 0.5% impurity.
  • compositions comprising a compound, or any isomer thereof, in any ratio, including racemic mixtures. Isotopic varients of the compounds are also provided.
  • the compounds depicted herein may be present as salts even if salts are not depicted and it is understood that the present disclosure embraces all salts and solvates of the compounds depicted here, as well as the non-salt and non-solvate form of the compound, as is well understood by the skilled artisan.
  • the salts of the compounds provided herein are pharmaceutically acceptable salts. Where one or more tertiary amine moiety is present in the compound, the N-oxides are also provided and described.
  • tautomeric forms may be present for any of the compounds described herein, each and every tautomeric form is intended even though only one or some of the tautomeric forms may be explicitly depicted.
  • the tautomeric forms specifically depicted may or may not be the predominant forms in solution or when used according to the methods described herein.
  • the present disclosure also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms of the compounds described.
  • the structure or name is intended to embrace all possible stereoisomers of a compound depicted, and each unique stereoisomer has a compound number bearing a suffix “a”, “b”, etc. All forms of the compounds are also embraced by the invention, such as crystalline or non-crystalline forms of the compounds.
  • Compositions comprising a compound of the invention are also intended, such as a composition of substantially pure compound, including a specific stereochemical form thereof, or a composition comprising mixtures of compounds of the invention in any ratio, including two or more stereochemical forms, such as in a racemic or non-racemic mixture.
  • the invention also intends isotopically-labeled and/or isotopically-enriched forms of compounds described herein.
  • the compounds herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compound is isotopically-labeled, such as an isotopically-labeled compound of the formula (I) or variations thereof described herein, where a fraction of one or more atoms are replaced by an isotope of the same element.
  • Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C 13 N, 15 O, 17 O, 32 P, 35 S, 18 F, 36 C1.
  • Certain isotope labeled compounds e.g. 3 H and 14 C
  • Incorporation of heavier isotopes such as deuterium ( 2 H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, or reduced dosage requirements and, hence may be preferred in some instances.
  • Isotopically-labeled compounds of the present invention can generally be prepared by standard methods and techniques known to those skilled in the art or by procedures similar to those described in the accompanying Examples substituting appropriate isotopically-labeled reagents in place of the corresponding non-labeled reagent.
  • the invention also includes any or all metabolites of any of the compounds described.
  • the metabolites may include any chemical species generated by a biotransformation of any of the compounds described, such as intermediates and products of metabolism of the compound, such as would be generated in vivo following administration to a human.
  • Articles of manufacture comprising a compound described herein, or a salt or solvate thereof, in a suitable container are provided.
  • the container may be a vial, jar, ampoule, preloaded syringe, i.v. bag, and the like.
  • the compounds detailed herein are orally bioavailable.
  • the compounds may also be formulated for parenteral (e.g., intravenous) administration.
  • One or several compounds described herein can be used in the preparation of a medicament by combining the compound or compounds as an active ingredient with a pharmacologically acceptable carrier, which are known in the art.
  • a pharmacologically acceptable carrier which are known in the art.
  • the carrier may be in various forms.
  • the manufacture of a medicament is for use in any of the methods disclosed herein, e.g., for the treatment of cancer.
  • the compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter (such as the schemes provided in the Examples below).
  • the symbols when used in the formulae depicted are to be understood to represent those groups described above in relation to the formulae herein.
  • a particular enantiomer of a compound this may be accomplished from a corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers.
  • diastereomeric derivatives may be produced by reaction of a mixture of enantiomers, e.g., a racemate, and an appropriate chiral compound. The diastereomers may then be separated by any convenient means, for example by crystallization and the desired enantiomer recovered. In another resolution process, a racemate may be separated using chiral High Performance Liquid Chromatography. Alternatively, if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described.
  • Chromatography, recrystallization and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify a product of a reaction.
  • Solvates and/or polymorphs of a compound provided herein or a pharmaceutically acceptable salt thereof are also contemplated.
  • Solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
  • Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and/or solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.
  • compounds of the formula (I) may be synthesized according to Scheme 1.
  • compounds of the formula (I) may be synthesized according to Scheme 1, 2, 3, 4, 5 or 6.
  • Scheme 1 wherein L, A, B and D are as defined for formula (I), or any variation thereof detailed herein; and X is a leaving group (e.g., alkoxy or halogen).
  • compositions of any of the compounds detailed herein are embraced by this disclosure.
  • the present disclosure includes pharmaceutical compositions comprising a compound as detailed herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid.
  • Pharmaceutical compositions may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation.
  • a compound as detailed herein may in one aspect be in a purified form and compositions comprising a compound in purified forms are detailed herein.
  • Compositions comprising a compound as detailed herein or a salt thereof are provided, such as compositions of substantially pure compounds.
  • a composition containing a compound as detailed herein or a salt thereof is in substantially pure form.
  • the compounds herein are synthetic compounds prepared for administration to an individual.
  • compositions are provided containing a compound in substantially pure form.
  • the present disclosure embraces pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier.
  • methods of administering a compound are provided.
  • the purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein.
  • a compound detailed herein or salt thereof may be formulated for any available delivery route, including an oral, mucosal (e.g ., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery form.
  • oral e.g ., nasal, sublingual, vaginal, buccal or rectal
  • parenteral e.g., intramuscular, subcutaneous or intravenous
  • topical or transdermal delivery form e.g., topical or transdermal delivery form.
  • a compound or salt thereof may be formulated with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs.
  • suitable carriers include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultic
  • One or several compounds described herein or a salt thereof can be used in the preparation of a formulation, such as a pharmaceutical formulation, by combining the compound or compounds, or a salt thereof, as an active ingredient with a pharmaceutically acceptable carrier, such as those mentioned above.
  • a pharmaceutically acceptable carrier such as those mentioned above.
  • the carrier may be in various forms.
  • pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.
  • Formulations comprising the compound may also contain other substances which have valuable therapeutic properties.
  • Pharmaceutical formulations may be prepared by known pharmaceutical methods. Suitable formulations can be found, e.g., in Remington’ s Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 20 th ed. (2000), which is incorporated herein by reference.
  • Compounds as described herein may be administered to individuals in a form of generally accepted oral compositions, such as tablets, coated tablets, and gel capsules in a hard or in soft shell, emulsions or suspensions.
  • carriers which may be used for the preparation of such compositions, are lactose, corn starch or its derivatives, talc, stearate or its salts, etc.
  • Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid poly-ols, and so on.
  • pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.
  • any of the compounds described herein can be formulated in a tablet in any dosage form described, for example, a compound as described herein or a pharmaceutically acceptable salt thereof can be formulated as a 10 mg tablet.
  • compositions comprising a compound provided herein are also described.
  • the composition comprises a compound or salt thereof and a pharmaceutically acceptable carrier or excipient.
  • a composition of substantially pure compound is provided.
  • Compounds and compositions detailed herein such as a pharmaceutical composition containing a compound of any formula provided herein or a salt thereof and a pharmaceutically acceptable carrier or excipient, may be used in methods of administration and treatment as provided herein.
  • the compounds and compositions may also be used in in vitro methods, such as in vitro methods of administering a compound or composition to cells for screening purposes and/or for conducting quality control assays.
  • a method of treating a disease in an individual comprising administering an effective amount of a compound of formula (I) or any embodiment, variation or aspect thereof (collectively, a compound of formula (I) or the present compounds or the compounds detailed or described herein) or a pharmaceutically acceptable salt thereof, to the individual.
  • a method of treating a disease mediated by a G protein coupled receptor signaling pathway in an individual comprising administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to the individual.
  • the disease is mediated by a class A G protein coupled receptor.
  • the disease is mediated by a class B G protein coupled receptor.
  • the disease is mediated by a class C G protein coupled receptor.
  • the G protein coupled receptor is a purinergic G protein receptor.
  • the G protein coupled receptor is an adenosine receptor, such as any of the A 1 ,
  • A2A, A2B, and A3 receptors are A2A, A2B, and A3 receptors.
  • the present compounds or salts thereof are believed to be effective for treating a variety of diseases and disorders.
  • the present compositions may be used to treat a proliferative disease, such as cancer.
  • the cancer is a solid tumor.
  • the cancer is any of adult and pediatric oncology, myxoid and round cell carcinoma, locally advanced tumors, metastatic cancer, human soft tissue sarcomas, including Ewing's sarcoma, cancer metastases, including lymphatic metastases, squamous cell carcinoma, particularly of the head and neck, esophageal squamous cell carcinoma, oral carcinoma, blood cell malignancies, including multiple myeloma, leukemias, including acute lymphocytic leukemia, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, and hairy cell leukemia, effusion lymphomas (body cavity based lymphomas), thymic lymphoma lung cancer, including small cell carcinoma, cutaneous T cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cancer of the adrenal cortex, ACTH-producing tumors, nonsmall cell cancers, breast cancer,
  • the present compounds or salts thereof are used in treatment of tumors which produce high levels of ATP and/or adenosine.
  • the extracellular concentration of adenosine is 10-20 times higher in the tumor compared to adjacent tissue.
  • the present compounds or salts thereof are used in treatment of tumors that express high levels of an ectonucleotidase.
  • the ectonucleotidase is CD39.
  • the ectonucleotidase is CD73.
  • Also provided herein is a method of enhancing an immune response in an individual in need thereof comprising administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to the individual.
  • Adenosine receptors are known to play an immunosuppressive role in cancer biology. High levels of adenosine present in the tumor microenvironment bind to adenosine receptors on immune cells to provide an immunosuppressive microenvironment. Specifically, binding of adenosine to the A 2A receptor provides an immunosuppressive signal that inhibits T cell proliferation, cytokine production and cytotoxicity.
  • the immune response is enhanced by a compound of formula (I) or a salt thereof enhancing activity of natural killer (NK) cells.
  • the present compounds or salts thereof increase NK cell-meditated cytotoxicity.
  • the immune response is enhanced by enhancing the activity of CD8 + T cells.
  • the present compounds or salts thereof cause an inflammatory response in the tumor microenvironment.
  • the present disclosure further provides a method of increasing the activity of a natural killer cell in an individual comprising administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to the individual.
  • the present compounds or salts thereof increase NK cell-meditated cytotoxicity.
  • a compound of formula (I) or a salt thereof increases the number of NK cells.
  • a compound of formula (I) or a salt thereof may be useful for modulating the activity of G protein receptor coupled signaling pathway proteins.
  • a compound of formula (I) or a salt thereof activates a G protein receptor coupled signaling pathway protein (i.e. is an agonist of a G protein receptor).
  • a compound of formula (I) or a salt thereof inhibits a G protein receptor coupled signaling pathway protein (i.e., is a G protein receptor antagonist).
  • a compound of formula (I) or a salt thereof is an adenosine receptor antagonist.
  • a compound of formula (I) or a salt thereof is an antagonist of any of the A 1 , A 2A , A 2B , and A3 receptors.
  • a method of modulating the activity of an A 2A receptor in an individual comprising administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof to an individual.
  • a compound of formula (I) or a salt thereof is an A 2A receptor antagonist.
  • a compound of formula (I) or a salt thereof reduces A 2A receptor signaling by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%.
  • a compound of formula (I) or a salt thereof reduces A 2A receptor signaling by 40-99%, 50-99%, 60-99%, 70-99%, 80-99%, 90-99%, or 95-99%.
  • a compound of formula (I) or a salt thereof binds to the A 2A receptor with an IC50 of less than 1 mM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 10 nM, less than 1 nM or less than 100 pM.
  • [compound x] binds to the A 2A receptor with an IC50 of 500 nM to 100 pM, 400 nM to 100 pM, 300 nM to 100 pM, 200 nM to 100 pM, or 100 nM to 100 pM.
  • Also provided herein is a method of modulating the activity of an A 2B receptor in an individual comprising administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof to an individual.
  • a compound of formula (I) or a salt thereof is an A 2B receptor antagonist.
  • a compound of formula (I) or a salt thereof reduces A 2B receptor signaling by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%.
  • a compound of formula (I) or a salt thereof reduces A 2B receptor signaling by 40- 99%, 50-99%, 60-99%, 70-99%, 80-99%, 90-99%, or 95-99%.
  • a compound of formula (I) or a salt thereof binds to the A 2B receptor with an IC50 of less than 1 ⁇ M, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 10 nM, less than 1 nM or less than 100 pM.
  • a compound of formula (I) or a salt thereof binds to the A 2B receptor with an IC50 of 500 nM to 100 pM, 400 nM to 100 pM, 300 nM to 100 pM, 200 nM to 100 pM, or 100 nM to 100 pM.
  • Also provided herein is a method of modulating the activity of an A3 receptor in an individual comprising administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof to an individual.
  • a compound of formula (I) or a salt thereof is an A3 receptor antagonist.
  • a compound of formula (I) or a salt thereof reduces A3 receptor signaling by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%.
  • a compound of formula (I) or a salt thereof reduces A3 receptor signaling by 40- 99%, 50-99%, 60-99%, 70-99%, 80-99%, 90-99%, or 95-99%.
  • a compound of formula (I) or a salt thereof binds to the A3 receptor with an IC50 of less than 1 m M, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 10 nM, less than 1 nM or less than 100 pM.
  • a compound of formula (I) or a salt thereof binds to the A3 receptor with an IC50 of 500 nM to 100 pM, 400 nM to 100 pM, 300 nM to 100 pM, 200 nM to 100 pM, or 100 nM to 100 pM.
  • the present invention comprises a method of inhibiting tumor metastasis in an individual in need thereof comprising administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, to the individual.
  • the metastasis is to the lung, liver, lymph node, bone, adrenal gland, brain, peritoneum, muscle, or vagina.
  • a compound of formula (I) or a salt thereof inhibits metastasis of melanoma cells.
  • the present disclosure includes a method of delaying tumor metastasis comprising administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, to the individual.
  • the time to metastasis is delayed by 1 month, 2 months 3 months, 4 months, 5 months, 6 months, 12 months, or more, upon treatment with the compounds of the present invention.
  • a compound of formula (I) or a salt thereof is used to treat an individual having a proliferative disease, such as cancer as described herein.
  • the individual is at risk of developing a proliferative disease, such as cancer.
  • the individual is determined to be at risk of developing cancer based upon one or more risk factors.
  • the risk factor is a family history and/or gene associated with cancer.
  • the individual has a cancer that expresses a high level of a nucleotide metabolizing enzyme.
  • the nucleotide metabolizing enzyme is a nucleotidase, such as CD73 (ecto-5'-nucleotidase, Ecto5'NTase).
  • the individual has a cancer that expresses a high level of a nucleotidase, such as CD73.
  • the nucleotide metabolizing enzyme is an ecto-nucleotidase.
  • the ecto-nucleotidase degrades adenosine monophosphate.
  • the nucleotide metabolizing enzyme is CD39 (ecto-nucleoside triphosphate diphosphohydrolase 1, E-NTPDasel).
  • the individual has a cancer that expresses a high level of CD39.
  • the individual has a cancer that expresses a high level of an adenosine receptor, such as the A 2A receptor.
  • the presently disclosed compounds or a salt thereof may activate the immune system by modulating the activity of a G protein coupled receptor signaling pathway, for example acting as an A 2A receptor antagonist, which results in significant antitumor effects. Accordingly, the present compounds or a salt thereof may be used in combination with other anti-cancer agents to enhance tumor immunotherapy.
  • a method of treating a disease mediated by a G protein coupled receptor signaling pathway in an individual comprising administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and an additional therapeutic agent to the individual.
  • the disease mediated by a G protein coupled receptor signaling pathway is a proliferative disease such as cancer.
  • the additional therapeutic agent is a cancer immunotherapy.
  • the additional therapeutic agent is an immunostimulatory agent. In some embodiments, the additional therapeutic agent targets a checkpoint protein. In some embodiments, the additional therapeutic agent is effective to stimulate, enhance or improve an immune response against a tumor. [0110] In another aspect, provided herein is a combination therapy in which a compound of formula (I) is coadministered (which may be separately or simultaneously) with one or more additional agents that are effective in stimulating immune responses to thereby further enhance, stimulate or upregulate immune responses in a subject.
  • a method for stimulating an immune response in a subject comprising administering to the subject a compound of formula (I) or a salt thereof and one or more immunostimulatory antibodies, such as an anti-PD-1 antibody, an anti-PD-L1 antibody and/or an anti-CTLA-4 antibody, such that an immune response is stimulated in the subject, for example to inhibit tumor growth.
  • the subject is administered a compound of formula (I) or a salt thereof and an anti- PD- 1 antibody.
  • a method for stimulating an immune response in a subject comprising administering to the subject a compound of formula (I) or a salt thereof and one or more immunostimulatory antibodies or immunotherapy like Chimeric antigen receptor (CAR) T-celi therapy; immunostimulatory antibodies such as an anti-PD-1 antibody, an anti-PD-L1 antibody and/or an anti-CTLA-4 antibody, such that an immune response is stimulated in the subject, for example to inhibit tumor growth.
  • the subject is administered a compound of formula (I) or a salt thereof and an anti-PD-L1 antibody.
  • the subject is administered a compound of formula (I) or a salt thereof and an anti-CTLA-4 antibody.
  • the immunostimulatory antibody (e.g., anti-PD-1, anti-PD-L1 and/or anti-CTLA-4 antibody) is a human antibody.
  • the immunostimulatory antibody can be, for example, a chimeric or humanized antibody (e.g., prepared from a mouse anti-PD-1, anti-PD-L1 and/or anti-CTLA-4 antibody).
  • the subject is administered a compound of formula (I) or a salt thereof and CAR T- cells (genetically modified T cells).
  • the present disclosure provides a method for treating a proliferative disease (e.g., cancer), comprising administering a compound of formula (I) or a salt thereof and an anti-PD-1 antibody to a subject.
  • a compound of formula (I) or a salt thereof is administered at a subtherapeutic dose
  • the anti-PD-1 antibody is administered at a subtherapeutic dose
  • the present disclosure provides a method for altering an adverse event associated with treatment of a hyperproliferative disease with an immunostimulatory agent, comprising administering a compound of formula (I) or a salt thereof and a subtherapeutic dose of anti-PD-1 antibody to a subject.
  • the subject is human.
  • the anti-PD-1 antibody is a human sequence monoclonal antibody
  • the present invention provides a method for treating a hyperproliferative disease (e.g., cancer), comprising administering a compound of formula (I) or a salt thereof and an anti-PD-L1 antibody to a subject.
  • a compound of formula (I) or a salt thereof is administered at a subtherapeutic dose
  • the anti-PD-L1 antibody is administered at a subtherapeutic dose
  • both are administered at a subtherapeutic dose.
  • the present invention provides a method for altering an adverse event associated with treatment of a hyperproliferative disease with an immunostimulatory agent, comprising administering a compound of formula (I) or a salt thereof and a subtherapeutic dose of anti-PD-L1 antibody to a subject.
  • the subject is human.
  • the anti-PD-L1 antibody is a human sequence monoclonal antibody.
  • the combination of therapeutic agents discussed herein can be administered concurrently as a single composition in a pharmaceutically acceptable carrier, or concurrently as separate compositions each in a pharmaceutically acceptable carrier.
  • the combination of therapeutic agents can be administered sequentially.
  • an anti-CTLA-4 antibody and a compound of formula (I) or a salt thereof can be administered sequentially, such as anti-CTLA-4 antibody being administered first and a compound of formula (I) or a salt thereof second, or a compound of formula (I) or a salt thereof being administered first and anti-CTLA-4 antibody second.
  • an anti- PD- 1 antibody and a compound of formula (I) or a salt thereof can be administered sequentially, such as anti-PD- 1 antibody being administered first and a compound of formula (I) or a salt thereof second, or a compound of formula (I) or a salt thereof being administered first and anti- PD-1 antibody second.
  • an anti-PD-L1 antibody and a compound of formula (I) or a salt thereof can be administered sequentially, such as anti-PD-L1 antibody being administered first and a compound of formula (I) or a salt thereof second, or a compound of formula (I) or a salt thereof being administered first and anti-PD-L1 antibody second.
  • the combination of a compound of formula (I) or a salt thereof can be further combined with an immunogenic agent, such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune stimulating cytokines.
  • an immunogenic agent such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune stimulating cytokines.
  • a compound of formula (I) or a salt thereof can also be further combined with standard cancer treatments.
  • a compound of formula (I) or a salt thereof can be effectively combined with chemotherapeutic regimes.
  • it is possible to reduce the dose of other chemotherapeutic reagent administered with the combination of the instant disclosure “Mokyr et al. (1998) Cancer Research 58: 5301-5304).
  • Other combination therapies with a compound of formula (I) or a salt thereof include radiation, surgery, or hormone deprivation.
  • Angiogenesis inhibitors can also be combined with a compound of formula (I) or a salt thereof. Inhibition of angiogenesis leads to tumor cell death, which can be a source of tumor antigen fed into host antigen presentation pathways.
  • a compound of formula (I) or a salt thereof can be used in conjunction with anti-neoplastic antibodies.
  • treatment with an anti-cancer antibody or an anti-cancer antibody conjugated to a toxin can lead to cancer cell death (e.g., tumor cells) which would potentiate an immune response mediated by CTLA-4, PD-1, PD-L1 or a compound of formula (I) or a salt thereof.
  • a treatment of a hyperproliferative disease can include an anti-cancer antibody in combination with a compound of formula (I) or a salt thereof and anti-CTLA-4 and/or anti-PD-1 and/or anti-PD-L1 antibodies, concurrently or sequentially or any combination thereof, which can potentiate anti-tumor immune responses by the host.
  • Other antibodies that can be used to activate host immune responsiveness can be further used in combination with a compound of formula (I) or a salt thereof.
  • a compound of formula (I) or a salt thereof can be combined with an anti-CD73 therapy, such as an anti-CD73 antibody.
  • a compound of formula (I) or a salt thereof can be combined with an anti-CD39 therapy, such as an anti-CD39 antibody.
  • an anti-CD39 therapy such as an anti-CD39 antibody.
  • a compound of formula (I) or a salt thereof is administered in combination another G protein receptor antagonist, such as an adenosine A 1 and/or A3 antagonist.
  • the dose of a compound administered to an individual may vary with the particular compound or salt thereof, the method of administration, and the particular disease, such as type and stage of cancer, being treated.
  • the amount of the compound or salt thereof is a therapeutically effective amount.
  • the effective amount of the compound may in one aspect be a dose of between about 0.01 and about 100 mg/kg.
  • Effective amounts or doses of the compounds of the invention may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease to be treated, the subject’s health status, condition, and weight.
  • An exemplary dose is in the range of about from about 0.7 mg to 7 g daily, or about 7 mg to 350 mg daily, or about 350 mg to 1.75 g daily, or about 1.75 to 7 g daily.
  • Any of the methods provided herein may in one aspect comprise administering to an individual a pharmaceutical composition that contains an effective amount of a compound provided herein or a salt thereof and a pharmaceutically acceptable excipient.
  • a compound or composition of the invention may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer, which in some variations may be for the duration of the individual’s life.
  • the compound is administered on a daily or intermittent schedule.
  • the compound can be administered to an individual continuously (for example, at least once daily) over a period of time.
  • the dosing frequency can also be less than once daily, e.g., about a once weekly dosing.
  • the dosing frequency can be more than once daily, e.g., twice or three times daily.
  • the dosing frequency can also be intermittent, including a ‘drug holiday’ (e.g., once daily dosing for 7 days followed by no doses for 7 days, repeated for any 14 day time period, such as about 2 months, about 4 months, about 6 months or more). Any of the dosing frequencies can employ any of the compounds described herein together with any of the dosages described herein.
  • a drug holiday e.g., once daily dosing for 7 days followed by no doses for 7 days, repeated for any 14 day time period, such as about 2 months, about 4 months, about 6 months or more.
  • the compounds provided herein or a salt thereof may be administered to an individual via various routes, including, e.g., intravenous, intramuscular, subcutaneous, oral and transdermal.
  • a compound provided herein can be administered frequently at low doses, known as 'metronomic therapy,' or as part of a maintenance therapy using compound alone or in combination with one or more additional drugs.
  • Metronomic therapy or maintenance therapy can comprise administration of a compound provided herein in cycles.
  • Metronomic therapy or maintenance therapy can comprise intra-tumoral administration of a compound provided herein.
  • the invention provides a method of treating cancer in an individual by parenterally administering to the individual (e.g., a human) an effective amount of a compound or salt thereof.
  • the route of administration is intravenous, intra-arterial, intramuscular, or subcutaneous.
  • the route of administration is oral.
  • the route of administration is transdermal.
  • compositions including pharmaceutical compositions as described herein for the use in treating, preventing, and/or delaying the onset and/or development of cancer and other methods described herein.
  • the composition comprises a pharmaceutical formulation which is present in a unit dosage form.
  • articles of manufacture comprising a compound of the disclosure or a salt thereof, composition, and unit dosages described herein in suitable packaging for use in the methods described herein.
  • suitable packaging is known in the art and includes, for example, vials, vessels, ampules, bottles, jars, flexible packaging and the like.
  • An article of manufacture may further be sterilized and/or sealed.
  • kits for carrying out the methods of the invention which comprises one or more compounds described herein or a composition comprising a compound described herein.
  • the kits may employ any of the compounds disclosed herein.
  • the kit employs a compound described herein or a pharmaceutically acceptable salt thereof.
  • the kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for the treatment of cancer.
  • Kits generally comprise suitable packaging.
  • the kits may comprise one or more containers comprising any compound described herein.
  • Each component if there is more than one component
  • kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses.
  • kits may be provided that contain sufficient dosages of a compound as disclosed herein and/or a second pharmaceutically active compound useful for a disease detailed herein (e.g., hypertension) to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more.
  • Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).
  • kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present invention.
  • the instructions included with the kit generally include information as to the components and their administration to an individual.
  • Example Bl Radioligand binding competition assay
  • Binding of selected compounds to the adenosine A 2A , A I , A 2B , and A3 receptors is tested using a binding competition assay.
  • the general protocol for the radioligand binding competition assay is as follows. Competition binding is performed in duplicate in the wells of a 96 well plate (Master Block, Greiner, 786201) containing binding buffer (optimized for each receptor), membrane extracts (amount of protein/well optimized for each receptor), radiotracer (final concentration optimized for each receptor), and test compound. Nonspecific binding is determined by co-incubation with 200-fold excess of cold competitor. The samples are incubated in a final volume of 0.1 mL at 25°C for 60 minutes and then filtered over filter plates.
  • Filters are washed six times with 0.5 mL of ice-cold washing buffer (optimized for each receptor) and 50 m L of Microscint 20 (Packard) are added on each filter. The filter plates are sealed, incubated 15 min on an orbital shaker and scintillation counted with a TopCount for 30sec/filter.
  • GF/C filters Perkin Elmer, 6005174
  • Filters are washed six times with 0.5 mL of ice-cold washing buffer (50 mM Tris pH 7.4) and 50 ⁇ L of Microscint 20 (Packard) are added in each well. The plates are then incubated for 15 min on an orbital shaker and then counted with a TopCountTM for 1 min/well.
  • Radioligand binding assay used to evaluate the binding affinity for the adenosine A 2A receptor assay is performed in duplicate in the wells of a 384 plate.
  • Assay buffer contains DPBS 500 mM, MgCb 0.1 mM, and 1% DMSO.
  • Membrane -bead suspension is prepared by mixing 25.98 ⁇ L of human adenosine A 2A membrane preparation (Perkin Elmer, RBHA2AM400UA) at 33.4 ⁇ g/mL, 28 ⁇ L of ADA at 20 ⁇ g/mL, and 932 ⁇ L of SPA beads at 3.33 mg/mL) and the mixture is incubated for 20 min at room temperature.
  • adenosine A 1 radioligand binding competition assay For the adenosine A 1 radioligand binding competition assay, a similar procedure is used except that the following reagents are used: CHO-K1-A1 cell membranes; binding buffer comprising HEPES 25 mM pH 7.4, MgCb 5 mM, CaCb ImM, NaCl 100 mM, saponin 10 ⁇ g/mL; wash buffer comprising HEPES 25 mM pH 7.4, MgCb 5 mM, CaCb ImM, NaCl 100 mM; a Unifilter GF/B - treated for 2h with 0.5% PEI; and 1.6 nM of 3 H-DPCPX as the tracer.
  • binding buffer comprising HEPES 25 mM pH 7.4, MgCb 5 mM, CaCb ImM, NaCl 100 mM, saponin 10 ⁇ g/mL
  • wash buffer comprising HEPES 25 mM pH 7.4, MgCb
  • HEK-293-A 2B cell membranes 20 ⁇ g/well, preincubated 30 min at RT with 25 ⁇ g/mL Adenosine Deaminase; a binding buffer comprising HEPES 10 mM pH 7.4, EDTA 1 mM, 0.5% BSA; a wash buffer comprising HEPES 10 mM pH 7.4, EDTA 1 mM; a Unifilter GF/C - treated for 2h with 0.5% PEI; and 10 nM 3 H-DPCPX as the tracer.
  • CHO-K1-A3 cell membranes 1.5 ⁇ g/well; a binding buffer comprising HEPES 25 mM pH 7.4, MgCb 5 mM, CaCb ImM, 0.5% BSA; a wash buffer comprising HEPES 25 mM pH 7.4, MgCb 5 mM, CaCb ImM; a Unifilter GF/C - treated for 2h with 0.5% BS; and 0.4 nM of 125 I-AB- MECA as the tracer.
  • the results of the binding assay are given as percent residual binding at a given concentration. Percent of residual binding means binding of a compound in the presence of competitor normalized to the amount of binding in the absence of competitor.
  • a second A 2A adenosine receptor radioligand binding assay protocol is used.
  • the protocol uses adenosine A2a (human) membrane (PerkinElmer RBHA2AM400UA) at a concentration of 5 ⁇ g/well/100 ⁇ l and the radioligand [3H] CGS-21680 (Cat No. Perkin El mer- NET1021250UC) at a final concentration of 6 nM.
  • Testing compounds are diluted with DMSO to make 8-point 4-fold serial dilution, starting at 0.2 mM.
  • CGS- 15943 is the reference compound.
  • 1 ⁇ l of compounds/high control/low control is transferred to the assay plate according to a plate map, followed by 100 m ⁇ of membrane stocks and 100 m ⁇ of radioligand, in assay buffer (50 mM Tris-HCl, 10 mM MgCb, 1 mM EDTA, pH 7.4).
  • assay buffer 50 mM Tris-HCl, 10 mM MgCb, 1 mM EDTA, pH 7.4
  • the plate is sealed and incubated at RT for 2 hours.
  • Unifilter-96 GF/C filter plates (Perkin Elmer Cat#6005174) are soaked with 50 m ⁇ of 0.3% PEI per well for at least 0.5 hour at room temperature.
  • the reaction mixtures are filtered through GF/C plates using Perkin Elmer Filtermate Harvester, and each plate washed 4 times with cold wash buffer (50 mM Tris- HCl, 154 mM NaCl, pH 7.4).
  • the filter plates are dried for 1 hour at 50 degrees. After drying, the bottom of the filter plate wells is sealed, 50 m ⁇ of Perkin Elmer Microscint 20 cocktail is added, and the top of the filter plate is sealed. 3 H trapped on the filter is counted using Perkin Elmer MicroBeta2 Reader.
  • the data are analyzed with GraphPad Prism 5 to obtain binding IC50 values.
  • a second A 1 adenosine receptor radioligand binding assay protocol is used.
  • the protocol uses adenosine A1 (human) membrane (PerkinElmer ES-010-M400UA) at a concentration of 2.5 ⁇ g/well/100pl and the radioligand [3H] DPCPX (Cat No. PerkinElmer- NET974250UC) at a final concentration of 1 nM. Testing compounds are tested at a final concentration of 200 nM.
  • CGS- 15943, the reference compound is tested in an 8-point 4-fold serial dilution, starting at a top concentration of 1 mM.
  • 1 m ⁇ of compounds/high control/low control is transferred to the assay plate according to a plate map, followed by 100 m ⁇ of membrane stocks and 100 m ⁇ of radioligand, in assay buffer (25 mM HEPES, 5 mM MgCb, 1 mM CaCb, 100 mM NaCl, pH 7.4).
  • assay buffer 25 mM HEPES, 5 mM MgCb, 1 mM CaCb, 100 mM NaCl, pH 7.4
  • the plate is sealed and incubated at RT for 1 hour.
  • Unifilter- 96 GF/C filter plates (Perkin Elmer Cat#6005174) are soaked with 50 m ⁇ of 0.3% PEI per well for at least 0.5 hour at room temperature.
  • the reaction mixtures are filtered through GF/C plates using Perkin Elmer Filtermate Harvester, and each plate washed 4 times with cold wash buffer (25 mM HEPES, 5 mM MgCb, 1 mM CaCb, 100 mM NaCl, pH 7.4).
  • the filter plates are dried for 1 hour at 50 degrees. After drying, the bottom of the filter plate wells is sealed, 50 m ⁇ of Perkin Elmer Microscint 20 cocktail is added, and the top of the filter plate is sealed. 3 H trapped on the filter is counted using Perkin Elmer MicroBeta2 Reader.
  • the data are analyzed with GraphPad Prism 5 to obtain binding IC50 values for the reference compound.
  • Assay 1 The functional activity of compounds is tested using Assay 1 below, to detect the presence of cAMP.
  • Assay 2 is an alternative assay for this purpose.
  • Activation of G-protein coupled receptors results in activation of adenylyl cyclase which converts ATP into cAMP which is used as a downstream signaling molecule.
  • Molecules which act as GPCR (or specifically A 2A receptor) antagonists cause a decrease in intracellular cAMP concentration.
  • Assay 1 This assay uses HEK-293 cells expressing human recombinant adenosine A 2A receptor that are grown prior to the test in media without antibiotic. The cells are detached by gentle flushing with PBS-EDTA (5 mM EDTA), recovered by centrifugation and suspended in assay buffer (KRH: 5 mM KC1, 1.25 mM MgS0 4 , 124 mM NaCl, 25 mM HEPES, 13.3 mM Glucose, 1.25 mM KH2PO4, 1.45 mM CaCk, 0.5 g/L BSA, supplemented with Rolipram).
  • PBS-EDTA 5 mM EDTA
  • assay buffer KRH: 5 mM KC1, 1.25 mM MgS0 4 , 124 mM NaCl, 25 mM HEPES, 13.3 mM Glucose, 1.25 mM KH2PO4, 1.45 mM CaCk,
  • Assay 2 This assay uses HEK-293 cells expressing human recombinant adenosine A 2A receptor (or, alternatively, A 1 receptor) that are grown prior to the test in media without antibiotic. 100 nL of test articles at lOOx of final concentration are transferred to assay plate by Echo. Cells are washed twice with 5 mL, of PBS and 10 m L of cells are mixed with 5 mL PBS. After aspirating the PBS and adding 1.5 mL, versine, cells are incubated at 37°C for 2-5 min. After centrifugation, 4 mL of medium is added and cell density adjusted to 5,000 cells/well with Stimulation Buffer.
  • a scintillation proximity assay is used to determine the kinetic profile of the binding of test compound to the A 2A receptor.
  • membrane extracts are prepared from HEK-293 cells expressing recombinant human A 2A receptor, are mixed with GDP (volume: volume) and are incubated in assay buffer comprising 20mM HEPES pH 7.4; lOOmM NaCl, 10 ⁇ g/mL saponin, 5 mM MgCb for at least 15 min on ice.
  • GTP ⁇ [ 35 S] is mixed with the beads (volume: volume) just before starting the reaction.
  • Optiplate Perkin Elmer 25 ⁇ L of test compound or reference ligand, 25 ⁇ L of the membranes: GDP mix, 25 ⁇ L of reference agonist at historical ECso and 25 ⁇ L of GTPy[ 35 S] (PerkinElmer NEG030X), diluted in assay buffer to give 0.1 nM.
  • the plate is incubated at room temperature for 1 hour. Then, 20 ⁇ L of IGEPAL is added for 30 minutes at room temperature.
  • PBMCs peripheral blood mononuclear cells
  • 2xl0 5 PBMCs (in 100 ⁇ L) are plated to each well of a 96-well flat bottom plate.
  • 25 ⁇ L of 8x final concentration of 10-fold serial diluted or single concentration compounds are added to indicated wells and incubated for 30 mins in 37 °C/5% CO 2 .
  • 25 ⁇ L of 8x final concentration of NECA (1 ⁇ M) is added to indicated wells and incubated for 30 min in 37°C/5% CO 2 .
  • T cell activation/expansion kit (Miltenyi biotec Cat# 130-091-441) at a bead-to-cell ratio of 1:6 in 50 ⁇ L is added to all wells with the final concentration of DMSO at 0.1% and final volume at 200 ⁇ L. 60 ⁇ L of supernatant post 24 hr and 48 hr incubation is collected for TNF-a and IFN-g concentration evaluation using TNF-a ELISA ready-set-go kit (eBioscience, Cat# 88-7346-77) and IFN-g ELISA ready-set-go kit (eBioscience, Cat# 88-7316-77), respectively.
  • TNF-a ELISA ready-set-go kit eBioscience, Cat# 88-7346-77
  • IFN-g ELISA ready-set-go kit eBioscience, Cat# 88-7316-77
  • CD8 + T-cells (l x 10 5 ) are cultured alone, with 3 ⁇ M of NECA, or in the presence of 1 ⁇ M of the compound of interest with or without 3 mM of NECA.
  • the cells are incubated for 30 min at 37 °C and 5% CO 2 , and the reaction is stopped by addition of 200 ⁇ L, 0.1 M hydrochloric acid.
  • cAMP levels are determined by an ELISA kit.
  • mice are evaluated in selective mouse models (e.g., syngeneic model, xenograft model, or PDX) as a monotherapy or combination therapies.
  • MC-38 syngeneic model as an example: female C57BL/6 mice are inoculated subcutaneously at right flank with MC-38 cells for tumor development. Five days after tumor inoculation, mice with tumor size ranging from 40-85 mm 3 are selected and assigned into sub-groups using stratified randomization with 10 mice per group based upon their tumor volumes. Mice receive pre-defined treatments include vehicle, test article at various doses alone, test article at various doses plus other anti-cancer therapy, and other anti-cancer therapy control.
  • the tumor sizes are used for the calculations of both tumor growth inhibition (TGI) and T/C values.
  • TGI tumor growth inhibition
  • the termination endpoint e.g., with TV > 1000 mm 3
  • the mouse is euthanized.
  • the time from inoculation to the termination are deemed as its survival time. Survival curves are plotted by the Kaplan-Meier method.
  • plasma and tumor samples are collected to explore biomarkers.
  • IC50 values of compounds for reversal of NECA suppression of mlFNy release is determined in mouse splenocytes isolated from Balb/c mice.
  • the mlFNy release is CD3e/CD28- induced release.
  • Mouse splenocytes (2X10 5 cells/well) are activated with Anti-mouse CD3e (2.5 ⁇ g/ml, coated overnight at 4°C; Cat # 14-0032-82, eBioscience) and then incubated with serial dilutions of compounds (3 fold, 8 point dose response starting at 1 mM) in the presence of NECA (at a concentration such as 0.1, 3.0, or 6.0 mM; Cat # E2387, Sigma) for 30 min at 37°C, 5% CO 2 in an incubator (cell culture conditions) prior to treating them with Anti-mouse CD28 (0.1 ⁇ g/ml soluble; Cat # 16-0289-81, eBiosciences).
  • Splenocytes are further incubated under cell culture conditions for 72 hr; the supernatant is then harvested and diluted to 1:100, and ELISA is performed as per the manufacturer’s protocol (mIFN-g kit; Cat # 555138 & 550534, BD Biosciences). Plates are read in a plate reader by measuring absorbance at 450nm. Values for the reversal of NECA suppressed mIFN-g release by compounds are calculated by the following formula: where [mIFN- ⁇ ] test is the test reading, [mIFN- ⁇ ] blank is the average reading obtained from blank wells, and [mIFN- ⁇ ] NECA is the average reading obtained from NECA treated, activated cells.
  • the IC 50 values are calculated by fitting the curve to the “four-parameter variable slope logistic model” using Graph Pad Prism.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés d'aminopyrazine en tant que modulateurs d'un récepteur d'adénosine. Les composés peuvent être utilisés en tant qu'agents thérapeutiques pour le traitement de maladies médiées par une voie de signalisation du récepteur couplé à la protéine G et peuvent trouver une utilisation particulière en oncologie.
PCT/US2021/013740 2020-01-17 2021-01-15 Composés hétérocycliques en tant qu'antagonistes de l'adénosine WO2021146631A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11306071B2 (en) 2019-01-18 2022-04-19 Nuvation Bio Inc. Heterocyclic compounds as adenosine antagonists
WO2023201267A1 (fr) 2022-04-13 2023-10-19 Gilead Sciences, Inc. Polythérapie pour le traitement de cancers exprimant trop-2

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050113387A1 (en) * 2003-10-27 2005-05-26 Fujisawa Pharmaceutical Co. Ltd. Pyrazine derivatives and pharmaceutical use thereof
US20050222159A1 (en) * 2004-04-01 2005-10-06 Fujisawa Pharmaceutical Co. Ltd. Pyrazine derivatives and pharmaceutical use thereof
US20090042891A1 (en) * 2005-07-29 2009-02-12 Bernat Vidal Juan Pyrazine Derivatives Useful as Adenosine Receptor Antagonists
WO2020035052A1 (fr) * 2018-08-17 2020-02-20 Dizal (Jiangsu) Pharmaceutical Co., Ltd. Composés de pyrazine et leurs utilisations

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050113387A1 (en) * 2003-10-27 2005-05-26 Fujisawa Pharmaceutical Co. Ltd. Pyrazine derivatives and pharmaceutical use thereof
US20050222159A1 (en) * 2004-04-01 2005-10-06 Fujisawa Pharmaceutical Co. Ltd. Pyrazine derivatives and pharmaceutical use thereof
US20090042891A1 (en) * 2005-07-29 2009-02-12 Bernat Vidal Juan Pyrazine Derivatives Useful as Adenosine Receptor Antagonists
WO2020035052A1 (fr) * 2018-08-17 2020-02-20 Dizal (Jiangsu) Pharmaceutical Co., Ltd. Composés de pyrazine et leurs utilisations

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11306071B2 (en) 2019-01-18 2022-04-19 Nuvation Bio Inc. Heterocyclic compounds as adenosine antagonists
WO2023201267A1 (fr) 2022-04-13 2023-10-19 Gilead Sciences, Inc. Polythérapie pour le traitement de cancers exprimant trop-2

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